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Ovid: Oxford Handbook of Genitourinary Medicine, HIV, and Aids

Editors: Pattman, Richard; Snow, Michael; Handy, Pauline; Sankar, K. Nathan; Elawad, Babiker Title: Oxford Handbook of Genitourinary Medicine, HIV, and Aids, 1st Edition Copyright ©2005 Oxford University Press > Table of Contents > HIV/AIDS > Chapter 47 – HIV: endocrine and metabolic disorders Chapter 47 HIV: endocrine and metabolic disorders P.462
Introduction Metabolic disturbances and alterations in endocrine functions occur at all stages of HIV disease. HIV may directly infect endocrine glands but more commonly endocrine abnormalities are due to functional disturbances or 2° to drugs and intercurrent severe illnesses. Endocrine disturbances Pituitary function Panhypopituitarism is rare but selective failure can occur e.g. gonadotrophins. Pituitary infarction is found in up to 10% of autopsies of AIDS patients. The pituitary may also be involved by opportunistic infection (OI) such as toxoplasmosis, cytomegalovirus (CMV), and Mycobacterium avium complex (MAC). Thyroid disease Autopsy studies have shown infiltration by lymphoma, Kaposi’s sarcoma, and OIs such as MAC and CMV. These pathologies are not usually associated with abnormal thyroid function tests. Thyroid binding globulins are high and should be taken into consideration when interpreting total thyroid hormone levels. Thyroid dysfunction may occur in those with advanced HIV disease during intercurrent illnesses. Overt hypothyroidism is rare. Gonadal function 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 ↑ in 30–50%. Free testosterone levels are more reliable in the assessment of hypogonadism. Panhypopituitarism from hypothalamic and/or pituitary destruction causing gonadal failure is rare. The aetiology of gonadal dysfunction is often multifactorial. Severe systemic illness, OIs, malnutrition, weight loss, recreational drug use, chronic alcoholism, and abnormal levels of cytokines may be contributory. HIV-related gonadal failure results in loss of muscle mass, fatigue, sexual dysfunction, and ↓ quality of life. Unlike HIV negative men there is no ↑ in fat mass. Testicular function Total testosterone levels may be elevated in the early stages of HIV infection but tend to decline with disease progression. Erectile dysfunction is common in AIDS. Low testosterone levels may be due to a functional P.463
disorder of the hypothalamus, 1° testicular failure, or a combination of both. 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, well-being. Ovarian function Irregular periods, oligomenorrhoea, and amenorrhoea occur with ↑ frequency as HIV disease progresses. ↓ muscle mass is associated with androgen deficiency. Up to 67% of ♀ with AIDS wasting syndrome have ↓ levels of free testosterone. The mechanism of this is not known. P.464
Adrenal function 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. Adrenals may be directly infected by HIV. CMV adrenal gland involvement (found in 40–85% of autopsies) may lead to acute adrenal insufficiency. Features of adrenocortical disturbances found in HIV infection:

  • ↓ levels of dehydroepiandrosterone with ↑ cortisol.
  • low 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.
  • ketoconazole 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.1° adrenal insufficiency can be identified by measuring ACTH simultaneously with serum cortisol. Any severe illness may disturb the hypothalamic–pituitary–adrenal axis resulting in minor abnormalities of adrenal function tests. Aldosterone deficiency may occur (often with glucocorticoid deficiency) leading to persistent hyponatraemia, hyperkalaemia, and metabolic acidosis requiring replacement therapy. Management Patients with glucocorticoid insufficiency should receive replacement therapy with hydrocortisone 30mg/day in divided doses. Patients with aldosterone deficiency should receive fludrocortisone 50–300µg/day. Pancreatic function Both exocrine and endocrine functions are affected during HIV disease. Pancreatic endocrine function Insulin resistance occurs more frequently in HIV infection especially in those treated with protease inhibiters (PIs) and those with wasting syndrome. Diabetes is more likely to occur in those with other predisposing factors e.g. family history. P.465
Pentamidine, used in the treatment of Pneumocystis jiroveci (carinii) pneumonia (PCP), is toxic to pancreatic β cells inducing hypoglycaemia in 15–28% (2–3 times more common than in HIV -ve patients). The reason for this is unknown. Substantial destruction of β cells may later lead to diabetes mellitus. Management of diabetes should follow the same principles as for HIV -ve individuals. Pancreatic exocrine function (see p. 400) Reduced exocrine pancreatic function is common in HIV infection and may be asymptomatic. Severe chronic pancreatic insufficiency results in malabsorption. P.466
Metabolic disorders Lipodystrophy syndrome Lipodystrophy, dyslipidaemia, and hyperglycaemia (from insulin resistance) are often combined although each component may occur in isolation. May arise spontaneously but much more commonly associated with the use of HAART, especially if containing PIs. Lipodystrophy Found in ~4% of those with untreated HIV infection. Rate for those taking HAART is difficult to determine because of inconsistent diagnostic criteria but ranges from 20% up to 75% (median development time—18 months). Magnitude varies with individual PIs. Prevalence also related to long-term nucleoside reverse transcriptase inhibitor (NRTI) use, especially stavudine (D4T). More common in whites and almost twice as common in ♀. Lipohypertrophy (especially associated with PIs)

  • Dorsocervical fat pad—buffalo hump
  • Increased neck circumference (by 5–10cm)
  • Breast hypertrophy (♀ and ♂)
  • Central truncal adiposity—pot belly due to ↑ intraperitoneal fat.

Lipoatrophy (especially associated with NRTIs, particularly stavudine)

  • Loss of subcutaneous fat from cheeks—emaciated appearance
  • Peripheral subcutaneous fat loss from arms, shoulders, thighs, buttocks.

Dyslipidaemia HIV infection (especially when advanced) may cause abnormalities in lipid metabolism which include:

  • ↑ serum triglyceride
  • ↓ total cholesterol—both high-density lipoprotein (HDL) and low-density lipoprotein (LDL)
  • ↓ triglyceride clearance
  • predominance of small, dense LDL particles.

It is reported in up to 80% of those taking HAART and especially prevalent in those taking a PI-based regimen. Typical abnormalities:

  • hypercholesterolaemia—mostly very-LDL but also intermediate density lipoproteins. HDL unchanged or ↑
  • hypertriglyceridaemia.

More frequent and severe with ritonavir and lopinavir–ritonavir, followed by amprenavir and nelfinavir with indinavir and saquinavir having the fewest effects. Atazanavir appears to have little, or no, effect although further data is required. NRTIs are much less liable to be implicated although stavudine is more likely to be associated with ↑ in cholesterol and triglycerides. The nucleotide reverse transcriptase inhibitor, tenofovir, may ↑ cholesterol and triglyceride levels but less than with stavudine. Non-NRTIs can cause alterations in the lipid profiles but to a much lesser extent than PIs. Nevirapine produces marginally smaller changes than efavirenz and improvements in lipid levels when switching from PIs. P.467
Hyperglycaemia 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% although this is increased to 5.9% with concomitant hepatitis C virus infection. Strongly linked to the use of PIs occurring in up to 17% with a median onset of symptoms about 60 days after starting treatment. Although, discontinuation of PIs may reverse hyperglycaemia there is insufficient data to estimate this likelihood. Its incidence does not vary substantially by PI used. Assessment Patients on antiretroviral therapy 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. Management

  • General advice
    • Nutrition: assessment, dietetic advice (low fat), 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 HAART before CD4 <200cells/µL or AIDS is diagnosed.
  • Care with choice of initial regimen if possible:
    • avoid PIs and NRTI combinations with highest risk
    • use zidovudine or tenofovir instead of stavudine.
  • 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.
    • Pravastatin is the preferred statin as it is least likely to interact with PIs. Lovastatin may also be suitable. Atorvastatin must be used with caution and simvastatin avoided because of substantial risks of PI interaction.
    • 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 hepatoxicity.
  • Other drugs
    • Metformin for insulin resistance, dyslipidaemia, and fat accumulation.
    • Growth hormone for 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®) and Bio-Alcamid(™) injections for lipoatrophy.

P.468
Electrolytes and water imbalance Sodium and water Hyponatraemia is a common finding in patients with advanced HIV disease. Up to 60% of hospitalized patients have low plasma sodium levels, mostly due to gastrointestinal loss associated with hypovolaemia. Respiratory and central nervous system infections or certain drugs, e.g. antidepressants, may cause the syndrome of inappropriate secretion of antidiuretic hormone. This is characterized by hyponatraemia, inappropriately ↑urinary osmolality 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. Hyporeninaemic hypoaldosteronism should be considered when hyponatraemia is associated with hyperkalaemia, providing normally functioning kidneys and adrenals. Hyponatraemia may be caused by miconazole and pentamidine and hypernatraemia (and nephrogenic diabetes insipidus) by foscarnet. Potassium High dose co-trimoxazole may result in hyperkalaemia especially with pre-existing renal impairment. Other causes include pentamidine-associated tubular nephropathy, HIV-nephropathy, and 1° adrenal insufficiency. Calcium and phosphate Up to 20% of patients will have hypocalcaemia at some stage. Causes include:

  • HIV enteropathy (most common).
  • Vitamin D deficiency.
  • Severe intercurrent illness.
  • Drugs
    • foscarnet binds calcium resulting in decreased ionized calcium.
    • ketoconazole inhibits 1,25-dihydroxy cholecalciferol (vitamin D) synthesis.
    • pentamidine causes renal loss of magnesium with 2° hypocalcaemia.

Hypophosphataemia may occur with intercurrent illness. Tenofovir can lead to hypophosphataemia as a result of effect on tubular function. HIV-associated wasting syndrome Defined by CDC as involuntary loss of >10% of body weight, plus >30 days of either diarrhoea or weakness and fever in the absence of concurrent illness other than HIV infection. An AIDS defining illness, less common since the introduction of HAART, when it accounted for up to 37% of AIDS diagnoses. Still a common problem independently associated with an increased risk of OIs, disease progression and death. Weight loss is mainly due to muscle wasting and to a lesser extent, loss of fat. P.469
Additional factors that exacerbate wasting include:

  • depression
  • nutritional balance e.g. anorexia, dysphagia, poor nutrient absorption
  • OIs
  • metabolism e.g. increased resting metabolic rate, increased protein turnover, increased production of cytokines, and low testosterone.

Assessment

  • Weight and body mass index at regular intervals help with early recognition and monitoring.
  • Specialist nutritional review.
  • Testosterone measurement.
  • Measurement of body composition (bioimpedence analysis and anthropometry are useful in monitoring changes over time).
  • Techniques such as dual energy x-ray absorptiometry (DEXA) scan, magnetic resonance imaging (MRI), and total body electrical conductivity provide more accurate measurement of body composition.

Management

  • Treatment of contributing factors.
  • Improving food intake by appropriate strategies including dietary supplements, enteral and parentral feeding.
  • Pharmacologic agents:
    • Testosterone may be considered to reverse muscle loss but there is concern about the adverse effects of long-term administration.
    • Megestrol an appetite stimulant (side-effects include hypogonadism, adrenal insufficiency, deep venous thrombosis, and avascular necrosis).
    • Growth hormone administration results in increase in 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 is beneficial, side-effects include liver toxicity.

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