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Chronic hepatitis B and fatty liver: Issues in clinical management Rajneesh Kumar a,b,∗, George Boon-Bee Goh a a b

Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore Cancer research centre of Lyon (CRCL), INSERM U1052, Lyon, France

Summary With an increasing incidence of non-alcoholic fatty livers, the existence of concomitant hepatitis B and fatty liver is becoming more common in clinical practice. In clinical practice, the concomitant existence of hepatitis B and fatty livers raises practical issues in clinical management. It becomes more difficult for the clinician to decide on the mode of treatment in the case of elevated Alanine aminotransferase (ALT) and in deciding potential causes, whether they are related to chronic hepatitis B or to non-alcoholic steatohepatitis (NASH). With evolving changes in the practice and knowledge of non-alcoholic fatty liver disease and chronic hepatitis B, clinical judgment on the predominant disease becomes essential for their coexistence. This short review is aimed at reviewing the evidence available on the frequency of the two diseases existing concomitantly, possible ways of differentiating the two, the prognosis, outcomes of treatment and a possible common pathway. © 2016 Published by Elsevier Masson SAS.

Introduction Hepatitis B is prevalent in almost all countries of the world, with a higher prevalence in countries with a low standard of

Abbreviations: ALT, Alanine aminotransferase; CHB, chronic hepatitis B; AASLD, American association for study of liver disease; APASL, Asia-pacific association for study of liver; EASL, European association for study of liver; HCC, hepatocellular carcinoma; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; miRNA, microRNA; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis. ∗ Corresponding author. Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore. E-mail address: [email protected] (R. Kumar).

living [1,2]. The prevalence of hepatitis B is approximately 0.5% in the United States and 10% in African countries. The prevalence of hepatitis B has decreased with the increase of vaccinations [3]; on the contrary, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased in recent decades [4], and the prevalence of NAFLD varies between 20 to 51%, depending on the modality used for diagnosis and the study population [4—6]. A high prevalence of NAFLD has resulted in the increased coexistence of NAFLD with hepatitis B patients in the endemic population. Chronic hepatitis B is defined as the persistence of HBsAg (surface antigen) in the serum for more than six months. Fatty liver or non-alcoholic fatty liver disease (NAFLD) is defined as the presence of intrahepatic steatosis; other causes of steatosis have been excluded. Ultrasonography of

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the liver is commonly used for diagnosing fatty liver. Ultrasonography can detect fatty liver by increased echogenicity of more than 20% fat in the liver with an accuracy of 90% [7]. Non-alcoholic steatohepatitis (NASH) is defined as the presence of inflammation in association with fatty liver. A dilemma exists on the coexistence of the two entities and subsequent clinical management. This review addresses the prevalence, patient outcomes and possible ways to differentiate the predominant disease when the two coexist.

Prevalence of NAFLD and concomitant hepatitis B Irrespective of the geographical region, fatty livers are increasing in prevalence. As reflected by liver transplant recipients, more patients with fatty liver disease are undergoing transplantation than those with hepatitis B [8,9]. The concomitant existence of the two disease entities is interesting; however, the determining the prevalence of fatty livers has been limited by the methodology used for diagnosing a fatty liver. In a study of the Hong Kong population, 891 chronic hepatitis B patients were compared with 922 controls. The prevalence of NAFLD in patients with hepatitis B was 13.5% compared to the controls, where the prevalence was 28.3%. In this study, the diagnosis of NAFLD was based on MRI assessment of intrahepatic triglycerides [10]. In the Western population, Bondini et al. [11] found that biopsy-proven NAFLD was observed in 19% of the patients with chronic hepatitis B. In this study, 64 patients had liver biopsy data and the predominant population was of Asian descent. In a study by Thomopoulus et al., the prevalence of biopsy-proven NAFLD was 19% in a cohort of 234 patients with chronic hepatitis B [12]. Taking these studies into consideration, it can be reasonably concluded that the prevalence of a fatty liver in hepatitis B patients is approximately one in five, which is similar to the general population.

Raised alanine aminotransferase in patients with hepatitis B and fatty liver A raised ALT level is often observed in patients with hepatitis B in clinical practice, however both hepatitis B and NASH can cause a raised ALT level. Treating patients with hepatitis B where the indication does not exist carries the risk of inducing viral resistance and increases the cost of treatment. Yet, under-treating hepatitis B when there is inflammation in the liver carries the risk of progressive liver fibrosis and inflammation. In a study of patients with both a fatty liver and hepatitis B by Spradling, 1090 patients were followed-up over a period of 7.7 years [13]. They found that a raised ALT level was attributed to the fatty liver in 27% of patients, and in patients with a low HBV DNA the most common causes for a raised ALT level was fatty liver or alcohol consumption. Similarly, in a study by Demir K et al., they found that NASH was the cause for a raised ALT level in patients that were HBeAg negative, and had low HBV DNA chronic hepatitis B, where low HBV DNA was defined as < 2000 IU/mL [14].

The American association for the study of liver disease (AASLD), and the Asia pacific association for the study of the liver (APASL) guidelines recommend treatment of hepatitis if the ALT is more than two times the upper limit of normal, while the European association for the study of the liver (EASL) recommends treatment if the ALT is more than the upper limit of normal. Hepatitis B HBeAg negative treatment should be considered if the HBV DNA is more than 2000 IU/mL, and more than 20,000 IU/mL if HBeAg positive [15—17]. However, the guidelines do not mention the clinical condition when the raised ALT can be due to other causes, or in the case of concomitant diseases. The guidelines only provide guidance to clinicians when the raised ALT is attributed to hepatitis B. In patients with both a fatty liver and hepatitis B the clinical assessment is important for finding the cause of a raised ALT level. The cause can be a fatty liver in patients with low HBV DNA.

Fatty liver in hepatitis B and its clinical outcomes Many cross-sectional studies have been conducted to examine the impact of the both hepatitis B and fatty liver on the liver and the clinical impact. In his study from Taiwan, Lin et al. reported hepatitis B and fatty liver had a synergistic effect. Fatty liver was defined based on an ultrasound in a cohort of 5406 patients and liver disease was defined by an ALT more than 40 IU/mL. This was a cross-sectional, observational study [18]. However, in a larger study of a general population of 33,439 patients from Taiwan in 2013, where hepatitis B was observed in 3,642 patients, the authors concluded an inverse relation between the hepatitis B virus and fatty liver disease. In this study, there was a smaller prevalence of hepatitis B (38.9%) patients than those without hepatitis B (44.5%) in patients with a fatty liver (P < 0.001), and patients with a fatty liver had a smaller prevalence of hepatitis B at 11.9% versus 10.7% (P < 0.001). However, the ALT was higher in the fatty liver group. Similar findings were noted by Wong et al. in a study of 1013 patients in a Hong Kong population, where the presence of hepatitis B was associated with a smaller prevalence of fatty liver [9]. In a study by Bondini et al. on biopsy-proven NASH in 64 patients, they found that metabolic factors were related to superimposed NASH in patients with chronic hepatitis B [11]. In a meta-analysis by Machado et al. of 17 studies and 4100 patients with hepatitis B and hepatic steatosis [19], they came to the conclusion that the presence of hepatic steatosis was associated with metabolic factors and had no association with transaminase levels. Based on the conclusion of the meta-analysis, it can be reasonably concluded that metabolic factors determine the hepatic steatosis in patients with concomitant hepatitis B.

Differentiating between chronic hepatitis B and NASH When the ALT level is increased for a period of time in patients with hepatitis B, medications need to be started

Please cite this article in press as: Kumar R, Boon-Bee Goh G. Chronic hepatitis B and fatty liver: Issues in clinical management. Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2015.12.011

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Chronic hepatitis B and fatty liver: Issues in clinical management Table 1

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Portal inflammation Lobular hepatitis Perivenular fibrosis Lipid vesicles Ground glass appearance

NASH

Chronic hepatitis B

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to reduce the chances of developing cirrhosis. However, in patients with both hepatitis B and fatty liver, the differentiation between the two may be necessary for the optimisation of treatment. It is well known that the presence of NASH leads to the progression of cirrhosis and liver-related morbidity; in contrast, NAFLD without NASH is not considered sinister to liver-related morbidity [20]. A high ALT does not correspond to inflammation in NASH and a biopsy gives detailed information on the severity of inflammation. A liver biopsy remains one of the ways to differentiate between the two, but it is associated with the risks of complications, including rare cases of mortality [21]. The classic histological features that can differentiate the two are mentioned below. Table 1 lists the typical features of hepatitis B and NASH inflammation [35—37]. Of the blood/serum markers used, none have been used to differentiate the predominant entity in patients with concomitant infections. MicroRNA has been used to predict the development of liver injury in hepatitis B patients. In study by Zhang et al. they described the differential expression of miRNA and its utility in differentiating between NASH and chronic hepatitis B. AUROC of the microRNA, miR-122, mir-638, mir-572 and mir-744 was 0.94, 0.79,0.75 and 0.68, respectively, suggesting its possible role in diagnosis of predominant lesion [22]. However, miRNA is still not widely used in clinical decision-making and still comes short of clinical validation. In a study from China by Shen al., they found a significant increase in the levels of MCP-1 in patients with concomitant NAFLD plus hepatitis B, compared to hepatitis B. However, this does not help in differentiating the two concomitant aetiologies existing together, as there was significant overlap in the range of values [23]. Apart from a liver biopsy, there are no other methods or tests that can reasonably differentiate the predominant condition when both NASH and hepatitis B coexist.

Development of HCC in patients with fatty liver and hepatitis B Hepatitis B infection can cause hepatocellular carcinoma, and this can develop in patients with hepatitis B without cirrhosis, thus emphasising the need of continuous surveillance in patients with hepatitis B after a certain age [38]. One of the key questions that come to clinicians’ minds is whether the risk of getting HCC increases if the two factors coexist.

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Yu et al. found in a population-based study of 2903 patients over a follow-up period of 14.3 years, that a high body mass index (BMI) was one of the risk factors for developing HCC [24]. However, there was no mention of NASH in this study despite NASH being closely related with BMI as reported in one study’s findings. In a meta-analysis by Wang et al., diabetes was observed to be moderately associated with an increased risk of developing HCC [39]. The presence of diabetes can be a surrogate marker for metabolic syndrome and thus, a possible increased risk for HCC, but it remains unclear if the presence of both a fatty liver and HCC has an incremental effect on the development of HCC. In current studies, there is still a paucity of data showing the impact of steatosis or steatohepatitis in the development of HCC in patients with chronic hepatitis B.

Virologic response to treatment of chronic hepatitis B in patients with NASH The aim of treating patients with hepatitis B is to reduce virus replication and thus, reduce the chances of liver cirrhosis and possibly clear HBsAg (surface antigen) from the liver. If the patients with hepatitis B and NAFLD are started on treatment, we asked whether treatment would be more or less effective. After a review of the existing evidence, we found there was no significant difference in the efficacy of either oral medications or interferon. In study by Jin Xi et al. [25], it was shown that the presence of a fatty liver is an independent factor for entecavir failure in patients with hepatitis. Treatment failure was described as failure of viral suppression at 24 weeks, 48 weeks and 96 weeks. The rates of response to entecavir were 54.9%, 63.8% and 74.2% at 24 weeks, 48 weeks and 96 weeks, respectively. On multivariate analysis, hepatitis steatosis was found to be a significant risk factor for treatment failure. However, this study was not designed to study viral resistance, and the presence of detectable virus was defined as a ‘‘failure of viral suppression.’’ Similar observations have not been reported from other studies. However, the presence of a fatty liver did not result in worse or better outcomes. Longitudinal or long-term studies on the outcome of hepatitis B and fatty livers are lacking. With Interferon treatment, it has been shown that the outcomes are not different between patients with or without steatosis. In a study by Ates et al. [26] of 84 patients who received Interferon, there was no statistically significant difference in the sustained virologic response in patients who had hepatic steatosis and patients who did not, though there was a trend towards a poorer response in the hepatic steatosis patients. A similar conclusion was drawn by Condurak et al. [27] in their study on the impact of hepatic steatosis on the outcome of interferon therapy in patients with hepatic steatosis. They studied 142 patients with hepatitis B and followed-up after treatment with interferon. Shi et al. had similar findings in a study of 96 patients with HBeAg positive chronic hepatitis B receiving pegylated interferon, and found no difference in HBeAg seroconversion and found HBV DNA was undetectable at the end of treatment [28].

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Fatty liver and HBsAg clearance The final goal of oral medications is clearance of HBsAg from the liver and serum; existing oral medications have poor efficacy in clearing HBsAg. With such poor efficacy, we questioned whether nucleotide analogues also have their efficacy reduced. In a study of 155 patients, Chu et al. found that patients with a fatty liver on ultrasound had increased chances of HBsAg clearance compared to the patients without a fatty liver, but the patients with a fatty liver had an increased incidence of cirrhosis. This study emphasises that a fatty liver also has its risk of progression to liver cirrhosis [29]. However, this is the only study suggesting the impact of a fatty liver on HBsAg clearance. This is the only study available and there is paucity of data on the impact of HBsAg clearance in patients with hepatitis B.

Outcomes after surgery for Hepatocellular carcinoma (HCC) Development of HCC is one of the complications observed in patients with hepatitis B. The risk of HCC remains, but is reduced in patients on treatment with nucleoside analogues. It is unclear whether a patient that develops HCC has a different prognosis based on whether they have hepatitis B with or without a fatty liver. Most of the studies compared the outcomes of NASH and HCC with viral hepatitis and HCC. Studies from Japan did not show any significant differences in prognosis. In a study by Nisio et al. of 518 patients, there was no difference in overall survival or disease free survival in patients with hepatitis B- or hepatitis C-related HCC versus Non-B or non-C HCC. In a larger study by Hatanaka et al., a followup of 2542 patients found that non-hepatitis B or C patients with HCC had a better prognosis compared with hepatitis B patients. However, this study did not compare NASH and hepatitis B [30—32]. There is shortage of studies demonstrating the impact of concomitant hepatitis B and NASH on the long-term development of HCC.

Hepatitis B and fatty liver: A common link with the HBx gene From the basic research point of view, the HbX gene remains the common link between the hepatitis virus and fatty liver. Kim et al. initially linked the presence of the HbX gene to the development of hepatic steatosis [33]. Tae-Yong described the possible role of the HbX receptor and its downstream effects on regulating the lipoproteins, leading to increased steatosis. They proposed that the Hbx receptor induces expression of the LXR alpha and beta, which subsequently activate lipogenic target genes, such as the sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), and peroxisome proliferatoractivated receptor; furthermore, this is accompanied by the accumulation of lipid droplets and a significant increase in the expression of LXRbeta, SREBP-1c FAS, and

stearoyl-coenzyme A desaturase-1 in hepatocellular carcinoma (HCC) in comparison with adjacent non-tumorous nodules in human HBV-associated HCC specimens [33,34]. This is a possible gene-linked association between HCC, fatty liver and hepatitis B; however, there is still a lack of data from a large cohort of patients.

Conclusion The presence of hepatitis B and concomitant fatty liver is frequently observed in the hepatitis B endemic regions. A patient’s demographics and metabolic risk factors may help in assessing the presence of concomitant fatty liver. In patients with a high viral load, a liver biopsy may help in assessing the predominant lesion. The outcomes from treatment for hepatitis B may not be affected by the presence of a fatty liver. In the presence of concomitant NASH, strict control of metabolic factors must be emphasized to prevent progression to liver cirrhosis. Long-term follow-up studies are needed to emphasize the outcomes of combined NASH with chronic hepatitis B, especially outcomes regarding hepatocellular carcinoma and the progression to cirrhosis.

Disclosure of interest The authors declare that they have no competing interest.

Acknowledgements The authors acknowledge the guidance of Professor Chow Wan Cheng from the Department of Gastroenterology at Singapore General Hospital.

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Please cite this article in press as: Kumar R, Boon-Bee Goh G. Chronic hepatitis B and fatty liver: Issues in clinical management. Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2015.12.011

Chronic hepatitis B and fatty liver: Issues in clinical management.

With an increasing incidence of non-alcoholic fatty livers, the existence of concomitant hepatitis B and fatty liver is becoming more common in clinic...
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