liver - med study groupmsg2018.weebly.com/uploads/1/6/1/0/16101502/giliver_1.pdf• ↑ liver •...
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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 - 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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Normal liver
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Cross section of normal liver
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Liver zones
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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-Degeneration :
ballooning degeneration
feathery degeneration:retained biliary
material
accumulation of iron ,copper
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3-Steatosis ( fatty change)
microvesicular:
ALD
Reye syndrome
acute fatty change of pregnancy
macrovesicular:
DM
obesity
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Fatty change
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fatty change
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4-Necrosis
- Depending on the type:
Coagulative necrosis
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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Necrosis of liver
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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
bridging fibrosis
7-Cirrhosis
micronodular
Macronodular
8-Ductular proliferation
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CLINICAL SYNDROMES
• The major clinical syndromes of liver
disease are:
• 1-hepatic failure
• 2-cirrhosis
• 3-portal hypertension
• 4-cholestasis.
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liver failure
• The alterations that cause liver failure
fall into 3 categories:
• 1- Acute liver failure with massive hepatic necrosis
• 2- Chronic liver disease
• 3- Hepatic dysfunction without overt necrosis.
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1-Acute liver failure.
• This is most often caused by drugs or
fulminant viral hepatitis.
• Acute liver failure denotes clinical
hepatic insufficiency that progresses
from onset of symptoms to hepatic
encephalopathy within 2 to 3 weeks.
• A course extending as long as 3
months is called subacute failure.
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• The histologic correlate of acute liver failure is massive hepatic necrosis.
• It is an uncommon but life-threatening
condition that often requires liver
transplantation.
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2-Chronic liver disease
• This is the most common route to
hepatic failure and is the end point of
relentless chronic liver damage ending
in cirrhosis.
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Hepatic dysfunction without -3.overt necrosis
• Hepatocytes may be viable but unable
to perform normal metabolic function:
• 1- Acute fatty liver of pregnancy (which
can lead to acute liver failure a few
days after onset)
• 2- Tetracycline toxicity
• 3- Reye syndrome
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Clinical features
1-Jaundice
2-Hypoalbuminemia →edema
3-Hyperammonemia
4-hyperestrogenemia
5-Spider angiomas
6-Hypogonadism & gynecomastia
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Complications:
1-Multiple organ failure e.g lung
2-Coagulopathy → bleeding
def. factors II, VII, IX, X
3-Hepatic encephalopathy
4-Hepatorenal Syndrome
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Alcoholic liver disease
-Alcohol is most widely abused agent
-Excessive ethanol consumption causes more
than 60% of chronic liver disease in most
Western countries and accounts for 40-50%
of deaths due to cirrhosis.
-It is the 5th leading cause of death in USA due
to :
1.Accident
2.Cirrhosis
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Pathogenesis
• Short-term ingestion of as much as 80 gm of ethanol/d (8 beers or 7 ounces of 80-proof liquor) generally produces mild reversible hepatic changes.
• Chronic intake of 50 to 60 gm/day is considered a borderline risk for severe injury.
• Women seem to be more susceptible to hepatic injury than are men because of low gastric metabolism of ethanol and differences in body composition.
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-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
-In occasional drinkers, bl. Level of 200
mg/dl produces coma & death & resp.
failure at 300-400 mg/dl
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- 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
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Hepatic steatosis -Can occur following even moderate intake of
alcohol in form of microvesicular steatosis
- initially centrilobular but in severe cases it may
involve the entire lobule .
-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
-Hemosiderin deposition in hepatocytocytes & kupffer cells
2-Mallory-hayline bodies
-eosinoplilic 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 hepatitis
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Cholestasis
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Alcoholic cirrhosis
-Usually it develops slowly
-Initially the liver is enlarged yellow but over years it becomes brown shrunken non-fatty organ
s.t < l kg in wt.
-Micronodular → mixed micro & macronodular
-Laennec cirrhosis = scar tissue
-Bile stasis
-Mallory bodies are only rarely evident at this stage
-Irreversible
-It can develop rapidly in the presence of alcoholic hepatitis (within 1-2 yrs).
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Liver cirrhosis
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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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Mechanism of ethanol toxicity
1-Fatty change a-Shunting of lipid catabolism toward lipid bio-synthesis
due to excess production of NADH over NAD in cystol & mitochondria
b-Acetaldehyde forms adducts with tubulin & ↓ function of microtubules → ↓ in lipoprotein transport from liver
c- ↑ peripheral catabolism of fat → ↑ FFA delivery to the liver
d- ↓ sec. of lipoproteins from hepatocytes
e. ↓ oxidation of FFA by mitochondria
2-Induction of cytochrome P-450 enhances the metabolism of drugs to toxic metabolites (e.g acetominophen )
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3. ↑free radicals production due to activation of cytochrome P-4so leads to membrane & protein damage
4. Alcohol directly affect microtubular & mitochondrial function & membrane fluidity
5.Acetaldehyde causes lipid peroxidation & antigenic alteration of hepatocytes → immune attack
6. Superimposed HCV infection causes acceleration of liver injury (HCV hepatitis occurs in 30% of alcoholics )
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7. Alcohol → release of bacterial endotoxins into portal circulation from the gut → inflammation of the liver
8. Alcohol → regional hypoxia in the liver due to release of endothelins which are potent vasoconstrictors → ↓ hepatic sinusoidal perfusion
9. Alteration of cytokine regulation
TNF is a major effector of injury
IL6 IL8 IL18
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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
• Hepatosplenomegaly
• ↑ 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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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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• The development of cirrhosis requires
that cell death occur over long periods
of time and be accompanied by
fibrosis.
• Fibrosis progresses to scar formation
when the injury involves not only the
parenchyma but also the supporting
connective tissue.
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-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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• Vascular changes consisting of the
loss of sinusoidal endothelial cell
fenestrations and the development of
portal vein-hepatic vein and hepatic
artery-portal vein vascular shunts
contribute to defects in liver function.
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• Collagen deposition converts sinusoids
with fenestrated endothelial channels
that allow free exchange of solutes
between plasma and hepatocytes to
higher pressure fast-flowing vascular
channels without such solute
exchange.
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• The movement of proteins (e.g.,
albumin, clotting factors, lipoproteins
between hepatocytes and the plasma is
markedly impaired.
• These functional changes are
aggravated by the loss of microvilli
from the hepatocyte surface which
diminishes the transport capacity of the
cell.
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- The major source of collagen in cirrhosis is the perisinusoidal stellate cells (Ito cells) which lie in space of Disse
- Ito cells are perisinusoidal stellate cells act normally as storage cells for vit A & fat .
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• Activated stellate cells produce growth
factors, cytokines, and chemokines
that cause their further proliferation
and collagen synthesis.
• TGF-β is the main fibrogenic agent for
stellate cells.
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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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-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 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-Ascites
2-Portosystemic shunts
3-Hepatic encephalopathy
4-Splenomegaly
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Ascites
-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
N- thoracic duct lymph flow is 800-1000 ml/d
in cirrhosis it may approach 20L /day
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
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Caput medusae-abdominal skin
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Esophageal varicies
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- Gastroesophageal varicies appear in
65% of pts. with advanced cirrhosis &
cause death in 50% of then due to UGI
bleeding.
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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
flexion 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
-Acute insult : ↑ NH3 level in blood → generalized brain edema
impaired neuronal function
-Chronic insult: alteration in central nervous system aminoacid
metabolism
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Hepatorenal Syndrome
• appears in individuals with severe liver
disease.
• consists of the development of renal
failure without primary abnormalities of the
kidneys themselves.
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• Excluded by this definition are concomitant
damage to both liver and kidney, as may
occur with exposure to CCL4 and certain
mycotoxins and the copper toxicity of
Wilson disease.
• Also excluded are instances of advanced
hepatic failure in which circulatory collapse
leads to acute tubular necrosis & acute
renal failure. 85
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• Kidney function promptly improves if
hepatic failure is reversed.
• The exact cause is unknown.
• Systemic vasoconstriction leading to
severe reduction of renal blood flow
particularly to the cortex.
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• Onset of this syndrome is typically by a
drop in urine output associated with rising
BUN and creatinine values.
• The renal failure may increase the risk of
death in the patient with acute fulminant or
advanced chronic hepatic disease.
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Drug – lnduced liver disease
-Drug reactions:
1-Predictable (intrinsic)
2-Unpredictable (idiosyncratic)
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• Predictable drug reactions may occur in
anyone who accumulates a sufficient dose
(dose-dependent).
• Unpredictable reactions depend on
idiosyncrasies of the host:
• 1-the host's propensity to mount an immune
response to the antigenic stimulus.
• 2-the rate at which the host metabolizes the
agent.
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• The injury may be immediate or take weeks to months to develop.
• drug-induced chronic hepatitis is clinically and histologically indistinguishable from chronic viral hepatitis or autoimmune hepatitis and hence serologic markers of viral infection are critical for making the distinction.
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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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• Pattern of Injury Morphology Examples
• Cholestatic Bland hepatocellular cholestasis,
without inflammation Contraceptive
Anabolic steroids
• Cholestatic hepatitis Cholestasis with lobular
necroinflammatory activity Antibiotics; Phenothiazines
• Hepatocellular Spotty hepatocyte necrosis Methyldoya, Phenytoin
necrosis
Submassive necrosis, zone 3 Acetaminophen
Halothane
• Massive necrosis Isoniazid, Phenytoin
• Steatosis Macrovesicular Ethanol, Methotrexate
Corticosteroids
Total parenteral nutrition
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• Steatohepatitis Microvesicular
Mallory bodies Amiodarone,
Ethanol
• Fibrosis and Periportal and Methotrexate, Isoniazid
cirrhosis pericellular fibrosis Enalapril
• Granulomas non-caseating Sulfonamides
• Vascular lesions Sinusoidal obstruction High-dose chemotherapy
syndrome (veno- Bush teas
occlusivedisease)
Budd-Chiari Oral contraceptives(OCP)
syndrome
Sinusoidal dilatation Oral contraceptives (OCP)
Peliosis hepatis Anabolic steroids
(blood-filled cavities) Tamoxifen
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• Neoplasms
Hepatic adenoma OCP
Anabolic steroids
HCC Thorotrast
Cholangiocarcinoma Thorotrast
Angiosarcoma Thorotrast,
Vinyl chloride
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Drugs that may cause acute liver failure
1-Acetaminophen
2-Halothane
3-Antituberculosis drugs (rifampin, isoniazid)
4-Antidepressant monoamine oxidase inhibitors
5-Toxins as CCL4 & mushroom poisoning
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• The most common cause (46% of cases of
acute liver failure) is acetaminophen
intoxication.
• 60% of these are a consequence of
accidental overdosage.
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Morphology:
Massive necrosis → 500 – 700 gm liver
Submassive necrosis
Patchy necrosis
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• Patient survival for more than a week permits regeneration of surviving hepatocytes.
• Regeneration is initially in the form of strings of ductular structures which mature into hepatocytes.
• If the parenchymal framework is preserved liver architecture is restored.
• With massive destruction of lobules leads to formation of nodular masses of liver cells.
• Scarring may occur in patients with a protracted course of submassive or patchy necrosis representing a route for developing so-called macronodular cirrhosis
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Hepatocellular necrosis caused by acetaminophen overdose.
Confluent necrosis is seen in the perivenular region (large arrow) There is little inflammation.
The residual normal tissue is indicated by the asterisk
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Necrosis of hepatocytes
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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
• Hepatitis A ("infectious hepatitis") is a
benign, self-limited disease.
• incubation period of 15 to 50 days
(average 28 days).
• HAV does not cause chronic hepatitis or a carrier state and only rarely causes fulminant hepatitis.
• Fatality rate is 0.1%
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-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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• Waterborne epidemics may occur in developing countries where people live in overcrowded, unsanitary conditions.
• Among developed countries, sporadic infections may be contracted by the consumption of raw or steamed shellfish (oysters, mussels, clams), which concentrate the virus from seawater contaminated with human sewage.
• Ingestion of raw green onions contaminated with HAV caused outbreaks of the disease in the United States in 2003
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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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Hepatitis B Virus
• carrier rate of approximately 400 million.
• About 80% of all chronic carriers live in
Asia and the Western Pacific rim, where
prevalence of chronic hepatitis B is more
than 10%.
• In the United States there are
approximately 185,000 new infections per
year.
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-HBV is a hardy virus can withstand extremes
of temperature & humidity
-Prolonged IP 4-26 wks
-Prolonged viremia HBV remains in blood during
the last stages of incubation period and during
active episodes of acute and chronic hepatitis
-Present in all body fluids as tears, saliva,
sweat, breast milk, vaginal sec., semen &
pathological body fluids except stool
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• vertical transmission from mother to child during birth constitutes the main mode of transmission.
• horizontal transmission via:
• 1- transfusion
• 2- blood products
• 3- dialysis
• 4- needle-stick accidents among health care workers
• 5-IV drug abuse
• 6-sexual transmission (homosexual or heterosexual)
• 7-In 1/3 of patients the source of infection is unknown.
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• HBV infection in adults is mostly cleared,
but vertical transmission produces a high
rate of chronic infection.
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-Phases of infection :
1. Proliferative phase
2. Integrative phase
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HBV antigens : 1.HBc Ag(hepatitis B core antigen) - hepatocytes
2.HBe Ag(pre-core protein) -blood
3.HBs Ag -blood
-hepatocytes
4.DNA polymerase (HBV-DNA) (reverse transcriptase activity)
5.HBx protein ( transcriptional transactivator )
required for viral infectivity and may have a role in the causation of hepatocellular carcinoma by regulating p53 degradation and expression
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• HBsAg appears before the onset of symptoms, peaks during overt disease, and then declines to undetectable levels in 3 to 6 months.
• Anti-HBs antibody does not rise until the acute disease is over and is usually not detectable for a few weeks to several months after the disappearance of HBsAg.
• Anti-HBs may persist for life conferring protection
• HBV-DNA, and DNA polymerase appear in serum soon after HBsAg, and all signify active viral replication
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• Persistence of HBeAg is an important indicator of continued viral replication, infectivity, and probable progression to chronic hepatitis.
• The appearance of anti-HBe Abs shortly after the disappearance of HBeAg indicates the end of the infection.
• IgM anti-HBc becomes detectable in serum shortly before the onset of symptoms
• Over a period of months the IgM anti-HBc antibody is replaced by IgG anti-HBc.
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• Anti – HBs IgG: rise after the acute phase
is over & remains detectable after wks or
months after disappearance of HBsAg
• Hepatitis B can be prevented by
vaccination and by the screening of donor
blood, organs, and tissues
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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 (HCV)
• 3% (0.1-12%, depending on the country).
• Persistent chronic infection exists in 3 to 4 million persons in the United States.
• The number of newly acquired HCV infections per year dropped from 180,000 in the mid-1980s to about 28,000 in the mid-1990s due to the marked reduction in transfusion-associated HCV as a result of screening procedures and a decline of infections in intravenous drug abusers.
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• The major route of transmission is:
• 1- through blood inoculation
• 2- with intravenous drug use accounting for over 40% of cases in the United States.
• 3-via blood products is now fortunately rare, accounting for only 4% of all acute HCV infections.
• 4-Occupational exposure among health care workers accounts for 4% of cases.
• 5-The rates of sexual transmission and vertical transmission are low.
• 6- Sporadic hepatitis of unknown source accounts for 40% of cases.
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• HCV infection has a much higher rate than HBV of progression to chronic disease and eventual cirrhosis.
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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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• The IP 2-26 weeks ( mean of 6-12 weeks).
• The clinical course of acute hepatitis C is
asymptomatic in 75% of individuals and
is easily missed.
• HCV RNA is detectable in blood for 1-3
weeks and is accompanied by elevations
in serum aminotransferase.
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• Clinical syndromes associated with HCV:
• 1.Persistent infection with subclinical or
asymptomatic acute infection
• 2.Chronic hepatitis
• 3.Fulminant hepatitis rare
• 4.Cirrhosis 20%
• 5.Hepatocellular carcinoma
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Serological diagnosis
• 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%)
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Hepatitis D Virus
-Hepatitis delta virus
-Replication defective virus
-Causes infection only when it is
encapsulated by HBsAg
-I.P 4 – 7 wks in superinfection
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• 8% among HBsAg carriers in southern Italy to as
high as 40% in Africa and the Middle East.
• HDV infection is uncommon in Southeast Asia
and China, areas in which HBV infection is
endemic.
• In the United States HDV infection is largely
restricted to drug addicts and individuals
receiving multiple transfusions (e.g.hemophiliacs
who have prevalence rates of 1% to 10%).
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• Delta hepatitis arises in two settings:
• (1) acute coinfection after exposure to serum containing both HDV and HBV
• (2) superinfection of a chronic carrier of HBV with a new inoculum of HDV.
• Most coinfected individuals can clear the viruses and recover completely.
• in superinfected individuals there is an acceleration of hepatitis, progressing to more severe chronic hepatitis 4 to 7 weeks later.
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• Routes of transmission:
• Parenteral (close personal contact)
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• HDV Ag are detectable in the blood and liver just before and in the early days of acute symptomatic disease.
• IgM anti-HDV antibody is the most reliable indicator of recent HDV exposure, but its appearance is transient.
• acute coinfection by HDV and HBV is best indicated by detection of IgM against both HDV Ag and HBcAg
• With HDV superinfection, HBsAg is present in serum; and anti-HDV antibodies (IgM and IgG) persist in low titer for months or longer.
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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
• HEV hepatitis is an enterically transmitted, waterborne infection occurring primarily beyond the years of infancy.
• HEV is endemic in India
• Prevalence rates of anti-HEV IgG antibodies approach 40% in the Indian population.
• Sporadic infection seems to be uncommon & occurs mainly in travelers and accounts for more than 50% of cases of sporadic acute viral hepatitis in India.
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- 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 : serologic evidence only
A B C D E
2-Acute symptomatic hepatitis icteric or anicteric
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
A & C very rare
5-Chronic carrier state B,C
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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 viruses 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 ,dark stool, pruritus
.Prolonged PT, hyperglobulinemia, ↑ serum alkaline phosphatase
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• 1- diffuse swelling (ballooning degeneration)
• 2- cholestasis, with bile plugs in canaliculi and brown pigmentation of hepatocytes.
• 3-Fatty change is mild and is unusual except with HCV infection.
• 4- HBV infection may generate "ground-glass" hepatocytes
• a finely granular, eosinophilic cytoplasm shown by electron microscopy to contain massive quantities of HBsAg in the form of spheres and tubules.
• Other HBV-infected hepatocytes may have "sanded" nuclei, resulting from abundant intranuclear HBcAg.
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• 5- patterns of hepatocyte death are
seen.
• 6-confluent necrosis of hepatocytes
may lead to bridging necrosis
• 7-lobular disarray
• 8-Inflammation.
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• 9- Kupffer cells undergo hypertrophy and hyperplasia and are often laden with lipofuscin pigment caused by phagocytosis of hepatocellular debris.
• 10-The portal tracts are usually infiltrated with a mixture of inflammatory cells.
• 11-interface hepatitis) .
• 12-bile duct proliferation
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Acute viral hepatitis showing disruption of lobular architecture,
inflammatory cells in sinusoids, and apoptotic cells (arrow).
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Fulminant hepatitis
• Hepatic insufficiency that progresses from onset of symptoms to hepatic escepholopathy in 2-3 wks
• Subfulminant ( up to 3 mon)
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Causes :
1-Viral hepatitis 50 – 65% B,C,E
HBV 2x > HCV
2-Drugs & 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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Fulminant hepatitis
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Chronic Hepatitis
• Symptomatic, biochemical or serelogic evidence of continuing or relapsing hepatic disease for more than 6months
with histologically documented inflammation and 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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Chronic hepatitis
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Chronic hepatitis
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Chronic hepatitis C showing portal tract expansion with inflammatory
cells and fibrous tissue (arrow), and interface hepatitis with spillover of
inflammation into the parenchyma (arrowhead).
A lymphoid aggregate is present in the center of the picture.
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Necrosis of hepatocytes-councilman bodies
(arrows)
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Ground-glass hepatocytes (arrow) in chronic hepatitis
B, caused by accumulation of HBsAg in cytoplasm.
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Fibrosis in chronic hepatitis
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Fibrosis in chronic hepatitis
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Carrier state
• Carriers are:
• (1) those who harbor one of the viruses
but are suffering little or no adverse effects
• (2) those who have nonprogressive liver
damage but are essentially free of
symptoms or disability
• Both constitute reservoirs of infection.
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Predisposing factors
• 1-HBV infection early in life, particularly through vertical transmission during childbirth, produces a carrier state 90-95% of the time.
• only 1-10% of HBV infections acquired in adulthood yield a carrier state.
• 2-impaired immunity
• 3-HBV, HCV, ?HDV