Androgens The adrenal gland (zona reticularis and zona fasciculata) also produces sex stero ids, in the form of dehydroepiandrostenedione (DHEA) and androstenedione. The synthetic pat hway is under the control of ACTH. Urinary steroid pro \201 ling provides quantitative inf ormation on the biosynthetic and catabolic pathways. Pro \201 ling can be useful in the fo llowing: \200 Mineralocorticoid hypertension \200 Polycystic ovary syndrome \200 Cong enital adrenal hyperplasia \200 Steroid-producing tumors \200 Precocious puberty and vi rilization \200 Hirsutism Table 31.1 Adrenal cortex steroid production Adrenal cortex Cortisol Aldosterone DHEA DHEAS Production rate/24 hours 10 mg 100 mcg 10 mg 25 mg t 80 min 20 min 20 min 9 hr Control ACTH Renin ACTH ACTH 31-Draznin-Chap31.indd 166 4/1/2011 5:29:42 PM PHYSIOLOGY 167 Hypothalamus Aldosterone K+ ACTH Glomerulosa cells ? Angiotensin III Adrenal Angiotensin II Converting enzyme (ACE) Lungs Angiotensin I Renin Angiotensinogen Juxtaglomerular cells Sympathetic input Blood pressure Na+ Kidney Fig. 31.2 Physiological mechanisms governing the production and secretion of aldosterone. R eprinted with permission from Besser M, Thorner GM (1994). Clinical Endocrinology , 2nd ed. New York: Elsevier. Further reading Taylor NF (2006). Urinary steroid pro \201 ling. Method Mol Biol 324:159 \200\223175. 31-Draznin-Chap31.indd 167 4/1/2011 5:29:42 PM CHAPTER 32 Imaging 168 Imaging Computed tomography (CT) scanning CT is the most widely used modality for imaging the adren al glands. It is able to detect masses >5 mm in diameter. It can be useful in differentiati ng between different adrenal cortical pathologies ( Fig. 32.1 ). Adrenal adenoma Adrenal glands Fig. 32.1 Typical appearance of adrenal adenoma on CT scan. Magnetic resonance imaging (MRI) MRI can also reliably detect adrenal masses >5 \200\22310 mm in diameter and in some circumstances provides additional information to CT data, e.g., differentiation of cortical from medullary tumors. Ultrasound (US) imaging US detects masses >20 mm in diameter, but normal adrenal glands are not usually visible except in children. Body morphology and bowel gas can provide technica l dif \201 culties. 32-Draznin-Chap32.indd 168 4/1/2011 7:17:59 PM VENOUS SAMPLING 169 Normal adrenal Normal adrenal cortex is assessed by measuring limb thickness and is conside red enlarged at >5 mm, approximately the thickness of the diaphragmatic crus nearby. Radionucleotide imaging 123 Iodine-metaiodobenzylguanidine (MIBG) This is a guanethidine analog, concentrated in so me pheochromocytomas, paragangliomas, carcinoid tumors, and neuroblastomas, and is useful d iag- nostically. A different isotope, 131 I-MIBG, may be used therapeutically, e.g., in mal ignant pheochromocytomas when the diagnostic imaging shows uptake. 75 Se 6B-selenomethyl-19 -norcholesterol This isotope is concentrated in functioning steroid-synthesizing tissue and is used to image the adrenal cortex. It can be used in determining whether a nodule is fun ctioning or not and can be helpful in localizing residual adrenal tissue following failed b ilateral adrenalectomy. However, high-resolution CT and MRI have largely replaced it in local- izing functional adrenal adenomas. Positron emission tomography (PET) PET can be useful in locating tumors and metastases. Rad iopharmaceuticals for speci \201 c endocrine tumors are being developed, e.g., [11C] metah y- droxyephedrine for pheochromocytoma. Combined with CT (PET-CT) it may offer particular v alue in localizing occult neuroendocrine tumors. Venous sampling Adrenal vein sampling can be useful to lateralize an adenoma or to differen tiate an adenoma from bilateral hyperplasia. It is technically dif \201 cult \200\224parti cularly, catheterizing the right adrenal vein because of its drainage into the IVC. It may also be used to con \201 rm the diagnosis of bilateral pheochromo- cytoma. It is of particular value in lateralizing small aldosterone-producing adenomas that cannot easily b e visualized on CT or MRI. Further reading Pacak K, Eisenhofer G, Goldstein DS (2004). Functional imaging of endocrine tumors: role of posi- tron emission tomography. Endocr Rev 25(4):568 \200\223580. Peppercorn PD, Grossman AB, et al. (1998). Imaging of incidentally discovered adrenal masse s. Clin Endocrinol 48:379 \200\223388. Reznek RH, Armstrong P (1994). The adrenal gland. Cl in Endocrinol 40:561 \200\223576. 32-Draznin-Chap32.indd 169 4/1/2011 7:18:00 PM CHAPTER 33 Mineralocorticoid excess 170 Mineralocorticoid excess De \201 nitions Most cases of mineralocorticoid excess are due to excess aldosterone produ ction, which may be primary or secondary, and are typically associ- ated with hypertension and hypokalemia. Primary hyperaldosteronism is a disorder of autonomous aldosterone hypersecretion with suppressed renin levels. Secondary hyperaldosteronism occurs when aldosterone hypersecretion occurs secondary to ele vated circulating renin levels. This is typical of heart failure, cirrhosis, or nephrotic s yndrome, but can also be due to renal artery stenosis and, occasionally, a very rare renin- producing tumor (reninoma). Other mineralocorticoids may occasionally be the cause of this syndrome ( b see Box 33.1 ) . Box 33.1 Causes of mineralocorticoid excess Primary hyperaldosteronism \200 Conn \200\231s syndrome (aldosterone-producing adrenal ad enoma): 35% \200 Bilateral adrenal hyperplasia: 60% \200 Glucocorticoid remedial aldost eronism (GRA): <1% \200 Aldosterone-producing adrenal carcinoma Secondary hyperaldosteronism \200 Renal artery stenosis \200 Renal hypoperfusion \200 Cirrhosis \200 Congestive cardiac failure \200 Nephrotic syndrome \200 Renin-secreti ng tumor Other mineralocorticoid excess syndromes \200 Apparent mineralocorticoid excess ( b see p . 182) \200 Liquorice ingestion (p. 183) (inhibits II B HSOH) d aldosterone, d renin, d K + found in sweets, chewing tobacco, cough mixtures, and herbal medicines Deoxycorticosterone and corticosterone ( b see p. 183) \200 Ectopic ACTH secretion (b see p. 183) \200 Congenital adrenal hyperplasia (b see p. 239) \200 Exogenous mineralocort icoids Pseudoaldosteronism due to abnormal renal tubular transportation \200 b Bartter \200\231s syndrome (p. 191) \200 b Gitelman \200\231s syndrome (p. 190) \200 b Liddle \200\231s syndrome (p. 190) 33-Draznin-Chap33.indd 170 3/31/2011 2:57:29 PM CONN \200\231S SYNDROME \200\224ALDOSTERONE-PRODUCING ADENOMA 171 Primary aldosteronism Epidemiology Primary hyperaldosteronism is present in approximately 5% of hyperten- sive pa tients. The most common cause is bilateral adrenal hyperplasia (b see Table 34.1 ) . Pathophysiology Aldosterone causes renal sodium retention and potassium loss. This results in expansion of body sodium content, leading to suppression of renal renin synthesis. The direct action of aldosterone on the distal nephron causes sodium retention and loss of hydrogen and potassium ions, resulting in a hypoka- lemic alkalosis, although serum potassi um may not be signi \201 cantly reduced and may be normal in up to 50% of cases. Aldosterone has pathophysiological effects on a range of other tis- sues, causing cardiac \201 brosis, vascular endothelial dysfunction, and nephrosclerosis. Clinical features Moderately severe hypertension occurs, which is often resistant to conven tional therapy. There may be disproportionate left ventricular hypertrophy. Hypokalemia is usually asymptomatic. Occasionally, patients may present with tetany, myopat hy, polyuria, and nocturia (hypokalemic nephrogenic diabetes insipidus) due to severe hypok alemia. Conn \200\231s syndrome \200\224aldosterone- producing adenoma Very high levels of the enzy me aldosterone synthase are expressed in tumor tissue. Although aldosterone production is a utonomous, ACTH has a greater stimulatory effect than angiotensin II (aldosterone often dis plays a diurnal variation that mirrors that of cortisol), although a subtype that remain mo re responsive to angiotensin II has been described. Very rarely, Conn \200\231s adenomas may be part of the MEN1 syndrome. 34-Draznin-Chap34.indd 171 4/1/2011 6:40:58 PM 3 4 D r a z n i n C h a p 1 7 2 3 4 . i n d d Table 34.1 Causes of hyperaldosteronism C H A P T E R 1 7 2 Relative frequency Age Sex Condition Pathology Aldosteronoma (Conn \200\231s adenoma) 35% 3rd \200\2236th decade Predominant in women Benign, adenoma, <2.5 cm diameter, yellow because of high cholesterol content 3 4 P r i Idiopathic waldosteronism/ adrenal hyperplasia 60% Older than Conn \200\231s No sex difference Macronodular or micronodular hyperplasia m a r y Adrenal carcinoma Rare 5th \200\2237th decade (occasionally young) More common in women Tumor >4 cm in diameter, often larger, may be evidence of local invasion a l d o s t e r o n i s Glucocorticoid suppressible hyperaldosteronism Rare Childhood No sex difference Bilateral hyperplasia of zona glomerulosa m 4 / 1 / 2 0 1 1 6 : 4 0 : 5 8 P M ALDOSTERONE-PRODUCING CARCINOMA 173 Bilateral adrenal hyperplasia (bilateral idiopathic hyperaldosteronism) This is the most co mmon form of primary hyperaldosteronism in adults. Hyperplasia is more commonly bilateral t han unilateral and may be associated with micronodular or macronodular hyperplasia. However , CT-demonstrable nodules have a prevalence of 2% in the general pop- ulation, including hy pertensive patients without excess aldosterone production. The pathophysiology is not known, although aldosterone secretion is very sensitive to circu lating angiotensin II. The pathophysiology of bilateral adrenal hyperplasia is not understo od; it is possible that it represents an extreme end of the spectrum of low rennin-essentia l hypertension. Glucocorticoid-remedial aldosteronism (GRA) This is a rare autosomal dominantly inherited c ondition due to the pres- ence of a chimeric gene (8q22) containing the 5 sequence that d etermines regulation of the 11B-hydroxylase gene (CYP11B1) coding for the enzyme catalyzing the last step in cortisol synthesis, and the 3 sequence from the aldosterone synthase ge ne (CYP11B2) coding for the enzyme catalyzing the last step in aldosterone synthesis. This results in expression of aldosterone synthase in the zona fasicu- lata as well as the zona glomerulosa, and aldosterone secretion becomes under ACTH control. Glucocorticoids lea d to suppression of ACTH and suppression of aldosterone production. \200 There is early h ypertension and family history. \200 Hybrid steroids (18OHcortisol and 18oxocortisol) are elevated. Aldosterone-producing carcinoma This is rare and usually associated with excessive secretio n of other corti- costeroids (cortisol, androgen, estrogen). Hypokalemia may be profound, a nd aldosterone levels very high. 34-Draznin-Chap34.indd 173 4/1/2011 6:40:58 PM CHAPTER 34 Primary aldosteronism 174 Screening Indications \200 Patients resistant to conventional antihypertensive medication (i.e., no t controlled on three agents) Hypertension associated with hypokalemia (potassium < 3.7 mmol/L, irrespective of thiazide use) Hypertension developing before 40 years of age \200 Adrenal incidentaloma Method False-negative and false-positive results can occur if the test is not per- formed u nder controlled circumstances. \200 Give oral supplements of potassium to control hypokal emia. \200 Stop medication that can interfere with the test using appropriate washout period ( Table 34.2 ) . Blood pressure (BP) can be controlled using doxazosin or verapamil (rather than other calcium antagonists). Measure aldosterone/renin ratio. Table 34.2 Effects of medication on renin and aldosterone measurement Effect on screening test Magnitude of effect Drug Washout Methyl-dopa False positive Clonidine \200\223 \200\223 False positive B-Blockers, e.g., atenolol A-Blockers, e.g., doxazosin 2 62% ( 82) False positive na \200\2235% ( 26) Little effect ACE inhibitors, e.g., fosinopril 2 \200\22330% ( 24) False negative ARB, e.g., irbesartan 2 \200\22343% ( 24) False negative Ca antagonists, e.g., amlodipine 2 \200\22317% ( 32) False negative Diuretics 6 \200\223 False negative NSAIDS may give false positives. 34-Draznin-Chap34.indd 174 4/1/2011 6:40:58 PM SCREENING 175 A high ratio is suggestive of primary hyperaldosteronism (aldosterone [ng/dL]/plasma renin activity [ng/mL/h] >30 \200\22350). Newer assays that meas- ure renin mass (rather than act ivity) will require development of different cutoffs. The greater the ratio, the more likel y the diagnosis of primary aldosteronism. A false negative can occur in patients with chronic renal failure due to an inappropriately high plasma renin activity. 34-Draznin-Chap34.indd 175 4/1/2011 6:40:58 PM CHAPTER 34 Primary aldosteronism 176 Con \201 rmation of diagnosis Con \201 rmation of autonomous aldosterone production is ma de by dem- onstrating failure to suppress aldosterone in the face of sodium/volume loading. This can be achieved through a number of mechanisms after opti- mizing test conditions as described. Dietary sodium loading Patients can be instructed to take a diet with high sodium content ( suf- \201 cient to raise the sodium intake to 200 mmol/day for 3 days. If necessary, this can be achieved by adding supplemental sodium chloride tablets. It is important to ensure that potassium is maintained during this period; potassium supple mentation may also be required. Failure to suppress 24-hour urinary aldosterone secretion a t the end of this period is diagnos- tic of primary aldosteronism. Saline infusion test \200 Administer 2 L normal saline over 4 hours, preferably between 8 A.M. and noon. Measure plasma aldosterone at 0 and 4 hours. \200 Aldosterone fails to suppresses to <7.5 ng/mL (7.5 \200\22310 equivocal) in 80 \200\22390% of primary aldosteronism. Frequently, this test is followed by measurements of plasma rennin activity (PRA) with upri ght posture and use of a diuretic (furosemide up to 80 mg). Low PRA under these conditions supports the diagnosis. Other testing A number of tests have been described that are said to differentiate between the various subtypes of primary aldosteronism (solitary Conn \200\231s adenoma, bilateral a drenal hyperplasia, GRA). However, none of these are suf \201 ciently speci \201 c to in \202 uence management decisions, and more speci \201 c investigations (imaging and adrena l vein sampling) are necessary if there is doubt. Additional tests, such as postural response of aldosterone and the basal plasma 18-hydroxyc orticosterone >100 ng/dL, are suggestive of primary aldosteronism. Diagnosis of GRA is best made using a speci \201 c genetic test rather than on the ability of dexamethasone (0.5 mg q6h for 3 days) to suppress aldosterone. Other dynamic tests If these tests are nondiagnostic, then it is usual to proceed to venous sampling rather than dynamic testing. However, such tests can sometimes be helpful. 34-Draznin-Chap34.indd 176 4/1/2011 6:40:58 PM CONFIRMATION OF DIAGNOSIS 177 Captopril suppression test \200 Plasma aldosterone is measured in the sitting position, b asally, and 60 minutes after captopril 25 mg. Inhibition of angiotensin II leads to a fall in aldosterone in patients with idiopathic hyperaldosteronism but not in Conn \200\231s syndrome. Fludrocortisone suppression test \200 Give \202 udrocortisone 100 mcg q6h for 4 days. \200 Measure aldosterone basally and on last day. \200 Aldosterone is suppressed in hype rplasia but unchanged in adenomas. 34-Draznin-Chap34.indd 177 4/1/2011 6:40:59 PM 3 4 D r a z n i n C h a p 1 7 8 3 4 . i n d d Table 34.3 Differential diagnosis of primary hyperaldosteronism C H A P T E R 1 7 8 Condition Test Upright posture and time i i l d i ACE inhibitor i d l l i Dexamethasone suppression l l l l l Normal PRA 3 4 P r i Aldosterone Aldosterone-producing adenoma PRA m a r y Aldosterone Angiotensin-responsive adenoma (?720% adenomas) PRA a l d o s t e r o n i s i i i l d i d l l l l i Aldosterone Idiopathic adrenal hyperplasia PRA Aldosterone Glucocorticoid-suppressible hyperaldosteronism PRA m d l d Aldosterone 4 / 1 / 2 0 1 1 6 : 4 0 : 5 9 P M LOCALIZATION & CONFIRMATION OF DIFFERENTIAL DIAGNOSIS 179 Localization and con \201 rmation of differential diagnosis CT/MRI scan CT and MRI scanning are of value in identifying adrenal adenomas. It should be noted, however, that the frequency of adrenal incidentalomas rises with age and, for this r eason, it is prudent to consider adrenal vein sampling in older patients (age >50) with pri mary aldosteronism who have an apparent solitary adenoma on scanning. \200 Identi \201 e s most adenomas >5 mm diameter. Bilateral abnormalities or tumors <1 cm in diameter require further localization procedures. \200 In bilateral adrenal hyperplasi,a both glands can appear enlarged or normal in size. Macronodular hyperplasia may result in identi \201 able nodules on imaging. A mass >4 cm in size is suspicious of carcinoma but is unusual in Conn \200\231s syndrome. In essential hypertension, nodules are described. Adrenal vein sampling Aldosterone measurements from both adrenal veins allow a gradient bet ween the two sides to be identi \201 ed in the case of unilateral disease. It is the gold standard for differentiation between uni- and bilateral aldos- terone production, but cannu lating the right adrenal vein is technically dif \201 cult, as it drains directly into the inferior vena cava. Cortisol measurements must also be taken concomitantly with aldoster- one to con \201 rm s uccessful positioning within the adrenal veins and should be more than 3 \227 a peripheral sample (central/peripheral ratio >3). The aldosterone/cortisol ratio with an adenoma is >4. 1. Radiolabeled iodocholesterol scanning This test has low sensitivity and speci \201 city an d offers no advantage over a high-resolution CT or MRI with, where necessary, adrenal vein sampling. 34-Draznin-Chap34.indd 179 4/1/2011 6:40:59 PM CHAPTER 34 Primary aldosteronism 180 Treatment Surgery Laparascopic adrenalectomy is the treatment of choice for aldosterone- secreting ad enomas and is associated with lower morbidity than open adrenalectomy. Surgery is not indicated in patients with idiopathic hyperaldosteronism, as even bilateral adrenalectomy may not cure the hypertension. Presurgical spironolactone treatment may be used to correct potassium stores before surgery. The BP response to treatment with spironolactone (50 \200\223400 mg/day) before surgery can be used to predict the response to surgery of patients with adenomas. Hypertension is cured in about 70% of patients. If it persists (more likely in those with l ong-standing hypertension and increased age), it is more amenable to medical treatment. Overall, 50% become normotensive in 1 month and 70% within 1 year. Medical treatment Medical therapy remains an option for patients with a solitary adrenalad- enoma who are unlikely to be cured by surgery, who are un \201 t for opera- tion, or who express a preference for medical management. The aldosterone antagonist spironolactone (50 \200\223400 mg/day) has been used successfull y for many years to treat the hypertension and hypokalemia associated with bilateral adrena l hyperplasia and idiopathic hyperaldosteronism. There may be a delay in response of hypertension of 4 \200\2238 weeks. However, combination with other antihypertensive agents (ACE inhibitor and calcium channel blockers) is usually required. Side effects are common, particularly gynecomastia and impotence in men, menstrual irregularities in women, and GI effects. Eplerenone (50 \200\223100 mg/day) is a mineralocorticoid antagonist without antiandrogen effects and greater selectivity than that of spironolactone. Alternative drugs include the potassium-sparing diuretics amiloride and triamterene . Amilo ride may need to be given in high dose (up to 40 mg/day) in primary aldosteronism, and moni toring of serum potassium is essential. Calcium channel antagonists may also be helpful. Glucocorticoid-remedial aldosteronism can be treated with low-dose dexamethasone (0.5 mg on going to bed). Side effects often limit therapy, and spironolactone or amiloride treatment is often preferred. For adrenal carcinoma, surgery and postoperative adrenolytic therapy with mitotane is usual ly required, but the prognosis is usually poor ( b see Treatment, p. 186). 34-Draznin-Chap34.indd 180 4/1/2011 6:40:59 PM TREATMENT 181 Further reading Allolio BS, Hahner S, Weismann D, Fassnacht M (2004). Management of adrenoc ortical carcinoma. Clin Endocrinol 60:273 \200\223287. Espiner EA, Ross DG, Yandle TG, Richards AM, Hunt PJ (2003). Predicting surgically remedial primary aldosteronism: role of adrenal scanning, posture testing, and adrenal vein samplin g J Clin Endocrinol Metab 88(8):3637 \200\2233644. Funder JW, Carey RM, Fardella C, et al. (2008). Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline. J C lin Endocrinol Metab 93(9):3266 \200\2233281. Ganguly A (1998). Primary aldosteronism. N Engl J Med 339:1828 \200\2231833. Young WF (2007 ). Primary aldosteronism \200\224renaissance of a syndrome. Clin Endocrinol 66:607 \200\223 618. 34-Draznin-Chap34.indd 181 4/1/2011 6:40:59 PM CHAPTER 35 Excess other mineralocorticoids 182 Excess other mineralocorticoids Epidemiology Occasionally, the clinical syndrome of hyperaldosteronism is not associ- ated with excess aldosterone, and a process due to another mineralocor- ticoid is suspected. Thi s can either be due to an increase in an alternative mineralcorticoid or to i mineralocorti coid effect of cortisol. These condi- tions are rare. Apparent mineralocorticoid excess The aldosterone receptor has an equal af \201 nity for c ortisol and aldoster- one, but there is a 100-fold excess of circulating cortisol over aldo ster- one. The receptor is usually protected from the effects of stimulation by cortisol by the 11B-hydroxysteroid type 2 dehydrogenase enzyme, which converts cortisol to cortisone. In this syndrome, there is de \201 ciency of 11B-hydroxysteroid dehydroge- nase (HSD) enzy me type 2 encoded on chromosome 16q22. Congenital absence (autosomal recessive) of the enzy me or inhibition of its activity allows cortisol to stimulate the receptor and leads to sev ere hypertension. Type 1 is seen predominantly in children, presenting with failure to thri ve, thirst, polyuria, and severe hypertension. Patients are not cushin- goid as there is in tact negative feedback, and circulating cortisol levels are not raised. The urinary terahyd rocortisol and allotetrahydrocortisol-to- terahydrocortisone ratio is raised to 10 \227 no rmal. Type 2 is a milder form that may be a cause of hypertension in adoles- cence or early adult hood. The urinary terahydrocortisol and allo-tetrahy- drocortisol-to-terahydrocortisone rat io is normal. However, multiple mutations have been found in the 11B-HSD2 gene for both types, and some a uthors believe there is a spectrum of disease: mild forms may present with salt-sensitive h ypertension. Biochemistry \200 Suppression of renin and aldosterone \200 Hypokalemic alkalosis \200 Urinary free cortisol-to-cortisone ratio i \200 Ratio of urinary tetrahydrocortisol and allotetrahydrocortisol to tetrahydrocortisone is raised (>10 \227) in type 1 but is normal in type 2. Con \201 rm with genetic testing. 35-Draznin-Chap35.indd 182 3/31/2011 3:00:17 PM DEOXYCORTICOSTERONE (DOC) EXCESS 183 Treatment Dexamethasone leads to suppression of ACTH secretion, reduced cortisol concentrat ions, and lowered BP in 60%. It has a much lower af \201 nity for the mineralocorticoid re ceptor. Other antihypertensive agents are often required. One patient with hypertensive renal failu re was cured with a renal transplant. Licorice ingestion Licorice contains glycyrrhetinic acid, which is used as a sweetener. It inhib- its the action of 11B-HSD, making the aldosterone receptor more sensi- tive to corti sol. It is found in candies, chewing tobacco, cough mixtures, and some herbal medicines. Ectopic ACTH syndrome b See p. 184. In the syndrome of ectopic ACTH, the 11B-HSD protection is overcome because of high cortiso l secretion rates, which saturate the enzyme, leading to impaired conversion of cortisol to cortisone, and thus hypokalemia and hypertension. Deoxycorticosterone (DOC) excess Two forms of congenital adrenal hyperplasia ( b see Part 4 p. 239) are associated with excess production of DOC, which acts as an agonist at the mine ralocorticoid receptor, resulting in hypertension with suppres- sion of renin: \200 17A-h ydroxylase de \201 ciency \200 11B-hydroxylase de \201 ciency Glucocorticoid replacemen t to inhibit ACTH is effective treatment for these conditions. Adrenal tumors rarely secrete excessive amounts of DOC. Usually this is concomitant with ex cessive aldosterone production, but occasionally it may occur in an isolated fashion. 35-Draznin-Chap35.indd 183 3/31/2011 3:00:17 PM CHAPTER 36 Adrenal Cushing \200\231s syndrome 184 Adrenal Cushing \200\231s syndrome De \201 nition and epidemiology Cushing \200\231s syndrome results from chronic excess cor tisol and is described in Chapter 18 ( b Cushing \200\231s disease, p. 116). The causes may be classi \201 ed as ACTH dependent and ACTH inde- pendent. This section de scribes ACTH-independent Cushing \200\231s syndrome, which is due to adrenal tumors (benign and malignant) and is responsible for 10 \200\22320% cases of Cushing \200\231s syndrome. Adrenal tumors causing Cushing \200\231s syndrome are more common in women. The peak incidence is in the fourth and \201 fth decades. Causes and relative frequencies of adrenal Cushing \200\231s syndrome in adults are as follows: \200 Adrenal adenoma: 12%. \200 Adrenal carcinoma: 6%. \200 Bilateral micronodular adrenal hyperplasia: 1%. \200 Bilateral macronodular hyperplasia: 1%. Pathophysiology Benign adenomas are usually encapsulated and <6 cm in diameter. They are us ually associated with pure glucocorticoid excess. Adrenal carcinomas are usually >6 cm in diameter, although they may be smaller, and are oft en associated with local invasion and metastases at the time of diagnosis. They may be asso ciated with secretion of excess androgen production in addition to cortisol. Occasionally, they may be associated with mineralocorticoid or estrogen secretion. Carney complex ( b see Carney complex, p. 496) is an autosomal domi- nant condition charact erized by atrial myxomas, spotty skin pigmentation, peripheral nerve tumors, and endocrine disorders, e.g., Cushing \200\231s syn- drome due to pigmented adrenal nodular hyperplasia. Adrenal hyperplasia may be micronodular (<1 cm diameter) or macron- odular (>1 cm). Bilateral macronodular adrenal hyperplasia Most cases of bilateral macronodular hyperplasia do not have an identi \201 - able cause. Abnormal gastric inhibitory peptide (GIP), vasopressin, B-agonist, human chorionic gonadotr opin\luteinizing hormone, and serotonin receptors have been described. Several cases of food-dependent Cushing \200\231s syndrome have been described that are due to GIP receptor expression. 36-Draznin-Chap36.indd 184 3/31/2011 3:03:16 PM INVESTIGATIONS 185 Clinical features The clinical features of ACTH-independent Cushing \200\231s syndrome are as described in b Clinical features, p. 157 in Chapter 18, Cushing \200\231s disease. It is important to note that in patients with adrenal carcinoma, there may also be features rela ted to excessive androgen production in women, as well as a relatively more rapid time cour se of development of the syndrome. Investigations Once the presence of Cushing \200\231s syndrome is con \201 rmed ( b see Cl inical features, p. 157), subsequent investigation of the cause depends on whether ACTH is suppressed (ACTH independent), or measurable or elevated (ACTH dependent). Patients with ACTH-independent Cushing \200\231s syndrome do not suppress cortisol to <50% basal on high-dose dexamethasone testing and fail to show a rise in cortisol and ACTH follo wing administration of CRH. (The latter test is often important when patients have borderli ne or low ACTH to differentiate pituitary-dependent disease from adrenal diesase.) ACTH-independent causes are adrenal in origin, and the mainstay of further investigation is adrenal imaging. CT scanning allows excellent visualization of the adrenal glands and their anatomy. Adenomas are usually small and homogeneous and usually associated with contralateral gland atrophy. Adrenal carcinomas are usually >6 cm in diameter, are heterogeneous with calci \201 cation and necrosis, and have evidence of local invasion. Bilateral macronodular adrenal hyperplasia \200 Monitor ACTH and cortisol response to a m ixed meal, luteinizing hormone releasing hormone (LHRH), and posture. ACTH independent \200 Medical treatment may be possible, e.g., octreotide, for GIP-depend ent disease. 36-Draznin-Chap36.indd 185 3/31/2011 3:03:16 PM CHAPTER 36 Adrenal Cushing \200\231s syndrome 186 Treatment b See Treatment, p. 356. Adrenal adenoma Unilateral adrenalectomy (normally laparoscopic) is curative. Postoperative temporary adrenal insuf \201 ciency ensues because of long-term suppression of ACTH and the contralateral adrenal gland, requiring glucocorticoid replacement for up to 2 years. Adrenal carcinoma Surgery is useful to debulk tumor mass, and occasionally adrenalectomy an d local clearance leads to cure. However, most patients have distant metastases at the time of diagnosis. Postoperative drug treatment with the adrenolytic agent mitotane ( orthopara DDD) 3 \200 \22312 g daily may prolong survival. This may lead to adrenal insuf \201 ciency, and gluco corticoid replacement may be required. Side effects may limit therapy and include nausea and vomiting, dizziness, and diarrhea. Mo nitoring of drug levels can be helpful to ensure concentra- tions within the therapeutic ra nge (14 \200\22320 mcg/mL) and thus limit unwanted side effects. Other drugs may be required to control cortisol hypersecretion (e.g., metyrapone ). Newer treatments such as suramin, 5- \202 uorouracil , and gossypol have also been tried without evidence of bene \201 t. Bilateral adrenal hyperplasia Bilateral adrenalectomy is curative. Lifelong glucocorticoid and mineralo- corticoid treatment is required. Medical treatment may be possible for cases with aberrant receptors, e.g., octreotide for GIP-dependent disease. Prognosis Adrenal adenomas, which are successfully treated with surgery, have a good progno sis, and recurrence is unlikely. The prognosis depends on the long-term effects of excess c ortisol before treatment \200\224in particular, atherosclerosis and osteoporosis. The prognosis for adrenal carcinoma is very poor, despite surgery. Reports suggest a 5-year survival of 22% and median survival time of 14 months. Age >40 years and distant metastase s are associated with a worse prognosis. 36-Draznin-Chap36.indd 186 3/31/2011 3:03:16 PM SUBCLINICAL CUSHING \200\231S SYNDROME 187 Subclinical Cushing \200\231s syndrome This describes a subset of 5 \200\22310% of patients with an adrenal incidentaloma with autonomous glucocorticoid production that is insuf \201 cient to produce overt Cushing \200\231s syndrome. Urinary free cortisol measurement may be within the normal range, but there is a failure to suppress with low-dose dexamethasone. An associated i risk of diabetes mellitus, osteoporosis, and hyperten- sion has been reported. Data are insuf \201 cient to indicate the superiority of a surgical or nonsurgi- cal approach to management. Hypoadrenalism post-adrenalectomy has been reported that is due to suppression of the contr alateral adrenal gland. Perioperative steroid cover is therefore required with re-evaluatio n postoperatively. Further reading Allolio B, Fassnacht M (2006). Clinical review: adrenocortical carcinoma: c linical update. J Clin Endocrinol Metab 91(6):2027 \200\2232037. Lacroix A, N \200\231Diaye N, Tremblay J, et al. (2001). Ectopic and abnormal hormone recep tors in adre- nal Cushing \200\231s syndrome. Endocr Rev 22(1):75 \200\223110. Terzolo M, Angeli A, Fasscacht M, et al. (2007). Adjuvant mitotane treatment for adrenocort ical carcinoma. N Engl J Med 356(23):2372 \200\2232380. 36-Draznin-Chap36.indd 187 3/31/2011 3:03:16 PM CHAPTER 37 Adrenal surgery 188 Adrenal surgery Adrenalectomy Open adrenalectomy may still be necessary for large and complex pathology. Ho wever, laparoscopic adrenalectomy ( \201 rst performed in 1992) has become the procedure o f choice for removal of most adrenal tumors. Retrospective comparisons with open approaches suggest reduced hos- pital stay and analgesi c requirements and lower postoperative morbidity. However, there are few long-term outcome data on this technique. It is most useful in the management of small (<6 cm) benign adenoma s. Laparoscopic bilateral adrenalectomy, although technically demanding, offers a useful appro ach to patients with macronodular hyperplasia and in selected patients with ACTH-dependent Cushing \200\231s syndrome where alternative therapeutic options are not appropriate. Preoperative preparation of patients \200 Cushing \200\231s \200\224metyrapone or ketocon azole ( b see p. 123) \200 Phaeochromocytoma \200\224A- and B-blockade ( b see p. 218). Perioperative management See Box 37.1. 37-Draznin-Chap37.indd 188 3/31/2011 3:04:50 PM ADRENALECTOMY 189 Box 37.1 Perioperative management of patients undergoing adrenalectomy Management is for adrenal cortical tumors (benign and malignant) and bilateral adrenalectom y for Cushing \200\231s syndrome. Perioperative glucocorticoid cover is required, as even \200\234silent \200\235 adeno- mas may be associated with subclinical excess cortisol secretion and hence suppression of the contralateral adrenal gland. Hydrocortisone is given as for pituitary surgery \200\224100 mg IM with the premedication, and then continued every 6 hours for 24 \200\22348 hours, until the patient can take oral m edication and is eating and drinking. This is changed to oral hydrocortisone at double replacement dose \200\22420 mg on waking, 10 mg at lunchtime and 10 mg at 5 P.M., and mineralocorticoid replacement commenced if bila teral adrenalectomy has been performed (0.1 mg \202 udrocortisone daily). Electrolytes an d BP guide adequacy of treatment. Normal replacement hydrocortisone (20 \200\22325 mg/24 ho urs) can be commenced when the patient is recovered and may be omitted altogether if the pa tient did not have preoperative evidence of Cushing \200\231s syndrome/suppression of the c ontralateral gland/ bilateral adrenalectomy. Mineralocorticoid replacement is only required in patients who have had bilateral adrenalectomy. A Cortrosyn stimulation test (off hydrocortisone for at least 24 hours) is performed aft er at least 2 weeks to demonstrate ade- quate function of the contralateral adrenal. Howeve r, in patients with ACTH-independent Cushing \200\231s syndrome, it may take up to 2 years for full recovery of the contralateral adrenal gland to recover. The exception is patients undergoing adrenalectomy for miner- alocorticoid-secreting tumors . These patients do not usually require perioperative glucocorticoid replacement, but preop erative amiloride or spironolactone allows recovery of potassium stores and control of hype rtension prior to surgery. Further reading Dudley NE, Harrison BJ (1999). Comparison of open posterior versus transper itoneal laparoscopic adrenalectomy. Br J Surg 86:656 \200\223660. McCallum R, Connell JMC (2001). Laparoscopic adrenalectomy. Clin Endocrinol 55:435 \200\223 436. Wells SA, Merke DP, Cutler GB, et al. (1998). The role of laparoscopic surgery in adrenal d isease. J Clin Endocrinol Metab 83:3041 \200\2233049. 37-Draznin-Chap37.indd 189 3/31/2011 3:04:50 PM CHAPTER 38 Renal tubular abnormalities 190 Renal tubular abnormalities Background Bartter \200\231s syndrome is associated with hypokalemic alkalosis and activati on of the renin \200\223angiotensin system, but without hypertension. Liddle \200\231s syn- drome is associated with hypokalemic alkalosis and hypertension but low renin and aldoster one levels. Liddle \200\231s syndrome This is a rare autosomal dominant (AD) condition with variable pe ne- trance. Mutations have been localized to genes on chromosome 16. Cause A mutation occurs in the gene encoding the B- or G-subunit of the highly selective ep ithelial sodium channel in the distal nephron. This leads to con- stitutive activation of s odium transportation independent of circulating mineralo- corticoid; secondary activation o f the sodium \200\223potassium exchange occurs. Features \200 Hypokalemia and hypertension Investigation \200 Hypokalemic alkalosis \200 Suppressed renin and aldosterone levels \200 b See Table 38.1 Treatment Hypertension responds to amiloride (doses up to 40 mg/day) but not spironolactone , because amiloride acts on the sodium channel directly, whereas spironolactone acts on the mineralocorticoid receptor. Table 38.1 Summary of features of renal tubular abnormalities Urinary calcium i d N Syndrome* BP Renin i i d Aldosterone i i d Other Bartter \200\231s N d Mg Gitelman \200\231s N i Liddle \200\231s All three conditions have hypokalemic alkalosis. 38-Draznin-Chap38.indd 190 3/31/2011 3:05:22 PM BARTTER \200\231S SYNDROME 191 Bartter \200\231s syndrome Cause There is loss of function of the bumetanide-sensitive Na \200\223K \200\2232Cl co-tra ns- porter in the thick ascending limb of the loop of Henle. Mutations in three genes have been reported to account for the phenotype \200\224these encode regulatory ion channels (NK CC2, ROMK, CLCNKB) . Inactivation of the co-transporter leads to salt wasting, activation of the renin \200\223a ngiotensin system, and i aldosterone, which leads to i sodium reabsorption at the distal ne phron and causes hypokalemic alkalosis. Reabsorption of calcium also occurs in the thick as cending loop and thus inactivation leads to hypercalciuria. The lack of associated hypertension is thought to be due to i prostag- landin production fr om the renal medullary interstitial tissue in response to hypokalemia. Rare (71/million) autosomal recessive hypokalemic metabolic alkalosis is associated with salt wasting and normal or reduced BP. The syndrome is usually present at an early age (<5 years). Features \200 Intravascular volume depletion \200 Seizures \200 Tetany \200 Muscle weakness Investigations \200 Hypokalemic alkalosis \200 i PRA and aldosterone \200 Hypercalciu ria Treatment Potassium replacement Potassium-sparing diuretics may help, but they are usually inadequate to correct hypokalemia. Prostaglandin synthase inhibitors (NSAIDS), e.g., indometacin 2 \200\2235 mg/kg per day or ibuprofen, may be required. Further reading Amirlak I, Dawson KP (2000). Bartter \200\231s syndrome. QJM 93:207 \200 \223215. Furuhashi M. Kitamura K, Adachi M, et al. (2005). Liddle \200\231s syndrome caused by a nov el mutation in the proline-rich PY motif of the epithelial sodium channel B-subunit. J Clin Endocrinol Metab 90(1):340 \200\223344. 38-Draznin-Chap38.indd 191 3/31/2011 3:05:23 PM CHAPTER 39 Mineralocorticoid de \201 ciency