Levels of homocysteine are closely related to B vitamins; the conversion of homocysteine to methionine in the remethylation pathway requires folic acid and B12. The conversion of homocysteine to cystathionine and cysteine through transsulfation necessitates B6. Therefore, lowered levels of B12 or B6 can be associated with elevated homocysteine concentrations. Folic acid deficiency or methylenetetrahydrofolate reductase (MTHFR) deficiency are also causes of hyperhomocysteinemia. The recognition that homocysteine may play a role in hypercoagulability should raise consideration of nutritional replacement in patients with malignancy or pregnancy. Similarly, patients with known hypercoagulability due to inherited defects of the APC pathway should maintain adequate stores of folic acid, B12, and B6.
Hyperhomocysteinemia in pregnancy fin (1)
OverviewHyperhomocysteinemiaPrevalence in pregnancyClinical outcomes in PregnancyDiagnostic MeasuresTreatment with emphasis on empirical managementRole of vitamin B6, B9 and B12 in managementClinical Evidence
HomocysteineNaturally occurring sulphur containing amino acidResults from the demethylation of the essential amino acid methionine.Normal serum levels: 5 to 15 micromol/litreHyperhomocysteinemia –
Etiology of HyperhomocysteinemiaVitamin Deficiencies :Folate (B9)Methyl Cobalamin (B12)Pyridoxine (B6)Genetic causes:Defects (due to gene mutation )in Enzyme causing metabolism of homocysteine ( Rare ) Current Drug Metabol 2007 Jan;8(1):17-31
Homocysteine levels in vegetarian and nonvegetarian life style – Epidemiology in IndiaIndia predominantlyfollows vegetarian foodhabits Higher levels of homocysteine due to Vitamin B12 deficiency www.veganhealth.org as accessed on 28th April 2012 Homocysteine Levels
Homocysteine and Pregnancy Homocysteine conc. decreased in pregnancy due to Hemodilution Raised GFR Hormonal changes of pregnancy Increased fetal uptakeHague WM Best Practice & Research Clinical Obstetrics & Gynaecology 2003;17(3):459–469, 2003
Indian Study 2010 Hyperhomocysteinemia in Pregnancy In an Indian maternal nutrition study, two thirds of pregnant mothers had low levels of vitamin B12 Only an occasional mother had low folate concentration. Vitamin B12 and folate play vital role in one carbon (1-C) metabolism, crucial for fetal growth This study showed that the plasma tHcy concentration at 34 weeks gestation was lower in those who received vitamin B12 supplementation compared to those who received only folic acid or no supplementationKatre P et al. Vitamin B12 and folic acid supplementation and plasma total homocysteine concentrations in pregnant Indian women with low B12and high folate status Asia Pac J Clin Nutr 2010;19 (3):335-343
Hyperhomocysteinemia is an independent causal factor in pregnancy complications……..Current Drug Metabol 2007 Jan;8(1):17-31
Clinical outcomes in Pregnancy Approximately 2-fold to 3-fold increased risk for : • Pregnancy-induced hypertension • Abruptio placentae • Intrauterine growth restriction Cobalamine deficiency : • HELLP syndrome • Abruptio placentae • Intrauterine growth restriction • Intrauterine fetal death Pyridoxal 5-phosphate deficiency • Increased risk for pregnancy-induced hypertension 4-foldHyperhomocysteinemia, Pregnancy Complications and the Timing of InvestigationRe´gine P. Steegers-Theunissen,et al. VOL. 104, NO. 2, AUGUST 2004The American College of Obstetricians and Gynecologists as accessed on 29 th April 2012
Other congenital defects spontaneous miscarriage recurrent abortion NTDs IUGR HyperhomocysteinemiaPre-term labourIntrauterine fetal death Pre-eclampsia placental abruption Hyperhomocysteinemia, Pregnancy Complications and the Timing of Investigation Re´gine P. Steegers-Theunissen,et al. VOL. 104, NO. 2, AUGUST 2004 The American College of Obstetricians and Gynecologists as accessed on 29 th April 2012
Association of Hyperhomocysteinemia &Pregnancy complications, adverse pregnancy outcome.As evident by clinical studies………..
J Nutr. 2006 Jun;136(6 Suppl):1731S-1740SWomen with hyperhomocysteinemia haveincreased risk of pregnancy complicationsand adverse pregnancy outcome
BJOG. 2006 Dec;113(12):1412-8Maternal hyperhomocysteinemia is a risk factor forCongenital Heart DiseaseClin Chem Lab Med 2005; 43(10): 1052-7Early abortion, pregnancy complications and poorpregnancy outcomes have been linked tohyperhomocysteinemia
American Journal of Perinatology. January 2006; 23(1):31-35Hyperhomocysteinemia during pregnancy is a riskfactor for development of preeclampsia and itscomplicationsEur J. of Obs & Gynae & Reprod Biol 2003Numerous studies have demonstrated associationbetween increased levels of homocysteine andspontaneous miscarriages, IUGR, preeclampsiaand fetal death
Pregnancy outcomes are multi-factorialSundrani D.P. et al. / Medical Hypotheses 77 (2011) 878–883
Hyperhomocysteinemia as risk factorPregnant women with hyperhomocysteinemia have a 7.7-fold risk for preeclampsiaHyperhomocysteinemia associated with recurrent pregnancy lossMHTFR mutation in 16% cases LÃ³pez-Quesada E, Vilaseca MA, Lailla JM. Eur J Obstet Gynecol Reprod Biol. 2003 May 1;108(1):45-9.
Diagnostic Measures When to Screen ?Values in early pregnancy are more reliableSecond-trimester plasma homocysteine concentrations do not predict the subsequent development of pregnancy-induced hypertension, preeclampsia, and intrauterine growth restriction Hogg BB, Tamura T, Johnston KE, Dubard MB, Goldenberg RL. Am J Obstet Gynecol. 2000 Oct;183(4):805-9 Zeeman GG, Alexander JM, McIntire DD, Devaraj S, Leveno KJ. Am J Obstet Gynecol. 2003 Aug;189(2):574-6 as accessed on 28th April 2012
Sample CollectionOvernight fasting mustMorning sampleEDTA bulbTo be centrifuged immediatelyOr kept on wet ice till centrifugation
Treatment Dietary modification Folate supplementation[500-5000microgram/day] Vitamin B12 supplementation particulary for indian population due to high prevalance of vegeterian diet Supplementation of pyridoxine[B6]Sundrani D.P. et al. / Medical Hypotheses 77 (2011) 878–883Hague WM Best Practice & Research Clinical Obstetrics & Gynaecology 2003;17(3):459–469, 2003
Role of vitamin B6, B9 and B12 in managementMethionine is an essential amino acid obtained from protein in the dietSome methionine is turned into homocysteineThe body turns much of this homocysteine back into methionine with the help of vitamin B12Low vitamin B6 status can also cause elevated homocysteine in some peoplewww.brewboost.com as accessed on 1st May 2012
Role of vitamin B6, B9 and B12 in managementDemethylation Methionine synthase Cystathionine beta synthaseTranssulfuration Available at www.medscape.com as accessed on Aug 2012MTHFR- methyl tetrahydrofolate reductase
FOLIC ACIDImportant cofactor in the Remethylation of Homocysteine Making of new cells and cell replicatio n Folic acid-vitamin B supplementation significantly reduce total Hcy levels Low conc associated with risk of preterm delivery, Low birth weight infants and IUGRAJCN. 2000; 71: 1295S-1303S,Am J Obstet Gynecol. 2004 Dec;191(6):1851-7.Bostom et al, 2002
VITAMIN B12A cofactor, Methionine Synthetase (MS) in methylationEnzyme, catalyses the transfer of CH3 group from MethylTetrahydrofolate HomocysteineIn Vit. B12 def, folate is trapped as unusable MTHF, causing functional folate deficiency.Thus plays a key role in the remethylation of Homocysteine to Methionine.
VITAMIN B6 A cofactor, Pyridoxal Phosphate in methylation Reduces the level of homocysteine by the process of transulfuration to cysteine & hence related pregnancy complications are reduced Vitamin B6 levels of mothers at the onset of pregnancy have a positive correlation with birth weight of newborns Effective in the treatment of nausea and vomiting of pregnancyInt J Vitam Nutr Res. 1978;48(4):341-7
Folate, Vitamin B12 & B6 - effective & safe to reduce homocysteine levels The relationship between serum homocysteine (hcy) levels and pregnancy complications was studied Homocysteine lowering effects of folate, vitamin B12 and Vitamin B6 332 pregnant women They were given- folate- 5 mg/day, vitamin B12- 1000 mcg/day for 6 weeks and of vitamin B6- 1000 mcg/dayQuereshi S et al. JPMA 60:741; 2010
Folate, Vitamin B12 & B6 - effective & safe to reduce homocysteine levelsQuereshi S et al. JPMA 60:741; 2010
ConclusionFolate, Vitamin B12 & B6 supplementation is effective & safe to reducehomocysteine levelsQuereshi S et al. JPMA 60:741; 2010
ConclusionVitamins (folate, B6, B12) play important role in metabolism of homocysteineDeficiency of vitamins (folate, B6, B12) is associated with hyperhomocysteinemiaHyperhomocysteinemia may be associated with some of the complications in preganancySupplementation of Folic acid, B6 and B12 is effective and safe in reducing homocysteine levels
Prophylaxis Folic acid and vitamins B6 and B12 are necessary in metabolism of Hcys; therefore they can be used for both treatment and prophylaxis of hyperhomocysteinemia Proper diet Abstaining from tobacco or smoking Optimal physical activityhttp://www.czytelniamedyczna.pl/3431,prophylaxis-and-treatment-of-hyperhomocysteinemia.html
Top Three “Best Practices” to Improve Birth Outcomes & Reduce High Risk Births (NGA, June 2004) Improve access to medical care and health care services Encourage good nutrition and healthy lifestyles Eating healthy foods Taking folic acid (Methylating agents) Reduce use of harmful substancesAvailable at http://www.nga.org/cms/home/nga-center-for-best-practices/ as accessed on Aug 2012
SummaryHyperhomocysteinemia is independent causal factor for pregnancy complicationsFolic acid, methylcobalamin and pyridoxine deficiencies lead to hyperhomocysteinemia and are prevalent in pregnant womenSupplementation of folic acid, methylcobalamin and pyridoxine helps in management of hyperhomocysteinemia