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American Journal of Clinical Nutrition, Vol. 73, No. 5, 934-940, May 2001
© 2001 American Society for Clinical Nutrition

Original Research Communication

Serum retinyl esters are not associated with biochemical markers of liver dysfunction in adult participants in the third National Health and Nutrition Examination Survey (NHANES III), 1988–19941,2

Carol Ballew, Barbara A Bowman, Robert M Russell, Anne L Sowell and Cathleen Gillespie

1 From the Division of Nutrition and Physical Activity, National Centers for Chronic Disease Prevention and Health Promotion, and the Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, and the US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston.

2 Address reprint requests to C Ballew, Mailstop K-26, 4770 Buford Highway NE, Centers for Disease Control and Prevention, Atlanta, GA 30341. E-mail: ckb2{at}cdc.gov.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Serum retinyl ester concentrations are elevated in hypervitaminosis A. It was suggested that retinyl esters >10% of total serum vitamin A indicate potential hypervitaminosis, but this cutoff was derived from small clinical samples that may not be representative of the general population.

Objective: We sought to examine the distribution of serum retinyl ester concentrations and associations between retinyl ester concentrations and biochemical markers of liver dysfunction in a nationally representative sample.

Design: We assessed the associations between serum retinyl ester concentrations and 5 biochemical indexes of liver dysfunction by using multivariate linear and multiple logistic regression techniques and controlling for age, sex, use of supplements containing vitamin A, alcohol consumption, smoking status, and use of exogenous estrogens in 6547 adults aged >=18 y in the third National Health and Nutrition Examination Survey (NHANES III), 1988–1994.

Results: Thirty-seven percent of the sample had serum retinyl ester concentrations >10% of total serum vitamin A and 10% of the sample had serum retinyl esters >15% of total vitamin A. We found no associations between serum retinyl ester concentrations and 1) concentrations of any biochemical variable (multiple linear regression) or 2) risk of having biochemical variables above the reference range (multiple logistic regression). We did not find a serum retinyl ester value with statistically significant sensitivity and specificity for predicting increases in biochemical indexes of liver dysfunction.

Conclusions: The prevalence of serum retinyl ester concentrations >10% of the total vitamin A concentration in the NHANES III sample was substantially higher than expected but elevated retinyl ester concentrations were not associated with abnormal liver function.

Key Words: Retinyl esters • hypervitaminosis A • vitamin A • third National Health and Nutrition Examination Survey • NHANES III • liver dysfunction • liver function • vitamin A supplementation • retinol • vitamin A toxicity


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Vitamin A has a dual status as a public health issue. Vitamin A deficiency is common worldwide and is associated with a great burden of preventable morbidity and mortality (1) but vitamin A can also cause acute and chronic toxicity (2, 3). Although potentially inadequate vitamin A status still occurs in some segments of the US population, frank vitamin A deficiency is uncommon in the United States today (4, 5). There is now concern that the prevalence of hypervitaminosis A may increase in developed countries, where food supplies are rich in naturally occurring and fortified sources of vitamin A and supplements containing vitamin A are readily available and may be overused (2, 6–8). Chronic intake of vitamin A in excess of need may result in accumulation and liver damage (9–11). When intake exceeds the storage capacity of the liver or when liver function is compromised, vitamin A is released into the circulation as retinyl esters rather than bound to retinol-binding protein (12–15). Retinyl esters deliver free retinol to target tissues; this process is responsible for the damaging effects of hypervitaminosis A (12, 16).

Serum retinyl esters have been used as a marker of possible hypervitaminosis A (12, 17–19). It is generally accepted that normal serum concentrations of retinyl esters are <244 nmol/L (7 µg/dL) and retinyl esters normally make up <8% of total serum vitamin A (retinol bound to retinol-binding protein plus total retinyl esters) (12, 17–19). Retinyl esters >10% of total vitamin A are believed to reflect excess retinol stores and potential toxicity (17–19).

The reference ranges for serum retinyl esters that are generally used are based on small and possibly nonrepresentative groups of volunteers or patients (12, 19–22). We could not find previous reports on the distribution of retinyl esters in a large, nationally representative sample of the population, nor could we find reports on the association of retinyl esters with markers of possible liver dysfunction in such a sample. In this article, we report the distributions of serum retinyl ester concentrations and of retinyl esters as a percentage of total serum vitamin A in the third National Health and Nutrition Examination Survey (NHANES III), 1988–1994. We examined participant characteristics associated with variation in serum retinyl ester concentrations and percentages, as well as the relations between retinyl esters and biochemical markers of liver dysfunction.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
NHANES III was a nationally representative, complex probability survey of the noninstitutionalized population of the United States. Details of the study design and the interview and examination procedures were published previously (23). Laboratory analyses were performed at the National Center for Environmental Health of the Centers for Disease Control and Prevention. Serum retinol and retinyl ester concentrations were measured with HPLC (Waters Chromatography Division, Milford, MA) (24). Serum biochemistry analyses were performed with a Hitachi Model 737 multichannel analyzer (Boehringer Mannheim Diagnostics, Indianapolis). Detailed descriptions of the blood sampling and handling procedures for retinol analysis and of other laboratory procedures were published previously (23). Our analysis was based on the public-use data file (25).

We confined our analysis to adults aged >=18 y with complete data on serum retinol and retinyl esters, serum biochemistry, potential confounding factors, and exclusionary criteria. Of the 17324 individuals aged >=18 y in the original laboratory sample, 8056 had data for fasting (>=12 h) serum retinyl ester concentrations. We excluded nonfasting participants, pregnant women (n = 147), and participants with missing data on serum biochemistry (n = 100), body mass index (n = 11), or exclusionary criteria and covariates included in the analysis (n = 537). Other exclusion criteria were a history of physician-diagnosed liver disease or active hepatitis infection (n = 153); other acute infections or inflammatory conditions [on the basis of elevated C-reactive protein by using the cutoff applied in the NHANES III laboratory (>2.0 mg/dL (23), n = 250]; and a history of congestive heart failure, which is associated with elevated liver enzyme concentrations (n = 316). Some participants were excluded from our study on the basis of more than one of the exclusion criteria. The final sample included 6547 participants and was 49% male, 77% non-Hispanic white, 10% non-Hispanic black, 5% Hispanic, and 8% other racial or ethnic identities.

We classified participants as heavy drinkers if they reported consuming >=5 drinks/d more than once a month. There were 958 heavy drinkers in the sample. Participants were classified as current smokers or nonsmokers on the basis of self-report. There were 1668 smokers in the sample, 337 women who used oral contraceptives, and 257 women who used estrogen replacement therapy; these factors are known to affect serum retinol concentrations, but less is known about their associations with serum retinyl esters.

Participants were asked to report the details of their use of dietary supplements during the 30 d before the interview. Brand names were recorded and, if possible, bottles were examined to determine the nutrient content of each supplement reported. We linked supplement products to a nutrient content database (26) and calculated the total intake of preformed vitamin A from supplements for each participant. The range of preformed vitamin A obtained from supplements was 30–74312 µg RE/d; 73% of the sample took no supplemental vitamin A. Only 8 participants reported taking >10000 µg RE/d. The median for those who reported taking <=10000 µg RE/d was 1495 µg RE/d. We created an index of long-term exposure in retinol-months by multiplying vitamin A intake from supplements per month by duration of supplementation in months.

We did not include dietary intake of vitamin A in our analysis because 95% of the participants provided only a single 24-h dietary recall. Vitamin A is distributed unevenly in the diet and therefore many days of dietary data are required for an accurate estimate of intake (27). Software is available for computing the estimated usual intake of nutrients on the basis of the ratio of inter- to intraindividual variation in intake derived from participants who provide >1 d of recall data (28). However, the extremely high inter- and intraindividual variability of vitamin A intake in the sample did not allow the software to produce statistically reliable estimates on the basis of a 5% subsample with only 2 d of recall data. Other investigators reported that only vitamin A intake from supplements, not intake from foods, was significantly associated with serum retinol and retinyl ester concentrations (19, 20, 29).

The NHANES III biochemistry panel included alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and total bilirubin. Elevated ALP concentrations may be the most pathognomic for hypervitaminosis A (30, 31), but much of the literature reports AST, ALT, bilirubin, and occasionally LDH. The pattern of elevated or normal concentrations of these markers in documented hypervitaminosis A is extremely variable so we examined all the markers individually and in combination. We defined any value above the reference range used by the laboratory as indicative of possible liver dysfunction and any value more than twice the upper limit of the reference range as indicative of probable liver dysfunction (23). We performed analyses using the endpoints of one elevated marker or >=2 elevated markers.

We determined the distributions of retinyl ester concentrations and percentages of retinyl esters with SUDAAN software (32), taking into account the complex, stratified, and weighted nature of the sample. Because of small cell sizes or unbalanced representation of sampling strata, values could not be computed for some cells; these cells are indicated by dashes in the tables.

We used analysis of variance to compare serum retinyl ester concentrations and percentages of serum retinyl esters across strata for sex, age group, and use of supplements containing vitamin A. We used chi-square analysis to examine the prevalence of serum retinyl esters >=244 nmol/L (7 µg/dL) and >10% of total serum vitamin A and the prevalence of elevated markers of liver function across the following strata: sex, age group, use of supplements containing vitamin A, alcohol consumption, smoking status, and use of exogenous estrogens. We performed multiple linear regression analysis to assess the associations between serum retinyl ester concentrations or percentages and markers of liver function, controlling for known or suspected covariates and confounders (sex, age, use of supplements containing vitamin A, alcohol consumption, smoking status, estrogen use, and body mass index). We used multiple logistic regression to assess the associations between serum retinyl ester concentrations or percentages and the likelihood of having liver function markers above the laboratory reference ranges. We also performed multiple linear regression and multiple logistic regression using the integrated index of supplement use x duration (retinol-months) as a predictor of serum retinyl ester concentration, percentage retinyl esters, and serum biochemistry endpoints. We performed sensitivity and specificity tests with receiver operating characteristic curve analysis (33) in search of a sample-based cutoff that would indicate a concentration or percentage of serum retinyl esters associated with a significant increase in the risk of elevated serum biochemistry markers.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The median serum retinyl ester concentration was <244 nmol/L (7.0 µg/dL) in all sex and age strata of nonusers of supplements containing vitamin A and was <244 nmol/L in users of supplements containing vitamin A who were <50 y of age (Table 1Go). The 95th percentile was >=244 nmol/L in supplement nonusers and the 75th percentile was >=244 nmol/L in supplement users in all but one stratum. Serum retinyl ester concentration was not significantly different between men and women, was higher in users than in nonusers of supplements containing vitamin A, and increased with age on the basis of analysis of variance when the simultaneous effects of age, sex, and use of supplements containing vitamin A were controlled for.


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  		TABLE 1. Percentile distribution of serum retinyl ester concentrations of adult participants in the third National Health and Nutrition Examination Survey, 1988–19941
 
The median value for serum retinyl esters as a percentage of total vitamin A was <10% in nonusers of supplements containing vitamin A but was close to 10% in most strata of users of supplements containing vitamin A (Table 2Go). The 75th percentile value was >10% in all but one age-and-sex stratum in supplement nonusers and was >10% in all strata of supplement users. The 95th percentile was >15% for all strata of both supplement users and nonusers, although SEE values could not be computed for some strata. The value for serum retinyl esters as a percentage of total vitamin A was higher in women than in men, higher in users of supplements containing vitamin A than in nonusers, and increased with age, by analysis of variance.


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  		TABLE 2. Percentile distribution of serum retinyl esters as a percentage of total serum vitamin A in adult participants in the third National Health and Nutrition Examination Survey, 1988–19941
 
The prevalence of elevated serum retinyl esters, defined as >=244 nmol/L or >10% of total vitamin A, increased with age until the age stratum >=71 y in both men and women (Table 3Go). The prevalence of elevated serum retinyl esters was lower in smokers than in nonsmokers and higher in users than in nonusers of supplements containing vitamin A. Women who did not use exogenous estrogens had a higher prevalence of serum retinyl esters >10% of total vitamin A but not of retinyl esters >=244 nmol/L than did women who used exogenous estrogens. Heavy drinking was not associated with variation in the prevalence of elevated serum retinyl esters.


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  		TABLE 3. Prevalence of serum retinyl ester concentration >=244 nmol/L (7 µg/dL) and prevalence of serum retinyl esters >10% of total serum vitamin A in adult participants in the third National Health and Nutrition Examination Survey, 1988–19941
 
The prevalence of elevated serum markers of liver function was generally low in this sample, with the exception of ALP. The prevalence of elevated ALP concentrations was >10% in all groups except women who used exogenous estrogens and participants who used supplements containing vitamin A (Table 4Go). Men had significantly higher prevalences of elevated ALT and bilirubin than did women, but women had a significantly higher prevalence of elevated LDH than did men. Nonsmokers had a significantly higher prevalence of elevated LDH than did smokers. Heavy drinkers had significantly higher prevalences of elevated ALT, AST, and bilirubin than did other participants but had a significantly lower prevalence of elevated LDH. Women who used exogenous estrogens had significantly lower prevalences of elevated ALP and LDH than did women who did not use exogenous estrogens. Users of supplements containing vitamin A had a significantly lower prevalence of elevated ALP than did nonusers of such supplements.


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  		TABLE 4. Prevalence of elevated liver enzymes and bilirubin in adult participants in the third National Health and Nutrition Examination Survey, 1988–19941
 
In multiple linear regression models predicting the absolute value of serum markers of liver function, we found no significant associations between the concentration or percentage of retinyl esters and the biochemical markers (data not shown). In multiple logistic regression models, we found modest but statistically significant negative associations between percentage retinyl esters and the likelihood of having ALT or AST concentrations above the reference range (data not shown); the odds ratios were 0.99989 (99% CI: 0.99981, 0.99997) and 0.99988 (99% CI: 0.99980, 0.99997), respectively, and both were significant at P < 0.001. Although these are statistically significant associations, primarily because of the large sample size, the clinical significance of associations of this magnitude is negligible.

None of the regression models that tested the associations between retinyl esters and having serum markers of liver function greater than twice the reference range yielded significant results in the total sample (data not shown). In the subsample of participants who used supplements containing vitamin A, the models including the integrated index of supplement use x duration produced no significant associations between retinol-months and any of the serum biochemistry endpoints (data not shown).

We performed receiver operating characteristic analysis in an attempt to find a sample-based cutoff for serum retinyl esters that would be sensitive and specific for the likelihood of having serum markers of liver function above the laboratory reference range or above twice the laboratory reference range. For both concentration and percentage of serum retinyl esters, the analyses indicated that the sensitivity and specificity were negligible for predicting any of the endpoints tested (data not shown).

Eight participants reported taking >=10000 µg RE/d from supplements, although only one of them reported taking >30000 µg RE/d. Only 1 of these 8 individuals had a concentration and percentage of serum retinyl esters above normal. The 5 serum markers of liver function that we examined were within normal limits in all of these participants.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The estimated prevalence of elevated serum retinyl ester concentrations in the US adult population, on the basis of this analysis of NHANES III data, was much higher than expected. Thirty-seven percent of the sample had retinyl esters >10% of total serum vitamin A and 10% of the sample had retinyl esters >15% of total serum vitamin A. We found no significant associations between serum retinyl esters, either as a concentration or as a percentage of total serum vitamin A, and serum concentrations of markers of liver function exceeding the reference ranges. For the 5 serum markers of liver function that we examined, the prevalences of abnormal concentrations were relatively low. However, the prevalence of elevated serum ALP concentrations, considered the most specific marker of liver damage associated with hypervitaminosis A (30, 31), exceeded 10% in the sample, providing adequate statistical power to detect even a modest association with serum retinyl esters. Our search for sample-based cutoffs that might be more appropriate for screening than 244 nmol/L or 10% of total serum vitamin A was not successful.

In some case reports, hypervitaminosis A was accompanied by increases in serum retinyl esters in adults (9, 12, 22). Serum vitamin A concentrations may be within normal limits in the presence of substantially elevated serum retinyl ester concentrations (34). In many case reports, serum vitamin A concentrations were within normal limits in the presence of abnormal serum chemistries or liver pathology attributed to hypervitaminosis A, but retinyl ester concentrations were not reported (10, 30, 35). Case reports are inconsistent in their findings of altered serum biochemistry associated with hypervitaminosis A. In some patients, AST, ALT, ALP, LDH, or bilirubin, or some combination of these markers, was elevated (9–11, 30, 36–40), but in others, serum biochemistry was normal in the presence of elevated serum retinol and retinyl ester concentrations or liver pathology on biopsy attributable to hypervitaminosis A (12, 30, 31, 35, 41–43).

In this analysis, our ability to detect liver abnormality was limited to the standard serum biochemistry panel obtained in NHANES III. We had no direct measures of liver stores of vitamin A and no clinical data on liver pathology such as cirrhosis, fibrosis, Ito cell hyperplasia, or portal hypertension, which may be the first signs of liver injury in hypervitaminosis A (30, 31, 35, 36, 41, 44).

Some students of vitamin A nutriture argue that the US population is exposed to an excess of vitamin A from fortified foods and especially from the enthusiastic and nonchalant use of vitamin supplements (2, 6–8). Several investigators studied longitudinal changes in serum retinol and liver enzyme concentrations during the course of long-term retinol intake from supplements. Krasinksi et al (19) found that retinyl ester concentrations increased significantly across supplement intake categories (<=5000, 5001–10000, and >10000 IU/d) among 562 healthy elderly participants. Retinyl ester concentrations increased less dramatically among 194 healthy young adult participants. Furthermore, the authors found a substantial intake x duration effect among elderly participants, particularly those who took >5000 IU/d for >5 y and who had mean serum retinyl ester concentrations >244 nmol/L. Stauber et al (20) found that 69 healthy elderly participants who used supplements containing retinol for >=5 y had higher serum retinyl ester concentrations than did 47 participants who took no supplements. The authors also found that serum retinyl ester percentage increased with increasing supplement intake, from 6.9% of total serum vitamin A in participants who took <=10000 IU/d (3000 µg RE/d) to 10.3% in those who took >10000 IU/d. They found no increase in the prevalence of liver enzymes above normal values associated with retinol intake. Johnson et al (21) compared 260 postmenopausal women who did not take supplements with 24 women who took 250–5000 µg RE/d; supplement use was not associated with differences in serum retinol or retinyl ester concentrations or liver function test results in their small sample of supplement users. Chemoprevention trials in which participants took 25000 IU retinol/d (7500 µg RE/d) for >3 y showed modest increases in serum retinol and retinyl palmitate concentrations but no increases in the prevalence of elevated AST or ALP concentrations during follow-up periods of up to 3 y (45–47).

In the present analysis of cross-sectional data available for the NHANES III sample, serum retinyl ester concentrations and percentages of retinyl esters were higher in users of supplements containing vitamin A than in nonusers. Because retinol is stored in the liver, cumulative intake may be a better marker of potential risk from supplemental vitamin A than current use of supplements. We attempted to quantify total retinol exposure from supplements with an integrated index that reflected the amount of retinol intake adjusted for duration of intake. We found no association between our estimate of cumulative exposure and serum biochemistry endpoints. In the NHANES III interview, participants were asked to list supplements used in the 30 d before the interview and were then asked for additional information about duration of use for only those nutrients. Some participants who had previously taken vitamin A, perhaps at high dosages and perhaps for long periods, but who had discontinued taking it at the time of the interview, would have been classified as supplement nonusers in this analysis.

Given the inconsistent and possibly idiosyncratic nature of the signs and symptoms of hypervitaminosis A, diagnosis may be difficult and mild hypervitaminosis A may be more common than is generally recognized (41, 43). We cannot estimate the risk of hypervitaminosis A in the US population on the basis of the survey data available. There may be a segment of the population with what Hathcock et al (3) called latent hypervitaminosis A, in which liver stores are very high without elevation of serum vitamin A or retinyl esters or overt symptoms of disease until some insult to the liver precipitates a crisis. Although we cannot rule out the possibility of occult, subclinical liver changes associated with high serum retinyl ester concentrations in this sample, we found no evidence of overt liver dysfunction, even when we used the relatively lenient standard of biochemical markers above the laboratory reference range. We conclude that serum retinyl ester concentrations >=244 nmol/L or >10% of total serum retinol were not reliable screeners for potential hypervitaminosis A in this sample and we could not find other sensitive and specific cutoffs. These results do not negate the usefulness of elevated retinyl esters in confirming hypervitaminosis A in a clinical setting when the diagnosis is suspected because of suggestive clinical signs or symptoms.

Our examination of the distribution of serum retinyl ester concentrations in the NHANES III sample suggests that vitamin A intakes and physiologic retinol status in the population may be approaching what McLaren (6) called luxus levels, ie, intakes in excess of physiologic need that may lead to potentially harmful accumulation. Continued monitoring of serum retinol and retinyl ester concentrations in the population is therefore warranted.


   ACKNOWLEDGMENTS
 
We thank Clifford L Johnson and Cynthia Ogden of the National Center for Health Statistics, Centers for Disease Control and Prevention, for advice and support and for providing data sets for this analysis. We thank Jacqueline D Wright, also of the National Center for Health Statistics, for providing programming guidance in the analysis of nutrient intakes from dietary supplements. We also thank Alicia Carriquiry of the Department of Statistics, Iowa State University, for consultation on the use of SIDE/IML software and Dan Huff, Carolyn Hodge, and Patricia Yeager of the Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, for performing laboratory analyses of serum retinol.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication August 11, 2000. Accepted for publication October 2, 2000.




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