Helicobacter pylori: Effect of coexisting diseases and update on treatment regimens

Abstract

The presence of concomitant diseases is an independent predictive factor for non-Helicobacter pylori (H. pylori) peptic ulcers. Patients contracting concomitant diseases have an increased risk of developing ulcer disease through pathogenic mechanisms distinct from those of H. pylori infections. Factors other than H. pylori seem critical in peptic ulcer recurrence in end stage renal disease (ESRD) and cirrhotic patients. However, early H. pylori eradication is associated with a reduced risk of recurrent complicated peptic ulcers in patients with ESRD and liver cirrhosis. Resistances to triple therapy are currently detected using culture-based and molecular methods. Culture susceptibility testing before first- or second-line therapy is unadvisable. Using highly effective empiric first-line and rescue regimens can yield acceptable results. Sequential therapy has been included in a recent consensus report as a valid first-line option for eradicating H. pylori in geographic regions with high clarithromycin resistance. Two novel eradication regimens, namely concomitant and hybrid therapy, have proven more effective in patients with dual- (clarithromycin- and metronidazole-) resistant H. pylori strains. We aim to review the prevalence of and eradication therapy for H. pylori infection in patients with ESRD and cirrhosis. Moreover, we summarized the updated H. pylori eradication regimens.

Key Words: Concomitant diseases; Helicobacter pylori; Culture susceptibility; Concomitant therapy; Hybrid therapy

Core tip: The authors outline that patients contracting concomitant diseases have an increased risk of developing ulcer disease through pathogenic mechanisms distinct from those of Helicobacter pylori (H. pylori) infections. Early H. pylori eradication is associated with a reduced risk of recurrent complicated peptic ulcers in patients with end stage renal disease and liver cirrhosis. Two novel eradication regimens, namely concomitant and hybrid therapy, have proven more effective in patients with dual resistant H. pylori strains. High-dose amoxicillin therapy is promising and superior to standard regimens. Finally, culture and susceptibility testing should be performed before third-line treatment.

INTRODUCTION

Helicobacter pylori (H. pylori), a widespread human pathogen affecting more than 50% of the human population[1], has been implicated in the development of peptic ulcer disease (PUD), gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma[2-4]. Hopkins et al[5] reported that the recurrence of peptic ulcers can markedly decrease from 70% to 10% or lower following H. pylori eradication.

Interactions among hosts, pathogens, and environmental factors are crucial to H. pylori colonization[6,7]. The presence of concomitant diseases is an independent predictive factor for non-H. pylori peptic ulcers[8]. Patients contracting concomitant diseases have an increased risk of developing ulcer disease through pathogenic mechanisms distinct from those of H. pylori infections[9,10]. Another explanation for the reported association between concomitant diseases and H. pylori-negative peptic ulcers is that many patients with comorbid conditions require nonsteroidal antiinflammatory drugs (NSAIDs). Whether H. pylori eradication can protect all patients with concomitant diseases, such as end-stage renal disease (ESRD) and liver cirrhosis, from ulcer recurrence requires further exploration.

Triple therapy is one of the oldest methods for H. pylori eradication. Resistances to triple therapy are currently detected using culture-based and molecular methods. However, such methods are difficult to apply in clinical practice because of the long period necessary before obtaining results as well as the high costs of routine performance. No therapy regimen can cure H. pylori infections in all treated patients, and some patients remain infected despite several consecutive standard therapies[11]. Concomitant therapy is a combination of antibiotics, including amoxicillin, metronidazole, clarithromycin, and a proton pump inhibitor (PPI), for a period of 5-7 d. This is a novel regimen, regarding which only a few evaluation studies have been published. Thus, the optimal therapy duration and success rates in populations with high dual resistance remain undefined.

END-STAGE RENAL DISEASE

H. pylori prevalence among patients with end-stage renal disease

Studies on H. pylori infections in uremic patients have reported rates varying from 27% to 73.0%[12-20]. This variation may have been caused by small sample sizes, nonuniform duration of dialysis, and varying methodologies and enrollment criteria. The H. pylori infection rate is lower in chronic kidney disease (CKD) (58.52%) and ESRD (56.25%) patients with PUD than in PUD patients without CKD, according to a Taiwanese population-based study[21]. Sugimoto et al[20] reported an H. pylori infection rate of 38.3% in patients with ESRD receiving dialysis for 4 years, suggesting that longer durations of dialysis reduce the risk of H. pylori infection. Factors other than H. pylori seem critical to peptic ulcer recurrence in patients with ESRD patients. These results imply that the diverse gastric environment of ESRD patients. Factors such as reductions in mucosa prostaglandin[12], hypergastrinemia[22], drugs such as NSAIDs[23], and systemic and local circulatory failure[20] influence the onset of recurrent PUD in patients with ESRD.

H. pylori tests for patients with end-stage renal disease

Invasive and noninvasive methods are available to detect H. pylori infections. However, dialyzed patients are often reluctant to undergo invasive procedures such as endoscopies[24]. Because patients with ESRD receive antisecretory drugs and require multiple antibiotic treatments for septic complications, inadvertent eradication of H. pylori infections is possible. Therefore, many H. pylori-negative patients with positive serologies were previously infected with H. pylori and inadvertently cured. The 2007 Maastricht Consensus Report on the diagnosis and treatment of H. pylori infections does not recommend the serological determination of H. pylori infections in routine clinical practice[25]. Huang et al[26] proposed that the diagnostic accuracy of H. pylori detection in patients with ESRD can be improved by performing the ¹³C-urea breath test (UBT) after hemodialysis therapy and assessing the UBT with a cutoff excess 13CO2/12CO2 ratio value exceeding 5. However, the diagnostic efficacy of the UBT for patients with ESRD remains less accurate than that for dyspeptic patients without renal impairment.

The UBT seems to be the most reliable diagnostic method for H. pylori infections in patients with chronic renal failure (CRF), and stool antigen tests show heterogeneous results, with substantial differences among manufacturers[24]. However, Wang et al[27] proposed that stool antigen is a noninvasive and reliable tool for screening H. pylori infections before therapy and assessing the success of eradication therapy in patients with ESRD. Establishing the reliability of diagnostic methods for H. pylori is crucial for managing infection[28]. Patients contracting CRF often have reduced gastric acid secretion and increased levels of urea in the blood and gastric juices[29-31], which may affect the density and distribution of H. pylori infections and, consequently, the reliability of diagnostic tests. Because no diagnostic tests for H. pylori infections are 100% reliable, the European Helicobacter pylori Study Group guidelines[32] recommend determining a gold standard from at least two techniques. The approach of combining all techniques has been used in previous studies evaluating the methods of diagnosing H. pylori infections[24,33,34]. However, this approach is too costly for use in clinical practice.

H. pylori therapy in patients with end-stage renal disease

The optimal therapeutic regimen for H. pylori infection remains undefined in patients with ESRD. Few studies concerning triple therapy in uremic patients have been reported[27,35-39]. A 1-wk course of PPI-based triple therapy (omeprazole, 20 mg twice daily; amoxicillin, 1 g twice daily; and clarithromycin, 500 mg twice daily) achieved a high eradication rate of H. pylori infection in patients with CRF and a creatinine clearance (CrCl) of less than 30 mL/min per 1.73 m², similar to that of controls with normal renal function[35]. The regimen was tolerated favorably. Another study showed that 7-d triple therapy with a low-dose OAC (omeprazole, 40 mg daily; amoxicillin, 500 mg daily; and clarithromycin, 500 mg daily) regimen was effective and safe for eradicating H. pylori infections in hemodialysis patients[40].

Amoxicillin[41] and clarithromycin[42], which are primarily eliminated renally, necessitate dosage reduction in patients with renal impairment according to CrCl. Wang et al[27] used 7-d triple therapy with omeprazole (20 mg twice daily), amoxicillin (1 g twice daily), and clarithromycin (500 mg twice daily) and reported an eradication rate of 86.8% among 40 hemodialysis patients. Tsukada et al[38] reported an eradication rate of 82.0% among 39 hemodialysis patients using 7-d triple therapy with omeprazole (30 mg twice daily), amoxicillin (500 mg twice daily), and clarithromycin (400 mg twice daily). Itatsu et al[39] used 7-d triple therapy with lansoprazole (30 mg twice daily), amoxicillin (375 mg twice daily), and clarithromycin (200 mg twice daily) in 11 hemodialysis patients and achieved an eradication rate of 72.7%.

Ideal treatment regimens should be effective, simple, and safe with fewer adverse effects and high patient compliance. One of the main reasons for treatment failure is irregular therapy with low compliance[43]. The prevalence of resistance to antibiotics, particularly clarithromycin and nitroimidazoles varies with gender, ethnic group and country[44]. Resistance to amoxicillin does not appear to be a critical problem in H. pylori-infected ESRD and non-ESRD patients in Turkey. By contrast, rates of resistance to clarithromycin are high, particularly in the ESRD population[45]. Prospective studies on the optimal therapy protocol, including antibiotic combination, dosage, and duration, in ESRD patients are warranted.

H. pylori eradication and recurrent peptic ulcers in patients with end-stage renal disease

Patients with ESRD receiving hemodialysis often have various gastrointestinal (GI) problems such as nausea, dyspepsia, appetite loss, epigastric discomfort, and heartburn. Patients with ESRD exhibit a higher incidence of PUD than do patients without renal disease[12]. H. pylori is critical in the development of peptic ulcers[46]. Therefore, physicians must consider these two factors when treating ESRD in patients with upper GI disease.

ESRD is associated with a substantial health care burden in hospitalized patients with peptic ulcer bleeding (PUB). The presence of ESRD contributes to a higher mortality rate, longer hospital stay, and increased need for surgery among such patients[47]. A population-based study conducted in Taiwan[48] over a 10-year period revealed that PUD incidence was 10-12 times higher in patients with CKD than in those without CKD. Luo et al[49] reported that patients with ESRD receiving hemodialysis exhibited a high risk of PUB. Another study showed that patients with ESRD had a higher long-term risk of peptic ulcer rebleeding[50]. A crucial question is whether H. pylori eradication therapy is necessary for H. pylori-infected dialysis patients. Although H. pylori eradication is unequivocally effective in preventing peptic ulcer recurrence in the general population[3], such effectiveness has not been established in patients with ESRD. Tseng et al[12] conducted a prospective study in a single hospital and reported that H. pylori eradication in patients with ESRD reduces recurrent PUD. In addition, a higher recurrent peptic ulcer rate was noted after successful H. pylori eradication in H. pylori-infected ESRD patients. Sugimoto et al[20,51] reported that initiating hemodialysis treatment triggers a decrease in the prevalence of H. pylori infection. Moreover, receiving a maximum of 4 years of dialysis treatment has naturally cured H. pylori infection, thus supporting the practice of administering eradication therapy to H. pylori-infected dialysis patients, particularly those receiving dialysis for 5 years or more. However, a population-based study in Taiwan[52] revealed that early H. pylori eradication is associated with a reduced risk of recurrent complicated peptic ulcers in patients with ESRD; the authors recommended administering H. pylori eradication within 120 d after peptic ulcer diagnosis in H. pylori-infected ESRD patients who have developed peptic ulcers.

LIVER CIRRHOSIS

H. pylori prevalence in patients with liver cirrhosis

Cirrhotic patients with PUB have a 5-fold higher risk of complications or death[53]. H. pylori infection promotes the production of ammonia, which is an etiological factor involved in gastric mucosa disorders[54]. However, decompensated liver cirrhosis also involves hepatic encephalopathy because of higher serum ammonia levels. Thus, decompensated cirrhotic patients with H. pylori infections seem to have a higher risk of gastric mucosa lesions and GI complications.

Kim et al[55] revealed that H. pylori infection in cirrhotic patients may be inversely related to the severity of liver cirrhosis (Child-Pugh class A group: 51.5%, class B group: 30.5%, and class C group: 20%). Jung et al[56] also showed that the H. pylori infection rate is approximately 71.1% (162 of 228 patients) in all cirrhotic patients with peptic ulcers; however, the rate is only 50.0% (17 of 34 patients) in the Child-Pugh class C group. By contrast, Siringo et al[57] used serum anti-H. pylori IgG antibody levels to confirm a higher H. pylori infection rate of 76.5% in cirrhotic patients and 95.1% in cirrhotic patients with peptic ulcers. Such variability is likely explained by differences in H. pylori prevalence inherent in different populations and methodological differences among studies, including the means of testing used to define the presence of infection.

Bhargava et al[58] showed that gastric mucosa from patients with portal hypertension exhibited typical vascular dilatation and congestion, whereas the H. pylori infection rate was significantly lower in patients with portal hypertension (51.5% H. pylori infection rate) with particularly marked vascular dilatation (only 18.8% H. pylori infection rate) compared with the controls (75.5% H. pylori infection rate). Factors other than H. pylori seem critical in peptic ulcer recurrence in cirrhotic patients. In addition, H. pylori is not the predominant etiology for liver cirrhosis, particularly the decompensated type, with PUD or recurrent ulcer disease, according to a population-based study conducted in Taiwan[59]. This is consistent with previous studies[55,60,61], and a 35.6% to 51.92% H. pylori infection rate in cirrhotic patients with peptic ulcers.

H. pylori eradication and recurrent peptic ulcers in patients with liver cirrhosis

The prevalence of H. pylori in patients with cirrhosis and PUD is generally less than 60%[60,62-65], suggesting that the pathogenesis of ulcer disease in a substantial proportion of cirrhotic patients may not be related to H. pylori infection[66-69]. Host environments are crucial to H. pylori colonization[7,70]. H. pylori adapts to humans, colonizing in children and remaining persistent throughout life[71]. The pathogenesis of the high peptic ulcer rate in cirrhotic patients is multifactorial. Cirrhotic patients have a higher risk of gastric mucosa damage because of reduced mucosal prostaglandin, which is crucial in the cytoprotection of gastric mucosa, which causes PUD. Other factors including increased serum gastrin concentration[72], impaired mucus secretion[73], and portal hypertensive gastropathy[74,75] may contribute to peptic ulcers and peptic ulcer recurrence in cirrhotic patients.

Compared with the general population, patients with cirrhosis have greater bleeding complications, delayed healing, and higher ulcer recurrence rates[68]. Luo et al[76] proposed that the risk of developing PUB in liver cirrhosis patients is 4-fold. A group of researchers from Taiwan found that 21 (58%) patients in whom H. pylori infections were eradicated developed recurrent duodenal ulcers within a year[60]. These results suggest that the pathogenesis of ulcer disease in a substantial proportion of patients with cirrhosis may not be related to H. pylori infection, a possibility proposed by researchers[65,67]. However, early H. pylori eradication is associated with a lower risk of recurrent peptic ulcers in cirrhotic patients, according to a Taiwan population-based study[77]. H. pylori eradication therapy is the primary method of treating cirrhotic patients with peptic ulcers.

H. pylori eradication and hepatic encephalopathy in patients with liver cirrhosis

A meta-analysis showed that H. pylori infections are associated with elevated blood ammonia levels in cirrhotic patients. In addition, the association seems more prominent in Asian patients than in Caucasian patients[78]. Addressing whether H. pylori eradication may benefit the long-term management of hepatic encephalopathy. Some studies have shown the benefit of eradication therapy[79-81]; however, other studies have reported negative results[82-84].

An ideal study protocol should also address a homogenous study population according to the severity of liver cirrhosis, assessment of psychometric tests, and measurements of ammonia levels in the blood. Currently, the demonstrated beneficial effect of eradication therapy in H. pylori-positive cirrhotic patients is insufficient for recommending the use of this therapy in clinical practice. An appropriately randomized study designed to assess the influence of H. pylori eradication on hepatic encephalopathy in cirrhotic patients is warranted.

ENTEROHEPATIC HELICOBACTERS AND LIVER DISEASE

Bile-tolerant helicobacter species such as H. hepaticus and H. bilis have frequently been reported to cause hepatitis in mice and other rodents[85]. The most comprehensively studied member of this group of enterohepatic Helicobacter species is H. hepaticus[86]. H. bilis has been found in species of inbred mice and reported to induce chronic hepatitis and hepatocellular carcinomas[87]. H. hepaticus was initially detected by immunofluorescence, electron microscopy, and culture in the livers of certain inbred mice and has been shown to cause multifocal necrotizing hepatitis, hepatic adenomas, and hepatocellular carcinomas[88,89]. The reason for further study of the possible role of these new helicobacter species in human liver disease has been to develop noninvasive serological assays for determining the seroprevalence of hepatic helicobacter infections[85].

Fox et al[90] stated that H. hepaticus infection increased the risk of liver cancer in hepatitis C virus and/or Hepatitis B virus infection. Fukuda et al[91] revealed that serum anti-H. hepaticus and/or anti-H. bilis antibody levels were significantly higher in patients with liver disease that in patients with other autoimmune hepatitis. Liver cirrhosis patients exhibited a substantially higher anti-H. hepaticus serum antibody level than other liver disease and health donors[92]. Although Helicobacter spp. have been identified in the liver of humans, their pathogenic role in human liver diseases remains largely unclear[93]. Kleine et al[94] established an in vitro model for demonstrating the pathogenic effect of a Helicobacter spp. on human liver cells, resulting in an inflammatory response with increased synthesis of inflammatory mediators and consecutive monocyte activation. The higher prevalence of Helicobacter spp. associated with more advanced stages of liver disease supports the possibility of their role in the progression of chronic hepatitis toward cirrhosis and hepatocellular carcinoma. An interventional study aimed at eradicating Helicobacter spp. from the liver would elucidate this association between Helicobacter spp. and liver cirrhosis and is thus warranted[93].

UPDATED H. PYLORI THERAPY

Successful eradication of H. pylori is a major component in treating these conditions[95]. However, the rate of H. pylori eradication after triple therapy is decreasing, with standard amoxicillin plus clarithromycin-based triple therapy achieving eradication rates of only approximately 75% in many series[96,97]. Apart from the conventional first-line regimen (triple therapy), other therapies have been proposed (sequential, concomitant, quadruple, and miscellaneous) to face the growing problem of antibiotic resistance. Although unsuccessful eradication can be caused by increasing antimicrobial resistance, an additional critical contributor is the treatment-related side effects and resultant incomplete therapy. New treatment regimens for H. pylori infections should be optimized to achieve an eradication rate of ≥ 95%[98]. Patient allergies and the local availability of drugs should be considered when selecting a treatment. H. pylori eradication should be confirmed after treatment, and, if second-line therapy is required, clarithromycin or a fluoroquinolone should not be reused[99].

Sequential therapy

First developed in Italy in the 1990s, sequential therapy (5-d PPI and amoxicillin, followed by 5-d PPI, clarithromycin, and metronidazole), is a regimen that has proven more effective in eradicating H. pylori than has triple therapy in many studies[100-104]. Recent multicenter randomized trials conducted in Taiwan have shown the superiority of sequential therapy over standard triple therapy. These findings also support that the most effective eradication regimen should be chosen on the basis of the prevalence of antibiotic-resistant H. pylori in a region[105]. The ability of sequential therapy to eradicate clarithromycin-resistant bacteria has been demonstrated, and sequential therapy has been included in a recent consensus report as a valid first-line option for eradicating H. pylori in geographic regions with high clarithromycin resistance[106].

Hybrid and concomitant therapy

Two novel eradication regimens, namely concomitant and hybrid therapy, have proven more effective than triple and sequential therapy in the last few years, particularly in patients with dual- (clarithromycin- and metronidazole-) resistant H. pylori strains[107-111]. Meta-analyses have shown that the outcome of concomitant therapy is duration-dependent[112]. Molina-Infante et al[113] proposed that optimized nonbismuth quadruple hybrid (consisting of omeprazole 40 mg twice daily and amoxicillin 1 g twice daily for 14 d, plus clarithromycin 500 mg twice daily and nitroimidazole 500 mg twice daily for the final 7 d as a quadruple therapy) and concomitant (consisting of omeprazole 40 mg twice daily, amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily, and nitroimidazole 500 mg twice daily, all concurrently for 14 d) therapies cured more than 90% of patients with H. pylori infections in areas of high clarithromycin and metronidazole resistance. In concomitant therapy, all four drugs are administered for the entire therapy duration, indicating that this regimen is less complex than sequential therapy because it does not involve changing the number or type of drugs halfway through the therapy. A recently proposed hybrid therapy has proven as effective as a 14-d concomitant regimen in a pilot study[106].

High-dose amoxicillin therapy

The efficacy of treatment for H. pylori infection has decreased steadily because of increasing resistance to clarithromycin, metronidazole, and levofloxacin. Resistance to amoxicillin is generally low, and high intragastric pH increases the efficacy of amoxicillin. Therefore, Yang et al[114] proposed that a combination of a high-dose PPI and amoxicillin (dual therapy), consisting of rabeprazole (20 mg, four times daily) and amoxicillin (750 mg, four times daily) for 14 d, is superior to standard regimens as empirical first-line or rescue therapies for H. pylori infection and has similar safety profiles and tolerability.

Bismuth-based quadruple therapy

During the initial development of bismuth quadruple therapy, the dose and duration of bismuth therapy were shown to be crucial variables, particularly in regions where metronidazole resistance was common[115]. However, many studies on these regimens have used suboptimal doses and durations of bismuth therapy, producing relatively poor results[116]. Bismuth-containing quadruple therapy is an alternative to standard triple therapy in areas with low clarithromycin resistance and the main first-line therapeutic option in areas with high prevalence of clarithromycin resistance. Using this regimen at full doses for 14 d produces a 95% or greater treatment success rate, irrespective of the level of metronidazole resistance[117].

Salvage therapy

Tailored antimicrobial therapy for an infectious disease is typically selected on the basis of susceptibility testing[99,118]. The treatment of H. pylori infection differs from that of most common infectious diseases because culture and susceptibility testing is generally not offered for H. pylori infections by hospital laboratories. In addition, many H. pylori infections can be identified using noninvasive testing (such as UBT or stool antigen testing), indicating that endoscopies are neither necessary nor acceptable to patients, and clinicians must choose treatment empirically. Therefore, culture and susceptibility testing should be performed before third-line treatment[106]. Salvage therapy (after multiple treatment failures) should be chosen on the basis of susceptibility testing whenever possible[101].

Probiotic therapy

Song et al[119] proposed that supplementation with Saccharomyces boulardii could be effective for improving H. pylori eradication rates by reducing side effects, thus facilitating completion of eradication therapy. Probiotics are mostly administered by modulating the balance of its microflora[120]. Probiotic adjunct therapy is particularly useful in patients with a history of GI intolerance to antibiotic treatment[121]. These effects have been demonstrated for several species of probiotics, including Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus rhamnosus, and Bifidobacterium bifidum, among others[122-124]. Proposed mechanisms include modulating the colonization of the gastric mucosa and the direct killing of H. pylori through secreted metabolites with antimicrobial properties[95]. The lack of protocol standardization is problematic, and interpreting the various results is difficult.

CONCLUSION

Although other factors influence the onset of peptic ulcer and recurrent peptic ulcer in ESRD and cirrhotic patients, H. pylori eradication therapy is the primary method of treating ESRD and cirrhotic patients with peptic ulcers. Culture susceptibility testing before first- or second-line therapy is unadvisable. The known obstacles to culture susceptibility testing include the need for endoscopic examination and the fact that culture is time-consuming, costly, and not 100% sensitive. Using highly effective empiric first-line and rescue regimens can yield acceptable results[100,107,125]. In the near future, in vivo and in vitro studies may possibly be grouped according to geographic area to identify the most effective therapy for eradicating H. pylori, which relates to the local habitat.

ACKNOWLEDGMENTS

We wish to thank the Taiwan Ministry of Education for their support for this work through its “Aim for the Top University Plan”.