A young male teacher who visited our hospital in November 2017 has complained of recurrent jaundice and severe pruritus experienced for more than 15 years. His symptoms first occurred in 2002 while he was still 19 years old. He denied experiencing fever, chills, vomiting, abdominal pain, and weight loss. He also denied history of similar episodes among his family members. Thus, he visited a local hospital. His liver functional test showed total bilirubin (TB) level of over 50.0 mumol/L and slightly elevated transaminase level. Computed tomography of the abdomen showed no remarkable findings. His TB level increased gradually, reaching a maximum of 500.0 mumol/L during hospitalization. His condition improved gradually, and liver function tests normalized after 4 months. He experienced seven similar episodes over a span of 15 years, which sometimes aggravated after administering penicillin and ibuprofen for treating common cold. Two weeks before visiting our hospital, he took "Vitamin C Yinqiao Tablets," which is a traditional Chinese medicine for cold, for sore throat for 3 days. Further, he developed itchy skin (pruritis), his skin and sclera became increasingly yellow, and his urine and stool turned dark brown. On his visit to the local hospital, his liver functional tests revealed alanine aminotransferase (ALT) of 242.0 U/L, aspartate aminotransferase (AST) of 102.0 U/L, TB of 73.2 mumol/L, and direct bilirubin (DB) of 59.4 mumol/L. On admission, physical examination showed his skin and sclera were moderately yellow. His entire abdomen was soft and nontender. He neither had hepatomegaly nor splenomegaly. No spider angiomas or palmar erythema was observed on his skin. Dynamic changes of his liver test are shown in Table 1. Although his blood ammonia level was 104.0 mumol/L (normal range, 9.0-33.0 mumol/L), he did not show signs of central nervous system involvement or hepatic encephalopathy. His urine tested positive for bilirubin. Results of blood and fecal routine examination and coagulation functions were within normal ranges. The alpha-fetoprotein level was normal. Serum makers were negative for hepatitis A, B, C, D, and E viruses. The screening for toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus infections was negative. Deoxyribonucleic acid detection of Epstein-Barr virus and human cytomegalovirus were both negative. Autoimmune antibodies including anti-mitochondria antibody, anti-hepatorenal microsomal antibody, anti-hepatocyte solute antibody, and anti-soluble liver antigen antibody were negative. Serum levels of copper and ceruloplasmin were normal. Serum levels of thyroid hormones were normal. Ultrasonography revealed a normal liver echo texture and non-dilated biliary system. Magnetic resonance cholangiopancreatography confirmed the absence of dilatation of any intrahepatic or extrahepatic bile duct, except for mild splenomegaly.
With the collected evidence, common liver diseases causing jaundice were excluded. However, the cause of his obstructive cholestasis still remained unclear. After obtaining his consent, liver biopsy was performed. The result of biopsy reported mostly normal liver lobule structures and extensive cholestasis of hepatocytes in zone 3 accompanied by the formation of bile embolism; few lymphocytes, monocytes, and neutrophils were found infiltrating the portal areas. Positive cytokeratin 7 staining indicated slight proliferation of small bile ducts and cholestatic state in a part of the hepatocytes. Immunohistochemical staining of hepatitis B surface antigen and hepatitis B core antigen, periodic acid-Schiff staining, copper staining, and iron staining were negative (Figure 1).
On further molecular analysis of whole-exome sequencing for the ATP8B1 gene, homozygous variants, including c.1817T>C and p.I606T were revealed. This is a novel variant site that has been searched on certain databases including Genome Aggregation Database (gnomAD), Human Gene Variant Database, and Clinvar of NCBI. A familial genetic testing by sanger sequencing showed heterozygosity in his parents' ATP8B1 genes (Figure 2).
The diagnosis of intrahepatic cholestasis was made with total evaluation of case history, clinical features, examination, and liver biopsy as per the criteria proposed by Luketic and Shiffman. The patient was finally diagnosed with BRIC-1.
The patient was prescribed with ursodeoxycholic acid (UDCA). His symptoms relieved, and his liver function recovered 1 month after his discharge from the hospital. During the follow-up period of about 2 years (January 2020), the patient did not show any signs of jaundice or pruritus, and liver function tests were always normal (ALT, 31 U/L; AST, 25 U/L; TB, 14.3 mumol /L; DB, 4.2 mumol/L; gamma glutamyl transpeptidase [GGT], 14 U/L). His liver function tests in May 2021 were normal.