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Pathophysiology of jaundice

  •  Pre-hepatic
    • Increased breakdown of red cells leads to increased serum bilirubin. This unconjugated bilirubin isn’t water-soluble so can’t be excreted in the urine. Intestinal bacteria convert some of the extra bilirubin into urobilinogen, some of which is re-absorbed and IS excreted by the kidneys – hence urinary urobilinogen is increased.
  • Hepatic
    • Disorders of uptake, conjugation or secretion of bilirubin.
    • Usually divided into conjugated or unconjugated bilirubinaemia


The various causes of jaundice are traditionally classified into pre-hepatic, hepatic and post-hepatic (or cholestatic) groups according to the mechanism of the jaundice.


Pre-hepatic causes of jaundice

  • Congenital red cell issues
    • Cell shape
      • Sickle cell disease
      • Hereditary spherocytosis
      • Hereditary elliptocytosis
    • Enzyme
      • G6PD deficiency
      • Pyruvate kinase deficiency
    • Haemoglobin
      • Thalassemia
  • Autoimmune haemolytic anaemia
  • Drugs
    • Penicillins
    • Sulphasalazine
  • Infections
    • Malaria
  • Mechanical
    • Metallic valve prostheses
    • DIC
  • Transfusion reactions
  • Paroxysmal nocturnal haemoglobinuria


Hepatic causes of jaundice

  • Conjugated causes
    • Cirrhosis (see chronic liver disease for further causes)
    • Malignancy
      • Primary or metastases
    • Viral hepatitis
    • Drugs
      • Hepatitis
        • Isoniazid, rifampicin, atenolol, enalapril, verapamil, nifedipine, amiodarone, ketoconazole, cytotoxics, halothane
      •  Cholestasis
        • Ciclosporin, azathioprine, chlorpromazine, cimetidine, erythromycin, nitro, ibuprofen, hypoglycaemics
    • Enzymes
      • Dubin-Johnson syndrome (DJS)
        • Autosomal recessive (cMOAT gene) with excretion of conjugated bilirubin.
          • Leads to pigmented liver.
        • Increase in conjugated bilirubin with no other enzyme changes
        • High coproporphyrin
      • Rotor syndrome
        • Similar to DJS
        • Liver not pigmented
        • Normal coproporphyrin
  • Unconjugated causes of jaundice (sometimes classified as pre-hepatic causes)
    • Gilbert’s syndrome
      • Congenital hypo-activity of conjugation enzyme UGT-1. Benign and common (5%)
      • Normal LFTs except mildly elevated bilirubin, especially in times of physiological stress/illness
      • Normal life expectancy
    • Crigler-Najar syndrome
      • Autosomal recessive (type I) or dominant (type II). Severe unconjugated hyperbilirubinaemia.
      • Congenital absence (I) or decrease (II) of glucoronyl transferase.
      • Normal liver histology.
      • Treatment is liver transplant (only type II survive to adulthood)


Post-hepatic causes of jaundice

  • Biliary tree obstruction
    • Gallstones
    • Compression  e.g. pancreatitis, pancreatic tumour, lymph nodes, biliary atresia
    • Cholangiocarcinoma
    • Post-operative stricture
  • Primary biliary cirrhosis (see PBC section)
    • M:F = 1:9
    • ANA and Anti- mitochondrial antibodies
      • And anti-centromere for prognosis (though more association with CREST)
  • Primary sclerosing cholangitis (see PSC section)
    • 80% of PSC have UC
    • ANCA, anti-smooth muscle antibodies
    • Association with cholangiocarcinoma



Pregnancy-associated jaundice

  • Obstetric cholestasis
    • 0.1-0.2% of pregnancies
    • Presentation
      • Itching – jaundice later
      • Raised liver markers, esp ALP
    • Issues
      • Fetal mortality 3.5%
    • Often recurs in further pregnancies
    • Treatment
      • Ursodeoxycholic acid
  • HELLP (Haemolysis, Elevated Liver enzymes, Low Platelets)
    • Occurs in 1-2 out of 1000 pregnancies and 10-20% of severe pre-eclampsia
    • Leads to a variant of DIC
    • Needs steroids and prompt delivery
    • Maternal mortality 1-24%
  • Fatty liver of pregnancy
    • All LFTs including synthetic function go off
  • Hyperemesis gravidum
  • Pre-eclampsia
    • Associated with abnormal LFTs in 20% cases


History in jaundice

  • History of presenting complaint
    • Onset of jaundice
    • Pain/Painless
    • Fevers
    • Constitutional symptoms
    • Bowel symptoms
    • Dark urine/Pale stools
  • Past medical history
    • IBD
    • Viral hepatitis
    • Blood transfusions
    • Heart valve surgery
    • Autoimmune disorders
  • Medications
    • See drug causes above
  • Allergies
  • Family history
    • Thalassaemia/Sickle cell/
  • Social history
    • Alcohol consumption
    • Travel history: viral hepatitis, malaria
    • Ideas; concerns; expectations


Examination in jaundice

  • Features of chronic liver disease
    • Ascites
    • Hands: clubbing, Dupuytren’s contracture, palmar erythema
    • Spider naevi
    • Gynaecomastia
    • Portal hypertension: splenomegaly and caput medusae
    • Encephalopathy
  • Cachexia
  • Abdominal masses
  • Lymphadenopathy
  • Splenomegaly


Initial management of jaundice

  • Blood tests
    • Liver function tests (including bili, ALP, ALT, AST, GGT)
    • Full blood count, urea and electrolytes
    • Clotting screen
    • Liver screen
      • Autoimmune screen (ENA, ANA, ANCA)
      • Viral screen (Hep A,B,C)
      • Alfafetoprotein (AFP)
      • Serum caeruloplasmin
      • Ferritin
    • Blood film
  • Ultrasound of the abdomen


Further management of jaundice

  • Further investigation and management will be dictated by the aetiology – see the various sections for more information on this.


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