An impressive case of Cushing’s syndrome—Thank you for your silent message—

In 1971, I started my medical training at Kanazawa University Hospital. At that time, learning how to use routine laboratory techniques was common to medical interns. On advice from senior doctors, I joined a hypertension and endocrinology group, where they measured plasma renin activity using bioassay and urinary aldosterone excretion (UAE) by paper-chromatography. I learned plasma cortisol assay by Porter-Silber reaction, a method known for its accessibility to beginners. After extraction and a chemical reaction with sulfuric acid, 17-hydroxycorticosterone (17-OHCS) in the plasma yielded a yellow band at 410 nm UV. The comparative luminescence to an authentic reference steroid was semi-quantified.

One day, while I was on duty at an outpatient clinic in a suburban hospital, a middle-aged man came in seeking treatment for hypertension. The symptoms he had were the same as those for Cushing’s syndrome (CS), like what we read about in endocrinology textbooks. Then I brought the patient’s plasma to the lab and carried out a cortisol assay. I was excited to find strong UV-luminescence, indicating a high concentration of 17-OHCS. Afterward, the patient was transferred to the University Hospital for further evaluation, where they confirmed a diagnosis of ACTH-independent adrenal CS. A persistent severe hypokalemia was observed in this patient, suggesting potential overproduction of adrenal corticosteroids in a condition of suppressed renin levels and normal UAE. The patient then underwent adrenal surgery by transverse abdominal approach because no lateralization techniques, such as computed tomography imaging or adrenal venous sampling, were available at that time.

The following points remained undetermined before operation:

- cause of hypokalemia

- adrenal morphology

- possibility of ectopic ACTH production

Abdominal surgery revealed macroscopically obvious multiple large nodules on both adrenals, and bilateral adrenalectomy was performed on the spot. The patient was later discharged on hydrocortisone replacement therapy (HRT) without complications. In the postoperative days, his severe hypokalemia and hypertension were corrected. However, several years later in 1978, when I was studying abroad, I was informed that the patient committed suicide by throwing himself into a river.

When I recall this case with my current knowledge of recent advances in endocrinology, I believe that the cause of his hypokalemia was apparent mineralocorticoid excess (AME) syndrome, which is characterized by an exceedingly high concentration of cortisol that escapes deactivation by the enzyme 11β-hydrozysteroid dehydrogenase and subsequently binds to mineralocorticoid receptors (MRs). This finding is based on a novel experimental discovery by Professor John Funder (Fig. 1), which suggests that cortisol and aldosterone can bind to MR with equal affinity. Furthermore, the histopathology of the adrenal mass was likely to be what is currently referred to as bilateral macronodular hyperplasia (BMAH), which is a rare condition occurring in less than 5.8% of CS cases in Japan and even less in the US.

Fig. 1

Co-chairing with Professor John Funder at the 14^th International Congress of Endocrinology (ICE 2010) in Kyoto

The most serious outcome, suicide remains speculative. A question arises whether the dosage of HRT was appropriate or not. In fact, the dosage of hydrocortisone replacement for adrenal diseases was a topic at an endocrinology meeting in the US nearly two decades ago. I happened to attend the meeting and was impressed with a heated debate as to the optimal dosage. Chronic overdose should be avoided to prevent major side effects, such as depression. As I reflect on my case, I am concerned that my initial explanation to the patient “Your disease is rare but curable after an operation” might have been problematic, considering the need for life-long HRT as well as the dosage. Indeed, I learned many lessons from this patient and was motivated to study steroids and hypertension ever since.

Biographies

Isamu Miyamori

Honorary Member

Professor Emeritus, University of Fukui

Director, Uchinada Onsen Hospital

E-mail: [e-mail]

Careers in JES

2016– Honorary Member

2012– Senior Councilor

2001–2013 President for Hokuriku Regional Branch

1984– Councilor

1972– Member

Activities in JES

2006 Chair, 16th JES Clinical Update on Endocrinology & Metabolism

2002 Chair, 1st Annual Meeting of JES Hokuriku Regional Branch