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Ganong. 22nd edition: Enterohepatic circulation of bile salts. The solid lines entering the portal system represent bile salts of hepatic origin, whereas the dashed lines represent bile salts resulting from bacterial action.
(Ganong, 22nd edition, Metabolism of bilirubin in the liver. P, intracellular binding proteins; UDPGA, uridine diphosphoglucuronic acid; UDP, uridine diphosphate).
Pathophysiology of different types of jaundice
  1. Normal urine does not contain bilirubin because normal blood contains bilirubin in the unconjugated form.
  2. Unconjugated bilirubin is (water insoluble) because it is transported in the blood as a complex with albumin (albumin-bilirubin complex) which is not allowed to filter through the glomerulus.
  3. Unconjugated bilirubin is taken up from the systemic circulation by hepatocytes
  4. Unconjugated bilirubin is then conjugated to bilirubin glucuronide by glucuronyl transferase within the hepatocytes. This is the rate limiting step.
  5. Conjugated bilirubin is water soluble and filterable by the kidney
  6. Conjugated bilirubin is formed in the liver and directly excreted into the GIT through bile where it is reduced to urobilinogen and stercobilinogen.
  7. When there is hepatocellular dysfunction or bile flow is totally obstructed, conjugated bilirubin "leaks" into the systemic circulation
  8. This conjugated bilirubin may now be excreted by the kidney and be detected in urine.
Bilirubin in urine (bilirubinuria) (Ref. Hari. 18th ed., Pg-326)
  1. Bilirubinuria suggests of conjugated hyperbilirubinemia.
  2. Within the GIT conjugated bilirubin is degraded to urobilinogen and then to stercobilinogen
  3. Urobilinogen filterable by the kidney
  4. Normally, a small portion of the urobilinogen is reabsorbed from the gut and excreted by the kidney (<4 mg/day)
  5. In non obstructive hyperbilirubinemia (hemolytic, hepatocellular) urobilinogen is present in urine.
Liver Function Test
  1. Tests based on detoxification functions:
    1. Serum Bilirubin:
Important Points

Bilirubin occurs in plasma in four forms: (Ref. Hari. 18th ed., Pg - 1662-1663)

  1. Unconjugated bilirubin tightly bound to albumin;
  2. Free or unbound unconjugated bilirubin (the form responsible for kernicterus, because it can cross cell membranes);
  3. Conjugated bilirubin (the only fraction to appear in urine);
  4. Delta bilirubin (Conjugated bilirubin covalently bound to albumin), which appears in serum when hepatic excretion of conjugated bilirubin is impaired in patients with hepatobiliary disease. The δ fraction permits conjugated bilirubin to persist in the circulation and delays resolution of jaundice.
Isolated elevation of serum bilirubin:-
Unconjugated hyperbilirubinemia (D<15%)
The causes are:
  1. Hemolytic disorders (Hereditary spherocytosis, SSA, Thalassemia, G6PD def. Megaloblastic anemia) Q – In these conditions, serum bilirubin levels are usually less than 4 mg/dl. Increase retic count is the hallmarks
  2. Large hematoma
  3. Physiological jaundice of newborn (decreased conjugating enzyme (UGTA) actively) It never occurs on day 1, usually occurs after 48 hours
  4. Breast milk jaundice (glucuronidase present in breast milk de-conjugates the conjugated bilirubin)
  5. Drugs – rifampicin, probenecid, novobiocin, flavispidic acid, cholecystographic agents and ribavirin,
  6. Familial neonatal hyperbilirubinemia (lucey-driscoll syndrome)Q, in which there is a UGT1A1 inhibitor in maternal serum.
  7. Genetic disorders (Impaired bilirubin conjugation):-
Genetic disorders causing unconjugated hyperblirubimia
  1. Gilbert’s syndrome
  2. Crigler-Najjar type I & Type II
  1. Gilbert’s syndrome (Ref. Hari. 18th ed., Pg-326)
    1. Due to reduced activity (10-33%) of UDP glucuronyl transferase Q and also due to reduced uptake of bilirubin.
    2. It is autosomal dominantQ.
    3. Serum bilirubin levels are usually ≤ 4 mg/dl.
    4. Provocation test: The serum level of bilirubin fluctuate and increase during fastingQ. I/V nicotinic acid, also by Indinavir and atazanavir.
    5. PhenobarbitalQ administration normalizes serum bilirubin level.
    6. The patients have normal life expectancyQ.
Extra Edge
  1. IROTECAN not metabolized in Gilbert’s syndrome that lead to its ↑ toxicity (Harrison - 18th edition, Page 1930)
  2. Indinavir and atazanavir cause inhibit the enzyme UDP GT that results in more hyper bilirubinemia
    1. Crigler-Najjar
      Type I (Ref. Hari. 18th ed., Pg-326) – due to complete absence of bilirubin UDP glucuronyl transferaseQ activity. It is autosomal recessiveQ disorder found in neonates and characterized by severe jaundice (Bilirubin > 20 mg/dl) and kernicterus leading to death in infancyQ. They present on day one after birth.
    2. Type II –
      1. Due to reduced activity (0-10% of normal) of UDP glucuronyl transferaseQ. But there is no defiency of UDP glucuronyl transferase
      2. It is predominantly autosomal recessive.
      3. Serum bilirubin levels are in the range of 6-25 mg/dl.
      4. The patient usually survive into the adulthood, kernicterus is uncommon but may develop under the surgery or inter current illness.
      5. Serum bilirubin concentration decreases by >25% in response to enzyme inducers such as PhenobarbitalQ.
      6. Phototherapy is also helpful
      7. Phenobarbitone therapy is useful


Important Points:
Hereditary unconjugated hyperbilirubinemia
Feature Type I Crigler Najjar syndrome Type II Gilbert’s syndrome
Total serum bilirubin, (mg%) (Usually >20) (Usually ≤ 20) Typically [≤ 4]
Response to phenobarbitone None Decrease bilirubin by >25% Decrease bilirubin to normal
Kernicterus Usual Rare No
Bilirubin Glucuronyl Transferase activity
Typically absent

Markedly reduced
0 to 10% of normal

Reduced, typically
10-33% of normal
Inheritance Autosomal recessive Autosomal recessive Autosomal dominant
Kupffer cell
  1. Part of RES, have phagocytic action
  2. Lies in sinusoidal vascular space
Stellate cell
  1. Ito or fat storing cell
  2. Located in space of Disse
Causes: Conjugated hyperbilirubinemia (D>15% (Ref. Hari. 18th ed., pg - 1930):
  1. Biliary atresia
  2. Neonatal hepatitis
  3. DJS
  4. Rotor syndrome.
  1. Dubin-Johnson syndrome (DJS): (Ref. Hari. 18th ed., Pg-326)
    1. It is an autosomal recessive Q disorder due to defect in canalicular transport Q of organic anions because of mutation of MRP2 Q.
    2. Total bilirubin concentration are typically between 2-5 mg/dl.
    3. A cardinal feature of Dubin-Johnson syndrome is the accumulation of dark, coarsely granular pigments in Q the lysosomes of centrilobular hepatocytes. As a result liver may be grossly blackQ. (dark colour is due to Epinephrine Metabolite.)
    4. The diagnostic tests are:
      → Bromsulphalein excretion (BSP)Q – A characteristic rise in plasma concentration of BSP at 90 min after injection, due to reflux of BSP into the circulation from the hepatocyte. Preferential urinary excretin of corporphyrin
    5. Also non-visualization of gallbladder on oral cholecystographyQ.
    6. Alkaline phosphatase level are normal.
    7. Patients with Dubin Johnson’s syndrome are usually asymptomatic, and have normal life expectancy.
    8. Usually no treatment is required.
  2. Rotor syndrome – It is an autosomal recessive Q disorder clinically similar to the Dubin-Johnson syndrome. But, there is no pigmentation in the liver. There is defect in bilirubin storage in liver cell. It can be differentiated from Dubin-Johnson syndrome by:
    1. BSP excretionQ – clearance of BSP from plasma is delayed in rotor syndrome, but there is no reflux of conjugated BSP back into the circulation as seen in Dubin-Johnson syndrome. There is defect in intra hepato cellular storage of BSP.
    2. Gall bladder is visualized on oral cholecystography.Q
Differentiation between different types of congenital conjugated jaundice
Congenital Conjugated hyperbilirubinemia
Syndrome Inheritance Abnormality Clinical features / Treatment
Dubin – Johnson AR ↓ Canalicular excretion of organic anions including bilirubin Mild No treatment necessary
Rotor’s AR Defective intrahepatic storage of bilirubin Mild No treatment necessary
Approach to a case of jaundice
  1. Isolated elevation of bilirubin (Normal AST, ALT, ALP)
    1. Direct / Conjugated hyperbilirubinemia (Direct >15%)
      Inherited disorders:
      1. Dublin Johnson
      2. Rotors
    2. Indirect / Unconjugated hyperbilirubinemia (Direct <15%)
      1. i. Hemolytic disorders
      2. Ineffective erythropoiesis
      3. iii. Drugs: Rifampicin, Probenecid
      4. Inherited disorders
        1). Gilbert’s syndrome
        2). Crigler Najjar syndrome
  2. Bilirubin elevated along with derangement in other liver tests. i.e. ALT/AST & Alkaline phosphatase
    1. ALT/AST Elevated out of proportion to alkaline phosphatase
      Hepatocellular cause
      1. Viral hepatitis
      2. Toxic hepatitis
      3. Wilson’s disease
      4. Cirrhosis
    2. Alkaline phosphatase elevated out of proportion of AST/ALT
      Obstructive cause
      1. Extrahepatic cholestasis
      2. Intrahepatic cholestasis
Condition Serum Bilirubin Urine
Urine Bilirubin SGOT/SGPT ALP
Hemolytic anemia Indirect Increased Absent Normal Normal
Hepatitis Direct and indirect Increased Present Increase +++ Increase +
Direct Absent Present Increase + Increase +++


Important Points

Clinical features in cholestatic jaundice

Early features
Jaundice, Dark urine, Pale stools, Pruritus

Late features

  1. Xanthelasma and xanthomas (Hyperpigmentation in chronic cholestaticJaundice (Harrison, 18th edition, page 1920
  2. Malabsorption
    1. Weight loss
    2. Steatorrhea
    3. Osteomalacia
    4. Bleeding tendency

Clinical feature of Cholangitis: Fever, Rigors, Pain



Clinical Features suggesting an underlying cause of cholestatic jaundice.

  1. Jaundice: Carcinoma (Static or increasing jaundice), Stone (Fluctuating jaundice), Stricture, Pancreatitis, Choledochal cyst
  2. Abdominal pain: Stone, Pancreatitis, Choledochal cyst
  3. Cholangitis: Stone, Stricture, Choledochal cyst
  4. Irregular hepatomegaly: Hepatic carcinoma
  5. Palpable gallbladder: Carcinoma below cystic duct (usually pancreas)
  6. Abdominal mass: Carcinoma, Pancreatitis (Cyst), Choledochal cyst
  7. Occult blood in stools: Papillary tumour


Extra Edge
  1. Biliary atresia
  2. Neonatal hepatitis
  3. Gall stone,
  4. Ca head of pancreas cause conjugated or direct hyperbilirubinemia.
Lab Investigation in a case of liver disease
  1. Blood ammonia
    Ammonia is produced in the body during normal protein metabolism and by intestinal bacteria in the colon.
    The liver detoxify ammonia by converting it to urea Q which is excreted by the kidney.
    Serum ammonium levels are raised in liver disease in patients with mental status changesQ.
  2. Serum enzymes:
    1. Enzymes that reflects damage to hepatocytes:
      1. Aminotransferase are sensitive indicators of liver cell injuryQ. They are aspartate amino transferase (AST) and Alanine amino transferase (ALT).
      2. AST is found in liver > cardiac ms > skeletal muscle > kidney > brain > pancreas > lung > leucocyte > RBC.
      3. ALT is found predominantly in liver.Q
      4. Causes of raised hepatic enzyme SGOT – SGPT
        1) Viral hepatitisQ.
        2) Ischemic liver injury.Q
        3) Toxin Amanita phalloides or PCM drug induced Q liver damage.
        4) Auto immune hepatitis
      5. The AST:ALT ratio of >2:1 is suggestive of alcoholic liver disease.Q
      6. The Amino transferases are usually not greatly elevated in obstructive jaundice
      7. Lactic dehydrogenase (LDH) – LDH-5 isomer is elevated in liver disease.
A. Enzymes that reflect cholestasis:
  1. Alkaline phosphatase – the normal value is 30-120 IU/L.
    The sources are:
    i. Liver,
    ii. Bone
    iii. Placenta,
    iv. Small Intestine
    The causes of elevation of ALP are:
    1. Physiological:
      1. Age > 60 yr (11/2 times the normal).
      2. Adolescents – undergoing rapid bone growth.
      3. Pregnancy – In last trimester due to influx of placental ALP.
    2. Pathological:
      1. Hepatitis & obstructive jaundice.Q
      2. Primary or metastatic tumor of bone.
      3. Hodgkin’s disease
      4. Paget’s disease
      5. Osteomalacia
      6. Sclerosing cholangitis
NB: Level of ALP is normal in multiple myeloma.
Causes of Reduced ALP levels:-
  1. Magnesium deficiency
  2. Hypothyroidism
  3. Malnutrition
  4. Hemolytic anemia
  5. Wilson's Disease
  6. Post coronary bypass surgery
  7. Estrogen replacement therapy
  8. Congenital hypophosphatasia.
  9. Blood transfusion causes transient decreases in ALP, due to chelation of cations by citrate. (Ref. Hari. 18th ed., Pg - 1925) (AIIMS Nov 12)
  1. 5-nucleotidase:
    In screening for liver metastasis it has a high predictive value.Q
  2. Gamma-glutamyl transpeptidase –
    GGT is a potential marker of alcoholismQ.
  3. Leucine amino peptidase – This is useful in the diagnosis of biliary obstructive Q, space occupying Q and infiltrative disorder Q of the liver.
    Tests that measures biosynthetic function of the liver:
    1. Serum proteins – liver produces all the serum proteins Q – albumin, prothrombin, fibrinogen, alpha and beta globulin etc except gamma globulinQ.
      A reversal of A:G; ratio suggest a chronic liver diseaseQ.
      1. Serum albumin – It has a half life of 15-20 Q days, hence will be decreased in chronic liver disease.
      2. Serum globulins – They are made up of:
        1) Gamma globulin (Immunoglobulin) produced by B lymphocyteQ.
        2) Alpha & Beta globulin, produced by hepatocytesQ.
Increase in specific isotypes of gamma globulins are helpful in recognizing certain chronic liver diseases:


Important points
  1. Raised IgG – autoimmune hepatitisQ
  2. Raised IgM – Primary biliary Q cirrhosis
  3. Raised IgA – Alcoholic liver diseaseQ
Coagulation factors–
  1. The liver synthesize all the coagulation factors except factor VIII Q.
  2. The shortest half life is 6 hrs for factor VII and longest 5 days for fibrinogen.
  3. For this prothrombin time is used which measures factor II, V, VII and X.
  4. Prolongation of PT> 5 sec above control and not corrected by Parenteral vit K administration is a poor prognostic sign in liver diseases: Q (Important Points:– stored blood is deficient in Factor-V and Factor -VIII)

Extra Edge


Laboratory tests often detect liver disease before hepatic failure occurs. Prolong PT is the first abnormality to occur in liver failure, (even before ammonia rises) (LQ 2012) because factor VII, a liver synthesized vitamin K-dependent factor, has the shortest half-life. Serum PT may be rapidly prolonged with hepatic failure and is the first function tests to return to normal with recovery from acute hepatic disease.

Liver biopsy
  1. It is performed with a Tru-cut or Menghini needle.
  2. The main complications are abdominal and/or shoulder pain, bleeding and biliary peritonitis,
Radiological imaging in liver diseases
  1. Magnetic resonance cholangiopancreatography (MRCP) is a sensitive, noninvasive method of detecting bile duct stones, strictures, and dilation;
  2. MRCP less reliable than ERCP for distinguishing malignant from benign strictures. ERCP is used to demonstrate pancreatic or ampullary causes of jaundice to carry out papillotomy and stone extraction, or to insert a stent through an obstructing lesion.
  3. Complications of ERCP include pancreatitis, cholangitis, bleeding, or duodenal perforation after papillotomy.
  4. Percutaneous transhepatic cholangiography (PTC) is an alternative approach to evaluating the anatomy of the biliary tree.
  5. Dilated bile ducts by ultrasonography or CT scan indicates biliary obstruction (90-95%) sensitivity).
  6. MRI is the most accurate technique for identifying isolated liver lesions such as hemangiomas, focal nodular hyperplasia, or focal fatty infiltration and for detecting hepatic iron overload.
  7. Dynamic gadolinium enhanced MRI and administration of super paramagnetic iron oxide visualizes hepatic fibrosis.
  8. Endoscopic ultrasonography is the most sensitive test for detecting small lesions of the ampulla or pancreatic head and for detecting portal vein invasion by pancreatic cancer. It is also accurate in detecting or excluding bile duct stones.
  9. Hepatic angiography is now rarely needed, as both CT and MRI technology is able to characterize hepatic vasculature (arterial and venous). But may be necessary to image the hepatic veins further in patient with suspected hepatic venous outflow obstruction (Budd-Chiari)
  10. U/S electrography is being used to assess fibrosis in liver disease
  1. In HIDA Scan technetium 99m-labeled derivative of iminodiacetic acid is injected intravenously. It is picked up by the Kupffer’s cells in the liver and excreted in the bile.
  2. ii. It gives a clear visualization of tile biliary tree. The gallbladder is also visualized
  3. HIDA scan is most useful for tile diagnosis of acute cholecystitis ('non-visualization of the gall bladder) is highly diagnostic of acute cholecystitis.
  4. It is also useful for diagnosing biliary atresia.
HIDA scan for
  1. Acute cholecystitis
  2. Biliary atresia
Approach to a case of obstructive Jaundice
Protocol for investigating a patient with cholestatic serum profile.

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