Approach to jaundice based on Harrison's

Approach to different types of jaundice

1. Jaundice Moderator: Assoc. Prof Dr Ram Krishna Baral HOD, Department of Internal Medicine Nepal APF Hospital Presented by: Dr. Surendra Adhikari PG1, Internal Medicine

2. Contents Introduction Differential diagnosis of jaundice Production and metabolism of jaundice Pathophysiology Causes of jaundice Approach to jaundice

3. Introduction Jaundice is a yellowish discoloration of body tissues resulting from the deposition of bilirubin . Tissue deposition of bilirubin occurs only in the presence of serum hyperbilirubinemia and is a sign of either liver disease or, less often, a hemolytic disorder or disorder of bilirubin metabolism . Sclerae have a particular affinity for bilirubin due to their high elastin content, and the presence of scleral icterus indicates a serum bilirubin level of at least 3 mg/ dL or 51 μ mol /L (2.92 mg/dl Macleod’s 14 th edition).

4. PRODUCTION AND METABOLISM OF BILIRUBIN

5. Unconjugated bilirubin is insoluble and binds to plasma albumin; it is therefore not filtered by the renal glomeruli. In jaundice from unconjugated hyperbilirubinaemia , the urine is a normal colour ( acholuric jaundice). Bilirubin is conjugated to form bilirubin diglucuronide in the liver and excreted in bile, producing its characteristic green colour . In conjugated hyperbilirubinaemia , the urine is dark brown due to the presence of bilirubin diglucuronide . In the colon, conjugated bilirubin is metabolised by bacteria to stercobilinogen and stercobilin , which contribute to the brown colour of stool. Stercobilinogen is absorbed from the bowel and excreted in the urine as urobilinogen , a colourless , water-soluble compound.

6. MEASUREMENT OF SERUM BILIRUBIN N ormal serum bilirubin concentration usually is between 17 and 26 μmol /L (1 and 1.5 mg/ dL ). Unconjugated hyperbilirubinemia is present when the direct fraction is <15% of the total serum bilirubin . Any bilirubin found in the urine is conjugated bilirubin.

7. The presence of bilirubinuria on urine dipstick test indicates an elevation of the conjugated bilirubin fraction that cannot be excreted from the liver and implies the presence of hepatobiliary disease. A false negative result is possible in patients with prolonged cholestasis due to the predominance of delta bilirubin, which is covalently bound to albumin and therefore not filtered by the renal glomeruli.

8. Gilbert’s syndrome U nconjugated hyperbilirubinaemia . Serum liver enzyme concentrations are normal. J aundice is mild (plasma bilirubin < 100 μmol /L (5.85 mg/ dL )). I ncreases during prolonged fasting or intercurrent febrile illness.

9. Initial steps in patient with jaundice Whether the hyperbilirubinemia is predominantly conjugated or unconjugated in nature. Whether other biochemical liver tests are abnormal.

10. Pathophysiology Hyperbilirubinemia may be due to 1.excess production of bilirubin 2.decreased uptake of bilirubin into hepatic cells 3.disturbed intracellular protein binding or conjugation 4.disturbed secretion of conjugated bilirubin into the bile canaliculi , 5. intrahepatic or extrahepatic bile duct obstruction May be isolated or with elevated LFT

11. ISOLATED ELEVATION OF SERUM BILIRUBIN Excessive production Impaired Conjugation

12. History Age of onset. Acute or chronic onset. Chronology: D uration of jaundice, E pisodic vs Constant. Associated symptoms: Abdominal pain, abdominal distension, fever, urine and stool color changes, leg edema, pruritus , weight gain/loss, nausea/vomiting

13. Past History History of Hematologic conditions History of Pancreatic disease History of Cardiac disease History of Gallstone disease, Gilbert’s syndrome History of UC History of autoimmune diseases thyroid, celiac and RA History of HIV History of blood transfusion History of gb surgery

14. Medication History: Herbal supplements, dietary supplements, recreational drugs, Drug allergies, dose of PCM, recently prescribed drugs. Alcohol, smoking and IV drugs Sexual History: HBV, HIV risk factors Travel History: Malaria, HAV, Occupational History

15. Examination of Jaundice Scleral Icterus is seen in natural light. If the examiner suspects scleral icterus, a second site to examine is underneath the tongue . As serum bilirubin levels rise, the skin will eventually become yellow in light-skinned patients and even green if the process is long-standing; the green color is produced by oxidation of bilirubin to biliverdin .

16. D ifferential diagnosis of yellowing of the skin J aundice . Carotenoderma . D rugs like quinacrine , sunitinib , and sorafenib .

17. Carotenoderma I ngestion of an excessive amounts of vegetables and fruits such as carrots, leafy vegetables, squash, peaches, and orange . Also associated with diabetes, hypothyroidism, and anorexia nervosa . P igment is concentrated on the palms, soles, forehead, and nasolabial folds unlike uniform distribution in jaundice. Carotenoderma can be distinguished from jaundice by the sparing of the sclerae .

18. Physical Examination Anemia Features of CLD and Portal Hypertension Hyperpigmentation Fetor hepaticus and ‘ flapping ’ tremor indicate impending hepatic coma Purpuric spots, most often noticed on forearms , axillae or shins, may be related to the thrombocytopenia of cirrhosis Kayser -Fleischer rings in Wilson’s disease Xanthomas in chronic cholestatsis .

19. Physical Examination Temporal and proximal muscle wasting suggests long-standing disease such as pancreatic cancer or cirrhosis. An enlarged left supraclavicular node (Virchow’s node) or a periumbilical nodule (Sister Mary Joseph’s nodule) suggests an abdominal malignancy. Jugular venous distention, a sign of right-sided heart failure, suggests hepatic congestion. Right pleural effusion even in the absence of clinically apparent ascites may be seen in advanced cirrhosis.

20. A bdominal E xamination Pain/Tenderness S ize and consistency of the liver W hether the spleen is palpable W hether ascites is present

21. L arge nodular liver- HCC S mall liver – cirrhosis ( extrahepatic cholestasis in which the liver is enlarged and smooth). T ender edge of liver: Hepatitis , congestive heart failure, alcoholism. Murphy ’s sign: choledocholithiasis . S plenomegaly: Hemolytic states, portal hypertension, malaria. Ascites: Cirrhosis and abdominal malignancies.

22. Laboratory Investigations Total and direct serum bilirubin measurement with fractionation; determination of serum aminotransferase, A lkaline phosphatase, A lbumin concentration P rothrombin time tests USG, Cholangiography Other investigations tailored to each cause Hepatitis A IgM antibody assay, a hepatitis B surface antigen and core IgM antibody assay, a hepatitis C viral RNA test

23. H epatocellular process: High aminotransferases that is disproportionate to that in ALP. C holestatic process: High ALP that is disproportionate to aminotransferases . A lbumin level: Low in chronic process such as cirrhosis or cancer, normal in more acute process .

24. Acute viral hepatitis and toxin related injury severe enough to produce jaundice, typically have aminotransferase levels >500 U/L, with the ALT greater than or equal to the AST . Alcoholic hepatitis: AST-to- ALT ratio of at least 2:1, and the AST level rarely exceeds 300 U/L.

25. Jaundice can be emergency in: Clostridium perfringens sepsis or falciparum malaria Ascending cholangitis Fulminant hepatic failure

26. References Harrison’s P rinciples of Internal M edicine 22 nd edition Uptodate

27. In poorly controlled DM , there is decreased conversion of carotene to vit A in the liver plus hyperlipidemia also altered lipid metabolism, also more vegetables. Protein carotene malnutrition therer is decresed converiison of beta carotene to vitamin A.

28. Gallstone pancreatitis Pancreatic head inflammation may cause distal CBF compression and cause obstructive jaundice. In chronic pancreatitis fibrosis or stricture of intrapancreatic CBD Pancreatic head carcinoma Pancreatic pseudocyst

29. Posthepatic / cholestatic jaundice In biliary obstruction, conjugated bilirubin in the bile does not reach the intestine, so the stools are pale. Obstructive jaundice may be accompanied by pruritus ( generalised itch) due to skin deposition of bile salts. Obstructive jaundice with abdominal pain is usually due to gallstones; if fever or rigors also occur ( Charcot’s triad ), ascending cholangitis is likely. Painless obstructive jaundice suggests malignant biliary obstruction, as in cholangiocarcinoma or cancer of the head of the pancreas. Obstructive jaundice can be due to intrahepatic as well as extrahepatic cholestasis, as in primary biliary cirrhosis, certain hepatotoxic drug reactions and profound hepatocellular injury.