We appreciate the interest shown by Wagner

JOP. J Pancreas (Online) 2010 Nov 9; 11(6):652-653.

Reply to ‘Some More Comments on Folate Deficiency in Chronic Pancreatitis’

Gopalakrishna Rajesh¹, Banavara Narasimhamurthy Girish², Kannan Vaidyanathan³, Menon Saumya¹, Vallath Balakrishnan¹

Departments of ¹Gastroenterology, ²Physiology, and ³Biochemistry; Amrita Institute of Medical Sciences. Cochin, Kerala, India

Dear Sir,

We appreciate the interest shown by Wagner [1]. His comments highlight the complex interrelationship between folate, methyl group metabolism and choline metabolism.

Folate and betaine independently serve as methyl donors for homocysteine remethylation to methionine. Recently, Christensen et al. have demonstrated that increased utilization of betaine for homocysteine remethylation in folate deficiency may lead to steatosis by disrupting choline metabolism [2].

While betaine has been used in the treatment of homocystinuria due to cystathionine-beta-synthase deficiency, other approaches to homocystinuria include vitamin B₆ supplementation (in the responsive or milder phenotypic variant) and methionine restriction in addition to folate and vitamin B₁₂ supplementation. In our study, we demonstrated the defects in the trans-sulfuration pathway (cysteine and glutathione deficiency) in patients with chronic pancreatitis [3]. However, we did not estimate vitamin B₆ levels or cystathionine-beta-synthase activity which are important components of the trans-sulfuration pathway. In the case of isolated remethylation disorders such as methylenetetrahydrofolate reductase (MTHFR) deficiency, the very rare methionine synthase reductase (CbIE) and methionine synthase (CbIG) defects, and the recently identified CbID-variant-1 defect, the use of both oral folate and betaine supplements have been shown to have a favorable outcome when used in the early of treatment [4]. Of course, such rare primary single defects are a poor analogy for a complex disease, such as chronic pancreatitis.

Recently, Lee et al. have demonstrated among the participants of the Framingham Offspring Study that, while higher choline and betaine intakes were associated with lower concentrations of both fasting and post-methionine load homocysteine, especially in those with low folate and vitamin B₁₂ levels; the inverse association between choline and betaine intake with homocysteine concentrations was no longer present after folate fortification [5].

Thus, betaine supplementation as suggested by Wagner [1] may well have possible benefits in chronic pancreatitis but should probably be attempted in those with normal folate levels. We have recently demonstrated zinc deficiency in patients with chronic pancreatitis and have shown that this correlated with exocrine and endocrine insufficiency [6]. Interestingly, a recent study showed that zinc supplementation reduced serum homocysteine and increased vitamin B₁₂ and folate concentrations in type 2 diabetic patients with microalbuminuria [7]. In conclusion, recent literature suggests the need for developing a holistic view; additional studies are needed to establish evidence-based guidelines for the supplementation of antioxidants, methyl donors and lipotropes in patients with chronic pancreatitis.

Received August 31^st, 2010

Key words Exocytosis; Folic Acid; Methionine

Conflict of interest The authors have no potential conflict of interest

Correspondence
Vallath Balakrishnan
Department of Gastroenterology
Amrita Institute of Medical Sciences
AIMS Ponekkara P.O.
Cochin, 682 041, Kerala
India
Phone: +91-484.400.1225
Fax: +91-484.280.2020
E-mail: vbalakrishnan@aims.amrita.edu

References

1. Wagner C. Some more comments on 'Folate deficiency in chronic pancreatitis'. JOP. J Pancreas (Online) 2010; 11:646-7. [PMID 21068506]

2. Christensen KE, Wu Q, Wang X, Deng L, Caudill MA, Rozen R. Steatosis in mice is associated with gender, folate intake, and expression of genes of one carbon metabolism. J Nutr 2010; 140:1736-41. [PMID 20724492]

3. Girish BN, Vaidyanathan K, Rao NA, Rajesh G, Reshmi S, Balakrishnan V. Chronic pancreatitis is associated with hyperhomocysteinemia and derangements in transsulfuration and transmethylation pathways. Pancreas 2010; 39:e11-6 [PMID 20050230]

4. Schiff M, Benoist JF, Tilea B, Royer N, Giraudier S, Ogier de Baulny H. Isolated remethylation disorders: do our treatments benefit patients? J Inherit Metab Dis 2010; May 21. [PMID 20490923]

5. Lee JE, Jacques PF, Dougherty L, Selhub J, Giovannucci E, Zeisel SH, Cho E. Are dietary choline and betaine intakes determinants of total homocysteine concentration? Am J Clin Nutr 2010; 91:1303-10. [PMID 20219967]

6. Girish BN, Rajesh G, Vaidyanathan K, Balakrishnan V. Zinc status in chronic pancreatitis and its relationship with exocrine and endocrine insufficiency. JOP. J Pancreas (Online) 2009; 10:651-6. [PMID 19890187]

7. Heidarian E, Amini M, Parham M, Aminorroaya A. Effect of zinc supplementation on serum homocysteine in type 2 diabetic patients with microalbuminuria. Rev Diabet Stud 2009; 6:64-70. [PMID 19557297]