Evaluation of a patient with Jaundice

1. Evaluation of a patient with Jaundice ACCS 1 Training day Thanks to DrYousif. A Qari Assist prof. consultant gastroenterologist

2. Definition of Jaundice • Jaundice, as in the French jaune, refers to the yellow discoloration of the skin. • Abnormal accumulation of bilirubin in body tissues, which occurs when the serum bilirubin level exceeds 3 mg/dL or 50 mmol/L. • Hyperbilirubinaema

3. Investigation of a patient with jaundice • History of presentation • Medication use • Past medical history • Physical examination • Evaluation of liver function tests

4. First evaluating a patient with hyperbilirubinemia Quick assessment of the emergency of the situation • Fever, • Leukocytosis • Hypotension • Asterixis • Confusion • Stupor severe hepatocellular dysfunction fulminant hepatocellular failure Ascending cholangitis Immediate therapy

5. History • Family history of liver disease • Alcohol and drug history • Sexual history • Transfusion history • Nutrition history • Exposure to • Environmental toxins • Persons with jaundice • Drugs (e.g., prescription, nonprescription, intravenous) • , • Outbreaks or epidemics in the community • Previous liver function tests are valuable • History of biliary or pancreatic disease.

6. History • Shaking chills or fevers point toward cholangitis or bacterial infection • Abdominal pain may indicate pancreatic disease, especially if it radiates to the back • Right upper quadrant ache point toward Viral hepatitis • Weight loss, anorexia, nausea, and vomiting are not helpful signs because most patients with hepatobiliary disease or obstruction have anorexia and some weight • Pruritus can be associated with both intrahepatic cholestasis as well as biliary obstruction.

7. History Age: • Children and young adults ——› congenital,viralhepatitis • < 30 years ——›acute parenchymal disease • > 65 years ——› stones or malignancies • 30 - 50 years ——› chronic liver disease

8. History Sex: • Men are more likely to develop • Cirrhosis secondary to alcohol • Pancreatic cancer • Hepatocellular carcinoma, • Hemochromatosis • Women are more likely to have • Primary biliary cirrhosis • Gallstones • Chronic active hepatitis

9. Physical Examination • Jaundice must be differentiated from • Hypercarotenemia • Uremic pigmentation • Picric acid ingestion • Quinacrine therapy

10. Physical Examination • Shrunken, nodular liver may ——› cirrhosis • Palpable mass ——› abscess or malignancy • A liver span >15 cm ——› fatty infiltration, congestion other infiltrative diseases, or malignancy • Liver tenderness ——› acute disease but is generally not helpful

11. Physical Examination • Spider angioma • palmar erythema • distended abdominal veins • jaundice • Ascites • jaundice • Ascites indicate cirrhosis Acute hepatitis Cirrhosis Malignancy

12. Physical Examination • Splenomegaly • A palpable, distended gallbladder ——› malignant biliary obstruction • Asterixis • Fever Infections Infiltrative diseases Fulminant hepatic failure End-stage liver disease Billiary colic Infection

13. Laboratory Tests Total bilirubin and direct bilirubin assays . Conjugated hyperbilirubinemia Unconjugated hyperbilirubinemia

14. Heme Metabolism Fe3+ + CO NADP+ Hemoglobin – 80% Myoglobin Cytochrome P450s Hemoproteins O2 NADPH + H+ Heme Biliverdin Bilirubin Heme Oxygenase Biliverdin Reductase Macrophage of the reticuloendothelial system Blood

15. The Fate of Bilirubin… Alb B + GST ? B :GST B Alb Plasma Hepatic Cell Bile MRP2 B CB + UDPGA UGT1A1 sER Alb = albumin B = bilirubin GST = glutathione-S-transferase UDPGA = uridine diphosphoglucuronic acid; CB = conjugated bilirubin UGT1A1 = UDP-glucuronosyltransferase 1A1 MRP2 = Multi-drug Resistance Protein 2

16. feces Bilirubin Excretion Liver Enterohepatic circulation B CB Bile B-glucoronidase bacteria B CB ox Urobilin Urobilinogen Stercobilin Stercobilingogen bacteria Intestines

17. feces Bilirubin Excretion Liver Urobilin B CB Kidney ox Urobilinogen Urine Enterohepatic circulation Bile B-glucoronidase bacteria B CB ox Urobilin Urobilinogen Stercobilin Stercobilingogen bacteria Intestines

18. Hemolysis Glucose-6-phosphate deficiency Pyruvate kinase deficiency Drugs Ineffective erythropoiesis Neonatal causes Physiologic abnormalities Lucy-Driscoll syndrome Breast milk Uridinediphosphateglucuronosyltransferase deficiencies Gilbert syndrome Crigler-Najjar syndromes (I and II) Miscellaneous causes Drugs Hypothyroidism Thyrotoxicosis Pulmonary infarct Fasting Causes Of HyperbilirubinemiaUNCONJUGATED

19. Congenital causes Rotor syndrome Dubin-Johnson syndrome Choledochal cysts Familial disorders Benign recurrent intrahepatic cholestasis Cholestasis of pregnancy Hepatocellular defects Alcohol abuse Viral infection Sepsis Cholestatic Primary biliary cirrhosis Primary sclerosing cholangitis Biliary obstruction Pancreatic disease Systemic disease Infiltrative disorders Postoperative complications Renal disease Drugs Causes Of HyperbilirubinemiaCONJUGATED FORM

20. Several questions must be answered initially 1. Is the elevated bilirubin conjugated or unconjugated? 2. If the hyperbilirubinemia is unconjugated, is it caused by • increased production • decreased uptake • impaired conjugation 3. If the hyperbilirubinemia is conjugated, is the problem • intrahepatic or • extrahepatic? 4. Is the process acute or chronic?

21. Conjugated hyperbilirubinemia • Usually acquired disease • Intrahepatic or Extrahepatic (obstructive) cause. • Acute disease usually can be differentiated from chronic disease by the patient's history, physical examination, and laboratory tests • clinical evaluation • xanthelasma, • spider angioma, • ascites, • hepatosplenomegaly. • Laboratory evidence of chronic disease • Hypoalbuminemia, • Thrombocytopenia, • uncorrectable prolongation of the prothrombin time.

22. Cholestasis • Chronic cholestasis may arise from • Cirrhosis, • Primary sclerosing cholangitis, • Primary biliary cirrhosis, • Secondary biliary cirrhosis, • Carcinoma • Drugs. • Acute disease. • New-onset bilirubinuria • Fever • Right upper quadrant pain, • Tenderness, • Hepatomegaly,

23. Help from LFTs • ALT in hepatocyctes • Indicator of hepatocellular injury • High ALT↑↑↑, ALP ↑ suggests hepatocellular • ALP liver/ bile duct/ bone • Raised in cholestasis • ALP ↑↑, ALT↑ suggests cholestasis

24. GGT • Raised in biliary epithelium/ bile duct obstn • Raised in alcohol and phenytoin • ALP and GGT raised →cholestasis • ALP isolated = not hepatobiliary

25. Jaundiced ALT/ALP normal • Causes • Prehepatic • Haemolysis • Gilberts syndrome (most common)

26. Urine - Jaundice • Colour of urine and stools • Normal urine + normal stools = pre-hepatic cause • Dark urine + normal stools = hepatic cause • Dark urine + pale stools = post-hepatic cause (obstructive) • Bilirubin/urobilinogen

27. Livers main synthetic functions Conjugation and elimination of bilirubin Synthesis of albumin Synthesis of clotting factors Gluconeogenesis

28. Diagnosis Second-line tests for jaundice “focused” or “screen” • Anti-nuclear antibody • Anti-smooth muscle antibody • Immunoglobulins • Anti-mitochondrial antibody • hepatitis serologies • a1-antitrypsin • iron levels • Ceruloplasmin • a-fetoprotein

29. Diagnosis • Radiological tests: • Ultrasonography • Stones • Billiary ductal dilatation • Tumour masses, lymph nods etc. • Organomegaly • AsciCtes • CT scan abdomen • Endoscopic Retrograde Cholangiopancreatography (ERCP) MRCP • Liver Biopsy

30. Acetominophen Alcohol Amiodarone Azulfidine Carbenicillin Clindamycin Colchicine Cyclophosphamide Diltiazem Ketoconazole Methyldopa Niacin Nifedipine NSAIDs Propylthiouracil Pyridium Pyrazinamide Quinidine Rifampicin Salicylates Verapamil Common Drugs Associated With Hyperbilirubinemia HEPATOCELLULAR CAUSES

31. Amitriptyline Androgenic steroids (B) Atenolol Augmentin Azathioprine Bactrim (D) Benzodiazeprines Captopril Carbamazole Chlordiazepoxide (D)) Clofibrate Coumadin Cyclosporine Danazol (B) Dapsone Disopyramide Erythromycin Estrogens (B) Ethambutol Floxuridine 5-Flucytosine Fluoroquinolones Griseofulvin Haloperidol (D) Labetolol Nicotinic acid NSAIDs Penicillins Phenobarbital Phenothiazines (D) Phenytoin Tamoxifen Tegretol Thiabendazole (D) Thiazides Thiouracil Tolbutamide (D) Tricyclics (D) Verapamil Zidovudine Common Drugs Associated With Hyperbilirubinemia CHOLESTATIC CAUSES B. bland or noninflammatory cholestasis: D. ductopenic cholestasis or vanishing bile duct syndrome.

32. Acetohexamide Allopurinol Ampicillin Augmentin Cimetidine Dapsone Disulfiram Gold Hydralazine Lovostatin Nitrofurantoin NSAIDs Phenytoin Rifampicin Thiouracil Tetracycline Common Drugs Associated With Hyperbilirubinemia MIXED CAUSES

33. Any Questions

34. Diagnosis of hyperbilirubinemia. • Identify red flags for immediate treatment • Patient's history • Physical examination • Laboratory tests

35. References Geekymedics.com RCEM learning “search liver function” will link to Jaundice, ALF and Upper GI haemorrhage