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Zheng X, Chen Z, Liang M, Zhou L, Wang M, Zhang S, Zhang S, Ma L, Yi W, Liu X. Targeting UGT2B15 and NR1H4 interaction: a novel therapeutic strategy for polycystic ovary syndrome using naftopidil enantiomers. J Ovarian Res 2025; 18:13. [PMID: 39856707 PMCID: PMC11760714 DOI: 10.1186/s13048-025-01598-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 01/14/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder among women of reproductive age. It is characterized by hyperandrogenism, ovulatory dysfunction, and the presence of polycystic ovarian morphology (PCOM) on ultrasound, often accompanied by metabolic disturbances such as insulin resistance and obesity. Current treatments, including oral contraceptives and anti-androgen medications, often yield limited efficacy and undesirable side effects. This study investigates the role of UGT2B15, an essential enzyme for androgen metabolism, in PCOS pathogenesis and its potential as a therapeutic target. METHODS We used RNA sequencing to examine the effects of UGT2B15 knockdown in KGN cells. To modulate UGT2B15 expression, we employed siRNA and (R)/(S)-NAF (naftopidil), a chemical inducer of UGT2B15 identified in our previous studies on a prostate hyperplasia model. The effects of siRNA and (R)/(S)-NAF on dihydrotestosterone (DHT) levels, cell apoptosis, and the expression of apoptosis-related proteins in KGN cells were evaluated. In a PCOS mouse model, we assessed the effects of (R)-NAF and (S)-NAF on serum androgen levels, menstrual cycles, ovarian morphology, and UGT2Bs expression. Additionally, luciferase reporter and ChIP assays were utilized to study UGT2B15 regulation by NR1H4. RESULTS Elevated androgens were found to suppress UGT2B15 expression in ovarian granulosa cells, leading to DHT accumulation and apoptosis. (R)-NAF and (S)-NAF treatments reversed these effects, alleviating PCOS symptoms in mice such as hyperandrogenism, irregular menstrual cycles, and the presence of ovarian cysts. NR1H4 negatively regulated the transcription of UGT2B15 in KGN cells. (R)-NAF and (S)-NAF disrupted NR1H4 binding to the UGT2B15 promoter without affecting its protein levels, indicating direct interference with its regulation. CONCLUSIONS UGT2B15 represents a promising target for novel PCOS therapies by modulating androgen metabolism and protecting ovarian granulosa cells from apoptosis. (R)-NAF and (S)-NAF regulate UGT2B15 by disrupting NR1H4's binding to its promoter, implying potential therapeutic compounds for PCOS treatment.
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Affiliation(s)
- Xiufen Zheng
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Zikai Chen
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Miao Liang
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Liting Zhou
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Miaoru Wang
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Silin Zhang
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Shuyun Zhang
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Lei Ma
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Wei Yi
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
| | - Xiawen Liu
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
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Yu YM, So SK, Khallouq BB. The effect of metformin on vitamin B12 level in pediatric patients. Ann Pediatr Endocrinol Metab 2022; 27:223-228. [PMID: 35592896 PMCID: PMC9537665 DOI: 10.6065/apem.2142210.105] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 02/10/2022] [Indexed: 11/21/2022] Open
Abstract
PURPOSE Metformin is a common medication for patients with hyperglycemia. In adults, one well-documented side effect of metformin is vitamin B12 deficiency. However, this side effect has rarely been studied in pediatric patients. This study examined the changes of vitamin B12 level in pediatric patients being treated with metformin. METHODS Data were collected from pediatric patients (n=151) with at least 3 months of consecutive metformin intake. The effects of dose of metformin on the mean vitamin B12 level were investigated at 6, 12, 24, and 36 months. The effect of compliance of metformin intake on vitamin B12 level also was studied. RESULTS There was no significant decrease in mean vitamin B12 level at 6, 12, 24, or 36 months in patients treated with metformin. Mean vitamin B12 decrease was only noticeable (p<0.05) in patients taking a high dose of metformin with good compliance. Despite this change, the mean vitamin B12 remained well within the normal reference range. Furthermore, of the 151 patients studied, only 1 demonstrated vitamin B12 deficiency after 12 months of treatment. However, his B12 level was normal at 24 and 36 months without any vitamin B12 supplements. CONCLUSION Our findings suggest that metformin treatment in children does not cause vitamin B12 deficiency; however, the effect of long-term consistent high-dose treatment on vitamin B12 level remains unknown.
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Affiliation(s)
- Y. Miles Yu
- Pediatric Endocrinology, Nemours Children’s Hospital, Orlando, FL, USA,Address for correspondence: Y. Miles Yu Pediatric Endocrinology, Nemours Children's Hospital, Florida, 6535 Nemours Pkwy, Orlando, FL 32827, USA
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Juneja D, Nasa P, Jain R. Metformin toxicity: A meta-summary of case reports. World J Diabetes 2022; 13:654-664. [PMID: 36159225 PMCID: PMC9412858 DOI: 10.4239/wjd.v13.i8.654] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/17/2022] [Accepted: 07/25/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Metformin is arguably the most commonly prescribed oral hypoglycemic agent for the management of diabetes. Due to the lack of randomized control trials, most of the data pertaining to the clinical course, therapeutic interventions and outcomes of patients with metformin induced toxicity has come from case reports or series.
AIM To analyse the symptomology, clinical interventions and outcomes of patients presenting with severe metformin toxicity by reviewing the published case reports and series.
METHODS We performed a systematic search from PubMed, Science Direct, Reference Citation Analysis (https://www.referencecitationanalysis.com/) and Google Scholar databases using the terms “metformin” AND “toxicity” OR “overdose” OR “lactic acidosis” OR “hyperlactatemia”. The inclusion criteria were: (1) Case reports or case series with individual patient details; and (2) Reported toxicity or overdose of metformin in adults, published in the English language. Data regarding baseline demographics, clinical presentation, therapeutic interventions, intensive care unit course and overall outcome were collected.
RESULTS Two hundred forty-two individual cases were analysed, from 158 case reports and 26 case series, with a cumulative mortality of 19.8%. 214 (88.4%) patients were diabetics on metformin. 57 (23.6%) had acute ingestion, but a great majority (76.4%) were on metformin in therapeutic doses when they developed toxicity. Metformin associated lactic acidosis (MALA) was the most commonly reported adverse effect present in 224 (92.6%) patients. Most of the patients presented with gastrointestinal and neurological symptoms and a significant number of patients had severe metabolic acidosis and hyperlactatemia. The organ support used was renal replacement therapy (RRT) (68.6%), vaso-pressors (58.7%) and invasive mechanical ventilation (52.9%). A majority of patients (68.6%) received RRT for toxin removal, renal dysfunction and correction of MALA. Patients with lowest pH and highest serum lactate and metformin levels also had favourable outcomes with use of RRT.
CONCLUSION Most of the reported cases were on therapeutic doses of metformin but developed toxicity after an acute deterioration in renal functions. These patients may develop severe lactic acidosis, leading to significant morbidity and need for organ support. Despite severe MALA and the need for multiple organ support, they may have good outcomes, especially when RRT is used. The dose of metformin, serum pH, lactate and metformin levels may indicate the severity of toxicity and the need for aggressive therapeutic measures but may not necessarily indicate poor outcomes.
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Affiliation(s)
- Deven Juneja
- Institute of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi 110017, India
| | - Prashant Nasa
- Department of Critical Care Medicine, NMC Specialty Hospital, Dubai 7832, United Arab Emirates
| | - Ravi Jain
- Department of Critical Care Medicine, Mahatma Gandhi Medical College and Hospital, Jaipur 302022, India
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Out M, Kooy A, Lehert P, Schalkwijk CA, Stehouwer CDA. Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: Post hoc analysis of a randomized controlled 4.3year trial. J Diabetes Complications 2018; 32:171-178. [PMID: 29174300 DOI: 10.1016/j.jdiacomp.2017.11.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 10/16/2017] [Accepted: 11/01/2017] [Indexed: 01/03/2023]
Abstract
AIMS Metformin treatment is associated with a decrease of serum vitamin B12, but whether this reflects tissue B12 deficiency is controversial. We studied the effects of metformin on serum levels of methylmalonic acid (MMA), a biomarker for tissue B12 deficiency, and on onset or progression of neuropathy. METHODS In the HOME trial, 390 insulin-treated patients with type 2 diabetes were treated with metformin or placebo for 52months. In a post hoc analysis, we analyzed the association between metformin, MMA and a validated Neuropathy Score (NPS). RESULTS Metformin vs placebo increased MMA at the end of the study (95%CI: 0.019 to 0.055, p=0.001). Mediation analysis showed that the effect of metformin on the NPS consisted of a beneficial effect through lowering HbA1c (-0.020 per gram year) and an adverse effect through increasing MMA (0.042 per gram year), resulting in a non-significant net effect (0.032 per gram year, 95% CI: -0.121 to 0.182, p=0.34). CONCLUSION Metformin not only reduces serum levels of B12, but also progressively increases serum MMA. The increase of MMA in metformin users was associated with significant worsening of the NPS. These results provide further support that metformin-related B12 deficiency is clinically relevant. Monitoring of B12 in users of metformin should be considered.
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Affiliation(s)
- Mattijs Out
- Department of Internal Medicine, Care Group Treant, Location Bethesda Hoogeveen, 7909AA 1 Hoogeveen, Netherlands; Bethesda Diabetes Research Center, 7909AA 1 Hoogeveen, Netherlands
| | - Adriaan Kooy
- Department of Internal Medicine, Care Group Treant, Location Bethesda Hoogeveen, 7909AA 1 Hoogeveen, Netherlands; Bethesda Diabetes Research Center, 7909AA 1 Hoogeveen, Netherlands; Department of Internal Medicine, University Medical Center Groningen, Post Office 30.001, 9700 RB Groningen, Netherlands
| | - Philippe Lehert
- Department of Statistics, Faculty of Economics, Facultés Universitaires Catholiques de Mons, Louvain Academy, 7000 151 Mons, Belgium
| | - Casper A Schalkwijk
- Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, 6202 AZ 5800 Maastricht, Netherlands
| | - Coen D A Stehouwer
- Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, 6202 AZ 5800 Maastricht, Netherlands.
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Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ, Bray GA, Schade DS, Temprosa MG, White NH, Crandall JP. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab 2016; 101:1754-61. [PMID: 26900641 PMCID: PMC4880159 DOI: 10.1210/jc.2015-3754] [Citation(s) in RCA: 294] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
CONTEXT Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use. OBJECTIVE To assess the risk of B12 deficiency with metformin use in the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS). DESIGN Secondary analysis from the DPP/DPPOS. Participants were assigned to the placebo group (PLA) (n = 1082) or the metformin group (MET) (n = 1073) for 3.2 years; subjects in the metformin group received open-label metformin for an additional 9 years. SETTING Twenty-seven study centers in the United States. PATIENTS DPP eligibility criteria were: elevated fasting glucose, impaired glucose tolerance, and overweight/obesity. The analytic population comprised participants with available stored samples. B12 levels were assessed at 5 years (n = 857, n = 858) and 13 years (n = 756, n = 764) in PLA and MET, respectively. INTERVENTION Metformin 850 mg twice daily vs placebo (DPP), and open-label metformin in the metformin group (DPPOS). MAIN OUTCOME MEASURES B12 deficiency, anemia, and peripheral neuropathy. RESULTS Low B12 (≤ 203 pg/mL) occurred more often in MET than PLA at 5 years (4.3 vs 2.3%; P = .02) but not at 13 years (7.4 vs 5.4%; P = .12). Combined low and borderline-low B12 (≤ 298 pg/mL) was more common in MET at 5 years (19.1 vs 9.5%; P < .01) and 13 years (20.3 vs 15.6%; P = .02). Years of metformin use were associated with increased risk of B12 deficiency (odds ratio, B12 deficiency/year metformin use, 1.13; 95% confidence interval, 1.06–1.20). Anemia prevalence was higher in MET, but did not differ by B12 status. Neuropathy prevalence was higher in MET with low B12 levels. CONCLUSIONS Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia. Routine testing of vitamin B12 levels in metformin-treated patients should be considered.
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Affiliation(s)
- Vanita R Aroda
- MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461
| | - Sharon L Edelstein
- MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461
| | - Ronald B Goldberg
- MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461
| | - William C Knowler
- MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461
| | - Santica M Marcovina
- MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461
| | - Trevor J Orchard
- MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461
| | - George A Bray
- MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461
| | - David S Schade
- MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461
| | - Marinella G Temprosa
- MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461
| | - Neil H White
- MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461
| | - Jill P Crandall
- MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461
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Issac TG, Soundarya S, Christopher R, Chandra SR. Vitamin B12 deficiency: an important reversible co-morbidity in neuropsychiatric manifestations. Indian J Psychol Med 2015; 37:26-9. [PMID: 25722508 PMCID: PMC4341306 DOI: 10.4103/0253-7176.150809] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Vitamin B12 deficiency is a common condition causing neurologic, cognitive, psychiatric, and mood symptoms. With varied religious, ethnic, and socioeconomic heterogeneity among the people in India greatly influencing their dietary habits and with the high prevalence of Helicobacter pylori infection, Vitamin B12 deficiency is not uncommon, but is often under recognized due to the lack of classical symptomatic presentation. MATERIALS AND METHODS Retrospective study on Vitamin B12 deficiency with neuropsychiatric symptoms in patients who attended neurology, psychiatry, and geriatric OPDs for a period of 1 year in a specialized neuropsychiatric institute in South India. RESULTS Out of 259 patients who had Vitamin B12 deficiency (<220 pmol/L), 60 had neuropsychiatric symptoms. Among them the Vitamin B12 levels were <150 (severe), 150-200 (moderate), and 201-220 pmol/L (mild) in 19, 24, 17 patients, respectively. Twenty one were diagnosed with Posterior dementias, 20 with frontotemporal dementia, 7 with Schizophrenia, 4 each with Parkinson's disease and alcohol-dependent syndromes (ADS), 3 with bipolar affective disorder, and 1 with Creutzfeldt-Jakob disease. Eight patients also had hypothyroidism. First symptom of presentation was behavioral disturbances in 30 (50%), memory loss in 20 (33.9%), and sensorimotor and movement disorders in 9 (15.3%), and 56.7% were vegetarians while 43.3% were nonvegetarians. In our study, Vitamin B12 deficiency was more prevalent in elderly males (56.67%) and was associated with increased severity of behavioral disturbances (P = 0.043) which was the most common presentation. Memory loss was present in 16 (84.2%) patients of severe Vitamin B12 deficiency. Hindi mental status examination (HMSE) score was graded as <20, 20-24, 24-31 in 37 (61.7%), 10 (16.7%), and 13 (21.7%) patients, respectively. Cognitive decline in Vitamin B12 deficiency was significantly associated with increased serum cholesterol (P = 0.019) and was significantly prevalent in neurological disorders when compared with primary psychiatric illnesses (P = 0.001). Mean folate and mean homocysteine in our study was 11.7 ± 6.44 ng/ml and 17.77 ± 5.45 μmol/L, respectively. Eighty percent of the population had normal folate levels whereas mean homocysteine values were much higher than that of the western population (10-12 μmol/L). CONCLUSION Vitamin B12 deficiency though common in India is often overlooked. It increases the load of cognitive decline and accentuates vascular risk factors in neuropsychiatric illnesses. Vitamin B12 deficiency also increases homocysteine levels contributing to the vascular comorbidity in cerebro and cardiovascular illnesses. So prevention, early detection, and management of this reversible Vitamin B12 deficiency state is of profound importance.
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Affiliation(s)
- Thomas Gregor Issac
- Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Soundararajan Soundarya
- Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Rita Christopher
- Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
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