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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)
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
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
INFLAMMATORY LIVER DISEASES (HEPATITIS)
- ACUTE HEPATITIS
- Acute Liver Failure (Fulminant Hepatic Necrosis)
- ASCENDING CHOLANGITIS
- CHRONIC HEPATITIS
- Alcoholic Liver Disease
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
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!
- 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.
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.
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.
Hepatitis D Virus
- Special RNA virus that expresses HBsAg, the surface antigen of another virus.
- Also expresses delta antigen.
- 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.
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.
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.
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.
Convalescent Phase of acute hepatitis
- Macrophages come in and phagocytose apoptotic hepatocytes.
- Liver cells regenerate
Healed liver from acute hepatitis shows no fibrosis, nothing shows up in the trichrome stain.
Cholestatic hepatitis show low levels of aminotransferases, low inflammation, low cell death, increased level of billirubin, jaundice.
- 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.
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.
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
Alcoholic Liver Disease
Repeated bouts of Alcoholic Hepatitis causes Central vein sclerosis and progressive fibrosis, eventually develops into Cirrhosis
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)
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
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)
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
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.
- 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.
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
Symptoms of Ascending Cholangitis
- Similar to hepatitis
- pain, more prominent in the right upper quadrant
Laboratory finding of Ascending Cholangitis
- AST, ALT, alkaline phosphatase are all elevated (AST more than ALT)
- Leukocytosis (increased WBC) - particularly neutrophils
Course of Ascending Cholangitis
- Permanent periductal fibrosis, or if obstruction not relieved
- Develop into secondary biliary cirrhosis
- Mainly gram negative enteric bacteria, Candida, amebiasis
- Arise from ascending biliary tract infections or blood-borne
Causes of chronic hepatitis
- HCV infection - the major cause
- HBV +/- HDV
- Drug-induced (e.g. alphamethlyDOPA)
- Wilson's disease
- A1AT deficiency
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.
Special type of chronic hepatitis - Primary Biliary Cirrhosis (PBC)
Autoimmune disease: Granulomatous destruction of bile ducts causing cirrhosis and eventually death
Symptoms of chronic hepatits
- Similar to acute hepatitis plus fatigue or itching (PBC)
- Exacerbations and remissions
Laboratory features of chronic hepatitis
- Non-specific - ALT, AST increased (2-8 x normal)
- - 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)
- 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
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
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)
Laboratory findings of cirrhosis
- No major abnormalities or decreased serum albumin (& reversed A/G ratio)
- Decreased clotting factors (increased ProTime/ INR)
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
- Death usually due to bleeding varices, or pneumonia.
- 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.
Pathology of Hemochromatosis
- rusty look
- hemosiderin pigment
- Iron is demonstrated by Prussian blue
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.
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
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
- 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
- due to blockage of the portal vein by scarring
- Portal tributaries dilate
- Dilated spleen
- Esophageal vaices
Most common liver cancer is
- metastatic cancer
- Poor prognosis
- Rarely single discrete
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
Malignant Epithelial Tumors of Liver
- Hepatocellular carcinoma (HCC) - most common worldwide, relatively uncommon in US
- Cholangiocarcinoma (CC) - asian; parasites in bile duct.
Benign Stromal Tumors of Liver
- Mesenchymal hamartoma
- Inflammatory pseudotumor
- Peliosis hepatis
Malignant Stromal Tumors of Liver
- Angiosarcoma - occupational disease, working with vinyl chloride (PVC) without adequate protection
- Embryonal SA
Etiological Associations of Hepatocellular Carcinoma
- Hepatitis B virus
- Hepatitis C virus
- Cirrhosis (e.g. Hemochromatosis)
- Anabolic steroids
- Tyrosinemia/A1AT deficiency
Symtoms or signs of Hepatocellular Carcinoma
- Bloody ascites
- upper abdominal fullness
- jaundice or none
Laboratory findings of Hepatocellular Carcinoma
- Alpha-fetoprotein in serum
- increased AST, ALT
Course of Hepatocellular Carcinoma
- Metastasizes early (to lungs, heart, bone)
- Highly fatal within 1-2 yrs
Pathology of Hepatocellular Carcinoma
- Single lesion in non-cirrhotic liver
- In cirrhotic liver, there can be multiple tumors
- May produce bile
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)
- 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.
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
Alcohol abuse results in hyperstimulated alcohol dehydrogenase, affecting cytochrome pathways, leading to liver disease.
Phenobarbital is a nonspecific stimulator of the cytochrome pathway.
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)
Pathology of Drugs-Toxins Induced Liver Diseases
- Cholestasis - greenish tint to the cells, bile
- Fatty change
- Hepatitis - blotchy blue area, eosinophils, associated with hypersensitivity.
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
Diseases of the Gallbladder
- 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
Cholelithiasis is commonly associated with
Cholecystitis (mainly chronic, can also be acute)
Symptoms of cholecystitis
Right upper quadrant pain, particularly after a fatty meal
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
Course of cholecystitis
Persistent inflammation and stones may eventually cause carcinoma of the gallbladder
Acute and Chronic Cholecystitis related to the presence of stones or calculi in the gall-bladder or duct (cholelithiasis)
- can occur, much rare
- possibly due to ischemia
Acute hemorrhagic cholecystitis
- three f's - female, forty, fat
- caused by cholelithiasis
- most common indication for intra-abdominal surgery in US
Tumor of gallbladder is extremely rare
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)
Other tumors of gallbladder
- Squamous cell carcinoma
- malignant melanoma