Cholestasis and jaundice

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Chapter 32 CHOLESTASIS AND JAUNDICE

KEY POINTS

• Biliary, hepatocellular and systemic conditions may all cause cholestasis and jaundice.
• Elevated bilirubin and cholestatic enzymes (ALP and GGT) suggest a biliary cause. Elevated bilirubin and transaminases (ALT and AST) suggest a hepatocellular cause.
• Imaging with abdominal ultrasound is essential to evaluate for the presence of biliary obstruction and parenchymal liver disease, giving useful information about both the underlying cause for cholestasis and any complications of liver disease.
• A liver screen should be performed to narrow the differential diagnosis for cholestasis.
• Treatment of cholestasis is primarily aimed at treating the underlying cause.
• Pruritis is a troublesome symptom of cholestasis, and can occur with elevated bile acids, even when the bilirubin is within normal range. There is a range of specific treatments available.
• Cholestatic disorders contribute to mortality and morbidity and are, in some settings, an important indication for liver transplantation.

INTRODUCTION

Cholestasis and jaundice are common clinical occurrences which flag the presence of an underlying disease process. Diseases of the liver and biliary tree are a significant cause of morbidity and mortality and an important indication for liver transplantation in certain settings. This chapter outlines an approach to dealing with this common problem.

Definitions

Cholestasis can be defined as ‘the excess of biliary substances in the blood’. Cholestasis may be accompanied by jaundice and/or deranged liver biochemistry. Although cholestasis commonly occurs in the context of biliary obstruction, it may occur without evidence of biliary pathology.

CAUSES OF CHOLESTASIS

Cholestasis can broadly be divided into that caused by mechanical obstruction, and that caused by non-obstructive or hepatocellular causes. Table 32.1 lists the causes of cholestasis. Mechanical obstruction may develop in either the extrahepatic biliary tree or the smaller intrahepatic bile ducts. Non-obstructive intrahepatic cholestasis may arise from parenchymal disease affecting the small bile ducts and canaliculi or conditions affecting the hepatocytes directly (causing an excess of bile products to be formed). Considering the possible underlying causes of cholestasis will guide the history, examination and investigation of a patient with cholestasis. Important causes to consider include the following.

TABLE 32.1 Causes of cholestasis

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1. Cholelithiasis and choledocholithiasis: cholelithiasis (stones in gall bladder) is common, occurring in up to 25% of Caucasian population, and more in certain ethnic groups. Choledocholithiasis (stone in bile duct) complicates 15%–20% of patients with cholelithiasis. Major risk factors for cholelithiasis include age, female gender, family history, obesity, diabetes and hyperlipidaemia. States with elevated oestrogen and progesterone (pregnancy, oral contraceptives and hormone therapy) are also lithogenic.
2. Malignancy: malignancies (primary and secondary) can cause cholestasis both by mechanical obstruction (e.g. large intrahepatic tumours, cholangiocarcinomas or pancreatic tumours) or by disruption of normal hepatocyte function (hepatocyte destruction).
3. Primary sclerosing cholangitis (PSC): an idiopathic inflammatory disorder of bile ducts characterised by small and large bile duct strictures, portal fibrosis and cirrhosis. Patients have abnormal liver function tests at diagnosis, but only approximately half of the patients are symptomatic at this time. Coexisting inflammatory bowel disease is found in 62% of the patients. High-dose ursodeoxycholic acid has been used to manage cholestasis and endoscopic therapy for dominant bile duct strictures, however the role of these therapies requires further investigation. The risk of developing cholangiocarcinoma is high.
4. Primary biliary cirrhosis (PBC): an autoimmune disease of the bile ducts, occurring predominantly in women, which if untreated can progress to fibrosis and cirrhosis. Antimitochondrial antibodies are found in 95% of patients with PBC. Ursodeoxycholic acid is the only treatment established to modify disease progression in PBC.
5. Drug-induced cholestasis: this can occur with a number of pharmacological agents and may be associated with variable degrees of hepatitis. The offending drug should be promptly discontinued. In some circumstances, drug induced cholestasis may progress to vanishing bile duct syndrome, veno-occlusive disease or liver failure.
6. Hepatocellular causes: any acute or chronic hepatocellular injury can cause cholestasis (e.g. viral or alcoholic hepatitis). This is characterised by a predominant elevation in the serum transaminases and the cholestasis usually resolves sometime after the resolution of the underlying acute hepatocellular injury.
7. Congenital: a choledochocele is a cystic dilatation of the common bile duct, which may cause intermittent biliary obstruction. It is rare, occurring in approximately 1:100,000–150,000 live births. About 80% are diagnosed before 10 years of age, classically presenting as a triad of right upper quadrant pain, a mass and jaundice. In adults this is a rare presentation with abdominal pain and tenderness being the most common features. Endoscopic and surgical therapies are possible.
8. Inherited defects of bilirubin uptake, glucuronidation and transport:

a Unconjugated hyperbilirubinaemia:

i. Gilbert’s syndrome: the most common inherited disorder of bilirubin glucuronidation. Diagnosed in young adults who present with mild icterus or isolated hyperbilirubinaemia. Impaired conjugation of bilirubin is due to reduced bilirubin UDP glucuronosyl transferase activity.
ii. Crigler-Najjar syndrome (Type I & II): congenital non-haemolytic jaundice with glucuronosyltransferase deficiency. A rare, autosomal recessive disorder of bilirubin metabolism presenting as neonatal jaundice (kernicterus).

b Conjugated hyperbilirubinaemia: characterised clinically by mild icterus presenting in the second decade of life.

i. Dubin-Johnson syndrome: rare condition except in Sephardic Jews (incidence is 1:3000) due to altered excretion of bilirubin into the bile ducts.
ii. Rotor syndrome: due to defective hepatic storage of bilirubin.

c Defects in canalicular transport: a range of molecular defects can result in impaired transport of bile acids, phospholipids and ions that express as progressive familial forms of cholestasis.

9. Haemolysis: although haemolysis due to any cause leads to an excess of biliary substances in the blood (unconjugated hyperbilirubinaemia) and may cause clinically evident jaundice, it is not usually associated with cholestatic symptoms. An exception to this is haemolytic disease of the newborn which causes kernicterus, a condition with significant risks to the neonate.

ASSESSMENT

History

Fatigue is the most common symptom of chronic cholestasis. Other symptoms include jaundice, pruritis and steatorrhoea. There may be a history of haemorrhage due to poor vitamin K absorption or bone pain and fractures due to poor vitamin D and calcium absorption (in cases of chronic cholestasis resulting in hepatic osteodystrophy or osteoporosis).

Specific questioning will help determine the underlying aetiology of the cholestasis.

• Enquire about the presence, site and character of abdominal pain. The absence of pain is also relevant. Ask about associated nausea, vomiting and the timing of these symptoms.
• Fevers, chills and rigors suggest hepatobiliary obstruction or an infectious aetiology.
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