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. The normal serum bilirubin is approximately 3-20 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 the circulating bilirubin is unconjugated and bound to albumin.

• The bilirubin-albumin complex is broken down by hepatocytes leaving free albumin circulating. The bilirubin is excreted in bile but only when 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.

• Bilirubin is conjugated with glucuronic acid in the liver. Much of the conjugated bilirubin enters the intestine. Conjugated bilirubin is deconjugated into colourless urobilinogen by colonic bacteria. The urobilinogen can then be 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.

Jaundice symptoms and presentation¹

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 occurs before the patient becomes overtly jaundiced. The cause is unknown.

• 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 abuse.

  • Blood transfusions.

  • 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, indometacin, isoniazid, methyldopa, monoamine-oxidase inhibitors (MAOIs), oral contraceptive pill, rifampicin, salicylates, sulfonamides, 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.

  • Malignancy, particularly with breast or bowel carcinoma, may present with jaundice.

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

• Family history of jaundice

• Obstetric cholestasis is a cause of mild jaundice.

Examination

• Jaundice is most easily recognised in fair-skinned individuals and 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.

• it is yellow-green in appearance in chronic, severe obstructive jaundice (biliverdin).

• It should not to be confused with carotenaemia (the sclera remains white). Carotenaemia is prominent in the palms, soles and face.

• 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 posthepatic 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

By Sheila J. Toro (Own work), CC BY 4.0, via Wikimedia Commons

Differential diagnosis of jaundice

Difficulties can arise with overlapping of diseases such as autoimmune hepatitis with primary biliary cirrhosis (PBC) and autoimmune hepatitis with hepatitis C.

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.

Trauma².

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.^{3 4}

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.⁵

Hepatotoxic chemicals - eg, phosphorous, carbon tetrachloride and phenol.⁶

Decompensated cirrhosis.

Biliary obstruction may be mechanical and extrahepatic or by metabolic factors in the hepatic cells (intrahepatic). Overall, gallstones are the most common cause of extrahepatic obstruction:

Intrahepatic cholestasis.

PBC.

Drugs (for example, phenothiazines).

Primary sclerosing cholangitis.⁷

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

Rotor's syndrome.

Extrahepatic cholestasis may be from within the lumen, in the wall of the duct or from external compression:

Bile duct strictures (can be benign or malignant).

Common duct stone.

Cancer of the head of the pancreas.

Tumour of the ampulla of Vater.⁸

Pancreatitis.⁹

Cancer of the gallbladder.¹⁰

Investigations

Initial investigations

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 posthepatic. It is more difficult to differentiate hepatic and posthepatic, 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.

Checking LFTs
If normal, ask for:

• Levels of conjugated/unconjugated bilirubin (direct/indirect bilirubin). Light may reduce the bilirubin content and shaking the sample can artificially elevate the 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

Further investigations⁹

More investigations (listed with occasional notes on interpretation of results) will be necessary to allow further diagnostic differentiation:

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

• ESR may be elevated - for example, in PBC.

• 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.

  • 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-glutamyltransferase (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 PBC is antimitochondrial antibodies (90-95% of patients with PBC are positive); ANA is positive in 20-50% of patients with PBC.

• Serum immunoglobulins and serum electrophoresis in acute hepatitis when autoimmune hepatitis is suspected. IgG is raised in acute hepatitis, IgM is raised in autoimmune disease, PBC or chronic infection.

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

• Ferritin to screen for haemochromatosis.

• Imaging⁹ :
  

  • Plain radiographs are of little value, as few biliary tract calculi are radiopaque.

  • Abdominal ultrasound can detect liver abnormalities, hepatosplenomegaly and gallstones¹¹ . It is useful to identify the extrahepatic causes of biliary obstruction but is also good at identifying intrahepatic disease (for example, malignant disease)¹² .

  • CT scan.

  • MRI scanning and magnetic resonance cholangiopancreatography (MRCP): MRCP has been recommended with a predictive scoring system to reduce the number of patients undergoing unnecessary endoscopic retrograde cholangiopancreatography (ERCP). It may become the test of choice in obstructive jaundice¹³ .

  • Percutaneous transhepatic cholangiography is used much less often.

  • ERCP is accurate at diagnosing benign and extrahepatic obstruction and can be combined with procedures to relieve obstruction¹⁴ .

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

• Laparotomy may ultimately be required to make the diagnosis in some cases of jaundice¹⁵ .

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 treatment¹⁶ .