Diagnostic Approach To Jaundice

1. Diagnostic Approach To Jaundice By Dr. Mohamed M. Mohy Eldin Awad Professor of Internal Medicine Suez Canal University

4. Bilirubin Metabolism • Bilirubin  breakdown of mature RBCs in the RES. • 15% of bilirubin comes from the catabolism of other haem-containing proteins, such as myoglobin. • 250 – 300 mg of bilirubin are produced daily. • Biliverdin is formed from the haem and this is reduced to form bilirubin. • The bilirubin produced is unconjugated and is transported to the liver attached to albumen.

5. Jaundice is a common feature of both acute and chronic liver diseases as well as disorders of a non-hepatic origin. • Jaundice can be recognized clinically at serum bilirubin levels of 3mg/dl or more. • Besides a rise in the bilirubin level, yellowness of the skin can be due to carotenoderma, use of drug quinacrine & excessive exposure to phenols.

6. Jaundice can occur in four different ways: 1- Increased bilirubin load as in haemolysis. 2- Disturbance in the hepatic uptake & transport of bilirubin within the hepatocytes 3- Defects in conjugation. 4- Defects in the excretion of conjugated bilirubin across the canalicular cell membrane or an obstruction of the large biliary channels.

8. * Increasedbil. production (e.g. haemolysis), or resorption of haematoma.

9. Inability of the hepatocytes to take up bilirubin from the blood e.g. Gilbert & Crigler-Najjar syndromes.

10. By (for example) biliary calculi causes backup and reabsorption of conjugated bilirubin. Blood levels of conjugated bilirubin increase.

11. History: • The onset of Jaundice in viral hepatitis is associated with a prodrome of ANV, malaise & myalgia. • The onset of cholestasis is insidious, it is associated with pruritus. • A history of fever with rigors, Rt upper abd. pain or a past history of biliary surgery suggest cholangitis. • Dark urine & pale stool exclude the possibility of haemolytic jaundice. • A history of multiple sex partners, travel, ethanol intake, drugs, bl. transfusion, needlestick exposure & tattooing is also important.

12. Recent surgery with subsequent jaundice after one week may suggest halothane toxicity. • Previous biliary surgery with subsequent jaundice may suggest stricture, residual stones or hepatitis. • A family history of jaundice or liver disease suggests the possibility of hereditary hyperbilirubinaemia or genetic disorder such as Wilson disease.

13. The clinical assessment & basic biochemical parameters lead to three broad subgroups of patients: 1- Isolated elevation of s. bilirubin: when AST, ALT & ALP levels are normal. 2- Hepatocellular jaundice: when the AST & ALT levels are elevated out of proportion to the ALP levels. 3- Cholestatic jaundice: when the ALP level is elevated out of proportion to the AST & ALT levels.

14. Isolated elevation of serum Bilirubin Unconjugated Hyperbilirubinaemia * Increase bil. production (e.g. haemolysis, resorptionof haematoma) * Decrease hepatocellular uptake (e.g. rifampcin) * Decrease conjugation (Gilbert S, Crig. Nagar S) Conjugated Hyperbilirubinemia * Dubin-Junson syndrome * Roter syndrome

15. Hepatocellular Jaundice Acute or subacute hepatocellular injury Viral hepatitis, alcohol, drugs, ischemic hepatitis, Wilson's disease, acute fatty liver of pregnancy Chronic hepatocellular Disease: Viral hepatitis, alcoholic, autoimmune hepatitis, Wilson dis., Haemochromatosis, NASH, alpha 1 antitrypsin deficiency. Hepatic disorders with prominent cholestasis. * Diffuse infiltrative disorders (e.g. granulomat dise. as TB, sarcoidosis, lymphoma, drugs) Amyloidosis, malignancy. * Inflammation of intrahepatic bile ductules (PBC), GVHD, Drugs (chloropromazine) * Miscellaneous e.g. use of oestrogen & steroids, TPN, bact. Infection.

16. Obstruction of The bile duct Benign Choledocholithiasis, 1ry SC, AIDS, pancreatitis Malignant Carcinoma gallbladder, periampullary carcinoma, cholangiocarcinoma, Cancer head of pancreas

17. Mechanism Type of Jaundice Cause of Jaundice Isolated elevation Unconjugated * Bil. production (e.g. haemolysis, resorption of serum Bilirubin Hyperbilirubinaemia of haematoma) * Hepatocellular uptake (e.g. rifampcin) * conjugation (e.g. Gilbert S, Crig. Nagar S) Conjugated * Dubin-Junson sundrome Hyperbilirubinemia * Roter syndrom Hepatocellular Acute or subacute Viral hepatitis, alcohol, drugs, ischemic hepatiti Jaundice hepatocellular injury Wilsons disease, acute fatty liver of pregnancy Chronic hepatocellu Viral hepatitis, alcoholic, autoimmune hepatitis disease. Haemochromatosis, Wilson dis., NASH, alpha 1 antitrypsin deficiency. Hepatic disorders * Diffuse infiltrative disorders (e.g. granulomat with prominent dise. As TB, sarcoidosis, lymphoma, drugs) cholestasis. Amyloidosis, malignancy. * Inflammation of intrahepatic bile ductules (PBC), GVHD, Drugs (chloropromazine) * Miscellaneous e.g. use of oestrogen & steroids, TPN, bact. Infection. Obstruction of Benign Choledocholithiasis, 1ry SC, AIDS, pancreatitis The bile duct Malignant Carcinoma gallblader, periampullary carcinoma cholangiocarcinoma, Cancer head of pancreas

18. Physical Examination: -Stigmata of CLD  J. is hepatocellular in origin. -High fever, right upper abd. tenderness  cholangitis & choledocholithiasis. -Palpable abdominal mass  Malignant obstructive J. -Rt. upper abd. scar or palpable gallbladder  Obst. J. -Certain physical findings may suggest a particular liver disease: *Hyperpigmentation  haemochromatosis. *Xanthoma  PBC. *Kayser-Fleischer rings  Wilson disease.

19. -A systemic illness should be excluded e.g. distended jugular veins in constrictive pericarditis or Rt. Heart F in patient with hepatomegaly & ascites. -Hard nodular liver  1ry or 2ry malignancy. -Diffuse lymphadenopathy  infectious mononucleosis or lymphoma.

20. Stigmata of Chronic Liver Disease Palmar eryth. Spider nevi Parotid enlag Gynecomastia Muscle atrop. Astraxis Spooning LL edema

21. Laboratory, Radiological & Histological Evaluation: *Serum Biochemical Tests: Bilirubin: -The normal serum bilirubin is <1.5mg/dl of which <0.5% is conjugated. -In haemolysis or genetic disorders e.g. Gilbert synd., there is unconjugated hyperbilirubinaemia (>90%). -In hepatocellular j. >50% of bilirubin is conjugated. -In obstructive j., the circulating bilirubin is mainly conj. * The degree of elevation of s. bil., correlates poorly with clinical severity. * Unconjugated bil is not excreted in the urine & thus in unconjugated hyperbilirubinaemia, bil. is absent in urine.

22. Serum Enzymes: Enzymes raised in hepatocellular injury: Aminotransferases include ALT (located in cytosol) & AST (located in mitochondria & cytosol). ALT is found mainly in liver while AST is also found in other tissues such as skeletal & cardiac muscle. ALT is more specific than AST in detecting liver dise. AST & ALT are released following hepatocyte necrosis. A marked raise in transaminases > 1000 U/L, is seen in AVH, ischaemic hepatitis & drug-induced liver disease. In alcoholic liver disease, the enzyme levels are rarely > 200-300 U/L, with AST:ALT ratio >2:1.

23. Enzymes raised in cholestasis: Alkaline Phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) & 5’-nucleotidase (5’NT). ALP isoenzymes are also present in bone & placenta. Increase in ALP, GGT & 5’NT  hepatobiliary origin. GGT levels are often disproportionately elevated in alcoholic liver disease.

24. Proteins: Albumen: Albumen is synthesized by liver & has a half-life of 15-20 days. Decreased level of albumen are seen in advanced hepatic cirrhosis & signify severe hepatic dysfunction. S. albumen usually remain normal in acute hepatitis; falling values in this setting imply an unusual sever course Globulins: Non-specific diffuse elevation is common in CLD. There is a disproportionate elevation of IgG in autoimmune hepatitis, IgM in PBC & IgA in alcoholic liver disease.

25. International normalized ratio (INR) & Prothrombin time (PT): INR/PT is a valuable index of the ability of liver to synthesize vit. K-dependent clotting factors. An increasing INR/PT implies relatively severe hepatocellular dysfunction. The INR/PT may be deranged in cholestasis as well, but this is due to the malabsorption of vit. K & is rapidly corrected by parenteral administration of vit K.

26. Other tests: -Serological/replicative markers for specific diagnosis of acute or chronic viral hepatitis. -Antimitochondrial antibody (AMA) for PBC; antinuclear factor (ANA), anti-smooth muscle antibody (ASMA) & anti-liver kidney microsome (LKM) antibody seen in autoimmune hepatitis; alpha-fetoprotien, which is raised in HCC & s. caeruloplasmin for Wilson disease.

27. Imaging Procedures: Radiological imaging is important for the diagnosis of a focal liver mass or biliary disease. However, imaging plays little role in the evaluation of diffuse hepatocellular e.g. hepatitis

28. Ultrasonography (US): It is a valuable but operator-dependent investigation. It has sensitivity of 55-91% & specificity of 82-95% for biliary obstruction. Although US may not detect stones in the extrahepatic bile duct, which may be obscured by overlying gas, it reliably establishes the presence of a dilated bile ducts

29. Ultrasonography (US):Cont Beside it can differentiate intrahepatic from extrahepatic cholestasis, US can also detect the associated abnormalities such as portal hypertension, focal lesions & fatty liver.

30. Computerized Tomography (CT): CT has a sensitivity of 63-96% & a specificity of 93-100% to detect biliary obstruction. Non-calcified cholestrol gall stones can be easily missed on CT because they may be isodense with bile.

31. Endoscopic retrograde cholangiopancreaticography (ERCP): ERCP not only permits direct visualization of the biliary tree but also allows therapeutic intervention e.g. removal of CBD stones or biliary stenting. It is the gold standard test for the evaluation of extrahepatic biliary disease causing jaundice.

34. Percutaneous transhepatic cholangiography: PTC IN PTC, direct contrast visualization of the biliary tree is obtained via a percutaneous needle puncture of the liver. It is useful if there is high biliary obstruction e.g. a tumour at the bifurcation of the hepatic ducts. It also permits therapeutic intervention such as stent insertion to bypass a ductal malignancy.

35. Magnetic resonance cholaniopancreaticography: MRCP MRCP is superior to US & CT in detecting biliary obstruction. It has a sensitivity of 82-100% & a specificity of 92-98% to detect biliary obstruction.

36. Liver Biopsy: It has relatively low risk, it is needed in only a minority of cases with hepatic dysfunction. Major indications include chronic hepatitis, cirrhosis, unexplained liver enzyme abnormalities, hepatosplenomegaly of unknown aetiology, suspected infiltrative disorder, suspected granulomatous disease.

37. Liver Biopsy: Cont Relative contraindications include a tendency for clinical bleeding, INR>1.5 or PT >3 sec above the control, severe thrombocytopenia & marked ascites. The risk of fatal haemorrhage in patients undergoing LB is 0.4% if they have a malignancy & 0.04% if they have non-malignant disease.

38. Thank You