Cushing's Disease in Older Patients

Presentation and Outcome

Nidan Qiao; Brooke Swearingen; Nicholas A. Tritos

Clin Endocrinol. 2018;89(4):444-453.

Conclusions

Cushing's disease appears to have different manifestations in older as opposed to younger patients, including lower BMI, and increased muscle wasting, suggestive of a more catabolic phenotype. Several comorbidities associated with Cushing's disease (hypertension, diabetes mellitus, cardiovascular disease, and venous thromboembolism) may be more pronounced in the older age group, as the effects of normal ageing are compounded by pathologic hypercortisolemia. Surgical outcomes remain favourable in older patients with comparable remission rates and similarly low complication rates, despite the increased rate of comorbidities. In summary, our data suggest that the clinical phenotype in older patients with CD may be different from those of younger patients, which may compound the diagnostic difficulties, and merit increased attention from endocrinologists and neurosurgeons. More quantitative prospective studies would be helpful to confirm these findings and define the underlying mechanisms.

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Table 1. Basic characteristics, symptoms and comorbidities in older patients with CD and in control groups
	Patients with CD >60 y/o (n = 45)	Patients with CD <60 y/o (n = 90)	Patients with NFPA >60 y/o (n = 45)	p1^d	p2^d
Age	67.4 ± 6.6	40.8 ± 10.6	66.1 ± 5.0	<0.001	NS
Gender (Female/Male)	33/12	79/11	20/25	0.063	0.010
ASA3	22 (48.9%)	14 (15.6%)	5 (11.1%)	<0.001	<0.001
BMI (kg/m²)	30.2 ± 8.1	34.3 ± 10.5	29.2 ± 5.2	0.031	NS
Symptoms at presentation
Weight gain	27 (60.0%)	65 (72.2%)	0 (0.0%)	NS	<0.001
Central obesity	18 (40.0%)	26 (28.9%)	0 (0.0%)	NS	<0.001
Muscle wasting	20 (44.4%)	18 (20.0%)	0 (0.0%)	0.006	<0.001
Skin changes^a	21 (46.7%)	37 (41.1%)	0 (0.0%)	NS	<0.001
Alopecia	4 (8.9%)	11 (12.2%)	0 (0.0%)	NS	<0.001
Hirsutism^b	8 (24.2%)^b	38 (48.1%)^b	0 (0.0%)	0.033	<0.001
Fatigue	21 (46.7%)	41 (45.6%)	4 (8.9%)	NS	<0.001
Multiple fractures^a	8 (17.8%)	8 (8.9%)	0 (0.0%)	NS	<0.001
Hypokalemia	4 (8.9%)	5 (5.6%)	0 (0.0%)	NS	<0.001
Incidental	4 (8.9%)	2 (4.5%)	22 (48.9%)	NS	<0.001
Hypopituitarism	0 (0.0%)	0 (0.0%)	9 (20.0%)	NS	0.003
Apoplexy	0 (0.0%)	0 (0.0%)	1 (2.2%)	NS	1.000
Vision loss	0 (0.0%)	0 (0.0%)	12 (26.7%)	NS	<0.001
Comorbidities
Hypertension	36 (80.0%)	54 (60.0%)	22 (48.9%)	0.033	0.004
Diabetes Mellitus	20 (44.4%)	23 (25.6%)	5 (11.1%)	0.043	0.001
Cardiovascular disease^a	9 (20.0%)	1 (1.1%)	5 (11.1%)	<0.001	NS
Mood disorder^a	13 (28.9%)	26 (28.9%)	5 (11.1%)	NS	0.063
Venous thromboembolism	8 (17.8%)	1 (1.1%)	2 (4.4%)	<0.001	0.090
Laboratory tests
Free T4 (pmol/L)	15.4 ± 2.6	14.2 ± 5.1	14.2 ± 2.6	NS	0.067
TSH (mIU/L)	1.4 ± 1.0	1.4 ± 0.9	1.7 ± 1.3	NS	NS
IGF-1 (×UL)	0.65 ± 0.32	0.57 ± 0.27	0.31 ± 0.20	NS	<0.001
Testosterone^c (×UL)	0.37 ± 0.23	0.23 ± 0.16	0.25 ± 0.18	NS	NS

ASA, American Society of Anesthesiologists physical status classification system; BMI, Body mass index; CD, Cushing's disease; IGF-1, Insulin-like growth factor 1; NFPA, nonfunctional pituitary adenoma; NS, not significant; TSH, Thyroid-Stimulating Hormone; UL, upper limit of the normal range; y/o, years old.
^aSkin changes: thinning, acne, striae or poor healing; multiple fractures: history of more than one fracture; cardiovascular disease: any history of acute myocardial infarction or stroke; mood disorder: any history of depression, psychosis or anxiety.
^bIn women.
^cIn men.
^dp1, Patients with CD >60 y/o versus Patients with CD <60 y/o; p2, Patients with CD >60 y/o vs Patients with NFPA >60 y/o.

Table 2. Radiological and biochemical features in two groups with CD
	Patients with CD >60 y/o (n = 45)	Patients with CD <60 y/o (n = 90)	P
MRI
Negative	20 (44.4%)	38 (42.2%)	NS
Microadenoma^a	19 (42.2%)	37 (41.1%)	NS
Macroadenoma	6 (13.3%)	15 (16.7%)	NS
Cavernous sinus infiltration	1 (2.2%)	6 (6.7%)	NS
IPSS
Not performed^d	7 (15.6%)	31 (34.4%)	0.036
Positive at baseline	25/38 (65.8%)	46/59 (77.9%)	NS
Positive after CRH^c	33/38 (86.8%)	56/59 (94.9%)	NS
C/P at baseline	11.5 ± 22.5	21.3 ± 34.4	0.135^b
C/P after CRH	67.9 ± 110.4	100.8 ± 145.8	0.091^b
ACTH
Peak (×UL)	2.7 ± 9.2	1.4 ± 1.4	NS^b
Mean (×UL)	1.1 ± 1.0	1.0 ± 0.8	NS^b
LNSC
Peak (×UL)	5.8 ± 6.1	4.7 ± 8.7	0.072^b
Mean (×UL)	3.3 ± 3.2	2.6 ± 3.7	0.060^b
Positive	25/27 (92.6%)	41/45 (91.1%)	NS
UFC
Peak (×UL)	6.0 ± 9.3	4.8 ± 4.5	NS^b
Mean (×UL)	3.9 ± 7.5	3.2 ± 2.9	NS^b
Positive	38/44 (86.4%)	83/90 (92.2%)	NS

ACTH, Adrenocorticotropic hormone; C/P, Central/Peripheral; CD, Cushing's disease; CRH, Corticotropin-releasing hormone; IPSS, Inferior petrosal sinus sampling; LNSC, Late-night salivary cortisol; MRI, Magnetic resonance imaging; UFC, Urinary Free Cortisol; UL, upper limit of normal range; y/o, years old.
^aTwo patients with pacemaker implantation without MRI but microadenoma on CT.
^b P value from Mann-Whitney Test; Other p values were either from chi-square test or from Fisher's exact test (as appropriate).
^cNormalization against prolactin was available in one patient with no central ACTH gradient on IPSS and showed lack of central prolactin gradient.
^d19 patients had macroadenomas, 13 patients had relatively large microadenomas (≥7 mm), one patient had cyclic Cushing's disease where it was felt that IPSS might not accurately reflect the hypercortisolemic state, one patient had an allergy to iodinated contrast, one patient had recent pulmonary embolism, two patients did not undergo IPSS because the procedure was not covered by insurance, and one patient refused the procedure.

Table 3. Surgical outcomes in two groups with CD
	Patients with CD >60 y/o (n = 45)	Patients with CD <60 y/o (n = 90)	P
Type of Surgery
Selective resection	38/45 (84.4%)	75/90 (83.3%)	NS
Pathology
Confirmed ACTH-secreting pituitary adenoma	36 (80.0%)	68 (75.6%)	NS
Ki-67 index^a	1.6 ± 1.6	2.8 ± 3.5	0.082^e
Adverse events
Transient/permanent DI	4 (8.9%)/0(0.0%)	3 (3.3%)/0(0.0%)	NS
SIADH^b	4 (8.9%)	5 (5.6%)	NS
Haemorrhage requiring re-exploration	0 (0.0%)	1 (1.1%)	NS
CSF leakage requiring operation	0 (0.0%)	1 (1.1%)	NS
Death in 30 d^c	1 (2.2%)	0 (0.0%)	NS
Remission
Initial	34/45 (75.6%)	73/90 (81.1%)	NS
Early 2nd operation	4/5 (80.0%)	5/11 (45.5%)	NS
Overall	38/45 (84.4%)	78/90 (86.7%)	NS
MRI-negative	18/20 (90.0%)	29/38 (76.3%)	NS
Microadenomas	15/19 (78.9%)	37/37 (100%)	0.011
Macroadenomas	5/6 (83.3%)	12/15 (80.0%)	NS
Negative IPSS^d	4/5 (80.0%)	3/3 (100%)	NS
Recurrence
Overall	1/38 (2.6%)	15/78 (19.2%)	0.019
MRI-negative	1/18 (5.6%)	4/29 (13.8%)	NS
Microadenomas	0/15 (0.0%)	8/37 (21.6%)	0.087
Macroadenomas	0/5 (0.0%)	3/12 (25.0%)	NS
Mean Follow-up (months)	38.5 ± 39.3	46.9 ± 43.0	NS
Median Follow-up (range; months)	26 (1–162)	35 (1–168)	NS

^aAvailable in 21 patients in >60 y/o group and 50 patients in <60 y/o group.
^bHyponatremia and hypoosmolality.
^cThe patient had sudden death in rehabilitation centre 7 days after operation possibly because of pulmonary embolism.
^dExcluding those cases with negative IPSS, the remission rate for older versus younger was 30/40 versus 73/91 (P = 0.502).
^e P values from Mann-Whitney Test; Other p values were either from chi-square test or from Fisher's exact test (as appropriate). ACTH, Adrenocorticotropic hormone; CD, Cushing's disease; CSF, Cerebrospinal fluid; DI, Diabetes insipidus; IPSS, Inferior petrosal sinus sampling; MRI, Magnetic resonance imaging; SIADH, Syndrome of inappropriate antidiuretic hormone secretion; y/o, years old.

Supplement Table 1. Standardized method of data retrieval and definitions
Symptoms	Search criteria
Weight gain	"weight gain", "weight increase"
Central obesity	"central obesity", "centrally"
Muscle wasting	"proximal myopathy", "proximal muscle weakness", "unable to stand up"
Skin change	"easy bruisability", "infections of the skin", "acne", "pigmented striae"
Alopecia	"hair thinning", "hair loss"
Hirsutism	"hirsutism", "hair growth"
Fatigue	"fatigue", "decreased energy"
Symptoms	Definitions
Hypopituitarism	Deficiency of one or more pituitary hormones
Apoplexy	acute headache or vision loss with the evidence of intra-tumor hemorrhage on MRI
Vision loss	blurred vision or visual field defect
Multiple fractures	history of more than one fractures
Hypokalemia	presentation of low serum potassium level

MRI: magnetic resonance image

Supplement Table 2. Standardized method of data retrieval and definitions
		Negative IPSS
		Patients with CD > 60 y/o (n = 5)	Patients with CD < 60 y/o (n = 3)
Opacification	Patent sinus	3 (60%)	2 (67%)
	Unilateral failure cannulation	1 (20%)	0 (0%)
	Unknown	1 (20%)	1 (33%)
Outcomes	Positive immuno-staining	4 (80%)	2 (67%)
Outcomes	Remission	4 (80%)	3 (100%)

IPSS: Inferior petrosal sinus sampling; CD: Cushing's disease; y/o: years old

Supplement Table 3. The magnitude of hypercortisolism in patients without and without comorbidities
	LNSC (P value)	UFC (P value)
patients with multiple fractures versus patients without	0.60	0.22
patients with hypertension versus patients without	0.06	0.81
patients with diabetes mellitus versus patients without	0.06	0.18
patients with cardiovascular disease versus patients without	0.55	0.28
patients with venous thromboembolism versus patients without	0.78	0.40

LNSC: Late-night salivary cortisol; UFC: Urinary Free Cortisol

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