Individuals infected with the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) may manifest symptoms and signs of endocrine disorders or may present with incidental abnormal endocrine laboratory values on routine examination. Although many of these abnormalities may be common in any other systemic illness, some abnormalities are specific to HIV infection or therapies of HIV or AIDS and associated opportunistic infections . This chapter will focus on the laboratory assessment of endocrine and metabolic abnormalities specifically associated with HIV and AIDS.
Lipid, glucose, and fat metabolism
Alterations in lipid and glucose metabolism and body fat distribution are important consequences of HIV and AIDS, which are further accentuated with antiretroviral therapy (ART) . Although ART has led to major advances in mortality reduction associated with AIDS, the metabolic consequences of insulin resistance, lipodystrophy, and dyslipidemia increase the risk of diabetes and cardiovascular disease . These abnormalities are interlinked and hence are discussed together in this section.
It is recommended that a fasting lipid profile be obtained before initiating and switching therapy. One of the major metabolic abnormalities noted in patients with HIV or AIDS is an increase in plasma triglyceride and very low-density lipoprotein (VLDL) concentrations. Triglyceride concentration is reported to be elevated in asymptomatic HIV patients with cluster of differentiation 4 (CD4) counts less than 200 cells/mm 3 and worsens in symptomatic AIDS patients. The increase in plasma triglycerides is believed to be due to decreased clearance as well as increased production. The metabolism of VLDLs is decreased due to the reduced activity of lipoprotein lipase. Furthermore, increased de novo hepatic synthesis and increased peripheral lipolysis contribute to increased plasma free fatty acids, which, in turn, increases VLDL production. Plasma concentrations of triglycerides correlate with circulating levels of interferon α, and both the concentrations tend to fall with ART .
Plasma cholesterol concentrations are lower in patients infected with HIV before clinically significant disease develops. Plasma high-density lipoprotein (HDL) is also decreased in patients during early stages. The mechanism for lower cholesterol and HDL-cholesterol in early infection with HIV before immunosuppression has not been fully elucidated. However, the reduction of HDL has been linked to the activation of the immune system leading to an increase in lipid peroxidation, inflammatory cytokine production as well as changes in reverse cholesterol transport . With the development of advanced disease and opportunistic infections, gastrointestinal dysfunction and hepatic involvement may play a significant role. Development of insulin resistance and increased triglyceride concentrations may also contribute to lower concentration of HDL-cholesterol.
HIV infections is associated with increased levels of oxidative stress and an increase in atherogenic risk due to the changes in lipid metabolism. One of the first steps of the atherosclerotic process is the oxidative modification of low-density lipoprotein (LDL) particles. Increased levels of oxidized LDL particles have been identified in patients with HIV infection. Additionally, other lipoproteins including HDL have been reported to have increased levels of oxidation contributing to not only the pathogenesis of cardiovascular and metabolic disease but also affecting immune function in HIV-infected individuals .
ART can cause a significant rise in triglycerides, total cholesterol, and LDL cholesterol. Protease inhibitors (PIs) like ritonavir, amprenavir, and nelfinavir have been shown to increase triglyceride levels and has been the group of antiretrovirals (ARVs) most closely linked to the lipid metabolism disorders . The suggested mechanism for this elevation with ritonavir appears to be an increased VLDL production. It has been suggested that activated sterol binding proteins in the liver are involved in the increased VLDL production. Among the PIs, the second-generation drugs like atazanavir seem to be associated with a more favorable lipid profile and do not have an increase in triglycerides. Nucleoside reverse transcriptase inhibitors (NRTIs) like abacavir have been shown to improve metabolic abnormalities, particularly high cholesterol and triglycerides, when substituted for PIs. However, it is associated with higher virologic failure in patients with prior suboptimal nucleoside therapy. Nevirapine does not have an association with changes in triglyceride metabolism. There is no clear evidence regarding the effect of NRTIs on lipid metabolism. Stavudine is associated with an increase in triglycerides, but tenofovir does not appear to affect triglyceride levels. The fusion, integrase strand transfer, and entry inhibitor class of ARTs are reported to have little or no effect on lipid and glucose metabolism.
The drug–drug interaction is concerning in patients on ART with high triglycerides or cholesterol level when prescribed statins or fibrates. Although no large clinical trials are available to assess safety in patients on ART, both statins and fibrates are used widely in smaller doses in clinical practice. Because PIs inhibit the CYP3A4 enzyme, statins such as pravastatin and rosuvastatin, which are not affected by this enzyme, may be preferred in patients receiving ART therapy.
Glucose metabolism is also affected in multiple ways during different stages of HIV infection and therapy. Early in the stage of asymptomatic HIV infection, both insulin clearance and hepatic glucose output are increased. The mechanism of these changes in HIV infection is not well understood because in other systemic illnesses, there is an opposite effect with increased insulin resistance and hyperglycemia. Patients are likely to have pancreatic involvement with opportunistic infections or neoplasms; however, the majority of these lesions do not seem to affect pancreatic function significantly . The development of insulin resistance, abnormal fat distribution, and subsequent dysglycaemia and frank diabetes has been associated with the use of ART therapy. PIs and certain NRTIS can cause either loss of peripheral fat or deposition of central fat or both. NRTI-induced inhibition of the DNA polymerase y of mitochondria has been linked to the development of lipoatrophy. Other agents such as stavudine have also been linked to the development of lipoatrophy .
However, there is no consensus on the pathogenesis of central fat deposition and its link to lipoatrophy. Although PI therapy is thought to lead to central fat deposition, substitution with alternative ART, like NRTIs, did not decrease central fat. ART-naive patients have also manifested central fat depositions. Hepatic glucose production is also increased in some patients treated with PIs .
The changes in body fat distribution with central fat deposits and peripheral fat loss are also associated with insulin resistance and dyslipidemia prompting the comparison with metabolic syndrome observed in non-HIV-infected population in relation to obesity. However, the relationship between body fat and metabolic abnormalities is confounded by the use of ART. PIs cause insulin resistance and dyslipidemia independent of body fat changes . The development of central adiposity worsens the dyslipidemia with increasing triglycerides and decreasing HDL-cholesterol as well as insulin resistance and hyperglycemia. Although the incidence of diabetes due to use of ART is not known, worsening insulin resistance could lead to diabetes in susceptible individuals. In patients with lipoatrophy, adiponectin levels are decreased and could account for some of the insulin resistance. It is highly desirable to test various PIs that do not have significant effects on insulin sensitivity and body fat distribution to prevent complications of HIV therapy, which can lead to a potential increased risk of diabetes and cardiovascular disease. Highly active antiretroviral therapy (HAART) associated lipodystrophy and dyslipidemia has also been reported by some studies to be related to a genetic predisposition specifically polymorphisms in the APOCIII gene .
Other drugs used in the preventive strategy against opportunistic infections also play an important role in the development of diabetes. Pentamidine, which is used for prevention and treatment of Pneumocystis carinii , can cause pancreatic β-cell toxicity and acute hyperinsulinemia with hypoglycemia and long-term hyperglycemia due to β-cell destruction. Megestrol acetate used as an appetite stimulant to treat wasting in AIDS is also reported to cause hyperglycemia . However, the actual incidence of diabetes related to megestrol use in clinical trials appears to be low .
In summary, HIV infection, AIDS, and ART therapy–associated dyslipidemia, insulin resistance, central adiposity, and diabetes may predispose patients to increased atherosclerosis and risk for cardiovascular disease. The International AIDS Society-USA panel guidelines recommend measuring fasting glucose concentrations prior to and during PI therapy .
Oral glucose tolerance tests may be indicated for patients with risk factors for diabetes, peripheral lipoatrophy, or visceral lipohypertrophy. Long-term studies are lacking to answer this important question and to develop a preventive strategy in this vulnerable population.
Thyroid disorders
Thyroid dysfunction represents one of the most common endocrinopathies occurring in HIV infection with dysfunction occurring in up to 35% of HIV-infected patients in certain reports. Overt thyroid disease is less common. Thyroid function is normal in most patients with HIV infection during early stages of disease. When an advanced stage is reached, changes in thyroid function similar to those seen in any other serious illness (sick euthyroid/euthyroid sick) may be observed . Direct infiltration of the thyroid gland with infection or neoplasms specific to HIV/AIDS may seldom be observed . The occurrence of Graves disease has been reported during immune reconstitution . Overall, the most commonly occurring abnormality seen on thyroid function tests in patients with HIV infection is subclinical hypothyroidism. The most frequent abnormalities in thyroid function tests are those associated with subclinical hypothyroidism .
Additionally, the use of HAART also has been linked to thyroid dysfunction. Some studies have reported the use of stavudine to be associated with hypothyroidism . The influence of other ARVs on thyroid function has not been widely reported. Whilst several longitudinal studies have reported a significant association of HAART with the occurrence of thyroid dysfunction. Recently, in a longitudinal study performed in Denmark amongst a large cohort of HIV-infected individuals, no association between HIV infection and thyroid dysfunction was identified .
Medication used to treat HIV-associated diseases, such as rifampin, and ketoconazole, may also influence thyroid function by inducing the hepatic P450 enzyme. Rifampin is used in prophylaxis and treatment of Mycobacterium infection in HIV patients. Rifampin causes increased T 4 clearance by inducing hepatic microsomal enzyme. This results in lower T 4 and rT 3 concentrations and normal T 3 and thyroid-stimulating hormone (TSH) concentrations. The second line antituberculosis (TB) drugs used in the treatment of multidrug resistant TB have also been associated with the presence of thyroid function abnormalities . A study involving patients with multidrug resistant TB reported two times greater risk of hypothyroidism with use of p-aminosalicylic acid and ethionamide . Use of immunomodulatory agents has been associated with thyroid dysfunction in HIV-infected patients. Patients receiving levothyroxine replacement therapy may require higher doses. Highly active ART has been reported to be associated with the onset of autoimmune diseases, including Grave disease and Hashimoto thyroiditis. The patients develop thyroid antibodies. Interferon α is associated with autoimmune diseases of the thyroid, manifesting as hypo- and hyperthyroidism . Additionally, some studies have reported presence of hepatitis B or hepatitis C coinfection to increase the risk of thyroid abnormalities .
Infections and neoplasms
In autopsy studies of HIV/AIDS patients, various opportunistic infections such as cytomegalovirus (CMV), Cryptococcus neoformans , Pneumocystis jiroveci , Mycobacterium , and other infections as well as AIDS-related neoplasms such as Kaposi sarcoma have been found in the thyroid gland. Most of these patients were asymptomatic for any thyroid abnormality. However, a few of the pathogens, such as P. jiroveci , have been associated with inflammatory thyroiditis with hypo- or hyperthyroidism. Suppurative thyroiditis has been reported in Mycobacterium tuberculosis and C . neoformans infection. Thyroid involvement and destruction may occur with other opportunistic infection or neoplasm, leading to hypothyroidism. Thyroid enlargement may also occur in cases of infiltration with lymphoma and may lead to signs of obstruction. However, in the majority of patients, thyroid function remains normal or is reflective of changes noted in nonthyroidal illness .
The exact mechanism of thyroid dysfunction in HIV-infected individuals is still not completely elucidated it may be related to infection, disease progression and complications, or related to treatment, immune reconstitution, or a combination of any of these factors.
Thyroid function test profile
Thyroid function tests may be altered by any serious illness or starvation without underlying thyroid pathology, and these changes are referred to as euthyroid sick syndrome. Generally, euthyroid sick syndrome is characterized by impaired peripheral conversion of thyroxine (T 4 ) to triiodothyronine (T 3 ) by 5′-deiodinase, lower concentrations of T 3 , variable concentrations of T 4 , and increased levels of reverse T 3 (rT 3 ) due to decreased clearance of rT 3 . TSH concentrations tend to be normal in euthyroid sick syndrome; however, mild elevation may be noted during the recovery phase from nonthyroidal illness. It appears that lower concentrations of T 3 may have a protective role in preventing muscle catabolism during acute illness or starvation, and supplementation of T 3 is shown to be deleterious in these situations .
Some early studies reported lower serum T 4 and T 3 levels in patients with HIV infection with normal basal and peak TSH after thyrotropin-releasing hormone (TRH) stimulations . In postanalysis studies, the low T 3 levels were related to severity of the disease. However, on stratification of the data, a relationship was noted among weight loss, secondary infection, and T 3 levels, suggestive of euthyroid sick syndrome . However, contrary to sick euthyroid pattern in other nonthyroidal diseases where decreased T 4 to T 3 conversion is usually accompanied by increased levels of rT 3 , patients with HIV at all stages of disease were noted to have decreased or normal rT 3 . Thus, thyroid abnormalities in HIV infection leading to lower rT 3 concentrations are independent of euthyroid sick syndrome, and its clinical or functional significance is not known at this time.
In some early studies in patients with HIV infection, a higher concentration of serum T 4 was noted due to an increase in serum T 4 -binding globulin (TBG) . However, serum-free T 4 and TSH were normal in these individuals. TBG rises progressively with advancing immunosuppression and has an inverse association with CD4 levels. This increase in TBG is not associated with increased protein synthesis or decreased clearance of TBG . Although the mechanism of increase in TBG in HIV/AIDS is not known, it should be factored in when interpreting values of total T4 and T3 . However, serum FT3 and FT4 levels are less significantly affected .
FT3 and FT4 have been considered as biomarkers of HIV progression as their levels have been shown to be related to the state of HIV infection. CD4+ counts correlate with FT3 and FT4 levels and are inversely correlated to TSH levels . Another distinctive thyroid abnormality that has been reported in individuals with HIV infection is the presence of an isolated low serum-free T4 level within a normal TSH level. This is more often seen in patients on ARV therapy and has been reported to have a higher prevalence in children receiving HAART .
Adrenal disorders
Infection and neoplasm
In autopsy studies of patients with HIV/AIDS opportunistic infections such as CMV, Cryptococcus , Toxoplasma , Mycobacterium avium complex, or tuberculosis have been reported to infiltrate the adrenal gland. The extent of involvement varies from focal inflammation to extensive necrosis and hemorrhage. In most of the cases, the adrenal gland destruction was less than that believed to be necessary for clinical adrenal insufficiency. At least 90% damage to both adrenals is required to result in adrenal insufficiency. It appears that CMV retinitis is associated with increased rates of adrenal insufficiency. Also, some patients have a subnormal response to stimulated testing and may represent a group with partial adrenal insufficiency, which may unmask during acute stress. Less commonly, Kaposi sarcoma and lymphoma can involve the adrenals but rarely lead to clinical adrenal insufficiency .
Glucocorticoids
Patients with HIV/AIDS usually manifest symptoms of weakness, fatigue, and weight loss, which may be attributed to poor nutrition, opportunistic infections, HIV infection itself, depression, etc. However, potential adrenal insufficiency is likely in view of the symptomatology. Early during the HIV infection phase, most patients have normal or slightly increased basal serum cortisol and corticotropin (ACTH) concentrations. Several mechanisms have been postulated to result in this picture including activation of proinflammatory cytokines, peripheral increase in the conversion of cortisone to cortisol in adipose tissue, and a decrease in cortisol metabolism. With ACTH stimulation testing, pituitary adrenal reserve appears to be impaired; however, most of these patients do not need cortisol replacement. With the disease progression and severity, as in any other serious illness, serum cortisol concentrations rise. The increase in serum cortisol may be mediated by stress response of pituitary adrenal axis as well as direct stimulation by circulating cytokines such as interleukin (IL)-1 or tumor necrosis factor (TNF). IL-1 and TNF also appear to stimulate release of ACTH and corticotropin-releasing hormone (CRH). In any severe illness or stress, when cortisol concentrations are elevated, tests of adrenal functional reserve may not be normal but may return to normal at resolution of underlying condition. With high-dose (250 µg) ACTH stimulation, the majority of HIV patients have a normal cortisol response. When lower dose ACTH (10 µg) is used, nearly half of the critically ill and approximately 20% of outpatients were diagnosed with glucocorticoid insufficiency. Also, with CRH stimulation, a reduced ACTH or cortisol response was found in up to 50% of patients. During the evaluation of adrenal function, 24-h urine-free cortisol concentrations are not useful .
Some patients with HIV/AIDS have symptoms of adrenal insufficiency with weight loss, fatigue, weakness and hyperpigmentation, elevated cortisol, and mildly elevated ACTH concentrations. Mononuclear lymphocytes of these patients are reported to have an increased number of glucocorticoid receptors and decreased affinity of type II receptors for cortisol. These patients are thought to have peripheral resistance to glucocorticoid action. The incidence of this syndrome in HIV patients is currently not known, but in a series of HIV-infected patients, 17% were thought to have this syndrome. Suggestions for possible causes of this resistant state include the HI virus itself, presence of certain cytokines, or altered proportion of different isoforms of the glucocorticoid receptor .
With advancing disease and opportunistic infections, there is more likelihood of involvement of the adrenal gland. In patients with advanced AIDS, evidence of CMV or other opportunistic infection in the adrenal gland is reported in 50% of patients. Clinical adrenal insufficiency is reported in as many as 20% of patients with advanced AIDS. The majority of these patients have adrenal insufficiency due to direct infiltration of adrenal gland by infection, metastases, or adrenal hemorrhage. A very small number of individuals may develop secondary adrenal insufficiency due to involvement of the pituitary gland with opportunistic infection or lymphoma. HIV-associated malnutrition and weight loss are associated with an increased cortisol/dehydroepiandrosterone (DHEA) ratio .
Several medications used in patients with HIV have the potential for altering glucocorticoid metabolism. Rifampin and ketoconazole, which increase cortisol metabolism and inhibit cortisol synthesis, respectively, may precipitate symptomatic adrenal insufficiency in patients with limited reserve and subclinical adrenal insufficiency . Megestrol acetate, used in patients with cachexia and wasting as an appetite stimulant, has some glucocorticoid activity and may lower cortisol levels due to suppression of the hypothalamus–pituitary–adrenal axis. ACTH levels may remain low in response to metyrapone testing in patients taking megestrol. Whilst abrupt cessation of megestrol treatment has been reported to precipitate acute adrenal insufficiency . Iatrogenic Cushing syndrome has also been reported in patients on ritonavir, itraconazole, and inhaled steroids, such as fluticasone. This is particularly important in children and adolescents because iatrogenic Cushing syndrome can impair growth and cause adrenal failure .
In summary, the HIV patients with symptoms of adrenal insufficiency should undergo stimulation testing. Patients with equivocal results should be followed up with repeat testing when infection is treated. Although long-term replacement with steroids may not be warranted, a short course of steroids should be considered during periods of acute stress .
Mineralocorticoids
Mineralocorticoid deficiency without cortisol deficiency in patients with HIV is uncommon. Although electrolyte disturbances are frequent inpatients with HIV and other opportunistic infections, the mineralocorticoid axis is usually normal on evaluation by provocative testing. Basal and ACTH-stimulated concentrations of aldosterone are reported to be normal in a large series of patients with HIV. One longitudinal study showed that aldosterone concentrations in response to ACTH stimulation decreased progressively with time and advancing disease in HIV-infected subjects, but clinical hypoaldosteronemia did not develop. Whilst others have described impaired aldosterone response to ACTH . Certain medications may cause electrolyte changes that can appear like a mineralocorticoid disorder. Trimethoprim and pentamidine can cause hyperkalemia .
Hyporeninemic hypoaldosteronism is related to sulfonamides and hypokalemia with hypomagnesmia is associate with amphotericin B .
Gonadal function
Hypogonadism has long been recognized to be associated with HIV disease and has a multifactorial etiology. Most research, however, has focused on men. The reported prevalence is varied depending on testosterone measurement used, time of day of sampling, and definition of hypogonadism complaints of sexual dysfunction and muscle wasting are common with decreased libido and impotence reported to be up to 50% or more in the HIV-infected male cohorts investigated , respectively. Various studies report between a 30% and 57% prevalence of hypogonadism in their selected populations. More recent estimates following introduction of ART therapy and improved methods of testosterone measurement have been reported to range from 13% to 40% . Testosterone concentrations may be normal or elevated early in HIV infection. Patients have a diminished adrenal androgen response with ACTH stimulation and decreased basal adrenal androgen concentrations. In both men and women at all stages of HIV, there is a decreased concentration of adrenal androgens in the urine . An increased cortisol/DHEA ratio has been correlated with weight loss and HIV-associated malnutrition. Pathophysiology of testosterone decline has not been fully elucidated but is likely to be multifactorial. Some studies report primary gonadal failure, especially when the disease progresses to AIDS .
The classical risk factors in non-HIV-infected individuals for hypogonadism, for example (age, BMI, alcohol consumption, etc. ), have not shown strong association with low serum testosterone levels in HIV-infected males . Both hypothalamic-pituitary and primary testicular dysfunction have been described in HIV-infected males.
It appears that secondary hypogonadism is more prevalent than primary hypogonadism both prior to ART therapy introduction and thereafter since its introduction. The growth hormone (GH)–insulin growth factor axis is also impaired in HIV infection and this may also further contribute to hypogonadism. Other mechanisms described in contributing to hypogondadotrophic hypogonadism in HIV-infected individuals include the following:
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Direct effect of HI virus, which has been reported to be isolated in pituitary cells in a small number of cases.
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Pituitary infiltration by opportunistic infections for example Toxoplasma gondi .
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Effect of ART therapy on body composition, adiposity and visceral fat. There is an association with increased adiposity and increased aromatization of androgens to estrogens, which inhibit the secretion of gonadotrophins to a greater extent. The direct effects of ART on hypothalmic pituitary gonadal (HPG) axis have not been fully elucidated .
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Use of opiates and other substance in this group of patients that may suppress the hypothalamic–pituitary axis.
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Response to chronic, systemic illness, and other comorbid conditions .
Regarding primary hypogonadism, autopsy findings have reported decreased spermatogenesis, interstitial infiltrates, and thickened basement membrane in males with HIV infection. There are also reports of testicular infections with M. avium , toxoplasmosis, tuberculosis, CMV, and malignant invasion of Kaposi sarcoma. HIV-infected men have decreased sperm density in their ejaculate. Gonadal steroidogenesis is inhibited by ketoconazole and megestrol acetate, which also leads to low testosterone levels .
HIV-infected patients have been reported to have higher levels of sex hormone binding globuline (SHBG), which will increase total testosterone values. In order to circumvent the effect of increased SHBG on total testosterone measurements, free testosterone may be measured or calculated to provide a better indicator of testosterone sufficiency .
Low SHBG levels may also be found in HIV-infected males, particularly in the presence of severe liver dysfunction. Depending on the degree of liver dysfunction, SHBG may be elevated or reduced . Additionally, further complicating the biochemical diagnosis of hypogonadism is the lack of consensus with regards to testosterone cut-points and on which testosterone should be measured (total, free, calculated), as well as the different methodologies for measurement.
Testosterone deficiency has been linked to the occurrence of lipodystrophy, increased visceral fat, and also associated with poor glycemic control . At present, screening for hypogonadism is not routinely recommended .
Special consideration with regards to gonadal function/secondary sexual characteristics and cardiometabolic risk need to be reviewed further for specific groups of patients, for example, HIV-infected transgender individuals who are receiving hormone replacement as well as HAART .
Females
Secondary amenorrhea (hypogonadotrophic hypogonadism) in HIV-infected females may be a result of chronic illness, disruptions in energy balance, and loss of body fat as well as the use of various drugs including psychiatric medications, antiepileptics, chemotherapeutic agents, and opioids.
Occurrence of menopause at an earlier age in HIV-infected versus HIV noninfected women has been reported . Although vertical transmission of HIV continues to be a problem throughout the world indicating normal reproductive function in many HIV-positive women, subfertility may be present in women with higher viral loads and lower CD4+ counts. With HIV infection, fertility rates have been shown to decline .
Pituitary function
Anterior hypopituitarism is rare in patients with HIV. In autopsy studies, nearly 10% of cases were reported to have some degree of involvement of the pituitary gland with necrosis, infarction, opportunistic infection, or, rarely, central nervous system lymphoma. However, pituitary function was not reported in these series. Stimulation tests with TRH, CRH, and GnRH usually result in a normal response in HIV patients. Serum prolactin concentrations are usually unaffected. NRTIs have been reported to cause hyperprolactinemia in a few patients .
Height and weight growth impairment are often the most frequent manifestations of HIV infection in childhood particularly the rapid progressors who present in early childhood . GH concentrations are normal and insulin-like growth factor 1(IGF-I) concentrations may be low in most of the children affected with HIV and symptomatically ill with lower growth velocity. Lower IGF-I concentrations with normal GH are seen in children suffering from malnutrition. Children suffering from HIV infection are likely to be malnourished. Poor growth is more frequently seen in those starting ART treatment late. Adults with malnutrition may also have a similar presentation.
Hyponatremia
Hyponatremia is seen frequently in HIV patients who are severely ill. Hyponatremia in HIV/AIDS has been reported to occur in 20%–80% of hospitalized patients . Several conditions in this group of patients predispose to the development of hyponatremia including hypopituitarism, opportunistic infections, adrenal insufficiency, hypothyroidism, as well as fluid and salt loss via diarrhea and vomiting .
Syndrome of inappropriate antidiuretic hormone (SIADH) can occur in AIDS patients due to pulmonary or cerebral infections. Cerebral salt wasting associated with tuberculous meningitis or toxoplasmosis infections may also lead to serum hyponatremia. The introduction of the vaptan group of drugs (e.g., tolvaptan), which have an antagonistic effect at the level of the ADH V1/V2 receptor has been a major advancement in management of hyponatremia.
Opportunistic infections involving the pituitary may cause destruction of the posterior pituitary gland and lead to diabetes insipidus (DI), which is associated with a hypernatremia .
Bone and mineral metabolism
Calcium and bone abnormalities are reported in association with HIV infection. Osteonecrosis of the hip is reported in both adults and children infected with HIV . However, the mechanism of osteonecrosis in HIV is not well understood. Most of the patients with osteonecrosis have more severe disease and may have opportunistic infections. There is little evidence that ART plays a role in development of osteonecrosis .
Bone biopsy from HIV-infected patients showed decreased bone formation and bone turnover and presence of osteopenia or even osteoporosis. One study showed decreased levels of osteocalcin with HIV seroconversion and initiation of ART was associated with a decrease in sclerostin levels which is a negative regulator of bone formation .
The studies have reported higher incidence of osteopenia and osteoporosis in HIV patients on ART and with CD4 counts of <100/µL. Use of steroids for opportunistic infections and lymphoma contributes to osteopenia and osteoporosis. There is significant heterogeneity in the studies examining the associated between HIV infection and fracture risk; however, many but not all of these studies have demonstrated a significant increase in fracture risk . Persistent action of proinflammatory cytokines along with abnormalities in vitamin D metabolism are some of the mechanisms thought to be associated with HIV related osteopenia/osteoporosis. Reduced bone mineral density (BMD) is also strongly associated with the low BMI, which is common in HIV-affected vs HIV noninfected individuals. Hypocalcemia and hypercalcemia both have been reported in patients with HIV and drugs used for treatment of opportunistic infections. HIV patients have low 1,25-hydroxyvitamin D and normal 25-hydroxyvitamin D and vitamin D-binding protein .
The proposed mechanism is impairment in 1α-hydroxylation, which leads to mild hypocalcemia. Foscarnet used for CMV retinitis can cause hypocalcemia either by forming complexes with ionized calcium or renal tubule damage, promoting mineral loss .
Hypokalemia and hypomagnesemia may also be seen when renal tubule damage occurs. Similarly, pentamidine use may lead to hypocalcemia and hypomagnesemia. AIDS patients may also have impaired ability to respond to drug-induced hypocalcemia. NRTIs via toxic action on mitochondria may also be associated with BMD loss .
Effect of PIs or BMD have been inconclusive . The initiation of ART has shown in studies to be associated with decreases in BMD and increases in bone turnover markers irrespective of the regimen used .
Ketoconazole and rifampin can also affect levels of vitamin D, although clinically significant effects on calcium metabolism are not observed . Foscarnet use may also cause nephrogenic DI . Trimethoprim sulfamethoxazole and aminoglycosides are associated with hypocalcemia .
Hypercalcemia may also be observed in patients with HIV, especially in patients with AIDS-related lymphoma or M. avium complex P. jiroveci , C. neoformans , and Coccidioides immitis infection. This may be due to increased 1α-hydroxylation of 25-hydroxyvitamin D levels by the lymphoma or granulomas associated with the infection. Osteoclasts activated by T cells or proinflammatory cytokines can lead to hypercalcemia in CMV infection .
Tenofovir-induced hypophosphataemia
Tenofovir use has been associated with proximal renal tubular dysfunction and loss in BMD leading to osteomalacia or osteoporosis. The renal tubule abnormalities (Fanconi syndrome) that develop with tenofovir use result in renal phosphate wasting and hypophosphataemia. Tenofovir has also been described as effecting 1α-hydroxylation of vitamin D, thus leading to vitamin D deficiency .
Other
Autoantibodies
Overall, HIV infection is associated with increased levels of autoantibodies. These may have clinical effects but may also have interfering effects on measurement of various hormones when analyzed using commonly available immunoassay methodologies .
Endocrine and metabolic emergencies
Some of the above described endocrine disorders can present as life-threatening emergencies. This includes hyponatremia, adrenal crisis, diabetic ketoacidosis, hyperosmolar hyperglycemic coma, thyrotoxicosis, hypercalcemia, and lactic acidosis. Lactic acidosis is associated with mitochondrial toxicity that occur with use of NRTIs (more commonly linked with certain drugs in the class, such as stavudine and didanosine, which are largely no longer in use). It is characterized by increased plasma lactate levels typically >5 mmol/L with arterial blood gas pH <7.35 and/or a decreased bicarbonate (<20 mmol/L). Risk factors for NRTI-induced lactic acidosis include increased BMI, female sex, impaired renal function, and pregnancy .
Conclusions
Endocrine and metabolic changes are seen in patients with HIV/AIDS ( Table 13.1 ). Several factors including the disease, immune reconstitution, opportunistic infections, and antiretroviral therapies can contribute to the endocrine and metabolic abnormalities that manifest in these patients. However, there is a lack of long-term data evaluating endocrine functions during the course of HIV infections from early stages to advanced stage. Future studies should focus on evaluating factors that can modify endocrine functions such as viral load, concomitant therapies, CD4 count, severity of illness, and opportunistic infections.
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