Aliment Pharmacol Ther 2004; 19: 107–111.
Atrophic gastritis as a cause of hyperhomocysteinaemia L. SANTAR ELLI, M. GABR IELLI, F. CREMON INI, A . SANTOLIQUIDO, M. CAND ELLI, E. C. N ISTA , P. POLA, G. GA SBAR RINI & A. GASBARRINI Department of Internal Medicine, Gemelli Hospital, Catholic University of Sacred Heart, Rome, Italy Accepted for publication 17 October 2003
Background: Hyperhomocysteinaemia is an independent risk factor for atherosclerosis. It is often related to low levels of vitamin B12 and/or folate, enzymatic co-factors of methionine metabolism. Atrophic gastritis, often caused by Helicobacter pylori infection, may impair vitamin absorption. Aim: To assess whether the presence of atrophic gastritis is associated with hyperhomocysteinaemia via deficiency of its vitamin co-factors. Methods: Thirty-one patients with atrophic gastritis were recruited. The control group consisted of 28 patients with non-atrophic gastritis, matched with patients for sex, age and body mass index. The presence and degree of gastric atrophy were assessed by histology.
Hyperhomocysteinaemia is a well-established independent risk factor for the development of atheroscleroticrelated diseases by causing vascular endothelial damage.1 Elevated homocysteine levels may be due to genetic defects of enzymes in methionine metabolism.1 However, the majority of cases of hyperhomocysteinaemia are attributed to low levels of vitamin B12 and/or folic acid, which are co-factors of the most important enzymes of the methionine metabolic pathway.1 Recently, several studies have suggested an epidemiological association between Helicobacter pylori infection Correspondence to: Dr A. Gasbarrini, Department of Internal Medicine and Angiology, Catholic University of Sacred Heart, Gemelli Hospital, Largo Gemelli 8, 00168 Rome, Italy. E-mail: [email protected]
Ó 2003 Blackwell Publishing Ltd
H. pylori infection was assessed by histology/serology. Blood samples were collected for the measurement of homocysteine, vitamin B12 and folates. Results: Multiple logistic regression analysis showed that atrophic gastritis (odds ratio, 5.3; 95% confidence interval, 1.23–25.26; v2 ¼ 5.2; P ¼ 0.01) and low vitamin B12 (odds ratio, 3.7; 95% confidence interval, 1.03–22.08; v2 ¼ 3.6; P < 0.05) were both predictors of hyperhomocysteinaemia. None of the other variables considered in the analysis, including H. pylori status, showed a significant association with hyperhomocysteinaemia. Conclusions: The present study suggests that atrophic gastritis, rather than H. pylori infection per se, may be a contributing factor to hyperhomocysteinaemia, possibly via vitamin B12 malabsorption.
and atherosclerotic-related diseases.2, 3 An intriguing hypothesis postulates that the gastric damage induced by H. pylori infection may affect atherosclerotic processes via increased serum homocysteine levels.4 H. pylori infection is the main cause of chronic active gastritis.5 Long-lasting infection may lead to atrophic gastritis,5, 6 which may in turn impair folate and vitamin B12 absorption owing to diminished acid secretion, lower ascorbic acid levels in gastric juice and reduced secretion of intrinsic factor.7 Previous studies have shown no association between H. pylori positivity and increased serum levels of homocysteine.8–11 These studies, however, did not consider the severity of gastric damage. A recent study in patients with ischaemic heart disease reported a positive correlation between increased serum homocysteine levels and gastric atrophic scores.12 107
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The aim of the present study was to assess whether the presence of atrophic gastritis is associated with hyperhomocysteinaemia via a deficiency of its vitamin co-factors.
PATIENTS AND METHODS
Table 1. Classification of chronic gastritis (updated Sydney system)13 Type of gastritis Aetiological factors Non-atrophic
H. pylori ?Other factors
Autoimmunity H. pylori Dietary ?Environmental factors
Study population This study was conducted between March 2001 and November 2002. Thirty-one patients with atrophic gastritis were recruited. The control group consisted of 28 patients with non-atrophic gastritis, matched with the atrophic gastritis patients for sex, age and body mass index. The patients were all Caucasians and were from the same geographical area (urban Rome, Italy). The exclusion criteria were as follows: (i) previous H. pylori eradication; (ii) intake of antibiotics, proton pump inhibitors or H2-receptor blockers in the previous 2 months; (iii) impaired renal function (serum creatinine ¼ 1.5 mg/dL); (iv) use of drugs affecting plasma folic acid or vitamin B12 level; (v) vegetarian diet; (vi) history or presence of other causes of vitamin malabsorption, such as partial-subtotal gastrectomy, ileal resection, Crohn’s ileitis, coeliac disease or small bowel bacterial overgrowth; the first three conditions were excluded by clinical history, coeliac disease by the assessment of antiendomysial antibodies and bacterial overgrowth by performance of lactulose breath testing; (vii) underweight patients (body mass index < 18.5) and subjects with cachexia, malnourishment or with a reported history of an eating disorder. Informed consent was obtained from all participants in the study. Assessment and grading of atrophic gastritis Histological evaluation was performed on six biopsies (two from the antrum, two from the corpus and two from the fundus) taken using standard forceps. For routine histological determination, biopsies were fixed in 10% formalin, sectioned and stained using haematoxylin and eosin. The assessment of the presence and degree of atrophic gastritis was performed according to the updated Sydney system (Table 1).13 The following atrophy scores were assigned: 0, absence; 1, mild; 2, moderate; 3, marked. A diagnosis of atrophic gastritis was made when histological signs of chronic gastritis and atrophy
Special forms Chemical Radiation Others
Chemical irritation Radiation injury Others
Synonyms Superficial Diffuse antral gastritis Chronic antral gastritis Diffuse corporal
(scores 1–3) were present. A diagnosis of non-atrophic gastritis was made when histological signs of chronic gastritis were present, but atrophy was absent. The biopsies were assessed by two independent pathologists, blind to all the other study data. In the case of disagreement, the biopsies were re-examined simultaneously by both histopathologists until agreement was reached. Assessment of H. pylori infection H. pylori infection was assessed by both histology and serology. Histological assessment of H. pylori infection was performed by Genta staining of the sections. Blood samples were collected after overnight fasting in all patients and controls, and stored at )80 °C until analysis. Serological studies were performed blind; the sera of patients and controls were analysed at the same time. Specific anti-H. pylori immunoglobulin G antibodies were detected by enzyme-liked immunosorbent assay (Eurospital, Trieste, Italy) according to the manufacturer’s instructions. Values higher than 10 U/mL (sensitivity and specificity, > 95%) defined the infectious status. Subjects were considered to be positive for H. pylori infection when they were positive for histology or serology. Determination of plasma homocysteine, vitamin B12 and folate levels Blood samples were collected for the measurement of homocysteine, vitamin B12 and folates. Plasma homocysteine levels were measured by high performance Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 107–111
ATROPHIC GASTRITIS AS A CAUSE OF HYPERHOMOCYSTEINAEMIA
liquid chromatography, and plasma vitamin B12 and folates by radioimmunoassay. The normal ranges for homocysteine, vitamin B12 and folates adopted by our laboratory were 5–13 lmol/L, 200–1060 pg/mL and 5–14 ng/mL, respectively. High homocysteine plasma levels were defined as fasting serum total homocysteine levels of greater than 15 lmol/L. Vitamin B12 and folates were defined as low when vitamin B12 < 200 pg/mL and folates < 5 ng/mL.
Table 2. Population characteristics
Variable Age (years) Sex (males) (%) Body mass index (kg/m2) Smokers (current/past) (%) History of cardiovascular disease (%) H. pylori positivity (%)
Atrophic gastritis (n ¼ 31)
Non-atrophic gastritis (n ¼ 28)
54 ± 8 58 25 ± 3 48 19
51 ± 10 53.5 24 ± 4 50 14
N.S. N.S. N.S. N.S. N.S.
Assessment of functional polymorphisms for hyperhomocysteinaemia 25