Extrahepatic Manifestations PDF

Acute vs. Chronic Hepatitis Acute Hepatitis o Dead cells are replaced by scar tissue o Minimal inflammation of portal tract o “Spotty necrosis” or apoptosis of Lobular hepatitis o Mononuclear cell infiltrate o Confluent necrosis around central vein progressing to central-portal necrosis o Ballooned...

Acute vs. Chronic Hepatitis Acute Hepatitis o Dead cells are replaced by scar tissue o Minimal inflammation of portal tract o “Spotty necrosis” or apoptosis of Lobular hepatitis o Mononuclear cell infiltrate o Confluent necrosis around central vein progressing to central-portal necrosis o Ballooned hepatocytes (swollen, round) Chronic Hepatitis o Dead cells are replaced by scar tissue and become fibrotic o Mononuclear portal tract infiltration o Interface and lobular hepatitis o Bile duct proliferation o Fibrosis/scarring in portal tract progresses to BRIDGING fibrosis and cirrhosis HBV (chronic) o Ground glass cells (hallmark): Viral proteins (HBsAg) filled in cytoplasm of hepatocytes, ER swollen by HBsAg HCV (chronic) o Dense Lymphoid aggregates or fully formed lymphoid follicles in portal tract o Steatosis: Fat deposition in hepatocytes o The fat deposition pushes nucleus to the periphery of hepatocytes Steatosis = 1+ lipid droplets present in cytoplasm, very fatty hepatocytes Extrahepatic Manifestations NOT in acute, only in chronic Caused by chronic infection of HBV, HCV, HDV (due to co-infection) Once infected, plasma cells make antibodies and immune complexes Antibodies + Virus = immune complexes Immune complexes are deposited into tissues causing: o Arthritis in synovial joints o Vasculitis o Myocarditis/Pericarditis o Glomerulonephritis o Atypical Lymphocytes o Thrombocytopenia § Binds to RBCs: hemolytic anemia § Binds to Neutrophils: neutropenia HBV, HCV, HDV cause chronic hepatitis, leading to cell death which leads to (2): 1) Fibrosis: increases the risk of cirrhosis 2) Hepatocellular carcinoma due to cell dysplasia from mistakes in mitosis cell regeneration HAV (Picornavirus) Viral Hepatitis: Diagnosis and Treatment Tests Treatment - Supportive care, hydration, rest - Recovery time: 3-6wks - Anti-HAV IgM (active infection, produced early) - Vaxx present - Anti-HAV IgG (recovery/vaxx) - Prevented w serum Ig (when contact w infected) IgG is a protective Ab produced in later stages of infection - No risk of cirrhosis or carcinoma - Acute infection leaves on its own - HBsAg (active infection- surface antigen) - HBcAg (active viral replication- core antigen in capsid) - HBeAg (active viral replication, highly infect/transm, e antigen located between surface and core) HBV (DNA Hepadnavirus) - HCV (Flaviviridae) HDV (Deltaviridae) HEV (Hepevirus) Anti HBs (recovery/immunity) Anti HBc IgM (recent acute) Anti HBc IgG (resolved or chronic) Anti HBe (not as contagious) ELISA - Anti HCV IgG (resolved or chronic) Gold Test: HCV RNA test w PCR - Early detection (1-2wk) - Viral RNA in blood is detected - Anti HDV IgM, IgG (active infection) IgG not a protective antibody for HDV - Anti-HEV IgM (active infection) - Anti-HEV IgG (recovery) - Vaxx w HBsAg (stimulated antibodies) - Prevented w serum Ig HBsAb - Interferon-α (antiviral cytokine) - Can be given to HBV, HDV - No vaxx - Vaxx for HBV protects from HDV - Supportive care, hydration, rest - Recovery time: 3-6wks - Rarely leads to chronic, normally (unless imm.comp) - No Vaxx Alcoholic Liver Dz Toxin-induced liver disease o Amount of alcohol to cause liver injury o Short-term ingestion of 80 g (6 beers or 8 ounces of liquor) of ethanol over one to several days § Leads to reversible steatosis (fat) o Daily intake of 80 g or more leads to a significant risk of severe hepatic injury o Daily ingestion of 160 g for 10-20 years consistently leads to severe injury Other factors influencing the severity and risk of developing alcoholic liver disease: o Gender § Women more susceptible § Majority of pts with alcoholic cirrhosis are men o African-American > Caucasians o Genetic factors o Co-morbid conditions such as HCV, HBV, HDV Cirrhosis seen only in HBV, HCV, HDV Usually one exchange/drink of alcohol contains 14g of ethanol Alcohol is always inflammatory Alcoholic Liver Dz: Alcohol Metabolism Pathway Normal Pathway: o Alcohol goes to stomach/small intestine o Absorbed into liver via portal vein by 80% o Alcohol goes to hepatocytes § Ethanol converted to Acetaldehyde by ADH § Acetaldehyde enters mitochondria, converted to Acetyl-CoA by ALDH § Acety-CoA enters krebs cycle, converted to Co2 and water § NAD+ acts as substrate, converts to NADH during ethanol metabolism Alcohol dehydrogenase: ADH Acetaldehyde dehydrogenase: ALDH Alcoholic Liver Dz: Ethanol in Binge drinkers (>6 drinks) In ER, ethanol converted to acetaldehyde via CYP2E1 enzyme (microsomal ethanol oxidizing system) CYP2E1 also produces ROS in response to other stimuli like smoking, release them to body ROS causes damage to proteins, some cancers NAD+ acts as substrate, converts to NADH during ethanol metabolism Binge Drinkers (H202/Catalase) o Ethanol enters peroxisome, becomes acetaldehyde and water via H2O2/Catalase rxn o Amount of NAD+ reduced, NADH increased Acetaldehyde important for beta oxidation, fatty acid synthesis High NAD+ allows for fatty acid oxidation into usable substrate (FA -> acetyl CoA) High NADH activates Acetyl-CoA synthesis pathway o Acetyl Coa à FA synthesis stored as triglycerides in the liver o Causes fatty liver Ethanol damages and kills normal bacteria in the gut o ROS from MEOS o Increase in fat storage increased due to inc NADH o LPS produced from bacteria dying in small intestine leads to liver cirrhosis § LPS produced as inflammatory response from Kupffer cells, § LPS goes into circulation then to liver to cause inflammation Ethanol causes steatosis, dysfunction of mitochondrial and cellular membranes, disrupts cytoskeletal function, oxidative stress and decreased perfusion of hepatocytes o Decreased perfusion of sinusoids: § Alcohol stimulates endothelin release § Causes vasoconstriction, contraction of stellate cells § Increases pressure in portal vein Alcoholic Liver Dz Hepatic steatosis (fatty liver) o Reversible o Gross-yellow, greasy liver in severe steatosis o Microscopic-micro-vesicular lipid droplets in hepatocytes becomes Macro-vesicular globules with chronic intake o Nucleus pushed to periphery by fat Alcohol Hepatitis o Hepatocyte swelling (ballooning) and necrosis: due to fat, water and protein (keratin protein aggregates) o Mallory-Denk bodies: keratin protein aggregates o Neutrophilic reaction o Alcoholic Steatofibrosis; begins with central vein sclerosis, then spreads outward toward portal triad (chicken wire fence pattern) and eventually links to the portal tract and condenses into central-portal fibrous septa § Cirrhosis develops in ~10 to 15% § Laennec cirrhosis: term used for cirrhosis due to alcoholic liver disease Alcoholic steatosis and steatofibrosis o Mix of micro and macro fat droplets (seen as clear vacuoles) is most prominent around the central vein and extends outward to the portal tracts o Some fibrosis (stained blue) is present in a characteristic perisinusoidal chicken wire fence pattern. (Masson trichrome stain) Alcoholic cirrhosis: o Characterized by fibrosis and conversion of the liver architecture into micro/macro nodules o Fibrosis seen around nodules Mallory Body Alcoholic Liver Dz: Diagnosis and Treatment Keratin protein in aggregate cytoplasm of dying hepatocyte Diagnosis o Liver function tests o Blood tests o An ultrasound, CT or MRI scan of the liver o A liver biopsy, if other tests and imaging don't give a clear diagnosis or if you are at risk of other causes of hepatitis o Liver Biopsy is gold standard Treatment Goals o Quit drinking o Medications o Counselling Life threatening (cirrhosis)à liver transplant Non-Alcoholic Fatty Liver Dz The most common cause of chronic liver disease in the US Spectrum of diseases that goes from least to most severe: o Steatosis (least) o Steatohepatitis (inflammation from fat) o Fibrosis o Cirrhosis (most) NAFLD results from fat deposition in the liver, and it is NOT related to alcohol OR viral causes (HAV, B, C, D, E) Affects Individuals with metabolic syndrome that includes 3 of the 5 diagnoses: o Obesity Insulin Resistance: o HTN o Diabetes Insulin receptors become less o Hypertriglyceridemia responsive to insulin released o Hyperlipidemia (↑ LDL, ↓ HDL) Since metabolic syndrome has become very common, hence so has NAFLD (increased dramatically affecting children) Affects men and women equally NAFLD pathogenesis is unknown (strong association with insulin resistance) o Insulin resistance causes increased release of free fatty acids which are taken up by the liver and stored as TG o Increased de novo lipogenesis in hepatocytes Widespread steatosis: o Large o Soft o Liver lobes will be Yellow o Greasy Know Pathway to Over time, the fat in the hepatocytes becomes vulnerable to degradation Steatohepatitis o Unsaturated FA (with at least one double bond) have H that are especially vulnerable to initiators like ROS (Hydroxyl radical.OH with an unpaired electron) § Hydroxyl radical pairs with the vulnerable lipid hydrogen to make water and FA radical § The FA radical is unstable and reacts with non-radicals (molecular O2 and undamaged FA) § This goes on, until one radical species reacts with another radical species, terminating the reaction § Damages lipid membranes -> mitochondrial dysfunction and eventually cell death Cell death will generate inflammation, presence of steatosis and inflammation à STEATOHEPATITIS In the absence of alcohol, this is called non-alcoholic steatohepatitis or NASH Morphology of NAFLD has same features as alcoholic liver disease: o Isolated fatty liver - macrovesicular and microvesicular steatosis o Non-alcoholic steatohepatitis (NASH) § Steatosis (>5% of hepatocytes, main diff from alcoholic FLD) § Lobular inflammation § Ballooned hepatocytes § May develop chicken wire fibrosis § Cannot reliably distinguish NASH from alcoholic hepatitis § General: Histology Alcoholic hepatitis has less steatosis Macro and micro vesicular steatosis More ballooned hepatocytes Chicken wire Fibrosis Lobular inflammation Mallory-Denk bodies in ballooned Neutrophilic infiltrate (Damage attracts neutrophils) hepatocytes in nonalcoholic Cholestasis steatohepatitis Chronic steatohepatitis can cause stellate cells to lay fibrotic tissue àFibrosis May progress to cirrhosis NAFLD Symptoms Even at advanced stages there maybe no symptoms When symptoms are present, they are vague such as fatigue and malaise Once Liver damage is significant: o Hepatomegaly o Pain in UR quad o Jaundice o Ascites: Accumulation of fluid in the peritoneal cavity o AST ALT liver enzymes increased (Nash: á ALT Alcohol Liver Disease: á AST) AST/ALT ratio is < 1 in NASH but > 2 in alcoholic hepatitis Non-Alcoholic Fatty Liver Dz: Diagnosis Diagnosis: o Imaging studies: An ultrasound, CT or MRI (look for fatty infiltrate) o Blood tests (AST and ALT) o A liver biopsy can be used to assess the severity of the disease o Liver with more > 5 % fat content is considered abnormal Treatment Goal: reverse insulin resistance o Healthy diet and active lifestyle o Medications that control blood glucose levels if needed Life-threatening (cirrhosis) à liver transplant Fat deposited in liver from NAFLD ↓ Steatosis ↓ Steatosis Hepititis ↓ Fibrosis ↓ Cirrhosis