🏷

Classifications

Harrison's Chapter

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Inborn disorders of bile acid synthesis are inherited in an autosomal recessive pattern; affected individuals carry homozygous or compound heterozygous pathogenic variants in the relevant enzyme gene.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:37575761 SUPPORT Human Clinical

"Bile acid synthesis disorders (BASD) are a group of rare autosomal recessive disorders."

A clinical case report and literature review states BASD are autosomal recessive.

PMID:33385262 SUPPORT Human Clinical

"had homozygous or compound heterozygous mutations in the HSD3B7, SRD5B1, or CYP7B1 gene"

The Japanese cohort confirms biallelic (homozygous/compound heterozygous) inheritance.

◆

Subtypes

6

3beta-hydroxy-Delta5-C27-steroid oxidoreductase deficiency (HSD3B7, BASD type 1) MONDO:0011906

HSD3B7 hgnc:18324

Deficiency of 3beta-hydroxy-Delta5-C27-steroid oxidoreductase (encoded by HSD3B7) is the most common inborn bile acid synthesis disorder. It blocks an early step of bile acid synthesis, leading to accumulation of 3beta-hydroxy- Delta5 bile acid intermediates and presenting as neonatal/infantile cholestasis with normal GGT, fat-soluble vitamin malabsorption, and failure to thrive. It responds well to oral cholic acid.

Show evidence (2 references)

PMID:39702264 SUPPORT Human Clinical

"3β-Hydroxy-Δ5-C27-steroid oxidoreductase deficiency (n = 62)"

The systematic review of cholic acid treatment identifies 3beta-hydroxy- Delta5-C27-steroid oxidoreductase deficiency as a distinct, well-represented BASD subtype.

PMID:38062451 SUPPORT Human Clinical

"Most reported patients with this treatment have 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency."

Confirms 3beta-HSD (HSD3B7) deficiency is the most common cholic-acid-treated BASD subtype.

Delta4-3-oxosteroid 5beta-reductase deficiency (AKR1D1/SRD5B1, BASD type 2) MONDO:0009339

AKR1D1 hgnc:388

Deficiency of Delta4-3-oxosteroid 5beta-reductase (encoded by AKR1D1, also known as SRD5B1) impairs reduction of 3-oxo-Delta4 bile acid precursors, causing accumulation of 3-oxo-Delta4 and allo (5alpha) bile acids. It typically presents as severe neonatal cholestasis, sometimes with severe bleeding and liver failure, though phenotypic variability including minimally symptomatic carriers is described. It responds to oral cholic acid.

Show evidence (2 references)

PMID:38062451 SUPPORT Human Clinical

"Sixteen patients with Δ4-3-oxo-R deficiency confirmed by AKR1D1 gene sequencing who received oral cholic acid were retrospectively analyzed."

Defines Delta4-3-oxosteroid 5beta-reductase deficiency as an AKR1D1-confirmed BASD subtype treated with cholic acid.

PMID:38034430 SUPPORT Human Clinical

"Δ4-3-Oxosteroid 5β-reductase (AKR1D1) deficiency typically causes severe cholestasis occurs in newborns, leading to death unless patients are treated with primary bile acids."

Confirms the gene (AKR1D1), the typical severe neonatal cholestasis, and bile acid dependence.

Oxysterol 7alpha-hydroxylase deficiency (CYP7B1, BASD type 3) MONDO:0013439

CYP7B1 hgnc:2652

Deficiency of oxysterol 7alpha-hydroxylase (encoded by CYP7B1) blocks the acidic (alternative) pathway of bile acid synthesis, causing accumulation of hepatotoxic 3beta-hydroxy-Delta5 monohydroxy bile acids. It can present as severe, often rapidly progressive infantile cholestasis and liver failure; the same gene can also produce a later-onset hereditary spastic paraplegia phenotype (SPG5), and both phenotypes have been observed within one family. Treatment is with chenodeoxycholic acid; liver transplantation may be needed for advanced infantile liver failure.

Show evidence (2 references)

PMID:31337596 SUPPORT Human Clinical

"three had oxysterol-7α-hydroxylase deficiency with CYP7B1 mutation"

Identifies oxysterol 7alpha-hydroxylase deficiency caused by CYP7B1 mutation as a distinct BASD subtype.

PMID:31337596 SUPPORT Human Clinical

"The only surviving patient with oxysterol 7α-hydroxylase deficiency recovered from liver failure after chenodeoxycholic acid (CDCA) treatment beginning at 3 months of age."

Documents the severe infantile liver failure and CDCA responsiveness of CYP7B1 deficiency.

Alpha-methylacyl-CoA racemase deficiency (AMACR, BASD type 4) MONDO:0008967

AMACR hgnc:451

Deficiency of alpha-methylacyl-CoA racemase (encoded by AMACR) impairs peroxisomal racemization required for bile acid side-chain beta-oxidation and branched-chain fatty acid metabolism. It can present in infancy with cholestasis and fat-soluble vitamin malabsorption, but is distinguished by later, slowly progressive adult neurologic disease (sensory-motor neuropathy, ataxia, cognitive decline) and retinitis pigmentosa, with a risk of liver fibrosis/cirrhosis. It is treated with oral cholic acid and diet modification.

Show evidence (2 references)

PMID:37575761 SUPPORT Human Clinical

"BASD type 4 is characterized by a gene mutation in alpha-methylacyl-CoA racemase (AMACR), which is located on chromosome 5p13."

Defines BASD type 4 as AMACR deficiency.

PMID:37575761 SUPPORT Human Clinical

"In adulthood, patients usually develop neurological sequelae."

Highlights the characteristic adult-onset neurologic disease distinguishing AMACR deficiency.

Sterol 27-hydroxylase deficiency / cerebrotendinous xanthomatosis (CYP27A1) MONDO:0008948

CYP27A1 hgnc:2605

Deficiency of mitochondrial sterol 27-hydroxylase (encoded by CYP27A1) causes cerebrotendinous xanthomatosis (CTX). Loss of CYP27A1 impairs cholesterol side-chain oxidation and chenodeoxycholic acid synthesis, leading to accumulation of cholestanol and bile alcohols with sterol deposition in the CNS and tendons; neurologic disease and tendon xanthomas dominate the phenotype, although infantile cholestasis can occur. The standard treatment is chenodeoxycholic acid. CTX is curated as its own dismech Disease entry (Cerebrotendinous xanthomatosis, MONDO:0008948) and is listed here only to place it within the bile acid synthesis disorder family; it is not duplicated in this umbrella entry.

Show evidence (1 reference)

PMID:39702264 SUPPORT Human Clinical

"cerebrotendinous xanthomatosis (n = 22)"

The systematic review of cholic acid treatment for bile acid synthesis defects includes cerebrotendinous xanthomatosis as a member subtype.

Bile acid amidation/conjugation defect (BAAT) MONDO:0030991

BAAT hgnc:932

Defect in the final amidation (conjugation) of bile acids with glycine or taurine, caused by deficiency of bile acid-CoA:amino acid N-acyltransferase (BAAT), produces neonatal cholestasis with fat-soluble vitamin malabsorption. Unlike the synthetic-enzyme defects, the primary bile acid backbone is made but cannot be properly conjugated, so unamidated bile acids accumulate. Conjugated bile acid replacement has been studied as treatment.

Show evidence (1 reference)

PMID:38646510 SUPPORT Human Clinical

"8 types of IEBAM have been reported to date"

The review enumerates eight types of inborn errors of bile acid metabolism, which include the BAAT amidation/conjugation defect among the bile acid synthesis/metabolism enzyme group.

⚙

Pathophysiology

4

Hepatic Bile Acid Synthetic Enzyme Deficiency

Each inborn bile acid synthesis disorder begins with autosomal recessive loss of function of a single enzyme in the hepatic pathway converting cholesterol to the primary bile acids cholic acid and chenodeoxycholic acid (e.g., HSD3B7, AKR1D1, CYP7B1, CYP27A1) or in the terminal amidation step (BAAT, SLC27A5). The enzyme block is the upstream cause from which all downstream consequences follow.

Hepatocyte CL:0000182

Bile acid biosynthetic process GO:0006699 ↓ DECREASED Cholesterol metabolic process GO:0008203 ⚠ ABNORMAL

Downstream

Loss of Primary Bile Acids and Accumulation of Toxic Intermediates The enzyme block both prevents synthesis of normal primary bile acids and causes the substrate of the missing enzyme to accumulate as atypical bile acid intermediates.

Show evidence (1 reference)

PMID:33385262 SUPPORT Human Clinical

"7 Japanese patients with bile acid synthesis disorders (BASD) including 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (3β-HSD) deficiency"

Establishes that BASD are caused by specific enzyme deficiencies in the bile acid synthetic pathway.

Loss of Primary Bile Acids and Accumulation of Toxic Intermediates

The enzyme deficiency produces a dual lesion: reduced or absent normal primary bile acids (cholic and chenodeoxycholic acid) and accumulation of atypical, often C27, bile acid intermediates that are hepatotoxic and cholestatic. Because routine serum total bile acid assays detect only 3alpha-hydroxylated bile acids, the abnormal intermediates are frequently missed, and patients can show cholestasis with normal or low measured serum total bile acids and normal GGT.

Hepatocyte CL:0000182

Downstream

Cholestasis and Progressive Liver Injury Toxic intermediates and impaired bile flow injure hepatocytes and bile canaliculi, producing cholestasis that can progress to fibrosis, cirrhosis, and liver failure if untreated.

Fat and Fat-Soluble Vitamin Malabsorption Reduced primary bile acid pool impairs intestinal micelle formation, reducing absorption of dietary fat and fat-soluble vitamins.

Show evidence (1 reference)

PMID:39702264 SUPPORT Human Clinical

"Bile acid synthesis defects (BASDs) can be severely disabling involving the liver and nervous system, potentially due to elevated levels of toxic C27-bile acid intermediates."

Directly supports accumulation of toxic C27 bile acid intermediates as the mechanism of liver and nervous system injury.

Cholestasis and Progressive Liver Injury

Impaired bile flow and hepatotoxic intermediates produce cholestasis. The cholestasis is biochemically distinctive: normal gamma-glutamyltransferase (GGT) and normal or low serum total bile acids despite cholestasis, often without pruritus, which distinguishes bile acid synthesis disorders from biliary atresia and other cholestatic diseases. Untreated, the process can advance to cirrhosis and liver failure.

Hepatocyte CL:0000182 Cholangiocyte CL:1000488

Show evidence (2 references)

PMID:38646510 SUPPORT Human Clinical

"Laboratory tests in IEBAM are characterized by normal γ-glutamyltransferase (GGT) and serum total bile acid (STBA) levels despite the presence of cholestasis"

Supports the distinctive normal-GGT, normal/low-STBA cholestasis pattern of bile acid synthesis disorders.

PMID:31337596 SUPPORT Human Clinical

"Without timely primary bile acid treatment, patients may develop liver failure early in life."

Supports progression to liver failure when untreated.

Fat and Fat-Soluble Vitamin Malabsorption

The deficient bile acid pool impairs intestinal solubilization of dietary lipids, producing fat malabsorption, steatorrhea, fat-soluble vitamin (A, D, E, K) deficiency, failure to thrive, and, from vitamin K deficiency, a bleeding tendency.

Hepatocyte CL:0000182

Show evidence (1 reference)

PMID:37575761 SUPPORT Human Clinical

"malabsorption of fat, which can lead to fat-soluble vitamin deficiencies"

Supports fat malabsorption and fat-soluble vitamin deficiency as a core consequence.

⬡

Pathograph

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

●

Phenotypes

11

Blood 1

Abnormal bleeding Abnormal bleeding HP:0001892

Show evidence (1 reference)

PMID:38062451 SUPPORT Human Clinical

"14 and 3 patients having cholestatic jaundice and severe bleeding respectively"

Documents severe bleeding as an early manifestation in AKR1D1 deficiency.

Digestive 4

Cholestasis Cholestasis HP:0001396

Show evidence (1 reference)

PMID:38646510 SUPPORT Human Clinical

"Inborn errors of bile acid metabolism (IEBAM) cause cholestasis during the neonatal period"

Directly supports neonatal cholestasis as the core phenotype.

Prolonged neonatal jaundice Prolonged neonatal jaundice HP:0006579

Show evidence (1 reference)

PMID:38062451 SUPPORT Human Clinical

"14 and 3 patients having cholestatic jaundice and severe bleeding respectively"

Documents cholestatic jaundice as the dominant presentation in a Delta4-3-oxo-R deficiency cohort.

Steatorrhea Steatorrhea HP:0002570

Show evidence (1 reference)

PMID:37575761 SUPPORT Human Clinical

"malabsorption of fat, which can lead to fat-soluble vitamin deficiencies"

Supports fat malabsorption, which clinically manifests as steatorrhea.

Hepatic cirrhosis Cirrhosis HP:0001394

Show evidence (1 reference)

PMID:31337596 SUPPORT Human Clinical

"Without timely primary bile acid treatment, patients may develop liver failure early in life."

Supports progression to advanced liver disease/failure when untreated.

Eye 1

Rod-cone dystrophy Rod-cone dystrophy HP:0000510

Show evidence (1 reference)

PMID:39313810 SUPPORT Human Clinical

"retinitis pigmentosa, neuropathy, ataxia and cognitive decline"

A phenotype review of AMACR deficiency lists retinitis pigmentosa (rod-cone dystrophy) among the main signs of the adult multisystem neurodegenerative phenotype.

Metabolism 1

Elevated hepatic transaminases Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:38062451 SUPPORT Human Clinical

"serum liver tests normalized in all within 6-12 months of treatment"

Implies abnormal serum liver tests (transaminases) at baseline that normalize on cholic acid therapy.

Musculoskeletal 1

Spastic paraplegia Spastic paraplegia HP:0001258

Show evidence (1 reference)

PMID:31337596 SUPPORT Human Clinical

"can present as neonatal cholestasis or neurological diseases"

Supports the dual hepatic and neurologic phenotypic spectrum of bile acid metabolism disorders, of which CYP7B1-related spastic paraplegia is part.

Nervous System 1

Peripheral neuropathy Peripheral neuropathy HP:0009830

Show evidence (1 reference)

PMID:37575761 SUPPORT Human Clinical

"In adulthood, patients usually develop neurological sequelae."

Supports adult-onset neurologic disease (including neuropathy) in AMACR deficiency.

Growth 1

Failure to thrive Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:38646510 SUPPORT Human Clinical

"Inborn errors of bile acid metabolism (IEBAM) cause cholestasis during the neonatal period"

Neonatal cholestasis with fat malabsorption underlies the failure to thrive seen in these infants; supports the cholestatic basis.

Other 1

Conjugated hyperbilirubinemia Conjugated hyperbilirubinemia HP:0002908

Show evidence (1 reference)

PMID:31337596 SUPPORT Human Clinical

"can present as neonatal cholestasis or neurological diseases"

Neonatal cholestasis in these disorders manifests with conjugated hyperbilirubinemia; supports the cholestatic jaundice presentation.

💊

Medical Actions

5

Cholic Acid Replacement

Action: Pharmacotherapy NCIT:C15986

Agent: cholic acid CHEBI:16359

Oral cholic acid is the FDA-approved primary bile acid replacement therapy for most inborn bile acid synthesis disorders (notably 3beta-HSD, AKR1D1, and AMACR deficiencies). It restores the bile acid pool, promotes bile flow, suppresses endogenous synthesis of toxic precursors via feedback, and improves fat-soluble vitamin absorption. Typical dosing is approximately 10-15 mg/kg/day, with liver tests normalizing within 6-12 months and good long-term outcomes with native liver survival.

Show evidence (3 references)

PMID:38062451 SUPPORT Human Clinical

"Oral cholic acid therapy is a safe and effective treatment for patients with Δ4-3-oxo-R deficiency."

Demonstrates efficacy and safety of oral cholic acid in a bile acid synthesis disorder subtype.

PMID:38062451 SUPPORT Human Clinical

"All 16 patients received cholic acid from a median age of 8.1 months (range 3.1-159) and serum liver tests normalized in all within 6-12 months of treatment."

Documents the response to cholic acid replacement, including normalization of liver tests.

PMID:38062451 SUPPORT Human Clinical

"After a median cholic acid therapy of 4.5 years (range 1.1-24), all patients were alive with their native liver."

Demonstrates favorable long-term outcome (native liver survival) on cholic acid.

Chenodeoxycholic Acid Replacement

Action: Pharmacotherapy NCIT:C15986

Agent: chenodeoxycholic acid CHEBI:16755

Chenodeoxycholic acid (CDCA) is an alternative primary bile acid replacement and is the standard therapy for cerebrotendinous xanthomatosis (CYP27A1) and for oxysterol 7alpha-hydroxylase (CYP7B1) deficiency; it has also been used long-term where cholic acid is unavailable. Low-dose CDCA (5-10 mg/kg/day) improves hepatic function with a good long-term prognosis when started early.

Show evidence (2 references)

PMID:33385262 SUPPORT Human Clinical

"CDCA treatment is effective in 3β-HSD deficiency and 5β-reductase deficiency, as cholic acid has been in other countries."

Demonstrates efficacy of chenodeoxycholic acid replacement in bile acid synthesis disorders.

PMID:33385262 SUPPORT Human Clinical

"BASD carry a good prognosis following early diagnosis and initiation of long-term CDCA treatment."

Supports good long-term prognosis with early CDCA therapy.

Glycocholic Acid (Conjugated Bile Acid) Replacement

Action: Pharmacotherapy NCIT:C15986

Agent: glycocholic acid CHEBI:17687

For bile acid amidation/conjugation defects (notably BAAT deficiency), where the bile acid backbone is synthesized but cannot be conjugated, oral supplementation with the pre-conjugated bile acid glycocholic acid restores conjugated bile acids in bile and improves fat-soluble vitamin absorption and growth, with a favorable safety profile.

Show evidence (1 reference)

PMID:25163551 SUPPORT Human Clinical

"growth and fat-soluble vitamin absorption in children and adolescents with"

A treatment study of children/adolescents with BAAT-deficiency amidation defects shows oral glycocholic acid therapy is safe and effective in improving growth and fat-soluble vitamin absorption.

Fat-Soluble Vitamin Supplementation

Action: vitamin supplementation MAXO:0001129

Supplementation of fat-soluble vitamins (A, D, E, K) is used as supportive care to correct the deficiencies caused by fat malabsorption, including vitamin K to address bleeding tendency.

Show evidence (1 reference)

PMID:37575761 SUPPORT Human Clinical

"malabsorption of fat, which can lead to fat-soluble vitamin deficiencies"

Fat-soluble vitamin deficiency from malabsorption is the rationale for fat-soluble vitamin supplementation as supportive treatment.

Liver Transplantation

Action: organ transplantation MAXO:0010039

Liver transplantation is reserved for severe, progressive infantile liver failure not responsive to bile acid therapy, such as advanced oxysterol 7alpha-hydroxylase (CYP7B1) deficiency.

Show evidence (1 reference)

PMID:31337596 SUPPORT Human Clinical

"Without timely primary bile acid treatment, patients may develop liver failure early in life."

Progression to early liver failure is the indication for liver transplantation in severe, treatment-refractory subtypes.

{ }

Source YAML

click to show

name: Inborn Disorder of Bile Acid Synthesis
category: Mendelian
creation_date: '2026-06-17T22:30:00Z'
synonyms:
- Inborn errors of bile acid synthesis
- Inborn errors of bile acid metabolism
- IEBAM
- Bile acid synthesis disorders
- BASD
- Congenital bile acid synthesis defect
description: >
  Inborn disorders of bile acid synthesis (also called inborn errors of bile
  acid metabolism, IEBAM, or bile acid synthesis disorders, BASD) are a group of
  rare autosomal recessive genetic defects of the enzymes required to convert
  cholesterol into the primary bile acids cholic acid (CA) and chenodeoxycholic
  acid (CDCA). Each subtype is caused by deficiency of a specific enzyme in the
  hepatic bile acid synthetic pathway (e.g., HSD3B7, AKR1D1, CYP7B1, CYP27A1,
  AMACR) or in the final amidation/conjugation steps (BAAT, SLC27A5). Loss of
  enzyme activity produces two convergent consequences: failure to synthesize
  normal primary bile acids (impairing bile flow and intestinal fat and
  fat-soluble vitamin absorption) and accumulation of atypical, hepatotoxic and
  cholestatic C27 bile acid intermediates. Most subtypes present in the neonatal
  or infantile period with cholestasis that is characteristically accompanied by
  normal serum gamma-glutamyltransferase (GGT) and normal or low serum total
  bile acids, often without pruritus, a pattern that distinguishes them from
  biliary atresia and other cholestatic disorders. Some subtypes (AMACR, CYP7B1)
  also produce later-onset neurologic disease. Critically, most subtypes are
  treatable with oral primary bile acid replacement (cholic acid, FDA-approved;
  chenodeoxycholic acid), which suppresses production of toxic intermediates,
  restores bile flow, and can prevent progression to cirrhosis and liver
  failure. One enzyme-specific member, cerebrotendinous xanthomatosis (sterol
  27-hydroxylase / CYP27A1 deficiency), is curated separately in dismech as its
  own entry.
disease_term:
  preferred_term: Inborn disorder of bile acid synthesis
  term:
    id: MONDO:0019218
    label: inborn disorder of bile acid synthesis
parents:
- Inborn error of metabolism
- Cholestasis
references:
- reference: PMID:38646510
  title: "Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis."
- reference: PMID:39702264
  title: "The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review."
classifications:
  harrisons_chapter:
  - classification_value: GASTROINTESTINAL
    notes: >
      Inborn disorders of bile acid synthesis are primarily hepatic/biliary
      disorders presenting as cholestatic liver disease.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >
      As a group of inborn errors of metabolism affecting the bile acid
      synthetic pathway, these disorders also fall under metabolic disease.
inheritance:
- name: Autosomal recessive inheritance
  description: >
    Inborn disorders of bile acid synthesis are inherited in an autosomal
    recessive pattern; affected individuals carry homozygous or compound
    heterozygous pathogenic variants in the relevant enzyme gene.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:37575761
    reference_title: "Autoantibody Positivity in Two Bahraini Siblings With a Novel Alpha-Methylacyl-CoA Racemase Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bile acid synthesis disorders (BASD) are a group of rare autosomal recessive disorders."
    explanation: A clinical case report and literature review states BASD are autosomal recessive.
  - reference: PMID:33385262
    reference_title: "Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "had homozygous or compound heterozygous mutations in the HSD3B7, SRD5B1, or CYP7B1 gene"
    explanation: The Japanese cohort confirms biallelic (homozygous/compound heterozygous) inheritance.
has_subtypes:
- name: BASD Type 1
  display_name: 3beta-hydroxy-Delta5-C27-steroid oxidoreductase deficiency (HSD3B7, BASD type 1)
  description: >
    Deficiency of 3beta-hydroxy-Delta5-C27-steroid oxidoreductase (encoded by
    HSD3B7) is the most common inborn bile acid synthesis disorder. It blocks an
    early step of bile acid synthesis, leading to accumulation of 3beta-hydroxy-
    Delta5 bile acid intermediates and presenting as neonatal/infantile
    cholestasis with normal GGT, fat-soluble vitamin malabsorption, and failure
    to thrive. It responds well to oral cholic acid.
  subtype_term:
    preferred_term: 3beta-hydroxy-Delta5-C27-steroid oxidoreductase deficiency
    term:
      id: MONDO:0011906
      label: congenital bile acid synthesis defect 1
  genes:
  - preferred_term: HSD3B7
    term:
      id: hgnc:18324
      label: HSD3B7
  evidence:
  - reference: PMID:39702264
    reference_title: "The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3β-Hydroxy-Δ5-C27-steroid oxidoreductase deficiency (n = 62)"
    explanation: >
      The systematic review of cholic acid treatment identifies 3beta-hydroxy-
      Delta5-C27-steroid oxidoreductase deficiency as a distinct, well-represented
      BASD subtype.
  - reference: PMID:38062451
    reference_title: "∆4-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most reported patients with this treatment have 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency."
    explanation: Confirms 3beta-HSD (HSD3B7) deficiency is the most common cholic-acid-treated BASD subtype.
- name: BASD Type 2
  display_name: Delta4-3-oxosteroid 5beta-reductase deficiency (AKR1D1/SRD5B1, BASD type 2)
  description: >
    Deficiency of Delta4-3-oxosteroid 5beta-reductase (encoded by AKR1D1, also
    known as SRD5B1) impairs reduction of 3-oxo-Delta4 bile acid precursors,
    causing accumulation of 3-oxo-Delta4 and allo (5alpha) bile acids. It
    typically presents as severe neonatal cholestasis, sometimes with severe
    bleeding and liver failure, though phenotypic variability including
    minimally symptomatic carriers is described. It responds to oral cholic acid.
  subtype_term:
    preferred_term: Delta4-3-oxosteroid 5beta-reductase deficiency
    term:
      id: MONDO:0009339
      label: congenital bile acid synthesis defect 2
  genes:
  - preferred_term: AKR1D1
    term:
      id: hgnc:388
      label: AKR1D1
  evidence:
  - reference: PMID:38062451
    reference_title: "∆4-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sixteen patients with Δ4-3-oxo-R deficiency confirmed by AKR1D1 gene sequencing who received oral cholic acid were retrospectively analyzed."
    explanation: Defines Delta4-3-oxosteroid 5beta-reductase deficiency as an AKR1D1-confirmed BASD subtype treated with cholic acid.
  - reference: PMID:38034430
    reference_title: "Healthy Patients With AKR1D1 Mutation Not Requiring Primary Bile Acid Therapy: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Δ4-3-Oxosteroid 5β-reductase (AKR1D1) deficiency typically causes severe cholestasis occurs in newborns, leading to death unless patients are treated with primary bile acids."
    explanation: Confirms the gene (AKR1D1), the typical severe neonatal cholestasis, and bile acid dependence.
- name: BASD Type 3
  display_name: Oxysterol 7alpha-hydroxylase deficiency (CYP7B1, BASD type 3)
  description: >
    Deficiency of oxysterol 7alpha-hydroxylase (encoded by CYP7B1) blocks the
    acidic (alternative) pathway of bile acid synthesis, causing accumulation of
    hepatotoxic 3beta-hydroxy-Delta5 monohydroxy bile acids. It can present as
    severe, often rapidly progressive infantile cholestasis and liver failure;
    the same gene can also produce a later-onset hereditary spastic paraplegia
    phenotype (SPG5), and both phenotypes have been observed within one family.
    Treatment is with chenodeoxycholic acid; liver transplantation may be needed
    for advanced infantile liver failure.
  subtype_term:
    preferred_term: Oxysterol 7alpha-hydroxylase deficiency
    term:
      id: MONDO:0013439
      label: congenital bile acid synthesis defect 3
  genes:
  - preferred_term: CYP7B1
    term:
      id: hgnc:2652
      label: CYP7B1
  evidence:
  - reference: PMID:31337596
    reference_title: "AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "three had oxysterol-7α-hydroxylase deficiency with CYP7B1 mutation"
    explanation: Identifies oxysterol 7alpha-hydroxylase deficiency caused by CYP7B1 mutation as a distinct BASD subtype.
  - reference: PMID:31337596
    reference_title: "AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The only surviving patient with oxysterol 7α-hydroxylase deficiency recovered from liver failure after chenodeoxycholic acid (CDCA) treatment beginning at 3 months of age."
    explanation: Documents the severe infantile liver failure and CDCA responsiveness of CYP7B1 deficiency.
- name: BASD Type 4
  display_name: Alpha-methylacyl-CoA racemase deficiency (AMACR, BASD type 4)
  description: >
    Deficiency of alpha-methylacyl-CoA racemase (encoded by AMACR) impairs
    peroxisomal racemization required for bile acid side-chain beta-oxidation and
    branched-chain fatty acid metabolism. It can present in infancy with
    cholestasis and fat-soluble vitamin malabsorption, but is distinguished by
    later, slowly progressive adult neurologic disease (sensory-motor neuropathy,
    ataxia, cognitive decline) and retinitis pigmentosa, with a risk of liver
    fibrosis/cirrhosis. It is treated with oral cholic acid and diet
    modification.
  subtype_term:
    preferred_term: Alpha-methylacyl-CoA racemase deficiency
    term:
      id: MONDO:0008967
      label: congenital bile acid synthesis defect 4
  genes:
  - preferred_term: AMACR
    term:
      id: hgnc:451
      label: AMACR
  evidence:
  - reference: PMID:37575761
    reference_title: "Autoantibody Positivity in Two Bahraini Siblings With a Novel Alpha-Methylacyl-CoA Racemase Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BASD type 4 is characterized by a gene mutation in alpha-methylacyl-CoA racemase (AMACR), which is located on chromosome 5p13."
    explanation: Defines BASD type 4 as AMACR deficiency.
  - reference: PMID:37575761
    reference_title: "Autoantibody Positivity in Two Bahraini Siblings With a Novel Alpha-Methylacyl-CoA Racemase Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In adulthood, patients usually develop neurological sequelae."
    explanation: Highlights the characteristic adult-onset neurologic disease distinguishing AMACR deficiency.
- name: CTX
  display_name: Sterol 27-hydroxylase deficiency / cerebrotendinous xanthomatosis (CYP27A1)
  description: >
    Deficiency of mitochondrial sterol 27-hydroxylase (encoded by CYP27A1)
    causes cerebrotendinous xanthomatosis (CTX). Loss of CYP27A1 impairs
    cholesterol side-chain oxidation and chenodeoxycholic acid synthesis,
    leading to accumulation of cholestanol and bile alcohols with sterol
    deposition in the CNS and tendons; neurologic disease and tendon xanthomas
    dominate the phenotype, although infantile cholestasis can occur. The
    standard treatment is chenodeoxycholic acid. CTX is curated as its own
    dismech Disease entry (Cerebrotendinous xanthomatosis, MONDO:0008948) and is
    listed here only to place it within the bile acid synthesis disorder family;
    it is not duplicated in this umbrella entry.
  subtype_term:
    preferred_term: Cerebrotendinous xanthomatosis
    term:
      id: MONDO:0008948
      label: cerebrotendinous xanthomatosis
  genes:
  - preferred_term: CYP27A1
    term:
      id: hgnc:2605
      label: CYP27A1
  evidence:
  - reference: PMID:39702264
    reference_title: "The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cerebrotendinous xanthomatosis (n = 22)"
    explanation: >
      The systematic review of cholic acid treatment for bile acid synthesis
      defects includes cerebrotendinous xanthomatosis as a member subtype.
- name: Bile acid conjugation defect 1
  display_name: Bile acid amidation/conjugation defect (BAAT)
  description: >
    Defect in the final amidation (conjugation) of bile acids with glycine or
    taurine, caused by deficiency of bile acid-CoA:amino acid N-acyltransferase
    (BAAT), produces neonatal cholestasis with fat-soluble vitamin
    malabsorption. Unlike the synthetic-enzyme defects, the primary bile acid
    backbone is made but cannot be properly conjugated, so unamidated bile acids
    accumulate. Conjugated bile acid replacement has been studied as treatment.
  subtype_term:
    preferred_term: Bile acid conjugation defect 1
    term:
      id: MONDO:0030991
      label: bile acid conjugation defect 1
  genes:
  - preferred_term: BAAT
    term:
      id: hgnc:932
      label: BAAT
  evidence:
  - reference: PMID:38646510
    reference_title: "Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "8 types of IEBAM have been reported to date"
    explanation: >
      The review enumerates eight types of inborn errors of bile acid
      metabolism, which include the BAAT amidation/conjugation defect among the
      bile acid synthesis/metabolism enzyme group.
pathophysiology:
- name: Hepatic Bile Acid Synthetic Enzyme Deficiency
  description: >
    Each inborn bile acid synthesis disorder begins with autosomal recessive
    loss of function of a single enzyme in the hepatic pathway converting
    cholesterol to the primary bile acids cholic acid and chenodeoxycholic acid
    (e.g., HSD3B7, AKR1D1, CYP7B1, CYP27A1) or in the terminal amidation step
    (BAAT, SLC27A5). The enzyme block is the upstream cause from which all
    downstream consequences follow.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: Bile acid biosynthetic process
    term:
      id: GO:0006699
      label: bile acid biosynthetic process
    modifier: DECREASED
  - preferred_term: Cholesterol metabolic process
    term:
      id: GO:0008203
      label: cholesterol metabolic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33385262
    reference_title: "Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "7 Japanese patients with bile acid synthesis disorders (BASD) including 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (3β-HSD) deficiency"
    explanation: Establishes that BASD are caused by specific enzyme deficiencies in the bile acid synthetic pathway.
  downstream:
  - target: Loss of Primary Bile Acids and Accumulation of Toxic Intermediates
    description: >
      The enzyme block both prevents synthesis of normal primary bile acids and
      causes the substrate of the missing enzyme to accumulate as atypical bile
      acid intermediates.
    evidence:
    - reference: PMID:39702264
      reference_title: "The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "potentially due to elevated levels of toxic C27-bile acid intermediates"
      explanation: Supports accumulation of toxic C27 bile acid intermediates downstream of the enzyme deficiency.
- name: Loss of Primary Bile Acids and Accumulation of Toxic Intermediates
  description: >
    The enzyme deficiency produces a dual lesion: reduced or absent normal
    primary bile acids (cholic and chenodeoxycholic acid) and accumulation of
    atypical, often C27, bile acid intermediates that are hepatotoxic and
    cholestatic. Because routine serum total bile acid assays detect only
    3alpha-hydroxylated bile acids, the abnormal intermediates are frequently
    missed, and patients can show cholestasis with normal or low measured serum
    total bile acids and normal GGT.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:39702264
    reference_title: "The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bile acid synthesis defects (BASDs) can be severely disabling involving the liver and nervous system, potentially due to elevated levels of toxic C27-bile acid intermediates."
    explanation: Directly supports accumulation of toxic C27 bile acid intermediates as the mechanism of liver and nervous system injury.
  downstream:
  - target: Cholestasis and Progressive Liver Injury
    description: >
      Toxic intermediates and impaired bile flow injure hepatocytes and bile
      canaliculi, producing cholestasis that can progress to fibrosis,
      cirrhosis, and liver failure if untreated.
    evidence:
    - reference: PMID:39702264
      reference_title: "The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bile acid synthesis defects (BASDs) can be severely disabling involving the liver and nervous system"
      explanation: Supports that toxic intermediate accumulation produces disabling liver injury.
  - target: Fat and Fat-Soluble Vitamin Malabsorption
    description: >
      Reduced primary bile acid pool impairs intestinal micelle formation,
      reducing absorption of dietary fat and fat-soluble vitamins.
    evidence:
    - reference: PMID:37575761
      reference_title: "Autoantibody Positivity in Two Bahraini Siblings With a Novel Alpha-Methylacyl-CoA Racemase Mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "malabsorption of fat, which can lead to fat-soluble vitamin deficiencies"
      explanation: Supports that the reduced bile acid pool causes fat and fat-soluble vitamin malabsorption.
- name: Cholestasis and Progressive Liver Injury
  description: >
    Impaired bile flow and hepatotoxic intermediates produce cholestasis. The
    cholestasis is biochemically distinctive: normal gamma-glutamyltransferase
    (GGT) and normal or low serum total bile acids despite cholestasis, often
    without pruritus, which distinguishes bile acid synthesis disorders from
    biliary atresia and other cholestatic diseases. Untreated, the process can
    advance to cirrhosis and liver failure.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  evidence:
  - reference: PMID:38646510
    reference_title: "Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory tests in IEBAM are characterized by normal γ-glutamyltransferase (GGT) and serum total bile acid (STBA) levels despite the presence of cholestasis"
    explanation: Supports the distinctive normal-GGT, normal/low-STBA cholestasis pattern of bile acid synthesis disorders.
  - reference: PMID:31337596
    reference_title: "AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Without timely primary bile acid treatment, patients may develop liver failure early in life."
    explanation: Supports progression to liver failure when untreated.
- name: Fat and Fat-Soluble Vitamin Malabsorption
  description: >
    The deficient bile acid pool impairs intestinal solubilization of dietary
    lipids, producing fat malabsorption, steatorrhea, fat-soluble vitamin (A,
    D, E, K) deficiency, failure to thrive, and, from vitamin K deficiency, a
    bleeding tendency.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:37575761
    reference_title: "Autoantibody Positivity in Two Bahraini Siblings With a Novel Alpha-Methylacyl-CoA Racemase Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "malabsorption of fat, which can lead to fat-soluble vitamin deficiencies"
    explanation: Supports fat malabsorption and fat-soluble vitamin deficiency as a core consequence.
phenotypes:
- name: Cholestasis
  description: >
    Neonatal/infantile cholestasis is the hallmark presentation of most bile
    acid synthesis disorders, characteristically with normal GGT and normal or
    low serum total bile acids.
  phenotype_term:
    preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
  evidence:
  - reference: PMID:38646510
    reference_title: "Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inborn errors of bile acid metabolism (IEBAM) cause cholestasis during the neonatal period"
    explanation: Directly supports neonatal cholestasis as the core phenotype.
- name: Conjugated hyperbilirubinemia
  description: >
    Cholestatic infants show a direct (conjugated) hyperbilirubinemia,
    manifest as prolonged neonatal jaundice.
  phenotype_term:
    preferred_term: Conjugated hyperbilirubinemia
    term:
      id: HP:0002908
      label: Conjugated hyperbilirubinemia
  evidence:
  - reference: PMID:31337596
    reference_title: "AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "can present as neonatal cholestasis or neurological diseases"
    explanation: >
      Neonatal cholestasis in these disorders manifests with conjugated
      hyperbilirubinemia; supports the cholestatic jaundice presentation.
- name: Prolonged neonatal jaundice
  description: >
    Affected neonates commonly present with persistent cholestatic jaundice
    (cholestatic / conjugated), prompting evaluation for biliary atresia.
  phenotype_term:
    preferred_term: Prolonged neonatal cholestatic jaundice
    term:
      id: HP:0006579
      label: Prolonged neonatal jaundice
  evidence:
  - reference: PMID:38062451
    reference_title: "∆4-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "14 and 3 patients having cholestatic jaundice and severe bleeding respectively"
    explanation: Documents cholestatic jaundice as the dominant presentation in a Delta4-3-oxo-R deficiency cohort.
- name: Elevated hepatic transaminases
  description: >
    Serum liver enzyme (transaminase) elevation accompanies the cholestatic
    liver injury and normalizes with effective bile acid therapy.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:38062451
    reference_title: "∆4-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "serum liver tests normalized in all within 6-12 months of treatment"
    explanation: >
      Implies abnormal serum liver tests (transaminases) at baseline that
      normalize on cholic acid therapy.
- name: Steatorrhea
  description: >
    Fat malabsorption from the deficient bile acid pool produces steatorrhea
    and fatty stools.
  phenotype_term:
    preferred_term: Steatorrhea
    term:
      id: HP:0002570
      label: Steatorrhea
  evidence:
  - reference: PMID:37575761
    reference_title: "Autoantibody Positivity in Two Bahraini Siblings With a Novel Alpha-Methylacyl-CoA Racemase Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "malabsorption of fat, which can lead to fat-soluble vitamin deficiencies"
    explanation: Supports fat malabsorption, which clinically manifests as steatorrhea.
- name: Failure to thrive
  description: >
    Chronic cholestasis and fat malabsorption commonly cause poor weight gain
    and failure to thrive in infancy.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:38646510
    reference_title: "Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inborn errors of bile acid metabolism (IEBAM) cause cholestasis during the neonatal period"
    explanation: >
      Neonatal cholestasis with fat malabsorption underlies the failure to
      thrive seen in these infants; supports the cholestatic basis.
- name: Abnormal bleeding
  description: >
    Vitamin K malabsorption can produce a coagulopathy with a bleeding
    tendency, which may be a severe early manifestation, especially in
    Delta4-3-oxosteroid 5beta-reductase (AKR1D1) deficiency.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:38062451
    reference_title: "∆4-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "14 and 3 patients having cholestatic jaundice and severe bleeding respectively"
    explanation: Documents severe bleeding as an early manifestation in AKR1D1 deficiency.
- name: Hepatic cirrhosis
  description: >
    Untreated bile acid synthesis disorders may progress to cirrhosis and liver
    failure, sometimes requiring liver transplantation.
  phenotype_term:
    preferred_term: Cirrhosis
    term:
      id: HP:0001394
      label: Cirrhosis
  evidence:
  - reference: PMID:31337596
    reference_title: "AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Without timely primary bile acid treatment, patients may develop liver failure early in life."
    explanation: Supports progression to advanced liver disease/failure when untreated.
- name: Peripheral neuropathy
  category: Neurologic
  description: >
    In AMACR deficiency, adult-onset slowly progressive neurologic disease
    includes a sensory-motor peripheral neuropathy.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:37575761
    reference_title: "Autoantibody Positivity in Two Bahraini Siblings With a Novel Alpha-Methylacyl-CoA Racemase Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In adulthood, patients usually develop neurological sequelae."
    explanation: Supports adult-onset neurologic disease (including neuropathy) in AMACR deficiency.
- name: Spastic paraplegia
  category: Neurologic
  description: >
    Oxysterol 7alpha-hydroxylase (CYP7B1) deficiency is allelic with hereditary
    spastic paraplegia type 5 (SPG5); affected individuals or relatives can
    present with spastic paraplegia rather than, or in addition to, infantile
    liver disease.
  phenotype_term:
    preferred_term: Spastic paraplegia
    term:
      id: HP:0001258
      label: Spastic paraplegia
  evidence:
  - reference: PMID:31337596
    reference_title: "AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "can present as neonatal cholestasis or neurological diseases"
    explanation: >
      Supports the dual hepatic and neurologic phenotypic spectrum of bile acid
      metabolism disorders, of which CYP7B1-related spastic paraplegia is part.
- name: Rod-cone dystrophy
  category: Ophthalmologic
  description: >
    AMACR deficiency is associated with retinitis pigmentosa (rod-cone
    dystrophy) as part of its adult multisystem neurodegenerative phenotype.
  phenotype_term:
    preferred_term: Retinitis pigmentosa
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:39313810
    reference_title: "Redefining the phenotype of alpha-methylacyl-CoA racemase (AMACR) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "retinitis pigmentosa, neuropathy, ataxia and cognitive decline"
    explanation: >
      A phenotype review of AMACR deficiency lists retinitis pigmentosa (rod-cone
      dystrophy) among the main signs of the adult multisystem neurodegenerative
      phenotype.
treatments:
- name: Cholic Acid Replacement
  description: >
    Oral cholic acid is the FDA-approved primary bile acid replacement therapy
    for most inborn bile acid synthesis disorders (notably 3beta-HSD, AKR1D1,
    and AMACR deficiencies). It restores the bile acid pool, promotes bile flow,
    suppresses endogenous synthesis of toxic precursors via feedback, and
    improves fat-soluble vitamin absorption. Typical dosing is approximately
    10-15 mg/kg/day, with liver tests normalizing within 6-12 months and good
    long-term outcomes with native liver survival.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cholic acid
      term:
        id: CHEBI:16359
        label: cholic acid
  evidence:
  - reference: PMID:38062451
    reference_title: "∆4-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral cholic acid therapy is a safe and effective treatment for patients with Δ4-3-oxo-R deficiency."
    explanation: Demonstrates efficacy and safety of oral cholic acid in a bile acid synthesis disorder subtype.
  - reference: PMID:38062451
    reference_title: "∆4-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 16 patients received cholic acid from a median age of 8.1 months (range 3.1-159) and serum liver tests normalized in all within 6-12 months of treatment."
    explanation: Documents the response to cholic acid replacement, including normalization of liver tests.
  - reference: PMID:38062451
    reference_title: "∆4-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After a median cholic acid therapy of 4.5 years (range 1.1-24), all patients were alive with their native liver."
    explanation: Demonstrates favorable long-term outcome (native liver survival) on cholic acid.
- name: Chenodeoxycholic Acid Replacement
  description: >
    Chenodeoxycholic acid (CDCA) is an alternative primary bile acid
    replacement and is the standard therapy for cerebrotendinous xanthomatosis
    (CYP27A1) and for oxysterol 7alpha-hydroxylase (CYP7B1) deficiency; it has
    also been used long-term where cholic acid is unavailable. Low-dose CDCA
    (5-10 mg/kg/day) improves hepatic function with a good long-term prognosis
    when started early.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: chenodeoxycholic acid
      term:
        id: CHEBI:16755
        label: chenodeoxycholic acid
  evidence:
  - reference: PMID:33385262
    reference_title: "Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CDCA treatment is effective in 3β-HSD deficiency and 5β-reductase deficiency, as cholic acid has been in other countries."
    explanation: Demonstrates efficacy of chenodeoxycholic acid replacement in bile acid synthesis disorders.
  - reference: PMID:33385262
    reference_title: "Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BASD carry a good prognosis following early diagnosis and initiation of long-term CDCA treatment."
    explanation: Supports good long-term prognosis with early CDCA therapy.
- name: Glycocholic Acid (Conjugated Bile Acid) Replacement
  description: >
    For bile acid amidation/conjugation defects (notably BAAT deficiency), where
    the bile acid backbone is synthesized but cannot be conjugated, oral
    supplementation with the pre-conjugated bile acid glycocholic acid restores
    conjugated bile acids in bile and improves fat-soluble vitamin absorption and
    growth, with a favorable safety profile.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: glycocholic acid
      term:
        id: CHEBI:17687
        label: glycocholic acid
  evidence:
  - reference: PMID:25163551
    reference_title: "Treatment of bile acid amidation defects with glycocholic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "growth and fat-soluble vitamin absorption in children and adolescents with"
    explanation: >
      A treatment study of children/adolescents with BAAT-deficiency amidation
      defects shows oral glycocholic acid therapy is safe and effective in
      improving growth and fat-soluble vitamin absorption.
- name: Fat-Soluble Vitamin Supplementation
  description: >
    Supplementation of fat-soluble vitamins (A, D, E, K) is used as supportive
    care to correct the deficiencies caused by fat malabsorption, including
    vitamin K to address bleeding tendency.
  treatment_term:
    preferred_term: vitamin supplementation
    term:
      id: MAXO:0001129
      label: vitamin supplementation
  evidence:
  - reference: PMID:37575761
    reference_title: "Autoantibody Positivity in Two Bahraini Siblings With a Novel Alpha-Methylacyl-CoA Racemase Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "malabsorption of fat, which can lead to fat-soluble vitamin deficiencies"
    explanation: >
      Fat-soluble vitamin deficiency from malabsorption is the rationale for
      fat-soluble vitamin supplementation as supportive treatment.
- name: Liver Transplantation
  description: >
    Liver transplantation is reserved for severe, progressive infantile liver
    failure not responsive to bile acid therapy, such as advanced oxysterol
    7alpha-hydroxylase (CYP7B1) deficiency.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  evidence:
  - reference: PMID:31337596
    reference_title: "AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Without timely primary bile acid treatment, patients may develop liver failure early in life."
    explanation: >
      Progression to early liver failure is the indication for liver
      transplantation in severe, treatment-refractory subtypes.
diagnosis:
- name: Urinary bile acid profiling by mass spectrometry
  description: >
    Because routine enzymatic serum total bile acid assays detect only
    3alpha-hydroxylated bile acids and miss the atypical intermediates,
    diagnosis relies on urinary bile acid profiling by liquid or gas
    chromatography-mass spectrometry (LC/MS or GC/MS), followed by confirmatory
    genetic testing.
  evidence:
  - reference: PMID:38646510
    reference_title: "Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "liquid chromatography-mass spectrometry (LC/MS) analysis of urinary bile acids is needed to optimize diagnostic and therapeutic efficacy"
    explanation: Supports urinary bile acid profiling by mass spectrometry as the key diagnostic test.
- name: Serum GGT and total bile acids to distinguish from biliary atresia
  description: >
    Measuring serum GGT and total bile acids early in the evaluation of neonatal
    cholestasis is essential: a normal GGT with normal/low serum total bile
    acids despite cholestasis raises suspicion for a bile acid synthesis
    disorder and helps avoid unnecessary invasive procedures intended for
    biliary atresia.
  evidence:
  - reference: PMID:38646510
    reference_title: "Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "measuring STBA and GGT is essential to distinguishing biliary atresia from IEBAM"
    explanation: Supports GGT and serum total bile acid measurement to differentiate from biliary atresia.
epidemiology:
- name: Proportion of unexplained cholestasis
  description: >
    Inborn errors of bile acid metabolism are rare; they account for
    approximately 2% of cases of cholestasis of unknown cause.
  evidence:
  - reference: PMID:38646510
    reference_title: "Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IEBAM accounts for approximately 2% of cases of cholestasis of unknown cause."
    explanation: Provides the proportion of unexplained cholestasis attributable to these disorders.
- name: Possible underdiagnosis
  description: >
    Prevalence may be higher than recognized because of underdiagnosis,
    supported by the presence of heterozygous causative mutations in the general
    population (e.g., CYP7B1 p.R112X allele frequency of 0.16% in healthy
    controls).
  evidence:
  - reference: PMID:31337596
    reference_title: "AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IEBAM prevalence rates may be higher than expected due to the presence of heterozygous mutations in the general population."
    explanation: Supports possible underdiagnosis of these disorders.
progression:
- phase: Treated long-term outcome
  notes: >
    With early diagnosis and primary bile acid replacement, the prognosis is
    generally good: liver disease stabilizes or improves, fibrosis can regress,
    and patients survive with their native liver and normal growth and quality
    of life.
  evidence:
  - reference: PMID:38062451
    reference_title: "∆4-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had normal growth and quality of life."
    explanation: Documents favorable outcomes (normal growth and quality of life) with cholic acid therapy.
  - reference: PMID:33385262
    reference_title: "Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 7 patients, who had homozygous or compound heterozygous mutations in the HSD3B7, SRD5B1, or CYP7B1 gene, are currently in good health without liver dysfunction."
    explanation: Documents good long-term health outcomes following treatment.

📚

References & Deep Research

References

2

PMID:38646510

Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis.

No top-level findings curated for this source.

PMID:39702264

The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Summary Tables

Edison Scientific Literature 30 citations 2026-06-17T22:05:56.896950

1. Disease Information

1.1 Concise overview (current understanding)

“Inborn errors of bile acid metabolism” (IEBAM) are congenital genetic defects of enzymes required to synthesize the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA), leading to cholestasis and/or systemic toxicity from accumulating atypical C27 bile acid intermediates (nittono2024navigatingcholestasisidentifying pages 1-2, nittono2024navigatingcholestasisidentifying pages 3-4). A major diagnostic pitfall is that patients can have cholestasis despite normal/low serum total bile acids (STBA) and normal γ-glutamyltransferase (GGT), which can resemble or be confused with other neonatal cholestasis etiologies (nittono2024navigatingcholestasisidentifying pages 1-2, nittono2024navigatingcholestasisidentifying pages 3-4).

Nittono et al. (Frontiers in Pediatrics; Apr 2024; https://doi.org/10.3389/fped.2024.1385970) explicitly emphasizes that IEBAM causes neonatal cholestasis and “accounts for approximately 2% of cases of cholestasis of unknown cause” (nittono2024navigatingcholestasisidentifying pages 1-2).

1.2 Key identifiers and terminologies

OMIM identifiers for key defect types and genes were available in the retrieved literature (but not ICD/Orphanet/MONDO): - HSD3B7 deficiency (3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency): OMIM 607765 (nittono2024navigatingcholestasisidentifying pages 1-2, kimura2021bileacidsynthesis pages 1-5) - SRD5B1 / AKR1D1 deficiency (Δ4-3-oxosteroid 5β-reductase deficiency): OMIM 235555 (nittono2024navigatingcholestasisidentifying pages 1-2, kimura2021bileacidsynthesis pages 1-5) - CYP7B1 deficiency (oxysterol 7α-hydroxylase deficiency): OMIM 603711 (nittono2024navigatingcholestasisidentifying pages 1-2, kimura2021bileacidsynthesis pages 1-5) - CYP27A1 (CTX) sterol 27-hydroxylase deficiency: OMIM 213700 (nittono2024navigatingcholestasisidentifying pages 1-2) - Additional gene OMIMs available from a review table (Obuz & Lay 2019; Dec 2019; https://doi.org/10.32552/2019.actamedica.404): AKR1D1 604741; CYP7A1 118455; SLC27A5 603314; BAAT 602938; AMACR 604489 (obuz2019pathwaysandinborn pages 4-6).

MeSH terms (as represented in ClinicalTrials.gov metadata): ClinicalTrials.gov record for compassionate CA treatment lists condition mappings including “Metabolism, Inborn Errors” and related peroxisomal disorder terms (NCT00007020 chunk 1).

ICD-10/ICD-11 / Orphanet: Not present in the retrieved evidence; would require dedicated lookup.

1.3 Synonyms/alternative names in practice

“Congenital bile acid synthesis defect type 3” for CYP7B1 deficiency is used in case literature (Tang et al., BMC Gastroenterology; Apr 2021; https://doi.org/10.1186/s12876-021-01749-x) (chen2020akr1d1andcyp7b1 pages 1-2).
“BASD type 4” used for AMACR deficiency in a recent case report (Cureus; Jul 2023; https://doi.org/10.7759/cureus.41720) (isa2023autoantibodypositivityin pages 1-2).

1.4 Evidence sources (patient-level vs aggregated)

Much of the evidence base remains case reports/series and retrospective cohorts (e.g., Japanese cohort of 7 patients over 21 years; and AKR1D1 cohort of 16 patients) (kimura2021bileacidsynthesis pages 1-5, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2).
A 2024 systematic review concluded that CA evidence is predominantly case reports/series with substantial bias risk (polak2024theclinicaland pages 5-6).

2. Etiology

2.1 Disease causal factors

Primary causal factors are germline genetic variants causing enzyme deficiencies in bile acid synthesis, conjugation/amidation, or peroxisomal side-chain processing pathways (nittono2024navigatingcholestasisidentifying pages 1-2, obuz2019pathwaysandinborn pages 4-6).

Representative genes explicitly listed for IEBAM include HSD3B7, SRD5B1, CYP27A1, CYP7B1, BAAT, SLC27A5, AMACR, CYP7A1 (nittono2024navigatingcholestasisidentifying pages 1-2).

2.2 Risk factors

Genetic (causal): autosomal recessive inheritance is explicitly stated for BASD (kimura2021bileacidsynthesis pages 1-5). Cohorts and case reports include homozygous/compound heterozygous variants (kimura2021bileacidsynthesis pages 1-5, chen2020akr1d1andcyp7b1 pages 1-2).
Environmental: Not well characterized as “risk factors” for the monogenic disorders themselves in the retrieved sources; however, misdiagnosis risk is influenced by routine bile acid assays that only detect 3α-hydroxylated bile acids (nittono2024navigatingcholestasisidentifying pages 3-4).

2.3 Protective factors

Not established in the retrieved evidence. Some phenotypic variability is described (e.g., AKR1D1 mutation carriers without severe neonatal cholestasis) but protective variants or modifiers are not identified (kimura2023healthypatientswith pages 1-2).

2.4 Gene–environment interactions

Not directly addressed in the retrieved evidence for IEBAS/IEBAM.

3. Phenotypes

3.1 Core phenotype domain: neonatal/infantile cholestasis

Across IEBAM, hallmark lab patterns include: - Cholestasis with normal or low STBA and normal GGT in many types (nittono2024navigatingcholestasisidentifying pages 1-2, nittono2024navigatingcholestasisidentifying pages 3-4). - Absence of pruritus is highlighted as a clue in BASD (kimura2021bileacidsynthesis pages 1-5, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2).

Nittono et al. (Apr 2024) explicitly states: “Laboratory tests in IEBAM are characterized by normal γ-glutamyltransferase (GGT) and serum total bile acid (STBA) levels despite the presence of cholestasis” and that measuring STBA and GGT is essential for distinguishing biliary atresia from IEBAM (nittono2024navigatingcholestasisidentifying pages 3-4, nittono2024navigatingcholestasisidentifying pages 1-2).

Example quantitative baseline (Japan cohort, n=7): median direct bilirubin 4.5 mg/dL with median total bile acids 3.4 μmol/L (kimura2021bileacidsynthesis pages 16-19).

3.2 Nutritional/malabsorption phenotypes

Fat-soluble vitamin malabsorption/deficiency is emphasized as a clinical feature in BASD, and bleeding can occur: - In AKR1D1 deficiency cohort (Δ4-3-oxo-R), 3/16 had severe bleeding as early manifestations (gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2).

3.3 Neurologic and multi-system phenotypes (defect-dependent)

AMACR deficiency: a 2024 cohort described adult-onset neurologic disease: “All adult patients subsequently developed neurological signs and symptoms after the age of 40 years; most frequently neuropathy, ataxia and cognitive decline…” (Orphanet J Rare Dis; Sep 2024; https://doi.org/10.1186/s13023-024-03358-9) (polak2024theclinicaland pages 5-6).
CYP7B1 deficiency: phenotype can vary within siblings, with infantile liver disease in one and adolescent spastic paraplegia features in another (chen2020akr1d1andcyp7b1 pages 1-2).

3.4 Suggested HPO terms (examples)

(These are ontology suggestions; not all are explicitly asserted in the retrieved texts.) - Cholestasis (HP:0001396) - Neonatal jaundice (HP:0006579) - Conjugated hyperbilirubinemia (HP:0002904) - Elevated hepatic transaminases (HP:0002910) - Fat malabsorption / steatorrhea (HP:0002570) - Fat-soluble vitamin deficiency (HP:0031034; consider also vitamin K deficiency bleeding) - Failure to thrive (HP:0001508) - Normal gamma-glutamyltransferase in cholestasis (no single HPO term; can encode as “Cholestasis” + lab observation) - Ataxia (HP:0001251), Peripheral neuropathy (HP:0009830), Cognitive decline (HP:0001268), Retinitis pigmentosa (HP:0000510) for AMACR deficiency.

3.5 Phenotype frequencies

Robust frequencies across the entire IEBAS category are not available in the retrieved evidence; however, subtype cohorts include: - Δ4-3-oxo-R/AKR1D1 deficiency: 14/16 cholestatic jaundice; 3/16 bleeding; 4 had liver failure at CA start (gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2). - AMACR deficiency: retinitis pigmentosa in 5/9 adults (polak2024theclinicaland pages 5-6).

4. Genetic / Molecular Information

4.1 Causal genes (human germline)

Genes repeatedly identified across IEBAM/BASD include: - HSD3B7 (3β-HSD deficiency) (nittono2024navigatingcholestasisidentifying pages 1-2, kimura2021bileacidsynthesis pages 1-5) - SRD5B1 and/or AKR1D1 (Δ4-3-oxo-5β-reductase deficiency) (nittono2024navigatingcholestasisidentifying pages 1-2, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2) - CYP7B1 (oxysterol 7α-hydroxylase deficiency) (nittono2024navigatingcholestasisidentifying pages 1-2, chen2020akr1d1andcyp7b1 pages 1-2) - CYP27A1 (CTX) (nittono2024navigatingcholestasisidentifying pages 1-2) - BAAT (BACD1) (bile acid conjugation defect-1) (nittono2024navigatingcholestasisidentifying pages 2-3) - SLC27A5 (bile acid-CoA ligase deficiency is listed as an IEBAM type) (nittono2024navigatingcholestasisidentifying pages 1-2) - AMACR (BASD type 4) (isa2023autoantibodypositivityin pages 1-2) - CYP7A1 (cholesterol 7α-hydroxylase deficiency is listed as a type) (nittono2024navigatingcholestasisidentifying pages 1-2)

4.2 Variant types and examples

In Japan BASD cohort, patients had “homozygous or compound heterozygous mutations” in HSD3B7, SRD5B1, CYP7B1 (kimura2021bileacidsynthesis pages 1-5).
A CYP7B1 case reported compound heterozygous nonsense mutations p.R63X / p.R112X (chen2020akr1d1andcyp7b1 pages 1-2).
The Japan cohort tables include multiple variant notations across HSD3B7/SRD5B1/CYP7B1 (e.g., splice site, deletions, missense) (kimura2021bileacidsynthesis pages 16-19).

4.3 Functional consequences (mechanistic framing)

The core biochemical consequence is impaired formation of CA/CDCA, leading to: 1) reduced bile flow and fat absorption, and 2) accumulation of atypical “unusual” bile acids/intermediates (often C27 intermediates), some described as hepatotoxic (nittono2024navigatingcholestasisidentifying pages 3-4, kimura2021bileacidsynthesis pages 7-11).

5. Environmental Information

IEBAS/IEBAM are primarily monogenic disorders; specific environmental toxins/lifestyle factors are not established causes in the retrieved sources. However, pre-analytical handling of samples (cooling and rapid processing) is highlighted as important to avoid oxidation artifacts that could confound diagnosis (nittono2024navigatingcholestasisidentifying pages 3-4).

6. Mechanism / Pathophysiology

6.1 Causal chain (general)

A synthesized mechanistic chain supported by retrieved sources is: - Inherited enzyme deficiency in bile acid synthesis/conjugation → low/absent primary bile acids (CA/CDCA) and accumulation of unusual bile acids (including non-3αOH bile acids) → impaired bile formation/flow and fat-soluble vitamin absorption + direct hepatotoxic effects of intermediates → cholestasis, progressive liver injury/fibrosis, and (in some subtypes) neurologic sequelae from systemic metabolite accumulation (nittono2024navigatingcholestasisidentifying pages 3-4, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2, polak2024theclinicaland pages 5-6).

Nittono et al. emphasize that routine STBA assays measure only 3αOH bile acids and can miss IEBAM, underscoring the biochemical distinctiveness of the accumulated metabolites (nittono2024navigatingcholestasisidentifying pages 3-4).

6.2 Upstream vs downstream mechanisms

Upstream: enzyme deficits in steroid/bile acid biosynthetic pathway (HSD3B7, AKR1D1/SRD5B1, CYP7B1, etc.) (nittono2024navigatingcholestasisidentifying pages 1-2).
Downstream: cholestasis with “normal GGT and normal STBA despite cholestasis,” fat-soluble vitamin deficiency and bleeding, fibrosis (nittono2024navigatingcholestasisidentifying pages 1-2, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2).

6.3 Suggested pathway and ontology terms

GO Biological Process (suggested): bile acid biosynthetic process (GO:0006699); cholesterol metabolic process (GO:0008203); lipid digestion/absorption-related processes.
Cell types (CL; suggested): hepatocyte (CL:0000182); cholangiocyte (CL:0000068).

7. Anatomical Structures Affected

7.1 Primary organs

Liver (primary; cholestasis, fibrosis, liver failure) (gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2, nittono2024navigatingcholestasisidentifying pages 3-4).
Intestine (secondary; fat absorption and enterohepatic circulation disruption; vitamin malabsorption) (NCT01115582 chunk 1, NCT01589523 chunk 1).

7.2 Secondary organ involvement (defect-dependent)

Central/peripheral nervous system in certain defects (e.g., AMACR neurologic phenotype; CYP7B1 spastic paraplegia association) (polak2024theclinicaland pages 5-6, chen2020akr1d1andcyp7b1 pages 1-2).
Eye/retina in AMACR deficiency (retinitis pigmentosa) (polak2024theclinicaland pages 5-6).

7.3 UBERON suggestions

Liver (UBERON:0002107)
Intrahepatic bile duct (UBERON:0003704)
Small intestine (UBERON:0002108)
Retina (UBERON:0000966) (AMACR)

8. Temporal Development

8.1 Onset

Many IEBAM present in the neonatal/early infancy period (nittono2024navigatingcholestasisidentifying pages 1-2, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2).
Δ4-3-oxo-R deficiency cohort: median first symptoms 2 months (gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2).

8.2 Progression

Without appropriate bile acid replacement, disorders may progress to cirrhosis/liver failure; case series highlight need for timely therapy and/or transplantation in severe infantile phenotypes (NCT01115582 chunk 1, chen2020akr1d1andcyp7b1 pages 1-2).

AMACR deficiency can have adult slowly progressive neurologic course with late diagnosis (median 56 years in one cohort) (polak2024theclinicaland pages 5-6).

9. Inheritance and Population

9.1 Inheritance

Autosomal recessive inheritance is described for BASD (kimura2021bileacidsynthesis pages 1-5).

9.2 Epidemiology and underdiagnosis

IEBAM proportion among unexplained cholestasis: approximately 2% (nittono2024navigatingcholestasisidentifying pages 1-2).
Japan cohort screening-based estimate: among 1010 infants with unexplained cholestasis (1996–2017), BASD prevalence was 0.7% (kimura2021bileacidsynthesis pages 5-7).
Underdiagnosis evidence: a Taiwanese cohort notes possible underdiagnosis and provides a control allele frequency for a CYP7B1 variant (p.R112X) of 0.16% (2/1216 alleles) in 608 controls (chen2020akr1d1andcyp7b1 pages 1-2).

9.3 Demographics

The retrieved evidence includes regional observations (Japan: only 10 identified IEBAM cases in one clinic’s experience, supporting rarity and diagnostic challenge) (nittono2024navigatingcholestasisidentifying pages 1-2, nittono2024navigatingcholestasisidentifying pages 2-3).

10. Diagnostics

10.1 Core diagnostic strategy

A recurring recommended workflow in the retrieved sources: 1) In neonatal/infantile cholestasis, check direct bilirubin, GGT, and STBA early; normal GGT and normal/low STBA raise suspicion for IEBAM and may help avoid unnecessary invasive procedures intended for biliary atresia (nittono2024navigatingcholestasisidentifying pages 1-2, nittono2024navigatingcholestasisidentifying pages 2-3). 2) Perform urinary bile acid profiling by LC–MS or GC–MS, as routine enzymatic STBA assays may miss non-3αOH bile acids (nittono2024navigatingcholestasisidentifying pages 3-4). 3) Confirm with genetic testing (targeted sequencing/NGS panels/WES) (nittono2024navigatingcholestasisidentifying pages 3-4, chen2020akr1d1andcyp7b1 pages 1-2).

Direct quote (abstract-level, Frontiers in Pediatrics 2024): “With suspected IEBAM, liquid chromatography–mass spectrometry (LC/MS) analysis of urinary bile acids is needed…” (nittono2024navigatingcholestasisidentifying pages 1-2).

10.2 Diagnostic tests and biomarkers

Urinary bile acid profiling (LC–MS / GC–MS): key test; detects unusual bile acids and supports subtype inference (nittono2024navigatingcholestasisidentifying pages 3-4, nittono2024navigatingcholestasisidentifying pages 2-3).
Serum/urine ‘unusual bile acid’ fractions: in Japan cohort, unusual bile acids often comprised the majority of measured bile acids at baseline in certain defects (e.g., 87.5–100% in 3β-HSD deficiency) (kimura2021bileacidsynthesis pages 5-7).
Impact of UDCA on profiles: UDCA can markedly alter bile-acid profiles; recommendation to measure STBA after stopping UDCA (nittono2024navigatingcholestasisidentifying pages 4-5, nittono2024navigatingcholestasisidentifying pages 3-4).

10.3 Differential diagnosis

Biliary atresia is specifically discussed as a key differential; BA typically has elevated STBA/GGT and requires prompt surgery (nittono2024navigatingcholestasisidentifying pages 2-3).

10.4 Screening

Newborn screening is described as “emerging” via dried blood spot bile acid metabolite detection (nittono2024navigatingcholestasisidentifying pages 5-6).

11. Outcome / Prognosis

11.1 Prognosis with treatment

Δ4-3-oxo-R (AKR1D1/SRD5B1) treated with CA (n=16): all were alive with native liver after median 4.5 years; liver tests normalized within 6–12 months; fibrosis stabilized/improved (gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2).
Japan cohort (n=7) treated largely with long-term CDCA (because CA unavailable): “All 7 patients… are currently in good health without liver dysfunction.” (Digestive Diseases and Sciences; Jan 2021; https://doi.org/10.1007/s10620-020-06722-4) (kimura2021bileacidsynthesis pages 1-5).

11.2 Prognosis without treatment / severe disease

The ClinicalTrials.gov description notes that inborn errors “are progressive and potentially lead to cirrhosis and liver failure if untreated” (NCT01115582 chunk 1).

11.3 Quality of life

The AKR1D1/SRD5B1 cohort explicitly reports “normal growth and quality of life” on CA (gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2).

12. Treatment

12.1 Standard disease-modifying approach: primary bile acid replacement

Cholic acid (CA) and chenodeoxycholic acid (CDCA) are the primary replacement therapies used to restore bile acid pool, promote bile flow, suppress endogenous synthesis of toxic intermediates, and improve fat-soluble vitamin absorption (NCT01115582 chunk 1, nittono2024navigatingcholestasisidentifying pages 3-4).

Direct quote (ClinicalTrials.gov NCT01115582): patients “lack the enzymes needed to synthesize the primary bile acids cholic acid and chenodeoxycholic acid (CDCA)” and CA monotherapy “inhibits endogenous production and accumulation of potentially hepatotoxic and cholestatic bile acid precursors” (NCT01115582 chunk 1).

Evidence-based dosing and outcomes

CA dosing in Phase 3 bridge trial: 10–15 mg/kg/day oral, divided doses (NCT01115582; completed; enrollment 16) (NCT01115582 chunk 1).
CA outcomes in Δ4-3-oxo-R deficiency (n=16; Orphanet J Rare Dis; Dec 2023; https://doi.org/10.1186/s13023-023-02984-z):
liver tests normalized in all within 6–12 months
median CA at last follow-up 8.3 mg/kg/day
all alive with native liver after median 4.5 years
12-fold decrease of urinary 3-oxo-Δ4 derivatives (gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2)
CDCA dosing in Japan cohort (n=5 treated): “low-dose (5 to 10 mg/kg/day)” with improved hepatic function and “No adverse effects were noted” (kimura2021bileacidsynthesis pages 1-5).
Systematic review of CA (Orphanet J Rare Dis; Dec 2024; https://doi.org/10.1186/s13023-024-03449-7): 14 publications, 162 total patients, but concluded “More controlled studies are required” and highlights heterogeneity/bias (polak2024theclinicaland pages 5-6).

12.2 Conjugated bile acids for amidation/conjugation defects

Glycocholic acid trial (NCT01589523; completed; enrollment 5) used 10–15 mg/kg/day in bile acid conjugation/amidation defects and collected liver tests, bile acid profiles, vitamin absorption, growth and histology endpoints (NCT01589523 chunk 1).

12.3 Alternative bile acids (emerging/experimental)

A 2024 case report (Frontiers in Pediatrics; Jun 2024; https://doi.org/10.3389/fped.2024.1418963) described glycine-conjugated deoxycholic acid (gDCA) as “alternative treatment” in HSD3B7 deficiency with improved weight and restored bile acid levels (kimura2021bileacidsynthesis pages 1-5).

12.4 Liver transplantation

Used for severe progressive infantile liver failure (e.g., oxysterol 7α-hydroxylase deficiency in Japan cohort; post-transplant bile acids normalized) (kimura2021bileacidsynthesis pages 1-5, kimura2021bileacidsynthesis pages 16-19).

12.5 Real-world implementation considerations

Misdiagnosis avoidance: STBA/GGT plus urinary LC–MS testing can prevent unnecessary invasive cholangiography intended for biliary atresia (nittono2024navigatingcholestasisidentifying pages 2-3).
Medication access: Japan cohort highlights lack of CA availability and pragmatic reliance on CDCA (kimura2021bileacidsynthesis pages 1-5).

12.6 MAXO (suggested) terms

Primary bile acid replacement therapy (e.g., MAXO: bile acid replacement therapy; terminology may vary)
Cholic acid therapy
Chenodeoxycholic acid therapy
Liver transplantation
Fat-soluble vitamin supplementation

13. Prevention

Primary prevention of the monogenic disorders is not addressed directly in the retrieved sources. Secondary/tertiary prevention is implicitly supported by: - early biochemical suspicion (STBA/GGT) and confirmatory bile acid profiling (nittono2024navigatingcholestasisidentifying pages 1-2, nittono2024navigatingcholestasisidentifying pages 3-4) - early initiation of bile acid replacement to prevent progression to liver failure and long-term complications (NCT01115582 chunk 1, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2).

14. Other Species / Natural Disease

Not established for this disease category in the retrieved evidence.

15. Model Organisms

Model organism evidence for these specific disorders was not retrieved in a form that directly supports disease-mechanism statements in this run; therefore, no curated model-organism summary is provided here.

Summary Tables

Defect / type	Gene	OMIM in evidence	Typical presentation notes	Key diagnostic test	Typical treatment	Key quantitative outcomes / doses
Aggregate concept: inborn disorders of bile acid synthesis/metabolism; synonyms include IEBAM, IEBAS, BASD (nittono2024navigatingcholestasisidentifying pages 1-2, kimura2021bileacidsynthesis pages 1-5, NCT00007020 chunk 1)	Multiple: HSD3B7, SRD5B1/AKR1D1, CYP7B1, CYP27A1, BAAT, SLC27A5, AMACR, CYP7A1 (nittono2024navigatingcholestasisidentifying pages 1-2, obuz2019pathwaysandinborn pages 4-6)	HSD3B7 607765; SRD5B1 235555; CYP27A1 213700; CYP7B1 603711; BAAT/BACD1 619232; AMACR 604489; additional gene OMIMs in evidence include AKR1D1 604741, CYP7A1 118455, SLC27A5 603314 (nittono2024navigatingcholestasisidentifying pages 1-2, obuz2019pathwaysandinborn pages 4-6, nittono2024navigatingcholestasisidentifying pages 2-3)	Usually neonatal/infantile cholestasis with normal or low GGT and normal/low serum total bile acids; often absent pruritus; fat-soluble vitamin deficiency/bleeding; some defects later show neurologic disease (nittono2024navigatingcholestasisidentifying pages 3-4, kimura2023healthypatientswith pages 1-2, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2)	Urinary bile acid profiling by LC-MS or GC-MS plus confirmatory genetic testing; STBA and GGT help distinguish from biliary atresia; newborn dried-blood-spot metabolite screening is emerging (nittono2024navigatingcholestasisidentifying pages 3-4, nittono2024navigatingcholestasisidentifying pages 5-6, nittono2024navigatingcholestasisidentifying pages 2-3)	Primary bile acid replacement, mainly cholic acid or chenodeoxycholic acid; defect-specific exceptions apply; liver transplantation for severe failure (nittono2024navigatingcholestasisidentifying pages 3-4, NCT01115582 chunk 1, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2)	IEBAM may account for ~2% of cholestasis of unknown cause; open-label cholic acid trials used 10–15 mg/kg/day; Japanese BASD prevalence among 1010 unexplained cholestasis cases was 0.7% (nittono2024navigatingcholestasisidentifying pages 1-2, NCT01115582 chunk 1, kimura2021bileacidsynthesis pages 5-7)
3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency (3β-HSD deficiency) (nittono2024navigatingcholestasisidentifying pages 1-2, kimura2021bileacidsynthesis pages 1-5)	HSD3B7 (nittono2024navigatingcholestasisidentifying pages 1-2, kimura2021bileacidsynthesis pages 16-19)	607765 in evidence (nittono2024navigatingcholestasisidentifying pages 1-2, kimura2021bileacidsynthesis pages 1-5)	Cholestatic jaundice, acholic/fatty stools, failure to thrive, fat-soluble vitamin deficiency; often low/normal GGT and low/normal STBA (nittono2024navigatingcholestasisidentifying pages 2-3, nittono2024navigatingcholestasisidentifying pages 3-4, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2)	Urine/serum bile acid profiling showing high atypical 3β-hydroxy-Δ5 bile acids; sequencing of HSD3B7 (nittono2024navigatingcholestasisidentifying pages 2-3, nittono2024navigatingcholestasisidentifying pages 3-4)	Cholic acid standard; alternative bile acid approaches reported when needed, including glycodeoxycholic acid case use (NCT01115582 chunk 1, NCT01589523 chunk 1, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2)	In long-term CA cohort including 13 HSD3B7 patients, mean daily CA dose 6.9 mg/kg/day and fibrosis improved/disappeared after 10–24 years; gDCA case restored normal bile acid levels and improved weight without liver toxicity (gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2, kimura2021bileacidsynthesis pages 1-5)
Δ4-3-oxosteroid 5β-reductase deficiency (5β-reductase deficiency; Δ4-3-oxo-R) (gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2, kimura2021bileacidsynthesis pages 1-5)	SRD5B1 / AKR1D1 (nittono2024navigatingcholestasisidentifying pages 1-2, kimura2021bileacidsynthesis pages 1-5, kimura2021bileacidsynthesis pages 16-19)	235555 for disorder; AKR1D1 gene OMIM 604741 in evidence set (nittono2024navigatingcholestasisidentifying pages 1-2, obuz2019pathwaysandinborn pages 4-6)	Usually severe neonatal cholestasis, sometimes severe bleeding and liver failure; can be variable, including minimally symptomatic mutation carriers; pruritus often absent; GGT/TBA often normal or slightly raised (kimura2023healthypatientswith pages 1-2, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2)	Urinary bile acid LC-MS/GC-MS showing 3-oxo-Δ4 derivatives and allo-bile acids; AKR1D1/SRD5B1 sequencing (kimura2023healthypatientswith pages 1-2, gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2)	Cholic acid preferred; UDCA may partially improve before diagnosis; some Japanese patients treated long-term with CDCA where CA unavailable (gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2, kimura2021bileacidsynthesis pages 5-7)	In 16 CA-treated patients: median onset 2 months, CA started median 8.1 months, liver tests normalized in all within 6–12 months, median last dose 8.3 mg/kg/day, 12-fold urinary metabolite decrease, all alive with native liver after median 4.5 years; 15/16 had prior UDCA with partial improvement in 8 (gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2)
Oxysterol 7α-hydroxylase deficiency / congenital bile acid synthesis defect type 3 (nittono2024navigatingcholestasisidentifying pages 1-2, kimura2021bileacidsynthesis pages 1-5)	CYP7B1 (nittono2024navigatingcholestasisidentifying pages 1-2, kimura2021bileacidsynthesis pages 16-19)	603711 in evidence (nittono2024navigatingcholestasisidentifying pages 1-2, kimura2021bileacidsynthesis pages 1-5)	Severe infantile progressive cholestasis/liver failure in infancy; can also present later with hereditary spastic paraplegia phenotype, even within the same family (chen2020akr1d1andcyp7b1 pages 1-2)	Urinary bile acid analysis showing atypical hepatotoxic 3β-hydroxy-Δ5 bile acids; CYP7B1 genetic testing (chen2020akr1d1andcyp7b1 pages 1-2, nittono2024navigatingcholestasisidentifying pages 2-3)	Chenodeoxycholic acid; liver transplantation when progressive failure is advanced (chen2020akr1d1andcyp7b1 pages 1-2, kimura2021bileacidsynthesis pages 16-19)	Case evidence: CDCA begun while awaiting transplant led to rapid liver improvement and normalized urine atypical bile acids by follow-up at 23 months; in Japanese cohort 1 patient required liver transplantation and later recovered (chen2020akr1d1andcyp7b1 pages 1-2, kimura2021bileacidsynthesis pages 16-19)
α-Methylacyl-CoA racemase deficiency / BASD type 4 (isa2023autoantibodypositivityin pages 1-2)	AMACR (isa2023autoantibodypositivityin pages 1-2)	604489 in evidence (nittono2024navigatingcholestasisidentifying pages 2-3)	Neonatal cholestasis or later slowly progressive adult neurologic disease with retinitis pigmentosa, neuropathy, ataxia, cognitive decline; risk of liver fibrosis/cirrhosis/HCC (isa2023autoantibodypositivityin pages 1-2, polak2024theclinicaland pages 5-6)	Urine metabolite testing and/or serum C27 bile acid intermediates with genetic confirmation; MRI may support adult diagnosis (isa2023autoantibodypositivityin pages 1-2, polak2024theclinicaland pages 5-6)	Oral cholic acid plus diet modification reported; CA also represented in systematic review data (isa2023autoantibodypositivityin pages 1-2, polak2024theclinicaland pages 5-6)	Fewer than 20 cases in prior literature; 2024 cohort described 12 genetically confirmed patients, median diagnosis age 56 years, mean follow-up 6 years, retinitis pigmentosa in 5/9 adults, neurologic symptoms in all adults after age 40 (polak2024theclinicaland pages 5-6)
Sterol 27-hydroxylase deficiency / cerebrotendinous xanthomatosis (CTX) (nittono2024navigatingcholestasisidentifying pages 1-2, obuz2019pathwaysandinborn pages 4-6)	CYP27A1 (nittono2024navigatingcholestasisidentifying pages 1-2)	213700 in evidence (nittono2024navigatingcholestasisidentifying pages 1-2)	Systemic disease with bile acid deficiency and cholestanol/bile alcohol accumulation; neurologic sequelae dominate, rather than neonatal cholestasis in most cases (nittono2024navigatingcholestasisidentifying pages 1-2, polak2024theclinicaland pages 5-6)	Biochemical profiling of cholestanol/bile alcohols and genetic testing (polak2024theclinicaland pages 5-6)	Chenodeoxycholic acid standard in CTX; CA represented in systematic review but defect-specific standard remains CDCA (polak2024theclinicaland pages 5-6)	CA systematic review included 22 CTX patients; separate cohort evidence for CDCA shows long-term biochemical and clinical improvement in many patients (polak2024theclinicaland pages 5-6)
Bile acid amidation / conjugation defects (bile acid conjugation defect-1) (nittono2024navigatingcholestasisidentifying pages 2-3, obuz2019pathwaysandinborn pages 4-6)	BAAT; related ligase defect SLC27A5 (nittono2024navigatingcholestasisidentifying pages 2-3, obuz2019pathwaysandinborn pages 4-6)	BACD1/BAAT 619232; SLC27A5 gene OMIM 603314 in evidence (nittono2024navigatingcholestasisidentifying pages 2-3, obuz2019pathwaysandinborn pages 4-6)	Neonatal cholestasis with fat-soluble vitamin malabsorption; unconjugated bile acids and compensatory urinary sulfate/glucuronide conjugates; GGT may remain normal (nittono2024navigatingcholestasisidentifying pages 4-5, nittono2024navigatingcholestasisidentifying pages 2-3)	Specialized bile acid profiling showing unamidated bile acids; confirmatory sequencing (obuz2019pathwaysandinborn pages 4-6, nittono2024navigatingcholestasisidentifying pages 2-3)	Glycocholic acid/conjugated cholic acid; UDCA may be considered in some related defects (NCT01589523 chunk 1, nittono2024navigatingcholestasisidentifying pages 3-4)	Phase 3 glycocholic acid study enrolled 5 patients and used 10–15 mg/kg/day, with outcomes including liver tests, bile acid profiles, vitamin absorption, growth, and histology (NCT01589523 chunk 1)

Table: This table summarizes the main inborn bile acid synthesis/metabolism defects represented in the retrieved evidence, including genes, OMIM identifiers, presentations, diagnostics, treatments, and key quantitative outcomes. It is useful as a compact reference for comparing subtype-specific clinical and management features.

Recent developments (2023–2024) highlighted

1) Precision diagnosis emphasis: 2024 perspective stresses STBA/GGT patterns and urinary LC–MS bile acid profiling to distinguish IEBAM from biliary atresia and to avoid invasive procedures (nittono2024navigatingcholestasisidentifying pages 3-4, nittono2024navigatingcholestasisidentifying pages 2-3). 2) Larger contemporary single-defect cohort: 2023 Orphanet J Rare Dis cohort (n=16) provides quantitative CA effectiveness/safety for Δ4-3-oxo-R deficiency (gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2). 3) Evidence synthesis and evidence gaps: 2024 systematic review (162 patients, mostly case series) concludes controlled studies and an independent international registry are needed (polak2024theclinicaland pages 5-6). 4) Phenotype expansion: 2024 AMACR cohort “redefining phenotype” indicates adult slowly progressive neuro-ophthalmologic pattern and liver cancer risk requiring monitoring (polak2024theclinicaland pages 5-6).

References

(nittono2024navigatingcholestasisidentifying pages 1-2): Hiroshi Nittono, Mitsuyoshi Suzuki, Hiromi Suzuki, Satoru Sugimoto, Jun Mori, Rieko Sakamoto, Yugo Takaki, Hisamitsu Hayashi, Hajime Takei, and Akihiko Kimura. Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis. Frontiers in Pediatrics, Apr 2024. URL: https://doi.org/10.3389/fped.2024.1385970, doi:10.3389/fped.2024.1385970. This article has 5 citations.
(obuz2019pathwaysandinborn pages 4-6): Ufuk Bozkurt Obuz and Incilay Lay. Pathways and inborn errors of bile acid synthesis. Acta Medica, 50:48-56, Dec 2019. URL: https://doi.org/10.32552/2019.actamedica.404, doi:10.32552/2019.actamedica.404. This article has 0 citations.
(kimura2021bileacidsynthesis pages 1-5): Akihiko Kimura, Tatsuki Mizuochi, Hajime Takei, Akira Ohtake, Jun Mori, Kunihiro Shinoda, Takuji Hashimoto, Mureo Kasahara, Takao Togawa, Tsuyoshi Murai, Takashi Iida, and Hiroshi Nittono. Bile acid synthesis disorders in japan: long-term outcome and chenodeoxycholic acid treatment. Jan 2021. URL: https://doi.org/10.1007/s10620-020-06722-4, doi:10.1007/s10620-020-06722-4. This article has 20 citations and is from a peer-reviewed journal.
(NCT00007020 chunk 1): Compassionate Treatment of Patients With Inborn Errors of Bile Acid Metabolism With Cholic Acid. Mirum Pharmaceuticals, Inc.. 1992. ClinicalTrials.gov Identifier: NCT00007020
(nittono2024navigatingcholestasisidentifying pages 3-4): Hiroshi Nittono, Mitsuyoshi Suzuki, Hiromi Suzuki, Satoru Sugimoto, Jun Mori, Rieko Sakamoto, Yugo Takaki, Hisamitsu Hayashi, Hajime Takei, and Akihiko Kimura. Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis. Frontiers in Pediatrics, Apr 2024. URL: https://doi.org/10.3389/fped.2024.1385970, doi:10.3389/fped.2024.1385970. This article has 5 citations.
(chen2020akr1d1andcyp7b1 pages 1-2): Ju-Yin Chen, Jia-Feng Wu, Akihiko Kimura, Hiroshi Nittono, Bang-Yu Liou, Chee-Seng Lee, Ho-Sheng Chen, Yu-Chun Chiu, Yen-Hsuan Ni, Steven Shinn-Forng Peng, Wang-Tso Lee, I-Jung Tsai, Mei-Hwei Chang, and Huey-Ling Chen. Akr1d1 and cyp7b1 mutations in patients with inborn errors of bile acid metabolism: possibly underdiagnosed diseases. Pediatrics and neonatology, 61:75-83, Feb 2020. URL: https://doi.org/10.1016/j.pedneo.2019.06.009, doi:10.1016/j.pedneo.2019.06.009. This article has 31 citations and is from a peer-reviewed journal.
(isa2023autoantibodypositivityin pages 1-2): Hasan M Isa, Ahmed D Khudair, Rachel A Marshall, Aiman D Khudair, Thuraiya H Al-Rawahia, and Maryam Y Busehail. Autoantibody positivity in two bahraini siblings with a novel alpha-methylacyl-coa racemase mutation. Cureus, Jul 2023. URL: https://doi.org/10.7759/cureus.41720, doi:10.7759/cureus.41720. This article has 1 citations.
(gardin2023∆43oxo5βreductasedeficiencyfavorable pages 1-2): Antoine Gardin, Mathias Ruiz, Jan Beime, Mara Cananzi, Margarete Rathert, Barbara Rohmer, Enke Grabhorn, Marion Almes, Veena Logarajah, Luis Peña-Quintana, Thomas Casswall, Amaria Darmellah-Remil, Ana Reyes-Domínguez, Emna Barkaoui, Loreto Hierro, Carolina Baquero-Montoya, Ulrich Baumann, Björn Fischler, Emmanuel Gonzales, Anne Davit-Spraul, Sophie Laplanche, and Emmanuel Jacquemin. ∆4-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid. Orphanet Journal of Rare Diseases, Dec 2023. URL: https://doi.org/10.1186/s13023-023-02984-z, doi:10.1186/s13023-023-02984-z. This article has 9 citations and is from a peer-reviewed journal.
(polak2024theclinicaland pages 5-6): Yasmin Polak, Laura van Dussen, E. Marleen Kemper, Frédéric M. Vaz, Femke C. C. Klouwer, Marc Engelen, and Carla E. M. Hollak. The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03449-7, doi:10.1186/s13023-024-03449-7. This article has 8 citations and is from a peer-reviewed journal.
(kimura2023healthypatientswith pages 1-2): Akihiko Kimura, Jun Mori, Anh-Hoa Nguyen Pham, Kim-Oanh Bui Thi, Hajime Takei, Tsuyoshi Murai, Hisamitsu Hayashi, and Hiroshi Nittono. Healthy patients with akr1d1 mutation not requiring primary bile acid therapy: a case series. JPGN Reports, 4:e372-e372, Oct 2023. URL: https://doi.org/10.1097/pg9.0000000000000372, doi:10.1097/pg9.0000000000000372. This article has 5 citations.
(kimura2021bileacidsynthesis pages 16-19): Akihiko Kimura, Tatsuki Mizuochi, Hajime Takei, Akira Ohtake, Jun Mori, Kunihiro Shinoda, Takuji Hashimoto, Mureo Kasahara, Takao Togawa, Tsuyoshi Murai, Takashi Iida, and Hiroshi Nittono. Bile acid synthesis disorders in japan: long-term outcome and chenodeoxycholic acid treatment. Jan 2021. URL: https://doi.org/10.1007/s10620-020-06722-4, doi:10.1007/s10620-020-06722-4. This article has 20 citations and is from a peer-reviewed journal.
(nittono2024navigatingcholestasisidentifying pages 2-3): Hiroshi Nittono, Mitsuyoshi Suzuki, Hiromi Suzuki, Satoru Sugimoto, Jun Mori, Rieko Sakamoto, Yugo Takaki, Hisamitsu Hayashi, Hajime Takei, and Akihiko Kimura. Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis. Frontiers in Pediatrics, Apr 2024. URL: https://doi.org/10.3389/fped.2024.1385970, doi:10.3389/fped.2024.1385970. This article has 5 citations.
(kimura2021bileacidsynthesis pages 7-11): Akihiko Kimura, Tatsuki Mizuochi, Hajime Takei, Akira Ohtake, Jun Mori, Kunihiro Shinoda, Takuji Hashimoto, Mureo Kasahara, Takao Togawa, Tsuyoshi Murai, Takashi Iida, and Hiroshi Nittono. Bile acid synthesis disorders in japan: long-term outcome and chenodeoxycholic acid treatment. Jan 2021. URL: https://doi.org/10.1007/s10620-020-06722-4, doi:10.1007/s10620-020-06722-4. This article has 20 citations and is from a peer-reviewed journal.
(NCT01115582 chunk 1): Efficacy of To Be Marketed (TBM) Cholic Acid Capsules Used to Treat Children With Inborn Errors of Bile Acid Synthesis. Mirum Pharmaceuticals, Inc.. 2010. ClinicalTrials.gov Identifier: NCT01115582
(NCT01589523 chunk 1): GlycoCholic Acid Treatment for Patients With Inborn Errors in Bile Acid Synthesis. Children's Hospital Medical Center, Cincinnati. 2006. ClinicalTrials.gov Identifier: NCT01589523
(kimura2021bileacidsynthesis pages 5-7): Akihiko Kimura, Tatsuki Mizuochi, Hajime Takei, Akira Ohtake, Jun Mori, Kunihiro Shinoda, Takuji Hashimoto, Mureo Kasahara, Takao Togawa, Tsuyoshi Murai, Takashi Iida, and Hiroshi Nittono. Bile acid synthesis disorders in japan: long-term outcome and chenodeoxycholic acid treatment. Jan 2021. URL: https://doi.org/10.1007/s10620-020-06722-4, doi:10.1007/s10620-020-06722-4. This article has 20 citations and is from a peer-reviewed journal.
(nittono2024navigatingcholestasisidentifying pages 4-5): Hiroshi Nittono, Mitsuyoshi Suzuki, Hiromi Suzuki, Satoru Sugimoto, Jun Mori, Rieko Sakamoto, Yugo Takaki, Hisamitsu Hayashi, Hajime Takei, and Akihiko Kimura. Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis. Frontiers in Pediatrics, Apr 2024. URL: https://doi.org/10.3389/fped.2024.1385970, doi:10.3389/fped.2024.1385970. This article has 5 citations.
(nittono2024navigatingcholestasisidentifying pages 5-6): Hiroshi Nittono, Mitsuyoshi Suzuki, Hiromi Suzuki, Satoru Sugimoto, Jun Mori, Rieko Sakamoto, Yugo Takaki, Hisamitsu Hayashi, Hajime Takei, and Akihiko Kimura. Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis. Frontiers in Pediatrics, Apr 2024. URL: https://doi.org/10.3389/fped.2024.1385970, doi:10.3389/fped.2024.1385970. This article has 5 citations.

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Classifications

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Medical Actions

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 Concise overview (current understanding)

1.2 Key identifiers and terminologies

1.3 Synonyms/alternative names in practice

1.4 Evidence sources (patient-level vs aggregated)

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Core phenotype domain: neonatal/infantile cholestasis

3.2 Nutritional/malabsorption phenotypes

3.3 Neurologic and multi-system phenotypes (defect-dependent)

3.4 Suggested HPO terms (examples)

3.5 Phenotype frequencies

4. Genetic / Molecular Information

4.1 Causal genes (human germline)

4.2 Variant types and examples

4.3 Functional consequences (mechanistic framing)

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Causal chain (general)

6.2 Upstream vs downstream mechanisms

6.3 Suggested pathway and ontology terms

7. Anatomical Structures Affected

7.1 Primary organs

7.2 Secondary organ involvement (defect-dependent)

7.3 UBERON suggestions

8. Temporal Development

8.1 Onset

8.2 Progression

9. Inheritance and Population

9.1 Inheritance

9.2 Epidemiology and underdiagnosis

9.3 Demographics

10. Diagnostics

10.1 Core diagnostic strategy

10.2 Diagnostic tests and biomarkers

10.3 Differential diagnosis

10.4 Screening

11. Outcome / Prognosis

11.1 Prognosis with treatment

11.2 Prognosis without treatment / severe disease

11.3 Quality of life

12. Treatment

12.1 Standard disease-modifying approach: primary bile acid replacement

Evidence-based dosing and outcomes

12.2 Conjugated bile acids for amidation/conjugation defects

12.3 Alternative bile acids (emerging/experimental)

12.4 Liver transplantation

12.5 Real-world implementation considerations

12.6 MAXO (suggested) terms

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary Tables

Recent developments (2023–2024) highlighted

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