Thyroid Function Abnormalities among Patients with HIV/AIDS in South-Western Nigeria

Adesegun O

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OJHAS Vol. 18, Issue 1: (January-March 2019)

Original Article
Thyroid Function Abnormalities among Patients with HIV/AIDS in South-Western Nigeria

Authors:
Akolade O. Idowu, Department of Internal Medicine, Benjamin S. Carson School of Medicine, Babcock University Ilishan-Remo, Ogun State, Nigeria, Department of Internal Medicine, Babcock University Teaching Hospital Ilishan-Remo, Ogun State, Nigeria,
Olatunde Odusan, Department of Internal Medicine, Obafemi Awolowo College of Health Sciences, Olabisi Onabanjo University, Sagamu, Ogun State, Nigeria,
Olatunbosun Olawale, Department of Chemical Pathology, Olabisi Onabanjo University Teaching Hospital, Sagamu, Ogun State, Nigeria,
Theophilus Ajiro, Department of Internal Medicine, Babcock University Teaching Hospital Ilishan-Remo, Ogun State, Nigeria,
Oluwaseyitan Adesegun, Department of Internal Medicine, Babcock University Teaching Hospital Ilishan-Remo, Ogun State, Nigeria,
Ayokunle Osonuga, Department of Internal Medicine, Babcock University Teaching Hospital Ilishan-Remo, Ogun State, Nigeria,
Olumide Abiodun, Department of Community Medicine, Benjamin S. Carson School of Medicine, Babcock University Ilishan-Remo, Ogun State, Nigeria, and Center for Epidemiology and Clinical Research, Sagamu, Nigeria.

Address for Correspondence
Oluwaseyitan Adesegun,
Department of Internal Medicine, Babcock University Teaching Hospital,
Ilishan-Remo,
Ogun State, Nigeria.
E-mail: oluwaseyitanaadesegun@gmail.com.

Citation
Idowu AO, Odusan O, Olawale O, Ajiro T, Adesegun O, Osonuga A, Abiodun O. Thyroid Function Abnormalities among Patients with HIV/AIDS in South-Western Nigeria. Online J Health Allied Scs. 2019;18(1):6. Available at URL: https://www.ojhas.org/issue69/2019-1-6.html

Submitted: Mar 8, 2019; Accepted: Apr 11, 2019; Published: Apr 30, 2019

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This work is licensed under a Creative Commons Attribution-No Derivative Works 2.5 India License

Abstract: Sub-Saharan Africa accounts for a huge proportion of the global burden of Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS). However, there is paucity of local studies assessing thyroid dysfunction among HIV/AIDS patients in Sub-Saharan Africa. The purpose of this study was to determine the prevalence, severity and correlates of thyroid function abnormalities among HIV positive patients. We recruited 300 participants for this study conducted at a tertiary hospital in Nigeria. One Hundred were HIV positive on HAART, another 100 were HIV positive but HAART-naīve and the remaining 100 participants that served as control were apparently healthy HIV negative individuals. Venous blood samples were collected from all the study groups for quantitative determination of Thyrotropin and free thyroid hormones, while thyroid autoantibodies were assayed in the two HIV positive study groups. The prevalence of thyroid function abnormalities among HIV positive subjects from this study was 33%. The mean free triiodothyronine (FT3) and free Thyroxine (FT4) were lowest in the HIV positive HAART naīve group (p<0.05). Correspondingly thyroid autoantibodies and CD4 counts were also significantly lower in HAART naīve group (p<0.05). In conclusion, abnormal thyroid function tests are common findings among HIV positive subjects, which is a more frequent occurrence among HIV positive HAART naīve subjects who usually present at CD4 nadirs with concurrently low thyroid hormone levels.
Key Words: Thyroid Function Test, Human Immunodeficiency Virus (HIV), Free T4, Free T3, Thyrotropin, Nigeria

Introduction:

Human Immunodeficiency Virus (HIV) infection affects multiple systems in the body among which is the endocrine system, with gonadal, adrenal and thyroid gland dysfunctions commonly reported among HIV positive patients(1). Endocrine functions of the affected organs, may be altered in these individuals for the following reasons; the direct invasion of the glands by the HIV, the destruction of the glands by opportunistic pathogens (e.g. Pneumocystis jirovecii or cytomegalovirus), the invasion of the glands by tumors (e.g. Kaposi sarcoma and lymphoma), systemic complications, and adverse effects of medications used in the treatment of these disorders (2,3). A previous study has shown that chronic illnesses associated with malnutrition or chronic tissue inflammation seen in HIV positive individuals can cause abnormalities in thyroid function(4). An earlier study done on the thyroid functional status of subjects with HIV/AIDS showed that just 6.3% of HIV positive subjects manifested overt thyroid disease, while subtle abnormalities of thyroid function were more prevalent(5).

The abnormalities of thyroid function that have been identified among patients infected with HIV include: overt hypothyroidism, subclinical hypothyroidism, Graves disease, subclinical hyperthyroidism, Isolated low free T4 (FT4), Isolated low free T3 (FT3), acute suppurative thyroiditis, and sick euthyroid syndrome (non-thyroidal illness). Thyroid hormones are crucial for optimal function of the immune system (6). A study conducted in southern Nigeria found that seropositive subjects who progressed to clinical AIDS, were more likely to be hypothyroid while HIV negative subjects were more likely to have normal or abnormally high thyroid hormone levels(7). This was similar to a finding of lower thyroid hormone levels in HIV positive patients compared to HIV negative controls in another study(4). A study carried out by Unachukwu et al. in southeast Nigeria, found the prevalence of sick euthyroid syndrome and subclinical hypothyroidism to be 48% and 3.5-12.2% respectively among patients with advanced AIDS(8).

With the advent of highly active antiretroviral therapy (HAART), there has been significant progress in the management of HIV infection. However, the drugs have numerous adverse effects of which thyroid dysfunction has been reported(5). Autoimmunity in patients infected with HIV may occur due to loss of immune competence and after commencement of HAART(9). Autoimmunity resulting from immune reconstitution after commencement of HAART has been recognized as an unfavorable event in HIV positive patients (10).

Most of the studies conducted previously did not assay for thyroid autoantibodies, which could have been helpful in elucidating the important role of HAART in HIV positive patients with thyroid function abnormalities. They also did not establish whether thyroid hormone status of these patients is a primary factor or surrogate marker for disease progression in HIV/AIDS.
The aim of this study was to assess the prevalence of thyroid function abnormalities in HIV positive subjects, and investigate if there is any relationship between these abnormalities and the severity of HIV infection. The ultimate goal is to increase the awareness of clinicians in our setting and beyond, towards improving the quality of care and by extension quality of life of people living with HIV/AIDS.

Materials and Methods

Study Setting
The study was conducted at the Institute of Human Virology Nigeria (IHVN) Treatment Centre at the Olabisi Onabanjo University Teaching Hospital (OOUTH), Sagamu, Ogun State, Nigeria. The institute is an annex of the primary institute in Annapolis, Maryland United States of America. It provides free HIV/AIDS screening and care within the community, neighbouring towns and adjoining states.

The IHVN clinic runs four times per week with an average of five newly diagnosed HIV positive patients per clinic day.

Study Design
This was a cross-sectional comparative hospital based study.

Recruitment of Subjects
We recruited 300 subjects into the study. A hundred of them were HIV positive patients who had been on HAART for a minimum period of six months recruited consecutively at the IHVN treatment centre of OOUTH. We recruited another study group comprising 100 HAART naīve patients who we matched for age and sex from the same centre.

A control group comprising of 100 apparently healthy HIV negative subjects were recruited from the HIV Counseling and Testing (HCT) unit of OOUTH. We also matched the control group for age and sex.

Subjects aged 18 years and above who gave informed consent and were confirmed to have HIV infection by Western Blot test from the IHVN clinic were included in the study.

All subjects from the three study groups did not have pre-existing thyroid abnormalities, had not undergone previous thyroid surgery, and were not on any medication that could affect thyroid function. Pregnant women and very ill HIV positive individuals were excluded from the study.

Ethical consideration
Approval for the study was obtained from the Health Research and Ethics Committee of OOUTH. We obtained written informed consent from each participant.

Sampling design
The sample size was calculated using the Cochran formula N=Z2pq/d2. With a prevalence of 6.3% (5), this resulted in a sample size of 90.71 approximated to 100 for each study group to accommodate for attrition.

Data collection
We obtained demographic data, anthropometric indices, and relevant clinical history from all the participants. The blood pressure was measured in all subjects.

Laboratory assessment included collection of 5mls of venous blood taken from the ante-cubital vein via venipuncture into a plain specimen bottle after routine aseptic preparation. The samples were allowed to clot for 30 minutes, and thereafter centrifuged at 3000 revolutions per minute for five minutes, so as to extract the serum into Eppendorf bottles. The sera were stored frozen at -200C until needed for quantitative measurements of FT3, FT4, TSH, Antithyroid peroxidase (Anti-TPO) and Antithyroglobulin (Anti-TG) within 6 weeks of collection. Anti-TPO and Anti-TG were assayed for and the most recent CD4 count values were retrieved from the clinical records for the two HIV positive study groups only.

Thyroid function test was carried out by double assay from sera of subjects using a Microplate Enzyme Immunoassay (Monobind Inc. Ltd., USA). Thyroid autoantibodies (Anti-TPO and Anti-TG) were assayed using Enzyme Immunoassay test kits (Genway Biotech, Inc, Ltd., USA).

Definition of terms
Overt hyperthyroidism is defined as elevated FT3 or FT4 levels in the presence of a very low to undetectable serum TSH levels. Subclinical hyperthyroidism is defined as low TSH level but normal FT4 level. Overt hypothyroidism is defined as a high TSH level and a low FT4 level. Subclinical hypothyroidism is defined a high TSH level and a normal FT4 level.

Isolated low FT4 is defined as low FT4 level in the presence of normal serum level of TSH and FT3. Isolated low FT3 is defined as low FT3 level in the presence of normal serum levels of TSH and FT4.

HIV positive subjects are those who have been exposed to the Human Immunodeficiency Virus (HIV), and the two HIV testspreliminary enzyme immunoassay (EIA) and a confirmatory Western blot are both positive for antibodies to HIV. Whereas, HIV negative subjects did not have any HIV antibodies detected in their blood samples using immunoassay method at the point of taking their blood samples. An exception to this is the window period when the body has not developed any detectable antibodies.

Grading of severity of immunosuppression using CD4 count (11):

Not significant immunosuppression - >500/mm³
Mild immunosuppression 350-499/mm³
Advanced immunosuppression 200-349/mm³
Severe immunosuppression - <200/mm³

Statistical Analysis
The Data were analyzed using the statistical package for social sciences (SPSS) version 23 software. Continuous variables were expressed as mean (ąSD). Descriptive analyses were presented with frequency tables as appropriate.

Analysis of variance (ANOVA) was used to compare continuous variables among the three groups while students t test was used to compare continuous variable when two groups were involved.
Classification of the severity of HIV infection using CD4 counts between the two HIV groups was done using chi-square test with the level of statistical significance set at p < 0.05, and the degree of correlation between thyroid function and severity of HIV infection was determined using Spearmans rank correlation coefficient.

Results

Demographic and clinical parameters of the study participants: Three hundred consecutive subjects were recruited for this study, and were divided into three groups of 100 participants each. The subjects age range was 19 to 70 years with mean age of 43.04ą9.40 years, and was comparable across the groups (F=1.72, P=0.785), as shown in Table 1.

The participants were all Nigerian and the predominant ethnic group were the Yorubas as they accounted for 85% of the participants, while other ethnic groups accounted for the remaining 15%. Majority of the participants were women (n=190; 63.3%) with men (n=110; 36.7%) accounting for slightly above one-third of the study population. The three groups were significantly different in the mean values of their height, weight and body mass index (p<0.05) while the mean systolic & diastolic blood pressures were similar in all study groups. The mean duration of HIV infection in years was higher among HIV positive subjects on HAART, than the HIV positive HAART naīve subjects (p<0.05), as illustrated in Table 1.

Table 1: Demographic and clinical parameters of the study participants
Characteristics	HIV-P1 [ n=100]	HIV-P2 [n=100]	CN [n=100]	Total	Test Statistics Value	p-Value
Mean of Age	44.36±8.56	41.92±9.98	42.85±9.94	N/A	F=1.72	0.785
Tribe
Yoruba	79(79.0%)	85(85.0%)	91(91.0%)	255(85%)	F=9.727	0.137
Hausa	4(4.0%)**	7(7.0%)	2(2.0%)**	13(4.3%)
Igbo	11(11.0%)	6(6.0%)	4(4.0%)**	21(7.0%)
Others	6(6.0%)	2(2.0%)**	3(3.0%)**	11(3.7%)
Gender
Male	39(39.0%)	36(36.0%)	35(35.0%)	110(36.7%)	F=0.373	0.830
Female	61(61.0%)	64(64.0%)	65(65.0%)	190(63.3%)	F=0.373	0.830
Mean Duration of HIV (Years)	7.90±4.18	5.25±2.53	N/A	N/A	t=5.42	0.001
Height(m)	1.64±0.08	1.64±0.07	1.67±0.08	N/A	F=7.673	0.001*
Waist Circumference (cm)	86.35±13.92	84.45±10.11	78.68±17.25	N/A	F=8.066	0.001*
Weight (kg)	65.80±18.01	60.66±14.39	69.14±15.59	N/A	F=7.068	0.001*
Body Mass Index (kg/m²)	24.51±6.16	22.64±5.26	24.73±5.63	N/A	F=4.076	0.018*
Systolic Blood Pressure (mmHg)	122.48±10.07	122.52±13.33	119.08±11.92	N/A	F=2.778	0.064
Diastolic Blood Pressure (mmHg)	73.66±6.29	73.97±8.64	72.22±9.42	N/A	F=1.289	0.277
HIV-P1: HIV Positive on HAART, HIV-P2: HIV Positive HAART naïve, CN: HIV Negative Control, N/A: Not Applicable, n:Total Number, p value <0.05 is statistically significant, *Yates correction applied.

Thyroid hormone Parameters of the study participants: The mean values for FT4 and FT3 were lowest in the HIV positive HAART naīve group (p<0.05), while TSH values were comparable among the three study groups as presented in Table 2.

Table 2: Thyroid hormone Parameters of the study participants
Characteristics	HIV-P1 (Mean±SD)	HIV-P2 (Mean±SD)	CN (Mean±SD)	Test statistics value (ANOVA)	p-value
TSH(µIU/ml)	2.18±1.65	2.30±1.89	2.08±1.35	0.398	0.672
FT4 (ng/dl)	1.03±0.27	0.92±0.28	1.14±0.18	20.11	0.001*
FT3 (pg/ml)	2.68±0.56	2.13±0.61	2.95±0.79	39.90	0.001*
HIV-P1: HIV Positive on HAART, HIV-P2: HIV Positive HAART naïve, CN: HIV Negative Control, n: Total Number, TSH: Thyrotropin, FT4: Free Thyroxine, FT3: Free Tri-iodothyronine, *P value <0.05 is statistically significant. Normal ranges: TSH – 0.5-6 µIU/ml; FT4 – 0.7-1.9 ng/dl; FT3 – 2.57 – 4.43 pg/ml

Mean serum thyroid autoantibodies and CD4 counts in HIV positive groups: The mean thyroid autoantibodies (Anti-TPO and Anti-TG) and CD4 counts were significantly lower in the HIV positive HAART naīve group (p<0.05) as shown in Table 3.

Table 3: Mean serum thyroid autoantibodies and CD4 counts in HIV positive groups
Characteristics	HIV-P1(Mean±SD)	HIV-P2 (Mean±SD)	Test statistics value (t-test)	p-value
Anti-TPO (AU/ml)	8.05±9.25	4.41±5.43	3.38	0.001*
Anti-TG (AU/ml)	4.68±3.65	2.76±2.61	4.33	0.001*
Current CD4 Count (Cell/mm³)	482.34±225.02	292.73±154.86	6.94	0.001*
HIV-P1: HIV Positive on HAART, HIV-P2: HIV Positive HAART naïve, CN: HIV Negative Control, Anti-TPO: Anti-thyroid peroxidase, Anti-TG: Anti-thyroglobulin, *P value <0.05 is statistically significant Normal values: Anti-TPO - <35IU/ml; Anti-TG - <20IU/ml; CD4 count – 500-1400 cells/mm³ of blood

Thyroid function abnormalities among study participants: Seventy-three (24.3%) of all the 300 subjects in the study had abnormalities of thyroid hormone parameters. The prevalence of thyroid function abnormalities among HIV positive subjects from this study was 33%. Isolated low free T4 was the most common abnormality observed in the HIV positive study subjects (n=35, 11.7%). A large percentage of the subjects with isolated low free T4 were in HIV positive HAART naīve group n=23, constituting 65% of those with this deranged parameter. None of the subjects in the control group had this abnormality. The second commonest abnormality found among the study participants was subclinical hyperthyroidism (n=14, 4.7%). Equal proportion of HIV positive on HAART and HIV positive HAART naīve groups had subclinical hyperthyroidism,(n=5, 5%) each. This abnormality was only seen in 4% of HIV negative control. Overt hypothyroidism was observed among 8 (2.7%) study participants. None of the subjects in the apparently healthy HIV negative control group had overt hypothyroidism, while 3 (3%) and 5 (5%) of HIV positive on HAART subjects and HIV positive HAART naīve subjects respectively had overt hypothyroidism as shown in Table 4.

Table 4: Thyroid function abnormalities among study participants
Thyroid Abnormalities	HIV-P1 [N=100]	HIV-P2 [N=100]	CN [N=100]	Total	Test Statistics (Χ²)
Normal	78(78.0)	56(56.0)	93(93.0)	227(75.7)
Sc Hypo	1(1.0)**	3(3.0)**	3(3.0)**	7(2.3)
SES	0(0.0)**	1(1.0)**	0(0.0)**	1(0.3)	Χ²=69.527
IL FT4	12(12.0)	23(23.0)	0(0.0)**	35(11.7)	p=0.001*
IL FT3	0(0.0)**	7(7.0)	0(0.0)**	7(2.3)
Sc Hyper	5(5.0)	5(5.0)	4(4.0)**	14(4.7)
Ovt Hypo	3(3.0)**	5(5.0)	0(0.0)**	8(2.7)
Graves’ Dx	1(1.0)**	0(0.0)**	0(0.0)**	1(0.3)
HIV-P1: HIV Positive on HAART, HIV-P2: HIV Positive HAART naïve, CN: HIV Negative Control, n:Total Number, Sc Hypo: Subclinical Hypothyroidism, SES: Sick Euthyroid Syndrome, IL FT4: Isolated Low Free T4 IL FT3: Isolated Low Free T3, Sc Hyper: Subclinical hyperthyroidism, Ovt Hypo: Overt Hypothyroidism P value <0.05 is statistically significant, *Yates correction applied, Dx: Disease.

Relationship between thyroid hormone abnormalities and the severity of HIV infection: Out of the 38 subjects with severe immunosuppression, 13 (34.2%) had no thyroid abnormalities, while 8 (21.1%) had overt hypothyroidism. Seven (18.4%) had isolated low Free T4, 4 (10.5%) had isolated low free T3, 3 (7.9%) had subclinical hyperthyroidism, 2 (5.3%) had subclinical hypothyroidism and only one (2.6%) had sick euthyroid syndrome. A total of 57 study subjects had advanced immunosuppression. Thirty-eight of them (66.7%) had no thyroid abnormalities, while 15 (49.2%) had isolated low Free T4, 2 (3.5%) had subclinical hyperthyroidism and 1 (1.8%) had subclinical hypothyroidism and Graves disease respectively. Forty-Eight study subjects had mild immunosuppression, 32 (66.7%) of which had no thyroid abnormalities while 9 (18.8%) had isolated low free T4, 4 (8.3%) had subclinical hyperthyroidism and 3 (6.2%) had isolated low Free T3. Fifty-Seven of the HIV positive subjects had no significant immunosuppression as shown in Table 5.

Table 5: Relationship between thyroid hormone abnormalities and the severity of HIV Infection
Thyroid Abnormalities	Severe-I (%) (<200 cells/mm³)	Adv-I (%) (200-349 cells/mm³)	Mild-I (%) (350-499 cells/mm³)	Not-Sig I (%) (>500 cells/mm³)
Normal	13(34.2)	38(66.7)	32(66.7)	51(89.5)
ScHypo	2(5.3)**	1(1.8)**	0(0.0)**	1(1.8)**
SES	1(2.6)**	0(0.0)**	0(0.0)**	0(0.0)**
IL FT4	7(18.4)	15(26.3)	9(18.8)	4(7.0)**
IL FT3	4(10.5)**	0(0.0)**	3(6.2)**	0(0.0)**
ScHyper	3(7.9)**	2(3.5)**	4(8.3)**	1(1.8)**
Ovt Hypo	8(21.1)**	0(0.0)**	0(0.0)**	0(0.0)**
Graves	0(0.0)**	1(1.8)**	0(0.0)**	0(0.0)**
Total	38(100)	57(100)	48(100)	57(100)
HIV-P1: HIV Positive on HAART, HIV-P2: HIV Positive HAART naīve, CN: HIV Negative Control, n:Total Number, Sc Hypo: Subclinical Hypothyroidism, SES: Sick Euthyroid Syndrome, IL FT4: Isolated Low Free T4, IL FT3: Isolated Low Free T3, Sc Hyper: Subclinical Hyperthyroidism, Ovt Hypo: Overt Hypothyroidism, Severe-I: Severe Immunosuppression, Adv-I: Advanced Immunosuppression, Mild-I: Mild Immunosuppression, No-SigI: No Significant Immunosuppression,p value <0.05 is statistically significant, Yates correction applied. Χ²(21) = 69.572, p=0.001

Correlation of Severity of HIV infection and Thyroid Hormone levels in the HIV positive group: There was a weak positive correlation between severity of infection using CD4 counts and FT3 levels in HIV positive HAART naīve subjects. Other thyroid hormones did not have statistically significant correlations with severity of HIV infection in both HIV positive groups, as illustrated in Table 6.

Table 6: Correlation of Severity of HIV infection and Thyroid Hormone levels in the HIV positive groups
Independent Variable	Dependent Variable	HIVP1 [n=100 (%)]		HIVP2 [n=100 (%)]
Independent Variable	Dependent Variable	R	p	r	p
Severity of HIV infection (CD4 counts)	FT4	0.866	0.100	0.121	0.232
	FT3	0.751	0.563	0.223	0.026*
	TSH	0.120	0.234	0.005	0.951
HIV-P1: HIV Positive on HAART, HIV-P2: HIV Positive HAART naīve, n: Total Number, CD4 Counts, *p value <0.05 is statistically significant, r = Spearmans simple correlation coefficient.

Discussion

To the best of our knowledge, this study represents the first report on thyroid hormone abnormalities seen among HIV positive patients with the largest number of participants in Nigeria.
The mean age of participants were similar to that observed in previous studies (4,12,13). Most of the study subjects were from the Yoruba ethnic group (85%), and this is probably because the study was carried out in Sagamu, a core Yoruba settlement in the South-West geopolitical zone of Nigeria.

The prevalence of thyroid function abnormalities in HIV positive subjects from this study was 33%, which is comparable to 28% reported in South-West Nigeria (4) and 48% in South-South Nigeria (8). This was also akin to the findings made in China (13), Brazil (14) and USA (15) of 33.1%, 36% and 37% respectively. However, the prevalence in our study was higher than other findings in France (5) and Thailand (16) of 6.3% and 6.0% respectively. The difference in prevalence rates may be attributed to the longer duration of HIV infection in the participants of this study, low socio-economic status and ignorance, as well as geopolitical variations.

The serum FT3 and FT4 level were lower in both HIV positive groups (especially HAART naīve group) as compared to the HIV negative control group. These observations indicate that the serum levels of FT3 and FT4 were affected by the progression of HIV infection. This is in contrast to the work by Ji et al(13), where the FT3 and FT4 levels were lower in HIV positive on HAART group. There was also a weak but positive correlation between serum levels of FT3 and CD4 cell counts in the HIV positive HAART naīve group in our study, also very to findings by Ji et al(13). This implies that the higher the degree of immune-competence signified by the CD4 cell counts values, the higher the circulating levels of thyroid hormones. However, the weak correlation implies a lower likelihood of this relationship. The correlation observed between FT4, TSH and CD4 count though positive, lacked statistical significance. Other researchers have reported inverse relationships between CD4 count and TSH levels(17), alluding to the fact that hypothyroidism is often associated with increasing severity of immunosuppression.

The serum levels of thyroid autoantibodies were significantly higher in the HIV positive on HAART group, a finding in agreement with previous studies (1820), that reported elevated serum levels of thyroid autoantibodies in HIV positive subjects on HAART compared to HIV positive subjects who are yet to commence HAART. This can be attributed to autoimmunity due to immune reconstitution after HAART initiation. Most patients with concurrent hyperthyroidism and elevated serum levels of thyroid autoantibodies present as Graves disease. However, in our study only one subject with clinical features of Graves was found in the HIV positive on HAART group despite elevated levels of thyroid autoantibodies seen in this group, a finding in tandem with a study (15), showing that not all patients with positive thyroid autoantibodies develop autoimmune thyroid disease.

A previous study ascribed the elevated levels of thyroid autoantibodies to some non-specific consequences of increased B-cell activation seen in the clinical course of HIV infection as opposed to the Immune Reconstitution syndrome (21).

The mean CD4 cell counts was significantly higher in HIV positive on HAART subject group when compared to HIV positive HAART naīve group which is at variance with the finding in a similar study [4], ,that reported significantly lower CD4 cell counts in the HIV positive on HAART group. The therapeutic benefit of HAART in HIV positive subjects is to cause a dramatic decrease in plasma HIV ribonucleic acid (RNA), and increase in memory and naīve CD4 cells (22).

Isolated low FT4 was the most common thyroid function abnormality found in this study (11.7%). This is only slightly higher in comparison with previous studies, (5,23,24) which reported prevalence of 6.8%, 6.9% and 9.2% respectively. The observed differences in prevalence may be because of mild immunocompromised state, with subjects in those studies having a higher mean CD4 cell counts in contrast to the advanced state of immunosuppression, seen in our own study group (HIV positive HAART naīve group). Another explanation for this thyroid dysfunction is that of centrally mediated process with a failure of the hypothalamus or anterior pituitary gland secondary to background immunosuppression and low CD4 cell counts (5).

Another study reported isolated low FT4 among HIV positive patients receiving enzyme inducing medications like phenytoin or carbamazepine for neuropathic pain, (25) but none of the participants in our study was taking phenytoin or carbamazepine. The possibility of some HAART agents interfering with the assay of FT4 has been suggested (15), e.g. didanosine and ritonavir were associated with isolated low FT4 in a study by Beltran et al (5), but none of the subjects in this study were on any of these two agents.

Overt hypothyroidism was recorded in 2.7% of the study subjects and was mostly among HIV positive HAART naīve subject group. The prevalence in this study is similar to that of different studies in the past (23,24,26) that reported a prevalence of 0-2.6%.

In a previous study, it was found that despite the autoimmune aetiology of most cases of hypothyroidism, Hashimoto thyroiditis does not appear to be common among HIV positive patients (27). Our study found only one of the participants with elevated anti-TPO to have overt hypothyroidism, suggesting a different aetiology other than autoimmune.

This study did not find a statistically significant relationship between subclinical hypothyroidism and any drug or the degree of immunodeficiency. Also, there were no clear risk factors in HAART receiving subjects that were related to the occurrence of subclinical hypothyroidism.

However, it is important to periodically assess thyroid function in HIV positive patients, especially in view of the possibility that subclinical hypothyroidism might be a risk factor for cardiovascular disease (28).

One of the participants in the HIV positive HAART naīve group had thyroid function test parameters in keeping with sick euthyroid syndrome, with a very low CD4 cell count of 5 cell/mm³ and all TFTs parameters being low. A study reported a high prevalence of sick euthyroid illness (48%), though all the study participants were patients with advanced AIDS and were not on HAART (8).
This observation is probably a result of physiological response to ongoing illness and can be related to the progression of immunodeficiency state. The disparity in the prevalence noted in this study and our study could attributed to treatment with HAART in the latter.

Isolated low free T3 was present in 2.3% of subject who were all in the HIV positive HAART naīve group. This could represent the first change in the spectrum of the sick Euthyroid illness and occurs in patients who are severely immunosuppressed. A study found a very low Free T3 levels in non-survivors of P.jiroveci infection as compared to survivors (2). This further buttresses the importance of thyroid hormones in proper functioning of the immune system.

Most of the study subjects with isolated low Free T4 had advanced immunosuppression (42.9%), a finding that has been noted in previous studies (4,5). This common finding may be attributed to the role of thyroxine in the regulation of immune function.

Our limitations include; usage of Immunoenzymometric method to assay for TFT parameters due to unavailability of equilibrium dialysis which is a more preferred method. We were also not able to assay for HIV RNA viral loads, thyroid stimulating immunoglobulin, Thyroxine binding globulin due to financial constraint.

In conclusion, thyroid function abnormalities are common among HIV positive patients, and are characterized by reduction in serum thyroid hormonal levels, which worsen with the progression of the disease. These findings were noted in those with severe immunosuppression typified by CD4 cell count nadirs, especially those subjects who were HAART naīve. Isolated low FT4, subclinical hyperthyroidism, overt hypothyroidism and subclinical hypothyroidism were the most common thyroid abnormalities found among HIV positive subjects.

Screening of all newly diagnosed HIV positive patients for thyroid dysfunction and at least yearly TFTs measurement for those with subtle abnormalities is highly recommended. We propose that serum FT3 and FT4 assay could be considered as a surrogate biomarker to measure the severity of HIV infection.

What is known about this topic

Thyroid dysfunction is common amongst HIV positive individuals
HIV positive patients can have subtle or overt thyroid abnormalities

What this study adds

The commonest thyroid abnormality in HIV positive patients is Isolated low FT4.
There is a weak positive correlation between CD4 cell count and FT3 levels in HIV positive HAART naive patients, however this relationship requires further investigation.
Impact of HAART usage on serum thyroid autoantibodies.

Competing interests: Authors have declared that no competing interests exist.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgments:

We thank Drs Raimi T. H, Jemilohun A.C, and all the resident doctors in the department of Internal medicine and chemical pathology, OOUTH Sagamu Ogun-State Nigeria, for their contributions to the success of this study. We also acknowledge the contributions of physicians and staff of the IHVN treatment centre of OOUTH Sagamu Ogun-state Nigeria. We thank Dr Tinuade Ogunlesi for constructive suggestions and editing of this work.

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