- Open Access
The interplay between non-alcoholic fatty liver disease and innate immunity in hepatitis B virus patients
Egyptian Liver Journal volume 11, Article number: 16 (2021)
Non-alcoholic fatty liver disease (NAFLD) is the most epidemic liver disorder worldwide as a result of rapid lifestyle transformation over the past few decades and is expected to elevate in the next few years as well as it is ranging from plain hepatic steatosis via non-alcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma (HCC).
NAFLD can also stimulate the diseases progression as diabetes and cardiovascular. Therefore, understanding the NAFLD pathogenesis is of vital clinical interest additionally is a crucial for disease treatment and prevention. After analyzing NAFLD and liver diseases prevalence, it has been a belief regarding the interaction between NAFLD and chronic hepatitis B (CHB).
The liver is an essential innate immune organ with large numbers of innate immune cells that contribute in NAFLD pathogenesis, additionally play the influential role that control NAFLD progression in the hepatitis B patients. Here, we summarized the recent advances in understanding and managing the NAFLD patients with chronic hepatitis B infection and interplay with innate immunity.
In fact hepatitis B virus (HBV) infection is still a major public health problem that leads to complicated progression of severe liver diseases including cirrhosis and hepatocellular carcinoma . Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world with a global prevalence of 25.24%, and popularity is alarmingly expanding in adult, adolescent, and children populations, and it is a condition in which the aberrant lipid is accumulated and stored in the liver. There are many causes hepatic steatosis than consumption of alcohol [2, 3]. NAFLD includes a spectrum of disorders ranging from the simple fatty liver to non-alcoholic steatohepatitis (NASH), with developing fibrosis leading to cirrhosis . NAFLD significantly increases the risk of development of chronic kidney disease in type 2 diabetic patient , also patients with NAFLD have a super chance of evolving cardiovascular disease . The increasing rate of NAFLD among HBV-infected patients is alarming; it is estimated that as many as 29.6% of HBV patients worldwide have NAFLD . The reflective cohort study found that fatty liver disease in HBV patients can separately increase HBV-associated HCC progress by 7.3-fold . Also a meta-analysis comprising of 4100 HBV patients reported that body mass index (BMI), obesity; moderate alcohol consumption, diabetes mellitus, elevated serum triglycerides, and HBV viral load were risk factors of NAFLD in HBV patients .
A better understanding of the epidemiology of NAFLD among HBV patients is very important for the implementation of efficient preventive strategies with chronic HBV infected patients. The innate immune system is initiating the response of the organism to serious stressors, including pathogens, tissue injury, and malignity. The liver is a foremost innate immune organ with enormous numbers of innate immune cells, including natural killer T (NKT), natural killer (NK) cells, and Kupffer cells (KCs) which play crucial roles in the extravagant production of hepatic Th1 cytokines in NAFLD. Moreover, liver innate immune cells share in the pathogenesis of NAFLD . Abundant research data shows that innate immune processes both within and outside the liver is engaged with NAFLD .
Toll-like receptor 4 (TLR4) plays a chief role in the innate immune system that activate two specific intracellular signaling pathways via MyD88-independent pathways causing the stimulation of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and type 1 interferons (IFNs I) and also play a vital role in NAFLD progress . Many studies gave different conclusions about the correlation between NAFLD and HBV replication. Some of these studies showed increased rate of NAFLD in HBV patients, and showed suppression of viral replication by NAFLD . This review article is aimed to discuss the relationship and interplaying between NAFLD, innate immunity in HBV-infected patients, and valuable recommendations to avoid disease complications.
Molecular organization of HBV
HBV is a partially double-stranded relaxed circular DNA virus consists of 3.2 kb gnome that translated into four overlapping open reading frames (ORFs). Viral polymerase is the largest one which also has reverse transcriptase (RT) activity. Viral envelope proteins (large, middle, and small surface antigen (HBsAg). Pre-core protein that encode (HBeAg and HBcAg) which made the viral capsid. The smallest ORF is (HBx) protein which plays an important role in HBV replication and regulation in vitro and in vivo models [13,14,15]. The HBV viral ORFs were encoded in capped and polyadenylated RNAs transcripts that can classified into genomic and sub-genomic which play as a template for HBV proteins translation (0.7 kb) that encodes HBx proteins 2.1 kb and 2.4 kb HBsAg transcripts encoded (M, S, and L), respectively. On the other hand, HBV gnomic transcripts encode precore, core, and polymerase proteins and pregenomic RNA (pgRNA) which consider a template for HBV replication and reverse transcription to build HBV DNA genome [16,17,18]. HBV is classified into ten genotypes (A-J) due to high degree of genetic heterogeneity, variability, and about 8% complete genome differences. Some genotypes were sub-genotyped into sub-genotypes due to 4% sequence divergence. These genotypes and sub-genotypes can display complex ethnical, geographical distributions, and clinical implications [19,20,21].
HBV infection and epidemiology
The host and viral factors were affecting on HBV infection variations which can be classified into acute infection (presence of HBsAg and HBcAg-IgM). The presence of HBeAg indicting high level of HBV replication and most people during the acute infections have no symptoms. However, some patients developed acute illness with obvious symptoms for several weeks and rare patients can develop liver failure which can lead to death. Chronic HBV infection indicated presence of HBsAg more than 6 months. Persistence of HBsAg for long time is a marker for developing liver cirrhosis and hepatocellular carcinoma (HCC) in 20–30% of adults. In addition, some patients develop occult HBV infection (OHI) which characterized by presence of HBV DNA in the liver tissues and absence of HBsAg in serum [22,23,24]. Moreover, HBV infection is one of the major global health problems that mainly cause liver cirrhosis and liver cancer with 100-folds more that uninfected populations [25, 26]. WHO statistics were shown that about 337,000 annual deaths . In 2017, 257 million people had chronic HBV infection, which resulted in 887,000 deaths [28, 29]. HBV endemicity is classified into three groups: low (< 2%), low-intermediate (2–4.9%), high-intermediate (5–7.9%), and high (≥ 8%) .
Non-alcoholic fatty liver disease (NAFLD) definition and epidemiology
Non-alcoholic fatty liver disease (NAFLD) is defined by accumulation of triglyceride (TG) in hepatocytes (lipid droplets with 5% in hepatocytes cytoplasm) and can lead to non-alcoholic steatohepatitis (NASH), which is characterized by steatosis, inflammatory changes, and hepatocyte cell ballooning associated with varying degrees of liver fibrosis [2, 31]. NAFLD is considering a major cause of liver-related morbidity and mortality worldwide, and most common reason for chronic liver disease in the western world . NAFLD can be classified into two phenotypes: (I) steatosis (fatty liver) and (II) steatohepatitis. About 15–20% of non-alcoholic steatohepatitis (NASH) patients were progressed to liver cirrhosis and also a risk factor for heart disease [33, 34]. Recently, many studies have found development of liver cancer in NAFLD cases even in the absence of cirrhosis [35, 36]. These abnormalities were developed even in absence of extra-alcohol consumption . Globally, 25% of populations suffering from NAFLD, and the incidence were increased in the Middle East and South America rather than in Africa . The progression of NAFLD was different, it’s related to high obesity in North America and Europe (~ 83% of patients) and normal body mass index (BMI) in Asia with “lean NASH” .
NAFLD usually accompanied by many metabolic syndrome such as obesity, insulin resistance (IR), type 2 diabetes mellitus (T2DM) and dyslipidemia that exhibited an increased overall mortality compared to the general population [30, 39]. Moreover, NASH patients also have a higher risk of liver fibrosis, cirrhosis, and liver cancer that lead to mortality [40, 41]. There are different factors affecting on NAFLD progression and clinical manifestations such as environment, the micro-biome, metabolism, comorbidities, and genetic risk factors that have been underscored by studies identifying a higher risk of fibrosis among family members of those diagnosed with NASH [42, 43]. The host genetic factors were affecting on NAFLD subtypes that could be used as sensitive predictive and monitoring markers in NAFLD diagnosis and treatment .
Risk factors for NAFLD and NASH
The occurrence of metabolic syndrome (MetS) which consists of obesity, hyperglycemia, dyslipidemia, and systemic hypertension (HTN) is considered high risk factor of NAFLD  and the effective treatment of NASH could have the additional benefit of improving the features of MetS. MetS is also an important role in adverse cardiovascular (CV) events and overall mortality in patients with NAFLD [46, 47]. Type 2 diabetes mellitus (T2DM) has the clearest biologic link to the progression of NAFLD (75%) which can be developed to NASH and advanced fibrosis more than non-diabetics patients [48, 49]. Moreover, NAFLD and diabetes were considered risk factor to develop the liver related complications such as liver cirrhosis and hepatocellular carcinoma . Insulin resistance has been affecting on disease progression and integrated with NAFLD pathogenesis . On the other hand, bettering insulin resistance improves NASH. Although, patients with NAFLD are also at increased risk of incident diabetes .
Common pathogenic mechanisms of NAFLD
Hepatic steatosis is a precursor of NAFLD; steatosis can be occurred by several mechanisms such as increased fat supply, decreased fat export in the form of very low-density lipoprotein-triglyceride, decreased free fatty β-oxidation and increased de novo lipogenesis (DNL) . Molecular mechanisms affecting the prevalence of fatty liver due to certain cytokines derived from inflammation sites, especially from extra-hepatic adipose tissues. More importantly, insulin resistance (IR) appeared to play important role in massive metabolic dysregulations of NAFLD that initiate and progress hepatic steatosis. Simple hepatic steatosis, more characteristically, liver cell damage, and accompanying inflammation and/or fibrosis were considered pathological features of NASH. Currently, many pathogenic mechanisms and pathways have been proposed to explain the transition from simple steatosis to NASH, like lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress . Diacylglycerol (DAG) and ceramides are a lipid derived second messengers that generated by hepatic insulin resistance due to lipid accumulation. Furthermore, lipid accumulation in the liver lead to the progression of endoplasmic reticulum stress (ER stress), mitochondria stress, and impaired autophagy, resulting in the condition known as lipotoxicity. Finally, these events caused the immune response in the Kupffer cells and hepatic stellate cells, which leads to the progression of NASH, hepatic cirrhosis, and in some severe cases, hepatocellular carcinoma as shown in (Fig. 1) .
Diagnostic possibilities in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis
From many years ago, more systematic findings have discovered the risk of NAFLD and NASH. These risk factors were T2DM, obesity, hypertension, and dyslipidemia even with normal liver transaminases and enzymes. NAFLD and NASH could be suspected with further measurements like liver stiffness (fibroscan® test), CT-scan (sensitive and specific, but exposes the patient to radiation), or magnetic resonance induction (MRI), which is the gold standard, but most expensive to identify liver steatosis. Currently, the histological liver biopsy evaluation is the only reliable diagnostic tool for NASH with fibrotic stage of the liver to predict the liver cirrhosis . MRI elastography is the best method for fibrosis prediction but often not available or not tolerant by the patients. Many accurate non-invasive tests to examine the hepatic fibrosis were fibrosis-4 index, aminotransferase (AST), and platelet ratio (APRI) [56, 57].
In vitro models to study NAFLD
Human hepatoma cell lines such as HepG2 and immortalized primary human hepatocytes were used as in vitro models for NAFLD. But, it has some challenges such as complications of molecular pathways and some functional aberrations compared to non-immortalized primary human hepatocytes model [58,59,60,61]. Godoy et al. has reported that the use of liver biopsy-derived primary human hepatocytes as NAFLD model is applicable but also limited and can only cultivated for a few days and de-differentiation challenge . The application of hepatocytes cells as a robust in vitro model to examine the different aspects of liver functions and metabolic pathways such as cholesterol and glycogen metabolism has evaluated in recent years. But there are some limitations due to limited availability. In addition, PHHs culturing were quickly de-differentiated and lose their liver functions .
The most applicable and advanced in vitro model is human-induced pluripotent stem cell (iPSC)-derived hepatocytes that provide a good alternative model to PHHs due to easy reprogramming from dermal fibroblasts and then differentiated into hepatocyte-like cells (HLCs), which functionally look like PHHs . Many advantages were provided in iPSC-HLCs such as recapitulation of the metabolic variations observed in the population, potency in both short- and long-term drug screening and in investigating hepatotoxicity or developing novel therapeutics actions [65,66,67]. In addition, iPSC-HLCs have been utilized for fetal liver exposure to toxic substances  and identification non-coding micro-RNAs regulating human liver damage [69, 70]. Furthermore, HLCs have been successfully used as applicable in vitro models to study hepatic diseases such as systemic amyloidosis , liver-stage malaria and hepatitis C viral infection . IPSC-HLCs could also offer a gold model for examination basic liver metabolic mechanisms, e.g., lipid metabolism as well as its dysregulation is related to different diseases such as fatty liver disease or atherosclerosis.
The association between hepatitis B virus infection and non-alcoholic fatty liver disease (NAFLD)
An inverse association between HBV and some metabolic syndrome has been reported in recent studies . Furthermore, few studies have investigated the effect of HBV infection on the risk of NAFLD but still in debate. Liu et al. have reported that HBV patients have a lower level of triglycerides that may be affect NAFLD development . Moreover, some previous studies reported that HBX protein inhibits the secretion of apolipoprotein B, which play an important role in very low-density lipoprotein and low-density lipoprotein (VLDL) [75, 76]. In addition, other studies have showed the link between HBV seropositivity and low serum cholesterol levels [77, 78]. In human studies, HBV infection affecting the secretion of various adipokines and may decrease the lipid profile levels [79, 80]. On the other hand, Ramcharran et al. have reported that lipid metabolism has been implicated in hepatitis C viral entry, replication, and response to treatment and may be lipid metabolism affected by HBV replication . In depth understanding of mechanism between HBV replication and NAFLD may discover new treatment targets on NAFLD .
Limitations to study the relationship between NAFLD and HBV
Several limitations should be considered to study the association between HBV and NAFLD such as (1) Xiong’s meta-analysis study used different methods to diagnose the NAFLD outcomes, including ultrasound and proton-magnetic resonance spectroscopy (H-MRS) . But, their results with different diagnostic measures were combined that leads to heterogeneity regarding aspects in the meta-analysis process. In addition, the methodological differences may limit the comparability of studies and influence the impact identified on NAFLD risk. (2) Their results have been explained as a relationship between HBV and NAFLD only that may be confounding bias. Because, a number of adjusted factors should be considered and discussed such as physical activity and other dietary factors. For example, Zelber-Sagi et al. and Hallsworth et al. have showed that HBV patients have active physical activity and good dietary habits, which affect NAFLD incidence. (3) Failure to get information about HBV-infected patients under antiviral treatment may affect the development of NAFLD. (4) All included studies in their meta-analysis were carried out in Asia, and it is thus difficult to generalize their findings to the general population [84, 85].
Chinese studies confirmed the link between NAFLD and HBV
NAFLD was found in 23.3% of the studied group and linked to higher liver enzymes, TGs, and fasting blood sugar (FBS) in Chinese-based study . However, the accurate correlation between NAFLD and HBV infection has not been fully understood [7, 12, 82, 87, 88]. On the other hand, HBX protein affects lipogenic genes such as sterol regulatory element-binding protein1c (SREBP1C), fatty acid synthase, and peroxisome proliferator-activated receptor (PPAR) . On the contrary, many studies reported that HBV infection was not associated with hepatic steatosis and insulin resistance that may relate to metabolic factors but not viral factors [90,91,92].
In addition, HBV infection was related to lower prevalence of fatty liver, especially in overweight or obese subjects or were older than 50 years. However, the association between HBV and fatty liver was less obvious if patients were normal-weight or younger than 50 years. On the contrary, in subjects with fatty liver disease regardless of their age and BMI were correlated with HBV positivity , although many previous studies have tried to clarify the link between HBV infection and fatty liver disease [7, 12, 76, 82, 87, 88]. In China, a great difference in HBV-related fatty liver. In Beijing, the frequency of fatty liver in HBV patients is higher than that for the general population, but lower than that in HCV patients [91, 93]. On the contrary, in Shanghai, the prevalence of NAFLD in HBV patients was less than that for the general population [76, 94]. Moreover, Wang et al. 2008 showed that chronic HBV infection presented with no significant impact in the prevalence of fatty liver in patients younger than 50 years .
The association between NAFLD, innate immunity in HBV patients
NAFLD is becoming common in both general population and HBV patients that reflect the incidence of obesity in both western and eastern countries with broad spectrum ranging from simple hepatic steatosis through non-alcoholic steatohepatitis (NASH) to liver cirrhosis . Nowadays, many Asian patients are suffering from both NAFLD and chronic HBV infection. However, the mechanism of NAFLD and its effects on HBV infection have not yet been adequately clarified in patients with CHB [96, 97].
Some previous studies reported that hepatic steatosis in CHB patients is mainly associated with metabolic disorders, such as obesity, type 2 diabetes mellitus (T2DM), and dyslipidemia; it is not associated with HBV viral load or genotype [7, 82, 98, 99]. This is proved by the strongly expressive results indicating a negative association of hepatic steatosis with viral load. Thus, hepatic steatosis may enhance viral clearance and inhibit HBV DNA replication. However, we have not been successful in elucidating the mechanism underlying the association between steatosis and HBV [82, 98]. Some evidences indicate that toll-like receptor 4 (TLR4) signals the pathway associated with the pathogenesis of NAFLD in patients with HBV infection. TLRs are a family of pattern recognition receptors that play a critical role in the innate immune system as ten different types of TLRs are expressed in human beings. Toll-like receptor 4 is a cell surface receptor that is crucial for the activation of innate immune responses .
Machado et al. and Michelson et al. have explained the mechanism linked between TLR4 and NAFLD via MyD88-dependent and MyD88-independent pathways that activated with binding TLR4 to induce proinflammatory cytokine genes, such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and type 1 Interferon (IFNsI) [11, 101]. On the other hand, bacterial endotoxin lipopolysaccharide (LPS) is a well-known as TLR4 ligand [102, 103], and, non-bacterial substances such as free fatty acids (FFAs) may also function as TLR4 ligands. Palmitic acid (PA) and oleic acid (OA) are the most common FFAs that bind with TLR4 to activate the expression of proinflammatory cytokines in macrophages, adipocytes, and liver cells [100, 104, 105]. TLR4/MyD88 signaling pathways played an important role in NAFLD incidence. In addition, downstream proinflammatory cytokines (TNFα, IL-6) promoted the progression of NAFLD. However, the interaction between chronic HBV infection and TLR4 is complex; some studies have indicated that HBV replication is inhibited when LPS signals TLR4 to upregulate IFN-β expression levels through MyD88 independent pathway [106, 107]. On the other hand, some direct and indirect mediators inhibit viral replication such as IFNα/β, TNFα, IL-1, and nitric oxide [107, 108] as shown in (Fig. 2).
The relationship between serum HBV DNA level and NAFLD was investigated in previous studies that showed that HBV DNA levels were lower in NAFLD patients . In HBV transgenic rat model, when NAFLD developed, serum HBV DNA, HBsAg, and HBeAg levels were decreased, i.e., NAFLD was thought to suppress HBV replication . In another study, HBsAg-positive signals staining in liver biopsy samples was reported to be decreased in NAFLD compared with non-NAFLD patients . Chu et al. 2013 have reported that HBV infection patients who were HBsAg seroconversed in short time with NAFLD patients . Furthermore, NAFLD prevalence was found to be higher in patients with HBsAg seroconversion . Fas receptors increasing on the surface of hepatocytes has been thought to facilitate cell apoptosis, which resulted in increased viral clearance in patients with NAFLD .
On the contrary, there are also same studies that reported an increased rate of NAFLD with HBV patients [111, 113, 114]. Especially, HBX proteins that enhance the transcription of sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor (PPAR) that promote NAFLD by means of stimulating the synthesis of acetyl-CoA carboxylase1 and fatty acid synthase and detection of gene expression of the enzymes responsible for lipid degradation such as cyp4A [113, 114]. In another study, Jiang et al. 2011 have showed that, an increasing serum HBV DNA levels has been reported in increased SREBP-1c levels and NAFLD . Regarding to all these studies, one may consider that HBV infection increased the potential of NAFLD; however, this potential has been less than that of host factors such as metabolic syndrome. Moreover, NAFLD itself appears to suppress HBV viral replication. NAFLD was affected on virologic response to entecavir treatment in the literature and showed that virologic response at 24, 48, and 96 weeks of entecavir treatment was less in patients with NAFLD  and explained the role of decreased bioavailability of entecavir in fatty hepatocyte and cytochrome enzyme levels on drug metabolism [117, 118].
On the other hand, it has been proved that the HBV DNA levels decreased in animal models of liver steatosis . However, as indicated in epidemiological trials, the effect of host factors such as age and obesity on liver steatosis is more than the effect of HBV replication  and FAS receptors levels on the surface of hepatocytes causes more hepatocyte apoptosis . Also, in another study, serum HBV DNA levels were low in patients with liver steatosis . When they consider the previously conducted studies, they have thought that, instead of interpreting this situation as low HBV replication causes liver steatosis, saying that liver steatosis suppresses HBV replication would be more rational .
Both chronic hepatitis B and non-alcoholic fatty liver disease establish abnormalities of liver’s histopathology and enzymes that potentiate end-stage cirrhosis together along with HCC, consequently threatening the patient’s health. Toll-like receptor 4 (TLR4) plays a very critical role in innate immunity activation that essential to NAFLD pathogenesis in patients with HBV infection. Healthy lifestyle maybe needed to stop the progression of steatosis in chronic HBV infection. Since both hepatitis B and NAFLD are liver diseases, it is a vital to protect this organ, so changing patients’ lifestyle plays relevant role in the disease treatment, especially nutrition and physical exercise. Overweight persons respond more poorly to hepatitis B treatment so dietary modification as limiting and balanced nutritional scheme permits weight loss and subsequently improve diseases clinical picture, but rapid and uncontrolled weight loss are not recommended as it can be mischievous for patients and may even aggravate NAFLD clinical symptoms, additionally very low calorie diets (388 kcal/day) must be avoided as they can lead to serum bilirubin elevation and overall inflammation activation .
A recommended diet for NAFLD and hepatitis B patients must be rich in fibers, low in calories, and monounsaturated fatty acids. White meat is highly recommended as it is low in fat, and occasionally red meat is accepted. The diet should be rich in vegetables and fruits, which are good sources of antioxidative vitamins (β-carotene, vitamins C, and E). Good sources of vitamin C include red pepper, parsley leaves, and horseradish, while food products rich in β-carotene are carrot, parsley leaves, and onion leaves, and finally vitamin E can be found in wheat germ, sunflower oil, and fortified margarines . The antioxidants in foods help decrease inflammation by combating unstable free radicals, which play role in cell inflammation, and cancers. Walnuts are rich in α-linolenic fatty acid, and consumption of 30 g daily causes a decline in total cholesterol and LDL levels so it is highly recommended . Frying, soft drinks rich in a high-fructose corn syrup, and processed foods, in particular fast food, should be prevented . Oligofructose- prebiotics are highly recommended as a nutritional therapy as it reduce the triglycerides and glucose serum levels, also increase free fatty acid concentrations in the large intestine, moreover reduce the amount of food consumption increases concentration of serum glucagon-like peptide 1 (GLP-1), and finally its supplementation for 6 months regulates glycemia, decreases the risk of insulin resistance, also attenuates the inflammation within hepatocytes .
Sugar limitation is a vital part of an immune-boosting diet, as a high-sugar diet (HSD) induces type 2 diabetes (T2D) and obesity, also HSD induced the aberrant activation of the innate immune system, including inflammation, so patients should strive to limit the sugar intake to less than 5% of the daily calories . Patients must stay hydrated as dehydration can lead to complications that can elevate susceptibility to the illness. Sleep and immunity are closely tied, so patients should be sleep adequately at least 7 h at night that may strengthen the natural immunity. Keeping physically fit by regular exercise even walking can aid your liver in many ways, as it helps in burning of more calories and boosts the immune function plus the energy and mood. Moreover management and relieving of stress and anxiety are crucial for immune health [127, 128].
Availability of data and materials
Activated platelet ratio I
Body mass index
Chronic hepatitis B
Fasting blood sugar
Free fatty acids
Glucan-like protein 1
Hepatitis B core antigen
IgM antibody for hepatitis B core antigen
Hepatitis B envelope antigen
Hepatitis B surface antigen
Hepatitis B virus
Hepatitis B x antigen
Proton magnetic resonance spectroscopy
High sugar diet
- IFNs I:
Type I interferon
Induced pleuropotent stem cells
Magnetic resonance induction
MYD88 Innate Immune Signal Transduction Adaptor
Non-alcoholic fatty liver disease
Natural killer cells
Occult hepatitis infection
Open reading frames
Peroxisome proliferative activating receptor
Sterol regulatory element binding protein 1C
Diabetes mellitus type 2
T helper cells
Toll-like receptor 4
Tumor necrosis factor alpha
Very low density lipoprotein
Liang X, Bi S, Yang W et al (2009) Epidemiological serosurvey of hepatitis B in China–declining HBV prevalence due to hepatitis B vaccination. Vaccine 27(47):6550–6557
Brunt EM, Wong VW, Nobili V et al (2015) Nonalcoholic fatty liver disease. Nat. Rev. Dis. Primers 1:150–803
De Minicis S, Day C, Svegliati-Baroni G et al (2013) From NAFLD to NASH and HCC: pathogenetic mechanisms and therapeutic insights. Curr Pharm Des. 19:5239–5249
Azzam H, Malnick S (2015) Non-alcoholic fatty liver disease—the heart of the matter. World J Hepatol 7(10):1369–1376
Targher G, Bertolini L, Rodella S et al (2008) Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia 51:444–450
Schwimmer JB, Deutsch R, Kahen T et al (2006) Prevalence of fatty liver in children and adolescents. Pediatrics 118:1388–1393
Machado MV, Oliveira AG, Cortez-Pinto H et al (2011) Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients. J. Gastroenterol. Hepatol 26:1361–1367
Chan AW, Wong GL, Chan HY et al (2017) Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B. J. Gastroenterol. Hepatol 32(3):667–676
Nagy LE (2003) Recent insights into the role of the innate immune system in the development of alcoholic liver disease. Exp. Biol. Med 228:882–890
Maher JJ, Leon P, Ryan JC et al (2008) Beyond insulin resistance: Innate immunity in nonalcoholic steatohepatitis. Hepatol 48:670–678
Zhang Z, Pan Q, Duan XY et al (2012) Fatty liver reduces hepatitis B virus replication in a genotype B hepatitis B virus transgenic mice model. J. Gastroenterol. Hepatol 27:1858–1864
Bjorkbacka H, Kunjathoor VV, Moore KJ et al (2004) Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat. Med 10(4):416–421
Ali BA, Salem HH, Wang XM et al (2009) Detection of hepatitis B polymerase gene in early embryonic cells from golden hamster oocyte and human spermatozoa carrying HBV DNA. Int. J. Virol 5(4):164–169
Tsuge M, Hiraga N, Akiyama R et al (2010) HBx protein is indispensable for development of viraemia in human hepatocyte chimeric mice. J. Gen. Virol 91:1854–1864
Ali BA (2015) Hepatitis B Virus (HBV) and Its Vertical Transmission. LAP Lambert Academic Publishing, Germany, Editor, ISBN: 978-3-659-71140-4.
Seeger C, Zoulim F, Mason WS et al (2014) Hepadnaviruses. In: Knipe DM, Howley PM (eds) Field’s Virology, 6th edn. Wolters Kluwer/Lippincott Williams & Wilkins Health, Philadelphia, PA, pp 3376–3436
Nassal M (2015) HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 64:1972–1984
Seeger C, Mason WS (2015) Molecular biology of hepatitis B virus infection. Virol 479(480C):672–686
Schaefer S (2007) Hepatitis B virus genotypes in Europe. Hepatol Res 37:S20–S26
Tatematsu K, Tanaka Y, Kurbanov F et al (2009) A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J. Virol 83:10538–10547
Kramvis A (2014) Genotypes and genetic variability of hepatitis B virus. Intervirol 57:141–150
Raimondo G, Allain JP, Brunetto MR et al (2008) Statements from the Taormina expert meeting on occult hepatitis B virus infection. Hepatol 49:652–657
Torbenson M, Thomas DL (2002) Occult hepatitis B. Lancet Infect. Dis 2:479–486
Muhlemann B, Jones TC, Damgaard PDB et al (2018) Ancient hepatitis B viruses from the bronze age to the medieval period. Nature 557:418–423
Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer Incidence and Mortality Worldwide: Sources, Methods and Major Patterns in Globocan 2012. Int J Cancer 136:E359–E386
El-Serag HB (2012) Epidemiology of Viral Hepatitis and Hepatocellular Carcinoma. Gastroenterol 142:1264–1273 e1261
WHO? Global Health Estimates. (2015). Estimated Deaths by Cause, 2000 and 2015. Available online: http://www.who.int/entity/healthinfo/global_burden_disease/GHE2015_Deaths_Global_2000_2015.xls. (Accessed on 10 April 2017).
World Health Organization (2017) Global Hepatitis Report. WHO, Geneva, p 2017
Centers for Disease Control and Prevention. (2017). Preventing hepatitis B. https://www.cdc.gov/globalhealth/immunization/othervpds/preventing_hepatitisb.html. Retrieved March 30, 2018.
Vanni E, Marengo A, Mezzabotta L et al (2015) Systemic complications of nonalcoholic fatty liver disease: when the liver is not an innocent bystander. Semin Liver Dis 35:236–249
Brunt EM (2010) Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 7:195–203
Vernon G, Baranovam A, Younossim ZM et al (2011) Systematic review: the epidemiology and natural history of non- alcoholic fatty liver disease and non- alcoholic steatohepatitis in adults. Aliment Pharm Ther 34:274–285
Musso G, Gambino R, Cassader M et al (2011) Meta- analysis: natural history of non- alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non- invasive tests for liver disease severity. Annu. Rev.Med 43:617–649
Chalasani N, Younossi Z, Lavine JE et al (2012) The diagnosis and management of non- alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatol 55:2005–2023
Adams LA, Lymp JF, St-Sauver J et al (2005) The natural history of nonalcoholic fatty liver disease: a population- based cohort study. Gastroenterol 129:113–121
Bhala N, Angulo P, Van-der Poorten D et al (2011) The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatol (Baltimore, MD) 54:1208–1216
Younossi ZM (2016) Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatol 64:73–84
Loomba R, Sanyal AJ (2013) The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 10:686–690
European Association of Study Liver, European Association of Study Diabetes, European Association of Study Obstetrics (2016) EASL-EASDEASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. Hepatol 64:1388–1402
Satapathy SK, Sanyal AJ (2015) Epidemiology and natural history of nonalcoholic fatty liver disease. Sem Liver Dis 35:221–235
Angulo P, Kleiner DE, Dam-Larsen S et al (2015) Liver fibrosis, but no other histological features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterol 149:389–397
Caussy C (2017) Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis. J clin invest 127:2697–2704
Loomba R (2015) Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterol 149:1784–1793
Pouladi N, Bime C, Garcia JGN et al (2016) Complex genetics of pulmonary diseases: lessons from genome-wide association studies and next-generation sequencing. Transl Res 168:22–39
Huang PL (2009) A comprehensive definition for metabolic syndrome. Dis Model Mech 2:231–237
Käräjämäki AJ (2017) Non-alcoholic fatty liver disease with and without metabolic syndrome: different long-term outcomes. Metabolism 66:55–63
Allen AM (2018) Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: a 20 year-community study. Hepatol 67:1726–1736
Bazick J, Donithan M, Neuschwander-Tetri B et al (2015) Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD. Diabetes Care 38:1347–1355
Kwok R (2016) Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut 65:1359–1368
Anstee QM, Targher G, Day CP et al (2013) Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 10:330–344
Choudhury J, Sanyal AJ (2008) Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease. Clin Liv Dis 8:575–594
Ballestri S (2016) Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J. Gastroenterol. Hepatol 31:936–944
Ballestri S (2016) Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis J Gastroenterol Hepatol. 2016;31(5):936-44. https://doi.org/10.1111/jgh.13264. PMID:26667191
Neuschwander-Tetri BA (2010) Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatol 52:774–788
Banini BA, Sanyal AJ (2016) Nonalcoholic fatty liver disease: epidemiology, pathogenesis, natural history, diagnosis, and current treatment options. Clin Med Ins Ther 8:75–84
Usluer G, Erben N, Aykin N et al (2012) Comparison of non-invasive fibrosis markers and classical liver biopsy in chronic hepatitis C. Eur J Clin Microl 31:1873–1878
Arora A, Sharma P (2012) Non-invasive diagnosis of fibrosis in non-alcoholic fatty liver disease. Clin Exp Hepatol 2:145–155
De Gottardi AM, Vinciguerra A, Sgroi M et al (2007) Microarray analyses and molecular profiling of steatosis induction in immortalized human hepatocytes. Lab Invest 87:792–806
Ricchi MMR, Odoardi L, Carulli C et al (2009) Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes. J. Gastroenterol. Hepatol 24:830–840
Currie EA, Schulze R, Zechner TC et al (2013) Cellular fatty acid metabolism and cancer. Cell Metab 18:153–161
Cantor JR, Sabatini DM (2012) Cancer cell metabolism: one hallmark, many faces. Cancer Discov 2:881–898
Godoy P, Hewitt NJ, Albrecht U et al (2013) Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and nonparenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Ach. Toxicol 87:1315–1530
Elaut G, Henkens T, Papeleu P et al (2006) Molecular mechanisms underlying the dedifferentiation process of isolated hepatocytes and their cultures. Curr. Drug. Metab 7:629–660
Hu C, Li L (2015) In vitro culture of isolated primary hepatocytes and stem cell-derived hepatocyte-like cells for liver regeneration. Protein Cell 6:562–574
Holmgren G, Sjögren AK, Barragan I et al (2014) Long-term chronic toxicity testing using human pluripotent stem cellderived hepatocytes. Drug Metab Dispos 42:1401–1406
Medine CN, Lucendo-Villarin B, Storck C et al (2013) Developing high-fidelity hepatotoxicity models from pluripotent stem cells. Stem Cells Transl Med 2:505–509
Szkolnicka D, Farnworth SL, Lucendo-Villarin B et al (2014) Accurate prediction of drug-induced liver injury using stem cell-derived populations. Stem Cells Transl Med 3:141–148
Lucendo-Villarin B, Filis P, Swortwood MJ et al (2017) Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells. Ach Toxicol 91:1–11
Szkolnicka D, Lucendo-Villarin B, Moore JK et al (2016) Reducing hepatocyte injury and necrosis in response to paracetamol using noncoding RNAs. Stem Cells Transl Med 5:764–772
Yang D, Yuan Q, Balakrishnan A et al (2016) MicroRNA-125b-5p mimic inhibits acute liver failure. Nat. Commun 7:11916
Leung A, Nah SK, Reid W et al (2013) Induced pluripotent stem cell modeling of multisystemic, hereditary transthyretin amyloidosis. Stem Cell Rep 1:451–463
Zhou X, Sun P, Lucendo-Villarin B et al (2014) Modulating innate immunity improves hepatitis C virus infection and replication in stem cell derived hepatocytes. Stem Cell Rep 3:204–214
Wang CC, Tseng TC, Kao JH (2015) Hepatitis B virus infection and metabolic syndrome: fact or fiction? J. Gastroenterol. Hepatol 30:14–20
Liu J, Yang HI, Lee MH et al (2010) Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community-based follow-up study. Gastroenterol 139:474–482
Kang SK, Chung TW, Lee JY, Lee et al (2004) The hepatitis B virus X protein inhibits secretion of apolipoprotein B by enhancing the expression of N-acetylglucosaminyltransferase III. J biol chem 279:28106–28112
Chiang CH, Yang HI, Jen CL et al (2013) Association between obesity, hypertriglyceridemia and low hepatitis B viral load. Int j Obes 37:410–415
Su TC, Lee YT, Cheng TJ et al (2004) Chronic hepatitis B virus infection and dyslipidemia. J Formos Med Assoc 103:286–291
Chen JY, Wang JH, Lin CY et al (2010) Lower prevalence of hypercholesterolemia and hyperglyceridemia found in subjects with seropositivity for both hepatitis B, C strains independently. J. Gastroenterol. Hepatol 25:1763–1768
Wong VW, Wong GL, Yu J et al (2010) Interaction of adipokines and hepatitis B virus on histological liver injury in the Chinese. Am. J. Gastroenterol. Suppl 105:132–138
Hui CK, Zhang HY, Lee NP et al (2007) Serum adiponectin is increased in advancing liver fibrosis and declines with reduction in fibrosis in chronic hepatitis B. Hepatol 47:191–202
Ramcharran D, Wahed AS, Conjeevaram HS et al (2010) Associations between serum lipids and hepatitis C antiviral treatment efficacy. Hepatol 52:854–863
Wong VW, Wong GL, Chu WC et al (2012) Hepatitis B virus infection and fatty liver in the general population. Hepatol 56:533–540
Johnson NA, Walton DW, Sachinwalla T et al (2008) Noninvasive assessment of hepatic lipid composition: Advancing understanding and management of fatty liver disorders. Hepatol 47:1513–1523
Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R et al (2007) Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population-based study. Hepatol 47:711–717
Hallsworth K, Fattakhova G, Hollingsworth KG et al (2011) Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut 60:1278–1283
Hou XH, Zhu YX, Lu HJ et al (2011) Non-alcoholic fatty liver disease’s prevalence and impact on alanine aminotransferase associated with metabolic syndrome in the Chinese. J. Gastroenterol. Hepatol 26:722–730
Hsu CS, Liu CH, Wang CC et al (2012) Impact of hepatitis B virus infection on metabolic profiles and modifying factors. J Viral Hepatitis 19:e48–e57
Lee IC, Huang YH, Chan CC et al (2011) Impact of body mass index and viral load on liver histology in hepatitis B e antigen-negative chronic hepatitis B. Clin Nutri 30:647–652
Na TY, Shin YK, Roh KJ et al (2009) Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus associated hepatocellular carcinoma. Hepatol 49:1122–1131
Jan CF, Chen CJ, Chiu YH et al (2006) A population based study investigating the association between metabolic syndrome and hepatitis B/C infection (Keelung Community-based Integrated Screening study No. 10). Intern j Obes 30:794–799
Peng D, Han Y, Ding H et al (2008) Hepatic steatosis in chronic hepatitis B patients is associated with metabolic factors more than viral factors. J. Gastroenterol. Hepatol 23:1082–1088
Shi JP, Fan JG, Wu R et al (2008) Prevalence and risk factors of hepatic steatosis and its impact on liver injury in Chinese patients with chronic hepatitis B infection. J. Gastroenterol. Hepatol 23:1419–1425
Shi JP, Fan JG, Wu R et al (2008) Prevalence and risk factors of hepatic steatosis and its impact on liver injury in Chinese patients with chronic hepatitis B infection. J Gastroenterol Hepatol. 2008;23(9):1419-25. https://doi.org/10.1111/j.1440-1746.2008.05531.x. PMID: 18853998.
Fan JG, Farrell GC (2009) Epidemiology of non-alcoholic fatty liver disease in China. Hepatol 50:204–210
Wang CC, Hsu CS, Liu CJ et al (2008) Association of chronic hepatitis B virus infection with insulin resistance and hepatic steatosis. J. Gastroenterol. Hepatol 23:779–782
Wong GL, Wong VW, Choi PC et al (2009) Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B. Gut 58(1):111–117
Rastogi A, Sakhuja P, Kumar A et al (2011) Steatosis in chronic hepatitis B: prevalence and correlation with biochemical, histologic, viral, and metabolic parameters. Indian J Pathol Micr 54(3):454–9.4
Fan JG, Jia JD, Li YM et al (2011) Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010: (published in Chinese on Chinese Journal of Hepatology 2010; 18:163-166). J Dig Dis 12(1):38–44
Yun JW, Chom YK, Parkm JH et al (2009) Hepatic steatosis and fibrosis in young men with treatment-naive chronic hepatitis B. Liver Int 29(6):878–883
Paik YH, Schwabe RF, Bataller R et al (2003) Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatol 37(5):1043–1055
Michelsen KS, Wong MH, Shah PK et al (2004) Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. PNAS 101(29):10679–10684
Spruss A, Kanuri G, Wagnerberger S et al (2009) Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatol 50(4):1094–1104
Rivera CA, Adegboyega P, Van Rooijen N et al (2007) Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. Hepatol 47(4):571–579
Yang L, Seki E (2012) Toll-like receptors in liver fibrosis: cellular crosstalk and mechanisms. Front Physiol 3:138
Lee JY, Sohn KH, Rhee SH et al (2001) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. Biol Chem 276(20):16683–16689
Chen Z, Cheng Y, Xu Y et al (2008) Expression profiles and function of Toll-like receptors 2 and 4 in peripheral blood mononuclear cells of chronic hepatitis B patients. J. Clin Immunol 128(3):400–408
Wu J, Lu M, Meng Z et al (2007) Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice. Hepatol 46(6):1769–1778
Sweet MJ, Hume DA (1996) Endotoxin signal transduction in macrophages. J. Leukoc. Biol 60(1):8–26.21
Wang MM, Wang GS, Shen F et al (2014) Hepatic steatosis is highly prevalent in hepatitis B patients and negatively associated with virological factors. Digest Dis Sci 59:2571–2579
Chu CM, Lin DY, Liaw YF (2013) Clinical and virological characteristics post HBsAg seroclearance in hepatitis B virus carriers with hepatic steatosis versus those without. Digest Dis Sci 58:275–281
Chu CM, Lin DY, Liaw YF (2007) Does increased body mass index with hepatic steatosis contribute to seroclearance of hepatitis B virus (HBV) surface antigen in chronic HBV infection? Int J of Obes 31:871–875
Feldstein AE, Canbay A, Angulo P et al (2003) Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterol 125:437–443
Brown AJ (2008) Viral hepatitis and fatty liver disease: how an unwelcome guest makes pâté of the host. Biochem 416:e15–e17
Hajjou M, Norel R, Carver R et al (2005) cDNA microarray analysis of HBV transgenic mouse liver identifies genes in lipid biosynthetic and growth control pathways affected by HBV. J Med Virol 77:57–65
Jiang CY, Zeng WQ, Chen YX et al (2011) Effect of HBV on the expression of SREBP in the hepatocyte of chronic hepatitis B patients combined with hepatic fatty change. Zhonghua Gan Zang Bing Za Zhi 19:608–613
Jin X, Chen Y, Yang Y et al (2012) Association between hepatic steatosis and entecavir treatment failure in Chinese patients with chronic hepatitis B. PloS One 7:e34198
Taliani G, Duca F, Lecce R et al (1995) Hepatic lidocaine metabolism in chronic hepatitis C virus hepatitis with or without steatosis. Hepatol 21:1760–1761
Leclercq I, Horsmans Y, Desager JP et al (1998) Reduction in hepatic cytochrome P-450 is correlated to the degree of liver fat content in animal models of steatosis in the absence of inflammation. Hepatol 28:410–416
Poortahmasebi V, Alavian SM, Keyvani H et al (2014) Hepatic steatosis: prevalence and host/viral risk factors in Iranian patients with chronic hepatitis B infection. Asian Pac J Cancer P 15:3879–3884
Ceylan B, Arslan F, Batırel A et al (2016) Impact of fatty liver on hepatitis B virüs replication and virolojik response to tenofovir and entecavir. Turk J of Gastroenterol 27:42–46
Jarosz M, Respondek W, Grzymisławski M (2010) Dietary recommendations and lifestyle [Polish]. In: Jarosz M (ed) Nonalcoholic fatty liver disease. PZWL, Warsaw, pp 45–56
Sauberlich HE (2007) Nutrition of human with elements of biochemistry [Polish]. In: Ciborowska H, Rudnicka A (eds) Dietetics. Nutritional therapy for healthy and ill patients. PZWL, Warsaw, pp 280–289
Zivkovic AM, German JB, Sanyal AJ (2007) Comparative review of diets for the metabolic syndrome: implications for nonalcoholic fatty liver disease. Am J Clin Nutr 86:285–300
York LW, Puthalapattu S, Wu GY (2009) Nonalcocholic fatty liver disease and low-carbohydrate diets. Annu Rev Nutr 29:365–379
Cani PD, Knauf C, Iglesias MA et al (2006) Improvement of glucose tolerance and hepatic insulin sensitivity by oligofructose requires a functional glucagon-like peptide 1 receptor. J. Diabetes 55:1484
Yu S, Zhang G, Jin LH (2018) A high-sugar diet affects cellular and humeral immune responses in Drosophila. Exp Cell Res 368(2):215–224
Bae YS, Shin EC, Bae YS et al (2019) Editorial: Stress and Immunity. Front Immunol 10:245
Ott JJ, Stevens GA, Groeger J et al (2012) Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 30:2212–2219
The authors would like to thank to Stem Cell Research Center, Research Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, China, and Department of Nucleic Acid Research, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt, for their complete kind help and support.
This work was supported by grants from the National Natural Science Foundation of China (Nos. 81571994, 81570567, and 81870432); the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, and the Li Ka-Shing Shantou University Foundation. The role of the funding body was represented in design of the study and collection, analysis and interpretation of data, and in writing the manuscript.
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Megahed, F.A.K., Zhou, X., Sun, P. et al. The interplay between non-alcoholic fatty liver disease and innate immunity in hepatitis B virus patients. Egypt Liver Journal 11, 16 (2021). https://doi.org/10.1186/s43066-021-00084-w
- Fatty liver
- Innate immunity