Does hepatic steatosis impact chronic hepatitis B?

Chronic hepatitis B virus (HBV) infection is a global health problem affecting approximately 316 million people, with a global prevalence of 4.1%.1 Fatty liver affects at least 25% of the global adult population and frequently coexists with chronic hepatitis B.2 However, the clinical significance of the co‐occurrence of these two common liver conditions remains a matter of debate. In Hepatology this month, a systematic review and meta‐analysis by Mao and colleagues shed light on several key questions in this area.3 DOES HEPATIC STEATOSIS INCREASE THE RISK OF HEPATOCELLULAR CARCINOMA? The authors identified 34 studies on the significance of hepatic steatosis in patients with chronic hepatitis B from PubMed, Embase, and Cochrane Library, among which 16 were on hepatocellular carcinoma (HCC), eight on cirrhosis, 14 on advanced fibrosis, and six on hepatitis B surface antigen (HBsAg) seroclearance. They found that hepatic steatosis was associated with an increased risk of HCC, with a pooled odds ratio (OR) of 1.59. In subgroup analyses, the association remained significant among cohort studies, studies from Asia (but not outside Asia), studies published since 2016, studies with a median follow‐up of ≥5 years (but not shorter ones), and after exclusion of alcohol use. The authors did not observe an association in patients treated with antiviral drugs. These subgroup analyses should be interpreted with caution because of the smaller numbers of patients and events in some subgroups and uncertainty regarding the difference in clinical characteristics between patients with and without hepatic steatosis in these subgroups. DOES HEPATIC STEATOSIS INCREASE THE RISK OF ADVANCED FIBROSIS AND CIRRHOSIS? Similarly, hepatic steatosis was associated with an increased risk of cirrhosis with a pooled OR of 1.52. The association remained significant after excluding patients with alcohol use and including only studies published since 2016. In contrast, no significant association was observed between hepatic steatosis and advanced liver fibrosis (pooled OR, 1.08). Because cirrhosis is the most important risk factor of HCC,4 the parallel trends for cirrhosis and HCC are reasonable. In a retrospective cohort study of 1089 patients with chronic hepatitis B from two tertiary centers, the presence of steatohepatitis on liver biopsy was associated with an increased risk of advanced fibrosis, HCC, and death.5 In patients taking long‐term tenofovir disoproxil fumarate for chronic hepatitis B, a normal body mass index and absence of diabetes were associated with a higher chance of regression of cirrhosis.6 All these results support the notion that hepatic steatosis contributes to fibrosis progression and hinders fibrosis improvement in patients with chronic hepatitis B. On the other hand, as a patient must develop advanced fibrosis before cirrhosis, the lack of association between hepatic steatosis and advanced fibrosis in the current meta‐analysis is likely due to selection bias and ascertainment bias (for both steatosis and advanced fibrosis) in some of the included studies.3 DOES HEPATIC STEATOSIS AFFECT THE RATE OF HBsAg SEROCLEARANCE? HBsAg seroclearance, defined as the loss of HbsAg detectability for at least 6 months with or without seroconversion to antibody against HbsAg, is considered the functional cure of HBV. Patients with chronic HBV infection who achieved HbsAg seroclearance have a favorable prognosis and a minimal subsequent risk of developing hepatic decompensation and HCC if they are young and noncirrhotic at the time of HbsAg loss.7 Additionally, the protection of HbsAg seroclearance is usually sustainable, as the risk of HBsAg seroreversion (i.e., the reappearance of HBsAg after HBsAg seroclearance) is generally low. Even if HBsAg seroreversion occurs, it is usually transient with low serum HBsAg and HBV DNA levels. Interestingly, unlike the increased risk of HCC and cirrhosis with coexisting hepatic steatosis, the presence of hepatic steatosis was correlated with a higher likelihood of HBsAg seroclearance (Figure 1), with a pooled OR of 2.22. The association remained significant among cohort studies, studies from Asia, studies published since 2016, studies that defined HBsAg seroclearance by more than 1 year of HBsAg negativity, after exclusion of alcohol use, and among studies with full adjustments for covariates.3 The mechanism behind the association between hepatic steatosis and HBsAg seroclearance remains elusive. A potential mechanism is that the presence of fat within hepatocytes can change the distribution of HBsAg in the cytoplasm, which may lead to steatosis‐induced apoptosis, suppression of viral replication, and HBsAg loss.8FIGURE 1: Natural history of chronic hepatitis B and the impact of hepatic steatosis. Solid arrows represent increased risk, whereas dotted arrows represent reduced risk. ?, Uncertain role in increasing the risk of hepatocellular carcinoma; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.METHODOLOGY IN THE CURRENT STUDY However, the findings from the current study should be interpreted with caution because of potential oversimplification.3 First, hepatic steatosis was defined by any metabolic dysfunction–associated fatty liver, fatty liver, and/or steatohepatitis, which can be diagnosed with different thresholds using different modalities including liver biopsy, transient elastography, ultrasonography, computed tomography, or magnetic resonance imaging. These methods possess different sensitivity to detect hepatic steatosis and are usually utilized in different patient settings. The diagnostic accuracy of ultrasonography is generally low in patients with <20% hepatic steatosis, so those with mild steatosis might be missed. Liver biopsy is only performed in a selected population of patients with chronic hepatitis B. The resulting selection bias cannot be fully addressed by meta‐analysis with sensitivity analyses and subgroup analyses. Moreover, simple steatosis and steatohepatitis are markedly different in terms of pathophysiology, diagnosis, management, and prognosis. Hence, simple steatosis and steatohepatitis can impact differently on clinical outcomes in patients with chronic hepatitis B. Combining them in the meta‐analysis might result in loss of important information. On the other hand, hepatic steatosis is closely related to metabolic syndrome, especially diabetes. Diabetes is a known risk factor for cirrhosis and HCC in patients with chronic hepatitis B. In the subgroup analysis of six studies with individual data by Mao and colleagues, steatosis is associated with a higher HCC risk in patients without diabetes, but not in patients with diabetes.3 In addition, some well‐known risk factors of HBV‐related cirrhosis and HCC include advanced age, high HBV DNA level, and hepatitis B e antigen (HBeAg) status. Although these factors were not considered in the primary analysis, the association between steatosis and HCC was shown to be affected by HbeAg status and HBV DNA level in the subgroup analysis of the six studies with individual data. Also, the association between steatosis and HCC disappeared among antiviral‐treated patients with chronic hepatitis B. Regarding the inconsistent association between steatosis and HCC in different HBV subgroup populations, further studies are warranted to understand the independent effect of hepatic steatosis on clinical outcomes in patients with chronic hepatitis B after considering traditional risk factors for HCC and cirrhosis, as well as coexisting metabolic risk factors. UNANSWERED QUESTIONS AND THE WAY FORWARD Like all good studies, the systematic review and meta‐analysis by Mao and colleagues raise some very interesting questions.3 HbsAg seroclearance is an important point in the natural history of chronic hepatitis B and is associated with a marked reduction in the risk of HCC and cirrhotic complications.7 To what extent the risk of these liver‐related outcomes persists after HbsAg seroclearance in patients with hepatic steatosis deserves further studies. For example, diabetes and suboptimal glycemic control have been shown to be risk factors of HCC after HbsAg seroclearance.9 Perhaps what is more difficult is how to discern the independent effects of hepatic steatosis and the associated metabolic disorders. Studies more than a decade ago have already revealed that patients with diabetes and obesity with chronic hepatitis B are more likely to develop HCC and cirrhosis than those who are metabolically healthy. It is unclear if hepatic steatosis is a necessary intermediate step in liver disease progression or an innocent bystander. Numerous mechanistic studies in animal models of fatty liver would suggest the former is the case, but we need to understand whether molecular changes of fatty liver are similar in the presence of concomitant HBV infection. On the management side, it would be interesting to consider whether the detection of hepatic steatosis should affect decisions on antiviral treatment, fibrosis assessment, and HCC surveillance. A number of metabolic drugs such as statins, aspirin, and metformin appear to reduce the risk of HCC and/or cirrhotic complications in patients with chronic viral hepatitis, though high‐quality data from randomized controlled trials are largely lacking. Future studies should examine if these drugs may preferentially benefit patients with hepatic steatosis or certain metabolic conditions. Looking ahead, as numerous drugs are being developed for the treatment of NASH, their role in the management of patients with chronic hepatitis B and hepatic steatosis deserves further evaluation.10