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Steatotic liver disease, whose incidence is increasing worldwide, can worsen the prognosis of other chronic liver diseases. Nearly one‑third of patients with chronic hepatitis B virus infection receiving antiviral treatment had coexisting steatohepatitis. Although these patients had higher aminotransferase activity and were more often diagnosed with cirrhosis, their response to antiviral treatment was comparable to that observed in the patients without steatosis. The uniqueness of our analysis lies in the assessment of the coexistence of hepatitis B virus infection and hepatic steatosis in a white population, as most studies on this topic have focused on Asian populations.

Introduction

The term steatotic liver disease (SLD) replaced nonalcoholic fatty liver disease (NAFLD) following publication of the 2023 multisociety Delphi consensus statement.¹ SLD serves as an umbrella term for hepatic steatosis of various etiologies, including metabolic disorders, alcohol abuse, specific etiologies in the course of drug‑induced liver injury, monogenic diseases, and other conditions. This new nomenclature is changing our understanding of the disease, whose prevalence is increasing globally.

SLD unrelated to alcohol abuse is estimated to affect approximately one‑third of the world’s adult population. However, when alcoholic steatohepatitis (that fit the current SLD definition) is included, the true burden of the disease appears to be even greater.² This makes SLD a leading cause of chronic liver disease worldwide. The rising prevalence of diabetes, obesity, and cardiovascular diseases—cardiometabolic risk factors for hepatic steatosis—is expected to further drive the growing incidence of SLD, thus increasing its burden both globally and locally.^2,3

Regardless of its etiology, SLD can lead to cirrhosis, increasing the risk of liver failure and hepatocellular carcinoma (HCC).^4,5 These risks are further heightened when SLD is complicated by liver damage of other etiologies, such as chronic infection with hepatotropic viruses (eg, hepatitis B virus [HBV] and hepatitis C virus [HCV]).^6-8 The global burden of chronic HBV infection and SLD co‑occurrence is particularly significant, with HBV infection affecting an estimated 250 million people worldwide, resulting in over 1 million new infections and about 1.1 million deaths annually, primarily due to cirrhosis and HCC.⁹

A comprehensive understanding of the interplay between hepatic steatosis and HBV infection—both at the molecular and clinical levels—is crucial for optimizing patient management. This interaction can influence the prognosis of individuals with chronic hepatitis B (CHB) infection as well as the course and outcomes of antiviral therapy.^10-12 Most of the studies that have evaluated the characteristics of patients with CHB infection and concomitant hepatic steatosis, its impact on the progression of the disease, and the outcome of antiviral therapy relative to patients without steatosis, have been conducted in highly endemic Asian populations.^6,10,13,14 However, given the distinct characteristics of CHB infection in Asian populations—including high prevalence of hepatitis B envelope antigen (HBeAg), increased viral replication, differing HBV genotypes, and varying risk of HCC—studies from other geographic regions are necessary.

To address this gap, we conducted a retrospective, real‑world study comparing patients with and without SLD treated for CHB infection with nucleos(t)ide analogs (NAs) in Poland, a Central European country with low HBV endemicity.

Patients and methods

Results

Characteristics of the study population

We included 273 consecutive white patients treated with NAs for CHB. All participants underwent abdominal ultrasound; additionally, 72 patients underwent liver biopsy and 56 underwent FibroScan. SLD was diagnosed in 86 individuals (31.5%); of those, 20 underwent liver biopsy and 23 FibroScan.

Patient demographic and clinical characteristics are presented in Table 1. At the time of evaluation, the median age was comparable between the SLD and non‑SLD groups. Both subpopulations were predominantly male, with a higher proportion in the SLD group (P = 0.02). The patients with SLD had a higher burden of comorbidities (P <⁠0.001), particularly diabetes, gout, and obesity. The distribution of body mass index in both groups is presented in Figure 1.

Table 1. Demographic and clinical characteristics of the study population with regard to the presence of steatotic liver disease

Parameter		SLD (n = 86)	Non‑SLD (n = 187)	P value
Data are presented as number (percentage) unless otherwise indicated. Abbreviations: BMI, body mass index; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IQR, interquartile range; SLD, steatotic liver disease
Sex	Women	19 (22.1)	68 (36.4)	0.02
	Men	67 (77.9)	119 (63.6)
Age, y, median (IQR; range)		52 (44–60; 31–71)	50 (39–60; 28–98)	0.5
BMI, kg/m2, median (IQR)		28.5 (25.8–32.5)	23.8 (21.8–26.2)	<⁠0.001
Overweight		29 (33.7)	55 (29.4)	0.47
Obesity		34 (39.5)	15 (8)	<⁠0.001
Any comorbidity		57 (66.3)	74 (39.6)	<⁠0.001
Chronic kidney disease		3 (3.5)	17 (9.1)	>0.99
Hypertension		34 (39.5)	46 (24.6)	0.14
Ischemic heart disease		4 (4.7)	15 (8)	>0.99
Stroke		0	1 (0.5)	>0.99
Non‑HCC malignancy		11 (12.8)	24 (12.8)	>0.99
Autoimmune disease		5 (5.8)	11 (5.9)	>0.99
Diabetes		13 (15.1)	6 (3.2)	0.004
Dyslipidemia		19 (22.1)	19 (10.2)	0.09
Gout		5 (5.8)	0	0.03
Chronic respiratory disease		3 (3.5)	7 (3.7)	>0.99
History of HCC		1 (1.2)	1 (0.5)	0.53
HCV coinfection		1 (1.2)	11 (5.9)	0.11
HIV coinfection		0	0	–
History of alcohol intake		7 (8.1)	7 (3.7)	0.13
Cirrhosis		14 (16.3)	22 (11.8)	0.31
History of liver decompensation	Ascites	1 (1.2)	3 (1.6)	>0.99
	Hepatic encephalopathy	1 (1.2)	0	0.32

There were no cases of HIV infection, while HCV coinfection was diagnosed in 12 patients, mainly in the non‑SLD group (Table 1). A small percentage of patients in both groups reported a history of alcohol abuse (defined as alcohol intake >20 g/d for women and >30 g/d for men), but all declared abstinence since qualifying for antiviral therapy and during the treatment. Among the patients with SLD, 79 (91.9%) met the criteria for metabolic dysfunction–associated SLD, 7 (8.1%) for metabolic dysfunction and alcohol–related liver disease, and none for alcohol‑related liver disease.

HBV genotype determination data were available for 64 patients, with a majority being infected with genotype A, and its distribution was comparable between the SLD and non‑SLD groups. Cirrhosis was diagnosed in 16.3% of the patients with SLD and 11.8% of those without SLD (P = 0.31). Liver disease severity was evaluated by liver biopsy in 72 patients, by TE in 56 patients, and by shear wave elastography in 78 patients. In the remaining 67 patients, clinical assessment was supplemented with the calculation of the serum FIB‑4 index.

Treatment characteristics

The treatment characteristics of the study population are presented in Table 2. There were less treatment‑experienced patients in the SLD group, as compared with the non‑SLD group. Lamivudine was the most common drug in the whole study population. The primary reason for switching antiviral drugs in most patients was treatment inefficacy. However, in 4 individuals from each group, the switch to the analog was prompted by changes in the provisions of the National Health Fund drug program, and in these cases, HBV DNA was already undetectable at the start of the current therapy.

Table 2. Characteristics of the past and current antiviral therapy

Parameter		SLD (n = 86)	Non‑SLD (n = 187)	P value
Data are presented as number (percentage) unless otherwise indicated. Abbreviations: ADV, adefovir; ETV, entecavir; HBV, hepatitis B virus; HDV, hepatitis D virus; HBeAg, hepatitis B envelope antigen; LMV, lamivudine; (peg)IFN, pegylated interferon; TDV, tenofovir disoproxil; others, see Table 1
Treatment‑experienced	Total	31 (36)	95 (50.8)	0.02
	ETV	5 (16.1)	16 (16.8)	>0.99
	TDV	2 (6.5)	1 (1.1)	0.23
	ADV	2 (6.5)	4 (4.2)	>0.99
	LMV	13 (41.9)	49 (51.6)	0.04
	(peg)IFN	9 (29)	25 (26.3)	0.49
Current therapy	ETV	55 (64)	128 (68.4)	0.46
	TDV	31 (36)	59 (31.6)
Time on the current therapy, y, median (IQR; range)		5 (2–10; 0–16)	6 (3–11; 0–17)	0.07
HBeAg(+) at baseline		7 (8.1)	42 (22.5)	0.004
HBe seroconversion during therapy in relation to HBeAg(+) patients, n/N (%)		3/7 (42.9)	18/42 (42.9)	>0.99
HBV DNA at baseline, IU/ml, median (IQR)		6442 (1 280–69 250)	11 820 (2 180–103 000)	0.29
HBV DNA clearance in the 1st year of therapy in relation to HBV DNA–positive at baseline, n/N (%)		57/82 (69.5)	122/183 (66.7)	0.65
HBV DNA clearance during therapy in relation to HBV DNA–positive at baseline, n/N (%)		80/82 (97.6)	179/183 (97.8)	0.89
HCC diagnosed during therapy		1 (1.2)	3 (1.6)	>0.99
Liver decompensation during therapy		0	0	–
HDV coinfection diagnosed during therapy		0	1 (0.5)	>0.99

The median HBV DNA load at baseline and the distribution of baseline viremia were comparable between the groups (Table 2, Figure 2). However, the proportion of patients with HBeAg positivity was lower in the SLD group (P = 0.004; Table 2). The patients with SLD also exhibited higher median aminotransferase activity, as compared with those without steatosis (P <⁠0.001 for ALT and P = 0.004 for AST; Table 3, Figure 3). Liver function parameters, including bilirubin level and INR, were similar in both subpopulations, while albumin concentrations were lower in the patients with SLD (P = 0.02).

Table 3. Laboratory parameters of the study patients at baseline of therapy

Parameter	SLD (n = 86)	Non‑SLD (n = 187)	P value
Data are presented as median (IQR). SI conversion factors: to convert ALT or AST to µkat/l, multiply by 0.0167; PLT to × 109/l, by 1; creatinine to µmol/l, by 88.4; bilirubin to µmol/l, by 17.1; albumin to g/l, by 10. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio; PLT, platelet count; others, see Table 1
ALT, IU/l	47 (29–82)	30 (21–52)	<⁠0.001
AST, IU/l	38 (27–63)	28 (21–44)	0.004
PLT, × 1000/µl	174 (147.5–227.5)	199 (168–244)	0.005
Creatinine, mg/dl	0.9 (0.8–1.1)	0.9 (0.8–1.1)	0.75
INR	1.1 (1–1.1)	1 (1–1.1)	0.84
Bilirubin, mg/dl	0.8 (0.6–1.1)	0.7 (0.6–1)	0.52
Albumin, g/dl	4.2 (3.8–4.5)	4.3 (4.1–4.7)	0.02

Discussion

The evolution of the terminology related to liver steatosis, with the most recent change in June 2023, has resulted in different terms for steatohepatitis being used in papers published at different time points. This should be acknowledged to clarify any inconsistencies in naming conventions.

A recent global analysis estimated the prevalence of NAFLD at 32.4%. Although the study included data from only 17 of 195 countries, the results are in line with reports from Europe and the National Health and Nutrition Examination Survey, which indicate SLD prevalence of 26.9% and 31.3% in the general population, respectively.^6,18,19 Among the HBV‑infected patients, the rate of comorbid SLD was approximately 32% and was higher in men (P = 0.009). No differences in prevalence were noted based on geographic regions or diagnostic techniques.²⁰ Our findings are consistent with these results, as we identified SLD in 31.5% of the patients treated for CHB, with a higher prevalence in men (P = 0.02).

The novelty and uniqueness of our study stem from its evaluation of the coexistence of HBV infection and liver steatosis in a white population, whereas most research on this topic has focused on Asian populations.

The molecular mechanisms underlying liver steatosis in patients with CHB infection remain unclear. The HBx protein has been suggested as a contributing factor, as it interferes with lipid secretion by apolipoprotein B. Additionally, HBx can modulate the expression of genes involved in lipid synthesis and degradation, leading to abnormal lipid accumulation within hepatocytes.^10-12

We documented male predominance in our study population, consistent with previous reports indicating a higher risk of HBV chronification in men.^21-24 The liver is considered a sexually dimorphic organ, with its cells expressing androgen and estrogen receptors that respond to the respective sex hormones. Androgen stimulation has been shown to increase HBV transcription, whereas estrogen has the opposite effect. In addition, HBx protein increases androgen receptor activity in the liver.²⁴

The predominance of men in the study population was even more pronounced among the patients diagnosed with SLD, which is consistent with the results of a worldwide analysis indicating a higher proportion of men (52.3%) among patients with NAFLD.¹⁸ This trend is also influenced by sex hormones, with testosterone increasing the risk of SLD, and estrogen acting as a protective factor through estrogen receptor-α signaling. Estrogen also mitigates the risk of insulin resistance, a known risk factor for SLD, and reduces lipogenesis.²⁵ Differences in chromosomal composition have also been implicated in hepatic steatosis, as demonstrated by studies on animals and individuals with genetic syndromes involving an extra chromosome X.²⁶

Our study revealed a significantly higher burden of comorbidities in the patients with SLD, as compared with those without steatosis. Established metabolic risk factors for SLD, such as diabetes mellitus and obesity, were more prevalent among the patients with steatosis (P = 0.004 for diabetes mellitus and P <⁠0.001 for obesity). Similarly, other risk factors, including dyslipidemia and hypertension, were more common among the patients with SLD than in the HBV‑infected individuals without steatosis, although statistical significance was not reached. These findings are consistent with previous studies.^10,27 Additionally, we observed a higher prevalence of gout in the patients with SLD. A cross‑sectional study involving more than 4000 individuals in the United States demonstrated that higher uric acid levels are independently associated with an increased risk of liver steatosis.²⁸

Alcohol consumption is another important risk factor for SLD.^29,30 Our findings did not show any difference in the history of alcohol abuse; however, it was more frequently reported in the patients with SLD than in those without steatosis. Notably, since the initiation of antiviral therapy, all patients in our analysis declared abstinence, which allowed us to assess the impact of past alcohol consumption.

The effect of hepatic steatosis on liver disease progression in HBV‑infected patients, including fibrosis and HCC, remains a subject of an ongoing debate. Some studies suggest that fatty liver disease accelerates liver disease progression, while others show no significant association.^13,14,20,31 In our study, although the percentage of cirrhosis cases was higher in the SLD group, the difference did not reach significance. Similarly, a retrospective study of 555 patients with CHB infection who received treatment (187 with NAFLD and 368 without) found comparable rates of compensated cirrhosis (P = 0.84) and similar odds of advanced fibrosis / cirrhosis assessed noninvasively by FIB‑4 (P = 0.28).¹³ Severe or advanced liver fibrosis has been linked more closely to the degree of necrotizing inflammation and host factors rather than hepatic steatosis in patients with CHB infection.³¹ However, several previous works, including a meta‑analysis of 20 studies involving 6232 patients, indicated an association between hepatic steatosis and advanced fibrosis in CHB infection, suggesting that steatosis may contribute to fibrosis.^14,20

We found no difference in HCC history between the SLD and non‑SLD groups. This is in contrast to some studies that reported a limited impact of hepatic steatosis on HCC in patients with CHB infection.^32,33 However, our results are in line with those of a retrospective cohort study, which also found no association between hepatic steatosis and HCC risk.³⁴

Elevated liver enzyme activity is often a key indicator of liver damage and inflammation, making its association with hepatic steatosis in HBV‑infected patients a subject of ongoing research. In our study, we observed higher activity of ALT and AST in the SLD group, as compared with the non‑SLD group. However, meta‑analyses of 22 studies on ALT and 16 studies on AST reported no differences in liver enzyme activity between CHB patients with and without hepatic steatosis. These findings suggest that while hepatic steatosis can influence liver enzymes in certain contexts, its effects may not be universally observed across all CHB populations.³⁵

The present analysis showed that HBV DNA levels at the start of antiviral therapy were comparable in the SLD and non‑SLD groups. However, previous studies suggested an inverse relationship between HBV replication and hepatic steatosis. A meta‑analysis of 17 studies including 4100 patients with HBV infection found a strong negative association between HBV DNA levels and steatosis (P <⁠0.001), suggesting a potential protective effect of HBV infection against steatosis.³⁶ A review of studies conducted in Asian populations showed that concomitant NAFLD may inhibit HBV replication and promote the seroclearance of hepatitis B surface antigen.¹⁴ In contrast, a meta‑analysis by Jiang et al³⁵ did not show a relationship between HBV DNA levels and SLD.

Despite inconsistent findings regarding HBV DNA, it has been shown that patients with HBeAg‑positive CHB infection have a lower risk of hepatic steatosis. Jiang et al³⁵ reported an odds ratio (OR) of 0.81 (95% CI, 0.7–0.93) based on data from 34 studies. Similarly, another meta‑analysis with data from 13 151 patients found a reduced risk of hepatic steatosis in HBeAg‑positive individuals (OR, 0.82; 95% CI, 0.75–0.91; P <⁠0.001).²⁰ Our study confirms this relationship, showing a lower incidence of HBeAg positivity in the SLD group, as compared with the non‑SLD group (8.1% vs 22.5%; P = 0.004). This concordance highlights the potential interaction between HBV replication and metabolic factors in the pathogenesis of liver disease.

The impact of hepatic steatosis on the outcomes of antiviral treatment in patients with CHB infection remains unclear. An analysis of patients treated with pegylated interferon showed comparable treatment responses between groups with and without steatosis, regardless of HBeAg status.¹² Similarly, in patients with CHB infection receiving NA treatment, hepatic steatosis appears to have no impact on virological response.^12,37 On the other hand, a prospective study conducted among Chinese patients treated with entecavir showed that hepatic steatosis was an independent factor for treatment failure, possibly due to reduced entecavir bioavailability in hepatocytes caused by lipid accumulation and diminished cytochrome activity.³⁸ Furthermore, a global meta‑analysis identified hepatic steatosis as an independent negative predictor of virological response.³⁵ In our analysis, findings related to HBV DNA clearance and treatment duration were comparable between the groups.