INTRODUCTION — Severely malnourished children typically are brought to medical attention when a health crisis, such as an infection, precipitates the transition between marasmus (a state of nutritional adaptation) and kwashiorkor, in which adaptation is no longer adequate. The World Health Organization (WHO) classifies malnutrition based upon the degree of wasting or stunting and the presence of edema, as described in a separate topic review. (See "Malnutrition in children in resource-limited countries: Clinical assessment".)
Evaluation and management of the malnutrition depends on the clinical setting and cause of malnutrition. Although the principles of assessment and management of malnourished children from resource-rich countries are similar to those from resource-limited countries, the specific details may vary based on local customs and resources. (See "Laboratory and radiologic evaluation of nutritional status in children" and "Poor weight gain in children younger than two years in resource-abundant countries: Etiology and evaluation".)
The micronutrient deficiencies that are most commonly associated with protein-energy malnutrition (PEM) in children are discussed here. Deficiencies of fat-soluble vitamins, iron, and zinc are particularly common, but deficiencies of other water-soluble vitamins, minerals, and trace elements also may be found, varying with the region and chronicity of the malnutrition [1]. More detailed information about the biochemistry of these micronutrients and their deficiency states are discussed in separate topic reviews. The clinical assessment and treatment of these children, including definitions and anthropometric measurements, are discussed separately. (See "Malnutrition in children in resource-limited countries: Clinical assessment".)
WHOM TO EVALUATE
●In resource-limited settings, micronutrient deficiencies are common in any child with severe acute malnutrition. Deficiencies of fat-soluble vitamins, iron, and zinc are particularly common, but deficiencies of other water-soluble vitamins, minerals, and trace elements also may be found, varying with the region and chronicity of the malnutrition. In most cases, specific testing is not necessary, because empiric replacement of vitamins and minerals is routinely included in nutritional rehabilitation. For some deficiencies (eg, vitamin A), additional replacement doses are given to patients who are symptomatic (table 1). (See "Management of complicated severe acute malnutrition in children in resource-limited countries".)
●In resource-rich settings, malnutrition is typically caused by an underlying medical disorder or a diet that is atypical for the community. In this setting, concerns for specific deficiencies are guided by knowledge about the patient's specific risk factors, such as bowel anatomy or diet, as well as by clinical symptoms. For symptomatic patients, laboratory testing is appropriate to confirm the diagnosis before embarking on replacement since multiple deficiencies may be present and signs and symptoms often overlap (table 2).
As examples, assessment of fat-soluble vitamin levels may be warranted for patients with malabsorptive disorders. Evaluation of folate, vitamin B12, and zinc may be warranted in inflammatory bowel disease. (See "Laboratory and radiologic evaluation of nutritional status in children" and "Vitamin and mineral deficiencies in inflammatory bowel disease".)
ESSENTIAL FATTY ACID DEFICIENCY — Children with protein-energy malnutrition (PEM) may have deficiencies of the two primary essential fatty acids (EFA): linoleic and alpha-linolenic acid. EFA levels may be altered by diet, disease, or prematurity. EFA deficiency can be diagnosed by measuring the triene:tetraene ratio in blood; a ratio >0.2 suggests EFA deficiency [2]. This biochemical sign will be evident prior to any physical changes. Physical signs include scaly dermatitis, alopecia, and thrombocytopenia. Deficiency of EFA can affect growth and cognitive and visual function in infants [3].
FAT-SOLUBLE VITAMIN DEFICIENCIES — Children with protein-energy malnutrition (PEM) also may have deficiencies of the fat-soluble vitamins: A, D, E, and K (table 3). (See "Laboratory and radiologic evaluation of nutritional status in children".)
Vitamin A — Vitamin A deficiency is common in resource-limited countries (figure 1A-B) [4]. It is associated with a group of ocular signs known as xerophthalmia. The earliest symptom is night blindness, which is followed by xerosis (dryness) of the conjunctiva and cornea (picture 1), and development of Bitot spots (triangular areas of abnormal squamous cell proliferation and keratinization of the conjunctiva) (picture 2) [5-7]. Progression of disease includes keratomalacia (softening), ulceration, perforation, and scarring of the cornea; prolapse of the lens; and blindness. Other features of vitamin A deficiency include follicular hyperkeratosis, pruritus, growth retardation, and increased susceptibility to infection [8,9]. Randomized trials have shown that routine vitamin A supplementation to children in endemic areas is associated with a reduction in diarrhea-related, and possibly in all-cause, mortality. (See "Overview of vitamin A".)
The eyes should be examined very gently to avoid further damage to the cornea. If corneal inflammation or ulceration is present, the eye should be protected by pads soaked in saline and treated with tetracycline eye drops [10].
The World Health Organization (WHO) recommends empiric treatment of all children with severe malnutrition in resource-limited countries with large doses of vitamin A at the time of hospital admission for treatment of malnutrition. The doses supplied in the WHO-recommended therapeutic foods are sufficient for most children. Children with any clinical signs or symptoms of vitamin A deficiency should be given additional doses of vitamin A [10]. (See "Management of complicated severe acute malnutrition in children in resource-limited countries", section on 'Vitamin and mineral supplementation'.)
Vitamin D — Deficiency of vitamin D, typically caused by dietary deficiency and inadequate exposure to sunlight, is associated with hypocalcemia, hypophosphatemia, and rickets in children and osteomalacia in adults [11,12]. (See "Etiology and treatment of calcipenic rickets in children" and "Epidemiology and etiology of osteomalacia".)
Defective bone growth is caused by a failure of mineralization of uncalcified osteoid and cartilage, resulting in a wide, irregular zone of poorly supported tissue and numerous characteristic skeletal abnormalities, including:
●Craniotabes, caused by thinning of the outer table of the skull
●Enlargement and delayed closure of the anterior fontanelle
●Frontal bossing of the skull
●Delayed eruption of the teeth and tooth enamel defects
●Beading of the ribs (rachitic rosary)
●Scoliosis
●Exaggerated lordosis
●Bowlegs in older infants
●Greenstick fractures in the long bones
Radiographic changes include widening, concave cupping, and frayed poorly demarcated ends of long bones with metaphyseal flaring. (See "Overview of vitamin D".)
Vitamin E — Tocopherol deficiency can be associated with a progressive sensory and motor neuropathy, ataxia, retinal degeneration, and a hemolytic anemia [13]. (See "Overview of acquired peripheral neuropathies in children" and "Overview of vitamin E".)
Vitamin K — Deficiency of vitamin K results in a bleeding diathesis. Bleeding may be seen in the skin, gastrointestinal tract, genitourinary tract, gingiva, lungs, joints, or central nervous system. (See "Overview of vitamin K".)
WATER-SOLUBLE VITAMIN DEFICIENCIES — Deficiencies of water-soluble vitamins and fat-soluble vitamins are seen with protein-energy malnutrition (PEM) in resource-limited countries (table 1). Recommended intakes are summarized in the table (table 4), and details of metabolism and testing are discussed in a separate topic review. (See "Overview of water-soluble vitamins".)
Folate — Folate deficiency is characterized by hypersegmentation of neutrophils, megaloblastosis, and anemia. Low serum folate levels are also found in children with zinc and vitamin B12 deficiencies. Medications such as phenobarbital increase the need for folate [14].
For children with acute malnutrition, empiric supplements of folate are included in the therapeutic foods recommended by the World Health Organization (WHO) [10]. It is also important to provide adequate amounts of zinc at the same time (also included in the therapeutic foods) because folic acid treatment can inhibit zinc absorption. (See "Management of complicated severe acute malnutrition in children in resource-limited countries", section on 'Vitamin and mineral supplementation'.)
Thiamine — Thiamine (vitamin B1) deficiency is classically associated with beriberi, characterized by high-output cardiomyopathy and polyneuritis. Infantile beriberi occurs in infants between one and four months of age who have PEM, are receiving unsupplemented hyperalimentation fluid or boiled milk, or are breastfed by mothers who are deficient in thiamine [15]. Infants with beriberi have a characteristic hoarseness or aphonic cry caused by laryngeal paralysis. (See "Overview of water-soluble vitamins", section on 'Vitamin B1 (thiamine)'.)
Riboflavin — Riboflavin (vitamin B2) deficiency is characterized classically by angular stomatitis, glossitis (magenta tongue) (picture 3), seborrheic dermatitis around the nose and scrotum, and vascularization of the cornea [16]. (See "Overview of water-soluble vitamins", section on 'Vitamin B2 (riboflavin)'.)
Niacin — Niacin (vitamin B3) deficiency results in pellagra with dermatitis, diarrhea, dementia, and weakness. (See "Overview of water-soluble vitamins", section on 'Vitamin B3 (niacin)'.)
●The dermatitis is localized to sun-exposed areas of the body. The skin is dry, cracked, hyperkeratotic, and hyperpigmented.
●Watery diarrhea, as well as colitis, may be pronounced. Vomiting also may occur.
●Neurologic findings include peripheral neuropathy, irritability, headache, insomnia, loss of memory, emotional instability, toxic psychosis associated with delirium and catatonia, seizures, and coma.
●Oral manifestations include cheilosis, angular fissures, atrophy of the tongue, hypertrophy of the fungiform papillae, and painful inflammation of the mouth, which may lead to refusal of food.
Pyridoxine — Pyridoxine (vitamin B6) deficiency manifests as nonspecific stomatitis, glossitis (picture 3), cheilosis, irritability, confusion, weight loss, and depression. Peripheral neuropathy occurs in adolescents, whereas younger children develop encephalopathy with seizures. (See "Overview of water-soluble vitamins", section on 'Vitamin B6 (pyridoxine)'.)
Vitamin B12 — Vitamin B12 deficiency is uncommon in children but can occur in exclusively breastfed infants of mothers eating a strict vegetarian (vegan) diet, or with vitamin B12 malabsorption due to gastric bypass, short bowel syndrome, or pernicious anemia [17,18]. In undernourished children, subclinical vitamin B12 deficiency contributes to poor linear growth and weight gain [19]. Overt deficiency may cause megaloblastic anemia (picture 4), atrophic glossitis (picture 3), neuropathy, and demyelination of the central nervous system. Infants may present with nonspecific symptoms, including weakness, failure to thrive, developmental delay, afebrile seizures, involuntary movements, nystagmus, tremors, and irritability [20,21]. If untreated, irreversible cognitive deficits may occur [22]. (See "Treatment of vitamin B12 and folate deficiencies" and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)
Vitamin B12 deficiency in an infant causes elevation of the acylcarnitines propionylcarnitine (C3) and/or methylmalonyl-carnitine (C4DC), which are often measured as part of a newborn screening program for methylmalonic acidemia [23]. Thus, neonatal vitamin B12 deficiency due to maternal deficiency should be considered in the differential diagnosis of an infant with abnormal results on a newborn screening test. (See "Organic acidemias: An overview and specific defects", section on 'Methylmalonic acidemia'.)
Ascorbic acid — Ascorbic acid (vitamin C) deficiency results in the clinical manifestations of scurvy. Overt clinical scurvy presents with hemorrhage (petechiae, ecchymoses, bleeding gums) (picture 5), follicular hyperkeratosis, hemolytic anemia, hypochondriasis, hysteria, depression, and fatigue. Infantile scurvy typically presents with irritability, pseudoparalysis because of painful extremities, failure to thrive, and gingival hemorrhage. The prominence of hair follicles on the thighs and buttocks and the eruption of coiled, fragmented hair with a characteristic corkscrew appearance are specific features of vitamin C deficiency (picture 6). Petechiae found on the skin have a characteristic pale halo ring around a central erythematous core. (See "Overview of water-soluble vitamins", section on 'Vitamin C (ascorbic acid)'.)
MINERAL AND TRACE ELEMENT DEFICIENCIES — Children with protein-energy malnutrition (PEM) also may be deficient in minerals or trace elements. (See "Overview of dietary trace elements".)
Calcium, phosphate, and magnesium — Calcium deficiency occurs in conjunction with deficiency of vitamin D or parathyroid hormone. Clinical manifestations of hypocalcemia include tetany, Chvostek sign, Trousseau sign, and seizures. Severe hypophosphatemia (less than 1 mg/dL) can cause myopathy, rhabdomyolysis, bone pain, and osteomalacia or rickets. Hypomagnesemia typically is associated with hypocalcemia and hypokalemia and manifests with muscle fasciculations, tremors, or spasms; personality change; and seizures. (See "Hypophosphatemia: Clinical manifestations of phosphate depletion" and "Hypomagnesemia: Clinical manifestations of magnesium depletion".)
Iron — Iron deficiency is the most common nutritional deficiency in children and is particularly common in most of Africa, Latin America, and Southeast Asia (figure 2). Usually, it is manifested as a mild to moderate microcytic, hypochromic anemia (picture 7) in an otherwise asymptomatic infant or child. Severe iron-deficiency anemia presents with lethargy, pallor, irritability, cardiomegaly, poor feeding, tachypnea, and impaired psychomotor and cognitive development [24,25]. Spooning and pallor of the nail beds may be present on physical examination. Pagophagia, or pica for ice, is specific for the iron-deficient state. It may be present in children who are not anemic and responds rapidly to treatment with iron, often before any increase is noted in the hemoglobin concentration [26]. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)
Infants with severe malnutrition are almost always deficient in iron. Iron is supplemented via specially designed therapeutic foods during the rehabilitation phase. Additional iron supplementation beyond what is included in the therapeutic foods is unnecessary and may increase the risk for infections. (See "Management of complicated severe acute malnutrition in children in resource-limited countries", section on 'Vitamin and mineral supplementation'.)
Zinc — Zinc deficiency was originally described in a group of children with low levels of zinc in their hair, poor appetite, diminished taste acuity, hypogonadism, and short stature. Now zinc deficiency is recognized to be associated also with numerous other findings, including alopecia, dermatitis, growth failure, cognitive dysfunction, and increased susceptibility to infection (table 5) [27-31]. The dermatitis associated with zinc deficiency classically occurs in the perioral and perianal areas of the body and is characterized by flaming-red, easily denuded skin (picture 8). (See "Overview of dietary trace elements", section on 'Zinc'.)
Diarrhea can be both a cause and sign of zinc deficiency, and supplementation is recommended for children with acute or persistent diarrhea living in resource-limited ("developing") countries [32,33]. (See "Zinc deficiency and supplementation in children", section on 'Supplementation and food fortification in resource-limited settings'.)
Zinc supplementation is included in the oral rehydration solutions and refeeding solutions designed by the World Health Organization (WHO) for treatment of severe malnutrition in children, and these doses are sufficient for children with diarrhea. A trial of zinc supplements is also appropriate as part of nutritional rehabilitation for children with milder degrees of malnutrition if they are not receiving zinc through WHO therapeutic foods. (See "Management of complicated severe acute malnutrition in children in resource-limited countries", section on 'Vitamin and mineral supplementation'.)
Copper — Copper deficiency was first reported in infants recovering from PEM whose diet was based on cow's milk. It is seen also in infants receiving total parenteral nutrition without trace mineral supplementation. Copper deficiency is associated with a sideroblastic anemia, neutropenia, failure to thrive, and skeletal abnormalities including osteoporosis, enlargement of costochondral cartilage, cupping and flaring of long bone metaphyses, and spontaneous fractures of the ribs [34]. (See "Overview of dietary trace elements", section on 'Copper'.)
Selenium — Selenium deficiency can cause dilated cardiomyopathy with myocardial necrosis and fibrosis. This condition, known as Keshan disease, occurs primarily in children living in rural China [35]. Sporadic cases have been reported in the United States in individuals with poor nutritional intake, mostly in individuals on long-term home parenteral nutrition without trace mineral supplementation [36,37]. Muscle pain, myopathy, loss of hair pigment, and nail bed changes also may occur. (See "Overview of dietary trace elements", section on 'Selenium'.)
Iodine — Moderate iodine deficiency can lead to hyperplasia and hypertrophy of the thyroid gland or goiter to maintain a euthyroid state [38]. Severe dietary iodine deficiency results in hypothyroidism. Hypothyroidism during early critical periods of development can lead to permanent intellectual disability, hearing impairment, spastic diplegia, and strabismus. Clinical manifestations of congenital hypothyroidism include hypotonia, macroglossia, hoarseness, growth retardation, and constipation. (See "Iodine deficiency disorders".)
Infants born in regions of iodine deficiency (picture 1) are at risk for some degree of intellectual disability. The effects of iodine deficiency can be exacerbated by deficiencies of selenium and vitamin A and the ingestion of foods such as cassava or millet that contain goitrogenic substances. (See "Treatment and prognosis of congenital hypothyroidism", section on 'Prognosis'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vitamin deficiencies" and "Society guideline links: Pediatric iron deficiency" and "Society guideline links: Pediatric malnutrition".)
SUMMARY
●Acute malnutrition typically causes wasting (with reduced weight-for-height), while chronic malnutrition causes stunting (with reduced height-for-age). The severity of the malnutrition can be categorized based upon the degree of wasting or stunting and the presence of edema. (See 'Introduction' above and "Malnutrition in children in resource-limited countries: Clinical assessment".)
●Children with protein-energy malnutrition (PEM) frequently have clinical signs of micronutrient deficiencies (table 2). Deficiencies of fat-soluble vitamins, iron, and zinc are particularly common, but deficiencies of other water-soluble vitamins, minerals, and trace elements also may be found, varying with the region and chronicity of the malnutrition. (See 'Fat-soluble vitamin deficiencies' above and 'Mineral and trace element deficiencies' above and 'Water-soluble vitamin deficiencies' above.)
●Whether specific laboratory testing for these nutritional deficiencies is valuable depends on the clinical setting and cause of malnutrition. In resource-limited countries, an empiric approach to replacement often is most practicable. Children with severe malnutrition are routinely given a cocktail of vitamin and mineral supplements as part of the standard therapeutic feeding regimen. Iron supplements are added during the rehabilitation phase. (See 'Whom to evaluate' above and "Management of complicated severe acute malnutrition in children in resource-limited countries".)
●Vitamin A deficiency is a particularly common micronutrient deficiency in resource-limited countries (figure 1A-B). Empiric replacement of vitamin A is appropriate for all malnourished individuals, with additional doses for those with evidence of the ocular disease caused by the deficiency (night blindness, corneal xerosis, or Bitot spots). (See 'Vitamin A' above.)
●In resource-rich countries, children with malnutrition are more likely to have an underlying malabsorptive disorder. In this setting, specific testing for some micronutrient deficiencies may be appropriate, depending on the pathophysiology of the underlying disorder and physical signs. Assessment of fat-soluble vitamin levels may be warranted in malabsorptive syndromes. Evaluation of folate, vitamin B12, and zinc may be warranted in inflammatory bowel disease. (See "Laboratory and radiologic evaluation of nutritional status in children".)
