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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Helicobacter and bile
  5. Helicobacter species in animal models
  6. Detection of helicobacter species
  7. Associations with diseases
  8. Conclusions
  9. Acknowledgement
  10. References

Helicobacter species, which may colonize the biliary tract, have been implicated as a possible cause of hepatobiliary diseases ranging from chronic cholecystitis and primary sclerosing cholangitis to gall-bladder carcinoma and primary hepatic carcinomas.

Research in this area has been limited by the lack of a gold standard in the diagnosis of these organisms in bile. Most published data to date have been based on molecular techniques that detect the DNA of Helicobacter species in bile, rather than evidence of viable organisms in bile.

Helicobacter species have not been shown to induce histological injury to the biliary epithelium or liver parenchyma. The strongest association of the presence of these organisms in bile is with cholestatic conditions. This article reviews the literature on this newly developing field as it has evolved historically, taking pertinent methodological issues into account.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Helicobacter and bile
  5. Helicobacter species in animal models
  6. Detection of helicobacter species
  7. Associations with diseases
  8. Conclusions
  9. Acknowledgement
  10. References

The paradigm for peptic ulcer changed dramatically following the isolation of Helicobacter pylori, which is now known to be the most important cause of chronic gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma.1–3H. pylori infection has now also been implicated as a risk factor for various extraintestinal diseases, including coronary artery disease,4 autoimmune thrombocytopenia,5 skin diseases6 and impaired growth in children.7Helicobacter species have been suggested as a cause of hepatobiliary diseases in some animals.8 More recently, Helicobacter species have been detected in human bile,9 which has prompted a growing interest as to whether these organisms truly colonize the biliary tract of humans and cause hepatobiliary diseases.

Helicobacter and bile

  1. Top of page
  2. Summary
  3. Introduction
  4. Helicobacter and bile
  5. Helicobacter species in animal models
  6. Detection of helicobacter species
  7. Associations with diseases
  8. Conclusions
  9. Acknowledgement
  10. References

The Helicobacter species that have so far been implicated as a cause of hepatobiliary diseases are H. pylori, H. rodentium, ‘Flexispira rappini’ and H. pullorum, amongst others.9–12 The source of these organisms remains uncertain, but, as many of the implicated Helicobacter species inhabit the gastrointestinal tract and are not found in the portal circulation or lymphatics, ascending infection from the duodenum is the most likely route.13

Helicobacter and survival in bile

H. pylori has adaptive mechanisms that protect the organism from the hostile acidic environment of the stomach. If Helicobacter can truly survive in the biliary tract, it must have protective mechanisms directed against the adverse effects of an alkaline pH and bile acids. There is ongoing research into the differential expression of virulence factors by different Helicobacter species that may allow them to survive in different niches.14

Bile acids are generally known to have inhibitory effects on the adherence and growth of H. pylori in vitro.15, 16H. pylori survives better with taurine-conjugated bile acids than with glycine-conjugated bile acids. Taurine-conjugated bile acids are more stable than glycine-conjugated bile acids in an acidic environment, and this can promote H. pylori survival.17

The in vitro bacteriostatic effect of bile has not been demonstrated to the same degree in vivo, suggesting the adaptive conditioning of H. pylori. In vivo studies have shown an inverse correlation between the amount of duodenogastric bile reflux and the concentration of H. pylori in the stomach in patients who have had partial gastrectomies and in those who have not.18, 19 Another study examining bile pH showed that a lower pH was more conducive to the survival of H. pylori.15 Conditions such as biliary infection, cystic duct obstruction, common bile duct obstruction and acute cholecystitis have been shown to significantly and markedly decrease the pH in bile, and so Helicobacter species may be more likely to be found secondary to hepatobiliary diseases.20

Helicobacter and pathogenesis of hepatobiliary diseases

It is generally accepted that bacteria play an important role in the formation of pigment stones, but the exact mechanisms involved in stone formation remain unclear. Glucuronidases, produced by some Enterobacteriaceae, can deconjugate bilirubin diglucuronide and result in the precipitation of calcium bilirubinate and stone formation.21Helicobacter species may also interact with bile through the production of hydrolysing enzymes,22 chronic inflammation22 and nucleating proteins, such as immunoglobulins,23 and the bacteria or slime can act as a foreign body nidus.24, 25 As gallstone disease is a heterogeneous condition, one study correlated H. pylori infection in bile with subtypes of gallstone formation.22H. pylori antibodies, antigens and DNA were assessed from bile obtained during laparotomy. Markers of H. pylori infection were identified in composite gallstones (stones of different types within the gall-bladder) and brown gallstones in the common duct, but not in black stones or solitary cholesterol stones. This preliminary study requires further confirmation in studies of a larger scale.

Bile aminopeptidase N has previously been found to increase cholesterol crystallization in bile.26 Most strains of H. pylori also possess peptidase activity, and the CagA protein of H. pylori is of a similar size to aminopeptidase N. Figura et al. assessed whether antibodies against H. pylori and the CagA antigen may increase the risk of gallstone formation.13 Fifteen of 23 bile samples from H. pylori-infected patients (65.2%) contained anti-CagA antibodies. A 60-kDa antigen that reacted with an anti-CagA antibody was found in five bile samples (21.7%) from 23 infected patients. These two factors may be associated with gallstone formation. However, on sequencing of the CagA protein itself, there was only low sequence homology with aminopeptidase N. The relationship between CagA and aminopeptidase N requires further study for clarification.

Helicobacter species in animal models

  1. Top of page
  2. Summary
  3. Introduction
  4. Helicobacter and bile
  5. Helicobacter species in animal models
  6. Detection of helicobacter species
  7. Associations with diseases
  8. Conclusions
  9. Acknowledgement
  10. References

Bile-resistant Helicobacter species, such as H. hepaticus,8H. bilis10 and H. pullorum,11 have been discovered in animals. H. hepaticus has been detected by immunofluorescence, electron microscopy and culture from livers of some in-bred mice,8, 27, 28 and has also been shown to cause multifocal necrotizing hepatitis, hepatic adenomas and hepatocellular carcinomas in these mice. The inflammatory reaction of H. hepaticus is mediated through a T-helper cell 1 cytokine response.29H. bilis has also been found in species of in-bred mice, causing chronic hepatitis and hepatocellular carcinomas in some cases.10H. pullorum, found in the livers of chickens with hepatitis, has also been reported to cause enteritis in humans.11, 30 It remains uncertain how these organisms survive in bile, or whether infections in humans can be acquired zoonotically. From these animal models of infection, increasing interest has been shown and research has been performed on the role of Helicobacter species in human hepatobiliary diseases.

Detection of helicobacter species

  1. Top of page
  2. Summary
  3. Introduction
  4. Helicobacter and bile
  5. Helicobacter species in animal models
  6. Detection of helicobacter species
  7. Associations with diseases
  8. Conclusions
  9. Acknowledgement
  10. References

Polymerase chain reaction

Polymerase chain reaction (PCR) is a highly sensitive method for detecting H. pylori, and can selectively amplify the copies of a target gene by more than 106-fold.31, 32 This technique has been employed to detect Helicobacter species in the biliary tract and liver. The initial report of the detection of H. pylori in bile was in 1995, when Lin et al. used nested PCR targeting the urease A gene to identify Helicobacter DNA in bile.9 Seven patients with pancreatic, biliary or gastric diseases were included, all of whom had detectable H. pylori antibodies. Bile was collected by percutaneous transhepatic biliary drainage or by directed gall-bladder puncture during cholecystectomy, thereby reducing the chance of contamination from the stomach or duodenum. Three of the seven bile samples from patients with pancreatic cancer or invasive gastric cancer had detectable H. pylori DNA. Two patients were given antibiotics prior to bile collection and the third was not. Partial sequencing of the PCR products confirmed the specificity of the technique, and it showed a high degree of homology with the known H. pylori sequence.

The urease A gene, however, may cross-react with the urease gene of other organisms, and PCR based on the urease A gene may therefore produce a false positive result.33 Many studies have therefore used primers that target the 16s rRNA gene, which can identify the entire Helicobacter genus rather than being limited to Helicobacter species that produce urease. The 16s rRNA genome has also been used as a determinant for taxonomic and phylogenetic classification. The PCR technique, however, is less than perfect. Most PCR tests have been validated against H. pylori rather than against the non-pylori species, and may therefore miss the non-pylori species due to genomic divergence.34, 35 Furthermore, the high sensitivity of PCR is notoriously prone to the production of a false positive result due to contamination.36 An improved PCR method, which also detects non-pylori Helicobacter strains with minimal false positive results, would be desirable.

Serology

Serology has been developed to detect the non-pylori species of Helicobacter. Although relatively inexpensive and easy to perform in routine laboratories, there are limitations to the specificity of serology in detecting species and subspecies due to cross-reactivity of the closely related Helicobacter and Campylobacter organisms.35

Histology and immunohistochemistry

Histology of the gall-bladder using the haematoxylin and eosin, Warthin–Starry and Giemsa stains has identified bacteria morphologically similar to Helicobacter in a patient who underwent cholecystectomy for calculous cholecystitis.36 This was subsequently confirmed on immunohistochemistry of the gall-bladder to be a species of Helicobacter. However, a large-scale study specifically investigating the presence of H. pylori in gastric metaplastic segments of resected gall-bladders failed to identify this organism, suggesting that Helicobacter species only very rarely colonize the gall-bladder epithelium.37 There have not been any reports demonstrating the pathogenic effects of Helicobacter species on the biliary epithelium histologically.

Culture

Culture remains the definitive investigation to prove the viability of these organisms. Unfortunately, many studies have used frozen samples of bile. With the inhibitory effects of bile acid, the culture of these fastidious organisms is extremely difficult, if not impossible. Techniques to improve the yield of culture include the addition of cholestyramine to bind bile acids, which enhanced the detection of Helicobacter in stools.38 The first report of successful culture from a liver biopsy specimen has been reported only recently.39 Colonies of bacteria with a morphology indistinguishable from H. pylori were obtained from a patient with cirrhosis. Culture took place after 9 days of incubation under microaerophilic conditions at body temperature. The strain possessed catalase, oxidase and urease, the same as H. pylori. PCR sequencing showed a greater than 99% homology with H. pylori. Electron microscopy showed the bacteria to be slightly spiralled with three to four polar sheathed flagella with terminal bulbs. This patient also had H. pylori in the stomach. Presumably, gastric H. pylori may occasionally colonize the liver.

Summary

There is a lack of a gold standard for the identification of Helicobacter species in bile. Most studies available to date have relied on PCR instead of bacteriological culture of these organisms. There is also a lack of evidence supporting definite histological changes associated with immunohistochemical markers of infection to substantiate pathogenicity. It is arguable whether the finding of Helicobacter DNA represents the enterohepatic circulation of DNA in bile, transient colonization or colonization with pathogenicity.

Associations with diseases

  1. Top of page
  2. Summary
  3. Introduction
  4. Helicobacter and bile
  5. Helicobacter species in animal models
  6. Detection of helicobacter species
  7. Associations with diseases
  8. Conclusions
  9. Acknowledgement
  10. References

The true prevalence of Helicobacter species in the bile of the normal general population is unknown. So far, bile and hepatic specimens have been obtained from patients with pathology, and even controls may not truly reflect the normal population. Data on the correlation between Helicobacter and biliary diseases need to be interpreted with caution.

The hepatobiliary diseases that have been reported to be associated with Helicobacter species in humans range from benign diseases, such as chronic cholecystitis,40 hepatolithiasis,41, 42 primary sclerosing cholangitis12, 43 and primary biliary cirrhosis,44 to malignancies, such as gall-bladder carcinoma40 and primary hepatic carcinomas.45

Helicobacter and biliary diseases

Helicobacter species have been identified in bile and gall-bladder tissue in Chileans with chronic cholecystitis.40 The incidence of carcinoma of the gall-bladder and the biliary tract in Chile is among the highest in the world. In this study, bile and gall-bladder tissue was obtained from Chilean patients with chronic cholecystitis and from controls. Thirteen of 23 bile samples and nine of 23 gall-bladder tissues were positive for Helicobacter. Eight of the Helicobacter-specific PCR fragments were sequenced and subjected to phylogenetic analysis. Five sequences represented strains of H. bilis, two strains of Flexispira rappini and one strain of H. pullorum. In two gall-bladder specimens taken from patients, silver stains detected curved bacteria suggestive of Helicobacter species. The main limitation of this study was that there were only two controls. Both were patients from the USA, one undergoing liver transplantation and one who had died of heart failure. Therefore, the controls were not representative of the patient population, and we cannot exclude the possibility that these organisms are simply part of the normal biota in Chileans. Furthermore, impaired gall-bladder contractility in chronic cholecystitis may alter bile properties to favour the survival of Helicobacter species.

However, a similar study from Mexico, which also has a high incidence of H. pylori infection, failed to detect an association between gallstones and Helicobacter colonization when analysing gall-bladder tissue.46 In this study of patients with cholelithiasis, only one of the 95 gall-bladder specimens was positive for Helicobacter on immunohistochemistry, and only one of 32 by PCR. A study from Germany also produced a negative result.47 Seventy-three bile samples and 11 pancreatic juice samples from patients with acute cholecystitis, chronic cholecystitis or common bile duct occlusion were analysed using 16s rRNA PCR. The test was verified to detect as little as 100 fg of Helicobacter species, and the specificity was determined by southern blotting. None of the bile or pancreatic juice samples showed detectable Helicobacter DNA. Another study found that the prevalence of H. pylori infection, as determined by serology, in 112 patients with gallstones and in 112 controls was no different (82% and 80%, respectively).13

Myung et al. reported that 11% of Korean patients with hepatobiliary diseases had H. pylori infection in bile.41 Seven of 30 patients with hepatolithiasis had evidence of Helicobacter species in bile using PCR, but none of the patients with cholangiocarcinoma, benign strictures, papillomatosis or cystadenocarcinoma, and none of the control group without biliary diseases, had evidence of Helicobacter species in bile. H. pylori DNA was not present in the interior of intrahepatic stones or on the biliary epithelium. Our own data from patients in Hong Kong, who had bile prospectively collected at the time of endoscopic retrograde cholangiography, disclosed that only four of 29 patients with common bile duct stones or cholangitis had Helicobacter species as detected by PCR.48 Neither the two patients with cholangiocarcinoma nor the four controls with normal biliary tracts had Helicobacter genus DNA in their bile. The presence of Helicobacter species DNA in bile did not correlate with the presence of H. pylori in the antrum and the urease B gene was negative in these patients. All patients had received antibiotics prior to endoscopic retrograde cholangiography and culture was negative for Helicobacter species. The results of both of these studies41, 48 do not substantiate a definite role of Helicobacter species in the pathogenesis of biliary diseases, despite the fact that, in both studies, Helicobacter species were only found in patients with cholestasis due to biliary stones. A Japanese study assessed patients with intrahepatic duct stones and found that biliary Campylobacter, rather than the Helicobacter genus, was associated with hepatolithiasis.42Campylobacter is phylogenetically related to the Helicobacter genus, and can inhabit the human upper gastrointestinal tract. Both genera belong to the epsilon branch of the Proteobacter family of Gram-negative bacteria.

Helicobacter species have also been implicated as a cause of primary sclerosing cholangitis. Fox et al. identified Helicobacter species using PCR amplification and southern hybridization in five of eight patients with primary sclerosing cholangitis.12 Subsequent cloning and sequencing showed that these sequences had homology with H. rodentium, Flexispira rappini and H. pullorum. Similar findings of H. pylori DNA by PCR have also been made with regard to primary biliary cirrhosis.44 Confirmation of the bacteria was performed with immunohistochemistry utilizing Helicobacter-specific antibodies and transmission electron microscopy. Nilsson et al., using PCR on liver biopsy specimens, detected Helicobacter species in nine of 12 patients with primary sclerosing cholangitis, 11 of 12 patients with primary biliary cirrhosis and only one of 23 patients with non-cholestatic liver disease or no liver disease.43 Most of these Helicobacter species were shown to be H. pylori by specific primers, southern blot hybridization and sequencing, but not H. bilis, H. pullorum or H. hepaticus. There was no difference in Helicobacter species prevalence between primary sclerosing cholangitis and primary biliary cirrhosis. Among patients with cholestatic diseases, those who had detectable Helicobacter species had a significantly higher alkaline phosphatase level than those without Helicobacter species. This study therefore suggested an association between Helicobacter species and cholestatic diseases, especially in those with higher alkaline phosphatase levels, rather than specifically with either primary sclerosing cholangitis or primary biliary cirrhosis. A relationship between Helicobacter colonization and primary biliary cirrhosis could not be confirmed in another study.49 This study analysed 29 liver specimens from patients with primary biliary cirrhosis for evidence of infection with Helicobacter, mycobacteria, Eubacteria and Archaebacteria using PCR. Archaebacteria and mycobacteria were absent in all cases, and Helicobacter species were identified in only one patient with primary biliary cirrhosis. The difference between these studies may have been the result of the use of different PCR primers. Nilsson et al. detected more cases of H. pylori because two sets of primers were used, one directed against the 16s rRNA region and the other against a 26-kDa protein specific to H. pylori.43

Helicobacter and liver diseases

Several studies have examined the association between Helicobacter species and cirrhosis in patients with chronic liver diseases. Ponzetto et al. examined the seroprevalence of H. pylori in hepatitis C virus (HCV)-infected patients compared with sex- and age-matched controls, and found the prevalences of anti-H. pylori immunoglobulin G antibodies to be 77% and 59%, respectively (P = 0.004).50 Furthermore, analysis of Helicobacter species using PCR targeting the 16s rRNA gene detected Helicobacter species in 23 of 25 liver biopsies from the cirrhotic group. Sequencing showed homology with H. pylori and H. pullorum. The authors concluded that infection with Helicobacter species contributed to the progression of HCV infection. However, the fact that the patients in the control group were not infected with HCV reduces the impact of this study. The progression to cirrhosis may have been due to HCV alone. Longitudinal studies of patients with HCV infection alone compared to those with co-infection with HCV- and bile-resistant Helicobacter species are required to address the issue of whether Helicobacter species are independent risk factors in the development of cirrhosis. Siringo et al. reported that patients with cirrhosis have a higher H. pylori seroprevalence than asymptomatic blood donor controls based on immunoglobulin G serology.51 However, this may be confounded by the older age of the patients in the study group. Nilsson et al. used serology for H. hepaticus and reported that there was no difference in the prevalence of H. hepaticus antibodies between patients with chronic liver disease and controls without liver disease.52

A recent case series found Helicobacter species in eight of eight tumour samples of hepatocellular carcinoma or hepatocholangiocellular carcinoma, compared to only one of eight controls.45 A molecular technique with PCR directed against the 16s rRNA region was used. Sequencing showed that these Helicobacter species were not closely related to H. hepaticus, but rather were as yet unnamed species of hepatic Helicobacter. Histology and culture did not reveal these organisms. This retrospective study used unmatched controls with benign diseases. This raised the possibility that the hepatic carcinomas may have caused chronic intrahepatic cholestasis, with secondary colonization with Helicobacter species. This point was addressed in the study by Nilsson et al., which examined liver tissue surrounding resected primary cholangiocarcinoma or hepatocellular carcinoma and tissue from controls with metastasis from colorectal cancers.53 Twelve of 16 patients with hepatocellular carcinoma, 10 of 14 patients with cholangiocarcinoma but none of the 20 patients with colorectal metastasis had Helicobacter species in the liver samples using PCR. Sequencing of the 16s rDNA fragments showed homology with H. pylori and hepatic Helicobacter species.

Helicobacter and pancreatic diseases

Little is known about the effects of Helicobacter species on the pancreas. Pancreatic juice has antibacterial effects that can be deficient in chronic pancreatitis. In a study of 40 patients with alcoholic chronic pancreatitis, none had detectable H. pylori PCR in the pancreatic juice obtained during endoscopic retrograde cholangiography, despite the presence of H. pylori in the stomach.54 This study suggests that the adverse condition of pancreatic juice inhibits the survival of H. pylori even in the setting of chronic pancreatitis, and therefore it seems unlikely to contribute towards the pathogenesis of pancreatic diseases.

Table 1 illustrates a summary of some of the studies associating Helicobacter and Campylobacter species with hepatobiliary diseases.

Table 1.  Studies of Helicobacter and Campylobacter species and association with hepatobiliary diseases
ReferenceStudy designMethod of detectionSpecimenHepatobiliary diseaseHelicobacter in subjectsHelicobacter in controlsOrganism identified
  • CBD, common bile duct; CC, cholangiocarcinoma; HCC, hepatocellular carcinoma; NCLC, non-cholestatic liver condition; PBC, primary biliary cirrhosis; PCR, polymerase chain reaction; PSC, primary sclerosing cholangitis; UreA, urease A gene.

  • *

    P < 0.05.

Lin et al.9ObservationalPCRBileVarious, including3/7No control groupH. pylori
(UreA) malignancies   
Fox et al.40Case–controlPCRBile,Chronic cholecystitis,13/230/2Helicobacter species
(16s rRNA)gall-bladdergall-bladder carcinoma  (H. bilis, Flexispirarappini, H. pullorum)
Roe et al.34ObservationalPCRBileCC, pancreatic cancer,10/32No control groupHelicobacter species
(UreA, 16s rRNA) hepatolithiasis   
Myung et al.41Case–controlPCRBile, biliaryIntrahepatic7/300/13 other biliaryH. pylori
(26-Da antigen, UreA)calculiductal calculi diseases; 0/23 cholecystectomy; 0/8 controls  
Nilsson et al.43Case–controlPCRLiverPSC, PBC9/12* PSC,0/10 controls,Helicobacter species
(16s rRNA)  11/12* PBC1/13 NCLC 
Avenaud et al.45Case–controlPCRLiverPrimary hepatic8/8 primary1/8Hepatic Helicobacter
(16s rRNA) carcinomahepatic carcinomas species
Nilsson et al.53Case–controlPCRLiverCC, HCC12/16 CC,0/20H. pylori, hepatic
(16s rRNA)  10/14 HCC Helicobacter species
Harada et al.42Case–controlPCRBile, biliaryIntrahepatic3/14 bile,0/9 bile,Campylobacter
(16s rRNA)epitheliumductal calculi5/8* biliary epithelium0/7 biliary epitheliumspecies (C. rectus, C. showae)
Leong et al.48Case–controlPCRBileCBD stones,4/250/4Helicobacter species
(16s rRNA) cholangitis   

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Helicobacter and bile
  5. Helicobacter species in animal models
  6. Detection of helicobacter species
  7. Associations with diseases
  8. Conclusions
  9. Acknowledgement
  10. References

So far, there is at best only circumstantial evidence to support a cause-and-effect association between infection with Helicobacter species and hepatobiliary diseases in humans. Most studies to date have been small and cross-sectional, have lacked well-matched controls and have been limited by the methods of detection of these organisms. There is a lack of culture evidence to demonstrate the viability of these organisms. Molecular detection of organisms in bile may simply be due to the enterohepatic circulation of DNA. Furthermore, there is a paucity of histological evidence to demonstrate that these organisms cause injury. While there have been studies with negative results, studies with positive results have identified different candidate organisms as the cause of hepatobiliary diseases or similar organisms as the cause of different hepatobiliary diseases. The implicated organisms have included H. pylori, non-pylori species of Helicobacter and other members of the Proteobacter family. These discrepancies cannot justify a unifying causative role of a single species of Helicobacter in the pathogenesis of hepatobiliary diseases. Some of these inconsistencies may be attributed to geographical or regional variations in the distribution of bile-resistant Helicobacter species, the accuracies of different tests, different methods of obtaining bile or the fact that multiple organisms can inhabit the biliary tract, only some of which are identified. The use of antibiotics prior to bile collection, or the inhibitory effects of bile alone, may further inhibit the growth of the organisms, producing a false negative result.

The strongest association of the presence of hepatobiliary Helicobacter species in humans has been with bile stasis. This association may simply reflect the favourable environment of bile for the survival of these organisms induced by cholestasis, such as through a reduction of the bile pH, rather than the fact that Helicobacter species cause hepatobiliary diseases. Further studies are required, especially with regard to the effective culture of the organism from bile, the development of accurate tests to identify these bacteria, large-scale autopsy studies and experimental infection of the biliary tract in animal models. Studies are required with longitudinal follow-up, and with histological correlation associating Helicobacter species with hepatobiliary diseases.

It is, however, plausible that some Helicobacter species can escape the adverse environment of bile and exist in this niche milieu, much the same as H. pylori exists in the gastric mucus. By extrapolating from studies on H. pylori in gastroduodenal diseases, there remains much to explore in this relatively new area of hepatobiliary research.

Acknowledgement

  1. Top of page
  2. Summary
  3. Introduction
  4. Helicobacter and bile
  5. Helicobacter species in animal models
  6. Detection of helicobacter species
  7. Associations with diseases
  8. Conclusions
  9. Acknowledgement
  10. References

R. W. L. Leong is partially supported by an Overseas Research Fellowship from the University of Western Australia.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Helicobacter and bile
  5. Helicobacter species in animal models
  6. Detection of helicobacter species
  7. Associations with diseases
  8. Conclusions
  9. Acknowledgement
  10. References
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