Approach To Jaundice powerpoint presentation.pptx

Approach To Jaundice powerpoint presentation.pptx

1. Approach to jaundice Internal Medicine First Year Resident 21 st Aug, 2025

2. Definition Jaundice (Icterus): A clinical sign , not a disease. Refers to the yellow discoloration of skin, sclera, and mucous membranes. Hyperbilirubinemia: The underlying biochemical cause—an elevated serum bilirubin level. Clinical Correlation: Scleral icterus is visible when Total Bilirubin > 3.0 mg/dL. Skin yellowing is visible at higher levels. Normal Value: total bilirubin (0.3-1.0 mg/dL), direct bilirubin (0.1-0.3 mg/dL), and indirect bilirubin (0.2-0.8 mg/dL). These ranges can vary slightly between laboratories and individuals. 

3. BILIRUBIN METABOLISM

4. The Pathophysiologic Framework To identify the point of failure in the bilirubin pathway. Three Core Mechanisms: Overproduction: Too much bilirubin is made for the liver to handle (pre-hepatic). Impaired Uptake, Conjugation, or Secretion: Hepatocyte dysfunction (hepatic). Obstruction of Bile Flow: Blockage of bile ducts (post-hepatic/cholestatic).

5. Classification of jaundice Hepatic Post hepatic (conjugated hyperbilirubinemia ) Prehepatic jaundice (conjugated and unconjugated hyperbilirubinemia) (unconjugated hyperbilirubinemia) Increased Hepatocellular Cholestatic Malignant Benign production Decreased hepatic uptake Decreased conjugation

6. Pre-hepatic (Hemolytic / Overproduction of Bilirubin) Mainly causes unconjugated hyperbilirubinemia (no bilirubinuria). Hemolysis (increased RBC destruction) Autoimmune hemolytic anemia Hemoglobinopathies (sickle cell disease, thalassemia) G6PD deficiency Hereditary spherocytosis, elliptocytosis Microangiopathic hemolytic anemia (TTP, HUS, DIC, prosthetic valves) Ineffective erythropoiesis Megaloblastic anemia Bone marrow disorders Resorption of large hematomas Transfusion reactions

7. Hepatic (Defects in Hepatocyte Uptake, Conjugation, or Excretion) A. Impaired Uptake Drugs (rifampicin, probenecid) Sepsis B. Impaired Conjugation Gilbert’s syndrome Crigler-Najjar syndrome (type I & II) Advanced liver disease C. Hepatocellular Injury Viral hepatitis (A, B, C, D, E) Alcoholic hepatitis Drug-induced liver injury (DILI) (e.g., acetaminophen, isoniazid, amoxicillin-clavulanate) Ischemic hepatitis (shock liver) Autoimmune hepatitis Metabolic liver disease : Wilson’s disease, Hemochromatosis, α1- antitrypsin deficiency Non-alcoholic steatohepatitis (NASH) Infiltrative diseases : amyloidosis, lymphoma, metastasis D. Intrahepatic Cholestasis Sepsis-related cholestasis Drugs (chlorpromazine, erythromycin, anabolic steroids, OCPs) Pregnancy cholestasis Primary biliary cholangitis (PBC) Primary sclerosing cholangitis (PSC)

8. Post-hepatic (Obstructive / Cholestatic) Mainly causes conjugated hyperbilirubinemia (bilirubinuria, pale stools, pruritus). Choledocholithiasis (common bile duct stones) Malignancy Pancreatic carcinoma (head of pancreas) Cholangiocarcinoma Ampullary carcinoma Gallbladder carcinoma Benign strictures (post-surgical, post-inflammatory) Biliary parasites (Clonorchis, Ascaris) Primary sclerosing cholangitis (can be intra- or extrahepatic)

9. The Bedside Evaluation: History & Physical History: Pain (RUQ): Suggests biliary colic, cholangitis. Painless Jaundice: Alarming for malignancy (e.g., pancreatic cancer). Fever/Chills: Cholangitis, viral hepatitis. Pruritus: Suggests cholestasis. Risk Factors: Alcohol, IV drugs, travel, new medications, family history. Physical Exam Clues: Stigmata of Chronic Liver Disease: Spider angiomata , palmar erythema, ascites, caput medusae. Courvoisier's Sign: Palpable, non-tender gallbladder in a jaundiced patient (suggests malignant obstruction). Hepatosplenomegaly.

10. The Initial Labs The Essential Panel: Total and Direct (Conjugated) Bilirubin Aminotransferases (AST, ALT) Alkaline Phosphatase (ALP) & Gamma-glutamyl transpeptidase (GGT) Albumin and Prothrombin Time (PT)/INR (markers of synthetic function) The first question from this panel: Is it an isolated hyperbilirubinemia or is it associated with other LFT abnormalities ?

11. Isolated Hyperbilirubinemia Definition: Elevated total bilirubin with normal AST, ALT, and ALP. Next Step: Unconjugated or Conjugated ? Feature Indirect (Unconjugated) Direct (Conjugated) Water solubility Insoluble Soluble Albumin binding Strong Weak Urine presence Absent Present (bilirubinuria) Formed where Outside liver (RBC breakdown) Inside liver (after conjugation) Excretion Requires conjugation Directly excreted in bile/urine Clinical elevation Hemolysis, Gilbert, Crigler–Najjar Hepatitis , obstruction, Dubin –Johnson, Rotor

12. Isolated UNCONJUGATED Hyperbilirubinemia Two Mechanisms: Increased Production (Overwhelms the Liver): Hemolysis: Intravascular or extravascular. Ineffective Erythropoiesis: (e.g., thalassemia, megaloblastic anemia). Impaired Conjugation (Liver Can't Keep Up): Genetic: Gilbert's syndrome, Crigler-Najjar syndromes. Drugs: Rifampin, probenecid (inhibit uptake).

13. Workup for Hemolysis Clinical Suspicion: Anemia, splenomegaly, family history. Key Labs: CBC with peripheral smear (schistocytes, spherocytes). Reticulocyte count (elevated). Lactate Dehydrogenase (LDH) (elevated). Haptoglobin (decreased). Direct Coombs test.

14. Gilbert's Syndrome Pathophysiology: Mildly reduced (~30% of normal) UGT1A1 enzyme activity due to a common genetic polymorphism. Clinical Features: The most common inherited disorder of bilirubin metabolism. Benign, fluctuating, mild unconjugated hyperbilirubinemia (typically < 4 mg/dL). Triggers: Jaundice becomes apparent during fasting, dehydration, stress, or intercurrent illness. Management: Diagnosis is clinical. Reassurance is the only treatment needed.

15. Crigler-Najjar Syndromes Pathophysiology: Rare, severe inherited defects in UGT1A1 activity. Type I: Complete absence of UGT1A1. Presents in infancy with extreme unconjugated hyperbilirubinemia, leading to kernicterus. Fatal without phototherapy and eventual liver transplant. Type II (Arias Syndrome): Markedly reduced (<10%) UGT1A1 activity. Less severe. Can be treated with phenobarbital, which induces the UGT enzyme.

16. Isolated CONJUGATED Hyperbilirubinemia An extremely rare scenario resulting from inherited defects in the hepatocyte's ability to excrete conjugated bilirubin into the bile. Feature Dubin-Johnson Syndrome Rotor Syndrome Defect MRP2 transporter OATP1B1/OATP1B3 co-transporters Liver Biopsy Grossly black liver due to pigment deposition Normal histology Urine Test Normal coproporphyrin I High urine coproporphyrin I Prognosis Excellent Excellent

17. Jaundice with Abnormal LFTs: The Common Scenario Most jaundiced patients fall into this category. The Critical Next Step: Differentiate the pattern of liver injury. Hepatocellular: Primarily an AST/ALT elevation. Cholestatic: Primarily an ALP/GGT elevation.

18. Differentiating Hepatocellular vs. Cholestatic Injury Hepatocellular Pattern: Mechanism: Widespread hepatocyte inflammation or necrosis. Labs: Disproportionate elevation in AST/ALT compared to ALP. Cholestatic Pattern: Mechanism: Impaired bile formation or flow. Labs: Disproportionate elevation in ALP (and GGT) compared to AST/ALT.

19. The Hepatocellular Pattern: Differential Diagnosis Acute (AST/ALT >1000s): Acute Viral Hepatitis (A, B, E) Drug-Induced Liver Injury (DILI) - esp. Acetaminophen Ischemic Hepatitis ("Shock Liver") Subacute/Chronic: Alcoholic Hepatitis (AST:ALT > 2:1) Chronic Viral Hepatitis (B, C) Autoimmune Hepatitis Wilson's Disease, Hemochromatosis

20. Workup: Acute Viral Hepatitis Hepatitis A: Anti-HAV IgM Hepatitis B: HBsAg, Anti-HBc IgM Hepatitis C: HCV RNA (antibody may be negative early) Consider Hepatitis E (IgM) in travelers. Consider EBV and CMV as well.

21. Workup: Drug-Induced Liver Injury (DILI) The Great Mimicker: DILI can cause any pattern of liver injury. The single most important tool is a meticulous history: All prescription drugs. Over-the-counter medications (especially Acetaminophen). Herbal supplements, vitamins, illicit drugs. Diagnosis: Often a diagnosis of exclusion. Databases like LiverTox are invaluable resources.

22. Workup: Alcoholic Liver Disease History: Quantify alcohol intake. Classic Lab Finding: AST:ALT ratio > 2:1 (often with both values < 500). Why the ratio? Alcohol depletes pyridoxal 5'-phosphate, a necessary cofactor for ALT synthesis. Maddrey's Discriminant Function (MDF): Used to determine severity and guide corticosteroid therapy in severe alcoholic hepatitis.

23. Workup: Other Hepatocellular Causes Autoimmune Hepatitis: Suspect in women with other autoimmune conditions. Check ANA, anti-smooth muscle antibodies (ASMA), and serum immunoglobulins (IgG). Wilson's Disease: Must be considered in any patient < 40 years old with liver disease. Check ceruloplasmin levels. Ischemic Hepatitis: Look for a clinical history of profound hypotension or shock. Characterized by a massive, rapid spike in AST/ALT followed by a rapid fall.

24. The Cholestatic Pattern Reminder: Patient presents with jaundice and a predominantly elevated ALP and GGT. The Single Most Important Branching Point: Right Upper Quadrant Ultrasound Ducts Dilated → EXTRAHEPATIC (Obstructive) Cholestasis Ducts NOT Dilated → INTRAHEPATIC Cholestasis

25. Extrahepatic Cholestasis (Obstructive) Pathophysiology: A physical blockage of the biliary tree. Differential Diagnosis: Choledocholithiasis (gallstone in the common bile duct) - most common . Malignancy: Pancreatic head adenocarcinoma, Cholangiocarcinoma, Ampullary carcinoma. Benign Strictures: Post-surgical, chronic pancreatitis. Parasitic Infections: Ascaris (in endemic areas).

26. Cholestatic jaundice

27. Differentiating Causes of Obstruction Clinical Clues: Painful Jaundice: Suggests an acute obstruction like a gallstone. Painless, Progressive Jaundice with Weight Loss: Highly concerning for malignancy. Next Steps in Imaging: MRCP (Magnetic Resonance Cholangiopancreatography): Non-invasive, provides detailed anatomical mapping of the biliary tree. Excellent for diagnosis. ERCP (Endoscopic Retrograde Cholangiopancreatography): Invasive, but allows for therapeutic intervention (stent placement, stone removal, brushing for cytology).

28. Posthepatic jaundice/extrahepatic cholestasis Malignant Benign • Cholangiocarcinoma • Pancreatic cancer • Gallbladder cancer • Ampullary cancer • Choledocholithiasis • postoperative biliary strictures • primary sclerosing cholangitis • Chronic pancreatitis • Malignant involvement of the • AIDS cholangiopathy porta hepatis lymph nodes • mirizzi’s syndrome • parasitic disease [ascariasis]

29. Intrahepatic Cholestasis (Non-Obstructive) Pathophysiology: The ultrasound is normal because the problem is at the level of the hepatocyte or microscopic bile ducts. Bile flow is impaired within the liver. Differential Diagnosis is Broad: Primary Biliary Cholangitis (PBC) Primary Sclerosing Cholangitis (PSC) Drug-Induced Cholestasis Cholestasis of Sepsis Infiltrative Diseases (Sarcoidosis, Lymphoma, Amyloidosis) TPN-induced cholestasis Inherited Syndromes (e.g., PFIC)

30. PFIC vs BRIC • Benign Recurrent intrahepatic cholestasis(BRIC) • Benign, recurrent episodes of pruritus, cholestasis and jaundice begins at any a ge, frequency and severity decreases with age • Bile acids elevated during episodes, normal GGT • Progressive familial intrahepatic cholestasis( PFIC 1 -3) • Begins in childhood and progressive, elevated bile acids, type 3 is a/w increased GGT • Growth failure and progressive liver diseases

31. Workup: Primary Biliary Cholangitis (PBC) Classic Patient: Middle-aged woman. Symptoms: Often presents with fatigue and pruritus long before jaundice develops. Hallmark Lab Test: Antimitochondrial Antibody (AMA) is positive in >95% of cases. Confirmatory Test: Liver biopsy.

32. Workup: Primary Sclerosing Cholangitis (PSC) Classic Patient: Young man. Strong Association: Over 70% of patients with PSC have Inflammatory Bowel Disease (usually Ulcerative Colitis). Diagnostic Test: MRCP is the test of choice, showing characteristic multifocal stricturing and beading of the intra- and extrahepatic ducts. Key Risk: High lifetime risk of developing cholangiocarcinoma

33. The "Mixed" Pattern Clinical Reality: Not all cases fit neatly into a hepatocellular or cholestatic box. Examples: Some viral hepatitis can have a prominent cholestatic phase. A long-standing obstruction can eventually lead to secondary hepatocellular injury. Approach: Identify the dominant initial process and follow that algorithm, but be prepared for overlap.

34. The Role of Liver Biopsy When to Biopsy? To diagnose and stage indeterminate causes of hepatocellular injury (e.g., autoimmune hepatitis). To confirm and stage PBC or investigate suspected infiltrative disease when serologies and imaging are non-diagnostic. When multiple potential diagnoses exist. Less useful for: Diagnosing extrahepatic obstruction, where imaging is superior.

35. Emergency 1: Ascending Cholangitis Pathophysiology: Biliary obstruction plus infection. Charcot's Triad: Fever Right Upper Quadrant Pain Jaundice Reynolds' Pentad (indicates shock): 4. Hypotension 5. Altered Mental Status Management: This is a medical emergency. Requires IV antibiotics, fluid resuscitation, and urgent biliary decompression (usually via ERCP).

36. Emergency 2: Acute Liver Failure (ALF) Definition: The onset of hepatic encephalopathy and severe coagulopathy (INR ≥ 1.5) in a patient with jaundice but no pre-existing cirrhosis. Etiologies: Acetaminophen overdose is the most common cause in the US. Others include viral hepatitis, DILI, and Wilson's disease. Significance: Carries a very high short-term mortality.

37. Management of Acute Liver Failure ICU Admission and intensive monitoring. Immediate Action: Identify and treat the cause if possible (e.g., N-acetylcysteine for acetaminophen toxicity). Supportive care (manage cerebral edema, hypoglycemia, coagulopathy). Early consultation with a liver transplant center is critical.

38. Magnitude of AST and ALT elevations • Alcoholic liver disease – AST: ALT> 2, AST <8 times the upper limit, ALT <5 times the upper limit of normal. • Nonalcoholic fatty liver disease – AST and ALT <4 times the upper limit of normal. • Acute viral hepatitis or toxin-related hepatitis with jaundice – AST and ALT >25 times the upper limit of normal. • Ischemic hepatitis (ischemic hep ato pathy, shock liver, hypoxic hepatitis) – AST and ALT >50 times the upper limit of normal (Also LDH) is markedly elevated). • Chronic hepatitis C virus infection – Wide variability, typically normal to <2X the upper limit, rarely > 10 times the upper limit • Chronic hepatitis B virus infection – Levels vary; may be normal in inactive carriers, most patients with chronic hepatitis B have mild to moderate elevations (2X upper limit of normal); with exacerbations, levels are> 10 times the upper limit

39. Treatment/management Cholestatic / Obstructive Jaundice Ursodeoxycholic acid (UDCA) – improves bile flow, used in PBC, PSC, intrahepatic cholestasis. Cholestyramine – bile acid sequestrant for pruritus relief. Rifampicin – induces hepatic enzymes, also helps pruritus. Antibiotics – for cholangitis (e.g., ceftriaxone, piperacillin-tazobactam).

40. Treatment/management 3. Hepatocellular Injury (Deranged LFTs) N-acetylcysteine (NAC) – antidote for paracetamol-induced hepatotoxicity. Corticosteroids – autoimmune hepatitis. Antivirals – HBV → Tenofovir, Entecavir. HCV → Sofosbuvir, Ledipasvir, Daclatasvir etc. Chelators – Penicillamine, Trientine , Zinc (Wilson’s disease). 4. Supportive / Symptomatic Vitamin K – for coagulopathy due to impaired bile-dependent absorption. Lactulose, Rifaximin – for hepatic encephalopathy. Antioxidants (Silymarin, SAMe) – hepatoprotective (limited evidence).

41. Concluding Thoughts Jaundice is a cardinal sign of hepatobiliary disease. A systematic approach, grounded in the pathophysiology of bilirubin metabolism and the interpretation of liver function tests, allows for an accurate, efficient, and safe evaluation of the jaundiced patient.

42. References Content based on: John, S., & Pratt, D. Jaundice. In D. L. Kasper, S. L. Hauser, D. L. Longo, G. F. Fauci, & J. L. Jameson (Eds.), Harrison's Principles of Internal Medicine, 21 st Ed. UpToDate First aid Step 1 2024

43. Thank you