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Basic and Clinical Endocrinology 7th International student edition Edition

25

AIDS Endocrinopathies

Grace Lee MD

Carl Grunfeld MD, PhD

Symptoms consistent with endocrine disorders and alterations in endocrine laboratory values are not unusual in individuals infected with the human immunodeficiency virus (HIV). Some of these changes are common to any significant systemic illness; others appear to be more limited to patients with HIV infection or secondary to its therapies. Alterations in endocrine and metabolic function can be associated with HIV infection even before clinically significant immunocompromise occurs. As the infected individual becomes immunocompromised, opportunistic infections and neoplasms—as well as the agents used in the treatment of these disorders—can give rise to further changes in endocrine function. This chapter will discuss alterations in endocrine function that can accompany HIV infection and AIDS, focusing on evaluation and interpretation of clinical and laboratory findings.

THYROID DISORDERS

Opportunistic Infections & Neoplasms

Opportunistic pathogens and neoplasms have been found at autopsy in the thyroid glands of HIV-infected individuals. A few of these pathogens have been associated with clinical thyroid dysfunction. Pneumocystis carinii has been associated with inflammatory thyroiditis accompanied by hypothyroidism in seven cases, hyperthyroidism in three cases, and normal thyroid function in one case. Antithyroid antibodies were negative in all six cases in which they were measured. Radionuclide scanning in seven cases revealed poor visualization of the entire thyroid gland in patients with bilateral disease and nonvisualization of the affected lobe in patients with unilateral disease. Two patients with hyperthyroidism had normalization of thyroid function after treatment of the P carinii infection. Kaposi's sarcoma has also been reported to infiltrate the thyroid gland, resulting in significant destruction and hypothyroidism in at least one case. In two cases, lymphoma was associated with thyroid infiltration, causing thyroidal enlargement. Thyroid involvement may occur in patients who have disseminated opportunistic infections with Mycobacterium tuberculosis, cytomegalovirus, Cryptococcus neoformans, Aspergillus fumigatus, andRhodococcus equi. Typically, thyroid function tests in these types of infections are normal or reflect a pattern consistent with nonthyroidal illness (Chapter 7).

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Alterations in Thyroid Function Tests

In early studies of thyroid function tests in HIV-infected individuals, some patients were found to have lower thyroxine (T4) and triiodothyronine (T3) levels than HIV-negative controls. Patients with low T3 values in these studies had normal basal and peak TSH levels after TRH stimulation. In most studies, the low T3 levels were related to severity of disease. When HIV-infected patients were stratified by weight loss and the presence of secondary infection, T3 levels remained normal during asymptomatic HIV infection, decreased by 19% in AIDS patients who were free of active infection and had stable weight, and decreased by 45% in patients with active secondary infection and weight loss, consistent with the euthyroid sick syndrome. It is notable that even significantly ill HIV-infected patients often do not demonstrate the elevated reverse T3 (rT3) levels characteristic of the euthyroid sick syndrome. The significance of this difference, if any, is unknown.

Thyroxine-binding globulin (TBG) is elevated in HIV-infected patients and rises progressively with advancing immunosuppression. This increase does not appear to be due to generalized changes in protein synthesis, increases in sialylation and subsequent clearance of TBG, or changes in estrogen levels. The cause and clinical significance of the increased TBG found in HIV-infected patients are unknown. However, increases in TBG affect total T4 and T3 measurements, and this should be considered when interpreting these tests in HIV-infected patients.

Subtle alterations in TSH dynamics have been reported in stable HIV-infected patients. While their TSH and free T4 levels remain within the normal range, these individuals demonstrate significantly higher TSH values and lower free T4 values than uninfected controls. In circadian studies, HIV-infected individuals have higher TSH pulse amplitudes with unchanged pulse frequency as well as a higher peak TSH in response to TRH stimulation. These studies are consistent with a subtle state of compensated hypothyroidism in HIV infection; the mechanisms underlying these alterations have not been elucidated.

The typical pattern of alterations in thyroid function tests in HIV-infected patients is outlined in Table 25-1.

Medication Effects

Hepatic microsomal enzymes—and thus thyroid hormone clearance—are increased by rifampin, an agent used for Mycobacterium aviumprophylaxis. Patients with normal thyroid function should not be clinically affected, though decreases in T4 may be observed. Patients receiving l-thyroxine may require increased doses, and patients with decreased pituitary or thyroid reserve may develop clinically apparent hypothyroidism when treated with rifampin. Medications used in HIV-infected patients that can affect the endocrine system are listed inTable 25-2.

Table 25-1. Thyroid function tests in HIV-infected patients.

 

Basal

After TRH stimulation

T3

 

T4

Normal

rT3

Normal or ↓

TBG

TSH

Normal

↑ Pulse amplitude

↓ decreased; ↑ increased

With the advent of highly active antiretroviral therapy (HAART), there have been reports of newly diagnosed autoimmune diseases such as Graves' disease, Hashimoto's thyroiditis, and alopecia areata. Immune reconstitution with HAART raises the possibility of subsequent induction of autoimmune diseases. One study reported five patients who developed Graves' disease 14–22 months after starting HAART. Prior to starting HAART, none of the patients had thyroid antibodies, but after starting treatment all developed thyroid antibodies and symptoms of hyperthyroidism. Possible theories include thymic regeneration or peripheral T lymphocyte expansion causing irregularities in tolerance, leading to autoimmune dysfunction.

Summary of Thyroid Disorders

In summary, most alterations in thyroid function that occur in HIV infection are similar to those seen in the

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euthyroid sick syndrome. As with other causes of this syndrome, replacement with thyroid hormone is not warranted at this time. The clinical significance of the changes that appear to be specific to HIV infection, such as elevated TBG, is not certain.

Table 25-2. Medications that can affect the endocrine system used in HIV-infected patients.

Thyroid
      Rifampin
Adrenals, electrolytes
      Ketoconazole
      Megestrol acetate
      Rifampin
      Trimethoprim
      Pentamidine
      Sulfonamides
      Amphotericin B
      Foscarnet
Gonads
      Ketoconazole
      Megestrol acetate

Bone, calcium
      Foscarnet
      Pentamidine
      Ketoconazole
      Rifampin
Pancreas, glucose
      Pentamidine
      Trimethoprim-sulfameth-oxazole
      Dideoxyinosine (ddI)
      Dideoxycytosine (ddC)
      Megestrol acetate
      Protease inhibitors
Lipids
      Protease inhibitors

ADRENAL DISORDERS

Opportunistic infections commonly involve the adrenal glands but rarely occupy enough of the gland to cause adrenal insufficiency. Impaired adrenal reserve without overt symptoms of adrenal insufficiency has been described in the HIV population. Those patients with a subnormal response to dynamic testing represent a group for which there is controversy over when to give baseline replacement glucocorticoids and mineralocorticoids and increased doses in stressful situations, especially when baseline levels are normal or elevated. With restoration to health by treatment of opportunistic infections or HIV itself, many of these patients no longer have adrenal insufficiency.

Opportunistic Infections & Neoplasms

Opportunistic organisms are found commonly in the adrenal glands of patients dying of AIDS although they rarely cause clinical adrenal insufficiency. Cytomegalovirus has been associated with significant necrosis of the adrenal gland, though the amount of tissue affected rarely reaches the 90% thought necessary to cause clinical adrenal insufficiency. However, in one preliminary study, the presence of CMV retinitis was associated with an increased rate of adrenal insufficiency compared with AIDS patients without that disorder. Less common opportunistic infections involving the adrenals include Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, Cryptococcus neoformans, Histoplasma capsulatum, Pneumocystis carinii, and Toxoplasma gondii. In addition, Kaposi's sarcoma and lymphoma can involve the adrenals, but rarely to the extent of inducing adrenal insufficiency.

Glucocorticoids

Classic clinical symptoms of adrenal insufficiency are seldom seen, but some clinicians view the weakness and weight loss seen in patients with AIDS as an indicator of adrenal insufficiency. In addition, subclinical abnormalities in glucocorticoid dynamics are common. HIV-infected patients usually have normal or, even more commonly, elevated basal cortisol levels. ACTH levels in patients with elevated basal cortisol levels have been found to be normal or elevated. Some of these alterations may be mediated by cytokines; both interleukin-1 and TNF can directly stimulate cortisol secretion, while IL-1 and IL-6 can stimulate ACTH and CRH release. An increase in cortisol levels may also be a direct response to HIV infection itself. An increased cortisol to DHEA ratio has been correlated with body weight loss and HIV-associated malnutrition.

Nearly all HIV-infected patients have a normal cortisol response to high-dose (250 ľg) ACTH stimulation testing, but there is some evidence that adrenal reserve may be decreased in as many as half of patients with HIV infection. Recently, two studies have shown that low-dose cosyntropin stimulation (10 ľg) resulted in a diagnosis of glucocorticoid insufficiency in 21% of outpatients with HIV and up to 50% of critically ill HIV-infected patients. During CRH stimulation testing, a reduced ACTH or cortisol response was seen in up to 50% of stable HIV-infected patients with CD4 counts less than 500/ľL. Thus, HIV-infected patients may have decreased reserve either at the pituitary or at the adrenal level.

Clinically significant abnormalities in glucocorticoid secretion appear to be uncommon in HIV infection; subtle alterations in adrenal biosynthesis may be more common. HIV-infected patients have reduced products of the 17-deoxysteroid pathway (corticosterone, deoxycorticosterone, and 18-hydroxydeoxycorticosterone) with normal or elevated products of the 17-hydroxy pathway (cortisol) before and after ACTH stimulation. It is not known whether this alteration represents an early indication of evolving adrenal insufficiency or is an adaptive response that shifts adrenal synthetic activity to steroids that are crucially needed under conditions such as HIV infection that impose physical stress. Twenty-four hour urine free cortisol levels do not appear to be useful in the evaluation of subtle adrenal alterations in HIV-infected patients.

Glucocorticoid resistance has been described in HIV-infected patients. This syndrome is characterized by symptoms of weakness, fatigue, weight loss, and hyperpigmentation, with elevated cortisol levels and mildly increased ACTH levels. Decreased lymphocyte glucocorticoid receptor affinity for glucocorticoids, resulting in chronic interferon alpha stimulation, has been described in these patients. Partial glucocorticoid resistance could explain the finding of increased basal cortisol in HIV-infected patients; but the prevalence and clinical significance of this syndrome are uncertain.

Adrenal Androgens

HIV-infected patients have decreased basal adrenal androgen levels and impaired adrenal androgen responses to ACTH stimulation. Decreased urinary excretion of adrenal androgens has been seen at all stages of HIV infection as well as in HIV-negative intensive care unit patients. Women with HIV infection also have lower levels compared with women without the infection.

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Thus, this change may not be specific to HIV infection but may instead be a feature of the physiologic response to illness. In two studies, a fall in DHEA levels predicted progression to AIDS independent of CD4 cell counts. As DHEA has been shown in vitro to inhibit HIV replication, this raised the possibility that the decreased DHEA levels observed in HIV-infected patients might influence the effects of the HIV infection. The efficacy of DHEA replacement in HIV-infected patients has not been demonstrated.

Mineralocorticoids

Although electrolyte disturbances are not uncommon in HIV-infected patients, provocative testing of the mineralocorticoid axis has revealed few abnormalities. Basal and ACTH-stimulated aldosterone levels have been found to be normal in almost all HIV-infected patients studied, including both outpatients and hospitalized individuals. Longitudinal studies suggest that the aldosterone response to ACTH stimulation may diminish with progression to later stages of HIV infection in up to half of HIV-infected patients; however, basal levels of aldosterone and plasma renin activity remain normal, and clinically significant hypoaldosteronism does not develop.

The usual pattern of alterations in adrenal hormones is shown in Table 25-3.

Medication Effects

Several medications used in the treatment of HIV-related disorders can alter glucocorticoid metabolism. Ketoconazole inhibits the cytochrome P450 enzymes P450scc and P450c11, decreasing cortisol synthesis and leading to adrenal insufficiency in patients with decreased adrenal reserve. Rifampin increases hepatic metabolism of steroids and may lead to adrenal insufficiency in patients with marginal adrenal reserve. Megestrol acetate has intrinsic cortisol-like activity and also decreases serum cortisol and ACTH levels through suppression of the hypothalamic-pituitary-adrenal axis centrally. Patients taking megestrol have decreased cortisol and ACTH levels in response to metyrapone testing. HIV protease inhibitors block the metabolism of the inhaled steroid fluticasone by CYP 3A4 and can lead to Cushing's syndrome even in the absence of systemic steroid use.

Table 25-3. Usual pattern of adrenal hormones in HIV infection.

 

Basal

After ACTH Stimulation

Glucocorticoids

Normal or ↑ cortisol 
↓ 17-Deoxysteroids

Normal cortisol response

Mineralocorticoids

Normal

Normal

Androgens

↓ decreased; ↑ increased

Medications used to treat HIV-related illnesses can lead to electrolyte disturbances. Trimethoprim impairs sodium channels in the distal nephron, decreasing potassium secretion, which can result in hyperkalemia. Pentamidine has also been associated with hyperkalemia in rare instances, perhaps through nephrotoxicity. Sulfonamides are associated with interstitial nephritis and hyporeninemic hypoaldosteronism. Finally, amphotericin B causes renal potassium and magnesium wasting. Protease inhibitors do not seem to have an effect on plasma cortisol levels. However, there is debate in the literature about whether these agents increase or decrease urinary free cortisol or 17-hydroxycorticosteroid excretion.

Medications used in HIV-infected patients that can affect the endocrine system are listed in Table 25-2.

Summary of Adrenal Disorders

In summary, there is little evidence for clinically significant impairment of adrenal steroid excretion in HIV infection. The subtle alterations in the glucocorticoid and androgen synthesis pathways may be an adaptive response to physiologic stress and may occur with other illnesses. Patients with HIV infection who exhibit symptoms consistent with adrenal hormone deficiency should undergo provocative testing in the same manner as uninfected individuals. Patients with low baseline and abnormal glucocorticoid or mineralocorticoid responses to provocative testing should be treated with physiologic replacement doses of oral glucocorticoids or mineralocorticoids. These patients should also be covered with high doses of glucocorticoids (usually 150–300 mg of hydrocortisone per day or equivalent) during episodes of severe illness. Electrolyte abnormalities should prompt evaluation for medication effects and the presence of renal disease.

The HIV-infected patient with a minimally elevated or frankly high basal cortisol that does not increase significantly after ACTH stimulation poses a difficult problem. Most of these individuals will have normal responses to prolonged ACTH stimulation, and seronegative patients with significant illness can have similar patterns that revert to normal after treatment of the illness. Chronic glucocorticoid therapy may have significant adverse consequences in these individuals, who are already immunocompromised. Most HIV-infected patients with this pattern and even many with baseline low levels during acute illness do not appear to require long-term glucocorticoid replacement. Consideration

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could be given to administering short courses of steroid therapy during significant illness for individuals with indeterminate stimulation results.

BONE & MINERAL DISORDERS

Calcium and calciotropic hormone disturbances are associated with several HIV-related illnesses and medications. Hypercalcemia with an elevated 1,25-dihyroxyvitamin D level has been associated with both AIDS-related lymphoma and Mycobacterium avium complex infection, suggesting increased conversion of 24-hydroxyvitamin D to 1,25-dihydroxyvitamin D by the infection or tumor.

Histomorphometric analysis of bone biopsies from AIDS patients showed decreased bone formation and bone turnover; these changes were more marked in more severely affected patients. Early studies of patients with HIV did not find decreased bone mineral density. However, more recent studies have found osteopenia or even osteoporosis. There is no agreement yet as to whether osteopenia is the result of HIV infection itself, of prior glucocorticoid use during opportunistic infections, of the use of specific antiretroviral drugs such as protease inhibitors, or nucleoside reverse transcriptase inhibitor (NRTI)-induced hyperprolactinemia. There have been no clinical trials evaluating the efficacy of treatment of HIV associated osteopenia, and no current treatment guidelines exist. There is little evidence for an increase in prevalence of classic pathologic fractures of osteoporosis.

Osteonecrosis of the hip has been reported recently both in adults and in children infected with HIV. It is not known whether this condition is associated with HIV infection itself, with antiretroviral therapy, or with opportunistic infection.

Hypocalcemia has occurred during therapy for CMV retinitis with foscarnet, which can complex ionized calcium and may also have mineral wasting effects at the renal tubule, leading to concurrent hypomagnesemia and hypokalemia. Hypocalcemia and hypomagnesemia have also been reported during pentamidine treatment, and the combination of foscarnet and pentamidine can result in severe, even fatal, hypocalcemia.

AIDS patients may have an impaired ability to respond to drug-induced hypocalcemia. PTH levels both at baseline and during EDTA-induced hypocalcemia are decreased in HIV-infected patients compared with seronegative individuals and seronegative hospitalized patients; all groups had normal magnesium levels. In addition to effects on calcium and magnesium, foscarnet can also cause nephrogenic diabetes insipidus. Ketoconazole and rifampin can alter vitamin D metabolism but may not produce clinically significant effects. Ketoconazole can reduce serum levels of 1,25-dihydroxyvitamin D and lower total—but not ionized—calcium levels; rifampin can decrease 25-hydroxyvitamin D levels but does not appear to change calcium or PTH levels.

Medications used in HIV-infected patients that can affect the endocrine system are listed in Table 25-2.

GONADAL DISORDERS

Testicular Function

Histopathologic changes in the testes of AIDS patients are common; decreased spermatogenesis, thickened basement membrane, and an interstitial infiltrate are often seen in autopsy series. The presence of Mycobacterium avium-intracellulare, toxoplasma, and CMV in testicular tissue is not unusual in patients systemically infected with these agents. Kaposi's sarcoma has also been reported in the epididymis of an AIDS patient.

Early in HIV infection, testosterone levels appear to be normal or even elevated. Elevated basal LH levels and an increased LH response to GnRH have been demonstrated in these patients, suggesting pituitary dysfunction. Gonadal function appears to be altered more significantly in the later stages of HIV infection. Low serum testosterone levels, often with symptoms of decreased libido or erectile dysfunction, are not uncommon in men with AIDS. In these hypogonadal men, LH and FSH levels have been found to be low, normal, or high. GnRH testing in hypogonadal men with HIV has been normal in most cases. Sex hormone-binding globulin has been found to be normal in HIV-infected men in all but one study. These results suggest that gonadal dysfunction in men with AIDS is not unusual and can occur at the level of the testis, the pituitary, or the hypothalamus.

The hypogonadism seen in AIDS may not be unique to HIV infection; hypogonadism also occurs with other significant systemic illness. This effect may be cytokine-mediated, since IL-1 and TNF can affect testicular function.

Testosterone replacement therapy in hypogonadal men with HIV results in improved sexual functioning, mood, and energy. Whether testosterone increases lean body mass in AIDS patients is controversial. Testosterone therapy does not appear to exacerbate Kaposi's sarcoma, though the studies of this relationship have been small.

Some medications used in the treatment of HIV-related illness can alter testicular function. Ketoconazole inhibits gonadal steroidogenesis, resulting in lower testosterone levels, oligospermia, and gynecomastia. Megestrol acetate, a progesterone-like agent, can lead to decreases in testosterone in HIV-infected men, perhaps through central feedback on gonadotropins.

Medications used in HIV-infected patients that can affect the endocrine system are listed in Table 25-2.

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Ovarian Function

Only recently have issues of ovarian function and fertility been explored in women with HIV infection. HIV can directly infect the female reproductive organs. Involvement of the uterine tubes, uterus, and cervix has been demonstrated, but direct ovarian infection has not yet been assessed.

There is little consensus about whether HIV infection is associated with menstrual irregularities and amenorrhea. Recent studies suggest that HIV infection itself has little impact on the menstrual cycle. However, high viral loads and low CD4 counts are associated with increased cycle variation. It is likely that these women have an increased rate of amenorrhea due to the classic euhormone-sick syndrome or a higher catabolic state. Protease inhibitor therapy has been reported to cause hypermenorrhea in a case series of four women. Similar to men, serum testosterone and adrenal androgen levels appear to be lower in women with advanced HIV disease. Androgen-deficient women may have subtle symptoms of decreased energy, libido, mood, strength, and bone mass. Laboratory diagnosis is difficult in the female population. Total testosterone levels may be increased due to elevations in SHBG in HIV-infected women, and free testosterone levels for women have not been well standardized in clinical laboratories. Thus, diagnosis of androgen deficiency in women has been largely restricted to the research setting. Two small clinical trials have shown that transdermal testosterone increased weight and improved quality of life in HIV-infected women and women with AIDS wasting syndrome. Androgen replacement in women should be approached with caution as certain preparations of androgens such as Estratest (combined estrogen and methyltestosterone) can cause liver dysfunction, and progestin replacement is required to prevent endometrial hyperplasia.

Pregnancy does not seem to affect either the maternal progression of HIV disease or the health status of live newborns at birth. Fertility rates in HIV infected women have been difficult to study because of confounding factors such as sociodemographics, drug use, weight loss, systemic illness, and sexually transmitted diseases. Generally, antiretroviral treatment of pregnant women is recommended because it decreases mother-to-child transmission.

PITUITARY DISORDERS

Opportunistic Infections & Neoplasms

In autopsy series of AIDS patients, nearly 10% of pituitary glands demonstrate some degree of infarction or necrosis; infectious organisms such as cytomegalovirus, P. carinii, Cryptococcus, Toxoplasma, and Aspergillus have been observed. Antemortem pituitary function was not reported in these patients.

Anterior Pituitary Function

Anterior hypopituitarism appears to be rare in AIDS patients; stimulation with TRH, GnRH, or CRH results in normal pituitary responses in almost all patients. Likewise, prolactin levels generally have been found to be normal, with a normal response to TRH stimulation. Some patients have shown a higher maximal pituitary response to stimulation testing compared with uninfected subjects, but the clinical significance of this alteration is not known.

The growth hormone axis has received particular attention in children with HIV who can have poor growth velocity, especially when symptomatically ill. Most of these children demonstrate normal GH levels, though low IGF-I levels can be seen. Low IGF-I in the setting of relatively normal GH is often seen in states of malnutrition, which may partially explain this finding. In adults, IGF-I levels may be low in malnourished or symptomatic HIV-infected patients but are usually normal in clinically stable individuals. Circadian GH secretion does not appear to be altered in adults with HIV infection.

Posterior Pituitary Function

Posterior pituitary function may be altered in HIV infection. Hyponatremia is common in both inpatients and outpatients with HIV. Inappropriately high serum antidiuretic hormone levels have been seen in euvolemic AIDS patients with hyponatremia; however, many of these patients had pulmonary or cerebral infections, which themselves can cause the syndrome of inappropriate antidiuretic hormone secretion. As with any patient, destruction of the posterior pituitary by infection or tumor can lead to neurogenic diabetes insipidus; like anterior pituitary destruction, this appears to be rare in HIV infection.

PANCREATIC DISORDERS

Opportunistic infections and tumors can be seen in the pancreases of AIDS patients at autopsy, though the lesions do not appear extensive enough to cause pancreatic dysfunction routinely.

Glucose homeostasis appears to be altered in divergent ways by HIV infection and its therapies. Early in the epidemic, clinically stable HIV-infected men were found to have higher rates of insulin clearance, increased sensitivity of peripheral tissues to insulin, and an increase in nonoxidative glucose disposal. Hepatic glucose production rates tend to increase, perhaps in response

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to the increased glucose disposal. In contrast, other infectious states, such as sepsis, are accompanied by insulin resistance and hyperglycemia.

Clinically significant pancreatic dysfunction in HIV-infected patients is often related to medication. With the introduction of HAART, insulin resistance has emerged as a problem. Some of the insulin resistance is attributable to protease inhibitor drugs, which can induce insulin resistance rapidly even in HIV-negative volunteers. However, increased insulin resistance has also been found in HIV-infected subjects on NRTI therapy. Indinavir has been shown to increase insulin resistance in HIV-infected subjects and in non-HIV infected, healthy subjects. In vitro studies suggest that indinavir, ritonavir, and amprenavir cause insulin resistance in part by acutely inhibiting the GLUT4 transporter. However, in one study of HIV-infected patients there was no increase in insulin resistance after 48 weeks of treatment with amprenavir. The effects of other protease inhibitor drugs need to be tested in HIV-infected and HIV-seronegative subjects. Hyperglycemia and diabetes in patients treated with protease inhibitors have been reported. The degree to which the prevalence of diabetes is increased in HIV-infected patients on HAART or protease inhibitors is currently under study, but the degree of insulin resistance seen in HIV-infected patients receiving therapy is of a magnitude that could increase the incidence of diabetes, especially in those with susceptibility, such as genetic background. The effects of protease inhibitor drugs on glucose and lipid metabolism are shown in Table 25-4.

Pentamidine causes pancreatic B cell toxicity, acutely leading to hypoglycemia and, over the long term, to diabetes mellitus. Hypoglycemia during pentamidine treatment is associated with increased length of treatment, higher cumulative doses, and renal insufficiency. Patients who develop hypoglycemia in association with pentamidine therapy are at increased long-term risk of developing diabetes mellitus. HIV-infected patients who develop diabetes mellitus following pentamidine therapy have low C-peptide levels, suggesting cell destruction. Aerosolized pentamidine therapy has also been reported to cause hypoglycemia and diabetes mellitus. Pentamidine—as well as trimethoprim-sulfamethoxazole and the nucleoside analogs ddI and ddC—have been associated with acute pancreatitis.

Table 25-4. Effect of protease inhibitors on glucose and lipid metabolism.

 

HIV Infection Without Protease Inhibitor

HIV Infection With Protease Inhibitor

Glucose

Normal or ↓

Normal or ↑

Insulin sensitivity

Cholesterol

↑ to normal

Triglycerides

LDL

↑ to normal

HDL

↓ decreased; ↑ increased

Megestrol acetate, which has intrinsic glucocorticoid activity, may be associated with diabetes mellitus in HIV-infected patients, though the rate of hyperglycemia in controlled clinical trials appears to be low.

Medications used in HIV-infected patients that can affect the endocrine system are listed in Table 25-2.

LIPID DISORDERS

Triglyceride levels rise progressively with advancing stages of HIV infection and average twice the normal values in patients with symptomatic AIDS infection. The increase in triglycerides appears to be due to an increase in VLDL. Metabolic changes associated with HIV infection that may contribute to the rise in triglycerides include a decrease in lipoprotein lipase activity, increased hepatic synthesis of free fatty acids, and increased peripheral lipolysis. The increased triglyceride levels correlate strongly with circulating levels of interferon alpha. Both triglyceride and interferon alpha levels fall with antiretroviral therapy, though the role of interferon alpha in triglyceride metabolism has not been fully elucidated.

Plasma cholesterol, HDL, and LDL are decreased in patients at early stages of HIV infection and AIDS. HDL levels tend to decrease first and are often low even before clinically significant immunosuppression occurs. The cause of the low cholesterol levels seen in HIV infection has not been determined. These changes occur early in clinically stable individuals and even before immunosuppression; thus, malabsorption does not appear to play a significant role.

During treatment with HIV protease inhibitor drugs, triglyceride, total cholesterol, and LDL levels increase. Given that earlier studies of antiretroviral therapy were associated with decreased triglyceride levels, it is likely that the increase in triglycerides is a direct effect of protease inhibitors. However, the ability to induce hypertriglyceridemia varies among these drugs. Ritonavir-containing regimens are more likely to induce hypertriglyceridemia. Consistent with these findings, ritonavir—but not indinavir—has been shown to increase triglycerides in HIV-negative volunteers. Therapy for hyperlipidemia is complicated by protease inhibitor

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inhibition of CYP 3A4, the enzyme responsible for metabolism of simvastatin and lovastatin; use of pravastatin or atorvastatin is a safer way to prevent rhabdomyolysis.

A series of reports of changes in fat distribution, including loss of peripheral fat (extremities and face) or gain in central fat (abdomen and dorsocervical)—or both effects—has been published in cross-sectional studies of patients treated with highly active antiretroviral therapy. Although initially attributed to HIV protease inhibitors, more recent reports of these changes in patients who have not been treated with protease inhibitors raise the possibility that the changes are related to HAART per se or specific NRTI drugs such as stavudine. Immune reconstitution and restoration to health may also play a role. There are no data supporting a linkage between the findings of fat loss and those of central gain, which must be taken into account when attempting to define the causes and effects of these changes in fat depots. A number of therapeutic interventions attempting to treat the adipose changes seen in HIV have had limited success, including recombinant growth hormone, anabolic steroids, metformin, and thiazolidinediones. Growth hormone treatment shows some decrease in truncal fat and increase in lean body mass at 6 months but is accompanied by significant transient insulin resistance. Metformin and thiazolidinediones reverse some metabolic changes. Metformin reduces visceral fat, but neither drug has significantly increased peripheral fat. Long-term effects on body composition, insulin resistance, lipids, and disease outcomes need to be evaluated.

The relationship between changes in body composition and alterations in metabolism such as hyperlipidemia and insulin resistance is also confounded by the effects of the antiretroviral therapies themselves. As mentioned above, protease inhibitor therapy induces hyperlipidemia and insulin resistance, and this has been shown to be independent of fat distribution. However, it is likely that the development of visceral obesity or severe peripheral fat loss will independently contribute both to hypertriglyceridemia and to insulin resistance.

HAART with a protease inhibitor does not have a major effect on the decreased HDL seen in HIV. Therapy with an NNRTI raises HDL in HIV-infected subjects. Both protease inhibitors and NNRTIs raise LDL.

The effects of HIV protease inhibitors on glucose and lipid metabolism are shown in Table 27-4.

The changes in lipid and glucose metabolism seen in HIV raise the question about whether atherosclerosis will be increased due to HIV or its therapies. Although studies published to date are not large enough for definitive answers, it appears that HIV infection itself is accompanied by increased atherosclerosis and that the use of protease inhibitors will lead to little increase. However, NNRTIs have a better antiatherogenic profile.

Anabolic steroids in experimental use for HIV-associated wasting and lipodystrophy raise LDL and dramatically lower HDL, leading to an atherogenic profile. Medications used in HIV-infected patients that can affect the endocrine system are listed in Table 25-2.

CONCLUSION

Many of the endocrine and metabolic changes that occur in HIV infection and AIDS are similar to the changes associated with any serious illness. The approaches to diagnosis and therapy are therefore the same as in other illnesses. Many of the changes that are unique to HIV infection do not have clear clinical significance. However, drug-induced changes are common and should be searched for.

In the past, the prognosis of AIDS has been poor. Now that highly active antiretroviral therapy is increasing life span, the long-term implications for endocrine and metabolic changes need to be determined.

REFERENCES

General

Sellmeyer DE, Grunfeld C: Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr Rev 1996;17:518.

Thyroid

Grunfeld C et al: Indices of thyroid function and weight loss in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Metabolism 1993;42:1270.

Hommes M et al: Hypothyroid-like regulation of the pituitary-thyroid axis in stable human immunodeficiency virus infection. Metabolism 1993;42:556.

Jubault V et al: Sequential occurrence of thyroid autoantibodies and Graves' disease after immune restoration in severely immunocompromised human immunodeficiency virus-1-infected patients. J Clin Endocrinol Metab 2000;85:4254.

LoPresti J et al: Unique alterations of thyroid hormone indices in the acquired immunodeficiency syndrome. Ann Intern Med 1989;110:970.

Adrenal

Findling J et al: Longitudinal evaluation of adrenocortical function in patients infected with the human immunodeficiency virus. J Clin Endocrinol Metab 1994;79:1091.

Honour J, Schneider M, Miller R: Low adrenal androgens in men with HIV infection and the acquired immunodeficiency syndrome. Horm Res 1995;44:35.

Jacobson M et al: Decreased serum dehydroepiandrosterone is associated with an increased progression of human immunodeficiency virus infection in men with CD4 cell counts of 200–499. J Infect Dis 1991;164:864.

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Mayo J et al: Adrenal function in the human immunodeficiency virus-infected patient. Arch Intern Med 2002;162:1095.

Membreno L et al: Adrenocortical function in acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1987;65:482.

Norbiato G et al: Glucocorticoid resistance and the immune function in the immunodeficiency syndrome. Ann N Y Acad Sci 1998;840:835.

Bone and Mineral

Aukrust P et al: Decreased bone formative and enhanced resorptive markers in immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J Clin Endocrinol Metab 1999;84:145.

Jaeger P et al: Altered parathyroid gland function in severely immunocompromised patients infected with human immunodeficiency virus. J Clin Endocrinol Metab 1994;79:1701.

Paton NIJ et al: Bone mineral density in patients with human immunodeficiency virus infection. Calcif Tissue Int 1997;61:30.

Miller KD et al: High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17.

Serrano S et al: Bone remodeling in human immunodeficiency virus-1-infected patients. A histomorphometric study. Bone 1995;16:185.

Gonads

Chirgwin K et al: Menstrual function in human immunodeficiency virus-infected women without acquired immunodeficiency syndrome. J Acquir Immune Defic Syndr Hum Retrovirol 1996;12:489.

Ellerbrock T et al: Characteristics of menstruation in women infected with human immunodeficiency virus. Obstet Gynecol 1996;87:1030.

Lo JC, Schambelan M. Reproductive function in human immunodeficiency virus infection. J Clin Endocrinol Metab 2001;86:2338.

Rabkin JG, Wagner GJ, Rabkin R: Testosterone therapy for human immunodeficiency virus-positive men with and without hypogonadism. J Clin Psychopharmacol 1999;19:19.

Shah PN et al: Menstrual symptoms in women infected by the human immunodeficiency virus. Obstet Gynecol 1994;83:397.

Pituitary

Agarwal A et al: Hyponatremia in patients with the acquired immunodeficiency syndrome. Nephron 1989;53:317.

Dobs A et al: Endocrine disorders in men infected with the human immunodeficiency virus. Am J Med 1988;84:611.

Pancreas

Bouchard P et al: Diabetes mellitus following pentamidine-induced hypoglycemia in humans. Diabetes 1982;31:40.

Carr A et al: Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999;353:2093.

Hadigan C et al: Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus-infected women. J Clin Endocrinol Metab 1999;84:1932.

Heyligenberg R et al: Non-insulin-mediated glucose uptake in human immunodeficiency virus-infected men. Clin Sci 1993; 84:209.

Hommes M et al: Insulin sensitivity and insulin clearance in human immunodeficiency virus-infected men. Metabolism 1991;40:651.

Kaufman MB, Simionatto C: A review of protease inhibitor-induced hyperglycemia. Pharmacotherapy 1999;19:114.

Murata H, Hruz PW, Mueckler M: Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS 2002;16:859.

Noor MA et al: Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS 2001;15:F11.

Osei K et al: Diabetogenic effect of pentamidine: in vitro and in vivo studies in a patient with malignant insulinoma. Am J Med 1984;77:41.

Uzzan B et al: Effects of aerosolized pentamidine on glucose homeostasis and insulin secretion in HIV-positive patients: a controlled study. AIDS 1995;9:901.

Waskin H et al: Risk factors for hypoglycemia associated with pentamidine therapy for Pneumocystis pneumonia. JAMA 1988; 260:345.

Lipids

Carr A et al: Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999;353:2093.

Dong KL et al: Changes in body habitus and serum lipid abnormalities in HIV-positive women on highly active antiretroviral therapy (HAART). J Acquir Immune Defic Syndr Hum Retrovirol 1999;21:107.

Gervasoni C et al: Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy. AIDS 1999;13:465.

Grunfeld C et al: Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992;74:1045.

Lo JC et al: The effects of recombinant human growth hormone on body composition and glucose metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab 2001;86:3480.

Mulligan K et al: Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acq Immune Defic Syndr Hum Retrovirol 2000;23:35.

Safrin S, Grunfeld C: Fat distribution and metabolic changes in patients with HIV infection. AIDS 1999;13:2493.

Saint-Marc T et al: Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study. AIDS 2000;14:37.


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