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Background

Older people have a high risk of vitamin B12 deficiency; this can lead to varying degrees of cognitive and neurological impairment. CBL deficiency may present as macrocytic anemia, subacute combined degeneration of the spinal cord, or as neuropathy, but is often asymptomatic in older people. Less is known about subclinical vitamin B12 deficiency and concurrent neuroconduction and cognitive impairment. A Programme of Complementary Feeding for the Older Population (PACAM) in Chile delivers 2 complementary fortified foods that provide approximately 1.4 μg/day of vitamin B12 (2.4 μg/day elderly RDA). The aim of the present study is to assess whether supplementation with vitamin B12 will improve neuroconduction and cognitive function in older people who have biochemical evidence of vitamin B12 insufficiency in the absence of clinical deficiency.

Methods

We designed a cluster double-blind placebo-controlled trial involving community dwelling people aged 70-79 living in Santiago, Chile. We randomized 15 clusters (health centers) involving 300 people (20 per cluster). Each cluster will be randomly assigned to one of three arms: a) a 1 mg vitamin B12 pill taken daily and a routine PACAM food; b) a placebo pill and the milk-PACAM food fortified to provide 1 mg of vitamin B12; c) the routine PACAM food and a placebo pill.

The study has been designed as an 18 month follow up period. The primary outcomes assessed at baseline, 4, 9 and 18 months will be: serum levels of vitamin B12, neuroconduction and cognitive function.

Conclusions

In view of the high prevalence of vitamin B12 deficiency in later life, the present study has potential public health interest because since it will measure the impact of the existing program of complementary feeding as compared to two options that provide higher vitamin B12 intakes that might potentially may contribute in preserving neurophysiologic and cognitive function and thus improve quality of life for older people in Chile.

Trial registration

ISRCTN: ISRCTN02694183

The neuropsychiatric states of 50 patients with vitamin B12 deficiency and 34 patients with folate deficiency presenting with megaloblastosis in a general hospital were examined and compared. Abnormalities of the nervous system were found in two-thirds of both groups. Peripheral neuropathy was the most common condition associated with vitamin B12 deficiency and affective disorder with folate deficiency. The proportions of patients with organic mental change were similar in the two groups. Subacute combined degeneration of the cord was an uncommon complication and occurred only in the patients with vitamin B12 deficiency. There was no relation between haematological and neuropsychiatric abnormalities. The neuropsychiatry of megaloblastic anaemia seen in this study of patients presenting to haematologists or general physicians contrasts with that reported previously, before haematological techniques for separating the two deficiencies were introduced.

Background

Pernicious anaemia is undeniably associated with vitamin B12 deficiency, but the association between subnormal vitamin B12 concentrations and anaemia in older people is unclear. The aim of this systematic review was to evaluate the association between subnormal vitamin B12 concentrations and anaemia in older people.

Methods

Clinical queries for aetiology and treatment in bibliographic databases (PubMed [01/1949-10/2009]; EMBASE [01/1980-10/2009]) were used. Reference lists were checked for additional relevant studies. Observational studies (≥50 participants) and randomized placebo-controlled intervention trials (RCTs) were considered.

Results

25 studies met the inclusion criteria. Twenty-one observational cross-sectional studies (total number of participants n = 16185) showed inconsistent results. In one longitudinal observational study, low vitamin B12 concentrations were not associated with an increased risk of anaemia (total n = 423). The 3 RCTs (total n = 210) were well-designed and showed no effect of vitamin B12 supplementation on haemoglobin concentrations during follow-up in subjects with subnormal vitamin B12 concentrations at the start of the study. Due to large clinical and methodological heterogeneity, statistical pooling of data was not performed.

Conclusions

Evidence of a positive association between a subnormal serum vitamin B12 concentration and anaemia in older people is limited and inconclusive. Further well-designed studies are needed to determine whether subnormal vitamin B12 is a risk factor for anaemia in older people.

Aims: To evaluate the effects of vitamin E supplementation on haemoglobin concentration and the requirement for transfusion in premature infants treated with erythropoietin and iron.

Methods: Randomised, double blind, placebo controlled trial. Thirty infants ≤32 weeks gestation and ≤1250 g birth weight, who were defined as stable based on minimal requirements for respiratory support and phlebotomy, and absence of major congenital anomalies were enrolled. All were treated with erythropoietin and iron, and were randomised to receive, in addition, either vitamin E 50 IU/day or placebo for eight weeks or until discharge, whichever came first.

Results: Despite higher vitamin E (α-tocopherol) levels in the experimental group in weeks 3 (49.0 v 28.1 µmol/l) and 8 (66.2 v 38.5 µmol/l), there were no differences in haemoglobin, reticulocyte count, iron concentration, or transfusion requirement.

Conclusions: Oral vitamin E supplementation at 50 IU/day does not increase the response of preterm infants to erythropoietin and iron. Vitamin E obtained through standard nutrition may have been sufficient or higher doses may be required.

Folic acid deficiency with the picture of a megaloblastic bone marrow may develop in haemolytic anaemia, and, on the other hand, both vitamin B12 and folic acid deficiency may produce signs of haemolysis. As the correct interpretation of a positive antiglobulin reaction associated with megaloblastic erythropoiesis is particularly important, the effect of deficiency of vitamin B12 and folic acid on the results of the test was investigated in 32 patients with vitamin B12 or folic acid deficiency and a positive antiglobulin reaction was obtained in ten. There was no correlation between the result of the test and the degree of anaemia, and there was no significant difference between the incidence of positive results associated with deficiency of vitamin B12 or folic acid. In determining the significance of a positive result, the time interval before agglutination occurs is sometimes of greater value than the strength of the reaction or the result of the gamma globulin neutralization test.

The thiamine transporter gene SLC19A2 was recently found to be mutated in thiamine responsive megaloblastic anaemia with diabetes and deafness (TRMA, Rogers syndrome), an early onset autosomal recessive disorder. We now report a novel G1074A transition mutation in exon 4 of the SLC19A2 gene, predicting a Trp358 to ter change, in a girl with consanguineous parents. In addition to the typical triad of Rogers syndrome, the girl presented with short stature, hepatosplenomegaly, retinal degeneration, and a brain MRI lesion. Both muscle and skin biopsies were obtained before high dose thiamine supplementation. While no mitochondrial abnormalities were seen on morphological examination of muscle, biochemical analysis showed a severe deficiency of pyruvate dehydrogenase and complex I of the respiratory chain. In the patient's fibroblasts, the supplementation with high doses of thiamine resulted in restoration of complex I activity. In conclusion, we provide evidence that thiamine deficiency affects complex I activity. The clinical features of TRMA, resembling in part those found in typical mitochondrial disorders with complex I deficiency, may be caused by a secondary defect in mitochondrial energy production.


Keywords: TRMA syndrome; SLC19A2 gene; complex I deficiency

Platelet monoamine oxidase activity has been measured in 17 patients with megaloblastic anaemia due to either vitamin B12 or folate deficiency, and in 20 healthy subjects. There was a highly significant increase in patients compared with controls. In two patients, platelet activity decreased following successful treatment. A significant correlation between platelet activity and the severity of bone marrow megaloblastic change, assessed by the deoxyuridine suppression test and bone marrow morphology, was also observed. If the change in activity also occurs in the nervous system, this may contribute to the mental disturbance associated with vitamin B12 or folate deficiency.

Generalized skin pigmentation in five African women with megaloblastic anaemia in the postnatal period was associated with low serum folate levels, as distinct from vitamin B12 deficiency. It is suggested that the occurrence of pigmentation in both folate and vitamin B12 deficiency may reflect a common abnormality of metabolism.

Images

Two elderly patients with vitamin B12 deficiency were found to have low immunoglobulin levels. These returned to normal on treatment with vitamin B12.

Very few cases of acquired severe copper deficiency have been described. The principal effects are haematological, but the precise abnormalities are uncertain due to the possible association of other deficiencies. A case of isolated severe copper deficiency associated with late onset hypogammaglobulinaemia is reported in which the chief findings were macrocytic anaemia, neutropenia and a decrease in mean platelet volume. All these abnormalities resolved when copper therapy was instituted and recurred when the medication was stopped.

Raised plasma lactate dehydrogenase (LDH) values were found in 26 patients with marked megaloblastic anaemia due either to vitamin B12 or folic-acid deficiency or a combination of these factors.

Minor megaloblastic changes were not usually accompanied by plasma LDH elevation. Serial LDH estimations were as valuable as serial reticulocyte counts in assessing the response to physiological doses of folic acid and therefore in deciding whether megaloblastic anaemia is partially or completely due to folic acid deficiency.

Purpose of study

This study was conducted to study the clinical and laboratory parameters in patients with macrocytic anemia and to determine the etiology of macrocytic anemia with special reference to megaloblastic anemia.

Materials and methods

This study was a cross-sectional descriptive study carried over a period of 18 months on 60 adult patients (age ≥13 years) of macrocytic anemia. Macrocytic anemia was identified when peripheral blood examination showed anemia with a mean red blood corpuscular volume of >95 fl.

Result

The most common cause of macrocytic anemia was megaloblastic anemia (38.4%). The major causes of nonmegaloblastic macrocytic anemia were primary bone marrow disorders (35%), liver diseases (15%) and hemolytic anemia (8.3%). There was a significant male preponderance in the study (65%). The megaloblastic anemias observed were due to either vitamin B12 deficiency (78.3%) or combined B12 and folate deficiency (21.7%). A significant proportion of non-vegetarians (73.9%) had megaloblastic anemia. Patients with an MCV of >110fl were more likely to have megaloblastic anemia (p value 0.0007). Three patients (mean age 55 years) with a megaloblastic marrow did not respond to vitamin replacement and were found to have myelodysplastic syndrome.

Conclusion

Megaloblastic anemia due to Vitamin B12 or folate deficiency remains the most important cause of macrocytic anemia. In settings with limited laboratory facilities, a therapeutic trial of vitamins B12 or folic acid is useful in determining the specific vitamin deficiency.

Urinary amino-acid chromatograms from 23 patients with megaloblastic anaemia have been studied before and after therapy. The most consistent abnormality was an increased taurine or increased taurine/glycine ratio. This was not related directly to deficiency of vitamin B12 or folic acid or to the degree of anaemia.

Ten patients with severe megaloblastic anaemia were studied to investigate whether the causative metabolic defects might predispose them to lactic or other acidosis. One patient had compensated acidosis with hyperlactataemia before treatment but there were obvious causes other than anaemia. No other patient developed an acidosis. Neither anaemia per se nor the metabolic defects of vitamin B12 or folic acid deficiency are likely to cause clinically significant lactic acidosis or hyperlactataemia.

Patients with cystic fibrosis tend to have reduced serum concentrations of vitamin E and are therefore at risk of developing the neurological complications associated with vitamin E deficiency. Improved survival in cystic fibrosis has resulted in an increasing number of older patients who may develop hepatobiliary complications which may further impair the absorption of vitamin E. In this study the vitamin E status and results of supplementation with oral vitamin E were compared in adult patients with and without evidence of liver involvement as assessed by routine liver function tests. The serum vitamin E concentrations were reduced below normal in 24 of 25 patients. The mean serum vitamin E concentration was significantly lower (p less than 0.05) in those patients with abnormal liver function. When vitamin E status was assessed as the serum vitamin E/cholesterol ratio, however, there was no significant difference between those patients with normal and abnormal liver function. After supplementation with oral vitamin E, either 10 mg/kg/day for one month or 200 mg/day (equivalent to 3.4 to 4.4 mg/kg/day) for up to three months, there was no significant difference in the vitamin E status between the two groups. The results of this study indicate that in general, patients with cystic fibrosis and abnormal liver function do not require increased supplements of vitamin E compared with those with normal liver function.

The greatest cause of fracture in older people is osteoporosis which contributes to increased morbidity and mortality in older people. A number of meta-analyses have been performed assessing the effectiveness of calcium supplementation alone, vitamin D supplementation alone and the combined therapy on bone loss and fracture reduction in older people. The results of these meta-analyses indicate that vitamin D supplementation alone is unlikely to reduce fracture risk, calcium supplementation alone has a modest effect in reducing total fracture risk, but compliance with calcium supplements is poor in the long term. The combination of calcium supplementation with vitamin D supplementation, particularly in those at risk of marginal and low vitamin D status reduces total fractures, including hip fractures. Therefore older people would be recommended to consume adequate dietary calcium (>1100 mg/day) together with maintaining adequate vitamin D status (>60 nmol/L 25(OH)D) to reduce risk of fracture. It is a challenge to consume sufficient dietary calcium from dietary sources, but the increasing range of calcium fortified foods could assist in increasing the dietary calcium intake of older people. In addition to the usual dairy based food sources, vitamin D supplements are likely to be required for older people with reduced mobility and access to sunlight.

Objectives:

Vitamin K has bone and cartilage effects, and previously shown to be associated with radiographic osteoarthritis. We evaluated vitamin K's effect on hand osteoarthritis in a randomised controlled trial.

Methods:

This was an ancillary study to a randomised controlled trial assessing the effects of phylloquinone supplementation (vitamin K arm) versus placebo on bone loss and vascular calcification among older adults regardless of their vitamin K status. At the final 3-year study visit, we assessed the effects of vitamin K versus placebo on hand x-ray features of osteoarthritis using logistic regression and intention to treat, and also restricted analysis to the subgroup that had insufficient vitamin K concentrations at baseline.

Results:

This ancillary study had 378 participants (193 in vitamin K arm, 185 in placebo arm). There were no effects of randomisation to vitamin K for radiographic osteoarthritis outcomes. Those with insufficient vitamin K at baseline who attained sufficient concentrations at follow-up had trends towards 47% less joint space narrowing (p = 0.02).

Conclusions:

There was no overall effect of vitamin K on radiographic hand osteoarthritis. Subjects that were insufficient in vitamin K at baseline who attained sufficient concentrations at follow-up may have had a benefit in joint space narrowing. A clinical trial in those who are vitamin K insufficient may be warranted.

Trial registration number:

NCT00183001.

Introduction

Subacute combined degeneration of the spinal cord is a rare cause of demyelination of the dorsal and lateral columns of the spinal cord and is a neurological complication of vitamin B12 deficiency. Subacute combined degeneration without anemia or macrocytosis is rare.

Case presentation

We present a case of cobalamin deficiency in a 29-year-old Moroccan woman who presented with subacute combined degeneration without evidence of anemia or macrocytosis. Magnetic resonance imaging of the spinal cord demonstrated abnormal hyperintense signal changes on T2-weighted imaging of the posterior and lateral columns from the medulla oblongata to the thoracic spine. A diagnosis of subacute combined degeneration of the spinal cord was considered and confirmed by low serum cobalamin. The patient was treated with vitamin B12 supplements and showed improvement in her clinical symptoms.

Conclusion

Physicians should diagnose subacute combined degeneration in patients early by having a high index of suspicion and using diagnostic tools such as magnetic resonance imaging.

Vitamin D3, or cholecalciferol, is the naturally occurring form of vitamin D that is converted in the skin and hydroxylated in the liver and kidney to the active form found in humans. The main role for vitamin D is calcium homeostasis, and low levels of vitamin D result in lower gastrointestinal absorption of calcium. Vitamin D is also critical for mineralization of bone tissue, muscle function, and coordination. Recent studies have found prevention of bone mass loss and reduction in falls and fractures in patients supplemented with vitamin D. A high percentage of systemic lupus erythematosus patients are reported to have insufficient or deficient levels of vitamin D. This paper reviews the biology of vitamin D, its role in calcium homeostasis, and how it contributes to the maintenance of bone, muscle, and joint function in older adults and individuals with systemic lupus erythematosus.

The incidence of megaloblastic anaemia in pregnancy and the puerperium in north Staffordshire has steadily declined as a result of prophylaxis with folic acid. In the presence of advanced folic acid deficiency and with a florid megaloblastic marrow, the anaemia is usually severe, but in many patients the disease is relatively mild and the degree of anaemia is determined more by blood loss or associated iron deficiency than by the megaloblastosis.

Microscopic examination of marrow films is still the most reliable method of diagnosis, although estimation of the labile serum folate has produced a 95% correlation with the marrow findings.

There are three main factors which operate in the pathogenesis of megaloblastic anaemia in pregnancy and the puerperium. First, the maternal stores of folic acid are used up by the growing foetus, and this process is accelerated in multiple pregnancies, after haemorrhage, or in women with haemolytic anaemia. Secondly, an insufficient intake of folic acid, due to poor diet in pregnancy, plays a part in many cases. The third, and possibly the most important, factor is an absorption defect. Folic acid absorption is usually impaired in established cases, and this can still be demonstrated years later in a majority of patients, when they are neither pregnant nor anaemic. More than 20% of all cases also show abnormal fat absorption.

An inherited defect in folic acid absorption may also explain why certain women appear to be constitutionally predisposed to megaloblastic anaemia of pregnancy and the puerperium, as shown by the abnormal blood group distribution in these patients and by the tendency of megaloblastic anaemia to recur not only in subsequent pregnancies, but, as in six of our cases, following other kinds of stress.

The significance of commonly associated conditions like pre-eclampsia and infection is still incompletely understood. Although the treatment of megaloblastic anaemia is simple and effective, the main emphasis should be placed on prophylaxis by administering folic acid to all pregnant women.

A 27-year-old housewife suffered from severe headaches for a period of 2 years which developed after she started taking an oral contraceptive pill. During this time she gradually developed folic acid deficiency anaemia. This resulted from the inhibition by ‘the pill’ of the intestinal conjugase system required to deconjugate polyglutamic folate. The patient's headache did not recur after stopping the pill and her anaemia improved with folic acid supplement. The relation between folic acid metabolism and ‘the pill’ is discussed.

Background

There are many studies that associate vitamin D serum levels in older persons with muscle strength, physical performance and risk of fractures and falls. However, current evidence is insufficient to make a general recommendation for administrating calcium and vitamin D to older persons. The objective of this study is to determine the effectiveness of calcium and vitamin D supplementation in improving musculoskeletal function and decreasing the number of falls in person aged over 65 years.

Methods/Design

Phase III, randomized, double blind, placebo-controlled trial to evaluate the efficacy of already marketed drugs in a new indication. It will be performed at Primary Care doctor visits at several Healthcare Centers in different Spanish Health Areas. A total of 704 non-institutionalized subjects aged 65 years or older will be studied (sample size calculated for a statistical power of 80%, alpha error 0.05, annual incidence of falls 30% and expected reduction of 30% to 20% and expected loss to follow up of 20%). The test drug containing 800 IU of vitamin D and 1000 mg of calcium will be administered daily. The control group will receive a placebo. The subjects will be followed up over two years. The primary variable will be the incidence of spontaneous falls. The secondary variables will include: consequences of the falls (fractures, need for hospitalization), change in calcidiol plasma levels and other analytical determinations (transaminases, PTH, calcium/phosphorous, albumin, creatinine, etc.), change in bone mass by densitometry, change in muscle strength in the dominant hand and change in musculoskeletal strength, risk factors for falls, treatment compliance, adverse effects and socio-demographic data.

Discussion

The following principles have been considered in the development of this Project: the product data are sufficient to ensure that the risks assumed by the study participants are acceptable, the study objectives will probably provide further knowledge on the problem studied and the available information justifies the performance of the study and its possible risk for the participants.

If calcium and vitamin D supplementation is effective in the prevention of falls and fractures in the elderly population, a recommendation may be issued with the aim of preventing some of the consequences of falls that affect quality of life and the ensuing personal, health and social costs.

Trial Registration

ClinicalTrials.gov: NCT01452243

Clinical trial authorized by the Spanish Medicines Agency: EudraCT number 2006-001643-63.

Thiamine-responsive megaloblastic anaemia (TRMA; OMIM 249270) syndrome is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anaemia, and sensorineural deafness. Progressive hearing loss is one of the cardinal findings of the syndrome and is known to be irreversible. Whether the deafness in TRMA syndrome can be prevented is not yet known. Here, we report a four-month-old female infant diagnosed with TRMA syndrome at an early age. There was no hearing loss at the time of diagnosis. The patient’s initial auditory evoked brainstem response measurements were normal. Although she was given thiamine supplementation regularly following the diagnosis, the patient developed moderate sensorineural hearing loss at 20 months of age, indicating that early diagnosis and treatment with oral thiamine (100 mg/day) could not prevent deafness in TRMA syndrome. It would be premature to draw general conclusions from one case, but we believe that further patient-based observations can shed light on the pathophysiology of this rare syndrome as well as prediction of its prognosis.

Conflict of interest:None declared.