serum gastrin concentrations in children with primary gastroesophageal reflux and gastroesophageal...

· Advances in Medical Sciences · Vol. 56 · 2011 · pp 186-192 · DOI: 10.2478/v10039-011-0053-8© Medical University of Bialystok, Poland

Serum gastrin concentrations in children with primary gastroesophageal reflux and gastroesophageal reflux

secondary to cow’s milk allergy

Department of Pediatrics, Pediatric Gastroenterology and Allergology, Medical University of Bialystok, Bialystok, Poland

Semeniuk J*, Kaczmarski M, Wasilewska J

ABSTRACT

Purpose: The assessment of the serum gastrin concentrations and the role of enterohormone in children with primary acid gastroesophageal reflux (GER) and GER secondary to cow’s milk allergy (CMA). Materials/Methods: 138 children were diagnosed with pathological acid GER on the basis of pH-metric examination. 76 (28.8%) patients had primary GER and 62 (23.5%) patients had GER secondary to CMA. Serum gastrin concentration (fasting and postprandial) was assessed before treatment and 1 and 2 years after initiation of the therapy. Results: The children with primary GER had the fasting gastrin concentration 69.46 ± 11.87 μU/ml before treatment, 77.86 ± 26.35 μU/ml after 1 year and 83.78 ± 25.21 μU/ml after 2 years of treatment. The children with GER secondary to CMA had gastrin concentrations 89.61 ± 26.75, 73.17 ± 19.49 and 73.90 ± 20.31 μU/ml respectively. The mean postprandial gastrin concentration after treatment was higher than before treatment in children with both primary and secondary GER. The primary GER group had postprandial gastrin concentration 96.07 ± 33.51 μU/ml before treatment and 116.06 ± 33.95 μU/ml and 118.48 ± 33.96 μU/ml after 1st and 2nd year of therapy respectively. The secondary GER group had postprandial gastrin concentration 85.33 ± 14.12 μU/ml before treatment and 106.55 ± 24.51 μU/ml and 110.36 ± 24.67 μU/ml after 1st and 2nd year of therapy respectively. Conclusions: The mean fasting serum gastrin concentrations in patients with primary and secondary GER were similar and mean postprandial concentrations were higher than fasting concentrations in both study groups.

Key words: serum gastrin, acid gastroesophageal reflux (GER), cow milk allergy (CMA), food allergy (FA), children

* CORRESPONDING AUTHOR:Department of Pediatrics, Gastroenterology and Allergology, Medical University of Bialystok, Waszyngtona 17, 15-274 Bialystok, PolandTel/Fax: +48 85 742 3841e-mail: [email protected] (Janusz Semeniuk)

Received 22.03.2011 Accepted 06.10.2011Advances in Medical SciencesVol. 56 · 2011 · pp 186-192DOI: 10.2478/v10039-011-0053-8© Medical University of Bialystok, Poland

INTRODUCTION

Gastroesophageal reflux (GER) is an involuntary return of the stomach contents back up into the esophagus due to transient or permanent functional and anatomical, or functional inefficiency of particular elements of the anti-reflux barrier, especially lower esophageal sphincter (LES) [1-4].GER may evoke various clinical symptoms at all age. According to the assessment of various authors and own studies, the return of the stomach contents back up into the esophagus, regardless of its intensity, is present in the majority of children, mainly in the first months of life (70-80%) [1-5].

With regard to pathogenesis, GER is commonly divided into primary (idiopathic) and secondary [1,2,5-10].

In 40-50% of infants primary GER of mild intensity is of functional character – not complicated and considered as a physiological phenomenon. However the intensive (massive) return of stomach contents is usually pathological with typical or atypical manifestation and in about 60-70% of the children reflux symptoms resolve spontaneously (usually at 10-12 months). In about 25% of children reflux symptoms persist until the 15th month and in the remaining 5% of children until the 18th month or longer [1,9,11-14].

Secondary GER is most often pathological and appears in the course of other diseases such as infectious, allergic,

Semeniuk J, Kaczmarski M, Wasilewska J

neurological, systemic, genetic, metabolic or other disorders [2, 9-11]. It is also known that the development and presence of recurrent or persistent reflux symptoms might be causally related or complicated with food hypersensitivity, mainly cow’s milk allergy (CMA) or other food, which leads to the diagnosis of food allergy (FA) [6, 10, 11].

Long-term follow-up and the results of clinical trials that we have conducted and the previous literature data other authors confirm the causative relationship between GER and CMA not only in the infant period but also in the older age [2, 6-11, 15-20].

The etiopathogenesis of the return of the stomach contents back up into the esophagus and/or pharynx concerns the significant role of gastrin, a peptide hormone produced, stored and released by the G cells of the gastric and duodenal mucosa. The wide spectrum of biological functions of gastrin comprises all main functions of the digestive system. The hormone stimulates the excretion of hydrochloric acid and pepsin in the stomach, stimulates the proliferative activity of the gastric, duodenal, and large intestine mucosa cells and increases the perfusion through the mucosal vessels [21-24].

From the point of view of own studies it is of great importance that gastrin also influence the motor activity of the gastrointestinal tract, which results in the increase of tension of the LES and pyloric sphincter, and delayed gastric emptying. The disturbances in these functions connected with the progressive failure of LES and the ability of esophageal clearance together with the increasing intensity of delayed gastric emptying contribute to the development of gastroesophageal reflux disease (GERD) and its complications [25].

The aforementioned considerations have contributed to the formulation of the following aim of the study:

the assessment of the serum gastrin concentrations, - fasting and postprandial, in children with primary GER and GER secondary to CMA;the assessment of the presumed pathogenetic role of the - enterohormone in the originating and development of the reflux symptoms in these children.

MATERIAL AND METHODS

Out of 264 children of both sexes suspected of GERD at 4-102 months (20.78 ± 17.23) 138 children (52.3%) were diagnosed with acid GER.

Primary GER in 76 (28.8%) children (group 1) was diagnosed on the basis of the clinical symptoms: typical and atypical, and the episodes of the return of acid gastric contents into the esophagus in 24-hour pH- monitoring.

Intraesophageal pH - monitoring was performed with one or two-channel antimony probe (proximal/ distal and proximal lead) and Digitrapper recorder: MK III or pH 400 by Synectics Medical, after previous patient’s preparation i.e. patient fasting

and without medications. The monitoring lasted 24 hours and included night sleep [26-28].

The diagnosis of the acid GER was established with the help of ESPGHAN criteria [29-31].

In children under 2 years of age the results of pH- monitoring of the esophagus were referred to the reference values prepared by Vandenplas et al. [32, 33] and other authors [34,35].

In older children (above 2 years of age) the borderline values at qualitative-quantitative assessment of pathological GER in both leads were defined in the following way [29, 31, 36-38]: total number of acid GER episodes (pH< 4.0/24 hrs) =50; the number of acid GER episodes lasting more than 5 minutes <= 2; the percentage of time with pH below 4.0 (%) –total acid GER index = 5.0%, the percentage of time with pH below 4.0(%) – acid GER index in supine position = 2.5%.

The diagnosis of GER secondary to CMA was made in 62 (23.5%) children (group 2) in the same way as in the case of primary reflux. Allergological and immunological examinations in these children confirmed hypersensitivity to cow’s milk being the cause of secondary reflux and differentiating it from the primary reflux [39]. The examinations comprised:

Prick tests performed with set of native food allergens i.e. fresh allergens; set of inhalant commercial allergens (Smith Kline Beecham- USA).

Total serum immunoglobulin E concentration (total IgE): Total IgE serum concentration was assessed with Fluoro-Fast method by 3M Diagnostic Systems (USA). The assessment of total IgE concentration in these patients was aimed at the differentiation of IgE-dependent and IgE-independent mechanisms. Total serum IgE > 50 IU/ml was considered as increased. With regard to limited specificity of a single measurement of total IgE concentration in the diagnostic work-up of the atopy, the examination was combined with the assessment of IgE specific for cow’s milk proteins.

Qualitative and quantitative assessment of IgE specific for cow’s milk proteins with Fluoro-FAST method by 3M Diagnostic Systems (USA). The assessment of allergen-specific immunoglobulins in the examined children facilitated the confirmation of the IgE-dependent pathomechanism of the food allergy and also the establishment of the possible food allergens allergenic for patients. The studies of this kind also turned out helpful if prick tests were impossible for various reasons, or when the results of Prick tests were questionable. Cow’s milk protein-specific IgE in class 2-5 was considered a positive result.

The positive result of the open challenge test with cow’s milk and the episodes of acid GER after its consumption in the 24-hour intraesophageal pH-monitoring were decisive for the diagnosis of food hypersensitivity [31,40,41].

In these children pathological acid GER was divided into:primary – in 76 (28.8%) patients (39 boys – 14.8%: -

37 girls -14%), at 4-102 months (25.20 ± 27.28) – group 1;secondary to CMA – in 62 (23.5%) patients (33 boys -

– 12.5%; 29 girls – 11.0%), at 4- 74 months (21.53 ± 17.79)-

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Serum gastrin concentrations in children with primary gastroesophageal reflux and gastroesophageal reflux secondary to cow’s milk allergy

group 2.In 126 (47.7%) of 264 children acid GER was not

confirmed. 32 (12.1%) patients of this group (19 boys – 7.2% and 13 girls – 4.9%) at 7-69 months (x = 23.70 ± 12.63) had cow’s milk allergy and/or other food allergy diagnosed – CMA/FA, without the clinical symptoms of GER. These children constituted group 3 – the reference group.

Serum gastrin concentration measurement: Quantitative assessment of serum gastrin, fasting and postprandial (an hour after a standard meal) was performed in 76 children with primary GER (group 1), 62 children with GER secondary to CMA (group 2) and in 32 children with CMA/FA with no clinical symptoms of GER (group 3).

Blood samples were collected twice in each patient: fasting (basic secretion) and postprandial (an hour after a standard meal).

Detailed analysis of the enterohormone concentrations showed its dynamic character as the concentrations were determined in the following periods of consecutive treatment (prospective study): before the treatment commencement (initial examination), after 1- year-follow-up and treatment (I follow up), after 2-year-follow-up and treatment (II follow up).

Patients underwent periodical anti-allergic and/or anti-reflux treatment during that time.

Serum gastrin was determined with the set by CIS Bio International (ref. GASK - P RJ125 , France), with radioimmunological method (RIA) in double samples. Normal gastrin concentrations: 28-185 μU/ml (method unit) [42]. Determinations were performed in the Department of Nuclear Medicine of the Medical University of Bialystok.

The statistical analysis of the results comprised measurable features: arithmetical mean, minimal and maximal values and standard deviation, and qualitative features - quantitative percentage distribution. Kolmogorov–Smirnov compatibility test was used to assess features compatible with normal distribution, comparisons between more than two study groups required the analysis of variance and post hoc Tukey test, whereas Kruskal – Wallis test was applied for features non-compatible with this distribution. The comparison between the two groups was performed with parametric t- Student test or non-parametric Mann-Whitney test. Parameters within the group, measured in time intervals were measured with paired t-Student test or Wilcoxon test for pairs. Also Pearson and Spearman correlation indices were calculated depending on the distribution. P<0.05 was considered statistically significant. Calculations were done with statistical package SPSS 12.0 PL and STATISTICA 6.1 PL. Statistical analysis of the results was performed in the Department of Statistics and Medical Informatics of the Medical University of Bialystok.

The study was approved by local Bioethical Committee of the Medical University of Bialystok.Informed written parental consent was obtained from parents of the examined children.

RESULTS

The assessment of the serum gastrin concentrations in the examined children – fasting and postprandial, before the treatment and after 1 year and 2 years of pharmacological

Table 1. Fasting and postprandial serum gastrin concentrations in children with primary acid GER and GER secondary to CMA and in children with CMA/FA, before and during pharmacological treatment (prospective study).

Study group(n=170)

Serum gastrin concentrations[N=28-185μU/ml]Range; mean value [x]; standard deviation(±SD); median; p

Before treatment(0) After 1-year treatment After 2-year treatment

fasting postprandial fasting postprandial fasting postprandial

Group 1Primary GER (n=76)

47.10 – 116.5069.46 ± 11.87(68.30)

51.70 – 264.9096.07 ± 33.51(90.75)

43.00 – 220.7077.86 ± 26.35(72.30)

47.10 – 185.60116.06 ± 33.95(107.47)

49.70 – 225.3083.78 ± 25.21(77.50)

50.10 – 188.60118.48 ± 33.96(105.60)

Statistical analysis of the particular groups

0 – 1, ns; 0 – 2, p=0.0001; 1 – 2, p=0.0554 (fasting)0 – 1, ns; 0 – 2, p=0.0001; 1 – 2, p=0.0001 (postprandial)

Group 2GER secondary to CMA(n=62)

53.30 – 217.4089.61 ± 26.75(87.25)

43.20 – 131.3085.33 ± 14.12(87.20)

43.40 – 148.1073.17 ± 19.49(70.20)

47.10- 138.50106.55 ± 24.51(115.30)

11.90 – 150.6073.90 ± 20.31(72.20)

52.10 – 143.50110.36 ± 24.67(118.35)


0 – 1, ns; 0 – 2, p=0.0001; 1 – 2, p=0.0001 (fasting)0 – 1, ns; 0 – 2, p=0.0001; 1 – 2, p=0.0001 (postprandial)

Group 3 – refer-ence groupCMA/ FA (n=32)

62.60 – 319.10124.95 ± 59.15(110.20)

38.20 – 136.5099.51 ± 23.27(105.25)

70.30 – 285.30109.49 ± 43.65(98.85)

97.50 – 320.30137.66 ± 60.66(117.95)

75.30 – 289.70114.08 ± 43.55(103.55)

102.50 – 325.30139.43 ± 59.06(121.55)


0 – 1, ns; 0 – 2, ns; 1 – 2, p=0.0001 (fasting)0 – 1, ns; 0 – 2, p=0.0001; 1 – 2, p=0.0001 (postprandial)

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treatment (anti-reflux and/or anti-allergic) is presented in Tab. 1, Fig. 1 and Fig. 2.

The highest mean gastrin concentrations fasting and before the commencement of dietary and pharmacological treatment were recorded in children with CMA/FA (124.95 ± 59.15 μU/ml) and the results were statistically different (p=0.0001) from the mean gastrin concentrations in children with primary GER (the lowest values - 69.46 ± 11.87 μU/ml) and in the group with GER secondary to CMA/FA (89.61 ± 26.75 μU/ml).

The concentrations of serum gastrin in fasting children with primary GER were 77.86 ± 26.35 μU/ml and 83.78 ± 25.21 μU/ml after 1 year and 2 years of pharmacological treatment, respectively.

The results from group 1 and the mean gastrin concentrations in fasting children with secondary GER i.e. 73.17 ± 19.49 μU/ml and 73.90 ± 20.31 μU/ml, respectively, were statistically

significantly lower than in the reference group in the follow-up period - 109.49 ± 43.65 μU/ml and 114.08 ± 43.55 μU/ml after 1 year and 2 years of pharmacological treatment, respectively.

After the food challenge mean serum gastrin concentrations in all 3 groups were higher than the corresponding fasting concentrations during the anti-reflux and/or anti-allergic treatment.

The reverse interdependence regarding statistical differences between the mean gastrin concentrations fasting and postprandial have been recorded before the treatment in children with GER secondary to CMA and in children with CMA/FA.

In the group of children with CMA/FA mean postprandial gastrin concentrations were the highest and amounted to 99.51 ± 23.27 μU/ml –before the treatment, 137.66 ± 60.66 μU/ml after 1 year of pharmacological treatment and 139.43 ± 59.06 after 2 years of pharmacological treatment.

The increase of mean gastrin concentrations in children with primary GER was also significant and amounted to 96.07 ± 33.51 μU/ml before the treatment, 116.06 ± 33.95 μU/ml after 1 year of pharmacological treatment and 118.48 ± 33.96 μU/ml after 2 years of pharmacological treatment also increased significantly.

DISCUSSION

Among the polypeptide hormones (enterohormones) synthesized by the APUD cells (Amine Precursor Uptake and Decarboxylation) in the gastrointestinal tract of the experimental animals and humans, gastrin was the subject of a debate in 70-80s of the previous century. Grand et al. [43] proved that gastrin is produced by the G cells of the duodenal mucosa in the 8-10 week of the fetal life of a human. Synthesis in the pylorus area takes place later i.e. between 19-20 week of gestation. There are numerous significant literature data concerning that period which show that hypergastrinemia is typical for the period directly after delivery, the neonatal period and the first three months of life [43,44].

Euler et al. [45], Lucas et al. [46,47], Chapoy et al. [48] and Sanna et al. [49] measured fasting serum gastrin concentrations directly after delivery which ranged from 68 pg/ml to 107 pg/ml. The concentration decreased to lower values after a few hours or days (68 ± 15 pg/ml). However the examined newborns always presented with higher values in comparison to serum gastrin concentrations of the mothers at delivery (67 pg/ml) and in the control group of adults (36 ± 9.0pg/ml). Rogers et al. are the authors of the study presenting a reverse phenomenon to the previously quoted data i.e. the increase of serum gastrin from the day of delivery [50]. The attempts to explain hypergastrinemia (basal concentration) comprised the phenomenon of delivery itself, medications administered during delivery (oxitocin), transplacental

Figure 1. rospective comparative analysis of fasting serum gastrin concentrations [μU/ml] in groups: group 1 (primary GER), group 2 (GER secondary to CMA), group 3 (CMA/FA).

Fasting gastrin: 0 (before treatment), 1 (after 1-year treatment), 2 (after 2-year treatment).

Figure 2. Prospective comparative analysis of postprandial serum gastrin concentrations [μU/ml] in groups: group 1 (primary GER), group 2 (GER secondary to CMA), group 3 (CMA/FA).

Fasting gastrin: 0 (before treatment), 1 (after 1-year treatment), 2 (af-ter 2-year treatment)

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transportation on the way mother-child and inefficient mechanism of enterohormone inactivation by the liver and kidneys of the newborn and in the early childhood (Konturek) [51]. Another interesting feature is the evaluation of gastrin concentration after strong stimulant such as food, especially protein or aminoacid fraction of the mother’s milk or formulas used in the nutrition of newborns and infants. Such results also vary and they have been explained with the increase of postprandial gastrin concentrations stimulated by the mother’s milk, which was observed by Aynsley-Green et al. [52] and Lucas et al. [46, 47]; and not confirmed by Rodgers et al. [53]. These discrepancies are explained with little sensitivity of gastrin receptors to protein stimulation in the first days of life [50, 53].

Own studies seem to complete the gap concerning serum gastrin concentration – basal and postprandial secretion in older children i.e. aged 4-102 months (20.78 ± 17.23). Not only the age group but also the type of pathology which was examined seems significant.

Own studies refer to serum gastrin concentrations in children with the symptoms of primary GER, GER secondary to CMA/FA and in children with CMA/FA with no clinical symptoms of the return of stomach contents into the esophagus. These are prospective studies and concern the determination of basal and postprandial concentrations at the time of their commencement i.e. before treatment, after 1 year and after 2 years of periodically administered dietary and/ or pharmacological treatment in these children. It was found that mean fasting gastrin concentrations before treatment were the lowest in the group with primary GER and amounted to 69.46 ± 11.87 μU/ml; in the group with GER secondary to CMA were statistically insignificantly higher (89.61 ± 26.75 μU/ml), and the highest statistically significant results (124.95 ± 59.15 μU/ml) were in the group with children with CMA/FA. These results were higher after a year (77.86 ± 26.35 μU/ml) and after 2 years of treatment (83.78 ± 25.21 μU/ml) in the group with primary GER. In the group with GER secondary to CMA the values after 1 year and 2 years were lower and amounted to (73.17 ± 19.49 μU/ml) and (73.90 ± 20.31 μU/ml), respectively, and these differences were statistically insignificant. A similar phenomenon was reported in children with food allergy – the results were lower after 1 year 109.49 ± 43.65 μU/ml and 2 years 114.08 ± 43.55 μU/ml of anti-allergic treatment (dietary and pharmacological). Contrary to the quoted studies referring to weak stimulation of gastrin release from G cells by meals are own studies which in each of the examined group present a positive reaction i.e. the increase of serum gastrin concentration after food challenge in children with primary GER (96.07 ± 33.51μU/ml; 116.06 ± 33.95; 118.48 ± 33.96). A similar tendency was observed in the group with secondary GER (85.33 ± 14.12 μU/ml; 106.55 ± 24.51; 110.36 ± 24.67) and food allergy (99.51 ± 23.27 μU/ml; 137.66 ± 60.66; 139.43 ± 59.06).

Hence own studies showed that serum fasting and postprandial gastrin concentrations vary depending on

the diagnosed and treated pathology, and in each of the examined group the results were higher that in the studies publisher so far [45-50]. With regard to the nomenclature of the other authors, these children suffered from fasting and postprandial hypergastrinemia, assessed dynamically. There is still a question how to interpret these results taking into consideration biological properties of gastrin, which influences the regulation of hydrochloric acid release by the parietal cells of the stomach and its further influence on the basal tone of the LES and its role in stomach emptying [25, 45-50]. It is difficult to refer the obtained results to the pathology diagnosed, however it seems that in the case of GER secondary to CMA and in children allergic to that protein the type of nutrition i.e. highly fractionated casein or whey protein hydrolysates play a significant role in maintaining high gastrin concentrations (especially postprandial). The treatment with these formulas for the period of two years seems to be an important factor stimulating gastrin cells of the antrum and duodenum to hormone secretion. Also mean age of the examined children is favorable for the sensitivity of G cells in comparison to the studies conducted in the early childhood period by Lucas, Rogers or Aynsley – Green [46, 47, 50, 52].Also worth mentioning is a trophic influence of gastrin on the gastric and duodenal mucosa, which very often becomes injured with the harmful influence of the food (gastrin concentration before treatment or during treatment) due to dietary mistakes. With regard to incorrect results of fasting and postprandial gastrin concentrations – higher than reported in the literature – in children with primary GER it seems that these results are strongly related to the administration of proton pomp inhibitors (in different periods).

In conclusion, it should be said that own studies are closely related to the results obtained by Moazam et al. [54]. The studies of this group also concern the determination of fasting and postprandial serum gastrin concentrations in 20 newborns and 11 infants up to 4 month of age and their mothers. The studies revealed that mean gastrin concentrations in mothers after delivery amounted to 44.0 ± 11.66 pg/ml and were statistically significantly lower than mean gastrin concentrations in children after delivery (fasting) 66.9 ± 12.65 pg/ml. Systematic increase of serum fasting gastrin concentrations which accounted for 87.3 ± 15.07 pg/ml - after a month, 161.7 ± 28.7 pg/ml - after 2 months and 134.5 ± 31.8 pg/ml - in 4 month (mean results comprising 4 determinations 1-4 months: 179.95 ± 31.49 pg/ml) was observed. Statistically insignificant increase of serum gastrin concentrations 30 minutes after a meal from 66.9 pg/ml to 72.3 pg/ml should be considered as a tendency towards the increasing postprandial serum gastrin concentrations in these children in the first 4 months of life [54].

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CONCLUSIONS

Mean fasting serum concentrations in patients with primary and secondary GER were similar. Children with primary GER presented with a tendency of increasing concentrations after a year and 2 years of follow-up, whereas lower concentrations were observed in children with GER secondary to CMA.

Mean postprandial gastrin concentrations were higher than fasting concentrations in children with primary and secondary GER and they were increasing during the follow-up period.

On the basis of own studies it could be assumed that changes in the gastrin concentrations (especially postprandial) support the hypothesis concerning the pathogenetic role of reflux symptoms especially in children with acid GER secondary to CMA.

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