First reports came in 1980s Problems
Inadequate systematic studies, inadequate female subjects, variable exclusion of OIs, neoplasms & drugs

Every endocrine organ affected Clinical significance
Some similar to other systemic illnesses Others unique to HIV infection

Pathogenetic Mechs: virus itself, OIs, Neops, Cytokines, Drugs True prevalence, relation to state of HIV, effects of replacement or other treatments ???

OIs & Neoplasms Affecting Endoc Glands
Cytomegalovirus Cryptococcus neoformans Mycobacterium avium intracellulare Mycobacterium tuberculosis Toxoplasmosis gondii Pneumocystis carinii (PCP) Histoplasma capsulatum Kaposi's sarcoma Lymphoma

Pneumocystis carinii (PCP) Cytomegalovirus (CMV)

Pneumocystis carinii (PCP) Cytomegalovirus Cryptococcus neoformans Aspergillus fumigatus Rhodococcus equi Haemophilus influenzae Microsporidia Histoplasma capsulatum Paracoccidiodes brasiliensis Mycobacterium avium intracellulare Mycobacterium tuberculosis Kaposi's sarcoma Lymphoma

Cytomegalovirus Toxoplasmosis gondii Mycobacterium avium intracellulare Kaposi's sarcoma Lymphoma

Cytomegalovirus (CMV) Pneumocystis carinii (PCP) Toxoplasmosis gondii Herpetic meningoencephalitis Lymphoma

Mycobacterium tuberculosis Mycobacterium avium intracellulare Pneumocystis carinii (PCP) Cytomegalovirus Toxoplasmosis gondii Kaposi's sarcoma

TFT abnormalities:
10-15% have altered thyroid function (both hypo & hyper) Euthyroid sick syndrome: Low T3, N/Low T4, N/Low/High TSH, High rT3
HIV: Low T3, N T4, High TBG, Low rT3 at all stages

Elevated TBG

With HAART, 10% of pts noted to have elevated TSH(?IRIS) Immune reconstitution Grave’s disease maybe a late cxn of HAART (9-48 months)

Alterations in TFT in HIV

HIV negative Non-thyroidal Illness T3 T4 rT3 TSH TBG N or / may be During recovery N N or N* N *

HIV Infected Stable Ill

N or N N or

*? IL-6, ? TNF

Causes of Thyroid Gland Dysf in HIV
OIs & tumors – CMV, Mycobacteria, Crypto, Toxo; KS
Mostly non-tender, diffuse enlargement Thyroid function usually normal

Pneumocystis thyroiditis: painful thyroiditis (tender gland, hyperthyroid, reduced uptake) Hypothalamic/pituitary diseases: Toxo, CMV,… Cytokines partly contribute (IL-6, TNF) Drugs:
Interferon: autoimmune hypothyroidism Rifampin: increased clearance higher L-T4 need

Clinical adrenal insufficiency not common Subtle deficiency of reserve common Causes:
Anatomic destruction of adrenal gland (Primary)
CMV, Mycobact, Metastases, Hemorrhage

Hypothalmic/Pituitary dysfunciton (Secondary)
Toxo, CMV, Lymphoma, KS, Direct HIV

Ketoconazole, Megestrol acetate, Rifampicin, Phenytoin, Opiates

Acquired GC Resistance:
Clinical hypoadrenalism; High cortisol; High ACTH Peripheral resistance to GC action

Adrenal Androgens:
Basal adrenal androgen secretion lower Low levels of DHEA & DHEA-sulfate Impaired response to ACTH Fall in DHEA may predict progression to AIDs

MC deficiency is uncommon Aldosterone response to ATCH found lower Electrolyte abnormalities not likely to be due to HIV (drug toxicities, interstitial kidney diseases, SIADH, …)

Usual Pattern of Adr Horm in HIV Pts
BASAL GLUCOCORTICOIDS MINERALOCORTICOIDS ANDROGENS Normal or cortisol; 17-deoxysteroids Normal AFTER ACTH Normal cortisol response Normal

Hypocalcemia: Calcium malabsorption, vitamin D deficiency Low PTH (baseline; response to low calcium), esp. in advanced HIV Drugs:
Pentamidine – hypocalcemia Ketoconazole – hypocalcemia (lowers 1,25(OH)D3 levels) Rifampin – lower 25-hydroxyvitamin D levels Amphotericin B – renal Mg & K wasting

Hypercalcemia: MAC – elevated 1,25-dihydroxy vitamin D Lymphoma – hypercalcemia with/without high 1,25(OH)D3 Local osteoclastic bone resorption – disseminated CMV PTHrP

HIV + HAART -- increased incidence of osteonecrosis & avascular necrosis of the hip & shoulders Osteonecrosis on MRI in 4.4% of asymptomatic pts
Lipid lowering agents, systemic GCs, testosterone, bodybuilding exercise, alcohol consumption

7% of women with HIV infection 41% have some degree of osteopenia

Clinical: decreased libido 2/3, impotence 1/3; overall 33-67% Biochemical evidences of hypogonadism: Common; increase with disease progression; + 50% in advanced HIV Low test with low/normal gonadotrophins (hypothalamic dysfunciton) Low testosterone with high gonadotrophins Testicular Pathology: Decreased spermatogenesis, Decreased number of interstitial cells Evidences of OI/neoplasm: Mycobacteria, Toxo, CMV, KS Androgen replacement should be considered in pts with symptomatic hypogonadism evidenced biochemically

Hypogonadotropic (Hypothalamo-pituitary)
Up to 75% Low GnRH – severe illness, malnutrition Low gonadotrophins (uncommon) – OI or neoplasms of pituitary

25-35% Tissue destruction, cytokine effect

SHBG increased by upto 50% (measure free values) Drugs:
Ketoconazole, Megestrole, Ganciclovir, Opiates

Not very well studied Available studies … variable results
Early stages: normal menstrual function Later stages: oligo/amenorrhea up to 25%+

Low levels of testosterone in 50-95%; correlated with
Lean body mass, exercise functional capacity (directly) HIV viral load (Indirectly)

Drugs, OIs & neoplasms have expected effects HIV infection does not seem to have a significant effect on the menstrual cycle outside the setting of advanced disease

Pan or isolated hypopituitarism is rare Pathology/Autopsy: OIs (CMV, Toxo, Crypto, P. jiroveci, Aspergillus); Neoplasms; Necrosis; Infarction Normal reserve in almost all pts PRL levels mostly normal; some have high values GH:
levels mostly normal Resistance to the growth-promoting effects of GH Low IGF-I despite ~ normal GH in acutely ill pts; wasting syndrome

SIADH: Central DI resported in pts with herpetic meningoencehalitis Low serum sodium may be also be due to adrenal insufficiency

Diabetes insipidus: rare
CDI reported in pt with herpetic meningoencephalitis

SIADH: common in HIV patients
Hyponatremia occurs in 30-50% of patients Mainly related to SIADH Other: hypoadrenalism Usually seen in conjunction with
Pulmonary disease: PcP, TB, Mech vent, …. CNS disease: Crypto, Lymphoma, Toxo, HIV-EP

Pancreatic Pathology:
A common target for OIs & malignancies Do not appear to be extensive enough to cause clinical dysfunction

Pentamidine, didanosine, zalcitabine Infiltration of gland (KS, NHL) Renal failure Critical illness with poor feeding ?? Directly HIV

Pentamidine, cotrimoxazole, didanosine, zalcitabine

Hyperglycemia: Glucose Homeostasis: Changes seen:
Higher rates of insulin clearance Increased sensitivity of peripheral tissues Increase in insulin-mediated glucose uptake Non-oxidative glucose disposal Hepatic glucose production rates tend to increase Insulin resistance state

Triglyceride levels elevated (VLDL)
Correlate with levels of interferon-alpha Decreased TG clearance Increased plasma FFAs - hepatic synthesis, peripheral lipolysis Decrease in lipoprotein lipase

Fatty acid oxidation tends to be increased in HIV Reduced TC, HDL, & LDL at all stages Increased prevalence of small dense LDL Lipid & lipoprotein abnormalities in HIV infection

Effect of HIV AIDS on Glucose & Lipid Metabolism Prior to Introduction of HAART
Insulin Resistance HIV AIDS Total Cholesterol Triglyceride VLDL LDL HDL

Peripheral fat wasting: face, arms, legs, buttocks Central fat accumulation: buffalo-hump, truncal obesity, breasts Metabolic features: elevated plasma TGs, TC, & apolipoprotein B, hyperinsulinemia & hyperglycemia (insulin resistance) 20% meet criteria for the metabolic syndrome 33-75% of pts receiving HAART Any time from ~6 weeks to several yrs following HAART initiation Seen with both protease-using & protease-sparing regimens Variable results on CV risk

Characteristics of Lipodystrophy.
A. Truncal obesity & buffalo hump. B. Facial wasting. C. Accumulation of intraabdominal fat on CT scan.

Pathogenesis: not clear LDL receptor inhibition, impaired Tg clearance Impaired ms glu transport (insulin resistance, GLUT-4 phosphorylation) Apoptosis of peripheral adipocytes, sparing of visceral adipocytes Mitochondrial toxicity Low serum adiponectin Treatment Options: Observation Management of high glucose & lipid levels
NECP guidelines should be followed in managing lipid abnormalities Mainly used are atorvastatin & gemfibrozil

Liposuction Insulin sensitizers: metformin, glitazones Metabolic: testosterone, GH, anabolic steroids

>10% involuntary wt loss + diarrhea >30 days/fever; Diagnosis of exclusion Mechanisms: Elevated REE (hypermetabolism) Reduced caloric intake Active secondary infections - rapid wt loss & then stability Gastrointestinal disease - slow persistent wt loss Endocrine: low testosterone; GH deficiency/resistance Cytokines – (no direct relation with cytokine or cytokine receptor levels) Treatments: Diet counseling has limited success HAART Testosterone (M,F): increased LBM, QOL; well tolerated GH: increased LBM, increased wt Megestrol acetate: stimulates appetite; steroidal side effects; hypogonadism hCG: increases testosterone Others: thalidomide, ARV, Exercise, Pentoxifylline, Dronabinol (THC), …

Rifampicin Ketoconazole Pentamidine

Mech of Action
Increased hormone clearance Inhibits P450 gonads Decreased steroidogenesis in adrenals &

Endoc/Metabolic Effects
If limited reserve: Hypothyroidism; hypoadrenalsism Hypoadrenalism Hypogonadism Hyperkelemia Acute hypoglycemia Chronic hyperglycemia Reduced cortisol Increased glucose Reduced testosterone Renal K & Mg wasting Hyperkalemia Hyponatremia Hyperglycemia Hyporeninemia hypoaldosteronism Hyperglycemia Impaired cortisol response to ACTH; Hypogonadism; Osteoporosis Glucose metabolic abnormalities Hypothyroidism; hypertriglyceridemia; exogenous Cushing’s syndrome Gynecomastia

Nephrotoxicity Pancreatic toxicity GC-like activity Progesterone activity Reduced tubular electrolyte reabsorption Blocks renal eipthelial Na channels Pancreatitis Interstitial nephritis Pancreatitis Alterations in HPA & HPG axes Insulin resistance; impaired insulin secretion Effect on hepatic cytochromes & drug metab Unclear mechanism

Megestrol acetate

Amphotericin B Trimethoprim

Sulfonamides Opiates PIs Ritonavir Efavirenz

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