CIRRHOSIS Pathophysiology & Complications

1. CIRRHOSIS Pathophysiology & Complications B.Shahbazkhani , MD Associate Professor of Internal Medicine Imam Khomini Hospital Tehran University of Medical Sciences

2. Normal liver functions • Carbohydrate Metabolism • Hypo- or hyperglycemia • Fatty Acids Metabolism • Lipid Transport • Hyper- or hypolipidemia • Proteins Metabolism • Serum Albumin • Vitamin K–Dependent Blood Coagulation Proteins • Bilirubin Metabolism • Bile Production • Fat-Soluble Vitamins • Detoxification • Drugs and hormones • Providing continual source of energy for entire body • Regulation of storage and modulate availability of systemic nutrients • Subject to hormonal modulation by endocrine organs • (Pancreas, adrenal gland, and thyroid, neuronal regulation)

3. THE NORMAL LIVER OFFERS ALMOST NO RESISTANCE TO FLOW Normal Liver Hepatic vein Sinusoid Liver Coronary vein Portal vein Splenic vein

4. Normal Liver Histology CV 2-3 mmHg 6 mmHg PV

5. ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE Hepatic cirrhosis

6. GROSS IMAGE OF A NORMAL AND A CIRRHOTIC LIVER Normal Cirrhosis Irregular surface Nodules

7. Cirrhosis Causes (Etiology of chronic necrosis) + Host (Liver reaction) Lead to Cirrhosis & complications

8. DEFINITION OF CIRRHOSIS Hepatic Cirrhosis • End stage of any chronic liver disease • Characterized histologically by regenerative nodules surrounded by fibrous tissue • Clinically there are two types of cirrhosis: • Compensated • Decompensated

9. HISTOLOGICAL IMAGE OF A NORMAL AND A CIRRHOTIC LIVER Normal Cirrhosis Nodules surrounded by fibrous tissue

10. HISTOLOGICAL IMAGE OF CIRRHOSIS Fibrosis Regenerative nodule

11. PATHOGENESIS OF LIVER FIBROSIS Normal Hepatic SInusoid Retinoid droplets Fenestrae Hepatic stellate cell Space of Disse Sinusoidal endothelial cell Hepatocytes

12. PATHOGENESIS OF LIVER FIBROSIS Alterations in Microvasculature in Cirrhosis • Activation of stellate cells • Collagen deposition in space of Disse • Constriction of sinusoids • Defenestration of sinusoids

14. ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE Cirrhotic Liver Portal systemic collaterals Distorted sinusoidal architecture leads to increased resistance Portal vein Splenomegaly

19. COMPLICATIONS OF CIRRHOSIS Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficiency Variceal hemorrhage Portal hypertension Spontaneous bacterial peritonitis Ascites Cirrhosis Hepatorenal syndrome Encephalopathy Liver insufficiency Jaundice

20. NATURAL HISTORY OF CHRONIC LIVER DISEASE Development of complications: • Variceal hemorrhage • Ascites • Encephalopathy • Jaundice Natural History of Chronic Liver Disease Chronic liver disease Compensated cirrhosis Decompensated cirrhosis Death

22. Decompensation Shortens Survival 10 SURVIVAL TIMES IN CIRRHOSIS 100 80 Median survival ~ 9 years All patients with cirrhosis 60 Probability of survival 40 20 Decompensated cirrhosis Median survival ~ 1.6 years 0 0 20 40 60 80 100 120 140 160 180 Months Gines et. al., Hepatology 1987;7:122

23. Aetiology • Chronic hepatitis B • Chronic hepatitis C • Alcohol • Autoimmune hepatitis Non-alcoholic fatty liver disease NASH Primary biliary cirrhosis Primary Sclerosing cholangitis

24. Cirrhosis – other causes • Hemochromatosis • Wilson’s Disease • Alpha1 Antitrypsin Deficiency • Cystic Fibrosis

25. Diagnostic approach Liver function test(PT,Alb.Plt, bil.) Liver damage test(AST,ALT,ALP) Liver ultrasound Etiological test Liver biopsy

26. Clinical manifestation No symptom # 40 % Impaired liver function Sign of Portal hypertension Sign of liver insufficiency

27. DIAGNOSIS OF CIRRHOSIS – LABORATORY STUDIES In Whom Should We Suspect Cirrhosis? Laboratory • Liver insufficiency • Low albumin (< 3.8 g/dL) • Prolonged prothrombin time (INR > 1.3) • High bilirubin (> 1.5 mg/dL) • Portal hypertension • Low platelet count (< 175 x1000/ml) • AST / ALT ratio > 1

28. DIAGNOSIS OF CIRRHOSIS – CLINICAL FINDINGS In Whom Should We Suspect Cirrhosis? • Any patient with chronic liver disease • Chronic abnormal aminotransferases and/or alkaline phosphatase • Physical exam findings • Stigmata of chronic liver disease (muscle wasting, vascular spiders, palmarerythema) • Small liver span • Splenomegaly • Signs of decompensation (jaundice, ascites, asterixis)

29. Signs of CLD

30. DIAGNOSIS OF CIRRHOSIS Cirrhosis - Diagnosis • Cirrhosis is a histological diagnosis • However, in patients with chronic liver disease the presence of variousclinical features suggests cirrhosis • The presence of these clinical features can be followed by non-invasive testing, prior to liver biopsy

33. Spider nevus.This very large spider nevus with its central arteriole developed in a patient with hepatic cirrhosis. Spider nevi develop through deficient estrogen metabolism, and a few can be seen in pregnancy or in patients taking the oral contraceptive. They occur in the distribution of the drainage of the superior vena cava and are therefore seen on the face, arms and upper trunk. Spider nevi will disappear following hepatic transplantation. Miles Allison, Newport, Wales

35. Palmar erythema

37. DIAGNOSIS OF CIRRHOSIS – CAT SCAN CT Scan in Cirrhosis Collaterals Splenomegaly Liver with an irregular surface

38. Prognosis- CHILD – PUGH Scoring

39. CHILD -PUGH SCORING SYSTEM • Class A – 5 to 6 points • Class B – 7 to 9 points • Class C – 10 to 15 points • B & C – Potential candidates for Hepatic transplantation

41. AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSION An Increase in Portal Venous Inflow Sustains Portal Hypertension 20 Distorted sinusoidal architechure Portal vein  Flow Mesenteric veins Splanchnic vasodilatation

43. VARICES INCREASE IN DIAMETER PROGRESSIVELY Varices Increase in Diameter Progressively No varices Small varices Large varices 7-8%/year 7-8%/year Merli et al. J Hepatol 2003;38:266

44. A THRESHOLD PORTAL PRESSURE OF ~12 mmHg IS NECESSARY FOR VARICES TO FORM A Threshold Portal Pressure of ~12 mmHg is Necessary for Varices to Form Varices Present (n=72) Varices Absent (n=15) 35 30 Hepatic Venous Pressure Gradient (mmHg) 25 20 P<0.01 15 12 10 5 Garcia-Tsao et. al., Hepatology 1985; 5:419

45. PROGNOSTIC INDICATORS OF FIRST VARICEAL HEMORRHAGE Varix with red signs Variceal hemorrhage • Predictors of hemorrhage: • Variceal size • Red signs • Child B/C NIEC. N Engl J Med 1988; 319:983

46. MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE - SUMMARY Diagnosis of Cirrhosis Endoscopy No Varices Medium/Large Varices Small Varices Follow-up EGD in 2-3 years* Follow-up EGD in 1-2 years* *EGD every year in decompensated cirrhosis Beta-blocker therapy No Contraindications • Stepwise increase until maximally tolerated dose • Continue beta-blocker (life-long) Contraindications or Beta-blocker intolerance Endoscopic Variceal Band Ligation Prophylaxis of Variceal Hemorrhage

47. TREATMENT OF ACUTE VARICEAL HEMORRHAGE Treatment of Acute Variceal Hemorrhage General Management: • IV access and fluid resuscitation • Do not overtransfuse (hemoglobin ~ 8 g/dL) • Antibiotic prophylaxis Specific therapy: • Pharmacological therapy: terlipressin, somatostatin and analogues, vasopressin + nitroglycerin • Endoscopic therapy: ligation, sclerotherapy • Shunt therapy: TIPS, surgical shunt

48. ENDOSCOPIC VARICEAL BAND LIGATION Endoscopic Variceal Band Ligation • Bleeding controlled in 90% • Rebleeding rate 30% • Compared with sclerotherapy: • Less rebleeding • Lower mortality • Fewer complications • Fewer treatment sessions

49. THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT Transjugular Intrahepatic Portosystemic Shunt Hepatic vein TIPS Splenic vein Portal vein Superior mesenteric vein

50. MANAGEMENT ALGORITHM IN ACUTE ESOPHAGEAL VARICEAL HEMORRHAGE Variceal Hemorrhage Suspected Initial Management Acute Hemorrhage Controlled? NO YES Balloon Tamponade Early rebleeding? YES NO Rescue TIPS/Shunt surgery 2nd Endoscopy Further bleeding Prophylaxis against recurrent hemorrhage 30 Management of Acute Variceal Hemorrhage