Abstract
Objective
This study aims to estimate the prevalence of thyroid diseases and anti-TPO status. We searched for an association among presence of immune reconstitution and use of stavudine, didanosine and protease inhibitors with thyroid diseases.
Materials and methods
A cross-sectional study was performed to analyze the records of 117 HIV-infected patients who had their CD4+ cell count, viral load, anti-TPO, TSH and free T4 levels collected on the same day. Immune reconstitution was considered in those whose T CD4+ count was below 200 cells/mm3, but these values increased above 200 cells/mm3 after the use of antiretrovirals. The odds ratio obtained by a 2x2 contingency table and a chi-square test were used to measure the association between categorical variables.
Results
The prevalence of thyroid disease was 34.18%; of these, 4.34% were positive for anti-TPO. There was an association of risk between stavudine use and subclinical hypothyroidism (OR = 4.19, 95% CI: 1.29 to 13.59, X2 = 6.37, p = 0.01). Immune reconstitution achieved protection associated with thyroid disease that was near statistical significance OR = 0.45, 95% CI: 0.19 to 1.04, X2 = 3.55, p = 0.059.
Conclusion
The prevalence of thyroid disease in the sample studied was higher than what had been found in the literature, with a low positive anti-TPO frequency. The historical use of stavudine has an association of risk for the presence of subclinical hypothyroidism, and immune reconstitution has trends towards protection for the presence of thyroid diseases.
AIDS; stavudine; immune reconstitution; thyroid diseases; hypothyroidism
INTRODUCTION
AIDS is an emerging disease and is one of the largest health problems today because of its pandemic status and severity characteristics. This disease is mainly characterized by a progressive loss of CD4+ T lymphocytes (CD4+), which cause immunosuppression and involvement by opportunistic diseases. The natural history of AIDS has been altered considerably by high activity antiretroviral therapy (HAART), which prevents the evolution of the loss of CD4+ to its final stage. Along with prevention campaigns, HAART contributes to the decline of the transmission and stabilization of the epidemic in many countries (11 Miller V, Hodder S. Beneficial impact of antiretroviral therapy on non-AIDS mortality. AIDS. 2014;28(2):273-4.).
Nevertheless, several complications have been reported with the use of HAART, among
them are hypertriglyceridemia, lipodystrophy, type 2 diabetes
mellitus, gonadal dysfunction, and osteoporosis (22 Brockmeyer N, Kreuter A, Bader A, Seemann U, Reimann G. Prevalence
of endocrine dysfunction in HIV-infected men. Horm Res.
2000;54(5-6):294-5.). The mechanism by which HAART causes these changes has not
been fully elucidated (33 Aukrust P, Liabakk NB, Müller F, Lien E, Espevik T, Frøland SS.
Serum levels of tumor necrosis factor (TNF) α and soluble TNF receptors in human
immunodeficiency virus type 1 infection-correlations to clinical, immunologic,
and virologic parameters. J Infect Dis. 1994;169 (2):420-4.
4 Serrano S, Marinoso ML, Soriano JC, Rubies-Prat J, Aubia J, Coll J,
et al. Bone remodelling in human immunodeficiency virus-1 infected patients. A
histomorphometric study. Bone. 1995;16(2):185-91.
5 Pacifici R. Estrogen, cytokines, and pathogenesis of postmenopausal
osteoporosis. J Bone Min Res. 1996;11(8):1043-51.-66 Poli V, Balena R, Fattori E, Markatos A, Yamamoto M, Tanaka H, et
al. Interleukin-6 deficient mice are protected from bone loss caused by estrogen
depletion. EMBO J. 1994;13(5):1189-96.). Another complication is immune reconstitution inflammatory
syndrome (IRIS). This condition occurs in some patients receiving HAART who develop
clinical deterioration by the reestablishment of immunity despite high
CD4+ counts and a low plasma viral load. Immune reconstitution (IR)
can be defined as an increased CD4+ count above 200 cells/mm3
in subjects who previously had CD4+ counts lower than 100-200
cells/mm3 (77 da Silva GAR, Azevedo MCVM, Motta RN, Pinto JFC, Sá CAM, Ferry FRA.
Herpes zoster oftálmico como manifestação de síndrome de reconstituição imune em
um paciente com AIDS. Relato de Caso Cad Bras Med.
2012;25:15-8.).
The development of autoimmune diseases in HIV patients is increasing (88 Reveille JD. The changing spectrum of rheumatic disease in human
immunodeficiency virus infection. Semin Arthritis Rheum.
2000;30(3):147-66.,99 Cuellar ML. HIV infection-associated inflammatory musculoskeletal
disorders. Rheum Dis Clinics N Am. 1998;24(2):403-21.).
HAART promotes increased patient survival and IR, which could be factors that
contribute to autoimmunity. A suggested mechanism of molecular mimesis involves an
opportunistic infectious agent that generates an autoimmunity trigger in IRIS or
immunodeficient patients (1010 Deas JE, Liu LG, Thompson JJ. Reactivity of sera from systemic lupus
erythematosus and Sjogren’s syndrome patients with peptides derived from human
immunodeficiency virus p24 capsid antigen. Clin Diagn Lab Immunol.
1998;5(2):181-5.
11 Shoenfeld Y. Common infections, idiotypic dysregulation,
autoantibody spread and induction of autoimmune diseases. J Autoimmun.
1996;9(2):235-9.-1212 Shoenfeld CY. The viral autoimmunity relationship. Viral Immunol.
1995;8(1):1-9.). In immunodeficient patients, as soon as
the CD4+ cells are depleted, autoimmune diseases can be mediated by
CD8+ T lymphocytes (1313 Zandman-Goddard G, Shoenfeld Y. HIV and autoimmunity. Autoimmun Rev.
2002;1(6):329-37.).
It is possible to relate the stages of HIV infection with the development of autoimmune diseases, which may arise during an acute viral infection (phase I). Autoimmune diseases also occur at the stage of clinical latency, and even without the overt manifestation of AIDS, there is a progressive decline of CD4+ cells (phase II). When the CD4+ count becomes profoundly low, autoimmune diseases related to CD4+ cells are more difficult to develop (phase III). After the initiation of HAART, IR occurs with increased CD4+ cells in addition to altered immune regulation, which may lead to autoimmune disease (stage IV) (1313 Zandman-Goddard G, Shoenfeld Y. HIV and autoimmunity. Autoimmun Rev. 2002;1(6):329-37.).
HIV-infected patients have a high overall frequency of autoantibodies, which may be
generated as a direct effect of the virus in the endothelium, synovial fluid and
hematopoietic cells, leading to the enchantment of the cytotoxic activity of immune
cells and autoantigen expression. Increased autoantibody expression, in most cases,
is associated with lower CD4+ cell counts and increased mortality without
a relationship with the clinical expression of autoimmune diseases (1313 Zandman-Goddard G, Shoenfeld Y. HIV and autoimmunity. Autoimmun Rev.
2002;1(6):329-37.,1414 Massabki PS, Accetturi C, Nishie IA, da Silva NP, Sato EI, Andrade
LE. Clinical implications of autoantibodies in HIV infection. AIDS.
1997;11(15):1845-50.).
Graves’ disease, rheumatoid arthritis and, rarely, Hashimoto’s thyroiditis were
reported as complications of IR (1515 Crum NF, Ganesan A, Johns ST, Wallace MR. Graves’ disease: an
increasingly recognized immune reconstitution syndrome. AIDS.
2006;20(3):466-9.
16 Hoffman CJ, Brown TT. Thyroid function abnormalities in HIV infected
patients. Clin Infect Dis. 2007;45(4):488-94.-1717 Bell C, Nelson M, Kaye S. A case of immune reconstitution rheumatoid
arthritis. Int J STD AIDS. 2002;13(8):580-1.).
Specifically in autoimmune thyroid disease, the prevalence of primary hypothyroidism
in AIDS is higher compared with the general population; however, it is not
necessarily associated with autoimmunity. The most common cause of primary
hypothyroidism in the population is Hashimoto’s thyroiditis, which has a prevalence
of 0.3% (1818 Golden SH, Robinson KA, Saldanha I, Anton B, Ladenson PW. Prevalence
and incidence of endocrine and metabolic disorders in the United States: a
comprehensive review. J Clin Endocrinol Metab.
2009;94(6):1853-78.,1919 Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW,
Spencer CA. Serum TSH, T(4), and thyroid antibodies in the United States
population (1988 to 1994): National Health and Nutrition Examination Survey
(NHANES III). J Clin Endocrinol Metab. 2002;87(2):489-99.). Among HIV-infected individuals, the prevalence of primary
hypothyroidism is approximately 2.6% (2020 Beltran S, Lescure FX, El Esper I, Schmit JL, Desailloud R.
Subclinical hypothyroidism in HIV infected patients is not an autoimmune
disease. Horm Res. 2006;66(1):21-6.
21 Madge S, Smith CJ, Lampe FC, Thomas M, Johnson MA, Youle M, et al.
No association between HIV disease and its treatment and thyroid function. HIV
Med. 2006;8(1):22-7.-2222 Noureldeen A, Qusti SY, Khoja GM. Thyroid function in newly
diagnosed HIV-infected patients. Toxicol Ind Health. 2014;30(10):
919-25.).
The prevalence of subclinical hypothyroidism in patients infected with HIV who were not treated varies between 8% and 10%, with a higher propensity in men. Among HAART users, the prevalence reaches up to 12.6%. Naive patients have a higher prevalence of subclinical hypothyroidism shortly after beginning HAART compared with those who have already been on HAART for at least 1 year, suggesting that thyroid dysfunction associated with medication is acute (2323 Parsa AA, Bhangoo A. HIV and thyroid dysfunction. Rev Endocr Metab Disord. 2013;14(2):127-31.).
A possible manifestation of hypothyroidism in AIDS is dysfunction in the basal
secretion of thyroid stimulating hormone (TSH) or central hypothyroidism. The
evaluation of TSH in patients with HIV demonstrates a significant reduction of the
nocturnal peak at midnight, which is considered to be a sensitive index for
evaluating central hypothyroidism (2424 Spinola-Castro AM, Siviero-Miachon AA, da Silva MTN, Guerra-Junior
G. O papel do hormônio de crescimento no tratamento dos distúrbios
endócrino-metabólicos do paciente com a síndrome da imunodeficiência adquirida
(Aids). Arq Bras Endocrinol Metab. 2008;52(5):818-32.).
Another manifestation consistent with central dysfunction is the presence of
isolated low levels of TSH with normal free T4 (FT4). This
condition was found in 1.3 to 6.8% of HIV-infected individuals, especially those in
advanced disease stages (2020 Beltran S, Lescure FX, El Esper I, Schmit JL, Desailloud R.
Subclinical hypothyroidism in HIV infected patients is not an autoimmune
disease. Horm Res. 2006;66(1):21-6.,2525 Madeddu G, Spanu A, Chessa F, Calia GM, Lovigu C, Solinas P, et al.
Thyroid function in human immunodeficiency virus patients treated with highly
active anti-retroviral therapy (HAART): a longitudinal study. Clin Endocrinol.
2006;64(4):375-83.
26 Sellmeyer DE, Grrunfeld C. Endocrine and metabolic disturbances in
human immunodeficiency virus infection and the acquired immune deficiency
syndrome. Endocr Rev. 1996;17(5):518-32.
27 Dobs AS, Dempsy MA, Ladenson PW, Polk BF. Endocrine disorders in men
infected with the human immunodeficiency virus. Am J Med. 1988;84(3 Pt
2):611-6.-2828 Raffi F, Brisseau JM, Planchon B, Rémi JP, Barrier JH, Grolleau JY.
Endocrine function in 98 HIV infected patients: a prospective study. AIDS.
1991;5(6):729-33.).
However, administration of exogenous TSH releasing hormone (TRH) did not alter the
response of TSH among individuals with low FT4, making hypothalamic or
pituitary insufficiency the least likely scenario (2929 Calza L, Manfredi R, Chiodo F. Subclinical hypothyroidism in
HIV-infected patients receiving highly active antiretroviral therapy. J Acquir
Immune Defic Syndr. 2002;31(3):361-3.). Therefore, the clinical significance of a low FT4 levels
is not clear because these patients did not experience a higher frequency of
hypothyroidism symptoms compared with control subjects. Thyroid function tests may
be requested annually, but levothyroxine therapy is not recommended (3030 Merenich J, McDermott T, Asp A, Harrison SM, Kidd GS. Evidence of
endocrine involvement early in the course of human immunodeficiency virus
infection. J Clin Endocrinol Metab. 1990;70(3):566-71.).
Euthyroid sick syndrome is characterized by normal or low FT4 levels, low T3 levels, elevated reverse T3 (rT3) levels and low or normal TSH levels (3131 LoPresti JS, Fried JC, Spencer CA, Nicoloff JT. Unique alterations of thyroid hormone indices in the acquired immunodeficiency syndrome. Ann Intern Med. 1989;110(12):970-5.). This is a physiological adaptive phenomenon of the body to conserve energy during periods of extreme stress and during an infection. HIV-infected patients characteristically have increased resting energy expenditure combined with a loss of appetite and subsequent weight loss. The mechanism involved is the reduction in peripheral conversion of T4 to T3, with accumulation of the inactive metabolite rT3. The degree of rT3 elevation and T3 and T4 suppression depends on the severity of the disease or stress. The euthyroid sick syndrome recovery phase can be observed with a transient increase in TSH and normal FT4 and T3 levels. Before the HAART era, this disturbance was a common feature of terminal phase AIDS patients (3232 Hoffman CJ, Brown TT. Thyroid function abnormalities in HIV infected patients. Clin Infect Dis. 2007;45(4):488-94.).
Thyroid dysfunction among HIV-infected individuals after HAART had an increased prevalence and is linked in most cases to asymptomatic patients, particularly those with subclinical hypothyroidism. Although the mechanism is not clear, stavudine has been suggested as a direct intervening agent in the production and/or metabolism of thyroid hormones, suggesting the need for monitoring thyroid function in HIV patients who have been treated with this medicine (2525 Madeddu G, Spanu A, Chessa F, Calia GM, Lovigu C, Solinas P, et al. Thyroid function in human immunodeficiency virus patients treated with highly active anti-retroviral therapy (HAART): a longitudinal study. Clin Endocrinol. 2006;64(4):375-83.,2828 Raffi F, Brisseau JM, Planchon B, Rémi JP, Barrier JH, Grolleau JY. Endocrine function in 98 HIV infected patients: a prospective study. AIDS. 1991;5(6):729-33.,2929 Calza L, Manfredi R, Chiodo F. Subclinical hypothyroidism in HIV-infected patients receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2002;31(3):361-3.). Drug interactions between protease inhibitors and levothyroxine have also been reported through a shared glucuronidation metabolic pathway. The frequency and clinical impact of these interactions are not known (3333 Touzot M, Le Beller C, Touzot F, Lou M, Piketty C. Dramatic interaction between levothyroxine lopinavir/ritonavir in an HIV-infected patient. AIDS. 2006;20(8):1210-2.).
MATERIALS AND METHODS
Cross-sectional studies analyzed the medical records of HIV-infected patients on regular outpatients at follow-up in the Immunology Service of the Gaffrée Guinle University Hospital (HUGG), Federal University of the State of Rio de Janeiro (UNIRIO) and were approved by the institution’s Ethics in Research Committee.
A total of 421 medical records were reviewed from all of the patients who attended the hospital from March 2013 through August 2013. Of these, 117 records met the inclusion criteria, which included CD4+ cell counts; HIV viral load; and anti-TPO, TSH and FT4 levels from the same sample. All of the records had information about the age, gender, date of HIV infection diagnosis and HAART history. The exam results were dated from 2012 or 2013. Patients were demonstrably infected with HIV, aged between 18 and 65 years and were submitted or not to HAART. Because TSH and FT4 levels are not routine tests for HIV patients, 304 records were excluded because of a lack of thyroid function data. A relative sample loss occurred in 17 patients who did not have anti-TPO records. The final sample consisted of 117 patients with complete data and 100 patients with incomplete data because of a lack of anti-TPO results. The database was stored in files from SPSS 17 and in files from Excel 2007.
Patients whose CD4+ counts were below 200 cells/mm3 but the values of which increased above 200 cells/mm3 after HAART were included in the IR group. The reference range for TSH was established as normal between 0.5 to 4.5 μUI/L, increased > 4.5 μUI/L, and decreased < 0.5 μUI/L. The reference range for FT4 was established as normal between 0.8 to 1.9 ng/dL, increased > 1.9 ng/dL, and decreased < 0.9 ng/dL. Anti-TPO levels were classified as normal if they were below 35 μUI/mL.
Descriptive analyses (means and frequencies) were analyzed using SPSS 17 software. Association measurements among categorical variables, such as the use of stavudine, didanosine and protease inhibitors, and the presence of IR and thyroid diseases were analyzed in a 2x2 contingency table by measuring the odds ratio (OR). We performed the uncorrected chi-square test (X2) using the significance value (α) of 0.05 and degrees of freedom = 1, which corresponded to a critical value of 3.84. The Epi Info 7 program was used for this statistical analysis.
RESULTS
After a descriptive and frequency evaluation, the results regarding gender, age, time since diagnosis and antiretroviral status are demonstrated in table 1. The mean CD4+ cell count did not differ between the groups, which were ranked according to thyroid dysfunction and measured by TSH levels according to the data contained in table 2.
Among 100 patients, 4% had increased anti-TPO (1% were diagnosed as subclinical hypothyroidism, 1% as secondary hyperthyroidism, and 2% had normal TSH and FT4).
Using the 117 patients selected for an unrelated anti-TPO analysis, thyroid disease diagnoses, as measured by thyroid function tests and frequency analyses, are contained in table 3.
By analyzing the contingency table and applying the chi-square test, we can identify a not statistically significant association with previous or current stavudine use and thyroid disease (OR = 2.23, 95%CI: 0,84 to 5.93, X2 = 2.68, p = 0.1). An analysis within the subclinical hypothyroidism group and according to current stavudine use demonstrated a statistically significant risk association (OR = 4.19, 95%CI: 1.29 to 13.59, X2 = 6.37, p = 0.01). The same analysis demonstrated no statistically significant association for the primary hypothyroidism (OR = 0.67, 95%CI: 0.07 to 5.82, X2 = 0.12, p = 0.72) and pituitary/central hypothyroidism or euthyroid sick syndrome group (OR = 1.25, 95%CI: 0.31 to 4.91, X2 = 0.1, p = 0.74).
By analyzing the contingency table and applying the chi-square test, we could not identify a statistically significant association with previous or current didanosine use on the presence of thyroid disease (OR = 1.64, 95%CI: 0,64 to 4.16, X2 = 1.09, p = 0.29). Analysis within the subclinical hypothyroidism group and a previous or current history of didanosine use demonstrate an insignificant association (OR = 2.33, 95%CI: 0.71 to 7.65, X2 = 2.03, p = 0.15). The same analysis for the primary hypothyroidism (OR = 0.56, 95%CI: 0.06 to 4.83 X2 = 0.27, p = 0.59), pituitary/central hypothyroidism or euthyroid sick syndrome groups resulted in an insignificant association (OR = 1.58, 95%CI: 0.45 to 5.53 X2 = 0.53, p = 0.46).
The calculations relating to prior or current protease inhibitor use in the presence of thyroid disease was not significant (OR = 0.64, 95%CI: 0.29 to 1.40, X2 = 1.19 p = 0.27). The analysis within the subclinical hypothyroidism group and a history of previous or current protease inhibitor use had an insignificant association (OR = 0.72, 95%CI: 0.23 to 2.17, X2 = 0.33 p = 0.56). The same analysis for the primary hypothyroidism (OR = 0.35, 95%CI: 0.06 to 1.82, X2 = 1.66, p = 0.19) and pituitary/central hypothyroidism or euthyroid sick syndrome groups (OR = 0.98, 95%CI: 0.33 to 2.91, X2 = 0.0008 p = 0.97) resulted in a not significant association.
Statistical analyses were used to identify a protection association between IR and thyroid disease that was close to statistical significance (OR = 0.45, 95% CI: 0.19 to 1.04, X2 = 3.55, p = 0.059). Individually, for each type of thyroid disease, there was an insignificant association for subclinical hypothyroidism (OR = 0.51, 95% CI: 0.15 to 1.74, X2 = 1.15, p = 0.28), statistically insignificant association from primary hypothyroidism (OR = 0.92, 95% CI: 0.2 to 4.05 X2 = 0.01, p = 0.91) and from pituitary/central hypothyroidism or euthyroid sick syndrome (OR = 0.51, 95% CI: 0.15 to 1.74, X2 = 1.15, p = 0.28). The contingency table for the calculations based on different categorical variables is demonstrated in table 4.
DISCUSSION
Cross-sectional studies have the limitation of not assessing a cause and effect relationship. The proposed study aims to evaluate only associative measures between the categorical variables of IR, use of stavudine, didanosine, and protease inhibitors in the presence of thyroid disease. These antiretrovirals were chosen based on previous publications and by the HAART profile, which was used in the hospital where the study was performed. The sample of HAART users as a whole had a history of using zidovudine and lamivudine, and these patients were excluded from the analysis.
Among HIV-infected individuals, approximately 1% to 2% has symptomatic thyroid
disease, and up to 35% may have only subtle abnormalities in thyroid function tests
(2323 Parsa AA, Bhangoo A. HIV and thyroid dysfunction. Rev Endocr Metab
Disord. 2013;14(2):127-31.). In this study, 6.83% of patients
had TSH values greater than 4.5 μUI/L and FT4 values less than 0.9 ng/dL,
which characterized them with primary hypothyroidism. These values were above the
averages that had been published previously for HIV-infected individuals, in whom
the prevalence was estimated from 2.6% up to 0.3% when compared with the general
population (1919 Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW,
Spencer CA. Serum TSH, T(4), and thyroid antibodies in the United States
population (1988 to 1994): National Health and Nutrition Examination Survey
(NHANES III). J Clin Endocrinol Metab. 2002;87(2):489-99.). Subclinical hypothyroidism
is characterized by slightly elevated TSH and normal FT4 levels. In the
present study, 12.82% of patients had these characteristics, which kept this result
above the average prevalence among HIV-infected persons of 3.5% to 12.2% (2020 Beltran S, Lescure FX, El Esper I, Schmit JL, Desailloud R.
Subclinical hypothyroidism in HIV infected patients is not an autoimmune
disease. Horm Res. 2006;66(1):21-6.
21 Madge S, Smith CJ, Lampe FC, Thomas M, Johnson MA, Youle M, et al.
No association between HIV disease and its treatment and thyroid function. HIV
Med. 2006;8(1):22-7.-2222 Noureldeen A, Qusti SY, Khoja GM. Thyroid function in newly
diagnosed HIV-infected patients. Toxicol Ind Health. 2014;30(10):
919-25.).
This result was elevated with respect to the overall population, for which the
prevalence is 4.3% (1919 Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW,
Spencer CA. Serum TSH, T(4), and thyroid antibodies in the United States
population (1988 to 1994): National Health and Nutrition Examination Survey
(NHANES III). J Clin Endocrinol Metab. 2002;87(2):489-99.). We can link this
response to the genetic and environmental profiles of the study population, issues
related to the HIV genotype, or HAART profile history in the sample. Another
possible reason is the lack of a definition in the literature relating the TSH
baseline and ultrasensitive detection assay development. Further analysis of these
assumptions may elucidate a mechanism for the high prevalence of primary
hypothyroidism in this population.
Another important finding was the prevalence of > 34 μUI/L anti-TPO in 4% of patients who had anti-TPO measurements. From all of the patients who had anti-TPO measurements, 1% had increased TSH with normal FT4 levels (subclinical hypothyroidism). In the other 1%, we identified isolated increased FT4 (secondary hyperthyroidism) levels, and another 2% had normal thyroid function. In the general population, hypothyroidism is most commonly caused by autoimmune thyroid destruction, in which 90% of cases were anti-TPO positive (3434 Saravanan P, Dayan CM. Assessment of thyroid function disease: thyroid autoantibodies. Endocrin Metab Clin. 2001;30(2):315-37.). In our study, only one of 23 patients was diagnosed with hypothyroidism or subclinical hypothyroidism and had positive anti-TPO values (4.34%). This value is below what is expected for the general population and gives consistency to the scientific evidence that HIV-infected patients with primary hypothyroidism have lower anti-TPO positivity (2020 Beltran S, Lescure FX, El Esper I, Schmit JL, Desailloud R. Subclinical hypothyroidism in HIV infected patients is not an autoimmune disease. Horm Res. 2006;66(1):21-6.,3232 Hoffman CJ, Brown TT. Thyroid function abnormalities in HIV infected patients. Clin Infect Dis. 2007;45(4):488-94.). The absence of anti-TPO does not mean that the patients do not have thyroid autoimmune disease. Tissue biopsies and imaging tests, such as an ultrasound, are necessary to identify whether patients with anti-TPO also demonstrate an absence of lymphocytic infiltration and heterogeneous aspects of the gland, which are characteristic of Hashimoto’s thyroiditis.
The onset of Graves’ disease appears to be possible after the IR. There are few case reports of Hashimoto’s thyroiditis that developed after initiating HAART (3535 Rosenfeld CR, Calabrese LH. Progression of autoimmune thyroiditis in an HIV-infected woman on HAART. AIDS Read. 1999;9(6):393-4.). In the present study, there was an association of protection that was very close to reaching statistical significance that was related to thyroid disease in the presence of IR history. This trend suggests that most thyroid dysfunction in AIDS cases are not immune-mediated but are related to specific antiretroviral drugs and the presence of disease activity as in the euthyroid sick syndrome.
The use of stavudine has been associated with subclinical hypothyroidism in a few studies. In one prospective study, abnormalities in thyroid function were found in 12.6%. Patients on stavudine had significantly lower FT4 levels with prolonged treatment (2525 Madeddu G, Spanu A, Chessa F, Calia GM, Lovigu C, Solinas P, et al. Thyroid function in human immunodeficiency virus patients treated with highly active anti-retroviral therapy (HAART): a longitudinal study. Clin Endocrinol. 2006;64(4):375-83.). In other study, the prevalence of subclinical hypothyroidism was 12.2% and the previous use of PI, especially stavudine, had a statistically significant risk association for hypothyroidism when compared to naïve patients (p < 0.05) (2929 Calza L, Manfredi R, Chiodo F. Subclinical hypothyroidism in HIV-infected patients receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2002;31(3):361-3.). As in the previously cited studies, an association of risk was observed among the historical use of stavudine and subclinical hypothyroidism OR = 4.19, 95%CI: 1.29 to 13.59, X2 = 6.37, p = 0.01). The underlying mechanisms involved in this association are unclear and deserve further investigation. The association analysis between stavudine use and thyroid diseases (general thyroid diseases, pituitary/central hypothyroidism, euthyroid sick syndrome, secondary hyperthyroidism, primary hypothyroidism or subclinical hyperthyroidism) was not statistically significant.
Isolated low FT4 levels with normal or low TSH levels are frequently
observed among HIV-infected individuals with a prevalence of 1.3% to 6.8% (2020 Beltran S, Lescure FX, El Esper I, Schmit JL, Desailloud R.
Subclinical hypothyroidism in HIV infected patients is not an autoimmune
disease. Horm Res. 2006;66(1):21-6.,2626 Sellmeyer DE, Grrunfeld C. Endocrine and metabolic disturbances in
human immunodeficiency virus infection and the acquired immune deficiency
syndrome. Endocr Rev. 1996;17(5):518-32.
27 Dobs AS, Dempsy MA, Ladenson PW, Polk BF. Endocrine disorders in men
infected with the human immunodeficiency virus. Am J Med. 1988;84(3 Pt
2):611-6.-2828 Raffi F, Brisseau JM, Planchon B, Rémi JP, Barrier JH, Grolleau JY.
Endocrine function in 98 HIV infected patients: a prospective study. AIDS.
1991;5(6):729-33.). Within these results, the
value in our study was higher than the average because 11.96% of patients had normal
TSH and low FT4 levels. In some cases, euthyroid sick syndrome or
pituitary or hypothalamus failure can lead to central hypothyroidism (secondary or
tertiary). In such cases, FT4 concentrations are low, and TSH
concentrations can be low or in the normal range.
In patients with low thyroid hormone levels and normal or low TSH (1 patient = 0.85%)
levels, pituitary/central hypothyroidism or euthyroid sick syndrome needs to be
considered. Euthyroid sick syndrome occurs during severe illnesses, including
advanced AIDS, where the most common pattern of thyroid function is reduced
T3 levels, high rT3 levels, varying FT4 levels,
and normal or decreased TSH levels, depending upon disease severity. However, a
smaller increase of rT3 levels was observed among patients with advanced
AIDS (3333 Touzot M, Le Beller C, Touzot F, Lou M, Piketty C. Dramatic
interaction between levothyroxine lopinavir/ritonavir in an HIV-infected
patient. AIDS. 2006;20(8):1210-2.). During disease recovery, TSH
levels may increase temporarily, sometimes exceeding the normal range, thus
returning FT4 and T3 levels to normal values, mimicking
subclinical hypothyroidism. Among the HIV-infected population, the highest frequency
of thyroid disease was reported in patients with terminal AIDS before HAART, with up
to 16% of patients affected (3030 Merenich J, McDermott T, Asp A, Harrison SM, Kidd GS. Evidence of
endocrine involvement early in the course of human immunodeficiency virus
infection. J Clin Endocrinol Metab. 1990;70(3):566-71.). In this
study, TSH and FT4 levels were obtained in low levels in only one patient
(0.85%). rT3 measurement in individuals that are not suspected of having thyroid
disease is not recommended and was not performed. The sum of patients with normal or
low TSH and low FT4 levels totaled 15 (12.82%), which was higher than
expected for HIV (1.3% to 6.8%) (2020 Beltran S, Lescure FX, El Esper I, Schmit JL, Desailloud R.
Subclinical hypothyroidism in HIV infected patients is not an autoimmune
disease. Horm Res. 2006;66(1):21-6.,2626 Sellmeyer DE, Grrunfeld C. Endocrine and metabolic disturbances in
human immunodeficiency virus infection and the acquired immune deficiency
syndrome. Endocr Rev. 1996;17(5):518-32.
27 Dobs AS, Dempsy MA, Ladenson PW, Polk BF. Endocrine disorders in men
infected with the human immunodeficiency virus. Am J Med. 1988;84(3 Pt
2):611-6.-2828 Raffi F, Brisseau JM, Planchon B, Rémi JP, Barrier JH, Grolleau JY.
Endocrine function in 98 HIV infected patients: a prospective study. AIDS.
1991;5(6):729-33.).
We conclude that the prevalence of thyroid disease in the sample studied was higher than what had been found in the literature, with a low positive anti-TPO frequency. The historical use of stavudine has an association of risk for the presence of subclinical hypothyroidism, and IR has a protection association close to statistical significance for the presence of thyroid diseases.
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Financial support: there was no financial support for this work.
Publication Dates
-
Publication in this collection
Apr 2015
History
-
Received
28 Aug 2014 -
Accepted
12 Dec 2014