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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