Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults.

The ATP binding cassette subfamily B member 4 (ABCB4) gene on chromosome 7 encodes the ABCB4 protein (alias multidrug resistance protein 3 [MDR3]), a P-glycoprotein in the canalicular membrane of the hepatocytes that acts as a translocator of phospholipids into bile. Several variants in ABCB4 have been shown to cause ABCB4 deficiency, accounting for a disease spectrum ranging from progressive familial cholestasis type 3 to less severe conditions like low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy or drug-induced liver injury. Furthermore, whole genome sequencing has shown that ABCB4 variants are associated with an increased incidence of gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis or elevated liver function tests. Diagnosis of ABCB4 deficiency-related diseases is based on clinical presentation, serum biomarkers, imaging techniques, liver histology and genetic testing. Nevertheless, the clinical presentation can vary widely and clear genotype-phenotype correlations are currently lacking. Ursodeoxycholic acid is the most commonly used medical treatment, but its efficacy has yet to be proven in large controlled clinical studies. Future pharmacological options may include stimulation/restoration of residual function by chaperones (e.g. 4-phenyl butyric acid, curcumin) or induction of ABCB4 transcription by FXR (farnesoid X receptor) agonists or PPARα (peroxisome proliferator-activated receptor-α)-ligands/fibrates. Orthotopic liver transplantation remains the last and often only therapeutic option in cirrhotic patients with end-stage liver disease or patients with intractable pruritus.

A female of progressive familial intrahepatic cholestasis type 3 caused by heterozygous mutations of ABCB4 gene and her cirrhosis improved after treatment of ursodeoxycholic acid: a case report.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of rapidly progressive autosomal recessive disorders characterized by intrahepatic cholestasis. PFIC-3 is caused by mutations in the ATP-binding cassette subfamily B member 4 gene (ABCB4), which encodes multidrug resistance protein 3 (MDR3/ABCB4). Patients are usually in infancy or childhood, but cirrhosis and portal hypertension may be the first manifestation in older children or young adults. CASE PRESENTATION: A 25-year-old young woman with recurrent abnormal hepatic function was mainly characterized by increased gamma glutamyl transpeptidase (GGT) and bile acid with cryptogenic cirrhosis. After 7 months of treatment with ursodeoxycholic acid (UDCA), her hepatic pathology suggested there were also obvious widening and venous fibrosis around the portal vein, and slight bile duct hyperplasia at the edge of the portal area. Infiltration of inflammatory cells around the portal vein and hepatocyte ABCB4/MDR3 protein was basically normal. Sequencing indicated the patient had heterozygous mutations in the ABCB4 gene: c.2696C > G and wes [hg19]7q21.12(87032513-87033422) × 1. Through SWISS-MODEL Predict for protein structures, the missense mutation results in protein side chain missing a methyl group (-CH3), and the deletion mutation results in the serious damage to the structure of MDR3 protein which lead to phosphatidylcholine deficiency of bile in the capillary bile ducts. The toxic effect of bile salts then damages the bile ducts, causing cholestasis and cholangitis, which can then develop into biliary cirrhosis. Through the analysis of pathogenicity prediction software, the mutations led to PFIC3. After treatment of UDCA for 29 months, her cirrhosis was improved, hepatic function was close to normal. CONCLUSION: Novel heterozygous mutations are the molecular pathological cause of PFIC3 in this patient. All young adult patients with occult cirrhosis should be tested for ABCB4. Early diagnosis of PFIC3 and continued treatment with UDCA are key to improving prognosis and delaying the onset of end-stage liver disease.

Novel ABCB4 mutations in an infertile female with progressive familial intrahepatic cholestasis type 3: A case report.

BACKGROUND: Mutations that occur in the ABCB4 gene, which encodes multidrug-resistant protein 3, underlie the occurrence of progressive familial intrahepatic cholestasis type 3 (PFIC3). Clinical signs of intrahepatic cholestasis due to gene mutations typically first appear during infancy or childhood. Reports of PFIC3 occurring in adults are rare. CASE SUMMARY: This is a case study of a 32-year-old infertile female Chinese patient with a 15-year history of recurrent abnormal liver function. Her primary clinical signs were elevated levels of alkaline phosphatase and γ-glutamyl transpeptidase. Other possible reasons for liver dysfunction were eliminated in this patient, resulting in a diagnosis of PFIC3. The diagnosis was confirmed using gene detection and histological analyses. Assessments using genetic sequencing analysis indicated the presence of two novel heterozygous mutations in the ABCB4 gene, namely, a 2950C>T; p.A984V mutation (exon 24) and a 667A>G; p.I223V mutation (exon 7). After receiving ursodeoxycholic acid (UDCA) treatment, the patient's liver function indices improved, and she successfully became pregnant by in vitro fertilization. However, the patient developed intrahepatic cholestasis of pregnancy in the first trimester. Fortunately, treatment with UDCA was safe and effective. CONCLUSION: These novel ABCB4 heterozygous mutations have a variety of clinical phenotypes. Continued follow-up is essential for a comprehensive understanding of PFIC3.

Case Report: A rare case of young adult progressive familial intrahepatic cholestasis-type 3 with a novel heterozygous pathogenic variant of ABCB4.

Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a rare autosomal recessive disorder with poor prognosis. It is caused by pathogenic variants of the ATP binding cassette subfamily B member 4 (ABCB4) gene and usually progresses from chronic cholestasis with or without jaundice to portal hypertension and end-stage liver disease within the first to second decade of life. Few reported PFIC-3 patients presented with atypical clinical symptoms, therefore, often misdiagnosed if without family history. Herein, we report a 16-year-old male who was admitted to our hospital due to acute episodes of jaundice and intense pruritus, subsequently progressed to end-stage liver disease. Laboratory examinations showed no evidence of liver injury caused by viral, autoimmune, drug or liver tumors. Ursodeoxycholic acid and dexamethasone did not relieve his symptoms and he underwent liver transplantation successfully. Targeted next-generation sequencing identified that the patient was a compound heterozygote for two missense mutations (c.959C > T/c.1429C > A) in the ABCB4 gene. The mutation c.1429C > A (p.Q477K) is a novel heterozygous mutation. We constructed a three-dimensional model of this novel pathogenic variant using the SWISS MODEL program and found that the patient's ABCB4 protein is an ATP hydrolysis deficient mutant. The postoperative pathological diagnosis showed intrahepatic cholestasis with progression to cirrhosis. Negative liver tissue immunohistochemistry of MDR3 was found in the explanted liver. The patient was diagnosed with PFIC-3, and his symptoms improved dramatically with liver transplantation. In conclusion, for young patients with acute cholestasis, pruritus, jaundice, growth retardation, and enlargement of the liver and spleen, the possibility of inherited metabolic liver diseases should be considered, detailed medical and family history should be collected, and metabolic screening tests as well as gene tests are necessary for correct diagnosis. Increasing the coverage of PFIC3 is meaningful and thus can improve the current understanding of this disease.

A novel etiologic factor of highly elevated cholestanol levels: progressive familial intrahepatic cholestasis.

Background Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an uncommon cholestatic liver disease caused by mutations in the ATP binding cassette subfamily B member 4 (ABCB4) gene. Although PFIC3 is frequently identified in childhood, ABCB4 disease-causing alleles have been described in adults affected by intrahepatic cholestasis of pregnancy, hormone-induced cholestasis, low-phospholipid-associated cholelithiasis syndrome or juvenile cholelithiasis, cholangiocarcinoma and in sporadic forms of primary biliary cirrhosis. Cholestanol is a biomarker which is elevated especially in cerebrotendinous xanthomatosis and rarely in primary biliary cirrhosis (PBC) and Niemann Pick type C. Case presentation Here we report a Turkish patient with compound heterozygous mutations in the ABCB4 gene, who has hepatosplenomegaly, low level of high-density lipoprotein, cholestasis and high level of cholestanol. Conclusion This is the first PFIC3 case with a high cholestanol level described in the literature. There are very few diseases linked to increased cholestanol levels, two of which are CTX and PBC. From this case, we can conclude that a high cholestanol level might be another indicator of PFIC type 3.

Novel ABCB4 mutation in a Chinese female patient with progressive familial intrahepatic cholestasis type 3: a case report.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a rare group of autosomal recessive hereditary hepatic diseases. There are three types of PFIC, classified according to the mutated gene. For example, PFIC type 3 (PFIC3) is due to mutations in the ABCB4 gene (encoding multidrug-resistant protein 3 [MDR3]). CASE PRESENTATION: We present a 19-year-old Chinese female patient who had a 2-year history of recurrent liver dysfunction, with mainly elevated alkaline phosphatase and γ-glutamyl transpeptidase(γ-GT) levels. After excluding other causes of abnormal liver function and cholestasis, the final diagnosis of PFIC3 was confirmed by histopathological examination and gene detection. The immunohistochemical results showed no MDR3 protein expression in the bile duct membrane. Genetic sequencing analysis revealed a novel heterozygous 2137G > A; p. V713M mutation (Exon 17) and a synonymous 504C > T; p. N168N mutation (Exon 6) in ABCB4. CONCLUSIONS: Our patient with long-term liver dysfunction demonstrated that elevated alkaline phosphatase and γ-GT levels should be associated with the diagnosis of PFIC3, and gene detection is the key to diagnosis. From our in silico analysis, the novel mutation p. V713M in Exon 17 was predicted to affect protein function, with a SIFT (Sorting Intolerant from Tolerant) score of 0.02, indicating a deleterious effect. Further studies are necessary to investigate the impact of the novel heterozygous 2137G > A; p. V713M mutation (Exon 17) on functional defects of MDR3 and PFIC3.

ABCB4 disease mimicking morbus Wilson: A potential diagnostic pitfall.

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.

Ductopenia and cirrhosis in a 32-year-old woman with progressive familial intrahepatic cholestasis type 3: A case report and review of the literature.

Progressive familial intrahepatic cholestasis type 3 is caused by a mutation in the ATP-binding cassette, subfamily B, member 4 (ABCB4) gene encoding multidrug resistance protein 3. A 32-year-old woman with a history of acute hepatitis at age 9 years was found to have jaundice during pregnancy in 2008, and was diagnosed as having intrahepatic cholestasis of pregnancy. In 2009, she underwent cholecystectomy for gallstones and chronic cholecystitis. However, itching and jaundice did not resolve postoperatively. She was admitted to our hospital with fatigue, jaundice, and a recently elevated γ-glutamyl transpeptidase level. Liver biopsy led to the diagnosis of biliary cirrhosis with ductopenia. Genetic testing revealed a pathogenic heterozygous mutation, ex13 c.1531G > A (p.A511T), in the ABCB4 gene. Her father did not carry the mutation, but her mother's brother carried the heterozygous mutation. We made a definitive diagnosis of familial intrahepatic cholestasis type 3. Her symptoms and liver function improved after 3 mo of treatment with ursodeoxycholic acid.