Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes

Diabetes mellitus(DM)is still one of the most common diseases worldwide,and its prevalence is still increasing globally.According to the American and European recommendations,metformin is considered a first-line oral hypoglycemic drug for controlling type 2 DM(T2DM)patients.Metformin is the ninth most often prescribed drug in the world,and at least 120 million diabetic people are estimated to receive the drug.In the last 20 years,there has been increasing evidence of vitamin B12 deficiency among metformin-treated diabetic patients.Many studies have reported that vitamin B12 deficiency is related to the malabsorption of vitamin B12 among metformin-treated T2DM patients.Vitamin B12 deficiency may have a very bad complication for the T2DM patient.In this review,we will focus on the effect of metformin on the absorption of vitamin B12 and on its proposed mechanisms in hindering vitamin B12 absorption.In addition,the review will describe the clinical outcomes of vitamin B12 deficiency in metformintreated T2DM.

Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind

To date,metformin remains the first-line oral glucose-lowering drug used for the treatment of type 2 diabetes thanks to its well-established long-term safety and efficacy profile.Indeed,metformin is the most widely used oral insulinsensitizing agent,being prescribed to more than 100 million people worldwide,including patients with prediabetes,insulin resistance,and polycystic ovary syndrome.However,over the last decades several observational studies and meta-analyses have reported a significant association between long-term metformin therapy and an increased prevalence of vitamin B12 deficiency.Of note,evidence suggests that long-term and high-dose metformin therapy impairs vitamin B12 status.Vitamin B12(also referred to as cobalamin)is a water-soluble vitamin that is mainly obtained from animal-sourced foods.At the cellular level,vitamin B12 acts as a cofactor for enzymes that play a critical role in DNA synthesis and neuroprotection.Thus,vitamin B12 deficiency can lead to a number of clinical consequences that include hematologic abnormalities(e.g.,megaloblastic anemia and formation of hypersegmented neutrophils),progressive axonal demyelination and peripheral neuropathy.Nevertheless,no definite guidelines are currently available for vitamin B12 deficiency screening in patients on metformin therapy,and vitamin B12 deficiency remains frequently unrecognized in such individuals.Therefore,in this“field of vision”article we propose a list of criteria for a cost-effective vitamin B12 deficiency screening in metformin-treated patients,which could serve as a practical guide for identifying individuals at high risk for this condition.Moreover,we discuss additional relevant topics related to this field,including:(1)The lack of consensus about the exact definition of vitamin B12 deficiency;(2)The definition of reliable biomarkers of vitamin B12 status;(3)Causes of vitamin B12 deficiency other than metformin therapy that should be identified promptly in metformin-treated patients for a proper differential diagnosis;and(4)Potential pathophysiological mechanisms underlying metformin-induced vitamin B12 deficiency.Finally,we briefly review basic concepts related to vitamin B12 supplementation for the treatment of vitamin B12 deficiency,particularly when this condition is induced by metformin.

Effect of vitamin B12 deficiency anemia on peripapillary retinal nerve fiber layer

AIM:To evaluate the effect of vitamin B12 deficiency anemia(BDA)on peripapillary retinal nerve fiber layer thickness(RNFLT)using spectral domain optical coherence tomography(SD-OCT),and to determine any correlation arising thereof.METHODS:In this cross-sectional observational study,99 eyes of 50 BDA patients of age 18-65 y were compared with 100 eyes of 50 healthy control subjects.All subjects underwent comprehensive clinical,ophthalmic,and hematological evaluation,followed by peripapillary RNFLT assessment using SD-OCT.RESULTS:The mean total,inferior,nasal,and temporal RNFLT were significantly lower in BDA group as compared to control group(P<0.05).The mean total,inferior and nasal RNFLT correlated significantly(P<0.05)with serum Hb%,B12 and mean corpuscular volume(MCV)level(r=0.310,0.435,-0.386 for total;r=0.932,0.481,-0.513 for inferior;r=0.344,0.254,-0.233 for nasal;respectively),while temporal and superior RNFLT quadrant did not show any correlation with any of the hematological parameters(r=0.144,0.167,-0.096;r=0.111,0.070,-0.099;respectively).The mean total RNFLT showed progressive thinning at par with the progression of anemia,except in very severe BDA,where an inverse relationship was documented.CONCLUSION:The mean total,inferior,nasal,and temporal peripapillary RNFLT was significantly thinner in BDA patients.Peripapillary RNFLT thinning seemed to proceed at par with the progression of severity of anemia,except in very sever grade.Early assessment of peripapillary RNFLT may be crucial in BDA patients to prevent potential blinding sequelae.Peripapillary RNFLT thinning in BDA patients should be considered in the differential diagnosis of other non-glaucomatous optic neuropathies,as well.

Association of autoimmune type atrophic corpus gastritis with Helicobacter pylori infection

AIM:To study the association between Helicobacter pylori(H.pylori)infection and autoimmune type atrophic gastritis. METHODS:Twenty-three patients with different grades of atrophic gastritis were analysed using enzyme immunoassay-based serology,immunoblot-based serology,and histology to reveal a past or a present H.pylori infection.In addition,serum markers for gastric atrophy(pepsinogenⅠ,pepsinogenⅠ/Ⅱand gastrin)and autoimmunity[parietal cell antibodies(PCA), and intrinsic factor(IF),antibodies]were determined. RESULTS:Of the 14 patients with severe gastricatrophy,as demonstrated by histology and serum markers,and no evidence for an ongoing H.pylori infection,eight showed H.pylori antibodies by immunoblotting.All eight had elevated PCA and 4/8 also had IF antibodies.Of the six immunoblot-negative patients with severe corpus atrophy,PCA and IF antibodies were detected in four.Among the patients with low to moderate grade atrophic gastritis(all except one with an ongoing H.pylori infection),serum markers for gastric atrophy and autoimmunity were seldom detected.However,one H.pylori negative patient with mild atrophic gastritis had PCA and IF antibodies suggestive of a pre-atrophic autoimmune gastritis. CONCLUSION:Signs of H.pylori infection in autoimmune gastritis,and positive autoimmune serum markers in H.pylori gastritis suggest an etiological role for H.pylori in autoimmune gastritis.

Diagnosis and clinical manifestations of subacute combined degeneration of the spinal cord: Analysis of 21 cases

BACKGROUND： Subacute combined degeneration of the spinal cord is caused by vitamin B12 deficiency and is a kind of degenerative disease owing the characteristics of nervous system diseases. In addition, different patients have variously clinical manifestations and various prognoses after vitamin B12 therapy. OBJECTIVE： To investigate and analyze diagnosis, clinical manifestations and prognosis of subacute combined degeneration of the spinal cord. DESIGN： Case analysis. SETTING： Department of Neurology, the Third Hospital of Peking University. PARTICIPANTS： A total of 21 subacute combined degeneration of the spinal cord patients including 14 males and 7 females aged from 33 to 82 years were selected from Department of Neurology, the Third Hospital of Peking University from January 1999 to December 2005. Duration from onset to final diagnosis lasted for 1.5 - 108 months. All patients had typically clinical manifestations; meanwhile, level of serum vitamin B12 was decreased and/or vitamin B12 therapy was effective. All patients provided the confirmed consent. METHODS： Clinical data of 21 subacute combined degeneration of the spinal cord patients were retrospectively analyzed, while general data and clinical characteristics were recorded at the same time. Levels of blood routine, serum vitamin B12 and homocysteine were measured at the phase of hospitalization. Normal value of serum vitamin B12 was 187 - 1 059 ng/L and normal value of serum homocysteine was 5 - 15μ mol/L. All patients received neuroelectrophysiological examination and 15 patients received MRI examinations of spinal cord. After final diagnosis, patients were given vitamin B12 therapy. And follow-up was performed to investigate the prognosis. MAIN OUTCOME MEASURES： （1） Levels of blood routine, serum vitamin B12 and homocysteine; （2） results of neuroelectrophysiological examination; （3） results of MRI examination of spinal cord; （4） prognosis. RESULTS： Clinical data of 21 patients and follow-up data of 20 patients were involved in the final analysis and 1 patient was lost because of living in the other province. （1） Clinical manifestations： All 21 patients had typically clinical manifestations. The original symptoms included numbness of lower and/or upper limbs （5 cases）, unstable gait （3 cases）, limb asthenia （4 cases）, limb numbness combined with light asthenia （5 cases）, limb numbness combined with unskillful activity （3 cases）, and limb numbness combined with unstable gait （1 case）. （2） Experimental results： Eight subacute combined degeneration of the spinal cord patients accompanied with mild-severe anemia and mean corpuscular volume of 13 patients were increased. Among 13 subacute combined degeneration of the spinal cord patients not administrating vitamin B12 before hospitalization, the levels of serum vitamin B12 of 2 patients were not measured but those of other patients were decreased. After vitamin B12 therapy,the levels of serum vitamin B12 of 8 patients were normal or increased. In addition, the levels of serum homocysteine of 6 patients were not measured but those of 7 patients were increased. While, the levels of homocysteine of 5 following-up patients were normal. The levels of serum vitamin B12 of 8 patients who received with vitamin B12 therapy before hospitalization were normal or increased. Among them,the levels of bomocysteine were not measured in 4 patients, those of 3 patients were increased, and that of 1 patient was normal. （3） Results of neuroelectrophysiological examination： Among all patients, 95% （20/21） patients had abnormal sensory-evoked potential, 89% （8/9） patients had abnormal motor evoked potential, 67% （10/15） patients had abnormal nerve conduction, 13% （2/15） patients had neurogenic muscle injury showed by electromyography （EMG）, 70% （7/10） patients had abnormal brain-stem auditory evoked potential, and 40% （4/10） patients had abnormal visual evoked potential. （4） Results of MRI examination of spinal cord： MRI examination demonstrated that 40% （6/15） patients had spinal cord lesion, but spinal cord lesion disappeared in 2 patients during follow up. In addition, clinical manifestations of patients were improved after standard vitamin B I2 therapy. CONCLUSION： Nervous system lesion caused by vitamin B 12 deficiency is not only involved in spinal cord, also in peripheral nerve, optic nerve, auditory pathway, etc. Diagnosis of the lesion depends on clinical characteristics and level of serum vitamin BI2. Especially, neuroelectrophysiological examination, measurement of homocysteine and MRI examination of spinal cord are beneficial for diagnosis and evaluation of therapeutic effects.

Lower folate levels in gastric cancer:Is it a cause or a result?

Folate deficiency and its association with cancer have been studied in the literature, but its clinical impact is still unknown. Folate deficiency and its result on gastric cancer is a mysterious part of oncology, with ongoing studies hopefully clarifying its impact on gastric cancer management. Lee et al studied folate deficiency and its impact on staging and clinical results. Here we try to contribute to the field by expressing our own thoughts about the paper.

Biermer Disease in an Unusual Neurological Presentation without Anemia: A Case Report

Background: Biermer disease is a megaloblastic disease caused by vitamin B12 deficiency. It is a rare clinical entity especially in subsahara Africa. Case presentation: We report the case of a 45 years old female patient who consulted for a one month history of generalised muscle cramps, weakness and numbness of all four limbs. Physical examination was relevant for a poor gait, poor coordination of both upper and lower limbs, a positive Romberg sign, normal muscle tone in all four limbs, reduced pallesthesia and deep tendon reflexes, abolished plantar reflexes. Paraclinical investigations revealed macrocytosis without anemia, a low cyanocobalamin (vitamin B12) level with a normal folic acid level, an atrophic corporeofundic mucosa which upon pathological analysis revealed a chronic atrophic gastritis with no Helicobacter pylori infection. Anti-intrinsic factor antibodies were positive while anti parietal cells antibodies were negative. The diagnosis of Biermer disease was considered and the patient did well on vitamin B12 supplementation. Conclusion: Though a rare disease, Biermer disease should be considered in a patient who consults for polyneuropathy even in the absence of anemia.