Dubin-Johnson Syndrome

Mendelian MONDO:0009380 Pathograph 6 Show in embeddings browser Liver Disease Inherited Metabolic Disorder

A benign, non-progressive autosomal recessive disorder of bilirubin transport caused by biallelic mutations in ABCC2, which encodes the ATP-dependent canalicular export pump MRP2. Loss of MRP2 blocks secretion of bilirubin glucuronides from the hepatocyte into bile; the conjugates are instead diverted into sinusoidal blood by the basolateral pump MRP3, producing chronic predominantly conjugated hyperbilirubinaemia with otherwise normal liver biochemistry. Two features are diagnostically characteristic: a grossly darkly pigmented liver with coarse brown pigment granules in hepatocytes, and an abnormal ratio of urinary coproporphyrin isomers I and III. Because bile acid secretion is carried by a different transporter (BSEP) and is unaffected, Dubin-Johnson syndrome is not cholestasis: there is no pruritus, no bile acid retention, and no progression to fibrosis. It requires no treatment, and the value of making the diagnosis is to stop repeated investigation of an otherwise unexplained jaundice.

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1
Inheritance
3
Pathophys.
2
Phenotypes
1
Gaps
6
Pathograph
1
Genes
1
Medical Actions
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Dubin-Johnson syndrome is inherited in an autosomal recessive manner: biallelic ABCC2 variants are required, and heterozygous carriers are unaffected. A reported family illustrates this directly - the affected proband was homozygous for p.Trp709Arg while the heterozygous mother was not affected by Dubin-Johnson syndrome.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:35860851 SUPPORT Other
"Inherited non-hemolytic conjugated hyperbilirubinemic conditions include Dubin-Johnson syndrome (caused by mutations affecting ABCC2 gene) and Rotor syndrome (caused by the simultaneous presence of mutations in SLCO1B1 and SLCO1B3 genes)."
Establishes the disorder as an inherited condition caused by ABCC2 mutations. Evidence source is OTHER because this is a narrative review.
PMID:36157610 SUPPORT Other
"Rotor and Dubin-Johnson syndromes are rare autosomal recessive liver diseases characterized by chronic conjugated hyperbilirubinemia"
States the autosomal recessive mode of inheritance directly. Evidence source is OTHER because this sentence states the general property of the two disorders rather than a pedigree finding in the reported patient.
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Discussions and Knowledge Gaps

1
Does loss of MRP2 in Dubin-Johnson syndrome confer a clinically meaningful increase in susceptibility to drug toxicity?
KNOWLEDGE GAP djs_drug_toxicity_susceptibility
Attached to
pathophysiology#Loss of Canalicular MRP2 Bilirubin Conjugate Export
MRP2 exports a broad range of organic anions besides bilirubin conjugates, so its loss is mechanistically plausible as a modifier of drug disposition, and the recent review literature raises this as a reason the condition is no longer regarded as purely academic. The evidence is suggestive rather than established, and no specific drug or dosing recommendation follows from it. Curators should not upgrade this to a management claim.
Proposed experiments
Pharmacokinetic study of MRP2 substrate drugs in genotyped patients
djs_mrp2_substrate_pharmacokinetics
Comparing plasma exposure and toxicity of known MRP2 substrate drugs in genotyped Dubin-Johnson patients against matched controls would establish whether the suggested susceptibility is real and large enough to change prescribing.
⚙

Pathophysiology

3
Loss of Canalicular MRP2 Bilirubin Conjugate Export
Biallelic pathogenic variants in ABCC2 abolish the function of MRP2, the ATP-dependent canalicular transporter that exports monoglucuronosyl and bisglucuronosyl bilirubin from the hepatocyte into bile. Bilirubin uptake and UGT1A1-mediated conjugation are intact, so the lesion is specifically one of conjugate disposal, not of conjugation. MRP2 also handles other organic anions, which is why the urinary coproporphyrin isomer pattern is disturbed and why carriers show altered handling of some drugs.
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.
ABCC2 hgnc:53 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ABCC2 (hgnc:53). hgnc:53 is a gene from the HUGO Gene Nomenclature Committee.
bilirubin transport GO:0015723 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased bilirubin transport (GO:0015723). GO:0015723 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
MRP3-Mediated Sinusoidal Diversion and Conjugated Hyperbilirubinaemia Conjugates that cannot leave the hepatocyte through the canalicular membrane are exported instead across the basolateral membrane into sinusoidal blood.
Hepatocellular Pigment Accumulation Loss of MRP2-mediated organic anion export leads to intracellular retention of pigmented metabolites in hepatocyte lysosomes.
Show evidence (3 references)
PMID:25315738 SUPPORT Other
"Dubin-Johnson syndrome is caused by a defect in the ATP-dependent canalicular transporter, multidrug resistance-associated protein 2 (MRP2), which mediates the export of conjugated bilirubin into bile."
States the transporter, its location, its substrate, and the defect that defines this node. Evidence source is OTHER because this is a review.
PMID:24459177 SUPPORT Other
"This efflux across the canalicular membrane is mediated by multidrug resistance protein 2 (MRP2 or ABCC2), which is a 190-kDa glycoprotein transporting with high affinity and efficiency monoglucuronosyl bilirubin and bisglucuronosyl bilirubin into bile. MRP2 is hereditarily deficient in human..."
Identifies the exact substrates MRP2 carries and states directly that it is the hereditarily deficient transporter in this disorder. Evidence source is OTHER because this is a review of hepatobiliary transport.
PMID:28923092 SUPPORT Human Clinical
"Genetic studies confirmed missense homozygous variant p.Trp709Arg in the ATP-binding cassette sub-family C member 2 gene ABCC2 that encodes the Multidrug resistance-associated protein 2 that causes Dubin-Johnson syndrome."
A genetically confirmed human example of the causal lesion at this node. Evidence source is HUMAN_CLINICAL because this is a patient case report with sequencing.
MRP3-Mediated Sinusoidal Diversion and Conjugated Hyperbilirubinaemia
The basolateral efflux pump MRP3 (ABCC3), which is upregulated when MRP2 is deficient, exports bilirubin glucuronides from the hepatocyte into sinusoidal blood. This is the step that actually raises plasma conjugated bilirubin: without it the pigment would simply be trapped intracellularly. The resulting biochemical picture is chronic, predominantly conjugated hyperbilirubinaemia - an increased proportion of direct relative to total bilirubin - with normal transaminases, normal synthetic function, and no haemolysis.
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.
bilirubin transport GO:0015723 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated bilirubin transport (GO:0015723). GO:0015723 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Show evidence (3 references)
PMID:24459177 SUPPORT Other
"Under pathophysiological conditions such as cholestatic liver injury and MRP2 inhibition, the basolateral efflux pump multidrug resistance protein 3 (MRP3 or ABCC3) is responsible for the occurrence of conjugated hyperbilirubinemia."
Supplies the specific mechanism by which loss of canalicular export raises plasma conjugated bilirubin, rather than merely trapping it in the hepatocyte. Evidence source is OTHER because this is a review.
PMID:24459177 SUPPORT Other
"In human and rat hepatocytes, MRP3/Mrp3 is strongly upregulated under conditions of cholestasis and MRP2 deficiency."
Establishes that MRP3 is specifically upregulated in the MRP2-deficient state, which is what makes this diversion route quantitatively important in this disorder. Evidence source is OTHER because this is a review covering human and rat data.
PMID:28923092 SUPPORT Human Clinical
"Dubin-Johnson syndrome should be considered when the common causes for conjugated hyperbilirubinaemia have been excluded, and patient has an increased percentage of direct bilirubin relative to total bilirubin concentration."
Gives the biochemical signature of this node as it presents clinically - a raised direct fraction with other causes excluded. Evidence source is HUMAN_CLINICAL because this is a patient case report.
Hepatocellular Pigment Accumulation
Coarse, dark brown pigment granules accumulate diffusely in the cytoplasm of hepatocytes, giving the liver its characteristic gross black appearance. The pigment is lysosomal and is thought to derive from metabolites whose export depends on MRP2. It is a histological hallmark of the disorder and, together with the urinary coproporphyrin isomer pattern, distinguishes Dubin-Johnson syndrome from Rotor syndrome, which shares its biochemical picture but has a normally coloured liver.
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.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:28923092 SUPPORT Human Clinical
"Dubin-Johnson syndrome may manifest as conjugated hyperbilirubinemia, darkly pigmented liver, presence of abnormal pigment in the parenchyma of hepatocytes and abnormal distribution of the coproporphyrin isomers I and III in the urine."
Enumerates the three diagnostic features of the disorder, of which the hepatocellular pigment is the one this node represents. Evidence source is HUMAN_CLINICAL because this is a patient case report.
PMID:28923092 SUPPORT Human Clinical
"She had conjugated hyperbilirubinaemia with diffuse, coarse brown pigments in the hepatocytes."
A direct histological observation of the pigment in a genetically confirmed patient. Evidence source is HUMAN_CLINICAL because this is a case report with liver biopsy.
⬡

Pathograph

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

Phenotypes

2
Digestive 1
Intermittent Jaundice HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952), qualified as temporality recurrent. HP:0000952 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:28923092 SUPPORT Human Clinical
"A Sri Lankan girl presented with recurrent episodes of jaundice."
Documents the recurrent-jaundice presentation in a genetically confirmed patient. Evidence source is HUMAN_CLINICAL because this is a case report.
Other 1
Conjugated Hyperbilirubinaemia Conjugated hyperbilirubinemia HP:0002908 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conjugated hyperbilirubinemia (HP:0002908), qualified as temporality chronic. HP:0002908 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:25315738 SUPPORT Other
"Both disorders are benign and not progressive and are characterised by elevated serum levels of mainly conjugated bilirubin."
States the biochemical phenotype and, equally importantly, the benign and non-progressive course. Evidence source is OTHER because this is a review.
🧬

Genetic Associations

1
ABCC2
Gene: ABCC2 hgnc:53 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ABCC2 (hgnc:53). hgnc:53 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:35860851 SUPPORT Other
"Inherited non-hemolytic conjugated hyperbilirubinemic conditions include Dubin-Johnson syndrome (caused by mutations affecting ABCC2 gene) and Rotor syndrome (caused by the simultaneous presence of mutations in SLCO1B1 and SLCO1B3 genes)."
Establishes ABCC2 as the causal gene and contrasts it with the two-gene requirement of Rotor syndrome. Evidence source is OTHER because this is a narrative review.
PMID:28923092 SUPPORT Human Clinical
"Genetic studies confirmed missense homozygous variant p.Trp709Arg in the ATP-binding cassette sub-family C member 2 gene ABCC2 that encodes the Multidrug resistance-associated protein 2 that causes Dubin-Johnson syndrome."
A specific reported causal variant with confirmed homozygosity. Evidence source is HUMAN_CLINICAL because this is a patient case report with sequencing.
💊

Medical Actions

1
Diagnosis and Reassurance
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
No treatment is required or effective. The disorder is benign and non-progressive, and the therapeutic value of establishing the diagnosis is negative rather than positive: it stops the repeated hospital admissions and invasive investigations that an unexplained conjugated hyperbilirubinaemia otherwise provokes. The one substantive caveat is drug handling - loss of MRP2 alters disposition of other organic anion substrates, so an increased susceptibility to drug toxicity has been raised, though it is not established.
Show evidence (2 references)
PMID:28923092 SUPPORT Human Clinical
"Its early diagnosis prevents repeated hospital admissions and investigations."
States the clinical benefit of diagnosis in a disorder that needs no treatment. Evidence source is HUMAN_CLINICAL because this is a patient case report.
PMID:35860851 SUPPORT Other
"Although classically viewed as benign conditions requiring no treatment, they lately gained an increased interest since recent studies suggested that mutations in the responsible genes leading to hyperbilirubinemia, as well as minor genetic variants, may result in an increased susceptibility to..."
Marked PARTIAL because it qualifies the no-treatment position with a suggested but unestablished drug-toxicity susceptibility. Evidence source is OTHER because this is a narrative review.
🔬

Biochemical Markers

2
Conjugated Bilirubin (INCREASED)
Context: Serum conjugated (direct) bilirubin is chronically elevated with an increased proportion of direct relative to total bilirubin. Transaminases, alkaline phosphatase, and synthetic function are normal, and there is no haemolysis - the pattern that separates this disorder from hepatocellular and cholestatic liver disease.
Pathograph Readouts
Readout Of MRP3-Mediated Sinusoidal Diversion and Conjugated Hyperbilirubinaemia Positive Diagnostic
The raised direct fraction with otherwise normal liver biochemistry reports failure of canalicular conjugate export with intact conjugation, rather than hepatocellular injury or cholestasis.
Show evidence (1 reference)
PMID:28923092 SUPPORT Human Clinical
"Dubin-Johnson syndrome should be considered when the common causes for conjugated hyperbilirubinaemia have been excluded, and patient has an increased percentage of direct bilirubin relative to total bilirubin concentration."
States the diagnostic use of this readout. Evidence source is HUMAN_CLINICAL because this is a patient case report.
Urinary Coproporphyrin Isomer I Fraction (INCREASED)
Context: In Dubin-Johnson syndrome total urinary coproporphyrin excretion is normal but over 80% is excreted as isomer I, reflecting increased reflux of that isomer back into the sinusoid when MRP2 is absent. This is the classical non-invasive discriminator from Rotor syndrome, where total urinary coproporphyrin is instead increased two- to five-fold with a lower isomer I fraction. The discrimination is not absolute: a genetically confirmed Rotor patient has been reported with a normal total coproporphyrin and 86% isomer I - a profile classified as compatible with Dubin-Johnson syndrome - so molecular testing, not coproporphyrin analysis, settles the diagnosis.
Pathograph Readouts
Readout Of Loss of Canalicular MRP2 Bilirubin Conjugate Export Positive Diagnostic
The shifted coproporphyrin isomer ratio reports loss of MRP2-dependent organic anion export, the trigger lesion of the disorder.
Show evidence (3 references)
PMID:28923092 SUPPORT Human Clinical
"Urine coproporphyrin examination suggested Dubin-Johnson syndrome."
Documents the diagnostic use of the urinary coproporphyrin pattern in a patient subsequently confirmed genetically. Evidence source is HUMAN_CLINICAL because this is a case report.
PMID:36157610 SUPPORT Human Clinical
"In DJS, total urinary coproporphyrin excretion is normal but over 80% is excreted as coproporphyrin I, due to an increased reflux of isomer I back into the sinusoid"
States the quantitative Dubin-Johnson coproporphyrin signature and the mechanism behind it. Evidence source is HUMAN_CLINICAL because this is a clinical case report discussing patient coproporphyrin measurements.
PMID:36157610 SUPPORT Human Clinical
"Clinical and laboratorial profile was compatible with Dubin-Johnson syndrome; however, exome sequencing and search for deletions in the ABBC2 gene (encoding MRP2) only found a heterozygous potentially pathogenic variant (c.1483A>G - p.Lys495Glu)."
Marked PARTIAL because it bounds the diagnostic claim: a Dubin-Johnson-compatible coproporphyrin and biochemical profile turned out on sequencing to be Rotor syndrome, so this readout is suggestive rather than definitive. Evidence source is HUMAN_CLINICAL because this is a patient case report.
{ }

Source YAML

click to show 
name: Dubin-Johnson Syndrome
creation_date: "2026-08-22T00:00:00Z"
category: Mendelian
description: >-
  A benign, non-progressive autosomal recessive disorder of bilirubin transport
  caused by biallelic mutations in ABCC2, which encodes the ATP-dependent
  canalicular export pump MRP2. Loss of MRP2 blocks secretion of bilirubin
  glucuronides from the hepatocyte into bile; the conjugates are instead
  diverted into sinusoidal blood by the basolateral pump MRP3, producing chronic
  predominantly conjugated hyperbilirubinaemia with otherwise normal liver
  biochemistry. Two features are diagnostically characteristic: a grossly
  darkly pigmented liver with coarse brown pigment granules in hepatocytes, and
  an abnormal ratio of urinary coproporphyrin isomers I and III. Because bile
  acid secretion is carried by a different transporter (BSEP) and is unaffected,
  Dubin-Johnson syndrome is not cholestasis: there is no pruritus, no bile acid
  retention, and no progression to fibrosis. It requires no treatment, and the
  value of making the diagnosis is to stop repeated investigation of an
  otherwise unexplained jaundice.
disease_term:
  preferred_term: Dubin-Johnson syndrome
  term:
    id: MONDO:0009380
    label: Dubin-Johnson syndrome
parents:
- Liver Disease
- Inherited Metabolic Disorder
pathophysiology:
- name: Loss of Canalicular MRP2 Bilirubin Conjugate Export
  description: >-
    Biallelic pathogenic variants in ABCC2 abolish the function of MRP2, the
    ATP-dependent canalicular transporter that exports monoglucuronosyl and
    bisglucuronosyl bilirubin from the hepatocyte into bile. Bilirubin uptake
    and UGT1A1-mediated conjugation are intact, so the lesion is specifically
    one of conjugate disposal, not of conjugation. MRP2 also handles other
    organic anions, which is why the urinary coproporphyrin isomer pattern is
    disturbed and why carriers show altered handling of some drugs.
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "bilirubin_conjugation_transport#Conjugated Bilirubin Transport Failure"
  genes:
  - preferred_term: ABCC2
    term:
      id: hgnc:53
      label: ABCC2
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: bilirubin transport
    term:
      id: GO:0015723
      label: bilirubin transport
    modifier: DECREASED
  evidence:
  - reference: PMID:25315738
    reference_title: "Gene replacement therapy for genetic hepatocellular jaundice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dubin-Johnson syndrome is caused by a defect in the ATP-dependent
      canalicular transporter, multidrug resistance-associated protein 2 (MRP2),
      which mediates the export of conjugated bilirubin into bile.
    explanation: >-
      States the transporter, its location, its substrate, and the defect that
      defines this node. Evidence source is OTHER because this is a review.
  - reference: PMID:24459177
    reference_title: "The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This efflux across the canalicular membrane is mediated by multidrug
      resistance protein 2 (MRP2 or ABCC2), which is a 190-kDa glycoprotein
      transporting with high affinity and efficiency monoglucuronosyl bilirubin
      and bisglucuronosyl bilirubin into bile. MRP2 is hereditarily deficient in
      human Dubin-Johnson syndrome.
    explanation: >-
      Identifies the exact substrates MRP2 carries and states directly that it
      is the hereditarily deficient transporter in this disorder. Evidence
      source is OTHER because this is a review of hepatobiliary transport.
  - reference: PMID:28923092
    reference_title: "Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic studies confirmed missense homozygous variant p.Trp709Arg in the
      ATP-binding cassette sub-family C member 2 gene ABCC2 that encodes the
      Multidrug resistance-associated protein 2 that causes Dubin-Johnson
      syndrome.
    explanation: >-
      A genetically confirmed human example of the causal lesion at this node.
      Evidence source is HUMAN_CLINICAL because this is a patient case report
      with sequencing.
  downstream:
  - target: MRP3-Mediated Sinusoidal Diversion and Conjugated Hyperbilirubinaemia
    causal_link_type: DIRECT
    description: >-
      Conjugates that cannot leave the hepatocyte through the canalicular
      membrane are exported instead across the basolateral membrane into
      sinusoidal blood.
  - target: Hepatocellular Pigment Accumulation
    causal_link_type: DIRECT
    description: >-
      Loss of MRP2-mediated organic anion export leads to intracellular
      retention of pigmented metabolites in hepatocyte lysosomes.

- name: MRP3-Mediated Sinusoidal Diversion and Conjugated Hyperbilirubinaemia
  description: >-
    The basolateral efflux pump MRP3 (ABCC3), which is upregulated when MRP2 is
    deficient, exports bilirubin glucuronides from the hepatocyte into
    sinusoidal blood. This is the step that actually raises plasma conjugated
    bilirubin: without it the pigment would simply be trapped intracellularly.
    The resulting biochemical picture is chronic, predominantly conjugated
    hyperbilirubinaemia - an increased proportion of direct relative to total
    bilirubin - with normal transaminases, normal synthetic function, and no
    haemolysis.
  role: central_effector
  biological_scale: ORGANISM
  conforms_to: "bilirubin_conjugation_transport#Hyperbilirubinaemia"
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: bilirubin transport
    term:
      id: GO:0015723
      label: bilirubin transport
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:24459177
    reference_title: "The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Under pathophysiological conditions such as cholestatic liver injury and
      MRP2 inhibition, the basolateral efflux pump multidrug resistance protein
      3 (MRP3 or ABCC3) is responsible for the occurrence of conjugated
      hyperbilirubinemia.
    explanation: >-
      Supplies the specific mechanism by which loss of canalicular export raises
      plasma conjugated bilirubin, rather than merely trapping it in the
      hepatocyte. Evidence source is OTHER because this is a review.
  - reference: PMID:24459177
    reference_title: "The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In human and rat hepatocytes, MRP3/Mrp3 is strongly upregulated under
      conditions of cholestasis and MRP2 deficiency.
    explanation: >-
      Establishes that MRP3 is specifically upregulated in the MRP2-deficient
      state, which is what makes this diversion route quantitatively important
      in this disorder. Evidence source is OTHER because this is a review
      covering human and rat data.
  - reference: PMID:28923092
    reference_title: "Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dubin-Johnson syndrome should be considered when the common causes for
      conjugated hyperbilirubinaemia have been excluded, and patient has an
      increased percentage of direct bilirubin relative to total bilirubin
      concentration.
    explanation: >-
      Gives the biochemical signature of this node as it presents clinically -
      a raised direct fraction with other causes excluded. Evidence source is
      HUMAN_CLINICAL because this is a patient case report.

- name: Hepatocellular Pigment Accumulation
  description: >-
    Coarse, dark brown pigment granules accumulate diffusely in the cytoplasm of
    hepatocytes, giving the liver its characteristic gross black appearance. The
    pigment is lysosomal and is thought to derive from metabolites whose export
    depends on MRP2. It is a histological hallmark of the disorder and, together
    with the urinary coproporphyrin isomer pattern, distinguishes Dubin-Johnson
    syndrome from Rotor syndrome, which shares its biochemical picture but has
    a normally coloured liver.
  role: effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:28923092
    reference_title: "Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dubin-Johnson syndrome may manifest as conjugated hyperbilirubinemia,
      darkly pigmented liver, presence of abnormal pigment in the parenchyma of
      hepatocytes and abnormal distribution of the coproporphyrin isomers I and
      III in the urine.
    explanation: >-
      Enumerates the three diagnostic features of the disorder, of which the
      hepatocellular pigment is the one this node represents. Evidence source is
      HUMAN_CLINICAL because this is a patient case report.
  - reference: PMID:28923092
    reference_title: "Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had conjugated hyperbilirubinaemia with diffuse, coarse brown pigments
      in the hepatocytes.
    explanation: >-
      A direct histological observation of the pigment in a genetically
      confirmed patient. Evidence source is HUMAN_CLINICAL because this is a
      case report with liver biopsy.
phenotypes:
- category: Clinical
  name: Intermittent Jaundice
  description: >-
    Recurrent episodes of mild jaundice, often first noticed in adolescence or
    early adulthood and exacerbated by intercurrent illness, pregnancy, or oral
    contraceptives. The course is benign and non-progressive.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
    temporality: RECURRENT
  evidence:
  - reference: PMID:28923092
    reference_title: "Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A Sri Lankan girl presented with recurrent episodes of jaundice.
    explanation: >-
      Documents the recurrent-jaundice presentation in a genetically confirmed
      patient. Evidence source is HUMAN_CLINICAL because this is a case report.
- category: Laboratory
  name: Conjugated Hyperbilirubinaemia
  description: >-
    Chronic elevation of the conjugated (direct) bilirubin fraction with an
    increased direct-to-total ratio, in the presence of normal transaminases,
    normal synthetic function, and no haemolysis.
  phenotype_term:
    preferred_term: Conjugated hyperbilirubinemia
    term:
      id: HP:0002908
      label: Conjugated hyperbilirubinemia
    temporality: CHRONIC
  evidence:
  - reference: PMID:25315738
    reference_title: "Gene replacement therapy for genetic hepatocellular jaundice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Both disorders are benign and not progressive and are characterised by
      elevated serum levels of mainly conjugated bilirubin.
    explanation: >-
      States the biochemical phenotype and, equally importantly, the benign and
      non-progressive course. Evidence source is OTHER because this is a review.
biochemical:
- name: Conjugated Bilirubin
  presence: INCREASED
  context: >-
    Serum conjugated (direct) bilirubin is chronically elevated with an
    increased proportion of direct relative to total bilirubin. Transaminases,
    alkaline phosphatase, and synthetic function are normal, and there is no
    haemolysis - the pattern that separates this disorder from hepatocellular
    and cholestatic liver disease.
  biomarker_term:
    preferred_term: conjugated bilirubin
    term:
      id: CHEBI:16990
      label: bilirubin IXalpha
  readouts:
  - target: MRP3-Mediated Sinusoidal Diversion and Conjugated Hyperbilirubinaemia
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The raised direct fraction with otherwise normal liver biochemistry
      reports failure of canalicular conjugate export with intact conjugation,
      rather than hepatocellular injury or cholestasis.
    evidence:
    - reference: PMID:28923092
      reference_title: "Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Dubin-Johnson syndrome should be considered when the common causes for
        conjugated hyperbilirubinaemia have been excluded, and patient has an
        increased percentage of direct bilirubin relative to total bilirubin
        concentration.
      explanation: >-
        States the diagnostic use of this readout. Evidence source is
        HUMAN_CLINICAL because this is a patient case report.
- name: Urinary Coproporphyrin Isomer I Fraction
  presence: INCREASED
  context: >-
    In Dubin-Johnson syndrome total urinary coproporphyrin excretion is normal
    but over 80% is excreted as isomer I, reflecting increased reflux of that
    isomer back into the sinusoid when MRP2 is absent. This is the classical
    non-invasive discriminator from Rotor syndrome, where total urinary
    coproporphyrin is instead increased two- to five-fold with a lower isomer I
    fraction. The discrimination is not absolute: a genetically confirmed Rotor
    patient has been reported with a normal total coproporphyrin and 86% isomer
    I - a profile classified as compatible with Dubin-Johnson syndrome - so
    molecular testing, not coproporphyrin analysis, settles the diagnosis.
  readouts:
  - target: Loss of Canalicular MRP2 Bilirubin Conjugate Export
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The shifted coproporphyrin isomer ratio reports loss of MRP2-dependent
      organic anion export, the trigger lesion of the disorder.
    evidence:
    - reference: PMID:28923092
      reference_title: "Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Urine coproporphyrin examination suggested Dubin-Johnson syndrome.
      explanation: >-
        Documents the diagnostic use of the urinary coproporphyrin pattern in a
        patient subsequently confirmed genetically. Evidence source is
        HUMAN_CLINICAL because this is a case report.
    - reference: PMID:36157610
      reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In DJS, total urinary coproporphyrin excretion is normal but over 80% is
        excreted as coproporphyrin I, due to an increased reflux of isomer I
        back into the sinusoid
      explanation: >-
        States the quantitative Dubin-Johnson coproporphyrin signature and the
        mechanism behind it. Evidence source is HUMAN_CLINICAL because this is a
        clinical case report discussing patient coproporphyrin measurements.
    - reference: PMID:36157610
      reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical and laboratorial profile was compatible with Dubin-Johnson
        syndrome; however, exome sequencing and search for deletions in the
        ABBC2 gene (encoding MRP2) only found a heterozygous potentially
        pathogenic variant (c.1483A>G - p.Lys495Glu).
      explanation: >-
        Marked PARTIAL because it bounds the diagnostic claim: a
        Dubin-Johnson-compatible coproporphyrin and biochemical profile turned
        out on sequencing to be Rotor syndrome, so this readout is suggestive
        rather than definitive. Evidence source is HUMAN_CLINICAL because this is a
        patient case report.
genetic:
- name: ABCC2
  notes: >-
    Biallelic pathogenic variants in ABCC2, encoding MRP2, cause Dubin-Johnson
    syndrome. Reported variants include missense changes such as the homozygous
    p.Trp709Arg allele. Heterozygous carriers are not affected.
  gene_term:
    preferred_term: ABCC2
    term:
      id: hgnc:53
      label: ABCC2
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:35860851
    reference_title: "Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia-A narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Inherited non-hemolytic conjugated hyperbilirubinemic conditions include
      Dubin-Johnson syndrome (caused by mutations affecting ABCC2 gene) and
      Rotor syndrome (caused by the simultaneous presence of mutations in
      SLCO1B1 and SLCO1B3 genes).
    explanation: >-
      Establishes ABCC2 as the causal gene and contrasts it with the two-gene
      requirement of Rotor syndrome. Evidence source is OTHER because this is a
      narrative review.
  - reference: PMID:28923092
    reference_title: "Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic studies confirmed missense homozygous variant p.Trp709Arg in the
      ATP-binding cassette sub-family C member 2 gene ABCC2 that encodes the
      Multidrug resistance-associated protein 2 that causes Dubin-Johnson
      syndrome.
    explanation: >-
      A specific reported causal variant with confirmed homozygosity. Evidence
      source is HUMAN_CLINICAL because this is a patient case report with
      sequencing.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Dubin-Johnson syndrome is inherited in an autosomal recessive manner:
    biallelic ABCC2 variants are required, and heterozygous carriers are
    unaffected. A reported family illustrates this directly - the affected
    proband was homozygous for p.Trp709Arg while the heterozygous mother was
    not affected by Dubin-Johnson syndrome.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:35860851
    reference_title: "Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia-A narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Inherited non-hemolytic conjugated hyperbilirubinemic conditions include
      Dubin-Johnson syndrome (caused by mutations affecting ABCC2 gene) and
      Rotor syndrome (caused by the simultaneous presence of mutations in
      SLCO1B1 and SLCO1B3 genes).
    explanation: >-
      Establishes the disorder as an inherited condition caused by ABCC2
      mutations. Evidence source is OTHER because this is a narrative review.
  - reference: PMID:36157610
    reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rotor and Dubin-Johnson syndromes are rare autosomal recessive liver
      diseases characterized by chronic conjugated hyperbilirubinemia
    explanation: >-
      States the autosomal recessive mode of inheritance directly. Evidence
      source is OTHER because this sentence states the general property of the
      two disorders rather than a pedigree finding in the reported patient.
treatments:
- name: Diagnosis and Reassurance
  description: >-
    No treatment is required or effective. The disorder is benign and
    non-progressive, and the therapeutic value of establishing the diagnosis is
    negative rather than positive: it stops the repeated hospital admissions and
    invasive investigations that an unexplained conjugated hyperbilirubinaemia
    otherwise provokes. The one substantive caveat is drug handling - loss of
    MRP2 alters disposition of other organic anion substrates, so an increased
    susceptibility to drug toxicity has been raised, though it is not
    established.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:28923092
    reference_title: "Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Its early diagnosis prevents repeated hospital admissions and
      investigations.
    explanation: >-
      States the clinical benefit of diagnosis in a disorder that needs no
      treatment. Evidence source is HUMAN_CLINICAL because this is a patient
      case report.
  - reference: PMID:35860851
    reference_title: "Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia-A narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although classically viewed as benign conditions requiring no treatment,
      they lately gained an increased interest since recent studies suggested
      that mutations in the responsible genes leading to hyperbilirubinemia, as
      well as minor genetic variants, may result in an increased susceptibility
      to drug toxicity.
    explanation: >-
      Marked PARTIAL because it qualifies the no-treatment position with a
      suggested but unestablished drug-toxicity susceptibility. Evidence source
      is OTHER because this is a narrative review.
discussions:
- discussion_id: djs_drug_toxicity_susceptibility
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does loss of MRP2 in Dubin-Johnson syndrome confer a clinically meaningful
    increase in susceptibility to drug toxicity?
  attaches_to:
  - "pathophysiology#Loss of Canalicular MRP2 Bilirubin Conjugate Export"
  rationale: >-
    MRP2 exports a broad range of organic anions besides bilirubin conjugates,
    so its loss is mechanistically plausible as a modifier of drug disposition,
    and the recent review literature raises this as a reason the condition is no
    longer regarded as purely academic. The evidence is suggestive rather than
    established, and no specific drug or dosing recommendation follows from it.
    Curators should not upgrade this to a management claim.
  proposed_experiments:
  - experiment_id: djs_mrp2_substrate_pharmacokinetics
    name: Pharmacokinetic study of MRP2 substrate drugs in genotyped patients
    description: >-
      Comparing plasma exposure and toxicity of known MRP2 substrate drugs in
      genotyped Dubin-Johnson patients against matched controls would establish
      whether the suggested susceptibility is real and large enough to change
      prescribing.