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chronic liver disease path
GI
40
Medical
Graduate
09/13/2010

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Term
what is cirrhosis?
Definition
the end stage of chronic liver disease, similar to fibrosis - but more extensive and organized, it consists of *fibrous septa surrounding regenerative nodules of hepatocytes resulting from persistent necrosis. there are multiple causes w/alcohol and hep B/C being amoung the most common.
Term
what are the common causes of cirrhosis?
Definition
alcohol, nonalcoholic fatty liver disease, chronic hepatitis, biliary disease (obstruction, primary biliary cirrhosis, and sclerosing cholangitis), and metabolic disease
Term
how is cirrhosis described morphologically?
Definition
by the size of the nodules: macro/micro
Term
what is micronodular cirrhosis? what is the most common cause?
Definition
micronodular (laennec) cirrhosis describes nodules less than *3 mm and is usually due to alcohol
Term
what is macronodular cirrhosis? what is the most common cause?
Definition
macronodular cirrhosis describes nodules more than *3 mm and is most often associated with chronic hep B/C
Term
can micronodular cirrhosis progress to macronodular?
Definition
yes, they may coalesce or result from confluent submassive necrosis
Term
what is the pathogenesis of cirrhosis?
Definition
collagen *types I and III deposit irreversibly in lobules - giving the liver a firm, hard, nodular, shrunken consistency. new vascular channels shunt around the parenchyma and there is loss of fenestrations in the endothelial cells lining the sinusoids.
Term
what does cirrhosis result in?
Definition
impaired secretion of proteins such as albumin, clotting factors and lipoproteins. clinically this increases risk of ascites formation (clear, straw-colored liquid in the peritoneal cavity), increased bleeding from decreased/impaired clotting factors, fatty liver due to impaired lipoprotein transport, and esophageal varicies (from shunting blood/increased pressure)
Term
what is a major source of collagen in the liver?
Definition
the *perisinusoidal stellate cells (ito cells) which normally function as vit A storage cells, but in the *presence of alcohol*, activate and increase mitotic activity, transforming to the *myofibroblast phenotype and increase production of extracellular matrix.
Term
what role do the kupffer cells play in fibrosis?
Definition
the kupffer cells secrete cytokines which stimulate the stellate cells including: TNF (contraction), IL-1, PDGF (contraction, chemotaxis), TGF beta (fibrogenic), ET-1 (contraction), and MCP-1 (chemotaxis).
Term
how does abnormal blood/bile flow happen in cirrhosis?
Definition
the hepatocytes may regenerate and proliferate as spheroid nodules, disrupting liver architecture
Term
what are the clinical features of cirrhosis?
Definition
anorexia, wt loss, debilitation, jaundice, pulmonary O2 impairment, complications of portal HTN, and development of hepatocellular CA
Term
what % of pt have problems related to alcohol abuse?
Definition
30%
Term
what are the different kinds of alcoholic liver disease?
Definition
hepatic steatosis (fatty change, perivenular fibrosis, reversible w/alcohol decrease), alcoholic hepatitis (liver cell necrosis, inflammation, mallory bodies, fatty change, results from severe alcohol exposure/steatosis, still potentially reversible), and cirrhosis (results from steatosis or hepatitis - irreversible fibrosis/hyperplastic nodules),
Term
what characterizes hepatic steatosis?
Definition
this can be due to DM pts or those on parenteral nutrition (NASH) as well as alcoholism and is due to *shunting of normal substances away from catabolism and toward lipid biosynthesis, which leads to increased mobilization of triglycerides, impaired assembly/secretion of lipoproteins, and increased peripheral catabolism of fat.
Term
how does hepatic steatosis start, what can it progress to?
Definition
hepatic steatosis may begin as *microvesicular, but progress to macrovesicular (displaces the nucleus to the periphery of the cell - DO NOT confuse w/micro-macronodular). steatosis is *reversible and has a fatty/greasy gross appearance, but if alcohol intake continues, fibrosis may begin to develop.
Term
what can hepatic steatosis result in?
Definition
some hepatomegaly, mild elevation of serum bilirubin/alk phos levels. severe hepatic dysfunction is unusual and death can occur in severe cases.
Term
what characterizes alcoholic hepatitis?
Definition
there is hepatocyte swelling and necrosis from the accumulation of fat, water and proteins. there may be cholestasis (greenish tint) present, accumulations of hemosiderin in hepatocytes/kupffer cells (golden brown), mallory bodies (cytokeratin intermediate filaments, other proteins), neutrophilic response, and sinusoidal/perivenular fibrosis separating the parenchyma (early, but stellate cells/portal tract fibroblasts are activated)
Term
how does alcoholic hepatitis appear?
Definition
mottled red w/bile stained areas
Term
what characterizes alcoholic cirrhosis?
Definition
initially the liver is yellow-tan fatty/enlarged, but it will progress to a shrunken brown, relatively non-fatty organ (this progression may occur quicker in the presence of alcoholic hepatitis). fibrotic septae progress from portal to portal, from sinusoids to central vein, until nodules form. fat is progressively lost, there is bile stasis and there are less mallory bodies at this stage.
Term
what are the clinical manifestations of alcoholic liver disease?
Definition
cirrhosis causes disruption/back flow of circulation surrounding the liver resulting in esophageal varices, caput medusae, hemorrhoids, spider angiomata, hepatic encephalopathy, splenomegaly (seen in almost everyone w/cirrhosis), as well as testicular atrophy (problems w/sex hormone metabolism) and malnourishment (prominent wasting of extremities)
Term
what causes alcohol to be toxic?
Definition
alcohol *impairs methionine, decreasing glutathione levels - making the liver more prone to oxidative injury. alcohol also *induces CYP, inducing toxic metabolites of drugs and ROSes. alcohol affects *microtuble/mitochondrial function. *acetaldehyde, a major metabolite of alcohol induces lipid peroxidation - injuring hepatocytes' cytoskeleton and cell membrane. cumulatively this all elicits an *inflammatory and immune reaction.
Term
can alcohol act as a food source?
Definition
yes, but it lacks vitamins/protein
Term
how does alcohol affect gut bacteria?
Definition
alcohol induces gut bacteria to be pathogenic, leading to further inflammation to the liver
Term
how does alcohol affect blood flow to liver cells?
Definition
alcohol induces endothelin release, which vasoconstricts - reducing blood flow to liver cells
Term
what are the clinical features of alcoholism?
Definition
initially asymptomatic, progressing to malaise, anorexia, wt loss, malnutrition, tender hepatomegaly, hyperbilirubinemia, increased LFTs, increased alk phos (damage to biliary ducts), hypoproteinemia, and a distended abdomen, muscle wasting, and jaundice.
Term
what are causes of death related to alcohol abuse?
Definition
younger: usually accident/OD. hepatic coma (due to decreased perfusion), massive GI hemorrhage (ruptured esophageal varices, acute gastritis, mallory-weiss tears), aspiration pneumonia (fall asleep when intoxicated - worse due to HCl), hepatorenal syndrome (kidney problems due to liver), hepatocellular CA, trauma (encephalopathy and shrinking of brain (so get larger subdural space) predisposing to a subdural hematoma), positional asphyxia
Term
what is hemochromatosis?
Definition
excessive accumulation of body iron, which can be primary/secondary. primary: due to genetic defect (autosomal recessive mutation on chr 6 - defect in HFE, an iron absorption regulatory gene that produces hepcidin) in *intestinal absorption of iron and secondary: sickle cell, hemolytic anemia, excessive transfusions
Term
what is the morphology of hemochromatosis?
Definition
hemosiderin deposits in the liver, pancreas and heart - leading to cirrhosis, pancreatic fibrosis, skin pigmentation, and deposition in synovial joint linings.
Term
what are clinical features of hemochromatosis?
Definition
primary type is seen in males. cirrhosis might be the initially presenting symptom, along with dark skin pigmentation and diabetes. *triad: liver abnormalities/hemoglobin problems/glucose intolerant* increased risk of hepatocellular CA. if secondary, you know the pt is getting too much iron from transfusions.
Term
what is wilson's disease?
Definition
disease of Cu deposition, which can occur in the liver (acute hepatitis, chronic hepatitis, cirrhosis), brain, and eye (kayser-fleisher rings on the cornea) resulting from the inability to properly excrete Cu into the bile.
Term
what is alpha1-antitrypsin deficiency?
Definition
alpha1-antitrypsin is a pleomorphic anti-elastase plasma glycoprotein and if have deficiency, the elastase progresses more rapidly. this is both a liver and lung disease. w/this deficiency, hepatocytes *retain cytoplasmic inclusions. pts with this have an increased risk of chronic hepatitis or cirrhosis as well as an increased risk of HCC.
Term
what are the genetics of alpha1-antitrypsin deficiency?
Definition
the gene for alpha1-antitrypsin is located on chr 14. the most common genotype is PiMM (good) and the most common genetic mutation is associated with a decrease in circulating levels is PiZ (bad).
Term
what is the pathogenesis of alpha1-antitrypsin deficiency?
Definition
alpha1-antitrypsin accumulates in the ER of hepatocytes, which causes an autophagic response, mitochondrial dysfunction, and *possible activation of pro-inflammatory NF-kB - leading to hepatocyte damage
Term
how can alpha1-antitrypsin deficiency be diagnosed?
Definition
a liver bx will show PAS+ (Periodic acid-Schiff stain) globules in a periportal area typically (also associated with wegener’s granulomatosis, bronchiectasis, and arterial aneurysms)
Term
what is neonatal hepatitis?
Definition
usually idiopathic, this consists of jaundice in the neonatal period (1wk-2 mos), focal necrosis, and giant cell transformation. long term prognosis is not good.
Term
what is reye's syndrome?
Definition
significant fatty liver infiltration and encephalopathy - associated with elevated serum ammonia levels and *ASA administration. fatty change may also occur in skeletal/cardiac muscle and the kidneys. it can be lethal, but most pts recover
Term
what is secondary biliary cirrhosis?
Definition
pts present with jaundice, pruritis, dark urine and itchiness due *conjugated hyperbilirubinemia as a result of some type of extrahepatic bile duct obstruction. can result in fibrosis/cirrhosis
Term
what is primary biliary cirrhosis?
Definition
an autoimmune disorder affecting mainly middle-aged women who have *antibodies against mitochondria leading to destruction of bile ducts - will see *increased levels of alkaline phosphatase and give rise to insidious liver failure.
Term
what is primary sclerosing cholangitis?
Definition
inflammation, fibrosis, dilation of obstructed bile ducts - *associated with IBD* and pts present with pruritis, fatigue, and jaundice. pts w/this have increased risk of *cholangiocarcinoma and the only definitive tx is liver transplant.
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