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.

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
 I have no relevant financial relationships with any
commercial supporters.
 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
 Initially, his dyspnea was with stairs
 Progressed to flat surfaces
 Baseline can walk a few miles, dyspnea with 1 city block and
then at time of admission at rest for past 1-2 days
 Dry cough for 7 days-no sputum or hemoptysis
 10 lb weight loss over last 6 weeks
 Denies any fevers
 Reports that his home blood pressures have been low
(systolic in 80s) so he stopped taking Lisinopril

5. Review of Systems
 Constitution-no fevers or chills, +fatigue
 HEENT-no sinus tenderness or rhinorrhea
 Chest-one episode of substernal chest pain 4 days prior to
admission-none at present, no palpitations
 Resp-DOE – now at rest shortness of breath, slight dry cough,
no sputum
 GI-no abdominal pain, baseline chronic diarrhea-slight
improvement recently
 GU-increased nocturia (baseline 1x/night, now 4x/night over
last 4 week)
 MSK-Significant improvement in shoulder function after
steroid injection in December
 Neuro-noncontributory

6. PMH
 HIV+; dx oct2006-presented with
AIDS with PCP and was admitted
with respiratory distress, requiring
corticosteroid therapy which
resulted in a flare of KS
 Currently undetectable on
Truvada/Atazanavir/ritonavir/Raltegr
avir
 Switched from Kaletra/Truvada to
RAL/3tc/Ataz/Rit on 16sep 2012,
previously on Atripla for short period
 Genotype 10/12/06: PI mutations:
I13V, M36L, L63P; no clinical
resistance
 Kaposi Sarcoma s/p systemic
chemotherapy (doxorubicin)-
Jan07-Nov07
 Cryptosporidium-treated with
nitazoxanide Sept10
 BPH
 HLD
 Left Shoulder tendonitis-steroid
injection Dec 2013
 HTN
 C diff-oct06
 PCP-oct06; based on BAL giemsa
 CKD (GFR 50)
 ED
 Stage I diastolic dysfunction
 3rd degree AV block s/p
pacemaker--2007, pacemaker
recently checked OS PVD-jul07
 B12 def.
 gynecomastia
 SCC L ear s/p MOHS-2008
 L ear AK cryotherapy-Dec10
 ?ABC hypersensitivity-Jul08
 Diarrhea predominant IBS-since
age 45; prior significant diarrhea
while on Kaletra

7. Medical History continued
 MEDS
 Truvada
 Raltegravir 400mg bid
 Atazanavir 300mg daily
 Ritonavir 100mg daily
 Uroxatral 10mg qd
 Lipitor 20mg qhs
 Synthroid 75
 Lisinopril 5mg-held for 1 day
 Fish oil 2 pills (1200mg) qam
 ASA 81mg qd
 MVI (Ocuvite)
 Allergies-Sulfa
 Past Surgical History
 Cholecystectomy 2009
 Septoplasty
 Skin excision for SCC
 Shoulder injection (Dec 2013)
 Social History
 Married-lives with wife
 Nonsmoker, No alcohol
 Retired Navy MCPO

8. Exposure History
 Travel: No travel outside US since 2006
 Animals: 2 dogs
 Food Exposure: noncontributory
 Soil Exposure: occasional gardening in home, does
not wear a mask
 Other: Denies sick contacts

9. Physical Exam
 T98.3 P94 R16 BP 132/72 99% RA wt 56 kg
 GEN: NAD, A&Ox4, WDWN
 HEENT: PERRL, EOMI, nl sclera, no photophobia, no throat inflammation.
 NECK: nl thyroid, no neck masses, no JVD
 HEART: RRR S1/S2, no M/G/R
 LUNGS: CTA Bilaterally
 ABD: Soft NT/ND, +BS, no HSM
 LYMPHATICS: No LE edema, no axillary, groin, neck adenopathy.
 EXT: No LE edema
 MUSCULOSKELETAL: no joint effusions or pain, no muscle tenderness
 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
 NEURO: CN 2-12 grossly intact, no focal deficits
 PSYCH: no perceived mood disorder, nl demeanor with appropriate behavior.
 LINES/DEVICES: Clean without signs of infection

10. Labs/Radiology
 CBC 4.9/11.3/33.2/181 N77.4 L16.5
 Lytes 131/3.6/93/26/31/1.3/200 Ca 8.9 Mg 2 P 2.1
 AST 16 ALT 20 Alk P 68
 T bili 2.6
 Alb 3.6 total protein 6.5

11. Normal Chest Xray

12. Differential

13. Patient Evaluation
 Urine Legionella pneumo Ag neg
 Urine Streptococcus pneumoniae Ag negative
 Urine Cultures negative
 Blood Cultures negative
 Respiratory Viral Panel-negative
 Sputum Culture-negative
 Sputum for silver stain-negative
 Sputum PCP PCR negative

14. Hospital Course
 CT Chest performed-negative
 ECG and cardiac enzymes unremarkable
 No antibiotics provided
 No bronchoscopy performed
 Diagnosed with a URI?
 Also diagnosed with new onset DM-HbA1C 6.6
 Diabetic teaching provided
 No medications initiated
 Held Lisinopril as possible source of cough
 Fatigue improved without significant intervention

15. Clinic Follow up
 Patient reports feeling very well
 Walking 1-2 miles per day
 Nocturia has returned to 1x per night (baseline)
 Diarrhea has remained – actually improved over last 2 months
 Shoulder feels very well
 Afebrile
 No cough or SOB
 Blood Pressures off Lisinopril 120s-130s
 Blood Sugars in 130-166

16. What Happened?

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
 Patient had intra-articular steroid injection (Aug
2013)-kenalog in left shoulder (2 years shoulder pain)
 Developed fatigue, shakiness and drenching night sweats
without fevers
 Wasting of arms and legs
 Dyspnea on exertion
 Abdominal bloating
 Increased urinary frequency (3x nocturia)
 A1C increased from 6.3->7 in one month-post-prandial glucose
180
 Lost 15 lbs in 4-6 weeks
 New skin lesions requiring surgical removal

19. Pertinent History Continued
 At time-period annotated on previous, he had a
recent decrease in CD4 from 504/19% to 214/11%
 Started on TMP/SMX
 Weight loss, change in CD4, history of KS & new skin lesions
 Concern of recurrence
 Bloating sensation with weight loss
 Received cholecystectomy
 Adrenal insufficiency was “ruled out” by primary
care provider

20. Past Medical History
 HIV diagnosed 1996 –
genotype 2001 M184V,
K103R, L63, M36
 Headache syndrome
 Depression
 Allergic rhinitis
 Kaposi’s sarcoma Jan 2012
 Radiation x 10
 BPH s/p TURP
 Herpes
 Resolved hepatitis B
 FHx
 Family medical history:
 Diabetes-maternal side
 Breast CA maternal aunt
 PSH
 PRK
 R inguinal hernia repair
 TURP-1999
 Cholecystectomy – Sep 13
 Septoplasty
 NKDA
 Social History
 Denies tobacco
 + EtOH 4X/week
 Denies ilicits
 Currently in monogamous
relationship, partner is
seronegative
 Works in health systems
management

21. Medications
 Atazanavir 300mg po daily
 Ritonavir 100mg po daily
 Truvada (tenofovir 300mg +Emtricitabine 200mg)
po daily
 Fexofenadine 60mg po bid
 Atorvastatin 20mg po daily
 Escitalopram 10mg po daily
 Sumitriptan prn
 Hydrocortisone
 TMP/SMX

22. Physical Exam
 T99.2 BP 134/86 P98 R14
 Gen well appearing
 Head-cushingoid with moon like facies
 Neck-increased fat on posterior neck and upper back
 Oral cavity normal
 Lymph nodes-no abnormalities noted
 Lungs cta (b)
 CV RRR no murmur
 Abd +bs, soft, NT, ND, well healed surgical scars
 Musculoskeletal-arm thinning (b)
 Neuro CN II-XII intact
 Skin scattered purple plaques on arms, legs and bilateral feet

23. Evaluation
 CBC 8.1/14.2/42.4/222 N 45.9 L 46.3 E 0.7
 Lytes 144/3.6/105/23/10/0.9/104 Ca 8.4 Mg 2.3
 Bili 2.1 Prot 6.5
 Alk P 52 ALT 43 AST 26
 UA SG 1.017 protein neg, gluc neg, pH 6
 Skin lesions evaluated by dermatology including bx
 Negative for KS

24. AM Cortisol
 Cortisol AM Site/Specimen 03 Oct 2013 0910
 Cortisol AM SERUM 9.760 <o> mcg/dL
(6.2-19.4)
 Cortisol AM Site/Specimen 03 Oct 2013 0840
 Cortisol AM SERUM 7.210 <o> mcg/dL
(6.2-19.4)
 Cortisol AM Site/Specimen 03 Oct 2013 0800
 Cortisol AM SERUM 0.778 (L) <o>mcg/dL
(6.2-19.4)

25. Additional Labs
 Thyroxine free 1.2 nl
 HBA1C 7 (previous 6.3)
 Liver enzymes (September) Alk P 213 ALT 162 AST
33 T bili 2.73 with dbili 0.35

26. Course continued
 As steroid level waned-fatigue worsened
 Endocrine consult-Diagnosed with Cushing’s
Syndrome with secondary adrenal insufficiency
 Started on hydrocortisone with taper
 Recognized that ritonavir may be issue
 Checked ACTH-low nml 8 (6-50 pg/mL)
 MRI brain- nondiagnostic
 Performed cosyntropin stimulation test normal
(7.94->19) in one hour, stopped hydrocortisone

27. Which of the following is an appropriate
screening test for Cushing’s Syndrome?
 Urine Cortisol
 Urine Metanephrines
 Salivary Metanephrines
 Cosyntropin (ACTH) stimulation test
 Serum Metanephrines

28. Which of the following is an appropriate
screening test for Cushing’s Syndrome?
 Urine Cortisol
 Confirmatory with Dexamethasone suppression test
 Urine Metanephrines
 Salivary Metanephrines
 Cosyntropin (ACTH) stimulation test
 Serum Metanephrines

29. Cushing’s Syndrome
 Iatrogenic hypercortisolism (most common)
 Ingested/injected/topical/inhaled steroids & megestrol acetate
 Ectopic ACTH syndrome- 20 to small cell lung cancer
or adrenal tumors
 Cushing’s Disease-pituitary ACTH source
 Factitious Cushing’s- surreptitious intake of steroids
 Hypercortisolism can occur
 Extreme stress (including sepsis)
 Obesity and polycystic ovary syndrome
 Severe prolonged major depressive disorder
 Chronic alcoholism

30. Clinical Manifestations
 Progressive Central obesity
 Children with generalized obesity and growth retardation
 Facial Fat accumulation “Moon facies”
 Buffalo hump
 Skin atrophy
 Easy bruisability
 Striae
 Fungal infections
 Hyperpigmentation-induced by increased ACTH (not
cortisol)-binds melanocyte-stimulating hormone
 Menstrual irregularities
 Proximal muscle wasting –catabolism
 Bone loss-can result in pathological fractures

31. Manifestations

32. Manifestations continued
 Glucose intolerance
 Stimulation of gluconeogenesis by cortisol & peripheral insulin
resistance
 Hyperglycemia in 10-15% of patients
 Cardiovascular disease
 Increased risk of MI and Stroke
 Hypertension
 Thromboembolic disease
 Neuropsychiatric (labile, depressed, anxiety, panic
attacks)
 Increased frequency of Infections-inhibited immune
system
 Ophthalmologic findings-increased IOP & cataracts

33. Test for Cushing’s Syndrome
 Daily urinary cortisol (24 hours best)
 10 pm-8 am is acceptable alternative
 Late evening salivary cortisol-only beneficial if
extremely elevated
 Low dose dexamethasone suppression test
 Should suppress ACTH and subsequently reduce urine cortisol

34. Test of Adrenal Insufficiency
 Morning cortisol level
 > 11 ug/dL not adrenal suppression
 <3 ug/dL adrenal suppression
 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?
 <5%
 10%
 25%
 33%
 66%

36. Although idiopathic adrenal insufficiency in HIV is rare, what
percentage of post-mortem evaluations of the adrenal gland
are abnormal?
 <5%
 10%
 25%
 33%
 66%-common sources include CMV,
Mycobacteria tuberculosis, Histoplasmosis,
PCP, Toxoplasmosis and Kaposi’s Sarcoma

37. Adrenal Function in HIV
 Higher basal cortisol & lower dehydroepiandrosterone
 Overt adrenal insufficiency is uncommon
 Hypercortisolism in the absence of Cushings
 No treatment required
 Hypocortisolism always requires treatment

38. Comparison with Lypodystrophy with PIs
“pseudo Cushings”
 Altered body adipose tissue
 Truncal obesity
 Peripheral wasting
 Breast hypertrophy
 “Buffalo hump”
 Insulin hypersensitivity
 Normal cortisol and normal dexamethasone
suppression tests
 Lack striae and easy bruisability

39. When combined with corticosteroids, which medication has
been reported to be a contributing factor in iatrogenic
Cushing’s Syndrome?
 Etravirine
 Ritonavir
 Zidovudine
 Tenofovir
 Emtricitabine

40. When combined with corticosteroids, which medication has
been reported to be a contributing factor in iatrogenic
Cushing’s Syndrome?
 Etravirine
 Ritonavir
 Zidovudine
 Tenofovir
 Emtricitabine

41. Ritonavir and Clearance of Steroids
 Iatrogenic Cushing’s Syndrome with
Osteoporosis and Secondary Adrenal Failure
in Human Immunodeficiency Virus-Infected
Patients Receiving Inhaled Corticosteroids
and Ritonavir-Boosted Protease Inhibitors:
Six Cases
 Samaras, K, Pett S, Gowers, A et al. J Clin Endo and
Metabolism 2005.
 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
 6 patients reported to develop iatrogenic Cushings
following inhaled fluticasone for asthma
 Adrenal suppression noted in all 6 patients
 When fluticasone removed-4/6 developed hypocortisolism
 3/6 developed osteoporosis with pathological fx (1/6)
 Exacerbation of DM (1/6)
 These patients had prior lipodystrophy delaying
diagnosis
 Fluticasone is lipophilic-prior lipodystrophy may contribute
 Wide range of variability of 24-hour urine free cortisol
levels
 Suppressed is suppressed
 Remained suppressed for > 5 months

43. Samaras et al 2005 cont.

44. Cushing’s 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
 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
 Iatrogenic Cushings w/ secondary adrenal suppression
 After cortisols resolved, Cushingoid habitus remained
 2010-Prior reported case of budesonide & PIs resulting in
Cushings in 37 year old African woman
 Budesonide, beclomethasone & triamcinolone
recommended as safer options
 Fluticasone longest half life and most lipophilic

45. Iatrogenic Cushing’s syndrome after intra-articular
triamcinolone in a patient receiving ritonavir-boosted
darunavir Hall JJ et al. 2013 Int J STD & AIDS
 Triamcinololone is metabolized by CYP3A4
 Ritonavir has greatest effect on CYP3A4 of the PIs
 Case: 53 year old woman on darunavir/r who
developed cushinoid symptoms 2 weeks after
receiving single triamcinolone dose in left shoulder
 Triamcinolone injection (both intra-articular and
epidural) related Cushing’s Syndrome has been
reported previously (usual dose 40-80 mg)
 Follow on HPA axis suppression usually 2-6 months
 No reports with cobicistat-but significant CYP3A4

46. Diabetes and Corticosteroids

47. Which of the following is the most sensitive test
for diagnosis of glucocorticoid induced diabetes?
 Random plasma glucose >200 mg/dl
 75 g oral glucose tolerance test (2 hour value)> 150
 Fasting plasma glucose>126
 Hemoglobin A1C>6.5%

48. Which of the following is the most sensitive test
for diagnosis of glucocorticoid induced diabetes?
 Random plasma glucose >200 mg/dl
 75 g oral glucose tolerance test (2 hour value)> 150
 Fasting plasma glucose>126
 Hemoglobin A1C>6.5%

49. Glucocorticoid Induced Diabetes and Adrenal
Suppression
 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.
 9% of patients with RA develop DM within 2 years of steroids
 All types of glucocorticoid formulations including eye drops
 Mechanism is insulin resistance in liver
 Peak effect 4-6 hours after dose
 Symptoms (either iatrogenic diabetes or Cushing’s) less likely
if regimen mimics physiology (diurnal variation)
 Insufficiency (Addison’s)-failure of adrenals or pituitary

50. Lansang et al. 2011 cont.

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.
 Mechanism-augmentation of hepatic
gluconeogenesis & inhibition of glucose uptake in
adipose tissue
 Since steroids are administered in am, most
hyperglycemia is afternoon post-prandial
 Author recommended dividing steroid dosing

52. References
 http://www.uptodate.com/contents/establishing-the-diagnosis-of-cushings-
syndrome?source=search_result&search=cushings&selectedTitle=1%7E150 Accessioned 31
March 2014
 http://www.uptodate.com/contents/epidemiology-and-clinical-manifestations-of-cushings-
syndrome?source=search_result&search=cushings&selectedTitle=2%7E150 Accessioned 31
March 2014
 Samaras, K, Pett S, Gowers, A et al. Iatrogenic Cushing’s 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.
 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.
 Yoganthan K et al. Cushing’s 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.
 Hall JJ et al. Iatrogenic Cushing’s syndrome after intra-articular triamcinolone in a patient
receiving ritonavir-boosted darunavir. Int J STD & AIDS. 2013: 24:748-756.
 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.
 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.
 Mayo, J et al. Adrenal Function in the Human Immunodeficiency Virus-Infected Patient. Arch
Intern Med. 2002: 162: 1095-1098.
 Foisy MM. et al. Adrenal suppression and Cushing’s syndrome secondary to an interaction
between ritonavir and fluticasone: a review of the literature.

53. Questions

54. Which of the following is the most sensitive test
for diagnosis of glucocorticoid induced diabetes?
 Random plasma glucose >200 mg/dl
 75 g oral glucose tolerance test (2 hour value)> 150
 Fasting plasma glucose>126
 Hemoglobin A1C>6.5%

55. Which of the following is the most sensitive test
for diagnosis of glucocorticoid induced diabetes?
 Random plasma glucose >200 mg/dl
 75 g oral glucose tolerance test (2 hour value)> 150
 Fasting plasma glucose>126
 Hemoglobin A1C>6.5%

56. When combined with corticosteroids, which medications has
been reported to be a contributing factor in iatrogenic
Cushing’s Syndrome?
 Etravirine
 Ritonavir
 Zidovudine
 Tenofovir
 Emtricitabine

57. When combined with corticosteroids, which medications has
been reported to be a contributing factor in iatrogenic
Cushing’s Syndrome?
 Etravirine
 Ritonavir
 Zidovudine
 Tenofovir
 Emtricitabine

58. Which of the following is an appropriate
screening test for Cushing’s Syndrome?
 Urine Cortisol
 Urine Metanephrines
 Salivary Metanephrines
 Cosyntropin (ACTH) stimulation test
 Serum Metanephrines

59. Which of the following is an appropriate
screening test for Cushing’s Syndrome?
 Urine Cortisol
 Confirmatory with Dexamethasone suppression test
 Urine Metanephrines
 Salivary Metanephrines
 Cosyntropin (ACTH) stimulation test
 Serum Metanephrines

60. Although idiopathic adrenal insufficiency in HIV is rare, what
percentage of post-mortem evaluations of the adrenal gland
are abnormal?
 <5%
 10%
 25%
 33%
 66%

61. Although idiopathic adrenal insufficiency in HIV is rare, what
percentage of post-mortem evaluations of the adrenal gland
are abnormal?
 <5%
 10%
 25%
 33%
 66%-common sources include CMV,
Mycobacteria tuberculosis, Histoplasmosis,
PCP, Toxoplasmosis and Kaposi’s Sarcoma