An approach to patient presenting with Jaundice

This slide highlights the approach to a patient present with jaundice with some brainstorming answer to questions such as
- Why is upper bulbar conjunctiva seen for icterus?
- Is every yellowish discoloration of skin jaundice (wait for the surprise at the last slide)
- Why does heme needs breakdown to biliverdin?
- Why does biliverdin needs breakdown in mammals? Is there any physiological role of bilirubin?

1. Approach to Jaundice Dr. Manoj Khadka First year resident Internal Medicine PAHS, Patan Hospital

2. Table of Content Introduction Differential diagnosis Bilirubin metabolism Causes of jaundice Approach History Examination Investigations Take home message

3. Introduction Yellowish discoloration of skin & mucous membrane due to deposition of bilirubin Sites to look Upper bulbar conjunctiva Sublingual mucosa Mucous membrane of palate Palms & soles Skin - Examined in natural light, not torch light

4. Why upper bulbar conjunctiva?

5. Upper Bulbar conjunctiva High affinity of bilirubin for elastin (abundant protein in the conjunctiva & episclera) - White background formed by sclera Why lower sclera/conjunctiva not seen Bilirubin converted to its soluble form on exposure to sunlight (mayn’t reveal mild jaundice-FN) Muddy sclera/conjunctiva (exposure to environment) Why upper bulbar conjunctiva?

6. Introduction Clinical Jaundice - Serum bilirubin > 3 mg/dL Latent jaundice - Serum bilirubin between 1-3 mg/dL Unilateral jaundice ( Good circulation necessary to stain tissues) Hemiplegia Unilateral edema Jaundice grading Mild (< 6 mg/dL) Moderate (6-15 mg/dL) Severe (>15 mg/dL)

7. Is every yellowish discoloration jaundice?

8. Differential diagnosis Carotenoderma sparing of sclerae (involve palm, sole, forehead, nasolabial folds) ingestion of excessive vegetables & fruits containing carotene diabetes, hypothyroidism, anorexia nervosa Drugs ( Q uinacrine, Tyrosine kinase inhibitors- sunitinib, sorafenib) Chemicals (acriflavin, picric acid) Diffuse xanthomatosis Muddy sclera Old conjunctival hemorrhage

9. Bilirubin Yellow-red color pigment End product of heme metabolism Excreted in in feces (stercobilin) & urine (urobilin) Types: Unconjugated (indirect) & Conjugated (direct) bilirubin * Delta bilirubin - Conjugated bilirubin bound to albumin - Clearance rate:12–14 days (T1/2 of albumin); rather than bilirubin (4 h) - Some patients with conjugated hyperbilirubinemia don’t exhibit bilirubinuria during recovery phase (not filtered by renal glomeruli) - Delayed resolution of jaundice

10. Van den Bergh reaction

11. Why is heme converted to bilirubin?

12. Bilirubin formation

13. Evolution of bilirubin Heme oxygenase Excess free heme toxic, so degraded (protect cell from oxidative damage) Biliverdin reductase - Biliverdin end product in lower vertebrates - In mammals, biliverdin reduced to bilirubin - Antioxidant role scavenges lipophilic ROS

14. Bilirubin metabolism

15. Causes of jaundice Increased production of unconjugated bilirubin ( Unconjugated hyperbilirubinemia - DB <15% of TB) Decreased excretion of conjugated bilirubin ( Conjugated hyperbilirubinemia )

16. 2.

17. History Duration Appetite, nausea, weight loss Color of urine & stool Pruritus Hepatitis risk factors Hep B/C: blood transfusions prior 1992, IV drug use, tattooing, high risk sexual behavior Hep A/E: contact with jaundice patient, recent outbreak, contaminated food, water Alcohol consumption Drug h/o (Rifampicin), herbal/ ayurvedic medications, Recreational drug use, HIV status

18. History Pain abdomen, fever (Charcot’s triad of cholangitis) GI bleeding (DCLD) History of abdominal operations (gallbladder/biliary surgery) Family h/o: Wilson’s disease, Hereditary spherocytosis O ccupational exposure to hepatotoxins ( mushroom picking, industrial chemicals-vinyl chloride) Associated conditions Right-sided heart failure (congestive hepatopathy) DM, skin pigmentation, arthritis, hypogonadism, DCM (hemochromatosis) Obesity (metabolic associated steatotic liver disease) Pregnancy (gallstones) Inflammatory bowel disease (primary sclerosing cholangitis, gallstones) Early onset emphysema (alpha-1 antitrypsin deficiency)

19. Physical examination Temporal and proximal muscle wasting (longstanding disease). Stigmata of chronic liver disease Dupuytren contractures, parotid gland enlargement, and testicular atrophy (advanced alcohol-associated cirrhosis) Enlarged left supraclavicular node (Virchow node), periumbilical nodule (Sister Mary Joseph nodule)- abdominal malignancy Increased JVP, a sign of right-sided heart failure (hepatic congestion) Skin hyperpigmentation (hemochromatosis) Xanthomas (Primary biliary cirrhosis)

20. Physical examination Abdominal examination - Ascites - RUQ tenderness with Murphy sign: Acute cholecystitis - Liver: size and consistency A grossly enlarged, hard, nodular liver or an obvious abdominal mass - malignancy An enlarged, tender liver- viral or alcohol-associated hepatitis, congestive hepatopathy secondary to right-sided heart failure or Budd-Chiari syndrome - Splenomegaly: Portal hypertension, extravascular hemolysis Chest : A right pleural effusion (advanced cirrhosis) CNS : - Neurologic & psychiatric signs and symptoms (Wilson disease) - Hepatic encephalopathy (decompensated cirrhosis)

21. Investigations Initial laboratory tests Serum total and direct bilirubin Aminotransferases (AST/SGOT and ALT/SGPT) Alkaline phosphatase Prothrombin time/international normalized ratio (INR) Albumin

22. Investigations Cholestatic injury pattern - Disproportionate elevation in ALP compared with ALT & AST ( R value ≤2) Serum bilirubin may be elevated Tests of synthetic function (albumin, PT/INR) may be abnormal Hepatocellular injury pattern Disproportionate elevation of ALT & AST compared to ALP (R value ≥5) Serum bilirubin may be elevated Tests of synthetic function (albumin, PT/INR) may be abnormal Mixed hepatocellular & cholestatic injury pattern Proportionate elevation of both aminotransferases & ALP (R value >2 to <5) Serum bilirubin may be elevated Isolated hyperbilirubinemia - Elevated bilirubin level with normal aminotransferases & ALP

23. Investigations Patients with hyperbilirubinemia & cholestatic injury pattern

24. Investigations Evaluation for intrahepatic cholestasis Primary biliary cholangitis: Antimitochondrial antibody Primary sclerosing cholangitis: MRCP Hepatitis A virus: Immunoglobulin M (IgM) antihepatitis A Hepatitis B virus: Hepatitis B surface antigen, IgM antihepatitis core antigen, antibody to hepatitis B surface antigen Hepatitis C virus: Antihepatitis C antibody, hepatitis C viral RNA Hepatitis E virus: Hepatitis E virus antibodies Cytomegalovirus (CMV): Anti-CMV antibodies, CMV antigen Epstein-Barr virus: Heterophile antibody Intrahepatic cholestasis of pregnancy: Serum pregnancy test, serum bile acids

25. Hepatocellular jaundice Alcohol-associated fatty liver disease - AST < 8X ULN; ALT < 5X ULN (AST/ALT >= 2) Metabolic dysfunction-associated steatotic liver disease - AST & ALT < 4X ULN Acute viral hepatitis/ toxin-related hepatitis - AST & ALT > 25X ULN (AST/ALT < 2) Ischemic hepatitis AST & ALT > 50X ULN LDH markedly increased Transient rise & rapid fall with reperfusion Chronic hepatitis C virus infection - Typically normal to < 2X ULN Chronic hepatitis B virus infection AST & ALT may be normal in inactive carriers, Most have mild to moderate elevations (approx. 2X ULN)

26. Hepatocellular jaundice

27. Investigations Prehepatic Hepatic Posthepatic Serum Bilirubin TB High High High DB Low High High IB High High Low Urine tests Urine bilirubin Absent Trace Present Urine urobilinogen High Low, if microbstruction Low Fecal tests Fecal urobilinogen High Variable Low Stool color Dark Normal usually Clay colored Enzymes AST High High Mild raise ALT Normal High Mild raise ALP Normal Normal High LDH High Normal Normal Proteins Haptoglobin Low Normal Normal Total protein, albumin Normal Low, if chronic Normal PT/ INR Normal May be prolonged Normal

28. References Harrison’s Principles of Internal Medicine. 21st ed. UpToDate Approach to the patient with abnormal liver tests Classification and causes of jaundice or asymptomatic hyperbilirubinemia Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia Kundu AK. Bedside Clinics in Medicine . 7 th ed. Boloor A, Padakanti A. Clinical Medicine Chiabrando D, Vinchi F, Fiorito V, Mercurio S, Tolosano E. Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes. Front Pharmacol . 2014 Apr 8;5:61.

29. Any questions? THANK YOU !

30. Every yellowish discoloration isn’t jaundice 