Assessment of Vitamin A Nutritional Status

An early sign of vitamin A deficiency is impaired dark adaptation - an increase in the time taken to adapt to seeing in dim light. The apparatus required is not suitable for use in field studies, or for use with children (the group most at risk from deficiency), and the dark adaptation test is largely of historical interest. Balance, color vision, and the senses of taste and smell are also affected in early deficiency, but none of these provides a sensitive or specific test of status.

Liver reserves of vitamin A can be estimated by isotope dilution after a test dose of isotopically labeled retinol, but this is not a suitable technique for assessment of status in population studies.

Assessment of vitamin A nutritional status depends on the biochemical criteria shown in Table 2.3.

2.4.1.1 Plasma Concentrations of Retinol and p-Carotene Because RBP is released from the liver only as the holo-protein and apo-RBP is cleared from the circulation rapidly after tissue uptake of retinol (Section 2.2.3), the fasting plasma concentration of retinol remains constant over a wide range of intakes. It is only when liver reserves are nearly depleted that it falls significantly, and it only rises significantly at the onset of toxic signs. Therefore, although insensitive to changes within the normal range, measurement of plasma retinol provides a convenient means of detecting people whose intake of vitamin A is inadequate to permit normal liver reserves to be maintained.

Interpretation of plasma concentrations of retinol is confounded by the fact that both RBP and transthyretin are negative acute phase proteins, and their synthesis falls, and hence the plasma concentration of retinol fall, in response to infection. Similarly, both protein-energy malnutrition and zinc deficiency result in a low plasma concentration, despite possibly adequate liver reserves as a result of impaired synthesis of RBP.

Carotene in plasma is mainly inlipoproteins; thus, as with vitamin E (Section 4.5), measurements of plasma concentrations of carotene should be related to either cholesterol or total plasma lipids. Only 10% to 20% of total plasma carotenoids is f -carotene, with a very wide range of individual variation. There are no reliable determinations of f -carotene or total provitamin A carotenoids

Table 2.3 Biochemical Indices of Vitamin A Status Liver Retinyl Esters (as Retinol) ^mol/kg

mg/kg

Adequate

>70

>20

Marginal

35-70

10-20

Poor

17.5-35

5-10

Deficient

<17.5

<5

Plasma Retinol

^mol/L

^g/L

Elevated

>1.75

>500

Normal

0.7-1.75

200-500

Unsatisfactory

0.35-0.7

100-200

Liver stores depleted/deficient

<0.35

<100

Plasma Total Carotenoids"

^mol/L

^g/L

Adult reference range

0.4-4.0

240-2,200

Acceptable

>0.75

>400

Hypercarotinemia

>5.6

>3,000

Plasma Retinoic Acid

nmol/L

^g/L

Adults

10-13

3-4

Plasma Retinol Binding Protein

^mol/L

^g/L

Adults

1.9-4.28

40-90

Preschool children

1.19-1.67

25-35

Relative Dose Response

Normal

<20%

Marginal deficiency

>20%

Modified Dose Response

Dehydroretinol/retinol

Normal

<0.03

Marginal deficiency

>0.03

a g-Carotene is 10% to 20% of total plasma carotenoids.

Sources: International Vitamin A Consultative Group, 1983; Underwood, 1990.

in appropriate populations to permit plasma concentrations of carotene to be related to vitamin A nutritional status.

2.4.1.2 Plasma Retinol Binding Protein Measurement of plasma concentrations of RBP may give some additional information. Indeed, it has been suggested that because retinol is susceptible to oxidation on storage of blood samples, measurement of RBP may be a better indication of the state of vitamin A status. In adequately nourished subjects, about 13% of immunologically reactive RBP in plasma is present as the apo-protein, whereas in vitamin A-deficient children, the proportion of apo-protein may rise to 50% to 90% of circulating RBP. Measurement of the ratio of plasma retinol:RBP may provide a sensitive index of status (Thurnham and Northrop-Clewes, 1999).

2.4.1.3 The Relative Dose Response (RDR) Test The RDR test is a test of the ability of a dose of vitamin A to raise the plasma concentration of retinol several hours later, after chylomicrons have been cleared from the circulation. What is being tested is the ability of the liver to release retinol into the circulation. In subjects who are retinol deficient, a test dose will produce a large increase in plasma retinol, because of the accumulation of apo-RBP in the liver in deficiency (Section 2.2.3). In those whose problem is due to lack of RBP, then little of the dose will be released into the circulation. An RDR greater than 20% indicates depletion of liver reserves of retinol to less than 70 ¿mol per kg (Underwood, 1990).

The test requires two samples of blood, taken before and 5 hours after the test dose of retinol. A modified RDR test involves giving a test dose of dehy-droretinol, then determining the ratio of dehydroretinol:retinol in a single plasma sample taken 30 hours later. Again, because of the accumulation of RBP in the liver in deficiency and because in deficiency there is less dilution of dehydroretinol with liver pools of retinyl esters, the ratio is inversely proportional to the liver stores of retinol (Tanumihardjo et al., 1987).

2.4.1.4 Conjunctival Impression Cytology Early changes in vitamin A deficiency include loss of the mucus-secreting goblet cells from the conjunctival epithelium, and the appearance of enlarged, flattened, and partially keratinized epithelial cells. An impression of the conjunctiva is taken by blotting onto cellulose acetate, then fixing and staining prior to histological examination. The technique detects children who do not yet show any clinical signs and whose serum retinol is within the normal range (Wittpenn et al., 1986; Natadisastra et al., 1987).

2.5 VITAMIN A REQUIREMENTS AND REFERENCE INTAKES

Very few direct studies have been performed to determine human vitamin A requirements. In the Sheffield study (Hume and Krebs, 1949), 16 subjects were depleted of vitamin A for 2 years; only three subjects showed clear signs of impaired dark adaptation. One of these subjects was repleted with 390 [g of retinol per day, which resulted in a gradual restoration of dark adaptation; the other two subjects received ^-carotene. On this basis, the minimum requirement was presumed to be 390 [ g, and the reference intake was set at 750 [ g.

Table 2.4 Reference Intakes of Vitamin A (^g/day)

U.K.

EU

U.S./Canada

FAO

Age

1991

1993

2001

2001

0-6 m

350

400

375

7-12 m

350

350

500

400

1-3 y

400

400

300

400

4-6 y

500

400

400

450

7-8 y

500

500

400

500

Males

9-10 y

500

500

600

600

11-13 y

600

600

600

600

>14 y

700

700

900

600

Females

9-10 y

500

500

600

600

11-13 y

600

600

600

600

>14 y

600

600

700

600

Pregnant

700

700

770

800

Lactating

950

950

900

850

EU, European Union; FAO, Food and Agriculture Organization; WHO, World Health Organization.

Sources: Department of Health, 1991; Scientific Committee for Food, 1993; Institute of Medicine, 2001; FAO/WHO, 2001.

EU, European Union; FAO, Food and Agriculture Organization; WHO, World Health Organization.

Sources: Department of Health, 1991; Scientific Committee for Food, 1993; Institute of Medicine, 2001; FAO/WHO, 2001.

Since then, eight more subjects have been studied (Sauberlich et al., 1974; Hodges et al., 1978). From these studies, the reference intake for adult men was set at 1,000 fig of retinol equivalent, with a minimum physiological requirement of 600 f g per day. Because the signs of deficiency only resolve slowly, it is possible that depletion/repletion studies overestimate requirements.

An alternative approach to determining requirements is to measure the fractional rate of catabolism of the vitamin by use of a radioactive tracer, then determine the intake that would be required to maintain an appropriate level of liver reserves. As discussed in Section 2.2.1.1, when the liver concentration rises above 70 f mol per kg, there is increased activity of the microsomal oxidation of vitamin A and biliary excretion of retinol metabolites. The fractional catabolic rate is 0.5% per day; assuming 50% efficiency of storage of dietary retinol, this gives a mean requirement of 6.7 f g per kg of body weight and a reference intake of 650 to 700 f g for adult men (Olson, 1987a). Reference intakes for vitamin A are shown in Table 2.4.

Although there is some evidence that f-carotene and other carotenoids may have actions in their own right, apart from their provitamin A activity (Section 2.6.3), there is no evidence on which to base any recommendations or suggestions of requirements for carotene other than as a precursor of retinol. There is no evidence of any carotene deficiency disease in depletion studies of people provided with an adequate intake of retinol (Institute of Medicine, 2001). The epidemiological evidence that shows a high intake of carotenoids to be associated with a lower incidence of cancer (Section 2.6.3) may reflect intake of (carotene-rich) fruits and vegetables, which are sources of other potentially protective compounds (Section 14.7), rather than carotene intake per se.

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