Acute nutritional axonal neuropathy.

INTRODUCTION: This study describes clinical, laboratory, and electrodiagnostic features of a severe acute axonal polyneuropathy common to patients with acute nutritional deficiency in the setting of alcoholism, bariatric surgery (BS), or anorexia. METHODS: Retrospective analysis of clinical, electrodiagnostic, and laboratory data of patients with acute axonal neuropathy. RESULTS: Thirteen patients were identified with a severe, painful, sensory or sensorimotor axonal polyneuropathy that developed over 2-12 weeks with sensory ataxia, areflexia, variable muscle weakness, poor nutritional status, and weight loss, often with prolonged vomiting and normal cerebrospinal fluid protein. Vitamin B6 was low in half and thiamine was low in all patients when obtained before supplementation. Patients improved with weight gain and vitamin supplementation, with motor greater than sensory recovery. DISCUSSION: We suggest that acute or subacute axonal neuropathy in patients with weight loss or vomiting associated with alcohol abuse, BS, or dietary deficiency is one syndrome, caused by micronutrient deficiencies. Muscle Nerve 57: 33-39, 2018.

Sugar and chromosome stability: clastogenic effects of sugars in vitamin B6-deficient cells.

Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, has been implicated in preventing human pathologies, such as diabetes and cancer. However, the mechanisms underlying the beneficial effects of PLP are still unclear. Using Drosophila as a model system, we show that PLP deficiency, caused either by mutations in the pyridoxal kinase-coding gene (dPdxk) or by vitamin B6 antagonists, results in chromosome aberrations (CABs). The CAB frequency in PLP-depleted cells was strongly enhanced by sucrose, glucose or fructose treatments, and dPdxk mutant cells consistently displayed higher glucose contents than their wild type counterparts, an effect that is at least in part a consequence of an acquired insulin resistance. Together, our results indicate that a high intracellular level of glucose has a dramatic clastogenic effect if combined with PLP deficiency. This is likely due to an elevated level of Advanced Glycation End-products (AGE) formation. Treatment of dPdxk mutant cells with α-lipoic acid (ALA) lowered both AGE formation and CAB frequency, suggesting a possible AGE-CAB cause-effect relationship. The clastogenic effect of glucose in PLP-depleted cells is evolutionarily conserved. RNAi-mediated silencing of PDXK in human cells or treatments with PLP inhibitors resulted in chromosome breakage, which was potentiated by glucose and reduced by ALA. These results suggest that patients with concomitant hyperglycemia and vitamin B6 deficiency may suffer chromosome damage. This might impact cancer risk, as CABs are a well-known tumorigenic factor.

Sphingosine 1-phosphate lyase inhibition by 2-acetyl-4-(tetrahydroxybutyl)imidazole (THI) under conditions of vitamin B6 deficiency.

Caramel food colorant 2-acetyl-4-(tetrahydroxybutyl)imidazole (THI) causes lymphopenia in animals through sphingosine 1-phosphate lyase (SPL) inhibition. However, this mechanism of action is partly still controversial because THI did not inhibit SPL in vitro either in cell-free or in cell-based systems. It is thought that the in vitro experimental conditions which have been used so far were not suitable for the evaluation of SPL inhibition, especially in case of cell-based experiments. We speculated that the key factor might be the coenzyme pyridoxal 5'-phosphate (PLP), an active form of vitamin B6 (VB6), because media used in cell-based assays usually contain an excess amount of VB6 which leads to the activation of SPL. By the use of VB6-deficient culture medium, we could regulate apo- (without PLP) and holo- (with PLP) SPL enzyme in cultured cells, resulting in the successful detection of SPL inhibition by THI. Although the observed inhibitory effect was not as strong as that of 4-deoxypyridoxine (a VB6 analog SPL inhibitor), these findings may be useful for further understanding the mechanism of action of THI.

Mechanisms of the beneficial effects of vitamin B6 and pyridoxal 5-phosphate on cardiac performance in ischemic heart disease.

Although vitamin B6 and its metabolite, pyridoxal 5'-phosphate (PLP), have been shown to exert beneficial effects in ischemic heart disease, the mechanisms of their action are not fully understood. Some studies have shown that ventricular arrhythmias and mortality upon the occlusion of coronary artery were attenuated by pretreatment of animals with PLP. Furthermore, ischemia-reperfusion-induced abnormalities in cardiac performance and defects in sarcoplasmic reticular Ca2+-transport activities were decreased by PLP. The increase in cardiac contractile activity of isolated heart by ATP was reduced by PLP, unlike propranolol, whereas that by isoproterenol was not depressed by PLP. ATP-induced increase in [Ca2+]i, unlike KCl-induced increase in [Ca2+]i in cardiomyocytes was depressed by PLP. Both high- and low-affinity sites for ATP binding in sarcolemmal membranes were also decreased by PLP. These observations support the view that PLP may produce cardioprotective effects in ischemic heart disease by attenuating the occurrence of intracellular Ca2+ overload due to the blockade of purinergic receptors.

Effect of vitamin B6 deficiency on glyoxylate metabolism in rats with or without glyoxylate overload.

We examined the effect of vitamin B6 deficiency on glyoxylate metabolism and hepatic alanine: glyoxylate aminotransferase (AGT) activity in rats with normal or high glyoxylate intake. Male rats were divided into four groups: a control group, a vitamin B6-free diet group, a glyoxylate water group, and a vitamin B6-free diet + glyoxylate water group. Each group was given special diet (control or vitamin B6-deficient diet) and drinking water (plain or 0.5% glyoxylate water) for 4 weeks, after which biochemical parameters and hepatic AGT mRNA level were measured. Compared with control rats, the urinary oxalate/creatinine ratio was higher in each of the other 3 groups. The urinary glycolate/creatinine ratio was also higher in the vitamin B6-free diet group and the vitamin B6-free diet + glyoxylate water group than the control group, while the urinary glycine/creatinine and citrate/creatinine ratio was lower in both groups. The hepatic AGT mRNA level was reduced in the vitamin B6-free diet group, but was increased in the glyoxylate water group than the control group. These results suggest that vitamin B6 is necessary for glyoxylate metabolism as a coenzyme of AGT. Especially in the presence of a high glyoxylate intake, vitamin B6 deficiency leads to severe hyperoxaluria and hypocituria.

Electrocardiographic changes in vitamin B6 deficient rats.

Serial electrocardiograms of vitamin B6 deficient rats show significant changes from those of rats on a complete diet. Animals fed a totally deficient diet from weaning grow slowly and die after about 12 weeks, often with a terminal weight loss. R and T amplitudes increase, then terminally decrease and are significantly greater than those of control animals. The PR interval is significantly shorter at times. Individuals have shown transient AV block, irregular sinus rhythm, wandering pacemaker, and inverted T waves. Autopsy findings include hypertrophy (89%), dilatation (61%) and atrial thrombi (44%). ECG's of adult animals remained normal for about three months after being fed the deficient diet. The two males developed premature ventricular contractions of several ectopic foci. Finally, split QRS complexes were observed. The female had a normal ECG until the final record at 234 days when some minor changes were seen. Extensive cardiomyopathic changes were found in two out of the three adults at autopsy.

Effects of maternal vitamin B6 deficiency and over-supplementation on DNA damage and oxidative stress in rat dams and their offspring.

Vitamin B6 is a cofactor for more than 140 essential enzymes and plays an important role in maternal health and fetal development. The goal of this study was to investigate the effects of maternal vitamin B6 on DNA damage and oxidative stress status in rat dams and their offspring. Female Wistar rats were randomly assigned to three dietary groups fed a standard diet (control diet), a diet supplemented with 30 mg/kg of vitamin B6, or a deficient diet (0 mg/kg of vitamin B6) for 10 weeks before and during mating, pregnancy and lactation. The dams were euthanized at weaning, and their male pups were euthanized either 10 days or 100 days after birth. We found that maternal vitamin B6 deficiency increased the micronucleus frequency in peripheral blood and bone marrow cells and also increased the concentration of hepatic TBARS (thiobarbituric acid reactive substances) in newborn pups (10 days old). In conclusion, maternal 5- to 6-fold over-supplementation of vitamin B6 had no adverse effects, however its deficiency may induce chromosomal damage and hepatic lipid peroxidation in the offspring.

Oral exposure to the anti-pyridoxine compound 1-amino D-proline further perturbs homocysteine metabolism through the transsulfuration pathway in moderately vitamin B6 deficient rats.

Pyridoxal 5'-phosphate (PLP; a B6 vitamer) serves as an important cofactor in a myriad of metabolic reactions, including the transsulfuration (TS) pathway, which converts homocysteine (Hcy) to cysteine. While overt vitamin B6 deficiency is rare, moderate deficiency is common and may be exacerbated by anti-pyridoxine factors in the food supply. To this end, we developed a model of moderate B6 deficiency and a study was conducted to examine the in vivo effect of 1-amino D-proline (1ADP), an anti-pyridoxine factor found in flaxseed, on indices of Hcy metabolism through the TS pathway in moderately B6 deficient rats. Male weaning rats received a semi-purified diet containing either 7 mg/kg (control; CD) or 0.7 mg/kg (moderately deficient; MD) diet of pyridoxine·hydrochloride (PN∙HCl), each with 1 of 4 levels of 1ADP, viz. 0, 0.1, 1 and 10 mg/kg diet for 5 weeks. Perturbations in vitamin B6 biomarkers were more pronounced in the MD group. Plasma PLP was significantly reduced, while plasma Hcy (8-fold) and cystathionine (11-fold) were increased in rats consuming the highest amount of 1ADP in the MD group. The activities of hepatic cystathionine ß-synthase and cystathionine γ-lyase enzymes were significantly reduced in rats consuming the highest 1ADP compared to the lowest, for both levels of PN∙HCl. Dilation of hepatic central veins and sinusoids, mild steatosis and increased liver triglycerides were present in MD rats consuming the highest 1ADP level. The current data provide evidence that the consumption of an anti-pyridoxine factor linked to flaxseed may pose a risk for subjects who are moderate/severe vitamin B6 deficient.

Electroencephalographic changes and periodontal status during short-term vitamin B-6 depletion of young, nonpregnant women.

As part of a larger investigation to determine the effect of animal vs. plant proteins on the vitamin B-6 requirement of young women, clinical changes during vitamin B-6 depletion were documented. Eight healthy young women were confined to a metabolic unit and fed a defined formula diet nearly devoid of vitamin B-6 (less than 0.05 mg/d). Serial electroencephalographic (EEG) tracings, peripheral nervous system tests, periodontal evaluations, and biochemical measures of vitamin B-6 status were conducted. Within 12 d on the depletion diet, two of the eight women exhibited abnormal EEG tracings. These changes were readily reversed by repletion of vitamin B-6 at the 0.5-mg/d level. Biochemical measures reflected lowered vitamin B-6 status but were not predictive of the onset of EEG changes. No detectable alterations in oral or periodontal status were found, nor did plaque flora change markedly. This study is the first report of EEG changes occurring in women undergoing vitamin B-6 depletion and the first report to document EEG changes in adults within 12 d on a vitamin B-6-depletion regimen.

Brain cell alterations suggesting premature aging induced by dietary deficiency of vitamin B6 and/or copper.

Weanling albino rats were fed semisynthetic diets deficient or sufficient in vitamin B6 or copper, or both, for 2 or 3 months. Brains were examined by light and electron microscopy after Golgi impregnation or conventional tissue processing for electron microscopy. Golgi impregnation revealed that some pyramidal cells of the cerebral cortex, particularly in layers III and V, showed partial to nearly complete dendritic loss. This occurred in all deficient groups but was most typical of deficiency of vitamin B6. Swelling in dendrites or perikarya was more typical of copper deficiency. Ultrastructural observation revealed large vacuoles in cellular processes of the cerebral cortex in deficient groups. The hippocampus of copper-deficient rats contained dark, apparently degenerating processes while axonal swellings were seen in vitamin B6 deficiency. These abnormalities are discussed as evidence for accelerated aging of neurons related to poor nutritional status.

Vitamin B-6 deficiency and renal function and structure in chronically uremic rats.

In preliminary studies, rats with chronic renal failure (CRF) demonstrated worsening renal function, as measured by urea clearance, when fed vitamin B-6-deficient diets. However, urea clearance is not a precise measure of glomerular filtration rate (GFR) and these studies did not indicate the mechanism for the reduced GFR. To measure renal function more precisely and to assess whether B-6 deficiency augments renal injury, we examined [14C]inulin clearance, urine oxalate excretion, and renal histopathology in rats with CRF pair fed to receive a pyridoxine-replete or -deficient diet for 3 or 6 wk. After 3 or 6 wk, pyridoxine-deficient rats had significantly lower [14C]inulin clearances and increased urine oxalate excretion. Histological evaluation indicated increased renal damage in kidneys from pyridoxine-deficient rats as compared with tissue from pyridoxine-replete rats. These findings suggest that in rats with CRF, vitamin B-6 deficiency reduces the GFR and increases renal scarring.

Pyridoxine deficiency affects biomechanical properties of chick tibial bone.

The mechanical integrity of bone is dependent on the bone matrix, which is believed to account for the plastic deformation of the tissue, and the mineral, which is believed to account for the elastic deformation. The validity of this model is shown in this study based on analysis of the bones of vitamin B6-deficient and vitamin B6-replete chick bones. In this model, when B6-deficient and control animals are compared, vitamin B6 deficiency has no effect on the mineral content or composition of cortical bone as measured by ash weight (63 +/- 6 vs. 58 +/- 3); mineral to matrix ratio of the FTIR spectra (4.2 +/- 0.6 vs. 4.5 +/- 0.2), line-broadening analyses of the X-ray diffraction 002 peak (beta 002 = 0.50 +/- 0.1 vs. 0.49 +/- 0.01), or other features of the infrared spectra. In contrast, collagen was significantly more extractable from vitamin B6-deficient chick bones (20 +/- 2% of total hydroxyproline extracted vs. 10 +/- 3% p < or = 0.001). The B6-deficient bones also contained an increased amount of the reducible cross-links DHLNL, dehydro-dihydroxylysinonorleucine, (1.03 +/- 0.07 vs. 0.84 +/- 0.13 p < or = 0.001); and a nonsignificant increase in HLNL, dehydro-hydroxylysinonorleucine, (0.51 +/- 0.03 vs. 0.43 +/- 0.03, p < or = 0.10). There were no significant changes in bone length, bone diameter, or area moment of inertia. In four-point bending, no significant changes in elastic modulus, stiffness, offset yield deflection, or fracture deflection were detected. However, fracture load in the B6-deficient animals was decreased from 203 +/- 35 MPa to 151 +/- 23 MPa, p < or = 0.01, and offset yield load was decreased from 165 +/- 9 MPa to 125 +/- 14 MPa, p < or = 0.05. Since earlier histomorphometric studies had demonstrated that the B6-deficient bones were osteopenic, these data suggest that although proper cortical bone mineralization occurred, the alterations of the collagen resulted in changes to bone mechanical performance.

Neuronal development in vitamin B6 deficiency.

The morphological changes observed in developing brain regions associated with maternal vitamin B6 deficits are summarized in Table 4. Brain development is a complex and orderly process consisting of cell division, proliferation, migration, and maturation. In the rat, vitamin B6 deficits imposed in utero and up to 30 days postnatal interfere with this orderly process. Deficits of the vitamin imposed in utero have been associated with reduced numbers of total and normal neurons in neocortex and with increased shrunken neurons (700-1500% of controls) in this region. These changes reflect the critical role of vitamin B6 in both neurogenesis and neuron longevity in neocortex. Postnatal cellular events in the neocortex, that is, neuron differentiation and synaptogenesis, were also altered by vitamin B6 deficits; higher order dendrites were reduced on stellate neurons in Layer II and on pyramidal neurons in Layer V. Synaptic density was less in the neutrophil of neocortex and in caudate/putamen, but structural integrity of the synapse was maintained. In cerebellum, both the molecular and granular areas were reduced, the monolayer organization of Purkinje cells was disrupted, and dendritic arborization of the cells was decreased. The number of myelinated axons, as determined by electron microscopy, was decreased in the mediodorsal portion of the pyramidal tract in the medulla oblongata as well as the specific activity of myelination of the total brain. Thus the functional consequences of vitamin B6 deficits during neuronal development may be through reduced connections among neurons and decreased myelination, which alter the rate and magnitude of transmission of nerve impulses.

Pathologic effects of antimetabolites on the hippocampus of diet controlled mice.

Marked histological changes are observed in the hippocampi of mice maintained on a niacin deficient diet following a single injection of 3-acetylpyridine (antimetabolite of nicatinamide). Extensive neuronal damage occurs in areas H2, H3 and to a lesser degree in the dentate gyrus. The neurons appear to be shrunken, deeply basophilic and exhibit a loss of intracellular architecture. The neuronal response in pyridoxine deficient mice treated with 4-methoxypyridoxine (antimetabolite of pyridoxine) is not remarkable.

Reaction patterns of cell organelles in vitamin B6 deficiency. Ultrastructural-morphometric analysis of the liver parenchymal cell.

Under the influence of seven weeks of vitamin B6-free nutrition, the hepatocyte single volume is diminished in the face of an unchanged nuclear single volume, posing the question of whether there is proportional atrophy of all cell organelles or single organelle atrophy with counter-regulatory hyperplasia in other cellular compartments. The nucleoli hypertrophy, as the result of segregation and protein synthesis inhibition. The rough endoplasmic reticulum experiences hypoplasia, but the ultrastructural-morphometric analysis does not determine which metabolic steps are attacked. By contrast one observes hyperplasia in the smooth endoplasmic reticulum, which may be regarded as a counter-regulatory mechanism to the choking of protein synthesis. As with the rough endoplasmic reticulum, the mitochondria also show hypoplasia. This is due to the dependency of the mitochondria upon the endoplasmic protein synthesis. The disturbed functional output of the endoplasmic reticulum is seen in the reduced number of orthoperoxisomes as well. The Golgi apparatus experiences hypoplasia as a result of B6 hypovitaminosis, and this must be considered in the context of fatty change in the liver.

Loss of decorin from the surface zone of articular cartilage in a chick model of osteoarthritis.

The objective of this study was to immunolocalize decorin and to assess changes as a result of pyridoxine (PN) deficiency in chick articular cartilage from femoral condyles. After maintenance on a normal diet for the first two weeks after hatching, 15 broiler chickens were deprived of this vitamin for 6 weeks. It was previously shown that the ankle joints of PN-deficient animals are swollen with effusions. They also present an abnormal gait, enlarged bony margins, and fissuring of the articular cartilages. Milder changes (no fissures) were also shown in the knee joints. Data from a previous study were suggestive that sulfated glycosaminoglycans are lost from the knee cartilage surface into synovial fluid. The current study was focused on the small proteoglycan, decorin, which coats the surface of collagen fibrils and may regulate their morphology. To examine decorin in normal and PN-deficient articular cartilage, a monoclonal antibody to an epitope on the protein core of decorin was used for immunohistochemical staining of tissue sections and for Western Blot analysis of cartilage extracts. Reduction of staining with the antibody was demonstrated in the tangential surface zone of PN-deficient cartilage, and Western Blot analysis showed reduced intensity of decorin bands compared to normal controls. These data suggest that a lack of decorin may play a role in the enlargement of collagen bundles in the tangential zone of PN-deficient articular cartilage as observed in a previous electron microscopic study.

Tubuloreticular structures in pyridoxine deficiency.

Electron microscopic studies on renal tissue obtained from animals subjected to pyridoxine deficiency have revealed the presence of round and/or tubular bodies in the cytoplasm of endothelial cells of the glomeruli. The bodies generally occur as aggregates in association with the endoplasmic reticulum. Along with the round forms other profiles are also observed. It is believed that they represent one of the many images of a system of undulating tubules. Since these bodies occur irrespective of the presence of virus particles in the tissue under study it is concluded that they are not viral in nature.

Effect of pyridoxine deficiency and prednisolone on beta-alanine-oxoglutarate aminotransferase and D-3-aminoisobutyrate aminotransferase in rat liver and kidney.

beta-Alanine-oxoglutarate aminotransferase (beta-Ala-TI) was found to be distributed mainly in liver, brain, kidney, and testis (decreasing order of enzyme activity in the rat). D-3-Aminoisobutyrate aminotransferase (beta-Ala-T II) was distributed in kidney and liver. Both beta-Ala-T I and beta-Ala-T II were localized in the mitochondrial fraction in rat kidney. beta-Ala-T I in the liver of rats fed on pyridoxine-deficient or control diets was induced by injecting with prednisolone, while beta-Ala-T II in the liver of these rats was unaffected by prednisolone injection. The activities of beta-Ala-T I and beta-Ala-T II in the liver of rats fed on pyridoxine deficient diet did not change. However, in kidney, pyridoxine deficiency suppressed both enzyme activities, while treatment with prednisolone did not induce either enzyme. The ratios of the apo- to holo-enzyme for beta-Ala-T I and beta-Ala-T II in control rat kidney were 1.04 and 0.11, respectively. The values increased to 2.69 and 1.53, respectively, in pyridoxine-deficient rat kidney. These experiments indicate that pyridoxine deficiency and prednisolone affect the activities of beta-alanine degrading enzymes, but that the degree is different between liver and kidney.

Effects of modifying dietary protein in the presence and absence of vitamin B6, on the regulation of plasma calcium and phosphorus levels--positive impact of yeast Saccharomyces cerevisiae.

Vitamin B6 status has been assessed according to the activation coefficient (AC) of plasma aspartic aminotransferase (AST) activity. Fast-growing male one-day-old broiler chicks, divided into two groups (supplemented with pyridoxine or not), were fed a soy protein isolate (Soyamin) or a purified amino acid diet containing or not Saccharomyces cerevisiae yeast (2%), primarily used to promote the growth of the B6-deficient animals. In one experiment, the protein level of the diet has been increased to augment the metabolic demand for PN. The B6-deficient Soyamin diet B containing yeast produced a mild deficiency (without incidence of morbidity and mortality) and the deficiency was severe (appearance of neurological symptoms after 10 days, AC 1.5) when yeast was deleted (diet A). The inclusion of yeast in both Soyamin and amino acid diets significantly increased plasma Ca and Pi levels (p < 0.001) whereas increasing the protein intake (diet C) had an inverse effect, reflecting an inhibitory effect on intestinal absorption of these minerals. Changes in plasma Ca and Pi levels due to dietary treatments were summarized in terms of their theoretical ion product. The amino acid diet D produced the lowest Ca x Pi ion product and the highest value was obtained with the yeast-containing diets B and E, regardless of the vitamin B6 intake and the dietary protein source. Plasma Ca and Pi levels were simultaneously elevated in severe vitamin B6 deficiency (diet A) as compared to control group (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of pyridoxine deficiency in the neuronally mature rat.

Pyridoxine deficiency was induced in neuronally mature rats by combination of dietary deprivation and ingestion of 4-deoxypyridoxine. Overt signs of deficiency were evident. At this time the activity of glutamic acid decarboxylase as also the content of serotonin decreased in several areas of the brain. Catecholamine contents were unchanged from controls. Light microscopic observations indicated no difference in CNS myelin between the deficient and control animals. There was no difference between deficient and control groups in their auditory evoked responses.