Approximately 66% of post-mortem evaluations of the adrenal gland in HIV patients show abnormalities. Common infectious etiologies include CMV, Mycobacterium tuberculosis, Histoplasmosis, PCP, Toxoplasmosis, and Kaposi sarcoma.
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Screening Test Reveals Cushing's Syndrome
1. M I C H A E L K A V A N A U G H
A P R I L 4 , 2 0 1 4
AIDS CLINICAL ROUNDS
2. Disclosures
ī I have no relevant financial relationships with any
commercial supporters.
ī Unlabeled/Investigational products and/or services
will be mentioned in this CME offering.
3. 67 y/o Caucasian man with
HIV/AIDS, OCT CD4+
437/14%/VL undetectable who
presents to NMCSD ER with
complaint of progressive dyspnea
and a mild dry cough for the last 7
days
4. History Continued
ī Initially, his dyspnea was with stairs
ī Progressed to flat surfaces
īĄ Baseline can walk a few miles, dyspnea with 1 city block and
then at time of admission at rest for past 1-2 days
ī Dry cough for 7 days-no sputum or hemoptysis
ī 10 lb weight loss over last 6 weeks
ī Denies any fevers
ī Reports that his home blood pressures have been low
(systolic in 80s) so he stopped taking Lisinopril
5. Review of Systems
ī Constitution-no fevers or chills, +fatigue
ī HEENT-no sinus tenderness or rhinorrhea
ī Chest-one episode of substernal chest pain 4 days prior to
admission-none at present, no palpitations
ī Resp-DOE â now at rest shortness of breath, slight dry cough,
no sputum
ī GI-no abdominal pain, baseline chronic diarrhea-slight
improvement recently
ī GU-increased nocturia (baseline 1x/night, now 4x/night over
last 4 week)
ī MSK-Significant improvement in shoulder function after
steroid injection in December
ī Neuro-noncontributory
6. PMH
ī HIV+; dx oct2006-presented with
AIDS with PCP and was admitted
with respiratory distress, requiring
corticosteroid therapy which
resulted in a flare of KS
īĄ Currently undetectable on
Truvada/Atazanavir/ritonavir/Raltegr
avir
īĄ Switched from Kaletra/Truvada to
RAL/3tc/Ataz/Rit on 16sep 2012,
previously on Atripla for short period
īĄ Genotype 10/12/06: PI mutations:
I13V, M36L, L63P; no clinical
resistance
ī Kaposi Sarcoma s/p systemic
chemotherapy (doxorubicin)-
Jan07-Nov07
ī Cryptosporidium-treated with
nitazoxanide Sept10
ī BPH
ī HLD
ī Left Shoulder tendonitis-steroid
injection Dec 2013
ī HTN
ī C diff-oct06
ī PCP-oct06; based on BAL giemsa
ī CKD (GFR 50)
ī ED
ī Stage I diastolic dysfunction
ī 3rd degree AV block s/p
pacemaker--2007, pacemaker
recently checked OS PVD-jul07
ī B12 def.
ī gynecomastia
ī SCC L ear s/p MOHS-2008
ī L ear AK cryotherapy-Dec10
ī ?ABC hypersensitivity-Jul08
ī Diarrhea predominant IBS-since
age 45; prior significant diarrhea
while on Kaletra
7. Medical History continued
ī MEDS
īĄ Truvada
īĄ Raltegravir 400mg bid
īĄ Atazanavir 300mg daily
īĄ Ritonavir 100mg daily
īĄ Uroxatral 10mg qd
īĄ Lipitor 20mg qhs
īĄ Synthroid 75
īĄ Lisinopril 5mg-held for 1 day
īĄ Fish oil 2 pills (1200mg) qam
īĄ ASA 81mg qd
īĄ MVI (Ocuvite)
ī Allergies-Sulfa
ī Past Surgical History
īĄ Cholecystectomy 2009
īĄ Septoplasty
īĄ Skin excision for SCC
īĄ Shoulder injection (Dec 2013)
ī Social History
īĄ Married-lives with wife
īĄ Nonsmoker, No alcohol
īĄ Retired Navy MCPO
8. Exposure History
ī Travel: No travel outside US since 2006
ī Animals: 2 dogs
ī Food Exposure: noncontributory
ī Soil Exposure: occasional gardening in home, does
not wear a mask
ī Other: Denies sick contacts
9. Physical Exam
ī T98.3 P94 R16 BP 132/72 99% RA wt 56 kg
ī GEN: NAD, A&Ox4, WDWN
ī HEENT: PERRL, EOMI, nl sclera, no photophobia, no throat inflammation.
ī NECK: nl thyroid, no neck masses, no JVD
ī HEART: RRR S1/S2, no M/G/R
ī LUNGS: CTA Bilaterally
ī ABD: Soft NT/ND, +BS, no HSM
ī LYMPHATICS: No LE edema, no axillary, groin, neck adenopathy.
ī EXT: No LE edema
ī MUSCULOSKELETAL: no joint effusions or pain, no muscle tenderness
ī DERM: Actinic keratoses on right cheek & on his forehead, also with 2 mm of purple
hyperpigmentation on right cheek. No lesions or sores visible elsewhere. (+) for
hyperpigmentation on right forearm from prior Kaposi's sarcoma
ī NEURO: CN 2-12 grossly intact, no focal deficits
ī PSYCH: no perceived mood disorder, nl demeanor with appropriate behavior.
ī LINES/DEVICES: Clean without signs of infection
10. Labs/Radiology
ī CBC 4.9/11.3/33.2/181 N77.4 L16.5
ī Lytes 131/3.6/93/26/31/1.3/200 Ca 8.9 Mg 2 P 2.1
ī AST 16 ALT 20 Alk P 68
ī T bili 2.6
ī Alb 3.6 total protein 6.5
14. Hospital Course
ī CT Chest performed-negative
ī ECG and cardiac enzymes unremarkable
ī No antibiotics provided
ī No bronchoscopy performed
ī Diagnosed with a URI?
ī Also diagnosed with new onset DM-HbA1C 6.6
īĄ Diabetic teaching provided
īĄ No medications initiated
ī Held Lisinopril as possible source of cough
ī Fatigue improved without significant intervention
15. Clinic Follow up
ī Patient reports feeling very well
īĄ Walking 1-2 miles per day
īĄ Nocturia has returned to 1x per night (baseline)
īĄ Diarrhea has remained â actually improved over last 2 months
īĄ Shoulder feels very well
īĄ Afebrile
īĄ No cough or SOB
ī Blood Pressures off Lisinopril 120s-130s
ī Blood Sugars in 130-166
17. Another Comparable Case
50 year old male with HIV+ CD4
503/13% VL undetectable, on
Truvada, atazanavir/ritonavir
(RV168 protocol patient), prior KS
(Jan 2012) treated with radiation
presents for clinic follow-up with 20
lb weight loss over last 6 months
18. Pertinent History
ī Patient had intra-articular steroid injection (Aug
2013)-kenalog in left shoulder (2 years shoulder pain)
īĄ Developed fatigue, shakiness and drenching night sweats
without fevers
īĄ Wasting of arms and legs
īĄ Dyspnea on exertion
īĄ Abdominal bloating
īĄ Increased urinary frequency (3x nocturia)
īĄ A1C increased from 6.3->7 in one month-post-prandial glucose
180
īĄ Lost 15 lbs in 4-6 weeks
īĄ New skin lesions requiring surgical removal
19. Pertinent History Continued
ī At time-period annotated on previous, he had a
recent decrease in CD4 from 504/19% to 214/11%
īĄ Started on TMP/SMX
īĄ Weight loss, change in CD4, history of KS & new skin lesions
īˇ Concern of recurrence
ī Bloating sensation with weight loss
īĄ Received cholecystectomy
ī Adrenal insufficiency was âruled outâ by primary
care provider
20. Past Medical History
ī HIV diagnosed 1996 â
genotype 2001 M184V,
K103R, L63, M36
ī Headache syndrome
ī Depression
ī Allergic rhinitis
ī Kaposiâs sarcoma Jan 2012
īĄ Radiation x 10
ī BPH s/p TURP
ī Herpes
ī Resolved hepatitis B
ī FHx
ī Family medical history:
īĄ Diabetes-maternal side
īĄ Breast CA maternal aunt
ī PSH
īĄ PRK
īĄ R inguinal hernia repair
īĄ TURP-1999
īĄ Cholecystectomy â Sep 13
īĄ Septoplasty
ī NKDA
ī Social History
īĄ Denies tobacco
īĄ + EtOH 4X/week
īĄ Denies ilicits
īĄ Currently in monogamous
relationship, partner is
seronegative
īĄ Works in health systems
management
21. Medications
ī Atazanavir 300mg po daily
ī Ritonavir 100mg po daily
ī Truvada (tenofovir 300mg +Emtricitabine 200mg)
po daily
ī Fexofenadine 60mg po bid
ī Atorvastatin 20mg po daily
ī Escitalopram 10mg po daily
ī Sumitriptan prn
ī Hydrocortisone
ī TMP/SMX
22. Physical Exam
ī T99.2 BP 134/86 P98 R14
ī Gen well appearing
ī Head-cushingoid with moon like facies
ī Neck-increased fat on posterior neck and upper back
ī Oral cavity normal
ī Lymph nodes-no abnormalities noted
ī Lungs cta (b)
ī CV RRR no murmur
ī Abd +bs, soft, NT, ND, well healed surgical scars
ī Musculoskeletal-arm thinning (b)
ī Neuro CN II-XII intact
ī Skin scattered purple plaques on arms, legs and bilateral feet
23. Evaluation
ī CBC 8.1/14.2/42.4/222 N 45.9 L 46.3 E 0.7
ī Lytes 144/3.6/105/23/10/0.9/104 Ca 8.4 Mg 2.3
ī Bili 2.1 Prot 6.5
ī Alk P 52 ALT 43 AST 26
ī UA SG 1.017 protein neg, gluc neg, pH 6
ī Skin lesions evaluated by dermatology including bx
īĄ Negative for KS
24. AM Cortisol
ī Cortisol AM Site/Specimen 03 Oct 2013 0910
ī Cortisol AM SERUM 9.760 <o> mcg/dL
(6.2-19.4)
ī Cortisol AM Site/Specimen 03 Oct 2013 0840
ī Cortisol AM SERUM 7.210 <o> mcg/dL
(6.2-19.4)
ī Cortisol AM Site/Specimen 03 Oct 2013 0800
ī Cortisol AM SERUM 0.778 (L) <o>mcg/dL
(6.2-19.4)
25. Additional Labs
ī Thyroxine free 1.2 nl
ī HBA1C 7 (previous 6.3)
ī Liver enzymes (September) Alk P 213 ALT 162 AST
33 T bili 2.73 with dbili 0.35
26. Course continued
ī As steroid level waned-fatigue worsened
ī Endocrine consult-Diagnosed with Cushingâs
Syndrome with secondary adrenal insufficiency
ī Started on hydrocortisone with taper
ī Recognized that ritonavir may be issue
ī Checked ACTH-low nml 8 (6-50 pg/mL)
ī MRI brain- nondiagnostic
ī Performed cosyntropin stimulation test normal
(7.94->19) in one hour, stopped hydrocortisone
27. Which of the following is an appropriate
screening test for Cushingâs Syndrome?
ī Urine Cortisol
ī Urine Metanephrines
ī Salivary Metanephrines
ī Cosyntropin (ACTH) stimulation test
ī Serum Metanephrines
28. Which of the following is an appropriate
screening test for Cushingâs Syndrome?
ī Urine Cortisol
īĄ Confirmatory with Dexamethasone suppression test
ī Urine Metanephrines
ī Salivary Metanephrines
ī Cosyntropin (ACTH) stimulation test
ī Serum Metanephrines
29. Cushingâs Syndrome
ī Iatrogenic hypercortisolism (most common)
īĄ Ingested/injected/topical/inhaled steroids & megestrol acetate
ī Ectopic ACTH syndrome- 20 to small cell lung cancer
or adrenal tumors
ī Cushingâs Disease-pituitary ACTH source
ī Factitious Cushingâs- surreptitious intake of steroids
ī Hypercortisolism can occur
īĄ Extreme stress (including sepsis)
īĄ Obesity and polycystic ovary syndrome
īĄ Severe prolonged major depressive disorder
īĄ Chronic alcoholism
30. Clinical Manifestations
ī Progressive Central obesity
īĄ Children with generalized obesity and growth retardation
ī Facial Fat accumulation âMoon faciesâ
ī Buffalo hump
ī Skin atrophy
ī Easy bruisability
ī Striae
ī Fungal infections
ī Hyperpigmentation-induced by increased ACTH (not
cortisol)-binds melanocyte-stimulating hormone
ī Menstrual irregularities
ī Proximal muscle wasting âcatabolism
ī Bone loss-can result in pathological fractures
32. Manifestations continued
ī Glucose intolerance
īĄ Stimulation of gluconeogenesis by cortisol & peripheral insulin
resistance
īĄ Hyperglycemia in 10-15% of patients
ī Cardiovascular disease
īĄ Increased risk of MI and Stroke
īĄ Hypertension
ī Thromboembolic disease
ī Neuropsychiatric (labile, depressed, anxiety, panic
attacks)
ī Increased frequency of Infections-inhibited immune
system
ī Ophthalmologic findings-increased IOP & cataracts
33. Test for Cushingâs Syndrome
ī Daily urinary cortisol (24 hours best)
īĄ 10 pm-8 am is acceptable alternative
ī Late evening salivary cortisol-only beneficial if
extremely elevated
ī Low dose dexamethasone suppression test
īĄ Should suppress ACTH and subsequently reduce urine cortisol
34. Test of Adrenal Insufficiency
ī Morning cortisol level
īĄ > 11 ug/dL not adrenal suppression
īĄ <3 ug/dL adrenal suppression
ī Follow up study is cosyntropin (ACTH) stimulation test
35. Although idiopathic adrenal insufficiency in HIV is rare, what
percentage of post-mortem evaluations of the adrenal gland
are abnormal?
ī <5%
ī 10%
ī 25%
ī 33%
ī 66%
36. Although idiopathic adrenal insufficiency in HIV is rare, what
percentage of post-mortem evaluations of the adrenal gland
are abnormal?
ī <5%
ī 10%
ī 25%
ī 33%
ī 66%-common sources include CMV,
Mycobacteria tuberculosis, Histoplasmosis,
PCP, Toxoplasmosis and Kaposiâs Sarcoma
37. Adrenal Function in HIV
ī Higher basal cortisol & lower dehydroepiandrosterone
ī Overt adrenal insufficiency is uncommon
ī Hypercortisolism in the absence of Cushings
īĄ No treatment required
ī Hypocortisolism always requires treatment
38. Comparison with Lypodystrophy with PIs
âpseudo Cushingsâ
ī Altered body adipose tissue
ī Truncal obesity
ī Peripheral wasting
ī Breast hypertrophy
ī âBuffalo humpâ
ī Insulin hypersensitivity
ī Normal cortisol and normal dexamethasone
suppression tests
ī Lack striae and easy bruisability
39. When combined with corticosteroids, which medication has
been reported to be a contributing factor in iatrogenic
Cushingâs Syndrome?
ī Etravirine
ī Ritonavir
ī Zidovudine
ī Tenofovir
ī Emtricitabine
40. When combined with corticosteroids, which medication has
been reported to be a contributing factor in iatrogenic
Cushingâs Syndrome?
ī Etravirine
ī Ritonavir
ī Zidovudine
ī Tenofovir
ī Emtricitabine
41. Ritonavir and Clearance of Steroids
ī Iatrogenic Cushingâs Syndrome with
Osteoporosis and Secondary Adrenal Failure
in Human Immunodeficiency Virus-Infected
Patients Receiving Inhaled Corticosteroids
and Ritonavir-Boosted Protease Inhibitors:
Six Cases
īĄ Samaras, K, Pett S, Gowers, A et al. J Clin Endo and
Metabolism 2005.
īĄ Review in 2008 reported 25 cases at that date of
ritonavir and fluticasone combination
42. Clearance of steroids can be delayed by PI
including ritonavir
ī 6 patients reported to develop iatrogenic Cushings
following inhaled fluticasone for asthma
īĄ Adrenal suppression noted in all 6 patients
īĄ When fluticasone removed-4/6 developed hypocortisolism
īĄ 3/6 developed osteoporosis with pathological fx (1/6)
īĄ Exacerbation of DM (1/6)
ī These patients had prior lipodystrophy delaying
diagnosis
īĄ Fluticasone is lipophilic-prior lipodystrophy may contribute
ī Wide range of variability of 24-hour urine free cortisol
levels
īĄ Suppressed is suppressed
īĄ Remained suppressed for > 5 months
44. Cushingâs syndrome with adrenal suppression induced by inhaled
budesonide due to a ritonavir drug interaction with a woman with
HIV infection. Yoganthan K et al. 2011 Int J STD and AIDS
ī 48 year old HIV+ woman with CD4 812 VL undetectable
on darunavir/ritonavir emtricatabine and efavirenz (stable
regimen for 3 years) presented with cushingoid features
after taking inhaled budesonide for 18 months
īĄ Iatrogenic Cushings w/ secondary adrenal suppression
īĄ After cortisols resolved, Cushingoid habitus remained
ī 2010-Prior reported case of budesonide & PIs resulting in
Cushings in 37 year old African woman
ī Budesonide, beclomethasone & triamcinolone
recommended as safer options
īĄ Fluticasone longest half life and most lipophilic
45. Iatrogenic Cushingâs syndrome after intra-articular
triamcinolone in a patient receiving ritonavir-boosted
darunavir Hall JJ et al. 2013 Int J STD & AIDS
ī Triamcinololone is metabolized by CYP3A4
ī Ritonavir has greatest effect on CYP3A4 of the PIs
ī Case: 53 year old woman on darunavir/r who
developed cushinoid symptoms 2 weeks after
receiving single triamcinolone dose in left shoulder
ī Triamcinolone injection (both intra-articular and
epidural) related Cushingâs Syndrome has been
reported previously (usual dose 40-80 mg)
ī Follow on HPA axis suppression usually 2-6 months
ī No reports with cobicistat-but significant CYP3A4
47. Which of the following is the most sensitive test
for diagnosis of glucocorticoid induced diabetes?
ī Random plasma glucose >200 mg/dl
ī 75 g oral glucose tolerance test (2 hour value)> 150
ī Fasting plasma glucose>126
ī Hemoglobin A1C>6.5%
48. Which of the following is the most sensitive test
for diagnosis of glucocorticoid induced diabetes?
ī Random plasma glucose >200 mg/dl
ī 75 g oral glucose tolerance test (2 hour value)> 150
ī Fasting plasma glucose>126
ī Hemoglobin A1C>6.5%
49. Glucocorticoid Induced Diabetes and Adrenal
Suppression
ī Lansang MC, Hustak L. Glucocorticoid-induced diabetes and
adrenal suppresion: How to detect and manage them. Cleveland
Clinic Journal of Medicine. 2011: 78: 748-756.
ī 9% of patients with RA develop DM within 2 years of steroids
īĄ All types of glucocorticoid formulations including eye drops
īĄ Mechanism is insulin resistance in liver
īˇ Peak effect 4-6 hours after dose
īĄ Symptoms (either iatrogenic diabetes or Cushingâs) less likely
if regimen mimics physiology (diurnal variation)
īĄ Insufficiency (Addisonâs)-failure of adrenals or pituitary
51. Early diagnosis and treatment of steroid-induced diabetes mellitus
in patients with rheumatoid arthritis and other connective tissue
diseases. Ito S et al. Modern Rheumatology 2014.
ī Mechanism-augmentation of hepatic
gluconeogenesis & inhibition of glucose uptake in
adipose tissue
ī Since steroids are administered in am, most
hyperglycemia is afternoon post-prandial
ī Author recommended dividing steroid dosing
52. References
ī http://www.uptodate.com/contents/establishing-the-diagnosis-of-cushings-
syndrome?source=search_result&search=cushings&selectedTitle=1%7E150 Accessioned 31
March 2014
ī http://www.uptodate.com/contents/epidemiology-and-clinical-manifestations-of-cushings-
syndrome?source=search_result&search=cushings&selectedTitle=2%7E150 Accessioned 31
March 2014
ī Samaras, K, Pett S, Gowers, A et al. Iatrogenic Cushingâs Syndrome with Osteoporosis and Secondary Adrenal Failure in
Human Immunodeficiency Virus-Infected Patients Receiving Inhaled Corticosteroids and Ritonavir-Boosted Protease
Inhibitors: Six Cases. J Clin Endo and Metabolism 2005: 90:2005-36.
ī Lansang MC, Hustak L. Glucocorticoid-induced diabetes and adrenal suppresion: Howe to detect and manage them.
Cleveland Clinic Journal of Medicine. 2011: 78: 748-756.
ī Yoganthan K et al. Cushingâs syndrome with adrenal suppression induced by inhaled
budesonide due to a ritonavir drug interaction with a woman with HIV infection. Int J STD and
AIDS. 2011:23:520-521.
ī Hall JJ et al. Iatrogenic Cushingâs syndrome after intra-articular triamcinolone in a patient
receiving ritonavir-boosted darunavir. Int J STD & AIDS. 2013: 24:748-756.
ī Ito S et al. Early diagnosis and treatment of steroid-induced diabetes mellitus in patients with
rheumatoid arthritis and other connective tissue diseases. Modern Rheumatology 2014. 24:52-
59.
ī Gerardo J et al. Prevalence of abnormal adrenocortical function in human immunodefiency
virus by low dose cosyntropin test. Int J of STD and AIDS. 2001: 12: 804-810.
ī Mayo, J et al. Adrenal Function in the Human Immunodeficiency Virus-Infected Patient. Arch
Intern Med. 2002: 162: 1095-1098.
ī Foisy MM. et al. Adrenal suppression and Cushingâs syndrome secondary to an interaction
between ritonavir and fluticasone: a review of the literature.
54. Which of the following is the most sensitive test
for diagnosis of glucocorticoid induced diabetes?
ī Random plasma glucose >200 mg/dl
ī 75 g oral glucose tolerance test (2 hour value)> 150
ī Fasting plasma glucose>126
ī Hemoglobin A1C>6.5%
55. Which of the following is the most sensitive test
for diagnosis of glucocorticoid induced diabetes?
ī Random plasma glucose >200 mg/dl
ī 75 g oral glucose tolerance test (2 hour value)> 150
ī Fasting plasma glucose>126
ī Hemoglobin A1C>6.5%
56. When combined with corticosteroids, which medications has
been reported to be a contributing factor in iatrogenic
Cushingâs Syndrome?
ī Etravirine
ī Ritonavir
ī Zidovudine
ī Tenofovir
ī Emtricitabine
57. When combined with corticosteroids, which medications has
been reported to be a contributing factor in iatrogenic
Cushingâs Syndrome?
ī Etravirine
ī Ritonavir
ī Zidovudine
ī Tenofovir
ī Emtricitabine
58. Which of the following is an appropriate
screening test for Cushingâs Syndrome?
ī Urine Cortisol
ī Urine Metanephrines
ī Salivary Metanephrines
ī Cosyntropin (ACTH) stimulation test
ī Serum Metanephrines
59. Which of the following is an appropriate
screening test for Cushingâs Syndrome?
ī Urine Cortisol
īĄ Confirmatory with Dexamethasone suppression test
ī Urine Metanephrines
ī Salivary Metanephrines
ī Cosyntropin (ACTH) stimulation test
ī Serum Metanephrines
60. Although idiopathic adrenal insufficiency in HIV is rare, what
percentage of post-mortem evaluations of the adrenal gland
are abnormal?
ī <5%
ī 10%
ī 25%
ī 33%
ī 66%
61. Although idiopathic adrenal insufficiency in HIV is rare, what
percentage of post-mortem evaluations of the adrenal gland
are abnormal?
ī <5%
ī 10%
ī 25%
ī 33%
ī 66%-common sources include CMV,
Mycobacteria tuberculosis, Histoplasmosis,
PCP, Toxoplasmosis and Kaposiâs Sarcoma