Presentation of Progressive Familial Intrahepatic Cholestasis Type 3 Mimicking Wilson Disease: Molecular Genetic Diagnosis and Response to Treatment

Boğa, Salih; Jain, Dhanpat; Schilsky, Michael L.

doi:10.5223/pghn.2015.18.3.202

Cited by 22 publications

(14 citation statements)

References 12 publications

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“…Similarly, Wilson disease has been misdiagnosed at an older age. (24) These findings illustrate the need for increased awareness for ABCB4 disease in different age groups combined with broadened diagnostic strategies.…”

Section: Discussionmentioning

confidence: 96%

“…Young patients of the cohort were misdiagnosed with biliary atresia as a common differential diagnosis at this age, but no obvious risk factors could be identified. Similarly, Wilson disease has been misdiagnosed at an older age . These findings illustrate the need for increased awareness for ABCB4 disease in different age groups combined with broadened diagnostic strategies.…”

Section: Discussionmentioning

confidence: 98%

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Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset

Schatz

Jüngst

Keitel

et al. 2018

Hepatology Communications

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Genetic variants in the adenosine triphosphate‐binding cassette subfamily B member 4 (ABCB4) gene, which encodes hepatocanalicular phosphatidylcholine floppase, can lead to different phenotypes, such as progressive familial intrahepatic cholestasis (PFIC) type 3, low phospholipid‐associated cholelithiasis, and intrahepatic cholestasis of pregnancy. The aim of this multicenter project was to collect information on onset and progression of this entity in different age groups and to assess the relevance of this disease for the differential diagnosis of chronic liver disease. Clinical and laboratory data of 38 patients (17 males, 21 females, from 29 families) with homozygous or (compound) heterozygous ABCB4 mutations were retrospectively collected. For further analysis, patients were grouped according to the age at clinical diagnosis of ABCB4‐associated liver disease into younger age (<18 years) or adult age (≥18 years). All 26 patients diagnosed in childhood presented with pruritus (median age 1 year). Hepatomegaly and splenomegaly were present in 85% and 96% of these patients, respectively, followed by jaundice (62%) and portal hypertension (69%). Initial symptoms preceded diagnosis by 1 year, and 13 patients received a liver transplant (median age 6.9 years). Of note, 9 patients were misdiagnosed as biliary atresia, Alagille syndrome, or PFIC type 1. In the 12 patients with diagnosis in adulthood, the clinical phenotype was generally less severe, including intrahepatic cholestasis of pregnancy, low phospholipid‐associated cholelithiasis, or (non)cirrhotic PFIC3. Conclusion: ABCB4 deficiency with onset in younger patients caused a more severe PFIC type 3 phenotype with the need for liver transplantation in half the children. Patients with milder phenotypes are often not diagnosed before adulthood. One third of the children with PFIC type 3 were initially misdiagnosed, indicating the need for better diagnostic tools and medical education. (Hepatology Communications 2018;2:504‐514)

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 98%

Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset

Schatz

Jüngst

Keitel

et al. 2018

Hepatology Communications

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“…However, elevated concentrations of copper in the liver tissue as well as increased urinary copper excretion have also been reported in liver disorders not related to WD, especially in patients with prolonged cholestasis 12 . We found only four reports [5][6][7][8] documenting abnormal or marginal hepatic copper content in five patients with PFIC3 mimicking WD (Table 1). Four patients had elevated urinary copper excretion, one had also decreased serum ceruloplasmin level.…”

Section: Discussionmentioning

confidence: 96%

“…Moreover, chronic cholestasis may be accompanied by increased urinary copper excretion and significant accumulation of copper in the liver, i.e., findings that may be potentially misinterpreted as Wilson disease (WD, gene ATP7B) (ref. [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

ABCB4 disease mimicking morbus Wilson: A potential diagnostic pitfall

Sticová

Neroldova

Kotalova

et al. 2020

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Introduction. Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare autosomal recessive cholestatic liver disorder caused by genetic deficiency of ATP-binding cassette subfamily B member 4 (ABCB4), a hepatocanalicular floppase translocating phospholipids from the inner to the outer leaflet of the canalicular membrane lipid bilayer. PFIC3 is characterised by production of hydrophilic bile with lithogenic properties which is harmful to the hepatobiliary epithelia. Chronic cholestasis in some patients may be accompanied by excessive accumulation of copper in the liver and by increased urinary copper excretion, the findings mimicking Wilson disease (WD). Methods and Results. We report an 11 y/o male patient with growth retardation, mild craniofacial dysmorphic features and chronic liver disease, initially diagnosed and treated as WD. Whereas genetic testing for WD was negative, further molecular and histopathological analysis revealed two novel mutations (c.833+1G>T and c.1798T>A) in ABCB4 and complete absence of the ABCB4/MDR3 protein in the liver, determining PFIC3 as the correct diagnosis. Conclusion. PFIC3 and WD display pleomorphic and sometimes overlapping clinical and laboratory features, which may pose a differential diagnostic problem. Since the patient management in WD and PFIC3 differs significantly, an early and accurate diagnosis is crucial for optimising of therapeutic approach and prevention of possible complications.

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“…Prolonged cholestasis in PFIC3 is associated with significant accumulation of copper in liver tissue and with increased urine copper excretion, i.e., findings that overlap with the diagnostic criteria for Wilson's disease [ 63 , 64 ].…”

Section: Familial Intrahepatic Cholestasismentioning

confidence: 99%

New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications

Sticová

Jirsa

Pawłowska

2018

Canadian Journal of Gastroenterology and Hepatology

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Cholestasis is characterised by impaired bile secretion and accumulation of bile salts in the organism. Hereditary cholestasis is a heterogeneous group of rare autosomal recessive liver disorders, which are characterised by intrahepatic cholestasis, pruritus, and jaundice and caused by defects in genes related to the secretion and transport of bile salts and lipids. Phenotypic manifestation is highly variable, ranging from progressive familial intrahepatic cholestasis (PFIC)—with onset in early infancy and progression to end-stage liver disease—to a milder intermittent mostly nonprogressive form known as benign recurrent intrahepatic cholestasis (BRIC). Cases have been reported of initially benign episodic cholestasis that subsequently transitions to a persistent progressive form of the disease. Therefore, BRIC and PFIC seem to represent two extremes of a continuous spectrum of phenotypes that comprise one disease. Thus far, five representatives of PFIC (named PFIC1-5) caused by pathogenic mutations present in both alleles of ATP8B1, ABCB11, ABCB4, TJP2, and NR1H4 have been described. In addition to familial intrahepatic cholestasis, partial defects in ATP8B1, ABCB11, and ABCB4 predispose patients to drug-induced cholestasis and intrahepatic cholestasis in pregnancy. This review summarises the current knowledge of the clinical manifestations, genetics, and molecular mechanisms of these diseases and briefly outlines the therapeutic options, both conservative and invasive, with an outlook for future personalised therapeutic strategies.

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Presentation of Progressive Familial Intrahepatic Cholestasis Type 3 Mimicking Wilson Disease: Molecular Genetic Diagnosis and Response to Treatment

Cited by 22 publications

References 12 publications

Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset

Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset

ABCB4 disease mimicking morbus Wilson: A potential diagnostic pitfall

New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications

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