lect 8 liver disease
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Pathology ofPathology ofHepatitis & CirrhosisHepatitis & Cirrhosis
SMS 2044
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Normal Liver
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The Liver
The right upper quadrant of the abdomen isdominated by the liver and its companion
biliary tree and gallbladder.
Residing at the crossroads between thedigestive tract and the rest of the body, the
liver has the enormous task of maintaining thebody's metabolic homeostasis.
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Autopsy
1.5 kg, wedge shape
4 lobes, Right, left,
Caudate, Quadrate.
Double blood supply
Hepatic arteries
Portal Venous blood
Acini / Portal triad.
Lobules central. V
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Normal Liver - Infant
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CT Upper abdomen - Normal
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N
OFIBROUS
TISSUE
Normal Liver - Microscopy
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Liver Functions:
Metabolism Carbohydrate, Fat & Protein
Secretory bile, Bile acids, salts & pigments
Excretory Bilirubin, drugs, toxins
Synthesis Albumin, coagulation factors
Storage Vitamins, carbohydrates etc.Detoxification toxins, ammonia, etc.
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GENERAL PRINCIPLES
The liver is vulnerable to a wide variety of metabolic,toxic, microbial, and circulatory insults.
In some instances, the disease process is primary to theliver. In others, the hepatic involvement is secondary,
often to some of the most common diseases in humans,such as cardiac decompensation, alcoholism, and
extrahepatic infections.
However, with progression of diffuse disease or strategicdisruption of the circulation or bile flow,
the consequences of deranged liver function becomelife-threatening.
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Cell Death
Virtually any significant insult to theliver may causehepatocyte
destruction.
In necrosis, poorly stained mummified
hepatocytes remain, most commonly
as the result of ischemia (coagulative
necrosis).
Cell death that is toxic orimmunologically mediated occurs via
apoptosis, in which isolated
hepatocytes become shrunken,
pyknotic, and intensely
eosinophilic.
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Alternatively, hepatocytes may osmotically swell and
rupture, so-called hydropic degeneration or lytic
necrosis.
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In the setting of ischemia and a number
of drug and toxic reactions, hepatocyte
necrosis is distributed immediately
around the central vein (centrilobular
necrosis).
With more severe inflammatory or toxic
injury, apoptosis or necrosis of
contiguoushepatocytes may spanadjacent lobules in a portal-to-portal,
portal-to-central, or central-to-central
fashion (bridging necrosis).
Destruction of entire lobules(submassive necrosis) or most of the
liver parenchyma (massive necrosis) is
usually accompanied by hepatic failure.
With bacterial infection, macroscopicabscesses may occur.
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Hepatitis:
Hepatitis: Inflammation of Liver
Viral, Alcohol, immune, Drugs & Toxins
Biliary obstruction gall stones.
Acute, Chronic & Fulminant - types
Viral Hepatitis
Specific Heptitis A, B, C, D, E, & other
Systemic - CMV, EBV, other.
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Pattern of Viral Hepatitis:
Carrier state / Asymptomatic phase
Acute hepatitis
Chronic Hepatitis Chronic Persistent Hepatitis (CPH)
Chronic Active Hepatitis (CAH)
Fulminant hepatitis
Cirrhosis
Hepatocellular Carcinoma
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Acute - Hepatitis - Chronic
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Acute Hepatitis:
Swelling and Apoptosis
Piecemeal or Bridging, panacinar necrosis
Inflammation lymphocytes, Macrophages
Ground glass hepatocytes HBV
Mild fatty change HCV
Portal inflammation and Cholestasis
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Foreign bodies, organisms, and a variety of drugs may incite
a granulomatous reaction.
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Signs and Symptoms
Abdominal pain
Joint and muscle pain
Change in bowel function Nausea, vomiting, anorexia
Lethargy, malaise
Fever (Hepatitis A)
Irritability
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More Signs and Symptoms
oJaundice
oclay colored stools
odark urine
oPruritis/urticaria
oSkin abrasions
oRash
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Fulminant Hepatitis:
Hepatic failure with in 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
Complete recovery or - cirrhosis.
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Chronic Hepatitis:
Persistent & Active types. CPH/CAH
Lymphoid aggregates
Periportal fibrosis
Necrosis with fibrosis bridging fibrosis.
Cirrhosis regenerating nodules.
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Acute viral Hepatitis:
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Acute viral Hepatitis:
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Acute viral Hepatitis:
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Acute viral Hepatitis C:
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Liver Biopsy CPH:
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Jaundice
Yellow discoloration of skin & sclera due toexcess serum bilirubin. >than 85 umol/l
(5 mg/dL)
Conjugated & Unconjugated types
Obstructive & Non Obstructive (clinical)
Pre-Hepatic, Hepatic & Post Hepatic types
Jaundice - Not necessarily liver disease *
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Hepatic bile formation serves two major functions.Bile constitutes the primary pathway for the elimination of
bilirubin, excess cholesterol, and xenobiotics that areinsufficiently water soluble to be excreted into urine.
Second, secreted bile salts and phospholipid moleculespromote emulsification of dietary fat in the lumen of thegut.
Thus, jaundice, a yellow discoloration of skin and sclerae(icterus), occurs when systemic retention of bilirubin
leads to elevated serum levels above 2.0 mg/dL, thenormal in the adult being less than 1.2 mg/dL.
Cholestasis,is defined as systemic retention of not onlybilirubin but also other solutes eliminated in bile(particularly bile salts and cholesterol).
Jaundice
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Common Causes of Jaundice
Pre Hepatic (Acholuric) - Hemolytic
Unconjugated/Indirect Bil, pale urine
Hepatic Viral, alcohol, toxins, drugs
Liver damage - unconjugated
Swelling, canalicular obstruction - Conjugated
Post Hepatic (Obstructive) Stone, tumor
Conjugated/Direct Bil, High colored urine,
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Normal bilirubin production (0.2 to
0.3 g/day) is derived primarily from
the breakdown of senescent
circulating erythrocytes, with a minor
contribution from degradation of
tissue heme-containing proteins.
Extrahepatic bilirubin is bound to
serum albumin and delivered to the
liver.
Bilirubin metabolism and
elimination.
Hepatocellular uptake andglucuronidation by glucuronosyltransferase in the
hepatocytes generates bilirubin which are water
soluble and readily excreted into bile.
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Gut bacteria deconjugate the bilirubin and degrade it to
colorless urobilinogens.
The urobilinogens and the residue of intact pigments areexcreted in the feces, with some reabsorption and re-
excretion into bile.
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PATHOPHYSIOLOGY OFJAUNDICE
Both un-conjugated bilirubin and
bilirubin glucuronides may accumulate
systemically and deposit in tissues,
giving rise to the yellow discoloration of
jaundice.
This is particularly evident in the
yellowing of the sclerae (icterus).
There are two important pathophysiologic differences
between the two forms of bilirubin.
Un-conjugated bilirubin is tightly complexed to serum
albumin and is virtually insoluble in water at physiologic pH.
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This form cannot be excreted inthe urine even when blood levels
are high.
Normally, a very small amount
of unconjugated bilirubin is
present as an albumin-free
anion in plasma.
The unbound plasma fractionmay increase in severe
hemolytic disease or when
protein-binding drugs displace
bilirubin from albumin.
I t t j t d bili bi i
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In contrast, conjugated bilirubin is
water soluble, nontoxic, and only
loosely bound to albumin.
Because of its solubility and weakassociation with albumin, excess
conjugated bilirubin in plasma can
be excreted in urine.
With prolonged conjugated
hyperbilirubinemia, a portion of
circulating pigment may become
covalently bound to albumin.
This "delta fraction" may persist in
the circulation for weeks after
correction of a cholestatic insult,
owing to the plasma lifetime of
albumin.
In the normal adult serum bilirubin levels vary between 0 3 and 1 2
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In the normal adult, serum bilirubin levels vary between 0.3 and 1.2mg/dL
Jaundice becomes evident when the serum bilirubin levels riseabove 2.0 to 2.5 mg/dL; levels as high as 30 to 40 mg/dL can occur
with severe disease.
Jaundice occurs when the equilibrium between bilirubin productionand clearance is disturbed by one or more of the following
mechanisms:
(1) excessive production of bilirubin, (2) reduced hepatic uptake,
(3) impaired conjugation, (4) decreased hepatocellular excretion,and
(5) impaired bile flow (both intrahepatic and extrahepatic).
The first three mechanisms produce unconjugatedhyperbilirubinemia, and the latter two produce predominantly
conjugated hyperbilirubinemia.
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The morphologic alterations that cause liver failure fall into
three categories:
1. Massive hepatic necrosis. This is most often caused by
fulminant viral hepatitis (hepatotropic or nonhepatotropic
viruses).
Drugs and chemicals also may induce massive necrosis
1.Chronic liver disease. This is the most common route tohepatic failure and is the end point of relentless chronic liver
damage ending in:
2. Cirrhosis.
Clinical Features
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Clinical Features
Jaundice is an almost invariable finding.
Impaired hepatic synthesis and secretion of albumin leadsto hypoalbuminemia, which predisposes to peripheral edema.
Hyperammonemia is attributable to defective hepatic urea
cycle function.
Fetor hepaticus is a characteristic body odor variously
described as "musty" or "sweet and sour" and occurs
occasionally.
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A coagulopathy develops, attributable to impaired hepaticsynthesis of blood clotting factors II, VII, IX, and X.
The resultant bleeding tendency may lead to massive
gastrointestinal hemorrhage as well as petechial bleeding
elsewhere.
Hepatic encephalopathy
Hepatic encephalopathy is a feared complication of acute
and chronic liver failure
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Cirrhosis
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Cirrhosis
Fibrosis
Regenerating Nodule
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CIRRHOSIS, TRICHROME STAIN
f C
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Etiology of Cirrhosis
Alcoholic liver disease 60-70%
Viral hepatitis 10%
Biliary disease 5-10%
Primary hemochromatosis 5%
Cryptogenic cirrhosis 10-15%
Wilsons, 1AT def rare
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Pathogenesis:
Hepatocyte injury leading to necrosis. Alcohol, virus, drugs, toxins, genetic etc..
Chronic inflammation - (hepatitis).
Bridging fibrosis.
Regeneration of remaining hepatocytes
Proliferate as round nodules.
Loss of vascular arrangement results in
regenerating hepatocytes ineffective.
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Cirrhosis Features:
Liver Failure
Parenchymal regeneration but why ..??.
Portal obstruction, Porta systemic shunts
Portal hypertension, Splenomegaly
Jaundice, Coagulopathy, hypoproteinemia,
toxemia, Encephalopathy,
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Micronodular cirrhosis
A iti i Ci h i
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Ascitis in Cirrhosis
A iti i Ci h i
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Ascitis in Cirrhosis
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Micronodular cirrhosis:
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Macronodular Cirrhosis
Li Bi Ci h i
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Liver Biopsy Cirrhosis
Li Bi Ci h i
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Liver Biopsy Cirrhosis:
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Nutmeg Liver-Cardiac Sclerosis
Cli i l F t
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Clinical Features
Hepatocellular failure. Malnutrition, low albumin & clotting factors,
bleeding.
Hepatic encephalopathy.
Portal hypertension.
Ascites, Porta systemic shunts, varices,
splenomegaly.
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CirrhosisClinical
Features
Gynaecomastia in cirrhosis
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Gynaecomastia in cirrhosis
Porta-systemic anastomosis:
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Porta systemic anastomosis:Prominent abdominal veins.
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MRI Cirrhosis
Complications:
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Complications:
Congestive splenomegaly.
Bleeding varices.
Hepatocellular failure.
Hepatic encephalitis / hepatic coma.
Hepatocellular carcinoma.
Alcoholic Liver Injury:
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Alcoholic Liver Injury:
Ethyl alcohol : Common cause ofacute/Chronic liver disease
Alcoholic Liver disease - Patterns
Fatty change,
Acute hepatitis (Mallory Hyalin)
Chronic hepatitis with Portal fibrosis
Cirrhosis, Chronic Liver failure
All reversible except cirrhosis stage.
Alcoholic Liver Injury: Pathogenesis
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Alcoholic Liver Injury: Pathogenesis
Acetaldehyde metabolite hepatotoxicDiversion of metabolism fat storage.
Oxidation of ethanol NAD to NADH. NAD is
required for the oxidation of fat..
Increased peripheral release of fatty acids.
Inflammation, Portal bridging fibrosis
Stimulates collagen synthesis fibrosis.
Micronodular cirrhosis.
Alcoholic Liver Damage
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Alcoholic Liver Damage
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Alcoholic Fatty Liver
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Alcoholic Fatty Liver
Alcoholic Fatty Liver
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Alcoholic Fatty Liver
Alcoholic Hepatitis
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Alcoholic Hepatitis
Normal Liver Histology
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Normal Liver Histology
CV
PT
f
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BRAIN
LIVER
Toxic N2 metabolites
From Intestines
Porta systemic
shunts
Pathogenesis of Hepatic Encephalopathy
Bleeding in Liver disease:
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Bleeding in Liver disease:
vitamin K in livergamma-carboxyglutamicacid for coagulation factors II, VII, IX, and X.
Liver disease factor VII is the first to go
so the defect will appear initially in theextrinsic pathway, i.e., abnormal PT. When
severe it affects both pathways.
Conclusions:
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Conclusions:
Common end result of diffuse liver damage.(Viral hepatitis, Alcohol, congenital, drugs, toxins & Idiopathic)
Characterised by diffuse loss of architecture.
Fibrous bands & regenerating nodules distortand abstruct blood flow. (inefficient function)
Hepatocellular insufficiency & portal
hypertension.Shrunken, scarred liver, ascitis,
spleenomegaly, liver failure, CNS toxicity.
Prevention Teaching
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Prevention Teaching
What would you teach?
Adequate sanitation andhygiene
Wash hands before eatingand after using the toilet
Drink only purified or bottledwater
No sharing of eating utensils,needles, toothbrushes,razors, etc.
Use a