NOTICE
The Journal of Cardiometabolic Syndrome (ISSN 1524-6175) is published quarterly (March, June, Sept., Dec.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Karen Hurwitch at KHurwitch@bos.blackwellpublishing.com or 781-388-8470.
CASE REPORT
id: 7304
Melvin R. Hayden, MD, Section Editor
High-Cortisol States Can Masquerade as the Cardiometabolic Syndrome
O ☐ besity and type 2 diabetes mellitus (T2DM) have assumed epidemic proportions and are associated with other comorbidities such as hyperten- sion and hyperlipidemia, constituting the cardiometabolic syndrome (CMS).1 Studies suggest that CMS affects about 20% of the US population and the syn- drome’s prevalence is rapidly increasing, placing a tremendous burden on the health care system worldwide.2
Currently, the pathogenesis of CMS is not completely understood and remains an active field for research. High-cortisol (HC) states such as Cushing disease or syndrome exhibit physiologic and phenotypic features similar to those of CMS, thus raising the possibility of similar pathogenesis in both these condi- tions. Even though plasma cortisol levels are not elevated in CMS, recent studies have suggested altered tissue sensitiv- ity to glucocorticoids in these patients because of variations in enzymes such as 11ß hydroxysteroid dehydrogenases (11ßHSDs) at the prereceptor level.3 Thus, altered corticosteroid homeostasis seems to be a connecting link between these 2 conditions. Similar features may cause a delay in the diagnosis of HC states, which sometimes can be more aggressive than CMS and fatal.
This case report presents a patient with features typical of CMS who ini- tially presented with nonspecific com- plaints and was later found to have a more sinister disease: an endocrine para- neoplastic syndrome due to an ectopic adrenocorticotropic hormone (ACTH)- secreting small cell lung cancer.
Case Report
A severely obese (body mass index 36 kg/m2), hypertensive (212/91 mm Hg) 70-year-old Caucasian woman
Poorna R. Karuparthi, MD;” Preethi Yerram, MD, MSG;1 Diptesh Gupta, MBBS, MRCP;4 Melvin R. Hayden, MD1,2,3
From the Department of Internal Medicine,’ Division of Endocrinology, Diabetes, and Metabolism,2 and the Diabetic and Cardiovascular Research Center,3 University of Missouri School of Medicine, Columbia, MO;3 and the Department of General Medicine, Birmingham Heartlands Hospital, Birmingham, United Kingdom4
Address for correspondence:
Poorna R. Karuparthi, MD, Department of Internal Medicine, University of Missouri- Columbia School of Medicine, Health Sciences Center, MA406, DC043.00, Columbia, MO 65212 E-mail: rkaruparthi@yahoo.com
presented with a 4- to 6-week history of dyspnea and wheezing not responding to salbutamol, with dull left lateral chest wall pain and left costovertebral pain (Table I and Table II). A preliminary diagnosis of pyelonephritis was made based on clinical and initial laboratory findings, and intravenous antibiotics and aggressive respiratory therapy were initiated. A thiazide diuretic was added for uncontrolled hypertension; after she received 2 doses of bendrofluazide (2.5 mg), her serum potassium level dropped to 2.1 mEq/L. The patient remained profoundly hypokalemic despite potas- sium supplementation and cessation of diuretics (Figure 1) (Table III). Uncontrolled hypertension, a transtu- bular potassium gradient (TTKG) of 13.7, and hypokalemic alkalosis sug- gested mineralocorticoid excess. An HC state was suspected based on the pres- ence of cushingoid features along with a recent history of weight gain, new-onset T2DM, and worsening hypertension. A negative high-dose dexamethasone sup- pression test suggested ectopic ACTH production. Repeat chest x-ray (Figure 2) and subsequent computed tomo- graphic scan findings (Figure 3A and Figure 3B) done in the interim were suggestive of a mass in the right lung,
and subsequent biopsy results demon- strated a small cell carcinoma of the lung (Figure 3C and Figure 3D) as the likely source of ectopic ACTH produc- tion. The patient died of carcinomatosis on the 25th day of hospitalization.
Discussion
Ectopic ACTH syndrome is one of the most common endocrine paraneoplas- tic syndromes. It accounts for approxi- mately 15% of all cases of endogenous Cushing syndrome.4 This condition is rapidly progressive, with clinical fea- tures such as muscle wasting and weight loss, seen in patients with more aggres- sive tumors like small cell lung cancer.5 However, the presentation may also be similar to pituitary ACTH-dependent Cushing disease with cushingoid fea- tures in slower growing nonpituitary tumors such as indolent carcinoids.4,5 Interestingly, this patient did exhibit signs of hypercortisolism, including moon facies, truncal obesity, buffalo hump, easy bruising, weight gain, wors- ening of hypertension, and newly diag- nosed T2DM. It is important to note that several of the above components are also seen in CMS, which could dis- tract clinicians from initially consider- ing ectopic ACTH syndrome.
NOTICE
The Journal of Cardiometabolic Syndrome (ISSN 1524-6175) is published quarterly (March, June, Sept., Dec.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Karen Hurwitch at KHurwitch@bos.blackwellpublishing.com or 781-388-8470.
| Table I. Medical History | ||
|---|---|---|
| MEDICAL HISTORY | MEDICATION HISTORY | PERSONAL HISTORY |
| Diabetes | Aspirin 75 mg daily | 28-pack-year history of smok- ing; quit 30 years ago |
| Hypertension | Nifedipine 60 mg daily | Family history |
| Dyslipidemia | Fenofibrate 160 mg daily | Sister and mother had breast cancer. Father died of lung cancer at the age 66 |
| Ischemic heart disease | Calcium carbonate 1250 mg and cholecalciferol 400 IU, 1 tablet daily | |
| Hypothyroidism | Levothyroxine 25 µg daily | |
| Osteoarthritis | Salbutamol inhaler 2 puffs as needed 4 times daily | |
| Table II. Results of Initial Investigations at the Time of Admission | |
| Temperature | 37°℃ |
| Pulse rate | 64 beats per minute |
| Blood pressure | 212/91 mm Hg |
| Oxygen saturation | 95% on room air |
| Urine analysis | + Nitrites, +protein, + leukocytes |
| Chest radiography | Indiscernible |
| Electrocardiogra | Unremarkable |
| White blood cell count | Leukocytosis |
| Basic metabolic profile | Within normal limits |
| Blood glucose | 180 mg/dL |
6
5
4
mmol/L
Upper Range
3
Lower Range
Value
2
1
0
04/11/05
14/11/05
24/11/05
Role of Glucocorticoids in CMS. Cortisol is produced from the adrenal gland, has diverse physiologic roles, and is essential in the presence of stressors
such as inflammation and infection. The normal metabolic actions of cortisol include effects on lipid, glucose, and protein metabolism, and on homeostasis.
On the other hand, chronic elevated states of plasma cortisol due to a tumor or exogenousadministration produce features similar to the individual components of CMS, which suggests a possible role of corticosteroids in the pathogenesis of CMS.6 This hypothesis is further supported by several human and animal studies. For example, adrenalectomy in a rodent model caused amelioration of obesity and metabolic disturbances, and similar features developed with the reinstitution of glucocorticoids.7 In contrast to the elevated plasma cortisol levels seen in HC states, the plasma cortisol levels are either normal or subnormal in obesity and CMS.8
Cortisol Homeostasis in the Plasma and Tissues. Under physiologic conditions, the plasma cortisol level is regulated by ACTH produced under the control of the hypothalamic- pituitary-adrenal (HPA) axis, depending directly on the rate of cortisol secretion and its clearance. Tissue-level cortisol sensitivity, on the other hand, is determined not only by the circulating plasma cortisol regulatory factors but also by the variations in cortisol receptors and the availability of active cortisol in the intracellular compartment, which is controlled by local enzymes.9,10 One hypothesis regarding regulation of cortisol in CMS suggests possible increases in the clearance or inactivation of cortisol, which results in increased cortisol production because of a lack of negative feedback at the HPA axis.8 These opposing actions (increased clearance of cortisol, eventually leading to its increased production) are likely responsible for normal or decreased plasma cortisol levels in these patients. Tissue-specific intracellular elevation of glucocorticoids is noted in animal models, especially in the liver and adipose tissues, which has also been demonstrated in human adipose tissues.10 The intracellular enzyme 11ßHSD1 is found to be responsible for increased intracellular cortisol levels.3,9
Role of 11ßHSD in the Metabolism of Glucocorticoids. Two isoforms exist of the enzyme 11ßHSD: 11@HSD1
NOTICE
and 11ßHSD2 (Figure 4). The first, 11HSD1, is a bidirectional enzyme (ie, it catalyzes both oxidation and oxo-reduction reactions). Under in vivo conditions, however, it acts as an oxo-reductase that is dependent on the reduced form of nicotinamide adenine
dinucleotide phosphate (NADPH) and generates endogenous cortisol from its inactive circulating form of cortisone.11 This enzyme is present in higher concentrations in specific tissues such as the liver and adipose tissue, where it acts to maintain intracellular concentrations of cortisol even in the setting of low plasma cortisol levels.11 Tissue-specific dysregulation of 11ßHSD1 is seen in obesity and CMS, and its importance in CMS has also been confirmed in many animal studies. 11ßHSD1 knockout rats do not develop obesity or lipid and glucose abnormalities even on a high-fat diet.12 Similarly, transgenic rat models with overexpression of this enzyme produce features of CMS associated with increased intracellular cortisol concentrations.13
The second isoform of 11ßHSD, 11ßHSD2, converts active cortisol to inactive cortisone, specifically in the aldosterone-sensitive target tissues such as kidney, colon, and salivary glands. Its main role is at the distal nephron where it regulates the mineralocorticoid receptors (MRs) free from cortisol by inactivating it to cortisone.14 Plasma cortisol concentra- tion is greater than that of aldosterone and thus is essential to inactivate cortisol at the MR level.15 In HC states, however, this enzyme is unable to inactivate the higher concentrations of cortisol.16 As seen in our patient, this results in excess MR activation leading to an apparent mineralocorticoid excess state character- ized by hypertension, hypokalemia, and fluid retention. One possible explana- tion for the onset of hypokalemia with diuretics in our patient could be from the high sodium load at the distal nephron sensitized by an apparent mineralocor- ticoid excess state (the normal effect of mineralocorticoid is to absorb sodium and secrete potassium). The inhibition of the Na+ and Cl- transport in the corti- cal thick ascending limb and early distal tubule by thiazide diuretic causes excess
| Table III. Post-Diuretic Use Laboratory Results | ||
|---|---|---|
| VARIABLE | PATIENT'S VALUES | REFERENCE RANGE |
| Potassium, mEq/L | 2.3 (pre-diuretic 4.1) | 3.5-5.0 |
| Sodium, mEq/L | 141 | 133-147 |
| Blood urea nitrogen, mg/dL | 10.08 | 7-21 |
| Creatinine, mg/dL | 0.63 | 0.55-1.21 |
| Magnesium, mEq/L | 1.96 | 1.4-2.2 |
| Corrected calcium, mg/dL | 9.84 | 8.2-10.4 |
| Phosphate, mg/dL | 3.21 | 2.48-4.5 |
| Urine potassium, mEq/L | 32 | <15 |
| Urinary osmolality, mOsm/kg | 316 | 50-1100 |
| Serum osmolality, mOsm/kg | 299 | 275-295 |
| TTKG | 13.76 | >4 with hypokalemia suggests increased distal secretion of K+ |
| pH | 7.597 | 7.35-7.45 |
| Serum bicarbonate, mEql/L | 41.6 | 22-30 |
| Base excess, mEq/L | 23.5 | +2 to -2 |
| 24-Hour urinary cortisol, | 244.09 | 1.3-7.38 |
| µg/dL | ||
| Random serum cortisol, µg/dL | 60.336 | |
| Serum aldosterone, ng/dL | 5.776 | 1.011-16.06 |
| Serum ACTH, pg/mL | 430 | <46 |
| Abbreviations: ACTH, adrenocorticotropic hormone; TTKG, transtubular potassium gradient = (urine potassium/serum potassium)/(urine osmolality/serum osmolality). | ||
sodium delivery to a distal nephron. This may cause an excess absorption of Na+ in exchange for potassium and hydrogen ion loss, leading to hypokalemic alkalosis.
Future Directions for Therapy. Most of the HC-related physiologic and morphologic features are reversible once the source of excess cortisol has been treated. This is best accomplished by removing the ACTH-producing tumor if possible; in patients who are not surgical candidates, it is highly recommended to start medical treatment to control blood cortisol levels before starting chemotherapy, for the better prognostic outcome.17 In contrast, plasma cortisol levels are already low in obese patients or those with CMS, so any attempts to decrease the production or increase the clearance of cortisol would result in further activation of the HPA axis, excess cortisol production, and associated adrenal androgen production.18 Tissue- specific manipulation of glucocorticoid effects may, therefore, be a more useful strategy. Multiple in vivo and in vitro
R
studies have shown promising results with 11ßHSD1 inhibition,19,20 and this could be a viable treatment option because it does not alter circulating levels of cortisol and the HPA stress response.
Conclusions
The concept of an “apparent gluco- corticoid excess” condition located at the local tissue level in CMS is now evolving, and the role of 11@HSD1 in the pathogenesis of this state is being increasingly recognized. While
NOTICE
A
B
*
*
*
*
*
R
R
C
D
*
Į Insulin sensitivity
Cortisone
11ßHSD 1
Cortisol
Gluconeogenesis
NADPH/NADP-dependent (liver, adipose tissue)
Adipocyte differentiation
11BHSD 2
Apparent mineralocorticoid excess state (at greater concentrations)
Cortisol
Cortisone
NAD-dependent (kidney, colon)
Figure 4. The equations of the subtypes of 11ßhydroxysteroid dehydrogenase (11ßHSD) enzyme. Tissue-level local cortisol concentration is maintained by reductase activity of 11BHSD type 1, which, in turn, depends on the avail- ability of the cofactor, the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH). This reaction is tissue specific and may play an important role in the pathogenesis of the cardiometabolic syndrome. 11(HSD type 2 (nicotinamide adenine dinucleotide [NAD+] dependent) is abundant in mineralocorticoid receptor-rich tissues such as kidney and colon. Its role is to keep the mineralocorticoid recep- tors free from the activation by cortisol. If concentration of cortisol is greater than the enzyme’s ability to inactivate the receptors (as in the patient in this case report), then a state of apparent mineralocorticoid excess results from the excess activation of mineralocorticoid receptors by cortisol.
it is important to implement a global risk reduction strategy and treat the individual components of CMS, recent studies have suggested that the enzyme 11ßHSD1 could be a potential target as a therapeutic option in the treatment of CMS. The treatment of HC states, on the other hand, requires removal of the source of excess glucocorticoid produc- tion; early recognition of this condition as being a separate entity from CMS is of paramount importance.
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