CHRONIC HEPATITIS CHRONIC HEPATITIS

The contours of the liver and spleen as wellas the gall bladder in the right and left

hypochondrium

THE ANATOMY

OF THE PORTAL VENOUS SYSTEM

CHRONIC CHRONIC HEPATITISHEPATITIS

Chronic hepatitis is generally defined as disease that has lasted for 6 months or

longer

InflammationInflammation

Walls of scar tissue begin to form

Healthy liver cells become trapped by a wall of scar tissue

CYTOLYTIC SYNDROMECYTOLYTIC SYNDROME alanine aminotransferase increased, alanine aminotransferase increased, aspartate aminotransferase increasedaspartate aminotransferase increased Increased LDHIncreased LDH Increased ferritinIncreased ferritin HyperbilirubiemiaHyperbilirubiemia

CCholestasis holestasis abdominal mass (e.g. cancer)abdominal mass (e.g. cancer) biliary atresia and other pediatric biliary atresia and other pediatric

liver diseasesliver diseases biliary traumabiliary trauma congenital anomalies of the biliary congenital anomalies of the biliary

tracttract gallstonesgallstones intrahepatic cholestasis of intrahepatic cholestasis of

pregnancy (obstetric cholestasis)pregnancy (obstetric cholestasis) primary biliary cirrhosis, an primary biliary cirrhosis, an

autoimmune disorderautoimmune disorder primary sclerosing cholangitis, primary sclerosing cholangitis,

associated with inflammatory associated with inflammatory bowel diseasebowel disease

some drugs, (e.g. flucloxacillin and some drugs, (e.g. flucloxacillin and erythromycin)erythromycin)

ABCC2 gene polymorphismABCC2 gene polymorphism

Alkaline phosphatase Alkaline phosphatase elevations of serum bile acid elevations of serum bile acid

levelslevels elevated levels of Gamma elevated levels of Gamma

Glutamyl Transferase [GGT]Glutamyl Transferase [GGT]

itchiness (pruritus). Pruritus is the itchiness (pruritus). Pruritus is the primary symptom of cholestasis primary symptom of cholestasis

jaundice. jaundice. pale stool. This symptom implies pale stool. This symptom implies

obstructive cholestasis.obstructive cholestasis. dark urinedark urine

HHepatocellularepatocellular insufficiency insufficiency

AlbuminAlbumin TransferrineTransferrine CholesterolCholesterol protro,mbineprotro,mbine CholinesterasaCholinesterasa ΑΑ-lipoproteins-lipoproteins HyperbilirubinemiaHyperbilirubinemia

Mesenchymal inflammation

Hyper-γ globulinemia

CRP ESR

Signs of CLDSigns of CLDSigns of CLDSigns of CLD

CHRONIC HEPATITIS CHRONIC HEPATITIS CLASSIFICATION CLASSIFICATION

CChronic hronic VViral iral HHepatitis epatitis BB CChronic hronic VViral iral HHepatitis epatitis CC CChronic hronic VViral iral HHepatitis epatitis DD CChronic hronic VViral iral HHepatitis epatitis nonidentificatednonidentificated Autoimmune Autoimmune HHepatitisepatitis (type 1, 2 ,3) (type 1, 2 ,3) Toxic HToxic Hepatitisepatitis, , Drug-Induced HepatitisDrug-Induced Hepatitis CCryptogenic ryptogenic HHepatitisepatitis Alcoholic HAlcoholic Hepatitisepatitis Metabolic HMetabolic Hepatitisepatitis Cholestatic HCholestatic Hepatitisepatitis Nonspecific Reactive HNonspecific Reactive Hepatitisepatitis

Grades of Inflammationand Stages of Fibrosis on Liver

Biopsies

CHRONIC HEPATITIS CHRONIC HEPATITIS CLASSIFICATIONCLASSIFICATION

ACCORDING TO SEVERITY ACCORDING TO SEVERITY (level of (level of Aminotransferases))

A C T I V ITYA C T I V ITY

MILDMODERATE SEVERE

CHRONIC HEPATITISCHRONIC HEPATITISCOMPLICATIONSCOMPLICATIONS

HEPATIC ENCEPHALOPATHY HEPATIC ENCEPHALOPATHY VVARICEAL BLEEDINGARICEAL BLEEDING ASCITESASCITES GLOMERULONEPHRITISGLOMERULONEPHRITIS OTHERSOTHERS

General ConceptsGeneral Concepts Hepatitis = 'inflammation of the liver'.Hepatitis = 'inflammation of the liver'. six medically important viruses are commonly six medically important viruses are commonly

described as “hepatitis viruses”:described as “hepatitis viruses”:

HAV,HBV,HCV,HDV,HEV,HGVHAV,HBV,HCV,HDV,HEV,HGV. .

AA“ Infectious”

“ Serum”

Viral hepatitis

Entericallytransmitted

Parenterallytransmitted

F, G, TTV? other

EE

NANBNANB

BB DD CC

Viral Hepatitis - Historical Perspectives

CHRONIC VCHRONIC VIRALIRAL HEPATITISHEPATITIS 5 5 to to 10% 10% of cases of hepatitis of cases of hepatitis В В (with or without hepatitis (with or without hepatitis

D virus co-infection)D virus co-infection) and about and about 75% 75% of cases of hepatitis C become chronic. of cases of hepatitis C become chronic. Infection with hepatitis A virus or hepatitis E virus is not a Infection with hepatitis A virus or hepatitis E virus is not a

cause of cause of Chronic HepatitisChronic Hepatitis. .

HBVHBV : Structure: Structure

HBV Structure & Antigens Dane Dane particleparticle

HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr)

HBcAg = inner core protein (a single serotype)

HBeAg = secreted protein; function unknown

Possible Outcomes of HBV InfectionPossible Outcomes of HBV Infection

Acute hepatitis B infection

Chronic HBV infection

3-5% of adult-acquired infections

95% of infant-acquired infections

Cirrhosis

Chronic hepatitis

12-25% in 5 years

Liver failure Hepatocellular carcinoma

Liver transplant

6-15% in 5 years 20-23% in 5 years

DeathDeath

Laboratory DiagnosisLaboratory Diagnosis

CHRONIC VCHRONIC VIRALIRAL HEPATITISHEPATITIS

Hepatitis B virus and hepatitis C virus are the major causes of chronic hepatitis in the world.

Approximately 80% of individuals infected with HCV will become chronic carriers, of whom a majority will develop a degree of liver damage ranging from fatty liver to cirrhosis.

Chronic HBV and HCV infection predispose patients to developing hepatocellular carcinoma.

Natural History of Hep CNatural History of Hep C

Adapted from Lauer and Walker, NEJM 2001

Healthy Liver

Acute Infection

Chronic Infection

20% Clear the

Virus

80% Virus Continues to Damage

Liver

Only 20% willshow symptomsInitially !

Natural History Con’tNatural History Con’t

ChronicHepatitis

Cirrhosis20-30%

LiverCancer

1-4%/year

Most symptoms begin to show only when liver is more severely damaged

Patients with severe disease who are

treated with corticosteroids have a 10-year

survival rate of 60% to 70%,

whereas untreated patients have a survival rate of less than 30%.

AUTOIMMUNE HEPATITIS

Autoimmune HepatitisAutoimmune HepatitisHistologyHistology

Lymphoplasmacytic Lymphoplasmacytic infiltrateinfiltrate

Interface hepatitisInterface hepatitis

Portal inflammation and invasion of limiting plate

Autoimmune HepatitisAutoimmune HepatitisHistologyHistology

Prominent lobular Prominent lobular infiltrate composed of infiltrate composed of mononuclear and mononuclear and plasma cellsplasma cells

Lobular infiltrate

Autoimmune HepatitisAutoimmune HepatitisHistologyHistology

Prominent plasma Prominent plasma cells appreciated in cells appreciated in this specimenthis specimen

Plasma cells

DRUG-INDUCED CHRONIC DRUG-INDUCED CHRONIC HEPATITISHEPATITIS

Hepatotoxic drugsHepatotoxic drugs::

- Paracetamol- Isoniazid

- Oestrogens- Antibiotics

-Methotrexate-others

> 1000 Hepatotoxic drugs

Diversemechanisms

Variety of liver diseases

DIVERSITY

METABOLIC ACTIVATION

Protein

(Low Amounts)

Immune reactions

Extensive covalent binding GSH

(High Amounts)

Direct toxicity

Reactive metabolite

Drug

CYP

Drugs

Beta-oxidation

Respi-ration

Steatosis Cell dysfunctionCell death

Lactic acidosis

MITOCHONDRIAL DYSFUNCTION

FATTY LIVER Fat droplets appear in the

cytoplasm of hepatocytes; they may appear a few days

after an alcohol binge, but are almost always present in heavy drinkers (> 80 g of alcohol per day for > 5 years).

Fatty liver may occur, however, with obesity, diabetes mellitus, starvation and chronic hepatitis C virus infection

Fatty Liver

ALCOHOLIC HALCOHOLIC HEPATITISEPATITIS

Alcohol abuse is a massive international problem which has huge resource implications both for the community as a whole and also for health care.

Alcohol is enjoyed by many and used safely by the majority of people who drink it.

Alcohol abuse may be denied or not recognized by individuals or their families and friends.

Alcohol damages not only the liver, but many other organs also.

Effects of alcohol abuse

Ethanol

Alcohol dehydrogenase (ADH)Peroxisomal Catalase

Miscrosomal ethanol-oxidising system (CYP 2E1)

Acetaldehyde

Acetate

Acetaldehyde dehydrogenase

Damage

Gultathione depletion

ROS &Free radicals

Altered membrane proteinsNeoantigens formation

Impaired cytoskeletal transportStimulation of HSC

Immunological injuryDamage to cell

membranes

Alcoholic HepatitisMechanisms of liver injury

Free radicalsOxidative injuryHeat

Downregulated inchronic alcohol use

TNFα IL-1, IL-8

Gut Permeability Endotoxaemia Kupfer cell activation

TNFα

GeneticsPolymorphismsMale vs Female

Race

ALCOHOLIC HALCOHOLIC HEPATITISEPATITIS Alcoholic liver disease may develop in Alcoholic liver disease may develop in

women after less alcohol consumptionwomen after less alcohol consumption than than is necessary to cause is necessary to cause hepatitis or hepatitis or cirrhosis in cirrhosis in men.men.

Daily alcoholDaily alcohol consumption of approximately consumption of approximately 50 g for 10 to 15 years is associated with 50 g for 10 to 15 years is associated with alcoholic liver diseasealcoholic liver disease

in women, whereas in women, whereas 80 g80 g is associatedis associated with alcoholic cirrhosis with alcoholic cirrhosis in men. in men.

Pathology of Alcoholic HepatitisPathology of Alcoholic Hepatitis

Mallorys Hyaline

Centrilobular necrosis

Fatty change

Hepatocyte ballooning

PMN infiltrate

Pericellular fibrosis

ALCOHOLIC HALCOHOLIC HEPATITISEPATITIS Alcoholic hepatitisAlcoholic hepatitis

refers to the refers to the pathologic Mallorypathologic Mallory stain findings of stain findings of alcoholic hyalin alcoholic hyalin surrounded by surrounded by polymorphonucleapolymorphonuclearr cell inflammationcell inflammation

CHRONIC HEPATITISCHRONIC HEPATITISDIAGNOSISDIAGNOSIS

LABORATORY SYNDROMESLABORATORY SYNDROMES:: CytoliticCytolitic syndrome ( syndrome (↑AST, ↑ALT, ↑GGT, ↑AST, ↑ALT, ↑GGT,

↑Bilirubin↑Bilirubin )) CholestaticCholestatic syndrome ( syndrome (↑conjugated Bilirubin, ↑conjugated Bilirubin,

↑↑Alkaline phosphatase, ↑GGT, ↑cholesterol)↑GGT, ↑cholesterol) Liver cellular insufficiency Liver cellular insufficiency syndrome (↓syndrome (↓Albumine,

↓↓prothrombin, ↓cholesterol, ↓fibrinogen)↓cholesterol, ↓fibrinogen) Mesenchyme-inflammatory Mesenchyme-inflammatory syndrome (↑ESR, syndrome (↑ESR,

(globulins, ↑timol test ↑Le, ↑C-react. protein)-globulins, ↑timol test ↑Le, ↑C-react. protein-الال↑↑ Hypersplenism Hypersplenism (anemia, thrombocytopenia, (anemia, thrombocytopenia,

leukocytopenia)leukocytopenia)

CCHRONIC HRONIC VVIRAL IRAL HHEPATITISEPATITIS TREATMENTTREATMENT

ANTIVIRAL THERAPY (Interferon therapy, Lamivudine therapy)

Corticosteroids are contraindicated, Corticosteroids are contraindicated, because viral replication is enhancedbecause viral replication is enhanced

INTERFERON THERAPY (Intron A, Velferon, Reaferon, Laferon)

CCHRONIC HRONIC VVIRALIRAL HHEPATITIS EPATITIS BB: :

5-105-10 millionmillion UnitsUnits 3 3 times times a aweekweek s/c or i/m s/c or i/m

for 3-for 3- 4-124-12monthsmonths

CCHRONIC HRONIC VVIRALIRAL HHEPATITIS EPATITIS CC:: 3-3-55 million unitsmillion units33 times a week times a week

for 12for 12-18-18 monthsmonths

CCHRONIC HRONIC VVIRAL IRAL HHEPATITIS EPATITIS DD:: 1010 million unitsmillion units33 times a week times a week

for 12for 12-18-18 monthsmonths

Autoimmune Autoimmune HHepatitisepatitis

WeekWeek MonotherapyMonotherapy

Prednisolone,Prednisolone,

mgmg

PrednisolonePrednisolone (mgmg) and Azathioprine (mg/kg) combination therapycombination therapy

Prednisolone Prednisolone Azathioprine

11 5050 5050 50-15050-150

22 5050 4040 50-15050-150

33 4040 3030 50-15050-150

44 3030 2020 50-15050-150

55 2525 1515 50-15050-150

66 2020 12,512,5 50-15050-150

7,87,8 1515 1010 50-15050-150

HEPATOPROTECTORSPlantPlant Carsil, Legalon, Carsil, Legalon,

Hepabene, Chofitol Hepabene, Chofitol

Essential phospholipidsEssential phospholipids Essentiale, EnerlivEssentiale, Enerliv

AminoacidsAminoacids Glutargin, CitrargininGlutargin, Citrarginin

αα-- lipoic acid lipoic acid BerlithionBerlithion

Ursodezoxycholic acidUrsodezoxycholic acid Ursofalc, UrsosanUrsofalc, Ursosan

SyntheticSynthetic Thiotriazolin, AntralThiotriazolin, Antral

AnimalAnimal Vitohepat, SireparVitohepat, Sirepar

HomeopathicHomeopathic HalstenaHalstena