Case Report: Intrahepatic cholestasis: a diagnostic dilemma

Version Changes

Revised. Amendments from Version 1

The revised version of this case report includes revisions made based on the expert comments of the peer reviewers. Details have been added to the case presentation to improve clarity. New figure has been added to show the trend of ALP change during hospital stay and follow-up as was suggested by the reviewers.

Abstract

Cholestasis is an impairment of bile formation or bile flow. The mechanisms of cholestasis can be broadly classified into intrahepatic and extrahepatic. Most of the time, etiology can be determined with proper history, physical examination, and diagnostic testing including laboratory and imaging tests. This is a case report of a patient with severe cholestasis who underwent extensive evaluation to determine the etiology of intrahepatic cholestasis.

This Case Report details a 28-year-old male who presented with seven days’ history of yellowish discoloration of eyes, the passage of dark-colored urine, generalized body itching, and the passage of clay-colored stool. The patient had no similar episode in the past. Laboratory investigations showed unconjugated hyperbilirubinemia and increased alkaline phosphatase. Magnetic resonance cholangiopancreaticography was unremarkable and liver biopsy was suggestive of cholestatic pattern and negative for acute hepatitis. The bilirubin level started decreasing after a month.

The etiology of intrahepatic cholestasis remained unknown. Genotyping could not be done due to limited available resources. It may have helped to diagnose familial hepatocellular cholestasis such as benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis. Gamma-glutamyl transferase is normal or mildly elevated in patients with BRIC. A similar picture was seen in our case as well. If the patient presents again with similar symptoms and findings, we can consider the diagnosis of BRIC.

Introduction

Cholestasis is an impairment of bile formation or bile flow. Patients with cholestasis present with fatigue, pruritus, and jaundice. Cholestasis may be intrahepatic or extrahepatic ¹ . The presentation of intrahepatic cholestasis and associated biochemical abnormalities may mimic biliary obstruction and can generate diagnostic confusion. Causes of intrahepatic cholestasis include primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drugs and toxins, sepsis, malignancy, granulomatous liver disease, intrahepatic cholestasis of pregnancy, viral hepatitis, alcoholic hepatitis, genetic disorders, total parenteral nutrition associated cholestasis, graft versus host disease, post liver transplant cholestasis, etc ^{2, 3} .

Clinically, cholestatic disorder manifests as jaundice, pruritus and symptoms secondary to malabsorption of fat and fat-soluble vitamins ⁴ . Biochemical markers of cholestasis include predominant elevation of serum alkaline phosphatase (ALP) relative to aminotransferases. Intrahepatic cholestatic disorders can be categorized histologically as infiltrative, those associated with injury to cholangiocytes within intrahepatic bile ductules, and those in which major histologic changes are not evident ³ .

The diagnosis of intrahepatic cholestasis is made after imaging rules out extrahepatic biliary obstruction. Depending on the clinical situation, evaluation requires different serological studies in order to determine etiology, and sometimes it needs to be confirmed with a liver biopsy ^{5, 6} . Here we report a case of a patient who presented in a tertiary care hospital in Nepal in which the etiology of intrahepatic cholestasis remained unknown even after extensive workup.

Case report

A 28-year-old male, Newar by ethnicity, from central Nepal and journalist by occupation, previously healthy, presented with seven days’ history of yellowish discoloration of eyes, passage of dark-colored urine, generalized body itching, and passage of clay-colored stool. The patient denied history of fever, abdominal pain, or viral prodrome. He used to consume alcohol on social occasions with the last intake around one month prior to the illness. He did not have a history of intake of any medications including herbal supplements and had not previously had biliary tract surgery. There was no family history of jaundice or liver disease. Physical examination revealed icterus and excoriation marks all over the body. Other examination findings were unremarkable. Initial laboratory investigations revealed total bilirubin of 30.1 mg/dl (Reference: 0.4-1), direct bilirubin 19.3 mg/dl (Reference: 0.04-1), aspartate aminotransferase (AST) 14 units/liter (Reference: 0-37), alanine aminotransferase (ALT): 21.0 units/Liter (Reference: 5-35), alkaline phosphatase (ALP): 418 units/liter (Reference: 53-125), and gamma-glutamyl transferase (GGT):17 units/liter (Reference: 8-61). Serum Albumin was 4.8 g/dl (Reference: 3-5), prothrombin time (PT): 14.7 (Reference: 11-14), international normalized ratio (INR): 1.05 (Reference: 1.0-1.3). Serological markers for hepatitis A, hepatitis B, hepatitis C, hepatitis E, and human immunodeficiency virus (HIV) were negative.

The patient was initially admitted to the surgical ward for evaluation of obstructive jaundice. Ultrasound of the abdomen done soon after admission showed no abnormality in the biliary tree. Contrast-enhanced computed tomography (CECT) of the abdomen (done on day three) and magnetic resonance cholangiopancreatography (MRCP) (done on day four) also did not show any abnormality in the biliary tract, pancreas, and peripancreatic region. After ruling out extrahepatic causes with imaging studies, the patient was shifted to the medical ward for further evaluation of intrahepatic cholestasis. Various investigations to determine the etiology of intrahepatic cholestasis were done including thyroid function tests, antinuclear antibody (ANA), liver kidney muscle-1 (LKM-1) antibody, anti-smooth muscle antibody (ASMA), antimitochondrial antibody (AMA), immunoglobulin G (IgG) -total, carcinoembryonic antigen (CEA), carbohydrate antigen 19.9 (CA-19.9), alpha-fetoprotein (AFP), serum ceruloplasmin, 24-hour urinary copper and iron profile; the results of which did not reveal the etiology of intrahepatic cholestasis. Blood culture did not reveal any growth; serologies for brucellosis, leptospirosis, and scrub typhus were all negative. Malaria antigen was negative. Because of the persistent pruritus, the patient was managed with ursodeoxycholic acid 15 mg/kg/day in 2 divided doses, cholestyramine 4 g twice daily and, levocetirizine 5 mg once daily. As fat-soluble vitamins are low in cholestasis, empiric supplementations were done with cholecalciferol oral 60000 IU once and Inj. vitamin K 10mg iv once. The pruritus decreased after the treatment. The trends of bilirubin and ALP during his illness have been shown in Figure 1 and Figure 2 below. GGT was normal throughout, while ALT and AST had increased during the hospital stay (up to 91 and 127 U/L) which later normalized until discharge.

Figure 1. Trend in bilirubin level of the patient.

Figure 2. The trend in ALP level of the patient.

During the hospital stay, he developed hospital-acquired pneumonia which was managed with Inj. piperacillin-tazobactam 4.5g IV thrice daily for seven days, and the patient recovered from pneumonia. He also developed acute kidney injury which got resolved with intravenous fluids. A liver biopsy was performed. The patient’s symptoms gradually improved, and his bilirubin also started to decrease gradually. So, he was discharged after 34 days of hospital stay, with advice to follow up with liver biopsy report. On follow-up seven days after discharge, a histopathology report of liver biopsy showed bile stasis with minimal inflammatory cell infiltration, suggestive of cholestatic pattern and negative for acute hepatitis. However, the etiology of intrahepatic cholestasis still remained unknown. The patient was regularly followed. His bilirubin normalized in about 8 weeks and ALP normalized in about 16 weeks after the onset of illness.

Discussion

Intrahepatic cholestasis is considered once the extrahepatic cholestasis is ruled out by imaging modalities ⁴ , as in our case in which CECT abdomen and MRCP were normal. On the evaluation of the etiology of intrahepatic cholestasis, our patient did not have a history of any drug intake or significant alcohol consumption. Serology for viral hepatitis and autoimmune hepatitis were negative. Test results were also negative for primary biliary cirrhosis and primary sclerosing cholangitis as AMA and MRCP were normal, respectively. Liver biopsy ruled out small duct PSC. Serum ceruloplasmin, slit-lamp exam for Kayser Fleischer ring, and 24-hour urinary copper were negative for Wilson`s disease. Iron studies did not suggest hemochromatosis as the cause of intrahepatic cholestasis. Genetic testing should also be considered such as mutations in the hepatobiliary transporters ATP8B1, ABCB11 and ABCB4 in the evaluation of familial hepatocellular cholestasis like progressive familial intrahepatic cholestasis (PFIC) or benign recurrent intrahepatic cholestasis (BRIC). However, genetic testing, though a gold standard test, was not done in our case because of the limited available resources.

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of disorders, characterized by defective secretion of bile acids or other components of bile. PFIC is unlikely in our case as these disorders usually present during infancy or childhood, and are associated with growth failure and progressive liver disease.

Benign recurrent intrahepatic cholestasis (BRIC) is characterized by recurrent cholestatic episodes. Patients present with this disease for the first time at a young age (usually at teens or twenties). The frequency of attacks can vary, ranging from once in a few months to once in a decade. During the attacks, the patients present with malaise, anorexia, pruritus, weight loss, jaundice, and malabsorption. Laboratory tests reveal biochemical evidence of cholestasis (conjugated hyperbilirubinemia, raised ALP). GGT is normal or mildly elevated in patients with BRIC. A similar picture was seen in our case as well.

There was one factor which made the diagnosis of BRIC challenging in our case. BRIC is a recurring disease. But our patient had no similar episode in the past. The diagnosis of BRIC could not be ascertained due to it being the first presentation. Genetic testing, if performed, could have led to the diagnosis of BRIC in just one attack.

There is no specific treatment for BRIC. Bile acid sequestrants such as Cholestyramine, opioid antagonists such as Naltrexone, antihistamines, Rifampin, Ursodeoxycholic acid, Sertraline, and nasobiliary drainage may improve pruritus in a patient with BRIC.

Liver biopsy is important in the workup of patients with cholestatic jaundice who have normal imaging and no other obvious etiology ¹ . However, it may not be adequately sensitive, and may have complications such as bleeding. Although histological examination of liver tissue confirmed the diagnosis of intrahepatic cholestasis, the cause still remained unanswered in this case.

If the patient presents again with similar symptoms and findings, we can consider the diagnosis of BRIC. Genotyping would be helpful in reaching the diagnosis.

Informed consent

Written informed consent was taken from the patient before submission.

Funding Statement

This work was supported by Wellcome [106680, <a href=https://doi.org/10.35802/106680>https://doi.org/10.35802/106680</a>].

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data availability

All data underlying the results are available as part of the article and no additional source data are required.