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 192 Mineralocorticoid de \201 ciency Epidemiology This de \201 ciency is rare, apart from the hyporeninemic hypoaldosteronism a ssociated with diabetes mellitus. Causes Congenital \200 Adrenal hypoplasia: X-linked failure of development of the adrenal gland. Presents in infancy with salt-losing state. Differentiated from CAH by normal external gen italia and steroid levels Congenital adrenal hyperplasia (CAH): certain types, most commonly 21-hydroxylase de \201 ciency, are associated with MC de \201 ciency; b see p. 239. Rare inherited disorders of aldosterone biosynthesis \200 Adrenoleukodystrophy: X-linked affecting 1/20,000 men, where very long-chain fatty acids cannot be oxidized in peroxisomes and accumulate in tissues. CN S symptoms may be absent but progressive demyelination can lead to hypertonic tetraparesis, dementia, epilepsy, coma, or death. Pseudohypoaldosteronism: inherited resistance to the action of aldosterone; b see p. 570. Autosomal dominant and recessive forms are described. Usually pr esents in infancy. Treated with sodium chloride Acquired \200 Adrenal insuf \201 ciency: b see p. 193 \200 Drugs: heparin (heparin for >5 days may cause severe hyperkalemia due to a toxic effect on the zona glomerulosa); ciclosporin Hyporeninemic hypoaldosteronism: interference with the renin \200\223 angiotensin system le ads to mineralocorticoid de \201 ciency and hyperkalemic acidosis (type IV renal tubular a cidosis), e.g., diabetic nephropathy. Treatment is \202 udrocortisone and potassium restr iction. ACE inhibitors may produce a similar biochemical picture, but here the PRA will be elevated as there is no angiotensin II feedback on renin. Treatment \200 Fludrocortisone 39-Draznin-Chap39.indd 192 3/31/2011 3:06:36 PM DEFINITION 193 Adrenal insuf \201 ciency De \201 nition Adrenal insuf \201 ciency results from inadequate adrenocortical function and may be due to destruction of the adrenal cortex (primary or Addison \200\231s disease) or to disordered pituitary and hypothalamic function (secondary). 40-Draznin-Chap40.indd 193 3/31/2011 3:11:44 PM CHAPTER 40 Adrenal insuf \201 ciency 194 Epidemiology \200 The prevalence of Addison \200\231s disease is approximately 93 \200 \223140/million adults. Incidence is 4.7 \200\2236.2 per million in the white population. Secondary adrenal insuf \201 ciency is most commonly due to suppression of pituitary \200\223hypothalamic function by exogenous glucocorticoid administration. Causes of secondary adrenal insuf \201 ciency Lesions of the hypothalamus and/or pituitary gland \200 Tumors \200\224pituitary tumor, m etastases, craniopharyngioma \200 Infection \200\224tuberculosis \200 In \202 ammation \200\224sarcoidosis, histiocytosis X, hemochromatosis, lymphocytic hypophysitis Iatrogenic \200\224surgery, radiotherapy \200 Other \200\224isolated ACTH de \201 ciency , trauma Suppression of the hypothalamic \200\223pituitary \200\223adrenal axis \200 Glucocorticoi d administration \200 Cushing \200\231s disease (after pituitary tumor removal) Features of secondary adrenal insuf \201 ciency As primary ( b see Clinical features, p. 1 98), except: \200 Absence of pigmentation \200\224skin is pale \200 Absence of mineralo coticoid de \201 ciency \200 Associated features of underlying cause, e.g., visual \201 eld defects if there is a pituitary tumor Other endocrine de \201 ciencies may manifest due to pituitary failure ( b see p. 352). Acute onset may occur due to pituitary apoplexy. Isolated ACTH de \201 ciency \200 Rare \200 Pathogenesis is unclear. It may be autoimm une (associated with other autoimmune conditions, and antipituitary antibodies are describe d in some patients). Absent ACTH response to CRH \200 POMC mutations and POMC processing abnormalities (e.g., proconvertase PC1). 40-Draznin-Chap40.indd 194 3/31/2011 3:11:44 PM PATHOPHYSIOLOGY 195 Pathophysiology Primary Adrenal gland destruction or dysfunction occurs from a disease process that usually involves all three zones of the adrenal cortex, resulting in inadequate glucocorticoid, mi neralocorticoid, and androgen secretion. Autoimmunity is the main etiologic factor. The manifestations of insuf \201 ciency do not usually appear until at least 90% of the gl and has been destroyed and are usually gradual in onset, with partial adrenal insuf \201 c iency leading to an impaired cortisol response to stress, and the features of complete insu f \201 ciency occurring later. Acute adrenal insuf \201 ciency may occur in the context of acute septicemia (e.g., meningococcal or hemorrhage). Mineralocorticoid de \201 ciency leads to reduced sodium retention and hypotension with d intravascular volume, in addition to hyperkalemia due to d renal potassium and hydrogen ion excretion. Androgen de \201 ciency presents in women with reduced axillary and pubic hair and reduced libido. (Testicular production of androgens is more important in men.) Lack of cortisol negative feedback increases CRH and ACTH secretion. An increase in other P OMC-related peptides leads to skin pigmentation and other mucous membranes. Secondary Inadequate ACTH results in de \201 cient cortisol production (and d androgens in women). There is no pigmentation because ACTH and POMC secretion is reduced. Mineralocorticoid secr etion remains normal, as it is mainly regulated by the renin \200\223angiotensin system. The onset is usually gradual with partial ACTH de \201 ciency resulting in reduced respons e to stress. Prolonged ACTH de \201 ciency leads to atrophy of the zona fasiculata and red uced ability to respond acutely to ACTH. Investigations b See p. 94 for pituitary/hypothalamic disease and p. 206 for long-term endo genous or exogenous glucocorticoids. 40-Draznin-Chap40.indd 195 3/31/2011 3:11:45 PM CHAPTER 41 Addison \200\231s disease 196 Addison \200\231s disease Causes of primary adrenal insuf \201 ciency \200 Autoimmune \200\224most common cause in the developed world (approximately 70% cases). Autoimmune polyglandular de \201 ciency \200\224type 1 or 2 ( b see p. 198, 199). Malignancy \200 Metastatic (lung, breast, kidney \200\224adrenal metastases found in 750% of patients, but symptomatic adrenal insuf \201 ciency much less common) Lymphoma In \201 ltration \200 Amyloid \200 Hemochromatosis Infection \200 Tuberculosis (medulla more frequently destroyed than cortex) \200 Fungal , e.g., histoplasmosis, cryptococcosis \200 Opportunistic infections in, e.g., AIDS \200 \224CMV, mycobacterium intracellulare, cryptococcus (up to 5% patients with AIDS develop primary adrenal insuf \201 ciency in the late stages) Vascular hemorrhage \200 Anticoagulants \200 Waterhouse \200\223Friedrichson syndrome i n meningococcal septicemia Infarction \200 E.g., secondary to thrombosis in antiphospholipid syndrome Adrenoleucodys trophy \200 Inherited disorder of fatty acid metabolism \200 Diagnosed by measuring ver y long-chain fatty acids \200 Presents in childhood \200 Progresses to quadraparesis an d dementia in association with adrenal failure Treat with Lorenzo \200\231s oil Congenital adrenal hyperplasia \200 b See p. 239 Congenital adrenal hypoplasia \200 Rar e familial failure of adrenal cortical development due to mutations and deletion of DAX 1 gene 41-Draznin-Chap41.indd 196 4/1/2011 5:31:42 PM AUTOIMMUNE ADRENALITIS 197 Iatrogenic \200 Adrenalectomy \200 Drugs: ketoconazole and \202 uconazole (inhibit co rtisol synthesis), phenytoin, rifampicin (increases cortisol metabolism), etomidate, aminog lutethamide (usually do not cause hypoadrenalism unless reduced adrenal or pituitary reserv e) Autoimmune adrenalitis This is mediated by humoral and cell-mediated immune mechanisms. Aut oimmune insuf \201 ciency associated with polyglandular autoimmune syn- drome is more comm on in women (70%). Adrenal cortex antibodies are present in the majority of patients at diagnosis, and althoug h titers decline and eventually disappear, they are still found in approximately 70% of pat ients 10 years later. Up to 20% patients/year with positive adrenal antibodies develop adre nal insuf \201 - ciency. Antibodies to 21-hydroxylase are commonly found, although the exa ct nature of other antibodies that block the effect of ACTH for exam- ple are yet to be elu cidated. Antiadrenal antibodies are found in <2% of patients with other autoim- mune endocrine disea se (Hashimoto \200\231s thyroiditis, diabetes mellitus, autoimmune hypothyroidism, hypopara thyroidism, pernicious anemia). In addition, antibodies to other endocrine glands are commo nly found in patients with autoimmune adrenal insuf \201 ciency (thyroid microsomal in 50% , gastric parietal cell, parathyroid, and ovary and testis). Polyglandular autoimmune conditions also occur ( b see Autoimmune polyglandular syndrome [A PS] type 1, p. 198; APS types 2 \200\2234, p. 199). The presence of 17-hydroxylase antibodi es in association with 21-hydroxylase antibodies is a good marker of patients at risk of de veloping premature ovarian failure in association with primary adrenal failure. Patients with type 1 diabetes mellitus and autoimmune thyroid disease only rarely develop a utoimmune adrenal insuf \201 ciency. Approximately 50% of patients with Addison \200\231s disease have other autoimmune or endocrine disorders. 41-Draznin-Chap41.indd 197 4/1/2011 5:31:42 PM CHAPTER 41 Addison \200\231s disease 198 Clinical features Chronic \200 Anorexia and weight loss (>90%) \200 Tiredness \200 Weakness \200\224gen eralized, no particular muscle groups \200 Pigmentation \200\224generalized, but most com mon in light-exposed areas and areas exposed to pressure (elbows and knees, and under bras and belts); mucosa and scars acquired after onset of adrenal insuf \201 ciency. Look at pa lmar creases in Caucasians. Dizziness and postural hypotension \200 GI symptoms \200\224nausea and vomiting, abdomina l pain, diarrhea \200 Arthralgia and myalgia \200 Symptomatic hypoglycemia \200\224rare in adults \200 d Axillary and pubic hair and reduced libido in women \200 Pyrexia of u nknown origin \200\224rarely Associated conditions \200 Vitiligo \200 Features of other autoimmune endocrinopathies Laboratory investigations \200 Hyponatremia \200 Hyperkalemia \200 Elevated urea \200 Anemia (normocytic normochromic) \200 Elevated ESR \200 Eosinophilia \200 Mild hypercalcemia \200\224d absorption, d renal absorption of calcium Autoimmune polyglandular syndrome (APS) type 1 \200 Also known as autoimmune polyendocrin opthy, candidiasis, and epidermal dystrophy (APECED) Autosomal recessive with childhood onset \200 Chronic mucocutaneous candidiasis \200 Hy poparathyroidism (90%), primary adrenal insuf \201 ciency (60%) \200 Primary gonadal fai lure \200 Primary hypothyroidism \200 Rarely hypopituitarism, diabetes insipidus, type 1 diabetes mellitus \200 Associated chronic active hepatitis (20%), malabsorption (15%), alopecia (40%), pernicious anemia, vitiligo Mutations in the AIRE (autoimmune regulator) gene located on chromosome 21p22.3 41-Draznin-Chap41.indd 198 4/1/2011 5:31:42 PM APS TYPES 2 \200\2234 199 APS types 2 \200\2234 \200 Autosomal recessive, autosomal dominant, polygenic \200 Adul t onset \200 Adrenal insuf \201 ciency (100%) \200 Primary hypothyroidism (69%) \200 Type 1 diabetes mellitus (52%) \200 Primary gonadal failure (4 \200\22310%) \200 Rarel y diabetes insipidus (<0.1%) \200 Associated vitiligo, myasthenia gravis, alopecia, perni cious anemia, immune thrombocytopenic purpura APS3 \200\224thyroid disease without adrenal insuf \201 ciency \200 APS4 \200\224adrenal insuf \201 ciency without thyroid disease Eponymous syndromes Schmidt syndrome \200 Addison \200\231s disease and \200 Autoimmune hypothyroidism Carpenter syndrome \200 Addison \200\231s disease and \200 Autoimmune hypothyroidism an d/or \200 Type 1 diabetes mellitus Screening recommendations \200 2.4% of patients with a monoglandular autoimmune endocrino pathy have APS2 on subsequent follow-up. Functional screening is recommended every 3 years until the age of 75 years. \200 Serum Na + , K + , Ca 2+ , blood cell count \200 TSH, free T 4 \200 FSH, LH, testosterone, or estradiol \200 Fasting morning cortisol and glucose \200 Optional: ACTH stimulation test If a second endocrinopathy is diagnosed, measure organ-speci \201 c autoantibodies and consider functional screening in \201 rst-degree relatives. \200 Isl et cells, GAD, IA2 \200 TPO, TSH receptor \200 Cytochrome P450 enzymes \200 H + -K + -ATPase of the parietal cells, intrinsic factor \200 Transglutaminase, gliadin Further reading Dittmar M, Kahaly GJ (2003). Polyglandular autoimmune syndromes: immunogene tics and long-term follow-up. J Clin Endocrinol Metab 88(7):2983 \200\2232992. 41-Draznin-Chap41.indd 199 4/1/2011 5:31:42 PM CHAPTER 41 Addison \200\231s disease 200 Investigation of primary adrenal insuf \201 ciency Electrolytes \200 Hyponatremia is present in 90% and hyperkalemia in 65%. \200 Elevated urea Serum cortisol and ACTH Undetectable serum cortisol is diagnostic of adrenal insuf \201 ci ency, but the basal cortisol is usually in the normal range. A cortisol >21 mcg/dL preclude s the diagnosis. At times of acute stress, an inappropriately low cortisol is very suggesti ve of the diagnosis. Simultanous 8 A.M. cortisol and ACTH will show an elevated ACTH for the level of cortisol. This is a very sensitive means of detecting Addison \200\231s disease. Drugs causing i cortisol-binding globulin (e.g., estrogens) will result in higher total cortisol concentration measurements. Response to ACTH Cortrosyn stimulation test Following basal cortisol measurement, 250 mcg Cortrosyn is adminis- tered IM and serum cortisol checked at 30 and 60 minutes. Serum cortisol should rise to a peak of 21 mcg/dL (note that this cutoff may depend on local assay conditions). Failure to respond suggests adrenal failure. Increased plasma renin activity (assessment of mineralocorticoid suf \201 ciency) This is one of the earliest abnormalities in developing primary adrenal insuf \201 ciency. Thyroid function tests Reduced thyroid hormone levels and elevated TSH may be due to a dire ct effect of glucocorticoid de \201 ciency (cortisol inhibits TRH) or to associated autoim mune hypothyroidism. Re-evaluation is therefore required after adrenal insuf \201 ciency h as been recti \201 ed. 41-Draznin-Chap41.indd 200 4/1/2011 5:31:42 PM INVESTIGATION OF PRIMARY ADRENAL INSUFFICIENCY 201 Establish cause of adrenal insuf \201 ciency Adrenal autoantibodies These detect antibodies to adrenal cortex and, more recently, spe- c i \201 c antibodies to 21-hydroxylase, side-chain cleavage enzyme, and 17-hydroxylase. 21-hydroxylase antibodies are the major component of adrenal cortex antibodies and are pres ent in 80% of recent-onset autoimmune adrenali- tis. Adrenal cortex antibodies (present in 80% patients with recent-onset autoimmune adrenalitis) are not detectable in non-autoimmune primary adrenal failure. Imaging Adrenal enlargement with or without calci \201 cation may be seen on CT of the abd omen, suggesting tuberculosis, in \201 ltration, or metastatic disease. The adrenals are s mall and atrophic in autoimmune adrenalitis. Speci \201 c tests These include serological or microbiological investigations directed at particular infections, or very long-chain fatty acids (adrenoleucodystro- phy) in men and women with antibody-negative isolated primary adrenal insuf \201 ciency. Acute adrenal insuf \201 ciency Clinical features \200 Shock \200 Hypotension (often not responding to measures such as inotropic support) Abdominal pain (may present as acute abdomen) \200 Unexplained fever \200 Often precipi tated by major stress such as severe bacterial infection, major surgery, unabsorbed glucoco rticoid medication due to vomiting Occasionally occurs due to bilateral adrenal infarction Investigations \200 As chronic \200 In the acute situation, if the diagnosis is suspect ed, an inappropriately low cortisol (i.e., <19 mcg/dL) is often suf \201 cient to make the diagnosis. b See Box 41.1 for Emergency management. 41-Draznin-Chap41.indd 201 4/1/2011 5:31:43 PM CHAPTER 41 Addison \200\231s disease 202 Box 41.1 Emergency management of acute adrenal insuf \201 ciency This is a life-threatening emergency and should be treated if there is strong clinical susp icion, rather than waiting for con \201 rmatory test results. Blood should be taken for urgent analysis of electrolytes and glucose, in addition to cortisol and ACTH. Fluids Large volumes of 0.9% saline may be required to reverse the volume depletion and sod ium de \201 ciency. Several liters may be required in the \201 rst 24 \200\22348 hours, but caution should be exercised where there has been chronic hyponatremia; in this circumst ance rapid correction of the de \201 - cit exposes the patient to risk of central pontine myelinolysis. If plasma sodium is <120 mmol/L at presentation, aim to correct this by no more than 10mmol/L in the \201 rst 24 hours. Hydrocortisone A bolus dose of 100 mg hydrocortisone is administered intravenously. Hydroco rtisone 100 mg IM is then continued 6-hourly for 24 \200\22348 hours or until the patient c an take oral therapy. Double replacement dose hydro- cortisone (20, 10, and 10 mg orally) c an then be instituted until well. This traditional regimen causes supraphysiological replacement, and some authors suggest lower doses, e.g., 150 mg IV/24 hours. Speci \201 c mineralocorticoid replacement is not required, as the high- dose glucocortico id has suf \201 cient mineralocorticoid effects (40 mg hydrocortisone 7100 mcg \202 udro cortisone). Once the dose of glucocor- ticoid is reduced after a couple of days and the pat ient is taking food and \202 uids by mouth, \202 udrocortisone 100 mcg/day can be comme nced. Glucose supplementation Occasionally, this is required because of risk of hypoglycemia (low glyco- gen stores in the liver as a result of glucocorticoid de \201 ciency). Investigate and treat precipitant This is often infection. Monitoring treatment Monitor electrolytes, glucose, and urea. 41-Draznin-Chap41.indd 202 4/1/2011 5:31:43 PM TREATMENT 203 Treatment Maintenance therapy Glucocorticoid replacement Hydrocortisone is the treatment of choice for replacement therap y, as it is reliably and predictably absorbed and allows biochemical monitoring of levels. It is administered 3 \227 daily 10 mg on waking, 5 mg at midday, and 5 mg at 6 P.M. Some p atients can be managed adequately with twice-daily adminis- tration of hydrocortisone. An alternative is prednisone 5 mg once daily. This has the disadvantage that levels cannot be biochemically monitored, but its longer t may lead to better suppression of ACTH if pi gmentation and markedly elevated morning ACTH levels are a problem. Occasionally, dexametha sone is required for this purpose. Mineralocorticoid replacement Fludrocortisone (9- \202 urohydrocortisone) is given at a do se of 0.1 mg daily. Aim to avoid signi \201 cant postural fall in BP (>10 mmHg). Occasionally, lower (0.05 mg) or higher (0.2 mg) doses are required. A dose of 40 mg hydroc ortisone has the equivalent mineralocortisone effects as 0.1 mg \202 udrocortisone. Renin activity can help guide adequacy of therapy. DHEA replacement Dihydroepiandrosterone (DHEA) is also de \201 cient in hypoadrenalism. DHEA replacement (25 \200\22350 mg/day) may improve mood and well-being (as dietary supplement). Monitoring of therapy Clinical \200 For signs of glucocorticoid excess, e.g., i weight \200 BP (including pos tural change) Hypertension and edema suggest excessive mineralocorticoid replace- ment, whe reas postural hypotension and salt craving suggest insuf \201 cient treatment. Biochemical \200 Serum electrolytes \200 Plasma renin activity (elevated if insuf \201 cient \202 udrocortisone replacement). Very dependent on when the last dose was taken Cortisol day curve to assess adequacy of treatment Monitor ACTH levels prior to and followi ng morning glucocorticoid replacement if the patient develops i pigmentation. If levels are elevated or rising with little suppression following glucocorticoid, obtain an MRI scan to exclude the rare possibility of pituitary hyperplasia or, very rarely, the development of a corticotrope adenoma. 41-Draznin-Chap41.indd 203 4/1/2011 5:31:43 PM CHAPTER 41 Addison \200\231s disease 204 Intercurrent illness Cortisol requirements increase during severe illness or surgery. For moderate elective procedures or investigations, e.g., endoscopy or angiography, patient s should receive a single dose of 100 mg hydrocorti- sone before the procedure. For major surgery, patients should take 20 mg hydrocortisone orally or 100 mg intramuscularly with the premedication and receive: \200 50 \200\223100 mg IM hydr ocortisone 6-hourly for the \201 rst 3 days or \200 100 \200\223150 mg per 24 hours IV in 5% dextrose before reverting rapidly to a maintenance dose. To cover severe illness, e.g., pneumonia, patients should receive 50 \200\223100 mg IM hydr ocortisone q6h until resolution of the illness. Box 41.2 Adrenal insuf \201 ciency in pregnancy b Also see Normal changes during pregnancy (p. 361). During normal pregnancy: Cortisol-binding globulin gradually increases. \200 Free cortisol increases in the third trimester. \200 Progesterone increases exerting an antimineralocorticoid effect. \200 R enin levels increase. In Addison \200\231s disease, therefore: \200 The usual glucocortic oid and mineralocorticoid replacement is continued initially. Increase the hydrocortisone 50% in the third trimester. \200 Adjust mineralocorticoids to BP and serum potassium (not renin). Severe hyperemesis gravidarum during the \201 rst tr imester may require temporary parenteral therapy and patients should be warned about this t o avoid precipitation of a crisis. During labor and for 24 \200\22348 hours: Parenteral glucocorticoid therapy is administered (100 mg IM every 6 hours). Or hydrocortisone 100 mg IV in 5% dextrose per 24 hours. \200 Fluid replacement with IV 0 .9% saline may be required. Drug interactions Rifampicin \200 Increases the clearance of cortisol \200 Double usual dose of hydrocort isone Mitotane \200 Increases cortisol binding globulin \200 Double usual dose of hydrocortis one 41-Draznin-Chap41.indd 204 4/1/2011 5:31:43 PM TREATMENT 205 Education of the patient Patient education is the key to successful management. Patients mu st be taught never to miss a dose. They should be encouraged to wear a Medic Alert bracelet . Every patient should know how to double the dose of glucocorticoid during febrile illness a nd to get medical attention if unable to take the tab- lets because of vomiting. They shoul d have a vial of 100 mg hydrocortisone with a syringe, diluent, and needle for times when p arenteral treatment may be required. Further reading Arlt W (2009) The approach to the adult with newly diagnosed adrenal insuf \201 ciency. J Clin Endocrinol Metab 94(4):1059 \200\2231067. Arlt W, Allolio B (2003). Adrenal insuf \201 ciency. Lancet 361:1881 \200\22393. Hunt PJ, Gurnell EM, Huppert FA, et al. (2000). Improvement in mood and fatigue after dehyd roepi- androsterone replacement in Addison \200\231s disease in a randomized, double blind trial. J Clin Endocrinol Metab 85(12):4650 \200\2234656. Kong MF, Lawden M, Howlett T (2008). The Addison \200\231s disease dilemma \200\224autoimmu ne or ALD? Lancet 371:1970. Oelkers W (1996). Adrenal insuf \201 ciency. N Engl J Med 335:1206 \200\2231212. 41-Draznin-Chap41.indd 205 4/1/2011 5:31:43 PM CHAPTER 42 Long-term glucocorticoid administration 206 Long-term glucocorticoid administration Both exogenous glucocorticoid administration and endogenous excess glucocorticoids (Cushing \200\231s syndrome) lead to a negative feedback effect on the hypothalamo \200\223pituitar y \200\223adrenal (HPA) axis, leading to suppression of both CRH and ACTH secretion and atr ophy of the zona fasiculata and reticularis of the adrenal cortex. Short-term steroids Any patient who has received glucocorticoid treatment for <3 weeks is u nlikely to have clinically signi \201 cant adrenal suppression, and if the medi- cal condi tion allows it, glucocorticoid treatment can be stopped acutely. A major stress within a we ek of stopping steroids should, however, be covered with glucocorticoids. Exceptions to this are patients who have other possible reasons for adrenocortical insuf \201 ciency, who have received >40 mg prednisolone (or equivalent), where a short course ha s been prescribed within 1 year of ces- sation of long-term therapy, or evening doses (i HP A axis suppression). Steroid cover While receiving glucocorticoid treatment and within 1 year of steroid withdra wal, patients should receive standard steroid supplementation ( Box 42.1 ) at times of stre ss, e.g., major trauma, surgery, and infection ( b p. 562) . Box 42.1 Steroid equivalents \200 1 mg hydrocortisone \200 1.25 mg cortisone acetate \200 0.25 mg prednisolone \200 0.20 mg prednisone \200 3.75 mcg dexamethasone 4 mg pre dnisolone \211 20 mg hydrocortisone \211 75 mcg dexamethasone 42-Draznin-Chap42.indd 206 3/31/2011 2:45:36 PM CUSHING \200\231S SYNDROME 207 Box 42.2 Dehydroepiandrosterone (DHEA) \200 DHEA is an abundant circulating adrenal andro gen with a production rate of 25 \200\22350 mg/day. Its levels undergo a progressive declin e with i age, and there has been interest in its physiological role. Epidemiological data suggest a link between changes in DHEA and age-related changes including an inverse relationship between DHEA and cardiovascular disea se, Alzheimer disease, and malignancy. Although animal studies have suggested potential therapeutic bene \201 t of DHEA therapy, small studies in humans have so far failed to demonstrate convincing bene \201 t otherwise and apart from short-term improvement in well-being. Recent evidence suggests that DHEA replacement in patients with Addison \200\231s disease may have bene \201 cial effects on well-being. Long-term steroids When patients are receiving supraphysiological doses (>5.0 mg prednis- o ne, or equivalent) of glucocorticoid, dose reduction depends on disease activity. Once a da ily equivalent of 5.0 mg prednisone is reached, the rate of reduction should be slower to a llow recovery of the HPA axis. If concerned about disease resolution, the rate of reduction of gluco- corticoids is determ ined by the disease process until 5.0 mg equivalent is reached. If the disease has resolved , the dose can be rapidly reduced to 5.0 mg prednisone by a reduction of 2.5 mg every 3 \200\2235 days. Once the patient is established on 5.0 mg prednisolone, consider chang- ing to hydrocortiso ne (20 mg in the morning), as this has a shorter t and will therefore lead to less prolon ged suppression of ACTH. The daily hydrocortisone dose should be reduced by 2.5 mg every 1 \200\2232 weeks or as tol erated until a dose of 10 mg is reached. After 2 \200\2233 months, a 9 A.M. cortisol is che cked 24 hours after last dose of hydrocortisone. If it is >10 mcg/dL, then hydrocortisone c an be stopped and a Cortrosyn test performed. If the 9 A.M. cortisol is <10 mcg/dL, then continue hydrocorti- sone 10 mg for another 2 \200\2233 months and repeat the 9 A.M. corti sol. When basal cortisol is >14 mcg/dL, stop regular hydrocortisone and administer in emergency only. Supplemental steroids during intercurrent illness are not required. Cushing \200\231s syndrome Patients with Cushing \200\231s syndrome who are on metyrapone o r have recently treated disease, whatever the cause, may also have HPA axis suppression and may therefore need steroid replacement at times of stress. Further reading Baulieu E (1996). DHEA: a fountain of youth? J Clin Endocrinol Metab 81:314 7 \200\2233151. Nippoldt TB, Nair KS (1998). Is there a case for DHEA replacement? Balli \200\231re Clin Endocrinol Metab 12:507 \200\223520. 42-Draznin-Chap42.indd 207 3/31/2011 2:45:36 PM CHAPTER 43 Adrenal incidentalomas 208 Adrenal incidentalomas De \201 nition and epidemiology A true incidentaloma is an incidentally detected lesion wi th no patho- physiological signi \201 cance. It needs to be differentiated from incidental ly detected but clinically relevant masses. The incidental detection of an adrenal mass is becoming more common as i numbers of imaging procedures are performed and with technological improvements in imaging. Autopsy studies suggest an incidence of adrenal adenomas of 1 \200\2236%. Imaging studies suggest an incidence of approximately 3.5%. Importance It is important to determine whether the incidentally discovered adrenal mass is \200 Malignant \200 Functioning and associated with excess hormonal secretion Differential diagnosis of an incidentally detected adrenal nodule \200 Cortisol-secreting adrenal adenoma causing Cushing \200\231s syndrome or subclinical Cushing \200\231s syndrome (5.2%) Mineralocorticoid-secreting adrenal adenoma \200 Androgen-secreting adenoma \200 CAH \200 Adrenal carcinoma (12%) \200 Metastasis (2%) \200 Pheochromocytoma (11%) \200 A drenal cysts (5%) \200 Lipoma \200 Myelolipoma (8%) \200 Hematoma \200 Ganglioneuro ma (4%) 43-Draznin-Chap43.indd 208 3/31/2011 2:45:56 PM MANAGEMENT 209 Investigations \200 Clinical assessment for symptoms and signs of excess hormone secretion and signs of extra-adrenal carcinoma Urinary free cortisol and overnight dexamethasone suppression test \200 Urinary free cate cholamines/metadrenalines \200 Plasma free metanephrines if available ( b see p. 215) \200 Aldosterone/renin ratio if hypertensive or hypokalemic \200 A homogeneous mass with a low attenuation value (<10 HU) on CT scan is likely to be a benign adenoma. Additional tests if adrenal carcinoma suspected: \200 24-hour urinary excretion of cortic osteroid metabolites \200 DHEA, 17A OH progesterone \200 17A estradiol (in males only) \200 Testosterone, androstendione (in virilizing tumors) Management Up to 20% of patients may develop hormonal excess during follow-up. This is unli kely if the tumor is <3 cm. Cortisol is the most common excess hormone. Surgery is indicated if there is the following: Evidence of a syndrome of hormonal excess attributable to the tumor \200 Biochemical evid ence of pheochromocytoma \200 Mass diameter >4 cm (i likelihood of malignancy and de \201 nitely if >6 cm in diameter) Imaging features suggestive of malignancy (e.g., lack of clearly circumscribed margin, vascular invasion) Nonsurgical management includes the following: \200 Repeat MRI at 6 and 12 months \200 Repeat biochemical screening annually \200 In patients with tumors that remain stable on two imaging studies carried out at least 6 months apart and do not exhibit hormonal hyperse cretion over 4 years, further follow-up may not be warranted. Further reading Chidiac RM, Aron DC (1997). Incidentalomas. Endocrinol Metab Clin North Am 26:233 \200\223253. Kloos RT, Gross MD, Francis IR, et al. (1995). Incidentally discovered adrenal masses. Endo cr Rev 16:460 \200\223484. Mansmann G, Lau J, Balk E, et al. (2004). The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev 25(2):309 \200\223340. Newell-Price J, Grossman A (1996). Adrenal incidentaloma. Postgrad Med J 72:207 \200\223210 .