1. HBV & HCV induced Liver Cirrhosis Iradj Maleki MD Gut & Liver Research Center Mazandaran University of Medical Sciences

2. Definition of Cirrhosis Final pathway for a wide variety of chronic liver diseases A pathologic entity Diffuse hepatic fibrosis Replacement of the normal liver architecture by nodules The rate of progression of chronic liver disease to cirrhosis may be quite variable Weeks in patients with complete biliary obstruction Decades in patients with chronic hepatitis C

4. Cirrhosis in the natural history of HBV hepatitis Interplay between Virus replication Host immune response Other factors Gender alcohol consumption concomitant infection with other hepatitis viruses The outcome of chronic HBV infection depends upon the severity of liver disease at the time HBV replication is arrested

5. Spectrum of Chronic HBV Infection Inactive carrier state Chronic hepatitis Cirrhosis Hepatic decompensation Hepatocellular carcinoma (HCC) Extrahepatic manifestations Death Long-term follow-up studies of hepatitis B surface antigen (HBsAg) positive blood donors have shown that the majority remain asymptomatic with a very low risk of cirrhosis or HCC

6. Prognosis of Chronic HBV Infection The prognosis is worse in HBV-infected patients from endemic areas and in patients with chronic hepatitis B The estimated five-year rates of progression are: Chronic hepatitis to cirrhosis – 12 to 20% Compensated cirrhosis to hepatic decompensation – 20 to 23% Compensated cirrhosis to HCC – 6 to 15% The cumulative survival rate at each of these stages of progressive disease is: Compensated cirrhosis – 85 % at five years Decompensated cirrhosis – 55 to 70 % at one year and 14 to 35 % at five years

8. Cirrhosis in the natural history of HCV hepatitis The majority of patients who acquire HCV do not spontaneously clear the virus They develop chronic HCV infection Chronic infection results in liver fibrosis and ultimately cirrhosis in a subset of patients Patients who develop cirrhosis are at further risk for: Complicating events (such as variceal hemorrhage, ascites, and encephalopathy) Hepatocellular carcinoma

9. Factors Associated with Disease Progression Baseline liver histology Age Ethnic background Gender Alcohol use Diabetes mellitus and insulin resistance Comorbidities such as obesity Viral coinfection (HIV, HBV) HCV-specific cellular immune response Vitamin D deficiency Higher levels of dietary cholesterol consumption Daily coffee consumption and Atorvastatin use have inhibitory effects

11. Clinical Presentation (Patient’s complaints) Compensated Cirrhosis Asymptomatic Anorexia Weight loss Weakness Fatigue Decompensated Cirrhosis Jaundice Pruritus upper gastrointestinal bleeding abdominal distension from ascites confusion due to hepatic encephalopathy muscle cramps, …

12. Clinical Presentation (Physical Findings) General Low blood pressure - Those patients with previous hypertension may become normo- or hypotensive Skin/ Head findings Jaundice Spider angiomata Parotid gland enlargement Fetor hepaticus

13. Clinical Presentation (Physical Findings) Abdominal findings Ascites Splenomegaly Hepatomegaly or liver nodularity Caput medusa Extremity findings Palmar erythema Nail changes Clubbing Hypertrophic osteoarthropathy Dupuytren's contracture. Other Findings: Asterixis Gynecomastia

14. Diagnosis of Cirrhosis in Chronic Viral hepatitis Cirrhosis is a pathologic diagnosis, but liver biopsy is not necessary in most cases for the diagnosis A combination of clinical, laboratory and imaging studies can usually confirm the diagnosis Findings of above mentioned physical findings may suggest development of cirrhosis

15. Diagnosis of Cirrhosis in Chronic Viral hepatitis Patients with chronic viral hepatitis with varices, ascites or encephalopathy are likely to have cirrhosis Splenomegaly and laboratory findings like low platelet count, increased PT, decreased serum albumin may suggest cirrhosis A lot of panels and tests are available for the early diagnosis of liver fibrosis The most popular and the most studied tool is transient elastography (Fibroscan)

16. Management of Cirrhosis Cirrhosis due to HBV or HCV Control/ eradication of the virus Management of sequella of hepatic failure and portal hypertension

17. Management of Cirrhosis Slowing/reversing the progression of liver disease Preventing superimposed insults to the liver (Alcohol, immunizations!) dose adjustments for medications Managing symptoms and laboratory abnormalities Preventing/treating the complications of cirrhosis Liver transplantation Ascites Varices and variceal bleeding Encephalopathy Nutrition & vitamin deficiency Muscle cramp Quality of life measures

18. Management of HBV in Cirrhosis Compensated disease In patients with clinically compensated cirrhosis: Normal hepatic synthetic function Minimal or no evidence of portal hypertension treatment options for HBV control are: Interferon (may be used with caution) Nucleos(t)ide analogues are safer Tenofovir Entecavir

19. Management of HBV in Cirrhosis Decompensated disease Entecavir or Tenofovir can be used to treat patients Interferon is contra-indicated!

20. Management of HCV in Cirrhosis All patients with chronic HCV infection should be considered for treatment The direct-acting antivirals (DAAs) have revolutionized therapy of HCV infection Antiviral therapy of HCV has been rapidly evolving Regimen selection varies by genotype and other patient factors, such as the presence of cirrhosis and treatment history

21. Management of HCV in Cirrhosis

22. Management of HCV in Cirrhosis Genotype 1 & 4

23. Management of HCV in Cirrhosis Genotype 2

24. Management of HCV in Cirrhosis Genotype 3 Difficult to treat genotype now!

25. Is Liver Fibrosis Reversible? Liver fibrosis was thought to be irreversible Studies have shown that fibrosis can regress if the etiology is corrected (chronic biliary obstruction relief) Liver fibrosis is an active research field in hepatology Although earlier stages of fibrosis may resolve, advanced stages of fibrosis may not be reversible

26. HCC screening Plan for HCC screening in all patients who have liver fibrosis for a life-long period!

27. Prognosis Liver related mortality = 8 th cause in USA In persons 45-65 yrs old: cirrhosis is the 3 rd cause of mortality (USA) Compensated cirrhosis: 5x increased risk of death Decompensated cirrhosis: 10x increased risk of death Median survival: Compensated cirrhosis: 9-12 yrs Decompensated cirrhosis: 2 yrs

28. Conclusion Cirrhosis is a later phase in the natural history of chronic HBV and HCV hepatitis Early diagnosis and treatment of infection can prevent the development of it Development of cirrhosis deteriorates the prognosis With the newer anti-HCV drugs the course of cirrhosis is changing Beside the viral etiology of these patients, general aspects of liver failure and portal hypertension should be managed properly

29. Many thanks for your attention