Clinical Manifestations of Nutrient Deficiencies and Toxicities1



Clinical Manifestations of Nutrient Deficiencies and Toxicities1


Douglas C. Heimburger





Nutritional disorders result from imbalances between the body’s requirements for nutrients and energy sources and the supplies of these substrates of metabolism. These imbalances may take the form of either deficiency or excess and may be attributable to inappropriate intake or to defective utilization or, frequently, a combination of both.

Despite our extensive understanding of human nutritional requirements for maintenance of health, malnutrition continues to be one of the main causes of morbidity and mortality in low- and middle-income countries, especially in young children (1). In technologically advanced societies, undernutrition resulting from dietary restriction no longer constitutes a major hazard to health, but it continues to occur in hospitalized patients and in other especially vulnerable groups. However, deficiency states continue to arise in patients with certain cultural or religious precepts, long-term alcohol or drug abuse, debilitating disease, or food faddism. Vigilance is needed to detect secondary undernutrition resulting from malabsorption; failure in transport, storage, or cellular utilization; excessive losses; or inactivation by genetic mutations of essential metabolic pathways that increase needs. The improper use of nutrient supplements, often because of ignorance about proper dosage or by failure of excretion through renal failure with continued nutrient intake, has been a major cause of toxicity (2).

This chapter addresses clinical manifestations of nutritional disorders related to vitamins, minerals, and essential fatty acids. It has been included because the chapters concerned with the individual nutrients do not uniformly discuss clinical aspects of deficiencies and excesses. Descriptions of clinical symptoms of deficiency of each nutrient are followed by brief consideration of who is likely to be at risk of deficiency and, if relevant, who is likely to be at risk of toxic levels.


VITAMINS


Vitamin A (Retinol)


Deficiency

The symptoms and signs of vitamin A deficiency have been studied in greater detail than those of any other nutritional deficiency disorder (3, 4). The eye is primarily involved, and the condition, given the general name of xerophthalmia, predominantly affects young children. Impaired dark adaptation or night blindness (i.e., decreased vision in dim light) is an early symptom and can be elicited by a careful history and some simple tests in a poorly illuminated room (5). Photopic and color vision, mediated by the retinal cones, is usually unaffected.


Dryness (xerosis) and unwettability of the bulbar conjunctiva follow. Conjunctival impression cytology is abnormal at this stage. Bitot spot, an accumulation of desquamated cells most commonly seen in the interpalpebral fissure on the temporal aspect of the conjunctiva, is another sign (Fig. 57.1A). In older children and adults, Bitot spots may be stigmata of past deficiency, or they may be entirely unrelated to vitamin A deficiency when local trauma is responsible. Corneal involvement, starting as a superficial punctate keratopathy (6) and proceeding to xerosis (see Fig. 57.1B) and varying degrees of “ulceration” and liquefaction (keratomalacia) (see Fig. 57.1C), frequently results in blindness. Punctate degenerative changes in the retina (xerophthalmic fundus) are rare signs of chronic deficiency usually seen in older children (7). Corneal scars may have many causes, but those that are bilateral in the lower and outer part of the cornea of a person with a history of past malnutrition or measles, or both, often signal earlier vitamin A deficiency.

Extraocular manifestations include perifollicular hyperkeratosis, an accumulation of hyperkeratinized skin epithelium around hair follicles most commonly seen on the lateral aspects of the upper arms and the thighs. This finding is also seen in starvation and has been attributed to a deficiency of B-complex vitamins or essential fatty acids. Other changes may occur, including impaired taste, anorexia, vestibular disturbance, bone changes with pressure on cranial nerves, increased intracranial pressure, infertility, and congenital malformations (8).


Toxicity (Hypervitaminosis A)

Most of the features relate to a rise in intracranial pressure: nausea, vomiting, headache, vertigo, irritability, stupor, fontanel bulging (in infants), papilledema, and pseudotumor cerebri (mimicking brain tumor) (9). Pyrexia and peeling of the skin also occur.

Chronic poisoning produces a bizarre clinical picture that is often misdiagnosed because of failure to consider excessive vitamin A intake (9). It is characterized by anorexia, weight loss, headache, blurred vision, diplopia, dry and scaling pruritic skin, alopecia, coarsening of the hair, hepatomegaly, splenomegaly, anemia, subperiosteal new bone growth, cortical thickening (especially bones of hands and feet and long bones of the legs), and gingival discoloration. The x-ray appearance may assist in making a correct diagnosis. Cranial sutures are widened in the young child.

Vitamin A and other retinoids are powerful teratogens in both pregnant experimental animals and women (9). Birth defects have been reported in the children of women receiving 13-cis-retinoic acid (isotretinoin) during pregnancy (10). An increased risk of birth defects is present in infants of women taking more than 10,000 IU/day of supplementary preformed vitamin A before the seventh week of gestation (11). Significant evidence indicates that long-term intake of larger-dose supplements of retinol is associated with increased risk of bone fractures in older Swedish men (12) and women (13) as well as in women in the United States (14).


Hypercarotenosis

Excessive intake of carotenoids can cause hypercarotenosis. Yellow or orange discoloration of the skin (xanthosis cutis, carotenoderma) affects areas where sebum secretion is greatest—-nasolabial folds, forehead, axillae, and groin—and keratinized surfaces such as the palms and soles (see Fig. 57.1F). The sclerae and buccal membranes are not affected—a feature that distinguishes this condition from jaundice, in which these tissues are yellowed. No toxicity is apparent, and the discoloration gradually disappears with reduction of intake.


Vitamin D (Calciferol)


Deficiency

Vitamin D deficiency is manifested as rickets in children and osteomalacia in adults. Persons with those forms not resulting from primary vitamin D or calcium deficiency— previously termed metabolic rickets—also exhibit signs and symptoms of the underlying disease and hypocalcemia.


Rickets.

The rachitic infant is restless and sleeps poorly. Craniotabes, softening of the bones of the skull and their ready depression on palpation, is often the earliest sign; but it must be present away from the suture lines to be diagnostic of rickets. Frontal bossing occurs, and the fontanels close late. Sitting, crawling, and walking are all delayed. If the disease is active when these activities occur, weight bearing results in bowing of the arms, knock-knees (genu valgum), or outward bowing (genu varum) (Fig. 57.2A and B). The characteristic x-ray appearance usually precedes clinical signs. Bone morphology is discussed elsewhere in this text.

Occasionally, stridor and intermittent sudden airway obstruction resulting from laryngospasm may manifest in infancy as a result of hypocalcemia accompanying biochemical and x-ray evidence of rickets but without the classic bony physical signs (15). A few instances of congenital cataract appeared to be caused by vitamin D deficiency in the mother (16).


Osteomalacia.

The main features of osteomalacia are bone pain and tenderness, skeletal deformity, and weakness of the proximal muscles. Muscle weakness is a subtle indicator of vitamin deficiency (17). In severe cases, all the bones are painful and tender, often enough to disturb sleep. Tenderness may be particularly marked over Looser zones (Milkman lines), usually occurring in the long bones, pelvis, ribs, and around the scapulae in a bilaterally symmetric pattern. These radiotranslucent zones are sometimes termed pseudofractures. True fractures of the softened bones are common. The proximal muscle weakness, the cause of which is uncertain, is more marked in some forms of osteomalacia than in others. Osteomalacia usually results in a waddling gait and in difficulty going up and down the stairs. In elderly persons, it may simulate paraplegia; in younger persons, it may simulate muscular dystrophy.



Toxicity (Hypervitaminosis D)

Some of the symptoms and signs are related to hypercalcemia and are common to all causes of that condition. Anorexia, nausea, vomiting, and constipation are usually present. Weakness, hypotonia, stupor, and hypertension are less common. Polyuria and polydipsia are caused by hypercalciuria. Renal colic resulting from stone formation may result. Radiography of the skeleton may assist in diagnosis. Epiphyseal bone density is increased in response to excessive calcium deposition.

Vitamin D excess has been reported to take two forms: mild and severe. In the mild form, the patient is usually 3 to 6 months of age, and the symptoms and signs are those already described. In the severe form, also seen in infants, in addition to the manifestations of hypercalcemia, patients have mental retardation, stenosis of the aorta and the pulmonary arteries, and a characteristic facial appearance termed elfin facies (18).


Vitamin E (Tocopherol)


Deficiency

The molecular basis of two conditions in which vitamin E deficiency has long been known to figure prominently has been discovered (19). In spinocerebellar ataxias of the Friedreich type, patients have a defect in the α-tocopherol transfer protein (α-TTP), and in abetalipoproteinemia (Bassen-Kornzweig syndrome, acanthocytosis), patients have mutations in the gene coding for one subunit of the microsomal triglyceride transfer protein. Friedreich ataxia manifests in childhood with progressive ataxia of gait, dysarthria, areflexia, extensor plantar signs, and impaired vibratory and positional sense. In abetalipoproteinemia, patients have steatorrhea, acanthocytes (erythrocytes with spiny projections of the membrane), retinitis pigmentosa-like changes in the retina, ataxia, and mental retardation.


Toxicity

Reports that low birth weight infants receiving pharmacologic doses of vitamin E had a high incidence of sepsis and necrotizing enterocolitis (20) have not been confirmed. A metaanalysis reporting increased all-cause mortality in adults taking daily vitamin E supplements of 400 mg or more (21) has prompted discussion of whether the tolerable upper limit should be reduced from its current level of 1000 mg/day.


Vitamin K (Phylloquinone)


Deficiency

Deficiency of vitamin K in the newborn is usually classified into three syndromes: early, classic, and late (22). The early form manifests within 0 to 24 hours of birth, and the most common bleeding sites are the brain, the gut, and around the genitalia. Classic hemolytic disease of the newborn (HDN) manifests on day 1 to 7, with the bleeding usually gastrointestinal, dermal, nasal, or from circumcision. The peak incidence of late HDN is from the third to the sixth week, and intracranial hemorrhage (rare in classic HDN) accounts for approximately 50% of the bleeding episodes at presentation. Late HDN may occur over weeks 2 to 12 and also commonly affects the skin and gastrointestinal tract. This deficiency led to the widespread intramuscular injection of small doses of phylloquinone to the newborn that has markedly reduced the incidence of HDN. The current recommendation is 0.5 to 1.0 mg (23).

Babies of mothers taking vitamin K antagonists during pregnancy were found to be at risk of congenital malformations (24). This led to the discovery of protein-bound α-carboxyglutamate-containing proteins with vitamin K as the cofactor and to the new knowledge of the manifestations of dietary vitamin K deficiency as a risk for fractures (25). In adults, bleeding from vitamin K deficiency is most common in chronic liver disease, in obstructive jaundice, and in patients receiving anticoagulants or prolonged antibiotic therapy. Claims that bone loss in patients with Crohn disease or hip fracture in women on low vitamin K diets may be related to vitamin K deficiency require more substantial evidence to establish causation.


Toxicity

The dietary reference intake (DRI) report on vitamin K states that “search of the literature revealed no evidence of toxicity associated with the intake of either phylloquinone or menaquinone forms of vitamin K … A synthetic form of vitamin K, menadione, has been associated with liver damage … and therefore is no longer used therapeutically” (26).


Thiamin (Vitamin B1)


Deficiency


Cardiovascular Beriberi.

Cardiovascular beriberi (so-called wet beriberi) usually manifests as chronic highoutput right- and left-sided heart failure with tachycardia, rapid circulation time, elevated peripheral venous pressure, sodium retention, and edema (27). A much less common acute fulminating form of heart failure (sometimes called shoshin) is characterized by severe metabolic lactic acidosis, intense dyspnea, thirst, anxiety, and cardiovascular collapse. Signs also include stocking-glove cyanosis, extreme tachycardia, cardiomegaly, hepatomegaly, and neck vein distention. Edema is usually absent (28).


Beriberi of the Nervous System


Cerebral Beriberi (Wernicke-Korsakoff Syndrome).

Cerebral beriberi involves mental confusion accompanied by ophthalmoplegia resulting from paralysis of the sixth cranial nerve and leading to coma. Korsakoff psychosis consists of loss of memory for distant events, inability to form new memories, and loss of insight and initiative (29). The patient is alert and can converse, think, and solve problems. Response to thiamin is complete in only 25% of cases and partial in 50%. Ethanol is thought to have a direct part in neurotoxicity (30, 31). Wernicke encephalopathy is most likely to occur in patients with chronic
alcoholism who have a high-carbohydrate diet without adequate thiamin replacement or in nonalcoholic depleted patients given glucose infusions without adequate thiamin. This disorder is also encountered as a complication of bariatric surgery (32).


Peripheral Neuropathy.

The most characteristic features of peripheral neuropathy are symmetric footdrop, associated with marked tenderness of the calf muscles, and a mild disturbance of sensation over the outer aspects of the legs and thighs and in patches over the abdomen, chest, and forearms. Ataxia with loss of position and vibration sense, burning paresthesias in the feet, and amblyopia are less common.


Infantile Beriberi.

Early manifestations of infantile beriberi are anorexia, vomiting, pallor, restlessness, and insomnia. The disease progresses typically to (a) an acute cardiac form in infants 2 to 4 months old, (b) a subacute aphonic form in those 5 to 7 months old, and (c) a chronic, pseudomeningeal form in those between 8 and 10 months of age. The acute form manifests with dyspnea, cyanosis, a rapid, thready pulse, and other signs of acute heart failure. In the subacute form, aphonia or a characteristic hoarse cry, dysphagia, vomiting, and convulsions predominate. The chronic form is characterized by neck retraction, opisthotonos, edema, oliguria, constipation, and meteorism (33).


Subacute Necrotizing Encephalomyopathy (Leigh Disease).

Subacute necrotizing encephalomyopathy may be related to a defect in thiamin metabolism. The onset is usually before 1 year of age. Hypoventilation and apnea, cranial neuropathies, and hypotonia are the most common features.


Possible Toxicity

Large doses of thiamin are routinely given to patients with alcoholism. Adverse effects, including sensitization of an anaphylactic nature, have been reported only rarely (34, 35). No anaphylactic reactions have been reported with multivitamins containing thiamin used in total parenteral nutrition (TPN) solutions.


Riboflavin


Deficiency

The skin and mucous membranes are affected in what is known as the oculoorogenital syndrome. Areas of skin involved are usually those containing many sebaceous glands, mainly the nasolabial folds, alae nasi, external ears, eyelids, scrotum in boys and men, and labia majora in girls and women (see Fig. 57.2I). These areas become reddened, scaly, greasy, painful, and pruritic. Photophobia, lacrimation, and conjunctival injection are also present. Plugs of inspissated sebum may accumulate in the hair follicles and may give the appearance known as dyssebacia, or sharkskin.

At the angles of the mouth, patients have painful fissures known as angular stomatitis when these lesions are active (see Fig. 57.1D). Vertical fissures of the vermilion surfaces of the lips constitute cheilosis. These and the angular lesions may become infected with Candida albicans, thus giving rise to the appearance known as perlèche. The tongue may be painful, swollen, and magenta (see Fig. 57.1E). These mucocutaneous changes may also be seen in other nutrient deficiencies or in elderly edentulous persons with chronically moist angles of the mouth. Because deficiency is often multiple, it is rarely possible in clinical practice to demonstrate the precise cause.

Corneal neovascularization, common in experimental animals, is rarely seen in humans. The hemopoietic and nervous systems are occasionally affected. Normocytic normochromic anemia, reticulocytopenia, leukopenia, thrombocytopenia from marrow hypoplasia, and peripheral neuropathies with hyperesthesia, altered temperature sensation, and pain have been reported (36).


Toxicity

No adverse effects have been noted with riboflavin intakes from food or supplements. In fact, single oral doses approximately 38 times the recommended dietary allowance that were given as a single bolus had no adverse effect (37).


Niacin


Deficiency

Pellagra affects primarily the skin, gastrointestinal tract, and nervous system and produces the “four Ds” of dermatitis, diarrhea, dementia, and ultimately death. Dermatitis is usually the earliest and most prominent manifestation. It is symmetric and appears on parts exposed to sunlight or trauma. Erythema progresses to keratosis and scaling with pigmentation. The back of the hands, wrists, forearms, face, and neck (Casal necklace) are typically affected (see Fig. 57.2C). The skin and mucous membrane changes of riboflavin deficiency are also commonly present (see earlier). The tongue often has a “raw beef” appearance and is bright red, swollen, and painful. Symptoms of gastritis, bouts of diarrhea, and signs of malabsorption suggest similar changes in the gastrointestinal tract.

Nervous system involvement is suggested in the early stages by periods of depression with insomnia, headaches, and dizziness. Later, tremulous movement or rigidity of the limbs occurs with loss of tendon reflexes, numbness, and paresis of the extremities. In profound deficiency, encephalopathy has been described resembling that of acute cerebral beriberi (see the earlier section on thiamin), but it responds to some extent to niacin. Mental disturbance is so prominent in some patients that a real danger exists that the true diagnosis may be missed and the patient may be incarcerated in a mental institution.


Toxicity

Side effects of megadoses of niacin (e.g., 1 to 3 g/day), which are effective in treating many dyslipidemias, include vasodilatation, flushing, pruritus, blistering of the skin with brown pigmentation, nausea, vomiting, and
headache (38). Liver dysfunction manifesting as elevated serum liver enzymes is reasonably common, and liver failure can occur. Diabetic patients also require special monitoring of glucose because niacin may worsen insulin resistance. Sustained-release forms of niacin are used to minimize these effects.


Pyridoxine (Vitamin B6)


Deficiency

Pyridoxine deficiency induced by poor intake in adults is rarely severe enough to produce signs or symptoms. Volunteers receiving a deficient diet and a pyridoxine antagonist became irritable and depressed. Seborrheic dermatitis affected the nasolabial folds, cheeks, neck, and perineum. Several subjects also developed glossitis, angular stomatitis, blepharitis, and peripheral neuropathy. Pyridoxine deficiency can also manifest as microcytic anemia, particularly in infants (39, 40, 41). An uncommon form of sideroblastic anemia, often severe, has been reported to respond in some instances to pyridoxine, but most cases appear to result from dependency rather than deficiency (42). An inherited error in the vitamin B6-dependent enzyme cystathionine β-synthase leads to severe abnormalities at an early age.

Only gold members can continue reading. Log In or Register to continue

Jul 27, 2016 | Posted by in PUBLIC HEALTH AND EPIDEMIOLOGY | Comments Off on Clinical Manifestations of Nutrient Deficiencies and Toxicities1
Premium Wordpress Themes by UFO Themes
%d bloggers like this: