Fat-Soluble Vitamins at a Glance
- Vitamin A, D, E, K.
- Vitamin A deficiency is the most common cause of preventable childhood blindness in the world.
- Carotenemia results from excess carotene not converted to vitamin A in the intestinal mucosa deposits in stratum corneum.
- Understanding of the full function of vitamin D is still evolving.
- Vitamin D supplementation is recommended for exclusively breast-fed infants, and others who have inadequate oral intake or sun exposure.
- Hemorrhagic disease of the newborn results from vitamin K deficiency and can present with a spectrum of bleeding, from ecchymoses to intracranial hemorrhage.
Etiology and Pathogenesis
Vitamin A is a fat-soluble vitamin important in retinal photoreceptor function, epithelial proliferation, and keratinization. The two most clinically important metabolites of vitamin A are retinal, which is a key component of rhodopsin generation, and retinoic acid, which regulates cell differentiation.27 Dietary intake of vitamin A derive from both plant and animal sources. Plant sources include dark, green, leafy vegetables, red palm oil, and brightly colored fruits such as papaya, mango, carrots, tomatoes, apricots, and cantaloupe. In plants, the vitamin A precursor β-carotene can be found as a two-molecule complex of the carotenoid known as retinal. The retinal can be later reduced to retinol in the intestinal villous cells. Animal sources of vitamin A include egg yolk, liver, fish, fortified milk, and other dairy products. In animal sources, vitamin A exists as retinyl esters, which are then hydrolyzed to retinol in the intestinal lumen and then absorbed into intestinal mucosal cells. All retinol vitamin A alcohol is esterified to retinyl esters within the intestinal mucosa, released into the bloodstream bound to chylomicrons, and then transported to the liver for storage. Here, retinol can be stored as retinyl esters in the liver; when needed, this storage form may be converted to retinol and bound to retinol binding protein and transthyretin and circulated throughout the body.
Vitamin A deficiency (VAD) can result in cutaneous as well as ocular complications. It is, in fact, the most common cause of preventable blindness in children according to the World Health Organization. VAD has also been associated with defects in immune regulation.
Etiology and Pathogenesis
The primary causes of VAD continue to be inadequate intake, fat malabsorption states, and liver disease. In the United States, inadequate intake can be seen in individuals with eating disorders, restrictive diets, and chronic illness. Since vitamin A is fat-soluble, conditions associated with malabsorption of fat such as pancreatic or biliary tract disease, celiac disease, Crohn disease, Shwachman–Diamond syndrome, cystic fibrosis, cholestatic liver disease, chronic intestinal parasitic infection, and gastric bypass surgery can predispose to VAD.
(See Box 130-5). The earliest manifestations of VAD are ocular changes. Impaired dark adaptation (nyctalopia), is followed by xerophthalmia, and as corneal keratin desquamates and overgrowth of Corynebacterium xerosis on the sclera occurs, white patches known as Bitot spots develop. Severe deficiency may lead to corneal xerosis, ulceration, and keratomalacia, which may result in corneal perforation, prolapse of the iris, and blindness (Fig. 130-5).
Box 130-5 Manifestations of Vitamin A Deficiency ||Download (.pdf)
Box 130-5 Manifestations of Vitamin A Deficiency
- Impaired dark adaption
- Corneal xerosis, ulceration, keratomalacia
- Corneal perforation, blindness
- Cutaneous, Mucocutaneous
- Skin fissuring (dermatomalacia)
Vitamin A deficiency, advanced keratomalacia, in a 5-month-old Arab child. Note hyperkeratosis of facial skin. Serum vitamin A level was 2 μg/dL (normal, 20–50 μg/dL).
The cutaneous findings of VAD are the result of abnormal keratinization. Mild deficiency may manifest as xerosis and scaling, while more severe deficiency may result in deep skin fissuring referred to as dermomalacia. Squamous metaplasia of the salivary glands as well as the nasal and oral mucosa may occur, leading to xerostomia, hyposmia, and hypogeusia. Laryngeal, bronchial, and vaginal mucosa can also become involved.
Phrynoderma, “toad skin,” (Greek for toad + skin) is typically associated with VAD. These keratotic follicular papules often first develop on the anterolateral thighs and posterolateral upper arms, which then spread to extensory surfaces of the extremities, shoulders, abdomen, back, buttocks, face, and posterior neck (Fig. 130-6). Lucius Nicholas noted the association between this hyperkeratotic folliculitis or phrynoderma with VAD in 1933 when he observed these cutaneous findings among East African workers who developed night blindness and xerophthalmia.28 While originally reported in association with VAD, phrynoderma is a nonspecific finding that can be observed with deficiencies in B-complex vitamins, vitamins C, E, as well as essential fatty acid deficiency, PEM, and general malnutrition states.29
Vitamin A deficiency. Typical perifollicular hyperkeratosis of the chest in a Tanzanian adult male.
Vitamin A levels can be measured from serum. Normal serum levels are between 20 and 50 μg/dL. Recently, assessment for the hydrolysis of retinoyl glucuronide to retinoic acid has shown promise as an adjunctive test for VAD. Retinoyl glucuronide is a water-soluble form of vitamin A that is not absorbed or hydrolyzed to retinoic acid in vitamin A-replete humans. The presence of serum retinoic acid for 4 hours after oral administration of retinoyl glucuronide was correlated with low serum retinol.30
The recommended daily allowance (RDA) of vitamin A is between 1,000 and 5,000 IU, with younger individuals requiring a lower intake of vitamin A. Recommended treatment for VAD is 100,000–300,000 IU of oral vitamin A daily until symptoms resolve and serum levels normalize.
In 1856, Elisha Kent Kane published his two-volume Arctic Explorations, which included accounts of vitamin A toxicity that resulted after his team ingested polar bear liver during his expedition. The toxic substance in polar bear liver was later identified as vitamin A. Since that time, studies have shown that animal livers contain exceptionally high amounts of vitamin A.
Vitamin A toxicity is the result of excess intake of vitamin A and can occur on an acute or chronic basis. Acute toxicity occurs when excessive amounts of vitamin A are ingested over a period of several hours or days. Toxicity typically results when intake exceeds 20 times the RDA in a child or 100 times the RDA in an adult. Chronic toxicity results from daily ingestion of greater than 25,000 IU for more than 6 years or greater than 100,000 IU for more than 6 months of preformed vitamin A. Children appear to be more sensitive to vitamin A intake than adults. Individuals most at risk for toxicity include patients taking systemic vitamin A derivatives for the treatment of dermatologic conditions such as acne, psoriasis, and ichthyosis. The other population at risk includes vitamin food faddists who consume large quantities of nonprescription vitamin A supplements.31 Two notable episodes of vitamin A toxicity occurred in the 1950s when very high levels of vitamin A supplementation were added to infant formulas and the 1970s when high doses of vitamin A were used to treat a variety of dermatologic diseases.32
Recently, vitamin A derivatives have been studied in chemoprevention of keratinocytic carcinomas, such as squamous cell and basal cell carcinomas. A large, blinded randomized controlled study of elderly men with a history of two keratinocytic carcinomas in the 5 years prior to initiation of the study compared topical tretinoin 0.1% cream to placebo. Surprisingly, the study was terminated 6 months early because of a statistically significant increase in all-cause mortality in the tretinoin group compared to the placebo group.33 Analysis of this increased risk was limited by its post hoc nature and suggests that further studies are needed to clarify this association.
(See Box 130-6). Individuals with acute vitamin A toxicity have dry, scaly skin, with large areas of desquamation and fissuring of the lips and angles of the mouth. Other signs and symptoms include headache, fatigue, anorexia, nausea, vomiting, blurred vision, pseudotumor cerebri, myalgias, and arthralgias. An early cutaneous sign of chronic vitamin A toxicity in adults is dryness of the lips, which may progress to diffuse, dry, pruritic, scaly skin with peeling of palms and soles, alopecia, follicular hyperkeratosis, and hyperpigmentation of the face and neck. Anorexia, fatigue, and weight loss may also occur. It is interesting to note that follicular hyperkeratosis may occur in the settings of both VAD and toxicity.
Box 130-6 Manifestations of Vitamin A Toxicity ||Download (.pdf)
Box 130-6 Manifestations of Vitamin A Toxicity
- Dry, scaly skin with desquamation
- Peeling of palms and soles, follicular hyperkeratosis
- Cheilitis, fissuring of lips and angles of mouth
- Anorexia, nausea, vomiting
- Myalgias, arthralgias
- Blurred vision, pseudotumor cerebri
- Skeletal changes: premature closure of the epiphyses, spontaneous bone fractures
In children, chronic toxicity presents as coarse hair with diffuse alopecia, coarse skin with generalized exfoliation, hyperpigmentation, and exfoliative cheilitis. Associated pseudotumor cerebri with headaches and papilledema, and in infants may a bulging fontanelle may be present. Skeletal changes are common with vitamin A toxicity, and may present with growth retardation secondary to premature closure of the epiphyses and spontaneous bone fractures. Proposed mechanisms for the pathologic bone findings seen in vitamin A toxicity involves antagonism between vitamin A- and vitamin D-mediated intracellular signaling pathways and interactions with calcium-regulating hormones.19,31
Laboratory findings in patients with hypervitaminosis A include elevated levels of calcium and alkaline phosphatase. This alteration in calcium homeostasis can lead to calcification of tendons, ligaments, and soft tissues. Deposition of excess vitamin A in adipose tissue and perisinusoidal fibrosis of the liver, which can lead to cirrhosis, are the most significant effect of long-term vitamin A toxicity.
Almost all of the symptoms of vitamin A toxicity subside after the excess vitamin intake is discontinued, with the exception of liver cirrhosis and consequences of pseudotumor cerebri.
Carotenemia and Carotenoderma
While hypervitaminosis A is a disease that causes a broad spectrum of clinical findings, excessive intake of carotene results in a benign disorder characterized by yellow–orange skin pigmentation. The condition was described as “carotenemia” in 1919 by Hess and Meyers who reported a connection between yellow skin pigmentation and increased serum carotene levels.34 During World War I and World War II, carotenemia was more commonly seen because of the dietary shift from a meat-based diet to a more plant-based diet due to food shortages.
As antioxidants, carotenoids have also been studied in cancer prevention. Interestingly, β-carotene supplementation of 20–30 mg per day was associated with an increased risk of lung and gastric cancers.35,36 β-Carotene supplementation is also associated with an increased risk of aggressive prostate cancer.37 Animal studies suggest that excessive carotenoids may increase cyclic AMP signaling and cause deleterious effects on oxidative stress pathways, leading to the increased risk of malignancy.38,39
Etiology and Pathogenesis
Carotenes are not synthesized endogenously and are obtained through intake of carotene-rich foods. Plant carotenes are converted to vitamin A in the gastrointestinal tract, but approximately one-third of carotene is directly absorbed. Several factors can affect carotene absorption, including thyroid hormone, pancreatic lipase and bile acid concentrations, processing of foods, and dietary fat and fiber content. Hypothyroid patients notice an elevation of carotene levels as a result of decreased conversion to retinol. Pancreatic lipase and bile acids digest carotene so that a deficiency of these enzymes due to pancreatic or biliary or hepatic dysfunction could result in elevated carotene levels. Mashing, cooking, and pureeing fruits and vegetables increase the availability of carotene because cell membranes are ruptured in the process. Dietary fiber decreases absorption. Because carotene is fat-soluble, a high-fat meal increases absorption. Patients with conditions that lead to hyperlipidemia, like diabetes mellitus, nephrotic syndrome, and hypothyroidism, also predispose patients to carotenemia because of a linear relationship between the amount of β-lipoprotein and carotene. Impaired conversion of carotene to vitamin A in patients with hypothyroidism and liver disease further contributes to carotenemia. Some patients with anorexia nervosa can present with carotenemia because of increased intake of vegetables. Other groups at risk for carotenemia are food faddists, those with excessive intake of nutritional supplements, dried seaweed (nori), carrots, and papayas, and infants ingesting a large amount of pureed vegetables.40–42
Excessive ingestion of carotenes does not result in hypervitaminosis A because the slow conversion of carotene to vitamin A in the intestinal mucosa is not rapid enough to produce toxic amounts of vitamin A.
Carotene deposits in the stratum corneum because of its high lipid content. The yellow discoloration of skin secondary to carotenemia is called carotenoderma. The carotene is excreted by sebaceous glands and in sweat, so the yellow pigmentation appears first on the face, predominantly in the nasolabial folds and forehead, and then progresses to manifest diffusely, especially on the palms and soles. The pigmentation is particularly noticeable in artificial light. Of note, carotenoderma, in contrast to jaundice, spares mucous membranes, like the sclera.
Carotenemia does not occur until serum levels reach three to four times normal levels, greater than 250 μg/dL, and is detectable approximately 4–7 weeks following initiation of a carotenoid-rich diet.
Treatment involves discontinuation of excessive carotene intake, and carotenoderma typically fades as the intake of carotene decreases.
Etiology and Pathogenesis
Vitamin D is essential for regulation of calcium and phosphorus metabolism. Vitamin D acts on the gastrointestinal tract to increase dietary calcium and phosphate absorption, stimulates increased bone resorption of calcium and phosphate, and stimulates the renal tubules to increase reabsorption of calcium and phosphate.
Humans obtain vitamin D from two sources: (1) dietary intake, and (2) synthesis in the skin from exposure to ultraviolet light. Common dietary sources of vitamin D include fortified milk, fish oil, and fishes such as salmon, sardines, herring, tuna, cod, and shrimp. Vitamin D can also be synthesized in the epidermis from the precursor molecule 7-dehydrocholesterol (provitamin D3) by ultraviolet light in the 290–320 nm range. Previtamin D3 then undergoes a spontaneous, temperature-dependent isomerization to vitamin D3 (cholecalciferol), which enters the dermal capillaries. At this point, endogenous vitamin D3 joins with exogenous D2 (ergocalciferol) for hydroxylation in the liver to 25-hydroxyvitamin D. This molecule travels to the kidney where it is again hydroxylated to make mature vitamin D (1,25-hydroxyvitamin D, also known as calcitriol).
The most common disorder seen with vitamin D is vitamin D-deficient rickets related to decreased dietary intake of vitamin D. Several genetic causes of rickets also deserve mention. Two types of vitamin D-dependent rickets have been described. Type I represents an autosomal recessive defect in renal vitamin D-1α-hydroxylase, and is therefore treated with supplements of 1,25-hydroxyvitamin D. Type II, also referred to as hereditary vitamin-D resistant rickets, is associated with a rare autosomal recessive end-organ resistance to physiologic levels of 1,25-hydroxyvitamin D. Supplementation with high doses of 1,25-hydroxyvitamin D and calcium may overcome this resistance.
A surge in interest regarding the multisystem effect of vitamin D has spurred numerous studies. Evidence suggests that vitamin D deficiency is associated with increased systolic blood pressures,43 fasting plasma glucose and insulin concentrations,44 risk of cardiovascular disease,45–47 risk of hip fractures in postmenopausal women,48 and colon cancer mortality.49 Vitamin D deficient individuals have an increased rate of all cause mortality when compared to those who are vitamin D replete.47,50 Studies into the function of vitamin D in the immune system have indicated that vitamin D is involved in the innate immune response. Toll-like receptors (TLR) activation triggers expression of vitamin D receptor and vitamin D-1-hydroxylase, which promotes macrophage activation.51 A low vitamin D level is associated with an increased risk of active Mycobacterium tuberculosis infection.52
Bony deformities in children have been described by artifacts dating back to the first and second centuries c.e
. The earliest classic descriptions of the clinical symptoms of rickets appeared separately in 1645 by Daniel Whistler and in 1650 by Francis Glisson. These two men described children in southwest England, where rickets was endemic. At the time they did not understand its etiology. As early as 1824, cod liver oil was noted to help cure rickets. In 1861, Trousseau of France hypothesized that rickets was caused by inadequate diet and sun exposure, but Theodor Palm was the first to study and conclude that there was also a connection between rickets and lack of sun exposure. During the Industrial Revolution, a combination of poor diet, smog and tall buildings obscuring the sun, as well as inadequate time outdoors all contributed to the persistence of rickets in the United States and Europe. By 1918, John Howland, Edward Park, and Paul Shipley had used rat models of rickets to identify the anti-rachitic molecule in cod liver oil, vitamin D.53
In the past preterm infants were at risk for rickets because of an inadequate supply of calcium and phosphorus at the time of birth.
Following feeding with unsupplemented breast milk, their phosphorus levels would fall over the first 2 weeks of life with a subsequent increase in alkaline phosphatase activity at 4-8 weeks, indicating vitamin D deficiency.54
Since the introduction of breast milk fortifiers and preterm formulas, the incidence of rickets of prematurity has decreased dramatically. Rickets also occurs with greater frequency during puberty, when physical and behavioral changes modulate vitamin D availability. The pubertal growth spurt places greater demands for more calcium and phosphorus needed for bone growth, so increased levels of vitamin D are required. In settings where women are expected to cover their skin with the onset of puberty for cultural reasons, the scant opportunities for sun exposure increases the risk for vitamin D deficiency if dietary intake is insufficient to meet daily requirements.
Vitamin D-deficient rickets continues to occur in modern times. Groups at risk for vitamin D deficiency include those with inadequate diet, malabsorption, and decreased exposure to sunlight. This includes the elderly or debilitated who have decreased sun exposure or decreased vitamin intake; patients on anticonvulsant therapy; those with malabsorption from gastrointestinal surgery, celiac disease, or pancreatic or biliary disease; those with chronic renal failure; dark-skinned individuals living in areas with poor sun exposure; and breast-fed babies exclusively breastfed without vitamin supplementation.
A recent resurgence in vitamin D-deficient rickets has prompted further evaluation of those at risk. A review of 166 cases of rickets in the United States between 1986 and 2003 showed that most cases presented between 4 and 54 months of age. Eighty-three percent were African-American or black and 96% were breastfed.55
These results emphasized that exclusively breastfed infants, especially those with dark skin tones, may require vitamin supplementation. In response to the continued increase in cases of vitamin D-deficient rickets, the American Academy of Pediatrics in 2003 outlined three populations who should be given supplemental vitamin D (200 IU): 1) all breastfed infants unless they take in 500 mL/day of fortified formula or milk; 2) all non-breastfed infants taking in less than 500 mL/day of fortified formula or milk; and 3) children and adolescents who do not obtain regular sun exposure, do not ingest at least 500 mL of fortified milk a day, or do not take a multivitamin with at least 200 IU vitamin D.56
Vitamin D-deficient rickets has been associated with congenital ichthyoses, such as lamellar ichthyosis,57–59 nonbullous ichthyosiform erythroderma,60 X-linked ichthyosis,58 and epidermolytic hyperkeratosis.61 Factors contributing to vitamin D deficiency include avoidance of sun exposure, excessive transepidermal calcium loss, defective vitamin D synthesis in affected skin, and decreased intestinal calcium absorption secondary to systemic retinoid therapy.
Given the movement to encourage sunscreen use, there has been concern regarding secondary vitamin D deficiency. Theoretically, regular use of the recommended amount of sunscreen can decrease 25-hydroxyvitamin D levels, but with real-life application of inadequate amounts of sunscreen and the tendency for increased sun exposure in individuals wearing sunscreen, there seems to be no significant impact on the incidence of vitamin D deficiency.62
At the same time, it appears that only limited sunlight exposure is necessary to produce adequate amounts of vitamin D3. For patients with Fitzpatrick skin type II, it has been calculated that only 5 minutes of summertime noon sun 2–3 times weekly provides adequate vitamin D production to satisfy physiologic requirements (see also Chapter 90).63,64
The classic manifestations of vitamin D-deficient rickets are skeletal (Box 130-7). Calcium and phosphorus deficiency leads to poor calcification of new bones, resulting in fraying and widening of the metaphysis. This can be seen at costochondral junctions of the anterior ribs, creating the well-known “rachitic rosary.” Poor calcification of the skull bones results in craniotabes, a softening of the skull bones giving them a ping-pong ball feel. As the bones become weaker, they cannot support the weight of the child and progressive lateral bowing of the lower extremities occurs. Other findings can include frontal bossing, widening of the wrists, scoliosis, hypotonia, fractures, dental defects, and rarely hypocalcemic seizures or tetany. Early radiographic signs of rickets include widening of the epiphyseal plate and blurring of the epiphyseal and metaphyseal junction. If the disease progresses, deformities at the growth plate develop, including cupping, splaying, formation of cortical spurs, and stippling. The bone cortices appear thinner and generalized osteopenia is noted.
Box 130-7 Clinical Manifestations of Rickets ||Download (.pdf)
Box 130-7 Clinical Manifestations of Rickets
- Rachitic rosary
- Craniotabes, frontal bossing
- Lateral bowing of lower extremities
- Widening of wrists, scoliosis, fractures
- Dental defects
- Rarely hypocalcemic seizures
A potentially fatal manifestation of vitamin D deficiency is a dilated cardiomyopathy. In a report of 16 British cases, three infants died and six additional infants were successfully resuscitated from cardiopulmonary arrest.65 Importantly, the cardiomyopathy is responsive to vitamin D supplementation and can result in complete resolution.65–67
Vitamin D-dependent rickets type II has also been associated with cutaneous features that are clinically indistinguishable from the syndrome of generalized atrichia associated with mutations in the hairless gene.68,69 Affected patients in both conditions are born with hair. However, within a few months after birth, scalp and body hair are lost with the exception of eyebrows and eyelashes. Small papules and cysts representing abnormal, rudimentary hair structures characteristically develop on the face and scalp. These cysts typically show disintegration of the lower two-thirds of the follicular unit. While the cutaneous features—notably the alopecia and cysts—are phenotypically and histologically identical, these are distinct clinical entities (Table 130-1).
Table 130-1 Comparison of Vitamin D-Resistant Rickets and Generalized Atrichia ||Download (.pdf)
Table 130-1 Comparison of Vitamin D-Resistant Rickets and Generalized Atrichia
Vitamin D-Resistant Rickets Type I
Mutations in vitamin D receptor (Zn finger)
Mutations in human hairless gene (Zn finger)
End-organ unresponsiveness to Vitamin D
Defect in catagen remodeling
Atrichia with papules and milia;
Atrichia with papules and milia;
Alopecia by 1–3 months of age
Alopecia by 40 days to 4 months
In addition to the clinical and radiological signs of rickets, laboratory examination may be helpful. Elevated alkaline phosphatase levels and low serum 25-hydroxyvitamin D levels are often useful laboratory indicators of vitamin D deficiency. In the early stages of rickets, parathyroid hormone levels increase to compensate, but this compensatory mechanism becomes inadequate if the deficiency continues.
The recommended daily value of vitamin D is 5–10 μg. Treatment includes oral vitamin D repletion with dihydroxyvitamin D in addition to a calcium-rich diet. Supplementation with 200–400 μg vitamin D per day until resolution of symptoms, about 2–3 months, is usually adequate.176 Additional therapy can include judicious sun exposure.
Two additional therapies can be used in cases of hepatic rickets, which is unresponsive to oral vitamin D supplementation because of decreased intraluminal bile salts. d-α-tocopheryl polyethylene glycol-1,000 succinate (TPGS), a water-soluble vitamin E that forms micelles at low concentrations, enhances vitamin D absorption and successfully treated eight pediatric cases of hepatic rickets. These patients maintained adequate levels of vitamin D while on continued TPGS and vitamin D supplementation, without elevation of vitamin E levels.70 Promoting cutaneous synthesis of vitamin D through ultraviolet radiation successfully treated two cases of hepatic rickets secondary to chronic cytomegalovirus hepatitis and to Alagille's syndrome.71 Ultraviolet light therapy has also treated an Asian male with poor dietary intake of vitamin D.72
Vitamin E is rarely associated with deficiency or excess states of disease. Found in oils and shortenings, as well as various fortified grains, dark-green leafy vegetables, legumes, nuts, avocado, and small fishes such as herring and sardines.73 Because it is a fat-soluble vitamin, excessive intake may augment the effects of anticoagulant medications leading to purpura and propensity for hemorrhage.74 Deficiency states are rare. However, ataxia with isolated vitamin E deficiency (AVED) is a rare and severe spinocerebellar neurodegenerative disorder with autosomal recessive inheritance. Patients with mutations in the α-tocopherol transfer protein are unable to properly transfer α-tocopherol from lysosomes into lipoproteins that results in a predisposition to oxidative stress in affected cells.75–77
Etiology and Pathogenesis
Vitamin K is a necessary cofactor in the carboxylation of glutamate residues on coagulation factors II, VII, IX, X, and proteins C and S. Dietary vitamin K, phylloquinone, is found in green, leafy vegetables, certain legumes, soybeans, cereals, and beef liver. Phylloquinone is actively transported in the distal small bowel. Approximately half of the body's vitamin K is obtained though these dietary sources, and the other half is synthesized by gastrointestinal flora as menaquinones, which are passively absorbed in the distal small bowel and colon.
Vitamin K is derived from the German word “Koagulationsvitamin,” which literally translates to mean “clotting vitamin.” In the early-1900s, Henrik Dam of Denmark discovered an “antihemorrhagic factor” that reversed diet-induced bleeding disorders in chicks. In 1943, Edward Doisy and Henrik Dam were awarded the Nobel Prize in Physiology and Medicine for their separate work on isolating vitamin K.
Vitamin K deficiency leads to impaired coagulation and hemorrhage, which in neonates is referred to as hemorrhagic disease of the newborn (HDN). Neonates are particularly prone to vitamin K deficiency because of poor transplacental transfer, low dietary intake, and a sterile bowel. HDN is divided into early presentation and late presentation. The incidence of early HDN is 0.25%–1.7% and causes unexpected bleeding in the first week of life in an otherwise healthy neonate. It can present as ecchymoses, cephalohematomas or nasal, subgaleal, umbilical, intestinal, or intracranial hemorrhages. Late HDN is defined by the American Academy of Pediatrics as unexpected bleeding from severe vitamin K deficiency in 2–12 week old infants who are primarily breastfed and who received no or inadequate neonatal vitamin K prophylaxis.78 Vitamin K deficiency beyond the newborn period is rare, but may result from malabsorption, liver disease, inadequate dietary intake, or medications. Fat malabsorption occurs in conditions such as regional ileitis, topical sprue, celiac disease, cystic fibrosis, pancreatic insufficiency, and biliary obstruction. Antibiotic use can result in vitamin K deficiency by altering the populations of normal bowel flora. Coumarin interferes with vitamin K epoxide reductase, an enzyme important in the recycling of inactive vitamin K into its active form. Other medications that can interfere with vitamin K metabolism include anticonvulsants (phenytoin), rifampin, isoniazid, high-dose salicylates, cholestyramine, and cephalosporins.11,79 Vitamin K deficiency in older children and adults can present as purpura, ecchymoses, gingival bleeding, and gastrointestinal, genitourinary, and retroperitoneal hemorrhage.
Because vitamin K is a key cofactor in the coagulation pathway, deficiency of vitamin K typically manifests as elevations in both prothrombin time and activated partial thromboplastin time (PT and PTT). Serum levels of vitamin K can also be measured.
While des-γ-carboxyprothrombin (DCP), also known as the abnormal “protein induced by vitamin K absence” (PIVKA), can be a sensitive indicator for vitamin K deficiency, its presence has also been strongly linked to certain malignancies, in particular, hepatocellular carcinoma. It appears that hepatocellular carcinoma cells produce DCP directly rather than as a byproduct of low vitamin K levels, which may be normal in patients with hepatocellular carcinoma.80
Neonatal prophylaxis is traditionally with a single intramuscular dose of 0.5–1.0 mg vitamin K. There have been some studies regarding the use of oral vitamin K prophylaxis, but there is no definitive data on efficacy, safety, or bioavailability.78
Acute treatment is with fresh frozen plasma to replace deficient coagulation factors. Vitamin deficiency can also be treated with parenteral or intramuscular 5–10 mg vitamin K per day to correct severe deficiency.
Water-Soluble Vitamins at a Glance
- B complex vitamins, vitamin C, biotin.
- Niacin supplementation should be given with isoniazid therapy to prevent pellagra, characterized by a photosensitive dermatitis, diarrhea, dementia, and death.
- Vitamin C is an essential cofactor in multiple biologic reactions, including collagen synthesis. Deficiency causes scurvy, which presents with follicular hyperkeratosis, curled corkscrew hairs, and a bleeding diathesis.
Etiology and Pathogenesis
Disorders of thiamine may have broad-ranging implications because thiamine is an essential coenzyme for three separate enzymes involved in NADPH synthesis, carbohydrate metabolism, and deoxyribose and ribose synthesis. Thiamine is used as a coenzyme for transketolase in the pentose phosphate pathway to produce NADPH. Thiamine pyrophosphate acts as a coenzyme in pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, which are involved in oxidative decarboxylation reactions in the metabolism of carbohydrates and branched-chain amino acids.
Thiamine is obtained from whole grains, enriched bread products, dried peas and beans, potatoes, and fish. Polished rice eliminates the thiamine-containing husk and predisposes to thiamine deficiency.
Disorders of thiamine excess are extremely rare. Most arise as a result of intravenous administration for suspected thiamine deficiency in the context of chronic alcoholism. Local irritation at the site of intravenous administration, generalized pruritus, and anaphylactic or anaphylactoid reactions have been described.81 Neurotoxicity can occur in experimental settings when thiamine is administered directly into the central nervous system.82 In general, thiamine excess states are extremely rare in humans.
Beriberi refers to a thiamine deficiency state. The word is derived from Sinhalese meaning “extreme weakness.” The symptoms of beriberi have been recognized in East Asian countries for thousands of years because polished white rice is a dietary staple. The Japanese navy observed in the 1890s that beriberi could be eradicated by adding meat, fish, and vegetables to the diet.83 Beriberi became an epidemic in the Dutch East Indies in the late 1800s. Christiaan Eijkman was part of the medical team stationed in the Dutch East Indies to study beriberi. In 1929, Eijkman was awarded the Nobel Prize in Physiology and Medicine for his work starting in 1886 studying the effect of polished rice and unpolished rice on the incidence of beriberi in chickens. Through a series of detailed experiments on populations of chickens fed various diets and injected with various bacteria, he concluded that there was a direct correlation between diet and beriberi, but like many, had initially misattributed the cause to a nonexistent infectious agent in polished rice. In 1926, Barend Coenraad Petrus Jansen and William Frederick Donath successfully isolated thiamine from rice polishings, and Robert Williams was able to synthesize thiamine in the 1930s.84
Thiamine deficiency in the United States is now rare. Predisposing factors for pediatric thiamine deficiency include unsupplemented parenteral nutrition, breastfed infants of thiamine-deficient mothers, congestive heart failure,85 and severe malnutrition. Early signs include irritability, apathy, restlessness, and vomiting. As the disease progresses, neurologic signs of Wernicke's encephalopathy may develop, such as ophthalmoplegia, ataxia, nystagmus, and characteristic laryngeal nerve paralysis resulting in aphonia, which is a classic manifestation of infantile beriberi. Other symptoms include congestive heart failure, tachycardia, dyspnea, and cyanosis. In 2003, a series of infants presenting with ophthalmoplegia as a manifestation of Wernicke's encephalopathy was reported in Israel as a result of a thiamine-deficient infant soy formula. In all these cases, a prodromal illness was observed. Early symptoms included vomiting, anorexia, diarrhea, lethargy, irritability, and developmental delay. Upbeat nystagmus and ophthalmoplegia were the primary neurological signs. Following treatment, those with early disease had complete recovery, but those with severe disease had residual neurological complications.86
Adult beriberi has been categorized into dry and wet forms. Dry beriberi describes a symmetric distal peripheral neuropathy involving both sensory and motor systems. Wet beriberi includes neuropathy and signs of cardiac involvement, including cardiomegaly, cardiomyopathy, congestive heart failure, peripheral edema, and tachycardia. Rarely, wet beriberi can be associated with pulmonary hypertension that is reversible after thiamine supplementation.87 A red, burning tongue and peripheral edema have also been observed with wet beriberi.
Diagnosis of thiamine deficiency is made by measurement of erythrocyte thiamine transketolase or blood thiamine concentration. The more reliable measure is erythrocyte thiamine transketolase before and after thiamine pyrophosphate stimulation, represented as a percentage of thiamine pyrophosphate effect (TPPE). Normal values are up to 15%.
Because thiamine is a cofactor in a variety of metabolic pathways, daily thiamine requirements are calculated from an individual's ideal total caloric intake, with current recommendations indicating 0.5 mg per 1,000 kcal.
Treatment of thiamine deficiency can be via intravenous, intramuscular, or oral routes of administration. Usually, treatment for beriberi is initiated with intravenous or intramuscular thiamine of 50–100 mg per day for 7–14 days, then oral supplementation is provided until full recovery is documented.
Etiology and Pathogenesis
Riboflavin was discovered in 1879 as a fluorescent yellow–green substance found in milk. Its chemical structure was later determined in 1933. Riboflavin is used in two coenzymes, (1) flavin mononucleotide (FMN) and (2) flavin-adenine dinucleotide (FAD), both of which are involved in oxidation-reduction reactions in cellular respiration and oxidative phosphorylation. These two enzymes are also involved in pyridoxine (vitamin B6) metabolism. Recent studies have suggested that riboflavin deficiency may contribute to increase plasma homocysteine levels, impaired handling of iron, and night blindness.88
Riboflavin is typically obtained through dairy products, nuts, meat, eggs, whole grain and enriched bread products, fatty fish, and green leafy vegetables. A small amount of dietary riboflavin is present as free riboflavin; most are found as FAD or FMN. Dietary FAD and FMN are hydrolyzed to riboflavin by brush border membranes or enterocytes. Free riboflavin in the intestinal lumen is then taken up by active transport in the proximal small bowel.
Deficiency states can be caused by decreased intake, inadequate absorption, and phototherapy. Alcoholics, elderly, and adolescents are groups at risk for riboflavin deficiency secondary to poor nutritional intake. Malabsorption after gastric bypass surgery can also predispose individuals to riboflavin deficiency.89 In areas of India, China, and Iran, riboflavin deficiency is endemic because of their dependence on an unenriched cereal diet. Infants of riboflavin-deficient mothers are also at risk of deficiency because breast milk concentrations of the vitamin are proportional to maternal concentrations. Once weaned from the breast, these infants are at additional risk if they are not transitioned to milk. When confounded by PEM, riboflavin deficiency may be worsened because the usual renal compensatory mechanism of increased riboflavin absorption is impaired in this setting. Visible light phototherapy for jaundiced neonates causes photodecomposition of riboflavin.90 Certain drugs also affect riboflavin levels through effects on absorption or metabolic inhibition. Chlorpromazine and other tricyclic drugs inhibit transport of riboflavin in the gastrointestinal tract predisposing to deficiency states.91 Borate displaces riboflavin from binding sites, increases urinary riboflavin excretion, and inhibits riboflavin-dependent enzymes contributing to riboflavin deficiency.92
Signs of acute riboflavin deficiency include a deep red erythema, epidermal necrolysis, and mucositis. The severity of symptoms depends on the severity of deficiency93 (Box 130-8).
Box 130-8 Clinical Signs of Riboflavin Deficiency ||Download (.pdf)
Box 130-8 Clinical Signs of Riboflavin Deficiency
- Epidermal necrolysis
- Angular stomatitis
- Cheilosis with erythema, xerosis, and fissuring
- Seborrheic dermatitis-like dermatitis affecting typical sites and flexural areas of limbs and genitalia
- Photophobia and conjunctivitis
Clinical signs of chronic riboflavin deficiency or ariboflavinosis begin 3–5 months after initiation of an inadequate diet. Skin and mucous membrane findings predominate. Initially, angular stomatitis manifests as small papules at the corners of the mouth that enlarge and ulcerate before developing into macerated fissures that extend laterally and often bleed (Fig. 130-7). Pronounced cheilosis with erythema, xerosis, and vertical fissuring of lips can occur. Early glossitis appears as prominent lingual papillae, but after these papillae are lost, the tongue becomes smooth, swollen, and magenta in color. The dermatitis of riboflavin deficiency resembles seborrheic dermatitis in that it involves the nasolabial folds, nostrils, nasal bridge, forehead, cheeks, and posterior auricular regions. Flexural areas of the limbs may also be affected. Plugging of the sebaceous glands (dyssebacia) may be observed around the nose. The dermatitis can affect the genitalia, more often to a greater extent in males than in females. A red, confluent, crusty, or lichenified dermatitis of the scrotum often spreads to involve the inner thighs. In general, the dermatitis is worse in areas of chafing or trauma. Infants frequently manifest the dermatitis in the inguinal areas. In older individuals, the dermatitis is often more pronounced in facial creases and wrinkles, and if incontinent, can involve the perianal and buttock areas. Cutaneous findings are not aggravated by light exposure, but are exacerbated by heavy physical activity. Ocular findings are also a prominent feature of this disorder with photophobia and conjunctivitis being most notable. Oculo-orogenital syndrome is the term used to describe this constellation of symptoms.
Riboflavin deficiency. Angular stomatitis with maceration in an Arab child. Riboflavin excretion in the urine was diminished.
A normochromic, normocytic anemia may be observed. Erythrocyte glutathione reductase activity can be used as a screening test, but a trial of riboflavin supplementation is often the most optimal method to confirm a riboflavin deficiency.
The recommended daily value of riboflavin is 0.6 mg per 1,000 kcal. Treatment for deficient infants and children are 1–3 mg per day, and 10–20 mg in adults.
Etiology and Pathogenesis
Niacin is a vitamin cofactor that can be obtained for the diet or synthesized endogenously from the essential amino acid tryptophan. Niacin is found in whole grains and enriched bread products, nuts, dairy products, liver, animal meat, mushrooms, and dried beans. Dietary niacin exists primarily in the form of nicotinamide-adenine dinucleotide (NAD) and nicotinamide-adenine dinucleotide phosphate (NADP). NAD and NADP are hydrolyzed in the intestinal lumen to form nicotinamide. Nicotinamide can be converted to nicotinic acid by intestinal bacteria or be absorbed into plasma. Nicotinamide and nicotinic acid then travel to the liver, kidney, enterocytes, where they are converted back to NAD and NADP. These two agents act as hydrogen donors and acceptors in oxidation-reduction reactions involved in the synthesis and metabolism of carbohydrates, fatty acids, and proteins.
Deficiency of niacin or vitamin B3 results in pellagra.
In 1735, Gasper Casal noted poor peasants in northern Spain were particularly affected by a skin disorder referred to then as “mal de la rose,” so named because of the reddish, glossy rash on the dorsum of the hands and feet. He noted that these peasants were all poor, ate mainly maize, and rarely ate fresh meat. Francois Thierty published the first description of pellagra in 1755, but it was Francesco Frapoli who coined the name pellagra after the Italian words “pelle,” meaning skin, and “agra,” meaning rough.
During the nineteenth century, the cause of many diseases was attributed to infectious agents, and pellagra had been thought to be related to some infectious microorganism. While working as for the United States Public Health Service, Joseph Goldberger first suggested that pellagra might be caused by an amino acid deficiency in 1922 and that a dietary “pellagra-preventative factor” existed. Pellagra was endemic in the southern United States in the early 1900s because of a ubiquitous diet consisting principally of corn bread, molasses, and pork fat. Beginning in 1914, Goldberger worked with two orphanages and one sanitarium in the South. By increasing the amount of fresh animal meat and vegetables available at the three institutions, Goldberger was able to significantly decrease the incidence of pellagra. He went on to investigate pellagra among male prisoners. Using 12 prisoners from the Mississippi State Penitentiary and offering prisoners pardons as an incentive to participate, he successfully demonstrated that pellagra could be induced by a monotonous cereal-based, low calorie, and protein diet. In order to disprove the allegation that pellagra was caused by an infectious agent, he subjected 16 volunteers to the blood, urine, feces, and epidermal scales of pellagrous patients and showed that they were not predisposed to develop pellagra.94
Goldberger died before he identified the pellagra-preventative factor, but in 1937, Conrad Elvanhjem identified niacin
as the antipellagra factor.95
Pellagra remains endemic in parts of the world, including South Africa, China, and India, where corn and maize continue to be a dietary mainstay. Corn and maize contain bound niacin, so without alkaline hydrolysis to release the niacin, it is unavailable for absorption. Jowar, a type of millet found in parts of India, contains adequate levels of niacin, but large quantities of leucine interfere with the conversion of tryptophan to niacin.96 Although Mexicans have a predominantly maize-based diet, pellagra is relatively uncommon because preparation of the maize includes washing it in lime water, which releases the complexed niacin.
Because niacin is absorbed from the gastrointestinal tract, gastrointestinal disorders can predispose to pellagra. Impaired absorption of tryptophan and niacin occurs in patients with jejunoileitis, gastroenterostomy, prolonged diarrhea, chronic colitis, ulcerative colitis, cirrhosis, Crohn disease, and subtotal gastrectomy.97 Patients with Hartnup disease, a rare autosomal recessive disorder, develop pellagra-like symptoms in childhood. This is caused by a defect in the neutral brush border system, resulting in malabsorption of amino acids, including tryptophan. Alcoholics develop pellagra from a combination of poor diet and malabsorption. Overly restrictive diets from eating disorders such as anorexia nervosa, presumed food allergies, or food faddism can also cause pellagra.
Patients with increased metabolic needs as seen in carcinoid syndrome can develop pellagra. Normally, about 1% of tryptophan is metabolized to serotonin, but in carcinoid syndrome, an excessive amount, about 60%, of tryptophan is converted to serotonin. Because of this diversion of tryptophan to serotonin production, less tryptophan is available to make niacin.
Medications can also induce pellagra symptoms. Isoniazid is a competitive inhibitor of NAD because of their similar structures, and also impairs pyridoxine functioning, which is essential for niacin synthesis from tryptophan. 5-fluorouracil inhibits conversion of tryptophan to niacin, and 6-mercaptopurine inhibits NAD phosphorylase, which inhibits NAD production. Other implicated medications include phenytoin, chloramphenicol, azathioprine, sulfonamides, and antidepressants.98
Pellagra is classically described with the four Ds of (1) dermatitis, (2) diarrhea, (3) dementia, and (4) death. The characteristic dermatitis begins as painful, erythematous, pruritic patches in photodistributed areas. The skin becomes progressively more edematous, and several days later may develop vesicles and bullae, which can rupture, leaving crusted erosions, or develop into brown scales. Over time, the skin thickens into sharply demarcated, keratotic, hyperpigmented plaques. Painful fissures can develop in the palms and soles, resembling goose skin. The dorsum of the hands is the most commonly affected sites, and when the rash extends proximally, more on the radial than ulnar side, it forms the “gauntlet” of pellagra (Fig. 130-8A). A butterfly distribution may be apparent on the face when it extends from the nose to the cheeks, chins, and lips. When the dermatitis affects the upper central portion of the chest and neck, it is referred to as “Casal's necklace” (Fig. 130-8B). It can sometimes extend down over the sternum to create a “cravat.” Mucous membrane involvement may manifest as cheilitis, angular stomatitis, a red tongue, and ulceration of the buccal mucosa and vulva. Half and half nails may also be present99 (Box 130-9).
Pellagra. Acute dermatosis. A. “Glove” or “gauntlet” exudative and crusted lesions on the hands. B. “Casal's necklace” on the neck with facial involvement.
Box 130-9 Clinical Manifestations of Pellagra ||Download (.pdf)
Box 130-9 Clinical Manifestations of Pellagra
- Painful pruritic dermatitis in photo-exposed areas
- May be vesicular, crusted, and develops into scaly, keratotic plaques
- Dorsum of hands (“gauntlet”), neck (Casal's necklace), dorsa of feet (“gaiter” of pellagra); butterfly distribution in face.
- Angular stomatitis, cheilitis, glossitis
- Diarrhea, nausea, vomiting, abdominal pain, anorexia
- Insomnia, fatigue, nervousness, apathy, impaired memory, depression, psychosis, dementia
Gastrointestinal symptoms may represent the earliest signs of pellagra. Diarrhea, nausea, vomiting, abdominal pain, and anorexia have been reported. Neurologic symptoms, such as insomnia, fatigue, nervousness, apathy, impaired memory, and depression, can progress to psychosis and dementia in later stages. Without treatment, pellagra leads to death from multiorgan failure.
Diagnosis is primarily made on clinical grounds and through a rapid response to vitamin supplementation. However, measurement of urinary metabolites of niacin—N-methylnicontinamide and pyridone—may be used to aid in the diagnosis.
The recommended daily value of niacin is 15–20 mg of niacin, or about 60 mg of exogenous tryptophan. Treatment with 500 mg per day of nicotinamide or nicotinic acid is given over several weeks. Nicotinamide is preferred over nicotinic acid because nicotinic acid is frequently associated with headache and flushing. Neuropsychiatric symptoms may remit after 24–48 hours of treatment, but skin lesions often take 3–4 weeks to clear.100
Etiology and Pathogenesis
Pyridoxine deficiency was elucidated by Albert Szent-Gyorgi in 1934 while studying pellagra in rats. Esmond Snell identified the two other forms of vitamin B6 and worked extensively to clarify the biochemical properties of these molecules in the mid 1900s.
Vitamin B6 describes three interchangeable molecules: (1) pyridoxine, (2) pyridoxamine, and (3) pyridoxal. Humans are unable to synthesize any of these molecules, but fortunately they are widely available in both plant and animal products. Meats, whole grains, vegetables, and nuts are the best sources for vitamin B6. Processing of these foods can decrease the amount of vitamin available. They are absorbed through passive diffusion in the jejunum and undergo phosphorylation to become components of active coenzymes. The most common form existing is pyridoxal-5-phosphate. Vitamin B6 is employed in multiple pathways including the decarboxylation and transamination of amino acids, gluconeogenesis, and conversion of tryptophan to niacin, sphingolipid synthesis, prostaglandin synthesis, and neurotransmitter synthesis. As such, clinical features of pyridoxine deficiency may overlap with those of niacin deficiency.
Due to the availability of dietary vitamin B6, deficiency is seldom caused by inadequate intake, but can occur in alcoholics due to poor diet. More commonly, malabsorption and medication-induced deficiency is etiologic. Small bowel disorders, such as Crohn disease and celiac disease, can interfere with absorption and produce deficiency. Medications that have been implicated in causing deficiency include isoniazid, hydralazine, penicillamine, and oral contraceptives. Isoniazid, hydralazine, and penicillamine bind to pyridoxal-5-phosphate to increase excretion or decrease activity of the coenzyme.
Vitamin B6 toxicity from excessive intake does not typically produce skin findings, although it can be associated with peripheral neuropathy.
Vitamin B6 deficiency classically presents as a seborrheic-like dermatitis of the face, scalp, neck, shoulders, buttocks, and perineum. Clinical features overlap those of niacin deficiency including features of photodermatitis, glossitis, and cheilitis. Glossitis appears as redness, burning, and ulceration of the tongue, leading to flattening of the filiform papillae. Other areas of oral mucosa also become red and ulcerated, resulting in angular stomatitis, cheilosis, and conjunctivitis. This condition produces an oculo-orogenital syndrome quite similar to that seen with riboflavin deficiency.101 Neurological signs such as somnolence, peripheral neuropathy, paresthesias, weakness, and confusion. Other signs and symptoms are nonspecific, and include nausea, vomiting, depression, anorexia, and anemia. The clinical manifestations of vitamin B6 deficiency often resemble pellagra because vitamin B6 is needed for the conversion of tryptophan to niacin.
Vitamin B6 can be evaluated by mean measurement of plasma pyridoxal-5-phosphate. Low levels of plasma pyridoxal-5-phosphate indicate deficiency.
Recommended daily values of pyridoxine depend on age and gender. Adult males require at least 2 mg per day; adult females require at least 1.6 mg per day; and infants require about 0.3 mg per day. Treatment involves discontinuation of inciting medication and initiating replacement therapy of 100 mg of pyridoxine per day. Oral lesions resolve in days, skin, and hematologic changes resolve in weeks and neurologic symptoms over several months.11
Etiology and Pathogenesis
Folate can be found in almost all foods, particularly in liver, wheat bran and other grains, leafy green vegetables, and dried beans. Tetrahydrofolate, the coenzyme form of folate, is used for single-carbon transfers in amino acid, purine, and pyrimidine metabolism. The poor diets of alcoholics, malabsorption, and medications can produce folate deficiency. Malabsorptive states (such as celiac disease, chronic diarrhea, status post total gastrectomy) and antifolate medications (such as methotrexate, trimethoprim, oral contraceptives and pyrimethamine) have been implicated in producing folate deficiency. The antiepileptics phenobarbital and phenytoin can also lead to folate deficiency states through induction of microsomal hepatic enzymes by antiepileptics, which deplete folate stores.102 In children, folate deficiency can be also be associated with excessive boiling of milk, or a goat's milk diet. Human milk has greater bioavailability of folate when compared with goat's milk.103,104
As with vitamin B12 deficiency, the primary manifestation is hematologic: hypersegmented neutrophils, followed by macrocytosis and megaloblastic anemia. Neutropenia, thrombocytopenia, diarrhea, and irritability may also be observed. In contradistinction to vitamin B12 deficiency, folate deficiency is not associated with neurologic symptomatology.
Mucocutaneous findings include glossitis with atrophy of the filiform papillae, angular cheilitis, mucosal ulceration, perirectal ulcerations, perineal seborrheic dermatitis, and diffuse brown hyperpigmentation concentrated in the palmar creases and flexures.105,106
Macrocytic and megaloblastic anemia with hypersegmentation of neutrophils is suggestive. Diagnostic confirmation can be accomplished through measurement of serum folic acid levels.
Folic acid supplementation is typically curative. Discontinuation of antifolate agents is recommended if involved. Ruling-out concurrent vitamin B12 deficiency is crucial before initiating treatment for folate deficiency. If vitamin B12 deficiency is present but not treated, the hematologic symptoms may be respond to folate, but the neurologic symptoms will progress. Treatment involves 1–5 mg of folic acid per day.
Some controversy exists as to who documented the earliest report of pernicious anemia. Thomas Addison is often credited with the first published description in 1855, but others like James Combe and Antoine Biemer also deserve some measure of credit. Pernicious anemia was a recognized entity in the late 1800s, and strides were made in the early twentieth century toward a better understanding of pernicious anemia. As understanding of other diseases such as pellagra and beriberi began to emerge, researchers began to wonder if pernicious anemia was also caused by a dietary deficiency. George Whipple published results in 1920 from studies he did on anemic dogs. Whipple-induced anemia in dogs by bleeding them. After trials of different foods to recover the hemoglobin level, Whipple observed the greatest improvement with liver. George Minot and William Murphy won the 1934 Nobel Prize in Physiology and Medicine along with Whipple for their work in documenting that meat and liver could be employed to treat anemic patients.107,108
Around the same time, William Castle utilized controls and patients with pernicious anemia to prove that an essential interaction between meat (extrinsic factor) and a component of normal human gastric secretions (intrinsic factor) were required for resolution of anemia. Finally, in 1948, Karl Folkers’ team successfully crystallized vitamin B12
and in 1964 Philippus Hoedenmaeker showed that Castle's intrinsic factor was produced by the gastric parietal cell. The well-known Schilling test to assess intrinsic factor deficiency was described by Robert Schilling in 1953.109
Etiology and Pathogenesis
Vitamin B12 is an important coenzyme for two biochemical pathways in humans. The first enzyme uses methylcobalamin as a coenzyme for methyltransferase to methylate homocysteine to methionine, which is used in DNA, protein, and lipid metabolism. The second requires 5′-adenosylcobalamin to catalyze the reaction by methylmalonyl CoA mutase to convert methylmalonic acid to succinyl-CoA, which is used in fat and carbohydrate metabolism.
Vitamin B12 is found primarily in animal products, with liver, eggs, milk, beef, and organ meats being excellent sources. Gastric acid separates vitamin B12 from food proteins so it can bind to intrinsic factor in the duodenum. This complex is taken up by specific ileal receptors in the terminal ileum. In the enterocyte, vitamin B12 dissociates from intrinsic factor and enters the portal circulation bound to transcobalamin II for transport to tissues. Between 1% and 5% of free cobalamin is absorbed along the intestinal wall by passive diffusion. The body is able to store large amounts of vitamin B12, so symptoms of deficiency often take 3–6 years to develop.
Causes of vitamin B12 deficiency can be divided into three groups: inadequate intake, malabsorption, and other. Elderly individuals and psychiatric patients with poor diets, and strict vegetarians and their breastfed infants are most likely to become deficient from inadequate intake. Cases related to malabsorption can be further divided into four groups: (1) decreased gastric acid states leaving more B12 food-bound (chronic proton pump inhibitors and histamine H2 receptor blockers), (2) decreased intrinsic factor (pernicious anemia, atrophic gastritis, postgastrectomy), (3) microbial competition in the gut (bacterial overgrowth, Diphyllobothrium latum infection), and (4) impaired absorption (Crohn disease, Whipple disease, Zollinger–Ellison syndrome, celiac disease, short bowel syndrome). The other causes of cobalamin deficiency relate to inborn errors of transport or metabolism.110
Vitamin B12 deficiency manifests primarily in four systems. As with cases of folate deficiency, mucocutaneous manifestations include glossitis, angular cheilitis, hair depigmentation, and cutaneous hyperpigmentation. Glossitis is characterized by an atrophic, red, and painful tongue with atrophy of the filiform papillae, which is referred to as Hunter's glossitis. Early vitamin B12 deficiency can manifest as a linear glossitis.111 Hair depigmentation may be localized or diffuse. Hyperpigmentation can be diffuse and symmetric or few scattered macules. The greatest concentration is usually observed on the hands, nails, and face, with the most commonly affected areas being the palmar creases, flexural regions, and pressure points. This hyperpigmentation often resembles Addison's disease, but patients show no evidence of adrenal insufficiency.112–115
Three proposed hypotheses exist regarding the pathophysiology of the hyperpigmentation. Vitamin B12 maintains glutathione in reduced form, which is used to regulate tyrosinase, an enzyme necessary in melanogenesis. In B12 deficiency, increased tyrosinase activity results in hypermelanosis. Another proposed hypothesis involves defective melanin transport between melanocytes and keratinocytes. Finally, megaloblastic changes in keratinocytes from B12 deficiency may affect melanin distribution.11,19,114,115
The importance of cobalamin deficiency lies in its association with the classically described neurologic manifestations of subacute combined degeneration of the dorsal and lateral spinal column. Generalized weakness with paresthesias progresses to ataxia and symmetric loss of vibration and proprioception, worse in the lower extremities, eventuating in severe weakness, spasticity, paraplegia, and incontinence. Other neurological findings include apathy, somnolence irritability, memory loss, dementia, and psychosis. Early neurologic findings may present before hematologic signs.
The hematologic findings are similar to those found in folate deficiency, namely macrocytic anemia and hypersegmented neutrophils. Bone marrow biopsy reveals a hypercellular marrow secondary to disordered maturation.
Deficiency is diagnosed by measuring serum cobalamin levels, with levels less than 200 pg/mL indicating definite B12 deficiency and 200–300 pg/mL being borderline low.
Treatment depends on treating the cause of deficiency and supplementing with vitamin B12. Oral and parenteral supplementations have both been used. Oral supplementation can even be used in patients with pernicious anemia, but require much larger doses of enteral B12 than when parental since absorption has to be through the intrinsic-factor-independent mechanism. Supplementation with cyanocobalamin of some form is 1 mg per week for 1 month. If symptoms persist, or if deficiency is to be a long-term problem, as in pernicious anemia, then addition supplementation is with 1 mg of cyanocobalamin every month.
Vitamin C (Ascorbic Acid)
Etiology and Pathogenesis
Vitamin C is an antioxidant and essential cofactor in several biological reactions, including collagen biosynthesis, prostaglandin metabolism, fatty acid transport, and norepinephrine synthesis. Humans are unable to synthesize ascorbic acid because they lack gulonolactone oxidase, an enzyme most other animals possess use to convert glucose to ascorbic acid. Other organisms that require ascorbic acid include: the guinea pig, the fruit bat, and certain fish and bird species.
The majority of Western dietary vitamin C is obtained from fruits and vegetables, like potatoes, tomatoes, berries, citrus fruits, and green vegetables. Vitamin C is absorbed in the distal small bowel. Most dietary vitamin C is completely absorbed, but there is a decrease in absorption as dietary intake increases. Vitamin C is found in greatest concentration in the pituitary, adrenal glands, liver, leukocytes, and eyes. Depletion of body stores occurs after 1–3 months of a deficient diet.
As a water-soluble vitamin, ascorbic acid excess states are not typically associated with significant clinical disease. However, vitamin C deficiency is a disease of both great clinical importance and one of great historical significance. Vitamin C deficiency results in scurvy.
Scurvy, the disease of vitamin C deficiency, has been documented since antiquity. Ancient Greek, Roman, and Egyptian texts describe cases of scurvy. The Ebers papyrus, which dates to about 1552 b.c.e.
documents cases of scurvy that were successfully treated with onions. Scurvy-plagued sailors for hundreds of years before its cause was fully understood. One of the earliest reports dates to the 1497 expedition of India by Vasco da Gama. On this journey, many of the crew members developed scurvy, but da Gama noted that their symptoms improved after they traded for fresh oranges with locals in East Africa. After their supply of fresh oranges were depleted, da Gama observed the symptoms returned, so at their next landfall, they again sought locals with oranges to cure their disease. Other ships were not as fortunate as da Gama's crew. George Anson's pursuit of Spanish ships in 1740–1744 began with more than 1,400 crew members. By the end of the 4-year journey, he returned with only 145 of his original crew members with only four killed in enemy action and over 1,300 having died from scurvy.116
In 1747, James Lind devised one of the earliest clinical trials to investigate crew members from the HMS Salisbury afflicted with scurvy. Lind selected 12 seamen with severe scurvy and divided them into six groups of two, and each group was assigned to receive a different dietary therapy: hard apple cider, elixir of vitriol, vinegar, sea water, two oranges and one lemon daily for 6 days, and a medicinal paste. Lind published his findings in his Treatise of the Scurvy
in 1753 where he concluded that oranges and lemons were the most effective treatment for scurvy.117
Although Lind's findings were published in 1753, it was not until 1793 that lemon juice to be a required daily provision on long sea voyages under the advice of Gilbert Blaine.118
As the incidence of scurvy decreased at sea, several epidemics on land occurred. The Great Potato Famine of 1845–1848, World War I, and World War II were times of were times of nutritional impoverishment. The armies of the Crimean War and American Civil War, Arctic explorers, and California gold rush communities suffered from scurvy in large numbers. In the late nineteenth and early twentieth centuries, an explosion in cases of infantile scurvy occurred in the United States because of the trend toward heated milk and proprietary foods. As shown by James Lind, heating of vitamin C decreased its biological activity. Alfred Hess reported that pasteurization of milk likewise decreases its vitamin C concentration.119
Proprietary food at that time was of poor nutritional quality. Interestingly, most of the affected infants were from affluent families who thought they were providing superior nutrition for their children.120
Vitamin C was isolated by Albert Szent-Gyorgyi in 1927 when he isolated a compound found in high concentrations in the adrenal cortex, oranges, cabbages, and paprika.
Etiology and Pathogenesis
Causes of scurvy include insufficient vitamin C intake, increased vitamin requirement, and increased loss. Inadequate intake is the most common cause. Elderly individuals living alone may have limited diets as a result of poverty, immobility, poor dentition, poor access to groceries, or dementia.121,122 Alcoholics, food faddists, individuals with presumed food allergies, and cancer patients may have decreased overall dietary intake or may simply avoid fruit and vegetables.123 Iatrogenic scurvy occurs when physicians recommend dietary restrictions for certain conditions, such as in ulcerative colitis, Whipple disease, peptic ulcers, and gastroesophageal reflux, or with inadequate vitamin supplementation with parenteral nutrition. Increased vitamin C requirements are encountered with certain drugs, including aspirin, indomethacin, tetracycline, oral contraceptives, corticosteroids, and tobacco smoking. Scurvy has been reported as a complication of interleukin-2 treatment of metastatic renal cell carcinoma.124 Peritoneal dialysis and hemodialysis can induce scurvy because the water-soluble vitamin is removed during the dialyzing process.125 Scurvy has also been reported among patients receiving liver transplants.126
Impaired collagen synthesis is the basis for many cutaneous manifestation of scurvy. Ascorbic acid is required for the hydroxylation of proline residues on procollagen, allowing the formation of hydrogen–hydrogen bonding in the triple helix of mature collagen. Without ascorbic acid, the polypeptides are unstable and unable to form stable triple helices. This results in decreased collagen secretion from fibroblasts, increased collagen solubility, and unstable collage fibrils. This abnormal collagen creates pathology in skin, mucous membranes, blood vessels, and bone, leading to the four Hs of scurvy: (1) hemorrhagic signs, (2) hyperkeratosis of hair follicles, (3) hypochondriasis, and (4) hematologic abnormalities (Box 130-10).
Box 130-10 Clinical Manifestations of Scurvy ||Download (.pdf)
Box 130-10 Clinical Manifestations of Scurvy
Follicular keratotic plugging
Lower extremity edema with ecchymosis
Poor wound healing and dehiscence
Swelling, ecchymoses, and bleeding of gingiva
Hemorrhagic gingivitis, necrosis, loss of teeth
Hemorrhagic intraarticular, subperiosteal, intramuscular, disruption of growth plates, bowing of bones, depressed sternum
Epistaxis, hematuria, gastrointestinal, and cerebral hemorrhage
(See Box 130-10). The earliest cutaneous sign of scurvy is phrynoderma—enlargement and keratosis of hair follicles, especially on the posterolateral aspect of the arms, resembling keratosis pilaris. The keratotic plugging generalizes, extending to the back, buttocks, posterior thighs, calves, and shins. The hairs within these plugged follicles become curled, resulting in corkscrew hairs. The corkscrew hair results from impaired keratin cross-links by disulfide bonds. As the disease progresses, the follicles red from congestion and proliferation of surrounding blood vessels, then turn purple, and finally red and hemorrhagic (Fig. 130-9). This palpable perifollicular purpura is characteristically found on the legs. Lower extremity edema is often referred to as “woody edema,” associated with pain and ecchymosis. Other nonspecific cutaneous findings include xerosis and acne. Poor wound healing and even dehiscence of old wounds involving skin and bone can occur because vitamin C is necessary for wound healing and maintenance of healed wounds. Hemorrhage in the nail bed is noted as subungual linear (splinter) hemorrhages.
Vitamin C deficiency in an 18-year-old girl after gastrointestinal surgery. Note the “corkscrew” or “swan-neck” hairs associated with perifollicular purpura.
Oral manifestations are common. Gingival disease manifests as swelling, ecchymoses, bleeding, and loosening of teeth. Interdental and marginal gingivae become red, smooth, swollen, and shiny before becoming purple, black, and necrotic. This hemorrhagic gingivitis is secondary to poor osteodentin formation, which produces softer teeth that are prone to infection. Existing gingivitis and poor dentition predispose to more severe disease, but those without teeth do not develop hemorrhagic gingivitis.
Hemorrhage can occur in areas other than the skin, mouth, and nails. Bone disease is a frequent manifestation in children. Hemorrhage can be intra-articular, intramuscular, and subperiosteal. All of the above can lead to pain and disruption of the growth plates. Bowing of the long bones and a depressed sternum with and outward projection of the end of the ribs are noted on musculoskeletal examination. Metaphyseal spurs with marginal fractures (Pelkan sign), a ring of increased density surrounding the epiphysis (Wimberger sign), widening of the zone of provisional calcification (white line of Frankl), and a transverse band of radiolucency in the metaphysis (scurvy line or Trummerfeld zone) are seen on radiographs of extremities. Periosteal bleeding may occur. Epistaxis, hematuria, intracerebral hemorrhage, subconjunctival hemorrhage, and gastrointestinal hemorrhage have been reported. Weakness, fatigue, emotional lability, hypochondriasis, weight loss, arthralgias, hypotension, anorexia, and diarrhea are nonspecific findings associated with vitamin C deficiency.
The causes of a normochromic, normocytic anemia are multifactorial, including blood loss from hemorrhage, intravascular hemolysis, intracellular iron depletion, and decreased folate levels.
Scurvy is a clinical diagnosis, but when unsure of the diagnosis, measurement of leukocyte ascorbate level can be helpful. Levels less than 75 mg/L indicate a deficient state.
Recommended daily intake of vitamin C is 40–60 mg of ascorbic acid. With vitamin C supplementation, clinical symptoms rapidly improve within several days following initiation of supplementation. Therapeutic doses of 100–300 mg of ascorbic acid are administered daily until symptoms completely resolve.
Etiology and Pathogenesis
Biotin is an essential cofactor for four carboxylating enzymes: (1) acetyl-CoA carboxylase in fatty acid synthesis and lipogenesis, (2) pyruvate carboxylase in gluconeogenesis, and (3) propionyl-CoA carboxylase (4) 3-methylcrotonyl-CoA carboxylase—both involved in amino acid catabolism.
Eggs, liver, milk, peanuts, mushrooms, chocolates, and hazelnuts are common sources of biotin. Release of protein-bound dietary biotin depends on pancreatic biotinidase. Free biotin diffuses across the gut to bind to plasma proteins. Since biotin is found in many dietary sources and can be synthesized by enteric bacteria, deficiency is uncommon. In 1941, Paul Gyorgy described that avidin in egg white bound and inactivated biotin. Virgil Sydenstricker took this observation and induced biotin deficiency by feeding normal volunteers raw egg white rich diets. Avidin, a protein found in egg whites, binds free biotin in the bowel, therefore preventing absorption of both dietary and synthesized biotin. Although an uncommon cause of biotin deficiency, individuals following fad diets high in raw egg whites can be at risk for deficiency.127 Biotin deficiency may arise from long-term parenteral nutrition without biotin supplementation.128 Individuals on unsupplemented parenteral nutrition and on long-term antibiotics are particularly at risk because the antibiotics eradicate biotin-producing enteric flora.129 Anticonvulsants, such as valproic acid, carbamazepine, and phenytoin, can increase biotin catabolism or impair liver function, leading to biotin deficiency.130–132 A series of biotin deficiency cases were reported in Japan secondary to an elemental infant formula without supplemental biotin.133,134
Symptoms can develop 3–6 months after initiation of unsupplemented parenteral nutrition or raw egg white rich diet, but appear earlier in infants because of the greater biotin requirement for growth. The cutaneous manifestations are similar to those of acrodermatitis enteropathica (AE) (see below) and essential fatty acid deficiency (see above) (Box 130-11). An erythematous, scaling, and crusting dermatitis usually begins around the eyes, nose, and mouth and continues to involve multiple periorificial areas, including the perianal region. Alopecia, conjunctivitis, and glossitis have also been associated. Neurological findings include irritability, lethargy, paresthesias, hypotonia, developmental delay, and myalgias. Nausea and anorexia have also been described.
Box 130-11 Clinical Manifestations of Biotin Deficiency and Multiple Carboxylase Deficiency ||Download (.pdf)
Box 130-11 Clinical Manifestations of Biotin Deficiency and Multiple Carboxylase Deficiency
- Erythematous, crusting, scaly dermatitis around eyes, nose, mouth, and other periorificial areas
- Alopecia, glossitis, conjunctivitis
- Irritability, lethargy, paresthesias, hypotonia, developmental delay
Two inborn errors of metabolism, both autosomal recessive multiple carboxylase deficiencies, also alter normal biotin metabolism. The neonatal (early onset) form is associated with a defect in holocarboxylase synthetase. This enzyme is used to catalyze the formation of the amide bond linking biotin to several carboxylase enzymes. Symptoms develop during the first 6 weeks of life and the condition is typically fatal. Patients present with a bright red scaling dermatosis that starts on the scalp, eyebrows, and eyelashes, which can spread to involve the perioral, perinasal, and intertriginous regions. Hair thinning can progress to patchy or total alopecia. Holocarboxylase synthetase deficiency can also present as a collodion membrane and subsequent ichthyosis.135 Neurological findings are common and manifest as difficulty feeding and breathing, hypotonia, ataxia, seizures, lethargy, and global developmental delay. Associated metabolic derangements are metabolic acidosis, mild-to-moderate hyperammonemia, lactic acidosis, ketoacidosis, and organic aciduria, all of which can be exacerbated by intercurrent illness.136
The juvenile (infantile or late-onset) form presents after 3 months of age and is caused by biotinidase deficiency. Biotinidase is found in pancreatic secretions to recycle endogenous biotin and release protein-bound dietary biotin. Since symptoms derive from a relative biotin deficiency, large supplemental doses of biotin are used to treat this disorder. In biotinidase deficiency, children present with a scaly, erythematous periorificial dermatitis. Severe cases develop lichenification, crusting, and eroded lesions, which can become infected by Candida. Keratoconjunctivitis, total alopecia including eyebrows and eyelashes, and glossitis are associated mucocutaneous findings. Ataxia, developmental delay, hypotonia, seizures, optic nerve atrophy, hearing loss, and myoclonic spasms are common neurological findings. Hypertonia does not rule out this deficiency.137 Sensorineural hearing loss is preventable with early diagnosis of biotinidase deficiency, but once present, is irreversible.138 In contrast, the metabolic encephalopathy is reversible once appropriate therapy is initiated.139 Like holocarboxylase synthetase deficiency, metabolic acidosis, lactic acidosis, and organic aciduria are found. Humoral and cellular immunodeficiencies can predispose to cutaneous and systemic infections.
If dietary history is not explanatory, consultation to evaluate for inborn errors of metabolism is recommended in children who present with findings suggestive of a biotin deficiency. Biotinidase levels, serum amino acids, urine organic acids, carnitine studies, and ammonia may be helpful in differentiating this disorder from other metabolic diseases.
The recommended daily value increases from 30 μg in neonates to 100–200 μg in adults. Acquired deficiency is treated with 150 μg of biotin per day until resolution of symptoms. Although holocarboxylase synthetase deficiency can be treated with 10–40 mg of biotin per day to reverse cutaneous symptoms, neurological deficits may persist. Patients with biotinidase deficiency are treated with 5–10 mg of biotin and have better clinical outcomes than that seen with holocarboxylase synthetase deficiency.
Minerals at a Glance
- Cutaneous changes associated with iron deficiency include koilonychia, spoon-shaped nails; brittle, lusterless hair; aphthous stomatitis; and angular stomatitis.
- Acrodermatitis enteropathica is an inherited defect in the intestinal zinc transporter ZIP4.
- Zinc deficiency presents with a periorificial and acral eczematous and erosive dermatitis.
- Zinc status can be measured by serum zinc or alkaline phosphatase, a zinc-dependent enzyme.
- Menkes disease is an X-linked disorder of intestinal copper transport, and results in characteristic kinking of the hair and neurologic deficits.
Etiology and Pathogenesis
Copper is an essential component of several metalloenzymes, including tyrosinase and lysyl oxidase. Tyrosinase is involved in melanin biosynthesis, and lysyl oxidase deaminates lysine and hydroxylysine in the first step in collagen cross-linking. Other copper enzymes are involved in catecholamine production, free radical detoxification, and oxidation-reduction reactions.
Copper is found in fish, oysters, whole grains, beef and pork liver, chocolate, eggs, and raisins. Copper deficiency is uncommon, but can result from malnutrition, malabsorptive states, chronic unsupplemented parenteral nutrition, infants with a strictly cow's milk diet, and excessive intake of antacids, zinc, iron, or vitamin C, that can interfere with absorption. Celiac disease, cystic fibrosis, gastric bypass surgery, and short bowel syndrome lead to malabsorption of dietary copper.
Clinical manifestations in these cases include hypopigmentation of hair and skin and bony abnormalities (osteoporosis, fractures, periosteal reaction, and flaring of anterior ribs). Copper deficiency myeloneuropathy presents as a progressive and symmetric sensory loss and motor weakness of both upper and lower extremities.140–142 All sensory modalities are affected. If untreated, optic nerve involvement may occur, with permanent vision loss.142 Copper supplementation prevents further neurologic deterioration, but recovery of function is not guaranteed.
Microcytic anemia, neutropenia, hypocupremia, and hypoceruloplasminemia can be observed. Neutropenia is the earliest and most common sign of copper deficiency and is a sensitive measure of treatment adequacy.
Treatment is with supplemental copper in the diet.
Copper and Menkes Disease
Menkes disease, also known as kinky hair disease, was described by John Menkes in 1962 as a multifocal degenerative disease of gray matter. The connection between copper deficiency and demyelinating disease was first suggested in the 1930s by Australian veterinarians after observing ataxia in lambs born to mothers grazing in copper-deficient pastures. Menkes described five male infants born into an English-Irish family who showed an X-linked syndrome of neurologic degeneration, particular hair, and failure to thrive. The incidence of Menkes’ disease ranges from 1 in 100,000 to 1 in 250,000 live births.
Etiology and Pathogenesis
The Menkes gene, MNK, was identified on chromosome Xq13 in 1993. The protein product is a copper-transporting P-type ATPase, which is expressed in almost all tissues, except the liver. Mutations in MNK lead to decreased concentrations of copper because of impaired intestinal absorption and consequent decreased activity of cuproenzymes.
Classically, signs of Menkes disease begin at 2–3 months of age, although neonatal indicators include preterm labor, large cephalohematomas, hypothermia, hypoglycemia, and jaundice. The characteristic facies of Menkes disease is a cherubic appearance with a depressed nasal bridge, ptosis, and reduced facial movements. At 2–3 months of age, there is loss of developmental milestones, hypotonia, seizures, and failure to thrive. Structural changes in the hair are seen, with the general appearance of short, sparse, lusterless, tangled, and depigmented hair. The eyebrows have the same steel wool appearance as scalp hair. On light microscopy, pili torti is classically seen. Monilethrix, segmental shaft narrowing, and trichorrhexis nodosa, small beaded swelling of the hair shaft with fractures at regular intervals, may also be observed. Other cutaneous findings include follicular hyperkeratosis and soft, inelastic, depigmented skin especially at the nape of the neck, axillae, and trunk. A high arched palate and delayed tooth eruption may be noted on oral examination (Box 130-12).
Box 130-12 Clinical Features of Menkes Disease ||Download (.pdf)
Box 130-12 Clinical Features of Menkes Disease
- Depressed nasal bridge, ptosis, and reduced facial movements
- Loss of developmental milestones, hypotonia, seizures, hypothermia, and failure of thrive
- Steel wool appearance of hair: short, sparse lusterless, tangled, and depigmented. Microscopically: pili torti, trichorrhexis nodosa
- Follicular hyperkeratosis, inelastic depigmented skin at nape of neck, axillae, and trunk
- Arched plate, delayed tooth eruption
- Severe neurologic deficits
- Bony and renal changes
Neurologic deficits represent the major morbidity in this disorder. Profound truncal hypotonia with poor head control is typical, while appendicular tone may be increased. Deep tendon reflexes are hyperactive. Suck and cry remain strong. Optic disks are pale with impaired visual fixation and tracking. Hearing remains normal. Developmental arrest occurs at occasional smiling and babbling. Bony changes most often involve the extremities and the skull, and less often the thorax, vertebrae, and pelvis. They include osteoporosis, metaphyseal widening and lateral spur formation, ossification of sutures, a diaphyseal periosteal reaction, and scalloping of the posterior aspects of the vertebral bodies, and subperiosteal new bone formation. Renal involvement as hydronephrosis, hydroureter, and diverticula of the bladder can occur. Elongation and tortuosity of many large vessels lead to severe arterial disease, a frequent cause of death by age of 3–4 years.
Diagnosis is through the clinical history, physical examination, and reduced levels of serum ceruloplasmin and copper.
Early treatment with copper histidinate has resulted in good outcomes, including normal neurodevelopmental milestones, in some patients. Initiation of therapy in older patients may be helpful in alleviation of symptoms like irritability and insomnia.143,144
Etiology and Pathogenesis
Selenium is an essential component of glutathione peroxidase, an antioxidant. Selenium is found in seafood, red meat, egg yolks, grain products, and chicken. The amount of selenium available in cereal grains depends on the selenium content of the soil where it was grown. An area with low soil selenium is Keshan, China, where selenium deficiency in humans is endemic. Selenium-deficient soil is seen in the context of heavy erosion of the surface soil, resulting in trace mineral depletion.145,146
Selenium deficiency is primarily seen in geographic areas where low soil selenium exists, but can also occur in the context of restricted protein diets, unsupplemented parenteral nutrition, malabsorption states, and increased losses.147,148
Two disorders have been attributed to selenium deficiency: (1) Keshan disease and (2) Kaschin–Beck disease. These diseases have only been reported in endemic areas of Asia.
Keshan disease is a multifocal myocarditis leading to fatal cardiomyopathy that is seen primarily in women and young children in endemic areas. Acute or chronic insufficiency of cardiac function, cardiomegaly, arrhythmias, and electrocardiographic abnormalities have been noted. Muscle pain and weakness with hepatic congestion, mesenteric lymphadenosis, erythrocyte macrocytosis without anemia, and pancreatic exocrine dysfunction have also been seen. Cutaneous findings in these patients have included white nail beds, similar to those of Terry's nails in hepatic cirrhosis, and hypopigmentation of skin and hair (pseudoalbinism). These findings resolve with selenium supplementation.
Kaschin-Beck disease is an osteoarthropathy that affects the epiphyseal and articular cartilage and the epiphyseal growth plates, resulting in enlarged joints, and shortened fingers and toes.
Diagnosis of selenium deficiency is through measurement of plasma selenium levels and glutathione peroxidase activity.
Selenium supplementation is used for both acute correction and long-term maintenance.
Selenium toxicity can be acutely fatal. Cases of toxicity have been associated with increased soil selenium. Marco Polo described findings consistent with selenium poisoning in Western China during his explorations in 1,295. In the 1960s, reports of selenium toxicity came out of Enshi County in Hubei, China. The cause of this endemic toxicity arose from coal contaminated with selenium that was then used to fertilize the soil.149 Sporadic cases of selenium intoxication secondary to excess supplement ingestion have been reported.150 Additional cases of acute selenium toxicity have been documented after ingestion of glass blue (used in stained glass manufacturing),151 selenite broth (enriched culture media used to isolate Salmonella bacilli), and gun bluing agent (a finishing product for firearms).152
Hair becomes dry and brittle in association with an exfoliative dermatitis on the scalp, often resulting in broken hairs and alopecia. Nails also become brittle with white horizontal streaking on the surface. Breaks in the wall of then nail eventually leads to nail loss. The new nail is fragile and thickened with a rough surface. Nails, hair, and teeth can all develop a reddish hue. Skin on the extremities and neck can become red, swollen, blistered, and occasionally ulcerate that heal slowly. Neurologic complaints of peripheral anesthesia, hyperreflexia, numbness, convulsions, and paralysis have been reported. Nausea, vomiting, diarrhea, garlic or sour-milk breath odor, and hypersalivation can occur. Severe corrosive hemorrhagic gastritis can progress into a deep gastric ulcer after acute intoxication. Acute tubular necrosis of the kidneys with the potential for acute renal failure requiring dialysis may also complicate selenium toxicity.153
Screening of plasma can be used to document elevation selenium levels.
Treatment involves removal of the source of excess selenium and supportive care for complications.
Etiology and Pathogenesis
Manganese activates glycosyltransferases used in the synthesis of glycosaminoglycans and glycoproteins and is used in two metalloenzymes [(1) pyruvate carboxylase and (2) superoxide dismutase]. Manganese is also found in high concentrations in melanocytes. Reported cases of manganese deficiency are rare. Manganese deficiency was reported during a study of vitamin K requirements, when a study subject was accidentally placed on a manganese-deficient diet. He developed a mild dermatitis, reddening of his black hair, slowed hair and nail growth, and occasional nausea and vomiting with moderate weight loss. A subsequent study of manganese-deficient states showed no hair changes, but miliaria crystallina developed in half the subjects, and disappeared after repletion. Long-term parenteral nutrition without adequate supplementation can induce manganese-deficient states.154 Likewise, in cases where manganese is supplemented in parenteral nutrition, hypermagnesemia can occur and has been associated with neurologic sequelae.155
Iron is used in several biological pathways including heme synthesis, oxidation-reduction reactions, collagen synthesis, and as a cofactor for enzymes such as succinic dehydrogenase, monoamine oxidase, and glycerophosphate oxidase. Iron is found in red meats, egg yolks, dried beans, nuts, dried fruits, green leafy vegetables, and enriched grain products.
Iron deficiency continues to be an international problem that crosses socioeconomic and ethnic divides. Deficiency states result from inadequate intake or chronic blood loss. Groups at high risk include infants, menstruating females, and individuals with chronic gastrointestinal bleeds. Infants on an iron-fortified formula are at risk for deficiency 3–6 months after transitioning to cow's formula because of the lower iron content of cow's milk.156
Skin changes have been seen in iron deficiency involve the skin, mucous membranes, hair, and nails (Box 130-13). Moderate iron deficiency causes fragile, longitudinally ridged, lamellated, or brittle nails. As deficiency progresses, the nail plate shows thinning, flattening, and a spoon-shaped convexity known as koilonychia. The index and third fingernails are usually the most severely involved. Even after iron replacement therapy begins, koilonychia resolves slowly.
Box 130-13 Cutaneous Features of Iron Deficiency ||Download (.pdf)
Box 130-13 Cutaneous Features of Iron Deficiency
Fragile, longitudinally ridged
Lamellated brittle nails → thinning, flattening of nail plate, koilonychia
Lusterless, dry, focally narrow and split hair shafts, heterochromia of black hair. Hair loss.
Aphthous stomatitis, angular stomatitis, glossodynia, atrophied tongue papillae
Hair changes include a lusterless, brittle, dry, and focally narrow or split hair shafts, likely caused by impaired keratin production. Heterochromia of black scalp hair with alternating segments of dark brow, white, and liver bands have been described. Cunningham noted in 1932 that hair loss occurred in iron deficiency, but Hard was the first to show an etiologic connection between iron deficiency anemia and diffuse scalp hair loss.157,158 However, the role of iron deficiency in hair loss continues to be a controversial topic.159,160
Mucous membrane manifestations include aphthous stomatitis, angular stomatitis, glossodynia, and absent or atrophied tongue papillae. Blue sclerae that persists after iron replacement is likely secondary to impaired collagen synthesis. Generalized pruritus of variable severity has been reported in some individuals with iron deficiency, and sometimes associated with dermatitis herpetiformis. Plummer–Vinson syndrome is an iron deficiency associated syndrome encountered predominantly in middle-aged women with microcytic anemia, dysphagia, glossitis, koilonychia, and angular stomatitis. This is considered to be a precancerous phenomenon, associated with carcinoma of the mouth or upper respiratory tract.
Iron deficiency in a microcytic anemia is diagnosed by measurement of serum iron levels, ferritin, total iron binding capacity, transferrin saturation, as well as free or zinc protoporphyrin levels. Treatment involves appropriate iron supplementation.
Chronic iron overload, hemosiderosis, can be associated with tissue injury, which is called hemochromatosis. Hyperpigmentation and ichthyosis-like changes of the skin are seen. Associated findings are cirrhosis of the liver, diabetes mellitus, and cardiomyopathy.
Zinc is an important micronutrient that is an essential component of many metalloenzymes involved in a variety of metabolic pathways and cellular functions, and is particularly important in protein and nucleic acid synthesis. Adequate zinc levels are also important for wound healing and for T-cell, neutrophil, and natural killer cell function. Zinc homeostasis depends on adequate zinc absorption and maintenance of appropriate intracellular and extracellular zinc levels as well as its regulated transport across luminal surfaces. Dietary sources of zinc include meat, fish, shellfish, eggs, dairy products, and legumes, with the highest and most bioavailable forms of zinc found in meats, fish, and shellfish. Other vegetables, fruits, and refined carbohydrates contain very little zinc. Phytates (found in cereal grains, legumes, and nuts) and fiber interfere with intestinal zinc absorption. Human breast milk contains very high levels of zinc during the first 1–2 months of lactation, averaging 3 mg/L; subsequently, zinc levels decrease. Human breast milk also contains a zinc-binding ligand that increases the bioavailability of breast milk zinc. Although cow's milk formula contains higher levels of zinc, the bioavailability is significantly less than that in human breast milk.
Enteral zinc absorption occurs in the small intestine. Zinc excretion occurs primarily via the gastrointestinal tract via pancreatic and intestinal secretions, with lesser amounts excreted in the urine complexed to free amino acids. Two important families of zinc transporter proteins, including 9 ZnT (zinc transporter) genes and 15 Zip (Zrt- and Irt-like proteins) transporters, have been identified in humans.
Although total body zinc is stored primarily in the bones, muscles, prostate, and skin, there is no free exchange of stored zinc, and metabolic needs must be met by a continued supply of dietary zinc. In plasma, approximately 50% of the total zinc is complexed with albumin, while the remainder is bound to other serum proteins, including transferrin and α2-macroglobulin, or bound to free amino acids. Plasma levels may decrease transiently in response to intercurrent illness, surgery, or other stressors. Excess plasma zinc levels inhibit copper absorption, possibly through competitive inhibition of a common divalent cationic transporter. Zinc deficiency also results in impaired mobilization of hepatic retinol stores and is associated with impaired night vision (nyctalopia). Conversely, excessive calcium intake can interfere with normal zinc absorption, likely also a result of competitive inhibition.
Zinc deficiency occurs worldwide. Populations at special risk include patients with intestinal malabsorption syndromes liver disease, anorexia nervosa or food faddism, extensive cutaneous burns, and nephritic syndrome. Iatrogenic zinc deficiency may result from prolonged parenteral or enteral nutrition that contains inadequate zinc levels to meet the metabolic demands. Certain rural populations with diets high in phytates, as have been reported in certain parts of Iran, Turkey, and the former Yugoslavia, are also at risk for acquired zinc deficiency (AZD).
Etiology and Pathogenesis
Zinc deficiency may be either inherited, a form commonly referred to as AE, or acquired, and therefore referred to as AZD.
AZD may result from states associated with inadequate intake, impaired absorption, or increased excretion, including pregnancy, lactation, extensive cutaneous burns, generalized exfoliative dermatoses, food faddism, parenteral nutrition, anorexia nervosa, and even excessive sweating. Intestinal malabsorption syndromes, such as inflammatory bowel disease and cystic fibrosis, result in impaired intestinal absorption of zinc, whereas alcoholism and nephrotic syndrome result in increased renal zinc losses. Penicillamine has been reported to cause zinc deficiency in a patient with Wilson disease. Ornithine transcarbamylase deficiency has also been associated with zinc deficiency.
The inherited form of zinc deficiency, AE, is a rare autosomal recessive disorder of zinc absorption. These infants have a defect in an intestinal zinc transporter, the human ZIP4 protein encoded on the SLC39A4 gene. Mutations in this gene prevents appropriate enteral zinc absorption.161–163
AE classically presents during infancy on weaning from breast milk to formula or cereal, which have lower zinc bioavailability than breast milk. There is a form of AZD that may also present during infancy but, in contrast to AE, these infants become symptomatic while breast-feeding and improve after weaning to formula or table foods. Many of these reported infants have been premature, but cases have also been reported in full-term infants. The mothers of these infants have a presumed defect in mammary excretion of zinc into their breast milk, resulting in inadequate zinc intake in their infants.164,165 In a case we evaluated, breast milk zinc deficiency occurred as a result of excessive maternal intake of calcium that the mother was taking in the belief that calcium supplements might mitigate postpartum depression. Measured breast milk zinc levels were significantly decreased and rebounded to normal levels upon discontinuation of maternal calcium supplementation. Measurement of breast milk zinc levels is a useful tool and is diagnostic when less than 70 μg/dL.
AE presents soon after weaning in affected infants or during the fourth to tenth week of life in infants who are not breast-fed. The classic features of AE include alopecia, diarrhea, lethargy, and an acute eczematous and erosive dermatitis favoring periorificial (perioral, periocular, anogenital) and acral areas (hands and feet) (Box 130-14). The cutaneous findings are highly characteristic and often present initially as a nonspecific, acrally distributed, symmetric, eczematous dermatitis. Over time, bullae and erosions with a characteristic peripheral crusted border develop (Fig. 130-10). Vitiligo-like depigmented patches have been described.167 In addition to dry and brittle hair, alternating dark and light bands with polarized light can be seen.168 Patients also appear to be predisposed to systemic infections as a result of impaired cell-mediated immunity, and superinfection with Candida albicans and bacteria, usually Staphylococcus aureus, is common. Delayed wound healing, acute paronychia, conjunctivitis, blepharitis, and photophobia may also be observed. Diarrhea may be prominent but is not seen in all cases. If untreated, the disease is fatal.
Box 130-14 Clinical Features of Acrodermatitis Enteropathica ||Download (.pdf)
Box 130-14 Clinical Features of Acrodermatitis Enteropathica
- Eczematous and erosive dermatitis
- Preferentially localized to periorificial and acral areas
- Lethargy, irritability
- Whining and crying
- Superinfection with Candida albicans and Staphylococcus aureus
A. Patient with acrodermatitis enteropathica. These clinical findings resolved within 2 weeks of initiating zinc supplementation. B. This crusted and scaly, erosive, and sharply demarcated eruption appeared shortly after weaning. The child was highly irritable, whining and crying, and had diarrhea.
Acute AZD secondary to impaired absorption of zinc, inadequate intake, or excessive renal or intestinal losses may result in a clinical picture that resembles AE (see above) and occurs also in adults (Fig. 130-11).
Zinc deficiency. A. There are plaques of dry, scaly, eczematous skin around the buttocks. The lesions often become secondarily infected with Candida albicans. B. Hands. The fingers are enlarged, and there are paronychia and bright erythema on the terminal phalanges.
A chronic or subacute form of zinc deficiency is also recognized. These patients often have zinc levels in the mildly deficient range (40–60 μg/dL). Clinical manifestations include growth retardation in children and adolescents, hypogonadism in males, dysgeusia, poor appetite, poor wound healing, abnormal dark adaptation, and impaired mentation. Cutaneous manifestations, when present, are usually less striking and present predominantly as a psoriasiform dermatitis involving the hands and feet and, occasionally, the knees.
A low plasma zinc level is the gold standard for diagnosing zinc deficiency. Use of contaminated needles, catheters, and sample tubes may lead to erroneously high measured zinc levels. Contact with collection tubes with rubber stoppers should be avoided as they may contain high levels of zinc. Normal plasma zinc levels range from 70 to 250 μg/dL. Measurement of serum alkaline phosphatase—a zinc-dependent enzyme—is another useful and rapid indicator of zinc status, as alkaline phosphatase may be low-normal; serum alkaline phosphatase will increase with zinc supplementation, thus confirming the diagnosis.
In cases in which the plasma zinc level is equivocal and the diagnosis is uncertain, skin biopsy for routine histology may be helpful. The characteristic features are variable psoriasiform hyperplasia with confluent parakeratosis, spongiosis and pallor of the upper epidermis, focal dyskeratosis, and variable epidermal atrophy. However, these findings are not specific; and may be seen in a number of other nutritional deficiencies.
Zinc supplementation with either an enteral or parenteral formulation is appropriate. Clinical response is usually rapid, with initial improvement noted within several days. Irritability and whining disappear first, followed by improvement of skin lesions. Although several zinc formulations are available, the most commonly used enteral formulation is zinc sulfate. Zinc chloride is recommended for parenteral supplementation.
In children, 0.5–1.0 mg/kg of elemental zinc given as one to two daily doses is recommended for mild-to-moderate zinc deficiency. Higher doses may be required in cases of AZD due to intestinal malabsorption. In adults, 15–30 mg of elemental zinc per day is usually sufficient in cases of AZD. Serum zinc levels should be monitored during therapy. Patients with AE require lifelong treatment. Patients with AZD may need variable levels of supplementation, depending on their underlying disease. Of note, excess zinc levels may interfere with copper metabolism.
Zinc toxicity has been reported with exposure to zinc-containing fumes, intravenous poisoning, and ingestion of large amounts of zinc. There are no cutaneous manifestations, but patients may present with severe vomiting, nausea, lethargy, dizziness, neuropathy, and dehydration. Hypocupremia may result.