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ORIGINAL AR ICLE

Acta Medica Indonesiana - Te Indonesian Journal of Internal Medicine

Prevalence of Hepatic Steatosis in Chronic Hepatitis BPatients and Its Association with Disease Severity

Laurentius A. Lesmana 1,2 , C. Rinaldi A. Lesmana 1,2 , Levina S. Pakasi 2 ,Ening Krisnuhoni 3 1 Department of Internal Medicine, Faculty of Medicine, University of Indonesia - dr. Cipto Mangunkusumo Hospital.Jl. Diponegoro no. 71, Jakarta Pusat 10430, Indonesia. Correspondence mail: medicaldr2001id@yahoo.com.2 Digestive Disease Center, Medistra Hospital, Jakarta, Indonesia.3 Department of Anatomical Pathology, Faculty of Medicine, University of Indonesia - dr. Cipto MangunkusumoHospital, Jakarta, Indonesia.

ABSTRAK

Tujuan: untuk mengetahui prevalensi steatosis hepatis pada pasien hepatitis B kronik (HBK) dan menelitiapakah hal tersebut berkaitan dengan penyakit yang lebih progresif. Metode: penelitian dengan desain potong lintang dilaksanakan di Rumah Sakit Cipto Mangunkusumo dan Rumah Sakit Medistra, Jakarta terhadap pasiendengan hepatitis B kronik dari tahun 2007 hingga 2009. Data yang diteliti meliputi data demogra pasien,antropometri, uji fungsi hati dan uji serologi Hepatitis B. Diagnosis steatosis hepatis dinilai berdasarkan biopsihati dan dinilai derajat keparahannya sebagai derajat ringan (66%).

Derajat brosis dan aktivitas nekroin amasi dinilai berdasarkan sistem METAVIR. Hasil: seratus tujuh puluhempat pasien ikut serta dalam penelitian ini; 99 (56,9%) di antaranya adalah laki-laki. Usia rata-rata pasienberkisar antara 39,9 + 10,69 tahun. Sekitar 56% kasus menunjukkan hasil HBeAg negatif. Prevalensi steatosishepatis adalah sebesar 29,9%. Pasien dengan steatosis hepatis secara bermakna mempunyai indeks massa tubuh

(25,1 + 3,3 vs. 22,7 + 3,33 kg/m 2 , p

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INTRODUCTION

Hepatic steatosis is the accumulation of lipid droplets in hepatocytes characterized bymicrovesicular and/or macrovesicular steatosis. 1

Hepatic steatosis is a common nding in patientswith chronic hepatitis B (CHB) with prevalencevaries from less than 20% 2,3 , 30-40% 4,5 tomore than 55%. 6,7 There is no explanation whythe prevalence varies greatly among studies.Altogether, the presence of hepatic steatosisin CHB was considered low compared tothose occurring in chronic hepatitis C (CHC);in which viral factors contributes directly tothe development of insulin resistance and fataccumulation in the liver. 8

The impact of hepatic steatosis on thenatural course of CHB is less recognizedcompared to those known in chronic hepatitis

C patients. While CHB patients have increasedrisk of developing cirrhosis and hepatocellular carcinoma (HCC), recently non-alcoholic fattyliver (NAFLD) has also been regarded as a risk factor for HCC. 9 Therefore, it is tempting toknow whether the presence of hepatic steatosisis associated to a more progressive disease, suchas liver brosis and cirrhosis.

The prevalence of hepatic steatosis in CHB patients and its impact has not been studied inIndonesia. Therefore, this study was primarily

aimed to nd the prevalence of hepatic steatosisin CHB patients and secondarily to evaluatewhether its presence was associated withdisease severity in terms of serum alanineaminotransferase (ALT) and hepatitis B virusdeoxyribonucleic acid (HBV-DNA) levels,hepatitis B e antigen (HBeAg) status, liver brosis and necroin ammatory grade.

METHODS

Study Design and SubjectsA cross-sectional study was done in Cipto

Mangunkusumo Hospital and Medistra Hospital,

Jakarta on CHB patients between 2007 and2010. Patients were included if they werewilling to undergo liver biopsy. Data on patientsdemography, anthropometry, liver functiontest and hepatitis B serology were collected.Body mass index (BMI) was calculated as bodyweight in kilograms divided by body height in

meter square (kg/m 2). Obesity was de ned bya body mass index of more than 25 kg/m 2 for Asian population, according to the World HealthOrganization.

Laboratory ProceduresBlood chemistry test was done by using

automated blood analyzer (Advia HematologyAnalyzer, Siemens Diagnostics, Bad Nauheim,Germany). Hepatitis B serology markers, i.e.HBsAg, HBeAg, and anti-HBe were checkedusing the enzyme-linked immunosorbent assay(ELISA) with commercial kits. Quantitativeserum HBV-DNA level was measured using the

polymerase chain reaction technique (COBAS

TaqMan HBV Test, Roche Diagnostics, Basel,Switzerland). The lower detection limit was4.700 copies/mL. Genotype analysis was

performed using speci c primers.

Liver BiopsyLiver biopsy was performed using a 16-gauge

Menghini needle (Hepa x, Braun, MelsungenAG, Germany) under local anesthesia. Thespecimens then were fixed in formalin andembedded in paraf n blocks. A 4-m thick of thespecimens were cut and stained with hematoxylineosin. Fibrosis was assessed with Massontrichrome staining. Histopathology assessmentwas done by an experienced pathologist, whowas blinded to the patients clinical history.Adequate specimens should be at least 15 mmlong and includes 5 portal systems. The degreeof steatosis was graded 1 to 3, according to the

percentage of cells with fatty droplets (grade1: (mild) 0-33%, grade 2 (moderate): 34-66%,grade 3 (severe): 67-100%). The stage of brosis

9.5+10.18 kPa) between patients with and without liver steatosis. The presence of signi cant brosis (61.5%vs. 69.7%; p=0.295) and necroin ammation (63.5% vs. 65.6%; p=0.789) was not differed between patientswith and without liver steatosis. Conclusion: liver steatosis was found in 30% of chronic hepatitis B patients.

Its presence was mostly associated with central obesity. Unlike chronic hepatitis C, liver steatosis in chronic

hepatitis B was not related to a more progressive disease.

Key words: liver steatosis, chronic hepatitis B, liver brosis.

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was measured based on the METAVIR scoringsystem (F0 = normal connective tissue; F1 = fociof perivenular and/or perisinusoidal brosis inzone 3; F2 = perivenular or pericellular brosisaffecting zones 3 and 2; F3 = septal or bridgingbrosis; and F4 = cirrhosis). 11,12

Liver Stiffness MeasurementThe l ive r s t i f fnes s was measured

using Fibroscan (Echosens, Paris, France).Examination procedure was done accordingto the previous technical description. 13 Tensuccessful measurements were performed oneach patient. The success rate was calculated asthe number of validated measurements divided

by the total number of measurements . The

results were expressed in kilopascals (kPa). Themedian value of successful measurements wasconsidered representative of the liver stiffness ina given patient, according to the manufacturersrecommendation (interquartile range [IQR] lessthan 30% of the median value and success rate>60%. 14

Statistical AnalysesCharacteristics of the study subjects

were presented descriptively; continuousvariables were expressed as mean + standard

deviation or median (range) while categoricalvariables were presented as frequency and

percentage. The association between liver steatosis and disease severity (serum alanineaminotransferase, serum HBV-DNA levels,fibrosis stage and necroinflammatory gradeaccording to METAVIR Score) was analyzedstatistically. Mean comparison was tested usingthe Mann-Whitney U test. A p value of

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Initial data suggest that hepatic steatosis inCHB is related to host factors such as metabolicsyndrome or its component. 2,5 In accordance to

previous reports, we found that hepatic steatosiswas signi cantly associated with higher bodymass index and waist circumference. Manystudies have reported the association of hepaticsteatosis and metabolic factors such as obesity

or high body-mass index,3-5

waist circumference,2

hypertriglyceridemia, 4 hyperglycemia, 3 diabetes, 7 and insulin resistance. 6 Therefore, experts

believe that host factors were responsible tointra-hepatic fat accumulation in CHB patients.

On the other hand, there is also no evidencethat viral factors cause insulin resistance whichwas seen in patients with CHC. It appears thathepatic steatosis did not affect the natural courseof CHB and may only re ect the host metabolic

pro le. 16 In the current study, we found thathepatic steatosis tended to present more among

patients with viral genotype C (37.9%) comparedto genotype B (24.0%). HBV genotype C has

been regarded as a less favourable type comparedto viral genotype B since it is associated tomore chronicity and less response to antiviraltreatment. 17 However, whether this viral typecontributes to hepatic steatogenesis is largelyunknown. No other study has associated viralgenotype with hepatic steatosis and the conceptof steatogenic genotypes for HBV remainsspeculative. 16 There are experimental datashowing that increased HBV X protein couldinduce lipid accumulation in the hepatocytes,

but clinical data do not support this nding. 18 All studies conducted so far, including ours,

had been done on archival data. Thus, the impactof hepatic steatosis on the natural history of CHBin long-term follow-up cohort was unknown.However, the fact that steatosis was not associatedwith brosis stage suggested that it was only a co-existence disease without negative consequence.Liver stiffness measurement supported thisnding ( Table 2 ). Even when cases were selectedto include only patients with brosis stage 2 or less (data not shown), the mean liver stiffnessdid not differ between patients with and withouthepatic steatosis (6.43 vs. 6.75; p=0.749). Itshould be noted, however; that our subjects were

predominated by mild degree of steatosis which

might not have clinical consequence at all.Another version of this kind of study has

been conducted in India, where insulin resistance(IR) among CHB patients was studied in moredetails. The investigators found that IR was

present in 49.3% of CHB patients, but therewas no signi cant association between IR andworsening liver brosis. Thus, although IR wasquite prevalent in CHB, its presence was only are ection of the host metabolic pro le and didnot affect histological severity. 19

CONCLUSION

Liver steatosis was found in 30% of chronichepatitis B patients. Its presence was mostlyassociated with central obesity. Unlike chronichepatitis C, liver steatosis in chronic hepatitis Bwas not related to a more progressive disease.

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Table 2. Association of hepatic steatosis and clinicalvariables in chronic hepatitis B patients (n=174)

Variables

Hepatic steatosis

p valueNo (N=114)n (%)

Yes (N=41)n (%)

Body massindex (kg/m2)

22.7 + 3.33 25.1 + 3.7

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