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Inheritance

1

Autosomal dominant HP:0000006

AIP is inherited as an autosomal dominant disorder with low clinical penetrance. Clinical expression is strongly modified by genetic and environmental factors; an oligogenic model has been proposed but is not established as a replacement for autosomal dominant inheritance.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (4 references)

PMID:9516674 SUPPORT Other

"Acute intermittent porphyria (AIP) is transmitted as an autosomal dominant disorder with incomplete penetrance."

This review directly states the inheritance pattern and incomplete penetrance of AIP.

PMID:29360981 SUPPORT Human Clinical

"Penetrance was estimated at 22.9% in families with AIP, but at only 0.5-1% in the general population."

Family and population estimates directly demonstrate incomplete and ascertainment-dependent penetrance; a single penetrance percentage would therefore be misleading.

PMID:29360981 SUPPORT Human Clinical

"An oligogenic inheritance model with environmental modifiers might better explain AIP penetrance and heritability."

The authors proposed, rather than established, an oligogenic explanation for the marked variability in clinical expression.

+ 1 more reference

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Mechanistic Hypotheses

2

Canonical Hepatic Precursor Overproduction Model

canonical_hepatic_precursor_overproduction_model CANONICAL

Evidence balance 4 support

Partial HMBS deficiency becomes clinically pathogenic when hepatic ALAS1 is induced, leading to excess upstream precursor synthesis and export.

HMBS deficiency and trigger-driven ALAS1 induction are parallel prerequisites for clinically important precursor accumulation: the HMBS defect does not itself induce ALAS1. Human intervention data support the hepatic precursor-overproduction model, but penetrance, mouse-only hepatic energetic effects, and liver-cancer associations are modeled separately.

Pathograph links

HMBS deficiency in hepatocytes -> Hepatic ALA and PBG accumulation INDIRECT KNOWN INTERMEDIATES Partial HMBS deficiency limits clearance of PBG when trigger-induced upstream flux rises. HMBS deficiency and ALAS1 induction are parallel contributors; the enzyme defect does not itself induce ALAS1. Intermediates: reduced conversion of PBG to hydroxymethylbilane across the partial HMBS block; trigger-induced upstream ALAS1 flux that exceeds residual HMBS pathway capacity

Triggered hepatic ALAS1 induction -> Hepatic ALA and PBG accumulation INDIRECT KNOWN INTERMEDIATES Increased ALAS1-driven flux produces ALA, which is converted to PBG by ALAD; the partial HMBS block then limits downstream PBG conversion. Intermediates: conversion of ALA to PBG by aminolevulinate dehydratase; limited PBG conversion across the partial HMBS block

Deep research

OpenScientist citations 21 citations 2026-05-23T03:52:27.508544

Show evidence (4 references)

PMID:9516674 SUPPORT Other

"Biochemical abnormalities are thought to result from primary defects of porphobilinogen deaminase (PBGD; also called hydroxymethyl bilane synthase), the third enzyme of the heme synthesis pathway, and consecutive hepatic overexpression of the first enzyme of the pathway, 5-aminolevulinate synthase."

This summarizes the joint HMBS bottleneck and hepatic ALAS1-overexpression model that drives AIP biochemistry without asserting that HMBS deficiency itself induces ALAS1.

PMID:32521132 SUPPORT Human Clinical

"Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria."

The AIP-specific randomized comparison provides intervention support for hepatic ALAS1 suppression reducing attack burden.

PMID:26062020 SUPPORT Human Clinical

"microsomal heme content was sufficient, and representative cytochrome P450 activities were essentially normal"

Detailed biochemical study of the AIP explanted liver shows preserved microsomal heme content and normal P450 activities despite massive ALA/PBG accumulation (ALAS1 ~5x activity, PBG ~1760x), directly supporting the hepatic-precursor-overproduction model over a generalized-heme-deficiency model.

+ 1 more reference

Canonical Precursor Neurotoxicity Model

canonical_precursor_neurotoxicity_model CANONICAL

Evidence balance 6 support

Acute attacks are causally linked to excess hepatic precursor burden rather than to generalized hepatic heme deficiency alone, while the responsible toxic species and molecular route remain incompletely resolved.

Lowering or removing the hepatic precursor source reduces attacks, and liver-directed correction prevents induced neuropathy in mice. ALA is the leading candidate neurotoxin; PBG is a strong biochemical marker but is not independently established as the toxic species. Proposed GABA-A, oxidative, mitochondrial, and vascular mechanisms remain uncertain at physiologic concentrations. Severe homozygous pediatric disease with local CNS precursor production is a comparator, not a direct model of classic heterozygous AIP.

Pathograph links

Hepatic ALA and PBG accumulation -> Neurovisceral attack susceptibility INDIRECT UNKNOWN INTERMEDIATES Intervention and model evidence link excess hepatic precursor burden to acute autonomic, peripheral, and central neurologic dysfunction, but the responsible toxic species and molecular route remain unresolved.

Deep research

OpenScientist citations 29 citations 2026-05-23T04:36:02.063864

Show evidence (6 references)

PMID:35067977 SUPPORT Other

"The clinical manifestations of AHP are attributed to the accumulation of the heme precursor 5-aminolevulinic acid (ALA) and porphobilinogen (PBG)."

This review directly links clinical manifestations in acute hepatic porphyrias to accumulation of ALA and PBG, matching the standard AIP neurotoxicity model.

PMID:20877347 SUPPORT Model Organism

"porphyrin precursors generated in the liver interfere with motor function"

Liver-specific AAV-PBGD gene therapy protects AIP mice against phenobarbital-induced precursor accumulation, axonal loss, and nerve conduction defects, providing direct causal evidence in the phenobarbital-induced mouse model that hepatic precursors drive motor neuropathy in that model.

PMID:19815305 SUPPORT Model Organism

"PBGD over-expression in hepatocytes, albeit in a low proportion, reduced precursor accumulation"

Genetic dissection in mouse models shows that PBGD restoration in hepatocytes (not erythrocytes) corrects precursor accumulation and motor disturbance, directly identifying hepatic rather than erythroid PBGD deficiency as the relevant pathogenic locus in the induced mouse model.

+ 3 more references

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Discussions and Knowledge Gaps

2

Which precursor species and molecular pathway connect hepatic precursor overproduction to the autonomic, peripheral-neuropathic, and central manifestations of classic heterozygous AIP attacks?

KNOWLEDGE GAP OPEN unresolved_precursor_neurotoxicity_route

Attached to

pathophysiology#Hepatic ALA and PBG accumulation pathophysiology#Neurovisceral attack susceptibility

Clinical interventions support precursor burden as causally important, but GABA-A interference, oxidative injury, mitochondrial dysfunction, and vascular effects remain candidate routes. Low adult blood-brain-barrier permeability also argues against treating severe homozygous CNS disease as a simple explanation for classic attacks.

Show evidence (2 references)

PMID:11478735 SUPPORT In Vitro

"ALA (0.1-10 mM) significantly inhibited the binding"

This supplies one plausible molecular interaction, qualified by the in vitro concentration range.

PMID:12493610 SUPPORT Model Organism

"uptake into the neonatal brain was 7-fold higher than in the adult"

Rat transport data identify an age-dependent blood-brain-barrier boundary rather than resolving classic adult human neurotoxicity.

How should findings from phenobarbital-induced T1/T2 mice and severe homozygous R167Q mice be translated to low-penetrance heterozygous human AIP?

HUMAN MODEL MISMATCH OPEN classic_and_homozygous_aip_model_boundaries

Attached to

pathophysiology#HMBS deficiency in hepatocytes pathophysiology#Neurovisceral attack susceptibility

The classic mouse requires pharmacologic induction and develops progressive neuropathy under repeated challenge, whereas the homozygous model has about 5% residual activity and early CNS-intrinsic disease. Each addresses a different mechanism boundary and neither reproduces the complete natural history of classic heterozygous AIP.

Show evidence (2 references)

PMID:20877347 SUPPORT Model Organism

"Phenobarbital injections in AIP mice induced porphyrin precursor accumulation, functional block of nerve conduction, and progressive loss of large-caliber axons in the sciatic nerve."

The classic model is explicitly challenge-induced and therefore does not reproduce spontaneous human disease expression.

PMID:30615115 SUPPORT Model Organism

"Human AIP heterozygotes have episodic acute neurovisceral attacks that typically start after puberty, whereas patients with homozygous dominant AIP (HD-AIP) have early-onset chronic neurological impairment, including ataxia and psychomotor retardation."

The paper itself states the human phenotype boundary that limits direct extrapolation from the severe homozygous model.

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Pathophysiology

6

HMBS deficiency in hepatocytes

Pathogenic HMBS variants reduce hepatic hydroxymethylbilane synthase activity, creating a partial block at the third enzymatic step of heme biosynthesis.

Canonical Hepatic Precursor Overproduction Model

hepatocyte CL:0000182

HMBS hgnc:4982 ↓ DECREASED

heme biosynthetic process GO:0006783 ↕ DYSREGULATED

hydroxymethylbilane synthase activity GO:0004418 ↓ DECREASED

liver UBERON:0002107

Downstream

Abnormal HMBS enzyme activity HMBS deficiency is the enzyme activity abnormality underlying acute intermittent porphyria.

Hepatic ALA and PBG accumulation Partial HMBS deficiency limits clearance of PBG when trigger-induced upstream flux rises. HMBS deficiency and ALAS1 induction are parallel contributors; the enzyme defect does not itself induce ALAS1.

Show evidence (1 reference)

PMID:19292878 SUPPORT Human Clinical

"Acute intermittent porphyria is an autosomal dominantly inherited disorder, classified as acute hepatic porphyria, caused by a deficiency of hydroxymethylbilane synthase (EC 2.5.1.61, EC 4.3.1.8, also known as porphobilinogen deaminase, uroporphyrinogen I synthase), the third enzyme in heme biosynthesis."

This directly identifies HMBS deficiency as the core molecular defect and places it at the third step of heme biosynthesis.

Triggered hepatic ALAS1 induction

Porphyrogenic triggers increase hepatic ALAS1 expression, pushing pathway flux into the segment upstream of the HMBS block.

Canonical Hepatic Precursor Overproduction Model

hepatocyte CL:0000182

ALAS1 hgnc:396 ↑ INCREASED

heme biosynthetic process GO:0006783 ↕ DYSREGULATED

5-aminolevulinate synthase activity GO:0003870 ↑ INCREASED

liver UBERON:0002107

Downstream

Hepatic ALA and PBG accumulation Increased ALAS1-driven flux produces ALA, which is converted to PBG by ALAD; the partial HMBS block then limits downstream PBG conversion.

Show evidence (2 references)

PMID:9516674 SUPPORT Other

"Biochemical abnormalities are thought to result from primary defects of porphobilinogen deaminase (PBGD; also called hydroxymethyl bilane synthase), the third enzyme of the heme synthesis pathway, and consecutive hepatic overexpression of the first enzyme of the pathway, 5-aminolevulinate synthase."

This review supports the key mechanistic pairing of HMBS deficiency with secondary hepatic ALAS1 overexpression.

PMID:29498764 SUPPORT Other

"Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic δ-aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency."

This study's background statement supports the accepted pairing of ALAS1 induction and HMBS deficiency; it is not classified as a patient-level result.

Hepatic ALA and PBG accumulation

Increased upstream pathway flux in the setting of partial HMBS deficiency causes excess production and systemic spillover of 5-aminolevulinic acid and porphobilinogen.

Canonical Precursor Neurotoxicity Model

hepatocyte CL:0000182

heme biosynthetic process GO:0006783 ↕ DYSREGULATED porphyrin-containing compound metabolic process GO:0006778 ⚠ ABNORMAL

liver UBERON:0002107

Downstream

Urinary 5-aminolevulinic acid Hepatic overproduction and systemic spillover of ALA produces increased urinary ALA during acute attacks.

Elevated urinary delta-aminolevulinic acid Excess hepatic ALA production spills into urine during acute attacks.

Urinary porphobilinogen Hepatic overproduction and systemic spillover of PBG produces increased urinary PBG during acute attacks.

Increased urinary porphobilinogen Excess hepatic PBG production spills into urine during acute attacks.

Porphyrinuria Excess upstream heme intermediates produce abnormal urinary porphyrin/precursor excretion.

Plasma 5-aminolevulinic acid Hepatic overproduction and systemic spillover of ALA produces increased plasma ALA during acute attacks.

Plasma porphobilinogen Hepatic overproduction and systemic spillover of PBG produces increased plasma PBG during acute attacks.

Neurovisceral attack susceptibility Intervention and model evidence link excess hepatic precursor burden to acute autonomic, peripheral, and central neurologic dysfunction, but the responsible toxic species and molecular route remain unresolved.

Porphyria-associated tubulointerstitial kidney injury Persistent precursor overproduction is associated with chronic tubulointerstitial kidney injury in symptomatic AIP, but the relative contributions of direct tubular toxicity, vascular injury, hypertension, and other factors remain uncertain.

Precursor-associated primary liver cancer risk Longitudinal AIP data associate persistently elevated urinary ALA and PBG with primary liver cancer risk, without establishing a specific carcinogenic mechanism.

Show evidence (2 references)

PMID:9516674 SUPPORT Other

"As a result of these enzymatic disturbances, heme precursors are synthesized in excess in the liver, and massive amounts of compounds upstream of the enzymatic block are excreted in urine."

This directly supports hepatic overproduction and excess excretion of pathway intermediates upstream of the HMBS block.

PMID:35067977 SUPPORT Other

"The clinical manifestations of AHP are attributed to the accumulation of the heme precursor 5-aminolevulinic acid (ALA) and porphobilinogen (PBG)."

This review supports the precursor-burden framework without independently identifying which precursor is toxic or resolving the molecular route.

Neurovisceral attack susceptibility

Acute attacks manifest as abdominal pain and neurologic dysfunction, including motor-predominant neuropathy and severe weakness. ALA is the leading candidate toxin, but the molecular mechanisms linking precursor burden to the full attack syndrome remain unresolved.

neuron CL:0000540

Experimental models

ALA exposure of human and rat cortical synaptic membranes OTHER Tests the candidate interaction between ALA and GABA-A receptor ligand binding without treating the membrane assay as a faithful model of an in vivo human AIP attack.

Downstream

Acute neurovisceral attack Neurovisceral susceptibility is expressed clinically as a multisystem acute porphyria attack; the molecular route to individual manifestations remains unresolved in the downstream symptom edges.

Abdominal pain Abdominal pain is the most common clinical expression of acute neurovisceral crises.

Nausea and vomiting Gastrointestinal neurovisceral attacks commonly include nausea and vomiting alongside abdominal pain.

Constipation Constipation is reported during acute neurovisceral attacks, but the specific causal route is not established by the frequency evidence.

Tachycardia Tachycardia is a prominent acute-attack manifestation; the cited clinical series does not isolate its molecular or autonomic intermediate.

Peripheral neuropathy Acute hepatic porphyria attacks can progress to motor-predominant porphyric neuropathy.

Cranial nerve paralysis Cranial nerve paralysis is reported in AIP, but its specific route from precursor burden is unresolved.

Muscle weakness Motor-predominant porphyric neuropathy can cause quadriparesis and respiratory weakness in severe attacks.

Hyponatremia Acute AIP presentations can include SIADH-associated hyponatremia as part of the neurovisceral attack spectrum.

Hypertension Hypertension can accompany acute attacks alongside tachycardia, while the cited attack series does not establish a specific intermediate mechanism.

Tetraparesis Severe porphyric neuropathy can progress to quadriparesis/tetraparesis.

Seizure Acute porphyria encephalopathy can include seizures during neuropsychiatric crises.

Psychosis Acute porphyria encephalopathy can include psychosis during neuropsychiatric crises.

Back pain Neurovisceral pain during attacks can include back pain.

Limb pain Neurovisceral and neuropathic pain during attacks can include limb pain.

Neck pain Neurovisceral pain during attacks can include neck pain.

Show evidence (3 references)

PMID:19292878 SUPPORT Human Clinical

"Clinical features include autonomous, central, motor or sensory symptoms, but the most common clinical presentation is abdominal pain caused by neurovisceral crises."

This patient molecular study's clinical background summary connects neurovisceral crises to abdominal pain and broad neurologic involvement in AIP.

PMID:33786855 SUPPORT Other

"Acute hepatic porphyrias are inherited metabolic disorders that may present with polyneuropathy, which if not diagnosed early can lead to quadriparesis, respiratory weakness, and death."

This review supports severe neuropathic weakness as a clinically relevant downstream consequence of acute hepatic porphyria attacks.

PMID:38715693 SUPPORT Human Clinical

"During acute attacks, serum NfL levels were 68 times higher compared to normal controls and disclosed a strong correlation with ALA and PBG levels; also exhibited elevated levels in patients with chronic symptoms regardless of the number of disease attacks compared to healthy controls, and at..."

This mixed acute-hepatic-porphyria cohort provides biomarker evidence for axonal injury during acute and chronic disease, but is not AIP-specific and does not resolve the toxic mechanism.

Porphyria-associated tubulointerstitial kidney injury

Symptomatic AIP is associated with a chronic tubulointerstitial nephropathy and progressive loss of kidney function. Precursor toxicity to proximal tubular cells is experimentally supported, while vascular injury, hypertension, and other contributors prevent assignment of a single proven human mechanism.

kidney UBERON:0002113

Experimental models

Porphyrin-precursor exposure of human proximal tubular cells OTHER Tests candidate precursor-induced endoplasmic-reticulum stress, apoptosis, and epithelial phenotypic change in human proximal tubular cells relevant to porphyria-associated kidney injury.

Downstream

Chronic kidney disease Persistent tubulointerstitial and vascular kidney injury can produce chronic loss of filtration in symptomatic AIP.

Show evidence (2 references)

PMID:25830761 SUPPORT Human Clinical

"The renal pathology was a chronic tubulointerstitial nephropathy, associated with a fibrous intimal hyperplasia and focal cortical atrophy."

AIP patient pathology directly establishes the characteristic chronic tubulointerstitial and vascular injury pattern.

PMID:34943561 SUPPORT Other

"Given the relevant role of the kidney in porphyrin metabolism, the mechanisms possibly intervening in causing renal damage in AHPs are different: among others, δ-aminolevulinic acid (ALA)-induced oxidative damage on mitochondria, intracellular toxic aggregation of porphyrins in proximal tubular..."

This review supports a multifactorial interpretation and cautions against reducing porphyria-associated kidney disease to one pathway.

Precursor-associated primary liver cancer risk

AIP cohorts show that persistently high urinary ALA and PBG are associated with primary liver cancer risk. The association is clinically important, but the molecular route and degree of direct precursor causality remain unresolved.

liver UBERON:0002107

Downstream

Hepatocellular carcinoma Persistent precursor elevation marks increased hepatocellular-carcinoma risk in AIP, without a proven molecular route from precursor exposure to malignant transformation.

Show evidence (2 references)

PMID:37650859 SUPPORT Human Clinical

"Increased urinary porphyrin precursors are associated with a high risk of developing PLC."

The AIP-specific case-control study establishes a risk association while leaving the carcinogenic mechanism unresolved.

PMID:39438413 SUPPORT Human Clinical

"HCC cases were observed with HCC incidence per 100 person years of 0.3 (0.2-0.5) in AHP, 0.4 (0.2-0.6) in AIP, 0.3 (0-0.4) in VP, and 0.2 (0.1-0.6) in HCP."

The meta-analysis directly reports the AIP-specific incidence estimate; its heterogeneous observational analyses and publication bias limit precision and generalizability but do not weaken claim-to-snippet fit.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

22

Cardiovascular 2

Tachycardia HP:0001649

Show evidence (1 reference)

PMID:4723462 SUPPORT Human Clinical

"In four young adult patients with acute attacks of acute intermittent porphyria tachycardia and hypertension were prominent features of the illness."

Human case-series data directly support tachycardia as a prominent autonomic manifestation during AIP attacks.

Hypertension HP:0000822

Show evidence (2 references)

PMID:4723462 SUPPORT Human Clinical

"In four young adult patients with acute attacks of acute intermittent porphyria tachycardia and hypertension were prominent features of the illness."

Human case-series data directly support hypertension during acute AIP attacks.

PMID:8046316 SUPPORT Human Clinical

"Hypertension was found in 56% of patients with manifest AIP, 33% of their controls (P = 0.041) and 16% of patients with latent AIP (P = 0.004)."

The population-based case-control study supports hypertension as a chronic association of manifest AIP in addition to its acute autonomic presentation.

Digestive 3

Nausea and vomiting HP:0002017

Show evidence (1 reference)

PMID:33139977 SUPPORT Other

"Acute AIP episodes may present with abdominal pain, nausea, and vomiting, and repeated episodes may result in a series of chronic injuries."

Review-level evidence supports nausea and vomiting as common acute neurovisceral symptoms in AIP.

Hepatocellular carcinoma HP:0001402

Show evidence (1 reference)

PMID:39438413 SUPPORT Human Clinical

"HCC cases were observed with HCC incidence per 100 person years of 0.3 (0.2-0.5) in AHP, 0.4 (0.2-0.6) in AIP, 0.3 (0-0.4) in VP, and 0.2 (0.1-0.6) in HCP."

The meta-analysis directly reports the AIP-specific incidence estimate; heterogeneity and publication bias qualify its precision and application to individual patients or populations.

Constipation FREQUENT HP:0002019

Show evidence (1 reference)

ORPHA:79276 SUPPORT Other

"HP:0002019 | Constipation | Frequent (79-30%)"

Orphanet reports constipation as frequent.

Genitourinary 1

Chronic kidney disease HP:0012622

Show evidence (2 references)

PMID:25830761 SUPPORT Human Clinical

"Chronic kidney disease occurred in up to 59% of the symptomatic AIP patients, with a decline in the glomerular filtration rate of ~1 ml/min per 1.73 m(2) annually."

The longitudinal AIP cohort directly supports chronic kidney disease and progressive filtration loss in symptomatic patients.

PMID:33639982 SUPPORT Human Clinical

"The earliest long-term clinical condition associated with SA-AIP was chronic kidney disease."

This sporadic-attack AIP cohort shows that kidney disease is not confined to patients with frequent recurrent attacks.

Metabolism 1

Hyponatremia HP:0002902

Show evidence (1 reference)

PMID:25796467 SUPPORT Human Clinical

"Acute intermittent porphyria (AIP) is a rare condition characterized by abdominal pain and a wide range of nonspecific symptoms. We report the case of a woman with abdominal pain and syndrome of inappropriate antidiuretic hormone secretion (SIADH) as clinical presentation of AIP."

Human clinical evidence supports SIADH-associated hyponatremia as an important electrolyte complication during acute AIP presentations.

Musculoskeletal 1

Muscle weakness HP:0001324

Show evidence (1 reference)

PMID:33786855 SUPPORT Other

"Acute hepatic porphyrias are inherited metabolic disorders that may present with polyneuropathy, which if not diagnosed early can lead to quadriparesis, respiratory weakness, and death."

Severe motor neuropathy with weakness is a key clinically relevant AIP manifestation.

Nervous System 4

Peripheral neuropathy HP:0009830

Show evidence (1 reference)

PMID:33786855 SUPPORT Other

"Acute hepatic porphyrias are inherited metabolic disorders that may present with polyneuropathy, which if not diagnosed early can lead to quadriparesis, respiratory weakness, and death."

This directly supports peripheral neuropathy as a core neurologic manifestation of acute attacks.

Seizure HP:0001250

Show evidence (1 reference)

PMID:26366103 SUPPORT Other

"Intensive abdominal pain without peritoneal signs, acute peripheral neuropathy, and encephalopathy usually with seizures or psychosis are the key symptoms indicating possible acute porphyria."

Review evidence lists seizures as a key encephalopathic symptom indicating acute porphyria.

Psychosis HP:0000709

Show evidence (1 reference)

PMID:26366103 SUPPORT Other

"Intensive abdominal pain without peritoneal signs, acute peripheral neuropathy, and encephalopathy usually with seizures or psychosis are the key symptoms indicating possible acute porphyria."

Review evidence lists psychosis as a key encephalopathic symptom indicating acute porphyria.

Cranial nerve paralysis FREQUENT HP:0006824

Show evidence (1 reference)

ORPHA:79276 SUPPORT Other

"HP:0006824 | Cranial nerve paralysis | Frequent (79-30%)"

Orphanet reports cranial nerve paralysis as frequent.

Constitutional 3

Abdominal pain HP:0002027

Show evidence (1 reference)

PMID:19292878 SUPPORT Human Clinical

"Clinical features include autonomous, central, motor or sensory symptoms, but the most common clinical presentation is abdominal pain caused by neurovisceral crises."

This directly identifies abdominal pain as the dominant acute clinical presentation in AIP.

Back pain FREQUENT HP:0003418

Show evidence (1 reference)

ORPHA:79276 SUPPORT Other

"HP:0003418 | Back pain | Frequent (79-30%)"

Orphanet reports back pain as frequent.

Limb pain FREQUENT HP:0009763

Show evidence (1 reference)

ORPHA:79276 SUPPORT Other

"HP:0009763 | Limb pain | Frequent (79-30%)"

Orphanet reports limb pain as frequent.

Other 7

Acute neurovisceral attack

Show evidence (2 references)

PMID:20301372 SUPPORT Other

"An acute porphyria attack is characterized by a urine porphobilinogen (PBG)-to-creatinine ratio ≥10 times the upper limit of normal (ULN) and the presence of ≥2 porphyria manifestations (involving the visceral, peripheral, autonomic, and/or central nervous systems) persisting for >24 hours in..."

GeneReviews directly supports the compound acute-attack clinical characteristic represented here.

PMID:20301372 SUPPORT Other

"Onset of acute attacks typically occurs in the second or third decade of life."

GeneReviews directly supports the typical onset of the attack phenotype.

Tetraparesis HP:0002273

Show evidence (1 reference)

PMID:33786855 SUPPORT Other

"Acute hepatic porphyrias are inherited metabolic disorders that may present with polyneuropathy, which if not diagnosed early can lead to quadriparesis, respiratory weakness, and death."

Review evidence explicitly supports quadriparesis as a severe porphyric neuropathy manifestation.

Abnormal HMBS enzyme activity VERY_FREQUENT Abnormal circulating enzyme concentration or activity HP:0012379

Show evidence (1 reference)

ORPHA:79276 SUPPORT Other

"HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent (99-80%)"

Orphanet reports abnormal enzyme/coenzyme activity as very frequent.

Elevated urinary delta-aminolevulinic acid VERY_FREQUENT HP:0003163

Show evidence (1 reference)

ORPHA:79276 SUPPORT Other

"HP:0003163 | Elevated urinary delta-aminolevulinic acid | Very frequent (99-80%)"

Orphanet reports elevated urinary delta-aminolevulinic acid as very frequent.

Increased urinary porphobilinogen VERY_FREQUENT HP:0012217

Show evidence (1 reference)

ORPHA:79276 SUPPORT Other

"HP:0012217 | Increased urinary porphobilinogen | Very frequent (99-80%)"

Orphanet reports increased urinary porphobilinogen as very frequent.

Porphyrinuria VERY_FREQUENT HP:0010473

Show evidence (1 reference)

ORPHA:79276 SUPPORT Other

"HP:0010473 | Porphyrinuria | Very frequent (99-80%)"

Orphanet reports porphyrinuria as very frequent.

Neck pain FREQUENT HP:0030833

Show evidence (1 reference)

ORPHA:79276 SUPPORT Other

"HP:0030833 | Neck pain | Frequent (79-30%)"

Orphanet reports neck pain as frequent.

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Genetic Associations

1

HMBS (Causative)

Gene: HMBS hgnc:4982 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:19292878 SUPPORT Human Clinical

"Molecular analyses of the hydroxymethylbilane synthase gene revealed seven mutations."

Patient-based molecular data directly support HMBS as the causative gene in AIP.

CGGV:assertion_eab4b1f6-2902-4ed3-9002-37c578aeaaba-2022-05-27T160000.000Z SUPPORT Other

ClinGen classifies the HMBS-acute intermittent porphyria gene-disease relationship as definitive with semidominant inheritance.

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Medical Actions

7

Trigger avoidance and adequate nutrition

Preventive care includes avoiding excessive alcohol and porphyrogenic drugs, maintaining adequate regular nutrition, and treating systemic illness or infection promptly. These measures reduce exposure to known inducers rather than correcting the inherited HMBS defect.

Mechanism Target:

INHIBITS Triggered hepatic ALAS1 induction — Avoiding excessive alcohol, fasting, and porphyrogenic drugs reduces exposure to factors supported to upregulate or dysregulate hepatic ALAS1. Adequate nutrition and timely illness treatment remain clinically supported prevention measures without assigning infection the same direct ALAS1 evidence.

Show evidence (2 references)

PMID:20301372 SUPPORT Other

"Individuals with AIP are advised to avoid excessive alcohol consumption, as alcohol upregulates the enzyme ALAS1, the first enzyme of hepatic heme biosynthesis, and thus could be a trigger for acute attacks."

GeneReviews directly supports prevention of an exposure that induces the modeled ALAS1 trigger event.

PMID:16122419 SUPPORT Model Organism

"The induction of ALAS-1 by fasting is lost in liver-specific PGC-1alpha knockout animals, as is the ability of porphyrogenic drugs to dysregulate heme biosynthesis."

Mouse data connect fasting and porphyrogenic drugs to ALAS1 regulation; PARTIAL preserves the boundary between this mechanism and preventive efficacy in human AIP.

Show evidence (2 references)

PMID:20301372 SUPPORT Other

"To reduce the frequency and/or severity of acute attacks, maintain adequate nutrition and seek timely treatment of systemic illness or infection."

GeneReviews directly recommends nutrition and timely illness treatment as attack-prevention measures.

PMID:20301372 SUPPORT Other

"Individuals with AIP are advised to avoid excessive alcohol consumption, as alcohol upregulates the enzyme ALAS1, the first enzyme of hepatic heme biosynthesis, and thus could be a trigger for acute attacks."

GeneReviews supports excessive-alcohol avoidance as a mechanism-linked preventive measure.

Intravenous hemin

Action: Pharmacotherapy NCIT:C15986

Agent: hemin CHEBI:50385

Standard treatment for severe acute attacks; exogenous hemin represses hepatic ALAS1 and is more effective than glucose alone in serious attacks.

Mechanism Target:

INHIBITS Triggered hepatic ALAS1 induction — Hemin represses hepatic ALAS1 during acute attacks.

Show evidence (1 reference)

PMID:29498764 SUPPORT Other

"So far, the treatment of choice is hemin which represses ALAS1."

This directly links hemin therapy to repression of the induced hepatic ALAS1 node.

INHIBITS Hepatic ALA and PBG accumulation — By repressing ALAS1, hemin lowers the precursor burden during more severe attacks.

Show evidence (1 reference)

PMID:19327613 SUPPORT Human Clinical

"Glucose administration, in contrast to heme therapy, was not sufficient to achieve clinical and biochemical remission in the more serious attacks."

This supports heme therapy as the more effective way to reverse the acute biochemical lesion in serious AIP attacks.

Show evidence (2 references)

PMID:19327613 SUPPORT Human Clinical

"Treatment is based on symptomatic relief together with carbohydrate loading and in more severe attacks heme therapy."

This study describes heme therapy as the escalation treatment for more severe acute attacks.

PMID:33786855 SUPPORT Other

"Timely treatment with intravenous heme, carbohydrate loading, and avoidance of porphyrinogenic medications can prevent further neurological morbidity and mortality."

This review supports intravenous heme as clinically important for limiting neurologic morbidity during porphyric attacks.

Givosiran

Action: Pharmacotherapy NCIT:C15986

Agent: givosiran NCIT:C146805

Liver-directed siRNA prophylaxis that lowers ALAS1, reduces ALA and PBG, and markedly decreases recurrent attack burden.

Mechanism Target:

INHIBITS Triggered hepatic ALAS1 induction — Givosiran suppresses hepatic ALAS1 expression as mechanism-directed prophylaxis.

Show evidence (1 reference)

PMID:35067977 SUPPORT Other

"The results of clinical trials have shown that givosiran treatment leads to a rapid and sustained reduction of ALAS1 mRNA, decreased heme precursor levels, and a decreased rate of acute attacks compared with placebo."

This directly supports ALAS1 silencing as the intended upstream mechanism of givosiran.

INHIBITS Hepatic ALA and PBG accumulation — Givosiran lowers urinary ALA and PBG toward normal by suppressing hepatic precursor production.

Show evidence (1 reference)

PMID:31994716 SUPPORT Human Clinical

"Givosiran treatment resulted in a rapid and dose-dependent reduction in urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) towards the upper limit of normal (ULN) in AHP patients."

This phase I study provides direct biochemical evidence that givosiran suppresses the precursor burden.

Show evidence (3 references)

PMID:32521132 SUPPORT Human Clinical

"Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria."

The pivotal randomized trial provides AIP-specific efficacy evidence.

PMID:32521132 SUPPORT Human Clinical

"The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events."

The AIP-specific trial also establishes the clinically important hepatic and renal safety signal.

PMID:37479139 SUPPORT Human Clinical

"These final 36-month results of ENVISION, a phase III study of givosiran in patients with AHP and recurrent attacks, show that long-term monthly treatment with givosiran leads to continuous and sustained reductions in annualized attack rate and use of hemin over time, as well as improved quality..."

Long-term phase III and open-label-extension evidence supports givosiran as effective mechanism-directed long-term prophylaxis for recurrent attacks.

Prophylactic hemin infusion

Action: Pharmacotherapy NCIT:C15986

Agent: hemin CHEBI:50385

Scheduled hemin infusion is an alternative prophylactic therapy to reduce frequency or severity of recurrent acute attacks when givosiran is not available. Long-term use is limited by iron overload, phlebitis, loss of venous access, and evidence that frequent infusions can promote chronic hepatic inflammation and recurrent ALAS1 elevation.

Mechanism Target:

INHIBITS Triggered hepatic ALAS1 induction — Hemin can repress ALAS1, but frequent prophylactic exposure is not modeled as simple sustained inhibition because hepatic inflammation and HO1 induction may maintain elevated ALAS1 between treatments.

Show evidence (1 reference)

PMID:29498764 SUPPORT Other

"So far, the treatment of choice is hemin which represses ALAS1."

This supports the negative-feedback mechanism, with PARTIAL support because the same study reports a countervailing effect of frequent infusions.

Show evidence (4 references)

PMID:20301372 SUPPORT Other

"Alternative medical therapies to reduce frequency and/or severity of acute attacks when givosiran is not available include suppression of ovulation and prophylactic hemin infusion."

GeneReviews supports prophylactic hemin infusion as an alternative preventive therapy when givosiran is unavailable.

PMID:26366103 SUPPORT Other

"management of patients with recurrent attacks: 1) evaluation of the lifestyle, 2) evaluation of hormonal therapy in women, 3) prophylactic heme therapy, and 4) liver transplantation in patients with severe recurrent attacks."

A clinical management review independently lists prophylactic heme therapy for patients with recurrent attacks.

PMID:29498764 SUPPORT Other

"both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence."

Mixed human-liver and animal evidence supplies the countervailing chronic inflammation and recurrent-ALAS1 caveat.

+ 1 more reference

Ovulation suppression

Action: hormone modifying therapy Ontology label: Hormone Therapy NCIT:C15445

Ovulation suppression is an alternative prophylactic strategy for women with recurrent attacks when givosiran is not available, addressing hormonally triggered attack recurrence.

Mechanism Target:

INHIBITS Neurovisceral attack susceptibility — Suppressing ovulation reduces hormonally driven recurrent attack susceptibility in women, although the endocrine intermediate is not separately modeled in this pathograph.

Show evidence (1 reference)

PMID:20301372 SUPPORT Other

"Alternative medical therapies to reduce frequency and/or severity of acute attacks when givosiran is not available include suppression of ovulation and prophylactic hemin infusion."

GeneReviews lists suppression of ovulation as an alternative therapy to reduce acute attack frequency or severity.

Show evidence (2 references)

PMID:20301372 SUPPORT Other

"Alternative medical therapies to reduce frequency and/or severity of acute attacks when givosiran is not available include suppression of ovulation and prophylactic hemin infusion."

GeneReviews supports ovulation suppression as an alternative preventive therapy when givosiran is unavailable.

PMID:26366103 SUPPORT Other

"management of patients with recurrent attacks: 1) evaluation of the lifestyle, 2) evaluation of hormonal therapy in women, 3) prophylactic heme therapy, and 4) liver transplantation in patients with severe recurrent attacks."

The recurrent-attack management review independently lists evaluation of hormonal therapy in women.

Liver transplantation

Action: liver transplantation Ontology label: Liver Transplantation NCIT:C15271

Liver transplantation is a curative option for selected patients with repeated life-threatening acute porphyria attacks or poor quality of life when givosiran is unavailable or insufficiently effective.

Mechanism Target:

RESTORES HMBS deficiency in hepatocytes — Transplantation replaces the HMBS-deficient hepatic compartment that drives attack biochemistry, restoring hepatic enzyme capacity at the organ level.

Show evidence (1 reference)

PMID:26062020 SUPPORT Human Clinical

"After OLT, the recipient's plasma and urinary ALA and PBG rapidly normalized, and her attacks immediately stopped."

Rapid biochemical normalization and attack cessation support replacement of the diseased hepatic compartment; PARTIAL reflects that HMBS activity itself was not reported as the outcome in this sentence.

INHIBITS Hepatic ALA and PBG accumulation — By replacing the hepatic source of excess precursor production, liver transplantation prevents recurrent severe attack biochemistry.

Show evidence (1 reference)

PMID:26062020 SUPPORT Human Clinical

"After OLT, the recipient's plasma and urinary ALA and PBG rapidly normalized, and her attacks immediately stopped."

This directly documents normalization of circulating and urinary precursors after removal of the hepatic source.

Show evidence (2 references)

PMID:20301372 SUPPORT Other

"Liver transplantation, as reported from several centers, is curative. Indications include repeated life-threatening acute porphyria attacks and poor quality of life when givosiran is not available or has shown insufficient medical efficacy."

GeneReviews supports liver transplantation as a curative option for severe recurrent AIP attacks when givosiran is unavailable or insufficiently effective.

PMID:26366103 SUPPORT Other

"management of patients with recurrent attacks: 1) evaluation of the lifestyle, 2) evaluation of hormonal therapy in women, 3) prophylactic heme therapy, and 4) liver transplantation in patients with severe recurrent attacks."

A clinical management review independently lists liver transplantation for patients with severe recurrent attacks.

Carbohydrate loading

Action: glucose supplementation Ontology label: Nutritional Support NCIT:C15433

High-carbohydrate intake is used as adjunctive therapy during milder attacks but is usually insufficient alone for serious episodes.

Mechanism Target:

MODULATES Triggered hepatic ALAS1 induction — Glucose administration is placed upstream of triggered hepatic ALAS1 induction as a nutritional intervention. PGC-1alpha links nutritional status to ALAS1 regulation, but the cited mechanistic study explicitly leaves the beneficial glucose mechanism unresolved, so this join is provisional.

Show evidence (2 references)

PMID:16122419 SUPPORT Model Organism

"Acute attacks are treated by heme infusion and glucose administration, but the mechanisms underlying the precipitating effects of fasting and the beneficial effects of glucose are unknown."

The study identifies glucose as an acute-attack intervention while explicitly limiting the certainty of its mechanistic connection.

PMID:16122419 SUPPORT Model Organism

"These data show that PGC-1alpha links nutritional status to heme biosynthesis and acute hepatic porphyria."

Mouse data support a nutritional-regulation join to the hepatic pathway without proving that glucose directly suppresses ALAS1 in human AIP.

Show evidence (2 references)

PMID:19327613 SUPPORT Human Clinical

"Treatment is based on symptomatic relief together with carbohydrate loading and in more severe attacks heme therapy."

This directly supports carbohydrate loading as standard supportive management during acute attacks.

PMID:19327613 SUPPORT Human Clinical

"Glucose administration, in contrast to heme therapy, was not sufficient to achieve clinical and biochemical remission in the more serious attacks."

This directly establishes the clinically important limitation that carbohydrate therapy is insufficient in more severe attacks.

🌍

Environmental Factors

1

Porphyrogenic attack triggers

Drugs, alcohol, low caloric intake or fasting, and infections can precipitate acute attacks by increasing hepatic pathway demand and inducing the triggered hepatic ALAS1 event represented in the pathophysiology graph.

Show evidence (2 references)

PMID:9516674 SUPPORT Other

"These symptoms occur during acute attacks, which are often precipitated by drugs, alcohol, low caloric intake, or infections."

This review directly names the common environmental and physiologic triggers that precipitate AIP attacks.

PMID:20301372 SUPPORT Other

"Individuals with AIP are advised to avoid excessive alcohol consumption, as alcohol upregulates the enzyme ALAS1, the first enzyme of hepatic heme biosynthesis, and thus could be a trigger for acute attacks."

GeneReviews directly connects a preventable exposure to ALAS1 induction and acute-attack triggering.

🔬

Biochemical Markers

4

Urinary 5-aminolevulinic acid (INCREASED)

Context: Urinary ALA rises during acute attacks and is part of the biochemical signature used to confirm and monitor active disease.

Pathograph Readouts

Readout Of Hepatic ALA and PBG accumulation Positive Diagnostic

Increased urinary ALA reports hepatic overproduction and systemic spillover of upstream heme precursors during an active attack.

Show evidence (1 reference)

PMID:19327613 SUPPORT Human Clinical

"During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine."

Human attack-monitoring data connect urinary ALA to hepatic precursor overproduction during active AIP attacks.

Pharmacodynamic Marker Of Triggered hepatic ALAS1 induction Positive Pharmacodynamic

Lower urinary ALA after ALAS1-suppressive therapy reports reduced hepatic precursor production.

Show evidence (1 reference)

PMID:31994716 SUPPORT Human Clinical

"Givosiran treatment resulted in a rapid and dose-dependent reduction in urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) towards the upper limit of normal (ULN) in AHP patients."

Human phase I pharmacodynamic data support urinary ALA as a marker of ALAS1-directed pathway suppression.

Correlates With Neurovisceral attack susceptibility Positive Monitoring

Higher ALA during symptoms supports an ongoing acute attack and can be tracked during treatment response.

Show evidence (1 reference)

PMID:19327613 SUPPORT Human Clinical

"These metabolites represent the acute phase reactants confirming an ongoing attack and are used to evaluate therapeutic measures."

Attack-monitoring data support ALA/PBG as biochemical correlates of ongoing attack state and treatment response.

Show evidence (1 reference)

PMID:19327613 SUPPORT Human Clinical

"During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine."

This directly supports increased urinary ALA as a hallmark biochemical abnormality during acute attacks.

Urinary porphobilinogen (INCREASED)

Context: Urinary PBG increases substantially during acute attacks and serves as a key biochemical disease marker.

Pathograph Readouts

Readout Of Hepatic ALA and PBG accumulation Positive Diagnostic

Increased urinary PBG reports hepatic overproduction and systemic spillover of upstream heme precursors during an active attack.

Show evidence (1 reference)

PMID:19327613 SUPPORT Human Clinical

"During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine."

Human attack-monitoring data connect urinary PBG to hepatic precursor overproduction during active AIP attacks.

Pharmacodynamic Marker Of Triggered hepatic ALAS1 induction Positive Pharmacodynamic

Lower urinary PBG after ALAS1-suppressive therapy reports reduced hepatic precursor production.

Show evidence (1 reference)

PMID:31994716 SUPPORT Human Clinical

"Givosiran treatment resulted in a rapid and dose-dependent reduction in urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) towards the upper limit of normal (ULN) in AHP patients."

Human phase I pharmacodynamic data support urinary PBG as a marker of ALAS1-directed pathway suppression.

Correlates With Neurovisceral attack susceptibility Positive Monitoring

Higher PBG during symptoms supports an ongoing acute attack and can be tracked during treatment response.

Show evidence (1 reference)

PMID:19327613 SUPPORT Human Clinical

"These metabolites represent the acute phase reactants confirming an ongoing attack and are used to evaluate therapeutic measures."

Attack-monitoring data support ALA/PBG as biochemical correlates of ongoing attack state and treatment response.

Show evidence (1 reference)

PMID:19327613 SUPPORT Human Clinical

"During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine."

This directly supports increased urinary PBG as a hallmark biochemical abnormality during acute attacks.

Plasma 5-aminolevulinic acid (INCREASED)

Context: Plasma ALA rises during acute attacks as a circulating marker of hepatic precursor overproduction.

Pathograph Readouts

Readout Of Hepatic ALA and PBG accumulation Positive Monitoring

Increased plasma ALA reflects hepatic precursor accumulation during an acute attack.

Show evidence (1 reference)

PMID:19327613 SUPPORT Human Clinical

"During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine."

The attack-monitoring study documents high plasma ALA during acute attacks.

Show evidence (1 reference)

PMID:19327613 SUPPORT Human Clinical

"During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine."

This directly supports increased plasma ALA during acute AIP attacks.

Plasma porphobilinogen (INCREASED)

Context: Plasma PBG rises during acute attacks and may track attack severity and treatment response more accurately than urinary precursor measurements.

Pathograph Readouts

Readout Of Hepatic ALA and PBG accumulation Positive Monitoring

Increased plasma PBG reflects hepatic precursor accumulation during an acute attack.

Show evidence (1 reference)

PMID:19327613 SUPPORT Human Clinical

"During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine."

The attack-monitoring study documents high plasma PBG during acute attacks.

Correlates With Neurovisceral attack susceptibility Positive Monitoring

Plasma PBG can track the clinical and therapeutic course of acute attacks.

Show evidence (1 reference)

PMID:19327613 SUPPORT Human Clinical

"Biochemical monitoring of an acute attack was more accurately reflected by plasma PBG than plasma ALA or urinary PBG and ALA."

The study conclusion supports plasma PBG as a sensitive monitoring marker for the attack course.

Show evidence (1 reference)

PMID:19327613 SUPPORT Human Clinical

"During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine."

This directly supports increased plasma PBG during acute AIP attacks.

🔬

Diagnosis

2

Urinary ALA and PBG measurement

Quantification of PBG and ALA, normalized to creatinine in a random urine sample collected during symptoms, establishes an active acute-hepatic-porphyria biochemical state and can track treatment response; the biochemical result alone does not distinguish AIP from the other acute hepatic porphyrias.

urine chemistry measurement NCIT:C61044

Results: Markedly elevated urinary PBG, usually with elevated ALA, supports an active acute hepatic porphyria attack and prompts porphyria-type confirmation.

Show evidence (3 references)

PMID:19327613 SUPPORT Human Clinical

"During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine."

This directly supports urinary ALA and PBG measurement as the key biochemical diagnostic readout during attacks.

PMID:20301372 SUPPORT Other

"When the diagnosis of an AIP attack is suspected based on clinical findings, establishing the diagnosis begins with biochemical testing."

GeneReviews explicitly places biochemical testing first in the diagnostic sequence.

PMID:36642627 SUPPORT Other

"Initial diagnosis of AHP should be made by biochemical testing measuring δ-aminolevulinic acid, porphobilinogen, and creatinine on a random urine sample."

The AGA expert review specifies the random-urine collection and creatinine correction needed to control for urine dilution.

Molecular genetic testing

HMBS molecular testing confirms AIP as the porphyria type after positive biochemistry and enables cascade screening. Because penetrance is very low, an HMBS variant alone does not establish that current symptoms constitute an acute attack.

molecular genetic testing NCIT:C19770

Results: A pathogenic HMBS variant confirms inherited AIP susceptibility; increased urinary PBG is also required to attribute current symptoms to an AIP attack.

Show evidence (1 reference)

PMID:20301372 SUPPORT Other

"If the urinary concentration of PBG is increased, molecular genetic testing is performed to confirm the diagnosis and/or to facilitate cascade screening of family members."

GeneReviews supports confirmatory HMBS testing after positive biochemical testing and its separate role in family screening.

📈

Progression

4

Latent or asymptomatic carrier state

Most people heterozygous for a pathogenic HMBS variant never develop an acute attack. This is a clinical category, not an obligatory first step in a linear progression sequence.

Show evidence (1 reference)

PMID:20301372 SUPPORT Other

"Latent (inactive) AIP: Urine PBG-to-creatinine ratio <4 times ULN and no acute porphyria-related manifestations to date."

GeneReviews defines latent AIP as an attack-free carrier state.

Episodic active acute intermittent porphyria

Age: Usually begins in the second or third decade Duration: Individual attacks and recovery vary from days to months

Susceptible carriers can experience trigger-associated acute neurovisceral attacks separated by non-attack intervals; attack occurrence and recovery are highly variable.

Show evidence (3 references)

PMID:20301372 SUPPORT Other

"The course of acute porphyria attacks is highly variable in an individual and between individuals."

GeneReviews supports the episodic and individually variable course.

PMID:20301372 SUPPORT Other

"Onset of acute attacks typically occurs in the second or third decade of life."

GeneReviews directly supports the usual age range for attack onset.

PMID:20301372 SUPPORT Other

"Recovery from acute porphyria attacks may occur within days; however, recovery from severe attacks that are not promptly recognized and treated may take weeks or months."

GeneReviews directly supports the stated range from rapid recovery to a prolonged course after severe, delayed-treatment attacks.

Sporadic, recurrent, or chronically symptomatic AIP

Some clinically manifest patients have sporadic or recurrent attacks, and chronic symptoms may persist between attacks even when attack frequency is low. These states are not experienced by every carrier.

Show evidence (1 reference)

PMID:33639982 SUPPORT Human Clinical

"AIP remains a chronically symptomatic disease that adversely affects health and quality of life, even in patients with low rate of acute attacks."

This AIP cohort documents clinically important chronic disease outside a simple recurrent-attack model.

Long-term complication risk

Clinically manifest AIP carries long-term risks that include chronic kidney disease, hypertension, and hepatocellular carcinoma; these are surveillance concerns rather than inevitable outcomes.

Show evidence (1 reference)

PMID:36642627 SUPPORT Other

"Patients should be counseled on the chronic and long-term complications of AHP, including neuropathy, chronic kidney disease, hypertension, and hepatocellular carcinoma, and need for long-term monitoring."

This expert review identifies the major long-term complications that require monitoring, while applying them across the acute hepatic porphyrias rather than asserting that every AIP carrier develops them.

📊

Prevalence

2

Asymptomatic heterozygous carriers in population studies

Carrier Frequency 50.0 per 100,000 1–9 per 10,000

Molecular carrier prevalence is substantially higher than overt clinical disease prevalence because penetrance is low.

Show evidence (1 reference)

PMID:9516674 SUPPORT Other

"Recent population studies suggest that the prevalence of asymptomatic heterozygotes for a mutant AIP gene may be in the range of 1 in 2,000."

This review provides a population-level estimate for asymptomatic HMBS mutation carriers and highlights the disease's incomplete penetrance.

Clinically symptomatic acute intermittent porphyria

Point Prevalence 1.0 per 100,000 1–9 per 100,000

Estimated prevalence of patients with symptomatic AIP.

Show evidence (1 reference)

PMID:36642627 SUPPORT Other

"Acute intermittent porphyria is the most common type of AHP, with an estimated prevalence of patients with symptoms of approximately 1 in 100,000."

The expert review distinguishes clinically symptomatic AIP prevalence from the much higher HMBS carrier frequency.

📊

Related Datasets

1

Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria geo:GSE146212

Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of heme biosynthesis due to a pathogenic mutation in the Hmbs gene, resulting in half-normal activity of hydroxymethylbilane synthase. Factors that induce hepatic heme biosynthesis induce episodic attacks in heterozygous patients. The clinical presentation of acute attacks involves the signature neurovisceral pain and may include psychiatric symptoms. Here we used a knock-in mouse line that is biallelic for the Hmbs c.500G>A (p.R167Q) mutation with ~5% of normal hydroxymethylbilane synthase activity to unravel the consequences of severe HMBS deficiency on affective behavior and brain physiology.

mouse BULK RNA SEQ n=12

PMID:32197664

Identified by GEO DataSets index search for Acute Intermittent Porphyria (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

🔬

Clinical Trials

1

NCT03338816 PHASE_III COMPLETED

ENVISION was the pivotal randomized phase III study of subcutaneous givosiran in patients with acute hepatic porphyrias, including acute intermittent porphyria, with recurrent attacks.

Show evidence (1 reference)

clinicaltrials:NCT03338816 SUPPORT Human Clinical

"The purpose of this study is to evaluate the effect of subcutaneous givosiran (ALN-AS1), compared to placebo, on the rate of porphyria attacks in patients with Acute Hepatic Porphyrias (AHP)."

ClinicalTrials.gov directly documents the pivotal phase III givosiran trial relevant to recurrent AIP attacks.

🧫

Experimental Models

2

Porphyrin-precursor exposure of human proximal tubular cells OTHER

Cultured proximal tubular cells exposed to porphyrin precursors were used to test candidate mechanisms for porphyria-associated kidney disease.

Cell source

Human proximal tubular cells

Culture

In vitro precursor-exposure assay

Publication

PMID:25830761

Pathograph links

Porphyria-associated tubulointerstitial kidney injury Tests candidate precursor-induced endoplasmic-reticulum stress, apoptosis, and epithelial phenotypic change in human proximal tubular cells relevant to porphyria-associated kidney injury.

Show evidence (1 reference)

PMID:25830761 SUPPORT In Vitro

"Our experimental data provide evidence that porphyrin precursors promote endoplasmic reticulum stress, apoptosis, and epithelial phenotypic changes in proximal tubular cells."

The experiment directly supports the cellular injury readouts, while the link remains PARTIAL for their contribution to human kidney disease.

Show evidence (1 reference)

PMID:25830761 SUPPORT In Vitro

"Our experimental data provide evidence that porphyrin precursors promote endoplasmic reticulum stress, apoptosis, and epithelial phenotypic changes in proximal tubular cells."

The assay supports candidate tubular-cell injury mechanisms while not proving their relative contribution in patients.

ALA exposure of human and rat cortical synaptic membranes OTHER

Isolated cortical synaptic membranes were exposed to ALA to test whether it interferes with GABA-A receptor ligand binding. The concentrations and membrane preparation make this a mechanistic candidate assay rather than a faithful model of in vivo AIP attacks.

Cell source

Human and rat cortical synaptic membrane preparations

Culture

Radioligand-binding membrane assay

Publication

PMID:11478735

Pathograph links

Neurovisceral attack susceptibility Tests the candidate interaction between ALA and GABA-A receptor ligand binding without treating the membrane assay as a faithful model of an in vivo human AIP attack.

Show evidence (1 reference)

PMID:11478735 SUPPORT In Vitro

"ALA (0.1-10 mM) significantly inhibited the binding"

The binding result supports the candidate mechanism link, but not its operation at physiologic concentrations during human attacks.

Show evidence (1 reference)

PMID:11478735 SUPPORT In Vitro

"ALA (0.1-10 mM) significantly inhibited the binding"

The evidence directly supports the in-vitro binding result modeled here; the description separately limits extrapolation to physiologic human precursor concentrations.

🐁

Animal Models

2

Partially Hmbs/PBGD-deficient T1/T2 model with approximately 30% residual activity Mus musculus

The classic heterozygous AIP model requires phenobarbital induction rather than developing spontaneous human-like attacks. Induction produces hepatic precursor accumulation, nerve-conduction block, axonal loss, and reversible hepatic energetic abnormalities; the energetic findings are preclinical and are not asserted as established chronic human AIP pathology.

Species

Mus musculus

Genotype

Partially Hmbs/PBGD-deficient T1/T2 model with approximately 30% residual activity

Show evidence (2 references)

PMID:20877347 SUPPORT Model Organism

"Phenobarbital injections in AIP mice induced porphyrin precursor accumulation, functional block of nerve conduction, and progressive loss of large-caliber axons in the sciatic nerve."

This defines the induced classic mouse phenotype and explicitly avoids implying that attacks arise spontaneously.

PMID:24727425 SUPPORT Model Organism

"These results suggest a cataplerosis of the TCA cycle induced by phenobarbital, caused by the massive withdrawal of succinyl-CoA by ALAS induction, such that the TCA cycle is unable to supply the reduced cofactors to the RC."

The induced mouse study supports a reversible hepatic energetic extension of the model, not an established human complication.

Homozygous Hmbs R167Q knock-in with approximately 5% residual activity Mus musculus

This severe homozygous model develops early ataxia, delayed myelination, and locally elevated CNS ALA/PBG. It models homozygous dominant AIP (HD-AIP), not the usual heterozygous, low-penetrance, episodic adult disease.

Species

Mus musculus

Genotype

Homozygous Hmbs R167Q knock-in with approximately 5% residual activity

Show evidence (1 reference)

PMID:30615115 SUPPORT Model Organism

"Homozygous R173Q mice were embryonic lethal, while R167Q homozygous mice (R167Q+/+) had ~5% of normal HMBS activity, constitutively elevated plasma and urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), profound early-onset ataxia, delayed motor development and markedly impaired..."

This directly supports the explicitly scoped severe biallelic model; the description separately limits extrapolation to classic heterozygous AIP.

{ }

Source YAML

click to show

name: Acute Intermittent Porphyria
creation_date: '2026-04-21T04:42:02Z'
category: Mendelian
synonyms:
- AIP
description: >-
  Acute intermittent porphyria (AIP) is a low-penetrance autosomal dominant
  acute hepatic porphyria caused by partial deficiency of
  hydroxymethylbilane synthase (HMBS), the third enzyme in heme biosynthesis.
  Most heterozygous carriers remain asymptomatic. In susceptible carriers,
  porphyrogenic triggers such as drugs, fasting, alcohol, infection, and
  hormonal change induce hepatic ALAS1, driving excess production of
  5-aminolevulinic acid (ALA) and porphobilinogen (PBG) upstream of the HMBS
  block. Clinically manifest AIP produces episodic abdominal pain and other
  neurovisceral manifestations; a single severe attack can include
  motor-predominant neuropathy. Long-term risks include chronic kidney disease,
  hypertension, and primary liver cancer and are not restricted to people with
  frequent recurrent attacks. Intravenous hemin remains standard therapy for
  severe attacks, and givosiran provides mechanism-directed prophylaxis for
  recurrent attacks.
disease_term:
  preferred_term: acute intermittent porphyria
  term:
    id: MONDO:0008294
    label: acute intermittent porphyria
parents:
- Metabolic Disease
- Inborn Error of Metabolism
inheritance:
- name: Autosomal dominant
  description: >-
    AIP is inherited as an autosomal dominant disorder with low clinical
    penetrance. Clinical expression is strongly modified by genetic and
    environmental factors; an oligogenic model has been proposed but is not
    established as a replacement for autosomal dominant inheritance.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: PMID:9516674
    reference_title: "Acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute intermittent porphyria (AIP) is transmitted as an autosomal
      dominant disorder with incomplete penetrance.
    explanation: >-
      This review directly states the inheritance pattern and incomplete
      penetrance of AIP.
  - reference: PMID:29360981
    reference_title: "From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Penetrance was estimated at 22.9% in families with AIP, but at only 0.5-1%
      in the general population.
    explanation: >-
      Family and population estimates directly demonstrate incomplete and
      ascertainment-dependent penetrance; a single penetrance percentage would
      therefore be misleading.
  - reference: PMID:29360981
    reference_title: "From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An oligogenic inheritance model with environmental modifiers might better
      explain AIP penetrance and heritability.
    explanation: >-
      The authors proposed, rather than established, an oligogenic explanation
      for the marked variability in clinical expression.
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each child of an individual with an HMBS pathogenic variant has a 50%
      chance of inheriting the pathogenic variant.
    explanation: >-
      GeneReviews provides the autosomal-dominant transmission risk used in
      genetic counseling; inheritance of the variant does not predict clinical
      expression because penetrance is low.
prevalence:
- population: Asymptomatic heterozygous carriers in population studies
  measure_type: CARRIER_FREQUENCY
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 50.0
  notes: >-
    Molecular carrier prevalence is substantially higher than overt clinical
    disease prevalence because penetrance is low.
  evidence:
  - reference: PMID:9516674
    reference_title: "Acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recent population studies suggest that the prevalence of asymptomatic
      heterozygotes for a mutant AIP gene may be in the range of 1 in 2,000.
    explanation: >-
      This review provides a population-level estimate for asymptomatic HMBS
      mutation carriers and highlights the disease's incomplete penetrance.
- population: Clinically symptomatic acute intermittent porphyria
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.0
  notes: Estimated prevalence of patients with symptomatic AIP.
  evidence:
  - reference: PMID:36642627
    reference_title: "AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Acute intermittent porphyria is the most common type of AHP, with an estimated prevalence of patients with symptoms of approximately 1 in 100,000."
    explanation: The expert review distinguishes clinically symptomatic AIP prevalence from the much higher HMBS carrier frequency.
progression:
- phase: Latent or asymptomatic carrier state
  notes: >-
    Most people heterozygous for a pathogenic HMBS variant never develop an
    acute attack. This is a clinical category, not an obligatory first step in
    a linear progression sequence.
  evidence:
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Latent (inactive) AIP: Urine PBG-to-creatinine ratio <4 times ULN and no
      acute porphyria-related manifestations to date.
    explanation: GeneReviews defines latent AIP as an attack-free carrier state.
- phase: Episodic active acute intermittent porphyria
  age_range: Usually begins in the second or third decade
  duration: Individual attacks and recovery vary from days to months
  notes: >-
    Susceptible carriers can experience trigger-associated acute neurovisceral
    attacks separated by non-attack intervals; attack occurrence and recovery
    are highly variable.
  evidence:
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The course of acute porphyria attacks is highly variable in an individual
      and between individuals.
    explanation: GeneReviews supports the episodic and individually variable course.
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Onset of acute attacks typically occurs in the second or third decade of
      life.
    explanation: GeneReviews directly supports the usual age range for attack onset.
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recovery from acute porphyria attacks may occur within days; however,
      recovery from severe attacks that are not promptly recognized and treated
      may take weeks or months.
    explanation: >-
      GeneReviews directly supports the stated range from rapid recovery to a
      prolonged course after severe, delayed-treatment attacks.
- phase: Sporadic, recurrent, or chronically symptomatic AIP
  notes: >-
    Some clinically manifest patients have sporadic or recurrent attacks, and
    chronic symptoms may persist between attacks even when attack frequency is
    low. These states are not experienced by every carrier.
  evidence:
  - reference: PMID:33639982
    reference_title: "Health impact of acute intermittent porphyria in latent and non-recurrent attacks patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AIP remains a chronically symptomatic disease that adversely affects
      health and quality of life, even in patients with low rate of acute
      attacks.
    explanation: >-
      This AIP cohort documents clinically important chronic disease outside a
      simple recurrent-attack model.
- phase: Long-term complication risk
  notes: >-
    Clinically manifest AIP carries long-term risks that include chronic kidney
    disease, hypertension, and hepatocellular carcinoma; these are surveillance
    concerns rather than inevitable outcomes.
  evidence:
  - reference: PMID:36642627
    reference_title: "AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients should be counseled on the chronic and long-term complications of
      AHP, including neuropathy, chronic kidney disease, hypertension, and
      hepatocellular carcinoma, and need for long-term monitoring.
    explanation: >-
      This expert review identifies the major long-term complications that
      require monitoring, while applying them across the acute hepatic
      porphyrias rather than asserting that every AIP carrier develops them.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_hepatic_precursor_overproduction_model
  hypothesis_label: Canonical Hepatic Precursor Overproduction Model
  status: CANONICAL
  description: >-
    Partial HMBS deficiency becomes clinically pathogenic when hepatic ALAS1 is
    induced, leading to excess upstream precursor synthesis and export.
  notes: >-
    HMBS deficiency and trigger-driven ALAS1 induction are parallel
    prerequisites for clinically important precursor accumulation: the HMBS
    defect does not itself induce ALAS1. Human intervention data support the
    hepatic precursor-overproduction model, but penetrance, mouse-only hepatic
    energetic effects, and liver-cancer associations are modeled separately.
  evidence:
  - reference: PMID:9516674
    reference_title: "Acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Biochemical abnormalities are thought to result from primary defects of
      porphobilinogen deaminase (PBGD; also called hydroxymethyl bilane
      synthase), the third enzyme of the heme synthesis pathway, and
      consecutive hepatic overexpression of the first enzyme of the pathway,
      5-aminolevulinate synthase.
    explanation: >-
      This summarizes the joint HMBS bottleneck and hepatic ALAS1-overexpression
      model that drives AIP biochemistry without asserting that HMBS deficiency
      itself induces ALAS1.
  - reference: PMID:32521132
    reference_title: "Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 89 patients with acute intermittent porphyria, the mean
      annualized attack rate was 3.2 in the givosiran group and 12.5 in the
      placebo group, representing a 74% lower rate in the givosiran group
      (P<0.001); the results were similar among the 94 patients with acute
      hepatic porphyria.
    explanation: >-
      The AIP-specific randomized comparison provides intervention support for
      hepatic ALAS1 suppression reducing attack burden.
  - reference: PMID:26062020
    reference_title: "Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microsomal heme content was sufficient, and representative cytochrome P450 activities were essentially normal"
    explanation: >
      Detailed biochemical study of the AIP explanted liver shows preserved
      microsomal heme content and normal P450 activities despite massive
      ALA/PBG accumulation (ALAS1 ~5x activity, PBG ~1760x), directly
      supporting the hepatic-precursor-overproduction model over a
      generalized-heme-deficiency model.
  - reference: PMID:16122419
    reference_title: "Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "5-aminolevulinate synthase (ALAS-1), is regulated by the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha)"
    explanation: >
      Identifies PGC-1α as the transcriptional link between fasting/drug
      triggers and ALAS1 induction, explaining the well-known "glucose
      effect" in AIP and providing the molecular mechanism connecting
      catabolic stressors to the canonical pathway.
- hypothesis_group_id: canonical_precursor_neurotoxicity_model
  hypothesis_label: Canonical Precursor Neurotoxicity Model
  status: CANONICAL
  description: >-
    Acute attacks are causally linked to excess hepatic precursor burden rather
    than to generalized hepatic heme deficiency alone, while the responsible
    toxic species and molecular route remain incompletely resolved.
  notes: >-
    Lowering or removing the hepatic precursor source reduces attacks, and
    liver-directed correction prevents induced neuropathy in mice. ALA is the
    leading candidate neurotoxin; PBG is a strong biochemical marker but is not
    independently established as the toxic species. Proposed GABA-A, oxidative,
    mitochondrial, and vascular mechanisms remain uncertain at physiologic
    concentrations. Severe homozygous pediatric disease with local CNS
    precursor production is a comparator, not a direct model of classic
    heterozygous AIP.
  evidence:
  - reference: PMID:35067977
    reference_title: "RNAi therapy with givosiran significantly reduces attack rates in acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The clinical manifestations of AHP are attributed to the accumulation of
      the heme precursor 5-aminolevulinic acid (ALA) and porphobilinogen (PBG).
    explanation: >-
      This review directly links clinical manifestations in acute hepatic
      porphyrias to accumulation of ALA and PBG, matching the standard AIP
      neurotoxicity model.
  - reference: PMID:20877347
    reference_title: "Sustained enzymatic correction by rAAV-mediated liver gene therapy protects against induced motor neuropathy in acute porphyria mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "porphyrin precursors generated in the liver interfere with motor function"
    explanation: >
      Liver-specific AAV-PBGD gene therapy protects AIP mice against
      phenobarbital-induced precursor accumulation, axonal loss, and nerve
      conduction defects, providing direct causal evidence in the
      phenobarbital-induced mouse model that hepatic precursors drive motor
      neuropathy in that model.
  - reference: PMID:19815305
    reference_title: "Porphobilinogen deaminase over-expression in hepatocytes, but not in erythrocytes, prevents accumulation of toxic porphyrin precursors in a mouse model of acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "PBGD over-expression in hepatocytes, albeit in a low proportion, reduced precursor accumulation"
    explanation: >
      Genetic dissection in mouse models shows that PBGD restoration in
      hepatocytes (not erythrocytes) corrects precursor accumulation and
      motor disturbance, directly identifying hepatic rather than erythroid
      PBGD deficiency as the relevant pathogenic locus in the induced mouse
      model.
  - reference: PMID:11478735
    reference_title: "5-Aminolevulinic acid inhibits [3H]muscimol binding to human and rat brain synaptic membranes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ALA (0.1-10 mM) significantly inhibited the binding"
    explanation: >
      In vitro evidence that ALA interferes with GABA-A receptor ligand binding
      (IC50 ~199-228 µM) provides a candidate molecular mechanism, but does not
      establish that the interaction produces human attack manifestations at
      physiologically relevant concentrations.
  - reference: PMID:12493610
    reference_title: "Transport of 5-aminolevulinic acid between blood and brain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "uptake into the neonatal brain was 7-fold higher than in the adult"
    explanation: >
      Rat transport data show limited adult blood-brain-barrier permeability
      and greater neonatal uptake. This constrains direct-diffusion models but
      does not by itself establish the route of human classic-AIP neurotoxicity.
  - reference: PMID:30615115
    reference_title: "Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ALA and PBG do not readily cross the blood-brain barrier"
    explanation: >-
      The study distinguishes phenobarbital-induced classic-model precursor
      accumulation outside the CNS from severe homozygous disease with local
      CNS precursor production; it therefore informs a model boundary rather
      than directly supporting classic heterozygous AIP neurotoxicity.
pathophysiology:
- name: HMBS deficiency in hepatocytes
  conforms_to: "heme_biosynthesis_porphyria#Heme Biosynthesis Enzymatic Block"
  description: >-
    Pathogenic HMBS variants reduce hepatic hydroxymethylbilane synthase
    activity, creating a partial block at the third enzymatic step of heme
    biosynthesis.
  genes:
  - preferred_term: HMBS
    term:
      id: hgnc:4982
      label: HMBS
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: heme biosynthetic process
    term:
      id: GO:0006783
      label: heme biosynthetic process
    modifier: DYSREGULATED
  molecular_functions:
  - preferred_term: hydroxymethylbilane synthase activity
    term:
      id: GO:0004418
      label: hydroxymethylbilane synthase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:19292878
    reference_title: "Acute intermittent porphyria--impact of mutations found in the hydroxymethylbilane synthase gene on biochemical and enzymatic protein properties."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute intermittent porphyria is an autosomal dominantly inherited
      disorder, classified as acute hepatic porphyria, caused by a deficiency
      of hydroxymethylbilane synthase (EC 2.5.1.61, EC 4.3.1.8, also known as
      porphobilinogen deaminase, uroporphyrinogen I synthase), the third
      enzyme in heme biosynthesis.
    explanation: >-
      This directly identifies HMBS deficiency as the core molecular defect and
      places it at the third step of heme biosynthesis.
  downstream:
  - target: Abnormal HMBS enzyme activity
    causal_link_type: DIRECT
    description: HMBS deficiency is the enzyme activity abnormality underlying acute intermittent porphyria.
    evidence:
    - reference: ORPHA:79276
      reference_title: "Acute intermittent porphyria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent (99-80%)"
      explanation: Orphanet reports abnormal enzyme/coenzyme activity as a very frequent phenotype.
  - target: Hepatic ALA and PBG accumulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced conversion of PBG to hydroxymethylbilane across the partial HMBS block
    - trigger-induced upstream ALAS1 flux that exceeds residual HMBS pathway capacity
    hypothesis_groups:
    - canonical_hepatic_precursor_overproduction_model
    description: >-
      Partial HMBS deficiency limits clearance of PBG when trigger-induced
      upstream flux rises. HMBS deficiency and ALAS1 induction are parallel
      contributors; the enzyme defect does not itself induce ALAS1.
    evidence:
    - reference: PMID:9516674
      reference_title: "Acute intermittent porphyria."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Biochemical abnormalities are thought to result from primary defects of
        porphobilinogen deaminase (PBGD; also called hydroxymethyl bilane
        synthase), the third enzyme of the heme synthesis pathway, and
        consecutive hepatic overexpression of the first enzyme of the pathway,
        5-aminolevulinate synthase. As a result of these enzymatic disturbances,
        heme precursors are synthesized in excess in the liver, and massive
        amounts of compounds upstream of the enzymatic block are excreted in
        urine.
      explanation: >-
        The review supports the HMBS bottleneck and increased upstream flux as
        joint prerequisites for excess precursor production.
- name: Triggered hepatic ALAS1 induction
  description: >-
    Porphyrogenic triggers increase hepatic ALAS1 expression, pushing pathway
    flux into the segment upstream of the HMBS block.
  genes:
  - preferred_term: ALAS1
    term:
      id: hgnc:396
      label: ALAS1
    modifier: INCREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: heme biosynthetic process
    term:
      id: GO:0006783
      label: heme biosynthetic process
    modifier: DYSREGULATED
  molecular_functions:
  - preferred_term: 5-aminolevulinate synthase activity
    term:
      id: GO:0003870
      label: 5-aminolevulinate synthase activity
    modifier: INCREASED
  chemical_entities:
  - preferred_term: 5-aminolevulinic acid
    term:
      id: CHEBI:17549
      label: 5-aminolevulinic acid
    modifier: INCREASED
  evidence:
  - reference: PMID:9516674
    reference_title: "Acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Biochemical abnormalities are thought to result from primary defects of
      porphobilinogen deaminase (PBGD; also called hydroxymethyl bilane
      synthase), the third enzyme of the heme synthesis pathway, and
      consecutive hepatic overexpression of the first enzyme of the pathway,
      5-aminolevulinate synthase.
    explanation: >-
      This review supports the key mechanistic pairing of HMBS deficiency with
      secondary hepatic ALAS1 overexpression.
  - reference: PMID:29498764
    reference_title: "Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute intermittent porphyria (AIP) is an inherited disorder of haem
      metabolism characterized by life-threatening acute neurovisceral attacks
      due to the induction of hepatic δ-aminolevulinic acid synthase 1 (ALAS1)
      associated with hydroxymethylbilane synthase (HMBS) deficiency.
    explanation: >-
      This study's background statement supports the accepted pairing of ALAS1
      induction and HMBS deficiency; it is not classified as a patient-level
      result.
  downstream:
  - target: Hepatic ALA and PBG accumulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - conversion of ALA to PBG by aminolevulinate dehydratase
    - limited PBG conversion across the partial HMBS block
    hypothesis_groups:
    - canonical_hepatic_precursor_overproduction_model
    description: >-
      Increased ALAS1-driven flux produces ALA, which is converted to PBG by
      ALAD; the partial HMBS block then limits downstream PBG conversion.
    evidence:
    - reference: PMID:9516674
      reference_title: "Acute intermittent porphyria."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Biochemical abnormalities are thought to result from primary defects of
        porphobilinogen deaminase (PBGD; also called hydroxymethyl bilane
        synthase), the third enzyme of the heme synthesis pathway, and
        consecutive hepatic overexpression of the first enzyme of the pathway,
        5-aminolevulinate synthase. As a result of these enzymatic disturbances,
        heme precursors are synthesized in excess in the liver, and massive
        amounts of compounds upstream of the enzymatic block are excreted in
        urine.
      explanation: >-
        Review evidence supports the mechanistic link between the HMBS/PBGD
        block, hepatic ALAS1 overexpression, excess hepatic heme precursors, and
        urinary excretion of upstream compounds.
- name: Hepatic ALA and PBG accumulation
  conforms_to: "heme_biosynthesis_porphyria#Accumulation of Porphyrin Precursors and Porphyrins"
  description: >-
    Increased upstream pathway flux in the setting of partial HMBS deficiency
    causes excess production and systemic spillover of 5-aminolevulinic acid
    and porphobilinogen.
  biological_processes:
  - preferred_term: heme biosynthetic process
    term:
      id: GO:0006783
      label: heme biosynthetic process
    modifier: DYSREGULATED
  - preferred_term: porphyrin-containing compound metabolic process
    term:
      id: GO:0006778
      label: porphyrin-containing compound metabolic process
    modifier: ABNORMAL
  chemical_entities:
  - preferred_term: 5-aminolevulinic acid
    term:
      id: CHEBI:17549
      label: 5-aminolevulinic acid
    modifier: INCREASED
  - preferred_term: porphobilinogen
    term:
      id: CHEBI:17381
      label: porphobilinogen
    modifier: INCREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:9516674
    reference_title: "Acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As a result of these enzymatic disturbances, heme precursors are
      synthesized in excess in the liver, and massive amounts of compounds
      upstream of the enzymatic block are excreted in urine.
    explanation: >-
      This directly supports hepatic overproduction and excess excretion of
      pathway intermediates upstream of the HMBS block.
  - reference: PMID:35067977
    reference_title: "RNAi therapy with givosiran significantly reduces attack rates in acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The clinical manifestations of AHP are attributed to the accumulation of
      the heme precursor 5-aminolevulinic acid (ALA) and porphobilinogen (PBG).
    explanation: >-
      This review supports the precursor-burden framework without independently
      identifying which precursor is toxic or resolving the molecular route.
  downstream:
  - target: Urinary 5-aminolevulinic acid
    causal_link_type: DIRECT
    description: >-
      Hepatic overproduction and systemic spillover of ALA produces increased
      urinary ALA during acute attacks.
    evidence:
    - reference: PMID:19327613
      reference_title: >-
        Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
        and therapeutic course of acute intermittent porphyria attacks.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        During an acute attack the heme precursors porphobilinogen (PBG) and
        5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
        are found in high concentrations in plasma and urine.
      explanation: >-
        Patient attack monitoring directly supports hepatic ALA production with
        increased urinary ALA.
  - target: Elevated urinary delta-aminolevulinic acid
    causal_link_type: DIRECT
    description: Excess hepatic ALA production spills into urine during acute attacks.
    evidence:
    - reference: ORPHA:79276
      reference_title: "Acute intermittent porphyria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003163 | Elevated urinary delta-aminolevulinic acid | Very frequent (99-80%)"
      explanation: Orphanet reports elevated urinary delta-aminolevulinic acid as very frequent.
  - target: Urinary porphobilinogen
    causal_link_type: DIRECT
    description: >-
      Hepatic overproduction and systemic spillover of PBG produces increased
      urinary PBG during acute attacks.
    evidence:
    - reference: PMID:19327613
      reference_title: >-
        Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
        and therapeutic course of acute intermittent porphyria attacks.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        During an acute attack the heme precursors porphobilinogen (PBG) and
        5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
        are found in high concentrations in plasma and urine.
      explanation: >-
        Patient attack monitoring directly supports hepatic PBG production with
        increased urinary PBG.
  - target: Increased urinary porphobilinogen
    causal_link_type: DIRECT
    description: Excess hepatic PBG production spills into urine during acute attacks.
    evidence:
    - reference: ORPHA:79276
      reference_title: "Acute intermittent porphyria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012217 | Increased urinary porphobilinogen | Very frequent (99-80%)"
      explanation: Orphanet reports increased urinary porphobilinogen as very frequent.
  - target: Porphyrinuria
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - urinary excretion of excess heme pathway intermediates
    description: Excess upstream heme intermediates produce abnormal urinary porphyrin/precursor excretion.
    evidence:
    - reference: ORPHA:79276
      reference_title: "Acute intermittent porphyria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0010473 | Porphyrinuria | Very frequent (99-80%)"
      explanation: Orphanet reports porphyrinuria as very frequent.
  - target: Plasma 5-aminolevulinic acid
    causal_link_type: DIRECT
    description: >-
      Hepatic overproduction and systemic spillover of ALA produces increased
      plasma ALA during acute attacks.
    evidence:
    - reference: PMID:19327613
      reference_title: >-
        Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
        and therapeutic course of acute intermittent porphyria attacks.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        During an acute attack the heme precursors porphobilinogen (PBG) and
        5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
        are found in high concentrations in plasma and urine.
      explanation: >-
        Patient attack monitoring directly supports hepatic ALA production with
        increased plasma ALA.
  - target: Plasma porphobilinogen
    causal_link_type: DIRECT
    description: >-
      Hepatic overproduction and systemic spillover of PBG produces increased
      plasma PBG during acute attacks.
    evidence:
    - reference: PMID:19327613
      reference_title: >-
        Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
        and therapeutic course of acute intermittent porphyria attacks.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        During an acute attack the heme precursors porphobilinogen (PBG) and
        5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
        are found in high concentrations in plasma and urine.
      explanation: >-
        Patient attack monitoring directly supports hepatic PBG production with
        increased plasma PBG.
  - target: Neurovisceral attack susceptibility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_precursor_neurotoxicity_model
    description: >-
      Intervention and model evidence link excess hepatic precursor burden to
      acute autonomic, peripheral, and central neurologic dysfunction, but the
      responsible toxic species and molecular route remain unresolved.
    evidence:
    - reference: PMID:35067977
      reference_title: "RNAi therapy with givosiran significantly reduces attack rates in acute intermittent porphyria."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The clinical manifestations of AHP are attributed to the accumulation of
        the heme precursor 5-aminolevulinic acid (ALA) and porphobilinogen (PBG).
      explanation: >-
        The review supports the precursor-burden framework but does not resolve
        which precursor or molecular route produces each manifestation.
  - target: Porphyria-associated tubulointerstitial kidney injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Persistent precursor overproduction is associated with chronic
      tubulointerstitial kidney injury in symptomatic AIP, but the relative
      contributions of direct tubular toxicity, vascular injury, hypertension,
      and other factors remain uncertain.
    evidence:
    - reference: PMID:25830761
      reference_title: "High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our experimental data provide evidence that porphyrin precursors promote
        endoplasmic reticulum stress, apoptosis, and epithelial phenotypic
        changes in proximal tubular cells.
      explanation: >-
        Human proximal-tubular-cell experiments provide a candidate mechanism,
        but do not establish that precursor toxicity is the sole route to kidney
        disease in patients.
  - target: Precursor-associated primary liver cancer risk
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Longitudinal AIP data associate persistently elevated urinary ALA and PBG
      with primary liver cancer risk, without establishing a specific
      carcinogenic mechanism.
    evidence:
    - reference: PMID:37650859
      reference_title: "Porphyrin precursors and risk of primary liver cancer in acute intermittent porphyria: A case-control study of 188 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Increased urinary porphyrin precursors are associated with a high risk
        of developing PLC.
      explanation: >-
        The AIP-specific case-control study supports an association between
        precursor excretion and cancer risk, not a resolved causal route.
- name: Neurovisceral attack susceptibility
  conforms_to: "heme_biosynthesis_porphyria#Neurovisceral Precursor Neurotoxicity"
  description: >-
    Acute attacks manifest as abdominal pain and neurologic dysfunction,
    including motor-predominant neuropathy and severe weakness. ALA is the
    leading candidate toxin, but the molecular mechanisms linking precursor
    burden to the full attack syndrome remain unresolved.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:19292878
    reference_title: "Acute intermittent porphyria--impact of mutations found in the hydroxymethylbilane synthase gene on biochemical and enzymatic protein properties."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features include autonomous, central, motor or sensory symptoms,
      but the most common clinical presentation is abdominal pain caused by
      neurovisceral crises.
    explanation: >-
      This patient molecular study's clinical background summary connects
      neurovisceral crises to abdominal pain and broad neurologic involvement
      in AIP.
  - reference: PMID:33786855
    reference_title: "Porphyric neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute hepatic porphyrias are inherited metabolic disorders that may
      present with polyneuropathy, which if not diagnosed early can lead to
      quadriparesis, respiratory weakness, and death.
    explanation: >-
      This review supports severe neuropathic weakness as a clinically relevant
      downstream consequence of acute hepatic porphyria attacks.
  - reference: PMID:38715693
    reference_title: "Neurofilament light chain as a biomarker for acute hepatic porphyrias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During acute attacks, serum NfL levels were 68 times higher compared to
      normal controls and disclosed a strong correlation with ALA and PBG levels;
      also exhibited elevated levels in patients with chronic symptoms regardless
      of the number of disease attacks compared to healthy controls, and at
      similar levels to patients with ATTRv-PN, which is a model of progressive
      neuropathy.
    explanation: >-
      This mixed acute-hepatic-porphyria cohort provides biomarker evidence for
      axonal injury during acute and chronic disease, but is not AIP-specific
      and does not resolve the toxic mechanism.
  downstream:
  - target: Acute neurovisceral attack
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Neurovisceral susceptibility is expressed clinically as a multisystem
      acute porphyria attack; the molecular route to individual manifestations
      remains unresolved in the downstream symptom edges.
    evidence:
    - reference: PMID:20301372
      reference_title: "Acute Intermittent Porphyria."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        An acute porphyria attack is characterized by a urine porphobilinogen
        (PBG)-to-creatinine ratio ≥10 times the upper limit of normal (ULN) and
        the presence of ≥2 porphyria manifestations (involving the visceral,
        peripheral, autonomic, and/or central nervous systems) persisting for
        >24 hours in the absence of other likely explanations.
      explanation: >-
        GeneReviews directly defines the compound clinical attack state linked
        from the mechanistic susceptibility node.
  - target: Abdominal pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abdominal pain is the most common clinical expression of acute
      neurovisceral crises.
    evidence:
    - reference: PMID:19292878
      reference_title: "Acute intermittent porphyria--impact of mutations found in the hydroxymethylbilane synthase gene on biochemical and enzymatic protein properties."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical features include autonomous, central, motor or sensory symptoms,
        but the most common clinical presentation is abdominal pain caused by
        neurovisceral crises.
      explanation: >-
        This patient-based molecular study's clinical summary directly connects
        neurovisceral crises to abdominal pain.
  - target: Nausea and vomiting
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Gastrointestinal neurovisceral attacks commonly include nausea and
      vomiting alongside abdominal pain.
    evidence:
    - reference: PMID:33139977
      reference_title: >-
        Acute intermittent porphyria: focus on possible mechanisms of acute and
        chronic manifestations.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Acute AIP episodes may present with abdominal pain, nausea, and vomiting,
        and repeated episodes may result in a series of chronic injuries.
      explanation: >-
        Review evidence supports nausea and vomiting as components of acute AIP
        episodes.
  - target: Constipation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Constipation is reported during acute neurovisceral attacks, but the specific causal route is not established by the frequency evidence.
    evidence:
    - reference: ORPHA:79276
      reference_title: "Acute intermittent porphyria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002019 | Constipation | Frequent (79-30%)"
      explanation: Orphanet reports constipation as frequent.
  - target: Tachycardia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Tachycardia is a prominent acute-attack manifestation; the cited clinical
      series does not isolate its molecular or autonomic intermediate.
    evidence:
    - reference: PMID:4723462
      reference_title: >-
        Acute intermittent porphyria: response of tachycardia and hypertension to
        propranolol.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In four young adult patients with acute attacks of acute intermittent
        porphyria tachycardia and hypertension were prominent features of the
        illness.
      explanation: >-
        Case-series evidence directly supports tachycardia during acute AIP
        attacks.
  - target: Peripheral neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Acute hepatic porphyria attacks can progress to motor-predominant
      porphyric neuropathy.
    evidence:
    - reference: PMID:33786855
      reference_title: "Porphyric neuropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Acute hepatic porphyrias are inherited metabolic disorders that may
        present with polyneuropathy, which if not diagnosed early can lead to
        quadriparesis, respiratory weakness, and death.
      explanation: >-
        Review evidence supports polyneuropathy as a neurologic manifestation of
        acute hepatic porphyrias.
  - target: Cranial nerve paralysis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cranial nerve paralysis is reported in AIP, but its specific route from precursor burden is unresolved.
    evidence:
    - reference: ORPHA:79276
      reference_title: "Acute intermittent porphyria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0006824 | Cranial nerve paralysis | Frequent (79-30%)"
      explanation: Orphanet reports cranial nerve paralysis as frequent.
  - target: Muscle weakness
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - motor-predominant porphyric neuropathy causing quadriparesis or respiratory weakness
    description: >-
      Motor-predominant porphyric neuropathy can cause quadriparesis and
      respiratory weakness in severe attacks.
    evidence:
    - reference: PMID:33786855
      reference_title: "Porphyric neuropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Acute hepatic porphyrias are inherited metabolic disorders that may
        present with polyneuropathy, which if not diagnosed early can lead to
        quadriparesis, respiratory weakness, and death.
      explanation: >-
        Review evidence supports severe weakness as a downstream consequence of
        porphyric neuropathy.
  - target: Hyponatremia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - autonomic and hypothalamic-pituitary dysregulation with inappropriate antidiuretic hormone secretion
    description: >-
      Acute AIP presentations can include SIADH-associated hyponatremia as part
      of the neurovisceral attack spectrum.
    evidence:
    - reference: PMID:26366103
      reference_title: "An update of clinical management of acute intermittent porphyria."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The clinical criteria of an acute attack include the paroxysmal nature
        and various combinations of symptoms, such as abdominal pain, autonomic
        dysfunction, hyponatremia, muscle weakness, or mental symptoms, in the
        absence of other obvious causes.
      explanation: >-
        Clinical management review evidence explicitly includes hyponatremia
        among acute attack criteria.
    - reference: PMID:25796467
      reference_title: >-
        Abdominal pain and syndrome of inappropriate antidiuretic hormone
        secretion as clinical presentation of acute intermittent porphyria.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Acute intermittent porphyria (AIP) is a rare condition characterized by
        abdominal pain and a wide range of nonspecific symptoms. We report the
        case of a woman with abdominal pain and syndrome of inappropriate
        antidiuretic hormone secretion (SIADH) as clinical presentation of AIP.
      explanation: >-
        Case-report evidence supports SIADH as an acute AIP presentation,
        matching the intermediate mechanism for hyponatremia.
  - target: Hypertension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypertension can accompany acute attacks alongside tachycardia, while the
      cited attack series does not establish a specific intermediate mechanism.
    evidence:
    - reference: PMID:4723462
      reference_title: >-
        Acute intermittent porphyria: response of tachycardia and hypertension to
        propranolol.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In four young adult patients with acute attacks of acute intermittent
        porphyria tachycardia and hypertension were prominent features of the
        illness.
      explanation: >-
        Case-series evidence directly supports hypertension during acute AIP
        attacks.
  - target: Tetraparesis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - motor-predominant porphyric neuropathy causing quadriparesis
    description: >-
      Severe porphyric neuropathy can progress to quadriparesis/tetraparesis.
    evidence:
    - reference: PMID:33786855
      reference_title: "Porphyric neuropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Acute hepatic porphyrias are inherited metabolic disorders that may
        present with polyneuropathy, which if not diagnosed early can lead to
        quadriparesis, respiratory weakness, and death.
      explanation: >-
        The porphyric neuropathy review explicitly identifies quadriparesis as a
        severe consequence of delayed diagnosis.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Acute porphyria encephalopathy can include seizures during
      neuropsychiatric crises.
    evidence:
    - reference: PMID:26366103
      reference_title: "An update of clinical management of acute intermittent porphyria."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Intensive abdominal pain without peritoneal signs, acute peripheral
        neuropathy, and encephalopathy usually with seizures or psychosis are the
        key symptoms indicating possible acute porphyria.
      explanation: >-
        Clinical management review evidence lists seizures as a key
        encephalopathic feature indicating acute porphyria.
  - target: Psychosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Acute porphyria encephalopathy can include psychosis during
      neuropsychiatric crises.
    evidence:
    - reference: PMID:26366103
      reference_title: "An update of clinical management of acute intermittent porphyria."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Intensive abdominal pain without peritoneal signs, acute peripheral
        neuropathy, and encephalopathy usually with seizures or psychosis are the
        key symptoms indicating possible acute porphyria.
      explanation: >-
        Clinical management review evidence lists psychosis as a key
        encephalopathic feature indicating acute porphyria.
  - target: Back pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Neurovisceral pain during attacks can include back pain.
    evidence:
    - reference: ORPHA:79276
      reference_title: "Acute intermittent porphyria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003418 | Back pain | Frequent (79-30%)"
      explanation: Orphanet reports back pain as frequent.
  - target: Limb pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Neurovisceral and neuropathic pain during attacks can include limb pain.
    evidence:
    - reference: ORPHA:79276
      reference_title: "Acute intermittent porphyria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0009763 | Limb pain | Frequent (79-30%)"
      explanation: Orphanet reports limb pain as frequent.
  - target: Neck pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Neurovisceral pain during attacks can include neck pain.
    evidence:
    - reference: ORPHA:79276
      reference_title: "Acute intermittent porphyria"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0030833 | Neck pain | Frequent (79-30%)"
      explanation: Orphanet reports neck pain as frequent.
- name: Porphyria-associated tubulointerstitial kidney injury
  description: >-
    Symptomatic AIP is associated with a chronic tubulointerstitial nephropathy
    and progressive loss of kidney function. Precursor toxicity to proximal
    tubular cells is experimentally supported, while vascular injury,
    hypertension, and other contributors prevent assignment of a single proven
    human mechanism.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  chemical_entities:
  - preferred_term: 5-aminolevulinic acid
    term:
      id: CHEBI:17549
      label: 5-aminolevulinic acid
    modifier: INCREASED
  - preferred_term: porphobilinogen
    term:
      id: CHEBI:17381
      label: porphobilinogen
    modifier: INCREASED
  evidence:
  - reference: PMID:25830761
    reference_title: "High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The renal pathology was a chronic tubulointerstitial nephropathy,
      associated with a fibrous intimal hyperplasia and focal cortical atrophy.
    explanation: >-
      AIP patient pathology directly establishes the characteristic chronic
      tubulointerstitial and vascular injury pattern.
  - reference: PMID:34943561
    reference_title: "Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Given the relevant role of the kidney in porphyrin metabolism, the
      mechanisms possibly intervening in causing renal damage in AHPs are
      different: among others, δ-aminolevulinic acid (ALA)-induced oxidative
      damage on mitochondria, intracellular toxic aggregation of porphyrins in
      proximal tubular cells, and derangements in the delicate microcirculatory
      balances of the kidney might be implicated.
    explanation: >-
      This review supports a multifactorial interpretation and cautions against
      reducing porphyria-associated kidney disease to one pathway.
  downstream:
  - target: Chronic kidney disease
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic tubulointerstitial nephropathy with progressive decline in glomerular filtration
    description: >-
      Persistent tubulointerstitial and vascular kidney injury can produce
      chronic loss of filtration in symptomatic AIP.
    evidence:
    - reference: PMID:25830761
      reference_title: "High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Chronic kidney disease occurred in up to 59% of the symptomatic AIP
        patients, with a decline in the glomerular filtration rate of ~1 ml/min
        per 1.73 m(2) annually.
      explanation: >-
        Longitudinal human data connect symptomatic AIP kidney injury with
        chronic decline in filtration.
- name: Precursor-associated primary liver cancer risk
  description: >-
    AIP cohorts show that persistently high urinary ALA and PBG are associated
    with primary liver cancer risk. The association is clinically important,
    but the molecular route and degree of direct precursor causality remain
    unresolved.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  chemical_entities:
  - preferred_term: 5-aminolevulinic acid
    term:
      id: CHEBI:17549
      label: 5-aminolevulinic acid
    modifier: INCREASED
  - preferred_term: porphobilinogen
    term:
      id: CHEBI:17381
      label: porphobilinogen
    modifier: INCREASED
  evidence:
  - reference: PMID:37650859
    reference_title: "Porphyrin precursors and risk of primary liver cancer in acute intermittent porphyria: A case-control study of 188 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased urinary porphyrin precursors are associated with a high risk of
      developing PLC.
    explanation: >-
      The AIP-specific case-control study establishes a risk association while
      leaving the carcinogenic mechanism unresolved.
  - reference: PMID:39438413
    reference_title: "Hepatocellular Carcinoma in Acute Hepatic Porphyria: A Meta-Analysis of Observational Studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HCC cases were observed with HCC incidence per 100 person years of 0.3
      (0.2-0.5) in AHP, 0.4 (0.2-0.6) in AIP, 0.3 (0-0.4) in VP, and 0.2
      (0.1-0.6) in HCP.
    explanation: >-
      The meta-analysis directly reports the AIP-specific incidence estimate;
      its heterogeneous observational analyses and publication bias limit
      precision and generalizability but do not weaken claim-to-snippet fit.
  downstream:
  - target: Hepatocellular carcinoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Persistent precursor elevation marks increased hepatocellular-carcinoma
      risk in AIP, without a proven molecular route from precursor exposure to
      malignant transformation.
    evidence:
    - reference: PMID:37650859
      reference_title: "Porphyrin precursors and risk of primary liver cancer in acute intermittent porphyria: A case-control study of 188 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Increased urinary porphyrin precursors are associated with a high risk
        of developing PLC.
      explanation: >-
        The AIP-specific case-control study supports the precursor-risk
        association, while leaving the molecular route to malignancy unresolved.
    - reference: PMID:39438413
      reference_title: "Hepatocellular Carcinoma in Acute Hepatic Porphyria: A Meta-Analysis of Observational Studies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        HCC cases were observed with HCC incidence per 100 person years of 0.3
        (0.2-0.5) in AHP, 0.4 (0.2-0.6) in AIP, 0.3 (0-0.4) in VP, and 0.2
        (0.1-0.6) in HCP.
      explanation: >-
        The AIP-specific HCC incidence establishes the phenotype target but does
        not independently support precursor causality; the unresolved route
        keeps the mechanistic edge at PARTIAL.
phenotypes:
- name: Acute neurovisceral attack
  description: >-
    Clinically active attacks are multisystem events lasting more than 24 hours,
    with at least two visceral, peripheral, autonomic, or central nervous system
    manifestations and a markedly elevated urine PBG-to-creatinine ratio. Attack
    onset typically occurs in the second or third decade, although not every
    carrier develops an attack.
  context: Clinically active acute intermittent porphyria
  evidence:
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      An acute porphyria attack is characterized by a urine porphobilinogen
      (PBG)-to-creatinine ratio ≥10 times the upper limit of normal (ULN) and the
      presence of ≥2 porphyria manifestations (involving the visceral,
      peripheral, autonomic, and/or central nervous systems) persisting for >24
      hours in the absence of other likely explanations.
    explanation: >-
      GeneReviews directly supports the compound acute-attack clinical
      characteristic represented here.
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Onset of acute attacks typically occurs in the second or third decade of
      life.
    explanation: GeneReviews directly supports the typical onset of the attack phenotype.
- name: Abdominal pain
  description: >-
    Severe abdominal pain is the most common presenting symptom during acute
    attacks.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:19292878
    reference_title: "Acute intermittent porphyria--impact of mutations found in the hydroxymethylbilane synthase gene on biochemical and enzymatic protein properties."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features include autonomous, central, motor or sensory symptoms,
      but the most common clinical presentation is abdominal pain caused by
      neurovisceral crises.
    explanation: >-
      This directly identifies abdominal pain as the dominant acute clinical
      presentation in AIP.
- name: Muscle weakness
  description: >-
    Motor-predominant porphyric neuropathy can progress to marked generalized
    weakness during severe attacks.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:33786855
    reference_title: "Porphyric neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute hepatic porphyrias are inherited metabolic disorders that may
      present with polyneuropathy, which if not diagnosed early can lead to
      quadriparesis, respiratory weakness, and death.
    explanation: >-
      Severe motor neuropathy with weakness is a key clinically relevant AIP
      manifestation.
- name: Peripheral neuropathy
  description: >-
    Acute attacks can include a predominantly motor polyneuropathy that may
    progress to quadriparesis and respiratory weakness if not recognized early.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:33786855
    reference_title: "Porphyric neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute hepatic porphyrias are inherited metabolic disorders that may
      present with polyneuropathy, which if not diagnosed early can lead to
      quadriparesis, respiratory weakness, and death.
    explanation: >-
      This directly supports peripheral neuropathy as a core neurologic
      manifestation of acute attacks.
- name: Tachycardia
  description: >-
    Acute neurovisceral attacks often feature autonomic overactivity with sinus
    tachycardia and accompanying hypertension.
  phenotype_term:
    preferred_term: Tachycardia
    term:
      id: HP:0001649
      label: Tachycardia
  evidence:
  - reference: PMID:4723462
    reference_title: >-
      Acute intermittent porphyria: response of tachycardia and hypertension to
      propranolol.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In four young adult patients with acute attacks of acute intermittent
      porphyria tachycardia and hypertension were prominent features of the
      illness.
    explanation: >-
      Human case-series data directly support tachycardia as a prominent
      autonomic manifestation during AIP attacks.
- name: Nausea and vomiting
  description: >-
    Gastrointestinal symptoms during acute attacks commonly extend beyond pain
    to include nausea and vomiting.
  phenotype_term:
    preferred_term: Nausea and vomiting
    term:
      id: HP:0002017
      label: Nausea and vomiting
  evidence:
  - reference: PMID:33139977
    reference_title: >-
      Acute intermittent porphyria: focus on possible mechanisms of acute and
      chronic manifestations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute AIP episodes may present with abdominal pain, nausea, and vomiting,
      and repeated episodes may result in a series of chronic injuries.
    explanation: >-
      Review-level evidence supports nausea and vomiting as common acute
      neurovisceral symptoms in AIP.
- name: Hyponatremia
  description: >-
    Acute attacks can be complicated by hyponatremia, often in the setting of
    syndrome of inappropriate antidiuretic hormone secretion.
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  evidence:
  - reference: PMID:25796467
    reference_title: >-
      Abdominal pain and syndrome of inappropriate antidiuretic hormone
      secretion as clinical presentation of acute intermittent porphyria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute intermittent porphyria (AIP) is a rare condition characterized by
      abdominal pain and a wide range of nonspecific symptoms. We report the
      case of a woman with abdominal pain and syndrome of inappropriate
      antidiuretic hormone secretion (SIADH) as clinical presentation of AIP.
    explanation: >-
      Human clinical evidence supports SIADH-associated hyponatremia as an
      important electrolyte complication during acute AIP presentations.
- name: Hypertension
  description: >-
    Hypertension can occur during autonomically active attacks and is also more
    common as a chronic condition in manifest than latent AIP.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:4723462
    reference_title: >-
      Acute intermittent porphyria: response of tachycardia and hypertension to
      propranolol.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In four young adult patients with acute attacks of acute intermittent
      porphyria tachycardia and hypertension were prominent features of the
      illness.
    explanation: >-
      Human case-series data directly support hypertension during acute AIP
      attacks.
  - reference: PMID:8046316
    reference_title: "Hypertension and renal disease in patients with acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertension was found in 56% of patients with manifest AIP, 33% of their
      controls (P = 0.041) and 16% of patients with latent AIP (P = 0.004).
    explanation: >-
      The population-based case-control study supports hypertension as a
      chronic association of manifest AIP in addition to its acute autonomic
      presentation.
- name: Chronic kidney disease
  description: >-
    Chronic kidney disease, usually with a tubulointerstitial pattern and little
    proteinuria, is an important long-term complication of symptomatic AIP.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:25830761
    reference_title: "High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chronic kidney disease occurred in up to 59% of the symptomatic AIP
      patients, with a decline in the glomerular filtration rate of ~1 ml/min
      per 1.73 m(2) annually.
    explanation: >-
      The longitudinal AIP cohort directly supports chronic kidney disease and
      progressive filtration loss in symptomatic patients.
  - reference: PMID:33639982
    reference_title: "Health impact of acute intermittent porphyria in latent and non-recurrent attacks patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The earliest long-term clinical condition associated with SA-AIP was
      chronic kidney disease.
    explanation: >-
      This sporadic-attack AIP cohort shows that kidney disease is not confined
      to patients with frequent recurrent attacks.
- name: Hepatocellular carcinoma
  description: >-
    Hepatocellular carcinoma is an uncommon but clinically important long-term
    risk in AIP. Incidence estimates derive from observational cohorts and do
    not imply that cancer is inevitable or that a specific precursor-mediated
    carcinogenic mechanism is proven.
  phenotype_term:
    preferred_term: Hepatocellular carcinoma
    term:
      id: HP:0001402
      label: Hepatocellular carcinoma
  evidence:
  - reference: PMID:39438413
    reference_title: "Hepatocellular Carcinoma in Acute Hepatic Porphyria: A Meta-Analysis of Observational Studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HCC cases were observed with HCC incidence per 100 person years of 0.3
      (0.2-0.5) in AHP, 0.4 (0.2-0.6) in AIP, 0.3 (0-0.4) in VP, and 0.2
      (0.1-0.6) in HCP.
    explanation: >-
      The meta-analysis directly reports the AIP-specific incidence estimate;
      heterogeneity and publication bias qualify its precision and application
      to individual patients or populations.
- name: Tetraparesis
  description: >-
    Severe motor-predominant porphyric neuropathy can progress to quadriparesis
    or tetraparesis.
  phenotype_term:
    preferred_term: Quadriparesis
    term:
      id: HP:0002273
      label: Tetraparesis
  evidence:
  - reference: PMID:33786855
    reference_title: "Porphyric neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute hepatic porphyrias are inherited metabolic disorders that may
      present with polyneuropathy, which if not diagnosed early can lead to
      quadriparesis, respiratory weakness, and death.
    explanation: >-
      Review evidence explicitly supports quadriparesis as a severe porphyric
      neuropathy manifestation.
- name: Seizure
  description: >-
    Acute neuropsychiatric crises can include encephalopathy with seizures.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:26366103
    reference_title: "An update of clinical management of acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Intensive abdominal pain without peritoneal signs, acute peripheral
      neuropathy, and encephalopathy usually with seizures or psychosis are the
      key symptoms indicating possible acute porphyria.
    explanation: >-
      Review evidence lists seizures as a key encephalopathic symptom indicating
      acute porphyria.
- name: Psychosis
  description: >-
    Acute neuropsychiatric crises can include encephalopathy with psychosis.
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: PMID:26366103
    reference_title: "An update of clinical management of acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Intensive abdominal pain without peritoneal signs, acute peripheral
      neuropathy, and encephalopathy usually with seizures or psychosis are the
      key symptoms indicating possible acute porphyria.
    explanation: >-
      Review evidence lists psychosis as a key encephalopathic symptom
      indicating acute porphyria.
- name: Abnormal HMBS enzyme activity
  frequency: VERY_FREQUENT
  description: >
    Reduced HMBS/PBGD activity is the enzymatic abnormality underlying AIP.
  phenotype_term:
    preferred_term: Abnormal HMBS enzyme activity
    term:
      id: HP:0012379
      label: Abnormal circulating enzyme concentration or activity
  evidence:
  - reference: ORPHA:79276
    reference_title: "Acute intermittent porphyria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent (99-80%)"
    explanation: Orphanet reports abnormal enzyme/coenzyme activity as very frequent.
- name: Elevated urinary delta-aminolevulinic acid
  frequency: VERY_FREQUENT
  description: >
    Urinary ALA is elevated during acute attacks because excess hepatic
    precursor production spills into urine.
  phenotype_term:
    preferred_term: Elevated urinary delta-aminolevulinic acid
    term:
      id: HP:0003163
      label: Elevated urinary delta-aminolevulinic acid
  evidence:
  - reference: ORPHA:79276
    reference_title: "Acute intermittent porphyria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003163 | Elevated urinary delta-aminolevulinic acid | Very frequent (99-80%)"
    explanation: Orphanet reports elevated urinary delta-aminolevulinic acid as very frequent.
- name: Increased urinary porphobilinogen
  frequency: VERY_FREQUENT
  description: >
    Urinary PBG is elevated during acute attacks because excess hepatic
    precursor production spills into urine.
  phenotype_term:
    preferred_term: Increased urinary porphobilinogen
    term:
      id: HP:0012217
      label: Increased urinary porphobilinogen
  evidence:
  - reference: ORPHA:79276
    reference_title: "Acute intermittent porphyria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012217 | Increased urinary porphobilinogen | Very frequent (99-80%)"
    explanation: Orphanet reports increased urinary porphobilinogen as very frequent.
- name: Porphyrinuria
  frequency: VERY_FREQUENT
  description: >
    Porphyrinuria reflects increased urinary excretion of heme pathway
    intermediates during active disease.
  phenotype_term:
    preferred_term: Porphyrinuria
    term:
      id: HP:0010473
      label: Porphyrinuria
  evidence:
  - reference: ORPHA:79276
    reference_title: "Acute intermittent porphyria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010473 | Porphyrinuria | Very frequent (99-80%)"
    explanation: Orphanet reports porphyrinuria as very frequent.
- name: Constipation
  frequency: FREQUENT
  description: >
    Constipation is a frequent gastrointestinal manifestation of acute
    neurovisceral attacks.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: ORPHA:79276
    reference_title: "Acute intermittent porphyria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002019 | Constipation | Frequent (79-30%)"
    explanation: Orphanet reports constipation as frequent.
- name: Cranial nerve paralysis
  frequency: FREQUENT
  description: >
    Cranial nerve paralysis is a frequent neurologic manifestation in Orphanet's
    AIP phenotype table.
  phenotype_term:
    preferred_term: Cranial nerve paralysis
    term:
      id: HP:0006824
      label: Cranial nerve paralysis
  evidence:
  - reference: ORPHA:79276
    reference_title: "Acute intermittent porphyria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006824 | Cranial nerve paralysis | Frequent (79-30%)"
    explanation: Orphanet reports cranial nerve paralysis as frequent.
- name: Back pain
  frequency: FREQUENT
  description: >
    Back pain is a frequent pain manifestation during acute intermittent
    porphyria attacks.
  phenotype_term:
    preferred_term: Back pain
    term:
      id: HP:0003418
      label: Back pain
  evidence:
  - reference: ORPHA:79276
    reference_title: "Acute intermittent porphyria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003418 | Back pain | Frequent (79-30%)"
    explanation: Orphanet reports back pain as frequent.
- name: Limb pain
  frequency: FREQUENT
  description: >
    Limb pain is a frequent pain manifestation in Orphanet's AIP phenotype
    table.
  phenotype_term:
    preferred_term: Limb pain
    term:
      id: HP:0009763
      label: Limb pain
  evidence:
  - reference: ORPHA:79276
    reference_title: "Acute intermittent porphyria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009763 | Limb pain | Frequent (79-30%)"
    explanation: Orphanet reports limb pain as frequent.
- name: Neck pain
  frequency: FREQUENT
  description: >
    Neck pain is a frequent pain manifestation in Orphanet's AIP phenotype
    table.
  phenotype_term:
    preferred_term: Neck pain
    term:
      id: HP:0030833
      label: Neck pain
  evidence:
  - reference: ORPHA:79276
    reference_title: "Acute intermittent porphyria"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030833 | Neck pain | Frequent (79-30%)"
    explanation: Orphanet reports neck pain as frequent.
biochemical:
- name: Urinary 5-aminolevulinic acid
  presence: INCREASED
  context: >-
    Urinary ALA rises during acute attacks and is part of the biochemical
    signature used to confirm and monitor active disease.
  biomarker_term:
    preferred_term: urinary 5-aminolevulinic acid
    term:
      id: CHEBI:17549
      label: 5-aminolevulinic acid
  readouts:
  - target: Hepatic ALA and PBG accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased urinary ALA reports hepatic overproduction and systemic spillover
      of upstream heme precursors during an active attack.
    evidence:
    - reference: PMID:19327613
      reference_title: >-
        Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
        and therapeutic course of acute intermittent porphyria attacks.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        During an acute attack the heme precursors porphobilinogen (PBG) and
        5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
        are found in high concentrations in plasma and urine.
      explanation: >-
        Human attack-monitoring data connect urinary ALA to hepatic precursor
        overproduction during active AIP attacks.
  - target: Triggered hepatic ALAS1 induction
    relationship: PHARMACODYNAMIC_MARKER_OF
    direction: POSITIVE
    endpoint_context: PHARMACODYNAMIC
    interpretation: >-
      Lower urinary ALA after ALAS1-suppressive therapy reports reduced hepatic
      precursor production.
    evidence:
    - reference: PMID:31994716
      reference_title: "Pharmacokinetics and Pharmacodynamics of the Small Interfering Ribonucleic Acid, Givosiran, in Patients With Acute Hepatic Porphyria."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Givosiran treatment resulted in a rapid and dose-dependent reduction in
        urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) towards the
        upper limit of normal (ULN) in AHP patients.
      explanation: >-
        Human phase I pharmacodynamic data support urinary ALA as a marker of
        ALAS1-directed pathway suppression.
  - target: Neurovisceral attack susceptibility
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Higher ALA during symptoms supports an ongoing acute attack and can be
      tracked during treatment response.
    evidence:
    - reference: PMID:19327613
      reference_title: >-
        Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
        and therapeutic course of acute intermittent porphyria attacks.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These metabolites represent the acute phase reactants confirming an
        ongoing attack and are used to evaluate therapeutic measures.
      explanation: >-
        Attack-monitoring data support ALA/PBG as biochemical correlates of
        ongoing attack state and treatment response.
  evidence:
  - reference: PMID:19327613
    reference_title: >-
      Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
      and therapeutic course of acute intermittent porphyria attacks.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During an acute attack the heme precursors porphobilinogen (PBG) and
      5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
      are found in high concentrations in plasma and urine.
    explanation: >-
      This directly supports increased urinary ALA as a hallmark biochemical
      abnormality during acute attacks.
- name: Urinary porphobilinogen
  presence: INCREASED
  context: >-
    Urinary PBG increases substantially during acute attacks and serves as a
    key biochemical disease marker.
  biomarker_term:
    preferred_term: urinary porphobilinogen
    term:
      id: CHEBI:17381
      label: porphobilinogen
  readouts:
  - target: Hepatic ALA and PBG accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased urinary PBG reports hepatic overproduction and systemic spillover
      of upstream heme precursors during an active attack.
    evidence:
    - reference: PMID:19327613
      reference_title: >-
        Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
        and therapeutic course of acute intermittent porphyria attacks.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        During an acute attack the heme precursors porphobilinogen (PBG) and
        5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
        are found in high concentrations in plasma and urine.
      explanation: >-
        Human attack-monitoring data connect urinary PBG to hepatic precursor
        overproduction during active AIP attacks.
  - target: Triggered hepatic ALAS1 induction
    relationship: PHARMACODYNAMIC_MARKER_OF
    direction: POSITIVE
    endpoint_context: PHARMACODYNAMIC
    interpretation: >-
      Lower urinary PBG after ALAS1-suppressive therapy reports reduced hepatic
      precursor production.
    evidence:
    - reference: PMID:31994716
      reference_title: "Pharmacokinetics and Pharmacodynamics of the Small Interfering Ribonucleic Acid, Givosiran, in Patients With Acute Hepatic Porphyria."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Givosiran treatment resulted in a rapid and dose-dependent reduction in
        urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) towards the
        upper limit of normal (ULN) in AHP patients.
      explanation: >-
        Human phase I pharmacodynamic data support urinary PBG as a marker of
        ALAS1-directed pathway suppression.
  - target: Neurovisceral attack susceptibility
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Higher PBG during symptoms supports an ongoing acute attack and can be
      tracked during treatment response.
    evidence:
    - reference: PMID:19327613
      reference_title: >-
        Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
        and therapeutic course of acute intermittent porphyria attacks.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These metabolites represent the acute phase reactants confirming an
        ongoing attack and are used to evaluate therapeutic measures.
      explanation: >-
        Attack-monitoring data support ALA/PBG as biochemical correlates of
        ongoing attack state and treatment response.
  evidence:
  - reference: PMID:19327613
    reference_title: >-
      Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
      and therapeutic course of acute intermittent porphyria attacks.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During an acute attack the heme precursors porphobilinogen (PBG) and
      5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
      are found in high concentrations in plasma and urine.
    explanation: >-
      This directly supports increased urinary PBG as a hallmark biochemical
      abnormality during acute attacks.
- name: Plasma 5-aminolevulinic acid
  presence: INCREASED
  context: >-
    Plasma ALA rises during acute attacks as a circulating marker of hepatic
    precursor overproduction.
  biomarker_term:
    preferred_term: plasma 5-aminolevulinic acid
    term:
      id: CHEBI:17549
      label: 5-aminolevulinic acid
  readouts:
  - target: Hepatic ALA and PBG accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Increased plasma ALA reflects hepatic precursor accumulation during an
      acute attack.
    evidence:
    - reference: PMID:19327613
      reference_title: >-
        Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
        and therapeutic course of acute intermittent porphyria attacks.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        During an acute attack the heme precursors porphobilinogen (PBG) and
        5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
        are found in high concentrations in plasma and urine.
      explanation: >-
        The attack-monitoring study documents high plasma ALA during acute
        attacks.
  evidence:
  - reference: PMID:19327613
    reference_title: >-
      Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
      and therapeutic course of acute intermittent porphyria attacks.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During an acute attack the heme precursors porphobilinogen (PBG) and
      5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
      are found in high concentrations in plasma and urine.
    explanation: >-
      This directly supports increased plasma ALA during acute AIP attacks.
- name: Plasma porphobilinogen
  presence: INCREASED
  context: >-
    Plasma PBG rises during acute attacks and may track attack severity and
    treatment response more accurately than urinary precursor measurements.
  biomarker_term:
    preferred_term: plasma porphobilinogen
    term:
      id: CHEBI:17381
      label: porphobilinogen
  readouts:
  - target: Hepatic ALA and PBG accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Increased plasma PBG reflects hepatic precursor accumulation during an
      acute attack.
    evidence:
    - reference: PMID:19327613
      reference_title: >-
        Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
        and therapeutic course of acute intermittent porphyria attacks.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        During an acute attack the heme precursors porphobilinogen (PBG) and
        5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
        are found in high concentrations in plasma and urine.
      explanation: >-
        The attack-monitoring study documents high plasma PBG during acute
        attacks.
  - target: Neurovisceral attack susceptibility
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Plasma PBG can track the clinical and therapeutic course of acute attacks.
    evidence:
    - reference: PMID:19327613
      reference_title: >-
        Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
        and therapeutic course of acute intermittent porphyria attacks.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biochemical monitoring of an acute attack was more accurately reflected
        by plasma PBG than plasma ALA or urinary PBG and ALA.
      explanation: >-
        The study conclusion supports plasma PBG as a sensitive monitoring
        marker for the attack course.
  evidence:
  - reference: PMID:19327613
    reference_title: >-
      Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
      and therapeutic course of acute intermittent porphyria attacks.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During an acute attack the heme precursors porphobilinogen (PBG) and
      5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
      are found in high concentrations in plasma and urine.
    explanation: >-
      This directly supports increased plasma PBG during acute AIP attacks.
genetic:
- name: HMBS
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: HMBS
    term:
      id: hgnc:4982
      label: HMBS
  notes: >-
    Heterozygous pathogenic HMBS variants underlie AIP by reducing activity of
    hydroxymethylbilane synthase, the third enzyme in heme biosynthesis.
  evidence:
  - reference: PMID:19292878
    reference_title: >-
      Acute intermittent porphyria--impact of mutations found in the
      hydroxymethylbilane synthase gene on biochemical and enzymatic protein
      properties.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular analyses of the hydroxymethylbilane synthase gene revealed
      seven mutations.
    explanation: >-
      Patient-based molecular data directly support HMBS as the causative gene
      in AIP.
  - reference: CGGV:assertion_eab4b1f6-2902-4ed3-9002-37c578aeaaba-2022-05-27T160000.000Z
    reference_title: "HMBS / acute intermittent porphyria (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HMBS | HGNC:4982 | acute intermittent porphyria | MONDO:0008294 | SD | Definitive"
    explanation: ClinGen classifies the HMBS-acute intermittent porphyria gene-disease relationship as definitive with semidominant inheritance.
environmental:
- name: Porphyrogenic attack triggers
  effect: TRIGGERS
  notes: >-
    Drugs, alcohol, low caloric intake or fasting, and infections can precipitate
    acute attacks by increasing hepatic pathway demand and inducing the
    triggered hepatic ALAS1 event represented in the pathophysiology graph.
  evidence:
  - reference: PMID:9516674
    reference_title: "Acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These symptoms occur during acute attacks, which are often precipitated
      by drugs, alcohol, low caloric intake, or infections.
    explanation: >-
      This review directly names the common environmental and physiologic
      triggers that precipitate AIP attacks.
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with AIP are advised to avoid excessive alcohol consumption,
      as alcohol upregulates the enzyme ALAS1, the first enzyme of hepatic heme
      biosynthesis, and thus could be a trigger for acute attacks.
    explanation: >-
      GeneReviews directly connects a preventable exposure to ALAS1 induction
      and acute-attack triggering.
treatments:
- name: Trigger avoidance and adequate nutrition
  description: >-
    Preventive care includes avoiding excessive alcohol and porphyrogenic drugs,
    maintaining adequate regular nutrition, and treating systemic illness or
    infection promptly. These measures reduce exposure to known inducers rather
    than correcting the inherited HMBS defect.
  therapeutic_modality: OTHER
  target_mechanisms:
  - target: Triggered hepatic ALAS1 induction
    treatment_effect: INHIBITS
    description: >-
      Avoiding excessive alcohol, fasting, and porphyrogenic drugs reduces
      exposure to factors supported to upregulate or dysregulate hepatic ALAS1.
      Adequate nutrition and timely illness treatment remain clinically
      supported prevention measures without assigning infection the same direct
      ALAS1 evidence.
    evidence:
    - reference: PMID:20301372
      reference_title: "Acute Intermittent Porphyria."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Individuals with AIP are advised to avoid excessive alcohol consumption,
        as alcohol upregulates the enzyme ALAS1, the first enzyme of hepatic heme
        biosynthesis, and thus could be a trigger for acute attacks.
      explanation: >-
        GeneReviews directly supports prevention of an exposure that induces
        the modeled ALAS1 trigger event.
    - reference: PMID:16122419
      reference_title: "Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The induction of ALAS-1 by fasting is lost in liver-specific PGC-1alpha
        knockout animals, as is the ability of porphyrogenic drugs to
        dysregulate heme biosynthesis.
      explanation: >-
        Mouse data connect fasting and porphyrogenic drugs to ALAS1 regulation;
        PARTIAL preserves the boundary between this mechanism and preventive
        efficacy in human AIP.
  evidence:
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To reduce the frequency and/or severity of acute attacks, maintain
      adequate nutrition and seek timely treatment of systemic illness or
      infection.
    explanation: >-
      GeneReviews directly recommends nutrition and timely illness treatment
      as attack-prevention measures.
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with AIP are advised to avoid excessive alcohol consumption,
      as alcohol upregulates the enzyme ALAS1, the first enzyme of hepatic heme
      biosynthesis, and thus could be a trigger for acute attacks.
    explanation: >-
      GeneReviews supports excessive-alcohol avoidance as a mechanism-linked
      preventive measure.
- name: Intravenous hemin
  description: >-
    Standard treatment for severe acute attacks; exogenous hemin represses
    hepatic ALAS1 and is more effective than glucose alone in serious attacks.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hemin
      term:
        id: CHEBI:50385
        label: hemin
  target_mechanisms:
  - target: Triggered hepatic ALAS1 induction
    treatment_effect: INHIBITS
    description: >-
      Hemin represses hepatic ALAS1 during acute attacks.
    evidence:
    - reference: PMID:29498764
      reference_title: "Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        So far, the treatment of choice is hemin which represses ALAS1.
      explanation: >-
        This directly links hemin therapy to repression of the induced hepatic
        ALAS1 node.
  - target: Hepatic ALA and PBG accumulation
    treatment_effect: INHIBITS
    description: >-
      By repressing ALAS1, hemin lowers the precursor burden during more severe
      attacks.
    evidence:
    - reference: PMID:19327613
      reference_title: "Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Glucose administration, in contrast to heme therapy, was not sufficient
        to achieve clinical and biochemical remission in the more serious
        attacks.
      explanation: >-
        This supports heme therapy as the more effective way to reverse the
        acute biochemical lesion in serious AIP attacks.
  evidence:
  - reference: PMID:19327613
    reference_title: "Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment is based on symptomatic relief together with carbohydrate
      loading and in more severe attacks heme therapy.
    explanation: >-
      This study describes heme therapy as the escalation treatment for more
      severe acute attacks.
  - reference: PMID:33786855
    reference_title: "Porphyric neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Timely treatment with intravenous heme, carbohydrate loading, and
      avoidance of porphyrinogenic medications can prevent further neurological
      morbidity and mortality.
    explanation: >-
      This review supports intravenous heme as clinically important for limiting
      neurologic morbidity during porphyric attacks.
- name: Givosiran
  description: >-
    Liver-directed siRNA prophylaxis that lowers ALAS1, reduces ALA and PBG,
    and markedly decreases recurrent attack burden.
  therapeutic_modality: SIRNA
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: givosiran
      term:
        id: NCIT:C146805
        label: Givosiran
  target_mechanisms:
  - target: Triggered hepatic ALAS1 induction
    treatment_effect: INHIBITS
    description: >-
      Givosiran suppresses hepatic ALAS1 expression as mechanism-directed
      prophylaxis.
    evidence:
    - reference: PMID:35067977
      reference_title: "RNAi therapy with givosiran significantly reduces attack rates in acute intermittent porphyria."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The results of clinical trials have shown that givosiran treatment
        leads to a rapid and sustained reduction of ALAS1 mRNA, decreased heme
        precursor levels, and a decreased rate of acute attacks compared with
        placebo.
      explanation: >-
        This directly supports ALAS1 silencing as the intended upstream
        mechanism of givosiran.
  - target: Hepatic ALA and PBG accumulation
    treatment_effect: INHIBITS
    description: >-
      Givosiran lowers urinary ALA and PBG toward normal by suppressing hepatic
      precursor production.
    evidence:
    - reference: PMID:31994716
      reference_title: "Pharmacokinetics and Pharmacodynamics of the Small Interfering Ribonucleic Acid, Givosiran, in Patients With Acute Hepatic Porphyria."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Givosiran treatment resulted in a rapid and dose-dependent reduction in
        urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) towards the
        upper limit of normal (ULN) in AHP patients.
      explanation: >-
        This phase I study provides direct biochemical evidence that givosiran
        suppresses the precursor burden.
  evidence:
  - reference: PMID:32521132
    reference_title: "Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 89 patients with acute intermittent porphyria, the mean
      annualized attack rate was 3.2 in the givosiran group and 12.5 in the
      placebo group, representing a 74% lower rate in the givosiran group
      (P<0.001); the results were similar among the 94 patients with acute
      hepatic porphyria.
    explanation: >-
      The pivotal randomized trial provides AIP-specific efficacy evidence.
  - reference: PMID:32521132
    reference_title: "Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The increased efficacy was accompanied by a higher frequency of hepatic
      and renal adverse events.
    explanation: >-
      The AIP-specific trial also establishes the clinically important hepatic
      and renal safety signal.
  - reference: PMID:37479139
    reference_title: "Efficacy and safety of givosiran for acute hepatic porphyria: Final results of the randomized phase III ENVISION trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These final 36-month results of ENVISION, a phase III study of givosiran
      in patients with AHP and recurrent attacks, show that long-term monthly
      treatment with givosiran leads to continuous and sustained reductions in
      annualized attack rate and use of hemin over time, as well as improved
      quality of life, with an acceptable safety profile.
    explanation: >-
      Long-term phase III and open-label-extension evidence supports givosiran
      as effective mechanism-directed long-term prophylaxis for recurrent
      attacks.
- name: Prophylactic hemin infusion
  description: >-
    Scheduled hemin infusion is an alternative prophylactic therapy to reduce
    frequency or severity of recurrent acute attacks when givosiran is not
    available. Long-term use is limited by iron overload, phlebitis, loss of
    venous access, and evidence that frequent infusions can promote chronic
    hepatic inflammation and recurrent ALAS1 elevation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hemin
      term:
        id: CHEBI:50385
        label: hemin
  target_mechanisms:
  - target: Triggered hepatic ALAS1 induction
    treatment_effect: INHIBITS
    description: >-
      Hemin can repress ALAS1, but frequent prophylactic exposure is not modeled
      as simple sustained inhibition because hepatic inflammation and HO1
      induction may maintain elevated ALAS1 between treatments.
    evidence:
    - reference: PMID:29498764
      reference_title: "Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        So far, the treatment of choice is hemin which represses ALAS1.
      explanation: >-
        This supports the negative-feedback mechanism, with PARTIAL support
        because the same study reports a countervailing effect of frequent
        infusions.
  evidence:
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Alternative medical therapies to reduce frequency and/or severity of acute
      attacks when givosiran is not available include suppression of ovulation
      and prophylactic hemin infusion.
    explanation: >-
      GeneReviews supports prophylactic hemin infusion as an alternative
      preventive therapy when givosiran is unavailable.
  - reference: PMID:26366103
    reference_title: "An update of clinical management of acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      management of patients with recurrent attacks: 1) evaluation of the
      lifestyle, 2) evaluation of hormonal therapy in women, 3) prophylactic heme
      therapy, and 4) liver transplantation in patients with severe recurrent
      attacks.
    explanation: >-
      A clinical management review independently lists prophylactic heme therapy
      for patients with recurrent attacks.
  - reference: PMID:29498764
    reference_title: "Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      both in animal model and in human liver, frequent hemin infusions generate
      a chronic inflammatory hepatic disease which induces HO1 remotely to hemin
      treatment and maintains a high ALAS1 level responsible for recurrence.
    explanation: >-
      Mixed human-liver and animal evidence supplies the countervailing chronic
      inflammation and recurrent-ALAS1 caveat.
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If the criteria for recurrent attacks are met, Givlaari® (givosiran)
      should be considered, as long-term complications of hemin such as iron
      overload, phlebitis, and loss of venous access can be avoided.
    explanation: >-
      GeneReviews identifies the principal access and iron-related limitations
      of repeated hemin therapy.
- name: Ovulation suppression
  description: >-
    Ovulation suppression is an alternative prophylactic strategy for women with
    recurrent attacks when givosiran is not available, addressing hormonally
    triggered attack recurrence.
  treatment_term:
    preferred_term: hormone modifying therapy
    term:
      id: NCIT:C15445
      label: Hormone Therapy
  target_mechanisms:
  - target: Neurovisceral attack susceptibility
    treatment_effect: INHIBITS
    description: >-
      Suppressing ovulation reduces hormonally driven recurrent attack
      susceptibility in women, although the endocrine intermediate is not
      separately modeled in this pathograph.
    evidence:
    - reference: PMID:20301372
      reference_title: "Acute Intermittent Porphyria."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Alternative medical therapies to reduce frequency and/or severity of
        acute attacks when givosiran is not available include suppression of
        ovulation and prophylactic hemin infusion.
      explanation: >-
        GeneReviews lists suppression of ovulation as an alternative therapy to
        reduce acute attack frequency or severity.
  evidence:
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Alternative medical therapies to reduce frequency and/or severity of acute
      attacks when givosiran is not available include suppression of ovulation
      and prophylactic hemin infusion.
    explanation: >-
      GeneReviews supports ovulation suppression as an alternative preventive
      therapy when givosiran is unavailable.
  - reference: PMID:26366103
    reference_title: "An update of clinical management of acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      management of patients with recurrent attacks: 1) evaluation of the
      lifestyle, 2) evaluation of hormonal therapy in women, 3) prophylactic heme
      therapy, and 4) liver transplantation in patients with severe recurrent
      attacks.
    explanation: >-
      The recurrent-attack management review independently lists evaluation of
      hormonal therapy in women.
- name: Liver transplantation
  description: >-
    Liver transplantation is a curative option for selected patients with
    repeated life-threatening acute porphyria attacks or poor quality of life
    when givosiran is unavailable or insufficiently effective.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: liver transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  target_mechanisms:
  - target: HMBS deficiency in hepatocytes
    treatment_effect: RESTORES
    description: >-
      Transplantation replaces the HMBS-deficient hepatic compartment that
      drives attack biochemistry, restoring hepatic enzyme capacity at the organ
      level.
    evidence:
    - reference: PMID:26062020
      reference_title: "Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        After OLT, the recipient's plasma and urinary ALA and PBG rapidly
        normalized, and her attacks immediately stopped.
      explanation: >-
        Rapid biochemical normalization and attack cessation support
        replacement of the diseased hepatic compartment; PARTIAL reflects that
        HMBS activity itself was not reported as the outcome in this sentence.
  - target: Hepatic ALA and PBG accumulation
    treatment_effect: INHIBITS
    description: >-
      By replacing the hepatic source of excess precursor production, liver
      transplantation prevents recurrent severe attack biochemistry.
    evidence:
    - reference: PMID:26062020
      reference_title: "Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        After OLT, the recipient's plasma and urinary ALA and PBG rapidly
        normalized, and her attacks immediately stopped.
      explanation: >-
        This directly documents normalization of circulating and urinary
        precursors after removal of the hepatic source.
  evidence:
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Liver transplantation, as reported from several centers, is curative.
      Indications include repeated life-threatening acute porphyria attacks and
      poor quality of life when givosiran is not available or has shown
      insufficient medical efficacy.
    explanation: >-
      GeneReviews supports liver transplantation as a curative option for
      severe recurrent AIP attacks when givosiran is unavailable or
      insufficiently effective.
  - reference: PMID:26366103
    reference_title: "An update of clinical management of acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      management of patients with recurrent attacks: 1) evaluation of the
      lifestyle, 2) evaluation of hormonal therapy in women, 3) prophylactic heme
      therapy, and 4) liver transplantation in patients with severe recurrent
      attacks.
    explanation: >-
      A clinical management review independently lists liver transplantation for
      patients with severe recurrent attacks.
- name: Carbohydrate loading
  description: >-
    High-carbohydrate intake is used as adjunctive therapy during milder attacks
    but is usually insufficient alone for serious episodes.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: glucose supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_mechanisms:
  - target: Triggered hepatic ALAS1 induction
    treatment_effect: MODULATES
    description: >-
      Glucose administration is placed upstream of triggered hepatic ALAS1
      induction as a nutritional intervention. PGC-1alpha links nutritional
      status to ALAS1 regulation, but the cited mechanistic study explicitly
      leaves the beneficial glucose mechanism unresolved, so this join is
      provisional.
    evidence:
    - reference: PMID:16122419
      reference_title: "Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Acute attacks are treated by heme infusion and glucose administration,
        but the mechanisms underlying the precipitating effects of fasting and
        the beneficial effects of glucose are unknown.
      explanation: >-
        The study identifies glucose as an acute-attack intervention while
        explicitly limiting the certainty of its mechanistic connection.
    - reference: PMID:16122419
      reference_title: "Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These data show that PGC-1alpha links nutritional status to heme
        biosynthesis and acute hepatic porphyria.
      explanation: >-
        Mouse data support a nutritional-regulation join to the hepatic pathway
        without proving that glucose directly suppresses ALAS1 in human AIP.
  evidence:
  - reference: PMID:19327613
    reference_title: "Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment is based on symptomatic relief together with carbohydrate
      loading and in more severe attacks heme therapy.
    explanation: >-
      This directly supports carbohydrate loading as standard supportive
      management during acute attacks.
  - reference: PMID:19327613
    reference_title: "Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Glucose administration, in contrast to heme therapy, was not sufficient
      to achieve clinical and biochemical remission in the more serious
      attacks.
    explanation: >-
      This directly establishes the clinically important limitation that
      carbohydrate therapy is insufficient in more severe attacks.
diagnosis:
- name: Urinary ALA and PBG measurement
  diagnosis_term:
    preferred_term: urine chemistry measurement
    term:
      id: NCIT:C61044
      label: Urine Chemistry Measurement
  description: >-
    Quantification of PBG and ALA, normalized to creatinine in a random urine
    sample collected during symptoms, establishes an active
    acute-hepatic-porphyria biochemical state and can track treatment response;
    the biochemical result alone does not distinguish AIP from the other acute
    hepatic porphyrias.
  results: Markedly elevated urinary PBG, usually with elevated ALA, supports an active acute hepatic porphyria attack and prompts porphyria-type confirmation.
  evidence:
  - reference: PMID:19327613
    reference_title: >-
      Plasma porphobilinogen as a sensitive biomarker to monitor the clinical
      and therapeutic course of acute intermittent porphyria attacks.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During an acute attack the heme precursors porphobilinogen (PBG) and
      5-aminolevulinic acid (ALA) are produced in high amounts by the liver and
      are found in high concentrations in plasma and urine.
    explanation: >-
      This directly supports urinary ALA and PBG measurement as the key
      biochemical diagnostic readout during attacks.
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      When the diagnosis of an AIP attack is suspected based on clinical
      findings, establishing the diagnosis begins with biochemical testing.
    explanation: >-
      GeneReviews explicitly places biochemical testing first in the diagnostic
      sequence.
  - reference: PMID:36642627
    reference_title: "AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Initial diagnosis of AHP should be made by biochemical testing measuring
      δ-aminolevulinic acid, porphobilinogen, and creatinine on a random urine
      sample.
    explanation: >-
      The AGA expert review specifies the random-urine collection and creatinine
      correction needed to control for urine dilution.
- name: Molecular genetic testing
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: HMBS
        term:
          id: hgnc:4982
          label: HMBS
  description: >-
    HMBS molecular testing confirms AIP as the porphyria type after positive
    biochemistry and enables cascade screening. Because penetrance is very low,
    an HMBS variant alone does not establish that current symptoms constitute
    an acute attack.
  results: A pathogenic HMBS variant confirms inherited AIP susceptibility; increased urinary PBG is also required to attribute current symptoms to an AIP attack.
  evidence:
  - reference: PMID:20301372
    reference_title: "Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If the urinary concentration of PBG is increased, molecular genetic
      testing is performed to confirm the diagnosis and/or to facilitate
      cascade screening of family members.
    explanation: >-
      GeneReviews supports confirmatory HMBS testing after positive biochemical
      testing and its separate role in family screening.
clinical_trials:
- name: NCT03338816
  phase: PHASE_III
  status: COMPLETED
  description: >-
    ENVISION was the pivotal randomized phase III study of subcutaneous
    givosiran in patients with acute hepatic porphyrias, including acute
    intermittent porphyria, with recurrent attacks.
  evidence:
  - reference: clinicaltrials:NCT03338816
    reference_title: "ENVISION: A Phase 3 Randomized, Double-blind, Placebo-Controlled Multicenter Study With an Open-label Extension to Evaluate the Efficacy and Safety of Givosiran in Patients With Acute Hepatic Porphyrias"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the effect of subcutaneous
      givosiran (ALN-AS1), compared to placebo, on the rate of porphyria
      attacks in patients with Acute Hepatic Porphyrias (AHP).
    explanation: >-
      ClinicalTrials.gov directly documents the pivotal phase III givosiran
      trial relevant to recurrent AIP attacks.
animal_models:
- species: Mus musculus
  genotype: Partially Hmbs/PBGD-deficient T1/T2 model with approximately 30% residual activity
  description: >-
    The classic heterozygous AIP model requires phenobarbital induction rather
    than developing spontaneous human-like attacks. Induction produces hepatic
    precursor accumulation, nerve-conduction block, axonal loss, and reversible
    hepatic energetic abnormalities; the energetic findings are preclinical and
    are not asserted as established chronic human AIP pathology.
  associated_phenotypes:
  - Peripheral neuropathy
  - Muscle weakness
  evidence:
  - reference: PMID:20877347
    reference_title: "Sustained enzymatic correction by rAAV-mediated liver gene therapy protects against induced motor neuropathy in acute porphyria mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Phenobarbital injections in AIP mice induced porphyrin precursor
      accumulation, functional block of nerve conduction, and progressive loss
      of large-caliber axons in the sciatic nerve.
    explanation: >-
      This defines the induced classic mouse phenotype and explicitly avoids
      implying that attacks arise spontaneously.
  - reference: PMID:24727425
    reference_title: "Acute intermittent porphyria causes hepatic mitochondrial energetic failure in a mouse model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results suggest a cataplerosis of the TCA cycle induced by
      phenobarbital, caused by the massive withdrawal of succinyl-CoA by ALAS
      induction, such that the TCA cycle is unable to supply the reduced
      cofactors to the RC.
    explanation: >-
      The induced mouse study supports a reversible hepatic energetic extension
      of the model, not an established human complication.
- species: Mus musculus
  genotype: Homozygous Hmbs R167Q knock-in with approximately 5% residual activity
  description: >-
    This severe homozygous model develops early ataxia, delayed myelination, and
    locally elevated CNS ALA/PBG. It models homozygous dominant AIP (HD-AIP), not
    the usual heterozygous, low-penetrance, episodic adult disease.
  associated_phenotypes:
  - Ataxia
  - Delayed myelination
  evidence:
  - reference: PMID:30615115
    reference_title: "Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous R173Q mice were embryonic lethal, while R167Q homozygous mice
      (R167Q+/+) had ~5% of normal HMBS activity, constitutively elevated plasma
      and urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), profound
      early-onset ataxia, delayed motor development and markedly impaired
      rotarod performance.
    explanation: >-
      This directly supports the explicitly scoped severe biallelic model; the
      description separately limits extrapolation to classic heterozygous AIP.
experimental_models:
- name: Porphyrin-precursor exposure of human proximal tubular cells
  description: >-
    Cultured proximal tubular cells exposed to porphyrin precursors were used to
    test candidate mechanisms for porphyria-associated kidney disease.
  experimental_model_type: OTHER
  cell_source: Human proximal tubular cells
  culture_system: In vitro precursor-exposure assay
  publication: PMID:25830761
  modeled_mechanisms:
  - target: Porphyria-associated tubulointerstitial kidney injury
    description: >-
      Tests candidate precursor-induced endoplasmic-reticulum stress,
      apoptosis, and epithelial phenotypic change in human proximal tubular
      cells relevant to porphyria-associated kidney injury.
    evidence:
    - reference: PMID:25830761
      reference_title: "High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our experimental data provide evidence that porphyrin precursors promote
        endoplasmic reticulum stress, apoptosis, and epithelial phenotypic changes
        in proximal tubular cells.
      explanation: >-
        The experiment directly supports the cellular injury readouts, while
        the link remains PARTIAL for their contribution to human kidney disease.
  evidence:
  - reference: PMID:25830761
    reference_title: "High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our experimental data provide evidence that porphyrin precursors promote
      endoplasmic reticulum stress, apoptosis, and epithelial phenotypic changes
      in proximal tubular cells.
    explanation: >-
      The assay supports candidate tubular-cell injury mechanisms while not
      proving their relative contribution in patients.
- name: ALA exposure of human and rat cortical synaptic membranes
  description: >-
    Isolated cortical synaptic membranes were exposed to ALA to test whether it
    interferes with GABA-A receptor ligand binding. The concentrations and
    membrane preparation make this a mechanistic candidate assay rather than a
    faithful model of in vivo AIP attacks.
  experimental_model_type: OTHER
  cell_source: Human and rat cortical synaptic membrane preparations
  culture_system: Radioligand-binding membrane assay
  publication: PMID:11478735
  modeled_mechanisms:
  - target: Neurovisceral attack susceptibility
    description: >-
      Tests the candidate interaction between ALA and GABA-A receptor ligand
      binding without treating the membrane assay as a faithful model of an in
      vivo human AIP attack.
    evidence:
    - reference: PMID:11478735
      reference_title: "5-Aminolevulinic acid inhibits [3H]muscimol binding to human and rat brain synaptic membranes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ALA (0.1-10 mM) significantly inhibited the binding"
      explanation: >-
        The binding result supports the candidate mechanism link, but not its
        operation at physiologic concentrations during human attacks.
  evidence:
  - reference: PMID:11478735
    reference_title: "5-Aminolevulinic acid inhibits [3H]muscimol binding to human and rat brain synaptic membranes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ALA (0.1-10 mM) significantly inhibited the binding"
    explanation: >-
      The evidence directly supports the in-vitro binding result modeled here;
      the description separately limits extrapolation to physiologic human
      precursor concentrations.
discussions:
- discussion_id: unresolved_precursor_neurotoxicity_route
  prompt: >-
    Which precursor species and molecular pathway connect hepatic precursor
    overproduction to the autonomic, peripheral-neuropathic, and central
    manifestations of classic heterozygous AIP attacks?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Hepatic ALA and PBG accumulation
  - pathophysiology#Neurovisceral attack susceptibility
  rationale: >-
    Clinical interventions support precursor burden as causally important, but
    GABA-A interference, oxidative injury, mitochondrial dysfunction, and
    vascular effects remain candidate routes. Low adult blood-brain-barrier
    permeability also argues against treating severe homozygous CNS disease as
    a simple explanation for classic attacks.
  evidence:
  - reference: PMID:11478735
    reference_title: "5-Aminolevulinic acid inhibits [3H]muscimol binding to human and rat brain synaptic membranes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ALA (0.1-10 mM) significantly inhibited the binding"
    explanation: >-
      This supplies one plausible molecular interaction, qualified by the in
      vitro concentration range.
  - reference: PMID:12493610
    reference_title: "Transport of 5-aminolevulinic acid between blood and brain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "uptake into the neonatal brain was 7-fold higher than in the adult"
    explanation: >-
      Rat transport data identify an age-dependent blood-brain-barrier boundary
      rather than resolving classic adult human neurotoxicity.
- discussion_id: classic_and_homozygous_aip_model_boundaries
  prompt: >-
    How should findings from phenobarbital-induced T1/T2 mice and severe
    homozygous R167Q mice be translated to low-penetrance heterozygous human AIP?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#HMBS deficiency in hepatocytes
  - pathophysiology#Neurovisceral attack susceptibility
  rationale: >-
    The classic mouse requires pharmacologic induction and develops progressive
    neuropathy under repeated challenge, whereas the homozygous model has about
    5% residual activity and early CNS-intrinsic disease. Each addresses a
    different mechanism boundary and neither reproduces the complete natural
    history of classic heterozygous AIP.
  evidence:
  - reference: PMID:20877347
    reference_title: "Sustained enzymatic correction by rAAV-mediated liver gene therapy protects against induced motor neuropathy in acute porphyria mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Phenobarbital injections in AIP mice induced porphyrin precursor
      accumulation, functional block of nerve conduction, and progressive loss
      of large-caliber axons in the sciatic nerve.
    explanation: >-
      The classic model is explicitly challenge-induced and therefore does not
      reproduce spontaneous human disease expression.
  - reference: PMID:30615115
    reference_title: "Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Human AIP heterozygotes have episodic acute neurovisceral attacks that
      typically start after puberty, whereas patients with homozygous dominant
      AIP (HD-AIP) have early-onset chronic neurological impairment, including
      ataxia and psychomotor retardation.
    explanation: >-
      The paper itself states the human phenotype boundary that limits direct
      extrapolation from the severe homozygous model.
references:
- reference: ORPHA:79276
  title: Acute intermittent porphyria
  findings: []
- reference: PMID:20301372
  title: "Acute Intermittent Porphyria."
  tags:
  - GeneReviews
  findings: []
datasets:
- accession: geo:GSE146212
  title: Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria
  description: Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of heme biosynthesis due to a pathogenic mutation in the Hmbs gene, resulting in half-normal activity of hydroxymethylbilane synthase. Factors that induce hepatic heme biosynthesis induce episodic attacks in heterozygous patients. The clinical presentation of acute attacks involves the signature neurovisceral pain and may include psychiatric symptoms. Here we used a knock-in mouse line that is biallelic for the Hmbs c.500G>A (p.R167Q) mutation with ~5% of normal hydroxymethylbilane synthase activity to unravel the consequences of severe HMBS deficiency on affective behavior and brain physiology.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 12
  publication: PMID:32197664
  notes: Identified by GEO DataSets index search for Acute Intermittent Porphyria (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

📚

References & Deep Research

References

2

ORPHA:79276

Acute intermittent porphyria

No top-level findings curated for this source.

PMID:20301372

Acute Intermittent Porphyria.

No top-level findings curated for this source.

Deep Research

1

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Acute Intermittent Porphyria. Core disease mechanisms, molecular and cellu...

Asta Scientific Corpus Retrieval 20 citations 2026-04-22T21:54:51.140210

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Acute Intermittent Porphyria. Core disease mechanisms, molecular and cellu...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Porphyrias in the Age of Targeted Therapies

Authors: Angelika L Erwin, M. Balwani
Year: 2021
Venue: Diagnostics
URL: https://www.semanticscholar.org/paper/ca5b48195af03a4b8fc46cc7eb530d0a711e62a4
DOI: 10.3390/diagnostics11101795
PMID: 34679493
PMCID: 8534485
Citations: 12
Influential citations: 1
Summary: The porphyrias are a group of eight rare genetic disorders, each caused by the deficiency of one of the enzymes in the heme biosynthetic pathway, resulting in the excess accumulation of heme precursors and porphyrins, which can result in severe clinical manifestations, long-term complications and a significantly diminished quality of life.
Evidence snippets:
Snippet 1 (score: 0.550) > The porphyrias are a group of eight rare genetic disorders, each caused by the deficiency of one of the enzymes in the heme biosynthetic pathway, resulting in the excess accumulation of heme precursors and porphyrins. Depending on the tissue site as well as the chemical characteristics of the accumulating substances, the clinical features of different porphyrias vary substantially. Heme precursors are neurotoxic, and their accumulation results in acute hepatic porphyria, while porphyrins are photoactive, and excess amounts cause cutaneous porphyrias, which present with photosensitivity. These disorders are clinically heterogeneous but can result in severe clinical manifestations, long-term complications and a significantly diminished quality of life. Medical management consists mostly of the avoidance of triggering factors and symptomatic treatment. With an improved understanding of the underlying pathophysiology and disease mechanisms, new treatment approaches have become available, which address the underlying defects at a molecular or cellular level, and promise significant improvement, symptom prevention and more effective treatment of acute and chronic disease manifestations.

[2] European porphyria initiative (EPI): a platform to develop a common approach to the management of porphyrias and to promote research in the field.

Authors: J. Deybach, M. Badminton, H. Puy, Sverre Sandberg, J. Frank et al.
Year: 2006
Venue: Physiological research
URL: https://www.semanticscholar.org/paper/4fc661b027e2d7ee6630dd73b664908fd6218aa7
DOI: 10.33549/physiolres.930000.55.s2.67
PMID: 17298223
Citations: 22
Influential citations: 1
Summary: The European Porphyria Initiative (EPI) network will set a pattern for establishing, and subsequently harmonising, between countries best clinical practice for a rare but important group of diseases, and will help to develop the optimal therapy and ensure its cost effectiveness.
Evidence snippets:
Snippet 1 (score: 0.540) > The porphyrias are uncommon inherited metabolic disorders of haem biosynthesis in which specific patterns of overproduction of haem precursors are associated with characteristic clinical features. Each type of porphyria is the result of a specific decrease in the activity of one of the enzymes of haem biosynthesis. > The porphyrias are inherited by a dominant autosomal mechanism, except in the cases of congenital erythropoietic porphyria and ALA-D deficiency (both extremely rare), which are inherited by a recessive autosomal mechanism. Porphyrias are classified as erythropoietic or hepatic in type, depending on the primary organ in which excess production of porphyrins ortheir precursors takes place. > Acute attacks occur in 4 of the porphyrias (acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP) and ALA-D deficiency); their diagnosis and management have been extensively reviewed (Anderson et al. Scriver, eighth edition, Deybach 2004). > The attacks consist of acute abdominal pain with vomiting and constipation, sometimes associated with neuro-psychiatric manifestations and may be followed by prolonged disability or end fatally. > The diagnosis of an acute attack of porphyria requires demonstration of increased urinary excretion of the haem precursor, porphobilinogen (PBG). Further investigation is needed to identify the type of porphyria, but this should not be allowed to delay treatment. > Specific treatment using intravenous haem should be started as soon as the diagnosis is established unless the attack is mild and clearly resolving. Any drugs or other potential provoking agents should be withdrawn. Care should be taken to avoid the risk of hyponatraemic seizures fromthe inappropriate use of intravenous fluids. > Family screening to identify those with the latent disease is essential for management of the autosomal dominant porphyrias. Patients and asymptomatic individuals who have inherited an acute porphyria must receive appropriate counselling, particularly about how to minimise the risk of an acute attack by avoiding drugs and other provoking factors.

[3] Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications

Authors: A. Ricci, C. Guida, P. Manzini, Chiara Cuoghi, P. Ventura
Year: 2021
Venue: Diagnostics
URL: https://www.semanticscholar.org/paper/3e9f74d999680cb364ec6e0e900b7f5cbed27124
DOI: 10.3390/diagnostics11122324
PMCID: 8700387
Citations: 23
Influential citations: 1
Summary: The role of the kidney in porphyrin metabolism, the available evidence in support of the current etiologic and pathogenetic hypotheses, and the known clinical features of renal involvement in acute hepatic porphyrias are outlined.
Evidence snippets:
Snippet 1 (score: 0.511) > Porphyrias are a group of rare disorders originating from an enzyme dysfunction in the pathway of heme biosynthesis. Depending on the specific enzyme involved, porphyrias manifest under drastically different clinical pictures. The most dramatic presentation of the four congenital acute hepatic porphyrias (AHPs: acute intermittent porphyria—AIP, ALAD deficiency, hereditary coproporphyria—HCP, and porphyria variegata—VP) consists of potentially life-threatening neurovisceral attacks, for which givosiran, a novel and effective siRNA-based therapeutic, has recently been licensed. Nonetheless, the clinical manifestations of acute porphyrias are multifaceted and do not limit themselves to acute attacks. In particular, porphyria-associated kidney disease (PAKD) is a distinct, long-term degenerating condition with specific pathological and clinical features, for which a satisfactory treatment is not available yet. In PAKD, chronic tubule-interstitial damage has been most commonly reported, though other pathologic features (e.g., chronic fibrous intimal hyperplasia) are consistent findings. Given the relevant role of the kidney in porphyrin metabolism, the mechanisms possibly intervening in causing renal damage in AHPs are different: among others, δ-aminolevulinic acid (ALA)-induced oxidative damage on mitochondria, intracellular toxic aggregation of porphyrins in proximal tubular cells, and derangements in the delicate microcirculatory balances of the kidney might be implicated. The presence of a variant of the human peptide transporter 2 (PEPT2), with a greater affinity to its substrates (including ALA), might confer a greater susceptibility to kidney damage in patients with AHPs. Furthermore, a possible effect of givosiran in worsening kidney function has been observed. In sum, the diagnostic workup of AHPs should always include a baseline evaluation of renal function, and periodic monitoring of the progression of kidney disease in patients with AHPs is strongly recommended. This review outlines the role of the kidney in porphyrin metabolism, the available evidence in support of the current etiologic and pathogenetic hypotheses, and the known clinical

[4] Orphan Peripheral Neuropathies

Authors: J. Finsterer, W. Löscher, J. Wanschitz, S. Iglseder
Year: 2020
Venue: Journal of Neuromuscular Diseases
URL: https://www.semanticscholar.org/paper/5312eea462296895ca08bbf73e9331ce2cc897eb
DOI: 10.3233/JND-200518
PMID: 32986679
PMCID: 7902989
Citations: 17
Summary: Though orphan neuropathies are rare per definition they constitute the majority of Neuropathies and should be considered as some of them are easy to identify and potentially treatable, as clarification of the underlying cause may contribute to the knowledge about etiology and pathophysiology of these conditions.
Evidence snippets:
Snippet 1 (score: 0.508) > Porphyrias are a group of ultrarare, mostly hereditary metabolic disorders due to a defective hem biosynthesis pathway [112]. Primary (hereditary) and secondary (acquired) porphyrias are differentiated. Primary porphyrias are subdivided into hepatic and erythropoetic forms. Among the hepatic porphyrias, acute porphyrias (acute intermittent porphyria, variegate porphyria, coproporphyria, DOSS porphyria (ALA-dehydratase (porphobilinogen synthase) deficiency), the most common of the porphyrias termed after Dr. Doss) and chronic porphyrias (porphyria cutanea tarda, hepato-erythropoetic porphyria) are delineated. The phenotype depends on the defective enzyme within the pathway and is due to accumulation of intermediate metabolites. Neuro-visceral porphyrias are characterized by recurrent, acute attacks, triggered by excessive hem synthesis, clinically manifesting as severe abdominal pain, vomiting, tachycardia, hypertension, hyponatremia, mild cognitive impairment, and peripheral neuropathy [112]. Severe attacks may manifest with seizures, psychosis, quadruparesis, respiratory failure, coma, or death [112]. Neuropathy occurs particularly in aminolevulinic acid dehydratase (ALAD1 gene) porphyria (DOSS porphyria), acute intermittent porphyria (HMBS gene), hereditary coproporphyria (CPOX gene), and variegate porphyria (PPOX gene) [112]. Not only peripheral nerves but also cranial nerves can be affected. Neuropathy is usually axonal and develops rapidly over 2-4 weeks with predominant proximal weakness [113]. Progression of neuropathy with affection of the nerves innervating respiratory muscles may lead to respiratory failure [112]. Porphyrias may respond to application of siRNA in the form of givosiran.

[5] ALAD Inhibition by Porphobilinogen Rationalizes the Accumulation of δ-Aminolevulinate in Acute Porphyrias

Authors: Itxaso San Juan, Tania Pereira-Ortuzar, Xabier Cendoya, A. Laín, J. To-Figueras et al.
Year: 2022
Venue: Biochemistry
URL: https://www.semanticscholar.org/paper/c1418aeeaf3560ef15ab2f3f8c621c85fc519515
DOI: 10.1021/acs.biochem.2c00434
PMID: 36241173
PMCID: 9631992
Citations: 10
Summary: Porphobilinogen, the natural product of δ-aminolevulinate deaminase, effectively inhibits its anabolic enzyme at abnormally low concentrations and can be explained by the interactions that porphobil inogen generates with the active site, most of them shared with the substrate.
Evidence snippets:
Snippet 1 (score: 0.507) > This bar plot is a semiquantitative estimate based on the reported literature and, for the acute porphyrias, it represents the situation after a crisis. Importantly, such abnormal metabolite accumulation is behind the molecular pathophysiology of porphyrias and, for instance, accumulation of ALA likely exerts toxic effects on nerves, either directly by interacting with receptors for the structurally similar neurotransmitter γ-aminobutyric acid or by forming free radicals and reactive oxygen species. 8 The observation that disorders associated with excess production of ALA but not PBG (hereditary tyrosinaemia or lead poisoning) have similar clinical presentations to acute porphyria 3 supports this hypothesis. > ALA accumulation is observed in ALA-dP and in AIP patients between 20-and 200-fold above normal levels (Figure 1B) 6 and, to a minor extent, in VP. AlP, the most common form of porphyria due to its autosomal dominant character, results from the deficiency in the activity of porphobilinogen deaminase (PBGD, hydroxymethylbilane synthase or uroporphyrinogen I synthase; EC 4.3.1.8). 9,10 Clinical expression of AIP is characterized by the intermittent occurrence of neurovisceral attacks, usually linked to environmental or acquired factors (nutritional status, steroid hormones or their metabolites, and drugs), which may intermittently induce acute exacerbations. 11 lbeit their clinical significance, the biochemical mechanism behind the accumulation of metabolites associated with acute porphyrias has not been experimentally demonstrated. It has been shown that some porphyrins are able to in vitro inactivate the ALAD enzyme. 12,13 Moreover, ALAD condensation reaction stalls at a covalently bound intermediate that resembles the product, 14 so ALAD inhibition by PBG seems plausible. Alternatively, an excess of PBG could also inhibit PBGD, providing an alternative explanation for the metabolite accumulation. Here, we have in vitro biophysically investigated the cytosolic moiety of the heme pathway to gain insight in the ALA accumulation under conditions resembling a crisis episode in AIP.

[6] An easily overlooked disease in the early stages: acute intermittent porphyria

Authors: Jing Wang, Jiurong Chen, Ke Xu, Zhizhong Li, Gang Yu et al.
Year: 2025
Venue: BMC Neurology
URL: https://www.semanticscholar.org/paper/5a4e4240439ac7bc4931294b46962a1e8f86607f
DOI: 10.1186/s12883-025-04064-0
PMID: 39948482
PMCID: 11823016
Citations: 2
Summary: This case unveils that AIP is a disease that can be easily overlooked in its early stages and timely screening through biochemical testing, including measurement of ALA, PBG and porphyrins in a random urine sample, is recommended.
Evidence snippets:
Snippet 1 (score: 0.501) > Porphyrias are inherited metabolic disorders characterized by defects in the enzymes involved in heme biosynthesis, leading to the abnormal accumulation of porphyrins or their precursors [1]. These disorders can be classified into eight types based on the specific enzyme defect. Among them, acute intermittent porphyria (AIP), an autosomal dominant inherited disease, is caused by mutations in the hydroxymethylbilane synthase (HMBS) gene, which encodes the third enzyme in the heme biosynthesis pathway [2]. The prevalence of pathogenic variants in the HMBS gene is approximately 1 in 1700, with about 0.5-1% of carriers in the general population developing clinically overt AIP with acute porphyria attacks [3,4]. Female patients with AIP experience a higher proportion of acute exacerbations compared to male patients. These attacks are commonly triggered by factors such as progesterone elevations during the luteal phase of the cycle, progesterone-containing oral contraceptives, cytochrome P450-inducing drugs, stress, alcohol consumption, smoking, fasting, strict carbohydrate-restrictive diets, or infectious diseases. Factors that precipitate acute attacks induce the synthesis of δ-aminolevulinic acid synthase 1 (ALAS1), the first and rate-limiting enzyme in the heme biosynthetic pathway, by directly promoting its transcription through mechanisms such as dieting or fasting or by increasing hepatic heme demand or consumption due to factors like drug use or illness [5]. When hepatic ALAS1 is induced, the deficiency in HMBS becomes the rate-limiting step in hepatic heme biosynthesis, leading to a significant accumulation of the potentially neurotoxic porphyrin precursors aminolevulinic acid (ALA) and porphobilinogen (PBG) [6]. > AIP is an inherited metabolic disorder that can affect the central, peripheral, and autonomic nervous systems. Therefore, its clinical presentation is diverse and may include abdominal pain, as well as neurological and psychiatric symptoms.

[7] Acute hepatic porphyria - classification, diagnosis and treatment

Authors: Aleksandra Czekaj, K. Ruszel, Robert Dubel, Julia Dubel, Natalia Namroży
Year: 2022
Venue: Journal of Education, Health and Sport
URL: https://www.semanticscholar.org/paper/c529a7a2df86cdca8724f42249a9ef253cb79e93
DOI: 10.12775/jehs.2023.13.01.019
Summary: In diagnostics, particular attention should be paid to the circumstances of the symptoms and the history of the patient's disease, which often includes numerous episodes of unexplained abdominal pain, which was so severe that it forced the patient to report to emergency departments.
Evidence snippets:
Snippet 1 (score: 0.486) > Porphyrias belong to the group of inherited metabolic diseases. Each of the four types of acute hepatic porphyria is caused by a different mutation in the gene of an enzyme involved in the heme biosynthetic pathway. The literature distinguishes between: Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), Variegate Porphyria (VP) and Aminolevulinic Dehydratic ADP (ADP) deficiency. -deficient Porphyria). Deficiency of individual enzymes leads to ineffective heme production and accumulation of neurotoxic intermediates - the so-called porphyrins. Two excess metabolites are of major importance in diagnostics - ALA (amionolevulinic acid) and PBG (porphobilinogen). In most cases, the activity of the less functional enzyme is so high that the disease never becomes apparent (latent form). Excessive accumulation of porphyrin precursors is associated with exposure to porphyrinogenic factors, leading to a seizure whose symptoms are closely related to autonomic, peripheral neuropathy, and accompanying neuropsychiatric disorders. In diagnostics, particular attention should be paid to the circumstances of the symptoms and the history of the patient's disease, which often includes numerous episodes of unexplained abdominal pain, which was so severe that it forced the patient to report to emergency departments. A severe attack of porphyria is a medical emergency and requires hospitalization. Failure to diagnose or properly treat it may result in flaccid tetraplegia, respiratory failure, brain edema, coma, and sudden circulation detention.

[8] Self-efficacy and self-management strategies in acute intermittent porphyria

Authors: Marte H. Hammersland, A. Aarsand, S. Sandberg, J. Andersen
Year: 2019
Venue: BMC Health Services Research
URL: https://www.semanticscholar.org/paper/7f405bc87d6e97dab61ab1952a981e1925c10ebf
DOI: 10.1186/s12913-019-4285-9
PMID: 31269991
PMCID: 6607542
Citations: 9
Summary: This study indicates that continuing to provide information, counseling and education is beneficial in AIP, and that HMBS mutation carriers, both those self-assessed as asymptomatic and as symptomatic, are using their knowledge to avoid triggering factors.
Evidence snippets:
Snippet 1 (score: 0.485) > Porphyrias are a group of rare, inherited metabolic disorders. Each is caused by reduced, or-in one disease-increased activity in one of the enzymes in the heme biosynthetic pathway and leads to symptoms in the form of acute neurovisceral attacks, skin lesions, or both [1]. Acute intermittent porphyria (AIP) is the most common of the acute porphyrias in most countries, with an estimated prevalence of 5.9 per million inhabitants in Europe [2]. The disease is characterized by acute attacks in the form of severe abdominal pain, in combination with pain in the back and thighs, polyneuropathy, nausea, vomiting and constipation [1,3]. Tachycardia, hypertension, electrolyte disturbances and neurological and mental complications are also frequent. Attacks of AIP have by some patients been described as excruciatingly painful [4]. Though most patients experience only one or a few acute attacks during their lifetime, more severely affected patients report a reduced quality of life. They can experience major life event consequences such as failure to secure or loss of employment, impact on family size, increased anxiety, and depression [4][5][6]. AIP is an autosomal dominant disease and is caused by mutations of the HMBS gene. Prevalence of mutations in the HMBS gene is probably underestimated in the healthy population [7,8]. Clinical penetrance has been estimated to be about 10% [9], even lower in a recent population study [10]. Studies indicate that drug use including alcohol and hormonal changes are the most frequent inducers of acute attacks [11], with additional triggers being smoking, infections, physical and psychological stress, hunger and crash dieting [12,13]. Avoidance of these triggers is recommended both to prevent HMBS mutation carriers not yet having symptoms from manifesting the disease, and to reduce the frequency and severity of attacks in patients who have already had symptoms of AIP. Among behavioral measures, avoiding the use of porphyrinogenic drugs is considered the single most important effort. In addition, a balanced diet with no prolonged fasting or crash dieting is generally recommended [14].

[9] Renal Failure Affects the Enzymatic Activities of the Three First Steps in Hepatic Heme Biosynthesis in the Acute Intermittent Porphyria Mouse

Authors: Carmen Unzu, A. Sampedro, Eliane Sardh, I. Mauleón, R. Enríquez de Salamanca et al.
Year: 2012
Venue: PLoS ONE
URL: https://www.semanticscholar.org/paper/01c0a1929871cf1777d0d620b3582ba7f0e95880
DOI: 10.1371/journal.pone.0032978
PMID: 22412963
PMCID: 3295788
Citations: 17
Influential citations: 3
Summary: In conclusion, high concentration of porphyrin precursors had little impact on renal function, however, progressive renal insufficiency aggravates porphyria attacks and increases the PBG/ALA ratio, which should be considered a warning sign for potentially life-threatening impairment in AIP patients with signs of renal failure.
Evidence snippets:
Snippet 1 (score: 0.484) > Acute intermittent porphyria (AIP, OMIM 176000) is an inherited metabolic disease characterized by partial deficiency of hepatic porphobilinogen deaminase (PBGD). The disease is inherited in an autosomal dominant manner and is the most common of the acute porphyrias [1]. The dominant clinical feature is characterized by acute attacks of abdominal pain, hypertension and neurovisceral and circulatory disturbances, a condition which if untreated may become life-threatening. An inherited deficiency of PBGD is not sufficient for the symptoms to appear. Acute attacks can be induced by various drugs, nutritional factors and hormonal changes [2]. Drugs metabolized by CYP450, such as phenobarbital, greatly increase hepatic heme demand and result in the up-regulation of hepatic aminolevulinate synthase (ALAS1), increasing the production of porphyrin precursors and precipitating the attack. Advances in medical care and self-care have improved the prognosis for symptomatic patients [3]. Still, some patients develop recurrent crises or progressive disease with disabling neurological dysfunction and/ or renal failure. > Chronic kidney disease may occur as a long-term complication of symptomatic disease in acute porphyrias, leading to vascular complications, progression of peripheral neuropathy and eventually need for dialysis. Chronic arterial hypertension and renal impairment become more common after middle age in AIP, especially in patients with frequent porphyric attacks [4,5]. Limited information is available on the characteristics and pathogenesis of renal disease in this patient group and little is known about the association between renal damage and acute porphyrias. The disease may be accompanied by electrolyte abnormalities. Hyponatremia is common during the acute attack and may be due to inappropriate secretion of antidiuretic hormones. The increased urinary excretion of catecholamines during an acute attack suggests up regulation of the sympathetic nervous system and may contribute to the etiology of renal damage. Chronic hypertension in AIP has an estimated incidence of 36-55% [3]. However, long-term treatment with modern antihypertensive drugs has

[10] Recent advances in the epidemiology and genetics of acute intermittent porphyria.

Authors: Liyan Ma, Yu Tian, Chenxing Peng, Yiran Zhang, Song-yun Zhang
Year: 2020
Venue: Intractable & rare diseases research
URL: https://www.semanticscholar.org/paper/e64f9792d907bc8cfb97cf85938db128f9961091
DOI: 10.5582/irdr.2020.03082
PMID: 33139978
Citations: 24
Influential citations: 3
Summary: The prevalence and penetrance of AIP are analyzed systematically, and the genetic traits of different populations and findings regarding the genotype-phenotype correlation are summarized.
Evidence snippets:
Snippet 1 (score: 0.459) > Porphyrias are a group of metabolic diseases that result from a specific abnormality in one of the eight enzymes of the heme biosynthetic pathway (1,2). In general, porphyrias are classified either as acute porphyrias or cutaneous porphyrias based on their clinical presentation or as hepatic and erythropoietic porphyrias based on the tissue where heme precursors are overproduced (3). > Acute intermittent porphyria (AIP, OMIM#176000), the most common and severe form of acute hepatic porphyrias (4), is an inherited metabolic disease that exhibits an autosomal dominant pattern of inheritance caused by partial deficiencies in hydroxymethylbilane synthase (HMBS; EC 2.5.1.61), the third enzyme in heme biosynthesis (5). AIP has significant molecular genetic heterogeneity and low penetrance (6). It leads to accumulation of upstream metabolites δ-aminolevulinic acid (ALA) and porphobilinogen (PBG), which induce toxicity to the neurologic system, and then trigger episodic, acute neurovisceral symptoms that can even be life-threatening (7)(8)(9)(10)(11). Studies of the prevalence, penetrance, and molecular genetic traits of AIP are crucial to its early diagnosis and rational management. Thanks to the rapid development of next-generation sequencing (NGS) technology, genetic sequencing has been widely used to detect HMBS gene mutations (12,13). Some studies based on genetic testing have revealed that the prevalence of HMBS variants was substantially underestimated, with extremely low penetrance in the general population but higher penetrance in families with AIP (14,15). > Findings regarding modifying genes and the correlation between genotype-phenotype warrant more attention in recent studies on AIP. Although a genotypephenotype correlation has not been identified, certain mutations may be relevant to penetrance or the severity of clinical manifestations.

[11] Current Understanding on the Genetic Basis of Key Metabolic Disorders: A Review

Authors: K. Rodrigues, W. T. L. Yong, Md. Safiul Alam Bhuiyan, S. Siddiquee, M. D. Shah et al.
Year: 2022
Venue: Biology
URL: https://www.semanticscholar.org/paper/dca9e833a364acec7f67a0c6bc823862c525de2a
DOI: 10.3390/biology11091308
PMID: 36138787
PMCID: 9495729
Citations: 10
Summary: The review focuses on fourteen of the most widely studied inherited MD, which are familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, Maple syrup urine disease, Metachromatic leukodystrophy, Mitochondrial encephalopathy lactic acidosis stroke-like episodes, Niemann-Pick disease, Phenylketonuria, Porphyria, Tay-Sachs disease, Wilson’s disease and Galactosemia.
Evidence snippets:
Snippet 1 (score: 0.459) > A collection of eight metabolic diseases of the heme biosynthesis pathway known as hereditary porphyrias are characterized by acute neurovisceral symptoms, skin lesions, or both.Each porphyria is caused by aberrant enzyme action, resulting in a particular buildup of heme precursors [112].The appropriate concentrations of vitamins and minerals in the tissues are required for certain enzymes involved in heme production.Furthermore, micronutrients required for the biosynthesis of succinyl CoA and other intermediates in the Krebs (TCA) cycle are also critical for heme metabolism indirectly [113] Givosiran, a small interfering RNA (siRNA)-based therapeutic developed for the treatment of acute intermittent porphyria (AIP), a condition that is characterized by life-threatening acute neurovisceral episodes, was approved by the US Food and Drug Administration (FDA) in November 2019 [114].Patients with acute intermittent porphyria who were administered givosiran had a reduced rate of porphyria attacks and better results for a variety of other disease symptoms than those who were given a placebo.A higher prevalence of hepatic and renal side effects followed the enhanced efficacy [115]. > Tay-Sachs disease (TSD) is a progressive, fatal neurodegenerative disorder caused by a lack of the enzyme hexosaminidase-A, which results in the accumulation of GM2 gangliosides.The disease is divided into three categories based on the age of onset: infantile, juvenile, and adult.The limited clinical symptoms and nonspecific biochemical data contribute to the difficulty in the early diagnosis of TSD.Accurate diagnosis is critical for proper management and the reduction of disease-related consequences [116].TSD treatment is currently focused on symptom alleviation and, in the case of the late-onset variant, delaying progression.There have also been clinical reports of miglustat and bone marrow or hematopoietic stem cell transplantation being used to lower the concentration of substrate.Gene therapy has been explored using adeno-or adeno-associated viruses as vectors for delivering cDNA encoding HexA subunit genes.

[12] Nutritional Interventions with Bacillus coagulans Improved Glucose Metabolism and Hyperinsulinemia in Mice with Acute Intermittent Porphyria

Authors: M. Longo, Daniel Jericó, K. Córdoba, J. Riezu-Boj, R. Urtasun et al.
Year: 2023
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/7f296f6980c32a15d01a1b08e422bad8e8ac1ee5
DOI: 10.3390/ijms241511938
PMID: 37569315
PMCID: 10418637
Citations: 4
Summary: Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (~1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a...
Evidence snippets:
Snippet 1 (score: 0.455) > Acute intermittent porphyria (AIP) is an autosomal dominant disorder characterized by a relatively high frequency of porphobilinogen deaminase (PBGD) gene mutations (1/1700 of newborns) [1,2] but low and incomplete clinical penetrance, encompassing ~1% of PBGD mutation carriers [3,4]. Although PBGD haploinsufficiency is at the core of the onset, upregulation of the first rate-limiting enzyme of the pathway, 5-aminolevulinic acid (ALA) synthase-1 (ALAS1), induces hepatic overproduction and a consequent accumulation of ALA and porphobilinogen (PBG) in plasma and urine. These heme precursors are associated with the complex set of neurotoxic manifestations exhibited by patients with AIP [5]. Chronic abdominal pain, gastrointestinal symptoms (abdominal pain, vomiting, nausea, and constipation), tachycardia, and hypertension are the major manifestations associated with these acute attacks. Peripheral motor neuropathy and central nervous system disturbances (seizures, weakness, insomnia, hallucinations, and confusion) are rare and occur only during severe and commonly prolonged attacks. Long-term complications in AIP include chronic pain, non-epicirrhotic hepatocellular carcinoma and nephropathy, thereby representing a long-life burden for patients and relatives [6][7][8][9]. > Acute attacks are associated with known trigger factors, including caloric deprivation and rapid weight loss, steroid hormones, medications and other chemicals, infections, stress and excess alcohol intake, which lead to the activation of hepatic ALAS1 transcription (see network resources of drugs database and acute porphyrias: "http://www. porphyriafoundation.com/drug-database (accessed on 22 July 2023))". Thus, disease stabilization consists of avoiding exposure to precipitating factors. For instance, AIP patients at-risk should not restrict calories, except for short periods and under the supervision of specialists.

[13] Clinical, Biochemical and Molecular Characteristics of the Main Types of Porphyria.

Authors: U. Szlendak, K. Bykowska, A. Lipniacka
Year: 2016
Venue: Advances in clinical and experimental medicine : official organ Wroclaw Medical University
URL: https://www.semanticscholar.org/paper/6c0e19725e79b758c96a3f792a86f5f4e42891d3
DOI: 10.17219/acem/58955
PMID: 27627571
Citations: 47
Influential citations: 7
Summary: Molecular analysis of gene mutations responsible for each type of porphyria is the best diagnostic approach for symptomatic as well as presymptomatic gene carriers.
Evidence snippets:
Snippet 1 (score: 0.449) > Porphyrias are diverse disorders that arise from various inherited enzyme defects in the heme biosynthesis pathway, except for porphyria cutanea tarda (PCT), in which the enzyme deficiency in most cases is acquired. The biosynthetic blocks resulting from the defective enzymes are largely expressed either in the liver or bone marrow, the sites where the majority of heme is produced. Although the pathophysiologic mechanisms of the clinical manifestations of the porphyrias are not fully understood, two cardinal features prevail: skin photosensitivity and neurologic symptoms of intermittent autonomic neuropathy, acute neurovisceral attacks, and disorders of the nervous system. The primary diagnosis of the proband is based on biochemical testing, which is not always able to identify acute porphyrias, especially in asymptomatic family carriers when heme precursors and porphyrins excretion is normal, low-normal and high-reduced values of enzyme activity overlap, and hematological diseases responsible for abnormal blood cells distribution coexist. Molecular analysis of gene mutations responsible for each type of porphyria is the best diagnostic approach for symptomatic as well as presymptomatic gene carriers.

[14] Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators

Authors: H. J. Bustad, J. Kallio, M. Vorland, Valeria Fiorentino, S. Sandberg et al.
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/7e8827ef09c5e408054e4888593bb68701ca655c
DOI: 10.3390/ijms22020675
PMID: 33445488
PMCID: 7827610
Citations: 41
Influential citations: 2
Summary: The present scenario appears promising for upcoming patient-tailored interventions in AIP, and novel mechanistic therapeutic approaches with the potential of prophylactic correction of the disease by totally or partially recovering the enzyme functionality are presented.
Evidence snippets:
Snippet 1 (score: 0.449) > Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease with low clinical penetrance, caused by mutations in the hydroxymethylbilane synthase (HMBS) gene, which encodes the third enzyme in the haem biosynthesis pathway. In susceptible HMBS mutation carriers, triggering factors such as hormonal changes and commonly used drugs induce an overproduction and accumulation of toxic haem precursors in the liver. Clinically, this presents as acute attacks characterised by severe abdominal pain and a wide array of neurological and psychiatric symptoms, and, in the long-term setting, the development of primary liver cancer, hypertension and kidney failure. Treatment options are few, and therapies preventing the development of symptomatic disease and long-term complications are non-existent. Here, we provide an overview of the disorder and treatments already in use in clinical practice, in addition to other therapies under development or in the pipeline. We also introduce the pathomechanistic effects of HMBS mutations, and present and discuss emerging therapeutic options based on HMBS stabilisation and the regulation of proteostasis. These are novel mechanistic therapeutic approaches with the potential of prophylactic correction of the disease by totally or partially recovering the enzyme functionality. The present scenario appears promising for upcoming patient-tailored interventions in AIP.

[15] Neurofilament light chain as a biomarker for acute hepatic porphyrias

Authors: Paulo Sgobbi, P. Serrano, Bruno Mattos Lombardi Badia, I. Farias, Hélvia Bertoldo de Oliveira et al.
Year: 2024
Venue: Frontiers in Neurology
URL: https://www.semanticscholar.org/paper/3e916d18c6a85cad72dc9e9083738d946f03b670
DOI: 10.3389/fneur.2024.1384678
PMID: 38715693
PMCID: 11075149
Citations: 2
Summary: This study represents the first to establish NfL as a biomarker for AHP, disclosing NfL as a sensitive biomarker for axonal damage and chronic symptom occurrence and reinforces the progressive and profoundly debilitating nature of acute and chronic symptoms observed in individuals with AHP.
Evidence snippets:
Snippet 1 (score: 0.447) > Hereditary porphyrias are a rare group of inherited metabolic disorders due to dysfunction in the heme biosynthesis pathway. They can be classified depending on the principal site of accumulation of toxic intermediates, either as erythropoietic or hepatic. Additionally, they can be categorized based on clinical manifestations as acute porphyrias, characterized by neurovisceral attacks, or chronic porphyrias, which involve prominent cutaneous manifestations in photo exposed skin areas (1,2). > Acute hepatic porphyrias (AHPs) represents a rare group of four inherited metabolic disorders: acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), with autosomal dominant trait inheritance caused by variants in the genes HBMS, PPOX and CPOX. These genes are responsible for encoding the porphobilinogen deaminase, protoporphyrinogen oxidase and coproporphyrinogen oxidase enzymes, respectively. Additionally, ALA (delta-aminolevulinic acid) dehydratase deficiency porphyria (also known as ALAD deficiency or Doss porphyria) is an autosomal recessive disease caused by biallelic variants on ALAD gene, which is responsible for the production of delta-aminolevulinate dehydratase enzyme (1,2). > AHPs are clinically characterized by life-threatening neurological manifestations that can occur either acutely or chronically, resulting in debilitating and progressive neurological impairment. The burden of these manifestations negatively impacts the quality of life (QoL) of patients. In addition, AHPs are associated with severe long-term complications such as hepatocellular carcinoma, chronic kidney disease and hypertension (1,2). > In AHPs, there is a pronounced overproduction of porphyrins in the liver, leading to the abnormal accumulation of toxic intermediate metabolites, primarily porphobilinogen (PBG) and ALA. This accumulation results in significant dysfunction of the nervous system through multiple mechanisms.

[16] Pathogenesis and clinical management of liver damage in porphyrias: Mechanisms and therapeutic approaches

Authors: Tao Zeng, Shuying Huang, Jian-ning Chen, Jia-Hui Pang, Yu-tian Chong et al.
Year: 2025
Venue: World Journal of Hepatology
URL: https://www.semanticscholar.org/paper/f3a1387e017ff27726ef71cb1e06dabf39201813
DOI: 10.4254/wjh.v17.i9.107705
PMID: 41024869
PMCID: 12476770
Summary: This review summarizes the pathophysiology, clinical manifestations, and diagnostic approaches for porphyria-associated liver injury, highlighting emerging therapies with the potential to improve patient outcomes.
Evidence snippets:
Snippet 1 (score: 0.440) > Porphyria refers to a group of rare inherited metabolic disorders caused by enzymatic deficiencies in the heme biosynthesis pathway. These deficiencies lead to the pathological accumulation of neurotoxic porphyrin precursors, resulting in multisystem damage. Currently, there are no curative therapeutic interventions, and patients frequently experience severe morbidity or life-threatening complications. Among the most critical manifestations is protoporphyric liver disease, in which hepatotoxic porphyrins and their precursors drive progressive hepatic injury and cholestasis. Persistent elevation of these metabolites can lead to irreversible parenchymal damage, significantly affecting both quality of life and long-term prognosis. The clinical presentation of porphyria-associated liver injury is highly variable and often has an insidious onset. However, a subset of patients may experience rapid progression to acute liver failure or fulminant hepatic dysfunction. Diagnosis is based on clinical evaluation and is confirmed by genetic testing. Current treatment strategies are focused on symptom management while underlying disease mechanisms remain unaddressed, posing significant therapeutic challenges. This review summarizes the pathophysiology, clinical manifestations, and diagnostic approaches for porphyria-associated liver injury, highlighting emerging therapies with the potential to improve patient outcomes.

[17] EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks

Authors: L. Gouya, P. Ventura, M. Balwani, D. Bissell, D. Rees et al.
Year: 2018
Venue: Hepatology (Baltimore, Md.)
URL: https://www.semanticscholar.org/paper/9f5626b78e6dc16ca3c12c86393c58bccb49f85b
DOI: 10.1002/hep.30936
PMID: 31512765
PMCID: 7255459
Citations: 138
Influential citations: 6
Summary: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis that can experience acute neurovisceral attacks, debilitating chronic symptoms, and long‐term complications.
Evidence snippets:
Snippet 1 (score: 0.440) > Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long‐term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients.

[18] A novel mutation c.457C > T p.Q153 in the HMBS gene in a Mexican woman with acute intermittent porphyria

Authors: J. Malagón-Rangel, J. G. Solís, Luis Fernando Zavala-Jonguitud, M. R. Basile-Álvarez, A. Malagón-Liceaga
Year: 2023
Venue: Clinical Case Reports
URL: https://www.semanticscholar.org/paper/7f4a2005f9788af7d51cb434fd625cee8e70ff28
DOI: 10.1002/ccr3.8100
PMID: 37900716
PMCID: 10600359
Summary: The detection of a novel HMBS gene mutation (c.457C > T) in a Mexican woman with acute intermittent porphyria underscores the importance of expanding genetic analyses in diverse populations to improve diagnosis, management, and knowledge of the disease's clinical implications.
Evidence snippets:
Snippet 1 (score: 0.438) > Acute intermittent porphyria (AIP) represents an autosomal dominant disorder stemming from a partial deficiency in the enzymatic activity of porphobilinogen deaminase, which is also referred to as hydroxymethylbilane synthase (HMBS), the third enzyme involved in the synthesis of heme. This deficiency leads to the accumulation of toxic heme metabolites, namely aminolevulinic acid (ALA), and porphobilinogen (PBG). 1 The precise mechanisms through which porphyrin precursors trigger the symptoms of AIP are not fully understood. 1,2 IP presents with a range of clinical manifestations that can be categorized into three distinct phases: the prodromal phase, the symptom phase, and the neurological phase. Prominent clinical symptoms include the occurrence of acute neurovisceral episodes, marked by intense abdominal pain, mental disturbances, and heightened sympathetic activity. 2 cute attacks of porphyria can be precipitated by a range of factors, comprising alcohol ingestion, stress, fasting, menstruation, surgical procedures, infection, and the administration of certain drugs. 1,3 Preliminary assessment for AIP involves the detection of markedly elevated porphyrin levels in urinary, stool or serum during an acute attack, followed by subsequent genetic analysis to confirm the presence of HMBS gene mutations. 4 The management of AIP encompasses a comprehensive approach that includes the management of acute attacks, prevention of future episodes, long-term monitoring, and the treatment of associated complications. 2 Among the various acute porphyrias, AIP is recognized as a prevalent condition on a global scale, being both the most common and severe form among the acute hepatic porphyrias. 5 AIP affects both males and females, however, in the context of AIP episodes, females tend to experience more severe impacts in terms of higher frequencies of attacks, longer durations of attacks, and an increased likelihood of requiring hospitalization. 6 he HMBS gene is situated at the chromosomal position 11q23.3 and has been linked to more than 400 pathogenic mutations. 5 Individuals harboring pathogenic variants of the HMBS gene, regardless of their symptomatic or latent status, are prone to experiencing acute attacks.

[19] Use of intrathecal drug infusion pump with combined morphine and bupivacaine medication for the treatment of abdominal pain due to Acute Intermittent Porphyria (AIP)

Authors: R. D. De Oliveira, R. F. Souza, Rômulo Sarrazin De Andrade, Larissa de Oliveira Campelo, Fabiana Dantas et al.
Year: 2022
Venue: Brazilian Journal of Case Reports
URL: https://www.semanticscholar.org/paper/2c00fec1548d1c2dc80b2796039a44f0d4b230bb
DOI: 10.52600/2763-583x.bjcr.2023.3.1.4-9
Summary: A 32-years-old Woman presented with severe and continual abdominal pain, described by the patient as the worst pain she has ever felt in her life, colic type in the mesogastric area and that radiated throughout the entire abdomen for six months is described.
Evidence snippets:
Snippet 1 (score: 0.434) > Porphyrias consist of nine genetic disorders, acquired or congenital, resulting from failures in the biosynthesis process of the heme group, resulting in the accumulation of metabolic intermediates in the human body, causing toxicity [1]. The heme group is indispensable for the performance of oxidation-reduction reactions, in addition to being essential for the functionality of several enzymes and proteins related to energy metabolism. Thus, porphyrias are conditions that contribute to increased production of products from heme synthesis, such as 5-aminolevulinic acid (ALA), porphobilinogen (PBG) and porphyrins [2], which are present in blood, urine and feces. There is also the possibility of pathological deposition in tissues and organs [3]. Porphyrias can be classified as hepatic or erythropoietic, depending on whether porphyrins accumulate in the liver or bone marrow, or acute and cutaneous, depending on the clinical features of the disease [4,5]. > In most countries, such as the United States, a genetic prevalence of porphyria is estimated in the order of 1/10.000 individuals, while the manifestation of the aforementioned disease, in the USA, is approximately 5/100.000 inhabitants, with no indication of seasonal predominance in the incidence of porphyria [6]. Patients affected by this condition may present, as symptoms, neurological dysfunctions (neuropathies, alternations in the level of consciousness, seizures and behavioral abnormalities), neurovisceral alterations (gastrointestinal symptoms) and cutaneous manifestations (cutaneous photosensitivity and hemolysis) [1]. > Acute intermittent porphyria (AIP), a hepatic form of porphyria and the most common form of porphyria, is an autosomal dominant and hereditary disease caused by successive mutations in the hydroxymethylbilane synthase (HMB-synthase) gene, responsible for the conversion of porphobilinogen to hydroxymethylbilane within the heme biosynthesis pathway, culminating in the accumulation of substrates, such as PBG and deltaaminolevulinic acid, in the liver [4].

[20] Porphyria Cutanea Tarda: A Phenotypic Expression of Several Genes

Authors: Sebastián J Vázquez-Folch, Gabriel A Jiménez-Berríos, N. Izquierdo, Victor J Vazquez
Year: 2025
Venue: Cureus
URL: https://www.semanticscholar.org/paper/c34bbf568bf2728a38f62f1e9295ca644ffb4251
DOI: 10.7759/cureus.83955
PMID: 40510110
PMCID: 12158825
Summary: This study presents three cases of porphyria in Puerto Rico, including erythropoietic protoporphyria (EPP) and porphyria cutanea tarda (PCT), and reveals a heterozygous mutation in the FECH gene in the EPP case and an HFE gene mutation in a PCT case with hereditary hemochromatosis.
Evidence snippets:
Snippet 1 (score: 0.423) > Porphyria is a group of rare inherited or acquired disorders resulting from the malfunction of the heme biosynthetic pathway, leading to the accumulation of porphyrins or their precursors [1,2]. The heme biosynthetic pathway is crucial for the production of heme, an essential component of hemoglobin, myoglobin, and various cytochromes [3]. Defects in this pathway may result in a variety of clinical manifestations, including the skin and nervous system [4]. > Porphyrias are classified and include erythropoietic protoporphyria (EPP), porphyria cutanea tarda (PCT), acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and congenital erythropoietic porphyria [5]. > EPP is primarily caused by autosomal recessive mutations in the FECH gene, which encodes the enzyme ferrochelatase [6]. This enzyme is responsible for the last step in heme production, where iron is inserted into protoporphyrin IX to form heme [7]. A deficiency in ferrochelatase leads to the accumulation of protoporphyrin IX in erythrocytes, plasma, and tissues. Patients with EPP typically have photosensitivity, experiencing burning pain and erythema upon exposure to sunlight. Upon chronicity, the disease may lead to liver complications due to the buildup of protoporphyrins in the bile [6]. > PCT is the most common type of porphyria and is usually acquired, although it may also have a genetic inheritance. PCT is characterized by a deficiency in the enzyme uroporphyrinogen decarboxylase (UROD), which leads to the accumulation of uroporphyrins in the liver, plasma, and skin [8]. This accumulation causes photosensitivity, resulting in painful blistering, fragility, and hyperpigmentation of sun-exposed skin areas [9]. PCT can be associated with liver dysfunction and iron overload, and it is often linked with genetic variants such as mutations in the HFE gene, leading to hereditary hemochromatosis [10].

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Acute Intermittent Porphyria. Core disease mechanisms, molecular and cellu...

Relevant Papers

[1] Porphyrias in the Age of Targeted Therapies

[2] European porphyria initiative (EPI): a platform to develop a common approach to the management of porphyrias and to promote research in the field.

[3] Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications

[4] Orphan Peripheral Neuropathies

[5] ALAD Inhibition by Porphobilinogen Rationalizes the Accumulation of δ-Aminolevulinate in Acute Porphyrias

[6] An easily overlooked disease in the early stages: acute intermittent porphyria

[7] Acute hepatic porphyria - classification, diagnosis and treatment

[8] Self-efficacy and self-management strategies in acute intermittent porphyria

[9] Renal Failure Affects the Enzymatic Activities of the Three First Steps in Hepatic Heme Biosynthesis in the Acute Intermittent Porphyria Mouse

[10] Recent advances in the epidemiology and genetics of acute intermittent porphyria.

[11] Current Understanding on the Genetic Basis of Key Metabolic Disorders: A Review

[12] Nutritional Interventions with Bacillus coagulans Improved Glucose Metabolism and Hyperinsulinemia in Mice with Acute Intermittent Porphyria

[13] Clinical, Biochemical and Molecular Characteristics of the Main Types of Porphyria.

[14] Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators

[15] Neurofilament light chain as a biomarker for acute hepatic porphyrias

[16] Pathogenesis and clinical management of liver damage in porphyrias: Mechanisms and therapeutic approaches

[17] EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks

[18] A novel mutation c.457C > T p.Q153 in the HMBS gene in a Mexican woman with acute intermittent porphyria

[19] Use of intrathecal drug infusion pump with combined morphine and bupivacaine medication for the treatment of abdominal pain due to Acute Intermittent Porphyria (AIP)

[20] Porphyria Cutanea Tarda: A Phenotypic Expression of Several Genes

Notes