Effect of Helicobacter pylori eradication in the glycemia of children with type 1 diabetes: a preliminary study.

ABSTRACT

Background. We previously reported that children with diabetes and Helicobacter pylori infection had higher levels of glycated hemoglobin ([HbA.sub.1c]) than uninfected peers. We sought to determine whether eradication of the infection could decrease their [HbA.sub.1c] level.

Methods. Eight children with type 1 diabetes and H pylori infection (cases) were treated to eradicate the infection. Cases were matched (2:1) with uninfected diabetic children (controls), and their [HbA.sub.1c] levels were monitored.

Results. As previously described, cases started with higher [HbA.sub.1c] values than controls. More than 2 years after treatment, cases showed a decreasing trend and controls an increasing trend in [HbA.sub.1c] values. At the end of the study, cases and controls had comparable [HbA.sub.1c] values.

Conclusion. These data suggest that eradication of H pylori infection in patients with type 1 diabetes might be associated with better control of glycemia.

**********

DIABETES MELLITUS affects more than 15 million individuals in the United States. (1) The importance of glycemia control has been emphasized lately by studies showing that diabetic patients with higher levels of [HbA.sub.1c] have significantly more long-term complications of the disease, such as retinopathy, nephropathy, and neuropathy. (2) Infections can lead to hyperglycemia in patients with diabetes mellitus; the mechanisms are unknown but are thought to include the secretion of counter-regulatory hormones due to stress, as well as the production of cytokines. Cytokines by themselves can stimulate the secretion of insulin counter-regulatory hormones, and they can also directly affect carbohydrate metabolism. (3) Helicobacter pylori is one of the most common chronic bacterial infections in the world, and infection with this bacterium has been associated with an increased production of cytokines such as tumor necrosis factor [alpha], interferon-[gamma], and interleukins 1, 6, and 8. (4)

Hence, we hypothesized that H pylori infection in children with diabetes mellitus might negatively affect their glycemia. Accordingly, we previously reported that among our patients with type 1 diabetes, those with concomitant H pylori infection required higher doses of insulin (1.2 vs 0.9 IU/kg per day, respectively) and yet had higher levels of [HbA.sub.1c] (14.9% vs 11.8%, respectively) than their uninfected counterparts. (5) These associations remained significant after controlling for possible confounding variables such as age, duration of diabetes, compliance, body mass index (BMI), income, sex, and race. To further evaluate the possible association between H pylori infection and metabolic control of diabetes, we proceeded to treat the infected individuals with antimicrobials to determine whether eradication of the infection would result in a decrease in their [HbA.sub.1c] level.

METHODS

In our previous work, (5) we identified 11 children with type 1 diabetes and asymptomatic H pylori infection, as diagnosed by serology (HM-CAP, Enteric Products Inc, Stony Brook, NY) (6) and confirmed with the urea-breath test (UBT) (Meretek UBT, Meretek Diagnostics Inc, Houston, Tex). (7) Of these 11 patients, 2 were lost to follow-up (one moved out of town and the other could not be located), and 9 received antimicrobial therapy. Treatment consisted of three medications with doses adjusted for age (<10 years or [greater than or equal to]10 years): omeprazole (10 mg or 20 mg), clarithromycin (250 mg or 500 mg), and metronidazole (250 mg or 500 mg) twice daily for 14 days. (8) Six weeks after completion of treatment, all patients had a UBT. Children with a negative UBT result (implying eradication of H pylon) were then paired with 2 uninfected subjects from the original cohort, matching for potential confounding variables such as age, race, BMI, duration of diabetes, and compliance with clinical appointments. Both groups were then seen periodically for approximately 2 years and information concerning their insulin requirement and [HbA.sub.1c] level obtained at each visit (approximately every 3 months).

Follow-up was done by a single investigator (R.G.) unaware of the patients' infection status and using the routine protocol of our endocrinology service. Measurement of [HbA.sub.1c] was done with a capillary isoelectric focusing system, previously described, (9) with a normal reference range of 5.7% to 8.1% (J. Hempe, PhD, oral communication, April 2001). Consent was obtained from the parents and assent from the participating children. The study was approved by the Institutional Review Board of the Louisiana State University Health Sciences Center.

Statistical analyses were done with Epi Info, version 6.0 software (Centers for Disease Control and Prevention, Atlanta, Ga). (10) Continuous variables were analyzed with the non-parametric Mann-Whitney rank sum test to compare distribution values for cases and controls. Time trends in [HbA.sub.1c] for cases and controls were estimated as the slope obtained by least squares simple linear regression, and the slopes were compared using the test of parallelism. (11) For baseline comparisons, two-sided tests were used to determine differences; for follow-up trends, one-sided tests were used to determine improvement after eradication of the infection.

RESULTS

Of the 9 patients who received antimicrobials, one was still infected after therapy (as evidenced by a posttreatment positive UBT). The remaining 8 patients with documented eradication of the infection (cases) and their 16 matched subjects (controls) constitute the study group. For the second year, 2 cases lost to follow-up and their 4 controls were excluded from analysis, leaving 6 cases and 12 controls.

At entry into the study, the median age of the participants was 12 years (range, 6 to 18 years), and 13 (52%) were male. The Table shows that because of matching, there was no difference between cases and controls in age, income, compliance rate, duration of diabetes, and BMI. During the 2-year study period the median compliance rate among cases (0.66) and controls (0.89) remained unchanged from preenrollment values, and the median BMI increased slightly for both cases and controls (to 21.7 and 23.7 kg/[m.sup.2], respectively).

The insulin requirements for cases and controls remained relatively constant over the observation period. The starting median values were 1.1 IU/kg/day and 0.9 IU/kg/day for cases and controls, respectively (P = .49), and the ending daily median values were 1.2 and 1.1 IU/kg, respectively (P = .77). The [HbA.sub.1c] values, on the other hand, as previously described, were higher among cases than controls at the beginning of the study (median, 13.6% and 11.0%, respectively; P = .07). After treatment, however, cases had a steady decrease in [HbA.sub.1c] level (slope = -0.10), whereas controls had a slightly increasing trend (slope = +0.03), as shown in the Figure. Comparison of the two curves (by test of parallelism) showed that the slopes were significantly different (P = .05). At the end of the observation period, the [HbA.sub.1c] values were similar among cases and controls (median, 11.7% and 11.4%, respectively; P = .69).

DISCUSSION

Our previous work suggested that the presence of H pylori infection was associated with poor control of glycemia in children with type 1 diabetes, manifested by an elevated [HbA.sub.1c] level. (5) One possible explanation of that finding was that patients with poorly controlled diabetes were more prone to become infected by H pylori, a notion that has not been well studied but that does not seem to be supported by the work of other authors. (12,13) Alternatively, the presence of H pylori could have caused the poor control of the glycemia. To test this hypothesis, in the present study we investigated the effect of antimicrobial treatment and found that control of the glycemia in our patients improved once the infection was eradicated. This was manifested by a progressive decrease in their [HbA.sub.1c] to levels almost identical to those seen among control subjects who had never been infected by H pylori. Yet, the Figure suggests that even though as a group the cases had a significant decrease in [HbA.sub.1c] l evels, there was marked variability in individual responses. Even though the effect on glycemia control was modest, with an average decrease in [HbA.sub.1c] of about 2% (ie, from 13.6% to 11.7%), this degree of decrease in [HbA.sub.1c] appears to be associated with fewer long-term diabetic complications. (2) The beneficial effect of treatment was evident during the first year after eradication of H pylori and persisted throughout the second year.

Data regarding the effect of H pylori infection on the severity of diabetes illness is scant. Ojetti et al, (14) in 1998, reported 119 adults with insulin-dependent diabetes, 42 (35%) of whom were infected with H pylori and described no difference between infected and uninfected patients in the daily dosage of insulin, which was not affected by H pylori eradication. In another report by Scaillon et al (15) in 1999, no change in the [HbA.sub.1c] level was found in adult diabetic patients after eradication of H pylori. The reason for the discrepancy with our results is unclear, but it might be caused by the study of different populations (ie, adults instead of children) or a shorter follow-up period (ie, less than 6 months instead of 2 years).

Potential limitations need to be considered in the interpretation of our findings. First, only 8 cases and 16 controls could be studied from our original cohort; larger studies will be necessary to confirm our results. Second, because of the small number of patients available, we elected not to randomize them to treatment or no treatment, but rather, we decided to treat all and to match them to uninfected patients, as controls. Even though matching appeared well attained in our study, this is artificial since no two patients are alike, especially when considering a chronic illness, such as diabetes. Third, the so-called "regression to the mean" phenomenon in which values in one extreme of the distribution are more likely to move toward than away from the mean. (16) In other words, if the differences initially detected were caused by sampling error and they did not represent true differences, on repeat testing subjects with poor diabetes control will tend to perform better (not worse), making it appear as if t he treatment did provide a beneficial effect. Randomized studies will be necessary to control for this phenomenon.

The possibility that cases might have improved as a result of increased surveillance from being in the study does not seem likely, since compliance did not vary before or during participation in the study neither for cases nor for controls. Also, we could not repeat the UBT at the end of the study to confirm the infection status of cases and controls. However, since the annual incidence of H pylori infections (17) and reinfections (18) in children appear to be small (about 2% for both), it is unlikely that new infections occurred in our study group.

We believe the results of the present study, along with our previous observations, serve as preliminary data to support the hypothesis that eradication of H pylori infection in patients with type 1 diabetes might be associated with better control of glycemia. Further studies will need to be conducted in a randomized clinical trial to confirm these findings and control for possible confounding variables. If confirmed, our findings could have important implications for better control of the glycemia of diabetic patients infected by H pylori.

[GRAPH OMITTED]

TABLE

Comparability of Cases and Control at Entry into the Study

                        Cases            Controls         P
Characteristic         (n = 8)           (n = 16)      Value *

Age (years)        13.0 (7-17)       12.0 (6-18)         .55
Annual income      14.5 (10-22)      12.0 (10-100)       .87
 (x $1,000)
Compliance rate    0.68 (0.50-1.00)  0.80 (0.50-1.00)    .22
Duration of        4.9 (0.3-14.1)    4.8 (0.7-9.0)       .77
 diabetes (years)
Body mass index    19.7 (14.5-24.8)  22.0 (14.2-33.0)    .22
 (kg/[m.sup.2])

Values represent median (range).

* Two-sided Mann-Whitney U test.

References

(1.) Kaufman FR: Diabetes mellitus. Pediatr Rev 1997; 18:383-392

(2.) DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977-986

(3.) McMahon MM, Bistrian BR: Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am 1995; 9:1-9

(4.) Genta RM: The immunobiology of Helicobacter pylori gastritis. Semin Gastroenterol Dis 1997; 8:2-11

(5.) Begue RE, Mirza A, Compton T, et al: Helicobacter pylon infection and insulin requirement among children with type 1 diabetes mellitus. Pediatrics 1999; 103(e83):1-4

(6.) Chong SK, Lou Q Asnicar MA, et al: Helicobacter pylori infection in recurrent abdominal pain in childhood: comparison of diagnostic tests and therapy. Pediatrics 1995; 96:211-215

(7.) Klein PD, Malaty HM, Martin RF, et al: Noninvasive detection of Helicobacter pylori infection in clinical practice: the [C.sup.13] urea breath test. Am J Gastroenterol 1996; 91:690-694

(8.) Dohil R, Israel DM, Hassall E: Effective 2-wk therapy for Helicobacter pylori disease in children. Am J Gastroenterol 1997; 92:244-247

(9.) Hempe JM, Granger JN, Craver RD: Capillary isoelectric focusing of hemoglobin variants in the pediatric clinic laboratory. Electrophoresis 1997; 18:1785-1795

(10.) Dean AG, Dean JA, Coulombier D, et al: Epi Info, Version 6: A Word Processing, Database, and Statistics Program for Public Health on IBM-Compatible Microcomputers. Atlanta, Ga, Centers for Disease Control and Prevention, 1996

(11.) Kleinbaum DG, Kupper LL, Muller KE, et al (eds): Applied Regression Analysis and Other Multivariable Methods. Pacific Grove, Calif, Duxbury Press, 3rd Ed, 1998, pp 322-324

(12.) Dore MP, Bilotta M, Malaty HM, et al: Diabetes mellitus and Helicobacter pylori infection. Nutrition 2000; 16:407-410

(13.) Gasbarrini A, Ojetti V, Pitocco D, et al: Helicobacter pylori infection in patients affected by insulin-dependent diabetes mellitus. Eur J Gastroenterol Hepatol 1998; 10:469-472

(14.) Ojetti V, Gasbarrini A, Pitocco D, et al: Effects of Helicobacter pylori eradication on insulin-dependent diabetes mellitus (Abstract). Gastroenterology 1998; 114:A247

(15.) Scaillon M, Dorchy H, Cadranel S: Pattern of Helicobacter pylori infection in insulin-dependent diabetic patients (IDDM) (Abstract). J Pediatr Gastroenterol Nutr 1999; 28:568

(16.) Yudkin PL, Stratton IM: How to deal with regression to the mean in intervention studies. Lancet 1996; 347:241-243

(17.) Malaty HD, Graham DY, Wattigney WA, et al: Natural history of Helicobacter pylori infection in childhood: 12-year follow-up cohort study in a biracial community. Clin Infect Dis 1999; 28:279-282

(18.) Kato S, Abukawa D, Furuyama N, et al: Helicobacter pylori reinfection rates in children after eradication therapy. J Pediatric Gastroenterol Nutr 1998; 27:543-546

RELATED ARTICLE: KEY POINTS

* Infections can elevate blood glucose levels in patients with diabetes. Helicobacter pylori is one of the most common chronic bacterial infections.

* Children with type 1 diabetes and H pylori infection had higher [HbA.sub.1c] values than uninfected counterparts. Administration of antibiotics to eradicate H pylori infection was followed by a decrease in the [HbA.sub.1c] value.

* These findings suggest that eradication of H pylori infection in patients with diabetes might be associated with better control of their glycemia.

From the Divisions of Infectious Diseases and Endocrinology, Department of Pediatrics, Louisiana State University Medical Center and Children's Hospital, New Orleans.

Reprint requests to Rodolfo E. Begue, MD, Children's Hospital, Division of Infectious Diseases, 200 Henry Clay Aye, New Orleans, LA 70118.