Box 24.2 Postoperative disorders of \202 uid balance \200 Acute and transient DI \200 Hyponatremia from excessive hypotonic \202 uid administration or SIADH Permanent DI \200\234classic triphasic DI response: \200\235 initial DI due to axon shock (hours \200\223days) followed by antidiuretic phase due to uncontrolled release of ADH from damaged posterior pituitary (2 \200\22314 days) followed by DI due to depletion of ADH. Pe rmanent DI complicates <2% of TSS. Isolated SIADH phase, delayed hyponatremia at 7 \200\22310 days postoperative, usually mild and self-limiting. More common in the elderly population. 24-Draznin-Chap24.indd 142 3/31/2011 2:50:54 PM TRANSFRONTAL CRANIOTOMY 143 Transfrontal craniotomy Indications Craniotomy is often the preferred surgical approach for a giant pituitary tumor (>4 cm) or a purely suprasellar location (e.g., craniopharyngiomas, meningiomas). Complications (see Table 24.1) Craniotomy has higher complication rates than does TSS. The potential complications are as listed for TSS (Box 24.1), and include the following: \200 Brain retraction may lead to cerebral edema or hemorrhage. \200 Manipulation of the opti c chiasm may lead to visual deterioration. \200 Damage to the olfactory nerve. Perioperative management \200 Recovery is typically slower than after transsphenoidal sur gery. \200 Prophylactic anticonvulsants are commonly used. \200 Patients are typically given dexamethasone over 1 \200\2232 weeks to minimize the risk of brain edema. Further reading Joshi SM, Cudlip S (2008). Transsphenoidal surgery. Pituitary 11:353 \200 \223360. Laws ER, Thapar K (1999). Pituitary surgery. Endocrinol Metab Clin N Am 28:119. Vance ML (2003). Perioperative management of patients undergoing pituitary surgery. Endocri nol Metab Clin N Am 32:355 \200\223365. Ciric I, Ragin A, Baumgartner A, Crain PA Pierce D (1997). Complications of transphenoidal surgery:results of a national survey, review of the literature and personal experience. Neu rosurgery 40:225 \200\223237. 24-Draznin-Chap24.indd 143 3/31/2011 2:50:54 PM CHAPTER 25 Medical treatment of pituitary tumors 144 Medical treatment of pituitary tumors Dopamine agonists (DA) For indications for use see Prolactinomas (p. 107) and Acromegaly (p . 114). DA formulations/doses \200 Bromocriptine (Parlodel): short-acting, non-ergot derivative. Usually administered orally, twice daily. Therapeutic daily dose for prolactinomas ranges b etween 5.0 and 30 mg; usual dose is 10 mg a day. Bromocriptine is the preferred medication in women seeking fertility because of the greater safety data during pregnancy. \200 Cabe rgoline (Dostinex): long-acting ergot derivative. Usually administered twice a week. The usual therapeutic dose is 1.0 mg a week. \200 Better side- effect pro \201 le and more ef \201 cacious than bromocriptine Pergolide (Permax): no longer available in the United States Mechanism of action DAs activate D 2 receptors, which are coupled to inhibitory G proteins, and decrease cAMP production. Side effects Side effects, particularly with bromocriptine, may be minimized by starting a low dose (e.g., 1.25 mg/day), and titrating up slowing. In females, vaginal administration can be tried if GI intolerance is dose limiting. Common side effects (>10%) \200 Nausea \200 Fatigue \200 Headache Less common side effects (<10%) \200 Postural hypotension, dizziness, nasal stuf \201 ne ss, constipation and a Raynaud-like phenomenon in the hands. Very rarely, patients develop hallucinations and psychosis (usually at higher doses). Uncommon side effects The problems of cardiac valvulopathy, as noted in Parkinson \200\231s patients on high-dose cabergoline (>3 mg/day), is uncommon in prolactinoma patients on sta ndard cabergoline doses ( < 2 mg/week). 25-Draznin-Chap25.indd 144 3/31/2011 2:51:14 PM SOMATOSTATIN ANALOGS 145 Somatostatin analogs Box 25.1 Uses of somatostatin analogs \200 Acromegaly \200 Carcinoid tumors \200 Panc reatic neuroendocrine tumors \200 TSH-secreting pituitary tumors Indications for use See Acromegaly (p. 114). Mechanism of action \200 Analogs of the naturally-occurring GH inhibitor somatostatin, bu t with increased serum half-lives and higher somatostatin receptor af \201 nities. \200 The somatostatin analogs signal predominantly through somatostatin receptors subtypes 2 and 5. Formulations/doses \200 Octreotide LAR (Sandostatin LAR) (10 \200\22330 mg intramuscul ar [IM]) administered every 4 \200\2236 weeks Lanreotide Autogel (Somatuline) (60 \200\223120 mg deep subcutaneous [SC]) administered every 4 \200\2236 weeks SC octreotide (50 \200\223200 mcg) administered 3 \227 daily. \200 Lanreotide SR (30 mg IM) administered every 7 \200\22314 days. Side effects \200 Gallstones or sludge develops in 720 \200\22330% of patients, but only 1%/year develop symptomatic cholecystitis. Abdominal cramps, bloating and mild steatorrhea, due to inhibition of motor activity and pancreatic enzymes secretion, commonly occur early in treatment, alth ough symptoms usually improve, or resolve, over the \201 rst few months. Transient worsening of diabetes (from inhibition of B-cell function). \200 Injection site pain is minimized by allowing the medication to warm to room temperature before administration. Hair loss (<10%) Issues \200 The long-acting somatostatin analogs have similar ef \201 cacies and side- effect pro \201 les. The need for dose titrations should be assessed at 3 month intervals, based on the IGF-1 levels. IGF-1 levels, but not GH-OGTT suppression tests, are recommended to monitor the therapeutic response to somatostatin analogs in acromegaly. 25-Draznin-Chap25.indd 145 3/31/2011 2:51:15 PM CHAPTER 25 Medical treatment of pituitary tumors 146 Growth hormone receptor antagonists Indications for use include medical therapy for acromeg alic patients who are incompletely responsive to, or intolerant of, somatostatin analogs. Mechanism of action \200 Mutated GH molecule that binds to peripheral GH receptors (predo minantly on the liver) and blocks GH receptor signaling Formulations and doses \200 Pegvisomant (Somavert) 40 mg SC loading dose, followed by 10 \200\22340 mg SC administered daily Side effects \200 Abnormal liver function tests (transaminitis), in 75%, but are usually transient Injection site reactions (i.e., atopic reactions or lipohypertrophy) Issues \200 High cost \200 Successful weekly and biweekly administrations of pegvisoman t have been reported, based on its long half-life (70 hours). 2 Therapeutic response is assessed by IGF-1 levels only (GH levels are elevated on GH antag onist therapy). \200 The need for dose titrations should be assessed at 73-month interval s. \200 Medication has no effect on tumor size. MRI of the pituitary is indicated 6 months after starting therapy and then annually thereafter. Long-term studies i ndicate a low risk for tumor growth (<5 % over 5 years). Pegvisomant can be given concomitantly with somatostatin analogs to control GH hypersecretion. Further reading Higham CE, Bidlingmaier M, Drake WM, Trainer PJ (2009). Successful use of w eekly pegvisomant administration in patients with acromegaly. Eur J Endocrinol 161:21 \200 \22325. Melmed S, Colao A, Barkan M, Molitch M, et al. (2009) Guidelines for acromegaly management: an update. J Clin Endocrinol Metab 94:1509 \200\2231517. Trainer PJ (2009). ACROSTUDY: the \201 rst 5 years. Eur J Endocrinol 161:S19 \200\223S24. Trainer PJ, Drake WM, Katznelson L, Freda PU, et al. (2000). Treatment of acromegaly with t he growth hormone receptor antagonist pegvisomant N Engl J Med 342:1171 \200\2231177. 25-Draznin-Chap25.indd 146 3/31/2011 2:51:15 PM TECHNIQUES TECHNIQUES 147 Pituitary radiotherapy Background Pituitary radiotherapy is used to control pituitary tumor growth and excess horm one secretion for patients with residual or recurrent tumors that are not adequately treate d by surgical and medical approaches. Techniques Conventional external beam radiation A three- \201 eld cross \201 re technique is used to deliver ionizing irradiation. The standard 45 \200\22350 Gy dose is delivered in 25 fracti ons (72 Gy/day) over 75 \200\2236 weeks. Stereotactic radiation therapy (see Box 26.1) This therapy represents improved immobilizati on, radiation beam focusing and imaging techniques. Stereotactic irradiation can be given a s a single- fraction radiosurgery (SRS) or delivered as fractionated doses. SRS is lim- ite d to relatively smaller tumors with tumor margins that are >5 mm from the optic apparatus. Box 26.1 Stereotactic forms of radiotherapy \200 Gamma knife: ionizing radiation from a c obalt 60 source delivered by convergent collimated beams LINAC: delivers photons via a linear accelerator and frequently incorporates a cyberknife. Proton beam: utilizes heavy-charge particle proton beams, produced by a cyccotron but has limited availability in the U.S. Cyber knife: a frameless, robotic radiosurgery delivery system 26-Draznin-Chap26.indd 147 3/31/2011 2:51:43 PM CHAPTER 26 Pituitary radiotherapy 148 Ef \201 cacy \200 Radiotherapy is effective and rapid in controlling pituitary adenoma g rowth, with progression-free survivals of 80 \200\22390% at 10 years. Effects of radiation therapy on normalizing hormone hypersecretion are delayed. For example, normalization of GH/IGF-1 levels is observed in 730 \200\22350% o f acromegalic patients at 75 \200\22310 years after conventional radiation therapy. Stereotactic techniques have the theoretical advantage, over conventional radiation therapy, of decreased complication rates (i.e., hypopituitarism), an d a more rapid normalization of hormone hypersecretion, although this is still a controvers ial area. To potentially optimize treatment ef \201 cacy, consideration should be given to the tempo rary discontinuation of pituitary-directed medications, such as somatostatin analogs (for a t least 1 month) prior to radiation therapy. 26-Draznin-Chap26.indd 148 3/31/2011 2:51:43 PM COMPLICATIONS 149 Complications Short-term \200 Fatigue \200 Nausea \200 Headache \200 Temporary hair loss at radio therapy entry portals Hypopituitarism \200 Anterior pituitary hormone de \201 ciency is the most common late complication of radiation therapy, and occurs in 30 \200\22360% of patients 710 years after conventional radiation (Fig. 26.1). The loss of anterior pituitary hormones, after radiation therapy, generally develops in a predictable order: GH 7 FSH/LH >> ACTH 7 TSH Posterior pituitary de \201 ciencies are rare after XRT. \200 Expectant management is re commended for hypopituitarism with biannual pituitary hormone testing to include basal ACTH, cortisol, free T 4 , IGF-1, testo sterone (in males), and estradiol (in females). Cosyntropin stimulation test is indicted fo r an equivocal A.M. cortisol value. 1.0 s i x a TSH l a m r o n 0.5 f o y t i l i b a b o r P LH/FSH ACTH GH 0 0 3 4 6 8 10 Years after treatment Fig 26.1 Life-table analysis indicating the probability of developing pituitary hormone de \201 ciencies after conventional radiation therapy. Reproduced with permission from Little y MD, Shalet SM, Beardwell CG, Ahmed, SR, et al. (1989). Q J Med 70:145 \200\223160. 26-Draznin-Chap26.indd 149 3/31/2011 2:51:43 PM CHAPTER 26 Pituitary radiotherapy 150 Visual impairment The optic chiasm is radiosensitive, whereas cranial nerves are generally radioresistant. The risk of vision impairment is related to the total admin- istered dose a nd the dose per fraction (highest with SRS). A standard total dose of 4500 cGy (and a daily dose of 180 cGy in conventional radiation) poses very little risk to the optic chiasm (<1% risk of blindness). Long-term radiation complications \200 Radiation is associated with the development of se condary brain tumors, particularly meningiomas and gliomas, with an estimated risk of 2.4% at 20 years. The effects of pituitary radiation on long-term neuro-cognitive and neuro-psychological function are not well de \201 ned. XIncreased cerebrovascular morbidity and mortality rates have been reported with convention al radiation treatment of pituitary adenomas, although the relative contribution of radiati on to stroke risk remains to be determined. Further reading Darzy KH, Shalet SM (2009). Hypopituitarism following radiotherapy. Pituita ry 12:40 \200\22350. Gittoes N (2005). Pituitary radiotherapy: current controversies. Trends Endocrinol Metab 6: 407 \200\223413. Minniti G, Gilbert DC, Brada M (2009). Modern techniques for pituitary radiotherapy. Rev En docrinol Metab Disord 10:135 \200\223144. Minniti G, Traish AS, Gonsalves A, Brada M (2005). Risk of second brain tumor after conserv a- tive surgery and radiotherapy for pituitary adenomas: update after an additional 10 year s. J Clin Endocrinol Metab 90:800 \200\223804. 26-Draznin-Chap26.indd 150 3/31/2011 2:51:44 PM CLASSIFICATIONS AND ETIOLOGIES CLASSIFICATIONS AND ETIOLOGIES (SEE BOX 27.1) 151 Diabetes insipidus (DI) De \201 nition DI is de \201 ned as the passage of large volumes (>40 ml/kg/day in adults ) of dilute urine. Classi \201 cations and etiologies (see Box 27.1) Neurogenic \200 Inadequate arginine vasopressin (AVP) secretion Nephrogenic \200 Inadequate renal response to AVP Dipsogenic \200 Compulsive polydipsia (psychogenic) \200 Disorders of hypothalamic thir st center 27-Draznin-Chap27.indd 151 4/1/2011 6:39:07 PM CHAPTER 27 Diabetes insipidus (DI) 152 Box 27.1 Etiologies of DI Neurogenic Congenital \200 Autosomal dominant (AVP-neurophysin gene mutation) \200 DIDM OAD syndrome ( d iabetes i nsipidus, d iabetes m ellitus, o ptic a trophy, d eafness) Acquired \200 Trauma \200\224head injury, neurosurgery \200 Tumors \200\224craniopharyn gioma, metastatic, germinoma \200 In \202 ammatory conditions \200\224sarcoidosis, TB, L angerhans \200\231 cell histiocytosis, lymphocytic hypophysitis Infections \200\224meningitis, encephalitis. \200 Vascular \200\224Sheehan \200\231s synd rome, cerebral hemorrhage or infarction \200 Idiopathic Nephrogenic Congenital \200 X-linked recessive \200\224vasopressin receptor gene \200 A utosomal recessive \200\224aquaporin-2 gene Acquired \200 Drugs \200\224lithium, demeclocycline, amphotericin B, cisplatin \200 Met abolic \200\224hypercalcemia, hypokalemia, hyperglycemia \200 In \201 ltrating lesions \200\224sarcoidosis, amylodosis \200 Chronic renal disease \200 Sickle cell anemia Dipsogenic \200 Psychogenic polydipsia \200 Hypothalamic diseases \200\224similar lesio ns as in neurogenic DI Features \200 Clinical presentation Adults-polyuria, polydipsia and nocturia \200 Children-polyuria, polydipsia, enuresis and failure to thrive. Rapid dehydration and hypernatremia can occur if the patient does not have access to water or has impaired thirst mechanisms. Transient DI complicates an estimated 10 \200\22315% of pituitary surgeries, although perma nent DI is uncommon (requires the destruction of >90% of AVP neurons). Pregnancy results in increased AVP metabolism from placental vasopressinase, but is generally not clinically relevant. 2 Neurogenic DI may be masked by cortisol de \201 ciency and uncovered by the administrati on of glucocorticoids. 27-Draznin-Chap27.indd 152 4/1/2011 6:39:07 PM INVESTIGATIONS 153 Investigations Diagnosis of DI \200 Con \201 rm large urine output (>40 mL/kg/day in adu lts) with a 24-hour urine collection. Exclude diabetes mellitus and renal failure (osmotic diuresis). \200 Exclude hypokalemia and hypercalcemia (nephrogenic DI). \200 Consider water deprivation test (see Box 27.2) \200 Pituitary MRI is recommended for suspected neurogenic DI. Box 27.2 Water deprivation test 1. The patient is water deprived in a monitored setting for 78 hours. 2 Urine output and osmolality are monitored hourly, and plasma sodium and osmolality are meas ured every 2 hours. The test is stopped when one of the following parameters is met: a. Uri ne osmolality is normal (>600 mOsm/kg), thereby excluding DI. b The plasma osmolality or sodium values become clearly 3 elevated. c The urine osmolality is stable (<10% change) on three consecutive readings. 4 A plasma sample is sent for ADH measurement and dDAVP is administered (1 \200\2232 mcg SQ), followed by hourly measurements of urinary volume and urine osmolality \227 2. 27-Draznin-Chap27.indd 153 4/1/2011 6:39:08 PM CHAPTER 27 Diabetes insipidus (DI) 154 Treatment Maintenance of adequate \202 uid input In patients with partial DI, mild polyuria and an intact thirst mechanism, drug therapy may not be necessary. Drug therapy Neurogenic DI \200 Arginine vasopressin (Pitressin): short half-life and vas opressor effect when administered intravenously limits its general utility. Desmopressin (1-deamino-8-D-arginine-vasopressin) Vasopressin analog, acts predominantly on the V2 receptors in the kidney, and has the follo wing advantages: longer half-life than the native hormone, increased antidiuretic ef \201 cacy, and no vasopressor (V1 receptor) activity. In the hospital setting: 1 \200\2232 mcg parenteral (SQ, IM, or IV) administration is preferred. Chronic administration: intranasal spray use is preferable (10 \200\22340 mcg/day in divide d doses) or oral tablets (50 \200\2231200 mg/day). Additional medications can be used to augment ADH release or actions (e.g., chlorpropamide, carbamazepine, clo \201 brate, NSAIDs), but these are less ef \201 cacious than dDAVP an d may cause adverse side effects. Nephrogenic DI \200 Correct underlying causes and discontinue offending drug when possible. Low-sodium/protein diets \200 Thiazide diuretic \200 Amiloride (for lithium-induced DI) \200 NSAIDs Dipsogenic Management is often dif \201 cult. Treat any underlying tumor or psychiatric di sorder, when possible. 27-Draznin-Chap27.indd 154 4/1/2011 6:39:08 PM CAVEATS FOR WATER DEPRIVATION STUDY 155 Caveats for water deprivation study \200 Differentiating between partial neurogenic/nephr ogenic DI and psychogenic polydipsia is best done by comparing the plasma AVP level with ur inary and plasma osmolalities (using established nomograms) during a hyperosmotic state. Chronic psychogenic polydipsia may result in reduced urine- concentrating ability because o f medullary solute washout. Test interpretation After \202 uid deprivation Urine Osm ADH After desmopressin Urine Osm i (>100%) % No change (<10%) i No change (<10%) Complete neuro DI No change No change i i Complete nephro DI Psychogenic polydipsia Further reading Loh JA, Verbalis JG (2008). Disorders of water and salt metabolism associat ed with pituitary disease. Endocrinol Metab Clin North Am 37:213 \200\223234. Verbalis JG (2002). Managment of disorders of water metabolism in patients with pituitary t umors. Pituitary 5:119 \200\223132. 27-Draznin-Chap27.indd 155 4/1/2011 6:39:08 PM CHAPTER 28 Hyponatremia 156 Hyponatremia Incidence Hyponatermia is the most common electrolyte abnormality in hospitalized patients. Mild to moderate hyponatremia (sodium 126 \200\223135 mmol/L) and severe hyponatremia (sod ium <125 mmol/L) occur in 14% and 1% of hos- pitalized patients, respectively. Etiologies Box 28.1 Causes of hyponatremia Excess water \200 i Water reabsorption: cirrhosis, congestive heart failure, nephrotic syndrome Reduced renal excretion of a water load: SIADH, glucocorticoid de \201 ciency, hypothyroidism Excess water intake: primary polydipsia Salt de \201 ciency \200 Renal loss: salt wasting nephropathy \200\224tubulointerstitial nephritis, polycystic kidney disease, analgesic nephropathy, recovery phase of acute tubul ar necrosis, cerebral salt wasting, mineralcorticoid de \201 ciencies Nonrenal loss: mucosal losses, burns, sweating, GI tract (bowel sequestration, \201 stulae, pancreatitis) Artifactual/pseudohyponatremia \200 Lipids, proteins (e.g., paraproteinemia) \200 Solut es (e.g., glucose, mannitol, ethanol) 28-Draznin-Chap28.indd 156 3/31/2011 2:52:43 PM CLASSIFICATION AND CLINICAL FEATURES 157 Neurosurgical hyponatremia Etiologies \200 Excessive hypotonic \202 uid administration \200 SIADH (e.g., pain, n ausea, medications) \200 Glucocorticoid de \201 ciency \200 Cerebral salt wasting Characterized by diuresis and natriuresis of unknown etiology \200 Associated with trauma tic brain injury, particularly subarachnoid hemorrhage Best distinguished from SIADH by hypovolemic status Classi \201 cation and clinical features See Table 28.1 for classi \201 cation. \200 Hy ponatremia clinically manifests with neurological symptoms from osmotic \202 uid shifts and brain edema. Symptoms range from asymptomatic to severe depending on the extent of hyponatremia and the rate of development (acute, <48 hours). Acute symptoms include head aches, fatigue, anorexia, nausea, vomiting, altered sensorium, seizure, coma, respiratory a rrest and death. Table 28.1 Pituitary hormone replacement regimens Clinical features Classi \201 cation <20 >20 Nonrenal losses Renal losses Hypovolemic Dry mucous membranes, poor skin turgor, hypotension, tachycardia Euvolemic Mild volume overload in SIADH is usually not clinically apparent. SIADH + \202 uid restriction SIADH Hypervolemic Peripheral edema, ascites, increased JVD, pulmonary edema Cirrhosis CHF Renal failure CHF + diuretics CHF, congestive heart failure; JVD, jugular venous distension. 28-Draznin-Chap28.indd 157 3/31/2011 2:52:43 PM CHAPTER 28 Hyponatremia 158 Investigations \200 Assess volume status \200 Serum osmolality (normal in pseudohyponat remia from hyper- lipidemia/paraproteinemia) \200 Urine sodium level (spot) \200 Other investigations as indicated (e.g., urine osmolality, cortisol, thyroid function tests, renal/liver biochemistry and B-type natriuretic peptide [BNP] level s). Hyponatremia treatment Hypovolemic hyponatremia \200 Treat underlying condition (e.g., diarrhea, vomiting, nephr opathy). \200 IV normal saline and increased dietary salts Traditional formula for calculating sodium de \201 cit \200 Na+ required = Total Body Wa ter (TBW) \227 Na(desired - current) \200 TBW = lean body weight \227 0.5 (females) and \227 0.6 (males) \200 Rate of Na+ normalization (mmol/h) varies by extent and acuity of hyponatremia. \200 Overly rapid correction of severe, chronic hyponatremia can lead to osmotic demyelination syndrome. In general, limit the rise of plasma sodium concentration by <8 \200\22312 mmol/L in the \201 rst 24 hours, and <18 \200\22324 mmol/L in the \201 rst 48 hours. Euvolemic hyponatremia/SIADH b See Syndrome of inappropriate ADH (SIADH) (p. 159). Hypervolemic hyponatremia \200 Treatment of underlying disorder (e.g., CHF, liver disease ) \200 Diuretics \200 Fluid restriction Artifactual/pseudohyponatremia Treat underlying disorder only (e.g., normalize hyperglycemi a). Further reading Moore K, Thompson C, Trainer R (2003). Disorders of water balance. Clin Med 3 :28 \200\22333. Sterns RH, Nigwekar SU, Hix, JK (2009). The treatment of hyponatremia. Semin Nephrol 29:282 \200\223299. 28-Draznin-Chap28.indd 158 3/31/2011 2:52:43 PM TYPES OF SIADH 159 Syndrome of inappropriate ADH (SIADH) De \201 nition SIADH is a syndrome of sustained AVP release or response in the absence of appropriate hyperosmotic or hypovolemic stimuli. Features \200 SIADH clinically manifests with neurological symptoms from hyponatremia cau sed by osmotic \202 uid shifts and brain edema. \200 Symptoms range from mild to severe depending on the extent of hyponatremia and the rate of development (acute, <48 hours). Sy mptoms include headaches, fatigue, anorexia, nausea, vomiting, altered sensorium, seizure, coma, respiratory arrest and death. \200 Mild chronic hyponatremia is common in the elder ly because of ineffective suppression of ADH. Criteria for diagnosis \200 Hyponatremia and hypotonic plasma (osmolality <275 mOsm/kg of water) Inappropriate urine concentration (>100 mOsm/kg) \200 Excessive renal sodium loss (>40 mm ol/L), with normal salt intake and exclusion of recent diuretic use Euvolemic status \200 Normal renal, adrenal and thyroid function Types of SIADH \200 Type AI \200\224erratic excess ADH secretion, unrelated to plasma osmolality (most common) Type B \200\224elevated basal secretion of AVP, despite normal regulation by osmolality Type C \200\224 \200\234reset osmostat, \200\235 AVP secretion at a lower serum osmolality \200 Type D \200\224low vasopressin secretion, possible vasopressin receptor defect b See Box 29.1 for causes of SIADH. 29-Draznin-Chap29.indd 159 3/31/2011 3:18:01 PM CHAPTER 29 Syndrome of inappropriate ADH (SIADH) 160 Box 29.1 Causes of SIADH Malignant diseases \200 Small-cell lung carcinoma, thymoma, lymphoma, leukemia, sarcoma, mesothelioma, GI/GU tumors Pulmonary disorders \200 Infections (pneumonia, tuberculosis, empyema) \200 Pneumothora x \200 Asthma \200 Respiratory failure, positive pressure ventilation CNS disorders \200 Infections (meningitis, encephalitis, abscess) \200 Vascular disorde rs (subarachnoid hemorrhage, cerebrovascular accident, traumatic brain injury, hydrocephalus) Other (multiple sclerosis, Guillain \200\223Barre, Shy \200\223Drager syndromes, HIV) Drugs \200 Chemotherapy (vincristine, vinblastine, cyclophosphamide) \200 Psychiatric d rugs (phenothiazines, SSRIs, TCAs) \200 Other (carbamazepine, clo \201 brate, chlorpropa mide, nicotine, narcotics, \200\230ectasy \200\231) Metabolic \200 Hypothyroidism \200 Glucocorticoid de \201 ciency \200 Other (pain, s tress, nausea, idiopathic) Treatment \200 Treat underlying cause. \200 Fluid restriction to 500 \200\2231000 mL/24 hours \200 Vasopressin antagonists (e.g., tolvaptan (oral route, V1 speci \201 c) and Conivaptan (IV route, V1/V2 antagonism). Expense currently limits their practical use in mo st cases Hypertonic saline (3% infusion) for severe symptomatic hyponatremia (eg. seizures or altere d mentation). It is important to limit the rate of sodium correction to (cid:3) 8 \200\2231 2 mmol/L during the \201 rst 24 hours to avoid central pontine myelinolysis, particularly if hyponatremia is chronic (>48 hours duration). Further reading Ellison DH, Berl T (2007). The syndrome of inappropriate antidiuresis. N En gl J Med 356:2064 \200\2232071. 29-Draznin-Chap29.indd 160 3/31/2011 3:18:01 PM INVESTIGATIONS AND STAGING 161 Pineal gland Physiology The pineal gland lies behind the third ventricle and produces melatonin, which i s important for sleep and entraining some pituitary hormones to light \200\223dark cycles. Pineal and intracranial germ cell tumors \200 Incidence: 0.5% \200\2233% intracranial neo plasms \200 Epidemiology: more common in children and in males \200 Three most common p ineal gland tumors: germ cell >> pineal parenchymal > gliomas; 2/3 malignant and 1/3 benign Germ cell tumors are classi \201 ed as germinomas or nongerminomatous. \200 Pineal paren chymal tumors and gliomas have histological subtypes that vary from low- to high-grade tumors. Features \200 Obstructive hydrocephalus: i intracranial pressure, headaches, vomiting, ataxia and lethargy Parinaud \200\231s syndrome (paralysis of upward gaze, convergent nystagmus, Argyll \200\223Robertson pupils) Vision disturbances (bitemporal hemianopsia) \200 Hypothalamic/pituitary dysfunction: hyp opituitarism and DI \200 Sexual precocity (if tumor secretes B-hCG which mimics LH) Investigations and staging \200 Imaging of craniospinal axis by MRI/CT \200 CSF cytolog y \200 Tumor markers (B-hCG, A-fetoprotein) \200 Tumor biopsy \200 Pituitary function assessment for hypopituitarism and DI 30-Draznin-Chap30.indd 161 3/31/2011 2:53:25 PM CHAPTER 30 Pineal gland 162 Management \200 Multimodal approach from among surgical resection, radiation therapy and chemotherapy, depending on the tumor type and stage. Pure germinomas are very radiosensitive. Prognosis The prognosis is excellent for germinomas (90% 5-year survival), but is less favo rable for nongerminomatous germ cell tumors (60 \200\22370% 5-year survival). Prognosis for pineal parenchymal tumors and gliomas, varies by histological sub-type and disease extent, and trends with tumor grade. Further reading Al-Hussaini M, Sultan I, Abuirmileh N, Jaradat I, et al. (2009). Pineal gla nd tumors: experience from the SEER database. J Neurooncol 94:351 \200\223358. Haddock MG, Schild SE, Scheithauer BW, Schomberg, PJ (1997). Radiation therapy for histolog ically con \201 rmed primary central nervous system germinoma. Int J Radiat Oncol Biol Phy s 38:915 \200\223923. Rosenblum MK, Nakazato Y, Matsutani M (2007). CNS germ cell tumors. In Louis D, Ohgaki H, W iestler O, Cavenee WK (eds.), WHO Classi \201 cation of Tumors of the Central Nervous Syst em , 3rd ed. Albany, NY: WHO Publication Center, pp. 197 \200\223204. 30-Draznin-Chap30.indd 162 3/31/2011 2:53:25 PM Part 3 Adrenals Boris Draznin 31 Anatomy and physiology 32 Imaging 33 Mineralcorticoid excess 34 Primary aldosteronism 35 Excess other mineralcorticoids 36 Adrenal Cushing \200\231s syndrome 37 Adrenal surgery 38 Renal tubular abnormalities 39 Mineralcorticoid de \201 ciency 40 Adrenal insuf \201 cie ncy 41 Addison \200\231s disease 42 Long-term glucocorticoid administration 43 Adrenal inci dentalomas 44 Pheochromocytomas and paragangliomas 164 168 170 171 182 184 188 190 192 193 196 206 208 210 31-Draznin-Chap31.indd 163 4/1/2011 5:29:40 PM CHAPTER 31 Anatomy and physiology 164 Anatomy and physiology Anatomy The normal adrenal glands weigh 4 \200\2235 g. The cortex represents 90% of the nor mal gland and surrounds the medulla. The arterial blood supply arises from the renal arteri es, aorta, and inferior phrenic artery. Venous drainage occurs via the central vein into th e inferior vena cava on the right, and into the left renal vein on the left. 31-Draznin-Chap31.indd 164 4/1/2011 5:29:41 PM ANATOMY 165 CH3 CO HO HO Cholesterol Pregnenolone 3 \200\2235 CH3 CO 17 CH3 CO O OH O OH 17-Hydroxypregnenolone OH Progesterone Dehydroeoiandrosterone 17 CH2OH CO 3 \200\2235 21 CH3 CO O OH O O O Deoxycorticosterone 17-Hydroxyprogesterone Androstenedione 11 21 CH2OH CO CH2OH CO OH HO O O Corticosterone 11-Deoxycortisol (substance \200\230S \200\231) 81 11 CH2OH CO CH2OH CO CH2OH CO O CH OH HO O HO HO O O O Cortisone Aldosterone Cortisol 3 \210\222 hydroxydehydrogenase, 5-isomerase 3 \200\2235 17 \210\222 hydroxylase 11 \210\222 hydroxylase 11 17 18 \210\222 hydroxylase 21 \210\222 hydroxylase 21 18 Fig. 31.1 Pathways and enzymes involved in synthesis of glucocorticoids, mineralocorticoids , and adrenal androgens from a cholesterol precursor. Reprinted with permission from Besser M, Thorner GM (1994). Clinical Endocrinology , 2nd ed. New York: Elsevier. 31-Draznin-Chap31.indd 165 4/1/2011 5:29:41 PM CHAPTER 31 Anatomy and physiology 166 Physiology Glucocorticoids Glucocorticoid (cortisol 10 \200\22320 mg/day) ( Table 31.1 ) production oc curs from the zona fasciculata, and adrenal androgens arise form the zona reticularis. Both of these are under control of ACTH, which regulates both steroid synthesis and adrenocorti cal growth. Mineralocorticoids Mineralocorticoid (aldosterone 100 \200\223150 mcg/day) ( Table 31.1 ) s ynthesis occurs in zona glomerulosa predominantly under the control of the renin \200\223an giotensin system (b see Fig 31.2 ), although ACTH also contributes to its regulation. 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.