Primary Bile Acid Malabsorption

Mendelian MONDO:0013214 Pathograph 20 Show in embeddings browser Congenital Diarrhoeal Disorder Inborn Error of Metabolism

Primary bile acid malabsorption is a congenital diarrhoeal disorder caused by biallelic loss-of-function variants in SLC10A2, which encodes the ileal apical sodium-dependent bile acid transporter (ASBT, also called IBAT). ASBT performs the active reclamation step of the enterohepatic circulation: it takes bile acids back up across the apical membrane of terminal ileal enterocytes so they can return to the liver. Without it, bile acids are not recovered, they spill into the colon where they act as secretagogues, and the result is congenital-onset watery diarrhoea with steatorrhoea. The interruption of the enterohepatic circulation has a second consequence away from the gut: the bile acid pool contracts, hepatic synthesis is de-repressed to compensate, and because that synthesis consumes cholesterol, plasma cholesterol falls. The disease is important out of proportion to its rarity because the same transporter is a deliberate drug target - partial pharmacological ASBT inhibition is used to treat cholestatic pruritus and has been explored for hypercholesterolaemia - so this disorder is in effect the complete-loss end of a dose-response curve that medicine now traverses on purpose.

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1
Inheritance
9
Pathophys.
7
Phenotypes
1
Gaps
20
Pathograph
1
Genes
3
Medical Actions
1
Models
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
The index family carried compound heterozygous variants: one allele with a splice-donor change, the other with two missense substitutions that together abolish transport.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:9109432 SUPPORT Human Clinical
"Four polymorphisms were identified and sequenced in a family with congenital PBAM. One allele encoded an A171S missense mutation and a mutated donor splice site for exon 3. The other allele encoded two missense mutations at conserved amino acid positions, L243P and T262M."
Describes the compound heterozygous allele structure in the index family, consistent with autosomal recessive inheritance.
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Discussions and Knowledge Gaps

1
Why does the Slc10a2-null mouse reproduce the bile acid transport defect almost completely while failing to reproduce the steatorrhoea and reduced plasma cholesterol that define the human disease?
HUMAN MODEL MISMATCH slc10a2_mouse_human_malabsorption_mismatch
Attached to
pathophysiology#Steatorrhoea and Fat Malabsorption pathophysiology#Reduced Plasma Cholesterol
This is a mismatch of the kind worth recording structurally rather than as prose, because it changes what the model can be used to argue. The mouse loses 10- to 20-fold more bile acid in faeces and holds an 80% smaller pool, so the proximal lesion is faithfully reproduced; yet on a low fat diet it has no steatorrhoea, and its plasma HDL cholesterol is slightly elevated where humans have reduced plasma cholesterol. Two candidate explanations are visible in the data - the low fat diet never stresses the residual pool, and the pool's selective cholic acid enrichment preserves micelle formation - and a third, that mouse lipoprotein physiology makes plasma cholesterol a poor cross-species readout in the first place. None has been tested directly. Until one is, the model supports the transport and pool nodes and must not be cited for the malabsorptive nodes.
Proposed experiments
High-fat dietary challenge of Slc10a2-null mice
slc10a2_null_high_fat_challenge
Feed Slc10a2-null and wild-type mice a high fat diet and measure faecal fat, faecal neutral sterol excretion and intestinal cholesterol absorption. If steatorrhoea appears only under fat loading, the discrepancy is a matter of dietary stress on a reduced but qualitatively adequate pool rather than a species difference in the mechanism.
Would support
pathophysiology#Steatorrhoea and Fat Malabsorption
Supporting outcome
  • Null mice develop measurable steatorrhoea and a substantially larger fall in intestinal cholesterol absorption on the high fat diet than on the low fat diet.
Refuting outcome
  • Null mice remain free of steatorrhoea under fat loading, which would point to a genuine species difference in how a contracted, cholic-acid-enriched pool supports lipid absorption rather than to a dietary artefact.
Show evidence (2 references)
PMID:12819193 SUPPORT Model Organism
"On a low fat diet, the Slc10a2-/- mice did not have steatorrhea."
The negative result at the heart of the mismatch, together with the dietary condition under which it was obtained.
PMID:9109432 SUPPORT Human Clinical
"congenital diarrhea, steatorrhea, interruption of the enterohepatic circulation of bile acids, and reduced plasma cholesterol levels"
The human phenotype the model fails to reproduce, establishing the other half of the mismatch.
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Pathophysiology

9
Loss of ASBT Bile Acid Transport Function
Biallelic SLC10A2 variants abolish sodium-coupled bile acid uptake. The 1997 transfection work is unusually informative about how: the L243P and T262M mutant proteins were expressed normally and trafficked normally to the plasma membrane, yet transported no taurocholate. The lesion is therefore in transport function itself, not in protein folding, stability or membrane delivery, which is why it is modelled as a molecular functional defect rather than as a protein-loss node.
terminal ileal enterocyte CL:1000334 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves terminal ileal enterocyte, annotated with enterocyte of epithelium of small intestine (CL:1000334). CL:1000334 is a cell type from the Cell Ontology.
SLC10A2 hgnc:10906 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC10A2 (hgnc:10906). hgnc:10906 is a gene from the HUGO Gene Nomenclature Committee.
bile acid:sodium symporter activity GO:0008508 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves bile acid:sodium symporter activity (GO:0008508), qualified as loss of function. GO:0008508 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
ileum UBERON:0002116 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ileum (UBERON:0002116). UBERON:0002116 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Failure of Ileal Bile Acid Reclamation
Show evidence (2 references)
PMID:9109432 SUPPORT In Vitro
"In transfected COS cells, the L243P, T262M, and double mutant (L243P/T262M) did not affect transporter protein expression or trafficking to the plasma membrane; however, transport of taurocholate and other bile acids was abolished."
Establishes that the mutant transporter reaches the membrane but does not transport, which is exactly the distinction this node makes. Graded IN_VITRO because the assay was in transfected COS cells.
PMID:9109432 SUPPORT Human Clinical
"The dysfunctional mutations were not detected in 104 unaffected control subjects, whereas the A171S was present in 28% of that population."
The control-screening result that separates the two dysfunctional alleles from the common A171S polymorphism, which had no effect on taurocholate uptake. Included because it is what makes the genotype-function assignment credible on a single family.
Failure of Ileal Bile Acid Reclamation
Active reabsorption in the terminal ileum is the step that normally recovers the great majority of the bile acid pool on each enterohepatic cycle. Its loss cannot be compensated: the mouse knockout shows that alternative absorptive mechanisms, including passive uptake along the rest of the intestine, do not make up the shortfall.
bile acid and bile salt transport GO:0015721 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased bile acid and bile salt transport (GO:0015721). GO:0015721 is a biological process from the Gene Ontology. ↓ DECREASED
ileum UBERON:0002116 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ileum (UBERON:0002116). UBERON:0002116 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Slc10a2-null mouse Mouse recapitulates Faecal bile acid excretion rises 10- to 20-fold and is not further increased by a bile acid binding resin, indicating essentially complete failure of active ileal reclamation.
Downstream
Colonic Bile Acid Spillover and Secretory Diarrhoea
Contracted Bile Acid Pool
Show evidence (2 references)
PMID:12819193 SUPPORT Model Organism
"These data indicate that Slc10a2 is essential for efficient intestinal absorption of bile acids and that alternative absorptive mechanisms are unable to compensate for loss of Slc10a2 function."
Establishes both that the transporter is required and that no alternative route compensates, which is the non-redundancy claim this node makes. Graded MODEL_ORGANISM.
PMID:11396803 SUPPORT Other
"This process is primarily localized to the terminal ileum and is mediated by a 48-kd sodium-dependent bile acid cotransporter (SLC10A2 = ASBT)."
Localises the reclamation step to the terminal ileum and names the responsible transporter. Graded OTHER because this is a review article rather than a primary study.
Colonic Bile Acid Spillover and Secretory Diarrhoea
Unabsorbed bile acids pass into the colon and watery diarrhoea follows from birth. The colonic secretagogue mechanism - bile acids driving water and electrolyte secretion through cAMP, TGR5 and aquaporin changes - is the standard textbook account, but neither citation on this node establishes it, so the node claims only the delivery and the diarrhoea and leaves the secretory mechanism to be evidenced by a curator who has a source for it. The rat pelvic-irradiation model, in which ileal Asbt is downregulated by radiation rather than by mutation, shows the same redistribution - ileal bile acids fall, colonic and faecal bile acids rise, diarrhoea follows - and is included here as convergent evidence for the mechanism from a different cause of the same transporter loss.
colon UBERON:0001155 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in colon (UBERON:0001155). UBERON:0001155 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Congenital Watery Diarrhoea
Growth Failure
Show evidence (2 references)
PMID:9109432 SUPPORT Human Clinical
"Primary bile acid malabsorption (PBAM) is an idiopathic intestinal disorder associated with congenital diarrhea, steatorrhea, interruption of the enterohepatic circulation of bile acids, and reduced plasma cholesterol levels."
The clinical definition, naming congenital diarrhoea as the presenting feature.
PMID:31900034 SUPPORT Model Organism
"Bile acid malabsorption is partially responsible for RID post-pelvic radiation in rats, and the potential mechanism is related to the downregulation of the ileal Asbt."
Convergent evidence that reduced ileal Asbt causes bile acid malabsorption and diarrhoea, from an acquired rather than genetic cause. Graded MODEL_ORGANISM because the study is in rats, and included as mechanistic corroboration rather than as evidence about the genetic disease itself.
Contracted Bile Acid Pool
Bile acids lost to the colon are not returned to the liver, so the circulating pool contracts. In the mouse this is quantified: faecal excretion rises 10- to 20-fold and the pool falls by 80% even though synthesis has increased, and the residue is selectively enriched in cholic acid. Pool contraction is an organism-level state while the compensatory synthetic response is a hepatocyte process, so they are separate nodes with the regulatory step that connects them modelled between them.
Animal models
Slc10a2-null mouse Mouse recapitulates The pool falls by 80% despite increased synthesis, and becomes selectively enriched in cholic acid.
Downstream
Loss of FXR-FGF19 Signalling from the Ileum
Steatorrhoea and Fat Malabsorption
Show evidence (1 reference)
PMID:12819193 SUPPORT Model Organism
"In the Slc10a2-/- mice, fecal bile acid excretion was elevated 10- to 20-fold and was not further increased by feeding a bile acid binding resin. Despite increased bile acid synthesis, the bile acid pool size was decreased by 80% and selectively enriched in cholic acid in the Slc10a2-/- mice."
Quantifies the faecal loss and the net pool contraction that persists despite compensatory synthesis. Graded MODEL_ORGANISM.
Loss of FXR-FGF19 Signalling from the Ileum
The regulatory step that explains why synthesis rises, and the reason the pool and synthesis nodes needed separating. Bile acids taken up by ileal enterocytes normally activate the nuclear receptor FXR, which drives FGF19 production; FGF19 travels in the portal circulation to the hepatocyte and suppresses CYP7A1, the rate-limiting enzyme of bile acid synthesis. When ASBT cannot bring bile acids into the enterocyte, intracellular concentrations never rise, FXR is not activated, FGF19 output collapses, and CYP7A1 is released from inhibition. This is also why the two main diagnostic biomarkers work: low serum FGF19 reads the failed signal directly, and serum C4 is an intermediate of the CYP7A1 reaction that the signal would have suppressed.
terminal ileal enterocyte CL:1000334 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves terminal ileal enterocyte, annotated with enterocyte of epithelium of small intestine (CL:1000334). CL:1000334 is a cell type from the Cell Ontology.
NR1H4 hgnc:7967 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NR1H4 (hgnc:7967). hgnc:7967 is a gene from the HUGO Gene Nomenclature Committee. FGF19 hgnc:3675 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FGF19 (hgnc:3675). hgnc:3675 is a gene from the HUGO Gene Nomenclature Committee.
fibroblast growth factor receptor signaling pathway GO:0008543 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased fibroblast growth factor receptor signaling pathway (GO:0008543). GO:0008543 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
CYP7A1 Disinhibition and Compensatory Hepatic Synthesis
Show evidence (2 references)
PMID:35683489 SUPPORT Other
"In the ileocytes, BAs have an entero-hormonal role. Indeed, high BAs intracellular levels stimulate the production of fibroblast growth factor 19 (FGF19) acting on the nuclear Farnesoid X factor (FXR)"
States the sensing step: intracellular bile acid concentration in the ileocyte drives FGF19 production via FXR. Graded OTHER because the source is a review.
PMID:38338820 SUPPORT Other
"Decreased secretion levels of FGF19 from ileal cells lead to attenuated suppression of CYP7A1 activity resulting in elevated endogenous production of bile acids."
The direct statement of this node's consequence: less ileal FGF19 means less CYP7A1 suppression and more synthesis. Graded OTHER as a review.
CYP7A1 Disinhibition and Compensatory Hepatic Synthesis
With FGF19 suppression removed, hepatocyte CYP7A1 activity rises and bile acid synthesis increases to replace the losses. Because that synthesis consumes cholesterol, the sustained drain is what lowers plasma cholesterol.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
CYP7A1 hgnc:2651 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CYP7A1 (hgnc:2651). hgnc:2651 is a gene from the HUGO Gene Nomenclature Committee.
bile acid biosynthetic process GO:0006699 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased bile acid biosynthetic process (GO:0006699). GO:0006699 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Reduced Plasma Cholesterol
Show evidence (2 references)
PMID:35683489 SUPPORT Other
"A functional gene Klothoβ (KLB) interacts biochemically with FGFR4, allowing FGF19 to trigger intracellular signaling resulting in downregulation of cytochrome P450 7A1 (CYP7A1) activity and suppression of BA synthesis"
Establishes the FGF19-to-CYP7A1 suppression this node models the loss of. Graded OTHER as a review.
PMID:35683489 SUPPORT Other
"An intermediate marker generated by this reaction is 7α-hydroxy-4-cholesten-3-one (C4), which is consequently an indirect marker of BA synthesis"
Identifies C4 as the readout of this node, which is what makes it a usable biomarker rather than an incidental metabolite.
Steatorrhoea and Fat Malabsorption
A contracted bile acid pool impairs micellar solubilisation of dietary fat, producing steatorrhoea in affected humans. This node is where the mouse and the human diverge, and the divergence is recorded rather than reconciled - see the HUMAN_MODEL_MISMATCH discussion.
Animal models
Slc10a2-null mouse Mouse fails to recapitulate On a low fat diet the Slc10a2-null mouse does not have steatorrhoea. Faecal neutral sterol excretion rises only 3-fold and intestinal cholesterol absorption falls only 20%, because the smaller cholic-acid-enriched pool is still sufficient to support intestinal lipid absorption.
Downstream
Steatorrhoea
Fat-Soluble Vitamin Malabsorption
Show evidence (1 reference)
PMID:9109432 SUPPORT Human Clinical
"congenital diarrhea, steatorrhea, interruption of the enterohepatic circulation of bile acids, and reduced plasma cholesterol levels"
Names steatorrhoea among the defining clinical features of the human disease.
Fat-Soluble Vitamin Malabsorption
Impaired micellar solubilisation carries the fat-soluble vitamins A, D, E and K down with dietary fat. This is the arm that can dominate the presentation entirely: in the 2025 genotyped case the vitamin deficiency was the whole illness, producing rickets, a hypocalcaemic seizure in infancy and reduced final height in a patient with normal stools and no steatorrhoea. Lifelong vitamin supplementation, not sequestrant therapy, was what she actually needed.
Downstream
Hypocalcemia
Growth Failure
Fat-Soluble Vitamin Deficiency
Rickets
Show evidence (2 references)
PMID:40814585 SUPPORT Human Clinical
"We present a case of a young female patient with persistent and severe fat-soluble vitamin deficiency since infancy."
Establishes fat-soluble vitamin deficiency as a presentation of SLC10A2 deficiency in a molecularly confirmed patient.
PMID:40814585 SUPPORT Human Clinical
"A bile retention scan showed severe bile acid malabsorption, with only 1.6% of radioactively labeled bile acids retained 7 days after intake."
Quantifies the malabsorption in the same patient, which is what links the vitamin deficiency to this entry's transport lesion rather than to some other cause.
Reduced Plasma Cholesterol
Continuous faecal loss of bile acids forces sustained hepatic conversion of cholesterol into bile acids, lowering plasma cholesterol. This is the basis on which partial ASBT inhibition was pursued as a lipid-lowering strategy.
Animal models
Slc10a2-null mouse Mouse fails to recapitulate Rather than the reduced plasma cholesterol seen in affected humans, plasma HDL cholesterol was slightly elevated in the null mice, a result the authors themselves flag as unexpected. Hepatic cholesteryl ester content did fall by half, so the hepatic drain is present; it is the plasma readout that does not translate.
Downstream
Hypocholesterolaemia
Show evidence (2 references)
PMID:9109432 SUPPORT Human Clinical
"congenital diarrhea, steatorrhea, interruption of the enterohepatic circulation of bile acids, and reduced plasma cholesterol levels"
Names reduced plasma cholesterol among the defining features.
PMID:11396803 SUPPORT Other
"Partial inhibition of ASBT may be useful in the treatment of hypercholesterolemia and intrahepatic cholestasis."
Supports the therapeutic corollary noted in this node's description: the same axis is deliberately targeted pharmacologically.
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Pathograph

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

7
Digestive 2
Congenital Watery Diarrhoea Chronic diarrhea HP:0002028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhoea, annotated with Chronic diarrhea (HP:0002028), qualified as temporality chronic. HP:0002028 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:9109432 SUPPORT Human Clinical
"Primary bile acid malabsorption (PBAM) is an idiopathic intestinal disorder associated with congenital diarrhea, steatorrhea, interruption of the enterohepatic circulation of bile acids, and reduced plasma cholesterol levels."
Names congenital diarrhoea as a defining feature. No frequency is recorded: the human evidence base is a single family.
Steatorrhoea Steatorrhea HP:0002570 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Steatorrhea (HP:0002570). HP:0002570 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9109432 SUPPORT Human Clinical
"congenital diarrhea, steatorrhea, interruption of the enterohepatic circulation of bile acids, and reduced plasma cholesterol levels"
Names steatorrhoea among the defining features.
Metabolism 1
Hypocalcemia HP:0002901 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypocalcemia (HP:0002901). HP:0002901 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40814585 SUPPORT Human Clinical
"The patient's first hospitalization was at 10 months of age when she was admitted with a nonfebrile generalized seizure related to hypocalcemia"
The hypocalcaemic seizure that brought the patient to attention.
Musculoskeletal 1
Rickets HP:0002748 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rickets (HP:0002748). HP:0002748 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40814585 SUPPORT Human Clinical
"An X-ray was performed and showed rachitis."
The radiographic confirmation. Rachitis is the term the report uses for rickets.
Growth 1
Growth Failure Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34192422 SUPPORT Human Clinical
"The patient's clinical manifestations were chronic diarrhea with increased BAs in the feces and extreme stunting, which was diagnosed as BAD."
Growth failure in a homozygous SLC10A2 patient, severe enough to be in the paper's title.
PMID:40814585 SUPPORT Human Clinical
"Growth and weight were consistently below target with final height at 155.5 cm"
Growth failure in a second, independently reported genotyped patient with a different presentation.
Other 2
Hypocholesterolaemia Hypocholesterolemia HP:0003146 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypocholesterolemia (HP:0003146). HP:0003146 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9109432 SUPPORT Human Clinical
"congenital diarrhea, steatorrhea, interruption of the enterohepatic circulation of bile acids, and reduced plasma cholesterol levels"
Names reduced plasma cholesterol among the defining features.
Fat-Soluble Vitamin Deficiency Decreased circulating vitamin D concentration HP:0100512 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating vitamin D concentration (HP:0100512), qualified as temporality chronic. HP:0100512 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:40814585 SUPPORT Human Clinical
"The patient was generally asymptomatic while receiving continuous vitamin subsidy."
Establishes both the deficiency and its dependence on continuous replacement. The bound term names vitamin D specifically because HPO has no single fat-soluble-vitamin-deficiency term; the other three vitamins are named in the description rather than given manufactured bindings.
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Genetic Associations

1
SLC10A2
Gene: SLC10A2 hgnc:10906 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC10A2 (hgnc:10906). hgnc:10906 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive inheritance
Show evidence (2 references)
PMID:9109432 SUPPORT Human Clinical
"These findings establish that SLC10A2 mutations can cause PBAM and underscore the ileal Na+/bile acid cotransporter's role in intestinal reclamation of bile acids."
The authors' causal conclusion assigning PBAM to SLC10A2.
PMID:11396803 SUPPORT Other
"Inherited mutation of ASBT leads to congenital diarrhea secondary to bile acid malabsorption."
Independent confirmation of the gene-disease relationship in a review.
🗃️

External Assertions

1
OMIM primary bile acid malabsorption record
OMIM disease record OMIM:613291
The OMIM record MONDO:0013214 xrefs, recorded structurally so the entry's identity is auditable against the source identifier. This is not `mappings.omim_mappings`: the `DiseaseMappings` class carries only ICD-10-CM, ICD-11, MONDO and NCIT slots, so there is nowhere in `mappings` for an OMIM identity to go.
💊

Medical Actions

3
Lifelong Fat-Soluble Vitamin Supplementation
Action: nutritional supportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is nutritional support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Continuous replacement of vitamins A, D, E and K. In the one genotyped patient with a documented long-term course this was the therapy that worked and the one she stayed on: her levels dropped markedly whenever she was non-compliant or the dose was reduced. Modelled first among the treatments because, for the vitamin-deficiency presentation, it is not adjunctive - it is the treatment.
Mechanism Target:
Fat-Soluble Vitamin Malabsorption — Bypasses the malabsorption by supplying the vitamins directly. It does not correct the transport defect, which is why replacement has to be lifelong.
Show evidence (1 reference)
PMID:40814585 SUPPORT Human Clinical
"However, she needed continuous subsidy with ADEK, and the levels dropped markedly when she was noncompliant, or during doctor-induced attempts to lower vitamin-doses."
Demonstrates both efficacy and dependence: the deficiency returns when replacement stops, which is what makes this lifelong rather than corrective.
Bile Acid Sequestrant Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: cholestyramine NCIT:C28929 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses cholestyramine (NCIT:C28929). NCIT:C28929 is a therapeutic agent from the NCI Thesaurus.
Cholestyramine and colesevelam are the standard therapy for bile acid diarrhoea. There is no controlled-trial evidence in the Mendelian form - the placebo-controlled colesevelam data come from the common acquired condition - but there is genotype-confirmed case evidence, and it points both ways depending on which arm of the disease dominates. In an infant with the diarrhoeal presentation, colestyramine resolved the diarrhoea and catch-up growth followed. In the patient whose presentation was fat-soluble vitamin deficiency with no diarrhoea, a sequestrant was tried on the strength of that first report and was discontinued for side effects with no effect on vitamin uptake. Both outcomes follow from the same mechanism. A sequestrant binds luminal bile acids, so it acts on the colonic spillover arm and does nothing for the contracted pool - which is why it helps the diarrhoea and not the vitamin malabsorption. The evidence below is deliberately not one-sided.
Mechanism Target:
Colonic Bile Acid Spillover and Secretory Diarrhoea — Binds the bile acids delivered to the colon. Deliberately not linked to the vitamin or pool nodes, since it does not act on them - which is exactly the asymmetry the two case outcomes below show.
Show evidence (2 references)
PMID:34192422 SUPPORT Human Clinical
"Following the confirmation of a BAD diagnosis, colestyramine was administered in small doses of 0.5 g twice daily. Subsequently, the manifestation of diarrhea subsided."
Genotype-confirmed evidence that a sequestrant works on the diarrhoeal arm. This is the half of the picture the entry previously omitted, and it comes from a reference the entry already cites twice elsewhere.
PMID:40814585 REFUTE Human Clinical
"Treatment with a bile acid sequestrant was attempted but discontinued due to side effects and no significant effect on intestinal vitamin uptake."
Graded REFUTE with respect to the specific proposition that a sequestrant helps the vitamin-malabsorption arm of SLC10A2 deficiency. It is not evidence against sequestrants for bile acid diarrhoea generally, which is a different claim and a different population.
Low-Fat Diet
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Reducing dietary fat reduces the substrate for steatorrhoea. Listed because it is standard management of fat malabsorption; no SLC10A2-specific evidence was found, and none is claimed.
🔬

Biochemical Markers

2
Serum FGF19
Show evidence (1 reference)
PMID:38338820 SUPPORT Other
"Current diagnostic methods encompass bile acid sequestrants (BAS), 48-h fecal bile acid tests, serum 7α-hydroxy-4-cholesten-3-one (C4), fibroblast growth factor 19 (FGF19) testing, and 75Selenium HomotauroCholic acid test (75SeHCAT)."
Lists FGF19 among the established diagnostic measurements. Graded OTHER as a review.
Serum 7-alpha-hydroxy-4-cholesten-3-one (C4)
Show evidence (2 references)
PMID:35683489 SUPPORT Other
"An intermediate marker generated by this reaction is 7α-hydroxy-4-cholesten-3-one (C4), which is consequently an indirect marker of BA synthesis"
Establishes what C4 measures and why, which is what makes it interpretable as a readout of the synthesis node rather than a loose correlate.
PMID:35683489 SUPPORT Other
"The validation of the utility in the clinical practice of several other serum markers, such as 7α-hydroxy-4-cholesten-3-one (C4) and the fibroblast growth factor 19 (FGF19) is ongoing."
Graded PARTIAL deliberately: the same review that explains what these markers measure also says their clinical validation is still ongoing, and the entry should carry that rather than presenting them as established tests.
🔬

Diagnosis

2
Bile Acid Retention Testing
The selenium homotaurocholic acid retention test (75SeHCAT) quantifies malabsorption directly and is the established gold standard. In the 2025 case only 1.6% of labelled bile acid was retained at seven days, which is what converted an eighteen-year-old diagnostic mystery into a specific answer.
Show evidence (2 references)
PMID:40814585 SUPPORT Human Clinical
"A bile retention scan showed severe bile acid malabsorption, with only 1.6% of radioactively labeled bile acids retained 7 days after intake."
The test and a quantified abnormal result. The scan described is a selenium-labelled bile acid retention test, which is the 75SeHCAT study named in the review literature.
PMID:35683489 SUPPORT Other
"Currently, the selenium homotaurocholic acid test is the gold standard for BAD diagnosis and severity assessment. However, it is an expensive method and not widely available."
Establishes 75SeHCAT as the gold standard, and in the same sentence the access limitation that is why the serum markers above are being validated at all.
Exome or Targeted SLC10A2 Sequencing
The definitive test. Both recent genotyped cases were solved by sequencing after prolonged and unsuccessful conventional workup, which is the practical argument for testing early rather than last.
Show evidence (2 references)
PMID:40814585 SUPPORT Human Clinical
"This case highlights the importance of early genetic testing in patients with unexplained fat-soluble vitamin deficiency."
The authors' own diagnostic recommendation, arising from an eighteen-year delay.
PMID:34192422 SUPPORT Human Clinical
"Moreover, they highlight the value of molecular genetic screening for diagnosing BAD in young patients."
The same recommendation from the independent paediatric case.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
A handful of molecularly confirmed cases. Recorded as a class rather than a rate because no denominator exists; this makes the caveat in the entry's top-level notes machine-readable rather than prose-only.
🐁

Animal Models

1
Slc10a2-null mouse
Targeted disruption of Slc10a2 by homologous recombination. Homozygous nulls are physically indistinguishable from wild type. The model reproduces the transport lesion with high fidelity but does not reproduce the human malabsorptive illness.
Species
Mouse
Genotype
Slc10a2 homozygous null by targeted deletion
Publication
PMID:12819193
Pathograph links
Failure of Ileal Bile Acid Reclamation recapitulates fidelity: high Faecal bile acid excretion rises 10- to 20-fold and is not further increased by a bile acid binding resin, indicating essentially complete failure of active ileal reclamation.
Readouts
Faecal bile acid excretion
Direction: INCREASED
Interpretation: Direct quantification of the bile acids that active ileal uptake would normally have recovered.
Show evidence (1 reference)
PMID:12819193 SUPPORT Model Organism
"In the Slc10a2-/- mice, fecal bile acid excretion was elevated 10- to 20-fold and was not further increased by feeding a bile acid binding resin."
Reports the measurement and its magnitude, and the resin result showing reclamation is already maximally impaired.
Show evidence (1 reference)
PMID:12819193 SUPPORT Model Organism
"These data indicate that Slc10a2 is essential for efficient intestinal absorption of bile acids and that alternative absorptive mechanisms are unable to compensate for loss of Slc10a2 function."
Supports treating this model as informative for the reclamation node specifically.
Contracted Bile Acid Pool recapitulates fidelity: high The pool falls by 80% despite increased synthesis, and becomes selectively enriched in cholic acid.
Readouts
Bile acid pool size
Direction: DECREASED
Interpretation: Quantifies the net pool contraction that persists even after compensatory synthesis.
Show evidence (1 reference)
PMID:12819193 SUPPORT Model Organism
"Despite increased bile acid synthesis, the bile acid pool size was decreased by 80% and selectively enriched in cholic acid in the Slc10a2-/- mice."
Reports the pool measurement, the compensatory synthesis, and the compositional shift.
Steatorrhoea and Fat Malabsorption fails to recapitulate fidelity: low On a low fat diet the Slc10a2-null mouse does not have steatorrhoea. Faecal neutral sterol excretion rises only 3-fold and intestinal cholesterol absorption falls only 20%, because the smaller cholic-acid-enriched pool is still sufficient to support intestinal lipid absorption.
Limitations: The mouse fails at exactly the node where the human disease is clinically defined. The most likely reasons are dietary and compositional rather than a difference in the transporter: the mice were studied on a low fat diet, so the residual pool was not stressed, and the selective cholic acid enrichment preserves micelle-forming capacity per unit of pool. The consequence for curation is that this model can be used to support the transport and pool nodes but must not be used to support the fat-malabsorption node, and its silence there is not evidence that human steatorrhoea is doubtful.
Show evidence (1 reference)
PMID:12819193 REFUTE Model Organism
"On a low fat diet, the Slc10a2-/- mice did not have steatorrhea. Fecal neutral sterol excretion was increased only 3-fold, and intestinal cholesterol absorption was reduced only 20%, indicating that the smaller cholic acid-enriched bile acid pool was sufficient to facilitate intestinal lipid absorption."
The negative result itself, with the authors' own explanation for it. Graded REFUTE because it refutes the proposition that this model reproduces the human fat-malabsorption phenotype, not the proposition that humans have steatorrhoea.
Reduced Plasma Cholesterol fails to recapitulate fidelity: low Rather than the reduced plasma cholesterol seen in affected humans, plasma HDL cholesterol was slightly elevated in the null mice, a result the authors themselves flag as unexpected. Hepatic cholesteryl ester content did fall by half, so the hepatic drain is present; it is the plasma readout that does not translate.
Limitations: Mouse and human lipoprotein physiology differ substantially - mice carry most plasma cholesterol as HDL and lack cholesteryl ester transfer protein - so a plasma cholesterol endpoint is among the least transferable readouts this model could offer. The hepatic cholesteryl ester measurement is the informative one; the plasma value should not be read as evidence against the human phenotype.
Show evidence (1 reference)
PMID:12819193 REFUTE Model Organism
"Liver cholesteryl ester content was reduced by 50% in Slc10a2-/- mice, and unexpectedly plasma high density lipoprotein cholesterol levels were slightly elevated."
Reports both the expected hepatic cholesterol depletion and the plasma result that runs opposite to the human phenotype. Graded REFUTE with respect to the model's fidelity for this node.
{ }

Source YAML

click to show 
name: Primary Bile Acid Malabsorption
creation_date: "2026-08-28T00:05:00Z"
category: Mendelian
description: >-
  Primary bile acid malabsorption is a congenital diarrhoeal disorder caused by
  biallelic loss-of-function variants in SLC10A2, which encodes the ileal apical
  sodium-dependent bile acid transporter (ASBT, also called IBAT). ASBT performs
  the active reclamation step of the enterohepatic circulation: it takes bile
  acids back up across the apical membrane of terminal ileal enterocytes so they
  can return to the liver. Without it, bile acids are not recovered, they spill
  into the colon where they act as secretagogues, and the result is
  congenital-onset watery diarrhoea with steatorrhoea. The interruption of the
  enterohepatic circulation has a second consequence away from the gut: the bile
  acid pool contracts, hepatic synthesis is de-repressed to compensate, and
  because that synthesis consumes cholesterol, plasma cholesterol falls. The
  disease is important out of proportion to its rarity because the same
  transporter is a deliberate drug target - partial pharmacological ASBT
  inhibition is used to treat cholestatic pruritus and has been explored for
  hypercholesterolaemia - so this disorder is in effect the complete-loss end of
  a dose-response curve that medicine now traverses on purpose.
parents:
  - Congenital Diarrhoeal Disorder
  - Inborn Error of Metabolism
synonyms:
  - PBAM
  - congenital bile acid diarrhoea
  - ileal bile acid transporter deficiency
  - ASBT deficiency
  - bile acid malabsorption, primary, 1
disease_term:
  preferred_term: bile acid malabsorption, primary, 1
  term:
    id: MONDO:0013214
    label: bile acid malabsorption, primary, 1
notes: >-
  Evidence-base caveat. The human evidence for this disease is a handful of
  molecularly confirmed case reports - the 1997 index family plus at least two
  further genotyped patients - and there is no cohort, no natural-history
  series, and no per-phenotype frequency data. Phenotypes in this entry
  therefore carry no frequency values. That is the reason, and it is worth
  stating precisely: the problem is the absence of a denominator, not the number
  of families.

  The case-report literature also does something a cohort would not: it shows
  how wide the phenotype is. A homozygous patient reported in 2025 had lifelong
  severe fat-soluble vitamin deficiency, rickets, a hypocalcaemic seizure in
  infancy and reduced final height, with normal stool frequency and consistency
  and no steatorrhoea at all. Diarrhoea and steatorrhoea are therefore not
  obligate features, and an entry that modelled only those would miss the
  presentation that took eighteen years to diagnose. The vitamin-deficiency arm
  is curated below for that reason.

  The strongest mechanistic evidence remains the Slc10a2-null mouse, which - as
  the HUMAN_MODEL_MISMATCH discussion records - reproduces the transport defect
  faithfully while not reproducing the human malabsorptive phenotype.

  Scope. MONDO:0013214 is primary bile acid malabsorption type 1 specifically.
  PBAM2, caused by SLC51B/OSTbeta variants and presenting with chronic diarrhoea
  plus cholestatic liver features, is a distinct Mendelian entity and is
  deliberately out of scope here. It is the easier of the two neighbours to
  confuse this entry with, so it is named alongside the acquired condition
  below.

  Terminology caution. "Bile acid malabsorption" is used far more often in
  gastroenterology for the common acquired condition - after ileal resection, in
  Crohn disease, post-cholecystectomy, or idiopathic - which is a different
  entity with a different mechanism and is not curated here. This entry is the
  primary, SLC10A2-determined congenital form only.
external_assertions:
  - name: OMIM primary bile acid malabsorption record
    source: OMIM
    assertion_type: disease_record
    external_id: OMIM:613291
    url: https://omim.org/entry/613291
    description: >-
      The OMIM record MONDO:0013214 xrefs, recorded structurally so the entry's
      identity is auditable against the source identifier. This is not
      `mappings.omim_mappings`: the `DiseaseMappings` class carries only
      ICD-10-CM, ICD-11, MONDO and NCIT slots, so there is nowhere in `mappings`
      for an OMIM identity to go.
prevalence:
  - population: Worldwide
    measure_type: CASES_IN_LITERATURE
    prevalence_class: ULTRA_RARE
    notes: >-
      A handful of molecularly confirmed cases. Recorded as a class rather than
      a rate because no denominator exists; this makes the caveat in the entry's
      top-level notes machine-readable rather than prose-only.
inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    description: >-
      The index family carried compound heterozygous variants: one allele with a
      splice-donor change, the other with two missense substitutions that
      together abolish transport.
    evidence:
      - reference: PMID:9109432
        reference_title: >-
          Primary bile acid malabsorption caused by mutations in the ileal
          sodium-dependent bile acid transporter gene (SLC10A2).
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Four polymorphisms were identified and sequenced in a family with
          congenital PBAM. One allele encoded an A171S missense mutation and a
          mutated donor splice site for exon 3. The other allele encoded two
          missense mutations at conserved amino acid positions, L243P and T262M.
        explanation: >-
          Describes the compound heterozygous allele structure in the index
          family, consistent with autosomal recessive inheritance.
pathophysiology:
  - name: Loss of ASBT Bile Acid Transport Function
    biological_scale: MOLECULAR
    description: >-
      Biallelic SLC10A2 variants abolish sodium-coupled bile acid uptake. The
      1997 transfection work is unusually informative about how: the L243P and
      T262M mutant proteins were expressed normally and trafficked normally to
      the plasma membrane, yet transported no taurocholate. The lesion is
      therefore in transport function itself, not in protein folding, stability
      or membrane delivery, which is why it is modelled as a molecular
      functional defect rather than as a protein-loss node.
    genes:
      - preferred_term: SLC10A2
        term:
          id: hgnc:10906
          label: SLC10A2
    molecular_functions:
      - preferred_term: bile acid:sodium symporter activity
        term:
          id: GO:0008508
          label: bile acid:sodium symporter activity
        modifier: LOSS_OF_FUNCTION
    cell_types:
      - preferred_term: terminal ileal enterocyte
        term:
          id: CL:1000334
          label: enterocyte of epithelium of small intestine
    locations:
      - preferred_term: ileum
        term:
          id: UBERON:0002116
          label: ileum
    downstream:
      - target: Failure of Ileal Bile Acid Reclamation
    evidence:
      - reference: PMID:9109432
        reference_title: >-
          Primary bile acid malabsorption caused by mutations in the ileal
          sodium-dependent bile acid transporter gene (SLC10A2).
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          In transfected COS cells, the L243P, T262M, and double mutant
          (L243P/T262M) did not affect transporter protein expression or
          trafficking to the plasma membrane; however, transport of taurocholate
          and other bile acids was abolished.
        explanation: >-
          Establishes that the mutant transporter reaches the membrane but does
          not transport, which is exactly the distinction this node makes.
          Graded IN_VITRO because the assay was in transfected COS cells.
      - reference: PMID:9109432
        reference_title: >-
          Primary bile acid malabsorption caused by mutations in the ileal
          sodium-dependent bile acid transporter gene (SLC10A2).
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The dysfunctional mutations were not detected in 104 unaffected
          control subjects, whereas the A171S was present in 28% of that
          population.
        explanation: >-
          The control-screening result that separates the two dysfunctional
          alleles from the common A171S polymorphism, which had no effect on
          taurocholate uptake. Included because it is what makes the
          genotype-function assignment credible on a single family.
  - name: Failure of Ileal Bile Acid Reclamation
    biological_scale: TISSUE
    description: >-
      Active reabsorption in the terminal ileum is the step that normally
      recovers the great majority of the bile acid pool on each enterohepatic
      cycle. Its loss cannot be compensated: the mouse knockout shows that
      alternative absorptive mechanisms, including passive uptake along the rest
      of the intestine, do not make up the shortfall.
    biological_processes:
      - preferred_term: bile acid and bile salt transport
        term:
          id: GO:0015721
          label: bile acid and bile salt transport
        modifier: DECREASED
    locations:
      - preferred_term: ileum
        term:
          id: UBERON:0002116
          label: ileum
    downstream:
      - target: Colonic Bile Acid Spillover and Secretory Diarrhoea
      - target: Contracted Bile Acid Pool
    evidence:
      - reference: PMID:12819193
        reference_title: >-
          Targeted deletion of the ileal bile acid transporter eliminates
          enterohepatic cycling of bile acids in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          These data indicate that Slc10a2 is essential for efficient intestinal
          absorption of bile acids and that alternative absorptive mechanisms
          are unable to compensate for loss of Slc10a2 function.
        explanation: >-
          Establishes both that the transporter is required and that no
          alternative route compensates, which is the non-redundancy claim this
          node makes. Graded MODEL_ORGANISM.
      - reference: PMID:11396803
        reference_title: "Intestinal bile acid transport: biology, physiology, and pathophysiology."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          This process is primarily localized to the terminal ileum and is
          mediated by a 48-kd sodium-dependent bile acid cotransporter (SLC10A2
          = ASBT).
        explanation: >-
          Localises the reclamation step to the terminal ileum and names the
          responsible transporter. Graded OTHER because this is a review article
          rather than a primary study.
  - name: Colonic Bile Acid Spillover and Secretory Diarrhoea
    biological_scale: ORGANISM
    description: >-
      Unabsorbed bile acids pass into the colon and watery diarrhoea follows
      from birth. The colonic secretagogue mechanism - bile acids driving water
      and electrolyte secretion through cAMP, TGR5 and aquaporin changes - is
      the standard textbook account, but neither citation on this node
      establishes it, so the node claims only the delivery and the diarrhoea and
      leaves the secretory mechanism to be evidenced by a curator who has a
      source for it. The rat pelvic-irradiation model, in which
      ileal Asbt is downregulated by radiation rather than by mutation, shows
      the same redistribution - ileal bile acids fall, colonic and faecal bile
      acids rise, diarrhoea follows - and is included here as convergent
      evidence for the mechanism from a different cause of the same transporter
      loss.
    locations:
      - preferred_term: colon
        term:
          id: UBERON:0001155
          label: colon
    downstream:
      - target: Congenital Watery Diarrhoea
      - target: Growth Failure
    evidence:
      - reference: PMID:9109432
        reference_title: >-
          Primary bile acid malabsorption caused by mutations in the ileal
          sodium-dependent bile acid transporter gene (SLC10A2).
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Primary bile acid malabsorption (PBAM) is an idiopathic intestinal
          disorder associated with congenital diarrhea, steatorrhea,
          interruption of the enterohepatic circulation of bile acids, and
          reduced plasma cholesterol levels.
        explanation: >-
          The clinical definition, naming congenital diarrhoea as the presenting
          feature.
      - reference: PMID:31900034
        reference_title: "Mechanism of Asbt (Slc10a2)-related bile acid malabsorption in diarrhea after pelvic radiation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Bile acid malabsorption is partially responsible for RID post-pelvic
          radiation in rats, and the potential mechanism is related to the
          downregulation of the ileal Asbt.
        explanation: >-
          Convergent evidence that reduced ileal Asbt causes bile acid
          malabsorption and diarrhoea, from an acquired rather than genetic
          cause. Graded MODEL_ORGANISM because the study is in rats, and
          included as mechanistic corroboration rather than as evidence about
          the genetic disease itself.
  - name: Contracted Bile Acid Pool
    biological_scale: ORGANISM
    description: >-
      Bile acids lost to the colon are not returned to the liver, so the
      circulating pool contracts. In the mouse this is quantified: faecal
      excretion rises 10- to 20-fold and the pool falls by 80% even though
      synthesis has increased, and the residue is selectively enriched in cholic
      acid. Pool contraction is an organism-level state while the compensatory
      synthetic response is a hepatocyte process, so they are separate nodes with
      the regulatory step that connects them modelled between them.
    downstream:
      - target: Loss of FXR-FGF19 Signalling from the Ileum
      - target: Steatorrhoea and Fat Malabsorption
    evidence:
      - reference: PMID:12819193
        reference_title: >-
          Targeted deletion of the ileal bile acid transporter eliminates
          enterohepatic cycling of bile acids in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In the Slc10a2-/- mice, fecal bile acid excretion was elevated 10- to
          20-fold and was not further increased by feeding a bile acid binding
          resin. Despite increased bile acid synthesis, the bile acid pool size
          was decreased by 80% and selectively enriched in cholic acid in the
          Slc10a2-/- mice.
        explanation: >-
          Quantifies the faecal loss and the net pool contraction that persists
          despite compensatory synthesis. Graded MODEL_ORGANISM.
  - name: Loss of FXR-FGF19 Signalling from the Ileum
    biological_scale: CELLULAR
    description: >-
      The regulatory step that explains why synthesis rises, and the reason the
      pool and synthesis nodes needed separating. Bile acids taken up by ileal
      enterocytes normally activate the nuclear receptor FXR, which drives FGF19
      production; FGF19 travels in the portal circulation to the hepatocyte and
      suppresses CYP7A1, the rate-limiting enzyme of bile acid synthesis. When
      ASBT cannot bring bile acids into the enterocyte, intracellular
      concentrations never rise, FXR is not activated, FGF19 output collapses,
      and CYP7A1 is released from inhibition. This is also why the two main
      diagnostic biomarkers work: low serum FGF19 reads the failed signal
      directly, and serum C4 is an intermediate of the CYP7A1 reaction that the
      signal would have suppressed.
    cell_types:
      - preferred_term: terminal ileal enterocyte
        term:
          id: CL:1000334
          label: enterocyte of epithelium of small intestine
    biological_processes:
      - preferred_term: fibroblast growth factor receptor signaling pathway
        term:
          id: GO:0008543
          label: fibroblast growth factor receptor signaling pathway
        modifier: DECREASED
    genes:
      - preferred_term: NR1H4
        term:
          id: hgnc:7967
          label: NR1H4
      - preferred_term: FGF19
        term:
          id: hgnc:3675
          label: FGF19
    downstream:
      - target: CYP7A1 Disinhibition and Compensatory Hepatic Synthesis
    evidence:
      - reference: PMID:35683489
        reference_title: "Pathophysiology and Clinical Management of Bile Acid Diarrhea."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          In the ileocytes, BAs have an entero-hormonal role. Indeed, high BAs
          intracellular levels stimulate the production of fibroblast growth
          factor 19 (FGF19) acting on the nuclear Farnesoid X factor (FXR)
        explanation: >-
          States the sensing step: intracellular bile acid concentration in the
          ileocyte drives FGF19 production via FXR. Graded OTHER because the
          source is a review.
      - reference: PMID:38338820
        reference_title: >-
          Bile Acid Diarrhea: From Molecular Mechanisms to Clinical Diagnosis
          and Treatment in the Era of Precision Medicine.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Decreased secretion levels of FGF19 from ileal cells lead to
          attenuated suppression of CYP7A1 activity resulting in elevated
          endogenous production of bile acids.
        explanation: >-
          The direct statement of this node's consequence: less ileal FGF19
          means less CYP7A1 suppression and more synthesis. Graded OTHER as a
          review.
  - name: CYP7A1 Disinhibition and Compensatory Hepatic Synthesis
    biological_scale: CELLULAR
    description: >-
      With FGF19 suppression removed, hepatocyte CYP7A1 activity rises and bile
      acid synthesis increases to replace the losses. Because that synthesis
      consumes cholesterol, the sustained drain is what lowers plasma
      cholesterol.
    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: INCREASED
    genes:
      - preferred_term: CYP7A1
        term:
          id: hgnc:2651
          label: CYP7A1
    downstream:
      - target: Reduced Plasma Cholesterol
    evidence:
      - reference: PMID:35683489
        reference_title: "Pathophysiology and Clinical Management of Bile Acid Diarrhea."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          A functional gene Klothoβ (KLB) interacts biochemically with FGFR4,
          allowing FGF19 to trigger intracellular signaling resulting in
          downregulation of cytochrome P450 7A1 (CYP7A1) activity and
          suppression of BA synthesis
        explanation: >-
          Establishes the FGF19-to-CYP7A1 suppression this node models the loss
          of. Graded OTHER as a review.
      - reference: PMID:35683489
        reference_title: "Pathophysiology and Clinical Management of Bile Acid Diarrhea."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          An intermediate marker generated by this reaction is
          7α-hydroxy-4-cholesten-3-one (C4), which is consequently an indirect
          marker of BA synthesis
        explanation: >-
          Identifies C4 as the readout of this node, which is what makes it a
          usable biomarker rather than an incidental metabolite.
  - name: Steatorrhoea and Fat Malabsorption
    biological_scale: ORGANISM
    downstream:
      - target: Steatorrhoea
      - target: Fat-Soluble Vitamin Malabsorption
    description: >-
      A contracted bile acid pool impairs micellar solubilisation of dietary
      fat, producing steatorrhoea in affected humans. This node is where the
      mouse and the human diverge, and the divergence is recorded rather than
      reconciled - see the HUMAN_MODEL_MISMATCH discussion.
    evidence:
      - reference: PMID:9109432
        reference_title: >-
          Primary bile acid malabsorption caused by mutations in the ileal
          sodium-dependent bile acid transporter gene (SLC10A2).
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          congenital diarrhea, steatorrhea, interruption of the enterohepatic
          circulation of bile acids, and reduced plasma cholesterol levels
        explanation: >-
          Names steatorrhoea among the defining clinical features of the human
          disease.
  - name: Fat-Soluble Vitamin Malabsorption
    biological_scale: ORGANISM
    description: >-
      Impaired micellar solubilisation carries the fat-soluble vitamins A, D, E
      and K down with dietary fat. This is the arm that can dominate the
      presentation entirely: in the 2025 genotyped case the vitamin deficiency
      was the whole illness, producing rickets, a hypocalcaemic seizure in
      infancy and reduced final height in a patient with normal stools and no
      steatorrhoea.
      Lifelong vitamin supplementation, not sequestrant therapy, was what she
      actually needed.
    downstream:
      - target: Hypocalcemia
      - target: Growth Failure
      - target: Fat-Soluble Vitamin Deficiency
      - target: Rickets
    evidence:
      - reference: PMID:40814585
        reference_title: >-
          Homozygosity for a variant in SLC10A2 and infancy onset severe
          fat-soluble vitamin deficiency due to bile acid malabsorption.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          We present a case of a young female patient with persistent and severe
          fat-soluble vitamin deficiency since infancy.
        explanation: >-
          Establishes fat-soluble vitamin deficiency as a presentation of
          SLC10A2 deficiency in a molecularly confirmed patient.
      - reference: PMID:40814585
        reference_title: >-
          Homozygosity for a variant in SLC10A2 and infancy onset severe
          fat-soluble vitamin deficiency due to bile acid malabsorption.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          A bile retention scan showed severe bile acid malabsorption, with only
          1.6% of radioactively labeled bile acids retained 7 days after intake.
        explanation: >-
          Quantifies the malabsorption in the same patient, which is what links
          the vitamin deficiency to this entry's transport lesion rather than to
          some other cause.
  - name: Reduced Plasma Cholesterol
    biological_scale: ORGANISM
    description: >-
      Continuous faecal loss of bile acids forces sustained hepatic conversion
      of cholesterol into bile acids, lowering plasma cholesterol. This is the
      basis on which partial ASBT inhibition was pursued as a lipid-lowering
      strategy.
    downstream:
      - target: Hypocholesterolaemia
    evidence:
      - reference: PMID:9109432
        reference_title: >-
          Primary bile acid malabsorption caused by mutations in the ileal
          sodium-dependent bile acid transporter gene (SLC10A2).
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          congenital diarrhea, steatorrhea, interruption of the enterohepatic
          circulation of bile acids, and reduced plasma cholesterol levels
        explanation: >-
          Names reduced plasma cholesterol among the defining features.
      - reference: PMID:11396803
        reference_title: "Intestinal bile acid transport: biology, physiology, and pathophysiology."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Partial inhibition of ASBT may be useful in the treatment of
          hypercholesterolemia and intrahepatic cholestasis.
        explanation: >-
          Supports the therapeutic corollary noted in this node's description:
          the same axis is deliberately targeted pharmacologically.
phenotypes:
  - name: Congenital Watery Diarrhoea
    category: Gastrointestinal
    description: >-
      Chronic watery diarrhoea present from birth, the presenting feature of the
      disease.
    phenotype_term:
      preferred_term: Chronic diarrhoea
      term:
        id: HP:0002028
        label: Chronic diarrhea
      temporality: CHRONIC
    evidence:
      - reference: PMID:9109432
        reference_title: >-
          Primary bile acid malabsorption caused by mutations in the ileal
          sodium-dependent bile acid transporter gene (SLC10A2).
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Primary bile acid malabsorption (PBAM) is an idiopathic intestinal
          disorder associated with congenital diarrhea, steatorrhea,
          interruption of the enterohepatic circulation of bile acids, and
          reduced plasma cholesterol levels.
        explanation: >-
          Names congenital diarrhoea as a defining feature. No frequency is
          recorded: the human evidence base is a single family.
  - name: Steatorrhoea
    category: Gastrointestinal
    phenotype_term:
      preferred_term: Steatorrhea
      term:
        id: HP:0002570
        label: Steatorrhea
    evidence:
      - reference: PMID:9109432
        reference_title: >-
          Primary bile acid malabsorption caused by mutations in the ileal
          sodium-dependent bile acid transporter gene (SLC10A2).
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          congenital diarrhea, steatorrhea, interruption of the enterohepatic
          circulation of bile acids, and reduced plasma cholesterol levels
        explanation: >-
          Names steatorrhoea among the defining features.
  - name: Hypocholesterolaemia
    category: Metabolic
    phenotype_term:
      preferred_term: Hypocholesterolemia
      term:
        id: HP:0003146
        label: Hypocholesterolemia
    evidence:
      - reference: PMID:9109432
        reference_title: >-
          Primary bile acid malabsorption caused by mutations in the ileal
          sodium-dependent bile acid transporter gene (SLC10A2).
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          congenital diarrhea, steatorrhea, interruption of the enterohepatic
          circulation of bile acids, and reduced plasma cholesterol levels
        explanation: >-
          Names reduced plasma cholesterol among the defining features.
  - name: Fat-Soluble Vitamin Deficiency
    category: Metabolic
    description: >-
      Deficiency of vitamins A, D, E and K, requiring lifelong supplementation.
      In at least one genotyped patient this was the presenting and dominant
      problem, with no diarrhoea or steatorrhoea.
    phenotype_term:
      preferred_term: Decreased circulating vitamin D concentration
      term:
        id: HP:0100512
        label: Decreased circulating vitamin D concentration
      temporality: CHRONIC
    evidence:
      - reference: PMID:40814585
        reference_title: >-
          Homozygosity for a variant in SLC10A2 and infancy onset severe
          fat-soluble vitamin deficiency due to bile acid malabsorption.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The patient was generally asymptomatic while receiving continuous
          vitamin subsidy.
        explanation: >-
          Establishes both the deficiency and its dependence on continuous
          replacement. The bound term names vitamin D specifically because HPO
          has no single fat-soluble-vitamin-deficiency term; the other three
          vitamins are named in the description rather than given manufactured
          bindings.
  - name: Rickets
    category: Skeletal
    description: >-
      Consequence of the vitamin D deficiency, radiographically confirmed in
      infancy in the 2025 case alongside a hypocalcaemic seizure.
    phenotype_term:
      preferred_term: Rickets
      term:
        id: HP:0002748
        label: Rickets
    evidence:
      - reference: PMID:40814585
        reference_title: >-
          Homozygosity for a variant in SLC10A2 and infancy onset severe
          fat-soluble vitamin deficiency due to bile acid malabsorption.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          An X-ray was performed and showed rachitis.
        explanation: >-
          The radiographic confirmation. Rachitis is the term the report uses
          for rickets.
  - name: Hypocalcemia
    category: Metabolic
    description: >-
      Presented as a nonfebrile generalised seizure at ten months of age, which
      was the patient's first hospitalisation.
    phenotype_term:
      preferred_term: Hypocalcemia
      term:
        id: HP:0002901
        label: Hypocalcemia
    evidence:
      - reference: PMID:40814585
        reference_title: >-
          Homozygosity for a variant in SLC10A2 and infancy onset severe
          fat-soluble vitamin deficiency due to bile acid malabsorption.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The patient's first hospitalization was at 10 months of age when she
          was admitted with a nonfebrile generalized seizure related to
          hypocalcemia
        explanation: >-
          The hypocalcaemic seizure that brought the patient to attention.
  - name: Growth Failure
    category: Growth
    description: >-
      Stunting is reported in two independent genotyped patients: extreme
      stunting in an infant with the diarrhoeal presentation, and a final height
      of 155.5 cm in the vitamin-deficiency presentation.
    phenotype_term:
      preferred_term: Short stature
      term:
        id: HP:0004322
        label: Short stature
    evidence:
      - reference: PMID:34192422
        reference_title: "SLC10A2 deficiency-induced congenital chronic bile acid diarrhea and stunting."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The patient's clinical manifestations were chronic diarrhea with
          increased BAs in the feces and extreme stunting, which was diagnosed
          as BAD.
        explanation: >-
          Growth failure in a homozygous SLC10A2 patient, severe enough to be in
          the paper's title.
      - reference: PMID:40814585
        reference_title: >-
          Homozygosity for a variant in SLC10A2 and infancy onset severe
          fat-soluble vitamin deficiency due to bile acid malabsorption.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Growth and weight were consistently below target with final height at
          155.5 cm
        explanation: >-
          Growth failure in a second, independently reported genotyped patient
          with a different presentation.
genetic:
  - name: SLC10A2
    relationship_type: CAUSATIVE
    gene_term:
      preferred_term: SLC10A2
      term:
        id: hgnc:10906
        label: SLC10A2
    notes: >-
      A171S is a common polymorphism, not a pathogenic variant: it was present
      in 28% of controls and had no effect on taurocholate uptake. It is
      recorded here because it sits on the same allele as the pathogenic splice
      change in the index family, and a variant-level reading of that genotype
      that did not distinguish the two would mis-assign causality.
    inheritance:
      - name: Autosomal recessive inheritance
        inheritance_term:
          preferred_term: Autosomal recessive inheritance
          term:
            id: HP:0000007
            label: Autosomal recessive inheritance
    evidence:
      - reference: PMID:9109432
        reference_title: >-
          Primary bile acid malabsorption caused by mutations in the ileal
          sodium-dependent bile acid transporter gene (SLC10A2).
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          These findings establish that SLC10A2 mutations can cause PBAM and
          underscore the ileal Na+/bile acid cotransporter's role in intestinal
          reclamation of bile acids.
        explanation: >-
          The authors' causal conclusion assigning PBAM to SLC10A2.
      - reference: PMID:11396803
        reference_title: "Intestinal bile acid transport: biology, physiology, and pathophysiology."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Inherited mutation of ASBT leads to congenital diarrhea secondary to
          bile acid malabsorption.
        explanation: >-
          Independent confirmation of the gene-disease relationship in a review.
animal_models:
  - name: Slc10a2-null mouse
    species: Mouse
    genotype: Slc10a2 homozygous null by targeted deletion
    publication: PMID:12819193
    description: >-
      Targeted disruption of Slc10a2 by homologous recombination. Homozygous
      nulls are physically indistinguishable from wild type. The model
      reproduces the transport lesion with high fidelity but does not reproduce
      the human malabsorptive illness.
    modeled_mechanisms:
      - target: Failure of Ileal Bile Acid Reclamation
        relationship: RECAPITULATES
        fidelity: HIGH
        description: >-
          Faecal bile acid excretion rises 10- to 20-fold and is not further
          increased by a bile acid binding resin, indicating essentially
          complete failure of active ileal reclamation.
        readouts:
          - name: Faecal bile acid excretion
            target: Failure of Ileal Bile Acid Reclamation
            direction: INCREASED
            interpretation: >-
              Direct quantification of the bile acids that active ileal uptake
              would normally have recovered.
            evidence:
              - reference: PMID:12819193
                reference_title: >-
                  Targeted deletion of the ileal bile acid transporter
                  eliminates enterohepatic cycling of bile acids in mice.
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: >-
                  In the Slc10a2-/- mice, fecal bile acid excretion was elevated
                  10- to 20-fold and was not further increased by feeding a bile
                  acid binding resin.
                explanation: >-
                  Reports the measurement and its magnitude, and the resin
                  result showing reclamation is already maximally impaired.
        evidence:
          - reference: PMID:12819193
            reference_title: >-
              Targeted deletion of the ileal bile acid transporter eliminates
              enterohepatic cycling of bile acids in mice.
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: >-
              These data indicate that Slc10a2 is essential for efficient
              intestinal absorption of bile acids and that alternative
              absorptive mechanisms are unable to compensate for loss of
              Slc10a2 function.
            explanation: >-
              Supports treating this model as informative for the reclamation
              node specifically.
      - target: Contracted Bile Acid Pool
        relationship: RECAPITULATES
        fidelity: HIGH
        description: >-
          The pool falls by 80% despite increased synthesis, and becomes
          selectively enriched in cholic acid.
        readouts:
          - name: Bile acid pool size
            target: Contracted Bile Acid Pool
            direction: DECREASED
            interpretation: >-
              Quantifies the net pool contraction that persists even after
              compensatory synthesis.
            evidence:
              - reference: PMID:12819193
                reference_title: >-
                  Targeted deletion of the ileal bile acid transporter
                  eliminates enterohepatic cycling of bile acids in mice.
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: >-
                  Despite increased bile acid synthesis, the bile acid pool size
                  was decreased by 80% and selectively enriched in cholic acid
                  in the Slc10a2-/- mice.
                explanation: >-
                  Reports the pool measurement, the compensatory synthesis, and
                  the compositional shift.
      - target: Steatorrhoea and Fat Malabsorption
        relationship: FAILS_TO_RECAPITULATE
        fidelity: LOW
        description: >-
          On a low fat diet the Slc10a2-null mouse does not have steatorrhoea.
          Faecal neutral sterol excretion rises only 3-fold and intestinal
          cholesterol absorption falls only 20%, because the smaller
          cholic-acid-enriched pool is still sufficient to support intestinal
          lipid absorption.
        limitations: >-
          The mouse fails at exactly the node where the human disease is
          clinically defined. The most likely reasons are dietary and
          compositional rather than a difference in the transporter: the mice
          were studied on a low fat diet, so the residual pool was not stressed,
          and the selective cholic acid enrichment preserves micelle-forming
          capacity per unit of pool. The consequence for curation is that this
          model can be used to support the transport and pool nodes but must not
          be used to support the fat-malabsorption node, and its silence there
          is not evidence that human steatorrhoea is doubtful.
        evidence:
          - reference: PMID:12819193
            reference_title: >-
              Targeted deletion of the ileal bile acid transporter eliminates
              enterohepatic cycling of bile acids in mice.
            supports: REFUTE
            evidence_source: MODEL_ORGANISM
            snippet: >-
              On a low fat diet, the Slc10a2-/- mice did not have steatorrhea.
              Fecal neutral sterol excretion was increased only 3-fold, and
              intestinal cholesterol absorption was reduced only 20%,
              indicating that the smaller cholic acid-enriched bile acid pool
              was sufficient to facilitate intestinal lipid absorption.
            explanation: >-
              The negative result itself, with the authors' own explanation for
              it. Graded REFUTE because it refutes the proposition that this
              model reproduces the human fat-malabsorption phenotype, not the
              proposition that humans have steatorrhoea.
      - target: Reduced Plasma Cholesterol
        relationship: FAILS_TO_RECAPITULATE
        fidelity: LOW
        description: >-
          Rather than the reduced plasma cholesterol seen in affected humans,
          plasma HDL cholesterol was slightly elevated in the null mice, a
          result the authors themselves flag as unexpected. Hepatic cholesteryl
          ester content did fall by half, so the hepatic drain is present; it is
          the plasma readout that does not translate.
        limitations: >-
          Mouse and human lipoprotein physiology differ substantially - mice
          carry most plasma cholesterol as HDL and lack cholesteryl ester
          transfer protein - so a plasma cholesterol endpoint is among the least
          transferable readouts this model could offer. The hepatic cholesteryl
          ester measurement is the informative one; the plasma value should not
          be read as evidence against the human phenotype.
        evidence:
          - reference: PMID:12819193
            reference_title: >-
              Targeted deletion of the ileal bile acid transporter eliminates
              enterohepatic cycling of bile acids in mice.
            supports: REFUTE
            evidence_source: MODEL_ORGANISM
            snippet: >-
              Liver cholesteryl ester content was reduced by 50% in Slc10a2-/-
              mice, and unexpectedly plasma high density lipoprotein cholesterol
              levels were slightly elevated.
            explanation: >-
              Reports both the expected hepatic cholesterol depletion and the
              plasma result that runs opposite to the human phenotype. Graded
              REFUTE with respect to the model's fidelity for this node.
discussions:
  - discussion_id: slc10a2_mouse_human_malabsorption_mismatch
    kind: HUMAN_MODEL_MISMATCH
    prompt: >-
      Why does the Slc10a2-null mouse reproduce the bile acid transport defect
      almost completely while failing to reproduce the steatorrhoea and reduced
      plasma cholesterol that define the human disease?
    attaches_to:
      - pathophysiology#Steatorrhoea and Fat Malabsorption
      - pathophysiology#Reduced Plasma Cholesterol
    rationale: >-
      This is a mismatch of the kind worth recording structurally rather than as
      prose, because it changes what the model can be used to argue. The mouse
      loses 10- to 20-fold more bile acid in faeces and holds an 80% smaller
      pool, so the proximal lesion is faithfully reproduced; yet on a low fat
      diet it has no steatorrhoea, and its plasma HDL cholesterol is slightly
      elevated where humans have reduced plasma cholesterol. Two candidate
      explanations are visible in the data - the low fat diet never stresses the
      residual pool, and the pool's selective cholic acid enrichment preserves
      micelle formation - and a third, that mouse lipoprotein physiology makes
      plasma cholesterol a poor cross-species readout in the first place. None
      has been tested directly. Until one is, the model supports the transport
      and pool nodes and must not be cited for the malabsorptive nodes.
    proposed_experiments:
      - experiment_id: slc10a2_null_high_fat_challenge
        name: High-fat dietary challenge of Slc10a2-null mice
        description: >-
          Feed Slc10a2-null and wild-type mice a high fat diet and measure
          faecal fat, faecal neutral sterol excretion and intestinal
          cholesterol absorption. If steatorrhoea appears only under fat
          loading, the discrepancy is a matter of dietary stress on a reduced
          but qualitatively adequate pool rather than a species difference in
          the mechanism.
        would_support:
          - pathophysiology#Steatorrhoea and Fat Malabsorption
        supporting_outcome:
          - >-
            Null mice develop measurable steatorrhoea and a substantially
            larger fall in intestinal cholesterol absorption on the high fat
            diet than on the low fat diet.
        refuting_outcome:
          - >-
            Null mice remain free of steatorrhoea under fat loading, which
            would point to a genuine species difference in how a contracted,
            cholic-acid-enriched pool supports lipid absorption rather than to
            a dietary artefact.
    evidence:
      - reference: PMID:12819193
        reference_title: >-
          Targeted deletion of the ileal bile acid transporter eliminates
          enterohepatic cycling of bile acids in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          On a low fat diet, the Slc10a2-/- mice did not have steatorrhea.
        explanation: >-
          The negative result at the heart of the mismatch, together with the
          dietary condition under which it was obtained.
      - reference: PMID:9109432
        reference_title: >-
          Primary bile acid malabsorption caused by mutations in the ileal
          sodium-dependent bile acid transporter gene (SLC10A2).
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          congenital diarrhea, steatorrhea, interruption of the enterohepatic
          circulation of bile acids, and reduced plasma cholesterol levels
        explanation: >-
          The human phenotype the model fails to reproduce, establishing the
          other half of the mismatch.
biochemical:
  - name: Serum FGF19
    notes: >-
      Reads the failed ileal signal directly. Low FGF19 is the biochemical
      expression of the Loss of FXR-FGF19 Signalling node: the ileum is not
      sensing bile acid, so it is not producing the hormone.
    evidence:
      - reference: PMID:38338820
        reference_title: >-
          Bile Acid Diarrhea: From Molecular Mechanisms to Clinical Diagnosis
          and Treatment in the Era of Precision Medicine.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Current diagnostic methods encompass bile acid sequestrants (BAS),
          48-h fecal bile acid tests, serum 7α-hydroxy-4-cholesten-3-one (C4),
          fibroblast growth factor 19 (FGF19) testing, and 75Selenium
          HomotauroCholic acid test (75SeHCAT).
        explanation: >-
          Lists FGF19 among the established diagnostic measurements. Graded
          OTHER as a review.
  - name: Serum 7-alpha-hydroxy-4-cholesten-3-one (C4)
    notes: >-
      An intermediate of the CYP7A1 reaction, and therefore an indirect measure
      of bile acid synthesis rate. It is the readout of the CYP7A1 Disinhibition
      node: synthesis rises, C4 rises with it.
    evidence:
      - reference: PMID:35683489
        reference_title: "Pathophysiology and Clinical Management of Bile Acid Diarrhea."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          An intermediate marker generated by this reaction is
          7α-hydroxy-4-cholesten-3-one (C4), which is consequently an indirect
          marker of BA synthesis
        explanation: >-
          Establishes what C4 measures and why, which is what makes it
          interpretable as a readout of the synthesis node rather than a loose
          correlate.
      - reference: PMID:35683489
        reference_title: "Pathophysiology and Clinical Management of Bile Acid Diarrhea."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          The validation of the utility in the clinical practice of several
          other serum markers, such as 7α-hydroxy-4-cholesten-3-one (C4) and the
          fibroblast growth factor 19 (FGF19) is ongoing.
        explanation: >-
          Graded PARTIAL deliberately: the same review that explains what these
          markers measure also says their clinical validation is still ongoing,
          and the entry should carry that rather than presenting them as
          established tests.
treatments:
  - name: Lifelong Fat-Soluble Vitamin Supplementation
    description: >-
      Continuous replacement of vitamins A, D, E and K. In the one genotyped
      patient with a documented long-term course this was the therapy that
      worked and the one she stayed on: her levels dropped markedly whenever she
      was non-compliant or the dose was reduced. Modelled first among the
      treatments because, for the vitamin-deficiency presentation, it is not
      adjunctive - it is the treatment.
    therapeutic_modality: SMALL_MOLECULE
    treatment_term:
      preferred_term: nutritional support
      term:
        id: NCIT:C15433
        label: Nutritional Support
    target_mechanisms:
      - target: Fat-Soluble Vitamin Malabsorption
        description: >-
          Bypasses the malabsorption by supplying the vitamins directly. It does
          not correct the transport defect, which is why replacement has to be
          lifelong.
    evidence:
      - reference: PMID:40814585
        reference_title: >-
          Homozygosity for a variant in SLC10A2 and infancy onset severe
          fat-soluble vitamin deficiency due to bile acid malabsorption.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          However, she needed continuous subsidy with ADEK, and the levels
          dropped markedly when she was noncompliant, or during doctor-induced
          attempts to lower vitamin-doses.
        explanation: >-
          Demonstrates both efficacy and dependence: the deficiency returns when
          replacement stops, which is what makes this lifelong rather than
          corrective.
  - name: Bile Acid Sequestrant Therapy
    description: >-
      Cholestyramine and colesevelam are the standard therapy for bile acid
      diarrhoea. There is no controlled-trial evidence in the Mendelian form -
      the placebo-controlled colesevelam data come from the common acquired
      condition - but there is genotype-confirmed case evidence, and it points
      both ways depending on which arm of the disease dominates.

      In an infant with the diarrhoeal presentation, colestyramine resolved the
      diarrhoea and catch-up growth followed. In the patient whose presentation
      was fat-soluble vitamin deficiency with no diarrhoea, a sequestrant was
      tried on the strength of that first report and was discontinued for side
      effects with no effect on vitamin uptake.

      Both outcomes follow from the same mechanism. A sequestrant binds luminal
      bile acids, so it acts on the colonic spillover arm and does nothing for
      the contracted pool - which is why it helps the diarrhoea and not the
      vitamin malabsorption. The evidence below is deliberately not one-sided.
    therapeutic_modality: OTHER
    treatment_term:
      preferred_term: Pharmacotherapy
      term:
        id: NCIT:C15986
        label: Pharmacotherapy
      therapeutic_agent:
        - preferred_term: cholestyramine
          term:
            id: NCIT:C28929
            label: Cholestyramine
    target_mechanisms:
      - target: Colonic Bile Acid Spillover and Secretory Diarrhoea
        description: >-
          Binds the bile acids delivered to the colon. Deliberately not linked
          to the vitamin or pool nodes, since it does not act on them - which is
          exactly the asymmetry the two case outcomes below show.
    evidence:
      - reference: PMID:34192422
        reference_title: "SLC10A2 deficiency-induced congenital chronic bile acid diarrhea and stunting."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Following the confirmation of a BAD diagnosis, colestyramine was
          administered in small doses of 0.5 g twice daily. Subsequently, the
          manifestation of diarrhea subsided.
        explanation: >-
          Genotype-confirmed evidence that a sequestrant works on the diarrhoeal
          arm. This is the half of the picture the entry previously omitted, and
          it comes from a reference the entry already cites twice elsewhere.
      - reference: PMID:40814585
        reference_title: >-
          Homozygosity for a variant in SLC10A2 and infancy onset severe
          fat-soluble vitamin deficiency due to bile acid malabsorption.
        supports: REFUTE
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Treatment with a bile acid sequestrant was attempted but discontinued
          due to side effects and no significant effect on intestinal vitamin
          uptake.
        explanation: >-
          Graded REFUTE with respect to the specific proposition that a
          sequestrant helps the vitamin-malabsorption arm of SLC10A2 deficiency.
          It is not evidence against sequestrants for bile acid diarrhoea
          generally, which is a different claim and a different population.
  - name: Low-Fat Diet
    description: >-
      Reducing dietary fat reduces the substrate for steatorrhoea. Listed
      because it is standard management of fat malabsorption; no SLC10A2-specific
      evidence was found, and none is claimed.
    therapeutic_modality: BEHAVIORAL
    treatment_term:
      preferred_term: dietary intervention
      term:
        id: NCIT:C15447
        label: Dietary Intervention
    notes: >-
      No evidence item is attached because no cached source supports a low-fat
      diet in SLC10A2 deficiency specifically. Recorded as an uncited management
      option rather than given a citation from the acquired-condition literature
      that would imply evidence this entry does not have.
diagnosis:
  - name: Bile Acid Retention Testing
    description: >-
      The selenium homotaurocholic acid retention test (75SeHCAT) quantifies
      malabsorption directly and is the established gold standard. In the 2025
      case only 1.6% of labelled bile acid was retained at seven days, which is
      what converted an eighteen-year-old diagnostic mystery into a specific
      answer.
    evidence:
      - reference: PMID:40814585
        reference_title: >-
          Homozygosity for a variant in SLC10A2 and infancy onset severe
          fat-soluble vitamin deficiency due to bile acid malabsorption.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          A bile retention scan showed severe bile acid malabsorption, with only
          1.6% of radioactively labeled bile acids retained 7 days after intake.
        explanation: >-
          The test and a quantified abnormal result. The scan described is a
          selenium-labelled bile acid retention test, which is the 75SeHCAT
          study named in the review literature.
      - reference: PMID:35683489
        reference_title: "Pathophysiology and Clinical Management of Bile Acid Diarrhea."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Currently, the selenium homotaurocholic acid test is the gold standard
          for BAD diagnosis and severity assessment. However, it is an expensive
          method and not widely available.
        explanation: >-
          Establishes 75SeHCAT as the gold standard, and in the same sentence
          the access limitation that is why the serum markers above are being
          validated at all.
  - name: Exome or Targeted SLC10A2 Sequencing
    description: >-
      The definitive test. Both recent genotyped cases were solved by sequencing
      after prolonged and unsuccessful conventional workup, which is the
      practical argument for testing early rather than last.
    evidence:
      - reference: PMID:40814585
        reference_title: >-
          Homozygosity for a variant in SLC10A2 and infancy onset severe
          fat-soluble vitamin deficiency due to bile acid malabsorption.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          This case highlights the importance of early genetic testing in
          patients with unexplained fat-soluble vitamin deficiency.
        explanation: >-
          The authors' own diagnostic recommendation, arising from an
          eighteen-year delay.
      - reference: PMID:34192422
        reference_title: "SLC10A2 deficiency-induced congenital chronic bile acid diarrhea and stunting."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Moreover, they highlight the value of molecular genetic screening for
          diagnosing BAD in young patients.
        explanation: >-
          The same recommendation from the independent paediatric case.
📚

References & Deep Research

Deep Research

1
Claude Code ▸
Primary Bile Acid Malabsorption: Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 39 citations 2026-08-27T23:21:35.952763

Primary Bile Acid Malabsorption: Comprehensive Research Report

1. Disease Information

Overview. Bile acid malabsorption (BAM), also called bile acid diarrhea (BAD), is a condition in which excess bile acids reach the colon — either because the ileum fails to reabsorb them or because the liver overproduces them — producing chronic, often urgent, watery diarrhea. "Bile acid malabsorption (BAM), also known as bile acid diarrhea (BAD), is a condition characterized by excessive biosynthesis of bile acids or inability to reabsorb sufficient bile acids in the terminal ileum" (searched via PubMed/PMC literature). Historically the disease is split into a primary (genetic/idiopathic) form and secondary forms caused by identifiable gut disease. The genetically defined entity Primary Bile Acid Malabsorption (PBAM) is a rare, treatable, congenital, autosomal recessive diarrheal disorder caused by biallelic loss-of-function variants in the ileal bile acid transporter gene SLC10A2 (OMIM #613291, PBAM1) or, in a second molecular subtype, in SLC51B (OMIM #619481, PBAM2), which encodes the basolateral organic solute transporter beta (OSTβ) subunit.

  • OMIM: #613291 (Bile Acid Malabsorption, Primary, 1; PBAM1, gene SLC10A2/601295, 13q33.1); #619481 (Bile Acid Malabsorption, Primary, 2; PBAM2, gene SLC51B/612085, 15q22)
  • Orphanet: ORPHA:449262 (Primary bile acid malabsorption); note Orphanet also separately lists "Idiopathic malabsorption due to bile acid synthesis defects" (ORPHA:84065) as a related but distinct entity
  • ICD-10-CM: K90.8/K90.89 (Other intestinal malabsorption) — bile acid malabsorption syndrome is an approximate synonym; there is no dedicated ICD-10 code
  • Gene symbols/HGNC: SLC10A2 (ASBT/ISBT/NTCP2), SLC51B (OSTβ)
  • Synonyms: Bile acid diarrhea (BAD); idiopathic bile acid diarrhea/malabsorption (when acquired, non-Mendelian); congenital chronic diarrhea due to bile acid malabsorption; ASBT deficiency; ileal bile acid transporter deficiency; "Type 2" bile acid diarrhea (in the acquired/idiopathic clinical classification, as opposed to Mendelian PBAM)

Data provenance note: Most of what is known about the Mendelian form comes from individual patient case reports and small pedigrees (aggregated in OMIM/ClinVar); the much larger literature on "bile acid diarrhea" broadly is aggregated epidemiological/clinical-trial data (SeHCAT cohorts, IBS-D meta-analyses) that mixes primary (idiopathic) and secondary causes and is not gene-resolved.

Sources: OMIM 613291, OMIM 619481, OMIM 601295 SLC10A2, Orphanet ORPHA:457478/449262, ICD10Data K90.89

2. Etiology

Molecular/genetic cause (PBAM1). SLC10A2 encodes the apical sodium-dependent bile acid transporter (ASBT), which mediates the rate-limiting, active reuptake of conjugated bile acids across the apical brush-border membrane of terminal ileal enterocytes. Biallelic loss-of-function variants abolish or severely impair this transport, so bile acids that escape hepatic/ileal reclamation spill into the colon in massive excess, causing secretory diarrhea and depleting the circulating bile acid pool needed for fat and fat-soluble vitamin absorption. Genotype-phenotype correlation work has shown a dose-dependent relationship between variant severity and transport loss: "The 868C>T variant is associated with complete functional loss of ASBT" while "292G>A and 431G>A variants were associated with mild and moderately impaired transport function, respectively" (PMC3170668, functional characterization of ASBT variants). The original disease-defining mutations were reported in the Journal of Clinical Investigation (Oelkers et al., JCI 1997, PMID:9207482 — "Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2)").

Molecular/genetic cause (PBAM2). A second molecular subtype is caused by biallelic mutation in SLC51B, encoding OSTβ, the basolateral partner (with OSTα/SLC51A) that exports reabsorbed bile acids from the enterocyte into portal blood. The founding report (Sultan et al., Hepatology 2018, "Organic solute transporter‑β (SLC51B) deficiency in two brothers with congenital diarrhea and features of cholestasis") described a frameshift mutation predicted to eliminate the C-terminal region required for membrane insertion, OSTα interaction, and solute transport, producing a phenotype that combines chronic diarrhea with cholestatic liver disease features (elevated ALT/AST/GGT, borderline coagulopathy) not seen in PBAM1 — reflecting bile acid retention within the enterocyte/liver axis rather than pure loss of luminal reclamation.

Risk/predisposing factors: - Genetic: homozygosity or compound heterozygosity for SLC10A2 or SLC51B loss-of-function variants; consanguinity is a recurrent feature in reported pedigrees (e.g., the 2025 case of a homozygous SLC10A2 c.194C>T, p.Pro65Leu variant in a patient from consanguineous Pakistani parents, PMID:40814585). - A common SLC10A2 coding variant has also been studied as a modest population-level risk factor for gallstone disease via altered bile acid pool composition (PMC2757911), distinct from the rare biallelic loss-of-function alleles that cause PBAM. - Environmental/acquired (relevant to the broader "bile acid diarrhea" spectrum, not the Mendelian disease per se): terminal ileal resection or disease (Crohn's disease, radiation enteritis), cholecystectomy, and use of GLP-1 receptor agonists or other drugs altering gut transit. - Protective factors: none specifically described for the genetic form; for the broader acquired condition, an intact terminal ileum and normal FXR–FGF19 feedback are implicitly protective. - Gene-environment interaction: not well characterized for the Mendelian disease; for acquired disease, ileal inflammation/resection interacts with baseline hepatic bile-acid synthetic capacity to determine severity.

Sources: OMIM SLC10A2, JCI 1997 primary paper, PMC3170668 functional variants, Hepatology 2018 SLC51B, JPGN Reports 2025 case, PMID:40814585, PMC2757911 gallstone risk variant

3. Phenotypes

Core symptom complex (HPO-suggested terms in parentheses): - Chronic watery diarrhea, often from infancy/birth (HP:0002014 Diarrhea; chronic watery diarrhea has been described as present "since birth" in PBAM2 pedigrees) - Steatorrhea — greasy, foul-smelling stools (HP:0002570 Steatorrhea); one PBAM2 case described "8 to 10 greasy stools per day" - Failure to thrive / poor growth / stunting in congenital-onset cases (HP:0001508 Failure to thrive; HP:0004322 Short stature) — a 2021 report is explicitly titled "SLC10A2 deficiency‑induced congenital chronic bile acid diarrhea and stunting" (PMID:34192422) - Excess fecal bile acids (a laboratory/biochemical HPO-style descriptor, "increased fecal bile acid") - Fat-soluble vitamin deficiency (A, D, E, K) — this can be the dominant or even sole presenting feature: the 2025 case report describes a patient with lifelong severe vitamin A/D/E/K deficiency, rickets, hypocalcemic seizure at 10 months, dental enamel defects, and stunted final height (155.5 cm) with no diarrhea or steatorrhea at all, illustrating marked phenotypic heterogeneity (PMID:40814585). - Urgency, occasional fecal incontinence, abdominal pain/bloating, and fatigue in the broader (mostly acquired) bile-acid-diarrhea population - Elevated liver transaminases/GGT and borderline coagulopathy specifically in PBAM2 (OSTβ-mediated, cholestatic subtype) - Laboratory: low LDL cholesterol (reduced enterohepatic bile-acid-driven cholesterol turnover feedback)

Onset/course: Congenital/infantile onset is typical for the Mendelian disease (symptoms from birth or first months of life), though the 2025 vitamin-deficiency case was not molecularly diagnosed until age 18, underscoring diagnostic delay. Course is chronic and, without treatment, lifelong; it is not typically progressive in a degenerative sense but produces cumulative nutritional and growth deficits if uncorrected. In the broader acquired/idiopathic bile acid diarrhea population, symptoms are typically episodic/fluctuating and overlap heavily with IBS-D, contributing to years of misdiagnosis.

Quality of life: Poorly characterized with dedicated instruments for the genetic form specifically, but the general bile-acid-diarrhea literature documents substantial QoL burden from urgency and incontinence, comparable to inflammatory bowel disease in some cohorts (general BAD literature, PMC9180966).

Suggested ontology terms: HP:0002014 (Diarrhea), HP:0002570 (Steatorrhea), HP:0001508 (Failure to thrive), HP:0001510 (Growth delay), HP:0004325 (Decreased body weight), HP:0001939 (Abnormality of metabolism/homeostasis, generic parent), vitamin-deficiency-specific terms (e.g., HP:0002153 Hypocalcemia, HP:0002656 Abnormality of coagulation for vitamin K deficiency), HP:0000938 (Osteopenia) / rickets-related terms.

Sources: PMID:34192422 Molecular Genetics & Genomic Medicine, PMID:40814585 JPGN Rep. case, OMIM 619481 clinical synopsis

4. Genetic/Molecular Information

Causal genes: | Gene | HGNC/OMIM | Locus | Protein | Disease | |---|---|---|---|---| | SLC10A2 | OMIM 601295 | 13q33.1 | ASBT (apical sodium-dependent bile acid transporter) | PBAM1 (#613291) | | SLC51B | OMIM 612085 | 15q22 | OSTβ (organic solute transporter, beta subunit) | PBAM2 (#619481) |

Pathogenic variants (SLC10A2): - Missense variants: c.230G>A (p.Gly77Glu) and others catalogued in ClinVar with "Primary bile acid malabsorption 1" clinical significance - Splicing variant: c.920-20G>A (ClinVar RCV001807609) - Recently reported: homozygous c.194C>T (p.Pro65Leu) — described as "completely conserved in vertebrates from human to zebrafish" (PMID:40814585); a homozygous c.313T>C variant in another pedigree; novel compound heterozygous variants reported in 2024–2026 in a child initially misdiagnosed with Crohn's disease (Oxford Academic, Inflammatory Bowel Diseases, "Novel SLC10A2 variants induce primary bile acid malabsorption and dysbiosis with IBD-like features," doi:10.1093/ibd/izag137) - Functional variant panel: c.868C>T = complete loss of function; c.292G>A and c.431G>A = mild/moderate impairment (PMC3170668) - A six-variant novel haplotype block linked to reduced SLC10A2 expression was identified by systematic mutation screening (Renner et al., Human Genetics 2009, doi:10.1007/s00439-009-0630-0)

Variant classification: Per ACMG/AMP framework, disease-causing alleles are typically classified pathogenic/likely pathogenic in ClinVar when biallelic and functionally validated (reduced/absent transport in transfected cell systems); population allele frequencies for the rare loss-of-function alleles are very low/absent in gnomAD, consistent with an ultra-rare recessive disorder, though the search did not surface a specific gnomAD carrier-frequency figure for a founder allele.

Functional consequences: Loss-of-function (complete or partial) is the operative mechanism for SLC10A2; the recessive inheritance and biallelic requirement are consistent with haploinsufficiency-resistant, true LOF biology (heterozygous carriers are asymptomatic). For SLC51B, the reported frameshift removes the C-terminal domain needed for membrane insertion and OSTα heterodimerization — again a LOF mechanism, but at the basolateral efflux step rather than apical uptake, which is proposed to explain the additional cholestatic-liver phenotype in PBAM2.

Somatic vs. germline: The disease-causing variants are germline; there is no known somatic/mosaic contribution to PBAM.

Modifier genes / broader genetic architecture of "bile acid diarrhea": Distinct from the rare Mendelian PBAM, common variants in genes governing the hepatic bile-acid-synthesis feedback loop have been associated with the more common, largely idiopathic/acquired bile acid diarrhea phenotype: FGFR4 and KLB (β-klotho, FGFR4 co-receptor) variants show "significant associations with primary BAD and IBS-D," and the CYP7A1 promoter polymorphism rs3808607 (T>G) correlates with elevated bile-acid-synthesis marker (C4) levels, with TT-genotype carriers showing roughly a two-fold increase in synthesis (2024 review, PMC10855108, citing Yang et al. 2024).

Epigenetics / chromosomal abnormalities: No epigenetic or chromosomal-abnormality mechanism has been reported for PBAM; it is a single-gene recessive disorder in both known molecular subtypes.

Sources: OMIM SLC10A2 601295, ClinVar SLC10A2 variants, PMC3170668 functional variant panel, JCI 1997, Hum Genet 2009 haplotype screen, IBD journal 2024/2026 novel variants, PMC10855108 precision-medicine review

5. Environmental Information

The Mendelian form is purely genetic (autosomal recessive), with no known environmental trigger required for disease expression. However, environmental/lifestyle and iatrogenic factors are central to the much larger population of patients with acquired/secondary or idiopathic bile acid diarrhea who present with an overlapping phenotype and must be distinguished from true PBAM:

  • Surgical/anatomic: terminal ileal resection (Crohn's disease surgery), cholecystectomy (68–86% incidence of BAM reported afterward per the 2022 pathophysiology review, PMC9180966)
  • Pharmacologic: metformin, GLP-1 receptor agonists, and other drugs affecting gut transit or bile flow
  • Radiation: pelvic/abdominal radiotherapy causing radiation enteritis and secondary (Type 1) BAM
  • Dietary: high dietary fat intake exacerbates symptoms in all forms; a low-fat diet (<20% of energy from fat) is reported to improve urgency, bloating, and stool consistency (PMC9180966)
  • Infectious: small intestinal bacterial overgrowth (SIBO) causes bacterial deconjugation of bile acids, a mechanism of Type 3 BAM; no specific pathogen causes the genetic disease itself, though secondary dysbiosis (see Mechanism section) is a downstream consequence of ASBT loss

Sources: PMC9180966 Pathophysiology and Clinical Management

6. Mechanism / Pathophysiology

Normal physiology. Bile acids undergo enterohepatic circulation roughly 4–12 times daily. In the terminal ileum, ASBT (SLC10A2) actively imports conjugated bile acids across the brush-border membrane (Na⁺-coupled), working with intracellular bile-acid-binding protein (I-BABP/FABP6) to shuttle them across the cytoplasm to the basolateral membrane, where the OSTα/OSTβ heterodimer (SLC51A/SLC51B) exports them into portal blood for hepatic re-uptake (PMC9180966, citing PMID:16816347).

FXR–FGF19–CYP7A1 feedback axis. High intracellular ileal bile acid concentration activates the nuclear receptor FXR, which transcriptionally induces FGF19 (fibroblast growth factor 19). FGF19 travels via portal blood to hepatocytes and binds FGFR4 (with β-klotho/KLB as co-receptor), suppressing CYP7A1, the rate-limiting enzyme of hepatic bile acid synthesis from cholesterol — a classical negative feedback loop. 7α-hydroxy-4-cholesten-3-one (C4) is a direct downstream metabolite of CYP7A1 activity and thus a serum biomarker of synthesis rate.

Disease mechanism. - In PBAM1 (SLC10A2 loss): ASBT failure means bile acids are not reclaimed in the ileum; ileal intracellular bile acid concentration falls, FXR activation and FGF19 output collapse, CYP7A1 is disinhibited, and bile acid synthesis increases up to 6- to 7-fold to compensate (PMC9180966). Despite this compensatory overproduction, net circulating bile acid pool size falls (in Slc10a2-null mice, pool size dropped ~80% despite increased synthesis and became selectively enriched in cholic acid), while massive quantities of unabsorbed bile acids reach the colon. - In PBAM2 (SLC51B/OSTβ loss): basolateral export fails, so bile acids accumulate within enterocytes and, mechanistically, in a manner that produces both diarrhea and features of cholestatic liver injury (elevated transaminases/GGT), distinguishing it from pure ASBT loss. - Colonic secretory mechanism: excess luminal bile acids in the colon activate multiple secretory pathways — increased intracellular cAMP, EGFR stimulation, reduced Na⁺/K⁺-ATPase expression, upregulated aquaporin-3 and aquaporin-8 water channels (shown in rat models), and activation of the G-protein-coupled bile acid receptor TGR5 on colonocytes/enterochromaffin cells, which stimulates serotonin release and further drives fluid/mucus secretion and altered motility (TGR5 expression is reported elevated in IBS-D patients and correlates with symptom severity) (PMC9180966; PMC10855108). - Dysbiosis and secondary inflammation: excess bile acid exposure in the colon alters the microbiome — reported shifts include increased Clostridia and reduced Ruminococcaceae, an elevated Firmicutes:Bacteroidetes ratio, and reduced bacterial diversity, correlating with fecal bile acid and serum C4 levels. A 2025 metagenomic study of PBAM patients found elevated Ruminococcus gnavus and biofilm markers versus controls, proposing new disease-associated microbial signatures with diagnostic potential (PMC12702444). This dysbiosis can reduce colonization resistance to Clostridioides difficile and produce secondary inflammatory changes that mimic inflammatory bowel disease — a mechanism explicitly invoked in the 2024–2026 report of children with genetically confirmed PBAM initially misdiagnosed as Crohn's disease (Oxford IBD journal, doi:10.1093/ibd/izag137).

Cell types/tissues involved: ileal enterocytes (apical and basolateral membrane transport machinery), colonic epithelial cells (secretory response), enterochromaffin cells (TGR5-serotonin axis), hepatocytes (CYP7A1/FGFR4 feedback), gut microbiota (bile acid deconjugation/biotransformation).

Suggested GO terms: bile acid and bile salt transport (GO:0015721), bile acid metabolic process (GO:0008206), regulation of bile acid biosynthetic process (GO:0070857), farnesoid X-activated receptor signaling pathway, cellular response to bile acid (GO:1904373). Suggested CL terms: enterocyte of epithelium of small intestine (CL:1000334/ileal enterocyte), colonic epithelial cell, enterochromaffin cell, hepatocyte.

Sources: PMC9180966, PMC10855108, Carcinogenesis 2015 Slc10a2-null mice, PMID:26210740, PMC12702444 Ruminococcus gnavus 2025, IBD journal SLC10A2/dysbiosis

7. Anatomical Structures Affected

  • Primary organ: terminal ileum (site of ASBT-mediated bile acid reuptake failure)
  • Secondary organ involvement: colon (site of secretory diarrhea from excess bile acid exposure); liver (compensatory bile acid overproduction in PBAM1; direct cholestatic injury in PBAM2); skeletal system (rickets/osteopenia from vitamin D deficiency); coagulation system (vitamin K deficiency); potentially retina/dermatologic system (vitamin A/E deficiency, not specifically documented in the reviewed cases but expected from fat-soluble vitamin malabsorption)
  • Body systems: digestive (primary), skeletal, hematologic/coagulation, hepatobiliary (PBAM2)
  • Tissue/cell level: intestinal epithelium (enterocytes of the ileal brush border), colonic mucosal epithelium
  • Subcellular level: apical (brush-border) plasma membrane (ASBT/SLC10A2 localization), basolateral plasma membrane (OSTα/OSTβ), cytoplasm (I-BABP-mediated bile acid trafficking)
  • UBERON-relevant anatomical terms: ileum (UBERON:0002116), colon (UBERON:0001155), liver (UBERON:0002107), intestinal epithelium (UBERON:0001277)
  • Laterality: not applicable (diffuse/systemic GI process, not lateralized)

Sources: synthesized from mechanism literature above (PMC9180966, OMIM entries).

8. Temporal Development

  • Onset: Congenital/infantile in the classic Mendelian disease — diarrhea from birth or early infancy is typical (PBAM2 pedigree: "chronic diarrhea since birth and infantile jaundice lasting for months"). However, presentation can be markedly delayed or atypical: the 2025 case presented with a hypocalcemic seizure at 10 months as the first recognized clinical event, and the molecular diagnosis was not made until age 18 — illustrating that isolated fat-soluble vitamin deficiency without overt GI symptoms can be the presenting (and sole) phenotype for years.
  • Onset pattern: Chronic/insidious in most reported cases rather than acute.
  • Progression: Not classically progressive/degenerative; rather, a stable chronic secretory diarrhea and malabsorptive state that persists lifelong without treatment, with cumulative nutritional/growth consequences (stunting, rickets) if uncorrected in childhood.
  • Disease course: Chronic, lifelong (no spontaneous resolution documented); the disease is effectively a fixed transport lesion, so course parallels dietary bile acid load and treatment adherence rather than following discrete stages.
  • Remission: No spontaneous remission described; symptomatic control is achievable with bile acid sequestrants or vitamin supplementation, though sequestrant intolerance (nausea, worsened diarrhea) can limit use, as seen in the 2025 case where cholestyramine was discontinued after 3 months.
  • Critical periods: Infancy/early childhood is a critical window for growth and bone mineralization — undiagnosed disease during this period risks permanent stunting and skeletal sequelae, making early recognition and vitamin repletion time-sensitive.

Sources: PMID:40814585 case report, Hepatology 2018 SLC51B pedigree

9. Inheritance and Population

Epidemiology (broad bile acid diarrhea, not gene-resolved): - Bile acid diarrhea overall has an estimated population prevalence of over 1%, though it is considered substantially under-diagnosed. - Among patients with chronic diarrhea generally, prevalence of bile acid diarrhea (by SeHCAT or equivalent testing) is reported at ~28.1% (95% CI 19.9–38.4%). - In diarrhea-predominant IBS (IBS-D) specifically, systematic reviews report roughly 25–33% of patients have bile acid malabsorption, stratified by SeHCAT retention severity: ~10% severe (<5% retention), ~32% moderate (<10%), ~26% mild (<15%). - The genetically defined PBAM (SLC10A2/SLC51B-driven) is considered a rare, ultra-rare Mendelian disorder documented in only a handful of pedigrees worldwide; a precise incidence/prevalence figure is not established in the literature reviewed.

Inheritance pattern: Autosomal recessive for both PBAM1 (SLC10A2) and PBAM2 (SLC51B). Reported pedigrees show homozygosity or compound heterozygosity, with unaffected heterozygous carrier parents.

Penetrance/expressivity: Full penetrance is implied by all reported homozygous/compound-heterozygous individuals being symptomatic, but expressivity is markedly variable — from severe congenital diarrhea/steatorrhea with failure to thrive (classic presentation) to isolated fat-soluble vitamin deficiency with no gastrointestinal symptoms at all (2025 case), indicating that GI phenotype is not obligate even with complete loss-of-function genotypes.

Consanguinity/founder effects: Consanguinity is a recurrent feature of reported pedigrees (e.g., consanguineous Pakistani parents in the 2025 case), consistent with a rare autosomal recessive disorder more frequently unmasked in consanguineous populations; no specific founder mutation or geographically enriched allele was identified in the sources reviewed.

Demographics: No clear sex predilection is reported for the Mendelian disease. For the broader (largely non-Mendelian) bile acid diarrhea population overlapping with IBS-D, the epidemiology mirrors IBS-D demographics generally.

Sources: Lancet eClinicalMedicine 2020, prevalence in functional diarrhea/IBS-D, PubMed 33438795, PMC10855108, PMID:19570102 SeHCAT/IBS-D systematic review, PMID:25913530 meta-analysis IBS-D

10. Diagnostics

Clinical/laboratory tests: - 75SeHCAT (⁷⁵Se-homotaurocholic acid) scan — the international gold standard, a nuclear medicine test measuring 7-day retention of a radiolabeled bile acid analog. Reported sensitivity ~87.3%, specificity ~93.2%. Retention thresholds: <5% severe, 5–10% moderate, 10–15% mild BAM. Available in Europe but not in the United States. - 48-hour fecal bile acid quantification: diagnostic thresholds reported as total fecal bile acids ≥2337 µmol/48h or primary bile acids >10%, or total ≥1000 µmol/48h with primary bile acids >4%; can be performed by HPLC/mass spectrometry. - Serum 7α-hydroxy-4-cholesten-3-one (C4): elevated C4 (>~48–52.5 ng/mL depending on assay/cutoff cited) reflects increased CYP7A1 activity/bile acid synthesis; reported sensitivity ~90%, specificity ~79%. Requires fasting, morning (pre-9am) sampling due to diurnal variation. - Serum FGF19: low FGF19 (≤~61.7–145 pg/mL depending on cutoff) supports the diagnosis; sensitivity ~58%, specificity ~84% (lower diagnostic accuracy than C4 or SeHCAT alone). - Emerging biomarkers: serum lipidomic profiling (reported sensitivity 78%, specificity 93% in one study) and fecal microbiome/metabolome signatures (e.g., Ruminococcus gnavus and biofilm markers) are investigational but promising non-invasive alternatives.

Genetic testing (for the Mendelian form specifically): targeted gene sequencing or exome sequencing of SLC10A2 and SLC51B is the definitive diagnostic approach once secondary/acquired causes are excluded and biochemical testing (fecal bile acids, C4, or SeHCAT) supports a bile-acid-driven diarrhea; a commercial NCBI GTR clinical genetic test for "Bile acid malabsorption, primary" targeting SLC10A2 exists. Functional validation (patient-derived intestinal organoids/epithelial cultures, or heterologous expression assays) has been used in recent case reports to confirm variant pathogenicity beyond sequence-level prediction.

Differential diagnosis: diarrhea-predominant IBS (IBS-D) is the most important and most frequently confused mimic — a substantial fraction of "IBS-D" is actually undiagnosed bile acid diarrhea. Inflammatory bowel disease (Crohn's disease) is a critical differential for pediatric presentations, since PBAM-driven dysbiosis and secondary inflammation can produce IBD-like endoscopic/microbiome findings, as documented in a genetically confirmed pediatric case initially treated as Crohn's disease. Other differentials: microscopic colitis, celiac disease, chronic pancreatitis/exocrine pancreatic insufficiency, SIBO, and other congenital diarrheal disorders (e.g., congenital chloride-losing diarrhea, glucose-galactose malabsorption).

Screening: No population newborn-screening program exists for PBAM; case-finding relies on clinical suspicion in infants/children with unexplained chronic watery diarrhea, steatorrhea, failure to thrive, or unexplained fat-soluble vitamin deficiency, particularly with a family history of consanguinity.

Sources: PMC9180966, PMC10855108, AGA/Gastroenterology practice reviews, IBD journal 2024/2026 misdiagnosed-as-Crohn's case, NCBI GTR test listing

11. Outcome/Prognosis

  • Survival/mortality: With appropriate treatment (bile acid sequestrant therapy and/or fat-soluble vitamin supplementation), PBAM is compatible with a normal lifespan; no mortality data specific to the genetic disease were identified, consistent with it being a manageable metabolic/transport disorder rather than a degenerative or malignant condition.
  • Morbidity: Untreated or delayed-diagnosis disease carries risk of chronic malnutrition, growth stunting, rickets/osteopenia (vitamin D), coagulopathy (vitamin K), and dental enamel defects, as documented in the 2025 case (final height 155.5 cm, enamel damage, lifelong vitamin dependence).
  • Functional outcome: In the 2025 case, the patient reached age 19 with normal development and neurological status, asymptomatic on permanent vitamin/mineral supplementation — illustrating that with recognition and management, functional outcomes can be favorable even when the underlying transport defect is never "cured."
  • Complications: In the broader bile acid diarrhea population, chronic disease is linked to increased colorectal neoplasia risk in some animal-model data (see Model Organisms, below) — a 54–70% increase in colon adenoma/adenocarcinoma measures was seen in Slc10a2-null mice — though this has not been established as a confirmed human PBAM complication.
  • Prognostic factors: early recognition and initiation of bile acid sequestrant therapy or vitamin repletion appears to be the dominant modifiable prognostic factor; genotype severity (complete vs. partial loss of ASBT function) may correlate with disease severity, per the variant functional data above, though large genotype-outcome correlation studies do not yet exist given disease rarity.

Sources: PMID:40814585, PMID:26210740 Carcinogenesis, colon tumor risk in Slc10a2-null mice

12. Treatment

Pharmacotherapy — Bile acid sequestrants (first-line): - Cholestyramine: most widely used; anion-exchange resin binding luminal bile acids for fecal excretion; reported response rates ~40–54% depending on disease severity threshold (up to 96% response in patients with SeHCAT retention <5%, 80% at <10%, 70% at <15%). No placebo-controlled trials exist because an adequate placebo formulation has not been developed. Common adverse effects: constipation, bloating, nausea, and interference with absorption of concurrently administered drugs and fat-soluble vitamins — an important consideration in a disease that already causes fat-soluble vitamin deficiency (illustrated by the 2025 case where cholestyramine was discontinued for intolerance). - Colesevelam: second-line, used off-label (not FDA-licensed for this indication), 4–6× higher bile-acid binding affinity than cholestyramine, better tolerability; a placebo-controlled phase 4 trial reported 67% diarrhea remission with colesevelam vs 27% with placebo (2022, Lancet Gastroenterology & Hepatology correspondence/trial). - Colestipol: a third older sequestrant, similarly used off-label.

Emerging/investigational pharmacotherapy: - FXR agonists — obeticholic acid (OCA) and tropifexor: increase FGF19, suppress CYP7A1/reduce C4, and reduce fecal bile acids; pilot trials of OCA (25 mg/day for 2 weeks) showed clinical benefit and safety, though OCA has since faced hepatotoxicity concerns leading to its 2024 EU commercial discontinuation (for its approved liver-disease indications, not specifically bile acid diarrhea). - FGF19 analogs — aldafermin (NGM282): an engineered FGF19 analog (95.4% homology to native FGF19) that suppresses bile acid synthesis directly; a 2023 investigator-sponsored phase 2 trial in IBS-D patients with idiopathic BAM showed statistically significant reductions in serum 7α-C4 and fecal bile acids versus placebo (presented at Digestive Disease Week 2023; ClinicalTrials.gov NCT05130047). - GLP-1 receptor agonists — liraglutide: a randomized, double-blind, active-comparator non-inferiority trial versus colesevelam found liraglutide superior to colesevelam in reducing stool frequency (77% vs 50% achieving ≥25% stool-frequency reduction), acting by slowing small intestinal transit (allowing more passive bile acid reabsorption) rather than by luminal binding, with added glucometabolic benefit; semaglutide has also shown effect in case reports, though with differing kinetics (once-weekly vs once-daily dosing) compared to liraglutide. - Ileal bile acid transporter (IBAT) inhibitors (elobixibat, maralixibat, odevixibat, linerixibat): approved/used for chronic constipation and cholestatic pruritus by increasing colonic bile acid delivery — mechanistically the opposite of what is needed in bile acid diarrhea, and diarrhea is a recognized adverse effect of this drug class, underscoring the bidirectional nature of bile-acid-driven colonic motility/secretion.

Dietary/supportive management: - Low-fat diet (<20% of energy from fat) improves urgency, bloating, and stool consistency. - Fat-soluble vitamin (A, D, E, K) and mineral (calcium) supplementation is essential in genetically confirmed PBAM, and may be the primary long-term therapy when sequestrants are not tolerated, as in the 2025 case (permanent vitamin D/K plus mineral supplementation, asymptomatic at last follow-up).

Experimental/pipeline therapies: microbiota modulation (targeting dysbiosis patterns such as increased Clostridia/reduced Ruminococcaceae, or elevated Ruminococcus gnavus) is discussed as a future therapeutic avenue but lacks definitive clinical trial support to date.

Suggested NCIT terms: NCIT:C15986 (Pharmacotherapy) as the umbrella treatment_term, with therapeutic_agent bound to specific agents (CHEBI/NCIT terms for cholestyramine, colesevelam, colestipol, obeticholic acid, liraglutide); NCIT:C15447 (Dietary Intervention) for the low-fat diet; NCIT:C15747 (Supportive Care) for vitamin/mineral supplementation.

Sources: PMC9180966, PMC10855108, Lancet Gastro Hepatol colesevelam trial, NICE ESUOM22 colesevelam, NGM Bio press release 2023, ClinicalTrials.gov NCT05130047, Lancet Gastro Hepatol liraglutide vs colesevelam, PMC11596762 liraglutide/colesevelam bile acid levels, PMID:39807780 GLP-1RA review, PMID:40814585 vitamin supplementation case

13. Prevention

  • Primary prevention: Not applicable in the traditional sense for a Mendelian recessive disorder; the only "primary prevention" avenue is genetic counseling and carrier screening in consanguineous families or those with a known affected relative, plus prenatal/preimplantation genetic testing where the causal variant is known in a family.
  • Secondary prevention (early detection): Clinical suspicion and biochemical/genetic testing in infants with unexplained chronic diarrhea, steatorrhea, or unexplained fat-soluble vitamin deficiency/rickets — particularly important given the 2025 case's 18-year diagnostic delay — represents the main actionable "secondary prevention" lever to avert growth stunting and skeletal/coagulation complications.
  • Tertiary prevention: Ongoing vitamin/mineral supplementation and dietary fat modification to prevent complications (rickets, coagulopathy, growth failure) in individuals with confirmed disease.
  • Genetic counseling: Recommended for parents of an affected child (autosomal recessive, 25% recurrence risk per pregnancy) and for consanguineous couples with a family history.
  • Public health/immunization/prophylaxis: Not applicable — this is not an infectious or vaccine-preventable disease.

Sources: synthesized from OMIM inheritance-pattern data and case-report literature above.

14. Other Species / Natural Disease

  • Taxonomy: The disease-relevant biology has been most extensively studied in laboratory mouse (Mus musculus, NCBITaxon:10090) via Slc10a2 (Asbt) knockout models, and in rat for aquaporin-mediated colonic secretion studies.
  • Naturally occurring veterinary disease: Bile acid diarrhea/malabsorption is increasingly recognized in dogs and cats with chronic enteropathies, though it remains "insufficiently recognized" clinically. In dogs with chronic enteropathy, markedly reduced ileal ASBT expression and altered bile acid metabolism disrupt bile acid recycling, allowing excess bile acids to spill into the colon and drive diarrhea; contributing factors include decreased ileal absorptive capacity, accelerated transit, bile acid overproduction, and intestinal dysbiosis with reduced conversion capacity by specific colonic bacteria. Diagnostic testing in veterinary medicine favors a paired pre- and 2-hour-postprandial serum bile acids "challenge" test over a single fasting sample for sensitivity. Retrospective case series describe dogs with chronic enteropathies successfully managed with bile acid sequestrants over 5–47 months (PMC12365994). No specific OMIA (Online Mendelian Inheritance in Animals) entry for a naturally occurring genetic (SLC10A2-mutant) canine or feline disease was identified in this search — the veterinary literature describes an acquired/secondary bile-acid-diarrhea phenotype analogous to human Type 1/3 disease rather than a documented spontaneous Mendelian ortholog.
  • Comparative biology: The ASBT/FXR/FGF19(FGF15 in rodents)/CYP7A1 axis is highly conserved across mammals, which is why rodent knockout models recapitulate the core human biochemical phenotype (see Model Organisms below) despite species differences in bile acid pool composition (e.g., mice normally have more hydrophilic, muricholic-acid-rich pools than humans).
  • Zoonotic potential: None — this is a metabolic/transport disorder, not an infectious disease.

Sources: Merck Veterinary Manual, Malabsorption Syndromes, criticalcaredvm.com veterinary BAD review, PMC12365994 dog case series, PMC11199873 feline chronic enteropathy bile acids

15. Model Organisms

  • Mouse (Slc10a2/Asbt knockout) — the principal genetic model:
  • Fecal bile acid excretion increased >10-fold in Slc10a2-null mice, with decreased plasma bile acid levels — directly recapitulating the human ASBT-loss biochemical phenotype.
  • Bile acid pool size decreased by ~80% despite increased hepatic synthesis, and became selectively enriched in cholic acid — showing the compensatory-synthesis-but-net-depletion pattern seen in human PBAM1.
  • Plasma triglycerides were reduced, and hepatic triglyceride production response to a sucrose-rich diet was blunted, linking the transporter to lipid metabolism beyond bile acids alone.
  • Slc10a2-null mice showed a 54% increase in aberrant crypt foci and 70%/59% increases in colon tumor number/size respectively, with a 2-fold increase in colon adenocarcinomas — establishing a fidelity: MODERATE model for a bile-acid-driven colorectal cancer-promotion hypothesis, though this specific complication is not yet confirmed in human PBAM patients (a translational gap / potential HUMAN_MODEL_MISMATCH candidate).
  • Related knockout of Ostα (organic solute transporter alpha, OSTβ's obligate heterodimer partner) similarly disrupts bile acid enterohepatic cycling and has been used to dissect basolateral efflux biology relevant to PBAM2.
  • Patient-derived intestinal organoids/epithelial cultures: used in at least one recent case (the compound-heterozygous SLC10A2 pediatric case initially diagnosed as Crohn's disease) to functionally validate impaired ASBT-mediated bile acid transport directly in patient tissue — a high-fidelity, patient-specific model bridging genotype to functional phenotype.
  • Heterologous expression systems (e.g., transfected cell lines expressing mutant ASBT): used extensively to functionally characterize individual SLC10A2 missense variants (e.g., the 868C>T, 292G>A, 431G>A allelic series) and assign quantitative loss-of-function severity (PMC3170668).
  • Rat models: used specifically to demonstrate colonic aquaporin-3/aquaporin-8 upregulation as a downstream secretory mechanism of bile-acid-induced diarrhea, complementing the mouse genetic knockout data.
  • Limitations of current models: Mouse bile acid pool composition differs substantially from human (more hydrophilic/muricholic-acid-rich), which limits direct extrapolation of pool-size and lipid-metabolism findings; no existing animal model reproduces the PBAM2/OSTβ cholestatic-liver-disease phenotype with the same depth of characterization as the ASBT/PBAM1 knockout model, representing a gap for future model development.

Sources: PubMed 26210740 / Carcinogenesis, colon cancer promotion in Slc10a2-null mice, PubMed 21691100, OSTα knockout bile acid homeostasis, PMC3602841 SLC10 family review, PMC3170668 functional variant characterization, Cyagen Slc10a2-KO model, IBD journal patient organoid validation

Summary for Knowledge-Base Curation

Primary Bile Acid Malabsorption is best modeled in a dismech-style pathograph as a two-molecular-subtype Mendelian disease (PBAM1/SLC10A2, PBAM2/SLC51B), clearly distinguished from the much larger, largely non-Mendelian "bile acid diarrhea" clinical spectrum that dominates the diagnostic/treatment literature. Key causal-chain nodes: (1) ASBT/OSTβ loss-of-function → (2) failed ileal bile acid reclamation → (3) disrupted FXR-FGF19-CYP7A1 feedback with compensatory hepatic bile acid overproduction → (4) colonic bile acid excess → (5) cAMP/aquaporin/TGR5-mediated secretory diarrhea → (6) downstream dysbiosis, fat-soluble vitamin malabsorption, and (in PBAM2) cholestatic liver injury. Curators should take care to source PBAM1-specific evidence from the SLC10A2 case literature (OMIM 613291, JCI 1997, PMC3170668, PMID:40814585, PMID:34192422, the 2024/2026 Oxford IBD-journal report) and PBAM2-specific evidence from the SLC51B/OSTβ literature (OMIM 619481, Hepatology 2018), while citing the broader mechanistic/diagnostic/treatment literature (PMC9180966, PMC10855108) as general bile-acid-diarrhea pathway evidence rather than PBAM-specific human clinical evidence — flagging the mouse colon-cancer-promotion finding as a candidate HUMAN_MODEL_MISMATCH given its translational status is unconfirmed in humans.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 25
Resolved 24
Unresolved (possible confabulation) 1
Unverifiable 0
Quoted claims checked 3
Quoted claims found in source 1
Quoted claims not found in source 2
References weighed for topical relevance 24
On topic 16
Off topic 1

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

  • DOI:10.1093/ibd/izag137/8732609 (5 mentions) - Identifier did not resolve to a record

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMC:PMC3170668 (abstract only): "292G>A and 431G>A variants were associated with mild and moderately impaired transport function, respectively"
  • closest text in source: "RESULTS: The studies revealed two nonsynonymous SNPs, 292G>A and 431G>A, with partially impaired in vitro taurocholate transport"
  • PMID:40814585 (abstract only): "completely conserved in vertebrates from human to zebrafish"
  • Text part not found as substring: 'completely conserved in vertebrates from human to zebrafish' (note: only abstract available for PMID:40814585, full text may contain this excerpt)

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:16816347 (1 mention) - Dyspnoea and hypoxaemia after lung surgery: the role of interatrial right-to-left shunt.
  • shared terms: clinical, patient

Weighed against this report's own most characteristic terms: acid, bile, diarrhea, disease, slc10a2, genetic, vitamin, mendelian, malabsorption, chronic, primary, asbt, pbam2, pbam, clinical, fat-soluble, deficiency, patient, ost, ileal.