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CHRONIC HEPATITIS The contours of the liver and spleen as well as the gall bladder in the right and left hypochondrium THE ANATOMY OF THE PORTAL VENOUS SYSTEM CHRONIC HEPATITIS Chronic hepatitis is generally defined as disease that has lasted for 6 months or longer Inflammation Walls of scar tissue begin to form Healthy liver cells become trapped by a wall of scar tissue CYTOLYTIC SYNDROME alanine aminotransferase increased, aspartate aminotransferase increased Increased LDH Increased ferritin Hyperbilirubiemia Cholestasis abdominal mass (e.g. cancer) biliary atresia and other pediatric liver diseases biliary trauma congenital anomalies of the biliary tract gallstones intrahepatic cholestasis of pregnancy (obstetric cholestasis) primary biliary cirrhosis, an autoimmune disorder primary sclerosing cholangitis, associated with inflammatory bowel disease some drugs, (e.g. flucloxacillin and erythromycin) ABCC2 gene polymorphism Alkaline phosphatase elevations of serum bile acid levels elevated levels of Gamma Glutamyl Transferase [GGT] itchiness (pruritus). Pruritus is the primary symptom of cholestasis jaundice. pale stool. This symptom implies obstructive cholestasis. dark urine Hepatocellular Mesenchymal insufficiency inflammation Albumin Transferrine Cholesterol protro,mbine Hyper-γ globulinemia CRP ESR Cholinesterasa Α-lipoproteins Hyperbilirubinemia Signs of CLD CHRONIC HEPATITIS CLASSIFICATION Chronic Viral Hepatitis B Chronic Viral Hepatitis C Chronic Viral Hepatitis D Chronic Viral Hepatitis nonidentificated Autoimmune Hepatitis (type 1, 2 ,3) Toxic Hepatitis, Drug-Induced Hepatitis Cryptogenic Hepatitis Alcoholic Hepatitis Metabolic Hepatitis Cholestatic Hepatitis Nonspecific Reactive Hepatitis Grades of Inflammation and Stages of Fibrosis on Liver Biopsies CHRONIC HEPATITIS CLASSIFICATION ACCORDING TO SEVERITY (level of Aminotransferases) A C T I V ITY MILD MODERATE SEVERE CHRONIC HEPATITIS COMPLICATIONS HEPATIC ENCEPHALOPATHY VARICEAL BLEEDING ASCITES GLOMERULONEPHRITIS OTHERS General Concepts Hepatitis = 'inflammation of the liver'. six medically important viruses are commonly described as “hepatitis viruses”: HAV,HBV,HCV,HDV,HEV,HGV. Viral Hepatitis - Historical Perspectives “Infectious” Viral hepatitis “Serum” Enterically E transmitted A NANB B D Parenterally C transmitted F, G, TTV ? other CHRONIC VIRAL HEPATITIS 5 to 10% of cases of hepatitis В (with or without hepatitis D virus co-infection) and about 75% of cases of hepatitis C become chronic. Infection with hepatitis A virus or hepatitis E virus is not a cause of Chronic Hepatitis. HBV : Structure HBV Structure & Antigens Dane particle HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr) HBcAg = inner core protein (a single serotype) HBeAg = secreted protein; function unknown Possible Outcomes of HBV Infection Acute hepatitis B infection 3-5% of adultacquired infections 95% of infantacquired infections Chronic HBV infection Chronic hepatitis 12-25% in 5 years 6-15% in 5 years Cirrhosis Hepatocellular carcinoma Death 20-23% in 5 years Liver failure Liver transplant Death Laboratory Diagnosis CHRONIC VIRAL HEPATITIS Hepatitis B virus and hepatitis C virus are the major causes of chronic hepatitis in the world. Approximately 80% of individuals infected with HCV will become chronic carriers, of whom a majority will develop a degree of liver damage ranging from fatty liver to cirrhosis. Chronic HBV and HCV infection predispose patients to developing hepatocellular carcinoma. Natural History of Hep C Only 20% will show symptoms Initially ! Healthy Liver Acute Infection Adapted from Lauer and Walker, NEJM 2001 20% Clear the Virus Chronic Infection 80% Virus Continues to Damage Liver Natural History Con’t Chronic Hepatitis Cirrhosis 20-30% Liver Cancer 1-4%/year Most symptoms begin to show only when liver is more severely damaged AUTOIMMUNE HEPATITIS Patients with severe disease who are treated with corticosteroids have a 10-year survival rate of 60% to 70%, whereas untreated patients have a survival rate of less than 30%. Autoimmune Hepatitis Histology Lymphoplasmacytic infiltrate Interface hepatitis Portal inflammation and invasion of limiting plate Autoimmune Hepatitis Histology Prominent lobular infiltrate composed of mononuclear and plasma cells Lobular infiltrate Autoimmune Hepatitis Histology Prominent plasma cells appreciated in this specimen Plasma cells DRUG-INDUCED CHRONIC HEPATITIS Hepatotoxic drugs: - Paracetamol - Isoniazid - Oestrogens - Antibiotics -Methotrexate -others DIVERSITY > 1000 Hepatotoxic drugs Diverse mechanisms Variety of liver diseases METABOLIC ACTIVATION Drug CYP Reactive metabolite (Low Amounts) (High Amounts) Protein Immune reactions Direct toxicity Extensive covalent binding GSH MITOCHONDRIAL DYSFUNCTION Drugs Betaoxidation Steatosis Respiration Cell dysfunction Cell death Lactic acidosis FATTY LIVER Fat droplets appear in the cytoplasm of hepatocytes; they may appear a few days after an alcohol binge, but are almost always present in heavy drinkers (> 80 g of alcohol per day for > 5 years). Fatty liver may occur, however, with obesity, diabetes mellitus, starvation and chronic hepatitis C virus infection Fatty Liver ALCOHOLIC HEPATITIS Alcohol abuse is a massive international problem which has huge resource implications both for the community as a whole and also for health care. Alcohol is enjoyed by many and used safely by the majority of people who drink it. Alcohol abuse may be denied or not recognized by individuals or their families and friends. Alcohol damages not only the liver, but many other organs also. Effects of alcohol abuse Alcoholic Hepatitis Mechanisms of liver injury Free radicals Oxidative injury Heat Gut Permeability Endotoxaemia Gultathione depletion Kupfer cell activation TNFα ROS & Free radicals Ethanol Alcohol dehydrogenase (ADH) Peroxisomal Catalase Miscrosomal ethanol-oxidising system (CYP 2E1) Downregulated in chronic alcohol use Acetaldehyde Acetaldehyde dehydrogenase Altered membrane proteins Neoantigens formation Acetate Impaired cytoskeletal transport Stimulation of HSC Genetics Polymorphisms Damage Male vs Female Race TNFα IL-1, IL-8 Immunological injury Damage to cell membranes ALCOHOLIC HEPATITIS Alcoholic liver disease may develop in women after less alcohol consumption than is necessary to cause hepatitis or cirrhosis in men. Daily alcohol consumption of approximately 50 g for 10 to 15 years is associated with alcoholic liver disease in women, whereas 80 g is associated with alcoholic cirrhosis in men. Pathology of Alcoholic Hepatitis Mallorys Hyaline Centrilobular necrosis Fatty change Hepatocyte ballooning PMN infiltrate Pericellular fibrosis ALCOHOLIC HEPATITIS Alcoholic hepatitis refers to the pathologic Mallory stain findings of alcoholic hyalin surrounded by polymorphonuclea r cell inflammation CHRONIC HEPATITIS DIAGNOSIS LABORATORY SYNDROMES: Cytolitic syndrome (↑AST, ↑ALT, ↑GGT, ↑Bilirubin ) Cholestatic syndrome (↑conjugated Bilirubin, ↑Alkaline phosphatase, ↑GGT, ↑cholesterol) Liver cellular insufficiency syndrome (↓Albumine, ↓prothrombin, ↓cholesterol, ↓fibrinogen) Mesenchyme-inflammatory syndrome (↑ESR, ↑ﻻ-globulins, ↑timol test ↑Le, ↑C-react. protein) Hypersplenism (anemia, thrombocytopenia, leukocytopenia) CHRONIC VIRAL HEPATITIS TREATMENT ANTIVIRAL THERAPY (Interferon therapy, Lamivudine therapy) Corticosteroids are contraindicated, because viral replication is enhanced INTERFERON THERAPY (Intron A, Velferon, Reaferon, Laferon) CHRONIC VIRAL HEPATITIS B: 5-10 million Units 3 times a week s/c or i/m for 3- 4-12 months CHRONIC VIRAL HEPATITIS C: 3-5 million units 3 times a week for 12-18 months CHRONIC VIRAL HEPATITIS D: 10 million units 3 times a week for 12-18 months Autoimmune Hepatitis Week Monotherapy Prednisolone, mg Prednisolone (mg) and Azathioprine (mg/kg) combination therapy Prednisolone Azathioprine 1 50 50 50-150 2 3 50 40 40 30 50-150 50-150 4 30 20 50-150 5 25 15 50-150 6 20 12,5 50-150 7,8 15 10 50-150 HEPATOPROTECTORS Plant Essential phospholipids Carsil, Legalon, Hepabene, Chofitol Essentiale, Enerliv Aminoacids Glutargin, Citrarginin α- lipoic acid Berlithion Ursodezoxycholic acid Ursofalc, Ursosan Synthetic Thiotriazolin, Antral Animal Vitohepat, Sirepar Homeopathic Halstena