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We read with interest the article by Nwokolo et al reporting raised serum ghrelin levels following Helicobacter pylori eradication (Gut 2003;52:637–40). There are some exceptions to the interpretation of the data that we would take.
The authors state that the increase in ghrelin levels seen in their study “lends support to the view that ghrelin could be involved in the long term regulation of body weight”. While there is growing evidence to support this in the literature,1–3 this study does not present any such data and is not methodologically geared towards addressing this question. The proposal that eradication of H pylori leads to an increase in ghrelin levels, which in turn leads to an increase in obesity, is also without foundation. The only known situation in which hyper-ghrelinaemia is associated with obesity is in Prader-Willi syndrome.4 In all other studies ghrelin levels correlate inversely with measures of body adiposity, and are altered in a compensatory manner by changes in body weight.5 To suggest therefore that H pylori eradication leads to a hyper-ghrelinaemic state that drives increased appetite is not physiologically feasible as any transient appetite increase would be expected to be countered by any increase in adiposity, which in turn would suppress ghrelin levels.
The authors’ proposal that “children with H pylori may have relatively low ghrelin concentrations contributing to growth retardation” is also without foundation. A recent study has shown H pylori status to have no effect on ghrelin levels.6 The role of ghrelin on the growth of children remains unclear. Ghrelin is an endogenous ligand to the growth hormone secretagogue receptor (GHS-R), and potently stimulates growth hormone release. It may indeed have a role to play in growth, as in patients with a genetic growth hormone releasing hormone deficiency nocturnal enhancement of growth hormone secretion remains,7 an effect that may be mediated by ghrelin.
One other proposal of the authors is that H pylori eradication increases 24 hour gastric acidity by a ghrelin dependent mechanism. While central and peripheral ghrelin administration has been shown to increase stomach acidity when given to rats,8 data are lacking in humans. The small but statistically significant increase in acidity seen here would be expected after H pylori eradication, and is likely to be secondary to parietal cell recovery following resolution of inflammation. The suggestion that hypergastrinaemia leads to lower ghrelin levels, and vice versa, is not supported in the literature.9
We would like to draw the attention of Drs Murry and Emmanuel to the objectives set out clearly in the introductory section of our paper.
Our study was not designed to address the question of whether ghrelin is involved in long term regulation of body weight. Furthermore, the duration of the study was too short to see any change in body mass index. More importantly, waist circumference would be a better anthropometric measure of change in body fat composition supported by sequential dual energy x ray absorptiometry or magnetic resonance imaging. The results of our study were unexpected and there was nothing in the literature that gave us forewarning. We would have designed the study to follow up the subjects for at least one year, monitoring their plasma ghrelin, and assessing changes in body composition using the techniques described above.
The authors refer to “physiological feasibility” and thereby miss the point that Helicobacter pylori infected stomachs exhibit distortion of normal physiological mechanisms. For example, the tight reciprocal relationship between gastrin and intragastric acidity seen in H pylori negative subjects is modified in H pylori positive subjects. We believe that a H pylori infected stomach produces less ghrelin, leading to decreased appetite and food intake. The physiological response should be that the resulting weight loss leads to a compensatory increase in ghrelin, increased appetite, and weight gain, and so on. We believe that this “physiological” mechanism is altered by the presence of H pylori, possibly by resetting a putative “ghrelin thermostat” at a lower level, allowing thinness and hypo-ghrelinaemia to occur together. Proof will come only from further experimentation.
The authors cite a study comparing spot measurements of plasma ghrelin in women with and without H pylori gastritis;1 this does not amount to a robust challenge to our hypothesis on H pylori, ghrelin, and children. The authors repeat the widely held although unproven belief that the increase in intragastric acidity after H pylori cure can be attributed to recovery of parietal cells from inflammation. They ignore our observation of a positive correlation between ghrelin and 24 hour intragastric acidity. We accept that the relationship between gastrin and ghrelin is unproven in humans but this emphasises the paucity of human data and the need for more studies.
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