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History and Epidemiology
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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
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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
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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.
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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.
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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
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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.
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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).
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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.
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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
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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
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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.
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Pharmacology, Pharmacokinetics, and Toxicokinetics
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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.
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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.
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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.
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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
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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.
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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
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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.
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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
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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 cirrhosis110,118,129,204 (Chap. 23).
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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
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Clinical Manifestations
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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.
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Hypercarotenemia produces a yellow-orange skin discoloration that can be differentiated from jaundice by the absence of scleral icterus.
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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
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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
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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
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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.
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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
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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
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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
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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.
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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.
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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.
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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.