A 49-year-old Caucasian female with no significant medical history was referred for evaluation of primary hyperparathyroidism. She reported increased thirst and urination and weight gain of 10 lbs in the previous year.
Q What are clinical features of Hypercalcemia ?
- GI symptoms
- abdominal pain (? Pancreatitis)
- Renal Symptoms- because of nephrogenic Diabetes insipidus
- CNS symptoms
- Loss of consciousness
- CVS symptoms
Paired corrected calcium, albumin, and intact PTH levels measured on 2 separate days 3 months apart were 9.82 mg/dL, 4.6g/dL, and 63.9 pg/mL and 10.0 mg/dL, 5.0 g/dL, and 58.9 pg/mL, respectively (normal ranges: 8.6–10.2 mg/dL, 3.5–5.2 g/dL, and <65 pg/mL). Her vitamin D-25 OH level was 31 ng/dL. Measurements for 24-hour urinary calcium and phosphate levels were 400 mg (normal: <250) and 1,169 mg (normal: 170–1,200). Urinary calcium/creatinine ratio was 299 mg/g (normal: <275). Serum total calcium levels obtained on 5 different occasions ranged from 9.7 to 10.8 mg/dL with inappropriately high PTH levels ranging from 53.3 to 97.7 pg/mL. A sestamibi scan did not reveal a parathyroid adenoma, but there was radioligand uptake in the midline at the skull base, a location consistent with a pituitary adenoma. (Figure)
Q Can a Sestamibi scan detect a Pituitary adenoma ?
Yes. Kojima et al have shown that Tc99 sestamibi can accumulate the in the Pituitary adenoma where as the tracer does not accumulate in normal pituitary.
Serum cortisol levels (7:15 am) 17.4 mcg/dL and 24-hour urinary free cortisol (UFC) levels were found to be elevated on 2 occasions 150 and 135.8 mcg (normal: <50). Her cortisol level was not suppressed after 1-mg overnight dexamethasone suppression test (DST) (presuppression: 18.3, postsuppresion: 6.3 mcg/dL). Measurements of 11 pm salivary cortisol levels on 2 separate days were elevated at 0.35 mcg/dL (normal: <0.09) and 0.14 mcg/dL (normal: <0.09).
Q What is your inference of the above cortisol reports ?
These reports suggest presence of Cushing’s syndrome.
Q What is the normal response expected in case of 1 mg overnight dexamethasone suppression test ?
The cortisol should be less than 1.8 ug/dl
Q What would you do further for evaluation of Cushing’s syndrome ?
Eventhough there is already a presence of a Pituitary tumor detected assuming we donot have an evidence of that I would check the ACTH level next.
Her baseline ACTH was 30 pg/mL.
Q What is interpretation of her ACTH level ?
ACTH <10 pg/ml suggest ACTH independent Cushing’s syndrome while level >25 pg/ml is suggestive of ACTH dependent Cushing’s. I would think this is ACTH dependent Cushing’s .
Q Again, forgetting that we already have a Pituitary tumor, what would be the next step in this case ?
Since we are suspected ACTH dependent Cushing’s I would a high dose dexamethasone suppression test.
With the high-dose overnight 8-mg DST, the cortisol levels were suppressed to 1.2 mcg/dL from 15.9 mcg/dL.
Q What is the interpretation of this high dose dexamethasone suppression test and what would be your next step ?
I would think we are dealing with either a Pituitary microadenoma or a rare possibility of Bronchial carcinoid secreting ACTH. My next step would be a MRI Pituitary protocol.
Q What would your next step be ?
We would probably consider doing a Bilateral inferior petrosal sinus sampling (BIPSS)
Q What is your interpretation of IPSS data ?
|Basal Central : Peripheral ratio (right)||2.5 :1|
|Basal Central : peripheral ratio (left)||1.25: 1|
|Stimulated Central : Peripheral ratio (right)||15.5 :1 (highest ratio is taken)|
|Stimulated Central : Peripheral ratio (right)||1.5 :1|
|Stimulated Right : Left||10:1|
From this IPSS report my interpretation is that we are dealing with a Right sided Pituitary microadenoma.
Note on Interpretation of IPSS
- Basal ratio ACTH – from central : peripheral > 2:1 – s/o of pituitary Cushing’s ie IPSS positive
- Post stimulated- take the highest ratio – central : peripheral > 3:1 – Positive IPSS
- For lateralization Central : peripheral ratio > 1.4:1 (both basal and stimulated) suggests Tumor of that side
Q So what is your interpretation at this stage ?
Since we are dealing with a Hyperparathyroidism with probably a Pituitary microadenoma (Cushing’s syndrome) I would think a possibility of MEN1 syndrome.
Q How will you explain the absence of any uptake on Sestamibi parathyroid scan ?
MEN1 syndrome patients often have Parathyroid hyperplasia and may not have a parathyroid adenoma. In presence of hyperplasia, the Parathyroid scan may not pick up any tracer uptake.
Contrast-enhanced CT scan of chest, abdomen, and pelvis did not reveal an ectopic ACTH source. A dual-energy X-ray absorptiometry scan performed in 2011 had revealed osteopenia of lumbar spine, osteoporosis of the right femoral neck, and osteopenia of left femoral neck (T-scores of –2.2, –2.5, and –2.1, respectively). The patient’s preoperative luteinizing hormone and follicle-stimulating hormone levels were 44.3 mU/mL and 50.1 mU/mL, respectively, confirming menopause. Her fasting glucose levels were consistently <100 mg/dL; therefore, no oral glucose tolerance test was performed.
Q What treatment would you offer here ?
I would refer to the neurosurgeon for a Transphenoidal hemi-hypophysectomy of the right side
Transsphenoidal resection of 40% of the pituitary gland revealed an ACTH-producing corticotroph adenoma.
Q What is the definition of remission after transsphenoid surgery for Cushing’s disease ?
Remission is defined as post operative Cortisol levels of <5 ug/dl within 7 days of surgery.
Q What the chances of remission in this case ?
Since this was a microadenoma, chances of remission are around 70% .
Q How long would glucocorticoid replacement be required in this case ?
It would be require till HPA axis recovers which could take 6-12 months.
Q Why do patients with Cushing’s who undergo a surgery feel worse after the surgery ?
This is because of sudden withdrawal of glucocorticoids (Glucocorticoid withdrawal syndrome) . It can last for upto 1 year after the surgery.
Q What is the dose of Hydrocortisone given at discharge in such patients ?
Hydrocortisone is given in the dose of 10-12 mg/m2/day in 2-3 divided doses
Q How do you taper the steroid dose in such a patients ?
- Patient is discharged on dose as mentioned above
- He is asked to get a morning cortisol done before the next steroid dose
- If the morning cortisol is <5 ug/dl then the same dose is continued and patient is rested after 3-6 months
- If the morning cortisol is >7.4 ug/dl then perform a ACTH stimulation test after stopping all glucocorticoids.
- If either the Baseline of post stimulated cortisol is >18 ug/dl – then the steroids may be stopped.
Q When should GH Levels be tested in adults with Cushing’s ?
Cushing’s also suppresses the GH axis. Hence the GH axis is tested 1 year after treatment of Cushing’s .
Q What else would you do for this patients ?
I would do a genetic testing for MEN1 syndrome. I would also consider doing a 3.5 resection of the parathyroid gland (since the patient has PTH dependent hypercalcemia)
The patient required postoperative steroids for 4.5 months before hypothalamic-pituitary-adrenal axis recovery. At 22 months after pituitary surgery, the patient is in remission with a normal 11 pm salivary cortisol level of 0.06 mcg/dL (normal: ≤0.09), normal plasma ACTH level of 9 pg/mL (normal: 6–50), and a normal 24-hour urinary cortisol level of 20.4 mcg/24 hours (normal: 4–50). Her body mass index had decreased from 27.1 to 25.6. Eight months after the transsphenoidal resection, her calcium levels remained mildly elevated (10.3 to 10.4 mg/mL). After receiving a second opinion, the patient underwent 3.5-gland parathyroidectomy, and her calcium levels remained mildly elevated (10.3–10.9 with a PTH level of 46.8). In the next few months, her calcium varied from 9.7 to 10.7 mg/mL with a PTH level of 41.1 A follow-up sestamibi scan 1 year after surgery continued to show midline pituitary uptake. Genetic testing for a MEN1 mutation was negative.
LEARNING POINTS FROM THIS CASE
- Sestamibi scan can pick up Pituitary adenoma especially ACTH producing adenomas
- On IPSS, Stimulated central:peripheral ratio of >3:1 is suggestive of Central cause of ACTH secreation (Positive IPSS)
- Cortisol level <5 ug/dl within 7 days of Pituitary surgery suggest remission from Cushing’s disease
- HPA axis post Cushing’s disease surgery may take 12-18 months to recover.
- Baseline and stimulated Cortisol level are tested every 3-6 months on follow up. If baseline or stimulated value are >18 ug/dl then it suggests recovery of HPA axis and glucocorticoids may be discontinued.