VDR, SOD-2, and CYP24A1 Gene Expression in Different Genotypes of BsmI SNP of the Vitamin D Receptor Gene in Individuals with Hypovitaminosis.

BACKGROUND: Hypovitaminosis D is a public health problem due to its implications for various diseases. Vitamin D has numerous functions, such as modulating the metabolism of cellular tissues, and it is expressed through the vitamin D receptor (VDR) gene that may influence gene expression modulation, which plays an important role in vitamin D metabolism. OBJECTIVE: To evaluate the effect of the genotypes of BsmI single nucleotide polymorphism (SNP) of the VDR gene on VDR, SOD2, and CYP24A1 gene expression in individuals with low serum vitamin D levels. METHODS: This was a cross-sectional analytical study. After signing the informed consent form, individuals were invited to participate and answered a structured questionnaire with identification data. Blood was collected for biochemical analysis, and vitamin D was measured by chemiluminescence; BsmI polymorphism was determined using real-time polymerase chain reaction (PCR) assays with TaqMan allelic discrimination, and gene expression was conducted by qRT-PCR using QuantiFast SYBR® Green PCR Master Mix. Data were analyzed using the SPSS 20.0 software, and differences were considered significant at p < 0.05. RESULTS: 98 individuals with vitamin D ≤ 20 ng/dL were evaluated, and the BsmI SNP of the VDR gene showed CYP24A1 overexpression and low SOD2 expression. CONCLUSION: BsmI SNP of the VDR gene can modulate the expression of the genes evaluated without interfering with serum levels.

Adolescent-Onset and Adult-Onset Vitamin-Responsive Neurogenetic Diseases: A Review.

Importance: Vitamin-responsive inherited diseases are among the rare genetic disorders with a specific pharmacological treatment. Many of these conditions have a prominent neurological phenotype that is mainly reported in children. Being rare and often strikingly different in adult-onset forms, they are still poorly known in the medical fields specific to adults. Observation: This article reviews all articles reporting cases of patients with a genetically confirmed inherited vitamin-responsive neurological disease and neurological onset after the age of 10 years. On this basis, 24 different diseases are described, involving vitamins A, B1, B2, B3, B6, B8, B9, B12, E, and tetrahydrobiopterin (BH4). Information such as clinical symptoms, disease course, imaging studies, biochemical alterations, and response to treatment present an overall picture of these patients. Conclusions and Relevance: Vitamin-responsive neurogenetic diseases represent a group of rare conditions that are probably underdiagnosed in adults and may have a dramatic response to treatment when started early in the course of the disease. In this review, main features of the adult-onset forms are defined and simple key messages are provided to help identify clinical situations when specific diagnostic tests should be performed and/or vitamins should be promptly administered.

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections.

In critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (GRα) and are associated with an enormous bioenergetic and metabolic cost. Appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. Emerging literature place the activated GRα at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. By the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. We review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. Importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. Since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing GRα and mitochondria number and function. Present understanding of the activated GC-GRα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. The activated GRα interdependence with functional mitochondria and three vitamin reserves (B1, C, and D) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis.

[MALABSORPTION FAT-SOLUBLE VITAMINS AND PROSPECTS OF THEIR USE IN LIVER DISEASES].

In a review article considers issues of efficiency and tactics of the purpose of fat-soluble vitamins, as in cholestatic and noncholestatic liver disease, as well as water-soluble vitamins, particularly vitamin C cholelithiasis. Oxidative stress due to chronic inflammation is one of the major conversion mechanisms of liver fibrosis in cirrhosis. The imbalance between production of reactive oxygen species and antioxidant defense causes a number of pathophysiological changes in the liver, including activation of hepatic stellate cells. The carriers of the I148M PNPLA3 mutation was not observed concentration reduction in liver vitamin A with increasing severity of the disease, but the observed decrease in the level of circulating retinyl palmitate and retinol-binding protein. To the appointment of vitamin A in liver disease should be approached with caution. Hypervitaminosis A leads to accelerated liver fibrosis and stimulates carcinogenesis. Currently actively studied the possibility of using vitamin E as an antioxidant, in patients with non-alcoholic fatty liver disease. His presence in the membranes phospholipid bilayer allows cells to prevent non-enzymatic oxidation of cell components by free radicals. Vitamin E can suppress the profibrotic processes. In patients with chronic cholestatic liver disease is common, vitamin K deficiency, even when administered, and is associated with the degree of cholestasis and severity of disease. The vitamin D deficiency, liver disease is also associated with the severity of disease correlated with the severity of liver failure and infectious complications. Vitamin D is an independent prognostic parameter for mortality risk in patients with liver cirrhosis.

Hydrosoluble vitamins.

The hydrosoluble vitamins are a group of organic substances that are required by humans in small amounts to prevent disorders of metabolism. Significant progress has been made in our understanding of the biochemical, physiologic and nutritional aspects of the water-soluble vitamins. Deficiency of these particular vitamins, most commonly due to inadequate nutrition, can result in disorders of the nervous system. Many of these disorders have been successfully prevented in developed countries; however, they are still common in developing countries. Of the hydrosoluble vitamins, the nervous system depends the most on vitamins B and C (ascorbic acid) for proper functioning. The B group vitamins include thiamin (vitamin B1), riboflavin (vitamin B2), niacin or niacinamide (vitamin B3), pantothenic acid (vitamin B5), pyridoxine or pyridoxal (vitamin B6) and cobalamin (vitamin B12). Clinical findings depend upon the deficiency of the underlying vitamin; generally, deficiency symptoms are seen from a combination rather than an isolated vitamin deficiency. True hereditary metabolic disorders and serious deficiency-associated diseases are rare and in general limited to particular geographic regions and high-risk groups. Their recognition is truly important as that determines the appropriate therapeutic management. The general availability of vitamins to practically everyone and several national health programs have saved many lives and prevented complications. However, there has been some apprehension for several decades about how harmless generous dosages of these vitamins are. Overt overdosages can cause vitamin toxicity affecting various body systems including the nervous system. Systemically, vitamin toxicity is associated with nonspecific symptoms, such as nausea, vomiting, diarrhea, and skin rash which are common with any acute or chronic vitamin overdose. At a national level, recommended daily allowances for vitamins become policy statements. Nutrition policy has far reaching implications in the food industry, in agriculture, and in food provision programs. Overall, water-soluble vitamins are complex molecular structures and even today, many areas of vitamin biochemistry still need to be explored. Many readers might be of the opinion that the classic forms of nutritional deficiency diseases have faded into the background of interesting history. This has caused their diverse symptoms to be neglected by most modern physicians since vitamin enrichment of many foods automatically erases them from their consideration in differential diagnosis. Vitamin B12 and folic acid deficiencies are discussed in other chapters.

Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency.

BACKGROUND & AIMS: The final step in bile acid synthesis involves conjugation with glycine and taurine, which promotes a high intraluminal micellar concentration to facilitate lipid absorption. We investigated the clinical, biochemical, molecular, and morphologic features of a genetic defect in bile acid conjugation in 10 pediatric patients with fat-soluble vitamin deficiency, some with growth failure or transient neonatal cholestatic hepatitis. METHODS: We identified the genetic defect that causes this disorder using mass spectrometry analysis of urine, bile, and serum samples and sequence analysis of the genes encoding bile acid-CoA:amino acid N-acyltransferase (BAAT) and bile acid-CoA ligase (SLC27A5). RESULTS: Levels of urinary bile acids were increased (432 ± 248 µmol/L) and predominantly excreted in unconjugated forms (79.4% ± 3.9%) and as sulfates and glucuronides. Glycine or taurine conjugates were absent in the urine, bile, and serum. Unconjugated bile acids accounted for 95.7% ± 5.8% of the bile acids in duodenal bile, with cholic acid accounting for 82.4% ± 5.5% of the total. Duodenal bile acid concentrations were 12.1 ± 5.9 mmol/L, which is too low for efficient lipid absorption. The biochemical profile was consistent with defective bile acid amidation. Molecular analysis of BAAT confirmed 4 different homozygous mutations in 8 patients tested. CONCLUSIONS: Based on a study of 10 pediatric patients, genetic defects that disrupt bile acid amidation cause fat-soluble vitamin deficiency and growth failure, indicating the importance of bile acid conjugation in lipid absorption. Some patients developed liver disease with features of a cholangiopathy. These findings indicate that patients with idiopathic neonatal cholestasis or later onset of unexplained fat-soluble vitamin deficiency should be screened for defects in bile acid conjugation.

Variable clinical spectrum of the most common inborn error of bile acid metabolism--3beta-hydroxy-Delta 5-C27-steroid dehydrogenase deficiency.

OBJECTIVE: We studied the clinical features of children with 3beta-hydroxy-Delta 5-C27-steroid dehydrogenase (3beta-HSDH) deficiency presenting to King's College and Great Ormond Street hospitals between 1989 and 2005. The diagnosis was made biochemically by detection of sulphated dihydroxycholenoic acids and trihydroxycholenoic acids in urine by fast atom bombardment mass spectrometry or electrospray ionisation tandem mass spectrophotometry and a plasma bile acid profile showing absent or low cholic and chenodeoxycholic acid levels and high concentrations of 3beta-7 alpha-dihydroxy-5-cholenoic acid and 3beta-7 alpha-12 alpha-trihydroxy-5-cholenoic acid. RESULTS: Eighteen children (12 male) with 3beta-HSDH deficiency were identified and diagnosed at a median age of 1.35 years (range 8 weeks-11 years). The presenting features included neonatal cholestasis (n = 11), rickets (n = 8, 1 of whom also had hypocalcaemic tetany, seizures, and normal liver biochemical markers), hepatomegaly (n = 7), pruritus (n = 3), and steatorrhoea and failure to thrive (n = 3). Ten children had low serum 25-OH vitamin D levels, of whom 8 also had low vitamin E and 6 had low vitamin A serum levels. Liver histology showed giant cell change and hepatocyte disarray in all with added features of cholestasis in 11, bridging fibrosis in 6, micronodular cirrhosis in 1, fatty change in 1, and active lobular and portal inflammation in 1. Five patients were treated with cholic acid and chenodeoxycholic acid (7 mg x kg(-1) x day(-1) of each), 7 with chenodeoxycholic acid only (7-18 mg x kg(-1) x day(-1)), and 1 with cholic acid (8 mg x kg(-1) x day(-1)) only. Repeated liver biopsies performed in 4 patients 6 months after starting replacement therapy showed improved histological changes. Three children died untreated before 5 years of age. After a median follow-up of 5.5 years (range 1-17 years) 12 out of 13 treated children have no clinical signs of liver disease or of fat-soluble vitamin deficiency. CONCLUSIONS: 3beta-HSDH deficiency is a rare inborn error of metabolism with diverse clinical features. Early replacement treatment leads to clinical and biochemical control and prevents chronic liver and bone disease, at least in the medium term.

Mild neonatal hypoxia exacerbates the effects of vitamin-deficient diet on homocysteine metabolism in rats.

Elevated plasma homocysteine has been linked to pregnancy complications and developmental diseases. Whereas hyperhomocysteinemia is frequently observed in populations at risk of malnutrition, hypoxia may alter the remethylation of homocysteine in hepatocytes. We aimed to investigate the combined influences of early deficiency in nutritional determinants of hyperhomocysteinemia and of neonatal hypoxia on homocysteine metabolic pathways in developing rats. Dams were fed a standard diet or a diet deficient in vitamins B12, B2, folate, month, and choline from 1 mo before pregnancy until weaning of the offspring. The pups were divided into four treatment groups corresponding to "no hypoxia/standard diet," "hypoxia (100% N2 for 5 min at postnatal d 1)/standard diet," "no hypoxia/deficiency," and "hypoxia/deficiency," and homocysteine metabolism was analyzed in their liver at postnatal d 21. Hypoxia increased plasma homocysteine in deficient pups (21.2 +/- 1.6 versus 13.3 +/- 1.2 microM, p < 0.05). Whereas mRNA levels of cystathionine beta-synthase remained unaltered, deficiency reduced the enzyme activity (48.7 +/- 2.9 versus 83.6 +/- 6.3 nmol/h/mg, p < 0.01), an effect potentiated by hypoxia (29.4 +/- 4.7 nmol/h/mg, p < 0.05). The decrease in methylene-tetrahydrofolate reductase activity measured in deficient pups was attenuated by hypoxia (p < 0.05), and methionine-adenosyltransferase activity was slightly reduced only in the "hypoxia/deficiency" group (p < 0.05). Finally, hypoxia enhanced the deficiency-induced drop of the S-adenosylmethionine/S-adenosylhomocysteine ratio, which is known to influence DNA methylation and gene expression. In conclusion, neonatal hypoxia may increase homocysteinemia mainly by decreasing homocysteine transsulfuration in developing rats under methyl-deficient regimen. It could therefore potentiate the well-known adverse effects of hyperhomocysteinemia.

DNA methylation and diet in cancer.

The studies reviewed here investigate the association between folate status and DNA methylation in cancer tissues. We evaluated tissue vitamin levels and global DNA methylation, a biomarker of neoplasia, in normal lung and lung cancer tissues. Lung squamous cell carcinoma tissues exhibited global DNA hypomethylation, with decreased folate and vitamin B-12 concentrations, and increased vitamin C concentrations, relative to matched uninvolved control tissues. Breast cancer tissues also had globally hypomethylated DNA and decreased vitamin B-12 and vitamin C levels, but folate concentrations were elevated in breast cancer tissues. Global DNA methylation status in buccal mucosal cells may reflect global methylation status in lung tissues, because there was a significant association between global DNA methylation in buccal mucosal cells and malignant tissues of the lung, but not between methylation in peripheral leukocytes and lung tissues. We found that global DNA hypomethylation, as assessed by a radiolabeled 5-methylcytosine technique, was associated with susceptibility for development of lung cancer, which is involved in the progression of the disease. DNA methylation was also associated with the development of squamous cell carcinomas in whites but not in blacks. Overall, these studies suggest that global DNA methylation patterns may vary depending on the type of cancer, that tissue vitamin levels are associated with global DNA methylation status and that ethnicity should be considered in studies of DNA methylation.

[Microsomal triglyceride transfer protein and abetalipoproteinemia]. / <> et abêtalipoprotéinémie

Microsomal triglyceride transfer protein (MTP) is a dimeric protein complex consisting of protein disulfide isomerase and a unique 97 kDa subunit. In vitro, MTP accelerates the transport of triglyceride, cholesteryl ester, and phospholipid between vesicles. It was recently demonstrated that abetalipoproteinemia, a disease characterized as an inability to produce chylomicrons and very low density lipoproteins in the intestine and liver, respectively, is the result of a genetic absence of MTP. Downstream effects resulting from this defect, include very low plasma cholesterol and triglyceride levels, absence of plasma apolipoprotein B and a lipid malabsorption syndrome, leading to lipo-soluble vitamin deficiencies. A low fat diet is instituted to eliminate the diarrhea. In addition, a therapy with vitamins A and E is essential to prevent patients from developing secondary effects such as neuropathy, muscle weakness, and retinopathy.

Genetic causes of rickets.

Dietary deficiency of vitamin D, genetic disorders of its bioactivation to 1,25-dihydroxyvitamin D [1,25(OH)2D], or disorders of vitamin D action can cause rickets. The rate-limiting, hormonally-regulated, biologically activating step in the synthesis of 1,25(OH)2D is the 1 alpha-hydroxylation of 25-hydroxyvitamin D, which occurs in kidney and other tissues and is mediated by a mitochondrial cytochrome P450 enzyme, P450c1 alpha. After many years of effort, the cDNA and gene for this enzyme were cloned in late 1997. Mutations in the P450c1 alpha gene, located on chromosome 12, cause 1 alpha-hydroxylase deficiency, also known as vitamin D-dependent rickets type I, an autosomal recessive disease characterized by rickets and impaired growth due to failure of renal synthesis of 1,25(OH)2D. X-linked hypophosphatemic rickets, a dominantly inherited disease, is caused by mutations in the PHEX gene, whose function in regulating renal phosphate and vitamin D metabolism remains to be elucidated.

Phenotype in retinol deficiency due to a hereditary defect in retinol binding protein synthesis.

PURPOSE: To describe the phenotype caused by a retinol deficiency in a family with compound heterozygous missense mutations (Ile41Asn and Gly75Asp) in the gene for serum retinol binding protein (RBP). METHODS: The two affected sisters, 17 (BR) and 13 (MR) years old, were examined clinically and with perimetry, color vision tests, dark adaptometry, rod- and cone-isolated electroretinograms (ERGs), multifocal ERGs, electrooculograms (EOGs), and laboratory tests. RESULTS: There were no complaints besides night vision problems and no history of systemic disease. Visual acuity was reduced to 20/40 (BR) and 20/25 (MR). Anterior segments were normal except for a discrete iris coloboma. Both patients showed a typical "fundus xerophthalmicus," featuring a progressed atrophy of the retinal pigment epithelium. Dark adaptation thresholds were elevated. In the scotopic ERG, only reduced mixed responses were recordable. The photopic ERG was reduced in BR and normal in MR; implicit times were highly (BR) to slightly (MR) elevated. There was no (BR) to little (MR) light reaction in the EOG. All-trans retinol levels were 0.19 microM and 0.18 microM (normal range, 0.7-1.5 microM) for BR and MR, respectively, and did not increase in a dose-response test. RBP was below detection threshold, and retinyl esters were normal. CONCLUSIONS: Both affected siblings had no detectable serum RBP, one sixth of normal retinol levels, and normal retinyl esters. The retinal pigment epithelium was severely affected, but besides acne there were no changes to other organs. This gives evidence for an alternative tissue source of vitamin A, presumably retinyl esters from chylomicron remnants. The normal retinol levels in the tear fluid explain the lack of xerophthalmia. However, considering the role of RBP in the tear fluid and, during development, in the yolk sac there is also evidence that there are organ-specific RBP forms not affected by the genetic defect.

Metaphyseal dysostosis. Review of literature; study of a case with cytogenetic analysis

The clinical, pathologic, and laboratory findings of a patient with severe metaphyseal dysostosis are described and the literature reacting to this disorder is reviewed. Chromosomal analysis suggests that some cells with trisomy for chromosome 16 may be present in this patient. Therapy with massive doses of vitamin D parenterally failed to influence the roentgenographic changes in the metaphyses.