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Liver
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• Function:
1-Metabolic : Glucose
2-Synthetic : Albumin, clotting factors …..
3-Detoxification : Drugs, hormones , NH3
4-Storage : Glycogen, TG, Fe, Cu, vit
5-Excretory : Bile
2
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- Net wt. 1400 – 1600gm (2.5% of body wt)
- Blood supply:
Portal v : 60 – 70%
Hepatic a : 30 0 40%
- Microstructure
- Hexagonal lobules →6 acini
- Acinus is divided into 3 zones:
1-Zone 1
Periportal areas – closet to the vascular supply
2-Zone 3
Pericentral area
3-Zone 2
Inrermediate bet. Zone 1&2
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Normal Liver
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The parenbchyma is organized into plates of hepatocytes
Hepatocytes are radially oriented around terminal hepatic vein ( central v.)
-Hepatocytes show only minimal variation in the
overall size but nuclei may vary in size ,
number & ploidy esp. with advancing age
-Vascular sinusoids present bet. cords of hepatocytes
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Hepatic injury
1-Inflammation (Hepatitis)
2-Ballooning degeneration :
-irregularly clumped cytoplasm showing
large, clear spaces.
-Substances may accumulate in viable
hepatocytes, including fat, iron, copper,
and retained biliary material
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3-Steatosis ( fatty change)
microvesicular:ALD,Reye syndrome,acute
fatty change of pregnancy
macrovesicular:DM,obese
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fatty change
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4-Necrosis
- Depending on the type:
Coagulative necrosis :around central v.
Councilman bodies
Lytic necrosis
Depending on the cause
Ischemic
Toxic
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-depending on location Centrilobular necrosis:
Mid zonal :
Periportal : interface hepatitis
Focal:
Piece meal necrosis
bridging necrosis
Diffuse:
massive & submassive necrosis
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5-Regeneration
-evidenced by increased mitosis or cell
cycle markers.
-the cells of the canal of Hering are the
progenitor for hepatocytes & bile duct cells
(oval cells ).
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6-Fibrosis
-portal or periportal fibrosis
-pericentral- around the central vein.
-pericellular fibrosis or fibrous tissue may be deposited directly within the sinusoids around single or multiple hepatocytes
-bridging fibrosis
bridging fibrosis
7-Cirrhosis
micronodular
Macronodular
8-Ductular proliferation
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Hepatic Failure
-It results when the hepatic functional capacity is almost totally lost ( 80 – 90%)
-Causes
1.Massive hepatic necrosis
-Fulminant viral hepatitis
-Drugs & chemicals
acetominophen
halothane
anti TB drugs
CCL4 poisoning
Mushroom poisoning
2-Chronic liver disease
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3-Hepatic dysfunction without overt cirrhosis
-Reye’s syndrome
-Tetracyline toxicity
-Acute fatty liver of
pregnancy
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Clinical features
1-Jaundice
2-Hypoalbuminemia →edema
3-Hyperammonemia
4-Fetor hepaticus (musty or sweet & sour)
5-Palmar erythema
hyperestrogenemia
6-Spider angiomas
7-Hypogonadism & gynecomastia
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Consequences:
1-Multiple organ failure kidneys & lung
2-Coagulopathy → bleeding
def. factors II, VII, IX, X
3-Hepatic encephalopathy
↓level of conseiousness
Rigidity
Hyperreflexia
EEG changes
Seizures
Asterixis
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4-Hepatorenal syndrome
Renal failure in patients with severe liver
disease with no morpholagic or functional
causes for renal failure
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Massive hepatic necrosis
-Fulminant hepatic failure from the onset of symptoms to hepatic encephalopathy (within 2 -3 wks).
Subfulminant ( within 3 months).
Causes: 1-Viral hepatitis 50 – 65% ( B, B-D, A,C hepatitis)
2-Drugs & chemicals 20 – 30%
3-Heat stroke
4-Hepatic vein obstruction
5-Wilson disease
6-Acute fatty liver of pregnancy
7-Massive malignant infiltration
8-Reactivation of chronic HBV hepatitis on HDV superimposed infection
9-Autoimmune hepatitis
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Alcoholic liver disease
-Alcohol is most widely abused agent
-It is the 5th leading cause of death in USA due to :
1.accidents
2.Cirrhosis
-80–100 mg/dl is the legal definition for driving under the influence of alcohol
-44 ml of ethanol is required to produce this level in 70kg person
-Short term ingestion of 80 gms/d of ethanol is associated with fatty change in liver
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- In occasional drinkers, bl. Level of 200 mg/dl
produces coma & death & resp. failure at
300-400 mg/dl
-Habitual drinkers can tolerate levels up to 700
mg/dl without clinical effect due to metabolic
tolerance explained by 5-10X induction of
cytochrome P-450 system that includes
enzyme CYP2E1 which increases the
metabolism of ethanol as well as other drugs
as cocaine & acetominophen
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• Forms of alcoholic liver
disease 1-Hepatic steatosis (90-100% of drinkers)
2-Alcoholic hepatitis (1- 35% of drinkers)
3-Cirrhosis ( 14% of drinkers)
- Steatosis & hepatitis may develop
independently 28
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Hepatic steatosis
-Can occur following even moderate intake of
alcohol in form of microvesicular steatosis
-Chronic intake → diffuse steatosis
-Liver is large ( 4 – 6 kg) soft yellow & greasy
-Continued intake →fibrosis
-Fatty change is reversible with complete
absention from further intake of alcohol
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Alcoholic hepatitis
Characteristic findings :
1-Hepatocyte swelling & necrosis
-Accumulation of fat & water & proteins
-Cholestasis
-Hemosidrein deposition in hepatocytocytes & kupffer cells
2-Mallory-hayline bodies
-easinoplilic cytoplasmic inclusions in degenerating hepatocytes formed of cytokeratin infermediate filaments & other proteins
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Mallory-hayline bodies
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-Mallory-hayline inclusions are
characteristic but not pathognomonic of
alcoholic liver disease.
- they are also seen in :
1-Primary biliary cirrhosis
2-Wilson disease
3-Chronic cholestatic syndromes
4-Hepatocellular carcinoma
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3-Neutrophilic reaction
4-Fibrosis
-Sinusoidal & perivenular fibrosis
-Periportal fibrosis
5-Cholestasis
6-Mild deposition of hemosiderin in hepatocytes & kupffer cells
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Alcoholic cirrhosis
-Usually it develops slowly
-It can develop rapidly in the presence of alcoholic hepatitis (within 1-2 yrs).
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Ethanol metabolism
Ethanol → acetaldehyde
CH3 CH2OH CH3 C=O
H
↑
-Alcohol dehydrogenase
(stomach + liver)
-Cytochrome P-450
-Catalase ( liver)
-
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Acetaldehyde → Acetic acid
↑
Aldehyde dehydrogenase
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- After absorption ethanol is distributed as Acetic acid in all tissues & fluid in direct proportion to blood level
- Women have lower levels of gastric alcohol
dehydrogenase activity than men & they may
develop higher blood Levels than men after
drinking the same quantity of ethanol.
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- less than 10% of absorbed ethanol is excreted
unchanged in urine sweat & breathe
-There is genetic polymorphism in aldehyde
dehydrogenase that affect ethanol metabolism
e.g 50% of chinese , vietnamase & Japanese
have lowered enzyme activity due to point
mutation of the enzyme. → accumulation of
acetaldehyde → facial flushing, tachycardia &
hyperventilation.
•-
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Clinical features
-Hepatic steatosis ( reversible )
↑ liver
↑ liver enz.
Severe hepatic dysfunction is unusual
-Alcoholic hepatitis
. 15-20 yr. of excessive drinking
. Non-specific symptoms, malaise, anorexia, wt. loss
↑ liver & spleen
↑ LFT
Each bout of hepatitis →10-20% risk of death
→ cirrhosis in 1/3 in few yrs.
-Cirrhosis
Portal hypertension
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• Causes of death in alcoholic liver
disease
1-hepatic failure
2-Massive GI bleeding
3-Infections
4-Hepatorenal syndrome
5-HCC in 3-6% of cases
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Cirrhosis
• It is a diffuse process characterized by
fibrosis & the conversion of liver
parenchyma into nodules .
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• Main characteristics
1.Bridging fibrous septae
2.Parenchymal nodules encircled by fibrotic
bands
3.Diffuse architecture disruption
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• Types :
Micronodules < 3mm in diameter
Macronodules > 3 mm in diameter
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Micronodular cirrhosis
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Macronodular cirrhosis
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Cirrhosis
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Causes of cirrhosis
1.Chronic alcoholism
2.Chronic viral infection HBV & HCV
3.Biliary disease
4.Hemochromatosis
5.Autoimmune hepatitis
6.Wilson disease
7.α-1- antitrypsin deficiency
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8. Rare causes
Galactosemia
Tyrosinosis
Glycogen storage disease III &IV
Lipid storage disease
Hereditary fructose intolerance
Drug induced e.g methyldopa
9. Cryptogenic cirrhosis 10%
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Pathogenesis of cirrhosis
-The mechanism of cirrhosis involves:
1-Hepatocellular death
2-Regeneration
3-Progressive fibrosis
4-Vascular changes
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Cell death should occur over a long period
of time & accompanied by fibrosis
-In normal liver the ECM collagen (types I,
III,V& XI) is present only in :
Liver capsule
Portal tracts
Around central vein
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-delicate framework of type IV collagen &
other proteins lies in space of Disse
-In cirrhosis types I & III collagen & others
are deposited in the space of Disse
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The major source of collagen in cirrhosis is the perisinusoidal stellate cells (Ito cells) which lie in space of Disse
-Perisinusoidal stellate cells act normally as storage cells for vit A & fat
upon stimulation myofibroblast- like cells
↓
transforming growth factor β
(TGF-β)
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The stimuli for the activation of stellate cells
& production of collagen are :
1-Reactive oxygen species
2-Growth factors
3-Cytokines TNF, IL-I, lymphotoxins
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-The vascular changes include :
1-Loss of sinusoidal endothelial cell fenestration
2-development of vascular shunts as
Portal v- hepatic v
Hepatic a – portal v
→defect in liver function
-Loss of microvilli from hepatocytes →↓ transport
capacity of the cells
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-Clinical features of cirrhosis :
-Silent
-Anorexia, wt loss, weakness
-Complications :
1-Progressive hepatic failure
2-Portal hypertension
3-Hepatocellular carcinoma
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Portal hypertension
- ↑ resistance to portal blood flow at the level of
sinusoids & compression of central veins by
perivenular fibrosis & parenchymal nodules
- Arterial – portal anastomosis develops in the
fibrous bands →increase in the blood pressure
in portal venous system
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Causes of portal hypertension
I.Prehepatic 1-Portal vein thrombosis
2-Massive splenomegaly
II. Post hepatic
1-Severe Rt.- sided heart failure
2-Constrictive pericarditis
3-Hepatic vein out flow obstruction
III. Hepatic
1-Cirrhosis
2-Schistosomiasis
3-Massive fatty change
4-Diffuse granulomatosis as sarcoidosis, TB
5-Disease of portal microcirculation as nodular regenerative hyperplasia
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Clinical consequence of portal
hypertension
1-Ascitis
2-Portosystemic shunts
3-Hepatic encephalopathy
4-Splenomegaly
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Ascitis
-Collection of excess fluid in peritoneal cavity
-It becomes clinically detectable when at least 500 ml have accumulated
-Features
1-Serous fluid
2-Contains as much as 3g/ml of protein (albumin)
3-It has the same concentration as blood of glucose, Na+, & K+
4-Mesothelial cells & lymphocytes
5-Neutrophils = infection
6-RBCs = DISSEMINATED CANCR
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Pathogenesis 1-Sinusoidal ↑ Bp
2-Hypoalbuminemia
3-Leakage of hepatic lymph into the peritoneal cavity
Normal thoracic duct lymph flow is 800-1000 ml/d
in cirrhosis is 20L /d
4-Renal retention of Na+ & water due to 2ry hyperaldosteronism
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Portosystemic shunt
-Because of ↑portal venous pressure bypasses develop wherever the
systemic & portal circulation share capillary beds
-Sites:
1-Around & within the rectum (Hemorrhoids)
2-Gastroesophageal junction (varicies )
3-Retroperitoneum
4-Falciform ligament of the liver (periumbilical & abdominal wall
collaterals ) → caput medusae
- Gastroesophageal varicies appear in 65% of pts. with advanced
cirrhosis & cause death in 50% of then due to UG1 bleeding
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caput medusae
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Esophageal varicies
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Splenomegaly
-Usu. 500-1000 gms (N <300gms)
-Not necessarily correlated with other
features of portal ↑Bp
-May result in hypersplenism
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splenomegaly
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Hepatic encephalopthy
-It is a complication of acute & chronic hepatic failure
-Disturbance in brain function ranging from behavioural changes to
marked confusion & sutpor to deep coma & death
-The changes may progress over hrs. or days
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Neurological signs:
Rigidity
Hyper-reflexia
Non – specific EEG
Seizures
Asterixis ( non-rhythmic rapid extension flexision movements of head & extremities .
-Brain shows edema & astrocytic reaction
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Pathogenesis
-Physiologic factors important in development of hepatic
encephalopathy :-
1-Severe loss of hepatocellular function
2-Shunting of blood around damaged liver
↓↓
Exposure of Brain to toxic metabolic products
↑ NH3 level in blood → generalized brain edema impaired neuronal
function
alteration in central nervous system AA metabolism
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Drug – lnduced liver disease
-Drug reactions:-
1-Predictable (intrinsic)
2-Unpredictable (idiosyncratic)
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-Predictable drug reactions depends on the dose (dose-dependent)
-Unpredictable drug reactions depend on :
a-The immune response of the host to the antigenic stimulus
b-The rate at which the host metabolizes the agent
-The injury m.b immediate or takes weeks to months
-Drug-induced chronic hepatitis is clinically & histologically indistinguishable from chronic viral or autoimmune hepatitis
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Predictable drugs: Acetaminophen
Tetracycline
Antineoplastic agents
CCL4
Alcohol
Unpredictable drugs Chlorpromazine
Halothane
Sulfonamides
Methyldopa
Allopurinol
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-Mechanism of drug injury :
1-Direct toxic damage
e.g acetaminophen
CCl4
mushroom toxins
2-Immune-mediated damage
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-Patterns of injury
1-Hepatocellular necrosis
2-Cholestasis
3-Steatosis
4-Steatohepatitis
5-Fibrosis
6-Vascular lesions
7-Granuloma
8-Neoplasms benign & malignant
-
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Drugs that may cause acute liver failure
1-acetaminophen most common
2-Halothane
3-antituberculosis drugs (rifampin, isoniazid)
4-antidepressant monoamine oxidase inhibitors
5-toxins as CCL4 & mushroom poisoning
-
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Morpholagy:
Massive necrosis → 500 – 700 gm liver
Submassive necrosis
Patchy necrosis
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Infections of Liver
1-Viral infections a-I.M EBV
b-CMV
c-Yellow fever
d-Rubella , herpesvirus
e-Adenoviruses enterovirus
f-Hepatitis viruses A B C D E G
2-Miliary tuberculosis
3-Malaria
4-Staphylococcal bacteremia
5-Salmonelloses
6-Candida
7-Amebiasis
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Hepatitis A virus
-Infectious hepatitis
-Benign & self limited
-25% of clinically evident acute hepatitis
-I.P 15 to 50 days (average 28 days)
-HAV does not cause chronic hepatitis, carrier state & only rarely cause falminant hepatitis
-Fatality rate is 0.1%
-Superimposed HAV infection on chronic hepatitis due to HBV, HCV or alcohol is more severe
-Transmission : Feco-oral rout
-Endemic in developing countries with low hygiene & sanitation → anti-HAV Abs by the age of 10yrs. →50% by the age of 50yrs.
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-Clinically the disease is mild to asymptomatic
affecting children of school age & rare
thereafter
-The virus is shed in bile & feces
-The virus is shed is the stool 2-3 wks before &
1wk after the onset of jaundice
-HAV is not shed in saliva, urine, or semen
-HAV viremia is transient & bI. Donors are not
screened for the virus
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Serelogic dx
Anti HAV IgM: at the onset of symptoms
→ ↓ in few months
Anti HAV IgG:appears later & persists for
life
-HAV vaccine is effective
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• Detection of anti-HAV IgM antibody is the best
diagnostic marker for the disease;
• IgG antibody persists beyond convalescence
and is the primary defense against reinfection.
• there are no routinely available tests for IgG anti-
HAV, and therefore the presence of this type of
antibody is inferred from the difference between
total and IgM anti-HAV.
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• In the United States, the prevalence of seropositivity increases gradually with age, reaching 50% by age 50 years.
• Prevention and management of hepatitis A include
• (1) hygienic measures focused on the disposal of human wastes and personal hygiene
• (2) passive immunization with immune serum globulin for individuals exposed to the virus or those traveling to high-exposure areas.
• (3) pre-exposure prophylaxis using a virus-inactivated vaccine.
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Hepatitis B Virus
-HBV is a hardy virus can withstand
extremes of temperature & humidity
-Prolonged IP 4-26 wks
-Prolonged viremia
-Present in all body fluids as tears,
saliva, sweat, breast milk, vaginal sec.
semen & pathological body fluids
except stool
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Routes of transmission
Parenteral bl. & bl. products
dialysis
needle – stick accidents
IV drug abuse
Homosexual activity
Vertical transmission ( 20-60% of births to infected mothers)
Unknown source in 1/3 of cases
Contact with body secretions
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Epidemiology
.Carrier rate : 350 million – 400 million
75% in Asia & Western Pacific
.Chronic hepatitis B
> 8% in Asia, Western Pacific
2-7% in Southern & Easten Europe
< 2% in Western Europe , North America & Australia
-HBV vaccine is effective
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-Phases of infection :
1. Proliferative phase
2. Integrative phase
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HBV antigens :
1.HBc Ag -hepatocytes
2.HBe Ag -blood
3.HBs Ag -blood , hepatocytes
4.DNA polymerase (HBV-DNA) (reverse transcriptase activity)
5.HBx protein ( transcriptional transactivator )
-
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Serologic diagnosis
.Acute phase lasts from wks-months
.HBsAg: appers befor the onset of symptoms, peaks during
overt disease
dissappears in 3 – 6 months
.HBeAg:
HBV-DNA, DNA polymerase:
appears in serum soon after HBsAg
signifies active viral replication & persistent infection
.
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Anti – HBc IgM: appears in serum shortly before the onset of symptoms & replaced by IgG after a month
Anti – HBe Abs: shortly after the disappearance of HBeAg indicating the end of the infection
Anti – HBs IgG: rise after the acute phase is over & remains detectable after wks or months after disappearance of HBsAg
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Clinical syndromes associated with HBV
infection
1-Acute hepatitis with recovery
2-Nonprogressive chronic hepatitis
3-Progressive chronic hepatitis ending in cirrhosis
4-Fulminant hepatitis with massive liver necrosis
5-Asymptomatic carrier state
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Hepatitis C Virus
-The most common chronic blood-born infection & accounts
for almost 50% of all patients in USA with chronic liver
disease
-Asymptomatic acute hepatitis C occurs in 75% of cases
-l.p 2 – 26 wks
-Carrier rate 0.1 – 12%
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Routes of transmission :
Parenteral
.bl. Transfusion 4%
.Inoculation < 5% of cases
.IV drug use 40% of cases
. Sexual transmission low
Perinatal transmission 6% of birth to infected mother
Unknown source 40%
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epidemiology
-40000 new cases/yr in USA
-1.8% of the population ( 4 millions) are seropositive 70% of which have chronic liver disease
-Anti HCV IgG occuring after active infection do not confer effective
immunity due to genomic instability of the virus & antigenic variability
-Anti HCV vaccine is not effective
-Repeatd bouts of HCV infection are common causing hepatic damage
is characteristic due to reactivation of a pre existing infection or emergence of
newly mutated strains
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• Clinical syndromes associated with HCV:
• 1.Persistent infection with subclinical or asymptomatic acute infection
• 2.Chronic hepatitis
• 3.Fulminant hepatitis
• 4.Cirrhosis 20%
• 5.Hepatocellular carcinoma
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Serological diagnosis
-I.P 2 – 26 wks ( mean 6 – 12 wks)
HCV RNA is detectable in bl. For 1 – 3 wks
peak coincides with ↑ in serum transaminases
-Anti HCV Abs detected in 50 – 70% of patients during
symptomatic acute infection
In 30 – 50% of patients the anti HCV Abs emerge
after
3 – 6 wks
-In chronic HCV infection circulating HCV-RNA persists
despite the presence of Abs in many patients ( >
90%)
-Episodic elevations in serum aminotransferases with
intervening normal or near-normal periods is quite
characteristic of HCV infection
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Hepatitis D Virus
-Hepatitis delta virus
-Replication defective virus
-Causes infection only when it is
encapsulated by HBsAg
-Routes of transmission:
Parenteral (close personal contact)
-I.P 4 – 7 wks in superinfection
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Epidemiology Prevalence rate : 20 – 40% in Africa, Middle east &
Southern Italy ( carriers of HBsAg)
1-10% in USA commonly in drug
addicts & hemophilics
Low risk in homosexuals & health care
workers, HBsAg carriers in south east
Asia & China
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Serologic diagnosis
.HDV-RNA is detectable in blood & liver just prior
to & in early days of acute symptomatic disease
.Anti HDV IgM = recent HDV infection
.Anti HDV IgM appears late & freq. short-lived
.Coinfection : IgM against HDV Ag & HBV Ag
.Superimposed infection: anti HDV IgM & HBsAg
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Hepatitis E virus
- Water-borne infection
- Young – middle – aged adults
- Rare in children
- Endemic infection in India, Africa, Mexico……
- Sporadic infection is uncommon & occurs mainly in
travelers
- Self-limiting mild disease except in pregnant women with
high mortality rate (20%)
- I.P: 6 wks ( range 2-8wks)
- No chronic liver disease or carrier state
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Serelogy
-HEV-RNA can be detected in stool & liver before the onset of clinical symptoms
-Anti HEV-IgM appears during acute illness & replaced by IgG when symptoms resolve (ie in 2 – 4 wks)
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Clinicopathologic Syndromes
1-Acute asymptomatic with recovery : serologic
evidence only A B C D E
2-Acute symptomatic hepatitis with recovery anicteric
or icteric
A B C D E
3-Chronic hepatitis with or without progression to
cirrhosis
B & C
4-Fulminant hepatitis with massive or submassive
hepatic necrosis B, D veryrare , A & C
5-Chronic carrier state
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Acute asymptomatic infection with
recovery
-Minimally ↑ serum tranaminases
-HAV & HBV infections are freq. subclinical
in childhood period
-HCV infection is subclinical in 75% of the
cases
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Acute symptomatic infection with recovery
-Can be caused by any hepatotropic viruases although it is uncommon in HCV infection
-Phases:
1-Incubation period
2-Symptomatic preicteric phase
.Malaise
.General fatigability
.Nausea
.Loss of appetite
.Fever, headaches, muscle pain, diarrhea
.10% of pts. Develop serum sickness-like synd. esp. with HBV infection (fever, rash, arthralgia ) due to circulating immune complexes
-
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3-Symptomatic icteric phase
.Usual in adults but not children with HAV
.Absent in 50% of cases of HBV & the majority of HCV
.Conj.hyperbilirubinemia, dark colored urine , pruritis
.Prolonged PT, hyperglobulinemia, ↑ serum alkaline phosphatase
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Fulminant hepatitis
Hepatic in sufficiency that progresses from onset of symptoms to
hepatic escepholopathy in 2-3 wks
Subfulminant ( up to 3 mon)
Causes :
1-Viral hepatitis 50 – 65%
HBV 2x > HCV
2-Drays & chemical 25- 50%
e.g Isoniazid , halothane , methyldopa & acetominophen
3-Obstruction of hepatic vein
4-Wilson’s disease
5-Acute fatty change of pregnancy.
6-Massive tumor infiltration
7-Reactivation of chronic hepatitis B
8-Acute immune hepatitis
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• Morphology
-↓ liver size ( 500 – 700 gm)
-Necrosis of hepatocytes
-Collapsed reticulin tissue
-Inflammatory infillrate
-Regenerative activity of hepatocytes
-Fibrosis
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Chronic Hepatitis
-Symptomatic, biochemical or serelogic evidence of
continuing or relapsing hepatic disease for more than 6 months with histologically documented inflammation & necrosis
-Progressive or non progressive
-HBV , HCV, HBV-HDV
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• Morphology of chronic hepatitis -Mild to severe
1.Protal inflammation
2.Lymphoid aggregate
3.Necrosis of hepatocytes-councilman bodies
4.Bile duct damage
5.Steatosis
6.Interface hepatitis
7.Bridging necrosis & fibrosis
8.Fibrosis
9.Ground-glass appearance
10.Sanded nuclei
11.Lobular disarray
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Carrier state
1.Serelogical evidence of viral infection but no clinical or histological effects
2.Serelogical evidence of viral infection, chronic liver disease but free of symptoms
3.Clinically symptomatic chronic disease
-Vertical transmission →90 – 95% carrier state
-Immune deficiency ↑ the risk of development of carrier state
-HBV, HCV, ?HDV
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