The unique features of this unfortunate case of sporadic MTC and ectopic ACTH CS include: 1) exceedingly elevated urinary free cortisol, 2) reversible combined neurogenic and nephrogenic DI, 3) CS remission with sorafenib without measurable reduction in cortisol concentration, 4) abdominal aortic dissection, 5) jejuno-jejunal intussusception, 6) development of autoantibodies against neuronal ganglionic acetylcholine receptor, and 7) development of acute liver failure.

CS refers to signs and symptoms caused by excessive glucocorticoids action through glucocorticoid and occasionally mineralocorticoid receptors. Ectopic CS occurs in 0.6 % of MTC patients, usually with advanced disease [7]. As expected, our patient had liver and lung metastasis and markedly elevated tumor markers. However, his exceedingly high serum cortisol and urinary free cortisol were unusual. Further, despite florid derangements related to activation of mineralocorticoid and androgen receptors, hyperglycemia was the only glucocorticoid receptor-related abnormality. Having normoglycemia prior to admission and normal BMI and mildly elevated glycated hemoglobin on admission, indicated that the hyperglycemia was CS-induced and suggested that the other glucocorticoid receptor-related manifestations of CS may take longer time to develop. Severe hypokalemia and hyperkaliuria were likely due to activation of mineralocorticoid receptors by elevated cortisol that evaded inactivation by 11-beta-hydroxysteroid dehydrogenase.

The polyuria in our patient was not explained by hyperglycemia as it persisted after its correction and was associated with low urine osmolality. Further, the degree and persistence of polyuria were more than expected from the degree of hypokalemia, suggesting a neurogenic DI component. This was confirmed by a partial response to DDAVP, recurrence after stopping DDAVP, and an ADH that was inappropriately in the low normal range. DI was reported in two MTC patients without CS [4, 5] and in two patients with small-cell lung cancer and CS [14, 15]. In all cases there was intrasellar metastasis. Pituitary MRI in our patient was normal, suggesting functional neurogenic DI. As little as 30 mg prednisolone for 5 days inhibited osmotically-stimulated ADH secretion, however, urine osmolar concentration was unaffected; perhaps due to ADH-independent renal compensatory mechanisms [6]. We postulate that elevated cortisol in our patient caused ADH suppression and hypokalemia prevented the proposed compensatory mechanisms. Interestingly, after blocking cortisol action and correction of hypokalemia, urine output normalized and mild hyponatremia developed.

This is the first reported case of failure of elevated cortisol to decrease in MTC-related CS treated with multikinase inhibitors. In the two cases treated with vandetanib [8, 9] and one case treated with sorafenib [10], cortisol normalized within a week. Nevertheless, CS was reversed in our patient, necessitating discontinuation of the previously-required, large doses of potassium, spironolactone, antihypertensives, and insulin. Although mifepristone may have played a role in diabetes mellitus remission, it could not explain remission of hypertension and hypokalemia, its dose was relatively small, and diabetes mellitus remission persisted despite its withdrawal.

The mechanisms underlying reduction of cortisol concentration in this setting may be multifactorial. In one case, vandetanib resulted in simultaneous decrease in cortisol and calcitonin and a blunted response of ACTH to DDAVP without reduction in tumor size, suggesting a direct antisecretory action [8]. In another case, sorafenib reduced cortisol and ACTH with modest reduction in calcitonin and CEA, suggesting a selective inhibition of ACTH and cortisol secretion; reduction in POMC mRNA expression through MAPK pathway inhibition, ACTH action down-regulation by downstream signaling pathway inhibition, and adrenal ischemia were postulated [10]. In the third case, vandetanib resulted in sustained (26 months) normalization of cortisol and ACTH. However, a mild re-increase in ACTH without an increase in cortisol occurred while on vandetanib [9]. In our patient, there was a remarkable decrease in DHEAS and elevation in progesterone, suggesting a direct adrenal action of sorafenib, namely, 21-hydroxylase and 17-hydroxylase inhibition. Progesterone exhibits the same affinity as aldosterone for the human mineralocorticoid receptor, acting as antagonist [16]. It has antagonistic activity at the glucocorticoid receptor especially with reduced receptors number [17]. Despite >10 fold increase, progesterone would not effectively compete with prevailing cortisol in our patient, since both are equally protein-bound [16]. Nevertheless, we could not exclude a role of progesterone in CS remission because of the possibility of spuriously high cortisol concentration. For example, 21-deoxycortisol, which is elevated by 21-hydroxylase inhibition, had 45 % cross-reactivity in our cortisol immunoassay [18]. Further, cortisol concentration was increased 7.8 fold over upper normal limit in our immunoassay compared to 4.6 fold in another immunoassay. Much to our regret, we did not measure cortisol concentration by a more specific liquid chromatography assay or 21-deoxycortisol concentration. Finally, sorafenib was shown to down regulate wild type and c-terminally truncated (lacking ligand binding domain) androgen receptors in prostate cancer cells and to inhibit their signaling [19]. We postulate a similar action of sorafenib on mineralocorticoid and glucocorticoid receptors in our patient. It is of note that insulin-independent hypoglycemia was induced by sorafenib in a patient with hemangiopericytoma and was responsive to glucocorticoid treatment [20].

Aortic dissection has been reported in 3 men with CS, two with adrenal adenoma and one with pituitary adenoma; all three presented with dissection-related symptoms [11]. In our patient, aortic dissection was discovered accidently. The prevalence of silent aortic dissection in CS is not known as most cases of CS are due to exogenous glucocorticoids or Cushing’s disease and abdominal imaging is not performed. A causal relationship between elevated cortisol and aortic dissection can be postulated; cortisol could increase blood vessels fragility through negative effects on collagen formation and connective tissue strength. Acute elevation in blood pressure is another potentially contributing factor.

Intestinal intussusception in adults is rare accounting for 5 % of all intussusceptions; most cases are secondary to lead lesions requiring surgical intervention; and presenting symptoms are usually chronic and nonspecific [12]. To the best of our knowledge, intestinal intussusception has not been reported in MTC, nor has intestinal metastasis. We postulate that the intussusception was the cause of the intermittent abdominal pain in our patient and that it was likely due to metastasis, however, functional intussusception cannot be excluded as a mass was not visualized.

Lambert-Eaton syndrome (LES), a rare neuromuscular transmission disorder, characterized by proximal muscle weakness, depressed deep tendon reflexes, post-tetanic potentiation, and autonomic dysfunction, is caused by autoimmunity against P/Q voltage-gated calcium channel [21, 22]. It is most commonly associated with small-cell lung cancer but has not been reported in MTC [22]. Our patient presented with normal power despite having profound hypokalemia and hypercortisolemia, started to have mild weakness 20 days later when hypokalemia was corrected, and his weakness rapidly progressed to the degree that he became bed-bound despite mifepristone treatment. Electrolytes and TSH were normal. 25- Hydroxyvitamin D concentration was low, however, this was likely due to low binding proteins since PTH and corrected calcium were normal, and he had been on 2000 U of vitamin D daily. Absence of deep tendon reflexes, markedly decreased salivation, and postural tachycardia suggested LES and autoimmune dysautonomia. We could not confirm LES diagnosis since repetitive stimulation testing was negative and P/Q voltage-gated calcium channel antibodies were only upper normal. However, electromyography revealed motor unit potentials of short duration and decreased amplitude as described in LES [23] and neuronal ganglionic acetylcholine receptor autoantibodies, the only proven effector of autoimmune dysautonomia [13], were markedly elevated; which to our knowledge has not been described in MTC.

Another challenge we encountered in managing the patient was related to using procalcitonin to diagnose bacterial infection. Elevated procalcitonin, in general, indicates bacterial infection [24]. However, procalcitonin was useless in our patient since it is elevated in MTC patients [25] and may be elevated in adrenal crisis [26].

About 50 % of sporadic MTC carry RET gene somatic mutations, and RAS mutations are observed in about 50 % of RET-negative tumors [27]. The multikinase inhibitors, vandetanib and cabozantinib, were recently approved to treat symptomatic or progressive MTC [10]. Sorafenib was investigated in Phase II trials [28] and was successfully used to treat CS in MTC [10]. Since vandetanib and cabozantinib were not available in our institution, we treated our patient with sorafenib. There was an initial 15 % decrease in calcitonin and CEA and regression in some of the liver and lymph node metastasis within 17 days of treatment, however, calcitonin and CEA quickly rebounded and liver metastasis progressed.

Acute liver failure, characterized by the development of jaundice, coagulopathy, and hepatic encephalopathy within 8 weeks in the absence of preexisting liver disease, was reported in a patient with liver metastasis from MTC [29]. Liver functions in our patient deteriorated rapidly over 7 weeks, while screening tests for hepatitis A, B, and C were negative. Although iatrogenic liver injury due to sorafenib could not be excluded, it is likely that progression of liver metastasis was the culprit as suggested by the results of hepatic ultrasound/Doppler results. Further, mild liver test abnormalities have been reported in <1 % of sorafenib treated patients, and severe acute hepatitis is very rare, usually of the hepatocellular type, and is associated with high fever and rash; [30] which was not the case in our patient.