Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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relationship has not been established for many of

them. These include benzodiazepines, ciprofloxacin,

etomidate, enflurane, fluoxetine, furosemide, halo-

thane, interferon-a, isoniazid, maprotiline, meflo-

quine, nefazodone, octreotide, phenytoin, and

selegiline.

Alcohol

0019 Alcohol inhibits hepatic gluconeogenesis by depleting

nicotinamide adenine dinucleotide levels and by

decreasing the flux of gluconeogenic substrates (i.e.,

alanine, glycerol, lactate). However, it does not affect

glycogenolysis. Therefore, in the well-fed person,

hypoglycemia does not occur until after depletion of

glycogen stores by fasting > 12 h, along with con-

sumption of 50–300 g of alcohol during the preceding

6–36 h. In the poorly nourished individual, less alco-

hol may induce hypoglycemia more quickly. Alcohol

may also potentiate insulin and sulfonylurea-induced

hypoglycemia. Intravenous glucose causes prompt

recovery, unlike glucagon, which is ineffective. With-

out treatment, the mortality rate is 10% in adults and

25% in children.

Protein–Energy Malnutrition

0020 There are many descriptions of hypoglycemia in

severe protein–energy malnutrition (PEM), although

there seems to be no consistent difference in the

severity of hypoglycemia between marasmus and

kwashiorkor. The frequency of hypoglycemia varies

geographically, ranging from 10% in Jamaica to 24%

in Uganda. Hypoglycemia is a poor prognostic factor,

as its presence increases the mortality in marasmic

infants by 1.6–3.1-fold, unless intravenous glucose is

given immediately. The pathogenesis is not clear, but

high rates of glucose utilization in the presence of

total body fat depletion, limitation of substrate avail-

ability for gluconeogenesis, or diminished activity of

gluconeogenic enzymes are possibilities. Hypogly-

cemia is also seen in anorexia nervosa.

Endocrine Deficiencies

0021Endocrine deficiencies are rare causes of hypogly-

cemia. Deficiencies of cortisol and/or growth hor-

mone impair gluconeogenesis, especially in the very

young, or if other hypoglycemic stressors are present.

These endocrinopathies limit the availability of glu-

coneogenic substrate availability and decrease the

activity of hepatic gluconeogenic enzymes. Combined

deficiencies, e.g., in hypopituitarism, cause more

severe hypoglycemia. Isolated glucagon or epineph-

rine deficiencies in infants can also cause hypogly-

cemia but are extraordinarily rare. They can occur

as an acquired condition in individuals with long-

standing type 1 diabetes. Hypothyroidism can reduce

the rate of glucose absorption from the gut and

decrease peripheral glucose utilization. However, al-

though hypothyroidism has been said to be a cause of

hypoglycemia, it rarely occurs in isolated thyroxine

deficiency. The concurrence of hypoglycemia and

hypothyroidism should suggest the presence of ad-

renal insufficiency.

Severe Medical Illness

0022Severe liver disease, e.g., hepatectomy or fulminant

hepatitis can cause profound hypoglycemia, as the

liver is the major source of endogenous glucose

production. Renal failure is also associated with

hypoglycemia. Multiple mechanisms are involved,

including cachexia, uremic inhibition of hepatic

gluconeogenesis, failure of renal gluconeogenesis,

decreased renal clearance of insulin (in patients with

concurrent diabetes), and dialysis. Hypoglycemia

occasionally occurs in congestive heart failure,and

it is suggested that it is due to hepatic congestion,

cachexia, and inhibition of gluconeogenesis. Sepsis

increases peripheral glucose utilization and inhibits

hepatic gluconeogenesis, mediated by cytokines such

as tumor necrosis factor-a, interleukin-1, and inter-

leukin-6.

tbl0003 Table 3 Drugs associated with hypoglycemia

Drug Mechanism of inducing hypoglycemia

Insulin Increase glucose uptake by peripheral tissues

Sulfonylureas Increase insulin secretion via sulfonylurea receptors on b-cells

Pentamidine Increases insulin secretion

Quinine Increases insulin secretion

Salicylates Unknown mechanism – ? increase peripheral glucose uptake; need large doses (4–6 g)

Sulfonamides Unknown mechanism

Angiotensin-converting enzyme inhibitors ? Increases insulin sensitivity

Acetaminophen Hepatic necrosis in acute toxic overdoses

Disopyramide Increases insulin secretion

Monoamine oxidase inhibitors Unknown mechanism, rare

b-adrenergic antagonists ? Increase peripheral glucose uptake; ? inhibit gluconeogenesis; more common in

patients with diabetes

HYPOGLYCEMIA (HYPOGLYCAEMIA) 3209

Ackee Poisoning (Jamaican Vomiting Sickness)

0023 A toxic hypoglycemia syndrome occurs whenever the

unripe fruit of ackee (Blighida sapida) is consumed, as

first reported in 1875. Ackee was imported to the

New World from West Africa in 1778 and is found

in the Caribbean, Central America, and Florida.

Poisoning is more common in children, especially if

undernutrition is present. Adults generally have a

chronic course with a self-limited cholestatic jaun-

dice. The unripe arillus of the fruit contains hypo-

glycin, which is sequentially transaminated and

decarboxylated to methylenecyclopropylacetyl-CoA.

This metabolite irreversibly inhibits acyl-CoA dehy-

drogenases (especially butyryl-CoA dehydrogenase),

leading to inhibition of fatty acid b-oxidation. The

metabolic consequences are an acquired organic acid-

emia (mostly glutaric and ethylmalonic acid), the

absence of ketosis or hyperinsulinemia, and impair-

ment of hepatic gluconeogenesis. Patients have severe

hypoglycemia, an acute encephalopathy similar to

Reye’s syndrome, and severe vomiting. Convulsion,

coma and death can follow. Treatment involves inten-

sive glucose infusions to maintain normoglycemia.

Cooking renders the fruit nontoxic, reducing hypo-

glycin levels 100-fold.

Insulinomas

0024 Insulinomas are rare tumors with an incidence of four

cases per million person-years. Approximately 10%

are malignant, 9% are multifocal, 8% are recurrent,

and 8% occur as part of multiple endocrine neopla-

sia-1 syndrome. They are evently distributed through-

out the pancreas, and ectopic locations are unusual.

Some tumors cosecrete gastrin, adrenocorticotropic

hormone, glucagon, and 5-hydroxyindole. The diag-

nosis relies on documentation of Whipple’s triad with

inappropriately high insulin (36 pmol l

1

), C-pep-

tide (0.2 nmol l

1

), and proinsulin (5 pmol l

1

)

levels during hypoglycemia. Surreptitious use of ex-

ogenous insulin and sulfonylureas has to be ruled out,

and a 72-h supervised inpatient fast may be required

(Table 4). After biochemical confirmation, the tumor

may be localized by conventional, intraoperative, or

endoscopic ultrasonography. Magnetic resonance im-

aging or selective intraarterial injection of calcium

with venous sampling for insulin may be useful.

Some are localized by surgical exploration. Treatment

is by surgical enucleation of the tumor, and chemo-

therapy is necessary for palliation in individuals with

metastases.

Noninsulinoma Tumor-associated Hypoglycemia

0025There are various noninsulinoma tumors that

induce hypoglycemia, most commonly mesenchymal

cancers, hepatoma, adrenocortical carcinoma, lymph-

oma, and gastrointestinal cancers. Generally, hypo-

glycemia is a late presentation, the tumor burden is

large (> 500 g), and metastases are commonly present.

Many of these tumors produce insulin-like growth

factor-II as the putative hypoglycemic agent. They

rarely produce ectopic insulin. Occasionally, some

induce hypoglycemia by increasing glucose consump-

tion in excess of the liver’s gluconeogenetic ability.

Miscellaneous Causes

0026Factitious hypoglycemia is due to the surreptitious

use of insulin or sulfonylureas. This may be due to

malingering, Munchausen syndrome, attempted sui-

cide/homicide, or pharmacy error. A proper biochem-

ical evaluation during a 72-h fast (Table 4) should

reveal the diagnosis. Insulin levels > 1200 pmol l

1

should generate suspicion of factitious causes. Very

rarely, in patients naı

ve to insulin, there may be a

spontaneous autoimmune antiinsulin antibody syn-

drome. This has been reported in Japanese patients

treated with thionamides or with other autoimmune

disorders. The mechanism involves an insulinomi-

metic action when the antiidiotypic antibodies to

antiinsulin antibodies interact with the insulin recep-

tor. An insulinomimetic action of antibodies against

the insulin receptor can cause hypoglycemia in type

B insulin resistance. Severe exercise, as seen in mara-

thon runners, has occasionally been associated with

hypoglycemia.

Childhood Hypoglycemia

0027As children have an increased ratio of brain to body

mass, they have higher rates of glucose flux. There is

also limited substrate availability for gluconeogenesis

due to their smaller muscle mass. Hence, they are not

tbl0004 Table 4 Interpretation of the results of a 72-h fast

Diagnosis Insulin C-peptide Proinsulin Plasma or urine sulfonylurea b-Hydroxybutyrate

Insulinoma Increased Increased Increased Negative None

Exogenous insulin Increased Decreased Decreased Negative None

Sulfonylurea ingestion Increased Increased Increased Present None

Noninsulin-mediated hypoglycemia Decreased Decreased Decreased Negative Increased

3210 HYPOGLYCEMIA (HYPOGLYCAEMIA)

able to tolerate hypoglycemia as easily as adults.

Their clinical presentation is more variable with

hypotonia, cyanosis, hypothermia, tachypnea, feed-

ing difficulties, and poor neuropsychiatric develop-

ment being prominent. Older children have more

adrenergic symptoms and may have focal neuro-

logical deficits and movement disorders.

0028 Most of the causes of hypoglycemia in adults are

also seen in children. Transient hyperinsulinism is the

most frequent cause of hypoglycemia in the infant, as

seen in the children of diabetic mothers, premature

infants, and small-for-gestational-age infants. Con-

genital hyperinsulinism, otherwise called nesidioblas-

tosis or persistent hyperinsulinemic hypoglycemia of

infancy, describes diffuse b-cell hyperplasia with

hyperinsulinemic hypoglycemia. Subtotal pancrea-

tectomy or medical treatment with diazoxide or

octreotide is advocated for symptomatic infants.

This is due to genetic mutations that affect the normal

intracellular events controlling insulin secretion. The

mutations include:

0029 mutations inactivating the ATP-sensitive potassium

channel in b-cells leading to membrane depolariza-

tion (SUR1 and Kir6.2 subunit mutations);

0030 activating mutations of the glucokinase gene

increasing glycolysis; and

0031 activating mutations of the glutamate dehydrogen-

ase gene causing an increased rate of glutamate

oxidation in b-cells (hyperinsulinism/hyperammo-

nemia syndrome, which includes leucine-sensitive

hypoglycemia, as leucine is an allosteric activator

of GDH and thus functions as an insulin secret-

agogue).

Hypoglycemia is also a consequence of inborn errors

of metabolism involving gluconeogenesis, glycogen

storage, fatty acid metabolism, and amino acid

metabolism.

0032 Ketotic hypoglycemia of childhood generally

begins between the ages of 1.5 and 5 years, and

resolves by age 10. It probably accounts for 90% of

children with hypoglycemia beyond infancy, and it

may represent a subset of children who are least

tolerant of fasting, especially during an intercurrent

illness. These children characteristically have rela-

tively decreased muscle mass, and there may be

a defect in mobilizing alanine for gluconeogenesis.

Although alanine administration increases blood

glucose levels, treatment generally involves avoiding

any prolonged fasting.

See also: Alcohol: Properties and Determination;

Diabetes Mellitus: Etiology; Problems in Treatment;

Glucose: Properties and Analysis; Function and

Metabolism; Maintenance of Blood Glucose Level;

Glucose Tolerance and the Glycemic (Glycaemic) Index;

Hormones: Pituitary Hormones; Malnutrition: The

Problem of Malnutrition

Further Reading

Bolli GB (1999) How to ameliorate the problem of hypo-

glycemia in intensive as well as nonintensive treatment

of type 1 diabetes. Diabetes Care 22 (supplement 2):

B43–B52.

Cryer PE (1997) Hypoglycemia: Pathophysiology, Diagno-

sis and Treatment. New York: Oxford University Press.

Haymond MW and Pagliara AS (1983) Ketotic hypo-

glycemia. Clinical Endocrinology and Metabolism 12:

447–462.

Hofeldt FD (1989) Reactive hypoglycemia. Endocrinology

and Metabolism Clinics of North America 18: 185–201.

Malouf R and Brust JCM (1985) Hypoglycemia: causes,

neurological manifestations and outcome. Annals of

Neurology 17: 421–430.

Marks V (1987) Functional hypoglycemia: fact or fancy. In:

Andreani D, Marks V and Lefebvre PJ (eds) Hypo-

glycemia: Serono Symposium, vol. 38, pp. 1–17. New

York: Raven Press.

Seltzer HS (1989) Drug-induced hypoglycemia. Endocrin-

ology and Metabolism Clinics of North America 18:

163–183.

Service FJ (1995) Hypoglycemic disorders. New England

Journal of Medicine 332: 1144–1152.

Service FJ (ed.) (1999) Hypoglycemic disorders. Endocrin-

ology Clinics of North America vol. 28(3). Philadelphia,

PA: W.B. Saunders.

Sovik O (1989) Inborn errors of amino acid and fatty

acid metabolism with hypoglycemia as a major clinical

manifestation. Acta Paediatrica Scandinavica 78:

161–170.

Sperling MA and Menon RK (1989) Hyperinsulinemic

hypoglycemia of infancy. Recent insights into ATP-

sensitive potassium channels, sulfonylurea receptors,

molecular mechanisms, and treatment. Endocrinology

and Metabolism Clinics of North America 28: 695–708.

Tanaka K and Ikeda Y (1990) Hypoglycin and Jamaican

vomiting sickness. Progress in Clinical and Biological

Research 321: 167–184.

HYPOGLYCEMIA (HYPOGLYCAEMIA) 3211

HYPOVITAMINOSIS A

V Reddy, Panjagutta, Hyderabad, India

Introduction

0001 Vitamin A is an essential nutrient required for normal

vision, growth, and development, maintenance of

epithelial cellular integrity, immune response, and a

variety of metabolic functions. It is a fat-soluble vita-

min and is stored in the body when intake exceeds

need. Depletion of stores occurs over time when the

diet does not provide enough vitamin A to replace the

amount used by the tissues. Signs of hypovitaminosis

A appear when the stores are depleted to the extent

that physiological functions are impaired. A series of

problems ranging from ocular changes to growth

retardation and increased mortality have been docu-

mented in vitamin A-deficient animals, while in

human vitamin A deficiency (VAD), attention is

focused on xerophthalmia because of the striking

changes in the eye. VAD is recognized as the most

important cause of childhood blindness in developing

countries. Apart from causing eye damage, VAD can

also affect host defense mechanisms, increasing sus-

ceptibility to infection. There is evidence that VAD,

even at subclinical level, increases the risk of morbid-

ity and mortality in vulnerable groups. Recognizing

the importance of the problem, heads of state and

other high-level policy makers gathered at the World

Summit for Children (1990) and the International

Conference on Nutrition (1992) adopted the goal

of elimination of VAD by the year 2000. Although

considerable progress has been made in the past

decade, VAD remains a public health problem in

many developing countries. There is a need to accel-

erate the intervention efforts to eliminate VAD and its

consequences.

Dietary Sources of Vitamin A

0002 Vitamin A is obtained through the diet as preform-

ed vitamin A or provitamin A carotenoids. Preformed

vitamin A is present in animal foods such as milk,

butter, eggs, liver, and fish. In most tropical countries,

where consumption of these foods is low, the main

sources of vitamin A in the diet are the provitamin A

carotenoids. These are present in dark-green leafy

vegetables, yellow/orange vegetables like carrots and

pumpkin, and fruits like mango and papaya. Red

palm oil, used mostly in African countries, has a

very high concentration of b-carotene. Of the various

carotenoids in foods, b-carotene has the maximum

vitamin A activity. Other provitamin A carotenoids

include a-carotene and b-cryptoxanthine, which

have approximately half the vitamin A activity of

b-carotene. Values of carotene/vitamin A given in

most food composition tables are overestimates, as

they are based on old analytical methods which do

not distinguish between provitamin A and other

carotenoids. Only recently have accurate values for

provitamin A carotenoids been obtained, using high-

performance liquid chromatography (HPLC)

technique.

Recommended Dietary Intakes

0003The recommended intakes of vitamin A for different

age groups are given in Table 1. These intakes are

designed to prevent deficiency and provide a safe

intake for a majority of the population. The values

are expressed in terms of retinol equivalents (RE) per

day, taking into account vitamin A activity of provi-

tamin A carotenoids. The Food and Agriculture Or-

ganization/World Health Organization (FAO/WHO)

expert committee has suggested a ratio of 6:1 for

converting b-carotene to vitamin A, assuming that

one-third of the carotene in the diet is absorbed and

half of it is converted to vitamin A. However, recent

studies showed lower bioavailability of carotene,

with a ratio of 26:1 for vegetables and 12:1 for fruits.

Bioavailability of dietary carotenoids is influenced by

a number of factors, including the food source,

method of preparation, amount ingested, and dietary

fat. Any single/average ratio for the conversion of

carotenoids to vitamin A is at best a rough estimate

that is not valid for all diets.

tbl0001Table 1 Recommended dietary intake of vitamin A

Group Age

(years)

Recommended intake

(mgREday

1

)

Both sexes 0–1 350

1–10 400

10–12 500

12–15 600

Boys 15–18 600

Men 18þ 600

Girls 15–18 600

Women 18þ 500

Pregnant women 600

Lactating women 850

RE, retinol equivalent.

Reproduced from FAO/WHO Consultation (1998) Requirements of Vitamin A,

Iron, Folate and Vitamin B

, pp. 16–31. Rome: FAO, with permission.

3212 HYPOVITAMINOSIS A

Assessment of VAD

0004 Several methods are available for assessing the

magnitude and severity of VAD in a population.

These include clinical, functional, and biochemical

indicators. The WHO monograph on indicators of

VAD provides guidelines on the selection and

interpretation of practical indicators for population

assessment.

Clinical Indicators

0005 Clinical indicators are useful for assessing the extent

of VAD in communities where clinical problem or

xerophthalmia exists. The core indicators and the

minimum prevalence criteria to define a public

health problem are given in Table 2. Corneal xero-

phthalmia indicates a serious problem but the

condition is relatively rare and requires a large

sample size to estimate the prevalence. Night

blindness (XN) and Bitot’s spots (X1B) are the two

indicators commonly used in community surveys.

Conjunctival xerosis is not a reliable sign, while xero-

sis with Bitot’s spot is more specific and a prevalence

above 5% in preschool children indicates a public

health problem.

Indicators of Subclinical Deficiency

0006 Serum retinol is the most commonly used biochem-

ical indicator. Values < 0.70 mmol l

1

are considered

as indicative of VAD in children. The cut-off levels of

prevalence used for defining a public health problem

of moderate to severe degree are shown in Table 3.It

is possible to estimate retinol concentration in finger-

prick blood samples using a filter paper technique,

which offers logistic advantages. Other indicators

include relative dose response (RDR) test for

assessing vitamin A stores and conjunctival impres-

sion cytology (CIC) for detection of conjunctival

changes that precede clinical signs. However, these

tests have limited application in field surveys.

Global Prevalence

0007Earlier estimates of VAD prevalence were based on

clinical signs of xerophthalmia, while more recent

surveys include data on subclinical deficiency based

on blood levels of vitamin A < 0.70 mmol l

1

.Itis

now estimated that VAD, including clinical and sub-

clinical forms of moderate to severe degrees of public

health significance, exists in 60 countries and it is

likely to be a problem in at least an additional 13

countries. On a regional basis, South-east Asia and

Africa account for just under 90% of the global prob-

lem (Figure 1). Although the prevalence of clinical

deficiency has shown a marked decline from 14 mil-

lion in 1994 to 3 million in 1996, estimates of

subclinical deficiency have gone up to 251 million,

with the increasing use of serum retinol concentration

for assessment. About 254 million children in the

world are thus at risk in terms of their health and

survival.

Epidemiology

Socioeconomic Factors

0008VAD occurs within an ambience of ecological, eco-

nomical, and social deprivations that characterize the

poor in developing countries. At the macro level,

adverse environment with infertile land and water

shortage limit the availability of foods rich in

vitamin A. Since animal foods containing prefor-

med vitamin A are expensive, poor families rely on

plant sources of provitamin A carotenoids. Illiterate

and impoverished mothers tend to follow traditional

feeding practices and do not fully utilize even the

available resources. High infection rates associated

with poor living conditions also contribute to hypo-

vitaminosis A.

Clustering

0009The occurrence of VAD tends to cluster rather than

to be evenly distributed. Clustering within high-risk

households and within communities has been de-

scribed primarily for clinical deficiency. Studies in

Asia show that siblings of xerophthalmic children

are 10 times more likely to have xerophthalmia than

tbl0002 Table 2 Classification of xerophthalmia and prevalence

criteria constituting a public health problem

Criteria Minimum prevalence

Night blindness (XN) > 1.0%

Bitot’s spots (X1B) > 0.5%

Corneal xerosis/ulceration > 0.01%

(X2, X3A, X3B)

Corneal scar (XS) > 0.05%

Data from: WHO (1995) Global Prevalence of Vitamin A Deficiency. Geneva:

WHO, with permission.

tbl0003 Table 3 Classification of subclinical deficiency (serum retinol

< 0.70 mmol l

1

)

Public health problem Prevalence inchildren

Mild 2–< 10%

Moderate 10–< 20%

Severe 20%

Data from: WHO (1995) Global Prevalence of Vitamin A Deficiency. Geneva:

WHO, with permission.

HYPOVITAMINOSIS A 3213

fig0001 Figure 1 Global prevalence of vitamin A deficiency. Reproduced from WHO (1995) Global Prevalence of Vitamin A Deficiency. Micronutrient Deficiency Information System. Working Paper #2.

WHO/NUT/95.3. Geneva: WHO, with permission.

those without. Neighboring children of xeroph-

thalmic children are also more likely to develop

xerophthalmia. This is due to sharing common socio-

cultural and economic conditions that result in fre-

quent infections, limited food availability, and poor

dietary practices that predispose to VAD.

Seasonal Patterns

0010 The occurrence of xerophthalmia follows a seasonal

pattern in different parts of the world. In South Asia,

for example, a distinct peak in the incidence of xer-

ophthalmia is observed in the month of May–June.

The peak appears to be related to the total food intake

and consequent growth spurt of children. It also coin-

cides with a general scarcity of provitamin A-rich

vegetables and fruits and a seasonal rise in the

incidence of diarrhea and respiratory infection.

Host Factors

0011 Age VAD is more common among children of pre-

school age. While xerophthalmia rarely occurs during

infancy, children between 1 and 4 years are at greater

risk. The potentially blinding corneal disease is most

prevalent during the weaning period and is associated

with severe protein-energy malnutrition (PEM).

Symptoms of milder xerophthalmia like Bitot spots

and night blindness are more common in older chil-

dren. Hypovitaminosis A persists throughout adoles-

cence and into adulthood, as judged by low serum

retinol levels. Clinical signs of xerophthalmia are rare

in adults except for maternal night blindness. Reports

from Asia indicate that about 10–20% of women

develop night blindness during pregnancy.

0012 Sex No consistent sex difference is demonstrated

based on physiological parameters. Differences have

been reported in some communities, which are more

likely to be related to sex differences in cultural prac-

tices of feeding and care rather than to physiological

differences.

Dietary Practices

0013 In poor communities, diets are deficient in several

nutrients, including vitamin A. Pregnant and lactating

women rarely take any extra food to meet their add-

itional needs. As a result, the offspring are born with

poor stores of vitamin A. During the first 6 months of

life, breast milk is the major source of vitamin A for

infants but the vitamin concentration of milk is low in

undernourished mothers. Although clinical signs of

VAD are rare in infants, their vitamin stores are de-

pleted. Complementary feeding is delayed and foods

rich in vitamin A are seldom given, increasing the risk

of VAD during the weaning period. Diet surveys in

countries of South Asia show that the daily intake of

vitamin A among preschool children is less than half

the recommended intake and most of it is derived

from plant sources of provitamin A carotenoids.

Bioavailability of plant carotenoids is low and it is

difficult to meet the needs of young children from

vegetable foods alone. Dietary fat is important for

the absorption of carotenoids but the weaning diets

contain little fat. These patterns signal the need to

improve child feeding practices in high-risk families

to sustain adequate vitamin A status.

Protein-Energy Malnutrition

0014VAD is often associated with protein-energy malnu-

trition (PEM) in children. Clinical studies show that

the prevalence of xerophthalmia is higher in children

with PEM than in those without. Almost all cases of

corneal xerophthalmia/keratomalacia are associated

with severe PEM. These observations suggest that

protein deficiency may aggravate VAD (often associ-

ated with protein-energy malnutrition in children).

Experimental studies show that there is a close

metabolic relationship between protein and vitamin

A. While the synthesis of retinol-binding protein

(RBP) that carries vitamin A is influenced by protein

nutrition, its release from the liver depends on vita-

min A status. Studies in malnourished children with

corneal xerophthalmia have shown that the concen-

tration of serum retinol was reduced to a greater

extent than that of RBP. Administration of vitamin

A to such children not only raised serum levels of

these components but also showed a rapid clinical

improvement. These observations indicate that the

role of vitamin A is more critical than that of protein

in the development of corneal lesions. Appreciation

of this fact has an important bearing on the treatment

and prevention of xerophthalmia.

Infections

0015Keratomalacia is often preceded by an episode of

infection: diarrhea and respiratory infection are

common precipitating factors. Prospective studies

also show that common childhood infections,

including diarrhea, respiratory illness, measles, and

chickenpox, induce hypovitaminosis A. During acute

infection, not only is the food intake reduced but

metabolic alterations are also known to occur. These

include decreased absorption of vitamin A, impaired

retinol transport, and increased renal excretion. Slow

normalization of these mechanisms coupled with low

dietary intake of vitamin A during the acute phase

and recovery lead to VAD. Parasitic infections like

ascariasis and giardiasis also aggravate VAD. Intes-

tinal worms may directly compete for uptake of

HYPOVITAMINOSIS A 3215

vitamin A, besides their more general impact on

health by suppressing appetite.

Xerophthalmia

0016 Although hypovitaminosis A affects many tissues in

the body, the most striking changes are seen in the

eye. The conjunctival and corneal epithelium undergo

keratinizing metaplasia. Columnar epithelial cells

become squamous and mucus-producing goblet

cells disappear, resulting in dryness/xerosis of the

ocular surfaces. Hypovitaminosis A also affects

the retinal function. Vitamin A is required for the

synthesis of rhodopsin, a photosensitive pigment in

the rod cells of retina that responds to light by releas-

ing vitamin A. If the vitamin is not replaced, rhodop-

sin production is reduced, resulting in impaired dark

adaptation and night blindness.

Night Blindness

0017 Night blindness is one of the early manifestations of

VAD and is marked by an inability to move around in

the dark. It is common among pregnant women

in endemic areas and often disappears after delivery

without any treatment. Night blindness is also

common among preschool children but its detection

is difficult in children below 2 years. In endemic

areas, a local term is often used for night blindness

that translates into ‘twilight blindness’ or ‘chicken

eyes’ (chicken have no rods and are therefore night-

blind), making the condition readily detectable by

history. Impaired dark adaptation is an early func-

tional abnormality which can be detected using a

dark adaptometer.

Conjunctival Changes

0018 Conjunctival xerosis appears as a dry, unwettable

surface of the bulbar conjunctiva. The conjunctival

changes that precede clinical signs can be detected

by filter-paper impression cytology. These include

keratinization/distortion of epithelial cells and disap-

pearance of goblet cells. In chronic cases, accumula-

tion of keratinized cells appears as white foamy

patches of oval or triangular shape called Bitot’s

spots. They are usually bilateral and seen on the

temporal side of the corneal limbus.

Corneal Changes

0019 Severe deficiency of vitamin A involves the cornea,

affecting the vision. The earliest corneal epithelial

changes appear as punctate defects, which can be

detected by a slit lamp. Clinically, the cornea appears

dry, hazy, and lusterless (X2). In severe cases, corneal

ulcers (X3A) appear as round or oval defects that

are usually shallow, but may progress to perforation

of cornea. Healed ulcers appear as white scars (XS)

and affect vision if they are centrally located. In

more advanced cases, there is necrosis and softening

of cornea (X3B). This condition, described as kera-

tomalacia, often results in permanent blindness.

Corneal xerophthalmia is invariably associated

with severe PEM and infection. Hospital studies

show high mortality in such cases, ranging from 5

to 25%.

Mortality

Childhood Mortality

0020Preschool age Vitamin A has been named as ‘anti-

infective vitamin’ as early as 1928, based on the evi-

dence obtained from animal studies. Although there

were several reports on the association of xerophthal-

mia with increased mortality among malnourished

children during the subsequent years, the importance

of vitamin A in child health and survival was not fully

recognized until late 1980s. Community studies in

Indonesia showed that preschool children with mild

xerophthalmia were two to three times more likely to

have developed diarrhea and respiratory illness than

those with normal eyes. The risk of mortality was also

higher in such cases. The effect of VAD on infection

may be mediated through several mechanisms, in-

cluding impairment of mucosal epithelial barrier

and of the immune response. Low T-cell count and

impaired blast transformation have been reported in

vitamin A-deficient children.

0021An intervention trial conducted in Indonesia

showed that administration of 6-monthly doses of

200 000 IU vitamin A to preschool children resulted

in 34% reduction in mortality. This stimulated a lot

of interest worldwide and led to a series of field trials

in Asia and Africa. Six out of eight controlled trials in

children showed mortality reductions ranging

from 19% to 54%. However, two studies reported

from India and Sudan showed no significant impact.

Metaanalysis of data from these studies has estimated

a reduction of total mortality by 30%.

0022Thus, vitamin A supplementation has resulted in

significant reductions in mortality in several, though

not all, community studies. Vitamin A had a protect-

ive effect against death from measles and diarrhea but

not from respiratory infection. The impact of vitamin

A may vary in different situations depending upon the

extent and severity of VAD, existence of concomitant

nutritional deficiencies, particularly PEM, and the

prevalence of infections in the community. The sup-

plements are expected to have a greater impact in

areas where VAD is highly prevalent.

3216 HYPOVITAMINOSIS A

0023 Early infancy A few studies have examined the effi-

cacy of vitamin A supplementation among apparently

normal infants under 6 months of age. Administra-

tion of a single dose of 50 000 IU vitamin A to neo-

nates in Indonesia resulted in a significant reduction

in the risk of death while no effect was observed in a

similar study in Nepal. Similarly, in a multicentric

WHO study conducted in India, Peru and Ghana,

administration of three doses of vitamin A along

with diphtheria, pertussis, typhoid (DPT) vaccine in

the first 4 months of age had no effect on infant

mortality or morbidity.

0024 Measles-related mortality Beneficial effect of vita-

min A on measles-related morbidity and mortality in

children was reported as early as 1932. In recent

placebo-controlled hospital studies conducted in

South Africa and Tanzania, administration of large

doses of vitamin A to children on admission for severe

measles resulted in a 60% reduction in case fatality.

The mortality reduction was higher (70%) when

measles was associated with pneumonia. The protect-

ive effect of the supplements was apparently greater

among infants than in older children.

Pregnancy-Related Mortality

0025 Although several studies have examined the impact of

vitamin A on child survival, maternal health has not

received much attention. Recently, a community trial

conducted in Nepal showed that weekly supplements

of vitamin A or b-carotene reduced pregnancy-related

mortality (mortality during pregnancy up to 12 weeks

postpartum). However, differences were only signifi-

cant when the two groups were pooled. It is surpris-

ing to note that the carotene group with lower retinol

concentration showed a greater reduction in mortal-

ity than the vitamin A group. Furthermore, supple-

mentation was associated with protection from

deaths due to injuries and miscellaneous causes but

had no impact on mortality ascribable to infections

and obstetric causes. Further studies are under way to

determine the role of vitamin A in maternal health

and survival.

Morbidity

0026 Unlike the impact on mortality, the effects of vitamin

A on morbidity have been more difficult to establish.

This may be due to variation in disease sensitivity to

vitamin A and inherent problems in assessing the

prevalence and severity of morbidity. Vitamin A

does not have much effect on the prevalence of

common childhood diseases but it appears to reduce

the severity of potentially fatal infections such as

measles, persistent diarrhea, and malaria, especially

in the presence of wasting malnutrition. The protect-

ive effect becomes stronger with the episode severity.

In Bangladesh, administration of vitamin A had no

impact on the duration of illness or stool output in

children with watery diarrhea, although children

with shigellosis who received vitamin A supplements

were 32% less likely to be clinically ill as compared

to placebo group. In Ghana, vitamin A supplemen-

tation was associated with fewer or less severe com-

plications and reduced rates of hospitalization for

severe measles. However, vitamin A has no effect on

nonmeasles respiratory disease. In some cases, sup-

plementation was associated with an increased risk of

lower respiratory infection. This appears a paradox,

considering the beneficial effect of vitamin A on the

epithelial structures.

0027Recent studies suggest that vitamin A may have

a role in other infections, particularly human

immunodeficiency virus (HIV) infection. In adults,

low plasma vitamin A concentration was associated

with increased clinical progress of HIV infection and

greater mortality. It was also found that low vitamin

A concentration during pregnancy was associated

with increased transmission of infection from mother

to child and also increased infant mortality. However,

clinical trials in South Africa and Tanzania showed

that vitamin A supplementation during pregnancy

had no effect on vertical transmission of the disease.

In another study, vitamin A supplements reduced

diarrheal morbidity in HIV-infected infants. Further

research is needed to explore the role of vitamin A in

HIV infection.

Treatment of Xerophthalmia

0028All individuals with xerophthalmia (except pregnant

women) should be treated with large oral doses of

200 000 IU vitamin A according to the WHO guide-

lines (Table 4). The age-specific dose should be given

on the first and second days and again 2 weeks later.

This applies to all stages of active xerophthalmia,

including night blindness, Bitot’s spots, and corneal

lesions. Corneal xerophthalmia is a medical emer-

gency and should be treated immediately on diagnosis

and then patients should be referred to a hospital

tbl0004Table 4 Treatment of xerophthalmia

Age (months) Dose of vitaminA (IU)

< 6 50 000

6 – 12 100 000

> 12 200 000

Three doses: on diagnosis þnext day þ2 weeks later.

HYPOVITAMINOSIS A 3217

for further treatment as they often present complex

problems. Topical application of antibiotic ointment

(tetracycline or chloramphenicol) is recommended

for corneal lesions to prevent secondary infection. In

addition, patients should be provided nutritional

support and medical therapy.

0029 Corneal xerosis shows improvement within a

week but in more advanced cases (corneal ulcer/

keratomalacia), healed scars remain as white opaci-

ties, resulting in partial or total blindness. Night

blindness responds in a couple of days while Bitot’s

spots take 3–10 days and some may persist, particu-

larly in older age groups.

0030 Pregnant women should be treated with small

doses of vitamin A, not exceeding 10 000 IU daily or

25 000 IU weekly, for about a month. Large doses of

vitamin A should be avoided during pregnancy to

avoid the risk of teratogenicity.

Prevention of VAD

0031 Inadequate dietary intake of vitamin A is the primary

cause of VAD and therefore the most rational ap-

proach to prevent the condition would be to improve

the diet and increase the intake of vitamin A. As a

short-term measure, however, vitamin A supplemen-

tation of the high-risk groups is suggested for provid-

ing immediate relief. Food fortification is also an

effective way of increasing vitamin A intake in the

population.

Vitamin A Supplementation

0032 Since vitamin A can be stored in the liver, periodic

administration of large doses of vitamin A has been

recommended for prevention of VAD. Children be-

tween 1 and 6 years of age are given an oral dose of

200 000 IU vitamin A every 4–6 months, while those

between 6 and 12 months are given half the dose.

Large-scale supplementation programs are now

in operation in many developing countries where

VAD is a major public health problem. Universal

distribution, involving administration of the dose to

all preschool children, is adopted by most countries.

In addition, targeted distribution of vitamin A is

recommended for the high-risk groups (severe

PEM, measles, siblings of children with xerophthal-

mia). Even in areas where a vitamin A program is in

operation, these children can be given an additional

dose of vitamin A if they had not received the supple-

ment in the previous month.

0033 Although vitamin A supplementation is widely im-

plemented, the coverage is inadequate in most areas.

It has been suggested that supplementation may be

linked with the national immunization program to

take advantage of immunization contacts for the de-

livery of vitamin A. In most national programs, the

first dose of vitamin A is given along with measles

vaccine at the age of 9 months. In Bangladesh, vita-

min A supplements are given earlier along with DPT

immunization. A higher incidence of side-effects like

nausea, vomiting, and bulging fontanel were ob-

served with this regimen, raising concern about sup-

plementation in early infancy. However, the

symptoms were mild and transient, disappearing

within 48 h and follow-up studies showed no long-

term sequelae. A WHO multicentric study conducted

more recently confirmed the safety of vitamin A sup-

plements but this regimen had no significant benefit

for the infants.

0034Administration of a large dose of 200 000 IU vita-

min A has been recommended for lactating mothers

within 8 weeks of delivery to raise vitamin A concen-

tration of milk and thus improve vitamin A status of

the infant. However, recent studies show that the dose

is not enough to produce any beneficial effect. In-

creasing the amount of vitamin A (two doses of

200 000 IU each) has been suggested. Further studies

are needed to determine the feasibility and safety of

administering two large doses within 8 weeks.

Food Fortification

0035Although vitamin A supplementation is a simple and

effective intervention, it does not correct the under-

lying dietary causes. In recent years, food-based ap-

proaches have been receiving increasing attention as a

long-term sustainable strategy. Food fortification

offers a direct, effective, and potentially sustainable

way to correct VAD. Vitamin A fortification of sugar

has been successfully implemented in Guatemala and

other Central American countries. However, a recent

survey in Guatemala showed a high prevalence of

VAD in children < 3 years, suggesting that fortification

of a single food may not ensure adequate vitamin A

status of the entire population. Fortification of mul-

tiple foods, including complementary foods targeted

to young children, has been suggested as an alternate

strategy. Other foods fortified with vitamin A include

margarine in the Philippines, monosodium glutamate

in Indonesia, and edible oils in India. Selection of

appropriate vehicle and adequate level of fortification

are important to meet the population needs.

0036Since VAD often coexists with deficiencies of other

micronutrients like iron, folate, and zinc, fortification

of foods with multiple nutrients has been suggested.

Further research is needed to understand the inter-

actions of various nutrients and to establish whether

fortification with multiple nutrients would facilitate

each other’s beneficial effects.

3218 HYPOVITAMINOSIS A