0
Review Article |

Non–Gastrointestinal Tract Associations of Helicobacter pylori Infection:  What Is the Evidence? FREE

Grigoris I. Leontiadis, MD; Virender K. Sharma, MD; Colin W. Howden, MD
[+] Author Affiliations

From the Department of Medicine, Democritus University of Thrace, General Hospital of Alexandroupolis, Alexandroupolis, Greece (Dr Leontiadis); and the Department of Internal Medicine, University of South Carolina, Columbia (Drs Sharma and Howden). Dr Howden is now with the Division of Digestive Diseases, Rush University Medical School, Chicago, Ill.


Arch Intern Med. 1999;159(9):925-940. doi:10.1001/archinte.159.9.925.
Text Size: A A A
Published online

Helicobacter pylori infection is linked to conditions of the upper gastrointestinal tract, including peptic ulcer and gastric adenocarcinoma. It has also been associated with a wide variety of non–gastrointestinal tract conditions. However, the evidence in support of H pylori infection as a cause of the non–gastrointestinal tract conditions is not widely understood. We reviewed the medical literature for publications and abstracts dealing with putative non–gastrointestinal tract associations of H pylori infection. We appraised the level of evidence and applied it to an established set of 9 criteria for determining causation. We found that many studies examining a possible causal relationship have been uncontrolled or inadequately controlled. Studies have often failed to control for socioeconomic status. Studies of treating H pylori infection in patients with these disorders have been poorly designed and inappropriately controlled, and therefore add little to the evidence base. Attention should be focused on appropriate testing for and treatment of H pylori infection in patients with conditions that are of proven association, notably peptic ulcer disease.

Helicobacter pylori has been conclusively linked to different forms of gastritis, as well as to peptic ulcer disease of the stomach and duodenum,1,2 gastric adenocarcinoma,15 and low-grade gastric lymphoma arising from mucosa-associated lymphoid tissue.4,6Helicobacter pylori may also have a role in dyspepsia and nonulcer dyspepsia, although this role is currently unresolved.79

In view of the excitement and interest generated by the link between H pylori and gastric abnormalities, different investigators have sought to determine a role for the infection in a variety of non–gastrointestinal tract disorders. This is despite our current understanding that H pylori infection is confined to gastric mucosa. Although the infection is noninvasive, it triggers a marked local inflammatory response and a systemic immune response.10,11Helicobacter pylori infection of the stomach could conceivably produce effects elsewhere by altering levels of systemic inflammatory mediators.12,13 Our aim is to review critically the evidence that H pylori infection causes various other disorders outside the alimentary tract.

Since H pylori infection is so common throughout the world,14,15 it is not surprising that it has been found in patients with other diagnoses. Such findings may have been because of chance alone. Therefore, assumptions that certain conditions are caused by H pylori infection might be spurious; association need not necessarily imply causation. Evidence in support of causation comes in different forms. The strongest evidence comes from randomized, controlled trials, which are seldom available. After those, in decreasing levels of strength, come cohort studies, case-control studies, and case series or single-case reports.16 Other forms of evidence reviewed herein include experimental studies and observational, cross-sectional studies (controlled or uncontrolled).

We conducted a fully recursive MEDLINE search for published articles dealing with H pylori infection and conditions outside the gastrointestinal tract. We supplemented this with a review of abstracts from recent national and international gastroenterology conferences and conferences specifically devoted to H pylori. We deliberately chose to include abstracts, since research on H pylori is developing rapidly, and we wanted to identify any recent important developments or trends. We reviewed in full those articles published in English. For articles published in other languages, we reviewed an English abstract.

The following 9 questions were conceived by Sackett et al16 for considering whether a possible association is causal:

  • Is there evidence from true experiments in humans?

  • Is the association strong?

  • Is the association consistent from study to study?

  • Is the temporal relationship correct?

  • Is there a dose-response relationship?

  • Does the association make epidemiological sense?

  • Does the association make biological sense?

  • Is the association specific?

  • Is the association analogous to a previously proven causal association?

These are listed in decreasing order of importance. We have attempted to answer these 9 questions for each of the conditions under review (Table 1). However, when considering a possible role for H pylori infection in a condition outside the gastrointestinal tract, it is not possible to answer each of these questions conclusively. For example, apart from 2 well-described case studies of self-inoculation,1719 there have been no direct experiments of H pylori infection in humans.

Table Graphic Jump LocationTable 1. Application of 9 Diagnostic Tests for Causes of Certain Non–Gastrointestinal Tract Conditions Proposed to Be Related to Helicobacter pylori Infection*

The means of testing for H pylori infection might influence the strength of association with any of the non–gastrointestinal tract conditions under review. Some studies have used highly sensitive and specific means for determining the presence of the infection, such as a carbon-labeled urea breath test (UBT) using carbon 13 or carbon 14. Such tests are highly accurate in determining active H pylori infection.20,21 Other studies have determined H pylori status by serological means. Generally, serological tests have lower sensitivity and specificity than UBT or endoscopic tests; their results may be false-positive in some patients successfully treated for H pylori infection in the past.21,22

It is seldom possible to assess the temporal relationship between the proposed cause (namely,H pylori infection) and the proposed outcome (viz, the non–gastrointestinal tract condition in question). However, our present understanding is that H pylori infection is generally acquired in childhood.2,14,15 Therefore, it might be reasonable to assume that acquisition of the infection would antedate the development of any condition presenting for the first time in adulthood.

It is generally impossible to know if a dose-response relationship exists between H pylori infection and another condition. The diagnosis of H pylori infection is essentially qualitative rather than quantitative. Since the infection is present or absent, its "dose" is unknown. Also, the duration of H pylori infection is usually unknown and cannot otherwise be assessed, although most infections are probably acquired in childhood. We have attempted to evaluate the scientific validity of the biological rationale for any proposed association. However, for many of the putative associations, there is no obvious biological rationale or pathogenetic mechanism.

Helicobacter pylori typically infects and is confined to gastric mucosa. Such mucosa is customarily restricted to the stomach but may also occur elsewhere in the alimentary tract. Heterotopic or metaplastic gastric mucosa infected with H pylori has been documented in the proximal esophagus,23,24 the distal esophagus,25,26 the duodenum,27,28 Meckel diverticulum,29,30 and the rectum.31

Changes in systemic inflammatory mediators could conceivably produce effects elsewhere in the body.12,13Helicobacter pylori infection may also be associated with altered coagulation.

Effects of H pylori Infection on Coagulation
Coagulation Factors.

In England, Patel and colleagues32 studied 72 middle-aged white men without a known history of coronary heart disease (CHD). They found a higher mean serum fibrinogen concentration in the men with serological evidence of H pylori infection compared with those who were uninfected (P=.007). In a case-control study of 388 men in England, their group confirmed a significantly raised mean serum fibrinogen concentration associated with H pylori infection.33 In a controlled study of patients recovering from acute myocardial infarction (MI), Rajput-Williams and colleagues34 found a higher mean serum fibrinogen level in their H pylori–infected healthy control subjects than in their noninfected controls (P=.04).

A case-control study involving more than 2000 men and women in Northern Ireland failed to demonstrate any association between H pylori infection and serum fibrinogen or plasma viscosity.35 In a study of patients with dyspepsia in England, no association was found between H pylori status and serum fibrinogen concentration or levels of other coagulation factors, including factors VII:c and VIII:c and von Willebrand factor.36 In 292 patients with CHD, H pylori status was not significantly associated with serum levels of fibrinogen, factor VII or von Willebrand factor.37

In Italy, Bierti and colleagues38 found a significantly higher mean serum fibrinogen level in 64 H pylori–infected patients compared with 66 noninfected patients (P=.04). They also found higher antigen levels of von Willebrand factor in the H pylori–infected group (P<.01). Levels of plasminogen activator inhibitor were no different between H pylori–infected and noninfected patients.

In 300 healthy blood donors from Italy, 53% were seropositive for H pylori infection.39 Levels of fibrinogen were no different between those who were seropositive and seronegative. Those who were seropositive for H pylori had higher concentrations of factor VII:c and prothrombin cleavage fragment. However, these differences disappeared after adjustment for age, sex, and social class.

No significant association was demonstrated between H pylori status and serum fibrinogen levels in almost 1500 male and female patients with CHD in Scotland.40 In a prospective study, Wald et al41 observed 21,520 professional men in England for a mean of 15.6 years. They found no association between H pylori status and serum fibrinogen levels. A recent meta-analysis found no significant association between H pylori status and serum fibrinogen level.42

The best evidence for an association between H pylori infection and hyperfibrinogenemia comes from cross-sectional or case-control studies. However, the association between H pylori infection and increased levels of fibrinogen or other coagulation factors is inconsistent. The largest and most robust studies and a meta-analysis failed to demonstrate any association.

Platelets.

Increased levels of circulating platelet aggregates were demonstrated in 5 patients with upper gastrointestinal tract complaints who were seropositive for H pylori, compared with 5 similar patients who were seronegative.43 There is no epidemiological evidence of an effect of H pylori infection on platelet function.

Effects of H pylori Infection on Markers of Systemic Inflammation
Leukocyte Counts.

A raised whole blood leukocyte count is associated with an increased risk for CHD.44 Patel et al33 found a significantly higher leukocyte count in 191 middle-aged white men who were seropositive for H pylori infection than in 197 who were seronegative. Karttunen et al45 from Finland studied 96 patients with dyspepsia, of whom 58 were seropositive for H pylori infection. Total whole blood leukocyte counts were significantly higher in the H pylori–positive group, as were absolute counts of lymphocytes and basophils. Three studies36,39,46 and a meta-analysis42 found no association between H pylori status and leukocyte counts.

The best evidence of an association between H pylori infection and a raised leukocyte count comes from case-control studies, but is inconsistent. Prospective studies and a meta-analysis do not confirm the effect.

C-reactive Protein and Tumor Necrosis Factor.

In a population-based, cross-sectional study of 388 middle-aged, white men in England, H pylori status was one of many variables found to correlate with serum levels of C-reactive protein (CRP).47 In turn, raised CRP levels were associated with elevated levels of serum fibrinogen, total cholesterol, triglyceride, and glucose. They were negatively associated with high-density lipoprotein (HDL) cholesterol concentration. Concentration of CRP is strongly associated with a propensity to CHD. Serum concentrations of tumor necrosis factor α are positively related to H pylori status.48 Tumor necrosis factor α is one of the cytokines that regulate CRP production by the liver. Higher circulating levels of soluble tumor necrosis factor receptor I are reported in patients with CHD who are seropositive for H pylori infection.49

Helicobacter pylori infection may elevate circulating levels of CRP. However, this is a very nonspecific finding.

Effects of H pylori Infection on Other Risk Factors for Cardiovascular Disease
Cholesterol, Triglyceride, and Glucose Levels.

Patel et al33 found no association between H pylori status and serum levels of cholesterol, triglyceride, apolipoproteins A or B, or glucose. Murray et al35 found no significant association between H pylori status and levels of total or HDL cholesterol. McDonagh et al40 found no association between H pylori status and total cholesterol levels.

Scragg et al50 studied a large group of asymptomatic, nondiabetic workers in New Zealand. They found no association between H pylori status and levels of total cholesterol, triglyceride, or glucose. Levels of HDL cholesterol were slightly lower in individuals who were seropositive for H pylori infection than in those who were seronegative (mean difference, 0.07 mmol/L [2.7 mg/dL]; P=.03). Infection with H pylori was also associated with a lower HDL cholesterol concentration in a cross-sectional study of the elderly in Finland.51

In a Spanish study of 112 patients with CHD admitted to a coronary care unit (CCU), there was no association seen between H pylori status and the presence of hypercholesterolemia or diabetes.52 In a cross-sectional study of 1756 Danish women, H pylori serological status did not correlate with serum triglyceride or cholesterol levels.53 In a United States–based study, H pylori serological status was determined in 103 patients undergoing coronary angiography for suspected CHD.54 Fifty-two patients (50%) were seropositive for H pylori. Serological status was not related to total cholesterol levels or to the presence of diabetes.

Among 91 elderly, dyspeptic patients in Italy, results of gastric histological and rapid urease tests were positive for H pylori infection in 60.55 There were no significant differences between the patients with positive and negative results with respect to mean levels of glucose, total cholesterol, HDL cholesterol, or triglyceride.

In a nested case-control study, Whincup et al46 studied 95 middle-aged British men who had survived an MI, 93 who had survived a stroke, and a similar number of matched controls. Helicobacter pylori status was not significantly associated with total cholesterol, HDL cholesterol, or triglyceride levels. However, serum glucose levels were significantly higher in the patients who were seropositive for H pylori (P = .006). In their prospective study of healthy English men, Wald et al41 found no association between H pylori status and total cholesterol or triglyceride levels.

In South Korea, Kang and colleagues56 studied 274 patients with suspected CHD who were undergoing coronary angiography. Of these, 64.1% were seropositive for H pylori infection. They found no association between H pylori status and hyperlipidemia or diabetes. However, the same group identified a significantly higher (P=.006) mean serum cholesterol level in association with H pylori infection in a study of 3274 healthy Korean adults.57 Although statistically significant, this difference was small and unlikely to be clinically meaningful.

The seroprevalence of H pylori infection was 53% in 381 healthy Spanish subjects without a history of peptic ulcer disease or hyperlipidemia.58 Although the H pylori–infected subjects had a higher mean total serum cholesterol level than those who were not infected, this difference was not apparent after adjustment for age and sex.

A meta-analysis found no significant association between H pylori status and serum cholesterol levels.42 However, it found a highly statistically significant, although quantitatively small, difference in HDL cholesterol levels (mean difference, −0.032 mmol/L [−1.2 mg/dL]; P<.001) between H pylori–infected and noninfected individuals. It found a small, statistically significant association between H pylori infection and serum or plasma glucose levels (mean difference, 0.14 mmol/L; P<.05), but no association with serum triglyceride levels.

The best evidence of an association between H pylori infection and hypercholesterolemia comes from cross-sectional studies. There is little consistency in results between different studies. The magnitude of effect, if any, is low. There may be a small, negative effect on HDL cholesterol levels.

Homocysteine.

A raised serum level of homocysteine is an independent risk factor for CHD.5961 Sung and Sanderson61 have proposed that H pylori infection prediposes to hyperhomocysteinemia through nutritional deficiencies of folate and vitamins B6 and B12. However, B12 malabsorption might only occur in few infected patients, and only after many years of H pylori infection associated with extensive atrophic gastritis and loss of parietal cell mass. Even then, body stores of vitamin B12 should be sufficient to delay the development of true deficiency for years. There is no particular reason why H pylori infection per se should be associated with dietary deficiencies of folate or vitamin B6.62

Whincup et al63 found no difference in serum homocysteine levels between 63 H pylori–infected and 55 noninfected individuals without CHD. Saxena et al64 found no significant difference in mean serum homocysteine levels between 122 patients seropositive for H pylori and 98 seronegative patients. Markus and Mendall65 found no association between H pylori status and serum levels of homocysteine or folate in a case-control study of patients with ischemic stroke. Two studies64,65 found a nonsignificant trend toward lower homocysteine levels in association with H pylori infection.

There is no evidence to suggest thatH pylori infection causes hyperhomocysteinemia.

Heat-Shock Proteins.

Heat-shock protein (hsp) 65 is a stress protein that is expressed in high concentrations in atherosclerotic tissue.66 Immunization of animals with hsp65 can induce atherosclerotic lesions in the absence of hypercholesterolemia. Levels of serum antibodies to hsp65 are significantly higher in patients with carotid atherosclerosis than in matched controls.66 An immune reaction to hsps might play a role in the pathogenesis of atherosclerosis.67 As a group, hsps have high homology among different species from bacteria to man.66Helicobacter pylori expresses an hsp10 known as hsp62 that is highly homologous with hsp65 and endogenously produced hsp60.68 Among 136 men consecutively investigated using cardiac catheterization for chest pain or valve abnormalities, there was a highly significant correlation (r = 0.39; P<.001) between the presence of antibodies to hsp65 and H pylori.68 The patients who were seropositive for H pylori had significantly higher levels of antibodies to hsp65 than those who were seronegative.

There may be an association between H pylori infection and the presence of antibodies to hsps. The relevance of this to the pathogenesis of atherosclerosis is not fully understood.

Cardiovascular Disorders
Coronary Heart Disease.

Mendall and colleagues69 in England found a 59% seroprevalence of H pylori infection in 111 consecutive white men with established CHD and a 39% seroprevalence in 74 community-based controls (P=.007). After adjustment for socioeconomic status and other cardiovascular risk factors, the odds ratio (OR) for CHD in the presence of H pylori infection was 2.15 (P=.03). However, others thought this association was not causal.70 In a cross-sectional study of a random sample of 388 white men in England, Patel and colleagues33 found an association between H pylori seropositivity and the presence of abnormal results of electrocardiography consistent with underlying CHD (OR=3.82; P<.01).

In the cross-sectional, population-based study from Northern Ireland by Murray and colleagues,35 there was only a weak association between H pylori status and CHD that did not reach statistical significance (OR=1.51; P=.10). McDonagh and colleagues40 in Scotland found no significant association between H pylori seropositivity and any measure of CHD among 1428 randomly selected men and women. In Finland, Niemalä and colleagues71 performed a case-control study in 116 patients with angiographic evidence of CHD and 116 age- and sex-matched community controls. Seroprevalence of H pylori infection was similar in both groups (64% vs 53%; OR=1.5). In a nested case-control study in the United Kingdom, Whincup and colleagues46 found a seroprevalence of H pylori infection of 70% in 95 middle-aged men who survived an MI and 57% of 78 age-matched controls (OR=1.77; P=.03). An analysis of the Eurogast database71 found that deaths due to CHD were negatively correlated with seropositivity for H pylori infection (r=−0.73; P<.05).

Morgando and colleagues72 from Italy studied the seropositivity of H pylori infection in 42 patients admitted to a CCU with acute MI and 198 hospital-based controls. The rates of seroprevalence were 85.7% and 57.1%, respectively. The controls were not well-matched for age, sex, or the absence of cardiac disease. In Spain, Martín-de-Argila and colleagues73 reported a 84.1% seroprevalence of H pylori infection in 101 patients with CHD admitted to the CCU, and a 58.8% prevalence in 68 healthy controls (P<.001) who were not well-matched for age or sex. In a similar study of 112 patients with CHD admitted to the CCU, 81.3% were seropositive for H pylori compared with 63.8% of 53 healthy controls (P<.01) matched roughly for age but not for sex.52

In another poorly controlled study, Ponzetto and colleagues74 reported a seroprevalence of 89% among 27 patients with acute MI and 47% among 619 blood donors (OR=4.4). Rathbone and colleagues75 performed a case-control study in 342 consecutive patients admitted to a CCU with acute MI and 236 population-based controls. Seroprevalence of H pylori infection was 60.2% in the patients and 55.9% in the controls (age- and sex-stratified OR=1.05; P=.87). In Italy, Parravicini and colleagues76 performed 13C-UBT on 137 patients with acute MI and 312 healthy blood donors, not well-matched for age. Helicobacter pylori infection was found in 86.1% of the patients and 58.6% of the blood donors, who were younger.

In Germany, Maier and colleagues77 performed a prospective serological study of 87 consecutive patients with known or suspected CHD who were undergoing coronary angiography. The seroprevalence of H pylori infection was no different in those with or without angiographic evidence of CHD (68.4% vs 80.0%; P=.04). Ossei-Gerning37 in England studied 292 patients having coronary angiography for suspected CHD; 204 had angiographic evidence of CHD, and the seroprevalence of H pylori infection in these 204 was 68%. Of the 88 patients without evidence of CHD, the seroprevalence was 50% (P=.003). However, a similar angiographic study of 70 patients in Germany found no significant difference in rates of H pylori infection, determined using endoscopy, in patients with and without CHD (56% vs 44%; P>.05).78 Furthermore, a study in Korea of 274 patients undergoing coronary angiography for suspected CHD found no difference in H pylori seroprevalence between patients without visible lesions and those with disease in 1, 2, or 3 coronary arteries.56 In a United States–based angiographic study, H pylori serologic studies were performed in 179 patients with suspected CHD79; 121 had angiographic evidence of CHD and 58 did not. Seroprevalence of H pylori infection was 45% in those with CHD and 47% in those without (P=.96).

Balaban and colleagues80 in the United States studied the seroprevalence of H pylori infection in 201 consecutive patients referred for noninvasive cardiac investigation because of suspected CHD. Adjusted ORs for an association with H pylori infection were not significant for CHD (OR=0.54; P=.10) or a previous MI (OR=2.14; P=.10). However, they found a significant relationship between H pylori infection and a history of MI in women (OR=10.9; P=.03), although the sample size was only 34.

In a prospective cohort study of elderly people in Finland, Strandberg and colleagues81 found no significant association between H pylori seropositivity and evidence of vascular disease. Cardiovascular and total mortality were not related to H pylori status. Similarly, Wald and colleagues in England found no association between H pylori seropositivity and death due to CHD in their prospective study (nested case-control design) of more than 21,000 professional men (OR=1.06).41

The best evidence of an association between H pylori infection and CHD comes from a nested case-control study. Larger prospective studies did not find a significant association. There is no consistent conclusion among different studies. In general, large controlled studies have not confirmed the findings of earlier smaller studies. Those that used appropriate controls were less likely to report a significant association.82

Cerebrovascular and Peripheral Vascular Disease.

In a nested case-control study, Whincup et al46 studied results of H pylori serologic testing in 137 middle-aged British men in whom a stroke developed before December 1991 and in 136 age-matched and geographically matched controls. Of the patients with stroke, 93 (67.9%) were seropositive for H pylori compared with 78 (57.4%) of the controls. The OR for stroke associated with H pylori infection was 1.57 (P=.07). After adjustment for socioeconomic status, smoking, and blood pressure, the OR was 0.96 (P=.92).

In a study of 91 elderly dyspeptic patients in Italy, 60 had results of gastric histological examination and rapid urease testing that were positive for H pylori.55 All patients underwent echodoppler ultrasonography of extracranial and peripheral arteries. Those with H pylori infection had a similar number of detectable atherosclerotic plaques as the uninfected patients and a similar number of arteries with detectable plaques. The prevalence of concomitant risk factors for atherosclerosis, including hypertension, diabetes, and hypercholesterolemia, was no different between H pylori–infected and noninfected patients.

In a case-control study, H pylori seropositivity was significantly more common in 238 patients with nonhemorrhagic stroke or transient ischemic attack (58.8%) than in a control group of the spouses of 119 patients (44.5%; OR=1.78; P<.01).65 This association held when controlled for other risk factors, including socioeconomic status. In subgroup analyses, the association was only true for large-vessel disease and lacunar stroke rather than for embolic stroke or stroke of unknown causes. Patients with stroke and those with transient ischemic attacks had similar rates of H pylori seropositivity (59.6% and 58.6%, respectively; P=.90).

In an Italian study of 45 patients with carotid or femoral arterial obstruction, 39 (86.7%) were seropositive for H pylori infection,83 compared with 111 (60.7%) of 183 blood donors who acted as controls. It is unclear how well matched the control group was.

The best evidence of an association between H pylori infection and stroke comes from a case-control study; the magnitude of effect was small.

Hypertension.

Barnes and colleagues84 from England observed 103 patients who had been investigated for dyspepsia between 1973 and 1980 and had normal upper endoscopic results. To look for evidence of H pylori infection, they reexamined gastric mucosal biopsy specimens that had been collected from all patients. They were unable to establish a link between H pylori status and the nature, severity, or progression of dyspeptic symptoms. However, they noticed an unexpected significant association between H pylori infection and hypertension.

Lip et al85 reported a significantly higher seroprevalence of H pylori infection in patients with hypertension compared with healthy controls. Of 124 hypertensive patients, 85% were seropositive compared with 66% of 38 healthy controls (P=.007). The seroprevalence of H pylori infection was not further increased in patients with malignant-phase hypertension.

Whincup et al46 found a nonsignificant association between H pylori positivity and systolic blood pressure (SBP) in their nested case-control study in England. Mean SBP was 143.7 mm Hg in 78 men with and 138.3 mm Hg in 58 men without H pylori infection (P=.06). Mean diastolic blood pressure (DBP) was 81.5 mm Hg in infected and 79.5 mm Hg in noninfected patients (P=.37).

At least 7 studies have failed to find an association between H pylori infection and hypertension.33,35,40,41,50,52,65 A meta-analysis42 found a statistically significant, although quantitatively small, difference in SBP between H pylori–infected and noninfected individuals (mean difference, 0.9 mm Hg; P<.05), but no association between H pylori status and DBP.

The best evidence of an association between H pylori infection and hypertension comes from a cross-sectional study. No consistent relationship was demonstrated. Most evidence points toward no association.

Idiopathic Arrhythmia.

In an uncontrolled study, the prevalence of H pylori infection among 54 patients with idiopathic arrhythmia was 42%.86 The rationale for this study was unclear. The prevalence was similar between those with supraventricular and ventricular arrhythmia.

There is no evidence to support an association between H pylori infection and idiopathic arrhythmia, and no apparent biological rationale for such an association.

Raynaud Phenomenon.

Investigators have examined a role of H pylori infection in other vascular conditions, based presumably on results of early studies in CHD. In an Italian study, the prevalence of H pylori infection using results of 13C-UBT was 81% in 26 patients with primary Raynaud phenomenon (PRP) and 20% in 10 age- and sex-matched controls.87 The same group of investigators also studied the effects of treatment of H pylori infection on the symptoms of PRP.88 Of 46 patients with PRP, 36 (78%) were infected with H pylori as judged using results of 13C-UBT. There was no difference in the frequency or severity of attacks of PRP between infected and noninfected patients. The infected patients were treated for H pylori infection, and successful eradication was achieved in 30 of 36. Up to 12 weeks after stopping treatment, 5 had complete resolution of the symptoms of PRP, and 18 others reported a marked improvement. In the noninfected patients who did not receive treatment for H pylori infection, there was no change in the frequency or severity of attacks of PRP. This study was not randomized or blinded and was not appropriately controlled.

There is little biological rationale for an association between H pylori infection and Raynaud phenomenon. The best evidence of such an association comes from an uncontrolled case series. Supportive evidence from a treatment study is very weak.

Migraine.

In an Italian study, the prevalence of H pylori infection assessed using results of 13C-UBT was 48% in 225 patients with primary migraine.89 These patients were treated for H pylori infection, and successful eradication was achieved in 84%. Of the patients with successful eradication, 23% had complete resolution of migraine for up to 24 weeks. Patients in whom eradication of H pylori infection failed did not improve. This study was not randomized, not blinded, and not appropriately controlled. The same investigators reported a higher prevalence of H pylori infection in patients with migraine (47% of 300) than in patients with tension headache (31% of 162; P<.05).90

There is no obvious biological rationale for an association between H pylori infection and migraine. The strongest evidence of such an association is from an uncontrolled case series. Supportive evidence from a treatment study is very weak.

Endocrine and Metabolic Disorders
Diabetes Mellitus.

Since diabetes mellitus may be associated with a variety of upper gastrointestinal tract complaints, investigators have sought to determine whether H pylori infection is linked to different forms of diabetes.

In a study from the Netherlands, Oldenburg and colleagues91 examined the seroprevalence of H pylori infection in 45 patients with type 1 diabetes, 98 with type 2 diabetes, and 159 outpatient controls. Seroprevalence was higher in some age groups of diabetic patients. However, the 3 groups were not adequately matched for age or socioeconomic status. Multiple statistical comparisons between groups increased the chance of a type I statistical error.92

In Italy, Pocecco and colleagues93 studied the seroprevalence of H pylori infection in 69 children and adolescents with type 1 diabetes and 310 age-matched controls without evidence of diabetes or gastrointestinal tract complaints. Controls were matched for age, geographic location, and socioeconomic status. There was a significantly higher seroprevalence in the diabetic patients than the controls (P<.001). Among the diabetic patients, H pylori infection did not influence diabetic control, insulin dose, height, or weight. In a US-based study, Begue and colleagues94 studied the prevalence of H pylori infection in 69 young diabetic patients (mean age, 11.2 years). Sixty-three of the patients had type 1 diabetes and 6 had type 2. Overall, 16% had serologic evidence of H pylori infection that was confirmed with results of UBT. Of the patients with type 1 diabetes, insulin requirements were significantly higher in the infected than in the noninfected patients (P=.03). There was a significantly higher mean glycosylated hemoglobin level among infected patients with type 2 diabetes than in the noninfected patients (P=.04). However, only 6 patients with type 2 diabetes were included.

In Spain, Martín-de-Argila and colleagues95 studied the seroprevalence of H pylori infection in 101 diabetic patients and 100 controls. Of the patients, 80 had type 1 and 21 had type 2 diabetes. The controls were roughly matched for age. The seroprevalence of infection was not significantly different between diabetic patients and controls. However, patients younger than 24 years and with type 1 diabetes had a higher seroprevalence than age-matched controls (P<.05). Among patients older than 24 years and with type 1 diabetes, there was a significantly lower seroprevalence of H pylori infection than in age-matched controls (P<.05).

Ojetti and colleagues96 in Italy studied the effects of treating H pylori infection on insulin requirements in patients with type 1 diabetes. They recruited 119 patients with type 1 diabetes, 42 of whom had H pylori infection determined by a 13C-UBT. There was no significant difference between infected and noninfected patients regarding mean daily insulin requirements. Of the 42 infected patients, 20 had successful eradication determined by repeated 13C-UBT. Eradication of H pylori infection did not influence diabetic control.

The best evidence of an association between H pylori infection and diabetes comes from case-control studies. There is, however, inconsistency among different studies. There is no substantial evidence that H pylori infection affects diabetic control or insulin requirements.

Thyroiditis.

Although there is no obvious link betweenH pylori and thyroid disease, the infection was found endoscopically in 16 of 30 patients with various autoimmune thyroid disorders and in 16 of 30 control subjects with dyspepsia but without a history of thyroid disease.97 In a separate study, serologic testing detected H pylori infection in 34 (71%) of 48 women with thyroid disease and antibodies to thyroglobulin and in 16 (48%) of 33 women who served as age-matched controls (P<.05).98 In infected patients with thyroid disease, levels of antibodies to thyroglobulin were no higher than in uninfected patients. Similarly, H pylori status did not appear to influence levels of thyroid hormones.

The best evidence of an association between H pylori infection and thyroid disease comes from a case-control study. There is no obvious biological rationale for such an association. There is no evidence that H pylori infection influences thyroid function.

Acromegaly.

Ten patients with acromegaly who had received octreotide acetate treatment for longer than 2 years complained of a variety of gastrointestinal tract problems.99 Upper endoscopy was performed in 9 patients, which showed evidence of H pylori infection in 8.

There was histological evidence of gastritis and H pylori infection in 10 of 33 untreated patients with acromegaly.100 Of patients treated for acromegaly with octreotide, 17 of 36 had evidence of H pylori infection. Of 21 patients studied before and during octreotide therapy, H pylori–related gastritis appeared to have developed in 3.

Helicobacter pylori infection was probably a chance finding in these acromegalic patients. There is no credible evidence of an association between H pylori infection and acromegaly.

Dermatological Disorders
Rosacea.

In the past, rosacea may have been erroneously linked to gastritis. However, based on a study published in 1967, gastritis was found in 11 of 18 patients with rosacea compared with 9 of 16 controls,101 suggesting no such association. An Italian group considered that rosacea and peptic ulcer disease showed seasonal variation, and that rosacea may be ameliorated by some of the antibiotics commonly used to treat H pylori infection, such as metronidazole and tetracycline.102 In an uncontrolled study, they determined that 85% of 31 patients with rosacea had some evidence of H pylori infection. The investigators then treated 5 patients with rosacea with metronidazole and observed them serologically, reporting a reduction in anti–H pylori IgG levels.

Some dermatologists have greeted the observations of Rebora and colleagues with enthusiasm.103 Anecdotal case reports suggest improvement in rosacea after systemic antibiotic treatment for H pylori infection.104

An uncontrolled study from Ireland reported a 95% seroprevalence of H pylori infection in a small group of patients with rosacea.105 However, 2 controlled studies do not support any association between H pylori infection and rosacea. In the first of these,106 the seroprevalence of H pylori infection in 94 patients with rosacea was 49%, compared with 53% in a control group of 32 patients with dermatitis. In the second,107 27% of 45 patients with rosacea were seropositive for H pylori infection compared with 35% of age-comparable healthy subjects without chronic skin disease.

The proposed biological rationale for an association between H pylori infection and rosacea is weak and probably based on erroneous assumptions. The only evidence of any association is from uncontrolled case series. Studies are inconsistent. Controlled studies of seroprevalence show no association.

Psoriasis.

A number of bacterial and fungal pathogens have been proposed as causal for psoriasis.108Helicobacter pylori is among the list of putative bacterial agents because of anecdotal case reports of improvement in psoriasis following treatment for this infection.108 Schneider et al106 found a seroprevalence of H pylori infection of 46.9% in 32 patients with psoriasis, compared with 53.1% of 32 patients with chronic dermatitis and 35.7% of 14 patients with other forms of skin disease.

In an uncontrolled study of 33 patients with psoriasis and without any history of chronic gastrointestinal tract complaints, the seroprevalence of H pylori infection was 27%.109 Three patients were treated for H pylori infection without apparent improvement in their psoriasis.

There is no evidence of an association between H pylori infection and psoriasis, and no obvious biological rationale for any association.

Chronic Urticaria.

Circulating immune complexes may trigger urticaria. Investigators have considered that H pylori infection might be a source of such complexes.

An uncontrolled study of 10 patients with urticaria in Germany found histological evidence of H pylori infection in 8.110 The authors reported improvement in features of cutaneous urticaria within days of starting treatment for H pylori infection. However, a study of 104 patients was unable to identify an association between H pylori infection and any 1 of 7 varieties of chronic urticaria.111

Tebbe and colleagues112 identified 25 patients with chronic urticaria. They assessed H pylori status by 13C-UBT and serological testing. Of the 25, they found H pylori infection in 17, each of whom was then treated for the infection. Results of repeated 13C-UBT verified eradication of infection in 14. Each of these 14 reported remission (>75% improvement) or partial remission (50%-75% improvement) in symptoms of urticaria for up to 10 weeks after treatment. There was no improvement in the 3 patients with failed eradication or in the uninfected patients who did not receive treatment for H pylori infection. This study was not randomized or blinded, and it is unclear if the patients were informed of their H pylori status or of the success or failure of eradication treatment.

Among 85 patients with chronic urticaria in Austria, 26 were seropositive for H pylori infection on results of endoscopy and biopsy.113 These patients were then randomized into 1 of 2 groups. Patients received standard treatment, along with ranitidine, for chronic urticaria and placebo or a combination of amoxicillin and metronidazole for H pylori infection. Chronic urticaria was unaffected by this relatively ineffective antimicrobial regimen for H pylori infection.

In a study from Italy, 22 of 32 consecutive patients with chronic urticaria were infected with H pylori as determined by serologic examination and 13C-UBT.114 The infected patients were randomized to treatment for H pylori infection or to no treatment. It is unclear if randomization was blinded or if concealed allocation was used. Despite successful eradication of H pylori infection in 10 of the 11 treated patients, their chronic urticaria was not improved. There was no significant difference among the untreated control patients.

In a separate study from Italy, H pylori infection was present in 23 of 42 patients with chronic urticaria.115 Eighteen patients completed treatment for H pylori infection, of whom 16 had successful eradication. Of these, 13 showed an apparent complete resolution of symptoms of chronic urticaria for up to 3 months after treatment. No such improvement was seen in untreated patients. This study was unblinded and not randomized.

There is no obvious biological rationale for an association between H pylori infection and urticaria. The best evidence of any association comes from uncontrolled case series. Supportive evidence from studies of treating H pylori infection in patients with urticaria is weak.

Schönlein-Henoch Purpura.

Schönlein-Henoch purpura associated with H pylori infection has been described in a 21-year-old woman. The condition regressed after initial, unsuccessful treatment for H pylori infection but later recurred. After a second course of the same treatment for the infection, the disease again went into clinical remission.116

The only evidence of an association between H pylori infection and Schönlein-Henoch purpura is from a single case report with incomplete follow-up.

Other Dermatological Disorders.

In a group of 68 consecutive patients with alopecia areata, the seroprevalence of H pylori infection was higher than in age-matched controls.117 There are isolated case reports linking H pylori infection to atopic dermatitis 118 and Sweet syndrome.119

The best evidence of an association between H pylori infection and alopecia areata is from a case-control study. Evidence of other dermatological conditions is based on individual case reports. A biological rationale for such associations is lacking.

Rheumatological Disorders
Rheumatoid Arthritis.

Seventeen of 54 patients with rheumatoid arthritis (RA) had cultures from gastric biopsy specimens that yielded H pylori.120 Eight of these patients were treated for H pylori infection and observed for 18 weeks. Their serum concentrations of anti–H pylori IgG fell significantly, but there was no discernible effect of treatment for H pylori infection on the course of their RA. The mean titer of anti–H pylori antibodies was not different between 14 patients with RA and 24 age-matched controls with chronic pulmonary disease.121

There is no evidence of a causal association between H pylori infection and RA, and no biological rationale for any such association.

Scleroderma.

In an uncontrolled study, 5 of 12 patients with scleroderma had evidence of H pylori infection on 13C-UBT.122 Scleroderma did not improve after treatment for H pylori infection. The mean titer of anti–H pylori antibodies was not different between 11 patients with scleroderma and 24 age-matched controls with chronic pulmonary disease.121

There is no evidence of and no obvious biological rationale for an association between H pylori infection and scleroderma.

Sjögren Syndrome.

In the Japanese study already referred to,121 the mean titer of anti–H pylori antibodies was significantly higher (P<.05) in 7 patients with Sjögren syndrome than in 24 age-matched controls with chronic pulmonary disease.

In an Italian study, H pylori infection was present in 71% of 21 patients with primary Sjögren syndrome and 63% of 80 controls with dyspepsia.123 In Finland, Collin and colleagues124 studied 32 consecutive patients with primary Sjögren syndrome and 64 age- and sex-matched controls using endoscopy. Although atrophic gastritis of the antrum was found more frequently in the patients with Sjögren syndrome (25% vs 4%; P=.01), there was no significant difference in the prevalence of H pylori infection (31% vs 39%; P>.05).

There is no evidence of and no obvious biological rationale for an association between H pylori infection and Sjögren syndrome.

Hematological Disorders
Iron Deficiency Anemia.

Certain bacteria, including H pylori, are able to acquire iron from their host.125 The elucidation of the genome of H pylori126 identified a number of genes that encode for iron-scavenging functions.127 By this mechanism, H pylori infection might lead to anemia from iron deficiency without blood loss. Helicobacter pylori infection acquired early in life might also lead to iron deficiency in adulthood by producing chronic atrophic gastritis, which impairs the absorption of dietary iron.

Isolated case reports have suggested an association between H pylori infection and iron deficiency anemia in children and young adults.128132 In at least 2 of these cases,129,131 iron deficiency anemia was not accompanied by detectable gastrointestinal tract blood loss. In all cases, anemia resolved with successful eradication of H pylori infection.

A cross-sectional study of 103 children in Bangladesh aged 6 months to 2 years found a significantly lower (P=.04) mean hemoglobin level in infected than in noninfected children.133 The anemia was presumed to have been due to iron deficiency.

If the association between iron deficiency anemia and H pylori infection is true, it may be confined to children. In a study of more than 2000 adults in Denmark, H pylori serologic status did not affect a number of red blood cell indices.134

The best evidence of an association between H pylori infection and iron deficiency anemia comes from a population-based cross-sectional study in children. There is a plausible biological rationale for such an association. Alternatively, H pylori infection might simply be a surrogate marker for poverty and malnutrition in childhood.

Autoimmune Thrombocytopenic Purpura.

Among 15 patients with autoimmune thrombocytopenic purpura and in whom other causes of thrombocytopenia had been excluded, the prevalence of H pylori infection assessed by the 13C-UBT was 67%.135 The 10 patients with H pylori infection were treated for it, and 7 had successful eradication. In these patients, platelet counts increased from a mean of 90,200/mm3 to a mean of 148,800/mm3 (P<.05). Antiplatelet antibodies became undetectable 6 weeks after treatment in 7 patients. In infected patients who were treated for H pylori infection but in whom eradication was unsuccessful, there was no change in platelet count or in the levels of antiplatelet antibodies.

The evidence of an association between H pylori infection and autoimmune thrombocytopenic purpura is from an uncontrolled case series. Objective evidence from an uncontrolled study of an increase in platelet count following treatment of H pylori infection in autoimmune thrombocytopenic purpura should be confirmed prospectively in a randomized controlled trial.

Hyperammonemia.

Plasma ammonia levels are generally increased in patients with hepatic encephalopathy,136 although this does not fully explain its clinical manifestations. Hyperammonemia in patients with hepatic encephalopathy is thought to be derived predominantly from bacterial activity in the colon. Helicobacter pylori has potent urease activity10 that may be a source of ammonia in circulating blood. Some investigators have studied the influence of H pylori infection on plasma ammonia levels and the risk for hepatic encephalopathy in patients with liver disease.

In a prospective, multicenter, Veterans Affairs–based study, Gubbins and colleagues137 studied 188 patients with moderate or severe alcoholic hepatitis. Of these, 117 had hepatic encephalopathy. There was a higher seroprevalence of H pylori infection in these patients with than in those without encephalopathy (79% vs 62%; P=.01). Using stepwise linear regression, H pylori infection was identified as an independent risk factor for hepatic encephalopathy.

Ito and colleagues138 from Japan described 2 patients with recurrent hepatic encephalopathy due to cirrhosis from chronic hepatitis C virus infection. Both had evidence of H pylori infection. After successful eradication of infection, plasma ammonia levels were reduced, and hepatic encephalopathy did not recur for at least 5 months. Both patients were subsequently observed for more than 2 years139; plasma ammonia levels stayed below those seen before treatment for H pylori infection.

In an experimental study in 20 patients with cirrhosis, Plevris and colleagues140 determined H pylori status by 14C-UBT and administered urea by mouth. Plasma ammonia levels rose in all patients irrespective of H pylori status, and there was no difference between the H pylori–infected and noninfected patients.

Kirchner and colleagues141 from Germany studied plasma ammonia levels and the H pylori status of 132 patients with cirrhosis, 38 patients with chronic viral hepatitis but without cirrhosis, and 39 age-matched controls. The controls had cardiovascular or cerebrovascular disease but no gastrointestinal tract complaints or evidence of liver disease. Patients with cirrhosis had higher seropositivity for H pylori infection (81%) than those with chronic viral hepatitis (62%) or controls (54%). However, there was no association between plasma ammonia levels and H pylori status.

Miyagi and colleagues142 in Japan studied 18 patients with cirrhosis and persistent hyperammonemia despite treatment with low-protein diet, kanamycin sulfate, lactulose, and branched-chain amino acids. They divided these 18 patients into 3 groups of 6 patients according to H pylori status as assessed endoscopically. One group had diffuse gastric involvement with H pylori, the second had more patchy involvement, and the third had no H pylori infection. Patients in all 3 groups received treatment for H pylori infection. The mean plasma ammonia level was initially reduced in all patients following the standard treatment for hepatic encephalopathy. However, there was a further reduction in plasma ammonia level in the 6 patients with diffuse gastric involvement and H pylori infection following eradication treatment. There was no further reduction in plasma ammonia levels in the other groups after similar treatment. In the patients who had diffuse gastric involvement with H pylori infection, plasma ammonia levels remained low for up to 12 weeks after eradication treatment.

Llach and colleagues143 from Spain found no difference in plasma ammonia concentration or in hepatic encephalopathy scores between 32 H pylori–infected and 30 noninfected patients with cirrhosis. Furthermore, treatment of H pylori infection did not produce any significant change in plasma ammonia concentrations or encephalopathy scores.

Cho and colleagues144 in South Korea studied levels of ammonia in plasma and gastric juice in 31 patients with cirrhosis and 34 controls. They determined H pylori status in all patients by serologic examination and endoscopic biopsy. Little information was provided on the control group, but they were not particularly well matched for age. Plasma ammonia levels were higher in the cirrhotic patients than the controls. Levels of ammonia in gastric juice were higher in H pylori–infected than in noninfected patients in both groups. Helicobacter pylori infection did not affect plasma ammonia concentrations in the patients with cirrhosis.

Among 55 patients with cirrhosis, 37 had clinical or neurophysiological evidence of chronic hepatic encephalopathy.145 The prevalence of H pylori infection determined by gastric mucosal biopsy and rapid urease testing was 67% in the encephalopathic group and 33% in the nonencephalopathic group (P=.002). Levels of ammonia in gastric juice were higher in the encephalopathic than in the nonencephalopathic patients (P=.05). Plasma ammonia levels were not reported. Seventeen encephalopathic patients, including 13 with and 4 without H pylori infection, had treatment with a relatively ineffective regimen for H pylori infection. Results of testing for encephalopathy improved in each of the H pylori–infected patients. The test results did not change appreciably in the 4 uninfected patients. Eradication of infection was not confirmed.

In an experimental study, Zullo and colleagues146 from Italy examined the effects of acetohydroxamic acid on plasma ammonia levels in 16 cirrhotic patients. Acetohydroxamic acid is a direct inhibitor of bacterial urease.147 Eight patients had H pylori infection determined by histological examination and a rapid urease test. Plasma ammonia levels did not change after acetohydroxamic acid administration in the 8 patients without H pylori infection. However, plasma ammonia concentration at 15 to 30 minutes after acetohydroxamic acid administration fell by a mean of 27% in the 8 patients with H pylori infection.

Patients with chronic renal insufficiency have high levels of urea in their gastric lumen.148 Those with H pylori infection might, therefore, have elevated plasma ammonia levels. However, comparison of 9 H pylori–infected and 7 noninfected uremic patients found similar plasma and intragastric concentrations of both urea and ammonia.148

Observational studies suggest a relationship between H pylori infection and raised plasma ammonia levels in patients with chronic liver disease. However, there is inconsistency among different studies. There is a plausible biological rationale for the association (Table 1). Experimental studies investigating the possible association have been inconsistent.

Miscellaneous Disorders
Sudden Infant Death Syndrome.

There are some similarities between the epidemiological features of sudden infant death syndrome (SIDS) and those of H pylori infection. Both are more common in families of lower socioeconomic status and from nonwhite ethnic groups. Furthermore, the incidence of both appears to be decreasing in parallel.149,150 Possible links between H pylori infection and SIDS include raised systemic levels of cytokines such as interleukin 1 that may promote fever, immune activation, and deep sleep.149 Alternatively, H pylori might be aspirated from the stomach into the airways, where the generation of ammonia through the action of H pylori urease might promote respiratory arrest.149

Helicobacter pylori was reported at autopsy in the gastric antrum and trachea in 7 infants who died of SIDS.151 However, the same investigators were subsequently unable to confirm this observation when examining autopsy material from 22 consecutive infants with a postmortem diagnosis of SIDS using histological or polymerase chain reaction testing.150 In a separate study, polymerase chain reaction testing on antral biopsy specimens from 11 infants who died of SIDS identified H pylori in 8 of 9 specimens when it was apparent histologically, and in 1 of 2 when it was not.152 Primary tracheal colonization by H pylori without gastric antral involvement has been reported in 3 of 12 infants with SIDS,153 suggesting possible transmission of H pylori by the respiratory route. Helicobacter pylori may have been isolated from tracheal secretions of adults in an intensive care unit.154

In autopsies of 37 infants with SIDS in 2 metropolitan areas in the United States, there was evidence of gastric antral H pylori infection in 20 (54%). Organisms compatible with H pylori were identified in tracheal specimens in 22 (59%).155

The best evidence of an association between H pylori infection and SIDS comes from uncontrolled case series. The temporal relationship for an association is correct, and there is a plausible biological rationale (Table 1). There is unconfirmed evidence of colonization of the upper airways of infants with SIDS by bacterial organisms that may be H pylori.

Growth Retardation in Childhood.

Patel and colleagues156 studied 554 11-year-old children in Scotland. Of these, 62 had evidence of H pylori infection since 7 years of age. On average, these children had grown 1.1 cm less than noninfected children from the ages of 7 through 11 years. Girls had grown 1.6 cm less than their noninfected peers had.

Raymond et al157 compared 77 French children infected with H pylori and 74 age-matched children without the infection. Compared with 23% of the controls, 27% of the infected group were of short stature. Of the children with short stature, there was no evidence of hypoproteinemia or malabsorption.

In a cross-sectional study from southern Italy, 49 of 216 children aged 3 through 14 years were infected with H pylori as determined by the 13C-UBT.158 Of the 49 infected children, 8 were below the 25th percentile for height, compared with 13 of 167 uninfected children. In the subgroup of children aged 8.5 through 14 years, 8 of 31 infected children were below the 25th percentile for height compared with 8 of 96 uninfected children (P=.02).

Oderda and colleagues159 in Italy found serologic evidence of H pylori infection in 20% of 134 consecutive children with short stature and in 13% of matched controls (P=.19). The authors con-cluded that H pylori infection was not an independent risk factor for short stature in childhood but that low socioeconomic status was of more importance.

In a population-based survey of more than 4700 people in Northern Ireland, the mean height of women older than 25 years who were infected with H pylori was 1.6 cm lower than in uninfected women (P<.01 after adjustment for age and socioeconomic status).160 Among 1756 Danish women in a random sample, those in the upper quartile for height were significantly less likely to be infected with H pylori than those in the lower quartile.53 The likelihood of H pylori infection was also related to late menarche, leading the investigators to speculate that an impaired pubertal growth spurt may have explained the finding. The Eurogast Study Group conducted a cross-sectional survey of the seroprevalence of H pylori infection in more than 3000 subjects in 2 age groups in various countries.161 In subjects aged 55 through 64 years, infection with H pylori tended to be associated with a low body mass index and short stature. However, this was not statistically significant after adjustment for other variables.

The best evidence of an association between H pylori infection and growth retardation in childhood comes from a cohort study. The temporal relationship for any association is correct (Table 1). There is some inconsistency between different studies. Helicobacter pylori infection might be a marker for low socioeconomic status and relative malnutrition in childhood.

Anorexia of Aging.

One report described 3 institutionalized, elderly patients with a variety of medical complaints that included anorexia.162 Each patient had evidence of H pylori infection. Treatment for the infection resulted in improvement in anorexia. Treatment regimens were suboptimal, and eradication of infection was not confirmed. Helicobacter pylori infection was not proven as the cause of the anorexia in any of the 3 patients.163

There is no evidence of an association between H pylori infection and the anorexia of aging.

Numerous different conditions have been linked preliminarily to H pylori infection. However, many of these associations are based on uncontrolled or inappropriately controlled observations. A biological rationale for an association with H pylori infection is often lacking.

Further research on the role of H pylori as a possible causal or contributory factor may be warranted for some conditions. Examples might include autoimmune thrombocytopenic purpura135 and SIDS.152,153,155 However, any such research should be conducted in a responsible, planned, and cautious manner.

Unfortunately, weak evidence of causation by H pylori infection in some conditions has already led to poor-quality studies of the effects of treatment for the infection.88,89,115 Sackett164 has proposed a 5-level system of grading evidence from treatment trials to help determine whether a treatment should be recommended. The highest level of evidence comes from large randomized controlled trials and carries a strong recommendation for adoption of the treatment into routine practice. Studies on the treatment of H pylori infection in the conditions reviewed herein have been nonrandomized, unblinded, and uncontrolled or inappropriately controlled.88,89,115 Therefore, these studies present evidence that is, at best, weak. Furthermore, treatment regimens have often been ineffective, and eradication of infection has not been confirmed.113,145,161

Rather than treating H pylori infection in all infected patients identified with a specific diagnosis, it would be of more value to randomize infected patients to receive active or placebo treatment in a double-blinded manner. Only then could investigators adequately assess any effects of treating H pylori infection on the underlying condition. Conceivably, antimicrobial therapy might improve 1 of the conditions in question through a mechanism unrelated to eradication of H pylori infection. For example, apparent improvement in patients with hepatic encephalopathy after antimicrobial treatment of H pylori infection could have been explained by a reduction in levels of colonic bacteria. Therefore, there may be a case for antibiotic treatment, as if for H pylori infection, in uninfected patients to eliminate any unrelated, beneficial effect of antimicrobial therapy.142,145

Although H pylori infection has been linked to a wide variety of non–gastrointestinal tract conditions, the level of supporting evidence is low (Table 1). Conversely, ample evidence links H pylori infection to various conditions of the upper gastrointestinal tract (Table 2). Limited experiments in humans have established a specific and direct relationship with gastritis, with consistent temporality.1719 Although there are no direct experimental data in humans that link H pylori infection with peptic ulcer disease, there is a mass of highly consistent and strong circumstantial evidence.2,28 Nested case-control studies165167 and a meta-analysis5 have established a strong and temporally correct relationship between H pylori infection and gastric adenocarcinoma. There is also a strong biological rationale for this association.3 Similarly, there is a strong, temporally correct association between H pylori infection and low-grade gastric lymphoma arising from mucosa-associated lymphoid tissue.6,168 However, even in these conditions of the upper gastrointestinal tract, about which there is broad agreement regarding causation by H pylori, it is not possible to answer affirmatively all 9 of the questions proposed by Sackett (Table 2).

Table Graphic Jump LocationTable 2. Application of 9 Diagnostic Tests for Causes of Upper Gastrointestinal Tract Conditions Generally Accepted to Be Related to Helicobacter pylori Infection*

Demonstration of H pylori infection would be unhelpful at present in an individual patient with any of the non–gastrointestinal tract conditions proposed to be associated with it. Since the infection is highly prevalent, it will be found by chance in many patients who seek medical attention for another condition. Demonstrating the infection in a patient with another disorder does not prove a causal link. Furthermore, the finding of an unexpected chronic bacterial infection might promote anxiety in a patient presenting with another disorder. Alternatively, it could lead to unwarranted optimism of a possible explanation for or cure of the primary condition. There is no current need for such patients to undergo testing for H pylori infection. Testing is only indicated in patients with present or past peptic ulcer disease or gastric lymphoma arising from mucosa-associated lymphoid tissue.22

Practitioners need to be aware of the proven and important association between H pylori infection and peptic ulcer disease.2,22 Patients with ulcer disease should undergo appropriate testing for H pylori infection. Those with positive test results should receive an effective combination drug regimen for eradication of the infection.2,22 These patients will derive the greatest benefit from testing for and treating H pylori infection. Many of the possible associations of H pylori infection discussed herein are speculative at best. Unfortunately, the excessive attention and publicity paid to these may detract from the proven and important role of H pylori in ulcer disease.

Accepted for publication September 3, 1998.

Reprints: Colin W. Howden, MD, Division of Digestive Diseases, Rush University Medical School, Rush-Presbyterian-St Luke's Medical Center, 1725 W Harrison St, Suite 206, Chicago, IL 60612 (e-mail: chowden@rush.edu).

Howden  CW Clinical expressions of H pylori infection. Am J Med. 1996;100 ((suppl)) 27S- 34S
Peura  DA The report of the Digestive Health Initiative International Update Conference on Helicobacter pyloriGastroenterology. 1997;113 ((suppl 1)) S4- S8
Asaka  MTakeda  HSugiyama  TKato  M What role does Helicobacter pylori play in gastric cancer? Gastroenterology. 1997;113 ((suppl 1)) S56- S60
Dixon  MF Commentary: role of Helicobacter pylori on gastric mucosal damage, gastric cancer, and gastric MALT lymphoma. Gastroenterology. 1997;113 ((suppl 1)) S65- S66
Huang  J-QSridhar  SChen  YHunt  RH Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology. 1998;1141169- 1179
Thiede  CMorgner  AAlpen  B  et al.  What role does Helicobacter pylori eradication play in gastric MALT and gastric MALT lymphoma? Gastroenterology. 1997;113 ((suppl 1)) S61- S64
Talley  NJHunt  RH What role does Helicobacter pylori play in dyspepsia and nonulcer dyspepsia? arguments for and against H pylori being associated with dyspeptic symptoms. Gastroenterology. 1997;113 ((suppl 1)) S67- S77
McColl  KELMurray  LSEl-Omar  E  et al.  UK MRC trial of H pylori eradication therapy for non-ulcer dyspepsia [abstract]. Gastroenterology. 1998;114A222
Talley  NJJanssens  JLauritsen  K  et al.  Long-term follow-up of patients with non-ulcer dyspepsia after Helicobacter pylori eradication: a randomized double-blind placebo-controlled trial [abstract]. Gastroenterology. 1998;114A305
Mobley  HLT Helicobacter pylori factors associated with disease development. Gastroenterology. 1997;113 ((suppl 1)) S21- S28
Ernst  PBCrowe  SEReyes  VE How does Helicobacter pylori cause mucosal damage? the inflammatory response. Gastroenterology. 1997;113 ((suppl 1)) S35- S42
Gasbarrini  AFranceschi  FGasbarrini  GPola  P Extraintestinal pathology associated with Helicobacter infection. Eur J Gastroenterol Hepatol. 1997;9231- 233
Ponzetto  A Extra-gastrointestinal diseases and Helicobacter pyloriEur J Gastroenterol Hepatol. 1997;9616
Cave  DR Transmission and epidemiology of Helicobacter pyloriAm J Med. 1996;100 ((suppl 5A)) 12S- 18S
Cave  DR How is Helicobacter pylori transmitted? Gastroenterology. 1997;113 ((suppl 1)) S9- S14
Sackett  DLHaynes  RBTugwell  P Clinical Epidemiology: A Basic Science for Clinical Medicine.  Boston, Mass Little Brown & Co1985;
Marshall  BArmstrong  JMcGechie  DGlancy  R Attempt to fulfill Koch's postulates for pyloric CampylobacterMed J Aust. 1985;142436- 439
Morris  ANicholson  G Ingestion of Campylobacter pyloridis causes gastritis and raised fasting pH. Am J Gastroenterol. 1987;82192- 199
Morris  AJAli  MRNicholson  GIPerez-Perez  GIBlaser  MJ Long-term follow-up of voluntary ingestion of Helicobacter pyloriAnn Intern Med. 1991;114662- 663
Cutler  AFHavstad  SMa  CKBlaser  MJPerez-Perez  GISchubert  TT Accuracy of invasive and non-invasive tests to diagnose Helicobacter pylori infection. Gastroenterology. 1995;109136- 141
Atherton  JC Non-endoscopic tests in the diagnosis of Helicobacter pylori infection. Aliment Pharmacol Ther. 1997;11 ((suppl 1)) 11- 20
Howden  CWHunt  RH Guidelines for the management of Helicobacter pylori infection. Am J Gastroenterol. 1998;932330- 2338
Borhan-Manesh  FFarnum  JB Study of Helicobacter pylori colonization of patches of heterotopic gastric mucosa (HGM) at the upper esophagus. Dig Dis Sci. 1993;38142- 146
Jacobs  EDehou  MF Heterotopic gastric mucosa in the upper esophagus: a prospective study of 33 cases and review of the literature. Endoscopy. 1997;29710- 715
Paul  GYardley  JH Gastric and esophageal Campylobacter pylori in patients with Barrett's esophagus. Gastroenterology. 1988;95216- 218
Sharma  VKTailon  DVasudeva  RHowden  CWDemian  SE In columnar-lined esophagus (CLE), H pylori (HP) is confined to gastric metaplasia [abstract]. Am J Gastroenterol. 1997;921604
Malfertheiner  PBoce  G Helicobacter pylori and the pathogenesis of duodenal ulcer disease. Eur J Gastroenterol Hepatol. 1993;51- 8
Peura  DA Helicobacter pylori and ulcerogenesis. Am J Med. 1996;100 ((suppl 5A)) 19S- 26S
Morris  ANicholson  GZwi  JVanderwee  M Campylobacter pylori infection in Meckel's diverticula containing gastric mucosa. Gut. 1989;301233- 1235
de Cothi  GANewbold  KMO'Connor  HJ Campylobacter-like organisms and heterotopic gastric mucosa in Meckel's diverticula. J Clin Pathol. 1989;42132- 134
Dye  KRMarshall  BJFrierson  HF  JrPambianco  DJMcCallum  RW Campylobacter pylori colonizing heterotopic gastric tissue in the rectum. Am J Clin Pathol. 1990;93144- 147
Patel  PCarrington  DStrachan  DP  et al.  Fibrinogen: a link between chronic infection and coronary heart disease [letter]. Lancet. 1994;3431634- 1635
Patel  PMendall  MACarrington  D  et al.  Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. BMJ. 1995;311711- 714
Rajput-Williams  JWilliams  NRJohnson  PGDickinson  RJ Fibrinogen and H pylori in asymptomatic post MI patients and healthy controls [abstract]. Gut. 1996;39 ((suppl 2)) A94
Murray  LJBamford  KBO'Reilly  DPJMcCrum  EEEvans  AE Helicobacter pylori infection: relation with cardiovascular risk factors, ischaemic heart disease, and social class. Br Heart J. 1995;74497- 501
Carter  AMMoayyedi  PCatto  AHeppel  RMAxon  ATGrant  PJ The influence of Helicobacter pylori status on circulating levels of the coagulation factors fibrinogen, von Willebrand factor, factor VII and factor VIII. Helicobacter. 1996;165- 69
Ossei-Gerning  N Helicobacter pylori infection is related to atheroma in patients undergoing coronary angiography. Cardiovasc Res. 1997;35120- 124
Bierti  LCernuschi  CAbbiati  C  et al.  Correlation between gastric infection with Helicobacter pylori and plasma levels of fibrinogen, plasminogen activator inhibitor (PAI) and von Willebrand factor (vWF) antigen [abstract]. Gut. 1996;39 ((suppl 2)) A90
Parente  FMaconi  GImbesi  V  et al.  Helicobacter pylori infection and coagulation in healthy people. BMJ. 1997;3141318- 1319
McDonagh  TAWoodward  MMorrison  CE  et al.  Helicobacter pylori infection and coronary heart disease in the North Glasgow MONICA population. Eur Heart J. 1997;181257- 1260
Wald  NJLaw  MRMorris  JKBagnall  AM Helicobacter pylori infection and mortality from ischaemic heart disease: negative result from a large, prospective study. BMJ. 1997;3151199- 1201
Danesh  JPeto  R Risk factors for coronary heart disease and infection with Helicobacter pylori: meta-analysis of 18 studies. BMJ. 1998;3161130- 1132
Elizalde  JIGómez  JPanés  J  et al.  Platelet activation in mice and human Helicobacter pylori infection. J Clin Invest. 1997;100996- 1005
Danesh  JCollins  RAppleby  PPeto  R Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998;2791477- 1482
Karttunen  TJNiemalä  SKerola  T Blood leukocyte differential in Helicobacter pylori infection. Dig Dis Sci. 1996;411332- 1336
Whincup  PHMendall  MAPerry  IJStrachan  DPWalker  M Prospective relations between Helicobacter pylori infection, coronary heart disease, and stroke in middle aged men. Heart. 1996;75568- 572
Mendall  MAPatel  PBallam  LStrachan  DNorthfield  TC C reactive protein and its relationship to cardiovascular risk factors: a population based cross sectional study. BMJ. 1996;3121061- 1065
Mendall  MAPatel  PAsante  M  et al.  Relation of serum cytokine concentrations to cardiovascular risk factors and coronary heart disease. Heart. 1997;78273- 277
Neri  MReale  MDi Febbo  C  et al.  Increased levels of soluble tumor necrosis factor receptor I (sTNF RI) in serum of Helicobacter pylori–positive ischemic heart disease patients [abstract]. Gastroenterology. 1996;110A209
Scragg  RKRFraser  AMetcalf  PA Helicobacter pylori seropositivity and cardiovascular risk factors in a multicultural workforce. J Epidemiol Community Health. 1996;50578- 579
Strandberg  TETilvis  RSVuoristo  MKosunen  TU H pylori infection and cardiovascular diseases in elderly population [abstract]. Gut. 1996;39 ((suppl 2)) A92
Martín-de-Argila  CBoixeda  DFuertes  A  et al.  High prevalence of Helicobacter pylori infection in coronary heart disease demonstrated by the 13C-urea breath test [abstract]. Gut. 1996;39 ((suppl 2)) A95
Rosenstock  SJAndersen  LPBonnevie  OJørgensen  T Serum lipids, body-indices, age at menarche, and Helicobacter pylori infection in 1756 Danish women [abstract]. Gut. 1996;39 ((suppl 3)) A62
Khurshid  APuetz  TFenske  TBajwa  TVakil  N Seroprevalence of Helicobacter pylori infection in patients with and without angiographic evidence of coronary heart disease [abstract]. Gastroenterology. 1996;110A154
Pilotto  ARumor  FNovello  RFranceschi  MValerio  G Helicobacter pylori infection and atherosclerosis: a study with endoscopy and vascular echodoppler ultrasonography in elderly subjects [abstract]. Gastroenterology. 1997;112A259
Kang  DHYoon  HSPark  DK  et al.  The association between Helicobacter pylori infection and coronary heart disease assessed by coronary angiography [abstract]. Gastroenterology. 1998;114A166
Kang  DHPark  DKYoon  HS  et al.  The association between Helicobacter pylori infection and transaminase [abstract]. Gastroenterology. 1998;114A166
Martín-de-Argila  CBoixeda  DCanton  R  et al.  Helicobacter pylori infection, serum triglyceride and serum cholesterol levels: a step athero-sclerosis [abstract]? Gastroenterology. 1998;114A218
Clarke  RDaly  LRobinson  K  et al.  Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991;3241149- 1155
Stampfer  MJMalinow  MRWillet  WC  et al.  A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA. 1992;268877- 881
Sung  JJYSanderson  JE Hyperhomocysteinaemia, Helicobacter pylori, and coronary heart disease. Heart. 1996;76305- 307
Go  MF What are the host factors that place an individual at risk for Helicobacter pylori–associated disease? Gastroenterology. 1997;113 ((suppl 1)) S15- S20
Whincup  PHMendall  MAPerry  IJStrachan  DP Hyperhomocysteinaemia, Helicobacter pylori, and coronary heart disease [letter]. Heart. 1997;78524
Saxena  VMarkus  HSwaminathan  SMendall  ME Hyperhomocysteinaemia, Helicobacter pylori, and coronary heart disease [letter]. Heart. 1997;78524
Markus  HSMendall  MA Helicobacter pylori infection: a risk factor for ischaemic cerebrovascular disease and carotid atheroma. J Neurol Neurosurg Psychiatry. 1998;84104- 107
Xu  QWillett  JMarosi  M  et al.  Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis. Lancet. 1993;341255- 259
Xu  QWick  G The role of heat shock proteins in protection and pathophysiology of the arterial wall. Mol Med Today. 1996;2372- 379
Birnie  DHolme  EMcKay  ICHood  SMcColl  KELHillis  WS Association between antibodies to mycobacterial heat shock protein 65 and coronary atherosclerosis: possible mechanism of action of Helicobacter pylori in increasing cardiovascular risk [abstract]. Heart. 1996;75 ((suppl 1)) P49
Mendall  MAGoggin  PMMolineaux  N  et al.  Relation of Helicobacter pylori infection and coronary heart disease. Br Heart J. 1994;71437- 439
Sandifer  QDLo  SVCrompton  G Association may not be causal [letter]. BMJ. 1996;312251
Niemalä  SKarttunen  TKorhonen  T  et al.  Could Helicobacter pylori infection increase the risk of coronary heart disease by modifying serum lipid concentrations? Heart. 1996;75573- 575
Morgando  ASanseverino  PPeroto  CMolino  FGai  VPonzetto  A Helicobacter pylori seropositivity in myocardial infarction [letter]. Lancet. 1995;3451380
Martín-de-Argila  CBoixeda  DCanton  RGisbert  JFuertes  A High seroprevalence of Helicobacter pylori infection in coronary heart disease [letter]. Lancet. 1995;346310
Ponzetto  ALa Rovere  MTSanseverino  PBazzoli  F Study confirms previous findings [letter]. BMJ. 1996;312251
Rathbone  BMartin  DStephens  JThompson  JRSamani  NJ Helicobacter pylori seropositivity in subjects with acute myocardial infarction. Heart. 1996;76308- 311
Parravicini  PPPellicano  RBigi  R  et al.  Helicobacter pylori infection and acute myocardial infarction in Northern Italy [abstract]. Gastroenterology. 1998;114A253
Maier  FAuricchio  ANilius  MKlein  HMalfertheiner  P Lack of association between Helicobacter pylori infection and angiographically documented coronary heart disease [abstract]. Gastroenterology. 1996;110A183
Menge  HLang  AHopert  RBrosius  BLollgen  HBoenigk  U Helicobacter pylori infection in patients with and without coronary heart disease [abstract]. Gastroenterology. 1998;114A226
Khurshid  AFenske  TBajwa  TBourgeois  KVakil  N A prospective, controlled study of Helicobacter pylori seroprevalence in coronary artery disease. Am J Gastroenterol. 1998;93717- 720
Balaban  DHPeura  DAWatson  DRembold  CShifflet  J Relationship between H pylori infection and ischemic heart disease [abstract]. Gastroenterology. 1996;110A55
Strandberg  TETilvis  RSVuoristo  MLindroos  MKosunen  TU Prospective study of Helicobacter pylori seropositivity and cardiovascular diseases in a general elderly population. BMJ. 1997;3141317- 1318
Danesh  JCollins  RPeto  R Chronic infections and coronary heart disease: is there a link? Lancet. 1997;350430- 436
Ponzetto  ASandrone  NPellicano  RArena  VRaso  AM Helicobacter pylori infection in patients with arterial obstruction [abstract]. Gastroenterology. 1998;114A260
Barnes  RJUff  JSDent  JCGear  MWWilkinson  SP Long-term follow up of patients with gastritis associated with Helicobacter pylori infection. Br J Gen Pract. 1991;41286- 288
Lip  GYHWise  RBeevers  G Association of Helicobacter pylori infection with coronary heart disease: study shows association between H pylori infection and hypertension [letter]. BMJ. 1996;312250- 251
Franceschi  FGasbarinni  ARuggieri  MP  et al.  Helicobacter pylori infection and idiopathic arrhythmias [abstract]. Gastroenterology. 1998;114A123
Gasbarinni  ASerricchio  MTondi  PGasbarrini  GPola  P Association of Helicobacter pylori infection with primary Raynaud phenomenon [letter]. Lancet. 1996;348966- 967
Gasbarinni  AMassari  ISerricchio  M  et al.  Helicobacter pylori infection in patients affected by Raynaud phenomenon: beneficial effects of eradication [abstract]. Gastroenterology. 1998;114A130
Gasbarrini  Ade Luca  AFiore  G  et al.  Beneficial effects of Helicobacter pylori eradication on migraine [abstract]. Gastroenterology. 1998;114A129
Gasbarrini  Ade Luca  AFiore  G  et al.  Helicobacter pylori infection in primary headache [abstract]. Gastroenterology. 1998;114A130
Oldenburg  BDiepersloot  RJAHoekstra  JBL High seroprevalence of Helicobacter pylori in diabetes mellitus patients. Dig Dis Sci. 1996;41458- 461
Danesh  JN H pylori and diabetes [letter]. Dig Dis Sci. 1997;422576
Pocecco  MBuratti  ETommasini  ATorre  GNot  T High risk of Helicobacter pylori infection associated with cow's milk antibodies in young diabetics. Acta Pediatr. 1997;86700- 703
Begue  REMirza  ACompton  TVargas  A Helicobacter pylori infection and the metabolic control of patients with diabetes type I and II [abstract]. Gastroenterology. 1998;114A71
Martín-de-Argila  CBoixeda  Dde Luis  DA  et al.  Helicobacter pylori infection and diabetes mellitus [abstract]. Gastroenterology. 1998;114A218
Ojetti  VGasbarini  APitocco  D  et al.  Effects of Helicobacter pylori eradication on insulin-dependent diabetes mellitus [abstract]. Gastroenterology. 1998;114A247
Cammarota  GTursi  Ade Marinis  L  et al.  Gastric mucosa-associated lymphoid tissue in autoimmune thyroid diseases. Scand J Gastroenterol. 1997;32869- 872
Figura  NGuarino  EGragnoli  A  et al.  H pylori (HP) infection and thyroid diseases [abstract]. Gut. 1996;39 ((suppl 2)) A93
Plockinger  UDienemann  DQuabbe  HJ Gastrointestinal side-effects of octreotide during long-term treatment of acromegaly. J Clin Endocrinol Metab. 1990;711658- 1662
Anderson  JVCatnach  SLowe  DGFairclough  PDBesser  GMWass  JA Prevalence of gastritis in patients with acromegaly: untreated and during treatment with octreotide. Clin Endocrinol. 1992;37227- 232
Marks  RBeard  RJClark  ML  et al.  Gastrointestinal observations in rosacea. Lancet. 1967;1739- 742
Rebora  ADrago  FPicciotto  A Helicobacter pylori in patients with rosacea [letter]. Am J Gastroenterol. 1994;891603- 1604
Parish  LCWitkowski  JA Acne rosacea and Helicobacter pylori betrothed. Int J Dermatol. 1995;34236- 237
Kolibášová  KTóthová  IBaumgartner  JFilo  V Eradication of Helicobacter pylori as the only successful treatment in rosacea [letter]. Arch Dermatol. 1996;1321393- 1394
Powell  FCDawa  MADuguid  C Positive Helicobacter pylori serology in rosacea patients [abstract]. Ir J Med Sci. 1992;161 ((suppl)) 75
Schneider  MASkinner  RBJRosenberg  EW  et al.  Serological determination of Helicobacter pylori in rosacea patients and controls [abstract]. Clin Res. 1992;40831A
Sharma  VKLynn  AKaminski  MVasudeva  RHowden  CW A study of the prevalence of Helicobacter pylori infection and other markers of upper gastrointestinal tract disease in patients with rosacea. Am J Gastroenterol. 1998;93220- 222
Rosenberg  EWNoah  PWSkinner  RB Microorganisms and psoriasis. J Nat Med Assoc. 1994;86305- 310
Halasz  CLG Helicobacter pylori antibodies in patients with psoriasis [letter] [published correction appears in Arch Dermatol. 1996;132:616]. Arch Dermatol. 1996;13295- 96
Bohmeyer  JHeller  AHartig  C  et al.  Association of chronic urticaria with Helicobacter pylori–induced antrum gastritis. Hautarzt. 1996;47106- 108
Morisset  Mde Korwin  JDLozniewski  AKanny  GPlenat  FMoneret-Vautrin  DA Chronic urticaria and Helicobacter pylori infection [abstract]. Gut. 1996;39 ((suppl 2)) A92
Tebbe  BGeilen  CCSchulzke  J-DBojarski  CRadenhausen  MOrfanos  CE Helicobacter pylori infection and chronic urticaria. J Am Acad Dermatol. 1996;34685- 686
Schrutka-Koebl  CHWasilewicz-Stephani  GGschwantler  MHorner  MStoltz-Szots  JWeiss  W The effect of eradication therapy in Helicobacter-positive patients with chronic urticaria [abstract]. Gastroenterology. 1997;112A283
Carnevale  PBierti  LPigatto  PMasellis  Pde Franchis  R Helicobacter pylori and chronic urticaria: the role of eradication [abstract]. Gastroenterology. 1998;114A84
di Campli  CGasbarrini  ANucera  E  et al.  Beneficial effects of Helicobacter pylori eradication on idiopathic chronic urticaria. Dig Dis Sci. 1998;431226- 1229
Reinauer  SMegahed  MGoerz  G  et al.  Schönlein-Henoch purpura associated with gastric Helicobacter pylori infection. J Am Acad Dermatol. 1995;33876- 879
Tosti  APretolani  SFigura  N  et al.  Helicobacter pylori and skin diseases. Gastroenterol Int. 1997;1037- 39
Murakami  KFujioka  TNishizono  A  et al.  Atopic dermatitis treated by eradication of Helicobacter pyloriJ Gastroenterol. 1996;31 ((suppl 9)) 77- 82
Kurkcuoglu  NAksoy  F Sweet's syndrome associated with Helicobacter pylori infection. J Am Acad Dermatol. 1997;37123- 124
Graff  LBAndersen  LPBremmelgaard  A  et al.  Changes in antibodies to Helicobacter pylori (Hp) and in joint manifestations in patients with rheumatoid arthritis (RA) after eradication from Hp: preliminary results [abstract]. Gut. 1996;39 ((suppl 2)) A89
Showji  YNozawa  RSato  KSuzuki  H Seroprevalence of Helicobacter pylori infection in patients with connective tissue diseases. Microbiol Immunol. 1996;40499- 503
Reinauer  SGoerz  GRuzicka  TSusanto  FHumfeld  SReinauer  H Helicobacter pylori in patients with systemic sclerosis: detection with the 13C-urea breath test and eradication. Acta Dermatol Venereol. 1994;74361- 363
Ferraccioli  GFSorrentino  DDe Vita  S  et al.  B cell clonality in gastric lymphoid tissues of patients with Sjogren's syndrome. Ann Rheum Dis. 1996;55311- 316
Collin  PKarvonen  ALKorpela  MLaippala  PHelin  H Gastritis classified in accordance with the Sydney system in patients with primary Sjogren's syndrome. Scand J Gastroenterol. 1997;32108- 111
Otto  BRVerweij-van Vught  AMJJMacLaren  DM Transferrins and heme-compounds as iron sources for pathogenic bacteria. Clin Rev Microbiol. 1992;18217- 233
Tomb  JFWhite  OKerlavage  AR  et al.  The complete genome sequence of the gastric pathogen Helicobacter pyloriNature. 1997;388539- 547
Lee  A The Helicobacter pylori genome: new insights into pathogenesis and therapeutics. N Engl J Med. 1998;338832- 833
Blecker  VRenders  FLanciers  SVandenplas  Y Syncopes leading to diagnosis of Helicobacter pylori positive chronic active hemorrhagic gastritis. Eur J Pediatr. 1991;150560- 561
Dufour  CBrisigotti  MFabretti  GLuxardo  PMori  PGBarabino  A Helicobacter pylori gastric infection and sideropenic refractory anemia. J Pediatr Gastroenterol Nutr. 1993;17225- 227
Bruel  HDabadie  APouedras  PGambert  CLe Gall  EJezequel  C Helicobacter pylori gastritis manifested by acute anemia. Ann Pediatr. 1993;40364- 367
Carnicer  JBadía  RArgemí  J Helicobacter pylori gastritis and sideropenic refractory anemia [letter]. J Pediatr Gastroenterol Nutr. 1997;25441
Marignani  MAngeletti  SBordi  C  et al.  Reversal of long-standing iron deficiency anaemia after eradication of Helicobacter pylori infection. Scand J Gastroenterol. 1997;32617- 622
Bardhan  PKHildebrand  PSarker  SA  et al.  Helicobacter pylori infection in children: is there an association with anemia [abstract]? Gastroenterology. 1997;112A65
Rosenstock  SMilman  NJorgensen  TAndersen  LPBonnevie  O Helicobacter pylori infection does not affect red blood cell characteristics in Danish adults [abstract]. Gastroenterology. 1998;114A271
Franceschi  FGasbarinni  ATartaglione  R  et al.  Regression of autoimmune thrombocytopenic purpura after Helicobacter pylori eradication [abstract]. Gastroenterology. 1998;114A124
Taylor-Robinson  SDJackson  NBuckley  C Helicobacter pylori, ammonia and the brain. Gut. 1997;40805- 806
Gubbins  GPMoritz  TEMarsano  LSTalwalkar  RMcClain  CJMendenhall  CL Helicobacter pylori is a risk factor for hepatic encephalopathy in acute alcoholic hepatitis: the ammonia hypothesis revisited. Am J Gastroenterol. 1993;881906- 1910
Ito  SMiyagi  HAzuma  T  et al.  Hyperammonemia and Helicobacter pylori [letter]. Lancet. 1995;346124- 125
Miyagi  HAzuma  TIto  S  et al.  The effect of eradication therapy for H pylori infection on hyperammonemia: two years follow up study in two effective cases [abstract]. Gastroenterology. 1998;114A230
Plevris  JNMorgenstern  RHayes  PCBouchier  IAD Hyperammonemia in cirrhosis and Helicobacter pylori infection [letter]. Lancet. 1995;3461104
Kirchner  GIWagner  SSchmidt  H  et al.  Pathogenic role of Helicobacter pylori infection in chronic liver disease [abstract]. Gastroenterology. 1996;110A157
Miyagi  HIto  SAzuma  T  et al.  Effects of Helicobacter pylori eradication therapy on hyperammonemia in patients with liver cirrhosis. Gut. 1997;40726- 730
Llach  JVasconez  CElizalde  JI  et al.  Helicobacter pylori, hyperammonemia and subclinical portosystemic encephalopathy: effects of eradication [abstract]. Gastroenterology. 1998;114A206
Cho  HGKwon  KSKim  PS  et al.  Correlation between hyperammonemia and gastric H pylori infection in patients with liver cirrhosis [abstract]. Gastroenterology. 1998;114A92
Dasani  BMSigal  SHLieber  CS Analysis of risk factors for chronic hepatic encephalopathy: the role of Helicobacter pylori infection. Am J Gastroenterol. 1998;93726- 731
Zullo  ARinaldi  VFolino  SDiana  FAttili  AF Helicobacter pylori urease inhibition and ammonia levels in cirrhotic patients [letter]. Am J Gastroenterol. 1998;93851- 852
El-Nujumi  AMDorrian  CAChittajallu  RS  et al.  Effect of inhibition of Helicobacter pylori urease activity by acetohydroxamic acid on serum gastrin in duodenal ulcer subjects. Gut. 1991;32866- 870
Fireman  ZCoscas  DSternberg  AWagner  YZonder  H Does Helicobacter pylori affect the blood ammonia level of hemodialysis patients [abstract]? Gut. 1996;39 ((suppl 2)) A95
Pattison  CPMarshall  BJ Proposed link between Helicobacter pylori and sudden infant death syndrome. Med Hypotheses. 1997;49365- 369
Ho  GYWindsor  HMPattison  CPVergara  GGMarshall  BJ Are there Helicobacter pylori on gastric mucosa in sudden infant death syndrome (SIDS) [abstract]? Gastroenterology. 1998;114A996
Pattison  CPMarshall  BJYoung  TWVergara  GG Is Helicobacter pylori the missing link for sudden infant death syndrome (SIDS) [abstract]? Gastroenterology. 1997;112A254
Pattison  CPSmoot  DTAshktorab  HVergara  GGYoung  TWSmith  GP Confirmation of Helicobacter pylori (Hp) by polymerase chain reaction (PCR) in sudden infant death syndrome (SIDS) [abstract]. Gastroenterology. 1998;114A899
Pattison  CPSmoot  DTAshktorab  HVergara  GGYoung  TWSmith  GP Is Helicobacter pylori (Hp) transmitted by the respiratory route? polymerase chain reaction (PCR) confirmation of tracheal colonization with Hp in sudden infant death syndrome (SIDS) [abstract]. Gastroenterology. 1998;114A899
Mitz  HSFarber  SS Demonstration of Helicobacter pylori in tracheal secretions. J Am Osteopath Assoc. 1993;9387- 91
Pattison  CPVergara  GGYoung  TWSmith  GP Prevalence of Helicobacter pylori (Hp) in sudden infant death syndrome (SIDS) [abstract]. Gastroenterology. 1998;114A900
Patel  PMendall  MAKhulusi  SNorthfield  TCStrachan  DP Helicobacter pylori infection in childhood: risk factors and effect on growth. BMJ. 1994;3091119- 1123
Raymond  JBergeret  MBenhamou  PHMensah  KDupont  C A 2-year study of Helicobacter pylori in children. J Clin Microbiol. 1994;32461- 463
Perri  FPastore  MLeandro  G  et al.  Helicobacter pylori infection and growth delay in older children. Arch Dis Child. 1997;7746- 49
Oderda  GPalli  DSaieva  CChiorboli  EBona  G Short stature and Helicobacter pylori infection in Italian children: prospective multicentre hospital based case-control study. BMJ. 1998;317514- 515
Murray  LJMcCrum  EEEvans  AEBamford  KB Epidemiology of Helicobacter pylori infection among 4742 randomly selected subjects from Northern Ireland. Int J Epidemiol. 1997;26880- 887
Eurogast Study Group, Epidemiology of, and risk factors for, Helicobacter pylori infection among 3194 asymptomatic subjects in 17 populations. Gut. 1993;331672- 1676
Portnoi  VA Helicobacter pylori and the anorexia of aging. Arch Intern Med. 1997;157269- 272
Howden  CW Lack of evidence for an association between Helicobacter pylori infection and the anorexia of aging [letter]. Arch Intern Med. 1997;1571771- 1773
Sackett  DL Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest. 1989;95 ((suppl)) 2S- 4S
Forman  DNewell  DGFullerton  F  et al.  Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. BMJ. 1991;3021302- 1305
Parsonnet  JFriedman  GDVandersteen  DP  et al.  Helicobacter pylori infection and the risk of gastric adenocarcinoma. N Engl J Med. 1991;3251127- 1131
Nomura  AStemmermann  GNChyou  PHKato  IPerez-Perez  GIBlaser  MJ Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991;3251132- 1136
Parsonnet  JHansen  SRodriguez  L  et al.  Helicobacter pylori and gastric lymphoma. N Engl J Med. 1994;3301267- 1271

Figures

Tables

Table Graphic Jump LocationTable 1. Application of 9 Diagnostic Tests for Causes of Certain Non–Gastrointestinal Tract Conditions Proposed to Be Related to Helicobacter pylori Infection*
Table Graphic Jump LocationTable 2. Application of 9 Diagnostic Tests for Causes of Upper Gastrointestinal Tract Conditions Generally Accepted to Be Related to Helicobacter pylori Infection*

References

Howden  CW Clinical expressions of H pylori infection. Am J Med. 1996;100 ((suppl)) 27S- 34S
Peura  DA The report of the Digestive Health Initiative International Update Conference on Helicobacter pyloriGastroenterology. 1997;113 ((suppl 1)) S4- S8
Asaka  MTakeda  HSugiyama  TKato  M What role does Helicobacter pylori play in gastric cancer? Gastroenterology. 1997;113 ((suppl 1)) S56- S60
Dixon  MF Commentary: role of Helicobacter pylori on gastric mucosal damage, gastric cancer, and gastric MALT lymphoma. Gastroenterology. 1997;113 ((suppl 1)) S65- S66
Huang  J-QSridhar  SChen  YHunt  RH Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology. 1998;1141169- 1179
Thiede  CMorgner  AAlpen  B  et al.  What role does Helicobacter pylori eradication play in gastric MALT and gastric MALT lymphoma? Gastroenterology. 1997;113 ((suppl 1)) S61- S64
Talley  NJHunt  RH What role does Helicobacter pylori play in dyspepsia and nonulcer dyspepsia? arguments for and against H pylori being associated with dyspeptic symptoms. Gastroenterology. 1997;113 ((suppl 1)) S67- S77
McColl  KELMurray  LSEl-Omar  E  et al.  UK MRC trial of H pylori eradication therapy for non-ulcer dyspepsia [abstract]. Gastroenterology. 1998;114A222
Talley  NJJanssens  JLauritsen  K  et al.  Long-term follow-up of patients with non-ulcer dyspepsia after Helicobacter pylori eradication: a randomized double-blind placebo-controlled trial [abstract]. Gastroenterology. 1998;114A305
Mobley  HLT Helicobacter pylori factors associated with disease development. Gastroenterology. 1997;113 ((suppl 1)) S21- S28
Ernst  PBCrowe  SEReyes  VE How does Helicobacter pylori cause mucosal damage? the inflammatory response. Gastroenterology. 1997;113 ((suppl 1)) S35- S42
Gasbarrini  AFranceschi  FGasbarrini  GPola  P Extraintestinal pathology associated with Helicobacter infection. Eur J Gastroenterol Hepatol. 1997;9231- 233
Ponzetto  A Extra-gastrointestinal diseases and Helicobacter pyloriEur J Gastroenterol Hepatol. 1997;9616
Cave  DR Transmission and epidemiology of Helicobacter pyloriAm J Med. 1996;100 ((suppl 5A)) 12S- 18S
Cave  DR How is Helicobacter pylori transmitted? Gastroenterology. 1997;113 ((suppl 1)) S9- S14
Sackett  DLHaynes  RBTugwell  P Clinical Epidemiology: A Basic Science for Clinical Medicine.  Boston, Mass Little Brown & Co1985;
Marshall  BArmstrong  JMcGechie  DGlancy  R Attempt to fulfill Koch's postulates for pyloric CampylobacterMed J Aust. 1985;142436- 439
Morris  ANicholson  G Ingestion of Campylobacter pyloridis causes gastritis and raised fasting pH. Am J Gastroenterol. 1987;82192- 199
Morris  AJAli  MRNicholson  GIPerez-Perez  GIBlaser  MJ Long-term follow-up of voluntary ingestion of Helicobacter pyloriAnn Intern Med. 1991;114662- 663
Cutler  AFHavstad  SMa  CKBlaser  MJPerez-Perez  GISchubert  TT Accuracy of invasive and non-invasive tests to diagnose Helicobacter pylori infection. Gastroenterology. 1995;109136- 141
Atherton  JC Non-endoscopic tests in the diagnosis of Helicobacter pylori infection. Aliment Pharmacol Ther. 1997;11 ((suppl 1)) 11- 20
Howden  CWHunt  RH Guidelines for the management of Helicobacter pylori infection. Am J Gastroenterol. 1998;932330- 2338
Borhan-Manesh  FFarnum  JB Study of Helicobacter pylori colonization of patches of heterotopic gastric mucosa (HGM) at the upper esophagus. Dig Dis Sci. 1993;38142- 146
Jacobs  EDehou  MF Heterotopic gastric mucosa in the upper esophagus: a prospective study of 33 cases and review of the literature. Endoscopy. 1997;29710- 715
Paul  GYardley  JH Gastric and esophageal Campylobacter pylori in patients with Barrett's esophagus. Gastroenterology. 1988;95216- 218
Sharma  VKTailon  DVasudeva  RHowden  CWDemian  SE In columnar-lined esophagus (CLE), H pylori (HP) is confined to gastric metaplasia [abstract]. Am J Gastroenterol. 1997;921604
Malfertheiner  PBoce  G Helicobacter pylori and the pathogenesis of duodenal ulcer disease. Eur J Gastroenterol Hepatol. 1993;51- 8
Peura  DA Helicobacter pylori and ulcerogenesis. Am J Med. 1996;100 ((suppl 5A)) 19S- 26S
Morris  ANicholson  GZwi  JVanderwee  M Campylobacter pylori infection in Meckel's diverticula containing gastric mucosa. Gut. 1989;301233- 1235
de Cothi  GANewbold  KMO'Connor  HJ Campylobacter-like organisms and heterotopic gastric mucosa in Meckel's diverticula. J Clin Pathol. 1989;42132- 134
Dye  KRMarshall  BJFrierson  HF  JrPambianco  DJMcCallum  RW Campylobacter pylori colonizing heterotopic gastric tissue in the rectum. Am J Clin Pathol. 1990;93144- 147
Patel  PCarrington  DStrachan  DP  et al.  Fibrinogen: a link between chronic infection and coronary heart disease [letter]. Lancet. 1994;3431634- 1635
Patel  PMendall  MACarrington  D  et al.  Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. BMJ. 1995;311711- 714
Rajput-Williams  JWilliams  NRJohnson  PGDickinson  RJ Fibrinogen and H pylori in asymptomatic post MI patients and healthy controls [abstract]. Gut. 1996;39 ((suppl 2)) A94
Murray  LJBamford  KBO'Reilly  DPJMcCrum  EEEvans  AE Helicobacter pylori infection: relation with cardiovascular risk factors, ischaemic heart disease, and social class. Br Heart J. 1995;74497- 501
Carter  AMMoayyedi  PCatto  AHeppel  RMAxon  ATGrant  PJ The influence of Helicobacter pylori status on circulating levels of the coagulation factors fibrinogen, von Willebrand factor, factor VII and factor VIII. Helicobacter. 1996;165- 69
Ossei-Gerning  N Helicobacter pylori infection is related to atheroma in patients undergoing coronary angiography. Cardiovasc Res. 1997;35120- 124
Bierti  LCernuschi  CAbbiati  C  et al.  Correlation between gastric infection with Helicobacter pylori and plasma levels of fibrinogen, plasminogen activator inhibitor (PAI) and von Willebrand factor (vWF) antigen [abstract]. Gut. 1996;39 ((suppl 2)) A90
Parente  FMaconi  GImbesi  V  et al.  Helicobacter pylori infection and coagulation in healthy people. BMJ. 1997;3141318- 1319
McDonagh  TAWoodward  MMorrison  CE  et al.  Helicobacter pylori infection and coronary heart disease in the North Glasgow MONICA population. Eur Heart J. 1997;181257- 1260
Wald  NJLaw  MRMorris  JKBagnall  AM Helicobacter pylori infection and mortality from ischaemic heart disease: negative result from a large, prospective study. BMJ. 1997;3151199- 1201
Danesh  JPeto  R Risk factors for coronary heart disease and infection with Helicobacter pylori: meta-analysis of 18 studies. BMJ. 1998;3161130- 1132
Elizalde  JIGómez  JPanés  J  et al.  Platelet activation in mice and human Helicobacter pylori infection. J Clin Invest. 1997;100996- 1005
Danesh  JCollins  RAppleby  PPeto  R Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998;2791477- 1482
Karttunen  TJNiemalä  SKerola  T Blood leukocyte differential in Helicobacter pylori infection. Dig Dis Sci. 1996;411332- 1336
Whincup  PHMendall  MAPerry  IJStrachan  DPWalker  M Prospective relations between Helicobacter pylori infection, coronary heart disease, and stroke in middle aged men. Heart. 1996;75568- 572
Mendall  MAPatel  PBallam  LStrachan  DNorthfield  TC C reactive protein and its relationship to cardiovascular risk factors: a population based cross sectional study. BMJ. 1996;3121061- 1065
Mendall  MAPatel  PAsante  M  et al.  Relation of serum cytokine concentrations to cardiovascular risk factors and coronary heart disease. Heart. 1997;78273- 277
Neri  MReale  MDi Febbo  C  et al.  Increased levels of soluble tumor necrosis factor receptor I (sTNF RI) in serum of Helicobacter pylori–positive ischemic heart disease patients [abstract]. Gastroenterology. 1996;110A209
Scragg  RKRFraser  AMetcalf  PA Helicobacter pylori seropositivity and cardiovascular risk factors in a multicultural workforce. J Epidemiol Community Health. 1996;50578- 579
Strandberg  TETilvis  RSVuoristo  MKosunen  TU H pylori infection and cardiovascular diseases in elderly population [abstract]. Gut. 1996;39 ((suppl 2)) A92
Martín-de-Argila  CBoixeda  DFuertes  A  et al.  High prevalence of Helicobacter pylori infection in coronary heart disease demonstrated by the 13C-urea breath test [abstract]. Gut. 1996;39 ((suppl 2)) A95
Rosenstock  SJAndersen  LPBonnevie  OJørgensen  T Serum lipids, body-indices, age at menarche, and Helicobacter pylori infection in 1756 Danish women [abstract]. Gut. 1996;39 ((suppl 3)) A62
Khurshid  APuetz  TFenske  TBajwa  TVakil  N Seroprevalence of Helicobacter pylori infection in patients with and without angiographic evidence of coronary heart disease [abstract]. Gastroenterology. 1996;110A154
Pilotto  ARumor  FNovello  RFranceschi  MValerio  G Helicobacter pylori infection and atherosclerosis: a study with endoscopy and vascular echodoppler ultrasonography in elderly subjects [abstract]. Gastroenterology. 1997;112A259
Kang  DHYoon  HSPark  DK  et al.  The association between Helicobacter pylori infection and coronary heart disease assessed by coronary angiography [abstract]. Gastroenterology. 1998;114A166
Kang  DHPark  DKYoon  HS  et al.  The association between Helicobacter pylori infection and transaminase [abstract]. Gastroenterology. 1998;114A166
Martín-de-Argila  CBoixeda  DCanton  R  et al.  Helicobacter pylori infection, serum triglyceride and serum cholesterol levels: a step athero-sclerosis [abstract]? Gastroenterology. 1998;114A218
Clarke  RDaly  LRobinson  K  et al.  Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991;3241149- 1155
Stampfer  MJMalinow  MRWillet  WC  et al.  A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA. 1992;268877- 881
Sung  JJYSanderson  JE Hyperhomocysteinaemia, Helicobacter pylori, and coronary heart disease. Heart. 1996;76305- 307
Go  MF What are the host factors that place an individual at risk for Helicobacter pylori–associated disease? Gastroenterology. 1997;113 ((suppl 1)) S15- S20
Whincup  PHMendall  MAPerry  IJStrachan  DP Hyperhomocysteinaemia, Helicobacter pylori, and coronary heart disease [letter]. Heart. 1997;78524
Saxena  VMarkus  HSwaminathan  SMendall  ME Hyperhomocysteinaemia, Helicobacter pylori, and coronary heart disease [letter]. Heart. 1997;78524
Markus  HSMendall  MA Helicobacter pylori infection: a risk factor for ischaemic cerebrovascular disease and carotid atheroma. J Neurol Neurosurg Psychiatry. 1998;84104- 107
Xu  QWillett  JMarosi  M  et al.  Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis. Lancet. 1993;341255- 259
Xu  QWick  G The role of heat shock proteins in protection and pathophysiology of the arterial wall. Mol Med Today. 1996;2372- 379
Birnie  DHolme  EMcKay  ICHood  SMcColl  KELHillis  WS Association between antibodies to mycobacterial heat shock protein 65 and coronary atherosclerosis: possible mechanism of action of Helicobacter pylori in increasing cardiovascular risk [abstract]. Heart. 1996;75 ((suppl 1)) P49
Mendall  MAGoggin  PMMolineaux  N  et al.  Relation of Helicobacter pylori infection and coronary heart disease. Br Heart J. 1994;71437- 439
Sandifer  QDLo  SVCrompton  G Association may not be causal [letter]. BMJ. 1996;312251
Niemalä  SKarttunen  TKorhonen  T  et al.  Could Helicobacter pylori infection increase the risk of coronary heart disease by modifying serum lipid concentrations? Heart. 1996;75573- 575
Morgando  ASanseverino  PPeroto  CMolino  FGai  VPonzetto  A Helicobacter pylori seropositivity in myocardial infarction [letter]. Lancet. 1995;3451380
Martín-de-Argila  CBoixeda  DCanton  RGisbert  JFuertes  A High seroprevalence of Helicobacter pylori infection in coronary heart disease [letter]. Lancet. 1995;346310
Ponzetto  ALa Rovere  MTSanseverino  PBazzoli  F Study confirms previous findings [letter]. BMJ. 1996;312251
Rathbone  BMartin  DStephens  JThompson  JRSamani  NJ Helicobacter pylori seropositivity in subjects with acute myocardial infarction. Heart. 1996;76308- 311
Parravicini  PPPellicano  RBigi  R  et al.  Helicobacter pylori infection and acute myocardial infarction in Northern Italy [abstract]. Gastroenterology. 1998;114A253
Maier  FAuricchio  ANilius  MKlein  HMalfertheiner  P Lack of association between Helicobacter pylori infection and angiographically documented coronary heart disease [abstract]. Gastroenterology. 1996;110A183
Menge  HLang  AHopert  RBrosius  BLollgen  HBoenigk  U Helicobacter pylori infection in patients with and without coronary heart disease [abstract]. Gastroenterology. 1998;114A226
Khurshid  AFenske  TBajwa  TBourgeois  KVakil  N A prospective, controlled study of Helicobacter pylori seroprevalence in coronary artery disease. Am J Gastroenterol. 1998;93717- 720
Balaban  DHPeura  DAWatson  DRembold  CShifflet  J Relationship between H pylori infection and ischemic heart disease [abstract]. Gastroenterology. 1996;110A55
Strandberg  TETilvis  RSVuoristo  MLindroos  MKosunen  TU Prospective study of Helicobacter pylori seropositivity and cardiovascular diseases in a general elderly population. BMJ. 1997;3141317- 1318
Danesh  JCollins  RPeto  R Chronic infections and coronary heart disease: is there a link? Lancet. 1997;350430- 436
Ponzetto  ASandrone  NPellicano  RArena  VRaso  AM Helicobacter pylori infection in patients with arterial obstruction [abstract]. Gastroenterology. 1998;114A260
Barnes  RJUff  JSDent  JCGear  MWWilkinson  SP Long-term follow up of patients with gastritis associated with Helicobacter pylori infection. Br J Gen Pract. 1991;41286- 288
Lip  GYHWise  RBeevers  G Association of Helicobacter pylori infection with coronary heart disease: study shows association between H pylori infection and hypertension [letter]. BMJ. 1996;312250- 251
Franceschi  FGasbarinni  ARuggieri  MP  et al.  Helicobacter pylori infection and idiopathic arrhythmias [abstract]. Gastroenterology. 1998;114A123
Gasbarinni  ASerricchio  MTondi  PGasbarrini  GPola  P Association of Helicobacter pylori infection with primary Raynaud phenomenon [letter]. Lancet. 1996;348966- 967
Gasbarinni  AMassari  ISerricchio  M  et al.  Helicobacter pylori infection in patients affected by Raynaud phenomenon: beneficial effects of eradication [abstract]. Gastroenterology. 1998;114A130
Gasbarrini  Ade Luca  AFiore  G  et al.  Beneficial effects of Helicobacter pylori eradication on migraine [abstract]. Gastroenterology. 1998;114A129
Gasbarrini  Ade Luca  AFiore  G  et al.  Helicobacter pylori infection in primary headache [abstract]. Gastroenterology. 1998;114A130
Oldenburg  BDiepersloot  RJAHoekstra  JBL High seroprevalence of Helicobacter pylori in diabetes mellitus patients. Dig Dis Sci. 1996;41458- 461
Danesh  JN H pylori and diabetes [letter]. Dig Dis Sci. 1997;422576
Pocecco  MBuratti  ETommasini  ATorre  GNot  T High risk of Helicobacter pylori infection associated with cow's milk antibodies in young diabetics. Acta Pediatr. 1997;86700- 703
Begue  REMirza  ACompton  TVargas  A Helicobacter pylori infection and the metabolic control of patients with diabetes type I and II [abstract]. Gastroenterology. 1998;114A71
Martín-de-Argila  CBoixeda  Dde Luis  DA  et al.  Helicobacter pylori infection and diabetes mellitus [abstract]. Gastroenterology. 1998;114A218
Ojetti  VGasbarini  APitocco  D  et al.  Effects of Helicobacter pylori eradication on insulin-dependent diabetes mellitus [abstract]. Gastroenterology. 1998;114A247
Cammarota  GTursi  Ade Marinis  L  et al.  Gastric mucosa-associated lymphoid tissue in autoimmune thyroid diseases. Scand J Gastroenterol. 1997;32869- 872
Figura  NGuarino  EGragnoli  A  et al.  H pylori (HP) infection and thyroid diseases [abstract]. Gut. 1996;39 ((suppl 2)) A93
Plockinger  UDienemann  DQuabbe  HJ Gastrointestinal side-effects of octreotide during long-term treatment of acromegaly. J Clin Endocrinol Metab. 1990;711658- 1662
Anderson  JVCatnach  SLowe  DGFairclough  PDBesser  GMWass  JA Prevalence of gastritis in patients with acromegaly: untreated and during treatment with octreotide. Clin Endocrinol. 1992;37227- 232
Marks  RBeard  RJClark  ML  et al.  Gastrointestinal observations in rosacea. Lancet. 1967;1739- 742
Rebora  ADrago  FPicciotto  A Helicobacter pylori in patients with rosacea [letter]. Am J Gastroenterol. 1994;891603- 1604
Parish  LCWitkowski  JA Acne rosacea and Helicobacter pylori betrothed. Int J Dermatol. 1995;34236- 237
Kolibášová  KTóthová  IBaumgartner  JFilo  V Eradication of Helicobacter pylori as the only successful treatment in rosacea [letter]. Arch Dermatol. 1996;1321393- 1394
Powell  FCDawa  MADuguid  C Positive Helicobacter pylori serology in rosacea patients [abstract]. Ir J Med Sci. 1992;161 ((suppl)) 75
Schneider  MASkinner  RBJRosenberg  EW  et al.  Serological determination of Helicobacter pylori in rosacea patients and controls [abstract]. Clin Res. 1992;40831A
Sharma  VKLynn  AKaminski  MVasudeva  RHowden  CW A study of the prevalence of Helicobacter pylori infection and other markers of upper gastrointestinal tract disease in patients with rosacea. Am J Gastroenterol. 1998;93220- 222
Rosenberg  EWNoah  PWSkinner  RB Microorganisms and psoriasis. J Nat Med Assoc. 1994;86305- 310
Halasz  CLG Helicobacter pylori antibodies in patients with psoriasis [letter] [published correction appears in Arch Dermatol. 1996;132:616]. Arch Dermatol. 1996;13295- 96
Bohmeyer  JHeller  AHartig  C  et al.  Association of chronic urticaria with Helicobacter pylori–induced antrum gastritis. Hautarzt. 1996;47106- 108
Morisset  Mde Korwin  JDLozniewski  AKanny  GPlenat  FMoneret-Vautrin  DA Chronic urticaria and Helicobacter pylori infection [abstract]. Gut. 1996;39 ((suppl 2)) A92
Tebbe  BGeilen  CCSchulzke  J-DBojarski  CRadenhausen  MOrfanos  CE Helicobacter pylori infection and chronic urticaria. J Am Acad Dermatol. 1996;34685- 686
Schrutka-Koebl  CHWasilewicz-Stephani  GGschwantler  MHorner  MStoltz-Szots  JWeiss  W The effect of eradication therapy in Helicobacter-positive patients with chronic urticaria [abstract]. Gastroenterology. 1997;112A283
Carnevale  PBierti  LPigatto  PMasellis  Pde Franchis  R Helicobacter pylori and chronic urticaria: the role of eradication [abstract]. Gastroenterology. 1998;114A84
di Campli  CGasbarrini  ANucera  E  et al.  Beneficial effects of Helicobacter pylori eradication on idiopathic chronic urticaria. Dig Dis Sci. 1998;431226- 1229
Reinauer  SMegahed  MGoerz  G  et al.  Schönlein-Henoch purpura associated with gastric Helicobacter pylori infection. J Am Acad Dermatol. 1995;33876- 879
Tosti  APretolani  SFigura  N  et al.  Helicobacter pylori and skin diseases. Gastroenterol Int. 1997;1037- 39
Murakami  KFujioka  TNishizono  A  et al.  Atopic dermatitis treated by eradication of Helicobacter pyloriJ Gastroenterol. 1996;31 ((suppl 9)) 77- 82
Kurkcuoglu  NAksoy  F Sweet's syndrome associated with Helicobacter pylori infection. J Am Acad Dermatol. 1997;37123- 124
Graff  LBAndersen  LPBremmelgaard  A  et al.  Changes in antibodies to Helicobacter pylori (Hp) and in joint manifestations in patients with rheumatoid arthritis (RA) after eradication from Hp: preliminary results [abstract]. Gut. 1996;39 ((suppl 2)) A89
Showji  YNozawa  RSato  KSuzuki  H Seroprevalence of Helicobacter pylori infection in patients with connective tissue diseases. Microbiol Immunol. 1996;40499- 503
Reinauer  SGoerz  GRuzicka  TSusanto  FHumfeld  SReinauer  H Helicobacter pylori in patients with systemic sclerosis: detection with the 13C-urea breath test and eradication. Acta Dermatol Venereol. 1994;74361- 363
Ferraccioli  GFSorrentino  DDe Vita  S  et al.  B cell clonality in gastric lymphoid tissues of patients with Sjogren's syndrome. Ann Rheum Dis. 1996;55311- 316
Collin  PKarvonen  ALKorpela  MLaippala  PHelin  H Gastritis classified in accordance with the Sydney system in patients with primary Sjogren's syndrome. Scand J Gastroenterol. 1997;32108- 111
Otto  BRVerweij-van Vught  AMJJMacLaren  DM Transferrins and heme-compounds as iron sources for pathogenic bacteria. Clin Rev Microbiol. 1992;18217- 233
Tomb  JFWhite  OKerlavage  AR  et al.  The complete genome sequence of the gastric pathogen Helicobacter pyloriNature. 1997;388539- 547
Lee  A The Helicobacter pylori genome: new insights into pathogenesis and therapeutics. N Engl J Med. 1998;338832- 833
Blecker  VRenders  FLanciers  SVandenplas  Y Syncopes leading to diagnosis of Helicobacter pylori positive chronic active hemorrhagic gastritis. Eur J Pediatr. 1991;150560- 561
Dufour  CBrisigotti  MFabretti  GLuxardo  PMori  PGBarabino  A Helicobacter pylori gastric infection and sideropenic refractory anemia. J Pediatr Gastroenterol Nutr. 1993;17225- 227
Bruel  HDabadie  APouedras  PGambert  CLe Gall  EJezequel  C Helicobacter pylori gastritis manifested by acute anemia. Ann Pediatr. 1993;40364- 367
Carnicer  JBadía  RArgemí  J Helicobacter pylori gastritis and sideropenic refractory anemia [letter]. J Pediatr Gastroenterol Nutr. 1997;25441
Marignani  MAngeletti  SBordi  C  et al.  Reversal of long-standing iron deficiency anaemia after eradication of Helicobacter pylori infection. Scand J Gastroenterol. 1997;32617- 622
Bardhan  PKHildebrand  PSarker  SA  et al.  Helicobacter pylori infection in children: is there an association with anemia [abstract]? Gastroenterology. 1997;112A65
Rosenstock  SMilman  NJorgensen  TAndersen  LPBonnevie  O Helicobacter pylori infection does not affect red blood cell characteristics in Danish adults [abstract]. Gastroenterology. 1998;114A271
Franceschi  FGasbarinni  ATartaglione  R  et al.  Regression of autoimmune thrombocytopenic purpura after Helicobacter pylori eradication [abstract]. Gastroenterology. 1998;114A124
Taylor-Robinson  SDJackson  NBuckley  C Helicobacter pylori, ammonia and the brain. Gut. 1997;40805- 806
Gubbins  GPMoritz  TEMarsano  LSTalwalkar  RMcClain  CJMendenhall  CL Helicobacter pylori is a risk factor for hepatic encephalopathy in acute alcoholic hepatitis: the ammonia hypothesis revisited. Am J Gastroenterol. 1993;881906- 1910
Ito  SMiyagi  HAzuma  T  et al.  Hyperammonemia and Helicobacter pylori [letter]. Lancet. 1995;346124- 125
Miyagi  HAzuma  TIto  S  et al.  The effect of eradication therapy for H pylori infection on hyperammonemia: two years follow up study in two effective cases [abstract]. Gastroenterology. 1998;114A230
Plevris  JNMorgenstern  RHayes  PCBouchier  IAD Hyperammonemia in cirrhosis and Helicobacter pylori infection [letter]. Lancet. 1995;3461104
Kirchner  GIWagner  SSchmidt  H  et al.  Pathogenic role of Helicobacter pylori infection in chronic liver disease [abstract]. Gastroenterology. 1996;110A157
Miyagi  HIto  SAzuma  T  et al.  Effects of Helicobacter pylori eradication therapy on hyperammonemia in patients with liver cirrhosis. Gut. 1997;40726- 730
Llach  JVasconez  CElizalde  JI  et al.  Helicobacter pylori, hyperammonemia and subclinical portosystemic encephalopathy: effects of eradication [abstract]. Gastroenterology. 1998;114A206
Cho  HGKwon  KSKim  PS  et al.  Correlation between hyperammonemia and gastric H pylori infection in patients with liver cirrhosis [abstract]. Gastroenterology. 1998;114A92
Dasani  BMSigal  SHLieber  CS Analysis of risk factors for chronic hepatic encephalopathy: the role of Helicobacter pylori infection. Am J Gastroenterol. 1998;93726- 731
Zullo  ARinaldi  VFolino  SDiana  FAttili  AF Helicobacter pylori urease inhibition and ammonia levels in cirrhotic patients [letter]. Am J Gastroenterol. 1998;93851- 852
El-Nujumi  AMDorrian  CAChittajallu  RS  et al.  Effect of inhibition of Helicobacter pylori urease activity by acetohydroxamic acid on serum gastrin in duodenal ulcer subjects. Gut. 1991;32866- 870
Fireman  ZCoscas  DSternberg  AWagner  YZonder  H Does Helicobacter pylori affect the blood ammonia level of hemodialysis patients [abstract]? Gut. 1996;39 ((suppl 2)) A95
Pattison  CPMarshall  BJ Proposed link between Helicobacter pylori and sudden infant death syndrome. Med Hypotheses. 1997;49365- 369
Ho  GYWindsor  HMPattison  CPVergara  GGMarshall  BJ Are there Helicobacter pylori on gastric mucosa in sudden infant death syndrome (SIDS) [abstract]? Gastroenterology. 1998;114A996
Pattison  CPMarshall  BJYoung  TWVergara  GG Is Helicobacter pylori the missing link for sudden infant death syndrome (SIDS) [abstract]? Gastroenterology. 1997;112A254
Pattison  CPSmoot  DTAshktorab  HVergara  GGYoung  TWSmith  GP Confirmation of Helicobacter pylori (Hp) by polymerase chain reaction (PCR) in sudden infant death syndrome (SIDS) [abstract]. Gastroenterology. 1998;114A899
Pattison  CPSmoot  DTAshktorab  HVergara  GGYoung  TWSmith  GP Is Helicobacter pylori (Hp) transmitted by the respiratory route? polymerase chain reaction (PCR) confirmation of tracheal colonization with Hp in sudden infant death syndrome (SIDS) [abstract]. Gastroenterology. 1998;114A899
Mitz  HSFarber  SS Demonstration of Helicobacter pylori in tracheal secretions. J Am Osteopath Assoc. 1993;9387- 91
Pattison  CPVergara  GGYoung  TWSmith  GP Prevalence of Helicobacter pylori (Hp) in sudden infant death syndrome (SIDS) [abstract]. Gastroenterology. 1998;114A900
Patel  PMendall  MAKhulusi  SNorthfield  TCStrachan  DP Helicobacter pylori infection in childhood: risk factors and effect on growth. BMJ. 1994;3091119- 1123
Raymond  JBergeret  MBenhamou  PHMensah  KDupont  C A 2-year study of Helicobacter pylori in children. J Clin Microbiol. 1994;32461- 463
Perri  FPastore  MLeandro  G  et al.  Helicobacter pylori infection and growth delay in older children. Arch Dis Child. 1997;7746- 49
Oderda  GPalli  DSaieva  CChiorboli  EBona  G Short stature and Helicobacter pylori infection in Italian children: prospective multicentre hospital based case-control study. BMJ. 1998;317514- 515
Murray  LJMcCrum  EEEvans  AEBamford  KB Epidemiology of Helicobacter pylori infection among 4742 randomly selected subjects from Northern Ireland. Int J Epidemiol. 1997;26880- 887
Eurogast Study Group, Epidemiology of, and risk factors for, Helicobacter pylori infection among 3194 asymptomatic subjects in 17 populations. Gut. 1993;331672- 1676
Portnoi  VA Helicobacter pylori and the anorexia of aging. Arch Intern Med. 1997;157269- 272
Howden  CW Lack of evidence for an association between Helicobacter pylori infection and the anorexia of aging [letter]. Arch Intern Med. 1997;1571771- 1773
Sackett  DL Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest. 1989;95 ((suppl)) 2S- 4S
Forman  DNewell  DGFullerton  F  et al.  Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. BMJ. 1991;3021302- 1305
Parsonnet  JFriedman  GDVandersteen  DP  et al.  Helicobacter pylori infection and the risk of gastric adenocarcinoma. N Engl J Med. 1991;3251127- 1131
Nomura  AStemmermann  GNChyou  PHKato  IPerez-Perez  GIBlaser  MJ Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991;3251132- 1136
Parsonnet  JHansen  SRodriguez  L  et al.  Helicobacter pylori and gastric lymphoma. N Engl J Med. 1994;3301267- 1271

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 66

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles