A 16-year-old male was hospitalized due to jaundice for 8 days and right lower abdominal pain for 2 days. He had thrombocytopenia, hypoalbuminemia and abnormal clotting. His liver was palpable 3 cm under costal margin, while the spleen edge was palpable 2.5 cm below the left costal margin. He had abnormal results in laboratory examinations: total bilirubin level (TBL) 393.5 micromol/L (normal range 0.0-26.0 micromol/L); direct bilirubin level (DBL) 206.7 micromol/L (normal range 0-6.8 micromol/L); alkaline phosphatase (ALP), 288.9 U/L (normal range 45.0-125.0 U/L); gamma-glutamyl transpeptidase activity (GGT), 113.2 U/L (normal range 10.0-60.0 U/L); total bile acid (TBA), 348.4 micromol/L (normal range 0.0-10.0 U/L); serum aspartate aminotransferase (AST), 120.3 U/L (normal range 15.0-40.0 U/L); alanine aminotransferase (ALT), 50.8 U/L (normal range 9.0-50.0 U/L); platelets (PLT), 35 x 109/L (normal range 100-300 x 109/L); serum albumin, 25.5 g/L (normal range 35-51 g/L); prothrombin time (PT), 25.1 s (normal range 12-14 s); activating partial thromboplastin time (APTT), 39.4 s (normal range 31-43 s); and prothrombin activity (PTA), 34% (normal range 75%-100%).Urine porphyrin concentrations were determined and considered within normal limits: hepta-carboxyprophyrin, 1.2 mcg/g creat (normal range 0-2.9 mcg/g creat); uroporphyrin I, 10.8 mcg/g creat (normal range 4.1-22.4 mcg/g creat); and coproporphyrin III, 26.8 mcg/g creat (normal range 4.1-76.4 mcg/g creat). Parameters suggestive of autoimmune or viral hepatitis, such as cytomegalovirus antibody, Epstein-Barr virus, antinuclear antibodies, antimitochondrial antibodies, hepatitis B surface antigen, and hepatitis C virus antibodies, were negative. Serum levels of copper, ceruloplasmin and tumor markers showed no abnormalities. CT documented irregular dilatation of intrahepatic bile ducts, cirrhosis, splenomegaly, collateral veins, ascites and gallbladder wall edema. He was allergic to dust, pollens, fish and seafood with reactions of pruritus. He had a medical history of eczema from around the age of 10 years, treated with topical steroid therapy for several years. Three months ago, he had stopped military training due to itching, tingling and redness on his skin from exposure to the sun. Because of his slow interval growth, he was given a course of growth hormone treatment, which resulted in increased growth velocity. At 16 years, he was 159 cm tall (3rd percentile in the Chinese Centers for Disease Control and Prevention growth charts) and had discontinued growth hormone treatment. There were no risk factors for liver injury, such as drug use, toxins or alcohol abuse. The patient had no similar episodes when he was a child and there were not any factors triggering the clinical onset of disease. His parents were non-consanguineous, and there was no family history of similar symptoms.
After hospital admission, the patient was given symptomatic treatment with liver protection, infusion of plasma, albumin, vitamin K1 and anti-inflammatory therapy. A week later, the patient's blood coagulation indexes were corrected, abdominal pain disappeared, and inflammatory markers returned to normal. However, the patient still had severe cholestasis associated with pruritus and jaundice. Accordingly, we adopted a policy of low-dose dexamethasone treatment, and the patient's bilirubin levels had slightly decreased after 3 days but no significant effects after 1 week. Examination of the bone marrow revealed no significant abnormality and primary hematologic dysfunction, or malignancy was excluded. Genetic metabolic diseases were considered, and we performed whole-exome sequencing (WES) and Sanger sequencing with the permission of the patient and his families. Targeted next-generation sequencing, involving 61 genes responsible for genetic disorders of hepatic cholestasis and we detected pathogenic variant in ABCB4 gene: c.959C > T (p.S320F)/c.1429C > A (p.Q477K) (Figure 1A). c.959C > T (p.S320F) has been reported previously in the literature, while c.1429C > A (p.Q477K) is a novel heterozygous pathogenic variant. ABCB4 c.959C > T (p.S320F) variant was identified in his father and c.1429C > A (p.Q477K) variant was identified in his mother. His parents are heterozygous carriers. Pedigrees for the patient are shown in Figure 1B.
The patient was treated with ursodeoxycholic acid (UDCA) 15 mg/(kg x d). Sadly, he was insensitive to UDCA and progressed to end-stage liver disease. Multiple liver failure complications plagued him, including jaundice, edema, ascites, spontaneous bacterial peritonitis, splenomegaly, esophageal varices, coagulopathy, and hepatic encephalopathy. At age 17, the patient underwent liver transplantation successfully. The postoperative pathological diagnosis showed intrahepatic cholestasis with progression to cirrhosis (Figure 2). Negative liver tissue immunohistochemistry of BSEP and MDR3 was found in the bile duct membrane. Immunohistochemistry showed absent MDR3 staining, confirming the diagnosis of MDR3 deficiency. The patient was discharged after one month with stable vital signs. Notably, during the 1-year follow-up visit, the patient's liver function was almost in complete remission. Dynamic changes of his liver test are shown in Table 1.