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Adrenal Insufficiency and HIV disease

Adrenal Insufficiency and HIV disease. Eileen Maziarz , MD MTRH Resident Lecture 30 March 2010. Case One, JJ.

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Adrenal Insufficiency and HIV disease

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  1. Adrenal Insufficiency and HIV disease Eileen Maziarz, MD MTRH Resident Lecture 30 March 2010

  2. Case One, JJ • 43 yo African female with HIV (on ARVs through AMPATH, last CD4 253 9/09), on anti-TB medications since 11/09 (basis of dx unclear) presenting with 4 week h/o abd pain, vomiting, weight loss and dizziness. • Admitted 2/2010 MTRH and presumptively treated for malaria; presentation at that time similar to current presentation

  3. Case One, JJ • PMHx • HIV, on combivir/efavirenz • No history or PCP, cryptococcal disease or other Ois • Last CD4 253 9/2009 • TB therapy initiated 11/09 • Unclear basis of diagnosis, on continuation phase currently • PUD • Completed triple therapy • Medications • Combivir • Efavirenz • Metronidazole (since 2/2010 admission) • Paracetamol

  4. Case One, JJ – exam VS BP 80s/50s P 130s RR 28 T 37.9 SpO2 92% on RA General: Wasted, cachectic, ill-appearing. Confused. HEENT: Bitemporalis wasting. Anicteric. Conj pallor. OP clear w/o thrush. Dry MMM. Neck: flat JVP. Shotty LAD in cervical chains. Cardiopulmonary exams: notable only for regular tachycardia. JVP flat. Abd: scaphoid. No HSM or masses. Soft, ttp diffusely but no peritoneal signs. BS decreased Ext: warm and well-perfused Neuro: grossly intact though disoriented to place, time. Unable to walk 2/2 global weakness Skin: without lesions but diffusely hyperpigmented, including palms and soles. Poor skin turgor.

  5. Case One, JJ – evaluation • CBC-- H/H: 12.5/35 (MCV 103); WBC 1.2K; Plt 120K; No eosinophilia • UEC – Na 123, K 5.3, Cl 108, BUN 3.58, Cr 44 • Amylase/lipase – normal • CT head – negative • CSF – not under pressure, glc 4, prot 65, WBC 0, india ink and CRAG negative, gram stain and cx negative • MPS –ve x 1

  6. Outline • Adrenal Insufficiency • Background • Acute v Chronic • Primary v Central • US perspective v Kenyan perspective • AI in the setting of HIV disease

  7. Background and definitions • Impairment in adrenocortical function relative to body’s stress level • Leads to decreased production of mineralocorticoids, glucocorticoids, and/or adrenal androgens • Caused by diseases affecting adrenal cortex (primary), pituitary gland (secondary), or hypothalamus (tertiary) • Fatal if left untreated

  8. Adrenal Insufficiency • Clinical manifestations related to: • Rate and extent of loss of adrenal function • Whether mineralocorticoid production is preserved • Degree of underlying stress • Presence of AI may go undetected until stress precipitates crisis Dr Thomas Addison, British physician, who first described the condition in 1849. All six of the patients in which he first observed this condition had TB.

  9. H-P-A axis Harrison’s. 17th ed. 2008.

  10. Adrenal Crisis • Development of acute AI in the setting of • Previously undxd primary disease and major stress / severe infxn • Known AI with failure to incrementally increase steroids • Bilateral adrenal injury (infarction or hemorrhage) • Central adrenal insufficiency during acute stress (less common) • Pituitary infarction / apoplexy** • Severe headache, loss of visual fields, and shock • Abrupt withdrawal of glucocorticoids at doses that cause secondary AI • Rarely seen in secondary AI

  11. Acute adrenal crisis: features • Shock / HoTN • Anorexia • Nausea, vomiting • Diffuse abdominal pain • Fever • Weakness • Fatigue • Lethargy • Confusion, disorientation • Coma Predominantly mediated by mineralocorticoid deficiency

  12. Chronic Primary Adrenal Insufficiency: Features • Malaise and fatigue • Generalized weakness • Anorexia and weight loss • Nausea, vomiting*, abd pain, diarrhea or constipation • Hypotension, orthostasis, syncope • Hyponatremia** (up to 90%), hyperkalemia (60-65%); hypercalcemia rare Reflect deficiency in glucocorticoid, mineralocorticoid, or androgen activity

  13. Chronic Primary Adrenal Insufficiency: Features • Hyperpigmentation (generalized) • Sun-exposed areas • Areas subjected to chronic pressure • Palmar crease, buccal mucosa, dental line, under tongue and on hard palate, hair, nails • Disappears after normalization of adrenal function with therapy • Vitiligo • Due to AI destruction of dermal melanocytes • 10-20% of patients with AI adrenalitis • Hypoglycemia – rare • Androgen deficiency (females*) • Loss of axillary and pubic hair, • Loss of libido • Amenorrhea (25%) • Psychiatric disturbance • Memory impairment • Confusion  stupor • Depression • Psychosis

  14. Central Adrenal Insufficiency • ACTH (2ary) or CRH (3ary) deficiency → underproduction of glucocorticoids from adrenal cortex • Tertiary adrenal insufficiency caused by prolonged supraphysiologic doses of steroids ( >/= prednisone 7.5mg daily for >/= 3wks) • Usually do not present in adrenal crisis

  15. Central Adrenal Insufficiency • Similar to primary AI, including exacerbation of symptoms in stress • Exceptions: • Hyperpigmentation NOT seen • ACTH secretion is not elevated • HoTN, GI symptoms less prominent • Electrolyte disturbances (esp hyperK) not as common (Aldo secretion via RAAS) • HypoNa may still be present b/c cortisol deficiency increases plasma vasopressin levels. • Hypoglycemia more common • Co-existent GH deficiency • May demonstrate other findings of hypo-pituitarism, VF loss, headache, etc

  16. Primary Adrenal Insufficiency – Etiologies Autoimmune adrenalitis (70-90% of cases) • 35 – 120 cases per million persons, female predominance • Autoimmune destruction of adrenal cortex (both CMI and humoral immunity) • Target -- steroidogenic enzymes. All three zones of cortex involved in up to 75% of cases • Occurs in spectrum of polyglandular autoimmune syndromes • Screening for adrenal insufficiency is recommended in certain populations (those with celiac disease, who have been shown to have an 11-fold increased risk), though not currently recommended in all patients with DM1 • Most common cause of AI in developed world

  17. Primary Adrenal Insufficiency - Infectious Etiologies Tuberculosis • Previously MCC of Addison’s disease • 7-20% of cases worldwide presently • Hematogenous spread during active infection • Gradual onset • Granulomatous infiltration early, then calcification and replacement by caseating nodules and late fibrosis • Tx does not normalize adrenal function Disseminated fungal • Histoplasmosis, paracoccidiomycosis • Adrenal function may return to normal after treatment Other: • Syphilis, African trypanosomiasis (infrequent)

  18. Primary Adrenal Insufficiency – Other Etiologies Hemorrhage / infarction • Meningococcemia, Pseudomonas, E Coli Metastases • Lung/breast/melanoma/colon/lymphoma  generally clinically silent Drugs • Inhibitors of cortisol synthesis • Etomidate, ketoconazole, metyrapone, suramin • Usually not clinically evident unless in the setting of limited adrenal reserve • Increased cortisol metabolism • Phenytoin, rifampin Infiltrative diseases • Sarcoidosis, hemochromatosis

  19. Central Adrenal Insufficiency -- Etiologies Secondary Tertiary Panhypopituitarism • Pituitary tumors, craniopharyngiomas • TB, histoplasmosis • Infiltrative disorders • Trauma; Infarction (Sheehan’s syndrome); Hemorrhage (apoplexy) Medications • Megace, opiates Chronic high-dose glucocorticoid therapy • Any route of administration • Most common cause of AI overall Tx of Cushing’s syndrome

  20. Diagnosis of Adrenal Insufficiency • In any setting, requires high level of suspicion! • Relative adrenal insufficiency can be seen in critical illness • Laboratory evaluation • Early AM cortisol (establishes diagnosis) • Cortisol < 3 mcg/dL  Suggestive of AI (Cosyntropin stim to confirm) • Cortisol 3-18 mcg/dL  Equivocal (Cosyntropin stim test needed) • Cortisol > 18 mcg/dL  AI unlikely • Concurrent ACTH • Cortisol very low, ACTH very high  primary AI • Cortisol AND ACTH low  central AI • Unfortunately rapid assays for ACTH not available for rapid assessment

  21. Cosyntropin/ACTH Stim Testing • Used to diagnose AI in equivocal cases • Dexamethasone can be used for tx as does not interfere with testing • Perform in early AM if possible • Step 1: Baseline ACTH, cortisol measured • Step 2: 250 mcg Cosyntropin IV administered • Step 3: Cortisol measured 30-60min later • Normal response is an increase to > 18-20mcg/dL or increase by > 9mcg/dL • Insulin-induced hypoglycemia and metyraponet tests also available

  22. Primary, secondary or tertiary? • Simultaneous cortisol and ACTH measurements • ACTH must be drawn prior to initiation of glucocorticoids • Prolonged (48h) ACTH stimulation • Identifies 2ary and 3ary AI • Not used clinically often • Metyrapone test, insulin induced hypoglycemia • Used to detect partial ACTH deficiency (metyrapone) • CRH test • Can distinguish between 2ary and 3ary

  23. Once the diagnosis and level are established… Primary Secondary / tertiary • CT abdomen (adrenals) • PPD/CXR • Lupus anticoagulant • FNA • Ca/PO4/TFTs/glc/FSH/LH • Pituitary imaging (MRI)

  24. Treatment: Adrenal Crisis • Replete volume losses! • Labs for evaluation (chemistry, cortisol, ACTH) asap • Glucocorticoids (improve vascular tone that is decreased d/t increased ADH) • Hydrocortisone 100mg IV, Dexamethasone 4mg IV, etc • More useful than mineralocorticoids in acute setting • Taper with clinical improvement to maint dose

  25. Long-term treatment AI • Educate • Sick day caution and stress dosing (3 x 3 rule) – parenteral if vomiting • Glucocorticoid replacement • No head-to-head comparison between different glucocorticoids (dex, pred, hydrocortisone) • Goals • Mimic cortisol metabolism  divided doses • Control symptoms • Limit adverse effects • Mineralocorticoid replacement • Needed for most patients with primary AI • Fludrocortisone (monitor improvement in orthostasis, K, BP to determeine dose) • Androgen replacement (DHEA) • Women • Improves mood and enhances quality of life

  26. Adrenal Insufficiency and HIV/AIDS • Post-mortem analysis of persons with HIV/AIDS estimate up to 2/3 have adrenal involvement • Proportion of pts with overt clinical manifestations is substantially lower • M Tb • CMV necrotizing adrenalitis • MAC, cryptococcus , histoplasma, toxoplasmosis • Kaposi’s mets, lymphoma • Medication interactions Arch Intern Med. 2002;162:1095-1098

  27. AI in sub-saharan Africa • Retrospective analysis of patients presenting to South African teaching hospital with acute ‘Addison’s disease’ • Fifty patients • Features • Hyperpigmentation (86%), • Wt loss (67%), • Abdominal pain (20%) • Diarrhea (16%). • HypnoNa 78%) • HyperK (52%) • Hypoglc 19% • HyperCa (21%) Clin Endocrinol (Oxf). 1999 Jan;50(1):115-20.

  28. AI in sub-saharan Africa • 40% had normal basal cortisol levels without significant rise with ACTH stim testing • CT performed in 24 pts (48%) --- 10 were normal; 14 abnormal (bilateral enlargement in 11, calcification in two and atrophic adrenals in one) • Etiologies • Idiopathic (42%) • TB (34%; 16% old, 18% active) • Autoimmune (12%) • Metastatic (6%) • Other: sarcoidosis, hemochromatosis, adrenoleukodystrophy • One month mortality 12% Clin Endocrinol (Oxf). 1999 Jan;50(1):115-20.

  29. Case Two, LF • 39 yo AAM with HIV/HCV co-infection (on ARVs with undetectable VL), mod persistent asthma, schizophrenia and presents for unscheduled clinic visit • Complains of generalized malaise and fatigue, weakness, and vague abdominal pain for 3-4 weeks with associated N/V. States that he has not felt this terrible in years. • He also requests that you look at a “bump on his neck” that has been present for the past 3 months • Reports 100% adherence to ARVs, denies any EtOH or substance abuse and overall his asthma has been very well-controlled

  30. Case Two, LF Past medical history Medications • HIV/AIDS x 20 years • CD4 10%/120 (nadir 12), HIV viral load ND • Chronic HCV • Genotype 1) , VL 3 million • Moderate persistent asthma • Good recent control • Schizophrenia • Polysubstance abuse • History of multiple incarcerations, homelessness 1. Albuterol inhaler PRN 2. Atazanavir 300 mg po q day 3. Ritonavir 100 mg po q day 4. Truvada one tab po q day 5. Azithromycin 1200 mg po q week 6. Fluoxetine 40 mg po bid 7. Zyprexa 5 mg po q day 8. Fluticasone-salmeterol BID 9. TMP/SMZ one DS daily 10. Valacyclovir 1000 mg po q day

  31. Case Two, LF Exam: VS T 98.1 P 60, RR 16, BP 96/48 Wt 169# Gen: AAO. NAD. HEENT/Neck: OP clear. No thrush. Increased fat deposition in bilat cheeks. Neck: Supple. No LAD or thyromegaly. Very clear increased deposition of fat on posterior aspect of neck, new since last visit. Lungs: CTAB no wheeze CV: RRR no m/g/r Abd: + abd striae. S/NT/ND. No organomegaly Ext: W/WP. No C/C/E. Skin:No rashes, jaundice. Striae b/l arms.

  32. Case Two, LF • Evaluation: • CBC, Routine chemistry panel normal • Cortisol < 0.4 • ACTH < 1.6 • VL < 48 copies, CD4 200/12% • On further questioning he reports stopping Advair inhaler 6 weeks ago due to finances

  33. Uh-oh! HIV Med. 2008 Jul;9(6):389-96. \

  34. Case Two • Atazanavir/ritonavir switched to raltegravir and placed on slow prednisone taper • Symptoms improved dramatically at 2 week and 4 week follow up

  35. References • Francque et al. Bilateral adrenal haemorrhage and acute adrenal insufficiency in a blunt abdominal trauma: a case-report and literaturereview. Eur J Emerg Med. 2004 Jun;11(3):164-7. • Margaretten et al. Septicemic adrenal hemorrhage. Am J Dis Child 1963; 105:346. • Oelkers, W. Adrenal Insufficiency. NEJM.1996. 335 (16). 1206-1211. • Presotto et al. Acute adrenal failure as the heralding symptom of primary antiphospholipid syndrome: report of a case and review of the literature. Eur J Endocrinol. 2005 Oct;153(4):507-14. Rao, RH. Bilateral massive adrenal hemorrhage. Med Clin North Am. 1995 Jan;79(1):107-29. • Rao, RH et al. Bilateral massive adrenal hemorrhage: early recognition and treatment. Ann Intern Med. 1989 Feb 1;110(3):227-35. • Simon, DR and Palese, MA. Clinical update on the management of adrenal hemorrhage.Curr Urol Rep. 2009 Jan;10(1):78-83. • Siu et al. Adrenal insufficiency from bilateral adrenal hemorrhage. Mayo Clin Proc. 1990 May;65(5):664-70 • Streeten, D. Adrenal hemorrhage. Endocrinologist 1996; 6:277. • Udobi et al. Adrenal crisis after traumatic bilateral adrenal hemorrhage.J Trauma. 2001 Sep;51(3):597-600. • UptoDate 17.3

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