An 18 month old boy is brought to the emergency room by police for evaluation. He and his siblings were all removed from their home earlier in the day, after a neighbor's complaint. There are no parents or guardians present to give a history, although the police officer comments that the mother is thought to be an injection drug user. The 12 year old sister, who seems to be the primary caregiver, is worried that the toddler is sick, stating that "he's gotten really skinny" and he "keeps a cold," with constant rhinorrhea and cough. She is unsure if he has seen a doctor, but thinks that he "got all his baby shots".

Diet history is revealing: meals are generally prepared by the 12 year old and 10 year old siblings, and consist of packaged macaroni and cheese, canned spaghetti or noodles, peanut butter and jelly sandwiches, and occasionally fast food drive-ins. The older kids usually drink juice and sodas, though the toddler also drinks some milk.

On exam, the toddler is anxious, clinging to his older sister. He appears thin, with a large head and subcutaneous wasting. Vital signs are appropriate for age. Weight is 9 kg (<3rd percentile); height is 72 cm (<3rd percentile); head circumference is 47 cm (10th percentile). Exam is significant for subcutaneous wasting, sparse hair, dry skin, and a scaling rash in the diaper area. There are no overt signs of trauma, and no focal neurologic deficits.

Laboratory evaluation is significant for a microcytic anemia and a decrease in serum albumin. The toddler is admitted to the hospital for protection, and monitoring during the refeeding process, which proceeds without incident. With concern for infectious risk factors, an HIV test is ordered - which is positive. CD4 count is 1500. Antiretroviral therapy is instituted, with good immunologic response. With the provision of sufficient calories and protein in the diet, weight gain begins to improve.

Protein-energy malnutrition unfortunately remains a significant problem, both in developing countries, and in poverty-stricken areas of the industrialized world. Children with chronic or acute illness are at particular risk, particularly those with acute illnesses including: burns, sepsis, head injury, trauma, malabsorptive disorders, chronic liver, renal, or cardiac diseases, cancers, and HIV. Protein-energy malnutrition may present as the classic syndromes of marasmus and kwashiorkor, or more commonly, with overlap between the two.

Marasmus (1,2) is a classic description of a deficiency in the somatic protein compartment, resulting from primarily a caloric or energy deficiency, and leading to generalized muscular wasting and the loss of subcutaneous fat. The skin appears dry, loose, and wrinkled. Hair may become thin, sparse, and brittle. Hypothermia, bradycardia, hypotension, and hypoglycemia may occur. The visceral protein compartment (discussed below) is relatively spared. As a result, serum albumin measurements are generally normal, though anemia and evidence of vitamin deficiencies are common. There may be a coexisting T cell-mediated immune deficiency.

Kwashiorkor (1,2), in contrast, is a deficiency of the visceral protein compartment, resulting from a protein deficiency (in excess of the caloric deficiency), and leading to edema, dermatoses (including hyperkeratosis, dyspigmentation), dry, brittle, and sometimes red or yellowish hair (if alternating periods of protein deprivation, they may have alternating bands of hair texture = flag sign), hepatomegaly (fatty infiltration), protruding abdomen, and impairment in T cell-mediated immune deficiency. Risk of secondary infections is therefore increased. Laboratory abnormalities may include a low serum albumin, mineral deficiencies (iron, zinc, copper), and elevated blood glucose, white blood cell count, urine nitrogen, and serum ferritin (as an acute phase reactant even if they are iron deficient) or other acute phase reactants (3). Kwashiorkor has been known to occur in toddlers weaned to a protein deficient diet (white rice, yams, cassava-a Latin American staple root otherwise known as manioc or yucca), or in chronically ill or hospitalized patients, in the industrialized world. If kwashiorkor develops in patients with acute illness, such as burns, sepsis, or trauma, it will not resolve entirely until the underlying illness resolves.

Marasmus and kwashiorkor are at two ends of a spectrum of protein-energy malnutrition. In the industrialized world, a mixed picture is most common, often in the setting of chronic disease (perhaps impairing protein absorption), or acute illness (leading to an increase in the basal metabolic rate). Those who live in poverty are at increased risk, as are infants, adolescents, pregnant women, alcoholics, and patients with eating disorders. Assessment should include a careful diet history, further history and physical exam, with the goal of eliciting underlying medical problems. Particular attention should be paid to identifying possible co-morbid conditions, and likely concurrent vitamin deficiencies. Growth measurements should include weight, height and head circumference with adjustments for age, weight for height comparisons, and a body mass index (kg/m2) calculation for children older than 2 years, to allow objective assessment of the degree of malnutrition. Children whose weights are less than 80% of expected (ideal body weight estimated by tracking growth over time, if known, as well as weight-for-height for infants or body mass index measurements for older children) are considered malnourished; children with marasmus generally fall as low as 60% of expected. Children with kwashiorkor (and concurrent edema) tend to fall between 60-80% of expected (2). A body mass index measurement of less than 18.5 is considered underweight (3). Treatment consists of the provision of adequate calories and protein to meet individual needs, and treatment of any underlying disease states. In severe malnutrition, close monitoring may be necessary to prevent complications such as refeeding syndrome (severe hypophosphatemia and consequences thereof, as complication of nutritional rehabilitation in severely malnourished patients) (1).

Vitamin deficiencies can be divided into deficiencies of fat-soluble vitamins (ADEK) and deficiencies of water-soluble vitamins, including vitamins B, C, folate, and niacin.

Vitamin A (2) (retinol, retinol ester, retinal, retinoic acid) is found in both plant and animal sources. Animal sources include liver, fish, eggs, milk, and butter. Plant sources include green leafy vegetables and some of the yellow vegetables, such as carrots and squash, as well. These also provide provitamins such as betacarotene, which may be further metabolized to vitamin A. Vitamin A functions as an essential component of visual pigments, and has a role in the maintenance of mucus-secreting epithelia, which may contribute to its role in resisting infection. Deficiency syndromes are therefore notable for: impaired vision, particularly at night, xerophthalmia (in which normal epithelium is replaced by keratinized epithelium), squamous metaplasia of the airways leading to secondary pulmonary infections, renal or urinary bladder stones, and immunodeficiencies. Vitamin A has also been studied as a supplement for use during acute infections, in the developing world. The mechanism is unclear, but it appears to be useful in particular disease states, with or without underlying vitamin A deficiency being demonstrated in these patients. This has led to a Red Book recommendation for vitamin A supplementation in some patients with measles (4,5).

Vitamin D (2) is found in two precursor forms: 7-dehydrocholesterol (provitamin D3) in the skin, and ergosterol in plants. It is synthesized endogenously from its precursor in the skin, and found in dietary sources such as: deep-sea fish, plants, and grains, as well. It serves in the maintenance of appropriate serum calcium and phosphorus levels, through the regulation of intestinal absorption of calcium/phosphorus, the PTH-mediated mobilization of calcium from bone, and the PTH-mediated stimulation of calcium reabsorption in the distal renal tubules. Deficiency states are referred to as rickets in children, or osteomalacia in adults. Populations at risk for deficiency states are usually marked by limited sun exposure, and therefore inadequate endogenous synthesis, as well as a diet limited in vitamin D. The classic syndrome of rickets is marked by: craniotabes, rachitic rosary, wrist thickening, pigeon breast deformity, Harrison groove, flaring epiphyses, and bowing of the legs. This might be seen in breast-fed infants or toddlers, whose mothers are not supplementing with vitamin D. These children would likely also have sun exposure that was limited in some way, such as during the winter in northern latitudes.

Vitamin E (2) consists of the group of tocopherols and tocotrienols, of which alpha-tocopherol is the most common. Sources include: vegetables, grains, nuts, dairy, fish, and meats. It serves as an antioxidant, and is especially important in the nervous system and mature red blood cells. Deficiency syndromes of vitamin E are extremely uncommon, and are usually seen only in patients with fat malabsorption or other complicating chronic medical conditions. Deficiency syndromes are marked by posterior column/dorsal root ganglion-related signs, including: absent tendon reflexes, ataxia, loss of position and vibration sense, loss of pain sensations. Ophthalmoplegia may occur. Anemia has been reported in premature babies.

Vitamin K deficiency (2) may produce hemorrhagic disease of the newborn, which is fortunately rare, as vitamin K prophylaxis at birth has become routine. Vitamin K is derived from vegetables and by synthesis by intestinal bacteria in the lower ileum and colon. Absorption of vitamin K in the small intestine is dependent on bile salts. After absorption, transport occurs to the liver. It is converted in the liver to the hydroquinone form, which acts as a cofactor in carboxylase reactions, including the carboxylation of glutamic acid residues, in the formation of factors II, VII, IX, X, protein C and protein S (6). It is readily recycled in a healthy liver, and is widely available in the diet. Deficiency usually occurs, therefore, only in high risk populations. All infants are at some risk for vitamin K deficiency, as: 1) liver reserves are limited in the neonatal period, 2) the bacterial flora which produce vitamin K have not yet been established, and 3) the level of vitamin K in breast milk is low. A 3% prevalence of vitamin K dependent bleeds in neonates (who have not received prophylaxis) has been estimated (2). By 1-2 weeks of age, the developing bacterial flora provide sufficient vitamin K for normal term infants' needs. Premature infants, for several reasons, may have persistent need for increased supplementation. In older children and adults, vitamin K deficiency may occur in those with fat malabsorption syndromes (biliary tract disease, short gut syndrome) and advanced liver disease, as hepatocyte dysfunction interferes with synthesis of vitamin-K-dependent coagulation factors, even in the presence of vitamin K levels considered sufficient in other settings (2,7). Vitamin K supplementation (in addition to other fat-soluble vitamins) is therefore recommended for patients with fat malabsorption, cholestasis, and advanced liver disease (7).

Vitamin B1 (2) (active coenzyme thiamine pyrophosphate) is found in a wide variety of dietary sources, with the notable exception of refined foods, such as polished rice, white flour, and white sugar. It participates in the regulation of ATP, as a cofactor in the pentose phosphate pathway. It also has a role in maintaining membranes and conduction pathways of the peripheral nerves. Populations that are particularly at risk for vitamin B1 deficiency include those whose diets are high in refined foods, such as polished rice, and those with alcoholism. Several clinical deficiency states have been described, including: dry beriberi (polyneuropathy with toedrop/footdrop/wristdrop), wet beriberi (cardiovascular manifestations including peripheral vasodilation and high output cardiac failure), and Wernicke-Korsakoff syndrome (encephalopathy, with ataxia and psychosis, including retrograde amnesia, confabulation).

Vitamin B2 (2), or riboflavin, is derived from meat, diary, and vegetable sources. It is involved in oxidation-reduction reactions, and is incorporated into mitochondrial enzymes. The clinical deficiency syndrome consists of: cheilosis (fissures in the lips), glossitis, keratitis/corneal ulceration, and a greasy scaling dermatitis over the nasolabial folds, progressing to a butterfly distribution.

Niacin (2), or nicotinic acid and its derivatives, is endogenously synthesized from tryptophan, and exogenously derived from grains (in some grains, such as corn, it exists only in the bound form and is therefore not absorbable), legumes, seed oils, and meats. It is a component of NAD and NADP, and acts as a coenzyme for dehydrogenation reactions, especially those in the hexose monophosphate shunt, in glucose metabolism. Populations at particular risk for niacin deficiency include: those with chronic diarrhea, those with protein-deficient diets, and those taking isoniazid and 6-mercaptopurine. The clinical deficiency syndrome of pellagra consists of dermatitis, diarrhea, and dementia.

Vitamin B6 (2), or pyridoxine and the phosphorylated forms thereof, is found in almost all foods, though they may be lost after processing (such as dried milk preparations). It acts as a cofactor for a large number of enzymes, including the transaminases, carboxylases, deaminases, in lipid metabolism, amino acid metabolism, and immune responses. An overt deficiency of B6 is rare, but the subclinical deficiency state is common, particularly in those being treated with pyridoxine antagonists, such as isoniazid, estrogens, penicillamines, and acetaldehyde (ETOH met). There is an increased demand for vitamin B6 during pregnancy. The clinical deficiency syndrome is similar to that seen in riboflavin or niacin deficiency: seborrheic dermatitis, cheilosis, glossitis, peripheral neuropathy, and sometimes seizures. Pyridoxine is used as a therapeutic reversal agent in pyridoxine-dependent seizures and in the acute management of INH overdose.

Vitamin B12 (2) is derived from animal sources (meats, milk, eggs), and is absorbed in the distal ileum, only after forming a complex with intrinsic factor (produced by gastric parietal cells). It is then transported by transcobalamin. Adequate B12 is required for normal folate metabolism, and also for DNA synthesis and the maintenance of myelinization of spinal cord tracts. Populations at particular risk for deficiency include: neonates (if the maternal diet is deficient), those with insufficient production of intrinsic factor (juvenile pernicious anemia), and those in whom the distal ileum has been surgically removed. The clinical deficiency state may include: megaloblastic anemia, leukopenia, thrombocytopenia, mild jaundice, and neurologic signs, such as posterior/lateral column demyelination, paresthesias, sensory deficits, loss of deep tendon reflexes, confusion, and memory deficits.

Folate (2) is derived from a variety of sources (whole wheat flour, beans, nuts, liver, green leafy vegetables), but is quite heat labile, and easily destroyed by cooking or processing raw foods. It acts as an essential cofactor in nucleic acid synthesis. Populations at particular risk include: 1.) fetuses with rapidly dividing cells (in whom an association with neural tube defects has been noted. Hence the recommendation for early supplementation, for all women of childbearing age); 2.) those on oral contraceptives, antiepileptics, ETOH, or with heavy cigarette use (decreases absorption); or 3.) those with intestinal malabsorption or metastatic disease. It is notable that adequate B12 is required for folate metabolism, leading commonly to concurrent deficiencies. Deficiency in folate alone will produce a megaloblastic anemia. In a deficiency of B12, supplementation of folate will reverse the megaloblastic anemia, but it will not reverse the neuropathic consequences of B12 deficiency.

Vitamin C (2), or ascorbic acid, is found in milk, liver, fish, fruits, and vegetables. It is involved in the activation of prolyl and lysyl hydroxylases from inactive precursors, therefore facilitating the hydroxylation of procollagen. Populations at particular risk for vitamin C include those with marginal or erratic diets (the classic example is of malnourished sailors without fresh vegetables), dialysis patients, or infants on processed milk only. The clinical spectrum of vitamin C deficiency encompasses bone disease (in growing children), hemorrhagic disease (skin, mucosal, and subperiosteal bleeds, bleeds into joint spaces), impaired wound healing, and anemia.

Questions

1. Name the classic syndrome:
. . . . A. Toddler with edema, hepatomegaly, protruding abdomen, alternating bands of light and dark hair, dry skin, and lethargy.
. . . . B. Cachectic infant with subcutaneous fat wasting, loose dry skin, brittle hair.

2. True/False: Serum albumin is usually decreased in kwashiorkor, or severe malnutrition affecting the visceral protein compartment.

3. True/False: Hemorrhagic disease of the newborn can be prevented with vitamin K prophylaxis (1 mg IM x 1) at birth.

4. Vitamin K is an important cofactor in the activation of which of the following coagulation factors:
. . . . a. factor VIII
. . . . b. factor X
. . . . c. protein S
. . . . d. von Willebrand's protein
. . . . e. factor IX

5. True/False: Vitamin D, in response to serum hypocalcemia, regulates the mobilization of serum calcium through three mechanisms: increased intestinal absorption of Ca and Phos, mobilization of Ca from bone, and increased reabsorption of Ca from the distal renal tubules.

6. The three D's of pellagra are:
. . . . a. diarrhea
. . . . b. dementia
. . . . c. deafness
. . . . d. dermatitis
. . . . e. dissociation

7. Cheilosis and glossitis are features of:
. . . . a. vitamin A deficiency
. . . . b. riboflavin (B2) deficiency
. . . . c. vitamin C deficiency
. . . . d. pyridoxine (B6) deficiency
. . . . e. vitamin E deficiency

8. True/False: Both folate and B12 deficiency produce a megaloblastic anemia. In addition, patients with B12 deficiency may exhibit posterior column defects, such as: paresthesias, sensory deficits, loss deep tendon reflexes, as well as confusion and memory deficits.

9. The features of scurvy, or vitamin C deficiency, include:
. . . . a. bone disease in growing children
. . . . b. hemorrhagic disease, including mucosal involvement, subperiosteal bleeds, and bleeding into joint spaces
. . . . c. cheilosis, glossitis
. . . . d. impaired wound healing
. . . . e. anemia

References

1. Leleiko NS, Chao C. Nutritional Deficiency States. In: Rudolph AM, et al (eds). Rudolph's Pediatrics, 20th edition. 1996, Stamford, CT: Appleton and Lange, pp. 1015-1017.

2. Kane AB, Kumar V. Food and Nutrition. In: Cotran RS, et al (eds). Robbins Pathologic Basis of Disease, 6th edition. 1999, Philadelphia: W.B. Saunders, pp. 436-456.

3. Hensrud DD. Nutrition Screening and Assessment. Med Clin North Am 1999;83(6):1525-1546.

4. Fawsi W, et al. Vitamin A Supplements and Diarrheal and Respiratory Infections Among Children in Dar es Salaam, Tanzania. J Pediatr 2000;137(5):660-667.

5. Measles. In: Pickering LK, et al (eds). 2000 Red Book: Report of the Committee on Infectious Diseases, 25th edition. 2000, Elk Grove Village, IL: American Academy of Pediatrics, pp. 385-396.

6. Bauer KA. Hemostasis and Thrombosis. In: Robinson SH, Reich PR (eds). Hematology. 1993, Boston: Little, Brown and Co., pp. 391-442.

7. Whitington P. Chronic Cholestasis of Infancy. Pediatr Gastroenterol 1996;43(1):1-23.

8. Blecker U, et al. Fat-Soluble Vitamin Deficiencies. Pediatr Rev 1999;20(11):394-395. Additional recommended reading for good brief discussion of fat-soluble vitamins and deficiencies thereof.

Answers to questions

1. A. kwashiorkor. B. marasmus

2. True

3. True

4. b, c, e

5. True

6. a, b, d

7. b, d

8. True

9. a, b, d, e