Download - Chronic Hepatitis
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Chronic HepatitisChronic Hepatitis
Cengiz PataCengiz Pata
Gastroenterology DepartmentGastroenterology Department Yeditepe UniversityYeditepe University
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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.
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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 ?)
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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
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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
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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
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Clinical Manifestations of Clinical Manifestations of haemochromatosishaemochromatosis
Skin pigmentationSkin pigmentation
Liver diseaseLiver disease
Diabetes mellitusDiabetes mellitus
ArthropathyArthropathy
ImpotenceImpotence
FatigueFatigue
CardiomegalyCardiomegaly
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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
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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
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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
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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
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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)
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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)
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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
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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
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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
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..
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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Management of NAFLDManagement of NAFLD
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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
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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.
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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
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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.
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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)
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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!!!
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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
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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
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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
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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
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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
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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)