Non-viral hepatitis, alcoholic fatty liver, mechanisms of hepatotoxic injury by ethanol, viral hepatitis, chronic liver disease, cirrhois, portal hypertension, ascites, spontaneous bacterial peritonitis, gall stones

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Department
Biomedical Science
Course
BMS 460
Professor
D.Rao Veeramachaneni
Semester
Fall

Description
16 October Non-viral Hepatitis Inflammation of the liver that usually results from exposure to certain chemicals and drugs, e.g., industrial chemicals, acetaminophen Hepatotoxicity accounts for 27% of the drugs withdrawn from the market since 1960 Acetaminophen is the leading cause of acute liver failure Hepatic cellular necrosis, scarring, Kupffer cell hyperplasia, and infiltration by mononuclear phagocytes occur with varying severity Alcohol, anoxia, and pre-existing liver disease worsen the effects of some toxins Alcoholic Fatty Liver: Steatosis, Steatohepatitis Has both direct and indirect effects Direct effects may result from increasing fluidity of biological membranes and thereby disrupting cellular function Indirect effects are in part a consequence of its metabolism Alcoholic fatty liver (Alcoholic steatohepatitis) Because of increased fatty acid synthesis (from glucose available after reaching ~100g threshold for storage as glycogen or from breakdown of stored glycogen), decreased fatty acid oxidation (use of fat as energy source), and decreased export of fats in the form of lipoproteins, alcohol invariably produces fatty changes in a dose-dependent manner Mechanisms of hepatotoxic injury by ethanol Disorganizes the lipid portion of cell membranes, leading to adaptive changes in their composition Alters the capacity of liver cells to cope with environmental toxins Oxidation of ethanol produces acetaldehyde, a toxic and reactive intermediate Mechanisms of hepatotoxic injury by ethanol Body uses 3 different enzymes to convert alcohol to acetaldehyde All 3 work by stripping two H atoms off the alcohol molecule Peroxisomes Ethanol acted on by catalase → acetaldehyde H O → H O 2 2 2 Microsomes Ethanol acted on by CYP2E1 → acetaldehyde NADPH + H + O → NA2P + 2H O + 2 Cytosol Ethanol acted on by ADH → acetaldehyde + NAD → NADH Mitochondria Acetaldehyde acted on by ALDH2 → acetate → circulation NAD → NADH The cytoplasmic alcohol dehydrogenase, ADH, is major pathway The microsome-ethanol oxidizing system, MEOS, is significant during chronic alcohol intake + An excess H and acetaldehyde produced in ADH pathway damages mitochondria, disrupts microtubules, and alters proteins that can induce autoimmune responses leading to hepatocyte injury The oxygen radicals produced in MEOS pathway in addition to acetaldehyde causes lipid peroxidation resulting in membrane damage. Furthermore, an up-regulated MEOS affects detoxification activity of hepatocytes resulting in accumulation of potential toxicants. Alcohol metabolism produces excess amounts of NADH. This excess of NADH can lead to acidosis from lactic acid build-up and hypoglycemia from lack of glucose synthesis. It can also lead to weight gain, fatty liver, and heart attack. Viral Hepatitis A common infection of the liver, resulting in hepatic cell destruction, necrosis, and autolysis. Edema and swelling of interstitium lead to collapse of capillaries and decreased blood flow, tissue hypoxia, and scarring and fibrosis. Five major forms are currently recognized; other types continue to be identified. Despite variation in symptoms, signs and epidemiologic progression of these diseases, it is often clinically impossible to differentiate them without serological tests Type A: Infectious or short-incubation hepatitis; contaminated food and water via fecal-oral route Type B: Serum or long-incubation hepatitis; transfusion and needles Type C: Accounts for ~20% of all viral hepatitis and most transfusion cases; risk of hepatocellular carcinoma Type D: Delta; requires presence of Type B; blood products and personal contact Type E: Most common in developing countries; contaminated water Prevention and treatment may include Vaccination against hepatitis A and B to provide immunity to these viruses before transmission occurs Rest to minimize energy demands Avoiding alcohol or other drugs, to prevent further hepatic damage Blood-borne or sexually transmitted → infection HBV (hepatitis B virus) → sub-clinical disease, acute liver failure HCV (hepatitis C virus) → sub-clinical disease, acute icterus, acute liver failure Sub-clinical disease → chronic hepatitis, recovery Acute icterus → recovery, chronic hepatitis Acute liver failure → death Chronic hepatitis → cirrhosis → cancer, death Cirrhois – liver transplant or death Changes in chronic liver disease Viral infection, alcohol, and bacterial toxins cause injury of hepatocytes by a mechanism involving the production of proinflammatory cytokines (tumor necrosis factor-α, transforming growth factor-β, and interleukin 6) produced by Kupffer cells Tumor necrosis factor-α causes a slowdown and arrest of the flow of bile in bile ducts (cholestasis) Interleukin-6 released by Kupffer cells stimulates the synthesis of acute-phase proteins by hepatocytes Transforming growth factor-β, secreted by Kupffer cells and hepatocytes, stimulates the synthesis of type I collagen by hepatic stellate cells. Fibrosis compromises the portal venous blood flow. Fat accumulates in hepatocytes (steatosis, or fatty liver). Steatosis is reversible if alcohol consumption stops Under normal conditions, hepatic perisinusoidal cells store fat-soluble vitamin A in the cytoplasm and produce collagen fibers and extracellular matrix components deposited in the perisinusoidal space of Disse and around the central vein of the hepatic lobule During cirrhosis, a diffuse condition of the liver associated with progressive fibrosis, the perisinusoidal cells transform into myofibroblasts and become the main collagen-producing cells of the cirrhotic liver Cytokines, produced by hepatocytes, Kupffer cells, and infiltrating lymphocytes in the space of Disse, stimulate the production of type I collagen by perisinusoidal cells. Deposit of type I collagen in the space of Disse results in fibrosis that alters the flow of portal venous blood into the hepatic sinusoids. Cirrhois Pathogenesis Alcohol causes Fatty liver Alcoholic hepatitis Scarring Viral infections cause Liver cell necrosis Inflammation Fibrosis Collectively, these changes result in cirrhosis – a chronic liver disease characterized by loss of normal structure and function Histologically, fibrosis and regenerating liver cell nodules replace normal parenchyma Clinical features Collateral veins Ascites Splenomegaly Jaundice Muscle wasting Hepatic renal syndrome Oliguria-anuria Edema Hepatic encephalopathy Ammonia -/→ urea
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