47: Vitamins

Vitamins are essential for normal human growth and development.⁴⁹ By definition, a vitamin is a substance present in small amounts in natural foods, is necessary for normal metabolism, and whose lack in the diet causes a deficiency disease.⁴²

A standard North American diet is sufficient to prevent overt vitamin deficiency diseases.^68,77 However, suboptimal vitamin status is common in Western populations and can be a risk factor for chronic diseases such as cardiovascular disease, cancer, and osteoporosis.^68,77 Groups at particular risk include the elderly, the hospitalized, alcohol-dependent individuals, pregnant women, and others with poor nutritional status. The American Dietetic Association posits that the best strategy for promoting optimal health and reducing chronic disease is to choose a wide variety of nutrient-rich foods, while the use of supplements can help some people meet their nutritional needs.¹⁵⁴ Health care professionals should identify patients with poor nutrition or other reasons for increased vitamin needs and offer guidance on vitamin supplementation. Some suggest that since most people do not consume an optimal amount of vitamins by diet alone, it is prudent for all adults to take vitamin supplements with physician guidance.^68,77

Dietary supplement use has increased over time in the United States. National Health and Nutrition Examination Survey (NHANES) data collected from 2003 to 2006 demonstrate that dietary supplement use was reported by 49% of the population age 1 year and older, an increase of approximately 10% from NHANES data from 1988 to 1994, with 79% of users taking them daily for the past 30 days.¹⁵ The categories of dietary supplements included multivitamin, multiminerals (MVMMs), botanicals, and amino acids. Among adults and children, MVMMs were the most commonly reported dietary supplement, with 33% of the population reporting use.

Unfortunately, many individuals share the mistaken beliefs that vitamin preparations provide extra energy or promote muscle growth and regularly ingest quantities of vitamins in great excess of the recommended dietary allowances (RDAs) (Table 47–1). The most commonly used MVMM preparations generally do not exceed 100% of the RDA, but excessive vitamin intake is more likely to occur in MVMM users who also take single vitamin supplements.¹⁹⁹ Excess vitamin intake may also occur in individuals taking an MVMM who ate a healthy diet that included fortified foods and beverages.¹⁶⁸ Some vitamins are associated with consequential adverse effects when ingested in very large doses. Adverse events also may be associated with the use of some vitamins at the RDA or at amounts less than or approaching the established tolerable upper intake level (UL) in certain populations. Those who smoke should avoid products containing large amounts of vitamin A and β-carotene because studies have linked use of these vitamins to an increased risk of lung cancer in smokers.¹⁹⁰ In one study, smokers taking 20 mg/day of β-carotene (UL 36 mg/day) had an 18% higher lung cancer rate than smokers taking a placebo.²²⁴ Individuals taking medications to reduce blood clotting, such as warfarin, should not take supplemental vitamin K since it is involved in blood clotting and may reduce the effectiveness of warfarin and similar medications.

Vitamins can be divided into two general classes. Most of the vitamins in the water-soluble class have minimal toxicity because they are stored to only a limited extent in the body. Thiamine, riboflavin, cyanocobalamin, pantothenic acid, folic acid, and biotin are not reported to cause any toxicity following oral ingestion.⁴⁹ Ascorbic acid (vitamin C), nicotinic acid (vitamin B₃), and pyridoxine (vitamin B₆) have associated toxicity syndromes. However, the fat-soluble vitamins can bioaccumulate to massive degrees. As a result, the potential for toxicity greatly exceeds that of the water-soluble group. Vitamins A, D, and E (but not K) are associated with toxicity following very large overdose or chronic overuse. The adverse effect secondary to vitamin K is limited to severe, and sometimes fatal, anaphylactoid reactions with rapid administration of the intravenous (IV) preparation.⁷⁵

History and Epidemiology

Two independent groups discovered vitamin A in 1913.^157,178 They reported that animals fed an artificial diet with lard as the sole source of fat developed a nutritional deficiency characterized by xerophthalmia. They found that this deficiency could be corrected by adding to the diet a factor contained in butter, egg yolks, and cod liver oil. They named the substance “fat soluble vitamin A.” The chemical structure of vitamin A was determined in 1930.¹²³ Vitamin A is also found naturally in liver, fish, cheese, and whole milk. In the United States and other parts of the world, including some developing countries, many cereal, grain, dairy, and other products, as well as infant formulas, are fortified with vitamin A.^6,240

Vitamin A toxicity can occur in people who ingest large doses of preformed vitamin A in their daily diets. Inuits in the sixteenth century recognized that ingestion of large amounts of polar bear liver caused a severe illness characterized by headaches and prostration.⁷⁶ Arctic explorers in the 1800s knew of the poisonous qualities of polar bear liver and described an acute illness following its ingestion.⁸⁵ Explorers also described a condition among the Inuit population known as pibloktoq, or “Arctic hysteria,” characterized by hysteria, depression, echolalia, insensitivity to extreme cold, and seizures, and believed to be related to ingestion of polar bear liver and other organ meats.¹⁸² Vitamin A toxicity is implicated in the etiology of pibloktoq as some somatic and behavioral effects of vitamin A toxicity closely parallel many of the symptoms reported in Inuit patients diagnosed with ­pibloktoq.¹³² However, the toxic substance in polar bear liver was not identified as vitamin A until 1942.²⁰⁰ The vitamin A content of polar bear liver is as high as 34,600 IU/g (10,400 RAE/g), supporting the view that vitamin A is the toxic factor in liver.²⁰³

Vitamin A toxicity was reported in an adult who chronically ingested large amounts of beef liver,¹¹⁴ as well as following ingestion of the liver of the grouper fish Cephalopholis boenak, which has a high content of vitamin A.⁴³ Ingestion of whale and seal liver, as well as the livers of large fish, such as shark, tuna, and sea bass, also is associated with development of vitamin A toxicity.

Vitamin A toxicity usually is not expected to occur following ingestion of large doses of provitamin A carotenoids. Vitamin A induced hepatotoxicity and neurotoxicity was believed to have developed in an 18 year-old girl who maintained a diet nearly limited to foods rich in the carotenoid β-carotene, including pumpkin, carrots, and laver (nori), for several years.¹⁷⁰ However, she also included an unspecified, although reportedly small, amount of fish, red meat, and liver in her diet.

Vitamin A toxicity is rare, with a reported average incidence of less than 10 cases per year from 1976 to 1987.²⁰ The majority of reported cases of vitamin A toxicity result from inappropriate use of vitamin supplements.^17,20 In the United States, 28% of the population report taking a dietary supplement containing vitamin A.¹⁵

Vitamin A is present in two forms. Preformed vitamin A as retinol is derived from retinyl esters, its storage form, in animal sources of food. Provitamin A carotenoids are vitamin A precursors and are found in plants. Among the carotenoids, β-carotene is most efficiently made into retinol. The term vitamin A was classically only used to refer to the compound retinol. Currently, it is used to describe all retinoids, compounds chemically related to retinol that exhibit the biological activity of retinol. Retinol can be converted in the body to the retinoids retinal and retinoic acid. Synthetic retinoids have been developed via chemical modification of naturally occurring retinoids, often for a specific therapeutic purpose. Vitamin A activity is expressed in retinol activity equivalents (RAEs). One RAE corresponds to 1 µg of retinol or 3.33 IU of vitamin A activity as retinol. One RAE also corresponds to 12 µg of β-carotene.

Vitamin A content varies widely among different food types. A 3 oz serving of cooked beef liver contains 30,325 IU (9100 RAE) of vitamin A, whereas 1 cup of whole milk contains 305 IU (92 RAE) of vitamin A. Fish-liver oils, such as swordfish and black sea bass, have extremely large amounts of vitamin A and may contain more than 180,000 IU (54,050 RAE) of vitamin A per gram of oil. Carotenoids are present in yellow and green fruits and vegetables. A raw carrot has a high β-carotene content of approximately 20,250 IU (6080 RAE). One half cup serving of spinach contains approximately 7400 IU (2220 RAE) of β-carotene, whereas an apricot or peach contains 500 to 600 IU (150–180 RAE). The average American diet provides about one half of its daily vitamin A intake as carotenoids and about one half as preformed vitamin A.⁴⁶ The RDA of vitamin A is 900 µg RAE/day (3000 IU/day) for adult men and 700 µg RAE/day (2300 IU/day) for women (Table 47–1).⁸⁰ The UL for adults is 3000 µg RAE/day (9900 IU/day).

As a group, retinoids have specific sites of action and varying degrees of biologic potency. Retinoic acid is primarily responsible for maintaining normal growth and differentiation of epithelial cells in mucus secreting or keratinizing tissue.¹⁵³ Vitamin A deficiency results in the disappearance of goblet mucous cells and replacement of the normal epithelium with a stratified, keratinized epithelium. Dermal manifestations are the earliest to develop and include dry skin and hair and broken fingernails. In the cornea, hyperkeratization is called xerophthalmia and can lead to permanent blindness. Alterations in the epithelial lining of other organ systems may lead to increased susceptibility to respiratory infections, diarrhea, and urinary calculi. Vitamin A, in the form of 11-cis-retinal, plays a critical role in retinal function.²³⁴ Deficiency results in nyctalopia, which is decreased vision in dim lighting, more commonly known as night blindness.

Vitamin A is prescribed for some people for dermatologic and ophthalmic conditions. Vitamin A toxicity often occurs in adults who continue to use the vitamin without medical supervision.⁸⁶

Isotretinoin (Accutane), 13-cis-retinoic acid, is prescribed for treatment of severe cystic acne. Of great concern is the teratogenicity associated with its use by pregnant women. There has not been any association between male use of isotretinoin during the time of conception and birth defects. The iPLEDGE program is a mandatory US Food and Drug Administration (FDA) risk evaluation and mitigation strategy for the distribution of isotretinoin that was initiated in 2006. Its goals are to inform prescribers, pharmacists, and patients about the serious risks of isotretinoin’s and safe-use conditions and to prevent fetal exposure to isotretinoin.²²⁸ Components of the program include mandatory enrollment, documentation of a negative pregnancy test and birth control use, and prescriber, pharmacist, and patient education. The iPLEDGE program replaced the FDA’s System to Manage Accutane-Related Teratogenicity (SMART) program that was initiated in 2002. Although both programs share many features, the SMART program was voluntary and did not include mandatory record keeping or reporting. A review after the implementation of the SMART program revealed that there was an increase in the number of pregnant women prescribed isotretinoin compared with the previous year. The review revealed that prescribers were not providing adequate patient education regarding the risk of teratogenicity and that there was not compliance with essential portions of the pregnancy prevention program.¹⁹⁸

All-trans-retinoic acid (ATRA), or tretinoin, is used as a differentiating chemotherapeutic in the treatment of acute promyelocytic leukemia (APL), a disease characterized by the accumulation of promyelocytic blasts in bone marrow due to obstruction of differentiation of granulocytic cells.¹³⁵ ATRA, in combination with anthracycline chemotherapy, improves the complete remission rate, often reported to be greater than 90%, and reduces the incidence of relapse to only 10% to 15% when used as maintenance therapy.⁷¹ APL differentiation syndrome (DS), previously known as ATRA syndrome or retinoic acid syndrome, is the main adverse effect and occurs in up 14% to 16% of patients who receive ATRA with an associated mortality of about 2%.¹⁸⁴ ATRA has also been used for the treatment of myelodysplastic syndrome and acute myelogenous leukemia.

Pharmacology, Pharmacokinetics, and Toxicokinetics

Absorption of vitamin A in the small intestine is nearly complete. However, some vitamin A may be eliminated in the feces when large doses are taken. The majority of vitamin A is ingested as retinyl esters, the storage form of retinol.¹⁵³ Retinyl esters undergo enzymatic hydrolysis to retinol by digestive enzymes in the intestinal lumen and brush border of the intestinal epithelial wall. A small portion of retinol is absorbed directly into the circulation, where it is bound to retinol-binding protein (RBP) and transported to the liver. Most of the retinol is taken into intestinal epithelial cells by RBP.¹⁷⁵ Subsequently, retinol is reesterified and incorporated into chylomicrons, which are released into the blood and taken up by the Ito cells of the liver. After large oral doses, significant amounts of retinyl esters coupled to chylomicrons circulate in association with low-density lipoprotein (LDL) and are delivered to the liver. ­Approximately 50% to 80% of the total vitamin A content of the body is stored in the liver as retinyl esters.²⁸ The liver releases vitamin A into the bloodstream to maintain a constant plasma retinol concentration and is thus delivered to tissues as needed.

Carotenoid absorption requires bile and absorbable fat in the stomach or intestine. These components combine with carotenoids to form mixed lipid micelles which move into the duodenal mucosal cells via passive diffusion. The majority of β-carotene that is metabolized undergoes central cleavage via oxidation to form retinal, which is then reduced to retinol. Retinol is then esterified with fatty acids and incorporated into chylomicrons, which are transported to the bloodstream via the lymphatics for delivery to the liver. Massive doses of β-carotene are rarely associated with vitamin A toxicity due to decreased efficiency in absorption secondary to saturation of dissolution in bulk lipid, micellar incorporation, and diffusion due to a reduction in the concentration gradient.¹⁸¹ Unabsorbed β-carotene is excreted in the feces. In addition, there is a decrease in the rate of conversion of carotenoids to vitamin A.⁶³ Hypercarotenemia develops when massive doses are ingested. Excess absorbed β-carotene is incorporated with lipoproteins and released into the bloodstream via the lymphatics for delivery to the adipose tissue and adrenals for storage. Hypercarotenemia usually is not associated with morbidity.

The normal serum retinol concentration is approximately 30 to 70 µg/dL.²¹⁴ These concentrations are maintained at the expense of hepatic reserves when insufficient amounts of vitamin A are ingested. A normal adult liver contains enough vitamin A to fulfill the body’s requirements for approximately 2 years.¹⁶³ Excessive intake of vitamin A is not initially reflected by elevated serum concentrations because vitamin A is soluble in fat but not in water. Instead, hepatic accumulation is increased. This storage system allows for cumulative toxic effects. Although no quantitative relationship exists between the magnitude of liver stores and serum concentrations of vitamin A, in chronic vitamin A toxicity serum concentrations are generally higher than 3.49 μmol/L (95 µg/dL).²⁰ Vitamin A has a half-life of 286 days.^216,238 Retinoids undergo a variety of metabolic and conjugation pathways and are subsequently eliminated in the feces, urine, or bile.

Clinical toxicity correlates well with total body vitamin A content, which is a function of both dose and duration of administration. A randomized double blind trial, in which 390 women received 400,000 IU (120,000 RAE) of vitamin A as a single dose were compared with 380 women who received placebo, suggested that dosing at this level is well tolerated.¹¹³ Doses of 100,000 IU (30,000 RAE) of vitamin A in infants aged 6 to 11 months and 200,000 IU (60,000 RAE) of vitamin A every 3 to 6 months for infants and children aged 12 to 60 months result in few adverse events.¹⁹ The minimal dose required to produce toxicity in humans is not established. However, an animal study has shown that the median lethal acute dose in monkeys is 560,000 IU (168,000 RAE) per kilogram of body weight.¹⁴⁸ In this study, all monkeys receiving more than 300,000 RAE/kg (999,000 IU/kg) died, whereas none died at a dose of 100,000 RAE/kg (333,000 IU/kg). Hepatotoxicity can occur in humans following an acute ingestion of a massive dose of vitamin A (>600,000 IU {180,000 RAE}).¹²⁹

Vitamin A toxicity may occur more frequently secondary to chronic ingestions of vitamin A. Hepatotoxicity typically requires vitamin A ingestions of at least 50,000 to 100,000 IU/day (15,000–30,000 RAE/day) for months or years.^6,129 One study found that in patients with vitamin A–induced hepatotoxicity, the average daily vitamin A intake was higher in patients who developed cirrhosis (135,000 IU/day 40,500 RAE/day) compared with patients who developed noncirrhotic liver disease (66,000 IU/day 20,000 RAE/day).⁸⁴ However, case reports have documented hepatotoxicity resulting from vitamin A doses as low as 25,000 IU/day (7500 RAE/day),^86,129 a dose widely available in nonprescription vitamin A preparations.

Pathophysiology

The mechanism of action for many of the toxic effects of vitamin A may be at the nuclear level. Retinoic acid influences gene expression by combining with nuclear receptors.¹⁵³ Retinoids also influence expression of receptors for certain hormones and growth factors. Thus, they are able to influence growth, differentiation, and function of target cells.¹⁴⁵

In epithelial cells and fibroblasts, retinoids affect changes in nuclear transcription, resulting in enhanced production of proteins such as fibronectin and decreased production of other proteins such as collagenase.¹⁵⁰ Excessive concentrations of retinoids where goblet cells are present lead to the production of a thick mucin layer and inhibition of ­keratinization. In addition, lipoprotein membranes have increased permeability and decreased stability, resulting in extreme thinning of the epithelial tissue.

In vitro studies in bone demonstrate that high doses of vitamin A are capable of directly stimulating bone resorption and inhibiting bone ­formation. This effect is secondary to increased osteoclast formation and activity and inhibition of osteoblast growth.^172,177,209

Hepatotoxicity may develop secondary to a single large acute overdose or ingestion of smaller doses if taken over a prolonged time.^86,129 A total of 90% of hepatic vitamin A stores are located in the Ito, or fat-storing, cells of the liver, which are located in the perisinusoidal space of Disse, and are responsible for maintaining normal hepatic architecture.^99,100 Ito cells undergo hypertrophy and hyperplasia as vitamin A storage increases.¹²⁹ This results in transdifferentiation of the Ito cell into a myofibroblastlike cell that secretes a variety of extracellular matrix components, leading to narrowing of the perisinusoidal space of Disse, obstruction to sinusoidal blood flow, and noncirrhotic portal hypertension (Fig. 47–1).^{54,91,110,124,129,206} Continued ingestion of vitamin A and hepatic storage may lead to obliteration of the space of Disse, sinusoidal barrier damage, perisinusoidal hepatocyte death, fibrosis, and cirrhosis^{110,118,129,204} (Chap. 23).

Vitamin A toxicity has long been thought to be the cause of the severe headaches and papilledema associated with idiopathic intracranial hypertension (IIH).¹⁹³ Increased concentrations of unbound retinol in the cerebral spinal fluid (CSF) of patients with IIH suggest that vitamin A is involved in the pathogenesis of IIH.^223,237 However, the mechanisms by which vitamin A leads to increased intracranial pressure (ICP) in IIH are not definitively known.¹⁹³ Unbound, circulating retinol and retinyl esters are proposed to be capable of interacting with cell membranes and producing damage by membranolytic surface-active properties.¹¹⁵ In the central nervous system (CNS), disruption of cell membrane integrity might lead to disruption of CSF outflow, thereby producing signs and symptoms consistent with IIH.^{88,115,127,149} It has also been suggested that vitamin A could lead to intracranial hypertension via enhanced transcription of genes involved in CSF secretion or absorption.⁹² Another explanation for the association of vitamin A with IIH involves the recent recognition of RBP as a signaling molecule altering CSF secretion or absorption.¹⁴²

Clinical Manifestations

Symptoms of an acute overdose of vitamin A often develop within hours to two days after ingestion.¹⁶³ Initial signs and symptoms include headache, papilledema, scotoma, photophobia, seizures, anorexia, drowsiness, irritability, nausea, vomiting, abdominal pain, liver damage, and desquamation.¹⁶³ Nonspecific symptoms include fatigue, fever, weight loss, edema, polydipsia, dysuria, hyperlipidemia, anemia, and menstrual abnormalities.

Hypercarotenemia produces a yellow-orange skin discoloration that can be differentiated from jaundice by the absence of scleral icterus.

Chronic toxicity of vitamin A affects the skin, hair, bones, liver, and brain. The most common skin manifestations include xerosis, which is associated with pruritus and erythema, skin hyperfragility, and desquamation.^60,61,243 Retinoid toxicity may cause hair thinning and even diffuse hair loss in 10% to 75% of patients.^79,89,126 In addition, the characteristics of the hair may change after regrowth. Hair sometimes becomes permanently curly or kinky.¹⁰ Nail changes include a shiny appearance, brittleness, softening, and loosening.⁷² Dryness of mucous membranes develops with chapped lips and xerosis of nasal mucosa, which sometimes is associated with nasal bleeding.⁵¹

Findings from epidemiologic studies are consistent with bone loss and a resulting increase in fracture risk. In northern Europe, the region with the highest incidence of osteoporotic fractures, dietary intake of vitamin A is high. A study of this population demonstrated that the risk of first hip fracture was increased by 68% for every 1 mg increase in RAE intake.¹⁵⁹ This study also showed that compared with intake less than 0.5 mg/day, intake greater than 1.5 mg/day reduced bone mineral density by 10% at the femoral neck, 14% at the lumbar spine, and 6% for the total body, doubling the risk of hip fracture. These findings are supported by other studies demonstrating an increased risk of hip fracture among women with elevated serum vitamin A concentrations and in women ingesting large daily amounts of vitamin A.^73,176 One study found that among women not taking supplemental vitamin A, a diet rich in vitamin A was also associated with an increased fracture risk.⁷³

Other musculoskeletal findings include skeletal hyperostoses, most commonly affecting the vertebral bodies of thoracic vertebrae, extraspinal tendon and ligament calcifications, soft-tissue ossification, cortical thickening of bone shafts, periosteal thickening, and bone demineralization.^51,163,165 Many of these findings are apparent on radiographs. Patients often complain of bone and joint pain and muscle stiffness or tenderness. Hypercalcemia, with low or normal parathyroid hormone (PTH) concentrations, likely results from increased osteoclast activity and bone resorption.³⁰ Patients with chronic kidney disease are at increased risk for developing hypercalcemia at vitamin A doses lower than usual toxic doses secondary to decreased renal metabolism of retinol. This complication occurred in an 8 year-old boy with chronic kidney disease following a dose of 12,000 IU/day (3600 RAE/day) for at least 2 years.⁵⁸ Premature epiphyseal closure in children is reported.¹⁸⁹ Teratogenic effects include interference with skeletal differentiation and growth.³⁰

The degree of hepatotoxicity appears to correlate with the dose of vitamin A and chronicity of use. With large doses, cirrhosis develops and may lead to portal hypertension, esophageal varices, jaundice, and ascites.^55,86,129 Hepatotoxicity may be manifested by elevations in bilirubin, aminotransferases, and alkaline phosphatase concentrations.

Idiopathic intracranial hypertension is characterized by elevated ICP in the absence of a structural anomaly. It occurs in patients with altered endocrine function, systemic diseases, impaired cerebral venous drainage, or ingestion of various xenobiotics, including excessive vitamin A (Table 47–2).⁵ The syndrome is most common in young obese women, but the etiology remains unknown in the majority of cases. The first case of IIH associated with vitamin A toxicity was described in 1954.⁸⁵ However, the symptoms were first described in 1856 by an Arctic explorer who noted vertigo and headache after eating polar bear liver.²¹³ Patients typically present with headache and visual disturbances, including sixth nerve palsies, visual field deficits, and blurred vision, and have a normal mental status. Despite severe papilledema, visual loss often is minimal. However, permanent blindness may result from optic atrophy.¹⁴⁷ Other symptoms of neurotoxicity include ataxia, fatigue, depression, irritability, and psychosis.²⁶

Isotretinoin is effective in the management of acne. However, its use is associated with teratogenicity. It is thought to interfere with cranial neural crest cells, which contribute to the development of both the ear and the conotruncal area of the heart, and may cause malformed or absent external ears or auditory canals and conotruncal heart defects.¹³¹ Although studies have not shown a teratogenic risk with topical preparations, case reports describe fetal malformations associated with topical preparation use during pregnancy.^{13,36,119,143,212} In addition, mucocutaneous abnormalities, IIH, corneal opacities, hypercalcemia, hyperuricemia, musculoskeletal symptoms, liver function abnormalities, elevated triglyceride concentrations, and spontaneous abortion are reported.^{3,78,84,96,97}

Acute promyelocytic leukemia DS is the main adverse effect of treatment with ATRA. The pathophysiology of DS is not well understood, but involves an inflammatory response. Proposed mechanisms include tissue infiltration of APL cells, particularly in the lungs but also in the liver, spleen, and heart, and leukocyte extravasation.¹³³ Onset of symptoms is typically 2 to 21 days after initiation of ATRA.¹⁸⁴ The hallmarks of DS are fever and respiratory distress.^184,201 Other common signs and symptoms include elevated white blood count, dyspnea, pulmonary edema, pulmonary infiltrates, and pleural and pericardial effusions.^184,201 Weight gain, bone pain, headache, hypotension, congestive heart failure, acute kidney injury, and hepatotoxicity occur less commonly.^184,201 There are no established criteria for diagnosis, but some suggest that three signs and symptoms are needed.²⁰¹ Elevated leukocyte counts at diagnosis or rapidly increasing counts during ATRA treatment predict the development of DS. Addition of dexamethasone to the ATRA treatment regimen decreases the incidence of DS to approximately 15% and its mortality to 1%.⁷⁰ However, other data demonstrated a 17% occurrence of DS despite concurrent use of steroids and not all authors support its use.^184,242

Diagnostic Testing

The diagnosis of vitamin A associated hepatotoxicity is supported by histologic evidence of Ito cell hyperplasia with fluorescent vacuoles on liver biopsy.⁸⁶ Laboratory testing should also include serum electrolytes including calcium, hepatic enzymes, a complete blood cell count, and a vitamin A concentration. Because the liver has a large storage capacity for excess vitamin A, hepatotoxicity may occur prior to an elevation in the serum concentration of vitamin A, which may be normal or even low, in the setting of an acute overdose. As the hepatic storage capacity is overwhelmed, the serum concentration may rapidly rise in a nonlinear fashion. Further evaluation should be guided by the clinical presentation and may include bone radiographs, computed tomography of the brain, and lumbar puncture.

Treatment

Management of a patient with a recent acute, large overdose should begin with gastrointestinal decontamination. This can be accomplished with a dose of activated charcoal. In extremely large overdoses that are expected to produce significant toxicity, gastric lavage may be ­considered. Although most signs and symptoms of vitamin A toxicity resolve within one week following vitamin A discontinuation and supportive care, papilledema, desquamation, and skeletal abnormalities may persist for several months. Hypercalcemia should be treated with IV fluids, loop diuretics, and prednisone 20 mg/day.²⁵ Bisphosphonates may be beneficial in refractory cases.

Idiopathic intracranial hypertension may require more aggressive therapy. Indications for treatment include visual field loss and symptoms of elevated ICP.¹⁹³ Acetazolamide, a carbonic anhydrase inhibitor, is the most commonly used treatment for IIH.¹⁹³ It is usually started at a dose of 0.5 to 1 g/day and gradually increased until clinical improvement is seen to 3 to 4 g/day.¹⁹³ Acetazolamide has teratogenic effects in animals and is designated FDA pregnancy category C. Topiramate, a partial carbonic anhydrase inhibitor that is used in the treatment of migraine headaches and epilepsy has demonstrated efficacy comparable to acetazolamide in the treatment of IIH.³⁸ Its adverse effect of weight loss may also be beneficial for patients with IIH. Furosemide is considered second-line treatment, but can be used in patients who cannot tolerate acetazolamide.^29,193 The role of corticosteroids in the treatment of IIH is controversial and they should not be used chronically for the treatment of papilledema.²⁹ However, a short course of high dose corticosteroids may be used in patients with acute visual loss from fulminant papilledema.¹⁴⁴ Patients with extremely high ICP may benefit from daily lumbar punctures with CSF drainage.

Treatment of DS involves prompt administration of corticosteroids, commonly dexamethasone 10 mg IV twice daily until symptoms resolve followed by a 2-week taper.²⁰¹ In severe cases, ATRA should be discontinued or another chemotherapeutic, typically cytarabine, should be added to ATRA in patients with high white blood cell counts.¹⁸⁴ ATRA can be reintroduced upon resolution of DS.

History and Epidemiology

Rickets, a disease of urban children living in temperate zones, was thought to result from the lack of a dietary factor or adequate sunshine. In 1919, two independent groups demonstrated that rickets could be prevented or cured by either the addition of cod liver oil to the diet or exposure to sunlight.^112,160 Vitamin D is found in cod liver oil and other foods, including butter, cheese, and cream, which contain 12 to 40 IU/100 g (0.3–1 µg/100 g), eggs, which contain 25 IU/100 g (0.6 µg/100 g), and fatty fish, such as salmon and mackerel, which contain 150 to 550 IU/100 g (4–14 µg/100 g) and 1100 IU/100 g (28 µg/100 g), respectively. Some foods typically are fortified with vitamin D, including cereals, bread, and milk.¹⁰⁵ Many dietary supplements, such as multivitamins, contain vitamin D.

Rickets has been eliminated as a major public health concern in children in Europe and North America since the fortification of milk with vitamin D. Outbreaks of vitamin D poisoning subsequently occurred in Europe in the 1950s because of excessive fortification of milk and cereals to compensate for wartime nutritional deprivation of children.⁵⁶ This vitamin D poisoning led to a period of prohibition of vitamin D fortification of foods.¹⁰⁵ More recently, a study showed that milk and infant formulas rarely contain the amount of vitamin D stated on the label and may be either significantly underfortified or overfortified, leading to vitamin D deficiency or toxicity.¹⁰⁵ One case series demonstrated vitamin D toxicity in eight patients who drank local dairy milk that was excessively fortified with vitamin D₃.¹¹⁷ Many cases of vitamin D toxicity result from continued supplementation of vitamin D and calcium initially prescribed for treatment of hypoparathyroidism, osteoporosis, or osteomalacia but inappropriately continued due among other reasons to inadequate patient physician communication.^53,137,185 Two reports describe vitamin D toxicity in families secondary to use of a highly concentrated vitamin D preparation in nut oil that was not intended for human consumption.^59,186 Another case report describes vitamin D poisoning secondary to contamination of table sugar with crystalline vitamin D₃.²³² Vitamin D toxicity has been reported in dogs secondary to vitamin D₃ exposure in the form of rodenticides.⁸¹ Vitamin D deficiency should not occur in individuals who eat a well-balanced diet and are exposed to adequate sunlight. Casual exposure of cutaneous tissues to ultraviolet light during the summer months should produce adequate vitamin D storage for winter months.⁹³ Total body sun exposure provides the vitamin D equivalent of 10,000 IU/day (250 µg/day); the body requires only a total vitamin D supply of 4000 IU/day (100 µg/day).²³⁰ Breast-fed infants may require supplemental vitamin D if they have limited exposure to sunlight because the vitamin D content of human milk is extremely low.⁴⁹ Other groups susceptible to vitamin D deficiency include the elderly, vegans, persons with darkly pigmented skin, and persons without adequate sunlight exposure such as those living in institutions.

The Institute of Medicine (IOM) recently found that although average total vitamin D intake was below the median requirement in North Americans, average serum concentrations of vitamin D were above the 20 ng/mL concentration that the IOM determined to be needed for good bone health. They suggested that sun exposure contributes meaningful amounts of vitamin D and that the majority of the population is meeting its needs for vitamin D.²⁰² Despite this finding, in 2010 the IOM revised its dietary reference intakes with an increase in the RDA for vitamin D across all age groups (Table 47–1). The new RDA assumes minimal sunlight exposure and is 600 IU/day (15 µg/day) for nonelderly adults. The new RDA may lead to an increased number of persons taking vitamin D either by prescription or in the form of a dietary supplement. In addition, the IOM found that testing for vitamin D deficiency has become widespread.²⁰² However, the measurements or cut-points of sufficiency or deficiency used by laboratories are not based on scientific studies and there is no central regulatory authority determining which cut-point should be used. The IOM found that many laboratories use an inappropriately high cut-point for deficiency, thereby leading to an increased number of diagnoses of vitamin D deficiency and possibly persons taking unnecessary vitamin D supplements.

The use of vitamin D supplements to prevent and treat a variety of illnesses has increased substantially over the past decade.⁹⁵ Vitamin D deficiency is linked to autoimmune disease, cancer, cardiovascular disease, depression, dementia, infectious disease, musculoskeletal decline, and more.⁹⁵ However, the IOM concluded that vitamin D supplementation for indications other than musculoskeletal health is not supported by adequate scientific evidence.²⁰² Vitamin D is used for the prophylaxis and treatment of rickets, osteomalacia, and osteoporosis. It is also used for the treatment of hypoparathyroidism and skin conditions, including psoriasis.

Vitamin D is the name given to both ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃). In humans, both forms of vitamin D have the same biologic potency. One microgram of vitamin D is equivalent to 40 IU of vitamin D.

Pharmacology, Pharmacokinetics, and Toxicokinetics

Vitamin D itself is not biologically active and must go through extensive metabolism to an active form, whether it is ingested from a food source in the form of vitamin D₂ and D₃ or synthesized in the body. Vitamin D₃ is synthesized in the skin from 7-dehydrocholesterol (provitamin D₃) in a reaction catalyzed by ultraviolet B irradiation (Fig. 47–2).¹³⁷ Vitamin D₃ then is bound to vitamin D-binding protein, a protein that also binds vitamin D from the diet, and afterward enters the circulation. In the endoplasmic reticulum of the liver, vitamin D is metabolized to 25-hydroxyvitamin D {25(OH)D} by vitamin D-25-hydroxylase.⁸² Once formed, 25(OH)D is again bound to vitamin D-binding protein and transported to the proximal convoluted tubule in the kidney for hydroxylation to 1,25-dihydroxyvitamin D {1,25(OH)₂D}, or calcitriol, by 25(OH)D-1-α-hydroxylase.⁸² Once formed, 1,25(OH)₂D is secreted back into circulation, bound to vitamin D-binding protein, and delivered to target cells where it binds to receptors.

Vitamin D might be more appropriately called a hormone rather than a vitamin because it is synthesized in the body, circulates in the blood, and then binds to receptors in order to evoke its biologic action. The primary role of vitamin D is regulation of calcium homeostasis via interactions with the intestines and bones. Protein bound calcitriol is taken up by cells and then binds to a specific nuclear vitamin D receptor protein that, in turn, binds to regulatory sequences on chromosomal DNA.¹³⁷ The result is induction of gene transcription and translation of proteins that carry out the cellular functions of vitamin D. In the intestines, calcitriol increases the production of calcium binding proteins and plasma membrane calcium pump proteins, thereby increasing calcium absorption through the duodenum.¹²⁰ In the bone, calcitriol stimulates osteoclastic precursors to differentiate into mature osteoclasts.¹⁰⁶ Mature osteoclasts, together with PTH, lead to mobilization of calcium stores from bone, thereby raising serum concentrations of calcium. Given sufficient serum concentrations of calcium, calcitriol promotes bone mineralization by osteoblasts, resulting in increased deposition of calcium hydroxyapatite into the bone matrix.¹⁰⁶ Calcitriol also binds to a vitamin D receptor in the parathyroid glands, which leads to decreased synthesis and secretion of PTH.¹⁷¹ The vitamin D receptor is present in most cells of the body including lymphocytes, epidermal skin cells, and tumor cells.²⁰⁵ The binding of calcitriol can inhibit proliferation and induce terminal differentiation.¹⁸⁸ Although the role of vitamin D has not been elucidated in all cells, abnormalities present during vitamin D deficiency may help identify the function of vitamin D in various tissues.

Vitamin D deficiency results in hypocalcemia, leading to increased secretion of PTH, which acts to restore plasma calcium concentrations at the expense of bone. In children, this situation leads to rickets in which newly formed bone is not adequately mineralized and results in bone deformities and growth defects. Adults develop osteomalacia, a disease characterized by undermineralized bone matrix. Patients typically present with bone pain and tenderness and proximal muscle weakness. Bone deformities are limited to the advanced stages of disease.

The literature varies regarding the toxic dose of vitamin D, with little scientific data available for corroboration. The current upper level intake is set at 4000 IU/day (100 µg/day) for persons aged 9 years and older, with lower levels set for children younger than 9 years of age.²⁰² This is an increase compared to the previous tolerable upper intake dose of 2000 IU/day (50 µg/day).²³⁰ There also are studies showing that doses as high as 4400 IU/day (110 µg/day) and 100,000 IU (2500 µg) for 4 days did not result in adverse effects.^219,226,230 Case reports describe toxicity in the setting of vitamin D intake of 50,000 to 600,000 IU or, simply, doses in the milligram range, daily for prolonged periods.^{53,90,146,185}

Pathophysiology

The hallmark of vitamin D toxicity is hypercalcemia. Vitamin D in the form of 1,25(OH)₂D promotes calcium absorption from the gut and mobilization of calcium from bone. Vitamin D toxicity may be associated with a serum concentration of 25(OH)D 20 times higher than normal, whereas the concentration of 1,25(OH)₂D remains exceedingly variable.^82,18625-Hydroxyvitamin D can mimic the action of 1,25(OH)₂D when it is present in excess and can bind to receptors usually specific for 1,25(OH)₂D.^82,137 Alternatively, 25(OH)D, which has a higher affinity for vitamin D-binding protein compared to 1,25(OH)₂D, may preferentially bind to vitamin D-binding protein when it is present in elevated concentrations, displacing 1,25(OH)₂D and allowing it to circulate in an unbound form, or loosely bound to albumin.²³¹ A study of patients with vitamin D toxicity who had normal or near normal total 1,25(OH)₂D concentrations had elevated free 1,25(OH)₂D concentrations.¹⁸⁶ The availability of 1,25(OH)₂D to its receptors likely is increased, resulting in vitamin D toxicity.

Clinical Manifestations

Patients with vitamin D toxicity present with signs and symptoms characteristic of hypercalcemia.¹³⁷ Early manifestations include weakness, fatigue, somnolence, irritability, headache, dizziness, muscle and bone pain, nausea, vomiting, abdominal cramps, and diarrhea or constipation (Chap. 19). As the calcium concentration increases, hypercalcemia may induce polyuria and polydipsia. Diuresis results in salt and water depletion, further impairing calcium excretion. Severe hypercalcemia may present with ataxia, confusion, psychosis, seizures, coma, and acute kidney injury. In addition, cardiac dysrhythmias result from a shortened refractory period and slowed conduction. Findings on electrocardiography include increased PR intervals, widening of QRS complexes, QT shortening, and flattened T waves (Chap. 16).¹⁷³ Patients can develop metastatic calcification of the kidneys, blood vessels, myocardium, lung, and skin. Several patients with vitamin D toxicity have presented with anemia.^191,207 Proposed mechanisms for anemia include a direct effect of vitamin D on hematopoietic cells and inhibition of erythropoietin production.¹⁹¹

Diagnostic Testing

Vitamin D toxicity should be considered in patients presenting with signs and symptoms of hypercalcemia. In addition to an elevated serum calcium concentration, laboratory results may reveal hyperphosphatemia given that vitamin D facilitates phosphate absorption in the small intestine, enhances its mobilization from bone, and decreases its excretion by the kidney.¹⁵¹ The diagnosis should be suspected in children with nephrocalcinosis and hypercalciuria even if serum calcium and phosphorus concentrations are normal.¹⁶⁶ Serum 25(OH)D can be measured, but it is unlikely that results will be available quickly. According to the IOM, the desired 25(OH)D concentration range is 20 to 50 ng/mL.²⁰² The IOM also found that concentrations higher than 30 ng/mL were not consistently associated with increased benefit and concentrations higher than 50 ng/mL may be cause for concern.

Management

Treatment of hypercalcemia in patients with vitamin D toxicity should include discontinuation of both vitamin D and calcium supplementation, maintenance of a low calcium diet, and administration of adequate volumes of oral or IV fluid to increase renal calcium clearance.¹³⁷ Many cases of hypercalcemia will respond to such supportive care. Following rehydration, a loop diuretic, such as furosemide, can be added to promote calcium excretion.¹³⁷ Corticosteroids, such as hydrocortisone 100 mg/day or prednisone 20 mg/day, improve hypercalcemia and hypercalciuria in vitamin D poisoning. Studies have attempted to explain this effect as being a result of either decreased intestinal calcium absorption or inhibition of bone resorption.^125,221 Bisphosphonates, such as pamidronate 90 mg IV and clodronate 600 mg IV, were used successfully in cases of severe hypercalcemia.^136,196 These drugs inhibit bone resorption via actions on osteoclasts. Their use may preclude the need for hemodialysis in refractory cases of hypercalcemia. Calcitonin, a hypocalcemic hormone secreted by the thyroid gland that directly inhibits osteoclast activity, can be used to decrease bone resorption. Salmon calcitonin was successfully used to treat refractory hypercalcemia in a child with vitamin D poisoning. The dose utilized was 4 units/kg IM twice daily until hypercalcemia resolved at 15 days.¹⁶¹ Of note, studies have led the FDA to conclude that salmon calcitonin in the form of a nasal spray for the treatment of postmenopausal osteoporosis is associated with an increased risk of cancer.³⁷

The antioxidants include vitamins E and C and β-carotene. During the 1990s, the concept that antioxidants had a protective effect against atherosclerosis and carcinogenesis was widely promoted. This notion was based on the “oxidative-modification hypothesis” of atherosclerosis, which proposes that atherogenesis is initiated by lipid peroxidation of LDL.⁵⁷ Unregulated or prolonged production of cellular oxidants leading to oxidant induced DNA damage is thought to be responsible for carcinogenesis.¹²⁸ Epidemiologic evidence seems to support the use of antioxidants for these indications.^130,194,218 However, several prospective, randomized, placebo controlled clinical trials, designed to test for the effect of antioxidant vitamins on cardiovascular disease and cancer, have consistently shown that commonly used antioxidant regimens do not significantly reduce or prevent overall cardiovascular events or cancer.^{34,98,102,174,224,245}

History and Epidemiology

The existence of vitamin E was first demonstrated in 1922 by researchers noting that female rats deficient in a dietary principle were unable to sustain a pregnancy.⁶⁶ Testicular lesions in male rats were described in deficiency states and vitamin E was referred to as the “anti-sterility vitamin.”¹⁵³ Vitamin E was first isolated from wheat-germ oil in 1936.⁶⁵ The richest sources of vitamin E include nuts, wheat germ, whole grains, vegetable and seed oils, including soybean, corn, cottonseed, and safflower, and the products made from these oils. In general, animal products are poor sources of vitamin E. Human milk, by contrast to cow’s milk, has sufficient vitamin E in the form of α-tocopherol to meet the needs of breast fed infants.¹⁵³ Supplementation should not be necessary in persons who consume a well-balanced diet.

Vitamin E deficiency occurs in patients with malabsorption syndromes, which may occur in the presence of pancreatic insufficiency or hepatobiliary disease, such as biliary atresia.²⁷ Patients with abetalipoproteinemia are at risk for vitamin E deficiency.¹⁴ In this rare disease, absorption and transport of vitamin E are impaired secondary to a lack of chylomicron and β-lipoprotein formation. Manifestations of deficiency are variable, but seem to have the most effect in organ systems that rely on vitamin E for normal functioning.¹⁵³ The clinical syndrome is primarily manifested by a peripheral neuropathy and spinocerebellar syndrome that improves with supplemental vitamin E.¹⁶² Symptoms include ophthalmoplegia, hyporeflexia, gait disturbances, and decreased sensitivity to vibration and proprioception.²⁷

Vitamin E is an essential nutrient. It is believed to be necessary for normal functioning of the nervous, reproductive, muscular, cardiovascular, and hematopoietic systems. Use of vitamin E has been proposed for a wide range of conditions. In most cases, scientific rationale for its use is lacking or is based on in vitro or animal data that have not been validated in humans or have demonstrated equivocal results.²⁷ As examples, vitamin E has been used for treatment of recurrent abortion, hemolytic anemias, claudication, wound healing, tardive dyskinesia, epilepsy, and adult respiratory distress syndrome. In addition, much research over the past decade has focused on the use of vitamin E for the prevention and treatment of cardiovascular disease and cancer, with disappointing results.²²⁵

Vitamin E includes eight naturally occurring compounds in two classes—tocopherols and tocotrienols—that have differing biologic activities. The most biologically active form is RRR-α-tocopherol, previously known as d-α-tocopherol, which is the most widely available form of vitamin E in food. A synthetic form of α-tocopherol, often used in vitamin supplements, contains a mixture of d and l isomers and is designated all-rac-α-tocopherol (previously d,l-α-tocopherol). One IU is equivalent to 1 mg α-tocopherol acetate (ALPHA-TA).

Pharmacology, Pharmacokinetics, and Toxicokinetics

Vitamin E absorption is dependent on the ingestion and absorption of fat. The presence of bile also is essential. Vitamin E is passively absorbed in the intestinal tract into the lymphatic circulation by a nonsaturable process. Approximately 45% of a dose is absorbed in this manner and subsequently enters the bloodstream in chylomicrons, which are taken up by the liver. Vitamin E then is secreted back into the circulation, where it is primarily associated with LDL. Vitamin E is distributed to all tissues, with the greatest accumulation in adipose tissue, liver, and muscle.

The primary biologic function of vitamin E is as an antioxidant. It prevents damage to biologic membranes by protecting polyunsaturated fats within membrane phospholipids from oxidation.³⁵ It accomplishes this task by preferentially binding to peroxyl radicals and forming the corresponding organic hydroperoxide and tocopheroxyl radical, which, in turn interacts with other antioxidant compounds, such as ascorbic acid, thereby regenerating tocopherol. Vitamin E may be responsible for cell growth and proliferation by combating the inhibitory effects of lipid peroxidation.¹⁶² Vitamin E may have a negative role in the regulation of cellular proliferation through its nonoxidant properties, such as inhibition of protein kinase C activity.¹⁶²

Large amounts of vitamin E, ranging from 400 to 800 IU/day (400–800 mg/day) for months to years, were previously thought to be without apparent harm.⁴⁹ Vitamin E supplementation results in few obvious adverse effects, even at doses as high as 3200 mg/day (3200 IU/day).²⁰ In several species, the oral median lethal dose was 2000 mg/kg (2000 IU/kg) or more, and significant adverse effects were observed only when daily doses were greater than 1000 mg/kg (1000 IU/kg), equivalent to 200 to 500 mg/kg (200–500 IU/kg) in humans.¹⁶³ However, a meta-analysis reveals that all cause mortality may increase at doses equal to or greater than 400 IU/day (400 mg/day).¹⁶⁴

Pathophysiology

In vitro studies demonstrate that in high doses vitamin E may have a paradoxical prooxidant effect.^2,33,164 The prooxidant effect of vitamin E on LDLs is related to the production of α-tocopheroxyl radicals, which normally are inhibited by other antioxidants such as vitamin C. High doses of vitamin E may displace other antioxidants, thereby disrupting the natural balance of the antioxidant system and increasing vulnerability to oxidative damage.¹¹¹ High doses of vitamin E may inhibit human cytosolic glutathione S-transferases, enzymes that are active in the detoxification of xenobiotics and endogenous toxins.²²⁹

Clinical Manifestations

Gastrointestinal symptoms, including nausea and gastric distress, were reported in patients who had received vitamin E 2000 to 2500 IU/day (2000–2500 mg/day).^103,239 Diarrhea and abdominal cramps were reported in patients who received a dose of 3200 IU/day (3200 mg/day).⁸ Reports of other adverse effects, including fatigue, weakness, emotional changes, thrombophlebitis, increased serum creatinine concentration, and decreased thyroid hormone concentrations, have not been reproduced in other case series or clinical trials.¹⁶³

The most significant toxic effect of vitamin E, at doses exceeding 1000 IU/day (1000 mg/day), is its ability to antagonize the effects of vitamin K.⁴⁹ Vitamin E appears to increase the epoxidation of vitamin K to its inactive form, thereby increasing the vitamin K requirement several fold.^21,233 Although high oral doses of vitamin E typically do not produce a coagulopathy in normal humans with adequate vitamin K stores, coagulopathy may develop in vitamin K deficient patients or those taking warfarin.^21,47,69,233 Animal studies demonstrate that absorption of both vitamins A and K is impaired by large doses of vitamin E.^27,197

Use of an IV vitamin E preparation (E-Ferol) was associated with a severe epidemic of unexplained thrombocytopenia, kidney dysfunction, hepatomegaly, cholestasis, ascites, hypotension, and metabolic acidosis in low birth weight infants in several neonatal intensive care units in the early 1980s.³² Use of polysorbate 20 and polysorbate 80 for emulsification of lipids and fat-soluble vitamins in this IV vitamin E product was implicated as the cause of this syndrome, rather than vitamin E.

History and Epidemiology

Vitamin C, also known as ascorbic acid, has long been used as a preventative for the common cold. Interestingly, an extensive review of 14 studies of the role of vitamin C in the treatment of the common cold suggested that only eight were valid investigations, and none of the studies demonstrated any therapeutic benefit.⁴¹ Its function as an antioxidant has led to its use for the prevention and treatment of cardiovascular disease and cancer. Human data from clinical trials have failed to demonstrate that vitamin C significantly reduces or prevents overall cardiovascular events or cancer. Vitamin C may have a role as a reducing agent in the treatment of idiopathic methemoglobinemia (Chap. 127). However, it is less effective than standard treatment with methylene blue; therefore, it is not routinely indicated.¹⁵² Vitamin C is popularly used to promote wound healing, treat cataracts, combat chronic degenerative diseases, counteract the effects of aging, increase mental attentiveness, and decrease stress.^47,163 However, little, if any, objective data demonstrate a benefit of treatment for any of these indications.⁴⁹

Vitamin C has long been associated with prevention of scurvy.¹⁵² In 1747, James Lind, a physician in the British Royal Navy, analyzed the relationship between diet and scurvy and confirmed the protective and curative effects of citrus fruits. Vitamin C was isolated from cabbage in 1928 and subsequently shown in 1932 to be the active antiscorbutic factor in lemon juice. It was given the name ascorbic acid to indicate its role in preventing scurvy. Other dietary sources of vitamin C include tomatoes, strawberries, and potatoes. Today, those at risk for developing scurvy include the elderly, alcoholics, chronic drug users, and others with inadequate diets, including infants fed formula diets with insufficient concentrations of vitamin C.¹⁵² Symptoms include gingivitis, poor wound healing, bleeding, and petechiae and ecchymoses. Musculoskeletal signs and symptoms consisting of arthralgias, myalgias, hemarthrosis, and muscular hematomas develop in 80% of cases.⁶⁷ Children experience severe pain in their lower limbs secondary to subperiosteal bleeding.⁶⁷

Pharmacology, Pharmacokinetics, and Toxicokinetics

Following ingestion, intestinal absorption of vitamin C occurs via an active transport system that is saturable.¹⁹⁵ The absorptive capacity is reached with ingestion of approximately 3 g/day, and vitamin C dietary supplements are commonly taken in doses of 500 mg/day. When given as a single oral dose, absorption decreases from 75% at 1 g to 20% at 5 g. Vitamin C is distributed from the plasma to all cells in the body. Tissue uptake is also a saturable process.¹⁶³ Metabolic degradation of vitamin C to oxalate accounts for 30% to 40% of oxalate excreted daily.⁹⁴ Because absorption and metabolic conversion are saturable, large ingestions of vitamin C should not significantly increase oxalate production.²¹¹ Only a small amount of vitamin C is filtered through the glomeruli, and tubular resorption, a saturable process that may compete with uric acid, usually is almost complete.²⁴ Plasma concentrations of vitamin C typically are maintained at approximately 1 mg/dL. The kidney efficiently eliminates excess vitamin C as unchanged ascorbic acid.

Vitamin C is a cofactor in several hydroxylation and amidation reactions by functioning as a reducing agent.^139,140 As a result, vitamin C plays an important role in the synthesis of collagen, carnitine, folinic acid, and norepinephrine. It also influences the processing of hormones such as oxytocin, antidiuretic hormone, and cholecystokinin. Vitamin C reduces iron from the ferric to the ferrous state in the stomach, thereby increasing intestinal absorption of iron. Vitamin C may be involved in steroidogenesis in the adrenals. Vitamin C also has a prooxidant effect in vivo.¹⁸⁷ This effect is not believed to occur at doses less than 500 mg/day but may occur in the setting of overdose.

Clinical Manifestations

The possibility of oxalate nephrolithiasis should not be a significant clinical concern.⁸⁴ Nevertheless, conflicting studies and reports exist regarding the association between vitamin C overdose and the development of oxalosis. A prospective study on the risk of kidney stones in men did not support an association between high daily vitamin C intake and stone formation.⁵⁰ This was also demonstrated in a study involving daily ingestion of 4 g of ascorbic acid for five days in healthy men in which there was no increase in urinary oxalate excretion.¹² Another study did show increased rates of oxalate absorption and endogenous synthesis contributing to hyperoxaluria, but this effect was found in individuals with a prior history of renal calcium oxalate stones and not in individuals without a prior history of calcium oxalate stones.⁴⁰ Some reports of high urine oxalate concentrations likely were erroneous because of conversion of ascorbate to oxalate in alkaline urine samples left standing after collection.^12,236 By contrast, other reports show an increase in urinary oxalate and calcium oxalate crystallization following ingestion of high doses of vitamin C in both stone-formers and non–stone-formers.^18,155 Individual case reports documenting the presence of oxalate stones in the setting of vitamin C overdose often have involved IV administration.^{48,83,134,156,222,244} Oxalosis is also more likely to develop in patients with chronic kidney disease.^16,163 Gastrointestinal effects of high doses of vitamin C may include localized esophagitis, given prolonged mucosal contact with ascorbic acid, and an osmotic diarrhea.^108,235

History

Pyridoxine, pyridoxal, and pyridoxamine are related compounds that have the same physiologic properties. Although all three compounds are included in the term vitamin B₆, the vitamin has been assigned the name pyridoxine. This vitamin was discovered in 1936 as the water-soluble factor whose deficiency was responsible for the development of dermatitis in rats.¹⁵² In humans, deficiency is characterized by cheilosis, stomatitis, glossitis, blepharitis, and a seborrheic dermatitis around the eyes, nose, and mouth.²⁰³ More importantly, pyridoxine deficiency is associated with seizures.

Pyridoxine is found in several foods, including meat, liver, whole-grain breads and cereals, soybeans, and vegetables.¹⁵² Deficiency should not occur in humans who eat a well balanced diet.²¹⁵

Pyridoxine is popularly used as a component of bodybuilding regimens and for treatment of premenstrual syndrome and carpal tunnel syndrome.^1,62 High doses have been used for treatment of schizophrenia and autism with variable results.^74,138

Pharmacology

All forms of vitamin B₆ are well absorbed from the intestinal tract. Pyridoxine is rapidly metabolized to pyridoxal, pyridoxal phosphate (PLP), and 4-pyridoxic acid.²⁴⁶ PLP accounts for approximately 60% of circulating vitamin B₆ and is the primary form that crosses cell membranes.¹⁵² Most vitamin B₆ is renally excreted as 4-pyridoxic acid, with only 7% excreted unchanged in the urine.^152,246 Experiments in anephric rats demonstrate an up to ten fold increase in susceptibility to pyridoxine induced neurotoxicity, suggesting a need for caution when prescribing pyridoxine to patients with chronic kidney disease.¹⁴¹

Pyridoxal phosphate is the active form of vitamin B₆. It is a coenzyme required for the synthesis of γ-aminobutyric acid (GABA), an inhibitory neurotransmitter. Decreased GABA formation in the setting of pyridoxine deficiency may contribute to seizures.¹⁵² Isoniazid and other hydrazines inhibit the enzyme responsible for conversion of pyridoxine to PLP (Chap. 58).¹⁰⁷ Therefore, pyridoxine should be administered concomitantly with isoniazid to limit the development of a peripheral neuropathy. Seizures resulting from isoniazid overdose often are successfully treated with pyridoxine (Antidotes in Depth: A14).

Pathophysiology

Interestingly, similar to pyridoxine deficiency, pyridoxine toxicity is characterized by neurologic effects. The pathophysiology of pyridoxine neurotoxicity is not well defined. However, studies indicate that the mammalian peripheral sensory nervous system is vulnerable to large doses of pyridoxine.²⁰⁸ Peripheral sensory nerves may be particularly vulnerable to circulating xenobiotics because of the permeability of their associated blood vessels.²⁰⁸ Compared with the CNS, these nerves lack the blood brain ­barrier. In addition, the nerves of the CNS may be relatively shielded from pyridoxine toxicity because pyridoxine is transported into the CNS by a saturable mechanism.²⁰⁸ In 1942, pyridoxine was recognized to cause severe weakness and pathological changes in peripheral nerves and dorsal root ganglia in dogs and rats.^9,217 Administration of IV pyridoxine 2 g/kg in two patients for the treatment of mushroom poisoning resulted in permanent dorsal root and sensory ganglia deficits.⁴

Clinical Manifestations

Chronic overdoses are associated with progressive sensory ataxia and severe distal impairment of proprioception and vibratory sensation. Touch, pain, and temperature sensation may be minimally impaired, and reflexes may be diminished or absent. These findings were first described in 1983 in a case series of seven patients who were taking pyridoxine 2–6 g/day for 2 to 40 months for premenstrual syndrome.²⁰⁸ Nerve conduction and somatosensory studies in these patients showed dysfunction in the distal sensory peripheral nerves. Nerve biopsy showed widespread, nonspecific axonal degeneration. This syndrome has since been reported with pyridoxine doses as low as 200 mg/day.¹⁸³ Among 26 patients with elevated serum pyridoxine concentrations, the most common symptoms reported were numbness (96%), burning pain (49.9%), tingling (57.7%), balance difficulties (30.7%), and weakness (7.8%).²¹⁰ In most cases, symptoms gradually improved over several months with abstinence from pyridoxine. However, symptoms may still progress for 2 to 3 weeks after pyridoxine discontinuation.²³

Acute neurotoxicity may occur when a massive amount of pyridoxine is administered as a single dose or given over a few days.⁴ Large overdoses of pyridoxine are associated with incoordination, ataxia, seizures, and death.²²⁷

History

Nicotinic acid, or niacin, was discovered to be an essential dietary component in the early 1900s.⁸⁷ A deficiency of this vitamin, also known as vitamin B₃, causes pellagra, which is characterized by dermatitis, diarrhea, and dementia. This disease had been prevalent for centuries in countries that heavily relied on maize as a dietary staple until it was determined that pellagra could be prevented by increasing dietary intake of fresh eggs, milk, and fresh meat, including liver.¹⁵² Other food sources of nicotinic acid include fish, poultry, nuts, legumes, and whole-grain and enriched breads and cereals. Supplementation of flour with nicotinic acid in 1939 probably is responsible for the near eradication of this disease in the United States. Chronic alcohol users still develop pellagra, likely secondary to malnutrition.

Niacin was introduced as a treatment for hyperlipidemia in 1955.⁷ Nicotinic acid reduces triglyceride synthesis, with a resultant drop in very-low-density lipoprotein cholesterol and LDL cholesterol and a rise in high-density-lipoprotein cholesterol.⁸⁷ Therapy usually is started with single doses of 100 to 250 mg. Frequency of dose and total daily dose are gradually increased until a dose of 1.5 to 2.0 g/day is reached. If the LDL cholesterol concentration is not sufficiently decreased with this dosing regimen, then the dose is further increased to 3.0 g/day. These doses of niacin are 100-fold higher than the amount necessary to meet adult nutritional needs.¹⁹²

More recently, the nonmedicinal ingestion of niacin for the purpose of altering or masking the results of urine testing for illicit drugs was noted.^11,39,167 However, there is no evidence that ingestion of niacin is capable of this effect.

Pharmacology, Pharmacokinetics, and Toxicokinetics

Nicotinic acid is well absorbed from the intestinal tract and is distributed to all tissues. With therapeutic dosing, little unchanged vitamin is excreted in the urine. When extremely high doses are ingested, the unchanged vitamin is the major urinary component. Nicotinic acid ultimately is converted to nicotinamide adenine dinucleotide (NAD⁺) and nicotinamide adenine dinucleotide phosphate (NADP⁺), which are the physiologically active forms of this vitamin. NADH and NADPH, the reduced forms of NAD⁺ and NADP⁺ respectively, act as coenzymes for proteins that catalyze oxidation–reduction reactions that are essential for tissue respiration.¹⁵²

Clinical Manifestations

The most common adverse effect associated with niacin use is a vasodilatory cutaneous flushing described as a sense of warmth in the face, ears, neck, trunk, and less frequently in the extremities, lasting less than 1 to 2.5 hours.¹¹⁶ Other symptoms include erythema, itching, and tingling. These effects may occur at doses of 0.5 to 1.0 g/day.¹⁵⁸ Symptoms commence within 15 to 30 minutes after ingestion of immediate-release niacin, 30 to 120 minutes after ingestion of extended-release niacin, and at more variable times after ingestion of sustained-release niacin.¹¹⁶ Symptoms are caused by the production of prostaglandin (PG) D₂ and E₂ via the G protein–coupled receptor, GPR109A.²² Flushing occurs because of the predilection of the skin as a site of prostaglandin production after niacin ingestion.²²⁰ PGD₂ and PGE₂ act on receptors DP₁ and EP_2/4 in dermal capillaries causing vasodilation.¹²² Vasodilatory adverse events occur in almost all of patients, particularly when given an immediate release form of niacin.¹⁵⁸ Many patients discontinue niacin use because of flushing. Long-term tolerance to flushing does develop with continued dosing of niacin, secondary to decreased PGD₂ output.¹¹⁶

Because rapid absorption of niacin seems to be related to development of flushing, modified release preparations of niacin were developed. A meta-analysis of 4000 patients who had used various time-release preparations of niacin showed that among the 70% of patients who experienced flushing, 85% had used immediate release niacin, 66% used extended release niacin, and 26% had used sustained-release niacin.³¹ The modified release preparations are more likely to produce gastrointestinal adverse events, such as epigastric distress, nausea, and diarrhea.¹⁵⁸ In addition, niacin-induced hepatotoxicity occurs more frequently and is more severe in patients treated with modified release niacin rather than immediate-release niacin.^44,192 Elevated hepatic aminotransferases may occur with doses as low as 1 g/day, whereas symptoms of hepatic dysfunction occur at doses of 2 to 3 g/day.¹⁵⁸ These patients may have elevated serum bilirubin and ammonia concentrations and a prolonged prothrombin time. They may present with fatigue, anorexia, nausea, vomiting, and jaundice. In most cases, liver function improves following niacin withdrawal.^64,158 Severe cases have progressed to fulminant hepatic failure and hepatic encephalopathy.^45,104,169

Niacin also causes amblyopia, hyperglycemia, hyperuricemia, coagulopathy, myopathy, and hyperpigmentation.¹⁰¹ A recent case of a 16 year-old boy who ingested 13 g of niacin over 48 hours described the development of metabolic acidosis, hypoglycemia, elevated hepatic aminotransferases, and coagulopathy.¹¹ The patient also complained of severe myalgias and chest and abdominal pain. His signs and symptoms resolved after 5 days with intravenous fluid resuscitation and bicarbonate infusion.

Management

A dose of 325 mg of aspirin taken 30 minutes before ingestion of niacin diminishes flushing.²⁴¹ This is because aspirin inhibits cyclooxygenase, thereby decreasing production of prostaglandins.

Other strategies for reducing flushing include dosing with meals, and avoidance of alcohol, hot beverages, spicy foods, and hot baths or showers close to or after dosing.⁵² Flushing may also be decreased by starting at a low dose and gradually increasing to the full dose. Tolerance to flushing may develop after several weeks, but flushing will recur if doses are missed.

Laropiprant, a PGD₂ antagonist at receptor DP₁, has demonstrated efficacy in numerous studies (phase 1, 2, and 3 trials) for reducing niacin-associated flushing.¹¹⁶ In Europe, laropiprant was approved for use in 2008 in the form of a combined tablet, 1000 mg of extended release niacin with 20 mg laropiprant, and sold under the trade name Tredaptive (Merck & Co; known outside the United States as MSD). Also in 2008, the FDA did not give approval for a similar product with the trade name Cordaptive made by the same pharmaceutical company. In 2013, the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) collaborative group reported an increased incidence of myopathy among patients taking simvastatin plus extended release niacin/laropiprant (ERN/LRPT) compared to those taking simvastatin plus placebo.¹⁰⁹ Also, ERN/LRPT in addition to statin therapy did not significantly reduce the risk of major vascular events in patients with well controlled LDL-cholesterol concentrations. As a result, the study was halted and Merck & Co plans to cease production of Tredaptive. Other findings included that 25.4% of participants taking ERN/LRPT stopped their randomized treatment compared with 16.6% taking placebo, mostly due to adverse dermatologic and gastrointestinal effects.

Recent in vitro studies demonstrate that methylnicotinate induces serotonin release from human platelets in addition to PGD₂ release from human mast cells.¹⁷⁹ Animal studies demonstrate the ability of various serotonin antagonists including cyproheptadine to inhibit the niacin-induced temperature increase, associated with flush, by 90%.¹⁷⁹ Flavanoids have been studied as a potential treatment for niacin flush due to their ability to inhibit both niacin-induced plasma PGD₂ and serotonin increase in a rat model.¹⁸⁰ In a small human study, a dietary supplement containing 150 mg of the flavanoid quercetin decreased the severity and longevity of erythema and burning sensation scores on a visual scale.¹²¹

• Healthy adults consuming a well-balanced diet do not require vitamin supplementation.

• Vitamins are popularly believed to be a panacea and are commonly taken in supraphysiologic doses.

• Because the therapeutic index is large, toxicity generally does not develop unless very large doses are taken for sustained periods.

• Health care professionals should consider hypervitaminosis in the differential diagnosis when patients present with symptoms consistent with a vitamin toxicity syndrome.

• A thorough history, with emphasis on diet and prescribed and supplemental vitamin use, is important.

Acknowledgment

Richard J. Hamilton, MD, contributed to this chapter in previous editions.

References