Published online before print November 3, 2008, doi: 10.1161/HYPERTENSIONAHA.108.121640
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(Hypertension. 2008;52:1001.)
© 2008 American Heart Association, Inc.
Hypertension Grand Rounds |
Cushing’s Disease, Hypertension, and Other Sequels
From the Medical Faculty of the Charité, Franz-Volhard Clinic, HELIOS Klinikum-Berlin, Berlin, Germany; and the Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
Correspondence to Friedrich C. Luft, Experimental and Clinical Research Center, Building 84, Max Delbrück Center, Robert-Rössle Str 10, 13125 Berlin, Germany. E-mail: luft{at}charite.de
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Introduction |
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 Top Introduction Case Report (Eugenia Singer,...Clinical Discussion of Cushing's...How Do ACTH and...Cushing's Syndrome and...Pathological Report (Dierk...Pathological DiagnosisReferences |
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In his biography of Harvey Cushing, Michael Bliss1 discusses Cushing’s perhaps most lasting scientific contribution as follows: "The old man’s hunch had played out. After all those years of gathering information and misinformation about the pituitary, Cushing had correctly identified basophil pituitary adenomas as one significant cause of hypersecretion from the adrenal cortex.2 In those cases, Cushing’s syndrome becomes Cushing’s disease." In his report, which was actually a lecture at the Yale Medical School, Cushing mentioned, "painful adiposity, particularly of the trunk and chest, without involvement of the extremities, rounded shoulders, amenorrhea, purple colored striae on the abdomen, hypertension, a tendency toward spontaneous ecchymoses and epistaxis, rough, dry skin, blue and dusky in appearance, pressure headaches with low-grade chocked discs, fragility of the bones, and excessive growth of hair on the lips and elsewhere over the body."2 Cushing also observed that the tumors were too small to cause changes in the sella turcica that could be observed roentgenographically. Although Cushing’s disease is not common, patients with the condition almost invariably are hypertensive, often severely so. Cushing mentioned all of the cardinal features, save for psychiatric manifestations; depression and even psychosis are also commonly present.3 Associated laboratory abnormalities include neutrophilic leukocytosis, hyperglycemia, hypokalemia, and hypercholesterolemia. Every medical student faithfully learns the above. Most have already observed the features of iatrogenic Cushing’s syndrome as a sequel to long-term therapeutic glucocorticoid exposure. Faculty-attending physicians have all encountered Cushing’s disease at some point in their careers and are, therefore, attuned. Nonetheless, when finally confronted, clinical reality often does not follow textbook rules. We recently encountered such a patient.
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Case Report (Eugenia Singer, Sebastian Strohm, Ursula Göbel, Markus Bieringer, Ralph Kettritz, and Friedrich C. Luft) |
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TopIntroductionCase Report (Eugenia Singer,...Clinical Discussion of Cushing's...How Do ACTH and...Cushing's Syndrome and...Pathological Report (Dierk...Pathological DiagnosisReferences |
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The patient was a 51 year-old white man who had immigrated to Germany from the Czech republic. He was self-employed as a sculptor. He came to the emergency department because of progressive dyspnea and chest discomfort over 3 days. His blood pressure was 240/120 mm Hg, and his heart rate was irregularly irregular at 120 bpm. The ECG showed rapid atrial fibrillation, narrow QRS complexes, and inverted T waves in the precordial leads. His troponin T was elevated, which prompted his referral to our coronary care unit and cardiac catheterization laboratory. A brief history disclosed that the patient had received antihypertensive treatment for 2 years. He reported that his blood pressure readings were nonetheless high. Atrial fibrillation had also developed earlier, and cardioversion was performed a year before at another hospital. After atrial thrombi were excluded with transesophageal echocardiography, the patient was cardioverted and taken to the catheterization suite. Coronary angiography disclosed the presence of coronary plaques; however, all 3 of the major coronary vessels were open, and no evidence for an acute coronary syndrome was identified.
The initial quantity of sodium was 143 mmol/L, potassium 2.7 mmol/L, chloride 99 mmol/L, and HCO3 31 mmol/L. The arterial pH was 7.53, PaCO2 38 mm Hg, and PaO2 121 mm Hg with supplemental oxygen. The hemoglobin level was 16.7 g/dL, and the hematocrit level was 51 vol%. Urine electrolytes were obtained, and the transtubular potassium gradient (urine/plasma potassium divided by urine/plasma osmolality) was calculated at 14. In patients with hypokalemia, the kidney should avidly be retaining potassium, and a gradient <5 would be expected. The creatinine level was 97 µmol/L (<107 µmol/L), the urea level was 9.6 mmol/L (<8.3 mmol/L), and the glucose level was 8.3 mmol/L. A urinalysis was performed, which was normal. The physicians considered a secondary hypertension through a mineralocorticoid effect because of the metabolic alkalosis, hypokalemia, and hypernatremia. The active renin was 26 ng/L (1.5 to 18 ng/L), the serum aldosterone concentration was 218 ng/L (29 to 163 ng/L), and the 24 hour urinary aldosterone excretion was 11.2 µg/24 hours (3 to 19 µg/24 hours). The aldosterone:renin ratio was reported at 8.4 (<50). However, the adrenocorticotropic hormone (corticotropin [ACTH]) concentration was 22.2 pmol/L (<10.3 pmol/L), the serum cortisol was 1750 nmol/L (171 to 536 nmol/L), and the urine cortisol excretion was 18 774 nmol/d (100 to 379 nmol/d). The thyrotropin level was low at 0.16 mU/L (0.27 to 4.20 mU/L), the free T3 was 2.8 pmol/L (2.8 to 7.8 pmol/L), and the free T4 was 9.9 pmol/L (12.0 to 22.0 pmol/L). We performed low- (2 mg at bedtime) and high-dose (2 mg 4 times per day) dexamethasone suppression tests, but neither test resulted in cortisol suppression. After 2 mg of dexamethasone at bedtime, ACTH stayed at 26.0 pmol/L, and cortisol was still >1750 nmol/L. After 8 mg of dexamethasone, the values were still at 27.5 pmol/L for ACTH and remained >1750 nmol/L for cortisol.
The patient had a generalized obesity. We examined him carefully for evidence of facial rounding, interscapular fat deposition, hirsutism, easy bruising, skin atrophy, purple striae, and proximal muscle weakness. However, we could not find any of these stigmata. We asked his wife to produce photographs of the patient from several years earlier. However, we could not discern any notable change in his appearance since that time, and his wife could not either. We considered the possibilities of Cushing’s syndrome and Cushing’s disease. Computed tomography (CT) of the head, chest, and abdomen disclosed no abnormalities. These studies were followed by MRI, and, again, no abnormalities were identified. Octreotide scintigraphy was performed that showed abnormal nuclide collection in the area of the pancreatic head. The possibility of a carcinoid tumor in that region was raised, although CT and MRI could not confirm this suspicion.
During the hospitalization and workup, the patient was treated with torasemide (20 mg twice daily), amlodipine 10 mg, spironolactone 100 to 200 mg daily, ramipril 10 mg daily, aliskiren to 300 mg daily, candesartan 32 mg daily, and clonidine 0.3 mg twice daily. These medications were not all given concomitantly but in various combinations, and thereby reasonable (<140/90 mm Hg) blood pressure control was achieved. We next planned inferior petrosal sinus ACTH sampling in conjunction with corticotropin releasing hormone (CRH) stimulation. We discussed the nature of, and reasons for, the test with the patient in detail, and written, informed consent was obtained. On the following morning of the planned procedure, the patient climbed out of his fourth floor hospital room window and leaped to the concrete below. He was killed instantly. The medical examiner’s office was contacted after the patient’s death was ascertained.
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Clinical Discussion of Cushing’s Syndrome |
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TopIntroductionCase Report (Eugenia Singer,...Clinical Discussion of Cushing's...How Do ACTH and...Cushing's Syndrome and...Pathological Report (Dierk...Pathological DiagnosisReferences |
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This patient and his tragic outcome bring to mind several important lessons. The "real world" deviates from textbooks. The presentation was that of acute heart failure, rapid atrial fibrillation, and the acute coronary syndrome with elevated troponin T values. This constellation calls for rapid response with acute cardioversion, treatment for pulmonary edema, and cardiac catheterization. Precisely, this cycle of events ensued. Cardioversion stabilized the patient, and his coronary arteries proved to be patent. There are numerous alternative explanations for elevated cardiac troponin levels, and sudden atrial fibrillation and cardiac failure serve to explain the findings.4 The patient had neither ST segment elevation nor ST segment depression; however, his inverted precordial T waves also facilitated his trip to the catheterization suite.
The house staff physicians in the coronary care unit were very attuned to the patient’s electrolyte disturbance on admission because of a similar patient we had several years ago with Cushing’s syndrome from a small cell lung cancer (unpublished observations). They reacted quickly and obtained renin, aldosterone, cortisol, and ACTH values before in-hospital treatment for hypertension was begun. The elevated cortisol and ACTH concentrations drew their attention away from the diagnosis of primary aldosteronism, although aldosterone values in serum and urine were on the high side of normal in this patient. The active renin was 26 ng/L (1.5 to 18.0 ng/L). In most clinical circumstances, renin is estimated by assays of plasma renin activity (PRA). PRA is measured by generating angiotensin I from endogenous angiotensinogen followed by measurement of angiotensin I by radioimmunoassay. PRA measurements are convenient for estimating the biological activity of the system. They do of course not give information on the real concentration of active renin. A new method for measuring direct renin by an automated immunochemiluminometric assay was used in this patient. The assay uses 2 specific monoclonal antibodies. The first is biotin-labeled and captures renin by recognizing both active renin and prorenin. The second antibody is labeled with acridinium ester and can detect active renin and activated prorenin. The acridinium ester emits light on treatment with hydrogen peroxide. Reasonable correlations between this direct renin assay and PRA have been reported.5 In our hospital, the clinical laboratory made no announcement that they would no longer offer PRA but instead would report direct renin. Because our department is probably the sole "user," this new reporting mechanism resulted in some confusion. This confusion was compounded when medications, particularly aliskiren, were added. We assume that the elevated direct renin, which we would have predicted should have been low, was relatively high in this patient initially because of rapid atrial fibrillation, heart failure, treatment for pulmonary edema, and other confounders.
Cushing’s syndrome or disease became the working diagnosis early in this patient’s hospital course. Irritating for us was the fact that the "classic" manifestations described in the textbook and literature, except for one, were not there. The house staff physicians were circumspect enough to obtain earlier photographs of the patient and to discuss with the spouse whether any morphological appearance changes had taken place. Central obesity was not present, although the patient was by no means thin. Facial rounding, interscapular fat deposition, hirsutism, easy bruising, skin atrophy, purple striae, and proximal muscle weakness were all conspicuous by their absence. The patient had type 2 diabetes mellitus, which is present in most patients with this level of obesity.
We can only speculate on why our patient did not look like the patients who Harvey Cushing described. However, there is a rare genetic condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. Charmandari et al6 recently reviewed the clinical aspects, molecular mechanisms, and implications of this disorder. They conducted a systematic review of the published, peer-reviewed medical literature. The clinical spectrum of primary generalized glucocorticoid resistance is broad and ranges from asymptomatic to severe cases of hyperandrogenism, fatigue, and/or mineralocorticoid excess. The molecular basis of the condition has been ascribed to mutations in the human glucocorticoid receptor gene, which impair glucocorticoid signal transduction and reduce tissue sensitivity to glucocorticoids. A consequent increase in the activity of the hypothalamic-pituitary-adrenal axis compensates for the reduced sensitivity of peripheral tissues to glucocorticoids at the expense of ACTH hypersecretion-related pathology.
We measured urinary free cortisol and midnight plasma cortisol in saliva (data not shown), and we performed low- and high-dose dexamethasone suppression tests. All supported the diagnosis of Cushing’s syndrome or disease. Once faced with the diagnosis, clinicians have to decide on the most likely source of Cushing’s syndrome or disease. In our patient, the Cushing’s was ACTH dependent. Thus, we were fairly certain that an adrenal adenoma or carcinoma was not responsible. CT imaging corroborated this opinion. We were left with the diagnosis of ACTH-dependent Cushing’s syndrome (disease). We strongly considered the possibility of a corticotroph tumor in this patient.3 Such tumors can be very small and exceptionally difficult to detect.7,8 With imaging techniques, we moved down both arms of the diagnostic tree. CT and MRI were not helpful in terms of thoracic or abdominal studies. Studies of the brain gave no additional information. We ordered an octreotide scintigraphic scan of the abdomen and obtained a questionable result in the pancreas. Ectopic adrenocorticotrophic hormone syndromes from carcinoid tumors are well known. For instance, Fazel et al9 reported a patient with refractory hypertension and a 9-cm pancreatic mass that proved to be a neuroendocrine tumor. Extensive liver and mediastinal metastases were also found, and the patient had all of the clinical stigmata of Cushing’s syndrome. She proved to have a carcinoid pancreatic tumor; however, a CT scan showed an obvious presence of the lesion in that patient. We were of course suspicious with the results of our octreotide imaging study but could not identify a substrate with either CT or MRI in the pancreas of our patient and, therefore, directed our attention elsewhere.
Lindholm et al10 reported on the incidence and late prognosis of noniatrogenic Cushing’s syndrome in Denmark. They retrieved data over an 11-year period and found that Cushing’s disease was most common at 1.2 to 1.7 per million per year, whereas adrenal adenomas were less common at 0.6 per million per year and carcinomas fortunately even less common at 0.2 per million per year. Those patients had an extremely poor prognosis, whereas patients with Cushing’s disease did fairly well, particularly those whose tumors were amenable to transsphenoidal neurosurgery. We directed our attention to that diagnosis and scheduled inferior petrosal sinus sampling.
The vast majority (90% to 95%) of patients with ACTH-dependent Cushing’s syndrome have a pituitary corticotroph microadenoma.11 We were concerned because our patient had prodigious hypercortisolism, hypokalemia, and an ACTH value that was fairly high. The octreotide scintigraphy gave us a positive result that we could not find with CT, MRI, or abdominal ultrasound. We elected to attempt pituitary imaging with MRI. Unfortunately, approximately half of corticotroph microadenomas causing Cushing’s syndrome in adults are not visible with this technique.12 Our patient’s MRI study was not informative. Inferior petrosal sinus ACTH sampling with CRH stimulation is the only study having the capacity to deliver a diagnostic sensitivity and specificity for Cushing’s disease higher than the pretest probability.10 In the presence of documented hypercortisolism, an unequivocal pituitary ACTH gradient (inferior petrosal sinus:peripheral ACTH ratio) >2.0 in the basal state and >3.0 after CRH provides a diagnostic sensitivity of 100%.13 On the basis of these data, we scheduled our patient for the study.
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How Do ACTH and Glucocorticoids Cause Hypertension? |
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TopIntroductionCase Report (Eugenia Singer,...Clinical Discussion of Cushing's...How Do ACTH and...Cushing's Syndrome and...Pathological Report (Dierk...Pathological DiagnosisReferences |
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Resistant hypertension was a significant comorbidity in our patient and interfered considerably with his workup. As our patient illustrates, hypertension in Cushing’s syndrome is almost invariably present and can be severe. Nagai et al14 presented a patient with malignant hypertension from Cushing’s disease, who had features similar to our patient. Their patient had blood pressure values of 290/160 mm Hg without treatment. The patient also had no classical stigmata of Cushing’s syndrome, aside from an elevated blood sugar. PRA was not maximally suppressed in their patient, and the serum aldosterone concentration was 11 pg/mL. Cortisol and ACTH levels were high and could not be suppressed. Pituitary imaging revealed a tumor that was removed, after which the hypertension and the diabetes resolved. The authors pointed out that the pressor responses to norepinephrine and angiotensin II are increased in patients with Cushing’s syndrome.14
The association between glucocorticoid excess and hypertension is complex and still poorly understood. Hypothesized mechanisms include increased hepatic angiotensinogen synthesis, central regulation of baroreflex function and sympathetic tone, inhibition of vasodilator and stimulation of vasoconstrictor systems in vascular tissue, enhanced glucocorticoid-mediated vascular reactivity to norepinephrine, effects on sodium and volume homeostasis, and increase of local endothelial growth factor activity.15 A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11 β-hydroxysteroid dehydrogenase (11 β-HSD)-1 regenerates active cortisol from inactive 11-keto forms, and mice with transgenic overexpression of 11 β-HSD-1 in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Masuzaki et al16 recently reported that these mice also have high blood pressure. Glucocorticoids are known to increase plasma angiotensinogen concentrations.17 In the absence of renin suppression, as was the case in our patient, considerable amounts of angiotensin II could be generated. Furthermore, ACTH can result in aldosterone release; aldosterone was also elevated in our patient.18 Glucocorticoids also act within the brain to regulate the baroreflex function and thereby influence sympathetic tone.19
The mineralocorticoid receptor could also have contributed to hypertension in our patient. In cases of cortisol excess, the main agonist of the receptor may be cortisol rather than aldosterone. The enzyme 11 β-HSD-2 converts cortisol to cortisone in the distal nephron to protect the mineralocorticoid receptor from the agonist cortisol; however, the enzyme is not 100% efficient. 11 β-HSD-2 activity in vascular tissue, the heart, and the central nervous system is uncertain.20 Our group recently demonstrated glucocorticoid-related signaling effects in vascular smooth muscle cells.21 We identified new mineralocorticoid receptor-dependent signaling pathways and suggested that glucocorticoids may contribute to vascular disease via mineralocorticoid receptor signaling, independent of circulating aldosterone. ACTH may decrease 11 β-HSD-2 and, thus, amplify the actions of cortisol on the mineralocorticoid receptor.22 Furthermore, glucocorticoid β-hydroxylation, which induces urinary sodium retention, is increased in patients with Cushing’s syndrome.23 Our patient had ample sodium retention. While residing in our intensive care unit, large amounts of sodium chloride-containing solutions were infused, in part because of an episode of local bleeding at the site of a femoral puncture for cardiac catheterization. Thus, mineralocorticoid action would appear to play a role in our patient’s hypertension, although spironolactone 200 mg/d had little apparent blood pressure-reducing effect in our patient.
The sodium pump possibly contributed to hypertension in our patient. The Na,K-ATPase contains a binding site for cardiac glycosides, such as ouabain, digoxin, and digitoxin, which is highly conserved among species. Dostanic-Larson et al24 showed recently that this site plays an important role in the regulation of blood pressure and that it specifically mediates ACTH-induced hypertension. They used genetically engineered mice in which the Na,K-ATPase 
2 isoform, which is normally sensitive to cardiac glycosides, was made resistant to these compounds. Chronic administration of ACTH caused hypertension in wild-type mice but not in mice with a ouabain-resistant 2 isoform of Na,K-ATPase. Their results demonstrate that the cardiac glycoside binding site of the Na,K-ATPase- isoforms have a physiological function. When overstimulated after high ACTH, as was the case in our patient, the Na,K-ATPase should serve for avid sodium reabsorption and could contribute to salt-sensitive hypertension. Evidence exists that the adrenal gland may be the source for endogenous glycosides in response to ACTH that regulate the sodium pump. Inhibition of the Na,K-ATPase raises intracellular sodium, which reverses the transport mode of the Na/Ca exchanger. The resultant influx of calcium could contribute to increased vascular smooth muscle cell tone.
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Cushing’s Syndrome and Psychiatric Illness |
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TopIntroductionCase Report (Eugenia Singer,...Clinical Discussion of Cushing's...How Do ACTH and...Cushing's Syndrome and...Pathological Report (Dierk...Pathological DiagnosisReferences |
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Where we failed was in recognizing our patient’s psychiatric illness and in not taking the proper precautions. German hospitals are, as a rule, not air conditioned, except for intensive care units and operating rooms. Wide windows that can be opened, even on upper stories, are nothing uncommon. Medical students learn that depression is a part of the Cushing’s syndrome complex, and that fact did not escape us. The chief of service, who saw this patient several times, recalls having wondered about the patient’s "flattened" affect. However, we failed to act, and no suicide precautions were initiated and no psychiatric consultation was obtained.
Decades ago, patients with depression were observed to exhibit hypersecretion of both cortisol and its metabolites.25 The observation that patients with Cushing’s disease or syndrome commonly experienced severe depression and anxiety and the increased production and secretion of glucocorticoids, such as cortisol, in healthy people exposed to stress contributed to the modern stress-diathesis hypothesis of depression in which excess secretion of cortisol is thought to play a significant pathophysiological role in the etiology of depression.26 The CRH receptor has become a drug target that could play a role in the treatment of depression.27 Investigations of CRH type 1 receptor nonapeptide antagonists suggest therapeutic potential for treatment of these and other neuropsychiatric diseases. Cushing’s disease and related pituitary/adrenal disorders could become obvious applications for CRH type 1 receptor antagonists. For overt psychosis, which our patient may have had, heroic measures are sometimes used. Bilgin et al28 reported on the use of etomidate, which blocks the cortisol synthesis, and mifepristone, which competes with cortisol for binding to cortisol receptors to manage a severe psychosis in a patient with Cushing’s syndrome from adrenal carcinoma.
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Pathological Report (Dierk Schmidt and Wolfgang Schneider) |
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TopIntroductionCase Report (Eugenia Singer,...Clinical Discussion of Cushing's...How Do ACTH and...Cushing's Syndrome and...Pathological Report (Dierk...Pathological DiagnosisReferences |
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The medical examiners determined that the patient died of injuries resulting from his fall. They were not interested in his medical problems, and their examination was conducted in a more leisurely fashion, some days after his death. Thus, the pituitary was not placed into formalin immediately, and paraffin embedding was necessarily delayed. This state-of-affairs made the pathologist’s work substantially more difficult and also limited the studies that could be performed. The pancreas was inspected and not found to contain a tumor.
The histological picture of the anterior pituitary was one of primary ACTH cell hyperplasia. The hyperplasia was predominantly nodular, and the acinar structures were not disrupted. However, the reticular pattern showed clear evidence of expansion. We performed ACTH immunohistochemistry staining (Figure, panel A). Ample numbers of ACTH (red) staining cells were identified, within a retained acinar structure. The ACTH-staining cells were observed to invade the neurohypophysis. This invasion was confirmed with periodic acid Schiff staining (Figure, panel B).
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Primary ACTH cell hyperplasia may result from excessive secretion of CRH or may be idiopathic.29–31 The hyperplasia is predominantly nodular but may be diffuse if CRH is stimulated. Patients with excess CRH production from ectopic sources such as neoplasms or gangliocytic hamartomas may present with Cushing’s syndrome, eg, from small cell lung cancer. In such cases, a full-blown picture of Cushing’s syndrome is not present because of the rapid course of the disease. Unfortunately, CRH was not measured in this patient. In pituitary hyperplasia because of ectopic hormone production, the adrenal glands may become markedly enlarged. In our patient, the glands were "plump" with imaging but were not markedly enlarged. Unfortunately, a precise assessment of the adrenal glands was not possible, because the medical examiners did not place this tissue at our disposal. ACTH cell hyperplasia may be difficult to diagnose in small biopsy specimens because of the variable pattern and distribution of ACTH cells in the normal pituitary. Ours was not a surgical specimen; however, the pituitary was removed under less-than-ideal conditions. Samples from the pars nervosa may show ACTH-positive cell invasion, as was the case in our patient. Purists could argue that our diagnosis is not proven without doubt; however, we believe our clinical arguments, and the histology that we do have are compelling.
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Pathological Diagnosis |
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TopIntroductionCase Report (Eugenia Singer,...Clinical Discussion of Cushing's...How Do ACTH and...Cushing's Syndrome and...Pathological Report (Dierk...Pathological DiagnosisReferences |
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We diagnosed pituitary hyperplasia with ACTH production.
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Acknowledgments |
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Disclosures
None.
Received August 17, 2008; first decision September 17, 2008; accepted October 8, 2008.
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References |
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TopIntroductionCase Report (Eugenia Singer,...Clinical Discussion of Cushing's...How Do ACTH and...Cushing's Syndrome and...Pathological Report (Dierk...Pathological DiagnosisReferences |
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