Rationale for the study

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2.8 ADRENAL INSUFFICIENCY AND HUMAN IMMUNODEFICIENCY VIRUS

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been implicated in the mechanism of adrenal insufficiency in HIV infected patients.^lii Endocrine effects following drugs used in the treatment of OIs such as anti tuberculous drugs e.g. rifampicin (increases cortisol metabolism), antifungal e.g. ketoconazole (inhibits the adrenal cytochrome P450 steroidogenic enzymes thus inhibiting cortisol synthesis and also blunts out cortisol response to ACTH) and an appetite stimulant, megestrol acetate (Megace) has also been reported to cause adrenal insufficiency in these patients. However, megace causes secondary adrenocortical insufficiency and not primary adrenal insufficiency. The glucocorticoid effect of megestrol acetate suppresses pituitary ACTH production and leads to secondary adrenocortical insufficiency.^liii Other co-morbid conditions, such as injection drug use, may also play a role.liv

Direct destruction of endocrine organs by HIV itself is also a well recognised cause of adrenal insufficiency in these patients.^lv Despite advances in ART, opportunistic viral infections continue to occur, particularly in severely immunosuppressed patients. HIV-associated malignancies such as KS and lymphomas have been detected in the pituitary and adrenal glands. Such occurrences were far more common in the pre-ART era but are also seen in patients who have antiretroviral drug resistant infection.

The predilection of CMV for the adrenal gland in comparison to other organs has long been recognized.^7-9,50 Autopsy studies of some HIV patients indicated CMV invasion of the adrenal gland in up to 90% of AIDS patients.^7-9 This is a common post mortem finding and can result in hypoadrenalism in vivo.^lvi,lvii This is becauseCMV has great adrenal tropism and it has been reported to be present in the adrenals of 40 - 88% of the patients dying of AIDS.

In a study carried out in Enugu, Nigeria, it was found that adrenal insufficiency was the commonest HIV endocrinopathy with cytomegalovirus adrenalitis occurring in 40 - 88% of cases.⁵⁰ Other studies observed similar findings of high prevalence rates.9,56, lviii

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Other OIs such as mycobacterium avium-intracellulare (MAI), toxoplasmosis, cryptococcus or pneumocystis carinii infection (PCP) have been reported but in a smaller percentage of cases.^9,lix A study, in New Orleans, USA, found that adrenal insufficiency may be relatively common in patients with HIV infection based on the finding of destructive adrenal lesions in a large number of the patients studied.^lx However, standard testing for adrenal reserve done in this population of patients found a normal response to a standard, short ACTH test. Thus, although adrenal involvement by various destructive lesions may be seen in patients with HIV/AIDS, clinically significant adrenal insufficiency does not appear to be common.⁶⁰ Adrenocortical dysfunction in some patients with HIV can be due to glucocorticoid resistance syndrome or acquired tissue specific corticosteroid resistance.^lxi This tends to present with features of adrenocortical insufficiency and mucocutaneous hyperpigmentation. It is associated with increased plasma and urinary cortisol levels and elevation in ACTH levels.

Hyperpigmentation in these patients with HIV is also thought to be due to elevated alpha-interferon level.

In addition, a change in hormone binding proteins has been reported in HIV infection.^lxii The described existence of antihormone antibodies in AIDS or the secretory potentialities of the activated lymphocytes might also contribute to the pathophysiology of the adrenal insufficiency in these patients.^lxiii

Other authors believe that the mechanisms of endocrine complications are poorly understood.

Apart from OIs and drugs, peculiarities related to the structure of HIV and interleukin 1 (IL1) may play a role, which makes the diurnal variation in cortisol secretion to be lost. This effect results in an increased production of corticotrophin releasing hormone and corticotrophin and a reduction in negative feedback from cortisol.^lxiv

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Stimulation of the HPA axis in the context of HIV infection may be caused by elevated levels of circulating cytokines (IL-2, IL-4), among other factors.⁶³ Cytokines (IL-2, IL-4) can induce resistance to glucocorticoids by decreasing the affinity of the glucocorticoid receptor to its hormone.^lxv HIV-1 stimulates glucocorticoid action by increasing glucocorticoid sensitivity through the direct effect of Vpr in target tissues. In HIV infection, cytokines have a central role in activating the HPA axis and thus in the regulation of the immune response.

This is presented in Figure 2.3

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Figure 2.3 Schematic representation of Human Immunodeficiency Virus-1 effects on the Hypothalamo - Pituitary - Adrenal axis.

Figure 2.3 shows the effect of Human Immunodeficiency Virus-1 envelope protein gp120 induces glucocorticoid secretion by direct stimulation of the HPA axis. Interleukins-1 and Interleukins -6 have a stimulatory effect on glucocorticoid secretion both directly by inducing secretion via the adrenal cortex and indirectly by activating CRH and ACTH secretion.

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Abnormalities of the HPA axis have been documented in HIV patients in the early as well as late stages of the infection and this range from subtle subclinical disturbances to frank adrenal insufficiency. ^lxvi There are few reports on HPA derangements in HIV-infected