Transcript Impending Adrenal Crisis in the Setting of Bilateral

Adrenal Insufficiency and HIV disease
EILEEN MAZIARZ, MD
MTRH RESIDENT LECTURE
30 MARCH 2010
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
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
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.
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
Outline
 Adrenal Insufficiency
 Background
 Acute
v Chronic
Primary
v Central
 US perspective v Kenyan perspective
 AI in the setting of HIV disease
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
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.
H-P-A axis
Harrison’s. 17th ed. 2008
.
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

Acute adrenal crisis: features
 Shock / HoTN
 Weakness
 Anorexia
 Fatigue
 Nausea, vomiting
 Lethargy
 Diffuse abdominal pain
 Confusion,
 Fever
disorientation
 Coma
Predominantly mediated by mineralocorticoid deficiency
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
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
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
Central Adrenal Insufficiency
 Similar to primary AI, including exacerbation of symptoms in stress
 Exceptions:

Hyperpigmentation NOT seen



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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


ACTH secretion is not elevated
Co-existent GH deficiency
May demonstrate other findings of hypo-pituitarism, VF loss, headache, etc
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
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




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Disseminated fungal
 Histoplasmosis, paracoccidiomycosis
Adrenal function may return to normal after treatment
Other:
 Syphilis, African trypanosomiasis (infrequent)
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
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
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

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
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
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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
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
Once the diagnosis and level are established…
Primary
Secondary / tertiary
 CT abdomen (adrenals)
 Pituitary imaging (MRI)
 PPD/CXR
 Lupus anticoagulant
 FNA
 Ca/PO4/TFTs/glc/FSH/LH
Treatment: Adrenal Crisis
 Replete volume losses!
 Labs for evaluation (chemistry, cortisol, ACTH) asap
 Glucocorticoids (improve vascular tone that is decreased
d/t increased ADH)


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Hydrocortisone 100mg IV, Dexamethasone 4mg IV, etc
More useful than mineralocorticoids in acute setting
Taper with clinical improvement to maint dose
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
Adrenal Insufficiency and HIV/AIDS
 Post-mortem analysis of persons with HIV/AIDS
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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
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.
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
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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.
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
Case Two, LF
Past medical history

HIV/AIDS x 20 years


Chronic HCV


CD4 10%/120 (nadir 12), HIV viral load ND
Genotype 1) , VL 3 million
Moderate persistent asthma

Good recent control
Schizophrenia
 Polysubstance abuse
 History of multiple incarcerations,
homelessness

Medications
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
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.
Case Two, LF
 Evaluation:



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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
Uh-oh!
HIV Med. 2008 Jul;9(6):389-96. \
Case Two
 Atazanavir/ritonavir switched to raltegravir and placed on
slow prednisone taper
 Symptoms improved dramatically at 2 week and 4 week
follow up
References
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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):7883.
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.
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