Cushing Syndrome Uncovered During Treatment of Hyperthyroidism

Cushing Syndrome Uncovered During Treatment of
Hyperthyroidism
Somnath Ghosh, MD, MS,* and David H. Madoff, MD, PhD†
"[...]CASE REPORT
A 48-year-old white female budget analyst with a
2-year history of palpitations was referred in March 2002 by her primary physician to evaluate an “overactive thyroid.”
She was well until 2 years prior, at which time she noticed occasional palpitations that she described as episodes of “heart racing,” lasting about 30 seconds. These episodes were
not associated with chest discomfort, lightheadedness, or syncope. She described poor sleep patterns, with frequent
early-morning awakening. Also noted were occasional hand tremors and emotional irritability, without significant change in her weight. She experienced typical vasomotor symptoms
of menopause, for which she was taking Premarin.
Her medical history was significant for neonatal jaundice,recent hemorrhoidectomy, and an uncomplicated pregnancy when she was 16 years old. There was no history of
radiation exposure to her face and neck. Her medications included Premarin, calcium, and vitamin D supplements. She was allergic to penicillin, to which she developed an anaphylactic
reaction 15 years ago. Her family history was significant for an unknown “thyroid condition” in her elder sister.
She was born and raised in Baltimore, MD, and lives with her husband and son. She states that her job could be stressful at times. She had a 25-pack/year smoking history, having quit 8 years before. She consumes alcohol occasionally.
Physical examination revealed normal vital signs, dry skin, and a multinodular goiter about 50 g in weight. There was no lagophthalmos, globeophthalmos, signs of orbitopathy,
thyroid acropachy, or pretibial myxedema. The cardiac examination was normal, and tendon reflexes were normal.
The remainder of the examination was normal.
Laboratory tests showed an undetectable thyroid stimulating hormone (TSH) level, free T4 1.4 ng/dL (nl 0.71–1.85), and total T3 106 ng/dL (nl 60–161). No old thyroid studies were available. Radioactive iodine uptake was 44% at 24 hours (nl 25–35), and radionuclide scanning showed heterogeneous uptake, with multiple cold nodules in both
lobes. Ultrasound-guided biopsy of 6 dominant nodules was negative for malignant cells and consistent with benign colloid nodules. Repeat thyroid function tests performed 2
months later were once again consistent with mild thyrotoxicosis due to a toxic multinodular goiter. Treatment options for her symptomatic thyrotoxicosis were discussed, including
radioiodine ablation and antithyroid medications. In May 2002, the patient decided to start methimazole 5 mg daily. In November 2002, she developed depressive symptoms.
She decreased methimazole to 5 mg 4 times a week, since the free T4 was 1.1 ng/dL and total T3 was 56 ng/dL, at the lower end of the normal range. A few months later she had an episode of chest pain, with a normal evaluation,
including a stress thallium study. Palpitations persisted and she was restarted on a daily dose of 5 mg methimazole. It is interesting to note that her TSH remained undetectable until
April 2004, when it was 0.32
Iu/mL. At that time, the free T4 was 0.83 ng/dL and total T3 was 99 ng/dL. She denied any thyrotoxic symptoms thereafter.
In December 2003, she presented with a 7-pound
weight gain and unexplained facial fullness. In addition, she complained of low energy and easy bruising. 

In contrast to her previously low blood pressure, her present blood pressure was labile and reached a documented maximum of 180/120
mm Hg. During this time, her free T4 and total T3 levels were normal; however, her TSH remained persistently suppressed.Methimazole was increased to 10 mg daily. Laboratory studies revealed unprovoked hypokalemia in the absence of
hyperaldosteronism. The patient denied exogenous glucocorticoid exposure from any source. To address the possibility of Cushing syndrome, an overnight 1-mg dexamethasone suppression
test was performed. The resultant 8 AM serum cortisol was 22.2
g/dL (nl 1.8
g/dL), and the concomitantsalivary cortisol was 3.77
g/dL (nl 0.18–0.95). Her 24-hour urine free cortisol was 171
g (nl
105
g). A morning adrenocorticotropic hormone (ACTH) level was undetectable,
and the corresponding morning cortisol was 21.1
g/dL.
A CT scan performed in March 2004 revealed a benignappearing 2.7-cm left adrenal tumor as the likely source of her ACTH-independent Cushing syndrome. Shortly thereafter, a laparoscopic left adrenalectomy was performed, without
complications. The pathology was consistent with a benign cortisol-producing adrenal adenoma.
Postoperatively she received an adequate replacement dose of prednisone in anticipation of adrenal insufficiency due to chronic preoperative suppression of the hypothalamicpituitary-adrenal
axis. An ACTH-stimulation test performed 1 week after surgery confirmed a markedly blunted cortisol
response to intravenous cosyntropin. Despite adequate glucocorticoid therapy, she had an episode consistent with mild
adrenal crisis 3 weeks after the adrenalectomy and required hospitalization. Glucocorticoid replacement therapy was gradually weaned and discontinued over the next year. The patient
returned to her usual state of health.

DISCUSSION
Our patient was initially treated for hyperthyroidism
with methimazole. She subsequently developed significant
Cushing-like features and hypercortisolism while on antithyroid
therapy. Laparoscopic surgery revealed a 2.7-cm cortisolproducing
left adrenal adenoma causing ACTH-independent
Cushing syndrome. This, to our knowledge, is the first documented
case of Cushing syndrome diagnosed during treatment
for thyrotoxicosis.
There have been many reports of exacerbation of
Graves disease and other autoimmune thyroid diseases following
unilateral adrenalectomy for Cushing syndrome.2–10
The pathophysiology in these cases is thought to be glucocorticoid-dependent
suppression of latent autoimmune thyrotoxicosis,
with the development of overt thyroid disease after the
abrupt reduction of plasma glucocorticoid levels following
adrenalectomy. This sequence of events is reversed in our
patient, and the pathophysiology is quite different.
In all likelihood, the adrenal adenoma was present and
metabolically active for years, yet she did not manifest the
signs and symptoms of Cushing syndrome until her hyperthyroidism
was treated. There are at least 3 possible explanations
for this clinical scenario. First, treatment of thyrotoxicosis
and expression of latent Cushing syndrome could be 2
chance events. We find this possibility highly improbable
since the secretory pattern of her adrenal adenoma would not
likely have changed substantially over the 20 months during
which she was treated with methimazole. Our patient clearly
had an abrupt and fairly defined onset of the Cushingoid
phenotype. Second, mild chronic thyrotoxicosis could have suppressed the Cushingoid phenotype, and treatment of her
thyrotoxicosis allowed for full-blown expression of Cushing
syndrome. Third, it is possible that longstanding, mild thyrotoxicosis
resulted in chronic cortisol hypersecretion and
autonomous growth of the left adrenal gland. The latter 2
possible explanations are not mutually exclusive. We will
discuss these 2 possibilities.
In 1958, Peterson11 demonstrated significantly increased
cortisol production and clearance rates in a group of
thyrotoxic patients. Treatment of hyperthyroidism in these
subjects returned cortisol metabolism to normal. McGuire
and Tomkins12 showed that the hyperthyroid state increased
cortisol degradation by enhancing the activity of hepatic
-4,5--reductase and -4,5--reductase. In 1961, Hellman et
al13 showed enhanced conversion of metabolically active cortisol
to the inactive metabolite cortisone via the enzyme 11-
hydroxysteroid dehydrogenase (11-HSD) in thyrotoxic human
subjects. By inactivating cortisol, overexpression of 11-HSD
would serve to buffer the thyrotoxic patient from the effects of
cortisol overproduction at the level of the glucocorticoid receptor.14
Plasma cortisol levels are normal in hyperthyroid patients
despite elevated production rates and enhanced inactivation to
cortisone. As a result, the total daily renal excretion of 17
hydroxy-corticoids is increased.15,16 In summary, in the thyrotoxic
state the adrenal glands chronically increase glucocorticoid
production to maintain normal serum cortisol levels in the
presence of enhanced cortisol catabolism.17 Indeed, secretion of
adrenocorticotropic hormone (ACTH) has been reported to be
elevated in the face of hyperthyroidism18, and bilateral adrenal
hypertrophy has been demonstrated in animals experimentally
rendered hyperthyroid.11
For many years, our patient most certainly had a small
cortisol-producing adrenal adenoma and subclinical Cushing
syndrome. The subsequent development of mild thyrotoxicosis
due to a toxic multinodular goiter resulted in increased
catabolism of cortisol and relative hypersecretion of ACTH
via the mechanisms described above. The thyrotoxic state
could well have accelerated ACTH-mediated growth of her
adrenal adenoma. At the same time, hyperthyroidism could
have suppressed the expression of Cushing syndrome by
maintaining relatively normal cortisol levels. Once the patient’s
thyrotoxicosis was treated with methimazole, hypercortisolism
became clinically evident and the adrenal adenoma
was discovered. Cushing syndrome resolved entirely
following laparoscopic adrenalectomy.[...]

Full paper found  at : https://dmadoffmdphd.com/wp-content/uploads/2014/09/Cushing-Syndrome-Uncovered-During-Treatment-of-Hyperthyroidism-2007.pdf