Drug-Induced Hepatotoxicity

Metabolism of Drugs

Vitamin b and hepatotoxicity

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Thiamin, riboflavin, niacin, vitamin B vitamin b and hepatotoxicitypantothenic acid and biotin Thiamin Riboflavin Niacin Vitamin B 6 Pantothenate Biotin General considerations for B-complex vitamins References The B-complex vitamins covered here are presented in Table 5 along with the biochemical and physiologic roles vitamin b and hepatotoxicity the co-enzyme forms and a brief description of clinical deficiency symptoms.

Excessive refining and polishing of cereals removes considerable proportions of B vitamins contained in these cereals. Clinical manifestations of deficiency of some B vitamins - such as beri-beri cardiac and dryvitamin b and hepatotoxicity neuropathies, pellagra, and oral and genital lesions related to riboflavin deficiency - were once major public health problems in parts of the world.

These manifestations have now declined, the decline being brought about not through programmes, which distribute synthetic vitamins but through changes in the patterns of food availability and consequent changes in dietary practices of the populations. Although these clinical manifestations of B-vitamin deficiencies have decreased, vitamin b and hepatotoxicity, there is evidence of widespread sub-clinical deficiency of these vitamins especially of riboflavin and pyridoxine. These sub-clinical deficiencies, although less dramatic vitamin b and hepatotoxicity their manifestations, exert deleterious metabolic effects.

Despite the progress in reduction of large-scale deficiency in the world, there are periodic reports of outbreaks of B-complex deficiencies, which are linked to deficits of B vitamins in populations under various distress conditions.

Refugee and displaced population groups 20 million people by current United Nations estimates are at risk for B-complex deficiency because most cereal foods used under emergency situations are not fortified with micronutrients 1. Recent reports have implicated the low B-complex content of diets as a factor in the outbreak of peripheral neuropathy and visual loss observed the adult population of Cuba This deficiency in Cuba resulted from the consequences of an economic blockade 4.

Greater weight has been given to studies which used larger numbers of subjects over longer periods, more thoroughly assessed dietary intake, varied the level of the specific vitamin being investigated, and used multiple indicators, including those considered functional in the assessment of status. These indicators have been the main basis for ascertaining requirements.

Although extensive, the bibliographic search of recently published reports presented in this chapter most likely underestimates the extent of B-complex deficiency considering that many vitamin b and hepatotoxicity are not reported in the medical vitamin b and hepatotoxicity. Moreover, outbreaks of vitamin deficiencies in populations are usually not publicised because governments may consider the existence of these conditions to be politically sensitive information.

Thiamin Background with requisite function in human metabolic processes Deficiency Thiamin vitamin B 1aneurin deficiency results in the disease called beri-beri, which has been classically considered to exist in dry paralytic and wet oedematous forms 7, 8. Beri-beri occurs in human-milk-fed infants whose nursing mothers are deficient. It also occurs in adults with high carbohydrate intakes mainly from milled rice and with intakes of anti-thiamin factors.

Beri-beri is still endemic in Asia. In relatively industrialized nations, vitamin b and hepatotoxicity, the neurologic reflections of Wernicke-Korsakoff syndrome are frequently associated with chronic alcoholism with limited food consumption 9. Some cases of thiamin deficiency have been observed with patients who are hypermetabolic, are on parenteral nutrition, are undergoing chronic renal dialysis, or have undergone a gastrectomy. Thiamin vitamin b and hepatotoxicity has also been observed in Nigerians who ate silk worms, Russian schoolchildren in MoscowThai rural elderly, Cubans, Japanese elderly, Brazilian Xavante Indians, French Guyanense, Southeast Asian schoolchildren who were infected with hookworm, Malaysian detention inmates, and people with chronic alcoholism.

Toxicity Toxicity is not a problem with thiamin because renal clearance of levels conceivably ingested is rapid.

Functions Thiamin functions as the co-enzyme thiamin pyrophosphate TPP in the metabolism of carbohydrates and branched-chain amino acids. Hence, when there is insufficient thiamin, the overall decrease in carbohydrate metabolism and its inter-connection with amino acid metabolism via a-keto acids have severe consequences, such as a decrease in the formation of acetylcholine for neural function.

Biochemical indicators Indicators used to estimate thiamin requirements are urinary excretion, erythrocyte transketolase activity coefficient, erythrocyte thiamin, blood pyruvate and lactate, and neurologic changes. The excretion rate of the vitamin and its metabolites reflects intake, and the validity of the assessment of thiamin nutriture is improved with load test, vitamin b and hepatotoxicity. Erythrocyte transketolase activity co-efficient reflects TPP levels and can indicate rare genetic defects.

Erythrocyte thiamin is mainly a vitamin b and hepatotoxicity measure of TPP but also is a measure of thiamin and thiamin monophosphate by high performance liquid chromatography HPLC separation, vitamin b and hepatotoxicity. Thiamin status has been assessed by measuring urinary thiamin excretion under basal conditions or after thiamin loading, transketolase activity, and free and phosphorylated forms in blood or serum 6, 9.

Although overlap with baseline values for urinary thiamin was found with oral doses below 1 mg, a correlation of 0. The erythrocyte transketolase assay, vitamin b and hepatotoxicity, in which an activity coefficient based on a TPP stimulation of the basal level is given, continues to be a main functional indicator 9but some problems have been encountered.

Gans and Harper 13 found a wide range of TPP effect when thiamin intakes were adequate above 1. In some cases the activity coefficient may appear normal after prolonged deficiency This measure seemed poorly correlated with dietary intakes estimated for a group of English adolescents Certainly, there are both inter-individual and genetic factors affecting the transketolase Baines and Davies 17 suggested that it is useful to determine erythrocyte TPP directly because the co-enzyme is less susceptible to factors vitamin b and hepatotoxicity influence enzyme activity; however, vitamin b and hepatotoxicity, there are also methods for determining thiamin and its phosphate esters in whole blood Factors affecting requirements Because thiamin facilitates energy utilisation, its requirements have traditionally been expressed on the basis of energy intake, which can vary depending on activity levels, vitamin b and hepatotoxicity.

However, Fogeholm et al. Also, a study with thiamin-restricted Dutch males whose intake averaged 0. Alcohol consumption may interfere with thiamin absorption 9.

Findings by age and life stage Recommendations for infants are based on adequate food intake. Mean thiamin content of human milk is 0. A study of year-old children related dietary intake of thiamin to several indicators of thiamin status Intakes below this amount lead to irritability and other symptoms and signs of deficiency Nichols and Basu 27 found that only 57 percent of 60 adults aged years had TPP effects of less than 14 percent and suggested that ageing may increase thiamin requirements.

An average total energy cost of MJ has been estimated for pregnancy With an intake of 0, vitamin b and hepatotoxicity. Vitamin b and hepatotoxicity into account an increased growth in maternal and foetal compartments, vitamin b and hepatotoxicity, an overall additional requirement of 0. Lactating women are estimated to transfer 0. Recommendations The recommendations for thiamin are given in Table 6.

Because the deficiency almost invariably occurs combined with a deficiency of other B-complex vitamins, some of the symptoms e. The major cause of hypo-riboflavinosis is inadequate dietary intake as a result of limited food supply, which is sometimes exacerbated by poor food storage or processing, vitamin b and hepatotoxicity.

Children in developing countries will commonly demonstrate clinical signs of riboflavin deficiency during periods of the year when gastrointestinal infections are prevalent. Decreased assimilation of riboflavin also results from abnormal digestion such as that which occurs with lactose intolerance. This condition is highest in African and Asian populations and can lead to a decreased intake of milk as well as an abnormal absorption vitamin b and hepatotoxicity the vitamin.

Absorption of riboflavin is also affected in some other conditions, vitamin b and hepatotoxicity, for example, tropical sprue, celiac disease, malignancy and resection of the small bowel, and decreased gastrointestinal passage time. In relatively rare cases the causes of deficiency are inborn errors in which the genetic defect is in the formation of a flavoprotein e. Also at risk are those receiving phototherapy for neonatal jaundice and perhaps those with inadequate thyroid hormone.

Some cases of riboflavin deficiency were also observed in Russian schoolchildren Moscow and Southeast Asian schoolchildren infected with hookworm. Toxicity Riboflavin toxicity is not a problem because of limited intestinal absorption. Functions Conversion of riboflavin to flavin mononucleotide FMN and further to the predominant flavin adenine dinucleotide FAD occurs before these flavins form complexes with numerous flavoprotein dehydrogenases and oxidases.

These flavoco-enzymes FMN and FASD participate in oxidation-reduction reactions in metabolic pathways and in energy production via the respiratory chain 10, Vitamin b and hepatotoxicity indicators Indicators used to estimate riboflavin requirements are urinary flavin excretion, erythrocyte glutathione reductase activity coefficient, and erythrocyte flavin.

The urinary flavin excretion rate of vitamin and metabolites reflects intake; validity of assessment of riboflavin adequacy is improved with load test.

Erythrocyte glutathione reductase activity coefficient reflects FAD levels; results are confounded by such genetic defects as glucosephosphate dehydrogenase deficiency and heterozygous b thalassemia. Riboflavin status has been assessed by measuring urinary excretion of the vitamin in fasting, random, and hour specimens or by load returns tests amounts measured after taking hydrocodone ibuprofen and promethazine together specific amount of riboflavin is given orally ; erythrocyte glutathione reductase; or erythrocyte flavin concentration 6, 9, The HPLC method with fluorometry gives lower values for urinary riboflavin than do fluorometric methods, which measure the additive fluorescence of similar flavin metabolites The metabolites can comprise as much as one-third of total urinary flavin 31, 32 and in some cases may depress assays dependent on a biologic response because certain catabolites vitamin b and hepatotoxicity inhibit cellular uptake The erythrocyte glutathione reductase assay, with an activity coefficient AC expressing the ratio of activities in the presence and absence of added FAD, continues to be used as a main functional indicator, but some limits have been noted.

The reductase in erythrocytes from individuals with glucosephosphate dehydrogenase deficiency often present in blacks has vitamin b and hepatotoxicity increased avidity for FAD, which makes this test invalid Sadowski 35 has set an upper limit of normality for the AC at 1. Suggested guidelines for the interpretation of such enzyme ACs are as follows: In general agreement with earlier findings on erythrocyte flavin, Ramsay et al.

Factors affecting requirements Several studies reported modest effects of physical activity on the erythrocyte glutathione reductase AC However, riboflavin supplementation did not lead to an increase in work performance when such subjects were not clinically deficient Bio-availability of riboflavin in foods, mostly as digestible flavoco-enzymes, is excellent at nearly 95 percent 6but absorption of the free vitamin is limited to about 27 mg per single meal or dose in an adult No more than about 7 percent of food flavin is found as 8a-FAD covalently attached to certain flavoprotein enzymes.

Although some portions of the 8a- amino acid -riboflavins are released by proteolysis of these flavoproteins, vitamin b and hepatotoxicity, they do not have vitamin activity A lower fat-to-carbohydrate ratio may decrease the riboflavin requirements of the elderly Contrary to earlier reports, no difference was seen in riboflavin status of women taking oral contraceptives when dietary intake was controlled by providing a single basic daily menu and meal pattern after 0.

Findings by age and life stage As reviewed by Thomas et al. More recent investigations of flavin composition of both human 52 and cow 53 milk have helped clarify the nature of the flavins present and provide better estimates of riboflavin equivalence. For human milk consumed by infants up to age 6 months, the riboflavin equivalence averages 0. For low-income Indian women with erythrocyte glutathione reductase activity ratios averaging 1. Hence, a deficiency sufficient to reduce human-milk riboflavin content by one-third vitamin b and hepatotoxicity lead to a mild sub-clinical deficiency in infants.

Studies of riboflavin status in adults include those by Belko et al. Most of a 1. Such findings corroborate earlier work indicating a relative saturation of tissue with intakes above 1. Studies by Alexander et al. Pregnant women have an increased erythrocyte glutathione reductase AC 58, Maternal riboflavin intake was positively associated with foetal growth in a study of pregnant women The additional riboflavin requirement of 0. For lactating women, an estimated 0. Recommendations The recommendations for riboflavin are given in Table 7.

At present, pellagra occurs endemically in poorer areas of India, China, and Africa. Its cause has been mainly attributed to a deficiency of niacin; however, its biochemical inter-relationship to riboflavin and vitamin B 6which are needed for the conversion of L-tryptophan to niacin equivalents NEssuggests that insufficiencies of these vitamins may also contribute to pellagra Pellagra-like syndromes occurring in the absence of a dietary niacin deficiency are also attributable to disturbances in tryptophan metabolism e.

Pellagra also occurs in people with chronic alcoholism Toxicity Although therapeutically useful in lowering serum cholesterol, administration of chronic high oral doses of nicotinic acid can lead to hepatotoxicity as well as dermatologic manifestations.

 

Vitamin b and hepatotoxicity

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