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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