Acute Intermittent Porphyria

Mendelian MONDO:0008294 Pathograph 24 Metabolic Disease Inborn Error of Metabolism

Acute intermittent porphyria (AIP) is an autosomal dominant acute hepatic porphyria caused by partial deficiency of hydroxymethylbilane synthase (HMBS), the third enzyme in heme biosynthesis. Attack susceptibility emerges when hepatic ALAS1 is induced by porphyrogenic triggers such as drugs, fasting, alcohol, and infection, driving excess production of 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) upstream of the HMBS block. Clinically, AIP presents with episodic severe abdominal pain and other neurovisceral manifestations including autonomic dysfunction, neuropathy, and weakness. Intravenous hemin remains standard therapy for severe attacks, and givosiran provides mechanism-directed prophylaxis for patients with recurrent attacks.

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1
Inheritance
4
Pathophys.
10
Phenotypes
2
Hypotheses
24
Pathograph
1
Genes
6
Treatments
1
Trials
1
References
1
Deep Research
2
Hyp. Reports
👪

Inheritance

1
Autosomal dominant HP:0000006
AIP is inherited as an autosomal dominant disorder with low clinical penetrance.
Autosomal dominant inheritance
Show evidence (1 reference)
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.
◈

Mechanistic Hypotheses

2
Canonical Hepatic Precursor Overproduction Model
canonical_hepatic_precursor_overproduction_model CANONICAL
Partial HMBS deficiency becomes clinically pathogenic when hepatic ALAS1 is induced, leading to excess upstream precursor synthesis and export.
Retained as CANONICAL. The 2026 openscientist hypothesis-search report (kb/hypotheses/Acute_Intermittent_Porphyria/canonical_hepatic_precursor_overproduction_model) reviewed 45 papers and found the model robustly validated by the givosiran ENVISION trial (74% attack-rate reduction with ALAS1 silencing), orthotopic liver transplant biochemistry, and PGC-1α identification as the molecular link between fasting/drug triggers and ALAS1 induction. Three qualifications expand the model: (1) ALAS1-driven succinyl-CoA withdrawal causes hepatic TCA cataplerosis with ~50% reductions in respiratory-chain complexes I-III activity, revealing a downstream energetic consequence beyond precursor accumulation; (2) population penetrance is far lower (~0.5-1%) than in AIP families (22.9%), implicating modifier genes and an oligogenic inheritance model; (3) chronic precursor elevation shows a quantitative dose-response with hepatocellular-carcinoma risk (86-fold elevation in AIP cohorts) operating largely through a non-cirrhotic pathway, likely driven by ALA-mediated oxidative DNA damage.
Deep research
OpenScientist citations 21 citations 2026-05-23T03:52:27.508544
Show evidence (8 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 canonical upstream HMBS defect plus compensatory ALAS1 induction model that drives AIP biochemistry.
PMID:32521132 SUPPORT Human Clinical
"74% lower rate in the givosiran group"
Pivotal Phase 3 ENVISION trial: silencing hepatic ALAS1 mRNA with givosiran reduces the annualized attack rate by 74% while sustainably lowering urinary ALA and PBG, providing direct pharmacological proof that hepatic ALAS1 induction is the proximate trigger of AIP attacks.
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.
+ 5 more references
Canonical Precursor Neurotoxicity Model
canonical_precursor_neurotoxicity_model CANONICAL
Acute attacks are attributed to accumulation of the neurotoxic precursors ALA and PBG rather than to generalized hepatic heme deficiency alone.
Retained as CANONICAL. The 2026 openscientist hypothesis-search report (kb/hypotheses/Acute_Intermittent_Porphyria/canonical_precursor_neurotoxicity_model) reviewed 59 papers and confirmed precursor neurotoxicity as the best- validated framework for AIP pathogenesis, supported by (1) liver transplantation (immediate attack cessation upon hepatic source removal), (2) givosiran ENVISION trial (74-97% attack reduction across 6-48 months), (3) mouse models proving that hepatic — not erythroid — PBGD deficiency causes the disease and that liver-directed gene therapy prevents motor neuropathy. Two molecular mechanisms are proposed but neither definitively established at physiological concentrations: GABA-A receptor mimicry (IC50 ~200 µM for ALA inhibition of [3H]muscimol binding) and oxidative-stress/mitochondrial dysfunction. A key mechanistic gap is the low adult BBB permeability to ALA, which limits CNS access via direct diffusion but is bypassed by carrier-mediated choroid-plexus transport and locally produced precursors in severe (homozygous) genotypes.
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 that hepatic precursors are the source of motor neuropathy.
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, not erythroid, PBGD deficiency as the pathogenic locus.
+ 3 more references
⚙

Pathophysiology

4
HMBS deficiency in hepatocytes
Pathogenic HMBS variants reduce hepatic hydroxymethylbilane synthase activity, creating a partial block at the third enzymatic step of heme biosynthesis.
hepatocyte link
HMBS link
heme biosynthetic process link ↓ DECREASED
hydroxymethylbilane synthase activity link ↓ DECREASED
liver link
Downstream
Triggered hepatic ALAS1 induction The partial HMBS block creates attack susceptibility when hepatic ALAS1 is induced by physiologic or environmental stressors.
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.
hepatocyte link
ALAS1 link
heme biosynthetic process link ↑ INCREASED
5-aminolevulinate synthase activity link ↑ INCREASED
liver link
Downstream
Hepatic ALA and PBG accumulation Increased ALAS1-driven upstream flux leads to overproduction of ALA and PBG across the partial HMBS block.
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 Human Clinical
"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 directly ties acute attack biology to hepatic ALAS1 induction in the setting of HMBS deficiency.
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.
hepatocyte link
heme biosynthetic process link ↕ DYSREGULATED
liver link
Downstream
Urinary 5-aminolevulinic acid Hepatic overproduction and systemic spillover of ALA produces increased urinary ALA during acute attacks.
Urinary porphobilinogen Hepatic overproduction and systemic spillover of PBG produces increased urinary PBG during acute attacks.
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 Excess precursor burden is linked to acute autonomic, peripheral, and central neurologic dysfunction.
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 identifies ALA and PBG accumulation as the proximate toxic biochemical lesion driving clinical disease.
Neurovisceral attack susceptibility
Acute attacks manifest as abdominal pain and neurologic dysfunction, including motor-predominant neuropathy and severe weakness.
Downstream
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.
Tachycardia Autonomic overactivity during attacks produces tachycardia and other dysautonomic manifestations.
Peripheral neuropathy Acute hepatic porphyria attacks can progress to motor-predominant porphyric neuropathy.
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 Autonomic overactivity during attacks can produce hypertension alongside tachycardia.
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.
Show evidence (2 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 review directly 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.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Acute Intermittent Porphyria Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Cardiovascular 2
Tachycardia 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 Hypertension (HP:0000822)
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 hypertension during acute AIP attacks.
Digestive 1
Nausea and vomiting 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.
Metabolism 1
Hyponatremia 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 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 3
Peripheral neuropathy 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 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 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.
Constitutional 1
Abdominal pain 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.
Other 1
Tetraparesis 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.
🧬

Genetic Associations

1
HMBS (Causative)
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
"HMBS | HGNC:4982 | acute intermittent porphyria | MONDO:0008294 | SD | Definitive"
ClinGen classifies the HMBS-acute intermittent porphyria gene-disease relationship as definitive with semidominant inheritance.
💊

Treatments

6
Intravenous hemin
Action: Pharmacotherapy NCIT:C15986
Agent: hemin ↗
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 Human Clinical
"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 ↗
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 toxic precursor burden.
Show evidence (1 reference)
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 evidence supports givosiran as an effective disease-modifying prophylactic therapy for recurrent attacks.
Prophylactic hemin infusion
Action: Pharmacotherapy NCIT:C15986
Agent: hemin ↗
Scheduled hemin infusion is an alternative prophylactic therapy to reduce frequency or severity of recurrent acute attacks when givosiran is not available.
Mechanism Target:
INHIBITS Triggered hepatic ALAS1 induction — Repeated hemin exposure provides negative feedback on hepatic ALAS1 to prevent recurrent attack biochemistry.
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 prophylactic hemin infusion as an attack-reducing alternative therapy when givosiran is unavailable.
INHIBITS Hepatic ALA and PBG accumulation — By suppressing ALAS1-driven pathway flux, prophylactic hemin reduces the precursor-accumulation branch that drives acute attacks.
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."
The GeneReviews attack-reduction statement supports an inhibitory link to the hepatic precursor-accumulation branch.
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 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.
Ovulation suppression
Action: Pharmacotherapy NCIT:C15986
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: organ transplantation MAXO:0010039
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: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 frames liver transplantation as curative for severe recurrent AIP attacks, supporting restoration of the hepatic disease source.
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: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."
Curative transplantation for repeated life-threatening attacks supports an inhibitory link to the hepatic precursor-accumulation branch.
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: dietary intervention MAXO:0000088
High-carbohydrate intake is used as adjunctive therapy during milder attacks but is usually insufficient alone for serious episodes.
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 PARTIAL Human Clinical
"Glucose administration, in contrast to heme therapy, was not sufficient to achieve clinical and biochemical remission in the more serious attacks."
This adds the clinically important limitation that carbohydrate therapy is not sufficient 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.
Show evidence (1 reference)
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.
🔬

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.
🔬

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.
{ }

Source YAML

click to show 
name: Acute Intermittent Porphyria
creation_date: '2026-04-21T04:42:02Z'
updated_date: '2026-05-20T20:01:55Z'
category: Mendelian
synonyms:
- AIP
description: >-
  Acute intermittent porphyria (AIP) is an autosomal dominant acute hepatic
  porphyria caused by partial deficiency of hydroxymethylbilane synthase
  (HMBS), the third enzyme in heme biosynthesis. Attack susceptibility emerges
  when hepatic ALAS1 is induced by porphyrogenic triggers such as drugs,
  fasting, alcohol, and infection, driving excess production of
  5-aminolevulinic acid (ALA) and porphobilinogen (PBG) upstream of the HMBS
  block. Clinically, AIP presents with episodic severe abdominal pain and other
  neurovisceral manifestations including autonomic dysfunction, neuropathy, and
  weakness. Intravenous hemin remains standard therapy for severe attacks, and
  givosiran provides mechanism-directed prophylaxis for patients with 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.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  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.
prevalence:
- population: Asymptomatic heterozygous carriers in population studies
  percentage: 1 in 2,000
  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.
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: >-
    Retained as CANONICAL. The 2026 openscientist hypothesis-search report
    (kb/hypotheses/Acute_Intermittent_Porphyria/canonical_hepatic_precursor_overproduction_model)
    reviewed 45 papers and found the model robustly validated by the
    givosiran ENVISION trial (74% attack-rate reduction with ALAS1
    silencing), orthotopic liver transplant biochemistry, and PGC-1α
    identification as the molecular link between fasting/drug triggers and
    ALAS1 induction. Three qualifications expand the model: (1)
    ALAS1-driven succinyl-CoA withdrawal causes hepatic TCA cataplerosis
    with ~50% reductions in respiratory-chain complexes I-III activity,
    revealing a downstream energetic consequence beyond precursor
    accumulation; (2) population penetrance is far lower (~0.5-1%) than in
    AIP families (22.9%), implicating modifier genes and an oligogenic
    inheritance model; (3) chronic precursor elevation shows a quantitative
    dose-response with hepatocellular-carcinoma risk (86-fold elevation in
    AIP cohorts) operating largely through a non-cirrhotic pathway, likely
    driven by ALA-mediated oxidative DNA damage.
  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 canonical upstream HMBS defect plus compensatory ALAS1
      induction model that drives AIP biochemistry.
  - reference: PMID:32521132
    reference_title: "Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "74% lower rate in the givosiran group"
    explanation: >
      Pivotal Phase 3 ENVISION trial: silencing hepatic ALAS1 mRNA with
      givosiran reduces the annualized attack rate by 74% while sustainably
      lowering urinary ALA and PBG, providing direct pharmacological proof
      that hepatic ALAS1 induction is the proximate trigger of AIP attacks.
  - 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.
  - reference: PMID:24727425
    reference_title: "Acute intermittent porphyria causes hepatic mitochondrial energetic failure in a mouse model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "cataplerosis of the TCA cycle induced by phenobarbital, caused by the massive withdrawal of succinyl-CoA by ALAS induction"
    explanation: >
      Extends the canonical model by showing that ALAS1 hyperactivity
      withdraws succinyl-CoA from the TCA cycle, impairing respiratory-
      chain complexes I-III by ~50% — a downstream energetic consequence of
      ALAS1 induction beyond simple precursor accumulation.
  - reference: PMID:29360981
    reference_title: "From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria."
    supports: PARTIAL
    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: >
      Qualifies the simple autosomal dominant model by demonstrating
      strikingly different penetrance in AIP families (22.9%) versus the
      general population (0.5-1%) — implicating oligogenic inheritance
      with environmental modifiers as critical determinants of clinical
      expression.
  - 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: "None of the 28 patients with all registered samples below the upper limit of normal (ULN) developed PLC"
    explanation: >
      Dose-response relationship between chronic precursor excretion and
      primary liver cancer risk (none of 28 patients with normal ALA/PBG
      developed PLC), directly linking the canonical precursor-overproduction
      model to a quantitative long-term carcinogenesis outcome.
  - reference: PMID:23344888
    reference_title: "High risk of primary liver cancer in a cohort of 179 patients with Acute Hepatic Porphyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall relative risk of primary liver cancer was 86"
    explanation: >
      Swedish cohort confirms an 86-fold relative risk of primary liver
      cancer in AIP — largely without underlying cirrhosis — consistent
      with the canonical model's prediction that chronic precursor exposure
      drives a distinct, non-cirrhotic hepatocarcinogenic pathway.
- hypothesis_group_id: canonical_precursor_neurotoxicity_model
  hypothesis_label: Canonical Precursor Neurotoxicity Model
  status: CANONICAL
  description: >-
    Acute attacks are attributed to accumulation of the neurotoxic precursors
    ALA and PBG rather than to generalized hepatic heme deficiency alone.
  notes: >-
    Retained as CANONICAL. The 2026 openscientist hypothesis-search report
    (kb/hypotheses/Acute_Intermittent_Porphyria/canonical_precursor_neurotoxicity_model)
    reviewed 59 papers and confirmed precursor neurotoxicity as the best-
    validated framework for AIP pathogenesis, supported by (1) liver
    transplantation (immediate attack cessation upon hepatic source
    removal), (2) givosiran ENVISION trial (74-97% attack reduction across
    6-48 months), (3) mouse models proving that hepatic — not erythroid —
    PBGD deficiency causes the disease and that liver-directed gene therapy
    prevents motor neuropathy. Two molecular mechanisms are proposed but
    neither definitively established at physiological concentrations: GABA-A
    receptor mimicry (IC50 ~200 µM for ALA inhibition of [3H]muscimol
    binding) and oxidative-stress/mitochondrial dysfunction. A key
    mechanistic gap is the low adult BBB permeability to ALA, which limits
    CNS access via direct diffusion but is bypassed by carrier-mediated
    choroid-plexus transport and locally produced precursors in severe
    (homozygous) genotypes.
  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 that hepatic
      precursors are the source of motor neuropathy.
  - 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, not erythroid,
      PBGD deficiency as the pathogenic locus.
  - reference: PMID:11478735
    reference_title: "5-Aminolevulinic acid inhibits [3H]muscimol binding to human and rat brain synaptic membranes."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "ALA (0.1-10 mM) significantly inhibited the binding"
    explanation: >
      In vitro evidence that ALA binds GABA-A receptors (inhibiting
      [3H]muscimol binding with IC50 of ~199-228 µM) provides a candidate
      molecular mechanism for the autonomic and neuropsychiatric features
      of acute attacks, but this mechanism is not definitively established
      at physiologically relevant in vivo concentrations.
  - reference: PMID:12493610
    reference_title: "Transport of 5-aminolevulinic acid between blood and brain."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "uptake into the neonatal brain was 7-fold higher than in the adult"
    explanation: >
      Identifies a key mechanistic gap: ALA has low BBB permeability in
      adult rats (~3-fold less than mannitol) but enters the CSF via
      carrier-mediated transport at the choroid plexus, and neonatal BBB
      permeability is 7-fold higher — partly explaining the predominance
      of peripheral (not CNS) symptoms in classical AIP and the severe CNS
      manifestations in pediatric homozygous AIP.
  - 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: >
      Homozygous HMBS R167Q mice with ~5% residual activity show locally
      elevated ALA/PBG in CSF/CNS and severe ataxia with delayed myelination,
      while heterozygous T1/T2 mice given phenobarbital accumulate
      precursors in liver/plasma but NOT in the CNS — distinguishing the
      pathogenesis of heterozygous AIP (peripheral, hepatic-precursor-
      driven) from homozygous AIP (CNS-intrinsic precursor production).
pathophysiology:
- name: HMBS deficiency in hepatocytes
  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: DECREASED
  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: Triggered hepatic ALAS1 induction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The partial HMBS block creates attack susceptibility when hepatic ALAS1 is
      induced by physiologic or environmental stressors.
    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: HUMAN_CLINICAL
      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: >-
        Human recurrent-AIP study background directly ties acute attack biology
        to hepatic ALAS1 induction in the setting of HMBS deficiency.
- 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: INCREASED
  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: HUMAN_CLINICAL
    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 directly ties acute attack biology to hepatic ALAS1 induction in the
      setting of HMBS deficiency.
  downstream:
  - target: Hepatic ALA and PBG accumulation
    causal_link_type: DIRECT
    description: >-
      Increased ALAS1-driven upstream flux leads to overproduction of ALA and
      PBG across the partial HMBS block.
    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
  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
  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 identifies ALA and PBG accumulation as the proximate toxic
      biochemical lesion driving clinical disease.
  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: 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: 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_KNOWN_INTERMEDIATES
    description: >-
      Excess precursor burden is linked to acute autonomic, peripheral, and
      central neurologic dysfunction.
    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: >-
        Review evidence supports accumulated ALA and PBG as the upstream driver
        of acute hepatic porphyria manifestations.
- name: Neurovisceral attack susceptibility
  description: >-
    Acute attacks manifest as abdominal pain and neurologic dysfunction,
    including motor-predominant neuropathy and severe weakness.
  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 review directly 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.
  downstream:
  - target: Abdominal pain
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - autonomic and visceral pain pathways during acute neurovisceral crises
    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_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - gastrointestinal involvement during acute AIP episodes
    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: Tachycardia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - autonomic overactivity during acute attacks
    description: >-
      Autonomic overactivity during attacks produces tachycardia and other
      dysautonomic manifestations.
    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_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - acute to subacute motor-predominant axonal porphyric neuropathy
    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: 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_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - autonomic overactivity during acute attacks
    description: >-
      Autonomic overactivity during attacks can produce hypertension alongside
      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: >-
        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.
phenotypes:
- 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: >-
    Acute attacks can feature autonomic overactivity with hypertension alongside
    tachycardia.
  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.
- 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.
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
  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
  notes: >-
    Drugs, alcohol, low caloric intake or fasting, and infections can precipitate
    acute attacks by increasing hepatic pathway demand.
  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.
treatments:
- 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.
  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: HUMAN_CLINICAL
      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.
  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 toxic precursor burden.
  evidence:
  - 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 evidence supports givosiran as an effective
      disease-modifying prophylactic therapy 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.
  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: >-
      Repeated hemin exposure provides negative feedback on hepatic ALAS1 to
      prevent recurrent attack biochemistry.
    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 prophylactic hemin infusion as an attack-reducing
        alternative therapy when givosiran is unavailable.
  - target: Hepatic ALA and PBG accumulation
    treatment_effect: INHIBITS
    description: >-
      By suppressing ALAS1-driven pathway flux, prophylactic hemin reduces the
      precursor-accumulation branch that drives acute attacks.
    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: >-
        The GeneReviews attack-reduction statement supports an inhibitory link
        to the hepatic precursor-accumulation branch.
  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.
- 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: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  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.
  treatment_term:
    preferred_term: liver transplantation
    term:
      id: MAXO:0010039
      label: organ 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: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 frames liver transplantation as curative for severe
        recurrent AIP attacks, supporting restoration of the hepatic disease
        source.
  - 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: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: >-
        Curative transplantation for repeated life-threatening attacks supports
        an inhibitory link to the hepatic precursor-accumulation branch.
  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.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  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: PARTIAL
    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 adds the clinically important limitation that carbohydrate therapy is
      not sufficient in more severe attacks.
diagnosis:
- name: Urinary ALA and PBG measurement
  diagnosis_term:
    preferred_term: urine chemistry measurement
    term:
      id: MAXO:0000789
      label: urine chemistry measurement
  description: >-
    Quantification of urinary ALA and PBG during symptoms helps confirm an acute
    porphyric attack and track biochemical response to treatment.
  results: Elevated urinary ALA and PBG support the diagnosis of active 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: >-
      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.
- name: Molecular genetic testing
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
    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 sequencing confirms the inherited diagnosis and is especially useful
    when biochemical testing or enzyme assays are equivocal.
  results: A pathogenic HMBS variant supports the diagnosis of AIP.
  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: >-
      Detection of DNA variations by molecular techniques allows a diagnosis of
      acute intermittent porphyria in situations where the measurement of
      porphyrins and precursors in urine and faeces and erythrocyte
      hydroxymethylbilane synthase activity is inconclusive.
    explanation: >-
      This directly supports HMBS molecular testing as a confirmatory diagnostic
      approach.
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
    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.
references:
- reference: PMID:20301372
  title: "Acute Intermittent Porphyria."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301372
Acute Intermittent Porphyria.
No top-level findings curated for this source.

Deep Research

1
Asta ▸
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].

Notes

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