Keywords
nutritional deficiency, neuropathy, copper deficiency, vitamin B 12 , cobalamine, thiamine, pyridoxine, vitamin D, vitamin E, folate, niacin, vitamin A, myelopathy, myeloneuropathy, Lathyrism, Konzo, Wernicke encephalopathy, Korsakoff encephalopathy, beriberi
Maintenance of medical and neurologic health requires adequate ingestion, absorption, and storage of vitamins and minerals. Nutritional deficiencies may result from inadequate intake or malabsorption of these critical vitamins and micronutrients. Individuals at risk of deficient nutrient intake include the impoverished in developed and underdeveloped countries (where certain nutritional disorders may be endemic), individuals with eating disorders or those engaging in fad or restrictive diets, chronic alcoholics, and those with chronic medical conditions that result in malabsorption or require prolonged parenteral nutrition.
Malabsorption may result from gastrointestinal surgery, including bariatric surgery for obesity, and from chronic gastrointestinal disorders such as celiac disease, Whipple disease, bacterial overgrowth, and inflammatory bowel disease. Excessive ingestion of certain substances, including vitamins and micronutrients, may result in neurologic impairment directly (e.g., vitamin B 6 excess) or indirectly by interfering with absorption of certain other vitamins (e.g., copper deficiency induced by high zinc levels). Awareness of the characteristic clinical features of the various nutritional disorders facilitates timely recognition and treatment, and directly impacts prognosis ( Table 15-1 ).
| Vitamin | Diagnosis | Treatment |
|---|---|---|
| Vitamin B 12 Deficiency |
| IM vitamin B 12 1000 μg for 5 days then once monthly or oral vitamin B 12 1000 μg daily |
| Nitrous Oxide |
| Stop nitrous oxide exposure; IM vitamin B 12 ; consider oral methionine |
| Folate Deficiency | Serum folate, homocysteine | Oral folate 1 mg tid initially; 1 mg daily thereafter |
| Copper Deficiency | Serum copper and ceruloplasmin; urinary copper | Discontinue zinc; oral copper 8 mg daily for 1 week; 6 mg daily for 1 week; 4 mg daily for 1 week; 2 mg daily thereafter |
| Vitamin E | Serum vitamin E; ratio serum vitamin E to sum of cholesterol and triglycerides | Vitamin E 200 mg–200 mg/kg daily oral or IM |
| Thiamine | Clinical diagnosis; brain MRI | Thiamine 100 mg IV followed by 50–100 mg IV or IM until nutritional status stable |
| Pyridoxine | Serum pyridoxal phosphate | Pyridoxine 50–100 mg daily |
| Niacin | Urinary excretion niacin metabolites | Nicotinic acid 25–50 mg oral or IM |
As is true with the evaluation of all suspected neurologic disorders, the identification of nutritional deficiencies requires a careful history and examination. A meticulous review of medication history, including prescription and over-the-counter medications, is necessary since certain drugs may increase an individual’s risk of developing a vitamin deficiency (e.g., H2 blockers and vitamin B 12 deficiency), and excessive ingestion of some supplement medications may result in vitamin malabsorption (e.g., zinc-induced copper deficiency) and deficiency. Review of past medical and surgical history is critical, as gastric bypass surgery, inflammatory bowel disease, celiac disease, and other medical and surgical conditions may compromise nutritional status ( Table 15-2 ). Knowledge of the time course over which various vitamin deficiencies may develop also is important. For example, body stores of thiamine are limited, and thiamine deficiency may develop within weeks, whereas cobalamin (vitamin B 12 ) deficiency only develops over years. The identification of a particular vitamin deficiency should prompt a thorough laboratory evaluation for other vitamin deficiencies, as multiple vitamin deficiencies often occur in the same patient.
| Pernicious anemia |
| Atrophic gastritis |
| Achlorhydria-induced cobalamin malabsorption |
| Partial gastrectomy |
| Ileal resection |
| Bariatric surgery |
| H2 receptor antagonists |
| Proton pump inhibitors |
| Glucophage |
| Bacterial overgrowth |
| Pancreatic disease |
| Celiac disease |
| Helicobacter pylori infection |
| Diphyllobothrium latum infection |
| Nitrous oxide |
| Dietary restriction |
Vitamin B 12 Deficiency
Vitamin B 12 (cobalamin) deficiency is a common condition, with estimated prevalence rates ranging from around 2 to 15 percent of the elderly, depending upon the population studied and diagnostic criteria used. Despite these high prevalence rates, no consensus exists on how best to diagnose and evaluate patients with suspected vitamin B 12 deficiency. Recognition of vitamin B 12 deficiency is critical, as the hematologic and neurologic manifestations are potentially reversible only if diagnosed and treated in a timely manner.
Vitamin B 12 is a cofactor for the enzymes methionine synthase and l -methylmalonyl-coenzyme A mutase, and is required for proper red blood cell formation, normal neurologic function, and DNA synthesis. It is necessary for the initial myelination, development, and maintenance of myelination within the central nervous system (CNS). Classically, vitamin B 12 deficiency results in a myelopathy, or “subacute combined degeneration,” which results from demyelination of the posterolateral columns of the cervical and thoracic spinal cord. Demyelination of cranial nerves, peripheral nerves, and brain may also occur and has been referred to as “combined-systems disease.” Vitamin B 12 deficiency may result in a megaloblastic anemia, with macrocytosis, anisocytosis, hypersegmented neutrophils, leukopenia, thrombocytopenia, pancytopenia, or some combination of these abnormalities.
Etiology
Vitamin B 12 is a water-soluble vitamin that exists in several forms, all of which contain cobalt and are collectively referred to as cobalamins. Methylcobalamin and 5-deoxyadensoylcobalamin are the forms of vitamin B 12 that are active in human metabolism. Vitamin B 12 is contained in a number of animal proteins, in fortified breakfast cereals, and in certain nutritional yeast products. Daily losses of vitamin B 12 are minimal, and even in cases of severe malabsorption, it may take 5 years or more to develop symptomatic vitamin B 12 deficiency.
Vitamin B 12 deficiency in elderly patients most commonly results from pernicious anemia, atrophic gastritis, and achlorhydria-induced cobalamin malabsorption ( Table 15-2 ). The incidence of atrophic gastritis increases with age and may at least partially explain the increased frequency of vitamin B 12 deficiency with aging. Achlorhydria results in impaired extraction of the vitamin from food sources. Partial gastrectomy, bariatric surgery, and ileal resection may result in malabsorption of vitamin B 12 , and partial gastrectomy has been associated with loss of intrinsic factor, which is necessary for its absorption. Gastroenterologic disorders such as celiac disease, Crohn disease, ileitis, pancreatic disease, and bacterial overgrowth may also result in vitamin B 12 deficiency. Certain medications, such as histamine (H2) blocking agents, proton pump inhibitors, and glucophage may also increase the risk of developing vitamin B 12 deficiency. Vitamin B 12 deficiency rarely results from inadequate intake in vegans and would be expected to develop only after many years, and may not be associated with any clinical manifestations of deficiency.
Nitrous oxide alters the cobalt core of cobalamin, converting it into an inactive, oxidized form. Hence, nitrous oxide exposure may result in cobalamin deficiency, with most reported cases associated with low or borderline low vitamin B 12 levels. A single exposure to nitrous oxide may be enough to precipitate neurologic impairment in an individual with unsuspected vitamin B 12 deficiency, with time to symptom onset ranging from immediately after exposure up to around 2 months. Nitrous oxide remains one of the more commonly used anesthetic agents worldwide, and can also be obtained for abuse in the form of whipped cream canisters and as “whippets,” which are small bulbs containing nitrous oxide (see Chapter 34 ). Surveys of medical and dental students in New Zealand and the United States revealed recreational nitrous oxide abuse in 12 and 20 percent, respectively.
Clinical Manifestations
Neurologic signs and symptoms may be the initial manifestation of vitamin B 12 deficiency. Paresthesias and a sensory ataxia are the most common initial symptoms. Classically, a myelopathy occurs and may be accompanied by a peripheral neuropathy. The myelopathy results from posterior column and lateral corticospinal tract dysfunction, with a combination of pyramidal signs and posterior column sensory loss evident on examination. The peripheral neuropathy is typically mild and is predominantly axonal on electrodiagnostic testing.
Neuropsychiatric manifestations include memory impairment, change in personality, delirium, and even psychosis. Optic neuropathy, resulting in diminished visual acuity, centrocecal scotomas, and optic atrophy may be seen. Symptoms of orthostatic hypotension are an uncommon manifestation. Other much less commonly encountered neurologic conditions attributed to vitamin B 12 deficiency include cerebellar ataxia, orthostatic tremor, ophthalmoplegia, and vocal cord paralysis. A number of constitutional symptoms may accompany these neurologic signs and symptoms, including fatigue, weight loss, fever, dyspnea, and gastrointestinal symptoms.
Diagnosis
Serum cobalamin is the initial screening test in patients with suspected vitamin B 12 deficiency ( Table 15-1 ). However, some patients will have normal serum cobalamin levels. In patients with borderline low serum levels, and particularly in those patients strongly suspected of vitamin B 12 deficiency, methylmalonic acid and homocysteine levels should also be checked. Methylmalonic acid and homocysteine levels are increased, suggesting intracellular deficiency of vitamin B 12 (although not completely specific), in as many as one-third of patients with low-normal serum cobalamin levels.
Once the diagnosis has been established, further testing may be pursued in order to determine the cause. Antibodies to intrinsic factor are seen in only 50 to 70 percent of patients with pernicious anemia, but are highly specific. Antiparietal cell antibodies lack sensitivity and specificity and have limited utility. Gastrin antibodies are 70 percent sensitive and specific for pernicious anemia. Elevated serum gastrin and decreased pepsinogen I levels have been reported to be abnormal in 80 to 90 percent of patients with pernicious anemia, but their specificity is limited. The Schilling test is rarely utilized today due to concerns about radiation exposure, cost, and diagnostic accuracy.
Nerve conduction studies and needle electromyography (EMG) may confirm the presence of an axonal sensorimotor peripheral neuropathy. Somatosensory evoked potentials may show slowing in central proprioceptive pathways. Brain and spinal cord magnetic resonance imaging (MRI) studies may demonstrate signal change in subcortical white matter and in the posterolateral columns of the spinal cord.
Treatment
Treatment involves the administration of high-dose oral, sublingual, or intramuscular cobalamin. With malabsorption, 1000 μg of cobalamin is administered intramuscularly for 5 days and monthly thereafter, although some have suggested more frequent administration after the first 5 days. There is evidence to suggest that 1000 μg of oral or sublingual cobalamin, given daily, is as effective as intramuscular administration. Lifelong vitamin B 12 supplementation therapy is typically necessary, unless a potentially reversible cause is identified and treated. Hematologic recovery occurs within the first 1 to 2 months and is complete. The neurologic condition should stabilize and improvement may occur over the first 6 to 12 months following the initiation of treatment. Neurologic recovery may be incomplete, particularly in those with significant neurologic deficits prior to the initiation of therapy. Methylmalonic acid and homocysteine levels should be utilized to monitor response to therapy, and typically should normalize within 10 to 14 days.
Patients with pernicious anemia should undergo endoscopy, as they are at higher risk of developing gastric and carcinoid cancers. Upper endoscopy should be considered in other patients as well, including those with other gastrointestinal symptoms and those with other concomitant vitamin deficiencies.
Folate Deficiency
The active form of folate, tetrahydrofolic acid, is essential in the transfer of one-carbon units to substrates utilized in the synthesis of purine, thymidine, and amino acids. Methyltetrahydrofolate is required for the cobalamin-dependent remethylation of homocysteine to methionine, and methylene tetrahydrofolate methylates deoxyuridylate to thymidylate. Although folate deficiency might be expected to result in similar complications as vitamin B 12 deficiency, neurologic manifestations of isolated folate deficiency are extremely uncommon.
Etiology
Folate is present in animal products, citrus fruits, and green, leafy vegetables. Normal body stores of folate range from 500 to 20,000 µg, and 50 to 100 µg are required daily. Serum folate declines within 3 weeks of diminished intake or malabsorption, and clinical signs of folate deficiency may occur within months. After ingestion, folate polyglutamates normally undergo hydrolysis to monoglutamates, which are absorbed in the proximal small intestine and ileum. Absorbed folate monoglutamates are then metabolized by the liver to 5-methyltetrahydrofolate, the principal circulating form of folate. The cellular uptake of 5-methyltetrahydrofolate is mediated by four different carrier systems: a proton-coupled folate transporter, a low-affinity high-capacity reduced folate carrier, and two high-affinity folate receptors.
Folate deficiency is one of the more common nutritional disorders worldwide. Risk factors include malnutrition, conditions associated with increased folate requirements (e.g., pregnancy, lactation, and chronic hemolytic anemia), gastroenterologic disorders, and certain medications ( Table 15-3 ). Gastroenterologic conditions that affect folate absorption in the small bowel include tropical sprue, celiac disease, bacterial overgrowth syndrome, inflammatory bowel disease, and pancreatic insufficiency. Gastric surgeries or medications that reduce gastric secretions may also result in folate deficiency. A number of other medications such as methotrexate, aminopterin, pyrimethamine, trimethoprim, and triamterene inhibit dihydrofolate reductase and may also result in folate deficiency. Mechanisms by which other medications such as anticonvulsants, sulfasalazine, oral contraceptives, and antituberculous drugs affect folate levels have not been established.
| Malnutrition (e.g., alcoholics, premature infants, adolescents) |
| Increased folate requirement (e.g., pregnancy, lactation, chronic hemolytic anemia) |
| Dietary restriction (e.g., phenylketonuria) |
| Malabsorption (e.g., tropical sprue, celiac disease, bacterial overgrowth, inflammatory bowel disease, giardiasis) |
| States of reduced gastric secretion (e.g., gastric surgery, atrophic gastritis, H2 receptor antagonists, proton pump inhibitors, treatment of pancreatic insufficiency) |
| Medications that inhibit dihydrofolate reductase (e.g., aminopterin, trimethoprim, methotrexate, pyrimethamine, triamterene) |
| Other medications (unclear mechanism) (e.g., anticonvulsants, antituberculous drugs, sulfasalazine, oral contraceptive agents) |
| Inborn errors of folate metabolism (e.g., hereditary folate malabsorption, cerebral folate transporter deficiency, glutamate formiminotransferase deficiency, severe methylenetetrahydrofolate reductase deficiency, dihydrofolate reductase deficiency, methylenetetrahydrofolate dehydrogenase 1 deficiency, functional methionine synthase deficiency) |
Eight inborn errors of folate absorption have been described, including hereditary folate malabsorption, cerebral folate transporter deficiency, glutamate formiminotransferase deficiency, severe methylenetetrahydrofolate reductase deficiency, dihydrofolate reductase deficiency, methylenetetrahydrofolate dehydrogenase 1 protein deficiency, and functional methionine synthase deficiency (due to deficiency of methionine synthase reductase or of the methionine synthase apoenzyme itself). Clinical manifestations of these disorders may include megaloblastic anemia, cognitive decline, seizures, movement disorders, and peripheral neuropathy. Early identification and treatment with folate may result in clinical improvement in some forms of these disorders. Methylenetetrahydrofolate reductase deficiency is the most common of these disorders, with variable neurologic and vascular manifestations including cognitive changes, seizures, motor and gait disorders, schizophrenia, and thromboses; laboratory studies show hyperhomocysteinemia and homocystinuria.
Clinical Manifestations
Maternal folate deficiency during or around the time of conception has been reported to cause more than 50 percent of neural tube defects. Myeloneuropathy, peripheral neuropathy, and megaloblastic anemia have been described with folate deficiency. These potential manifestations of folate deficiency are clinically indistinguishable from those seen with vitamin B 12 deficiency. Some reports suggest that folate deficiency may be associated with an increased risk of peripheral vascular disease, coronary artery disease, cerebrovascular disease, and cognitive impairment.
Diagnosis
Serum folate, erythrocyte folate, and homocysteine levels may be used to evaluate an individual with suspected folate deficiency. Results of these studies are highly dependent upon the methods and laboratories used. Serum folate levels fluctuate considerably and do not always accurately reflect tissue stores. Erythrocyte folate levels may more accurately predict tissue stores, but there is considerable laboratory assay variability. Homocysteine levels have been demonstrated to be elevated in 86 percent of patients with clinically significant folate deficiency. Typically, a serum folate level of 2.5 μg/l has been utilized as the cut-off for folate deficiency ; however, it has been suggested that levels in the range of 2.5 to 5 ng/ml may reflect mildly compromised folate status.
Treatment
Oral administration of folic acid may be adequate, typically 1 mg three times daily for 4 weeks followed by a maintenance dose of 1 mg daily. Parenteral administration of folic acid may be considered in acutely ill patients, and particularly in patients with malabsorption. Folate supplementation of at least 0.4 mg daily is recommended in women of childbearing age; higher doses are suggested for those taking anticonvulsant medications. Vitamin B 12 levels should also be assessed in patients with suspected folate deficiency and, if low, vitamin B 12 supplementation should be initiated immediately.
Copper Deficiency
Copper is a trace element involved in a number of metalloenzymes which are critical in the development and maintenance of nervous system structure and function. These enzymes include cytochrome c oxidase (used for electron transport and oxidative phosphorylation), copper/zinc superoxide dismutase (used for antioxidant defense), tyrosinase (used for melanin synthesis), dopamine β-hydroxylase (used for catecholamine synthesis), lysl oxidase (used for cross-linking collagen and elastin), and others.
Copper deficiency in animals was first recognized in sheep in 1937, manifesting as an enzootic ataxia (also known as swayback), and subsequently was noted to affect other animals similarly. Hematologic abnormalities were the first signs of acquired copper deficiency recognized in humans, with anemia, neutropenia, and sideroblastic anemia evident in some but not all patients. Neurologic manifestations of acquired copper deficiency are now increasingly recognized.
Etiology
Copper is present in a wide variety of foods, with shellfish, oysters, legumes, organ meats, chocolate, nuts, and whole-grain products being particularly rich in copper. The estimated daily requirement for copper is 0.70 mg, and the estimated total body copper content is 50 to 120 mg. Copper absorption occurs in the stomach and proximal small intestine via active and passive transport processes. The Menkes P-type ATPase ( ATP7A ) is responsible for copper efflux from enterocytes.
Malabsorption following prior gastric surgery and excessive, exogenous zinc ingestion are the most frequently identified causes of symptomatic copper deficiency (see Chapter 13 ). Copper deficiency may also occur in premature, low-birth-weight, and malnourished infants, and may occur as a complication of total parenteral or enteral nutrition. Chronic gastrointestinal conditions such as celiac disease, cystic fibrosis, inflammatory bowel disease, and bacterial overgrowth may result in copper malabsorption. Patients should be queried about the use of zinc supplements including denture creams, some of which have excessive zinc and may also induce copper deficiency. It is hypothesized that excessive zinc ingestion upregulates intestinal enterocyte metallothionein production, which has a higher affinity for copper than zinc, resulting in retention of copper in intestinal enterocytes and loss of copper in the stool. Some patients will not have any identifiable cause of copper deficiency.
Menkes disease is a congenital disorder with clinical signs and symptoms that result from copper deficiency. This condition results from a mutation in the ATP7A gene, which leads to failure of intestinal copper transport across the gastrointestinal tract and subsequent copper deficiency. Wilson disease is a disorder of copper toxicity that results from an impairment in biliary copper excretion (see Chapter 13 ).
Clinical Manifestations
Hematologic abnormalities have been well described in copper deficiency, and include primarily anemia and neutropenia. Failure to recognize hematologic derangements as resulting from copper deficiency leads to incorrect diagnoses such as myelodysplastic syndrome, aplastic anemia, and sideroblastic anemia. Patients with copper deficiency may develop a myeloneuropathy that resembles the syndrome of subacute combined degeneration associated with vitamin B 12 deficiency. Pyramidal signs, such as brisk muscle stretch reflexes at the knees and extensor plantar responses, are typically present, along with impairment in posterior column sensory modalities. Sensory loss is characteristically severe, and frequently leads to a sensory ataxia. Neuropathic extremity pain may be reported, and distal lower limb weakness and atrophy may develop, suggesting peripheral nerve involvement.
Diagnosis
Low serum copper and ceruloplasmin levels establish the diagnosis of copper deficiency. The 24-hour urinary copper level will often be decreased, in contrast to an elevation in urinary copper seen with Wilson disease. Serum and 24-hour urine zinc levels should also be assessed. Ceruloplasmin is an acute-phase reactant and may be increased in various conditions including pregnancy, oral contraceptive use, liver disease, malignancy, hematologic disease, smoking, diabetes, uremia, and other inflammatory and infectious diseases. In the presence of these conditions, copper deficiency may be masked. Serum copper and ceruloplasmin may occasionally be decreased in Wilson disease; hence laboratory evidence of copper deficiency needs to be correlated with clinical features consistent with the diagnosis.
Cervical spine MRI may show T2 hyperintensity involving the dorsal columns ( Fig. 15-1 ). Somatosensory evoked potentials often show slowing in central proprioceptive pathways, and nerve conduction studies and needle EMG demonstrate findings consistent with an axonal sensorimotor peripheral neuropathy. Brain MRI may show diffuse T2 hyperintensities involving the subcortical white matter, suggestive of demyelination.
Treatment
Treatment of copper deficiency involves copper supplementation and discontinuation of zinc in those with excessive zinc consumption. A recommended regimen is 8 mg of orally administered elemental copper daily for 1 week, followed by 6 mg daily for the next week, 4 mg daily during the third week, and 2 mg daily thereafter. Occasionally intravenous copper supplementation is necessary. Ongoing copper supplementation may not be necessary in patients with copper deficiency due to zinc excess (when zinc ingestion is discontinued) or in those with a treatable gastrointestinal condition resulting in copper malabsorption (e.g., celiac disease). Patients without an identifiable cause of copper deficiency or those with copper malabsorption due to gastric bypass surgery typically require lifelong copper supplementation.
Similar to vitamin B 12 deficiency, the hematologic abnormalities associated with copper deficiency normalize within 1 month of copper repletion. Neurologic deficits are expected to stabilize, but there may be little improvement in neurologic signs and symptoms, particularly in those with more severe neurologic impairment.
Vitamin E Deficiency
Vitamin E is a fat-soluble vitamin with important antioxidant properties, providing protection against oxidative stress and inhibiting the fatty acid peroxidation of membrane phospholipids. Vitamin E refers to a family of tocopherols and tocoretinols, of which α-tocopherol is the most abundant and active biologic form of vitamin E in the human diet.
Etiology
Nut oils, sunflower seeds, whole grains, wheat germ, and spinach are foods high in vitamin E. Vitamin E absorption requires both bile salts and pancreatic esterases. Vitamin E is incorporated into chylomicrons in intestinal enterocytes, and upon release into the circulation lipolysis ensues, resulting in the transfer of vitamin E to high-density and other lipoproteins. Alpha-tocopherol transfer protein in the liver is responsible for the incorporation of vitamin E into very-low-density lipoprotein (VLDL), which also delivers vitamin E to tissues.
Vitamin E absorption requires pancreatic and biliary secretions, and deficiency may therefore result from chronic cholestasis and pancreatic insufficiency. Chronic total parenteral nutrition with inadequate vitamin E supplementation may result in vitamin E deficiency. Other gastrointestinal disorders that result in vitamin E malabsorption include celiac disease, inflammatory bowel disease, blind loop syndrome, bacterial overgrowth, bowel irradiation, and cystic fibrosis (see Chapter 13 ). Genetic causes of vitamin E deficiency include ataxia with vitamin E deficiency resulting from α-tocopherol transport protein deficiency, apolipoprotein B mutations (homozygous hypobetalipoproteinemia), or a defect in the microsomal triglyceride transfer protein (abetalipoproteinemia).
Clinical Manifestations
Numerous neurologic manifestations of vitamin E deficiency have been reported including ophthalmoplegia, retinopathy, and a spinocerebellar syndrome with an associated peripheral neuropathy. The latter manifests with signs of a cerebellar ataxia, posterior column sensory loss, pyramidal signs, and sensory loss that resembles Friedreich ataxia. A myopathy has been associated with vitamin E deficiency with pathologic features of inflammatory infiltrates and rimmed vacuoles. Vitamin E deficiency has rarely been associated with a demyelinating neuropathy.
Diagnosis
Low serum vitamin E levels confirm the diagnosis. Serum lipids, cholesterol, and VLDL affect serum vitamin E levels, and serum vitamin E levels should be corrected for these factors by dividing the serum vitamin E value by the sum of serum triglycerides and cholesterol. Increased stool fat and decreased serum carotene levels may also be noted in patients with fat malabsorption as the etiology.
Spine MRI studies may show T2 hyperintensity in the dorsal columns, similar to that seen with vitamin B 12 and copper deficiency. Median and tibial somatosensory evoked potentials may demonstrate slowing in central proprioceptive pathways.
Treatment
Vitamin E supplementation with dosages ranging from 200 mg/day to 200 mg/kg daily should be administered. Parenteral administration may be necessary in some conditions, particularly for those with severe malabsorption. Unless there is a reversible cause of vitamin E deficiency, lifelong supplementation may be necessary.
Thiamine (Vitamin B 1 ) Deficiency
The active form of thiamine is thiamine pyrophosphate (TPP), which functions as a coenzyme in the metabolism of carbohydrates, lipids, and branched-chain amino acids. It is involved in decarboxylation of α-keto acids during adenosine triphosphate (ATP) synthesis and maintenance of reduced glutathione in erythrocytes. Thiamine pyrophosphate additionally serves as a coenzyme in myelin synthesis and has been hypothesized to play a role in cholinergic and serotonergic neurotransmission through effects on sodium channel function.
Etiology
Thiamine, or vitamin B 1 , is a water-soluble vitamin most commonly found in unrefined cereal grains, wheat germ, yeast, soybean flour, and pork. Since it is a water-soluble vitamin, hepatic storage is minimal, and excess is excreted in the urine. Its lack of storage and short (10- to 14-day) half-life necessitate a regular dietary supply of thiamine to prevent deficiency. The recommended daily allowance ranges from 1.0 to 1.5 mg/day, but requirements increase in proportion to carbohydrate intake and metabolic rate.
Thiamine is converted in the jejunum to thiamine pyrophosphate and absorbed throughout the small intestine, passing through the portal circulation prior to active and passive transport across the blood–brain barrier. Clinical manifestations of deficiency occur within days of depletion or reduced stores.
With thiamine supply being intake-dependent, deficiency is seen in persons with compromised nutritional status: reduced intake (e.g., alcoholism, starvation, fad dieting and dieting aids, acquired immunodeficiency syndrome, inadequate parenteral nutrition, thiaminase-containing foods), malabsorption (bariatric surgery, gastrointestinal/liver/pancreatic disease, excess antacid use), and increased losses (persistent emesis or diarrhea, renal failure/dialysis) (see Chapter 13 , Chapter 33 , and Table 15-4 ). Deficiency is also seen from increased thiamine requirements such as in high metabolic states including pregnancy, critical illness, hyperthyroidism, malignancy, and infection as well as with high carbohydrate intake (e.g., intravenous glucose administration, refeeding syndrome, parenteral nutrition). In these high carbohydrate states, the demand for thiamine, which is needed for glucose oxidation, exceeds replacement.
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