Ezgi Erol YEŞİL, Ebubekir ŞENATEŞ, Atakan YEŞİL, CAN SEVİNÇ, Fatma TUFAN, Ali ÖZDEMİR

Proton pompası kullanan hastalarda serum homosistein seviyesi artmış mıdır?

Giriş ve Amaç: Hücre bölünmesi ve çoğalması için gerekli olan DNA sentezi homosisteinin metionine dönüşmesiyle sağlanmaktadır. Vitamin B12 bu reaksiyonda rol alan metionin sentetazın kofaktörüdür. Vitamin B12 eksikliğinde homosistein birikimi olur. Hiperhomosisteinemi ise arterioskleroz ve serebral tromboemboli ile ilişkili bulunmuştur. Proton pompa inhibitörleri yaygın olarak kullanılan ilaçlardır. Bu ilaçlar paryetal hücrelerdeki proton pompasında bulunan H+/K+-ATPazı inhibe ederek HCl'yi inhibe ederler. Vitamin B12'nin gıdalardan ayrılmasında HCl gerektiğinden, proton pompa inhibitörü kullanımı vitamin B12 eksikliğine bu da hiperhomosisteinemiye yol açabilir. Çalışmamızda proton pompa inhibitörü kullanımının vitamin B12 ve homosistein düzeyine etkisini araştırdık. Gereç ve Yöntem: Çalışmaya Mart ve Temmuz 2009 arasında polikliniğimize başvuran ve çeşitli nedenlerle en az üç aydır proton pompa inhibitörü kullanan 44 (hasta grubu) ve daha önce hiç proton pompa inhibitörü kullanmamış 38 hasta (kontrol grubu) alındı. Hasta ve kontrol grubunun yaşı, serum homosistein düzeyi, vitamin B12, folik asit ve MCV değerleri ve hastaların proton pompa inhibitörü kullanım süresi kaydedildi. Ayrıca proton pompa inhibitörü kullanan hastalar kendi arasında, 2 yıldan az ve fazla proton pompa inhibitörü kullananlar olarak açlık serum homosistein düzeyi, vitamin B12 vitamini, folik asit ve MCV değerleri açısından karşılaştırıldı. Bulgular: Hasta grubunda proton pompa inhibitörü kullanım süresi ortalama 19.5 ay idi. Hasta ve kontroller arasında yaş (hasta grubu 39±14, kontrol grubu 41±5 p=0,7) ve cinsiyet (hasta grubunda19 erkek, 25 kadın; kontrol grubunda 13 erkek, 25 kadın p=0,4) açısından anlamlı bir fark yoktu. Hasta ve kontroller homosistein (hasta 9.98±4.79 kontrol 9.40±0.527 p=0.5), B12 vitamini (hasta 328±305 kontrol 264±105 p=0.2), folik asit (hasta grubunda 9.20±3.20 kontrol grubunda 8.91±2.94 p=0.7) ve MCV (hasta 83±11 kontrol 86±8 p=0.1) yönünden karşılaştırıldığında iki grup arasında anlamlı bir fark saptanmadı. Hasta grubu kendi arasında 2 yıldan az ve fazla proton pompa inhibitörü kullananlar şeklinde karşılaştırıldığında homosistein düzeyi, vitamin B12, folik asit ve MCV değerleri açısından anlamlı bir fark saptanmadı. Sonuç: Çalışmamıza göre, uzun süreli proton pompa inhibitörü kullanımının vitamin B12 ve buna bağlı olarak homosistein düzeyi üzerinde anlamlı bir etkisinin olmadığı ve bu sebeple bu hastaların hiperhomosisteineminin getirdiği kardiyovasküler risklere genel toplumdan daha fazla sahip olmadığı söylenebilir.

Anahtar Kelimeler:

Homosistein, vitamin B12, proton pompa inhibitörleri

Are serum homocysteine levels increased in patients using proton pump inhibitors?

Background and Aim: DNA synthesis, which is required for cell division and proliferation, is provided by transformation of homocysteine to methionine. Vitamin B12 is the cofactor of methionine synthesis that plays a role in this reaction. vitamin B12 deficiency causes the accumulation of homocysteine. Hyperhomocysteinemia has been associated with arteriosclerosis and cerebral embolism. Proton pump inhibitors are widely used drugs that inhibit H+/K+-ATPase, which is found in parietal cells. Because HCl is required for separation of vitamin B12 from food, the ingestion of proton pump inhibitors can cause vitamin B12 deficiency, which can lead to hyperhomocysteinemia. In our study, we investigated the effect of the use of proton pump inhibitors on vitamin B12 and serum homocysteine levels. Material and Methods: In this study, 44 patients who had been using proton pump inhibitorsfor at least 3 months because of various indications and 38 patients (control group) who had never used proton pump inhibitors who admitted to our outpatient clinic between March and July 2009 were included. The ages of the patients and the control group, serum levels of homocysteine, vitamin B12 and folic acid, mean corpuscular volume (MCV) values, and duration of proton pump inhibitors use were recorded. In addition, among the patients on proton pump inhibitors, the fasting serum levels of homocysteine, vitamin B12 and folic acid and MCV values were compared between patients using proton pump inhibitors for less than 2 years or more than 2 years. Results: The average duration of proton pump inhibitors use was 19.5 months in the patient group. There was no significant difference between patients and controls in mean age (in patient group: 39±14, in control group: 41±5; p=0.7) and gender (patient group: 19 men, 25 women, control group: 13 men, 25 women; p=0.4). No significant difference was detected between patient and control groups when comparing in terms of homocysteine (patients: 9.98±4.79, controls: 9.40±0.527; p=0.5), VB12 (patients: 328±305, controls: 264±105; p=0.2), folic acid (patients: 9.20±3.20, controls: 8.91±2.94; p=0.7), and MCV (patients: 83±11, controls: 86±8; p=0.1). There were no differences between homocysteine, vitamin B12, folic acid and MCV levels when the patients were compared among themselves regarding the use of proton pump inhibitorsfor more or less than 2 years. Conclusion: According to our study, long-term use of proton pump inhibitors showed no significant effect on the levels of vitamin B12 and consequently on the level of homocysteine. For this reason, we can say that these patients do not have greater cardiovascular risks caused by hyperhomocysteinemia with respect to the general population.

Keywords:

Homocysteine, vitamin B12, proton pump inhibitors,

PDF

___

Kuller LH, Evans RW. Homocysteine, vitamins, and cardiovascular disease Circulation 1998; 98: 196-9.
Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999; 354: 407-13.
Desouza C, Keebler M, McNamara DB, Fonseca V. Drugs affecting homocysteine metabolism: impact on cardiovascular risk. Drugs 2002; 62: 605-16.
Fellenius E, Berlingdh T, Sachs G, et al. Substituted benzimidazoles inhibit gastric acid secretion by blocking (H+ K+)ATPase. Nature 1981; 290: 159-61.
Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324: 1149-55.
Den Heijer M, Koster T, Blom HJ, et al. Hyperhomocysteinemia as a risk factor for deep vein thrombosis. N Engl J Med 1996; 334: 759-62.
Harker LA, Ross R, Slichter SI, Scott CR. Homocysteine-induced arteriosclerozis: The role of endothelial cell injury and platelet respofise in its genesis. J. Clin Invest 1976; 58: 731-41.
Parthasarathy S. Oxidation of low-density lipoprotein by thiol compounds leads two its recognition by the acetyl LDL receptor Biochim Biophys Acta 1987; 917: 337-40.
Fellenius E, Berlingdh T, Sachs G, et al. Substituted benzimidazoles inhibit gastric acid secretion by blocking (H+ +K+) ATPase. Nature 1981; 290: 159-61.
Saltzman JR, Kemp JA, Golner BB, et al. Effect of hypochloridia due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorbtion. J Am Coll Nutr 1994; 13: 584-91.
Rodgers GM, Conn MT. Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood 1990; 75: 895-901.
Nishinaga M, Ozawa T, Shimada K. Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expressian in cultured porcine aortic endothelial cells. J Clin Invest 1993; 92: 1381-6.
Stamler JS, Osbome JA, Jaraki O, et al. Adverse vascular effects ofhomocysteine are modulated by endothelium - derived relaxing factor and related oxides of nitrogen. J Clin Invest 1993; 91: 30818.
Chin JH, Azhar S, Hoffman BB. Inactivation of endothelial derived relaxing factor by oxidized lipoproteins. J Clin Invest 1992; 89: 10-8.
Bloom HJ, Kleinveld HA, Boers GH, et al. Lipid peroxidation and susceptibility of low-density lipoprotein to in vitro oxidation in hyperhomocysteinemia. Eur J Clin Invest 1995; 25: 149-54.
Upchurch GR Jr, Welch GN, Fabian AJ, et al. Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 1997; 272: 17012-7.
Harker LA, Harlan JM, Ross R. Effect of sulfinpyrazone on homocysteine-induced endothelial injury and arteriosclerosis in baboons. Circ Res 1983; 53: 731-9
Tsai JC, Perrela MA, Yoshizumi M, et al. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci USA 1994; 91: 6369-73.
Tsai JC, Wang H, Perella MA, et al. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells. J Clin Invest 1996; 97: 146-53.
Welch GN, Upchurch GR Jr, Farivar RS, et al. Homocysteine-induced nitric oxide production in vascular smooth muscle cells by NF- (kappa) B dependent transcriptional activation of Nos 2. Proc Assoc Am Physicians. 1998; 110: 22-31.
Bellas RE, Lee JS, Sonenshein GE. Expression of a constitutive NFkappa B-like activity is essential for proliferation of cultured bovine vascular smooth muscle cells. J Clin Invest 1995; 96: 2521-7.
Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med 1994; 120: 211-5.
Pounder R, Smith J. Drug induced changes in plasma gastrin concentrations. Gastroenterol Clin North Am 1990; 19: 141-53.
Lamberts R, Creutzfeldt W, Strüber HG, et al. Long term omeprazole therapy in peptic ulcer disease: gastrin, endocrine cell growth and gastritis. Gastroenterology 1993; 104: 1356-70.
Chourasia D, Misra A, Pandey R, Ghoshal UC. Gastric atrophy and intestinal metaplasia in a patient on long-term proton pump inhibitor therapy. Trop Gastroenterol 2008; 29: 172-4.
Howden CW. Vitamin B12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol 2000; 30: 29-33.
Koop H, Bachem MG. Serum iron, ferritin and vitamin B12 during prolonged omeprazole therapy. J Clin Gastroenterol 1992; 14: 28892.