SUMMARY
Objectives
To evaluate the prevalence of and factors associated with abnormal thyroid function in older men with or at risk for HIV infection.
Methods
Cross-sectional analysis of 636 men ≥49 years old including interviews, BMI, HIV-1 serology and viral load, CD4 counts, hepatitis C assays, TSH and free thyroid hormone levels.
Results
Participants were 54% black, 57% overweight/obese, 57% HIV seropositive, and 72% hepatitis C seropositive; 38% reported recent cocaine or heroin use. Decreased TSH was found in 56 (8.8%) and raised TSH in 23 (3.6%). Only three men had abnormal free thyroxine levels.
Conclusions
Abnormal TSH levels were noted in 12.4% of older men with or at risk for HIV infection, but nearly all reflected subclinical hyperthyroidism or subclinical hypothyroidism.
Keywords: epidemiology, endocrine, thyroid function tests, thyroid hormones, thyroid stimulating hormone
INTRODUCTION
Since the availability of highly active antiretroviral therapy (HAART), HIV-related mortality in treated individuals has been decreasing (1). The proportion of older people living with HIV and AIDS has been increasing and persons age fifty years and older now represents more than 24% of people living with HIV/AIDS in the United States (2).
The prevalence of thyroid dysfunction in the adult general population in the United States is considerable. Some 0.3% experience hypothyroidism, 4.3% subclinical hypothyroidism, 0.5% hyperthyroidism, and 0.7% subclinical hyperthyroidism (3,4). Thyroid dysfunction may contribute to morbidity from osteoporosis, hyperlipidemia, cardiovascular disease and neuropsychiatric illness, all of which have been associated with HIV infection or its treatment (5-7). With aging the prevalence of thyroid dysfunction increases (4,8).
Early in the AIDS epidemic, evaluation of thyroid function was performed predominantly on hospitalized patients, who were generally young and acutely ill. Several studies found lower free thyroxine (FT4) levels and higher thyroid binding globulin levels, associated with lower CD4 lymphocyte counts or advanced HIV infection (9-11). More recently, cross-sectional studies among HIV-infected patients showed an increased prevalence of subclinical hypothyroidism, ranging from 3.5-12.2% (12-14). Hypothyroidism has been reported to be to be more prevalent in HIV-infected men than women, different from the gender distribution in the general population, and thyroid dysfunction has been associated with receipt of stavudine, lamivudine, HAART, and low CD4 cell count (12-16). However several of these studies did not include a comparison group of participants without HIV infection nor adjust analyses for possible confounders. Understanding the possible association of thyroid disease with HIV infection, immunodeficiency, and antiretroviral treatment is important to assess the possible need for and benefit of detecting thyroid disease, especially in older persons with HIV infection. A recent review on thyroid function abnormalities in HIV infection concluded that larger studies are needed to examine the epidemiology and health consequences of mild thyroid dysfunction in HIV-infected patients and to better inform screening and treatment guidelines (17).
Therefore, we studied the prevalence of abnormal thyroid function and associated factors in a cohort of older men with or at risk for HIV infection to assess the possible impact of HIV infection, HAART, level of immunodeficiency, and illicit drug use on thyroid function.
METHODS
Study participants
The Cohort of HIV and At Risk Aging Men’s Prospective Study (CHAMPS) recruited 643 men within one year of their fiftieth birthday or older, with or at risk for HIV infection from injection drug use, unprotected sex with men, having 5 or more sexual partners within the last 5 years, exchange of sex for money or drugs, or unprotected sex with a woman who had HIV infection, had injected drugs, or had unprotected sex with a bisexual man or an injection drug user. Men were excluded if they were unable to participate in a detailed standardized interview or unable to provide a blood specimen. Details of CHAMPS patient recruitment and study design have been described previously (18). Standardized interviews gathered information about medical history, medication use, sexual and drug using behaviors, and hospitalizations. Illegal drug use was defined as use of Crack, cocaine, heroin, or speedball by snorting, smoking or injecting. Height and weight were measured. Phlebotomy was performed to measure HIV antibody, HIV viral load, hepatitis C antibody, hepatitis C RNA level, and CD4 lymphocyte count. Thyroid stimulating hormone (TSH) was performed on blood specimens from the baseline visit using the DELFIA ultra test (Perkin Elmer Life and Analytical Sciences, Wallac Oy, Turku, Finland), with a normal range of 0.6-4.2 mU/L. Coefficients of variation were calculated at three levels with 1.7-7.7% intra-assay and 2.6-3.1% inter-assay variation. The FT4 test was performed on specimens that had abnormal TSH levels using the Immulite 2000 (Diagnostic Products Corporation, Los Angeles, CA) test with a normal range of 10-25 pmol/L. The intra-assay coefficient of variation was calculated at six levels for FT4 and ranged from 4.4 to 7.5%. The free tri-iodothyronine (FT3) test was performed on specimens that had a decreased TSH and normal FT4 level using the Immulite 1000 (Diagnostic Products Corporation, Los Angeles, CA) test with a normal range of 3.5-6.5 pmol/L. The intra-assay coefficient of variation was calculated at six levels for FT3 and ranged from 5.8 to 14.1%. Bone mineral density was performed in 554 men at the subsequent research visit scheduled for six months after the baseline visit at which thyroid function tests were performed, as previously reported (5).
Hypothyroidism and hyperthyroidism were defined based on laboratory parameters. Subclinical hypothyroidism was defined as an elevated TSH (>4.2 mU/L) with a normal FT4 level. Subclinical hyperthyroidism was defined as a decreased TSH (<0.6 mU/L) without elevated FT4 or FT3 levels.
All participants provided written informed consent and the study was approved by the Institutional Review Board for the Protection of Human Subjects of Montefiore Medical Center.
Statistical methods/analysis
Univariate analyses were conducted using Wilcoxon rank-sum or Kruskal-Wallis tests for continuous variables and chi-square or Fisher’s exact tests for categorical variables. The outcome variable TSH was analyzed as a categorical measure. Ordinal logistic regression models were used to assess factors associated with abnormal thyroid function. The ordinal outcome variable was defined as decreased, normal, or increased TSH levels. Seven men were excluded from analyses because they reported taking thyroid medication at the time of interview, leaving a sample size of 636. Of the seven men who were excluded, five were receiving thyroid replacement and two were receiving thyroid suppressive therapy. Variables found significant on univariate analysis and those with biological plausibility were entered into multivariate models. Statistical Analyses were performed using STATA software, version 9.2 (StataCorp, College Station, TX) and SAS software, version 9.1 (SAS Institute, Cary, NC).
RESULTS
Characteristics of the cohort at baseline by HIV status are shown in Table I. As previously reported (18), the cohort included predominantly black and Latino men. Among the 362 (57%) HIV infected men, approximately 20% had CD4 counts <200/mm3, 29% had HIV-1 viral loads > 10,000 copies/ml, and 32% were not receiving HAART currently. HIV-infected men were more likely than HIV seronegative men to be black (OR 1.61, 95% CI 1.16-2.23), current nonsmokers, have a lower BMI, have a higher HCV RNA level, and less likely to have ever or recently used heroin, speedball, or cocaine.
TABLE 1.
Participant Characteristics*
| Characteristic | HIV-positive (N=362) | HIV-negative (N=274) | P value† |
|---|---|---|---|
| Age groups | 0.21 | ||
| 49-54 | 213/362 (58.8%) | 153/274 (55.8%) | |
| 55-59 | 96/362 (26.5%) | 71/274 (25.9%) | |
| 60-64 | 42/362 (11.6%) | 32/274 (11.7%) | |
| >64 | 11/362 (3.0%) | 18/274 (6.6%) | |
| Race | 0.03 | ||
| Black | 213/362 (58.8%) | 129/274 (47.1%) | |
| Latino | 83/362 (22.9%) | 78/274 (28.5%) | |
| White | 44/362 (12.2%) | 47/274 (17.2%) | |
| Other | 22/362 (6.1%) | 20/274 (7.3%) | |
| BMI | <0.001 | ||
| < 20 | 29/361(8.0%) | 6/274 (2.2%) | |
| 20 to 25 | 152/361 (42.1%) | 85/274 (31.0%) | |
| > 25 to <30 | 132/361 (36.6%) | 111/274 (40.5%) | |
| ≥ 30 | 48/361 (13.3%) | 72/274 (26.3%) | |
| Current cigarette smoking | 222/362 (61.3%) | 201/274 (73.4%) | 0.001 |
| Alcohol use | 0.35 | ||
| ≥ 2 CAGE questions | 175/346 (50.6%) | 121/259 (46.7%) | |
| Ever used illegal drugs‡ | 315/362 (87.0%) | 259/274 (94.5%) | 0.002 |
| Used illegal drugs‡ in past 5 years | 197/362 (54.4%) | 188/274 (68.6%) | <0.001 |
| Used illegal drugs‡ in past 6 months | 120/362 (33.2%) | 121/272 (44.5%) | 0.004 |
| Hepatitis C antibody seropositive | 254/353 (72.0%) | 192/266 (72.1%) | 0.95 |
| Detectable hepatitis C RNA | 220/337 (65.3%) | 158/253 (62.5%) | 0.35 |
| Ever treated with interferon | 30/360 ( 8.3%) | 20/273 ( 7.3%) | 0.75 |
| Low bone mineral density | 181/327 (55.4%) | 114/227 (50.2%) | 0.23 |
| CD4 lymphocytes/mm3 | |||
| <200 | 70/353 (19.8%) | ||
| 200-499 | 176/353 (49.9%) | ||
| ≥500 | 107/353 (30.3%) | ||
| HIV-1 viral load (copies/ml) | |||
| ≤75 | 140/362 (38.7%) | ||
| 76-1000 | 61/362 (16.9%) | ||
| 1001 -10,000 | 56/362 (15.5%) | ||
| >10,000 | 105/362 (29.0%) | ||
| HAART—current use | 242/354 (68.4%) | ||
| Protease inhibitor | |||
| Ever used | 264/354 (74.6%) | ||
| Use in last 6 months | 174/354 (49.2%) | ||
| Current use | 153/354 (43.2%) |
BMI = body mass index.
Percentages may not total 100% due to rounding or missing data.
P values were obtained by chi-square tests except for hepatitis C RNA level for which Wilcoxon rank-sum test was used.
Crack, cocaine, heroin, speedball by snorting, smoking or injecting.
Of the 636 men, 79 (12.4%) had an abnormal TSH. The prevalence of abnormal thyroid function is shown in Table 2. Decreased TSH was found in 56 (8.8%) and raised TSH in 23 (3.6%). Mean (± standard deviation) TSH value among those with decreased TSH was 0.43 mU/L (± 0.14) and among those with raised TSH was 5.81 mU/L (± 1.59). There was insufficient serum to measure FT4 in one man, so only 78 had a FT4 assayed. Of 55 with decreased TSH, FT4 was increased in one and decreased in one. Of 23 with elevated TSH, one had decreased FT4. Therefore, primary hyperthyroidism, primary hypothyroidism, and secondary hypothyroidism were each found in one man. Subclinical hypothyroidism was present in 3.5% (95% confidence interval [CI] 2.2%-5.2%) of the cohort, while 8.3% (95% CI 6.3%-10.8%) of the men had subclinical hyperthyroidism. Of 53 with decreased TSH and normal FT4 levels, 48 also had FT3 levels performed (five men did not have sufficient sera available) and none were elevated (95% CI 0-7.4%).
TABLE 2.
Prevalence of Abnormal Thyroid Function
| Thyroid Status | No. of Subjects (%) (N=636) |
|---|---|
| Euthyroid | 557 (87.6) |
| Decreased TSH* | 56 (8.8) |
| Subclinical hyperthyroidism | 53 (8.3) |
| Hyperthyroidism (high FT4) | 1 (0.16) |
| Secondary hypothyroidism (low FT4) | 1 (0.16) |
| Raised TSH | 23 (3.6) |
| Subclinical hypothyroidism | 22 (3.5) |
| Hypothyroidism (low FT4) | 1 (0.16) |
One man with decreased TSH did not have FT4 level determined.
The associations of TSH levels with participant characteristics on univariate analysis are shown in Table 3. Decreased TSH level was associated with being black and having used illegal drugs in the past 6 months. Although there was no association of subclinical hypothyroidism with low BMD in the cohort overall, among HIV seronegative men an association of low BMD with subclinical hypothyroidism did not quite achieve statistical significance (P=.06; data not shown). There were no significant associations of abnormal thyroid function with age, alcohol use, hepatitis C antibody status, HCV RNA level, or prior hepatitis C treatment with interferon. Although increased TSH was more common in HIV seropositive men (Odds Ratio 1.44, 95% confidence interval 0.56-3.76), the difference was not significant. CD4 lymphocyte count, HIV viral load, or current HAART or protease inhibitor use.
TABLE 3.
Associations of TSH Levels with Participant Characteristics (Univariate)*
| Participant Characteristic | Number of Men (row percent) | P value | ||
|---|---|---|---|---|
| Decreased TSH (N=56) | Normal TSH (N=557) | Increased TSH (N=23) | ||
| Age groups | 0.37 | |||
| 49-54 | 29/366 (7.9%) | 324/366 (88.5%) | 13/366 (3.6%) | |
| 55-59 | 20/167 (12.0%) | 140/167 (83.8%) | 7/167 (4.2%) | |
| 60-64 | 4/74 (5.4%) | 69/74 (93.2%) | 1/74 (1.4%) | |
| >64 | 3/29 (10.3%) | 24/29 (82.8%) | 2/29 (6.9%) | |
| Race | 0.02 | |||
| Black | 37/342 (10.8%) | 297/342 (86.8%) | 8/342 (2.3%) | |
| Latino | 11/161 (6.8%) | 145/161 (90.1%) | 5/161 (3.1%) | |
| White | 3/91 (3.3%) | 80/91 (87.9%) | 8/91 (8.8%) | |
| Other | 5/42 (11.9%) | 35/42 (83.3%) | 2/42 (4.8%) | |
| Cigarette | 0.09 | |||
| Nonsmoker | 12/213 (5.6%) | 191/213 (89.7%) | 10/213 (4.7%) | |
| Current smoker | 44/423 (10.4%) | 366/423 (86.5%) | 13/423 (3.1%) | |
| Alcohol use | 0.38 | |||
| ≥ 2 CAGE questions | ||||
| No | 27/309 ( 8.7%) | 267/309 (86.4%) | 15/309 ( 4.9%) | |
| Yes | 28/296 ( 9.5%) | 260/296 (88.2%) | 8/296 ( 2.7%) | |
| Used illegal drugs in past 5 years | 0.08 | |||
| No | 15/251 (6.0%) | 229/251 (91.2%) | 7/251 (2.8%) | |
| Yes | 41/385 (10.7%) | 328/385 (85.2%) | 16/385 (4.2%) | |
| Used illegal drugs in past 6 months | 0.003 | |||
| No | 23/393 (5.9%) | 356/393 (90.6%) | 14/393 (3.6%) | |
| Yes | 33/241 (13.7%) | 199/241 (82.6%) | 9/241 (3.7%) | |
| Hepatitis C antibody | 0.63 | |||
| Positive | ||||
| No | 15/173 ( 8.7%) | 154/173 (89.0%) | 4/173 ( 2.3%) | |
| Yes | 38/439 ( 8.7%) | 384/439 (87.5%) | 17/439 ( 3.9%) | |
| Detectable HCV RNA | 0.38 | |||
| No | 27/309 ( 8.7%) | 191/213 (89.7%) | 5/213 ( 2.3%) | |
| Yes | 28/296 ( 9.5%) | 330/381 (86.6%) | 17/381 ( 4.5%) | |
| Ever treated with interferon | 0.51 | |||
| No | 53/586 ( 9.0%) | 513/586 (87.5%) | 20/586 ( 3.4%) | |
| Yes | 3/50 ( 6.0%) | 44/50 (88.0%) | 3/50 ( 6.0%) | |
| BMI | 0.55 | |||
| < 20 | 1/35 (2.9%) | 32/35 (91.4%) | 2/35 (5.7%) | |
| 20 to 25 | 22/237 (9.3%) | 209/237 (88.2%) | 6/237 (2.5%) | |
| > 25 to <30 | 25/243 (10.3%) | 209/243 (86.0%) | 9/243 (3.7%) | |
| ≥ 30 | 8/120 (6.7%) | 106/120 (88.3%) | 6/120 (5.0%) | |
| Bone mineral density | 0.44 | |||
| Low | ||||
| Normal | 24/295 (8.1%) | 259/295 (87.8%) | 12/295 (4.1%) | |
| 25/259 (9.7%) | 228/259 (88.0%) | 6/259 (2.3%) | ||
| HIV status | 0.20 | |||
| Seronegative | 30/274 (11.0%) | 236/274 (86.1%) | 8/274 (2.9%) | |
| Seropositive | 26/362 (7.2%) | 321/362 (88.7%) | 15/362 (4.1%) | |
| CD4 lymphocytes/mm3† | 1.0 | |||
| <200 | 5/70 ( 7.1%) | 62/70 (88.6%) | 3/70 ( 4.3%) | |
| 200-499 | 12/176 ( 6.8%) | 156/176 (88.6%) | 8/176 ( 4.5%) | |
| ≥500 | 8/107 ( 7.5%) | 95/107 (88.8%) | 4/107 ( 3.7%) | |
| Protease inhibitor | 0.65 | |||
| Ever used | ||||
| No | 8/90 (8.9%) | 78/90 (86.7%) | 4/90 (4.4%) | |
| Yes | 16/264 (6.1%) | 237/264 (89.8%) | 11/264 (4.2%) | |
Percentages may not total 100% due to rounding.
Among HIV seropositive subjects
The variables examined in the multivariate ordinal logistic regression analysis were age, race, smoking, drug use in past 6 months, HIV, HCV, and bone mineral density. On multivariate analysis, black race (P=.03) and illegal drug use over the past 6 months (P=.02) were both associated with a decreased TSH.
DISCUSSION
The reported prevalence of thyroid dysfunction in HIV-infected adults has varied. Although previous studies have included participants of varying ages, few have included both older individuals and a demographically and behaviorally similar HIV-negative group for comparison.
Abnormal TSH levels were present in 12.4% of our cohort, with 3.5% and 8.3% showing laboratory abnormalities consistent with subclinical hypothyroidism and subclinical hyperthyroidism, respectively. The 8.3% prevalence of subclinical hyperthyroidism seen is substantially higher than the 0.7% prevalence reported in the general United States population (3,4). Although both hepatitis and interferon therapy have been associated with thyroid disease, and hepatitis C was highly prevalent in this study, we found no significant association of either hepatitis C or self-reported interferon therapy with abnormal function. There was no significant association of either subclinical hypothyroidism or subclinical hyperthyroidism with HIV status itself. The cause of the overall high prevalence of subclinical hyperthyroidism found here is unclear and warrants further study
Some study limitations should be noted. As with any cross-sectional analysis, we were only able to establish associations, not determine causality or subsequent disease progression. We measured FT4 levels only in men with abnormal TSH levels and isolated decreased FT4 levels may occur in some HIV-infected participants (14). Five men with subclinical hyperthyroidism did not have FT3 levels performed. Subclinical hypothyroidism is more prevalent in whites than blacks (3), and white men were underrepresented in our study sample. Although we determined hepatitis C antibody status and whether HCV RNA level was detectable, we did not have transaminase or albumin levels to assess liver inflammation or dysfunction. Participants were older than in most prior studies of persons with HIV infection, but our results should be generalized to the very old with caution since the number of such men was limited. The data on antiretroviral drug use were self-reported and did not contain details about dose, duration, intermittency of therapy, or adherence. Finally, even with more than 600 participants, the power to identify statistically significant differences among outcomes of interest that occur in only a small fraction of participants was limited; larger studies might find additional associations.
The predominant thyroid abnormalities found in this study were subclinical hyperthyroidism and subclinical hypothyroidism. The majority did not deviate dramatically from the normal range with only two men having a TSH <0.1 mU/L and one having a TSH >10 mU/L. Abnormalities of this magnitude are unlikely to progress to overt thyroid disease (19), although this has not been studied prospectively in older persons with HIV infection.
This study suggests that unrecognized thyroid dysfunction is not a major clinical problem for HIV-infected or at risk older men, and at present there is insufficient evidence to suggest a need for routine thyroid test screening in asymptomatic patients with or at risk for HIV infection. Nonetheless, one might consider evaluating blacks and cocaine or heroin users for thyroid disease because of the increased prevalence of thyroid dysfunction in these men. The majority of thyroid abnormalities detected in our cohort would not routinely be treated, and further study is needed to determine factors that might place some of these men at increased risk for clinical thyroid disease.
ACKNOWLEDGEMENTS
This study was supported by a grant (R01DA014998) from the National Institute on Drug Abuse and a Center for AIDS Research grant (P30AI051519) from the National Institute of Allergy and Infectious Diseases. Dr. Wiener was supported by an HIV/AIDS training grant (T32AI007501) from the National Institute of Allergy and Infectious Diseases.
This study was presented, in part, at the XVI International AIDS Conference. August 2006. Toronto, Canada.
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