Chronic HepatitisChronic Hepatitis

Cengiz PataCengiz Pata

Gastroenterology DepartmentGastroenterology Department Yeditepe UniversityYeditepe University

Chronic Liver DiseaseChronic Liver Disease: History: History

Symptoms of liver injury:Symptoms of liver injury: fatigue, weakness, icterus, fatigue, weakness, icterus, pruritis, dark urine, possible stool colour lightening, pruritis, dark urine, possible stool colour lightening, nausea, vomiting, RUQ discomfort, intolerance to dietary nausea, vomiting, RUQ discomfort, intolerance to dietary protein or cigarette smokeprotein or cigarette smoke

Symptoms of the consequences of cirrhosis:Symptoms of the consequences of cirrhosis: bleeding, bleeding, cachexia, edema, ascites, encephalopathy, skin cachexia, edema, ascites, encephalopathy, skin changes, gynecomastia etc.changes, gynecomastia etc.

Chronic Liver DiseaseChronic Liver Disease:Physical:Physical

What physical exam features should be What physical exam features should be emphasized in a patient with chronic emphasized in a patient with chronic transaminitis ? transaminitis ?

(Can you identify the physical signs on the following slides ?)(Can you identify the physical signs on the following slides ?)

Chronic Liver DiseaseChronic Liver Disease : Physical : Physical

Obviously trivia…..Obviously trivia…..Dermatitis herpetiformis: chronic herpetiform Dermatitis herpetiformis: chronic herpetiform lesions on extensor surfaces (in this case, lesions on extensor surfaces (in this case, elbows) in patients with Celiac Diseaseelbows) in patients with Celiac DiseaseKayser-Fleischer Rings, best appreciated with a Kayser-Fleischer Rings, best appreciated with a slit lamp, as brown pigmentary deposits on the slit lamp, as brown pigmentary deposits on the periphery of the cornea, in patients with periphery of the cornea, in patients with Wilson’s diseaseWilson’s diseaseTendon xanthomata, on the Achilles, in patients Tendon xanthomata, on the Achilles, in patients with hyperlipidemia due to cholestasis in liver with hyperlipidemia due to cholestasis in liver disease that also can have chronic transaminitis disease that also can have chronic transaminitis such as primary biliary cirrhosissuch as primary biliary cirrhosis

Prevalence of Inherited Liver DiseasesPrevalence of Inherited Liver Diseases

Disease HomozygoteFrequency

GeneFrequency

HeterozygoteFrequency

Haemochromatosis 1:400 1:20 1:10

α1AT Deficiency 1:1600 1:40 1:20

Cystic Fibrosis 1:2500 1:50 1:25

Wilson's Disease 1:30,000 1:170 1:85

Leggett et al Brit J. Haem. 1990

Genetics of HaemochromatosisGenetics of Haemochromatosis

Autosomal recessiveAutosomal recessive

Mutations in HFE gene (C282Y and H63D)Mutations in HFE gene (C282Y and H63D)

Cause increased intestinal absorption of Cause increased intestinal absorption of FeFe

C282Y/C282Y and C282Y/H63D are C282Y/C282Y and C282Y/H63D are responsible for 95% of genetic responsible for 95% of genetic haemochromatosishaemochromatosis

Clinical Manifestations of Clinical Manifestations of haemochromatosishaemochromatosis

Skin pigmentationSkin pigmentation

Liver diseaseLiver disease

Diabetes mellitusDiabetes mellitus

ArthropathyArthropathy

ImpotenceImpotence

FatigueFatigue

CardiomegalyCardiomegaly

Screening Strategy for HaemochromatosisScreening Strategy for Haemochromatosis(HFE Associated)(HFE Associated)

1.1. Perform transferrin saturation (or UIBC)Perform transferrin saturation (or UIBC)2. If 2. If 45% - repeat fasting 45% - repeat fasting3. If still 3. If still 45% - perform HFE testing 45% - perform HFE testing4. If C282Y +/+ or C282Y/H63D +/+:4. If C282Y +/+ or C282Y/H63D +/+:

- perform serum ferritin and LFT- perform serum ferritin and LFT- if SF > 1000 and/or LFT abnormal- if SF > 1000 and/or LFT abnormal

- Liver biopsy essential- Liver biopsy essential5. If C282Y +/- : 5. If C282Y +/- : - Counsel re:- Counsel re:

AlcoholAlcohol NASH NASH HCVHCV PCT PCT

6. Venesection and family screening6. Venesection and family screening

Type 1 Fat alone

Type 2 Fat + inflammation

Type 3 Fat + ballooning degeneration

Type 4 Fat + fibrosis and/or Mallory bodies

Only types 3 and 4 have been definitively shown to progress to advanced liver disease and can be classified as NASH

The spectrum of The spectrum of Nonalcoholic Fatty Liver DiseaseNonalcoholic Fatty Liver Disease

NAFLD - Classification and Causes NAFLD - Classification and Causes

PRIMARYPRIMARY

Increased insulin resistance syndromeIncreased insulin resistance syndrome

Diabetes mellitus (type II) Diabetes mellitus (type II)

ObesityObesity

HyperlipidemiaHyperlipidemia

NAFLD - NAFLD - Secondary CausesSecondary CausesDrugsDrugs Surgical Procedures Surgical Procedures MiscellaneousMiscellaneous Corticosteroids Corticosteroids GastroplexyGastroplexy Hepatitis C Hepatitis C

Synth oestrogens Synth oestrogens Jejunoileal bypass Jejunoileal bypass AbetalipoproteinaemiaAbetalipoproteinaemia

Amiodarone Amiodarone Extensive small bowel Extensive small bowel Weber-Christian Weber-Christian

Perhexiline Perhexiline resectionresection diseasedisease

NifedipineNifedipine Biliopancreatic diversionBiliopancreatic diversion TTPN with glucosePN with glucose

TamoxifenTamoxifen Environmental toxinsEnvironmental toxins

TetracyclineTetracycline S.bowel diverticulosisS.bowel diverticulosis

ChloroquineChloroquine Wilson’s diseaseWilson’s disease

SalicylatesSalicylates MalnutritionMalnutrition

IBDIBD

HIVHIV infection infection

Prevalence of NAFLD and Prevalence of NAFLD and NASHNASH

No good data - histological diagnosisNo good data - histological diagnosis

Car Crash post mortem study Car Crash post mortem study - 24% - 24% NAFL, 2.4% NASHNAFL, 2.4% NASH - Hilden et al 1977 - Hilden et al 1977 (n=503)(n=503)

USS - 16.4- 23% NAFLUSS - 16.4- 23% NAFL (Italy, and Japan) (Italy, and Japan)

Prevalence of NAFLD / NASHPrevalence of NAFLD / NASHHigh risk groupsHigh risk groups

Severely obese subjects - 25% incidence Severely obese subjects - 25% incidence of NASH at laparoscopyof NASH at laparoscopy

Type 2 diabetes - 28-55% NAFLType 2 diabetes - 28-55% NAFL

Hyperlipidaemia - 20-90% NAFLHyperlipidaemia - 20-90% NAFL

Approx 60% of NAFL occurs in femalesApprox 60% of NAFL occurs in females

Many patients are neither obese nor Many patients are neither obese nor diabetic diabetic (Bacon et al 1994, George et al 1998)(Bacon et al 1994, George et al 1998)

Obesity and Fatty liverObesity and Fatty liver

Prevalence increases with weightPrevalence increases with weightUp to 80% of obese individualsUp to 80% of obese individualsUp to 10-15% of normal subjectsUp to 10-15% of normal subjects

Correspondingly, 15-20% of morbidly Correspondingly, 15-20% of morbidly obese subjects and 3% of non-obese obese subjects and 3% of non-obese subjects have NASH subjects have NASH Increasing prevalence in childrenIncreasing prevalence in children

AGA, Gastroenterology 2002 AGA, Gastroenterology 2002

NAFLD - Clinical FeaturesNAFLD - Clinical Features

Mostly an incidental finding in Mostly an incidental finding in asymptomatic individualsasymptomatic individualsALT 2-5x normalALT 2-5x normalAST:ALT < 1 except in severe injuryAST:ALT < 1 except in severe injuryALP, GGT 2-3x normal <50%ALP, GGT 2-3x normal <50%Bilirubin rarely raisedBilirubin rarely raisedRUQ discomfort, fatigue and malaise RUQ discomfort, fatigue and malaise in some patients in some patients

NASH - Natural HistoryNASH - Natural History

15-50% of NASH patients have fibrosis or 15-50% of NASH patients have fibrosis or cirrhosis at index biopsy cirrhosis at index biopsy James and Day 1998James and Day 1998

In etiological studies NASH is now the most In etiological studies NASH is now the most common cause of cryptogenic cirrhosis common cause of cryptogenic cirrhosis Caldwell et al 1999, Poonwala et al 2000Caldwell et al 1999, Poonwala et al 2000

In a 19 year follow up study, steatosis In a 19 year follow up study, steatosis

(alone) did not progess histologically (alone) did not progess histologically Teli et al Teli et al

19951995

..

3.40

21

28

0

5

10

15

20

25

30

1 2 3 4

NAFL Types

%NASH - Natural HistoryNASH - Natural History

10 year retrospective follow up study10 year retrospective follow up studyn = 98 n = 98

11% Liver Related deaths in types 3 and 411% Liver Related deaths in types 3 and 480% of those developing cirrhosis had fibrosis at index biopsy80% of those developing cirrhosis had fibrosis at index biopsy

%Developing

Cirrhosis

Matteoni et al 1999

NASH-natural historyNASH-natural history

Steatosis only can progress to cirrhosis 1-2 % Steatosis only can progress to cirrhosis 1-2 % over 5-17yrs (Danish and Italian studies)over 5-17yrs (Danish and Italian studies)

NASH + fibrosis – cirrhosis 0% at 5yrs 12% at NASH + fibrosis – cirrhosis 0% at 5yrs 12% at 8ys8ys

Prognosis in cirrhotics poor-30% developing Prognosis in cirrhotics poor-30% developing liver-related morbidity or mortality (liver failure + liver-related morbidity or mortality (liver failure + HCC) over short periodHCC) over short periodAdams et al Gastroenterology 2005Adams et al Gastroenterology 2005

NASH - RISK FACTORS FOR NASH - RISK FACTORS FOR

FIBROSIS AND CIRRHOSISFIBROSIS AND CIRRHOSIS Independent risk factors in several studies:Independent risk factors in several studies:

Age >45Age >45ALT > 2x normalALT > 2x normalAST/ALT ratio > 1AST/ALT ratio > 1Obesity, particularly truncalObesity, particularly truncalType 2 diabetesType 2 diabetesInsulin ResistanceInsulin ResistanceHyperlipdaemia (trigycerides > 1.7)Hyperlipdaemia (trigycerides > 1.7)HypertensionHypertensionIron overloadIron overload

NB: Studies are in selected groups; may not apply to all patients

NASH - Who Should Have a NASH - Who Should Have a Liver biopsy?Liver biopsy?

To Identify Patients at Risk of Progression restrict biopsy to To Identify Patients at Risk of Progression restrict biopsy to patients with some, if not all of:patients with some, if not all of:

ALT > 2x normalALT > 2x normalAST > ALTAST > ALTAt least moderate central obesityAt least moderate central obesityNIDDM or Impaired glucose toleranceNIDDM or Impaired glucose toleranceHypertensionHypertensionHypertriglyceridaemiaHypertriglyceridaemia

Day, Gut 2002;50:5585-Day, Gut 2002;50:5585-588588

PATHOGENESIS OF NASHPATHOGENESIS OF NASHInsulin Resistance is the First HitInsulin Resistance is the First Hit

NASH should be viewed as part of a NASH should be viewed as part of a multifactorial diseasemultifactorial diseaseCommonly associated with syndrome X - Commonly associated with syndrome X - 85% in a retrospective study 85% in a retrospective study (Wilner et al 2001)(Wilner et al 2001)

Treatment strategies may be directed at Treatment strategies may be directed at Insulin ResistanceInsulin Resistance

NASH - TREATMENTNASH - TREATMENT

Steady Weight Loss - logical treatmentSteady Weight Loss - logical treatment– Reduces fatty infiltrationReduces fatty infiltration– Improves LFTsImproves LFTs– CAUTION - In some patients, inflammation CAUTION - In some patients, inflammation

and fibrosis increase especially with rapid wt and fibrosis increase especially with rapid wt loss (cf gastric and intestinal bypass)loss (cf gastric and intestinal bypass)

Improved diabetic control Improved diabetic control - little histological data- little histological dataExercise - Exercise - patients with NAFLD have very poor patients with NAFLD have very poor respiratory quotients. LFTs and RQ improve respiratory quotients. LFTs and RQ improve with exercise Elias 2001with exercise Elias 2001

NASHNASHDRUG TREATMENT DRUG TREATMENT

No completed RCTs to date No completed RCTs to date

CLOFIBRATCLOFIBRAT– No improvement in LFTs or histology over 1 No improvement in LFTs or histology over 1

year in NASH (n=16) year in NASH (n=16) Laurin et al 1996Laurin et al 1996

GemfobrozilGemfobrozil– One randomized study, improved LFTs after One randomized study, improved LFTs after

4 weeks (n=46) 4 weeks (n=46) Basaranoglu et al 1999Basaranoglu et al 1999

MetforminMetformin

NASH - Drug TREATMENT 2NASH - Drug TREATMENT 2

Ursodeoxycholic AcidUrsodeoxycholic Acid– 3 open label studies (n = 24, 24, 31)3 open label studies (n = 24, 24, 31)– One randomised (vs diet alone)One randomised (vs diet alone)– Improvement in aminotransferasesImprovement in aminotransferases– 12 month study demonstrated improvement 12 month study demonstrated improvement

in steatosis but not other histological featuresin steatosis but not other histological features– RCT trial now underwayRCT trial now underway

* * Laurin et al 1996, Guma et al 1997, Ceriani et al 1998Laurin et al 1996, Guma et al 1997, Ceriani et al 1998

NASH - DRUG TREATMENT 3NASH - DRUG TREATMENT 3ANTIOXIDANTSANTIOXIDANTS

Betaine (methionine) Betaine (methionine) – Improved LFTs, steatosis and inflammationImproved LFTs, steatosis and inflammation– n = 8, 12 months therapy, n = 8, 12 months therapy, Abdelmalek et al 2000Abdelmalek et al 2000

N-Acetylcysteine N-Acetylcysteine – Improved LFTsImproved LFTs– n = 11,n = 11, Gulbahar et al 2000 Gulbahar et al 2000

Vitamin E - TocopherolVitamin E - Tocopherol– Improved LFTs over 4-10 monthsImproved LFTs over 4-10 months– n = 11n = 11, Lavine et al 2000, Lavine et al 2000

NASH - DRUG TREATMENT 4NASH - DRUG TREATMENT 4Insulin Resistance Insulin Resistance

MetforminMetformin– Improves sreatosis in ob/ob leptin deficient mouse Improves sreatosis in ob/ob leptin deficient mouse – Decreased Transaminases in non-diabetic subjects with Decreased Transaminases in non-diabetic subjects with

NASH compared with diet alone over 4mNASH compared with diet alone over 4m– Reduced liver volumeReduced liver volume– n = 20, n = 20, Marchesini et al 2001Marchesini et al 2001

– RCT planned by BASLRCT planned by BASL

TroglitazoneTroglitazone– Improved LFTs but no histological changeImproved LFTs but no histological change– n = 6, 4 months, n = 6, 4 months, Caldwell et al 2001Caldwell et al 2001

Management of NAFLDManagement of NAFLD

NAFLD CONCLUSIONSNAFLD CONCLUSIONS

NAFLD is common NAFLD is common A small proportion progress to cirrhosisA small proportion progress to cirrhosisNASH is the commonest cause of NASH is the commonest cause of cryptogenic cirrhosiscryptogenic cirrhosisMore information needed on prevalence, More information needed on prevalence, pathogenesis and natural historypathogenesis and natural historyRCTs urgently needed - Metfomin, RCTs urgently needed - Metfomin, antioxidants and UDCA antioxidants and UDCA

Hepatits CHepatits C

Most asymptomatic; acute hepatitis with Most asymptomatic; acute hepatitis with jaundice is uncommonjaundice is uncommon

• 80% will have chronic / persistent infection. 80% will have chronic / persistent infection. Of these,Of these,

• 10% will develop cirrhosis of the liver 10 10% will develop cirrhosis of the liver 10 years after infectionyears after infection

• 20-30% will develop cirrhosis of the liver 30 20-30% will develop cirrhosis of the liver 30 years after infection years after infection

• 5% will develop hepatocellular carcinoma 5% will develop hepatocellular carcinoma (liver cancer) 20 years after infection.(liver cancer) 20 years after infection.

Hepatitis C: Factors associated Hepatitis C: Factors associated with progression of liver diseasewith progression of liver disease

• The genotype of the virus -IB The genotype of the virus -IB

• Acquiring the infection at an older ageAcquiring the infection at an older age

• Alcohol misuseAlcohol misuse

• Male genderMale gender

• Co-infection with Hepatitis B or HIVCo-infection with Hepatitis B or HIV

Treatment of Hepatitis CTreatment of Hepatitis C

Hep C RNA by PCRHep C RNA by PCRLiver biopsy for genotype I, treatment is Liver biopsy for genotype I, treatment is recommended for patients with moderate to severe recommended for patients with moderate to severe hepatitis hepatitis Peg-interferon given by sc injection 1/ week, Peg-interferon given by sc injection 1/ week, Ribavirin bd doseRibavirin bd dose

• Patients with genotypes II and III are treated with for Patients with genotypes II and III are treated with for 6 months. 6 months. Response rate 70%Response rate 70%

• Patients with genotypes I, IV, V, and VI are treated Patients with genotypes I, IV, V, and VI are treated with interferon and ribavirin for 12 months, if with interferon and ribavirin for 12 months, if responsive on viral load at 3/12. responsive on viral load at 3/12. Response rate 30%-Response rate 30%-40%.40%.

• Telaprevir(protease inh.Telaprevir(protease inh.

Novel Novel TreatmentTreatment for Hepatitis C for Hepatitis C in 2011in 2011

PegIFN/RBV+Telaprevir(12w)PegIFN/RBV+Telaprevir(12w)

++

PegIFN/RBV (12w)PegIFN/RBV (12w)

PegIFN/RBV(4w)PegIFN/RBV(4w)

++

PegIFN/RBV+Boceprevir (20w)PegIFN/RBV+Boceprevir (20w)

Telaprevir vs. BoceprevirTelaprevir vs. Boceprevir

FFirst-generation direct-acting antivirals irst-generation direct-acting antivirals (DAAs)(DAAs)

NS3/4A serine protease inhibitorsNS3/4A serine protease inhibitors

For patients with genotype IFor patients with genotype I

SVR %75 for telaprevir, %65 for SVR %75 for telaprevir, %65 for boceprevir boceprevir

Side efects!!!Side efects!!!

Novel Novel TreatmentTreatment for Hepatitis C for Hepatitis C in 2014in 2014

Sofosbufir: New nucleotide inhb.Sofosbufir: New nucleotide inhb.

Simeprevir: NS3/4A protease inhbSimeprevir: NS3/4A protease inhb

Daclatasvir: NS5B inhibitorDaclatasvir: NS5B inhibitor

For all genotypeFor all genotype

With or without RBV and IFNWith or without RBV and IFN

SVR %80-96 in genotype ISVR %80-96 in genotype I

SVR %60- 95 in other genotypeSVR %60- 95 in other genotype

17

CDC Fact Sheet http://www.cdc.gov/ncidod/diseases/hepatitis/b/fact.htm Accessed July 26 2005Lee WM N Engl J Med 1997; 337:1733–1745Lavanchy D J Viral Hepat 2004; 11:97–107

Transmission of HBVTransmission of HBV

Host Recipient Mother

Infant

Horizontal Transmission Vertical Transmission

Child-to-ChildContaminated Needles

SexualHealth Care Worker

Transfusion

Perinatal

6% infected after age 5 years becomechronically infected

90% infected infants becomechronically infected

No clear risk factors in 20 30% of patients

50

1. Torresi et al. Gastroenerology. 2000;118:S83–S1032. Fattovich et al. Hepatology 1995;21:77–823. Perrillo et al. Hepatology 2001;33:424–432

Chronic hepatitis B Chronic hepatitis B disease progressiondisease progression

Liver Cancer (HCC)

Cirrhosis

Liver Failure

ChronicInfection

Liver Transplantation Death

30%30%

55––10%10%

23% in 5 years23% in 5 years

Acute flareAcute flare

38

Normal or Normal or minimal minimal

inflammationinflammationNormalNormal

Low (< 10Low (< 1055))AntiAnti--HBeHBe

NonNon--replicativereplicative Phase Phase (Inactive HBsAg Carrier)(Inactive HBsAg Carrier)

Chronic Chronic inflammationinflammationElevatedElevated

High (> 10High (> 1055))HBeAg or HBeAg or antianti--HBeHBe

Immune Active Phase Immune Active Phase (Chronic Hepatitis B)(Chronic Hepatitis B)

Normal or Normal or minimal minimal

inflammationinflammationNormal Normal High (> 10High (> 1055))HBeAgHBeAgImmune Tolerant PhaseImmune Tolerant Phase

Liver Liver HistologyHistology

ALT LevelsALT LevelsHBV DNA HBV DNA

Levels Levels (copies/ml)(copies/ml)

HBeAg HBeAg StatusStatus

McMahon. Sem Liver Dis 2004;24:17–21

Phases of Phases of chrchronic hepatitis Bonic hepatitis B

75EASL International Consensus Conference on Hepatitis B. J Hepatology 2003;38:533–540

LaboratoryLaboratory mmonitoring (1)onitoring (1)

•• Patients with mild chronic hepatitis BPatients with mild chronic hepatitis B–– Every 6 monthsEvery 6 months

•• ALTALT

•• When there is a sustained increase of ALT levels to When there is a sustained increase of ALT levels to >2xULN antiviral treatment should be considered>2xULN antiviral treatment should be considered

•• Liver biopsy may be performed to confirm progression to Liver biopsy may be performed to confirm progression to moderate/severe hepatitis at longer time intervalsmoderate/severe hepatitis at longer time intervals

•• Patients with newly diagnosed HBeAg(+) moderate to Patients with newly diagnosed HBeAg(+) moderate to severe chronic hepatitis Bsevere chronic hepatitis B–– Every 1Every 1––3 months for 6 months3 months for 6 months

•• ALTALT

•• HBeAgHBeAg

•• HBV DNAHBV DNA

Tedavi SecenekleriTedavi Secenekleri

İntreferon ( kalıcı cvp yüksek, düşük viral yük İntreferon ( kalıcı cvp yüksek, düşük viral yük olmalı, Hbe Ag +, olmalı, dekompansasyon?)olmalı, Hbe Ag +, olmalı, dekompansasyon?)

Lamivudine (direnç, birinci ted.)Lamivudine (direnç, birinci ted.)

Adefovir (hepsera, direnç?)Adefovir (hepsera, direnç?)

Entecavir(Baraclude, direnç yok, ikinci ted.)Entecavir(Baraclude, direnç yok, ikinci ted.)

Tenofovir (viread, direnç yok, ikinci ted.)Tenofovir (viread, direnç yok, ikinci ted.)

Telbuvudine (sebivo, direnç?, ilk tedavi)Telbuvudine (sebivo, direnç?, ilk tedavi)