HELICOBACTER AND HEPATOBILIARY DISEASES: UPDATE 2023

Helicobacter pylori e as doenças hepatobiliares: atualização 2023

ABSTRACT

Helicobacter Pylori (H. pylori) is one of the main infectious causes of gastroduodenal diseases, however, its role in developing different extragastric diseases has been proven. The possible involvement of H. pylori in the pathogenesis of cardiovascular, metabolic, neurodegenerative, skin, and hepatobiliary diseases is suggested. The bacterium has been found in tissue samples from the liver, biliary tract, and gallstones of animals and humans. However, the role of H. pylori infection in the pathogenesis of liver and biliary diseases has not been finally established. The histopathological confirmation of the positive effect of H. pylori eradication is needed. In addition, there are discussions on the clinical significance of other Helicobacter species. The review presents the data available for and against the involvement of H. pylori in hepatobi­liary disease development and progression.

Keywords:
Helicobacter Pylori ; nonalcoholic fatty liver disease; autoimmune liver diseases; viral hepatitis; cirrhosis; cholelithiasis; cancer

HIGLIGHTS

•Clinical studies have shown that hepatobiliary diseases of inflammatory and neoplastic origin are associated with Helicobacter infection.

•Translocation and the ascending pathway are putative mechanisms for Helicobacter spp to enter the hepatobiliary system.

•H. pylori infection has a systemic effect through the activity of pro-inflammatory cytokines, TNF-α, leukotrienes, interferon-β, interferon-γ, and acute phase proteins.

•Histopathological confirmation is needed to present that H. pylori eradication prevents or improves hepatobiliary disease progression.

RESUMO

Helicobacter pylori (H. pylori) é uma das principais causas infecciosas de doenças gastroduodenais, no entanto, seu papel no desenvolvimento de diferentes doenças extragástricas tem sido comprovado. Sugere-se o possível envolvimento do H. pylori na patogênese de doenças cardiovasculares, metabólicas, neurodegenerativas, cutâneas e hepatobiliares. A bactéria tem sido encontrada em amostras de tecido do fígado, trato biliar e cálculos biliares de animais e humanos. No entanto, o papel da infecção por H. pylori na patogênese de doenças do fígado e das vias biliares ainda não foi estabelecido definitivamente. A confirmação histopatológica do efeito positivo da erradicação do H. pylori é necessária. Além disso, existem discussões sobre a importância clínica de outras espécies de Helicobacter. A revisão apresenta os dados disponíveis a favor e contra o envolvimento do H. pylori no desenvolvimento e progressão das doenças hepatobiliares.

Palavras-chave:
Helicobacter Pylori ; doença hepática gordurosa não alcoólica; doenças hepáticas autoimunes; hepatite viral; cirrose; colelitíase; câncer

INTRODUCTION

Helicobacter Pylori (H. pylori) infection is a major cause of gastroduodenal diseases, including distal cancer and gastric lymphoma. As shown by many studies over the past two decades, H. pylori infection is likely to be a risk factor for several extragastric diseases. Its role in developing idiopathic iron deficiency anemia, B12 deficiency anemia, and idiopathic thrombocytopenic purpura has been proven. The European Working Group on the study of H. pylori and microbiota included these diseases in the indications for eradicating H. pylori infection (Maastricht VI, 2022)¹. The involvement in the pathogenesis of cardiovascular, metabolic, neurodegenerative, skin, and other diseases is assumed. Many authors note the connection between H. pylori infection and chronic hepatobiliary diseases^2-4. In patients with hepatobiliary diseases living in different geographic regions, the presence of the bacterium was found in tissue samples of the liver, biliary tract, and gallstones². Progression of inflammation in the liver of any nature was also noted in the presence of H. pylori infection⁴. However, some researchers consider that there is no such correlation^5,6. The role of the bacterium in the development of liver and biliary tract diseases has not been proven. This review presents the data available on the possibility of involvement of H. pylori in the pathogenesis of hepatobiliary diseases.

HELICOBACTER SPP AND THE LIVER

Animal studies

The successful treatment of many diseases has been based on the study of animal models. Clinical studies have shown that diseases of the hepatobiliary system of inflammatory and neoplastic origin are associated with Helicobacter infection^7,8. In 1982, H. pylori was recognized as the cause of chronic gastritis, and later its role in developing a peptic ulcer and gastric cancer was established⁹. Since then, the Helicobacter has expanded to include over 30 officially named species, including the enterohepatic Helicobacter spp (EHS), which causes inflammation and cancer of the liver, gallbladder, and intestines in susceptible hosts¹⁰.

The results of studies on animals infected experimentally or naturally has shown that H. bilis and H. hepaticus are able to cause chronic active hepatitis, hepatocellular carcinoma and biliary tract carcinoma, typhlocolitis, and cancer of the lower intestine, although some individuals were recorded only asymptomatic carriage. EHS may cause cholesterol gallstone formation and intrahepatic cholelithiasis, as presented by recent studies in vivo¹¹.

In a study by Takemura et al.⁷, whose goal was to identify Helicobacter spp in the hepatobiliary tract of dogs and elucidate the possible association of these bacteria with liver diseases, Helicobacter was found in 21.2% of hepatobiliary system samples (15.2% in the liver and 9.1% in the gallbladder). The main defeat observed in infected animals was chronic hepatitis, associated or not associated with degenerative or proliferative changes. The analysis of the sequence of seven amplicons of the 16S rRNA gene of the Helicobacter genus from hepatobiliary samples has shown from 97.8 to 100% nucleotide identity with gastric Helicobacter, which confirms the hypothesis of the transfer of bacteria from the stomach to the liver by the biliary route. One amplicon of the ureA and ureB genes of the stomach Helicobacter showed nucleotide identity from 89.1 to 90.7% with H. heilmannii.

According to other studies, Helicobacter DNA fragments have been found in cats^12,13, dogs^7,14, ferrets¹⁵, rodents¹⁶, and monkeys¹⁷. These data are presented in Table 1.

TABLE 1
Helicobacter spp isolated from different animals.

Author	Year	Helicobacter spp	Animals	Diseases
Fox et al.17	2001	Helicobacter cinaedi	Monkey	Chronic colitis and hepatitis
Garcia et al.15	2002	Helicobacter cholecystus, Helicobacter spp. 266-1	Ferrets	Chronic cholangiohepatitis, carcinoma
Shen et al.16	2005	Helicobacter mastomyrinus	Rodents	Chronic hepatitis
Greiter-Wilke et al.12	2008	Helicobacter pylori, Helicobacter fenelliae/cinaedii, Helicobacter nemistrineae	Cats	Cholangiohepatitis
Beisele et al.14	2011	Helicobacter marmotae	Dogs	Chronic hepatitis, hepatocellular carcinoma
Takemura et al.8	2019	Helicobacter pylori, Helicobacter heilmannii	Dogs	Chronic hepatitis,
Elyasi et al.13	2020	Helicobacter pylori, Helicobacter bilis, Helicobacter canis	Cats	Chronic hepatitis, enterocolitis

Chronic active hepatitis has been detected in radiation experiments on male C3H/HeNrs mice in a study by Nam et al.¹⁸. Histopathologically, more than 10% of mice had liver lesions regardless of irradiation. Mild lesions have only shown focal necrosis and focal inflammation in the liver. Severe cases have been associated with hepatocytomegaly, bile duct hyperplasia, Kupffer cell hypertrophy and activation, cholangitis, pleomorphic hepatocytes, and/or tumor.

Translocation and the ascending pathway are putative mechanisms for Helicobacter spp to enter the hepatobiliary system⁷. These data are consistent with the results of a Brazilian study where Helicobacter has been found in 43.3% of cats in the liver¹³. In addition, H. pylori infection in both the liver and intestines in most of the cats has been found, demonstrating the ability for bacterial migration. These results prove the hypothesis that the bacterium can move from the intestine to the liver via the biliary tract.

Molecular methods such as polymerase chain reaction (PCR) and sequencing are used to identify Helicobacter in clinical specimens¹⁹. The whole genome sequencing has rapidly improved the characterization of Helicobacter spp. In 1997, the first H. pylori genome was published²⁰, and today the genomes of more than 1000 different strains are available. Bioinformatics analysis has provided invaluable insight into the physiology and mechanisms of H. pylori virulence. Later, in 2003, the genome sequence of the EHS prototype, H. hepaticus, was published. The genomic comparison of H. pylori and H. hepaticus revealed significant differences in gene structure and content, suggesting that essential differences underlie the contrasting colonization niches and pathogenic potentials of the stomach compared to EHS²¹. However, there are also common properties, H. hepaticus can cause persistent infection in its host, leading to chronic inflammation, which is a prerequisite for the progression of carcinogenesis. Inflammation has been related to the Th-1-associated cytokine profile, including increased expression of IFN-γ and interleukin (IL)-17 mRNA in the colon. The pro-inflammatory cytokine tumor necrosis factor (TNF)-α is also one of the oncogenic risk factors¹¹. Later, a whole genome sequencing report was published on seven EHSs, including H. bilis ATCC 43879, H. canis NCTC 12740, H. canadensis NCTC 13241, H. cinaedi CCUG 18818, H. macacae CCUG 55313^T, H. pullorum MIT 98-5489 and H. winghamensis ATCC BAA-430¹⁶.

EHSs have a larger additional gene pool than gastric Helicobacter spp, which may be due to their larger genome size (average genome length about 2 Mb compared to gastric ones: average genome length 1.63 Mb)²². It should also be taken into account that the intra-intestinal environment is less aggressive than the acidic environment in the stomach due to the hydrochloric acid and, thus, is inhabited by a more diverse microbiome, which suggests the possibility of genetic exchange. These adaptive mechanisms are a consequence of the evolution of pathogens. A study by Smet et al. examined the genetic features of H. pylori and EHS, as in recent studies, but by more than a 3-fold increase in the genomic sequences of gastric NHPH and EHS²². EHS-specific genes are associated with macrolide resistance and the ability to synthesize L-arginine from L-ornithine. Arginine and ornithine play an important role in intestinal permeability and adaptive responses. These results can probably help in the development of new therapeutic strategies for the eradication of Helicobacter, taking into account the knowledge of its protective methods.

CURRENT DATA FROM HUMAN BEINGS

Nonalcoholic fatty liver disease (NAFLD)

NAFLD is characterized by a fatty liver in the early stage that can progress to steatohepatitis, cirrhosis, liver cancer, and liver failure²³. The incidence of NAFLD increases annually and reaches 20-30% today, seriously affecting patient’s quality of life. Data from clinical and experimental studies on the involvement of the microbiota of the gastrointestinal tract in the pathogenesis of NAFLD, including H. pylori infection^2,24, have become known. However, there are still disagreements^25-27.

An important finding was that Cindoruk et al.²⁸ detected the presence of H. pylori 16S rDNA in a liver sample from a 44-year-old woman with NAFLD. In 2009, another study added credibility to this finding. Pirouz et al.²⁹ observed that patients with various chronic liver diseases were more likely to be positive for H. pylori 16S rDNA compared to controls. They found H. pylori DNA in 5 of 11 samples taken from patients with NAFLD. Genetic analysis has shown that H. pylori and NAFLD share common genetic bases (95 genes, P-value = 2.5E-72). Genetic network analysis has shown that there may be mutual regulation between H. pylori and NAFLD through 21 of 95 genes³⁰. There have been six systematic reviews with meta-analysis, all of which found a positive relation between H. pylori and NAFLD^23,30-35. A recent meta-analysis by Wei et al.(n=91,958) has also confirmed that H. pylori infection was associated with an elevated risk of NAFLD (Odds ratio (OR) = 1.38, 95% confidence interval (CI) 1.23-1.55, P<0.001)³⁶. The researchers point out the strengths and weaknesses of their study, and conclude that subsequent prospective studies are needed to confirm the association between H. pylori and NAFLD. If these data are verified, eradication of H. pylori may become a new promising point in the treatment of NAFLD.

Autoimmune liver diseases

Autoimmune liver diseases (ALD) are chronic inflammatory diseases of the hepatobiliary system that are common in clinical practice³⁷. ALD includes primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH)³⁸. Nilson et al.³⁹ have studied 36 blood samples of patients with PSC, 21 patients with PBC, 19 patients with AIH, and 80 blood donors by immunoblotting using Helicobacter pullorum, Helicobacter bilis, and Helicobacter hepaticus cell surface proteins as antigens. They have shown that the incidence of antibodies to non-gastric Helicobacter spp in patients with ALD was higher than in healthy volunteers (P<0.001).

PBC is an autoimmune liver disease whose pathognomonic manifestations are chronic progressive non-suppurative cholangitis or granulomatous cholangitis involving the small bile ducts. The disease can proceed in an asymptomatic form, but laboratory testing reveals an elevated alkaline phosphatase level, and antimitochondrial antibodies are found in 80-95% of patients with PBC⁴⁰.

Goo et al.⁴¹ reported a case of PBC in which a mouse was infected with H. pylori. Abenavoli et al.⁴² diagnosed PBC and celiac disease in H. pylori-positive woman. Their experience confirmed the pathogenic role of increased intestinal permeability in the induction of PBC in celiac disease and Helicobacter infection. Specific interactions of infections may increase the risk of PBC. There is a much higher prevalence of H. pylori antibodies in PBC patients than in controls (54% vs 31 %, P<0.01)⁴³. The mitochondrial auto-epitopic region of the pyruvate dehydrogenase complex E2 (PDC-E2) resembles H. pylori urease β, which may be related to the incidence of PBC⁴. Researchers have added H. pylori to the list of PBC etiopathogenetic factors due to presence of its DNA in the liver tissue and antibodies to H. pylori in the bile and serum of PBC patients⁴⁰.

PSC is an idiopathic progressive chronic intrahepatic cholestasis most commonly caused by fibrostenosis of the extrahepatic bile ducts. This can lead to biliary cirrhosis, which entails liver failure⁴⁰. An early study of PSC patients showed the detection of H. pylori DNA in the liver of patients with PSC and other liver diseases. This contributed to a series of subsequent studies investigating the role of Helicobacter species in PSC and other ALD⁴⁴. Krasinskas et al.⁴⁵ studied 25 end-stage PSC patients and 31 controls and found that 7 of 25 PSC patients (28%) and 3 of 31 controls (9.7%) were H. pylori positive (P=0.087). As shown by the results of the microdissection of the epithelium of the hilar bile ducts, patients with PSC are more often infected with H. pylori than the control group, presumably indicating bile reflux from the duodenum to the biliary tract. The development or progression of PSC may be associated with the entry of H. pylori into the proximal biliary system. These patients with PSC are more likely to develop ulcerative colitis, as increased intestinal permeability will stimulate H. pylori transport, triggering autoimmune mechanisms⁴⁰.

AIH is a rare syndrome that occurs without an established cause and is characterized by the destruction of liver cells by the immune system, mainly caused by autoantibodies⁴⁶. The inability to tolerate hepatic antigens is hypothesized to be due to environmental factors, which include xenobiotics and pathogens in genetically predisposed patients⁴⁷. H. pylori may be one of the triggers for this process. According to studies, the intestinal microbiota, which contains more genes than the human genome, has become a key factor in understanding the pathogenesis of liver diseases along the gut-liver axis⁴⁸. The inflammatory process caused by H. pylori alters the microbiota of the gastrointestinal tract, therefore, H. pylori can also promote the movement of pathogens and lead to the triggering of autoimmune processes in the liver, affecting the intestinal flora⁴⁹. H. pylori DNA has been detected in the liver tissues of a small number of patients with AIH, no significant differences have been found between these patients and controls⁴⁴. Durazzo et al.⁵⁰ showed that patients and controls had similar rates of H. pylori infection (P=0.3, OR=1.60, 95%CI 0.60-4.28). Peng et al.³⁹ reported that 61.67% of the 60 AIH patients were positive for H. pylori infection. Hepatic autoantibody profile rates in H. pylori-positive patients were significantly higher than in the negative group. But levels of liver function tests did not show any significant difference between H. pylori-positive or negative cases. Such pro-inflammatory cytokines as IFN-γ, IL-6, IL-10, and TNF-α were significantly higher in a blood sample of infected patients.

Viral hepatitis (HBV, HCV)

Hepatitis B and C viruses (HBV and HCV) are well-studied causative agents of liver cirrhosis. They are classified as type I liver carcinogens by the International Agency for Research on Cancer (IARC). Given that there are about 296 million people worldwide living with chronic hepatitis B according to WHO estimates⁵¹, and more than half of the population is affected by H. pylori, more and more studies are being conducted to demonstrate an association between H. pylori infection and HBV. The social significance of the proposed association is because 25-30% of patients with chronic HBV develop liver cirrhosis, hepatocellular carcinoma (HCC), or death. A large study (n=4645) conducted by Wang et al.⁵² aimed to demonstrate the role of H. pylori in the evolution of HBV and led to the recommendation to screen and treat H. pylori. This study showed some associations: a much higher prevalence of H. pylori among patients with HBV than in the healthy group (OR=3.17, 95%CI 2.38-4.22; P<0.01); the role of H. pylori as a risk factor in the development of HBV and the progression of chronic HBV to liver fibrosis; the prevalence of H. pylori infection in a group with B-viral cirrhosis (OR=4.28, 95%CI 2.99-6.13; P<0.01) is higher than in the healthy population.

A study by Segura-López et al.¹¹ has confirmed that the prevalence of H. pylori infection in patients with HBV-associated liver cirrhosis and HBV-associated cancer was significantly higher than in controls. Another study has demonstrated that the HBV-associated cirrhosis group had the highest incidence of H. pylori infection (79.3%) compared with chronic HBV, HBV-negative liver carcinoma, and the control group, indicating an increase in the incidence of H. pylori as the disease progressed in patients with HBV. The occurrence of H. pylori infection in patients with ≥10³ copies/mL HBV DNA was significantly higher than in patients with <10³ copies/mL HBV DNA (P<0.05), but there was no further correlation between H. pylori infection rate and viral load⁵³.

The Chinese multicenter observational study of 255 patients with HBV-induced cirrhosis treated with nucleoside analogues has demonstrated the effect of H. pylori infection on platelet levels in these patients. It was found that in individuals with H. pylori, the platelet count was significantly lower than in non-infected patients with compensated cirrhosis. During 2 years of follow-up, the platelet count has increased significantly in the presence of triple eradication therapy⁵⁴. It was suggested that H. pylori infection might be linked to the clinical manifestations and progression of HBV. Therefore, eradication of H. pylori in this category of patients might be beneficial, especially among those who had developed thrombocytopenia.

A growing body of evidence suggests that H. pylori may be a risk factor for liver cirrhosis and HCC in patients with HCV. According to the meta-analysis by Wang et al.⁵⁵, the prevalence of H. pylori is almost three times higher among patients with HCV than in the healthy population (OR=2.93, 95%CI 2.30-3.75, P=0.05). The main factor influencing the rate of positive H. pylori results among patients with HCV is the stage of the disease. Esmat et al.⁵⁶ has found correlation between HCV and H. pylori infection. It was performed on 85 patients, divided into five groups, where liver tissue samples have been taken and tested by PCR for the H. pylori Cag A DNA gene. The presence of the Cag A gene is the highest in the group with HCV-associated liver cirrhosis and HCC (75%), 52.9% in the group of patients with HCV-associated liver cirrhosis; and 32% in the group of patients with chronic HCV compared with controls, where the PCR positivity of the Cag A gene is significantly lower. In a study by Mahmoud et al.⁵⁷, antibodies to H. pylori IgG have been detected in the plasma of 59.6% of patients. Helicobacter DNA has been present in 11.5% of liver biopsies taken from HCV patients using Helicobacter genus-specific 16S rRNA gene primers. All cases positive for H. pylori DNA in tissue samples are positive for H. pylori IgG in plasma and negative for anti-schistosomal antibodies. H. pylori DNA-positive cases tend to be higher in HCV patients with high-stage liver fibrosis (33.3%) than those with low-stage liver fibrosis (2.7%) (P=0.0057). Thus, a strong association has been presented between H. pylori DNA in the liver and the fibrosis stage. However, no correlation has been found between H. pylori DNA in the liver and age, gender, liver function tests, alpha-fetoprotein levels, or HCV viral load. This discovery confirms the involvement of this bacterium in the progression of chronic HCV to HCC. Similar results have been obtained in a later study⁵⁸. Immunohistochemical detection of H. pylori has shown positive reactivity in 62 biopsies out of 100 biopsies (38% of HCV patients and 62% of HCV patients co-infected with H. pylori). The histological examination of the liver of HCV patients revealed microvesicular and macrovesicular steatosis, lymphocytic infiltration, fibrosis, and cirrhosis. Cirrhotic nodules and hepatic parenchymal involvement are common in HCV patients co-infected with H. pylori. HCV patients with H. pylori have higher NIC scores and advanced fibrosis stages than HCV patients. Glycogen and total protein decrease in hepatocytes and cirrhotic nodes in patients with HCV. This decrease has been noted in the liver of HCV patients co-infected with H. pylori. A recent study, which assesses the potential role of H. pylori in the progression of chronic liver disease associated with HCV is of interest⁵⁹. As a method of laboratory screening of H. pylori, the authors have used quantitative determination of the H. pylori antigen with a molecular weight of 58 kDa. The results have shown that H. pylori positivity increases significantly (P=0.021) with the progression of liver fibrosis, as it has been found in 44.45% of patients with fibrosis and 71.88% with cirrhosis. They have demonstrated that patients with F4 have been accompanied by a significant (P<0.05) increase in the concentration of H. pylori antigen with a 16.52-fold and 1.34-fold increase in its level compared with F0 and F1-F3, respectively. Patients co-infected with H. pylori and HCV are 3.19 times (219%) more likely to suffer from liver cirrhosis than patients with HCV mono-infection. This may prove that H. pylori infection may potentially affect liver disease progression. This highlights the importance of H. pylori screening in patients with HCV, as well as HBV, to select the correct treatment and prevent the further development of existing disease and the occurrence of cancer.

However, not all studies support the idea of correlation between HCV and H. pylori infection. In a study by Gutwerk et al.⁶⁰, seropositivity has been higher in the non-cirrhotic group than in the cirrhotic group (45.4% vs 20.0%, P<0.05). The IL28B SNP is well known to influence the spontaneous and treatment-induced clearance of HCV infection. For the first time, scientists have evaluated a possible link between the IL28B SNP and H. pylori. Still, no differences in IL28B genotypes among H. pylori-positive and H. pylori-negative groups have been found.

Cirrhosis

Several studies have shown that the prevalence of gastric and/or duodenal ulcers caused by H. pylori is much more often in patients with liver cirrhosis⁴. A meta-analysis by Feng et al.⁶¹ has shown that among groups of patients with cirrhosis, the rate of H. pylori infection is significantly higher than in controls (OR=2.05, 95%CI 1.33-3.18, P<0.0001). According to another study⁶², the number of patients with H. pylori and post-inflammatory liver cirrhosis is significantly higher (P=0.001) than those with alcoholic cirrhosis. Ammonia concentrations is significantly higher in H. pylori-infected patients compared to non-infected patients (129 vs 112 µmol/L; P=0.002). Helicobacter contributes to the development of hepatic encephalopathy and hyperammonemia. In a meta-analysis of six cohort studies involving 632 H. pylori-positive and 396 negative patients with cirrhosis, infection was associated with elevated blood ammonia levels. The effectiveness of H. pylori eradication in treating hepatic encephalopathy has not been thoroughly studied⁴.

Abdel-Razik et al. have succeeded to demonstrate a correlation between liver cirrhosis and HCC in patients infected with H. pylori⁶³. H. pylori is an independent risk variable for portal vein thrombosis and HCC (P=0.043, P=0.037). The study has also shown an increase levels of inflammatory factors such as serum C-reactive protein, TNF-α, IL-6, nitric oxide, and vascular endothelial growth factor in patients infected with H. pylori. A decrease in markers of inflammation and cirrhotic complications has been noted one year after H. pylori eradication.

Hepatobiliary cancer

Hepatobiliary cancer is a highly lethal cancer that includes a variety of invasive carcinomas developing in the liver (HCC), bile duct, intrahepatic and extrahepatic cholangiocarcinoma, gallbladder, and biliary tract cancer. These malignancies account for approximately 13% of all annual cancer deaths worldwide and 10-20% of deaths from hepatobiliary oncology¹¹. Since Helicobacter spp have been successfully isolated from the biliary system, a hypothetical question is raised about the role of these organisms in the development of biliary tract cancer.

HCC is the most common primary liver cancer, accounting for about 75-85% of liver cancers⁶⁴. H. pylori and similar species have been found in liver samples from patients with HCC⁶⁵. Pellicano et al. have demonstrated earlier that H. pylori infection is about 85% among patients who has developed HCC secondary to HCV-related cirrhosis⁶⁶. The incidence of H. pylori infection among patients with HBV-associated liver carcinoma (68.9%) and HBV-negative liver carcinoma (33.3%) is higher compared with controls (P<0.001)⁵³. In addition, a meta-analysis reports a positive relation between H. pylori and the risk of developing HCC⁶⁷. The incidence of H. pylori infection is 53.3% in HCC patients and 10.4% in controls, and the OR is 13.63 (95%CI 7.90-23.49) between H. pylori and the developing HCC. A recent large-scale meta-analysis by Madala et al.⁶⁴ including 26 studies has shown a significant difference in H. pylori infection in patients with HCC compared with controls. H. pylori infection is significantly higher in patients with HCC (OR= 4.75, 3.06-7.37). The results have shown an increased risk of developing HCC in the presence of Helicobacter infection, and the risk is significantly higher with HCV and H. pylori co-infection. Further prospective cohort studies are needed to prove a causal relationship, especially in cases of HBV and HCV coinfection and in patients with liver cirrhosis.

However, the studies of Helicobacter spp can enhance chronic parenchyma inflammation and lead to the development of HCC and other malignant neoplasms of the hepatobiliary system. Clinical studies using metagenomic analysis have shown that Methylophilaceae, Fusobacterium, Prevotella, Actinomyces, Novosphingobium, and H. pylori are increased in cholangiocarcinoma tissue samples compared with non-tumor tissue samples⁶⁸. A meta-analysis has examined the association between Helicobacter spp and biliary tract cancer. Helicobacter spp are detected by PCR or immunohistochemical analysis of bile samples and tissues. A significantly higher cumulative incidence of H. pylori and H. bilis is traced in the biliary tract of the malignancy group (P=0.0001) and benign biliary disease group (P=0.0001) than in the healthy controls⁸. In recent studies, there is increasing evidence that the East Asian liver fluke Opisthorchis viverrini may serve as a reservoir of Helicobacter, implicating Helicobacter in the pathogenesis of Opisthorchis’s-associated cholangiocarcinoma. Cholangiocytes affected by opisthorchiasis lining the intrahepatic biliary tract are considered to be the cell of origin of this malignant neoplasm. The authors investigate in vitro interactions between human cholangiocytes, H. pylori strain NCTC 11637, and the related bacillus H. bilis. Real-time quantification of cell proliferation, migration, and invasion by both H69 cholangiocytes and the CC-LP-1 cholangiocarcinoma cell line has shown that cell exposure to ≥10 H. pylori bacilli stimulates migration and invasion of cholangiocytes. In addition, 10 H. pylori bacilli stimulates contact-independent colony formation on soft agar⁶⁹. These data support the hypothesis that H. pylori infection promotes malignant transformation of the biliary epithelium. A meta-analysis of 10 case-control studies confirms a possible correlation between Helicobacter spp and cholangiocarcinoma (OR=8.88, 95%CI 3.67-21.49). When analyzing subgroups by geographic location, it has been found that H. pylori infection can be a risk factor not only in the Asian region with a high incidence of cholangiocarcinoma but also in Europe, where the incidence rate is much lower⁷⁰.

Cholelithiasis

Recent studies have investigated a possible risk affiliation between Helicobacter and the development of gallstones and cholecystitis. Studies have shown that H. pylori in bile may be a risk factor for its development⁷¹. For example, according to Zhang et al.⁷², age, aspartate aminotransferase, total cholesterol, H. pylori infection, HCV, and fatty liver are significantly associated with gallstones (P<0.05). The collated analysis has detected that gallstones among H. pylori-eradicated subjects are significantly lower compared to H. pylori-positive subjects (P<0.05). Moreover, a meta-analysis has demonstrated a positive correlation between H. pylori infection and chronic cholecystitis and cholelithiasis (OR=3.022; 95%CI 1.897-4.815; I²=20.1%)⁷³. Among the possible explanations for this phenomenon, it is believed that H. pylori can infect the biliary system, causing chronic inflammation of its mucosa and, as a result, leading to impaired acid secretion and a decrease in the solubility of calcium salts in bile, which predisposes to the formation of gallstones.

Mechanisms by which Helicobacter could generate damage

Inflammation and fibrosis are key factors in the progression of chronic liver diseases (Figure 1). Several theories explain how H. pylori infection can influence the development of hepatobiliary diseases⁷⁴. One of them is the violation of the epithelium of the gastrointestinal tract, the translocation of the microbiota and its metabolites into the portal system and the stimulation of inflammation through toll-like receptors (TLR) that transmit signals in hepatocytes. H. pylori induces human β-defensin-1, which may be a biomarker for bacterial translocation²⁶. H. pylori also induces the release of vasoactive and pro-inflammatory molecules such as IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, TNF-α, leukotrienes, prostaglandins, interferon-β, interferon-γ and acute phase proteins^24,63,66. It has been suggested that H. pylori infection has a systemic effect through the activity of these cytokines and the exacerbation of various inflammatory responses⁶³.

FIGURE 1
Mechanisms mediated by H. pylori infection leading to hepatic injury. CRP: C-reactive protein; IL: interleukin; JNK: c-Jun N-terminal kinase; PAMPs: pathogen-associated molecular patterns; TLR: toll-like receptors; TNF: tumor necrosis factor, VEGF: vascular endothelial growth factor.

A possible mechanism for the interaction between H. pylori infection and NAFLD involves Fetuin A or alpha-2-HS glycoprotein synthesized by hepatocytes and acting as a free fatty acid carrier. Higher serum levels of Fetuin A in H. pylori-positive patients correlate with insulin resistance. Fetuin A also acts as an endogenous adapter protein for free fatty acid-mediated TLR4 activation and triggers the release of inflammatory mediators. In addition to increasing Fetuin A levels, H. pylori infection may increase the permeability of the intestinal barrier, leading to the translocation of lipopolysaccharides and pathogen-associated molecular fragments (PAMPs) to the liver, which are known to be activators of Kupffer cells and stellate cells, promoting the development of fibrosis⁷⁵.

Recent work has suggested that H. pylori may lead to chronic vasculitis, thus causing endothelial dysfunction. Systemic inflammatory conditions caused by H. pylori increase NO production. Studies have shown that NO concentration was increased in cirrhotic patients infected with H. pylori. It is also known that excess NO generation can initiate neoplastic transformation⁶³. H. pylori is thought to increase vascular endothelial growth factor (VEGF) expression through a signaling pathway involving the MEK-ERK and NF-kB cascade. An increased concentration of VEGF has been associated with a significant increase in neoangiogenesis, as assessed by the definition of CD34-positive microvessels⁷⁶. VEGF is the main regulator of angiogenesis in malignant and normal tissues. It is vital in playing an important role in enhancing endothelial cell proliferation thereby and promoting neovascularization in and around malignant cells. It is involved in many other conditions such as receptor activation associated with tumor cell proliferation and endothelial cell recruitment⁶³. It has been declared that the bacterium enhances the secretion of adhesion molecules, which can improve the induction of neutrophils through the endothelium, which is a key crucial moment in the etiopathogenesis of endothelial dysfunction. The pro-oncogenic role of H. pylori infection is partly explained by the activation of the transforming growth factor β1-dependent oncogenic pathway, which affects the balance between hepatocyte proliferation and apoptosis in vitro models⁶³. Activation of a proto-oncogene may represent a crucial step in the mechanism of H. pylori-induced neoplasia⁶⁶. H. pylori has a pathological effect on HepG2 hepatoma cells, increasing the expression of some proteins associated with gene transcription and signal transduction⁶. The virulent type of H. pylori causes cell cycle arrest and apoptosis in Huh7 cells, another hepatoma cell line. According to Liu et al.⁷⁷, histidine-rich protein, a small histidine-rich H. pylori cytoplasmic protein, induces apoptosis by downregulating ubiquitin-specific peptidase 5 expressions and activating the P14-P53 signaling pathway. However, these data are only indirect findings from in vitro cancer cell line studies.

CONCLUSION

H. pylori, a known gastric carcinogen, is likely involved in developing many other extragastroduodenal diseases. Many studies show that H. pylori infection contributes to the etiopathogenesis of fatty liver disease. In addition, only a few studies have investigated the effect of H. pylori eradication on the development of NAFLD. Histopathological confirmation is needed to present that H. pylori eradication prevents or improves disease progression. The significance of H. pylori in the exacerbation of autoinflammatory processes of various origins should also be considered. The role of infectious agents in the development of HCC provides new insights into the pathogenesis of this disease and may influence future screening recommendations. In addition, the significance of other Helicobacter spp in hepatobiliary diseases is discussed. However, many conflicting results indicate that some evidence is inconclusive and further research is needed. Since access to the biliary pathways is only possible through invasive procedures or surgery, it is necessary to develop PCR protocols, more suitable antigens for immunohistochemistry, and simple and effective serological methods for the early detection of Helicobacter spp, which will help reduce morbidity and mortality associated with hepatobiliary diseases.

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• Disclosure of funding: no funding received

Publication Dates

• Publication in this collection
  04 Aug 2023
• Date of issue
  Apr-Jun 2023

History

• Received
  26 Jan 2023
• Accepted
  28 Apr 2023