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TRUE LIVER FUNCTION TESTS
- Test the capability of liver to synthesize and store
- Serum bilirubin: direct and indirect (mg/dL)
- Total serum proteins (except gamma-globulin) (g/dL)
- Albumin/globulin ratio - around 2:1, won't change until >90% of liver is destroyed
- Prothrombin time (secs., patient/control>1); INR (International normalized ratio)
- Serum cholesterol (mg/dL)
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LIVER “DAMAGE” TESTS - contents release after cell damage
- Serum aminotransferases (transaminases) (U/L)
- - Alanine aminotransferase (ALT) (SGPT is the old term): only found in liver
- - Aspartate aminotransferase (AST) (SGOT) - found in liver and muscle
- Serum alkaline phosphatase (ALP) (U/L)
- - 5’ nucleotidase
- Gamma-glutamyltransferase (GTP) (GGTP) (U/L) - only found in liver
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MISCELLANEOUS LIVER FUNCTION TESTS:
- Viral markers - HAAg, HBsAg, HBeAg, HBcAg, HDAg (Delta antigen); anti-HA; anti-HBs anti-HBc; anti-HC, quantitative HCV
- Anti-smooth muscle antibody (SMA), antinuclear Ab - autoimmune hepatitis
- Anti-mitochondrial antibody (AMA) - primary biliary cirrhosis
- Alpha-fetoprotein (AFP) (ng/mL) - hepatocellular carcinoma
- Transferrin, ferritin (mg/dL, ng/mL) - hemochromatosis
- Alpha-1-antitrypsin (A1AT) (mg/dL) - A1AT-deficiency
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INFLAMMATORY LIVER DISEASES (HEPATITIS)
- ACUTE HEPATITIS
- Acute Liver Failure (Fulminant Hepatic Necrosis)
- ASCENDING CHOLANGITIS
- ABSCESSES
- CHRONIC HEPATITIS
- Alcoholic Liver Disease
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ACUTE HEPATITIS - Causes
- Hepatitis A, B, C, D, E and other hepatotrophic viruses - Epstein-Barr virus, Herpes simplex virus, CMV, adenovirus
- Miliary tuberculosis, other bacteria
- Parasites (e.g. amebic abscess)
- Alcohol and other toxins
- Drugs - particularly anesthetic agents; also INH, Dilantin
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ACUTE HEPATITIS - Pathology
- Depends on the etiology
- All cause apoptosis of hepatocytes, some type of inflammation, and cholestasis (non-specific)
- Viruses: mononuclear cells, ballooning degeneration of hepatocytes + fatty change (Hep. C) +/- virus-specific inclusions (Herpes, CMV, Adenovirus)
- Tuberculosis: granulomas
- - Parasites: eosinophils +/- granulomas
- - Bacteria: acute inflammation
- - Alcohol: acute inflammation, fatty change, Mallory bodies (hyalin) -> Steatohepatitis
- **--Diabetes, Obesity -> Non-alcoholic steatohepatitis (NASH)
- - Toxins: acute inflammation, fatty change, zonal necrosis
- - Drugs: everything!
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Hepatitis A
- Caused by HAV, via feco-oral infection, most common with mini-outbreak.
- 99% Acute Hepatitis A have full recovery and complete immunity for future infection.
- The remaining either develops cholestasis and recover or develops fulminant hepatitis and recover or die from acute liver failure.
- Fever, malaise, jaundice, nausea, vomiting are classical signs of hepatitis (Not everyone gets the symptoms), however, when symptoms of acute hepatitis develop, the virus is almost cleared from the body.
- IgM increases, peaks, and decreases.
- IgG slowly raises and stays high during convalescence and recovery.
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Hep B Virus
- The only DNA virus among all hepatitis viruses
- Contains multiple antigen: surface (HBsAg), envelope (HBeAg), and core (HBcAg), can be detected when the patient is symptomatic.
- Moreover, the virus causes host cells to produce the virus' antigen in excess - surface (HBsAg) in sphere or in tubule when polymerized.
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Course of Hepatitis B virus infection
- 2/3 have subclinical disease (diagnosed accidentally), and recover completely.
- 1/4 develop acute hepatitis, 99% of which recover, and the remaining develop fulminant hepatitis and die.
- A small percentage are "healthy" carriers, symptoms free, due to lack of immune response, mainly mother-fetus infection, but eventually develop into hepatocellular carcinoma.
- A even smaller percentage of acute infection develop into persistent infection, majority of which have full recovery, the remaining develop into chronic hepatitis, which leads to cirrhosis, hepatocellular carcinoma, and death.
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Hepatitis D Virus
- Special RNA virus that expresses HBsAg, the surface antigen of another virus.
- Also expresses delta antigen.
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HDV infection
- Only occurs during coinfection with HBV or as a superinfection to HBV carriers
- In coinfection in healthy individuals, majority recover with immunity, some develop fulminant hepatitis and die, and rare cases develop into chronic HBV/HDV hepatitis and eventually cirrhosis.
- In superinfectino to HBV carriers, majority develops chronic HBV/HDV hepatitis and eventually cirrhosis, some have acute severe disease but recover, and some have fulminant hepatitis and die.
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Hepatitis C Virus
- Small single-stranded RNA virus
- 6 genotypes, vary with geography
- Most common bloodborne infection in U.S.
- Chronic infection is the most common indication for liver transplantation in U.S.
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Hepatitis C Virus Infection
- 3/4 develops subclinical disease, while 50% of which develops into chronic hepatitis
- 1/4 develops symptomatic disease, small percentage develops fulminant hepatitis, and 50% develops chronic hepatitis.
- 50% of chronic hepatitis become cirrhosis, which eventually die or become hepatocellular carcinoma and die.
- No immunity to HCV is developed. Even though the Anto-HCV is elevated, but non-neutralizing.
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During acute hepatitis - Micro
- inflammatory cell infiltration in the portal area, mononuclear for viral infection, neutrophils for alcoholic hepatitis.
- pale, swollen, ballooning hepatocytes under degeneration.
- The cells are impaired to excrete bile, results in elevated levels of billirubin, jaundice, cholestatsis.
- Liver cell apoptosis - contents leaked out, elevated serum level of aminotransferases. ALT greater than AST in virual infection. AST > ALT in alcoholic hepatitis.
- Fatty change - steatosis, vacuoles of fat, used to think it is due to alcoholism, now know it is associated with Hepatitis C.
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Convalescent Phase of acute hepatitis
- Macrophages come in and phagocytose apoptotic hepatocytes.
- Liver cells regenerate
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Healed liver from acute hepatitis shows no fibrosis, nothing shows up in the trichrome stain.
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Cholestatic hepatitis show low levels of aminotransferases, low inflammation, low cell death, increased level of billirubin, jaundice.
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Alchol metabolism
- Acetaldehyde is the intermediate of the breakdown of ethanol, and is toxic to the liver, causing the toxic effect.
- Fatty change without inflammation or cell death, levels of aminotransferases.
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Steatohepatitis - Micro
- also called alcoholic hepatitis.
- Fatty change.
- Mallory bodies - eosinophil clumps, precipitated intermediate filaments.
- PMNs - distinguish steatohepatitis from other hepatitis.
- Central vein sclerosis - Occludes the central vein and extends into the parenchyma. Thus, it's a central lobule disease, not portal disease.
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Alcoholic hepatitis =
- fatty change + PMNs + Mallory's bodies (hyalin) + central vein sclerosis
- Identical to non-alcoholic steatohepatitis (NASH), found in obese and type 2 diabetes.
- Liver function test findings - mildly raised aminotransferases (compared to viral infection); AST > ALT
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Alcoholic Liver Disease
Repeated bouts of Alcoholic Hepatitis causes Central vein sclerosis and progressive fibrosis, eventually develops into Cirrhosis
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Pathology of Alcoholic Liver Disease
- Fatty change (steatosis) only
- Fatty change + PMNs + Mallory’s hyalin + central vein sclerosis = steatohepatitis; same picture may be seen in non-alcoholics, e.g. Type II diabetics, Metabolic syndrome (Non-Alcoholic Steatohepatitis or NASH)
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Laboratory findings of alcoholic liver disease
- mildly increase AST and ALT (2 to 10 times normal level), AST more than ALT
- increased bilirubin
- increased GGT
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Acute Liver Failure - causes
- Toxin/Drug - e.g. CCl4, CCHI3, inorganic phosphorous, amanita mushroom, acetaminophen, halothane, etc.
- HBV +/- HDV
- HAV rare
- Reye's syndrome (children + flu + aspirin; no necrosis)
- Acute fatty liver of pregnancy
- Eclampsia (toxemia of pregnancy)
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Fulminant (Acute) Liver failure - Laboratory
- Elevated AST and ALT, then sudden drop when necrosis ceases due to total loss of parenchyma just before death
- Elevated serum NH3
- Elevated ProTime or INR due to loss of clotting factors
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Fulminant (Acute) Liver failure - Pathology
- Massive or zonal necrosis +/- fatty change
- Rarely microvesicular fatty change only (Reye's syndrome)
- Inflammation varies, either none or scattered PMNs or lymphocytes
- Shrunken liver
- Blotchy areas of hemorrhage
- Ghost outline of liver cells, no nuclei, all dead, no potential for regeneration.
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Ascending Cholangitis
- Inflammation in bile duct
- Happens when any part of extrahepatic biliary duct is obstructed, for any reason, usually by gallstones or tumors.
- Bile go upwards.
- Ascending infection (usually Gram negative) and inflammation.
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Pathology of Ascending Cholangitis
- Acute inflammation of the interlobular bile ducts; periductal edema
- if repeated, bile duct proliferation and periductal fibrosis
- May develop into abscesses
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Symptoms of Ascending Cholangitis
- Similar to hepatitis
- jaundice
- pain, more prominent in the right upper quadrant
- fever
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Laboratory finding of Ascending Cholangitis
- AST, ALT, alkaline phosphatase are all elevated (AST more than ALT)
- Leukocytosis (increased WBC) - particularly neutrophils
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Course of Ascending Cholangitis
- Permanent periductal fibrosis, or if obstruction not relieved
- Develop into secondary biliary cirrhosis
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ABSCESSES
- Mainly gram negative enteric bacteria, Candida, amebiasis
- Arise from ascending biliary tract infections or blood-borne
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Causes of chronic hepatitis
- HCV infection - the major cause
- HBV +/- HDV
- Autoimmune
- Drug-induced (e.g. alphamethlyDOPA)
- Wilson's disease
- A1AT deficiency
- Unknown
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Pathology of Chronic hepatitis
- Portal chronic inflammation
- Some parenchymal involvement, but less than acute.
- Interface hepatitis (piecemeal necrosis), parenchmal inflammation +/- apoptosis, periportal fibrosis leading to septa formation, bridging scarring, fibrosis, cirrhotic
- +/- fatty change
- Ground glass hepatocytes (if HBV carrier)
- Portal lymphoid nodules/follicles, may have germinal center (if HCV)
- Aminotrasferases elevation is much lower than that of acute hepatitis.
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Special type of chronic hepatitis - Primary Biliary Cirrhosis (PBC)
Autoimmune disease: Granulomatous destruction of bile ducts causing cirrhosis and eventually death
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Symptoms of chronic hepatits
- Similar to acute hepatitis plus fatigue or itching (PBC)
- Exacerbations and remissions
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Laboratory features of chronic hepatitis
- Non-specific - ALT, AST increased (2-8 x normal)
- Specific:
- - Anti-HCV and HCV RNA titers (if HCV)
- - HBsAg and anti-HBeAg (if HBV)
- - Globulins, Anti-smooth muscle antibodies (SMA), anti-liver/kidney microsome antibodies (if autoimmune)
- - Antimitochondrial antibodies, alkaline phosphatase, cholesterol (primary biliary cirrhosis)
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Cirrhosis
- End stage of all chronic liver disease.
- Diffuse fibrosis of liver, eventually Nodules of regenerating hepatocytes surrounded by fibrous tissue septae, frequently associated with bile duct hyperplasia (micro - no more than 3 mm, macro - no less than 3 mm) - even palpatable when serious.
- Fibrous tissue septa.
- Bile duct hyperplasia except in primary biliary cirrhosis.
- Hepatic artery-portal vein shunting, leads to portal venous hypertension.
- Yellow, green appearance on the outside
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Common causes of Cirrhosis
- Chronic alcoholism/NASH - most common reason worldwide is alcoholism, NASH for US
- Chronic Hepatitis C Virus infection
- Chronic Hepatitis B virus infection
- Pigmentary disorders (inherited) - process usually begins soon after birth
- - hemochromatosis: disease presents in 5th decade; individuals have inability to store large amounts of iron.
- - Wilson’s Disease (Cu): disease presents in 2nd decade.
- Primary biliary cirrhosis, Primary sclerosing cholangitis (PSC)
- Extrahepatic obstruction (secondary biliary cirrhosis)
- Alpha-1-antitrypsin deficiency
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Signs of cirrhosis
- None or signs of impending liver failure, i.e. liver flap, disordered consciousness, jaundice, ascites.
- Esophageal varices
- May see kidney problems (so-called hepatorenal syndrome), bleeding (hemorrhagic) diathesis, tendency to lethal infections, (e.g. pneumonia), hepatic coma, drug toxicity, signs of female sex characteristics (e.g. gynecomastia)
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Laboratory findings of cirrhosis
- No major abnormalities or decreased serum albumin (& reversed A/G ratio)
- Decreased clotting factors (increased ProTime/ INR)
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Course of cirrhosis
- Depends on the cause: if the cause persists, e.g. chronic hepatitis or alcohol ingestion, develop into gradual liver failure or vascular shunts, cause portal vein hypertension, then esophageal varices which may rupture and bleed out; tendency to drug toxicity
- Some may develop hepatocellular carcinoma
- Bronchopneumonia
- Death usually due to bleeding varices, or pneumonia.
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Hemochromatosis
- Most common inborn error of metabolism
- Abnormality of iron metabolism, absorbed too much and iron is slowly accumulated, which leads to progressive tissue injury and eventually cirrhosis and liver failure.
- Majority diagnosed at late stage with cirrhosis (or fibrosis), which is preventable if early diagnosed. Screened.
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Pathology of Hemochromatosis
- rusty look
- hemosiderin pigment
- Iron is demonstrated by Prussian blue
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Primary biliary cirrhosis
- Autoimmune disease, predominately of middle-aged women, presents with itching due to irritation of the nerve endings by bile precipitates, no hives.
- Chronic hepatitis in which non-necrotizing
- granulomas destroy intralobular bile ducts, causing cholangiolar proliferation, causing Cu++ retention, leading to fibrosis and then cirrhosis.
- Liver function test findings: Increased alkaline phosphatase, antimitochondrial antibodies (AMA), mild aminotransferase elevation.
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Pathology of Primary biliary cirrhosis
- stage 1: periductal granuloma
- stage 2: portal inflammation, absence of bile ducts
- stage 3
- stage 4: cirrhosis, septum without bile ducts, vascular shunts between hepatic artery and portal vein
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Complications of cirrhosis
- Hepatic encephalopathy - accumulated ammonia in blood due to impaired capability of liver to metabolize ammonia
- Coagulopathy - problems with clotting protein production, bleed excessively.
- Frequent infection - poor metabolism
- Renal failure
- Endocrine - sex hormone metabolism is affected with cirrhosis, males develop female sex characteristcs, gynecomastia
- Tumors
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Ascites
- Hallmark of cirrhosis
- Accumulation of fluid in abdomen
- Decrease in albumin production, lower colloid oncotic pressure, together with blockage of lymphatics, result in fluid enter the extravascular space
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Portal hypertension
- due to blockage of the portal vein by scarring
- Shunting
- Portal tributaries dilate
- Dilated spleen
- Esophageal vaices
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Most common liver cancer is
- metastatic cancer
- Poor prognosis
- Rarely single discrete
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Benign Epithelial Tumors of Liver
- Hepatic cell adenoma (HCA) - caused by first-generation oral contraceptive; regresses after stop taking.
- Focal nodular hyperplasia
- Bile duct hamartoma
- Bile duct adenoma
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Malignant Epithelial Tumors of Liver
- Hepatocellular carcinoma (HCC) - most common worldwide, relatively uncommon in US
- Cholangiocarcinoma (CC) - asian; parasites in bile duct.
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Benign Stromal Tumors of Liver
- Hemangioma
- Mesenchymal hamartoma
- Angiomyolipoma
- Leiomyoma
- Inflammatory pseudotumor
- Peliosis hepatis
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Malignant Stromal Tumors of Liver
- Angiosarcoma - occupational disease, working with vinyl chloride (PVC) without adequate protection
- Embryonal SA
- LeiomyoSA
- Lymphoma
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Etiological Associations of Hepatocellular Carcinoma
- Hepatitis B virus
- Hepatitis C virus
- Aflatoxin
- Cirrhosis (e.g. Hemochromatosis)
- Anabolic steroids
- Tyrosinemia/A1AT deficiency
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Symtoms or signs of Hepatocellular Carcinoma
- Bloody ascites
- upper abdominal fullness
- jaundice or none
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Laboratory findings of Hepatocellular Carcinoma
- Alpha-fetoprotein in serum
- increased AST, ALT
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Course of Hepatocellular Carcinoma
- Metastasizes early (to lungs, heart, bone)
- Highly fatal within 1-2 yrs
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Pathology of Hepatocellular Carcinoma
- Single lesion in non-cirrhotic liver
- In cirrhotic liver, there can be multiple tumors
- May produce bile
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Drug/Toxic-Induced Liver Injury (DILI)
- 2–5% of all cases of jaundice in hospitalized patients
- 30-40% of acute liver (fulminant hepatic) failure either dying or coming to liver transplant (most common cause: acetaminophen toxicity)
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Drugs metabolism
- Phase I - produces active metabolite and inactive metabolite, and inactive metabolite is excreted via kidney.
- Phase II - active metabolite is conjugated and excreted via liver.
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Mechanisms of Drug-Toxin Induced Liver Disease
- Type I - Intrinsic (“predictable”):
- a) Direct - acetaminophen overdose
- b) Indirect: interference with a metabolic pathway or process
- Type II - Idiosyncratic (“unpredictable”):
- a) Hypersensitivity-related - halothane
- 1) Immediate: antibody-mediated
- 2) Delayed: cell-mediated
- b) Toxic-metabolite related - INH
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Alcohol abuse results in hyperstimulated alcohol dehydrogenase, affecting cytochrome pathways, leading to liver disease.
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Phenobarbital is a nonspecific stimulator of the cytochrome pathway.
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Pathologic Effects of Drugs-Toxins on the Liver
- May be acute or chronic
- Any type of liver disease may be induced, e.g. cholestasis, fatty change, acute/chronic hepatitis, fibrosis/cirrhosis, benign/malignant tumors.
- Liver may be the only organ affected or one of many affected organs or tissues.
- Injury is usually primary but occasionally may be secondary (e.g. EMH when there is bone marrow suppression)
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Pathology of Drugs-Toxins Induced Liver Diseases
- Cholestasis - greenish tint to the cells, bile
- Fatty change
- Hepatitis - blotchy blue area, eosinophils, associated with hypersensitivity.
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Drug-Induced Liver Injury
- Cholestasis: Anabolic steroids, phenothiazine derivatives, TPN
- Fatty change: Steroids
- Acute Hepatitis: INH (treating tuberculosis), Phenytoin (Dilantin)
- Acute Liver Failure: Acetaminophen (overdose), Halothane (Hypersensitivity)
- Chronic Hepatitis: α-methylDOPA (aldomet, treating hypertension), INH, nitrofurantoin (UTI)
- Fibrosis/Cirrhosis: Methotrexate
- Granulomatous Hep.: Allopurinol, Sulfa drugs
- Hepatic Cell Adenomas: oral contraceptives
- Hepatocellular Carcinoma: Anabolic steroids
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Diseases of the Gallbladder
- Cholelithiasis
- Cholecystitis
- Adenocarcinoma
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Cholelithiasis
- Precipitate of over-saturating cholesterol in patients with obesity and hypercholesterolemia - cholesterol gallstones.
- Precipitate of excess bilirubin due to hemolytic diseases, parasites, conjugated bilirubin - bilirubin stone (calcium bilirubinate).
- Some are asymptomatic, some lead to inflammation
- Pigmented stones are black or brown
- Frequently seen in “3 F's”
- most common indication for intraabdominal surgery in the U.S.
- May result from excessive bile salt resorption, increased serum bilirubin or cholesterol, or disturbance in the bile salt/cholesterol/lecithin relationships (so-called “lithogenic bile”)
- may be radio-opaque or radiolucent
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Cholelithiasis is commonly associated with
Cholecystitis (mainly chronic, can also be acute)
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Symptoms of cholecystitis
Right upper quadrant pain, particularly after a fatty meal
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Laboratory findings of cholecystitis
- Frequently no abnormality
- Sometimes associated with hemolytic anemia (increased bilirubin) or hypercholesterolemia
- If stone gets into the common duct, it may cause ascending cholangitis
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Course of cholecystitis
Persistent inflammation and stones may eventually cause carcinoma of the gallbladder
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Calculous cholecystitis
Acute and Chronic Cholecystitis related to the presence of stones or calculi in the gall-bladder or duct (cholelithiasis)
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Acalculous cholecystitis
- can occur, much rare
- possibly due to ischemia
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Acute hemorrhagic cholecystitis
- three f's - female, forty, fat
- caused by cholelithiasis
- most common indication for intra-abdominal surgery in US
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Tumor of gallbladder is extremely rare
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Carcinoma of the Gallbladder
- Induced by cholelithiasis
- Elderly patients
- Invades directly into or metastasized to the liver, inoperable, Poor prognosis
- Cholangiocarcinoma (bile ducts) is related to liver fluke infections, PSC (Primary sclerosing cholangitis)
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Other tumors of gallbladder
- Squamous cell carcinoma
- malignant melanoma
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