Editorial

Thyroid Dysfunction in HIV-AIDS

Prema K Varthakavi

Prof. & Head, Dept. of Endocrinology, TN Medical College & BYL Nair Ch Hospital, Mumbai - 400 008

Human immunodeficiency virus (HIV) infection can lead to multiple organ involvement --- including the endocrine system. Endocrine function may be altered in these subjects because of the possible relationship between the immune and endocrine systems, direct involvement of the glands by the HIV itself, opportunistic infections or malignancies.1,2

Any chronic illness associated with malnutrition or inflammation can cause abnormalities in thyroid function tests (TFTs). There are contradictory reports about thyroid function tests in subjects with HIV/AIDS.2,3 Among individuals infected with HIV, 1-2% manifest overt thyroid disease and subtle abnormalities in thyroid functions are frequently encountered.4

Abnormal thyroid functions in these patients may be caused by the stress of advanced disease or concomitant morbidities and may manifest as the classic sick euthyroid syndrome3 probably due to a hypothalamic pituitary deficit related to the progress of immunodeficiency and cachexia.1 Cytokines such as IL-6 and TNF-α can acutely decrease TSH and T3 and increase rT3 levels.
LoPresti et al studied thyroid functions in HIV positive patients, to evaluate if they could be used to predict their progression and outcome. The nonsurvivors of P. carinii had lower T3 (0.56 nmols/L) than the survivors (1.3 nmol/L). The rT3 was higher in patients with AIDS-related complex (0.21 nmol/L) than in AIDS outpatients (0.17 nmol/L). As HIV infection progressed, rT3 decreased and thyroxine-binding globulin increased. They concluded that TFTs can provide information on the clinical course of HIV-infected patients and may be used to help make decisions regarding therapy.5

Bordoux found that thyroid binding globulin was increased in 16 out of 54 HIV infected patients and correlated inversely with CD4 counts.6 Grinspoon confirmed the fact that reverse T3 levels did not rise in association with decreasing T3 levels as expected in non-thyroidal illness.7

Jain et al in this issue of the journal, report abnormal thyroid levels which correlated with the CD4 counts and severity of the disease.8

These, however are not the only affectations of thyroid function in the HIV AIDS infection. Screening studies have demonstrated an increased prevalence of primary hypothyroidism in HIV infected patients. Beltran4 reported overt hypothyroidism in 2.6%, subclinical hypothyroidism in 6.6% and an isolated low T4 level in 6.8% of 350 subjects studied. Low free T4 levels (1.3%) and subclincal hypothyroidism (3.5%) which correlated with low CD4 counts were reported in a Spanish population.9

An infectious trigger for immune activation (by molecular mimicry) is one of the postulated mechanisms for autoimmune disease. However hypothyroidism in HIV infected patients is not associated with autoimmunity.10 One case of Hashimoto’s hypothyroidism has been reported so far after highly active anti-retroviral therapy (HAART) initiation.11

Thyroid disease in children is important to detect because it has an affect on growth and development. Chiarelli et al12 demonstrated the presence of the sick euthyroid syndrome, associated with the severity of immunosuppression in perinatally infected children. Fundaro13 demonstrated increased TSH levels (28%) and antithyroglobulin antibodies (34%) in symptomatic children. Growth rates increased in response to thyroid replacement in children with failure to thrive and exaggerated TSH responses to TRH testing.14

An increasing incidence of autoimmune disease and presence of auto antibodies is being recognized in HIV infected patients Goddard proposed a staging of autoimmune manifestations related to HIV/AIDS, total CD4 counts and viral load that may be beneficial in identifying the type of autoimmune disease and establishing proper therapy.15

Stage I: Acute HIV infection, the immune system is intact and autoimmune diseases may develop.

Stage II : The quiescent period without overt manifestations of AIDS associated with a declining CD4 count indicative of some immunosuppression. Autoimmune diseases are not found.

Stage III: Immunosuppression with a low CD4 count and the development of AIDS. CD8 T cells predominate and diseases such as psoriasis and diffuse immune lymphocytic syndrome (similar to Sjogren’s syndrome) may present or even be the initial manifestation of AIDS. No autoimmune diseases are found.

Stage IV: Restoration of immune competence following HAART. In this setting, there is a resurgence of autoimmune disorders.

The immune reconstitution syndrome that is described above is associated with autoimmune thyroid disease. Chen estimated the prevalence of immune reconstitution Autoimmune Thyroid Disease (AITD) (Graves’ Disease, hashithyrotoxicosis, and hypothyroidism) was 3% for women and 0.2% for men. The median duration of immune reconstitution was 17 months. Patients with lower CD4 counts at baseline who experienced greater increments in the CD4 counts following HAART were more likely to develop AITD.16

Subclinical hypothyroidism is more prevalent in the HIV infected population, compared to HIV-negative individuals.10,17 Quirino10 reported a similar prevalence of subclincal hypothyroidism in both naive and HAART treated subjects,

Beltran et al4 found that subclinical hypothyroidism was associated with the use of stavudine and lower CD4+ cell count, The cumulative daily dose of both stavudine and lamivudine was significantly related to the presence of hypothyroidism in Grappin’s series.17 Didanosine and ritonavir were associated with a low free T4.4

Bongiovanni18 studied subjects on stable HAART (for at least 1 year) at baseline and at month 24 (G1); subjects naïve at both baseline and month 24 (G2) and subjects starting HAART at baseline (G3). At baseline, the prevalence of subclinical hypothyroidism was similar in the three groups (14.4%, 10.6% and 8.7% respectively). At month 24, 4.8% (G1), 7.1% (G2) and 19.0% (G3) of the population developed de novo subclincal hypothyroidism, suggesting a possible acute effect of HAART on thyroid function.

The role of HAART was confirmed by a recent report that HAART interruption was associated with a normalization of TFTs.19

Besides HAART, IL-2 therapy is also reported to induce Graves’ disease.20

Thyroid dysfunction in HIV-positive individuals can result from gland destruction by opportunistic pathogens (Pneumocystis jirovecii or cytomegalovirus) or tumorigenic diseases (Kaposi’s sarcoma). These opportunistic infections could be associated with the sick euthyroid syndrome or could cause low reverse T3.5,21

Pneumocystis thyroiditis has been reported to cause a painful low uptake thyroiditis like picture with hyperthyroidism followed by hypothyroidism.22

We come now to the questions this review raises:

Should thyroid functions serve as surrogates for progressive HIV infection?

In the opinion of the author, today, we have available direct measures to establish the severity of HIV infection e.g. CD4 counts, viral load estimation and the presence of opportunistic infections and hence, surrogate makers should really not be relied upon.

Should we screen all patients with HIV infections for thyroid dysfunction?

This remains an area of controversy. In a large cohort of HIV positive subjects followed for 3 years, Madge et al23 found the prevalence of hypothyroidism to be 2.5% (overt) and 4% (subclinical). Hyperthyroidism (overt and subclinica)l occurred in <1%.of patients. Non-thyroidal illness was seen in 17% of patients whereas 75.5% had normal TFTs. Only eight new cases (1%) of overt thyroid disease occurred over 3 years. They made a strong case against universal screening in HIV positive subjects.

Nelson’s study24 revealed a higher than expected incidence of overt hyopothyroidism in patients receiving HAART and they recommend universal screening of subjects on therapy.

What should be the management protocols for the various abnormalities reported?

Overt Hypothyroidism should be treated with levothyroxine keeping in mind that drug interactions between levothyroxine and protease inhibitors have been reported, perhaps through the shared metabolic pathway of glucuronidation.25 Thyroid medications may also affect the course of the various co-morbidities in HIV infected subjects.

Subclinical Hypothyroidism : The TSH level should be determined again in 1–3 months, because the levels in 30% of HIV-uninfected patients normalize within 1 year However, the proportion of HIV-infected patients whose levels normalize is not known. Besides, during recovery from illness, the TSH level may temporarily overshoot the normal range, which may mimic subclinical hypothyroidism.19 No guidelines are available for the level of TSH that warrants the administration of therapy in this situation.

Hyperthyroidism: It would be important to differentiate between Graves’ disease or thyroiditis and the appropriate therapy should be considered.

To conclude, abnormal TFTs are encountered often in HIV positive individuals. Management guidelines exist for overt dysfunction as described above. However, larger studies are needed to evaluate the prevalence and outcomes of mild thyroid dysfunction in HIV-infected patients and to formulate screening and treatment guidelines.

References

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