Causes

• Viral hepatitis (A, B, C, E)
• Alcoholic hepatitis and cirrhosis
• Drug-induced or toxic injury (paracetamol, isoniazid, methyldopa, halothane)
• Autoimmune hepatitis
• Ischemic hepatitis and sepsis (benign postoperative jaundice)
• Wilson disease, hemochromatosis, and alpha-1 antitrypsin deficiency

• Drugs: estrogens and anabolic steroids, chlorpromazine, erythromycin estolate, amoxicillin-clavulanate, and others
• Primary biliary cholangitis (PBC)
• Primary sclerosing cholangitis (PSC), which can be intra- or extrahepatic
• Intrahepatic cholestasis of pregnancy
• Infiltrative disease (lymphoma, granulomas, amyloid, metastases, abscess)
• Total parenteral nutrition, sepsis, and congestive hepatopathy
• Hereditary cholestasis (PFIC, benign recurrent intrahepatic cholestasis)

• Common bile duct stones (choledocholithiasis)
• Carcinoma of the head of the pancreas, cholangiocarcinoma, or ampullary tumor
• Bile duct stricture, either postoperative or inflammatory
• Chronic pancreatitis
• Biliary atresia and choledochal cyst in infants
• Extrinsic compression, for example by lymph nodes at the porta hepatis
• Mirizzi syndrome, parasites (Ascaris, liver flukes), and AIDS cholangiopathy

• Dubin-Johnson syndrome: caused by an MRP2 (ABCC2) mutation. The liver is pigmented black and the gallbladder is not seen on oral cholecystography. Prognosis is benign.
• Rotor syndrome: the liver is not pigmented, and total urinary coproporphyrin is increased. Prognosis is benign.
• Both are autosomal recessive. Patients have asymptomatic jaundice and normal liver enzymes.

• Robbins lists transporter deficiency, hepatocellular disease, and impaired bile flow from duct obstruction or autoimmune cholangiopathies. (Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 793)
• Tietz groups the causes as decreased secretion of conjugated bilirubin into the canaliculi: hepatitis, intrahepatic cholestasis, Dubin-Johnson and Rotor syndromes, and drugs such as estradiol. (Tietz Textbook of Laboratory Medicine, 7th Edition)
• Harrison's describes Dubin-Johnson and Rotor syndromes as the two rare inherited causes of isolated conjugated hyperbilirubinemia. (Harrison's Principles of Internal Medicine 22E)

Clues to separate the groups

1. Check ALP, GGT, AST, ALT, PT/INR, and albumin.
2. Do a liver ultrasound to look for dilated bile ducts.
3. If the ducts are dilated, use MRCP, CT, or EUS.
4. If the ducts are not dilated, check viral and autoimmune serology (AMA, ANA, ASMA) and review drug history.
5. If enzymes are normal and the bilirubin is isolated and conjugated, think of Dubin-Johnson or Rotor syndrome.

Recent evidence check

Most likely explanations

• Aminotransferases peak early. Bilirubin and ALP then rise after them, and in some patients stay raised after the aminotransferases have normalized. Cholestasis can be substantial in acute HAV. (Kaplan & Sadock's Comprehensive Textbook of Psychiatry, hepatitis section)
• Typical features are pruritus, dark urine, pale stools, and sometimes fever, diarrhea, and weight loss.
• The prolonged form is defined by bilirubin above 10 mg/dL and a course of at least 12 weeks. It is more common in males and older patients. All patients recover without lasting sequelae, and some may benefit from corticosteroids. (Yamada's Textbook of Gastroenterology, 7th ed, Clinical course)

• This occurs in up to 20% of HAV cases and is biphasic. The patient recovers apparently, then has a recrudescence 5 to 10 weeks later.
• The second phase tends to have higher bilirubin and a longer course. Steroid use in the early phase and alcohol are risk factors. (Yamada's Textbook of Gastroenterology)
• Anti-HAV IgM is detectable again during relapse, and HAV can be found in stool. Complete resolution is the rule.
• Note that in a relapse, the ALT usually rises again together with the bilirubin. If the ALT keeps falling, a pure cholestatic picture is more likely.

Causes to exclude

• Biliary obstruction. Check for a CBD stone or gallbladder or biliary disease with an ultrasound.
• Hemolysis. This is a concern in G6PD deficiency, where HAV can trigger hemolysis. It would mainly raise indirect bilirubin, so look at the fractions, LDH, reticulocytes, and a peripheral smear.
• Drugs. Paracetamol overuse, herbal remedies, antibiotics such as amoxicillin-clavulanate, estrogens, and any new medicines can cause cholestatic injury.
• Co-infection or superimposed disease. Think of hepatitis E, hepatitis B (HBsAg, anti-HBc IgM), autoimmune hepatitis, and Wilson disease in younger patients.
• Pregnancy-related cholestasis, if the patient is pregnant.
• Worsening liver failure. This is the dangerous alternative. A falling ALT with a rising bilirubin can mean massive hepatocyte loss. Check PT/INR, albumin, mental status, and glucose. A rising INR (above 1.5) or any encephalopathy suggests acute liver failure. Acute liver failure occurs in 1 to 2% of acute HAV cases and needs urgent admission. (Yamada's Textbook of Gastroenterology)

Suggested workup

1. Repeat the full LFTs with ALP, GGT, and the direct and indirect bilirubin split.
2. PT/INR and albumin.
3. Abdominal ultrasound.
4. Anti-HAV IgM, plus HEV IgM and HBsAg or anti-HBc IgM.
5. CBC, smear, and reticulocytes if indirect bilirubin is also raised.
6. A review of all medicines taken.

Management

• Supportive care is the mainstay. Avoid alcohol, paracetamol overuse, and hepatotoxic or herbal drugs.
• For pruritus, use cholestyramine, and ursodeoxycholic acid is often used. Case reports describe its use in cholestatic and relapsing HAV, for example this pediatric case. The evidence is limited to case reports.
• A short steroid course is occasionally used in a prolonged, severe cholestatic course. It is not routine.
• Admit the patient if there is coagulopathy, drowsiness or confusion, persistent vomiting, or very high bilirubin.
• Review at 1 to 2 weeks, because bilirubin often normalizes slowly over weeks to months.