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SHORT COMMUNICATION  
Year : 2012  |  Volume : 9  |  Issue : 1  |  Page : 86-93
Nonalcoholic fatty liver disease and hepatitis B virus infection


Department of Gastroenterology, S.C.B. Medical College, Cuttack - 753 007, Odisha, India

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Date of Web Publication2-Nov-2016
 

   Abstract 

Nonalcoholic fatty liver disease [NAFLD] has rapidly emerged as the most common liver disorder not only in developed countries, but also in the developing countries. This entity encompasses a wide variety of liver abnormalities ranging from plain hepatic steatosis through nonalcoholic steatohepatitis [NASH] to cirrhosis of the liver and hepatocellular carcinoma [HCC]. NAFLD is now recognized as the hepatic manifestation of insulin resistance [IR], and an important marker of the metabolic syndrome [MS]. Although a number of advances have been made in elucidating the pathogenetic mechanisms involved in the causation and perpetuation of NAFLD, a great many unanswered questions remain unresolved yet. In view of the involvement of so many different pathways in the pathogenesis, there has always been a speculation regarding the interaction between NAFLD and other liver diseases especially chronic hepatitis C [CHC] and chronic hepatitis B [CHB], because of theubiquitous distribution of NAFLD and its common association with other liver diseases.

Keywords: Chronic hepatitis B, chronic hepatitis C, metabolic syndrome, nonalcoholic fatty liver disease

How to cite this article:
Misra B, Singh SP. Nonalcoholic fatty liver disease and hepatitis B virus infection. Hep B Annual 2012;9:86-93

How to cite this URL:
Misra B, Singh SP. Nonalcoholic fatty liver disease and hepatitis B virus infection. Hep B Annual [serial online] 2012 [cited 2018 Dec 10];9:86-93. Available from: http://www.hepatitisbannual.org/text.asp?2012/9/1/86/193290



   Introduction Top


Hepatitis B virus (HBV) infection is a global public health problem. It is estimated that there are more than 350 million HBV carriers in the world, of whom roughly one million die annually from HBV-related liver disease.[1] Despite all the progress and advances made in the field of the prevention and management of hepatitis B virus [HBV] infection, HBV infection still constitutes a serious health hazard, especially in the developing world. The prevalence of HBV infection in the United States is low. However, the prevalence rates are much higher in the developing countries. The developing countries have succeeded in controlling the HBV infection to manageable levels. In view of the high prevalence of NAFLD in the general population, there is bound to be a significant association between the incidence of this disorder and other liver diseases, including CHC and CHB.[2]

A major proportion of this would expectedly be due to the incidental coexistence of NAFLD and other liver diseases. In view of this, it would obviously be difficult to assess how much the hepatic viral infections could contribute to fatty liver disease. At the same time it would be more difficult to assess the effect of fatty liver on the progress and severity of chronic hepatitis due to HBV and hepatitis C virus [HCV] infection. There is now some literature on the association of HCV and fatty liver, and the interaction between HCV and NAFLD. There is some evidence, which suggests that HCV infection predisposes to fatty liver disease.

On the other hand, some studies suggest that fatty liver is associated with more severe disease and fibrosis in patients with CHC. Furthermore, in CHC, it has also been seen that the response to treatment is adversely affected by the presence of fatty liver. In contrast to this, there is very scanty literature on the relationship between HBV infection and NAFLD.

The relationship between HBV infection and NAFLD, and the interactions between HBV and NAFLD will be reviewed in the following sections. In this regard, the following pertinent questions would have to be answered.

  1. Does HBV infection predispose to fatty liver?
  2. Does fatty liver predispose to chronicity of HBV infection?
  3. Does NAFLD aggravate the coexistent CHB?
  4. Does NAFLD influence the outcome of treatment of CHB adversely?



   Prevalence of Fatty Liver in CHB Top


Non-alcoholic fatty liver disease (NAFLD) is one of the emerging liver diseases affecting 10-24% of the general population in various countries.[3] The prevalence of NAFLD has increased in the past couple of years in relation to the increasing number of obese, type 2 diabetic individuals.[4] Hepatic steatosis, which is the primary histological feature of NAFLD, has also been reported in chronic hepatitis C (CHC), and its prevalence and etiology are genotype-dependent. It is more pronounced in genotype 3 patients, where it is related to viral factors such as viral load,[5],[6] while it is less severe in genotype 1 patients, being mostly related to host metabolic factors.[7],[8]

Prevalence of histopathological steatosis in patients with CHB is around 28% (12-76%).[9] To date, only a few studies have addressed the prevalence of steatosis in biopsy-proven chronic hepatitis B (CHB) patients,[10],[11],[12],[13],[14],[15] wherein steatosis is seen to be associated only with metabolic factors, but not with the fibrosis.[11],[12] The prevalence of steatosis in CHB patients was significantly lower than in CHC patients. Diabetes mellitus is observed in more than 10% of the patients, with either HBeAg-negative chronic hepatitis B or chronic hepatitis C. The presence of diabetes is strongly associated with more severe liver fibrosis, but such an association may be related to the high prevalence of diabetes in patients with cirrhosis.[16]


   Does Hepatitis B Virus Infection Predispose to Fatty Liver? Top


The HBV genome consists of four overlapping open-reading frames, an encoding DNA polymerase, surface antigen, core protein, and a regulatory X protein [hepatitis B virus X protein (HBx)]. HBx, an essential factor for viral replication, is considered one of the most important determinants of HBV-induced hepatocarcinogenesis.[17] In recent times, Kim et al. has shown that increased HBx induces the expression of the Liver X receptor (LXR) and its lipogenic target genes, such as, sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), and the peroxisome proliferator-activated receptor, and this is accompanied by the accumulation of lipid droplets.[18] LXR represents a potential therapeutic target for the prevention of hepatic steatosis and its further progression to HCC, after chronic HBV infection.


   Does Fatty Liver Predispose to Chronic Hepatitis B Infection? Top


Hepatic steatosis may contribute to injury by increasing the sensitivity to oxidative stress and cytokine-mediated hepatic damage. The superimposed NAFLD and insulin resistance (IR) are associated with increased fibrogenesis in many studies on chronic hepatitis C (CHC) patients.[19],[20] In CHC, insulin resistance is considered a viral-induced effect and antecedes the emergence of diabetes. In contrast, steatosis is not associated with the HBV carrier status, indicating that chronic HBV infection seems not to be associated with hepatic steatosis.

Prevalence of fatty liver in HBsAg +ve patients is less than in their HBsAg –ve counterparts. HBsAg+ve carriers are not associated with HOMA-IR or presence of fatty liver.[21] In Taiwan, usually HBV carriers acquire the infection perinatally or during early childhood; therefore the mean age of this population can roughly estimate the duration of HBV infection. A recent study from Taiwan indicated that chronic HBV infection is not associated with the adverse outcomes of the metabolic syndrome, including hepatic steatosis and risk of carotid atherosclerosis.[22] Chronic HBV infection seems not to be associated with insulin resistance or development of hepatic steatosis in hepatitis B carriers


   Hepatitis B and Fatty Liver Causal or Coincidental? Top


Insulin resistance is a well-recognized factor that is associated with hepatic steatosis and even fibrosis in CHC, while its association with CHB is controversial.[23] Steatosis is a well-recognized factor that accelerates the progression of fibrosis in CHC through several potential mechanisms, such as, enhanced oxidative stress, increased susceptibility to apoptosis, and deregulated response to cellular injury.[11] In CHB patients, the severity of steatosis is not found to be associated with the severity of fibrosis.[24] The explanation for the lack of association may be due to the fluctuation of HBV replication in HBeAg-negative CHB patients, which means an intermittent progression of necroinflammation and fibrosis.[25] Chronic HBV infection seems not to be associated with insulin resistance or hepatic steatosis in HBV carriers.[26] Hepatic steatosis is detected in the majority of HBeAg-negative CHB patients, but it is less frequently present compared to genotype 1 CHC patients.

Steatosis in this setting of CHB is associated with the presence of host metabolic factors and does not seem to affect the severity of the liver histological lesions.[27]


   Effect of Coexistent Fatty Liver on the Treatment Outcome in Chronic Hepatitis B Top


It has been recently suggested that induction of insulin resistance and steatosis might express a survival benefit for HCV, which negatively affects the response to antiviral treatment, while this may not occur in CHB. It is seen that HBeAg negative carriers are associated more with steatosis than HBeAg-positive CHB patients. HBeAg-negative CHB is characterized by low spontaneous remission, frequent ALT flares, easy progression to cirrhosis, low HBV DNA titer, and curative difficulty, and thus hepatic steatosis will definitely increase the difficulty of therapy in HBeAg-negative HBV patients[2] The prevalence of steatosis is a common finding in CHB infection; however, it is not associated with viral load and treatment outcome.[27] Nevertheless, one study from Chu CM et al. shows that moderate-to-severe steatosis helps in seroclearance of HBSAg in chronic hepatitis B virus infection.[28] Further studies are required for clarification of this issue.


   Summary Top


  1. Prevalence of histopathological steatosis in patients with CHB is around 28% (12-76%)
  2. The prevalence of steatosis in CHB patients is significantly lower than in CHC patients
  3. Prevalence of fatty liver in HBsAg +ve patients is less than in their HBsAg -ve counterparts
  4. HBsAg +ve carriers are not associated with HOMA-IR or presence of fatty liver
  5. HBx, an essential factor for viral replication, induces lipogenesis by activating LXR, which may be the future therapeutic target for prevention
  6. HBeAg-negative CHB is characterized by low spontaneous remission, frequent ALT flare, easy progression to cirrhosis, low HBV DNA titer, and curative difficulty, and indicates that hepatic steatosis will definitely increase the difficulty of therapy in HBeAg-negative HBV patients.


 
   References Top

1.
Maynard JE. Hepatitis B: Global importance and need for control. Vaccine 1990;8(Suppl):S18.  Back to cited text no. 1
[PUBMED]    
2.
Gordon A, McLean CA, Pedersen JS, Bailey MJ, Roberts SK. Hepatic steatosis in chronic hepatitis B and C: predictors, distribution and effect on fibrosis. J Hepatol 2005;43:38-44.  Back to cited text no. 2
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3.
Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221-31.  Back to cited text no. 3
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4.
Sass DA, Chang P, Chopra KB. Nonalcoholic fatty liver disease: A clinical review. Dig Dis Sci 2005;50:171-80.  Back to cited text no. 4
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5.
Rubbia-Brandt L, Leandro G, Spahr L, Giostra E, Quadri R, Male PJ, et al. Liver steatosis in chronic hepatitis C: A morphological sign suggesting infection with HCV genotype 3. Histopathology 2001;2:119-24.  Back to cited text no. 5
    
6.
Rubbia-Brandt L, Fabris P, Paganin S, Leandro G, Male PJ, Giostra E, et al. Steatosis affects chronic hepatitis C progression in a genotype specific way. Gut 2004;3:406-12.  Back to cited text no. 6
    
7.
Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001;6:1358-64.  Back to cited text no. 7
    
8.
Monto A, Alonzo J, Watson JJ, Grunfeld C, Wright TL. Steatosis in chronic hepatitis C: Relative contributions of obesity, diabetes mellitus, and alcohol. Hepatology 2002;3:729-36.  Back to cited text no. 8
    
9.
Fan JG, Chitturi S. Hepatitis B and fatty liver: Causal or coincidental? J Gastroenterol Hepatol 2008;23:679-81.  Back to cited text no. 9
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10.
Asselah T, Boyer N, Guimont MC, Cazals-Hatem D, Tubach F, Nahon K, et al. Liver fibrosis is not associated with steatosis but with necroinflammation in French patients with chronic hepatitis C. Gut 2003;52:1638-4.  Back to cited text no. 10
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11.
Altlparmak E, Koklu S, Yalinkilic M, Yuksel O, Cicek B, Kayacetin E, et al. Viral and host causes of fatty liver in chronic hepatitis B. World J Gastroenterol 2005;11:3056-9.  Back to cited text no. 11
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12.
Thomopoulos KC, Arvaniti V, Tsamantas AC, Dimitropoulou D, Gogos CA, Siagris D, et al. Prevalence of liver steatosis in patients with chronic hepatitis B: A study of associated factors and of relationship with fibrosis. Eur J Gastroenterol Hepatol 2006;18:233-7.  Back to cited text no. 12
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13.
Malhotra V, Sakhuja P, Gondal R, Sarin SK, Siddhu M, Dutt N. Histological comparison of chronic hepatitis B and C in an Indian population. Trop Gastroenterol 2000;21:20-1.  Back to cited text no. 13
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14.
Bondini S, Gramlich T, Ramsey L, Ong JP, Jondle DM, Boparai N, et al. The impact of nonalcoholic fatty liver disease (NAFLD) on chronic hepatitis B. Hepatology 2006;44(S1):655A.  Back to cited text no. 14
    
15.
Tsochatzis E, Papatheodoridis GV, Manesis EK, Chrysanthos N, Kafiri G, Archimandritis AJ. Hepatic steatosis in chronic hepatitis B (CHB) is due to host metabolic factors. Hepatology 2006;44(S1):A652-3.  Back to cited text no. 15
    
16.
Papatheodoridis GV, Chrysanthos N, Savvas S, Sevastianos V, Kafiri G, Petraki K, et al. Diabetes Mellitus in Chronic Hepatitis B and C: Prevalence and Potential Association With the Extent of Liver Fibrosis. J Viral Hepat 2006;13:303-10.  Back to cited text no. 16
    
17.
Arbuthnot P, Capovilla A, Kew M. Putative role of hepatitis B virus X protein in hepatocarcinogenesis: Effects on apoptosis, DNA repair, mitogen activated protein kinase and JAK/STAT pathways. J Gastroenterol Hepatol 2000;15:357-68.  Back to cited text no. 17
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18.
Kim KH, Shin HJ, Kim K, Choi HM, Rhee SH, Moon HB, et al. Hepatitis B virus X protein induces hepatic steatosis via transcriptional activation of SREBP1 and PPAR_. Gastroenterology 2007;132:1955-67.  Back to cited text no. 18
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19.
Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C virus: Mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004;126:586-97.  Back to cited text no. 19
[PUBMED]    
20.
Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001;33:1358-64.  Back to cited text no. 20
[PUBMED]    
21.
Wang CC, Hsu CS, Liu CJ, Kao JH, Chen DS. Association of chronic hepatitis B virus infection with insulin resistance and hepatic steatosis J Gastroenterol Hepatol 2008;23:779-82.  Back to cited text no. 21
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22.
Yang KC, Chen MF, Su TC, Jeng JS, Hwang BS, Lin LY, et al. Hepatitis B virus seropositivity is not associated with increased risk of carotid atherosclerosis in Taiwanese. Atherosclerosis 2007;195:392-7.  Back to cited text no. 22
    
23.
Lonardo A, Lombardini S, Ricchi M, Scaglioni F, Loria P. Review article: hepatic steatosis and insulin resistance. Aliment Pharmacol Ther 2005;22 Suppl 2:64-70.  Back to cited text no. 23
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24.
Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigennegative chronic hepatitis B: natural history and treatment. Semin Liver Dis 2006;2:130-41.  Back to cited text no. 24
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25.
Bondini S, Kallman J, Wheeler A, Prakash S, Gramlich T, Jondle DM, et al. Impact of Nonalcoholic Fatty Liver Disease on Chronic Hepatitis. Liver Int 2007;27:607-11.  Back to cited text no. 25
    
26.
Tsochatzis E, Papatheodoridis GV, Manesis EK, Chrysanthos N, Kafiri G, Archimandritis AJ. Hepatic steatosis in chronic hepatitis B develops due to host metabolic factors: A comparative approach with genotype 1 chronic hepatitis C. Dig Liver Dis 2007;39:936-42.  Back to cited text no. 26
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27.
Cindoruk M, Karakan T, Unal S. Hepatic Steatosis has no Impact on the Outcome of Treatment in Patients With Chronic Hepatitis B Infection. J Clin Gastroenterol 2007;41:513-7.  Back to cited text no. 27
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28.
Chu CM, Lin DY, Liaw YF. Does increased body mass index with hepatic steatosis contribute to seroclearance of hepatitis B virus (HBV) surface antigen in chronic HBV infection? Int J Obes (Lond) 2007;31:871-5.  Back to cited text no. 28
[PUBMED]    

Top
Correspondence Address:
Shivaram Prasad Singh
Head, Department of Gastroenterology, SCB Medical College, Cuttack - 753 007
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-9747.193290

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