hepatitis & liver cirrhosishepatitis & liver cirrhosis - liver... · 5/28/2015 1...
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Pathophysiology of the liver:Pathophysiology of the liver:
Hepatitis & Liver cirrhosisHepatitis & Liver cirrhosisHepatitis & Liver cirrhosisHepatitis & Liver cirrhosis
Blagoi Marinov MD PhDBlagoi Marinov MD PhDBlagoi Marinov, MD, PhDBlagoi Marinov, MD, PhDPathophysiology Dept.,Pathophysiology Dept.,
Medical University of PlovdivMedical University of Plovdiv
Liver and bile system
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Architectonics of the Liver
EtiologyEtiology
Infectious agents Infectious agents Hepatotoxins Alcohol Drugs
Alimentary factorsAlimentary factors
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Alcohol
Alcoholic fatty liver Alcoholic hepatitis
<90% 10-30%
Regression Fibrosis Chronic alcoholic hepatitis Regression
10-15%
30-50% 50%40-50%
Cirrhosis DEATH
Hepatic cancer
Death,acute intoxication
Alcoholism(5-10% m; 3-5% f)
Hepatic syndromes
Jaundice Jaundice Portal hypertension Ascites Portosystemic shunt (PSS)
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JAUNDICEJAUNDICE
Yellowish discoloration of the skin, the conjunctival membranes over the sclerae and other mucous membranes caused by hyperbilirubinemia
Ludwig Courvoisier (1843Ludwig Courvoisier (1843--1918)1918)–– 'Courvoisier's law' is named after him stating that 'Courvoisier's law' is named after him stating that
'if in the presence of jaundice the gallbladder is palpable,'if in the presence of jaundice the gallbladder is palpable,then the jaundice is unlikely to be due to a stone.' then the jaundice is unlikely to be due to a stone.'
The pathology and Surgery of the Gallbladder – published 1809
Jaundice (Icterus)
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Bili bi f tiBili bi f ti
Bilirubin Metabolism
Bilirubin formationBilirubin formation
Transport of bilirubin in plasmaTransport of bilirubin in plasma
Hepatic bilirubin transport Hepatic bilirubin transport Hepatic uptakeHepatic uptake
ConjugationConjugation Conjugation Conjugation
Biliary excretionBiliary excretion
Enterohepatic circulationEnterohepatic circulation
Pathophysiologic classification of Jaundice
Hemolytic JaundiceHemolytic Jaundice
Hepatic JaundiceHepatic Jaundice
Obstructive Jaundice Obstructive Jaundice (Cholestasis)(Cholestasis)
Congenital JaundiceCongenital Jaundice
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Portal HypertensionPortal Hypertension
It is a high blood pressure in theIt is a high blood pressure in the It is a high blood pressure in the It is a high blood pressure in the portal vein and its tributaries(portal portal vein and its tributaries(portal venous system).venous system).
It is defined as a portal pressureIt is defined as a portal pressureIt is defined as a portal pressure It is defined as a portal pressure gradient (the difference in pressure gradient (the difference in pressure between the portal vein and the between the portal vein and the hepatic veins) of 8hepatic veins) of 8--1010 mm Hg or mm Hg or higher.higher.
Causes of portal Causes of portal hypertensionhypertension
Intrahepatic causes: liver cirrhosis and hepatic liver cirrhosis and hepatic fibrosis (e.g. due to Wilson's disease, fibrosis (e.g. due to Wilson's disease, hemochromatosis, or congenital fibrosis).hemochromatosis, or congenital fibrosis).
Prehepatic causes :Prehepatic causes : portal vein thrombosis or portal vein thrombosis or congenital atresiacongenital atresiacongenital atresia.congenital atresia.
Posthepatic obstructionPosthepatic obstruction occur at any level occur at any level between liver and right heart.between liver and right heart.
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Hepatic vascular blocksHepatic vascular blocks
Posthepatic block
Postsinusoidal block
Intrahepaticblock
Presinusoidal
Prehepatic block
А-V anastomoses
Presinusoidal block
Ascites
accumulation of fluid in the peritoneal accumulation of fluid in the peritoneal cavity 90% of the cases secondary to secondary to chronic liver condition (cirrhosis) chronic liver condition (cirrhosis)
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Pathogenesis of Pathogenesis of ascitesascites
AscitesAscites and caput and caput medusaemedusae
Elevated hydrostatic pressure in v. portae
Decreased oncotic pressure (hypoproteinemia)
Increased capillary Increased capillary permeability
Delayed lymph flow
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Patient with AscitesPatient with Ascites
Portosystemic shunts (PSS)
Bypass of the liver due to inability of the Bypass of the liver due to inability of the blood to circulate in the branches of portal vein (also known as a liver shunt)
Most common PSS Oesopageal varices Oesopageal varices Dilation of abdominal veins (Caput medusae) Hemorrhoidial venous collaterals
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Oesophageal varices
HepatitisHepatitis
The te m HEPATITIS s all efe s to
Acute
The term HEPATITIS usually refers to a group of viral infections that affect the liver as well as the consequences of that infection.
Chronic Chronic active hepatitis Chronic persistent hepatitis
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Type of Hepatitis
A B C D E
Source ofvirus
feces blood/blood-derived
body fluids
blood/blood-derived
body fluids
blood/blood-derived
body fluids
feces
Route oftransmission
fecal-oral percutaneousmucosal
percutaneousmucosal
percutaneousmucosal
fecal-oral
A B C D E
blood borne blood borne blood borneChronicinfection
no yes yes yes no
Prevention pre/post-exposure
immunization
pre/post-exposure
immunization
blood donorscreening;
risk behaviormodification
pre/post-exposure
immunization;risk behaviormodification
ensure safedrinking
water
Hepatitis A (HAV)Hepatitis A (HAV)
worldwide distributionworldwide distribution worldwide distributionworldwide distribution risk of ALF 0.01risk of ALF 0.01--0.1%0.1% usually hyperacuteusually hyperacute riskrisk
oo > 40 yrs> 40 yrsoo IVDUIVDU
h lh loo homosexualhomosexualoo CHB or CHC or alcoholic liver diseaseCHB or CHC or alcoholic liver disease
antianti--HAV IgM 95%HAV IgM 95% spontaneous survival relatively high (40spontaneous survival relatively high (40--60%)60%)
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Clinical FeaturesClinical Features
Low mortality in healthy peopleLow mortality in healthy people Low mortality in healthy peopleLow mortality in healthy people–– High mortality when older than age High mortality when older than age 60 60 –– High in presence of chronic liver diseaseHigh in presence of chronic liver disease
High morbidityHigh morbidity–– Around Around 2020% need hospitalization% need hospitalizationpp–– Lost work daysLost work days–– Most become jaundicedMost become jaundiced
Hepatitis B (HBV)Hepatitis B (HBV)
A DNA virus that infects only humansA DNA virus that infects only humans A DNA virus that infects only humansA DNA virus that infects only humans
Belongs to the family HepadnaviridaeBelongs to the family Hepadnaviridae
Knowledge of the Knowledge of the viral proteinsviral proteins that are that are perceived by the immune system as “antigens” perceived by the immune system as “antigens” aids understanding of the various tests used to aids understanding of the various tests used to diagnose acute, chronic, and resolved infection diagnose acute, chronic, and resolved infection and verify response to immunizationand verify response to immunization
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HBV AntigensHBV Antigens
Outer envelope contains a surface protein called Outer envelope contains a surface protein called p pp phepatitis B surface antigen (hepatitis B surface antigen (HBsAgHBsAg))
HBsAgHBsAg is a marker of viral replicationis a marker of viral replication
Inner core contains the genome, the DNA Inner core contains the genome, the DNA polymerase w/ reverse transcriptase activity, polymerase w/ reverse transcriptase activity, hepatitis B core antigen (hepatitis B core antigen (HBcAgHBcAg) particles. This) particles. Thishepatitis B core antigen (hepatitis B core antigen (HBcAgHBcAg) particles. This ) particles. This antigen is not detectable in serum antigen is not detectable in serum
A truncated form of the major core polypeptide A truncated form of the major core polypeptide known as hepatitis e antigen (HBeAg) is the third known as hepatitis e antigen (HBeAg) is the third antigen generated by virus activity. antigen generated by virus activity. Marker of high Marker of high infectivityinfectivity
Hepatitis B AntibodiesHepatitis B Antibodies
Hepatitis B surface antibody is the antibody toHepatitis B surface antibody is the antibody toHepatitis B surface antibody is the antibody to Hepatitis B surface antibody is the antibody to surface antigen. HBsAb is protective and indicates surface antigen. HBsAb is protective and indicates either either resolved infection or immunizationresolved infection or immunization
HBcAb is the antibody to core antigen. This is not a HBcAb is the antibody to core antigen. This is not a protective antibody. Only those who have been protective antibody. Only those who have been exposed to the virus will have this antibodyexposed to the virus will have this antibody
HBcAb is measured in serum as: HBcAb is measured in serum as: ( ll d f )( ll d f )–– Anti HBc IgM (usually indicates new infection)Anti HBc IgM (usually indicates new infection)
–– Anti HBc IgG (appears later)Anti HBc IgG (appears later) HBeAb is the antibody to e antigen. Loss of e HBeAb is the antibody to e antigen. Loss of e
antigen w/ gain of e antibody is called antigen w/ gain of e antibody is called seroconversion. Not a protective antibodyseroconversion. Not a protective antibody
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EpidemiologyEpidemiology
Prevalence of HBV varies markedly around the Prevalence of HBV varies markedly around the yyworld, w/ > 75% of cases in Asia and the Western world, w/ > 75% of cases in Asia and the Western PacificPacific
Vaccine available > 20 years, but perinatal and Vaccine available > 20 years, but perinatal and early life exposure continue to be a major source of early life exposure continue to be a major source of infection in endemic areasinfection in endemic areas
World wide, chronic HBV and its complications World wide, chronic HBV and its complications including hepatocellular carcinoma account for > 1 including hepatocellular carcinoma account for > 1 million deaths each yearmillion deaths each year
Prevalence of Hepatitis B carriersPrevalence of Hepatitis B carriers
(Courtesy Centers for Disease Control and Prevention, Atlanta.)
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Signs and SymptomsSigns and Symptoms
Incubation period: a few weeks toIncubation period: a few weeks to 66 monthsmonths Incubation period: a few weeks to Incubation period: a few weeks to 6 6 monthsmonths About About 3030% develop jaundice% develop jaundice 1010% to % to 2020% of patients develop serum % of patients develop serum
sickness, i.e., fever, arthralgias, rashsickness, i.e., fever, arthralgias, rash FatigueFatigue Fulminant hepatitis B occurs in <Fulminant hepatitis B occurs in < 11% of% of Fulminant hepatitis B occurs in < Fulminant hepatitis B occurs in < 11% of % of
cases. cases. 8080% mortality without liver % mortality without liver transplantationtransplantation
Enzyme elevations of Enzyme elevations of 11,,000000--22,,000 000 typicaltypical
Clinical outcomes of Hepatitis BClinical outcomes of Hepatitis B
From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 62, published by Mosby Philadelphia,,
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CirrhosisCirrhosis
GraduallyGradually developingdeveloping chronicchronicdiseasedisease ofof thethe liver,liver, whichwhich alwaysalwaysinvolvesinvolves thethe organorgan asas aa wholewhole.. ItItisis thethe irreversibleirreversible consequencesconsequencesandand finalfinal stagestage ofof variousvarious chronicchronicggliverliver diseasesdiseases ofof differentdifferent etiologyetiologyoror thethe resultresult ofof longlong--termtermexposureexposure toto variousvarious noxaenoxae..
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Liver cirrhosis is characterized Liver cirrhosis is characterized by the following 5 criteria:by the following 5 criteria:
Pronounced, insufficiently repaired necrosis of the Pronounced, insufficiently repaired necrosis of the , y p, y pparenchyma (with or without inflammatory process)parenchyma (with or without inflammatory process)
Diffuse connective tissue proliferationDiffuse connective tissue proliferation
Varying degrees of nodular parenchymal regenerationVarying degrees of nodular parenchymal regeneration
Loss and transformation of the lobular structure within Loss and transformation of the lobular structure within the liver as a wholethe liver as a whole
Impaired, intrahepatic and intraImpaired, intrahepatic and intra--acinar, vascular supply acinar, vascular supply with consecutive formation of arteriowith consecutive formation of arterio--venous and portovenous and porto--venous anastomoses.venous anastomoses.
CirrhosisCirrhosis--pathophysiologypathophysiology
Normal sinusoidal architectureLow matrix density
Liver injuryStellate cell proliferationIncreased density of matrixShrinkage of cilia and canaliculiLoss of fenestration
S.L. Friedman / Journal of Hepatology 38 (2003) S38–S53
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Anatomical types of Anatomical types of regenerating nodulesregenerating nodules
•• MicronodularMicronodular
•• MacronodularMacronodular•• MacronodularMacronodular
•• Mixed cirrhosisMixed cirrhosis
Micronodular cirrhosisMicronodular cirrhosis
Features: Thick regular septaFeatures: Thick regular septa•• Features: Thick regular septaFeatures: Thick regular septaRegenerating small nodules (<3mm)Regenerating small nodules (<3mm)Involvement of every lobuleInvolvement of every lobule
•• AlcoholismAlcoholismMalnutritionMalnutritionBiliary obstructionBiliary obstructionBiliary obstructionBiliary obstructionHemochromatosisHemochromatosisVenous outflow obstructionVenous outflow obstruction
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Macronodular cirrhosisMacronodular cirrhosis
•• Features: SeptaFeatures: SeptaNodules of variable size Nodules of variable size (>3mm, even 1~ 3 cm)(>3mm, even 1~ 3 cm)Normal lobules in the large nodulesNormal lobules in the large nodules
•• Two subtypes: Two subtypes: postnecroticpostnecroticposthepatiticposthepatitic
Mixed cirrhosisMixed cirrhosis
F tF tFeatures:Features:
•• Presenting both microPresenting both micro-- and and macronodulesmacronodulesFrom micronodules to macronodulesFrom micronodules to macronodules•• From micronodules to macronodules From micronodules to macronodules
•• AlcoholismAlcoholism•• Antitrypsin deficiencyAntitrypsin deficiency
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Signs and symptomsSigns and symptoms
Hepatomegaly and splenomegalyHepatomegaly and splenomegaly Hepatomegaly and splenomegalyHepatomegaly and splenomegaly JaundiceJaundice CholestasisCholestasis Portal HypertensionPortal Hypertension Oedema and AscitesOedema and Ascites Hepatic EncephalopathyHepatic Encephalopathy Hepatic EncephalopathyHepatic Encephalopathy Hepatorenal syndromeHepatorenal syndrome Hepatopulmonary syndromeHepatopulmonary syndrome Coagulopathy and HemorrhageCoagulopathy and Hemorrhage
Cirrhosis Cirrhosis –– clinical signsclinical signs
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Acute Acute Liver Liver FailureFailure--CharacteristicsCharacteristics
Impairment of liver functions,Impairment of liver functions,
JaundiceJaundice
EncephalopathyEncephalopathy
CoagulopathyCoagulopathy CoagulopathyCoagulopathy
Altered mental stateAltered mental state →→ comacoma
Acute liver failureAcute liver failurecausescauses
InfectionsInfections ((hepatiteshepatites -- 7575%)%)
IntoxicationsIntoxications ((fungifungi, , pesticitespesticites))
MedicationsMedications ((paracetamol, extasy,paracetamol, extasy, gold saltsgold salts,,NSAIDs, anesthetics, etc.NSAIDs, anesthetics, etc.))
C di lC di l CardiovascularCardiovascular MetabolicMetabolic OtherOther
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Metabolic alterationsMetabolic alterations
HaemorrhagesHaemorrhages –– altered vit. K absorbtionaltered vit. K absorbtion, , gg ,,and thus decreased coagulation factor and thus decreased coagulation factor synthesis, platelets synthesis, platelets
JaundiceJaundice –– inability to metabolise bilirubin inability to metabolise bilirubin ((bile salts in the skin bile salts in the skin →→ itchingitching))(( gg))
OsteoporosisOsteoporosis –– altered vit. K and Caaltered vit. K and Ca2+2+
metabolismmetabolism
Hepatic encephalopathyHepatic encephalopathy
Reversible decrease in neurologic function, Reversible decrease in neurologic function, based upon the disorder of metabolism which based upon the disorder of metabolism which are caused by severe decompensated liver are caused by severe decompensated liver diseasediseasediseasedisease
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Etiology of hepatic encephalopathy Etiology of hepatic encephalopathy
Fulminant hepatic failure Fulminant hepatic failure acute severe viral hepatitis, drug/toxinacute severe viral hepatitis, drug/toxinacute fatty liver of pregnancyacute fatty liver of pregnancyDue to acute hepatocellular necrosisDue to acute hepatocellular necrosis
Chronic liver diseaseChronic liver diseasecirrhosis of all types (70%), primary liver cancercirrhosis of all types (70%), primary liver cancersurgically induced portalsurgically induced portal--cava shuntscava shuntsDue to one or more potentially reversible Due to one or more potentially reversible precipitating factorsprecipitating factors
Hepatic encephalopathyHepatic encephalopathy((pathogenesispathogenesis))
Postulated factors/mechanisms:Postulated factors/mechanisms:
HyperamonemyHyperamonemy Synergistic effect of neurothropic toxinsSynergistic effect of neurothropic toxins
AmoniumAmonium Short chain fatty acidsShort chain fatty acids MerkaptansMerkaptans
Postulated factors/mechanisms:Postulated factors/mechanisms:
MerkaptansMerkaptans PhenolsPhenols
Phony neuromediatorsPhony neuromediators OctopaminOctopamin
gama amino butiric acidgama amino butiric acid ((GABAGABA))
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Hepatic EncephalopathyHepatic EncephalopathyClinical featuresClinical features
Reversal of sleep patternReversal of sleep pattern Disturbed consciousnessDisturbed consciousness Personality changesPersonality changes Intellectual deteriorationIntellectual deterioration Fetor hepaticusFetor hepaticus AstrexisAstrexis FluctuatingFluctuating
Clinical stages of HE
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Clinical stages of HE
Hepatic transplantation Hepatic transplantation ––the radical solutionthe radical solution
Between 5 and 10 000 transplantations/year (10 % of patients)
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Thank youThank you