Skin findings associated with nutritional deficiencies

VITAMIN A DEFICIENCY

Case: A girl with short-bowel syndrome on total parenteral nutrition

A 14-year-old girl who had been on total parenteral nutrition for the past 3 years due to short-bowel syndrome was admitted for evaluation for a second small-bowel transplant. She complained of dry skin and dry eyes. She was found to have rough, toad-like skin with prominent brown perifollicular hyperkeratotic papules on buttocks and extremities (Figure 5). Additionally, corkscrew hairs were noted. Physical examination was consistent with phrynoderma.

Blood work revealed low levels of vitamin A (8 µg/dL, reference range 20–120 µg/dL) and vitamin C (20 µmol/L, reference range 23–114 µmol/L). After bowel transplant, her vitamin A levels normalized within 2 weeks and her skin improved without vitamin A supplementation.

Essential for protein synthesis

Vitamin A is a group of fat-soluble isoprenoids that includes retinol, retinoic acid, and beta-carotene. It is stored in hepatic stellate cells, which can release it in circulation for distribution to peripheral organs when needed.¹⁶

Vitamin A is essential for protein synthesis in the eye and is a crucial component of phototransduction.¹⁷ It is also an important modulator of the immune system, as it enhances cytotoxicity and proliferation of T cells while suppressing B-cell proliferation.¹⁸ Additionally, vitamin A plays an important role in the skin, where it promotes cell mitosis and increases epithelial thickness, the number of Langerhans cells, and glycosaminoglycan synthesis.^19–21

Deficiency associated with malabsorption, liver disease, small-bowel surgery

Vitamin A deficiency is rare in developed countries overall, but it is associated with malabsorption, liver disease, and small-bowel surgery.²² Indeed, 4 years after undergoing bariatric surgery, 69% of patients in one series had deficiencies in vitamin A and other fat-soluble vitamins.²³ The typical manifestations are nyctalopia (night blindness) and xerophthalmia (inability to produce tears).

Phrynoderma, or “toad skin,” is a cutaneous manifestation of vitamin A deficiency. The association between phrynoderma and vitamin A deficiency was established in 1933 when prisoners in Africa with nyctalopia, xerophthalmia, and phrynoderma showed improvement in all three conditions when treated with cod oil, which is rich in vitamin A.²⁴

Phrynoderma is characterized by dry, hyperkeratotic papules with central intrafollicular plugs projecting from hair follicles.²⁵ The lesions are typically symmetrically distributed on the face, the skull, and the extensor surfaces of the shoulders, buttocks, and extremities, but they can extend to the entire body in severe cases.²⁵ They typically get better with improved nutrition.

Evidence is mounting to suggest phrynoderma is a cutaneous manifestation of diverse nutritional deficiencies, not just vitamin A. For example, some children with phrynoderma have normal levels of vitamin A,²⁶ and a trial showed that patients with phrynoderma benefited from intramuscular injections of either vitamin A or vitamin B complex, particularly when also treated with topical keratolytics.²⁷ Thus, patients who present with the typical lesions of phrynoderma should be screened for nutritional deficiencies beyond vitamin A.

VITAMIN B₆ DEFICIENCY

Case: A woman with sepsis

A 62-year-old woman with a 4-year history of unspecified dermatitis, intertriginous rashes, and skin ulcerations with polymicrobial infections was admitted for sepsis. She reported that her rash had worsened over the previous 2 weeks. Physical examination revealed generalized xerosis, an inflamed bright red tongue with atrophy of distal papillae, and red painful erosions in intertriginous areas (Figure 6).

Blood testing revealed low levels of vitamin B₂ (< 5.0 nmol/L, reference range 6.2–39 nmol/L) and vitamin B₆ (3.1 nmol/L, reference range 20–125 nmol/L). She was started on supplementation with vitamin B₆ 50 mg/day and vitamin B₂ 200 mg/day, and her dermatitis and ulcers improved.

Pyridoxine and its derivatives

Pyridoxine and its derivatives are collectively known as vitamin B₆. Vitamin B₆ can be stored throughout the body, particularly in muscle and the liver, whereas its oxidized version is excreted mostly in the urine.^28,29 Vitamin B₆ serves as a cofactor to more than 140 enzymes, it is required for tryptophan metabolism and synthesis of nicotinic acid, and it is a cofactor for alanine aminotransferase and aspartate aminotransferase.^28,29

Vitamin B₆ deficiency is rare in the general population. The median daily intake is 2 mg/day for men and 1.5 mg/day for women, whereas the RDA for adults is 1.3 mg/day. No signs of vitamin B₆ deficiency have been noted at intakes greater than 0.5 mg/day in clinical studies.²⁸

However, chronic alcoholism poses a high risk of this deficiency because it decreases the intake of vitamin B₆ and decreases the ability of the liver to store it. Additionally, patients with eclampsia or preeclampsia or who are on dialysis have higher vitamin B₆ requirements.²⁸ Certain medications are also associated with a low vitamin B₆ level, in particular the antituberculosis medication isoniazid, penicillamine, and hydralazine.²⁸

Although clinical manifestations of vitamin B₆ deficiency are rare, subclinical deficiency may be common, particularly in the elderly,²⁸ as up to 23% of people ages 65 to 75 and 40% of those older than 85 have vitamin B₆ deficiency.^30,31

Features of vitamin B₆ deficiency

Vitamin B₆ deficiency is associated with anemia (hypochromic, microcytic, iron-refractory), impaired immune function, seizures, peripheral neuropathy, and glossitis. Experimentally induced deficiency of vitamin B₆ results in periorificial dermatitis within 3 weeks.³² Intriguingly, multiple studies have shown an inverse correlation between B₆ levels and diverse cancers, including colorectal, pancreatic, and lung cancer.²⁸

Given its role in the synthesis of nicotinic acid, vitamin B₆ deficiency results in abnormal levels of B₃. Thus, vitamin B₆ deficiency may result in a pellagra-like presentation (reviewed in detail below in the discussion of vitamin B₃ deficiency). In this case, giving vitamin B₃ does not result in significant improvement, and this failure helps to establish the diagnosis of vitamin B₆ deficiency.³² It is believed that pellagrous lesions in vitamin B₆ deficiency are due to decreased synthesis of proline from ornithine, as suggested by decreased levels of the enzyme ornithine aminotransferase in patients with low vitamin B₆.³³ Other cutaneous manifestations of vitamin B₆ deficiency include eczema and seborrheic dermatitis.³³

Vitamin B₆ can be measured in blood and urine. Although these levels only reflect recent intake, plasma values lower than 20 nmol/L are indicative of vitamin B₆ deficiency.³⁴ Therapeutic oral supplementation of vitamin B₆ is the treatment of choice. Vitamin B₆ treatment is safe, but exposure to high levels of vitamin B₆ may result in photosensitivity and dermatitis.³⁵

Vitamin B₂ (riboflavin) deficiency

Riboflavin, or vitamin B₂, is a water-soluble vitamin involved in diverse reduction-oxidation reactions. Its active forms—flavin adenine dinucleotide and flavin mononucleotide—act as electron carriers in the respiratory electron transfer chain, and the former is necessary for the oxidation of fatty acids.³⁶ The human body does not store riboflavin, and excess intake is excreted in the urine.³⁶

Milk, dairy products, and meat are the major dietary sources of vitamin B₂. Additionally, some colonic bacteria synthesize it and provide an additional source.³⁶ Patients whose diets are low in dairy and meat products, in particular vegetarians, alcoholics, and the elderly, are at risk of this deficiency. Other populations at risk are pregnant women, lactating women, premature infants, infants exposed to phototherapy for hyperbilirubinemia, and infants of mothers with low vitamin B₂ levels.^36,37

The RDA for vitamin B₂ is 1.3 mg/day for men and 1.1 mg/day per women, with higher requirements for pregnant and lactating women. Fortunately, the median intake of riboflavin from diet in the United States is 2 mg/day for men and 1.5 mg/day for women.³⁸

Features of vitamin B₂ deficiency

Features of vitamin B₂ deficiency include angular stomatitis, glossitis, cheilosis, nasolabial dermatitis, and rarely corneal vascularization.^39,40 Dermatitic lesions around the scrotum and labia are common and are in many cases the initial manifestation of vitamin B₂ deficiency.^39,40 Riboflavin deficiency during development results in muscular, skeletal, and gastrointestinal abnormalities. In adults, riboflavin deficiency is associated with anemia, decreased iron absorption, neurodegeneration, and peripheral neuropathy.³⁶

Vitamin B₂ deficiency usually coexists with other deficiencies, and riboflavin is involved in the metabolism of other B vitamins including B₃, B₆, B₉ (folate), and B₁₂. Thus, the clinical presentation of vitamin B₂ deficiency is similar to that of vitamin B₃ and B₆ deficiency (reviewed above and below) and has been described as pellagra sine pellagra (pellagra without pellagra). Moreover, correction of riboflavin deficiency results in increased levels of vitamin B₃ and B₆.³⁶

Vitamin B₂ levels can be measured in the urine and blood.³⁷ Oral supplementation is safe (up to 60 mg/day) and is the treatment of choice.^36,38 Clearance of lesions within 3 to 5 days of riboflavin supplementation confirms the diagnosis.⁴⁰

Vitamin B₃ (niacin) deficiency

Niacin, or vitamin B₃, is a water-soluble vitamin abundant in meat, eggs, and legumes. It is an essential cofactor for coenzyme I and coenzyme II; therefore, it plays a crucial role in ATP synthesis, glycolysis, and metabolism of fatty acids and amino acids.^41,42

Most niacin is acquired in the diet, but humans can synthesize it from tryptophan in the presence of vitamin B₆ and thiamine.⁴² Thus, a deficiency in tryptophan, vitamin B₆, or thiamine can also lead to low niacin, and  an excess of dietary leucine can interfere with niacin synthesis and result in deficiency.⁴²

The RDA for niacin is 6 to 20 mg/day, based on sex and age, with higher requirements for pregnant and lactating women.³⁸

Pellagra, the clinical manifestation

Pellagra is the clinical manifestation of niacin deficiency, although it is thought that lack of tryptophan, vitamin B₆, or thiamine may also be required for clinical symptoms to appear.⁴¹

Sporadic cases of pellagra occur in homeless people, alcoholics, drug abusers, people with anorexia, and food faddists.^41,42 Symptoms typically develop after about 50 days of a niacin-free diet.⁴¹ Pellagra may also develop due to impaired absorption or metabolism, particularly in patients with prolonged diarrhea, colitis, ileitis, hepatic cirrhosis, or Hartnup disease.^42–45 Certain medications, eg, isoniazid, 5-fluorouracil, azathioprine, and 6-mercaptopurine, interfere with niacin synthesis and may induce pellagra in susceptible patients.⁴²

The clinical course of pellagra is often described by the four “Ds”: dermatitis, dementia, diarrhea, and, when not corrected, death. Early symptoms of insufficient vitamin B₃ are weakness, fatigue, loss of appetite, depression, and mood changes.⁴²

The cutaneous manifestations of pellagra are impressive and include photosensitive eruptions, perineal lesions, and thickened and pigmented skin.⁴¹ Biopsy of affected and unaffected skin in pellagra patients shows abnormal keratinization.

Photosensitivity is an initial manifestation of pellagra.⁴⁶ It is believed that vitamin B₃ deficiency results in a lack of urocanic acid, a compound that protects against ultraviolet B damage and accumulation of kynurenic acid, a known phototoxic agent.⁴⁷

The initial stage of acute pellagra can resemble a sunburn on the face, neck, and dorsal extremities⁴⁷ that becomes darker with time instead of fading.⁴⁶ Sharply demarcated hyperpigmented areas on the arms and legs are known as the “glove” and “boot” of pellagra.⁴⁶ Nearly all patients have involvement of the dorsum of the hand.⁴² The Casal necklace may be present, a characteristic eruption observed in up to 76% of patients on the front of the neck in the region of C3-C4.⁴⁸

As the disease progresses, lesions harden and become brittle—hence, the name pellagra, which means “rough skin.” Perineal lesions are also common, along with fissures and ulcerations. Additionally, about a third of pellagra patients have involvement of the lips, tongue, and oral mucosa.⁴² Notably, patients with drug-induced or Hartnup-related pellagra do not develop genital, perineal, oral, or hyperkeratotic lesions.⁴⁶

Although untreated pellagra can lead to death in 5 years,⁴² the disease responds dramatically to oral nicotinamide (250–500 mg/day), which is preferred over niacin due to the latter’s vasomotor effects.⁴¹ Therapy also includes caloric supplementation, other B vitamins, zinc, and magnesium.⁴²

NUTRITIONAL DEFICIENCIES TEND TO COEXIST

The clinical scenarios presented here emphasize how different nutritional deficiencies can manifest with overlapping features. But nutritional deficiencies, particularly those associated with underlying conditions, tend to coexist rather than occur in isolation.

Although associated with significant morbidity, nutritional deficiencies can be easily addressed, particularly when promptly identified. Careful evaluation of the history and clinical and serologic findings is necessary to correctly diagnose and address these conditions.