prevalence of metabolic disorders, such as insulin resistance, dyslipidaemia, abnormal body fat distribution, and abnormal bone metabolism.A wide range of endocrinopathies and metabolic disturbances occur at all stages of HIV disease. In patients with advanced disease in the pre-ART era, endocrine disturbances were often a result of a direct effect of HIV itself, and/or infiltration by neoplasms and OIs. However, commonly, endocrine abnormalities are due to functional disturbances, or 2° to drugs and intercurrent severe illnesses.
HIV infection is a persistent inflammatory state, even in those taking ART with fully suppressed blood virus. The persistent inflammation is multifactorial, in part due to immune dysregulation, coagulopathy, and occult viral replication. Elevated inflammatory factors (e.g. tumour necrosis factor-α) may alter the hypothalamus-pituitary-adrenal/thyroid/gonadal axes, which directly affect hormonal secretion at the cellular level.
In ART era, coupled with the survival benefit, there is prevalence of metabolic disorders, such as insulin resistance, dyslipidaemia, abnormal body fat distribution, and abnormal bone metabolism.
Pituitary gland involvement was seen in 30% of autopsies carried out in AIDS patients. Panhypopituitarism is rare, but selective failure, e.g. gonadotrophins is more common. Like other endocrine glands, the pituitary may be affected by OIs, infarction, haemorrhage, and neoplasms. Growth hormone deficiency (may contribute to insulin resistance), galactorrhoea, unexplained hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and central diabetes insipidus have all been described. Drugs and pathophysiological mechanisms are proposed reasons for these abnormalities.
Thyroid glands infiltration with malignancies and OIs seen in autopsies is not usually associated with abnormal thyroid function tests (TFTs). TFTs are often abnormal in HIV patients, but the prevalence of overt thyroid disorder is not higher than in the general population. CD4 count correlates inversely with thyroid-binding globulin (TBG). These changes may be a response to the stress of advanced disease state or comorbidities. Occasionally, the biochemical picture does not fully fit with sick euthyroid disease. Progression of HIV disease exhibits 
T3, TBG and reverse triiodothyronine (rT3) levels over time. Observations showed increased prevalence of overt and subclinical 1° hypothyroidism with absent antithyroid antibodies.
Thyroid dysfunction has also been described as a component of IRIS. Some of these patients have autoimmune thyroid disorder, Graves’ disease been the commonest.
In subclinical hypothyroidism with mildly elevated thyroid-stimulating hormone (TSH), the TSH level should be rechecked in 1–3 months. Levothyroxine may be considered with persistently elevated levels of TSH >10 mU/L. Routine screening of TFTs is not recommended in asymptomatic patients.
Dysfunction occurs in both sexes, especially in the late stages of HIV disease and in those with weight loss. Sex hormone-binding globulin levels are increased in 30–50%. Free testosterone levels are more reliable in the assessment of hypogonadism. The aetiology of gonadal dysfunction is often multifactorial. Severe systemic illness, OIs, malnutrition, weight loss, recreational drug use, chronic alcoholism, and increased levels of cytokines may be contributory. HIV-related gonadal failure results in loss of muscle mass, fatigue, sexual dysfunction, and decreased quality of life. Unlike HIV –ve men there is no increase in fat mass.
Male gonadal dysfunction is common. Two-thirds of male patients with advanced HIV disease complain of loss of libido. Erectile dysfunction is reported in up to 60% of HIV +ve male patients, which has no correlation with hypogonadism. HIV +ve men are prone to an early ‘andropause’ marked by dysregulation of hypothalamic–pituitary axis. Biochemical hypogonadism was reported in up to 50% of male AIDS patients. This dropped to around 20% in those receiving ART. Testicular dysfunction is mostly 2° to low gonadotropin levels due to inflammation, infection, undernutrition, and the effects of several drugs on gonadotropin production. Increased prolactin levels and gynecomastia have been reported. Gynecomastia has been seen in a small percentage of male patients with hepatitis C and lipodystrophy.
Free testosterone assay is recommended to diagnose hypogonadism.
Testicular function is affected by drugs such as:
• opiates—associated with hypogonadotropic hypogonadism.
• ketoconazole—causing oligospermia and gynaecomastia.
• megestrol acetate—inhibiting gonadotropin secretion.
Testosterone replacement lean body mass, body weight, and well-being.
Ovarian dysfunction among female AIDS patients is less common. Amenorrhoea, irregular periods, and oligomenorrhoea occur with increasing frequency with HIV disease progression. Early menopause has been seen in up to 8% of HIV +ve female patients. Up to 67% of females with AIDS wasting syndrome have low levels of free testosterone. The mechanism of this is not known.
The adrenal gland is the most commonly affected endocrine gland leading to glucocorticoid, and less commonly, aldosterone deficiency. Hypothalamic–pituitary–adrenal axis abnormalities in HIV are usually due to medications, destruction of the adrenals, or the anterior pituitary by OIs and malignancies, autoimmune adrenalitis, and abnormal cytokine levels. The adrenals may be directly infected by HIV. CMV adrenal gland involvement (found in 40–85% of autopsies) may lead to acute adrenal insufficiency.
In AIDS patients, subtle impairment of adrenal function is manifested as fatigue, hyponatremia, or rarely with clinical symptoms of adrenal insufficiency. Biochemical abnormalities of adrenal insufficiency are relatively common in hospitalized patients.
Increased cortisol levels may be seen in HIV-infected patients; mostly, a stress response to the disease burden. Cushing's syndrome has been reported, from concomitant use of PI and steroids (e.g. inhaled high dose steroids). Rarely, glucocorticoid resistance at receptor level has been shown in advanced disease. Such patients have increased cortisol and ACTH level with Addisonian symptoms. If suspected, risk factors (OIs, drugs) for adrenal insufficiency should be sought. Although chronic steroid replacement at supraphysiologic doses is not advocated in AIDS to prevent further immunosuppression, HIV is not a contraindication to pharmacologic steroid therapy.
Features of adrenocortical disturbances found in HIV infection:
• levels of dehydroepiandrosterone with cortisol.
• basal adrenal androgen levels.
• adrenal responses to adrenocorticotrophic hormone (ACTH).
Drugs may also compromise adrenal function:
• megestrol acetate (used as an appetite stimulant) plasma cortisol level and may lead to acute adrenal crisis if stopped abruptly after prolonged use
• Azoles results in cortisol and testosterone levels
• rifampicin enhances hepatic cortisol metabolism and causes adrenal insufficiency in patients with Addison’s disease who are on replacement therapy or in those with limited adrenal function.
Patients with fatigue, loss of weight, postural hypotension, hyponatraemia, and hyperkalaemia should be assessed with a short synacthen test. Primary adrenal insufficiency can be identified by measuring ACTH simultaneously with serum cortisol.
Aldosterone deficiency may occur (often with glucocorticoid deficiency) leading to persistent hyponatraemia, hyperkalaemia, and metabolic acidosis requiring replacement therapy.
Patients with glucocorticoid insufficiency should receive replacement therapy with hydrocortisone 30 mg/day in divided doses.
Patients with aldosterone deficiency should receive fludrocortisone 50–300 µg/day.
Both exocrine and endocrine functions can be affected in HIV. The pancreas is a target for OIs and malignancies (lymphoma, KS), but clinically significant endocrine dysfunction is rare. Major clinical manifestations are pancreatitis and hypoglycaemia. Pancreatitis is commonly seen as a drug effect (pentamidine, trimethoprim and didanosine). Elevated amylase levels may be due to macroamylasaemia or salivary gland disease. Hypoglycaemia can result from islet cell inflammation and insulin release by pentamidine with subsequent chronic hyperglycaemia. Megestrol acetate is associated with new-onset diabetes mellitus
Insulin resistance occurs more frequently especially in those treated with PIs and those with wasting syndrome. Diabetes is more likely to occur in those with other predisposing factors e.g. family history. Pentamidine is toxic to pancreatic β cells inducing hypoglycaemia in 15–28% (2–3 times more common than in HIV –ve patients). Substantial destruction of β cells may later lead to diabetes mellitus. Management of diabetes follows the same principles as for HIV –ve individuals.
Reduced exocrine pancreatic function is common in HIV infection and may be asymptomatic. Severe chronic pancreatic insufficiency results in severe diarrhoea and can be caused by HIV drugs, e.g. didanosine. Feacal elastase may be low. May require pancreatic enzyme supplements.
HIV lipodystrophy syndrome is characterized by abnormal body fat distribution and metabolic derangements. These features are often seen in combination, but may occur in isolation. While there is some resemblance to Cushing’s syndrome, HIV lipodystrophy lacks myopathy, bruising, and facial plethora, and has normal cortisol level with its normal diurnal variation and adequate suppressibility to dexamethasone. May arise spontaneously, but much more commonly associated with the use of ART, especially if containing PIs. The frequency and severity depend on gender, genetic factors and ethnicity, age, duration of HIV infection, length, and type of antiretroviral drugs.
Cardiovascular risk , especially in patients on ART
Found in 
4% of those with untreated HIV infection. Rate for those taking ART is difficult to determine because of inconsistent diagnostic criteria, but ranges from 20% to 75% (median development time, 18 months). Magnitude varies with individual PIs. Prevalence also related to duration of NRTI use, especially thymidine analogues such as zidovudine. More common in whites and almost twice as common in ♀.
• Dorsocervical fat pad: buffalo hump.
• Increased neck circumference (by 5–10 cm).
• Breast hypertrophy (♀ and ♂).
• Central truncal adiposity: pot belly due to intraperitoneal fat.
• Lipomas occur in 10% of these patients.
• Loss of SC fat from cheeks: emaciated appearance, can be disfiguring, may identify patients as having HIV infection, and may affect quality of life and compliance to drugs
• Loss of SC fat from arms, shoulders, thighs, and buttocks.
HIV infection may cause abnormalities in lipid metabolism, which include:
• total cholesterol, but HDL may be elevated in early stages and decrease with advanced disease.
• predominance of small, dense LDL particles.
It is reported in up to 80% of those taking ART and especially if PI-based. Typical abnormalities include:
• hypercholesterolaemia, mostly very-LDL, but also intermediate density lipoproteins. HDL unchanged or
More frequent and severe with ritonavir and lopinavir–ritonavir, followed by amprenavir and nelfinavir with indinavir and saquinavir having the fewest effects. Atazanavir and darunavir appear to have little effect.
NRTIs are implicated less, although stavudine is more likely to be associated with in cholesterol and triglycerides unlike lamivudine, emtricitabine, tenofovir and abacavir, which appear to have minimal or no effect on lipid metabolism.
NNRTIs can cause alterations in the lipid profiles, but to a lesser extent than PIs. Nevirapine produces marginally smaller changes than efavirenz and improvements in lipid levels when switching from PIs. Rilpivirine has a better effect on lipids than efavifenz.
Integrase inhibitors have very favourable lipid profile.
New-onset diabetes mellitus, diabetic ketoacidosis, and exacerbations of pre-existing diabetes mellitus have all been reported with rates of other risk factors, e.g. family history, pregnancy. Diabetes is directly associated with HIV infection, reported in 3.3% and increased to 5.9% with concomitant HCV infection. Impaired glucose tolerance and insulin resistance precede weight loss. Insulin resistance, rather than insulin deficiency, is usually implicated in the pathogenesis of diabetes in HIV-infected patients. Autoimmune diabetes has been reported in some HIV-infected patients after immune restoration during ART. Concurrent use of opiates may alter beta-cell function, while heroin addiction is associated with insulin resistance. HIV-associated insulin resistance and glucose dysregulation may lead to atherosclerosis and coronary heart disease. Stronger link is observed with most PIs. Darunavir and atazanavir are the least associated.
Patients on ART should have body weight, lipids, and blood sugar measured at regular intervals. Clinical examination and self-reporting of body shape changes help detect early signs. Photographs may aid in the early recognition of facial lipoatrophy. Additional cardiovascular risks, such as life style, smoking, hypertension, family history and age should also be assessed and managed as in the HIV –ve individuals.
• nutrition assessment, dietetic advice and possible benefit from dietary supplements (fibre, omega-3 fatty acids)
• exercise physical activity and exercise to build muscles, improve abdominal shape, and combat peripheral wasting.
• Start ART before CD4 <200 cells/µL or development of AIDS.
• Take care with choice of initial regimen if possible:
• avoid PIs and NRTI combinations with highest risk
• use lamivudine, emtricitabine, tenofovir instead of zidovudine.
• Switch to drugs with low or no association. Benefit of switching is inconsistent, morphological changes being more resistant.
• Fibrates and statins: used according to lipid profile.
• Hypercholesterolaemia managed with low-fat diet and statins.
• Hypertriglyceridaemia responds best to low-fat diet, fibrates, and statins.
• Most PIs inhibit the metabolism of most statins and can significantly increase serum statin levels, thus increasing the risk of toxicity, including myopathy and rhabdomyolysis. Pravastatin is the preferred statin as it is least likely to interact with PIs. Fluvastatin is an alternative. Atorvastatin must be used with caution. Simvastatin and lovastatin should be avoided. NNRTIs are enzyme inducers and higher levels of statins may be required.
• Fibrates (gemfibrozil, bezafibrate, fenofibrate) are usually used in combination with statins as more effective than fibrate monotherapy. Seek advice from lipidologist before starting. risk of rhabdomyolysis and hepatotoxicity.
• metformin (avoid if lipoatrophy) for insulin resistance, dyslipidaemia and fat accumulation
• glitazones for insulin resistance with weight loss.
• Invasive methods for lipodystrophy:
• plastic surgery, e.g. liposuction and breast reduction
• polylactic acid (New-Fill®) injections for lipoatrophy.
Hyponatraemia is a common finding in advanced HIV disease. It is reported in up to 20% of HIV +ve outpatients and up to 60% of hospitalized patients, when mostly due to GI loss associated with hypovolaemia. Respiratory and CNS infections, or certain drugs, e.g. antidepressants, may cause the SIADH. This is characterized by hyponatraemia, inappropriately urinary osmolality/Na for the degree of serum hypo-osmolality and normal blood volume in the context of normal adrenal and thyroid functions. Severe hyponatraemia causes confusion, seizures, and coma. Decreased water clearance from HIV-related nephropathy may exacerbate hyponatraemia. Manage SIADH by removing/treating the underlying cause, fluid restriction.
Hyporeninaemic hypoaldosteronism should be considered when hyponatraemia is associated with hyperkalaemia, providing normally functioning kidneys and adrenals. Hyporeninaemic hypoaldosteronism can rarely be caused by drugs like miconazole and pentamidine (pentamidine tubulopathy).
Hypernatremia may be seen in foscarnet-induced nephrogenic diabetes insipidus.
High dose co-trimoxazole may result in hyperkalaemia especially if pre-existing renal impairment. Pentamidine-associated tubular nephropathy, HIV-nephropathy, and 1° adrenal insufficiency are other causes of hyperkalaemia. Trimethoprim (similar structure to amiloride) reported the commonest cause of hyperkalaemia, occurring in nearly 20–50% AIDS patients. Trimethoprim inhibits tubular potassium excretion.
Serum calcium concentration decreases progressively with stage of HIV disease. Around half of the patients with hypocalcaemia have vitamin D deficiency, but without compensatory increase in parathyroid hormone (PTH). The reason for this is not known
Causes of hypocalcaemia include:
• malabsorption (AIDS enteropathy)
• decreased hydroxylation (PI-induced).
• Fanconi syndrome with hypophosphatemia (tenofovir).
• Severe intercurrent illnesses.
• foscarnet binds calcium resulting in decreased ionized calcium
• ketoconazole inhibits 1,25-dihydroxycholecalciferol synthesis
• pentamidine causes renal loss of magnesium with 2° hypocalcaemia.
Hypercalcaemia is rarely reported in AIDS, granuloma (tuberculosis, lymphoma), enhanced local osteoclastic resorption of bone (disseminated CMV), or activation of PTH-related protein (HTLV1).
Hypophosphataemia is very common in HIV +ve patients, occurs in 10% of patients not taking ART and in 20–31% of those on ART. Main causes are malnutrition, GI losses, osteomalacia, hyperparathyroidism, alcoholism, and intercurrent illness. Tenofovir causes hypophosphataemia by its effect on tubular function.
Osteopenia, osteoporosis, and fractures are more common in HIV +ve individuals compared with the general population, especially with age in the ART era. Tenofovir is associated with osteopenia.
• Fracture risk assessment (using FRAX score) at the time of diagnosis in all patients over 50 (>40 years if major risk factors), post-menopausal women, or in the presence of other risk factors. Stratify according to score:
• <10%—reassure and repeat after 3 years
• 10–20%—consider dual energy X-ray absorptiometry (DEXA) scan to refine risk estimate; if >10% fracture risk, provide lifestyle advice and optimize risk factors including vitamin D deficiency correction
• >20%—optimize risk factors, review ART (tenofovir) and lifestyle factors, and refer for osteoporosis treatment.
• Vitamin D/parathyroid hormone levels if increased fracture risk.
An AIDS-defining illness, defined by Centers for Disease Control (CDC) as involuntary loss of >10% of body weight, plus >30 days of either diarrhoea or weakness, and fever in the absence of illnesses other than HIV. It is becoming less common with the wide availability of ART. Independently associated with an increased risk of OIs, disease progression, and death. Mainly loss of lean body mass and, to a lesser extent, loss of fat.
Additional factors that exacerbate wasting include
• Nutritional factors, e.g. anorexia, dysphagia, poor nutrient absorption.
• Metabolism, e.g. resting metabolic rate, protein turnover production of cytokines, hypertriglyceridemia, and hypogonadism.
• Weight and BMI at regular intervals help with early recognition and monitoring.
• Specialist nutritional review.
• Techniques such as DEXA scan and MRI provide more accurate measurement of body composition.
• Treatment of contributing factors.
• Improving food intake by dietary supplements, enteral, and parenteral feeding.
• Testosterone may be considered to reverse muscle loss, but beware of the adverse effects of long-term administration.
• Megestrol an appetite stimulant (side effects—hypogonadism, adrenal insufficiency, deep venous thrombosis, and avascular necrosis).
• Growth hormone administration may increase lean body mass, but is expensive and benefit may be lost after discontinuation.
• Thalidomide results in significant weight gain, but has strict prescribing guidelines and has potential serious side effects.
• Anabolic hormones, e.g. oxymetholone, side-effects include liver toxicity. Nandrolone is effective in increasing lean body mass in both men and women, but long-term side effects are not known.