Jaundice

See also the separate Neonatal jaundice and Jaundice in pregnancy articles.

What is jaundice?

Jaundice is the yellow discolouration caused by accumulation of bilirubin in tissue. Normal serum bilirubin levels are between 3 and 20 μmol/L. Jaundice is not usually apparent until serum bilirubin is over 35 μmol/L. The detection and differential diagnosis of jaundice are important in clinical assessment. It is important to determine what investigations are appropriate and the significance of the results of investigations.

Jaundice results from interference in the normal metabolism of bilirubin (including uptake, transport, conjugation and excretion). This may result from:

• Pre-hepatic causes (unconjugated hyperbilirubinaemia) - eg, haemolytic anaemia.

• Hepatocellular disease.

• Cholestasis: intrahepatic or extrahepatic cholestasis.

Jaundice pathophysiology

• Bilirubin is produced from the breakdown of haemoglobin in the reticuloendothelial system. 95% of circulating bilirubin is unconjugated and bound to albumin.

• The bilirubin-albumin complex is broken down by hepatocytes, leaving free albumin circulating. Bilirubin is excreted in bile (after it has been made water-soluble by conjugation with glucuronic acid in the liver).

• Bile is stored and concentrated in the gallbladder and then excreted into the duodenum under the influence of cholecystokinin.

• After the bilirubin has been conjugated with glucuronic acid in the liver, much of the conjugated bilirubin enters the intestine. Conjugated bilirubin is then deconjugated into colourless urobilinogen by colonic bacteria. The urobilinogen is then oxidised to form urobilin and stercobilin, which colour the stools brown. A small trace of urobilinogen is reabsorbed into the enterohepatic circulation, either to be re-excreted in the bile or to pass through the kidneys to colour the urine yellow.

Epidemiology

Although the commonest cause of jaundice in adults in the UK over 45 remains gallstones, one study showed that over a quarter of cases of jaundice were caused by malignancy.¹

However, causes differ in their prevalence across the globe. A study in Mali, looking at all adults presenting with jaundice, showed that the commonest cause was hepatocellular carcinoma with 39.3% of patients being affected whilst the second most common cause, at 35.3%, was cirrhosis.² A similar study in Vietnam found pancreatic and biliary tract diseases accounted for 17.1% of cases, with cirrhosis occurring in 16.3% and liver malignancies in 14.7%.³ Patients presenting with jaundice in Brazil were found to have gallstones in almost 50% of cases. ⁴

Causes of jaundice⁵⁶

Pre-hepatic (unconjugated hyperbilirubinaemia):

• Gilbert's syndrome is the most common inherited cause of unconjugated hyperbilirubinaemia. It is caused by underactivity of the conjugating enzyme system. It is found in 3-7% of the population.

• Haemolytic anaemias - eg, spherocytosis, pernicious anaemia.

• Thalassaemia.

• Trauma.

• Crigler-Najjar syndrome is a rare autosomal recessive disorder of bilirubin metabolism, caused by deficient diphosphate glycosyltransferase.

Hepatocellular disease:

• Viral hepatitis (including hepatitis A and hepatitis B). Other possible infective causes include leptospirosis, brucellosis, Coxiella burnetii and glandular fever.^{7 8}

• Alcoholic hepatitis.

• Autoimmune hepatitis (10-20% of chronic hepatitis). Can be associated with other autoimmune diseases.

• Drug-induced hepatitis: paracetamol is by far the most common cause of drug-induced liver disease.⁹

• Hepatotoxic chemicals - eg, phosphorous, carbon tetrachloride and phenol.¹⁰

• Decompensated cirrhosis.

Biliary obstruction:

Biliary obstruction may be extrahepatic (caused by mechanical obstruction) or intrahepatic (caused by metabolic factors).

Extrahepatic biliary obstruction:

• Gallstones.

• Cancer of the head of the pancreas.

• Pancreatitis.

• Cancer of the gallbladder.

• Tumour of the ampulla of Vater.¹¹

• Bile duct strictures (can be benign or malignant).

• Parasitic infections (eg, Ascaris lumbricoides, liver flukes)

Intrahepatic biliary obstruction:

• Intrahepatic cholestasis.

• Drugs (for example, phenothiazines).

• Primary sclerosing cholangitis.¹²

• Primary biliary cholangitis.

• Dubin-Johnson syndrome: autosomal recessive disorder characterised by conjugated hyperbilirubinaemia and deposition of pigment in hepatocytes.

• Rotor's syndrome.

Jaundice symptoms and presentation⁵⁶¹³

A thorough history and examination are essential to determine any likely cause of the jaundice.

History

• Any prodromal flu-like illness may suggest viral hepatitis.

• Pain: sudden onset of jaundice with pain in an otherwise healthy individual suggests gallstones. Slow onset of painless jaundice with central abdominal ache, loss of appetite and loss of weight suggests carcinoma.

• The colour of urine and stools: in viral hepatitis and obstructive jaundice, pale stool and darkening urine precede the jaundice.

• Pruritus often occurs before the patient becomes overtly jaundiced.

• Ask about:

  • Weight loss - may suggest an underlying malignancy.

  • Travel to any country where hepatitis A or any other infective cause is endemic.

  • Alcohol consumption.

  • Drug use.

  • HIV status.

  • Contact with other jaundiced patients.

• Medication history (both prescribed and non-prescription drugs). Drugs associated with jaundice and contra-indicated in jaundice include: amitriptyline, chlorpromazine, erythromycin, halothane, imipramine, indomethacin, isoniazid, methyldopa, monoamine-oxidase inhibitors (MAOIs), rifampicin, salicylates, sulphonamides, thiouracil.

• Past medical history:

  • A past history of hepatitis raises the possibility of chronic active hepatitis.

  • A history of previous biliary surgery raises the possibility of a stone in the common bile duct.

  • Metastatic disease may present with jaundice. A history of bowel or breast cancer may be particularly pertinent.

  • A history of ulcerative colitis makes primary sclerosing cholangitis more likely.

• Occupational history may be important - eg, in sewage workers or people exposed to hepatotoxic chemicals.

• Family history of jaundice.

• Obstetric cholestasis is a cause of mild jaundice.

Examination⁵⁶

• Jaundice is most easily recognised in fair-skinned individuals and can be difficult to detect in darkly pigmented patients. It is most easily seen in the sclera and best seen in natural light by pulling down the lower eyelid to expose the sclera and asking the patient to look up.

• Signs of underlying liver disease include:

  • Spider naevi.

  • Liver palms (erythema of the thenar and hypothenar eminences; may also affect the soles of the feet).

  • Gynaecomastia.

  • Testicular atrophy.

  • Flapping tremor.

  • Splenomegaly.

  • Finger clubbing.

  • Ascites.

  • Peripheral oedema.

• Abdominal examination:

  • In viral hepatitis the liver is slightly enlarged and tender.

  • The liver edge in cirrhosis is firm.

  • An irregular liver edge suggests malignant disease.

  • If the gallbladder is palpable, it is probable that the cause of jaundice is not a stone (Courvoisier's law).

  • The liver is usually smoothly enlarged in post-hepatic obstructive jaundice.

  • Pancreatic tumours may be palpable.

  • Splenomegaly is suggestive of cirrhosis, haematological disorders or reticulosis.

  • Also check for lymphadenopathy.

Jaundice: yellowish pigmentation of the sclera

© Sheila J Toro, CC BY 4.0, via Wikimedia Commons

Investigations⁵¹³

See the separate Abnormal liver function tests article.

Jaundice will be apparent if the total bilirubin is >35 μmol/L. It is usually easy to differentiate pre-hepatic causes of jaundice from hepatic and post-hepatic. It is more difficult to differentiate hepatic and post-hepatic, as they often co-exist (eg, obstructive jaundice with biliary cirrhosis).

In jaundice, the essential and rapid differentiation of the main causes (hepatitis, biliary stasis, haemolysis, resolution of haematoma or congenital causes) can often be achieved by performing the following investigations.

• Levels of conjugated/unconjugated bilirubin (direct/indirect bilirubin).

  • Raised unconjugated (indirect) bilirubin suggests:

    • Gilbert's syndrome.

    • Haemolysis (reticulocytes, increased urinary urobilinogen, reduced serum haptoglobin).

    • Mild chronic hepatitis.

    • Crigler-Najjar syndrome (levels over 85 μmol/L).

  • Raised conjugated (direct) bilirubin (>10 μmol/L) suggests obstructive jaundice, including:

    • Liver disease

    • Pancreatic disease

    • Dubin-Johnson syndrome

• FBC should include a reticulocyte count and blood smear to detect haemolysis.

• ESR may be elevated - for example, in primary biliary cholangitis.

• Lactate dehydrogenase is raised in haemolysis.

• LFTs:

  • Alkaline phosphatase: considerably increased with either extrahepatic or intrahepatic biliary disease. The most common diseases associated with raised alkaline phosphatase include:

    • Gallstones causing bile duct obstruction.

    • Pancreatic cancer.

    • Pregnancy.

    • Drugs.

    • More rarely, PBC.

    • (Remember: Alkaline phosphatase is commonly raised in children as it becomes elevated during bone growth).

  • Serum transaminases are usually very high in hepatocellular disease (like viral hepatitis) but more modestly elevated in chronic hepatocellular damage and obstruction:

    • Aspartate aminotransferase (AST) is raised more than alanine aminotransferase (ALT) in cirrhosis, intrahepatic neoplasia, haemolytic jaundice and alcoholic hepatitis.

    • ALT is raised more than AST in acute hepatitis and in extrahepatic obstruction.

    • ALT levels of less than 100 IU/L with jaundice suggest obstructive jaundice.

    • ALT over 400 IU/L suggests diffuse acute hepatocellular damage (for example, in viral hepatitis).

    • ALT between 150-400 IU/L suggests chronic active hepatitis or viral or drug-induced hepatitis.

    • Very high levels of ALT (over 1,000 IU/L) suggest acute parenchymal disease.

  • Gamma-glutamyl transferase (GGT):

    • GGT is sensitive but not specific for excess alcohol intake.

    • A raised MCV with raised GGT is suggestive of alcohol abuse and, if accompanied by raised ALT, suggests liver cell damage.

    • Biliary obstruction and hepatic malignancies cause very high GGT levels (x 10 normal).

    • Raised GGT with raised alkaline phosphatase (over x 3 normal) suggests cholestasis.

• Hepatitis serology should be done in all patients with cholestasis, as differentiating hepatitis from extrahepatic obstructive causes may be very difficult.

• Prothrombin time may be prolonged because of vitamin K malabsorption. Injection of vitamin K will correct deficiency in cholestasis but not in parenchymal liver disease.

• Serum antinuclear antibodies (ANAs), anti-smooth muscle antibody (ASMA): the hallmark of primary biliary cholangitis is antimitochondrial antibodies (90-95% of patients with primary biliary cholangitis are positive); ANA is positive in 20-50% of patients with primary biliary cholangitis.

• Serum immunoglobulins and serum electrophoresis: IgG is raised in acute hepatitis, IgM is raised in autoimmune disease, primary biliary cholangitis or chronic infection.

• Alpha-1-antitrypsin levels: deficiency causes cirrhosis and emphysema.

• Ferritin to screen for haemochromatosis.

• Imaging:

  • Abdominal ultrasound can detect liver abnormalities, hepatosplenomegaly and gallstones. It is useful to identify the extrahepatic causes of biliary obstruction but is also good at identifying intrahepatic disease (for example, malignant disease).¹⁴

  • Endoscopic ultrasound is commonly used to image the pancreas and biliary tract.¹⁵

  • CT scan.

  • ERCP is accurate at diagnosing benign and extrahepatic obstruction and can be combined with procedures to relieve obstruction.¹⁶

  • MRI scanning and magnetic resonance cholangiopancreatography (MRCP) provides images which are diagnostically-equivalent images to ERCP and is a useful technique in high risk patients to avoid significant morbidity. ¹⁷¹⁸

• Liver biopsy can be done laparoscopically or percutaneously. It may be necessary, for example, to stage disease in PBC.

Jaundice treatment and management

This will depend on the diagnosis and cause of the jaundice in each individual case but factors to consider here include managing any pruritus that may be present - including lifestyle and dietary advice and cholestyramine treatment.