HEPATITIS Dr. FERDA ÖZKAN. Objectives and Aim To learn the types of inflammatory diseases of liver...
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Transcript of HEPATITIS Dr. FERDA ÖZKAN. Objectives and Aim To learn the types of inflammatory diseases of liver...
HEPATITIS
Dr. FERDA ÖZKAN
Objectives and Aim
To learn the types of inflammatory diseases of liver
To learn the inflammatory changes in liver
Inflammatory diseases Viral Hepatitis Autoimmune Hepatitis Fulminant Hepatitis Postnecrotic Cirrhosis Liver Abscesses.
Secondary infections: miliary tuberculosis,
malaria, staphylococcal bacteremia,
the salmonellosis, candida,
amebiasis.
Viral Hepatitis
Viral Hepatitis: Specific – Hepatitis A, B, C, D, E, &
others Systemic - CMV, EBV, yellow fever.
Infection of the liver caused by a small group of viruses having a particular affinity for the liver.
However, the anatomic pathology is generally similar.
Systemic viral infections (1) Infectious mononucleosis (Epstein-
Barr virus), which may cause a mild hepatitis during the acute phase;
(2) Cytomegalovirus, particularly in the newborn or immunosuppressed patient;
(3) Yellow fever, which has been a major and serious cause of hepatitis in tropical countries.
Patterns of Viral Hepatitis Carrier state / Asymptomatic phase Acute hepatitis Chronic Hepatitis
Chronic Persistent Hepatitis (CPH)Chronic Active Hepatitis (CAH)
Fulminant hepatitis Cirrhosis
Acute viral hepatitisAcute viral hepatitisWidespread liver cell injury
cell swelling ("hydropic change"; "cloudy swelling"; "ballooning degeneration")
necrosis & lysis (individually or in small groups due to the viruses or to antibodies)
apoptosis (individual liver cells as eosinophilic Councilman bodies)
hypertrophy/hyperplasia of Kupffer cells
inflammatory cells (mostly lymphocytes,
macrophages) in the portal areas, and some among the hepatocytes,
portal inflammation and cholestasis
hepatocyte regeneration (purple cells with big nuclei; during the recovery phase).
Patterns of Liver Damage
Porto-portal Bridging fibrosis
Porto-central fibrosis
Apoptotic body
Piece meal necrosis Centrilobulary
necrosis
Trichrome stain demonstrates the collapse of the liver parenchyma with viral hepatitis.
The blue-staining areas are the connective tissue of many portal tracts that have collapsed together
1. Carrier state: (a) without clinically apparent disease (b) with chronic hepatitis
2. Asymptomatic infection: serologic evidence only
3. Acute hepatitis: (a) anicteric (b) icteric.
4. Chronic hepatitis: without or with progression to cirrhosis.
5. Fulminant hepatitis: submassive to massive hepatic necrosis.
Councilman body
Viral hepatitis. A large pink cell undergoing
"ballooning degeneration" is seen below the right arrow.
Hepatitis A ("infectious
hepatitis“; HAV) Usually self-limited, RNA enterovirus (picornavirus), is transmitted by the fecal-oral route,
poor sanitation. Hepatitis A very seldom becomes
chronic or leads directly to cirrhosis. There is probably no carrier state. At worst, the disease might be a trigger
for autoimmune chronic hepatitis, but the virus won't stay around.
Hepatitis B Virus (HBV), serum
hepatitis World's most serious DNA-virus-related
health problem millions of carriers, Route:
blood transfusions, shared needles hospital (cuts, needle sticks) sex bugs vertical transmission (mother-to-child).
HBV can produce (1) acute hepatitis, (1) acute hepatitis, (2) chronic nonprogressive hepatitis, (2) chronic nonprogressive hepatitis, (3) progressive chronic disease ending (3) progressive chronic disease ending
in cirrhosis, in cirrhosis, (4(4) fulminant hepatitis with massive ) fulminant hepatitis with massive
liver necrosis, liver necrosis, (5) an asymptomatic carrier state with (5) an asymptomatic carrier state with
or without progressive diseaseor without progressive disease,,(6) (6) hepatocellular carcinoma.hepatocellular carcinoma.
Carrying hepatitis B (with or without on going liver disease) is an important cause of :hepatocellular carcinomaimmune complex, type III immune injury problemscryoglobulinemia polyarteritis nodosa of hepatitis B
Symptoms beginSymptoms begin when T-cells when T-cells are activated are activated with with
HBsAg and HBcHBsAg and HBc start killing the hepatocytesstart killing the hepatocytes Histopathologists find T-cytotoxic Histopathologists find T-cytotoxic
cells where the hepatocytes are cells where the hepatocytes are dying. dying.
TThe only surviving liver cells are he only surviving liver cells are the ones that won't continue the ones that won't continue making viruses, and these replenish making viruses, and these replenish the liver.the liver.
Hepatitis C Virus (non-A, non-B hepatitis)
Route: intravenous drug abusers (50 to 90%) blood transfusion (55 to 85%) hemodialysis (8 to 24%) Hospitals & dental clinics (cuts, needle sticks) vertical transmission (mother-to-child)
Patients with unexplained cirrhosis and hepatocellular carcinoma have anti-HCV prevalence rates exceeding 50%
In contrast to HBV, HCV has a high rate of progression to chronic disease and eventual cirrhosis, exceeding 70%
HHallmarksallmarks:: ppersistent infectionersistent infection,, chronic hepatitis,chronic hepatitis,ccirrhosis.irrhosis.
Chronic hepatitis graded by the degree of activity (necrosis and inflammation) and staged by the degree of fibrosis. necrosis
and inflammation are prominent, and there is some steatosis
Viral hepatitis C which is at a high stage with extensive fibrosis and progression to
macronodular cirrhosis, as evidenced by the large regenerative nodule at the center right.
Hepatitis D (HDV; hepatitis delta virus) Common in homosexual men and iv
drug-abusers. 1.Acute coinfection: occurs following
exposure to serum containing both HDV and HBV.
2. Superinfection of a chronic carrier: HBV with a new inoculum of HDV. The carrier may have been previously
“healthy” or may have had underlying chronic hepatitis.
Chronic Viral Hepatitis 1. Chronic persistent hepatitis:
inflammation is confined to the portal tracts.
2. Chronic active hepatitis: portal tract inflammation spills into the parenchyma and surrounds regions of necrotic hepatocytes.
3. Chronic lobular hepatitis: persistent inflammation is confined to the lobule.
Chronic Viral Hepatitis : as a complication
HAV: Extremely rare.
HBV: more than 90% of infected neonates 5% of infected adults one-fourth progress to cirrhosis.
HCV: more than 50% of infected patients half progress to cirrhosis.
HDV: most frequent outcome of HDV
superinfection.
Viral Hepatitis: Microbiology
Virus HAV HBV HCV
Agent ssRNA dsDNA ssRNA
Transmission Feco-oral Parenteral Parenteral
Carrier state None 0.1-1.0% 0.2-1.0%
Chronic Hepatitis None 5-10% >50%
The morphology of chronic hepatitisranges from exceedingly mild to severe,
to eventual cirrhosis. Mildest form (inflammatory infiltrate is
limited to portal tracts): lymphocytes, macrophages, occasional plasma cells, occasional rare neutrophil or eosinophil liver architecture is usually well
preserved but may exhibit vestiges of acute disease.
Progressive formPiecemeal necrosis, the chronic inflammatory infiltrate spills
out from portal tracts into adjacent parenchyma,
necrosis of hepatocytes lobular inflammation with focal necrosis
of hepatocytes. Continued loss of hepatocytes results in
fibrous septum formation,accompanied by hepatocyte regeneration, cirrhosis.
Autoimmune (lupoid) Hepatitis
without chronic virus infection but with evidence of immune injury
chronic hepatitis cirrhosis most common autoantibodies against
smooth muscle. Usually features a lot more plasma
cells than does viral chronic hepatitis.
Female predominance (70%), particularly young and perimenopausal women.
The absence of viral serologic markers.
Elevated serum IgG levels. High serum titers of autoantibodies in
80% of cases:anti-smooth muscle (SMA),antinuclear (ANA), antimitochondrial (AMA),anti-liver and kidney microsome (LKM)
antibodies.
Fulminant Hepatitis Hepatic insufficiency progresses from
onset of symptoms to hepatic encephalopathy (within 2 to 3 weeks),
Drug or chemical toxicity (25 to 30%): acetaminophen (in suicidal doses), isoniazid, antidepressants (particularly monoamine
oxidase inhibitors), halothane, methyldopa, mycotoxins (Amanita phalloides).
Fulminant hepatic failure may present with
jaundice, encephalopathy, fetor hepaticus, coagulopathy and bleeding instability, cardiovascular instability, renal failure, adult respiratory distress syndrome, electrolyte and acid-base disturbances, sepsis.
Hepatic failure within 2-3 weeks. Reactivation of chronic or acute hepatitis Massive necrosis, shrinkage, wrinkled Collapsed reticulin network Only portal tracts visible Little or massive inflammation – time More than a week – regenerative activity Cholestasis (blotchy green bile staining) Complete recovery – or - cirrhosis.
Histologically Necrosis
destroying the central and midzonal regions and sparing the periportal area of the lobule.
Complete destruction of contiguous lobules
There may be surprisingly little inflammatory reaction except possibly for an increase in
lymphocytes, macrophages, occasional neutrophils within the portal
tracts.
Survivors:secondary regeneration of
hepatocytes (primitive ductules)Kupffer cell proliferation (laden with
lipofuscin and cellular debris)nodular masses of liver cells broad bands of scar tissue postnecrotic cirrhosis.
Postnecrotic Cirrhosis Irregularly sized nodules (some several
centimeters in diameter) separated by variable but mostly broad
scars. Common causes:
Previous viral infection Hepatotoxin:
phosphorus carbon tetrachloride mushroom poisoning
Drugs: acetaminophen, oxyphenisatin, alpha-methyldopa.
Liver Abscess
The organisms reach the liver via (1) the portal vein, (2) arterial supply, (3) ascending infection in the biliary
tract (ascending cholangitis), (4) direct invasion of the liver from a
nearby source, (5) a penetrating injury.
Most abscesses are pyogenic, The majority of hepatic abscesses used
to result from portal spread of intra-abdominal infections:
appendicitis, diverticulitis, colitis.
Others:amebic, echinococcal, helminthic.
Biliary abscesses:usually multiple, purulent material in adjacent bile ducts.
Pyogenic hepatic abscesses: Solitary or multiple lesions,
Solitary abscess: direct extension and trauma usually cause a solitary large abscess,
Multiple small abscesses: bacteremic spread through the arterial or portal system tends to produce from millimeters to massive lesions many centimeters in diameter.
Complications
Sepsis & Pyemia Rupture
Rupture thoracic cavity: empyema lung abscess.
Rupture of subcapsular liver abscesses:
peritonitis localized peritoneal abscesses.
Drug-Induced and Toxin-Induced Liver Disease
Liver the major drug-metabolizing and drug-detoxifying organ subject to potential damage.
Injury may result from (1) direct toxicity; (2) hepatic conversion of a xenobiotic to an
active toxin; (3) via immune mechanisms,
usually when the drug or a metabolite acts as a hapten to convert a cellular protein into an immunogen.
The injury may be immediate or take weeks to months to develop, presenting only after severe liver damage has developed.
The injury may take the form of hepatocyte necrosis, cholestasis, or insidious onset of liver dysfunction.
Drug-induced chronic hepatitis is clinically and histologically indistinguishable from chronic viral hepatitis.
Exposure to a toxin or therapeutic agent should be included in the differential diagnosis of any form of liver disease.
Drugs: Acetaminophen
(paracetamol, "Tylenol") overdose
Acetaminophen + alcohol
Stimulants: Cocaine,Ecstasy & Amphetamine
Isoniazid Methyldopa Arsenic (as for syphilis
therapy)
Chemicals: Carbon tetrachloride Chloroform Phosphorus
Nature: Mushrooms
Amanita phalloides (the death angel)
There is extensive hepatocyte necrosis seen here in a case of acetaminophen overdose. The hepatocytes at
the right are dead, and those at the left are dying. This pattern can be seen with a variety of hepatotoxins. Acute liver failure leads to hepatic encephalopathy
Alcoholic Liver disease
Ethyl alcohol : Common cause of acute/chronic liver disease
Alcoholic Liver disease - PatternsFatty change, Alcoholic hepatitis (Mallory hyaline bodies)Alcoholic Hepatic fibrosis Alcoholic Cirrhosis
All reversible except cirrhosis stage.
Alcoholic Liver Injury: Pathogenesis
Diversion of fat & carbohydrate metabolism to alcohol – fat storage.
Acetaldehyde – metabolite – hepatotoxic Increased peripheral release of fatty
acids. Alcohol stimulates collagen synthesis Inflammation, Portal bridging fibrosis Micronodular cirrhosis.
Alcoholic Liver Disease (1) hepatic
steatosis
(2) alcoholic hepatitis and
alcoholic hepatic fibrosis
(3) cirrhosis
Alcohol intake: Moderate small
(microvesicular) lipid droplets in hepatocytes
Chronic lipid accumulates large clear macrovesicular spaces compressing and displacing the nucleus to the periphery
This transformation is initially centrilobular, but in severe cases, it may involve the entire lobule.
Alcoholic steatosis (alcoholic fatty
liver) Alcohol hepatocytes make too much
fatty acid make it into excess triglyceride instead of burning it can't complex the triglyceride to apolipoproteins can't export the lipoproteins Microvesicular steatosis.
Reversible. Microvesicular steatosis (smaller
vacuoles, usually several per cell): Alcoholic fatty liver, Reye's syndrome, Problem pregnancies, Mitochondrial problems Outdated-tetracycline poisoning.
Early phase of abuse:Enlarged (up to 4 to 6 kg), soft, yellow-
tan, greasy organ, little or no fibrosis.
Alcoholic Fatty Liver
Alcoholic hepatitis Serious. Dying liver cells in the centrilobular regions Mallory's alcoholic hyaline in the surviving liver
cells masses of altered prekeratin fibers plus stress
proteins, free Mallory's hyaline is chemotactic for neutrophils.
Minor scarring. Cholestasis:
bile lakes, bile plugs, regeneration of the bile ducts within the portal
areas.
Complications: Jaundice, Hepatic
encephalopathy, Portal
hypertension GI bleeding Deaths from
general anesthetics,
Differential diagnosis: Amiodarone (heart-
drug), Post-ileal bypass
hepatitis, Wilson's disease, East Indian
childhood cirrhosis, Non-alcoholic
steatohepatitis (NASH).
Mallory's alcoholic hyaline
Alcoholic cirrhosis ("Laennec's
cirrhosis“) Advanced scarring
fibrosis and nodules with proliferated bile ducts in the scar tissue small liver.
Early Laennec's cirrhosis has fine bands and a micronodular pattern.
Late, the pattern becomes post-necrotic.
Chronic alcohol abuse: fibrous tissue around the central veins extends into the adjacent sinusoidsa brown, shrunken, nonfatty organ sometimes less than 1 kg in weight
Regenerative activity of the entrapped parenchymal acini uniformly sized “micronodules.”
With time, the nodularity becomes more prominent scattered nodules become quite large occasionally nodules more than 2 cm in diameter may develop.
Fibrous septae dissect and surround nodules the liver becomes more fibrotic loses fat shrinks.
Parenchymal islands engulfed by bands of fibrous tissue mixed micronodular and macronodular patterns.
Ischemic necrosis and fibrous obliteration of nodules pale scar tissue leaving residual parenchymal nodules (protrude like “hobnails” from the surface of the liver) Laennec’s cirrhosis
Microscopy: Scattered
lymphocytes Reactive bile duct
proliferation in the septae
Bile stasis Mallory bodies
(rarely at this stage)
End-stage alcoholic cirrhosis (postnecrotic cirrhosis).
Inborn Errors of Metabolism and Pediatric Liver Disease
Hemochromatosis Wilson’s Disease 1–antitrypsin
deficiency Reye’s Syndrome Neonatal
Hepatitis
Hemochromatosis
Greatly increased absorption of iron from the gut (duodenum).
Excessive accumulation of body iron,
in the parenchymal cells, particularly liver pancreas
Fully developed cases exhibit a classical triad of: (1) micronodular
cirrhosis (2) diabetes mellitus
(bronze diabetes) (3) skin
pigmentation (bronze diabetes).
Iron accumulates as ferritin and
hemosiderin in the parenchymal
tissues of the body: liver, pancreas, myocardium, endocrine glands synovial membrane, bone marrow.
Liver: golden-yellow
hemosiderin granules Prussian blue reaction
(+) slightly larger than
normal, dense, chocolate brown. Fibrosis (micronodular
cirrhosis pigment cirrhosis
hepatocellular carcinoma.
Pancreas: intensely pigmented, interstitial fibrosis, parenchymal atrophy
glucose intolerance diabetes.
Additional Endocrine injuries:
loss of libido (testicular atrophy secondary to pituitary failure),
loss of secondary sex characteristics,
loss of testosterone osteoporosis.
Heart: enlarged, hemosiderin,
granules within the myocardial fibers,
brown coloration, delicate interstitial
fibrosis. Pump failure and/or
rhythm disturbances
Dilated cardiomyopathy.
Skin: excessive melanin
pigmentation, hemosiderin in
dermal macrophages and fibroblasts (metallic, slate-gray pigmentation).
Sepsis: Vibrio vulnificans Pasteurella
pseudotuberculosis Yersinia
enterocolitica E. coli
Secondary hemochromatosis: Sideroblastic
anemia, Thalassemia, Hemolytic anemias, Excess iron from
transfusions.
Wilson’s Disease
“hepatolenticular degeneration” Autosomal
recessive accumulation of
toxic levels of copper liver, brain, eye.
Liver: May exhibit only fatty
change and focal hepatocyte necrosis.
More severe disease: acute hepatitis (with
Mallory bodies) or chronic hepatitis
cirrhosis Histology cannot reliably
distinguish Wilson’s disease from viral-induced and drug-induced hepatitis (and vice versa).
Brain: Toxic injury to
neurons, most marked in the
basal ganglia, particularly the putamen,
leading to grossly visible cavitations.
Others: joints, proximal renal
tubuli, red cells (mild
hemolysis).
Eyes:Kayser-Fleischer
rings appear in the cornea green-to-brown
deposits of copper in Desçemet’s membrane (close to the limbus of the cornea)
are characteristic but not pathognomonic of Wilson’s disease
they may be found in other forms of chronic cholestasis.
1–antitrypsin deficiency
Autosomal recessive abnormally low
serum levels of major protease inhibitor (Pi).
leads to the development of: pulmonary disease
(emphysema) hepatic disease
(cholestasis or cirrhosis).
1 -AT small amino acid glycoprotein
major function is the inhibition of proteases, particularly neutrophil
elastase released at sites of cell injury and inflammation.
The predominant site of 1-AT synthesis is in hepatocytes with some synthesis in
macrophages.
Microscopy: round-to-oval cytoplasmic
globular inclusions of impounded 1-AT in hepatocytes
Reye’s Syndrome Rare; only in children characterized by
Fatty change in the liver
Encephalopathy. Develops 3 to 5 days
after a viral illness, The major pathologic
findings are in the liver and brain.
Liver: microvesicular hepatic
steatosis, Brain:
cerebral edema.
Mitochondrial damage.
Skeletal muscles, kidney, and heart may also reveal microvesicular fatty change.
Extreme elevations of serum ammonia.
Neonatal cholestasis Prolonged conjugated
hyperbilirubinemia in the neonate (neonatal cholestasis). Causes:
(1) cholangiopathies, extrahepatic biliary
atresia (2) disorders causing
conjugated hyperbilirubinemia.
Extrahepatic biliary atresia ("EHBA") birth defect common bile duct
and/or hepatic ducts ("extrahepatic") and/or many larger intra-hepatic ducts are without lumens.
Extrahepatic biliary atresia, o inflammation with stricture of hepatic or common bile
ductso marked cholestasis with intrahepatic bile duct
proliferation, fibrosis, and cirrhosis.
Extrahepatic biliary atresia with numerous brown-green bile plugs, bile duct
proliferation (seen at lower center), and extensive fibrosis.
Neonatal hepatitis The morphologic features of neonatal
hepatitis are as follows: 1. focal liver cell necrosis 2. giant cell transformation of hepatocytes 3. hepatocellular and canalicular
cholestasis 4. mild mononuclear infiltration of the
portal areas 5. reactive changes in the Kupffer cells 6. extramedullary hematopoiesis.
Neonatal giant cell hepatitis. o lobular disarray with focal hepatocyte
necrosis, o giant cell transformation, o Lymphocytic infiltration, o Kupffer cell hyperplasia,
Hepatotoxic substances
Drugs Causing Hepatic necrosis: Acetaminophen
("Tylenol") Alpha-methyldopamine Fenfluramine Halothane Hydrazine
Drugs causing Cholestasis: Anabolic steroids Chlorpromazine Estrogens
Cholestasis and thrombosis
Drugs causing hepatic Inflammation: Oxyphenisatin
("lupoid hepatitis“)
Methotrexate Pennyroyal
("holistic herbal tonic" / amateur abortifacient)
Amiodarone
Drugs Causing
Fatty change: Ethanol Isoniazid Tetracycline
(outdated) Total parenteral
nutrition
Drugs causing Granulomatous reaction in liver
Phenylbutazone Quinidine Allopurinol Carbamazepine Diltiazem Hydralazine
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