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.

See also Neonatal Jaundice and Jaundice in Pregnancy.

It is useful to briefly review bilirubin metabolism to appreciate the ways in which jaundice can be produced.

• 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 can be excreted only when made water soluble by conjugation with glucuronic acid in the liver.
• It is excreted in bile, a fluid made up of bile salts, cholesterol and bilirubin.
• Bile is stored and concentrated in the gall bladder then excreted under the influence of cholecystokinin via cystic duct, common bile duct and through the ampulla of Vater into the duodenum.
• In the gut it is converted with the help of bacteria to urobilinogen.
• It is then excreted either as urobilinogen from the kidney (only about 1%) or (the vast majority) as urobilin (brown colour) in the stool (having been broken down from urobilinogen by bacteria in the large bowel).

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

• Prehepatic causes (unconjugated hyperbilirubinaemia)
• Hepatocellular disease
• Intrahepatic cholestasis
• Extrahepatic cholestasis

This is determined by the epidemiology of the various diseases causing jaundice. It will vary accordingly and often quite markedly reflecting the different epidemiological patterns of disease. In less developed countries hepatitis is, for example more common.

In the history it is important to ask about:

• Any prodromal flu-like illness.This is suggestive of hepatitis.
• Pain. Is the jaundice associated with pain or is it painless? 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 weight loss suggests carcinoma.
• The colour of urine and stools. In viral hepatitis and obstructive jaundice, pale stool and darkening urine precede the jaundice.
• Whether pruritus experienced. Pruritus occurs before the patient becomes overtly jaundiced. The cause is unknown.
• Weight loss. Has there been marked weight loss? It is useful to gauge the amount of weight loss and over how long it has occurred.
• Travel. Has the patient travelled to a country where hepatitis A is endemic?
• Alcohol consumption. Is this excessive, or has it been excessive in the past?
• Drug abuse. Has the patient ever abused intravenous drugs?
• Blood transfusions. Has the patient ever had one?
• Contact with other jaundiced patients?
• Medication history. This should include a history of both prescribed and non-prescription drugs. Drugs associated with jaundice (and contraindicated in jaundice) are listed in the table below.
• 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. This may be important for example in sewerage workers or people exposed to hepatotoxic chemicals.
• Family history of jaundice
• Obstetric cholestasis is a cause of mild jaundice.

• Most easily recognised in fair-skinned individuals
• Difficult to detect in darkly pigmented patients
• Most easily seen in the sclera where the white background and affinity of bilirubin for elastin make it more obvious
• Best seen in natural light by pulling down the lower eye lid to expose the sclera, and asking the patient to look up.
• Yellow-green in appearance in chronic, severe obstructive jaundice (biliverdin).
• Not to be confused with carotenaemia (the sclera remains white). Carotenaemia is prominent in palms, soles and face.

Check for signs of the underlying disease. For example in cirrhosis:

• Spider naevi
• Liver palms
• Gynaecomastia
• Testicular atrophy
• Flapping tremor
• Splenomegaly
• Finger clubbing
• Ascites
• Leg oedema

Abdominal examination. Note:

• 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 gallbladder palpable, it is probable that the cause of jaundice is not a stone (Courvoisier's law)
• Liver usually smoothly enlarged in post-hepatic obstructive jaundice.
• Pancreatic tumours may be palpable.
• Splenomegaly is suggestive of cirrhosis, haematological disorders or reticulosis (check for lymphadenopathy).

• Gilbert's syndrome:first described in 1901 this 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.
• Dubin-Johnson syndrome:first described in 1954, is autosomal recessive disorder characterised by conjugated hyperbilirubinaemia and deposition of pigment in hepatocytes.
• Crigler-Najjar syndrome is a rare autosomal recessive disorder of bilirubin metabolism caused by deficient diphosphate glycosyltransferase.
• Difficulties can arise with overlapping of diseases such as autoimmune hepatitis with primary biliary cirrhosis and autoimmune hepatitis with hepatitis C.
• Biliary obstruction is the blockage of any of the ducts carrying bile from liver to gallbladder, or from gallbladder to small intestine. Obstruction can be by mechanical means and extrahepatic or by metabolic factors in the hepatic cells (or intrahepatic). Overall gallstones are the most common cause of extrahepatic obstruction.
• The most common cause of drug induced hepatocellular jaundice in 2005 study from Spain was amoxicillin-clavulanate.¹¹ In another study on outcome in severe drug-induced liver disease, the AST and bilirubin levels were the most important predictors of death or liver transplantation.¹²

Initial investigations

Jaundice will be apparent if the total bilirubin is >35μmol/l. It is usually easy to differentiate pre-hepatic causes of jaundice from hepatic and post-hepatic. It is more difficult to differentiate the latter as they often co-exist (for example 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:

• Checking urinary bilirubin and urobilinogen. Note that:
  • Raised urinary bilirubin, absent or reduced urobilinogen is suggestive of obstructive jaundice.
  • Normal or raised urinary bilirubin and urobilinogen suggests hepatocellular failure.
  • Normal urinary bilirubin, raised urinary urobilinogen suggests haemolytic jaundice.
  • Urine should be tested fresh using reagent dipsticks (if left standing pH changes and light degradation affect results).
  • If clinically jaundiced but serum bilirubin normal and negative urinary bilirubin then cause is hypervitaminosis A or high serum carotene from carrots, pumpkins etc. Normal range carotene is 0.7-3.7 μmol/l.
  • False negatives for urinary bilirubin occur with rifampicin, or if urine not fresh.
  • False positives for urobilinogen occur in acute porphyria.
  • False positive for urinary bilirubin may occur with phenothiazines.
• Checking liver function tests (see below), and if normal ask for
• Levels of conjugated/ unconjugated bilirubin (direct/indirect bilirubin). Note: Protect samples from light as this can reduce the bilirubin content. Shaking the sample can artificially elevate the bilirubin.
  • Raised unconjugated (indirect) bilirubin suggests:
    • Gilbert's syndrome (3-7% of the population)
    • Haemolysis (see also 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 investigations

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

• Full blood count. This may incorporate a reticulocyte count and blood smear to detect haemolysis.
• ESR. This may be elevated for example in primary biliary cirrhosis (PBC).
• Lactate dehydrogenase. Raised in haemolysis.
• Liver function tests:
  • Alkaline phosphatase. This is considerably increased with either extrahepatic or intrahepatic biliary disease. The commonest diseases associated with raised alkaline phosphatase include:
    • Gallstones causing bile duct obstruction
    • Pancreatic cancer
    • Pregnancy
    • Drugs
    • More rarely, PBC
  • Serum transaminases. These are usually very high in hepatocellular disease (like viral hepatitis), but more modestly elevated in chronic hepatocellular damage and obstruction. Note:
    • Aspartate aminotransferase (AST) is raised more than alanine amino transferase (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 suggests 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, viral or drug induced hepatitis.
    • Very high levels of ALT (over 1000 IU/l) suggests acute parenchymal disease.
  • Gamma-glutamyl transferase (GGT). Note:
    • 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 (x10 normal).
    • Raised GGT with raised alkaline phosphatase (over x3 normal) suggests cholestasis.
• Hepatitis serology. This should be done in all patients with cholestasis as differentiating hepatitis from extrahepatic obstructive causes may be very difficult.
• Prothrombin time. This may be prolonged because of vitamin K malabsorption. Injection of vitamin K will correct deficiency in cholestasis but not in parenchymal liver disease.
• Urine bilirubin. This is normally absent, but when present is conjugated bilirubin (evidenced by dark urine). Reagent strips are very sensitive and detect as little as 0.05 mg/dl of bilirubin (thus positive even when no hyperbilirubinaemia or jaundice).
• Serum antinuclear antibodies (ANA), 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 suspected). IgG is raised in acute hepatitis, IgM is raised in auto-immune disease, PBC or chronic infection.
• Alpha-1 antitrypsin levels. Deficiency causes cirrhosis and emphysema.
• Ferritin. This screens for haemochromatosis.
• Imaging.¹³ New techniques have been developed and some old imaging techniques are virtually obsolete. Techniques include:
  • Plain radiographs. These are of little value as few biliary tract calculi are radiopaque.
  • Abdominal ultrasound. This can detect liver abnormalities, hepatosplenomegaly and gallstones.¹⁴ It is useful to identify the extrahepatic causes of biliary obstruction but is also good at identifying intrahepatic disease (for example malignant disease).¹⁵
  • 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 ERPC.¹⁶ It may become the test of choice in obstructive jaundice.¹⁷
  • Percutaneous transhepatic cholangiography. This is used much less often.
  • Endoscopic retrograde cholangiopancreatography. This is accurate at diagnosing benign and extrahepatic obstruction and can be combined with procedures to relieve obstruction.¹⁵
• Liver biopsy. This can be done laparoscopically or percutaneously. It may be necessary for example to stage disease in PBC.
• Laparotomy may ultimately, as has always been the case, be required to make the diagnosis in some cases of jaundice.¹⁸

This will depend on the diagnosis and cause of the jaundice.