See also separate articles Neonatal Jaundice and Jaundice in Pregnancy.
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.
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- 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 in the gut is converted with the help of bacteria to urobilinogen.
- Excretion is then either as urobilinogen from the kidney (only about 1%) or as urobilin (the vast majority) in the stool (having been broken down from urobilinogen by bacteria in the large bowel).
A thorough history and examination are essential to determine any likely cause of the jaundice.
- 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 weight loss 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.
- 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:
- 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.
- Jaundice is most easily recognised in fair-skinned individuals and difficult to detect in darkly pigmented patients.
- 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.
- 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.
- Signs of underlying liver disease include:
- 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.
- 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.
- Crigler-Najjar syndrome is a rare autosomal recessive disorder of bilirubin metabolism, caused by deficient diphosphate glycosyltransferase.
- Viral hepatitis (including type A and type B). Other possible infective causes include leptospirosis, brucellosis, Coxiella burnetii) and glandular fever.
- 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.
- Hepatotoxic chemicals, eg phosphorous, carbon tetrachloride and phenol.
- Decompensated cirrhosis.
- Intrahepatic cholestasis.
- Extrahepatic cholestasis may be from within the lumen, in the wall of the duct or from external compression:
See also separate article Abnormal Liver Function Tests.
Jaundice will be apparent if the total bilirubin is >35 μmol/L. It is usually easy to differentiate prehepatic 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:
- Urinary bilirubin and urobilinogen:
- Urinary bilirubin is normally absent but is conjugated when present (dark urine).
- Raised urinary bilirubin with absent or reduced urobilinogen is suggestive of obstructive jaundice.
- Normal or raised urinary bilirubin with elevated urobilinogen suggests hepatocellular failure or increased red cell breakdown (eg haemolytic jaundice).
- Urine dipstick analysis: urine should be tested fresh using reagent dipsticks (if left standing, pH changes and light degradation affect results). Reagent strips are very sensitive and detect very low levels of bilirubin.
- If clinically jaundiced but serum bilirubin normal and negative urinary bilirubin then the cause is hypervitaminosis A or high serum carotene from carrots, pumpkins, etc..
- False negatives for urinary bilirubin occur with rifampicin or if the urine is not fresh.
- False positives for urobilinogen occur in acute porphyria.
- False positive for urinary bilirubin may occur with phenothiazines.
- Checking LFTs (see 'Further investigations', below) and, 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
- Raised unconjugated (indirect) bilirubin suggests:
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 primary biliary cirrhosis (PBC).
- Lactate dehydrogenase is raised in haemolysis.
- Alkaline phosphatase: considerably increased with either extrahepatic or intrahepatic biliary disease. The most common diseases associated with raised alkaline phosphatase include:
- 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 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 1,000 IU/L) suggests 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.
- Plain radiographs are of little value, as few biliary tract calculi are radiopaque.
- 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).
- 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 jaundice.
- 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 obstruction.
- 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 jaundice.
This will depend on the diagnosis and cause of the jaundice.
Further reading & references
- Theodossi A; The value of symptoms and signs in the assessment of jaundiced patients. Clin Gastroenterol. 1985 Jul;14(3):545-57.
- Labori KJ, Bjornbeth BA, Raeder MG; Aetiology and prognostic implication of severe jaundice in surgical trauma patients. Scand J Gastroenterol. 2003 Jan;38(1):102-8.
- Pappas G, Christou L, Akritidis NK, et al; Jaundice of unknown origin: Remember zoonoses! Scand J Gastroenterol. 2006 Apr;41(4):505-8.
- Crum NF; Epstein Barr virus hepatitis: case series and review. South Med J. 2006 May;99(5):544-7.
- Metha N et al, Drug-Induced Hepatotoxicity, Medscape, Apr 2010
- Suppiah A, Perry EP; Jaundice as a presentation of phenol induced hepatotoxocity following injection sclerotherapy for haemorrhoids. Surgeon. 2005 Feb;3(1):43-4.
- Worthington J, Chapman R; Primary sclerosing cholangitis. Orphanet J Rare Dis. 2006 Oct 24;1(1):41.
- Fang CL, Chu JS, Hsieh MC, et al; Signet-ring cell carcinoma of the ampulla of Vater. J Formos Med Assoc. 2004 Oct;103(10):793-6.
- Tunnemann J, Easterbrook JR, Firth J, et al; Management of acute pancreatitis: a comparative audit of clinical practice against the recommendations of the british society of gastroenterology Br J Surg. 2000 Mar;87(3):362-73.
- Hawkins WG, DeMatteo RP, Jarnagin WR, et al; Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer. Ann Surg Oncol. 2004 Mar;11(3):310-5.
- O'Regan D, Tait P; O'Regan D, Tait P; Imaging of the jaundiced patient. Hosp Med. 2005 Jan;66(1):17-22.
- Schirmer BD, Winters KL, Edlich RF; Cholelithiasis and cholecystitis. J Long Term Eff Med Implants. 2005;15(3):329-38.
- Pasanen PA, Partanen KP, Pikkarainen PH, et al; A comparison of ultrasound, computed tomography and endoscopic retrograde cholangiopancreatography in the differential diagnosis of benign and malignant jaundice and cholestasis. Eur J Surg. 1993 Jan;159(1):23-9.
- Topal B, Van de Moortel M, Fieuws S, et al; The value of magnetic resonance cholangiopancreatography in predicting common bile duct stones in patients with gallstone disease. Br J Surg. 2003 Jan;90(1):42-7.
- Vaishali MD, Agarwal AK, Upadhyaya DN, et al; Magnetic resonance cholangiopancreatography in obstructive jaundice. J Clin Gastroenterol. 2004 Nov-Dec;38(10):887-90.
- Scialpi M, Baraldi R, Campioni P, et al; Obstructive jaundice. Rays. 2005 Jul-Sep;30(3):263-7.
|Original Author: Dr Richard Draper||Current Version: Dr Colin Tidy|
|Last Checked: 22/06/2011||Document ID: 1109 Version: 23||© EMIS|
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