InternalMed_Harrison

InternalMed_Harrison. The majority of clinical signs and symptoms observed in Cushing’s syndrome are relatively nonspecific and include features such as obesity, diabetes, diastolic hypertension, hirsutism, and depression that are commonly found in patients who do not have Cushing’s. Therefore, careful clinical assessment is an important aspect of evaluating suspected cases. A diagnosis of Cushing’s should be considered when several clinical features are found in the same patient, in particular when more specific features are found. These include fragility of the skin, with easy bruising and broad (>1 cm), purplish striae (Fig. 406-9), and signs of proximal myopathy, which becomes most obvious when trying to stand up from a chair without the use of hands or when climbing stairs. Clinical manifestations of Cushing’s do not differ substantially among the different causes of Cushing’s. In ectopic ACTH syndrome, hyperpigmentation of the knuckles, scars, or skin areas exposed to increased friction can be


InternalMed_Harrison

InternalMed_Harrison. Cushing’s do not differ substantially among the different causes of Cushing’s. In ectopic ACTH syndrome, hyperpigmentation of the knuckles, scars, or skin areas exposed to increased friction can be observed (Fig. 406-9) and is caused by stimulatory effects of excess ACTH and other POMC cleavage products on melanocyte pigment production. Furthermore, patients with ectopic ACTH syndrome, and some with adrenocortical carcinoma as the cause of Cushing’s, may have a more brisk onset and rapid progression of clinical signs and symptoms.


InternalMed_Harrison

InternalMed_Harrison. Patients with Cushing’s syndrome can be acutely endangered by deep vein thrombosis, with subsequent pulmonary embolism due to a hypercoagulable state associated with Cushing’s. The majority of patients also experience psychiatric symptoms, mostly in the form of anxiety or depression, but acute paranoid or depressive psychosis FIGURE 406-9 Clinical features of Cushing’s syndrome. A. Note central obesity and broad, purple stretch marks (B. close-up). C. Note thin and brittle skin in an elderly patient with Cushing’s syndrome. D. Hyperpigmentation of the knuckles in a patient with ectopic adrenocorticotropic hormone (ACTH) excess.


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Adrenal Cortex 2316 may also occur. Even after cure, long-term health may be affected by A diagnosis of Cushing’s can be considered as established if the persistently impaired health-related quality of life and increased risk results of several tests are consistently suggestive of Cushing’s. These of cardiovascular disease and osteoporosis with vertebral fractures, tests may include increased 24-h urinary free cortisol excretion in depending on the duration and degree of exposure to significant cor-three separate collections, failure to appropriately suppress morning tisol excess. cortisol after overnight exposure to dexamethasone, and evidence of loss of diurnal cortisol secretion with high levels at midnight, theDiagnosis The most important first step in the management of time of the physiologically lowest secretion (Fig. 406-10). Factorspatients with suspected Cushing’s syndrome is to establish the correct potentially affecting the outcome of these diagnostic tests


InternalMed_Harrison

InternalMed_Harrison. time of the physiologically lowest secretion (Fig. 406-10). Factorspatients with suspected Cushing’s syndrome is to establish the correct potentially affecting the outcome of these diagnostic tests have to bediagnosis. Most mistakes in clinical management, leading to unneces-excluded such as incomplete 24-h urine collection or rapid inactivasary imaging or surgery, are made because the diagnostic protocol is tion of dexamethasone due to concurrent intake of CYP3A4-inducingnot followed (Fig. 406-10). This protocol requires establishing the drugs (e.g., antiepileptics, rifampicin). Concurrent intake of oral con-diagnosis of Cushing’s beyond doubt prior to employing any tests traceptives that raise CBG and thus total cortisol can cause failure toused for the differential diagnosis of the condition. In principle, after suppress after dexamethasone. If in doubt, testing should be repeatedexcluding exogenous glucocorticoid use as the cause of clinical signs after 4–6 weeks off estrogens.


InternalMed_Harrison

InternalMed_Harrison. In principle, after suppress after dexamethasone. If in doubt, testing should be repeatedexcluding exogenous glucocorticoid use as the cause of clinical signs after 4–6 weeks off estrogens. Patients with pseudo-Cushing states, i.e.,and symptoms, suspected cases should be tested if there are multiple alcohol-related, and those with cyclic Cushing’s may require further and progressive features of Cushing’s, particularly features with a testing to safely confirm or exclude the diagnosis of Cushing’s. Inpotentially higher discriminatory value. Exclusion of Cushing’s is also addition, the biochemical assays employed can affect the test results,indicated in patients with incidentally discovered adrenal masses. with specificity representing a common problem with antibody-based


InternalMed_Harrison

InternalMed_Harrison. Clinical suspicion of Cushing’s (Central adiposity, proximal myopathy, striae, amenorrhea, hirsutism, impaired glucose tolerance, diastolic hypertension, and osteoporosis) Screening/confirmation of diagnosis a.m.after 1 mg dexamethasone at 11 p.m.) If further confirmation needed/desired: • Low dose DEX test (Plasma cortisol >50 nmol/L after 0.5 mg dexamethasone q6h for 2 days) Pos. Neg. Neg.


InternalMed_Harrison

InternalMed_Harrison. Pos. Neg. Neg. Adrenal tumor workup Differential diagnosis 1: Plasma ACTH ACTH normal or high>15 pg/ml CRH test and highdose DEX positive ACTH suppressed to <5 pg/ml ACTH-dependent Cushing’s ACTH-independent Cushing’s Bilateral micronodular or macronodular adrenal hyperplasia Bilateral adrenal-ectomy Unilateral Unilateral adrenal mass CRH test and highEquivocal adrenal-ectomy Differential diagnosis 2 • MRI pituitary Unenhanced CT• CRH test (ACTH increase >40% at 15-30 min + cortisol increase >20%at 45-60 min after CRH 100 µg IV)• High dose DEX test (Cortisol suppression >50% after q6h 2 mg DEX for 2 days) Trans-Inferior petrosal sinus sampling Locate and sphenoidal(petrosal/peripheralremove surgery ACTH ratio >2 atbaseline, >3 at 2–5 minectopic after CRH 100 µg i.v.) source ACTH Ectopic ACTH production Cushing’s disease pituitary dose DEX negative results adrenals


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InternalMed_Harrison. FIGURE 406-10 Management of the patient with suspected Cushing’s syndrome. ACTH, adrenocorticotropic hormone; CRH, corticotropinreleasing hormone; CT, computed tomography; DEX, dexamethasone; MRI, magnetic resonance imaging. assays for the measurement of urinary free cortisol. These assays have been greatly improved by the introduction of highly specific tandem mass spectrometry.


InternalMed_Harrison

InternalMed_Harrison. Differential Diagnosis The evaluation of patients with confirmed Cushing’s should be carried out by an endocrinologist and begins with the differential diagnosis of ACTH-dependent and ACTH-independent cortisol excess (Fig. 406-10). Generally, plasma ACTH levels are suppressed in cases of autonomous adrenal cortisol excess, as a consequence of enhanced negative feedback to the hypothalamus and pituitary. By contrast, patients with ACTH-dependent Cushing’s have normal or increased plasma ACTH, with very high levels being found in some patients with ectopic ACTH syndrome. Importantly, imaging should only be used after it is established whether the cortisol excess is ACTH-dependent or ACTH-independent, because nodules in the pituitary or the adrenal are a common finding in the general population. In patients with confirmed ACTH-independent excess, adrenal imaging is indicated (Fig. 406-11), preferably using an unenhanced computed tomography (CT) scan. This allows assessment of adrenal


InternalMed_Harrison

InternalMed_Harrison. In patients with confirmed ACTH-independent excess, adrenal imaging is indicated (Fig. 406-11), preferably using an unenhanced computed tomography (CT) scan. This allows assessment of adrenal morphology and determination of precontrast tumor density in Hounsfield units (HU), which helps to distinguish between benign and malignant adrenal lesions.


InternalMed_Harrison

InternalMed_Harrison. For ACTH-dependent cortisol excess (Chap. 403), a magnetic resonance image (MRI) of the pituitary is the investigation of choice, but it may not show an abnormality in up to 40% of cases because of small tumors below the sensitivity of detection. Characteristically, pituitary corticotrope adenomas fail to enhance following gadolinium administration on T1-weighted MRI images. In all cases of confirmed ACTH-dependent Cushing’s, further tests are required for the differential diagnosis of pituitary Cushing’s disease and ectopic ACTH syndrome.


InternalMed_Harrison

InternalMed_Harrison. These tests exploit the fact that most pituitary corticotrope adenomas 2317 still display regulatory features, including residual ACTH suppression by high-dose glucocorticoids and CRH responsiveness. In contrast, ectopic sources of ACTH are typically resistant to dexamethasone suppression and unresponsive to CRH (Fig. 406-10). However, it should be noted that a small minority of ectopic ACTH-producing tumors exhibit dynamic responses similar to pituitary corticotrope tumors. If the two tests show discordant results, or if there is any other reason for doubt, the differential diagnosis can be further clarified by performing bilateral inferior petrosal sinus sampling (IPSS) with concurrent blood sampling for ACTH in the right and left inferior petrosal sinus and a peripheral vein. An increased central/peripheral plasma ACTH ratio >2 at baseline and >3 at 2–5 min after CRH injection is indicative of Cushing’s disease (Fig. 406-10), with very high sensitivity and specificity. Of note, the


InternalMed_Harrison

InternalMed_Harrison. central/peripheral plasma ACTH ratio >2 at baseline and >3 at 2–5 min after CRH injection is indicative of Cushing’s disease (Fig. 406-10), with very high sensitivity and specificity. Of note, the results of the IPSS cannot be reliably used for lateralization (i.e., prediction of the location of the tumor within the pituitary), because there is broad interindividual variability in the venous drainage of the pituitary region. Importantly, no cortisollowering agents should be used prior to IPSS.


InternalMed_Harrison

InternalMed_Harrison. If the differential diagnostic testing indicates ectopic ACTH syndrome, then further imaging should include high-resolution, fine-cut CT scanning of the chest and abdomen for scrutiny of the lung, thymus, and pancreas. If no lesions are identified, an MRI of the chest can be considered because carcinoid tumors usually show high signal intensity on T2-weighted images. Furthermore, octreotide scintigraphy can be helpful in some cases because ectopic ACTH-producing tumors often express somatostatin receptors. Depending on the suspected cause, patients with ectopic ACTH syndrome should also undergo blood sampling for fasting gut hormones, chromogranin A, calcitonin, and biochemical exclusion of pheochromocytoma.


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InternalMed_Harrison. FIGURE 406-11 Adrenal imaging in Cushing’s syndrome. A. Adrenal computed tomography (CT) showing normal bilateral adrenal morphology (arrows). B. CT scan depicting a right adrenocortical adenoma (arrow) causing Cushing’s syndrome. C. Magnetic resonance imaging (MRI) showing bilateral adrenal hyperplasia due to excess adrenocorticotropic hormone stimulation in Cushing’s disease. D. MRI showing bilateral macronodular hyperplasia causing Cushing’s syndrome. Disorders of the Adrenal Cortex Overt Cushing’s is associated with a poor prognosis if left untreated. In ACTH-independent disease, treatment consists of surgical removal of the adrenal tumor. For smaller tumors, a minimally invasive approach can be used, whereas for larger tumors and those suspected of malignancy, an open approach is preferred.


InternalMed_Harrison

InternalMed_Harrison. In Cushing’s disease, the treatment of choice is selective removal of the pituitary corticotrope tumor, usually via an endoscopic transsphenoidal approach. This results in an initial cure rate of 70–80% when performed by a highly experienced surgeon. However, even after initial remission following surgery, long-term follow-up is important because late relapse occurs in a significant number of patients. If pituitary disease recurs, there are several options, including second surgery, radiotherapy, stereotactic radiosurgery, and bilateral adrenalectomy. These options need to be applied in a highly individualized fashion.


InternalMed_Harrison

InternalMed_Harrison. In some patients with very severe, overt Cushing’s (e.g., difficult to control hypokalemic hypertension or acute psychosis), it may be necessary to introduce medical therapy to rapidly control the cortisol excess during the period leading up to surgery. Similarly, patients with metastasized, glucocorticoid-producing carcinomas may require long-term antiglucocorticoid drug treatment. In case of ectopic ACTH syndrome, in which the tumor cannot be located, one must carefully weigh whether drug treatment or bilateral adrenalectomy is the most appropriate choice, with the latter facilitating immediate cure but requiring life-long corticosteroid replacement. In this instance, it is paramount to ensure regular imaging follow-up for identification of the ectopic ACTH source.


InternalMed_Harrison

InternalMed_Harrison. Oral agents with established efficacy in Cushing’s syndrome are metyrapone and ketoconazole. Metyrapone inhibits cortisol synthesis at the level of 11β-hydroxylase (Fig. 406-1), whereas the antimycotic drug ketoconazole inhibits the early steps of steroidogenesis. Typical starting doses are 500 mg tid for metyrapone (maximum dose, 6 g) and 200 mg tid for ketoconazole (maximum dose, 1200 mg). Mitotane, a derivative of the insecticide o,p’DDD, is an adrenolytic agent that is also effective for reducing cortisol. Because of its side effect profile, it is most commonly used in the context of adrenocortical carcinoma, but low-dose treatment (500–1000 mg/d) has also been used in benign Cushing’s. In severe cases of cortisol excess, etomidate can be used to lower cortisol. It is administered by continuous IV infusion in low, nonanesthetic doses.


InternalMed_Harrison

InternalMed_Harrison. After the successful removal of an ACTHor cortisol-producing tumor, the HPA axis will remain suppressed. Thus, hydrocortisone replacement needs to be initiated at the time of surgery and slowly tapered following recovery, to allow physiologic adaptation to normal cortisol levels. Depending on degree and duration of cortisol excess, the HPA axis may require many months or even years to resume normal function. MINERALOCORTICOID EXCESS Epidemiology Following the first description of a patient with an aldosterone-producing adrenal adenoma (Conn’s syndrome), mineralocorticoid excess was thought to represent a rare cause of hypertension. However, in studies systematically screening all patients with hypertension, a much higher prevalence is now recognized, ranging from 5 to 12%. The prevalence is higher when patients are preselected for hypokalemic hypertension.


InternalMed_Harrison

InternalMed_Harrison. Etiology The most common cause of mineralocorticoid excess is primary aldosteronism, reflecting excess production of aldosterone by the adrenal zona glomerulosa. Bilateral micronodular hyperplasia is somewhat more common than unilateral adrenal adenomas (Table 406-3). Somatic mutations in channels and enzymes responsible for increasing sodium and calcium influx in adrenal zona glomerulosa cells have been identified as prevalent causes of aldosterone-producing adrenal adenomas (Table 406-3) and, in the case of germline mutations, also of primary aldosteronism due to bilateral macronodular adrenal hyperplasia. However, bilateral adrenal hyperplasia as a cause of mineralocorticoid excess is usually micronodular but can also contain larger nodules that might be mistaken for a unilateral adenoma. In rare instances, primary aldosteronism is caused by an adrenocortical carcinoma. Carcinomas should be considered in younger patients and in those with larger tumors, because benign


InternalMed_Harrison

InternalMed_Harrison. adenoma. In rare instances, primary aldosteronism is caused by an adrenocortical carcinoma. Carcinomas should be considered in younger patients and in those with larger tumors, because benign aldosterone-producing adenomas usually measure <2 cm in diameter.


InternalMed_Harrison

InternalMed_Harrison. A rare cause of aldosterone excess is glucocorticoid-remediable aldosteronism (GRA), which is caused by a chimeric gene resulting Causes of Mineralocorticoid Excess Mechanism % brane channel in open conformation for longer, enhancing mineralocorticoid action Abbreviations: ACTH, adrenocorticotropic hormone; DOC, deoxycorticosterone; ENaC, epithelial sodium channel; GR, glucocorticoid receptor; HSD11B2, 11β-hydroxysteroid dehydrogenase type 2; MR, mineralocorticoid receptor.


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InternalMed_Harrison. from cross-over of promoter sequences between the CYP11B1 and CYP11B2 genes that are involved in glucocorticoid and mineralocorticoid synthesis, respectively (Fig. 406-1). This rearrangement brings CYP11B2 transcription under the control of ACTH receptor signaling; consequently, aldosterone production is regulated by ACTH rather than by renin. The family history can be helpful because there may be evidence for dominant transmission of hypertension. Recognition of the disorder is important because it can be associated with early-onset hypertension and strokes. In addition, glucocorticoid suppression can reduce aldosterone production.


InternalMed_Harrison

InternalMed_Harrison. Other rare causes of mineralocorticoid excess are listed in Table 406-3. An important cause is excess binding and activation of the mineralocorticoid receptor by a steroid other than aldosterone. Cortisol acts as a potent mineralocorticoid if it escapes efficient inactivation to cortisone by 11β-HSD2 in the kidney (Fig. 406-7). This can be caused by inactivating mutations in the HSD11B2 gene resulting in the syndrome of apparent mineralocorticoid excess (SAME) that characteristically manifests with severe hypokalemic hypertension in childhood. However, milder mutations may cause normokalemic hypertension manifesting in adulthood (type II SAME). Inhibition of 11β-HSD2 by excess licorice ingestion also results in hypokalemic hypertension, as does overwhelming of 11β-HSD2 conversion capacity by cortisol excess in Cushing’s syndrome. Deoxycorticosterone (DOC) also binds and activates the mineralocorticoid receptor and can cause hypertension if its circulating concentrations are increased.


InternalMed_Harrison

InternalMed_Harrison. by cortisol excess in Cushing’s syndrome. Deoxycorticosterone (DOC) also binds and activates the mineralocorticoid receptor and can cause hypertension if its circulating concentrations are increased. This can arise through autonomous DOC secretion by an adrenocortical carcinoma, but also when DOC accumulates as a consequence of an adrenal enzymatic block, as seen in congenital adrenal hyperplasia due to CYP11B1 (11β-hydroxylase) or CYP17A1 (17α-hydroxylase) deficiency (Fig. 406-1). Progesterone can cause hypokalemic hypertension in rare individuals who harbor a mineralocorticoid receptor mutation that enhances binding and activation by progesterone; physiologically, progesterone normally exerts antimineralocorticoid activity. Finally, excess mineralocorticoid activity can be caused by mutations in the β or γ subunits of the ENaC, disrupting its interaction with Nedd4 (Fig. 406-7), and thereby decreasing receptor internalization and degradation. The constitutively active ENAC drives


InternalMed_Harrison

InternalMed_Harrison. in the β or γ subunits of the ENaC, disrupting its interaction with Nedd4 (Fig. 406-7), and thereby decreasing receptor internalization and degradation. The constitutively active ENAC drives hypokalemic hypertension, resulting in an autosomal dominant disorder termed Liddle’s syndrome.


InternalMed_Harrison

InternalMed_Harrison. Clinical Manifestations Excess activation of the mineralocorticoid receptor leads to potassium depletion and increased sodium retention, with the latter causing an expansion of extracellular and plasma volume. Increased ENaC activity also results in hydrogen depletion that can cause metabolic alkalosis. Aldosterone also has direct effects on the vascular system, where it increases cardiac remodeling and decreases compliance. Aldosterone excess may cause direct damage to the myocardium and the kidney glomeruli, in addition to secondary damage due to systemic hypertension.


InternalMed_Harrison

InternalMed_Harrison. The clinical hallmark of mineralocorticoid excess is hypokalemic hypertension; serum sodium tends to be normal due to the concurrent fluid retention, which in some cases can lead to peripheral edema. Hypokalemia can be exacerbated by thiazide drug treatment, which leads to increased delivery of sodium to the distal renal tubule, thereby driving potassium excretion. Severe hypokalemia can be associated with muscle weakness, overt proximal myopathy, or even hypokalemic paralysis. Severe alkalosis contributes to muscle cramps and, in severe cases, can cause tetany.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis Diagnostic screening for mineralocorticoid excess is not currently recommended for all patients with hypertension, but should be restricted to those who exhibit hypertension associated with drug resistance, hypokalemia, an adrenal mass, or onset of disease before the age of 40 years (Fig. 406-12). The accepted screening test is concurrent measurement of plasma renin and aldosterone with subsequent calculation of the aldosterone-renin ratio (ARR) (Fig. 406-12); serum potassium needs to be normalized prior to testing. Stopping antihypertensive medication can be cumbersome, particularly in patients with severe hypertension. Thus, for practical purposes, in the first instance the patient can remain on the usual antihypertensive medications, with the exception that mineralocorticoid receptor antagonists need to be ceased at least 4 weeks prior to ARR measurement. The remaining antihypertensive 2319 drugs usually do not affect the outcome of ARR testing, except that beta blocker


InternalMed_Harrison

InternalMed_Harrison. receptor antagonists need to be ceased at least 4 weeks prior to ARR measurement. The remaining antihypertensive 2319 drugs usually do not affect the outcome of ARR testing, except that beta blocker treatment can cause false-positive results and ACE/AT1R inhibitors can cause false-negative results in milder cases (Table 406-4).


InternalMed_Harrison

InternalMed_Harrison. ARR screening is positive if the ratio is >750 pmol/L per ng/mL per hour, with a concurrently high normal or increased aldosterone (Fig. 406-12). If one relies on the ARR only, the likelihood of a false-positive ARR becomes greater when renin levels are very low. The characteristics of the biochemical assays are also important. Some labs measure plasma renin activity, whereas others measure plasma renin concentrations. Antibody-based assays for the measurement of serum aldosterone lack the reliability of tandem mass spectrometry assays, but these are not yet ubiquitously available.


InternalMed_Harrison

InternalMed_Harrison. Diagnostic confirmation of mineralocorticoid excess in a patient with positive ARR screening result should be undertaken by an endocrinologist as the tests lack optimized validation. The most straightforward is the saline infusion test, which involves the IV administration of 2 L of physiologic saline over a 4-h period. Failure of aldosterone to suppress below 140 pmol/L (5 ng/dL) is indicative of autonomous mineralocorticoid excess. Alternative tests are the oral sodium loading test (300 mmol NaCl/d for 3 days) or the fludrocortisone suppression test (0.1 mg q6h with 30 mmol NaCl q8h for 4 days); the latter can be difficult because of the risk of profound hypokalemia and increased hypertension. In patients with overt hypokalemic hypertension, strongly positive ARR, and concurrently increased aldosterone levels, confirmatory testing is usually not necessary.


InternalMed_Harrison

InternalMed_Harrison. Differential Diagnosis and Treatment After the diagnosis of hyperaldosteronism is established, the next step is to use adrenal imaging to further assess the cause. Fine-cut CT scanning of the adrenal region is the method of choice because it provides excellent visualization of adrenal morphology. CT will readily identify larger tumors suspicious of malignancy but may miss lesions smaller than 5 mm. The differentiation between bilateral micronodular hyperplasia and a unilateral adenoma is only required if a surgical approach is feasible and desired. Consequently, selective adrenal vein sampling (AVS) should only be carried out in surgical candidates with either no obvious lesion on CT or evidence of a unilateral lesion in patients older than 40 years, because the latter patients have a high likelihood of harboring a coincidental, endocrine-inactive adrenal adenoma (Fig. 406-12). AVS is used to compare aldosterone levels in the inferior vena cava and between the right and left adrenal


InternalMed_Harrison

InternalMed_Harrison. likelihood of harboring a coincidental, endocrine-inactive adrenal adenoma (Fig. 406-12). AVS is used to compare aldosterone levels in the inferior vena cava and between the right and left adrenal veins. AVS requires concurrent measurement of cortisol to document correct placement of the catheter in the adrenal veins and should demonstrate a cortisol gradient >3 between the vena cava and each adrenal vein. Lateralization is confirmed by an aldosterone/cortisol ratio that is at least twofold higher on one side than the other. AVS is a complex procedure that requires a highly skilled interventional radiologist. Even then, the right adrenal vein can be difficult to cannulate correctly, which, if not achieved, invalidates the procedure. There is also no agreement as to whether the two adrenal veins should be cannulated simultaneously or successively and whether ACTH stimulation enhances the diagnostic value of AVS.


InternalMed_Harrison

InternalMed_Harrison. Patients younger than 40 years with confirmed mineralocorticoid excess and a unilateral lesion on CT can go straight to surgery, which is also indicated in patients with confirmed lateralization documented by a valid AVS procedure. Laparoscopic adrenalectomy is the preferred approach. Patients who are not surgical candidates, or with evidence of bilateral hyperplasia based on CT or AVS, should be treated medically (Fig. 406-12). Medical treatment, which can also be considered prior to surgery to avoid postsurgical hypoaldosteronism, consists primarily of the mineralocorticoid receptor antagonist spironolactone. It can be started at 12.5–50 mg bid and titrated up to a maximum of 400 mg/d to control blood pressure and normalize potassium. Side effects include menstrual irregularity, decreased libido, and gynecomastia. The more selective MR antagonist eplerenone can also be used. Doses start at 25 mg bid, and it can be titrated up to 200 mg/d. Another useful drug is the sodium channel


InternalMed_Harrison

InternalMed_Harrison. libido, and gynecomastia. The more selective MR antagonist eplerenone can also be used. Doses start at 25 mg bid, and it can be titrated up to 200 mg/d. Another useful drug is the sodium channel blocker amiloride (5–10 mg bid).


InternalMed_Harrison

InternalMed_Harrison. In patients with normal adrenal morphology and family history of early-onset, severe hypertension, a diagnosis of GRA should be Disorders of the Adrenal Cortex Clinical suspicion of mineralocorticoid excess Patients with hypertension and Severe hypertension (>3 BP drugs, drug-resistant) or Family history of early-onset hypertension or cerebrovascular events at < 40 years of age Measurement of aldosterone-renin ratio (ARR) on current blood pressure medication (stop spironolactone for 4 wks) and with hypokalemia corrected (ARR screen positive if ARR >750 pmol/L: ng/ml/h and aldosterone >450 pmol/L) (consider repeat off ˜-blockers for 2 wks if results are equivocal) Negative E.g., saline infusion test (2 liters physiologic saline over 4 h IV), oral sodium loading, fludrocortisone suppression Confirmation of diagnosis Rare: Both renin and Aldo suppressed


InternalMed_Harrison

InternalMed_Harrison. Unilateral adrenalectomy Drug treatment (MR antagonists, amiloride) Dexamethasone 0.125-0.5 mg/d Adrenal vein sampling Bilateral micronodular hyperplasia Normal adrenal morphology 24-h urinary steroid profile (GC/MS) Diagnostic for • Apparent mineralocorti-coid excess (HSD11B2 def.) • CAH (CYP11B1 or CYP17A1 def.) • Adrenal tumor-related desoxycorticosterone excess If negative, consider • Liddle’s syndrome (ENaC mutations) (responsive to amiloride trial) Family history of early onset hypertension? Screen for glucocorticoid-remediable aldosteronism Unenhanced CT adrenals Age <40 years Age >40 years (if surgery practical and desired) Pos. Pos. Neg. Neg. Unilateral adrenal mass* FIGURE 406-12 Management of patients with suspected mineralocorticoid excess. *Perform adrenal tumor workup (see Fig. 406-13). BP, blood pressure; CAH, congenital adrenal hyperplasia; CT, computed tomography; GC/MS, gas chromatography/mass spectrometry; PRA, plasma renin activity.


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InternalMed_Harrison. considered and can be evaluated using genetic testing. Treatment of GRA consists of administering dexamethasone, using the lowest dose possible to control blood pressure. Some patients also require additional MR antagonist treatment.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of nonaldosterone-related mineralocorticoid excess is based on documentation of suppressed renin and suppressed aldo-Effect on Effect on Net Effect sterone in the presence of hypokalemic hypertension. This testing is best carried out by employing urinary steroid metabolite profiling by β Blockers ↓↑ ↑ gas chromatography/mass spectrometry (GC/MS). An increased free α1 Blockers →→ → cortisol over free cortisone ratio is suggestive of SAME and can be treated with dexamethasone. Steroid profiling by GC/MS also detects the steroids associated with CYP11B1 and CYP17A1 deficiency or the carcinoma (Fig. 406-12). If the GC/MS profile is normal, then Liddle’s syndrome should be considered. It is very sensitive to amiloride treat-Diuretics (↑)(↑) →/(↓) ment but will not respond to MR antagonist treatment, because the Abbreviations: ACE, angiotensin-converting enzyme; AT1R, angiotensin II receptor type 1. defect is due to a constitutively active ENaC.


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InternalMed_Harrison. APPROACH TO THE PATIENT: INCIDENTALLY DISCOVERED ADRENAL MASS Epidemiology Incidentally discovered adrenal masses, commonly termed adrenal “incidentalomas,” are common, with a prevalence of at least 2% in the general population as documented in CT and autopsy series. The prevalence increases with age, with 1% of 40-year-olds and 7% of 70-year-olds harboring an adrenal mass. Etiology Most solitary adrenal tumors are monoclonal neoplasms. Several genetic syndromes, including MEN 1 (MEN1), MEN 2 (RET), Carney’s complex (PRKAR1A), and McCune-Albright (GNAS1), can have adrenal tumors as one of their features. Somatic mutations in MEN1, GNAS1, and PRKAR1A have been identified in a small proportion of sporadic adrenocortical adenomas. Aberrant expression of membrane receptors (gastric inhibitory peptide, αand β-adrenergic, luteinizing hormone, vasopressin V1, and interleukin 1 receptors) have been identified in some sporadic cases of macronodular adrenocortical hyperplasia.


InternalMed_Harrison

InternalMed_Harrison. The majority of adrenal nodules are endocrine-inactive adrenocortical adenomas. However, larger series suggest that up to 25% of adrenal nodules are hormonally active, due to a cortisolor aldosteroneproducing adrenocortical adenoma or a pheochromocytoma associated with catecholamine excess (Table 406-5). Adrenocortical carcinoma is rare but is the cause of an adrenal mass in 5% of patients. However, the most common cause of a malignant adrenal mass is metastasis originating from another solid tissue tumor (Table 406-5). Differential Diagnosis and Treatment Patients with an adrenal mass >1 cm require a diagnostic evaluation. Two key questions need to be addressed: (1) Does the tumor autonomously secrete hormones that could have a detrimental effect on health? (2) Is the adrenal mass benign or malignant?


InternalMed_Harrison

InternalMed_Harrison. Hormone secretion by an adrenal mass occurs along a continuum, with a gradual increase in clinical manifestations in parallel with hormone levels. Exclusion of catecholamine excess from a pheochromocytoma arising from the adrenal medulla is a mandatory part of the diagnostic workup (Fig. 406-13). Furthermore, autonomous cortisol and aldosterone secretion resulting in Cushing’s syndrome or primary Aldosterone-producing 2–5 Pheochromocytoma 5–10 Adrenal myelolipoma <1 Adrenal ganglioneuroma <0.1 Adrenal hemangioma <0.1 Adrenal cyst <1 Adrenal hematoma/hemorrhagic <1 Note: Bilateral adrenal enlargement/masses may be caused by congenital adrenal hyperplasia, bilateral macronodular hyperplasia, bilateral hemorrhage (due to antiphospholipid syndrome or sepsis-associated Waterhouse-Friderichsen syndrome), granuloma, amyloidosis, or infiltrative disease including tuberculosis.


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InternalMed_Harrison. aldosteronism, respectively, require exclusion. Adrenal incidentalomas 2321 can be associated with lower levels of autonomous cortisol secretion, and patients may lack overt clinical features of Cushing’s syndrome. Nonetheless, they may exhibit one or more components of the metabolic syndrome (e.g., obesity, type 2 diabetes, or hypertension). There is ongoing debate about the optimal treatment for these patients with mild or subclinical Cushing’s syndrome. Overproduction of adrenal androgen precursors, DHEA and its sulfate, is rare and most frequently seen in the context of adrenocortical carcinoma, as are increased levels of steroid precursors such as 17-hydroxyprogesterone.


InternalMed_Harrison

InternalMed_Harrison. For the differentiation of benign from malignant adrenal masses, imaging is relatively sensitive, although specificity is suboptimal. CT is the procedure of choice for imaging the adrenal glands (Fig. 406-11). The risk of adrenocortical carcinoma, pheochromocytoma, and benign adrenal myelolipoma increases with the diameter of the adrenal mass. However, size alone is of poor predictive value, with only 80% sensitivity and 60% specificity for the differentiation of benign from malignant masses when using a 4-cm cut-off. Metastases are found with similar frequency in adrenal masses of all sizes. Tumor density on unenhanced CT is of additional diagnostic value, with most adrenocortical adenomas being lipid rich and thus presenting with low attenuation values (i.e., densities of <10 HU). By contrast, adrenocortical carcinomas, but also pheochromocytomas, usually have high attenuation values (i.e., densities >20 HU on precontrast scans). Generally, benign lesions are rounded and homogenous,


InternalMed_Harrison

InternalMed_Harrison. adrenocortical carcinomas, but also pheochromocytomas, usually have high attenuation values (i.e., densities >20 HU on precontrast scans). Generally, benign lesions are rounded and homogenous, whereas most malignant lesions appear lobulated and inhomogeneous. Pheochromocytoma and adrenomyelolipoma may also exhibit lobulated and inhomogeneous features.


InternalMed_Harrison

InternalMed_Harrison. Additional information can be obtained from CT by assessment of contrast wash-out after 15 min, which is >50% in benign lesions but <40% in malignant lesions, which usually have a more extensive vascularization. MRI also allows for the visualization of the adrenal glands with somewhat lower resolution than CT. However, because it does not involve exposure to ionizing radiation, it is preferred in children, young adults, and during pregnancy. MRI has a valuable role in the characterization of indeterminate adrenal lesions using chemical shift analysis, with malignant tumors rarely showing loss of signal on opposed-phase MRI.


InternalMed_Harrison

InternalMed_Harrison. Fine-needle aspiration (FNA) or CT-guided biopsy of an adrenal mass is almost never indicated. FNA of a pheochromocytoma can cause a life-threatening hypertensive crisis. FNA of an adrenocortical carcinoma violates the tumor capsule and can cause needle track metastasis. FNA should only be considered in a patient with a history of nonadrenal malignancy and a newly detected adrenal mass, after careful exclusion of pheochromocytoma, and if the outcome will influence therapeutic management. It is important to recognize that in 25% of patients with a previous history of nonadrenal malignancy, a newly detected mass on CT is not a metastasis.


InternalMed_Harrison

InternalMed_Harrison. Adrenal masses associated with confirmed hormone excess or suspected malignancy are usually treated surgically (Fig. 406-13) or, if adrenalectomy is not feasible or desired, with medication. Preoperative exclusion of glucocorticoid excess is particularly important for the prediction of postoperative suppression of the contralateral adrenal gland, which requires glucocorticoid replacement periand postoperatively. If the initial decision is for observation, imaging and biochemical testing should be repeated about a year after the first assessment. However, this may be performed earlier in patients with borderline imaging or hormonal findings. There is no agreement with regard to the required long-term follow-up beyond 1 year in patients with normal biochemistry and no evidence of increased tumor size at follow-up.


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InternalMed_Harrison. Adrenocortical carcinoma (ACC) is a rare malignancy with an annual incidence of 1–2 per million population. ACC is generally considered a highly malignant tumor; however, it presents with broad interindividual variability with regard to biologic characteristics and clinical behavior. Somatic mutations in the tumor-suppressor gene TP53 are found in 25% of apparently sporadic ACC. Germline TP53 mutations are the cause of the Li-Fraumeni syndrome associated with multiple solid organ cancers including ACC and are found in 25% of pediatric Disorders of the Adrenal Cortex 24-h urine for free cortisol excretion, plasma ACTH, midnight plasma (or salivary) cortisol, dexamethasone 1 mg overnight test (perform at least two out of four tests) If tumor >2 cm: Serum 17-hydroxyprogesterone and DHEAS imaging suggestive of malignancy: • Size >4 cm Negative and imaging not suggestive of malignancy: Neg. Pos. Neg. Pos.


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InternalMed_Harrison. If tumor >2 cm: Serum 17-hydroxyprogesterone and DHEAS imaging suggestive of malignancy: • Size >4 cm Negative and imaging not suggestive of malignancy: Neg. Pos. Neg. Pos. FIGURE 406-13 Management of the patient with an incidentally discovered adrenal mass. CT, computed tomography; F/U, follow-up; MRI, Neg. magnetic resonance imaging. ACC cases; the TP53 mutation R337H is found in almost all pediatric ACC in Brazil. Other genetic changes identified in ACC include alterations in the Wnt/β-catenin pathway and in the insulin-like growth factor 2 (IGF2) cluster; IGF2 overexpression is found in 90% of ACC.


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InternalMed_Harrison. Patients with large adrenal tumors suspicious of malignancy should be managed by a multidisciplinary specialist team, including an endocrinologist, an oncologist, a surgeon, a radiologist, and a histopathologist. FNA is not indicated in suspected ACC: first, cytology and also histopathology of a core biopsy cannot differentiate between benign and malignant primary adrenal masses; second, FNA violates the tumor capsule and may even cause needle canal metastasis. Even when the entire tumor specimen is available, the histopathologic differentiation between benign and malignant lesions is a diagnostic challenge. The most common histopathologic classification is the Weiss score, taking into account high nuclear grade; mitotic rate (>5/HPF); atypical mitosis; <25% clear cells; diffuse architecture; and presence of necrosis, venous invasion, and invasion of sinusoidal structures and tumor capsule. The presence of three or more elements suggests ACC.


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InternalMed_Harrison. Although 60–70% of ACCs show biochemical evidence of steroid overproduction, in many patients, this is not clinically apparent due to the relatively inefficient steroid production by the adrenocortical cancer cells. Excess production of glucocorticoids and adrenal androgen precursors are most common. Mixed excess production of several corticosteroid classes by an adrenal tumor is generally indicative of malignancy.


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InternalMed_Harrison. Tumor staging at diagnosis (Table 406-6) has important prognostic implications and requires scanning of the chest and abdomen for local organ invasion, lymphadenopathy, and metastases. Intravenous contrast medium is necessary for maximum sensitivity for hepatic metastases. An adrenal origin may be difficult to determine on standard axial CT imaging if the tumors are large and invasive, but CT reconstructions and MRI are more informative (Fig. 406-14) using multiple planes and different sequences. Vascular and adjacent organ invasion is diagnostic of malignancy. 18-Fluoro-2-deoxy-D-glucose positron emission tomography (18-FDG PET) is highly sensitive for the detection of malignancy and can be used to detect small metastases or local recurrence that may not be obvious on CT (Fig. 406-14). However, FDG PET is not specific and therefore cannot be used for differentiating benign from malignant adrenal lesions. Metastasis in ACC most frequently occurs to liver and lung.


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InternalMed_Harrison. There is no established grading system for ACC, and the Weiss score carries no prognostic value; the most important prognostic histopathologic parameter is the Ki67 proliferation index, with Ki67 <10% indicative of slow to moderate growth velocity, whereas a Ki67 ≥10% is associated with poor prognosis including high risk of recurrence and rapid progression.


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InternalMed_Harrison. Cure of ACC can only be achieved by early detection and complete surgical removal. Capsule violation during primary surgery, metastasis at diagnosis, and primary treatment in a nonspecialist center are major determinants of poor survival. If the primary tumor invades adjacent organs, en bloc removal of kidney and spleen should be considered to reduce the risk of recurrence. Surgery can also be considered in a patient with metastases if there is severe tumor-related hormone excess. This indication needs to be carefully weighed against surgical risk, including thromboembolic complications, and the resulting delay in the introduction of other therapeutic options. Patients with confirmed ACC and successful removal of the primary tumor should receive adjuvant treatment with mitotane (o,p’DDD), particularly in patients with a high risk of recurrence as determined by tumor size >8 cm, histopathologic signs of vascular invasion, capsule invasion or violation, and a Ki67 proliferation index


InternalMed_Harrison

InternalMed_Harrison. particularly in patients with a high risk of recurrence as determined by tumor size >8 cm, histopathologic signs of vascular invasion, capsule invasion or violation, and a Ki67 proliferation index ≥10%. Adjuvant mitotane should be continued for at least 2 years, if the patient can tolerate side effects. Regular monitoring of plasma mitotane levels is mandatory (therapeutic range 14–20 mg/L; neurotoxic complications more frequent at >20 mg/L). Mitotane is usually started at 500 mg tid, with stepwise increases to a maximum dose of 2000 mg tid


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: ENSAT, European Network for the Study of Adrenal Tumors; TNM, tumor, node, metastasis.


InternalMed_Harrison

InternalMed_Harrison. in days (high-dose saturation) or weeks (low-dose saturation) as tolerated. Once therapeutic range plasma mitotane levels are achieved, the dose can be tapered to maintenance doses mostly ranging from 1000 to 1500 mg tid. Mitotane treatment results in disruption of cortisol synthesis and thus requires glucocorticoid replacement; glucocorticoid replacement dose should be at least double of that usually used in adrenal insufficiency (i.e., 20 mg tid) because mitotane induces hepatic CYP3A4 activity resulting in rapid inactivation of glucocorticoids. Mitotane also increases circulating CBG, thereby decreasing the available free cortisol fraction. Single metastases can be addressed surgically or with radiofrequency ablation as appropriate. If the tumor recurs or progresses during mitotane treatment, chemotherapy should be considered; the established first-line chemotherapy regimen is the combination of cisplatin, etoposide, and doxorubicin plus continuing mitotane. Painful bone metastasis


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InternalMed_Harrison. chemotherapy should be considered; the established first-line chemotherapy regimen is the combination of cisplatin, etoposide, and doxorubicin plus continuing mitotane. Painful bone metastasis responds to irradiation. Overall survival in ACC is still poor, with 5-year survival rates of 30–40% and a median survival of 15 months in metastatic ACC.


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InternalMed_Harrison. ADRENAL INSUFFICIENCY Epidemiology The prevalence of well-documented, permanent adrenal insufficiency is 5 in 10,000 in the general population. Hypothalamic-pituitary origin of disease is most frequent, with a prevalence of 3 in 10,000, whereas primary adrenal insufficiency has a prevalence of 2 in 2323 10,000. Approximately one-half of the latter cases are acquired, mostly caused by autoimmune destruction of the adrenal glands; the other one-half are genetic, most commonly caused by distinct enzymatic blocks in adrenal steroidogenesis affecting glucocorticoid synthesis (i.e., congenital adrenal hyperplasia.) Adrenal insufficiency arising from suppression of the HPA axis as a consequence of exogenous glucocorticoid treatment is much more common, occurring in 0.5–2% of the population in developed countries.


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InternalMed_Harrison. Etiology Primary adrenal insufficiency is most commonly caused by autoimmune adrenalitis. Isolated autoimmune adrenalitis accounts for 30–40%, whereas 60–70% develop adrenal insufficiency as part of autoimmune polyglandular syndromes (APS) (Chap. 408) (Table 406-7). APS1, also termed APECED (autoimmune polyendocrinopathy-candidiasisectodermal dystrophy), is the underlying cause in 10% of patients affected by APS. APS1 is transmitted in an autosomal recessive manner and is caused by mutations in the autoimmune regulator gene AIRE. Associated autoimmune conditions overlap with those seen in APS2, but may also include total alopecia, primary hypoparathyroidism, and, in rare cases, lymphoma. APS1 patients invariably develop chronic mucocutaneous candidiasis, usually manifest in childhood, and preceding adrenal insufficiency by years or decades. The much more prevalent APS2 is of polygenic inheritance, with confirmed associations with the HLA-DR3 gene region in the major histocompatibility


InternalMed_Harrison

InternalMed_Harrison. preceding adrenal insufficiency by years or decades. The much more prevalent APS2 is of polygenic inheritance, with confirmed associations with the HLA-DR3 gene region in the major histocompatibility complex and distinct gene regions involved in immune regulation (CTLA-4, PTPN22, CLEC16A). Coincident autoimmune disease most frequently includes thyroid autoimmune disease, vitiligo, and premature ovarian failure. Less commonly, additional features may include type 1 diabetes and pernicious anemia caused by vitamin B12 deficiency.


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InternalMed_Harrison. X-linked adrenoleukodystrophy has an incidence of 1:20,000 males and is caused by mutations in the X-ALD gene encoding the peroxisomal membrane transporter protein ABCD1; its disruption results in accumulation of very long chain (>24 carbon atoms) fatty acids. Approximately 50% of cases manifest in early childhood with rapidly progressive white matter disease (cerebral ALD); 35% present during adolescence or in early adulthood with neurologic features indicative of myelin and peripheral nervous system involvement (adrenomyeloneuropathy [AMN]). In the remaining 15%, adrenal insufficiency is the sole manifestation of disease. Of note, distinct mutations manifest with variable penetrance and phenotypes within affected families. Rarer causes of adrenal insufficiency involve destruction of the adrenal glands as a consequence of infection, hemorrhage, or infiltration


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InternalMed_Harrison. Rarer causes of adrenal insufficiency involve destruction of the adrenal glands as a consequence of infection, hemorrhage, or infiltration FIGURE 406-14 Imaging in adrenocortical carcinoma. Magnetic resonance imaging scan with (A) frontal and (B) lateral views of a right adrenocortical carcinoma that was detected incidentally. Computed tomography (CT) scan with (C) coronal and (D) transverse views depicting a right-sided adrenocortical carcinoma. Note the irregular border and inhomogeneous structure. CT scan (E) and positron emission tomography/ CT (F) visualizing a peritoneal metastasis of an adrenocortical carcinoma in close proximity to the right kidney (arrow). Disorders of the Adrenal Cortex Abbreviations: AIRE, autoimmune regulator; CMV, cytomegalovirus; DSD, disordered sex development; MC2R, ACTH receptor; MCM4, mini chromosome maintenance-deficient 4 homologue; MRAP, MC2R-accessory protein; NNT, nicotinamide nucleotide transhydrogenase.


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InternalMed_Harrison. (Table 406-7); tuberculous adrenalitis is still a frequent cause of disease in developing countries. Adrenal metastases rarely cause adrenal insufficiency, and this occurs only with bilateral, bulky metastases. Inborn causes of primary adrenal insufficiency other than congenital adrenal hyperplasia are rare, causing less than 1% of cases. However, their elucidation provides important insights into adrenal gland development and physiology. Mutations causing primary adrenal insufficiency (Table 406-7) include factors regulating adrenal development and steroidogenesis (DAX-1, SF-1), cholesterol synthesis, import and cleavage (DHCR7, StAR, CYP11A1), and elements of the adrenal ACTH response pathway (MC2R, MRAP) (Fig. 406-5), and factors involved in redox regulation (NNT) and DNA repair (MCM4, CDKN1C).


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InternalMed_Harrison. Secondary adrenal insufficiency is the consequence of dysfunction of the hypothalamic-pituitary component of the HPA axis (Table 406-8). Excluding iatrogenic suppression, the overwhelming majority of cases are caused by pituitary or hypothalamic tumors or their treatment by surgery or irradiation (Chap. 403). Rarer causes include pituitary apoplexy, either as a consequence of an infarcted pituitary adenoma or transient reduction in the blood supply of the pituitary during surgery or after rapid blood loss associated with parturition, also termed Sheehan’s syndrome. Isolated ACTH deficiency is rarely caused by autoimmune disease or pituitary infiltration (Table 406-8). Mutations in the ACTH precursor POMC or in factors regulating pituitary development are genetic causes of ACTH deficiency (Table 406-8).


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InternalMed_Harrison. Clinical Manifestations In principle, the clinical features of primary adrenal insufficiency (Addison’s disease) are characterized by the loss of both glucocorticoid and mineralocorticoid secretion (Table 406-9). In secondary adrenal insufficiency, only glucocorticoid deficiency is present, as the adrenal itself is intact and thus still amenable to regulation by the RAA system. Adrenal androgen secretion is disrupted in both primary and secondary adrenal insufficiency (Table 406-9). Hypothalamic-pituitary disease can lead to additional clinical manifestations due to involvement of other endocrine axes (thyroid, gonads, growth hormone, prolactin) or visual impairment with bitemporal hemianopia caused by chiasmal compression. It is important to recognize that iatrogenic adrenal insufficiency caused by exogenous glucocorticoid suppression of the HPA axis may result in all symptoms associated with glucocorticoid deficiency (Table 406-9), if exogenous glucocorticoids are stopped abruptly.


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InternalMed_Harrison. caused by exogenous glucocorticoid suppression of the HPA axis may result in all symptoms associated with glucocorticoid deficiency (Table 406-9), if exogenous glucocorticoids are stopped abruptly. However, patients will appear clinically cushingoid as a result of the preceding overexposure to glucocorticoids.


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InternalMed_Harrison. Chronic adrenal insufficiency manifests with relatively nonspecific signs and symptoms such as fatigue and loss of energy, often resulting in delayed or missed diagnoses (e.g., as depression or anorexia). A distinguishing feature of primary adrenal insufficiency is hyperpigmentation, which is caused by excess ACTH stimulation of melanocytes. Hyperpigmentation is most pronounced in skin areas exposed to increased friction or shear stress and is increased by sunlight (Fig. 406-15). Conversely, in secondary adrenal insufficiency, the skin has an alabaster-like paleness due to lack of ACTH secretion.


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InternalMed_Harrison. Hyponatremia is a characteristic biochemical feature in primary adrenal insufficiency and is found in 80% of patients at presentation. Hyperkalemia is present in 40% of patients at initial diagnosis. Hyponatremia is primarily caused by mineralocorticoid deficiency but can also occur in secondary adrenal insufficiency due to diminished inhibition of antidiuretic hormone (ADH) release by cortisol, resulting in mild syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Glucocorticoid deficiency also results in slightly increased TSH concentrations that normalize within days to weeks after initiation of glucocorticoid replacement.


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InternalMed_Harrison. Acute adrenal insufficiency usually occurs after a prolonged period of nonspecific complaints and is more frequently observed in patients with primary adrenal insufficiency, due to the loss of both glucocorticoid and mineralocorticoid secretion. Postural hypotension may progress to hypovolemic shock. Adrenal insufficiency may mimic features of acute abdomen with abdominal tenderness, nausea, vomiting, and fever. In some cases, the primary presentation may resemble neurologic disease, with decreased responsiveness, progressing to stupor and coma. An adrenal crisis can be triggered by an intercurrent illness, surgical or other stress, or increased glucocorticoid inactivation (e.g., hyperthyroidism). Abbreviations: ACTH, adrenocorticotropic hormone; GH, growth hormone; LH/FSH, luteinizing hormone/follicle-stimulating hormone; PRL, prolactin; TSH, thyroid-stimulating hormone.


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InternalMed_Harrison. Diagnosis The diagnosis of adrenal insufficiency is established by the short cosyntropin test, a safe and reliable tool with excellent predictive diagnostic value (Fig. 406-16). The cut-off for failure is usually defined at cortisol levels of <500–550 nmol/L (18–20 μg/dL) sampled 30–60 min after ACTH stimulation; the exact cut-off is dependent on the locally available assay. During the early phase of HPA disruption (e.g., within 4 weeks of pituitary insufficiency), patients may still respond to exogenous ACTH stimulation. In this circumstance, the ITT is an alternative choice but is more invasive and should be carried out only under a specialist’s supervision (see above). Induction of hypoglycemia is contraindicated in individuals with diabetes mellitus, cardiovascular disease, or history of seizures. Random serum cortisol measurements are of limited diagnostic value, because baseline cortisol levels may be coincidentally low due to the physiologic diurnal rhythm of cortisol secretion


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InternalMed_Harrison. of seizures. Random serum cortisol measurements are of limited diagnostic value, because baseline cortisol levels may be coincidentally low due to the physiologic diurnal rhythm of cortisol secretion (Fig. 406-3). Similarly, many patients with secondary adrenal insufficiency have relatively normal baseline cortisol levels but fail to mount an appropriate cortisol response to ACTH, which can only be revealed by stimulation testing. Importantly, tests to establish the diagnosis of adrenal insufficiency should never delay treatment. Thus, in a patient with suspected adrenal crisis, it is reasonable to draw baseline cortisol levels, provide replacement therapy, and defer formal stimulation testing until a later time.


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InternalMed_Harrison. TB>Fatigue, lack of energy Weight loss, anorexia Myalgia, joint pain Fever Normochromic anemia, lymphocytosis, eosinophilia Slightly increased TSH (due to loss of feedback inhibition of TSH release) Hypoglycemia (more frequent in children) Low blood pressure, postural hypotension Hyponatremia (due to loss of feedback inhibition of AVP release) Abdominal pain, nausea, vomiting Dizziness, postural hypotension Salt craving Low blood pressure, postural hypotension Increased serum creatinine (due to volume depletion) Hyponatremia Hyperkalemia Lack of energy Dry and itchy skin (in women) Loss of libido (in women) Loss of axillary and pubic hair (in women) Hyperpigmentation (primary adrenal insufficiency only) (due to excess of proopiomelanocortin [POMC]-derived peptides) Alabaster-colored pale skin (secondary adrenal insufficiency only) (due to deficiency of POMC-derived peptides) Abbreviations: AVP, arginine vasopressin; TSH, thyroid-stimulating hormone.


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InternalMed_Harrison. Once adrenal insufficiency is confirmed, measurement of plasma ACTH is the next step, with increased or inappropriately low levels defining primary and secondary origin of disease, respectively (Fig. 406-16). In primary adrenal insufficiency, increased plasma renin will confirm the presence of mineralocorticoid deficiency. At initial presentation, patients with primary adrenal insufficiency should undergo screening for steroid autoantibodies as a marker of autoimmune adrenalitis. If these tests are negative, adrenal imaging by CT is indicated to investigate possible hemorrhage, infiltration, or masses. In male patients with negative autoantibodies in the plasma, verylong-chain fatty acids should be measured to exclude X-ALD. Patients with inappropriately low ACTH, in the presence of confirmed cortisol deficiency, should undergo hypothalamic-pituitary imaging by MRI. Features suggestive of preceding pituitary apoplexy, such as sudden-onset severe headache or history of previous head


InternalMed_Harrison

InternalMed_Harrison. cortisol deficiency, should undergo hypothalamic-pituitary imaging by MRI. Features suggestive of preceding pituitary apoplexy, such as sudden-onset severe headache or history of previous head trauma, should be carefully explored, particularly in patients with no obvious MRI lesion.


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InternalMed_Harrison. Acute adrenal insufficiency requires immediate initiation of rehydration, usually carried out by saline infusion at initial rates of 1 L/h with continuous cardiac monitoring. Glucocorticoid replacement should be initiated by bolus injection of 100 mg hydrocortisone, followed by the administration of 100–200 mg hydrocortisone over 24 h, either by continuous infusion or by bolus IV or IM injections. Mineralocorticoid replacement can be initiated once the daily hydrocortisone dose has been reduced to <50 mg because at higher doses hydrocortisone provides sufficient stimulation of mineralocorticoid receptors. Glucocorticoid replacement for the treatment of chronic adrenal insufficiency should be administered at a dose that replaces the physiologic daily cortisol production, which is usually achieved by Disorders of the Adrenal Cortex


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InternalMed_Harrison. Disorders of the Adrenal Cortex FIGURE 406-15 Clinical features of Addison’s disease. Note the hyperpigmentation in areas of increased friction including (A) palmar creases, (B) dorsal foot, (C) nipples and axillary region, and (D) patchy hyperpigmentation of the oral mucosa.


InternalMed_Harrison

InternalMed_Harrison. the oral administration of 15–25 mg hydrocortisone in two to three divided doses. Pregnancy may require an increase in hydrocortisone dose by 50% during the last trimester. In all patients, at least one-half of the daily dose should be administered in the morning. Currently available glucocorticoid preparations fail to mimic the physiologic cortisol secretion rhythm (Fig. 406-3). Long-acting glucocorticoids such as prednisolone or dexamethasone are not preferred because they result in increased glucocorticoid exposure due to extended glucocorticoid receptor activation at times of physiologically low cortisol secretion. There are no well-established dose equivalencies, but as a guide, equipotency can be assumed for 1 mg hydrocortisone, 1.6 mg cortisone acetate, 0.2 mg prednisolone, 0.25 mg prednisone, and 0.025 mg dexamethasone.


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InternalMed_Harrison. Monitoring of glucocorticoid replacement is mainly based on the history and examination for signs and symptoms suggestive of glucocorticoid overor underreplacement, including assessment of body weight and blood pressure. Plasma ACTH, 24-h urinary free cortisol, or serum cortisol day curves reflect whether hydrocortisone has been taken or not, but do not convey reliable information about replacement quality. In patients with isolated primary adrenal insufficiency, monitoring should include screening for autoimmune thyroid disease, and female patients should be made aware of the possibility of premature ovarian failure. Supraphysiologic glucocorticoid treatment with doses equivalent to 30 mg hydrocortisone or more will affect bone metabolism, and these patients should undergo regular bone mineral density evaluation. All patients with adrenal insufficiency need to be instructed about the requirement for stress-related glucocorticoid dose adjustments. These generally consist of doubling


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InternalMed_Harrison. mineral density evaluation. All patients with adrenal insufficiency need to be instructed about the requirement for stress-related glucocorticoid dose adjustments. These generally consist of doubling the routine oral glucocorticoid dose in the case of intercurrent illness with fever and bed rest and the need for IV hydrocortisone injection at a daily dose of 100 mg in cases of prolonged vomiting, surgery, or trauma. Patients living or traveling in regions with delayed access to acute health care should carry a hydrocortisone self-injection emergency kit, in addition to their usual steroid emergency cards and bracelets.


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InternalMed_Harrison. Mineralocorticoid replacement in primary adrenal insufficiency should be initiated at a dose of 100–150 μg fludrocortisone. The adequacy of treatment can be evaluated by measuring blood pressure, sitting and standing, to detect a postural drop indicative of hypovolemia. In addition, serum sodium, potassium, and plasma renin should be measured regularly. Renin levels should be kept in the upper normal reference range. Changes in glucocorticoid dose may also impact on mineralocorticoid replacement as cortisol also binds the mineralocorticoid receptor; 40 mg hydrocortisone is equivalent to 100 μg fludrocortisone. In patients living or traveling in areas with hot or tropical weather conditions, the fludrocortisone dose should be increased by 50–100 μg during the summer. Mineralocorticoid dose may also need to be adjusted during pregnancy, due to the antimineralocorticoid activity of progesterone, but this is less often required than hydrocortisone dose adjustment.


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InternalMed_Harrison. Clinical suspicion of adrenal insufficiency (weight loss, fatigue, postural hypotension, hyperpigmentation, hyponatremia) Screening/confirmation of diagnosis CBC, serum sodium, potassium, creatinine, urea, TSH Differential diagnosis Plasma ACTH, plasma renin, serum aldosterone


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InternalMed_Harrison. Negative Adrenal autoantibodies • Autoimmune adrenalitis; • Autoimmune polyglandular syndrome (APS) Hypothalamic-pituitary mass lesion • History of exogenous glucocorticoid treatment? • History of head trauma? • Consider isolated ACTHdeficiency MRI Pituitary Secondary adrenal insufficiency (Low-normal ACTH, normal renin, normal aldosterone ) Primary adrenal insufficiency (High ACTH, high renin, low aldosterone) Glucocorticoid + mineralocorticoid replacement Glucocorticoid replacement Positive Positive Negative Positive Negative • Adrenal infection (tuberculosis), • Infiltration (e.g., lymphoma) • Hemorrhage;• Congenital adrenal hyperplasia (17OHP˜) • Autoimmune adrenalitis most likely diagnosis; • In men, consideradrenoleukodystrophy (VLCFA˜) • Chest x-ray • Serum 17OHP • In men: plasma very long chain fatty acids (VLCFA) • Adrenal CTFIGURE 406-16 Management of the patient with suspected adrenal insufficiency. ACTH, adrenocorticotropic hormone; CBC, complete blood count; MRI, magnetic


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InternalMed_Harrison. long chain fatty acids (VLCFA) • Adrenal CTFIGURE 406-16 Management of the patient with suspected adrenal insufficiency. ACTH, adrenocorticotropic hormone; CBC, complete blood count; MRI, magnetic resonance imaging; PRA, plasma renin activity; TSH, thyroid-stimulating hormone.


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InternalMed_Harrison. Plasma renin cannot serve as a monitoring tool during pregnancy, because renin rises physiologically during gestation. Adrenal androgen replacement is an option in patients with lack of energy, despite optimized glucocorticoid and mineralocorticoid replacement. It may also be indicated in women with features of androgen deficiency, including loss of libido. Adrenal androgen replacement can be achieved by once-daily administration of 25–50 mg DHEA. Treatment is monitored by measurement of DHEAS, androstenedione, testosterone, and sex hormone–binding globulin (SHBG) 24 h after the last DHEA dose.


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InternalMed_Harrison. (See also Chap. 410) Congenital adrenal hyperplasia (CAH) is caused by mutations in genes encoding steroidogenic enzymes involved in glucocorticoid synthesis (CYP21A2, CYP17A1, HSD3B2, CYP11B1) or in the cofactor enzyme P450 oxidoreductase that serves as an electron donor to CYP21A2 and CYP17A1 (Fig. 406-1). Invariably, patients affected by CAH exhibit glucocorticoid deficiency. Depending on the Disorders of the Adrenal Cortex exact step of enzymatic block, they may also have excess production of mineralocorticoids or deficient production of sex steroids (Table 406-10). The diagnosis of CAH is readily established by measurement of the steroids accumulating before the distinct enzymatic block, either in serum or in urine, preferably by the use of mass spectrometry–based assays (Table 406-10).


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InternalMed_Harrison. Mutations in CYP21A2 are the most prevalent cause of CAH, responsible for 90–95% of cases. 21-Hydroxylase deficiency disrupts glucocorticoid and mineralocorticoid synthesis (Fig. 406-1), resulting in diminished negative feedback via the HPA axis. This leads to increased pituitary ACTH release, which drives increased synthesis of adrenal androgen precursors and subsequent androgen excess. The degree of impairment of glucocorticoid and mineralocorticoid secretion depends on the severity of mutations. Major loss-of-function mutations result in combined glucocorticoid and mineralocorticoid deficiency (classic CAH, neonatal presentation), whereas less severe mutations affect glucocorticoid synthesis only (simple virilizing CAH, neonatal or early childhood presentation). The mildest mutations result in the least severe clinical phenotype, nonclassic CAH, usually presenting during adolescence and early adulthood and with preserved glucocorticoid production.


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InternalMed_Harrison. Androgen excess is present in all patients and manifests with broad phenotypic variability, ranging from severe virilization of the external genitalia in neonatal girls (e.g., 46,XX disordered sex development [DSD]) to hirsutism and oligomenorrhea resembling a polycystic ovary syndrome phenotype in young women with nonclassic CAH. In countries without neonatal screening for CAH, boys with classic CAH usually present with life-threatening adrenal crisis in the first few weeks of life (salt-wasting crisis); a simple-virilizing genotype manifests with precocious pseudo-puberty and advanced bone age in early childhood, whereas men with nonclassic CAH are usually detected only through family screening.


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InternalMed_Harrison. Glucocorticoid treatment is more complex than for other causes of primary adrenal insufficiency as it not only needed to replace missing glucocorticoids but also to control the increased ACTH drive and subsequent androgen excess. Current treatment is hampered by the lack of glucocorticoid preparations that mimic the diurnal cortisol secretion profile, resulting in a prolonged period of ACTH stimulation and subsequent androgen production during the early morning hours. In childhood, optimization of growth and pubertal development are important goals of glucocorticoid treatment, in addition to prevention of adrenal crisis and treatment of 46,XX DSD. In adults, the focus shifts to preserving fertility and preventing side effects of glucocorticoid overtreatment, namely, the metabolic syndrome and osteoporosis. Fertility can be compromised in women due to oligomenorrhea/amenorrhea with chronic anovulation as a consequence of androgen excess. Men may develop so-called testicular adrenal


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InternalMed_Harrison. and osteoporosis. Fertility can be compromised in women due to oligomenorrhea/amenorrhea with chronic anovulation as a consequence of androgen excess. Men may develop so-called testicular adrenal rest tumors (Fig. 406-17). These consist of hyperplastic cells with adrenocortical characteristics located in the rete testis and should not be confused with testicular tumors. Testicular adrenal rest tissue can compromise sperm production and induce fibrosis that may be irreversible.


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InternalMed_Harrison. Hydrocortisone is a good treatment option for the prevention of adrenal crisis, but longer acting prednisolone may be needed to control androgen excess. In children, hydrocortisone is given in divided doses at 1–1.5 times the normal cortisol production rate (about 10–13 mg/m2 per day). In adults, if hydrocortisone does not suffice, intermediate-acting glucocorticoids (e.g., prednisone) may be


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InternalMed_Harrison. FIGURE 406-17 Imaging in congenital adrenal hyperplasia (CAH). Adrenal computed tomography scans showing homogenous bilateral hyperplasia in a young patient with classic CAH (A) and macronodular bilateral hyperplasia (B) in a middle-aged patient with classic CAH with longstanding poor disease control. Magnetic resonance imaging scan with T1-weighted (C) and T2-weighted (D) images showing bilateral testicular adrenal rest tumors (arrows) in a young patient with salt-wasting congenital adrenal hyperplasia. (Courtesy of N. Reisch.) given, using the lowest dose necessary to suppress excess androgen production. For achieving fertility, dexamethasone treatment may be required, but should be only given for the shortest possible time period to limit adverse metabolic side effects. Biochemical monitoring should include androstenedione and testosterone, aiming for the normal sex-specific reference range. 17-Hydroxyprogesterone (17OHP) is a useful marker of overtreatment, indicated by 17OHP


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InternalMed_Harrison. monitoring should include androstenedione and testosterone, aiming for the normal sex-specific reference range. 17-Hydroxyprogesterone (17OHP) is a useful marker of overtreatment, indicated by 17OHP levels within the normal range of healthy controls. Glucocorticoid overtreatment may suppress the hypothalamic-pituitary-gonadal axis. Thus, treatment needs to be carefully titrated against clinical features of disease control. Stress dose glucocorticoids should be given at double or triple the daily dose for surgery, acute illness, or severe trauma. Poorly controlled CAH can result in adrenocortical hyperplasia, which gave the disease its name, and may present as macronodular hyperplasia subsequent to long-standing ACTH excess (Fig. 406-17). The nodular areas can develop autonomous adrenal androgen production and may be unresponsive to glucocorticoid treatment.


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InternalMed_Harrison. Mineralocorticoid requirements change during life and are higher in children, explained by relative mineralocorticoid resistance that diminishes with ongoing maturation of the kidney. Children with CAH usually receive mineralocorticoid and salt replacement. However, young adults with CAH should undergo reassessment of their mineralocorticoid reserve. Plasma renin should be regularly monitored and kept within the upper half of the normal reference range. Hartmut P. H. Neumann


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InternalMed_Harrison. Hartmut P. H. Neumann Pheochromocytomas and paragangliomas are catecholamine-producing tumors derived from the sympathetic or parasympathetic nervous system. These tumors may arise sporadically or be inherited as features of multiple endocrine neoplasia type 2, von Hippel–Lindau disease, or several other pheochromocytoma-associated syndromes. The diagnosis of pheochromocytomas identifies a potentially correctable cause of hypertension, and their removal can prevent hypertensive crises that can be lethal. The clinical presentation is variable, ranging from an adrenal incidentaloma to a hypertensive crisis with associated cerebrovascular or cardiac complications.


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InternalMed_Harrison. Pheochromocytoma is estimated to occur in 2–8 of 1 million persons per year, and ∼0.1% of hypertensive patients harbor a pheochromocytoma. The mean age at diagnosis is ∼40 years, although the tumors can occur from early childhood until late in life. The classic “rule of tens” for pheochromocytomas states that ∼10% are bilateral, 10% are extra-adrenal, and 10% are malignant.


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InternalMed_Harrison. Pheochromocytomas and paragangliomas are well-vascularized tumors that arise from cells derived from the sympathetic (e.g., adrenal medulla) or parasympathetic (e.g., carotid body, glomus vagale) paraganglia (Fig. 407-1). The name pheochromocytoma reflects the black-colored staining caused by chromaffin oxidation of catecholamines; although a variety of terms have been used to describe these tumors, most clinicians use this designation to describe symptomatic catecholamine-producing tumors, including those in extra-adrenal retroperitoneal, pelvic, and thoracic sites. The term paraganglioma is used to describe catecholamine-producing tumors in the skull base and neck; these tumors may secrete little or no catecholamine. In contrast to common clinical parlance, the World Health Organization (WHO) restricts the term pheochromocytoma to adrenal tumors and applies the term paraganglioma to tumors at all other sites.


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InternalMed_Harrison. The etiology of sporadic pheochromocytomas and paragangliomas 2329 is unknown. However, 25–33% of patients have an inherited condition, including germ-line mutations in the classically recognized RET, VHL, NF1, SDHB, SDHC, and SDHD genes or in the more recently recognized SDHA, SDHAF2, TMEM127, and MAX genes. Biallelic gene inactivation has been demonstrated for the VHL, NF1, and SDH genes, whereas RET mutations activate receptor tyrosine kinase activity. SDH is an enzyme of the Krebs cycle and the mitochondrial respiratory chain. The VHL protein is a component of a ubiquitin E3 ligase. VHL mutations reduce protein degradation, resulting in upregulation of components involved in cell cycle progression, glucose metabolism, and oxygen sensing.


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InternalMed_Harrison. Its clinical presentation is so variable that pheochromocytoma has been termed “the great masquerader” (Table 407-1). Among the presenting manifestations, episodes of palpitation, headache, and profuse sweating are typical, and these manifestations constitute a classic triad. The presence of all three manifestations in association with hypertension makes pheochromocytoma a likely diagnosis. However, a pheochromocytoma can be asymptomatic for years, and some tumors grow to a considerable size before patients note symptoms.


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InternalMed_Harrison. The dominant sign is hypertension. Classically, patients have episodic hypertension, but sustained hypertension is also common. Catecholamine crises can lead to heart failure, pulmonary edema, arrhythmias, and intracranial hemorrhage. During episodes of hormone release, which can occur at widely divergent intervals, patients are anxious and pale, and they experience tachycardia and palpitations. These paroxysms generally last <1 h and may be precipitated by surgery, positional changes, exercise, pregnancy, urination (particularly with bladder pheochromocytomas), and various medications (e.g., tricyclic antidepressants, opiates, metoclopramide). The diagnosis is based on documentation of catecholamine excess by biochemical testing and localization of the tumor by imaging. These two criteria are of equal importance, although measurement of catecholamines or metanephrines (their methylated metabolites) is traditionally the first step in diagnosis.


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InternalMed_Harrison. These two criteria are of equal importance, although measurement of catecholamines or metanephrines (their methylated metabolites) is traditionally the first step in diagnosis. Biochemical testing Pheochromocytomas and paragangliomas synthesize and store catecholamines, which include norepinephrine (noradrenaline), epinephrine (adrenaline), and dopamine. Elevated plasma and urinary levels of catecholamines and metanephrines form the cornerstone of diagnosis. The characteristic fluctuations in the hormonal activity of tumors results in considerable variation in serial catecholamine measurements. However, most tumors continuously leak O-methylated metabolites, which are detected by measurement of metanephrines.


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InternalMed_Harrison. Catecholamines and metanephrines can be measured by different methods, including high-performance liquid chromatography, enzyme-linked immunosorbent assay, and liquid chromatography/ mass spectrometry. When pheochromocytoma is suspected on clinical grounds (i.e., when values are three times the upper limit of normal), this diagnosis is highly likely regardless of the assay used. However, as summarized in Table 407-2, the sensitivity and specificity of available biochemical tests vary greatly, and these differences are important in assessing patients with borderline elevations of different compounds. Urinary tests for metanephrines (total or fractionated) and catecholamines are widely available and are used commonly for initial evaluation. Among these tests, those for the fractionated metanephrines and catecholamines are the most sensitive. Plasma tests are more convenient and include measurements of catecholamines and metanephrines. Measurements of plasma metanephrine are the most


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InternalMed_Harrison. and catecholamines are the most sensitive. Plasma tests are more convenient and include measurements of catecholamines and metanephrines. Measurements of plasma metanephrine are the most sensitive and are less susceptible to false-positive elevations from stress, including venipuncture. Although the incidence of false-positive test results has been reduced by the introduction of newer assays, physiologic stress responses and medications that increase catecholamine levels still can confound testing. Because the tumors are relatively rare, borderline elevations are likely to represent false-positive results. In 2330 Jugular v. Vagus n. Tympanic n. Jugular p. Intravagal p. Intercarotid p. Sup. laryngeal p. Inf. laryngeal p. Subclavian p. Pulmonary p. Descending aorta Glossopharyngeal n. Jugular ganglion Nodose ganglion Sup. laryngeal a. Int. laryngeal a. Recurrent laryngeal n. Aortico-pulmonary p. Coronary p. A Adrenal B Extra-adrenal C Head and neck paraganglioma


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InternalMed_Harrison. FIGURE 407-1 The paraganglial system and topographic sites (in red) of pheochromocytomas and paragangliomas. (Parts A and B from WM Manger, RW Gifford: Clinical and experimental pheochromocytoma. Cambridge, Blackwell Science, 1996; Part C from GG Glenner, PM Grimley: Tumors of the Extra-adrenal Paraganglion System [Including Chemoreceptors], Atlas of Tumor Pathology, 2nd Series, Fascicle 9. Washington, DC, AFIP, 1974.)


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InternalMed_Harrison. CliniCAl fEATuRES ASSoCiATED wiTH PHEoCHRomoCyTomA, this circumstance, it is important to exclude dietary or drug-related liSTED by fR£EquEnCy of oCCuRREnCE factors (withdrawal of levodopa or use of sympathomimetics, diuret 1. Headaches 10. Weight loss ics, tricyclic antidepressants, alpha and beta blockers) that might cause false-positive results and then to repeat testing or perform a clonidine 2. Profuse sweating 11. Paradoxical response to antihypertensive drugs suppression test (i.e., the measurement of plasma normetanephrine 3 h 3. Palpitations and tachycardia after oral administration of 300 μg of clonidine). Other pharmacologic 12. Polyuria and polydipsia 4. Hypertension, sustained or tests, such as the phentolamine test and the glucagon provocation test, paroxysmal 13. Constipation are of relatively low sensitivity and are not recommended. 5. Anxiety and panic attacks 14. Orthostatic hypotension


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InternalMed_Harrison. 5. Anxiety and panic attacks 14. Orthostatic hypotension Diagnostic Imaging A variety of methods have been used to local 6. Pallor 15. Dilated cardiomyopathy ize pheochromocytomas and paragangliomas (Table 407-2). CT and 7. Nausea 16. Erythrocytosis MRI are similar in sensitivity and should be performed with contrast. 8. Abdominal pain 17. Elevated blood sugar T2-weighted MRI with gadolinium contrast is optimal for detecting 9. Weakness 18. Hypercalcemia pheochromocytomas and is somewhat better than CT for imaging extraadrenal pheochromocytomas and paragangliomas. About 5% of adrenal incidentalomas, which usually are detected by CT or MRI, prove to be pheochromocytomas upon endocrinologic evaluation.


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InternalMed_Harrison. Tumors also can be localized by procedures using radioactive tracers, including 131Ior 123I-metaiodobenzylguanidine (MIBG) scintigraphy, 111In-somatostatin analogue scintigraphy, 18F-DOPA positron emission tomography (PET), or 18F-fluorodeoxyglucose (FDG) PET. Diagnostic Method Sensitivity Specificity Because these agents exhibit selective uptake in paragangliomas, nuclear imaging is particularly useful in the hereditary syndromes.


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InternalMed_Harrison. Differential Diagnosis When the possibility of a pheochromocytoma isFractionated ++++ ++ being entertained, other disorders to consider include essential hyper tension, anxiety attacks, use of cocaine or amphetamines, mastocytosisTotal metanephrines +++ ++++ or carcinoid syndrome (usually without hypertension), intracranial Plasma tests lesions, clonidine withdrawal, autonomic epilepsy, and factitious crises Catecholamines +++ ++ (usually from use of sympathomimetic amines). When an asymptomatic adrenal mass is identified, likely diagnoses other than pheochromocytoma include a nonfunctioning adrenal adenoma, an aldoste- ronoma, and a cortisol-producing adenoma (Cushing’s syndrome).


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InternalMed_Harrison. Somatostatin receptor ++ ++ Complete tumor removal, the ultimate therapeutic goal, can bescintigraphya achieved by partial or total adrenalectomy. It is important to pre18Fluoro-DOPA PET/CT +++ ++++ serve the normal adrenal cortex, particularly in hereditary disorders aValues are particularly high in head and neck paragangliomas. in which bilateral pheochromocytomas are most likely. Preoperative preparation of the patient is important. Before surgery, blood


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InternalMed_Harrison. Abbreviations: MIBG, metaiodobenzylguanidine; PET/CT, positron emission tomography plus CT. For the biochemical tests, the ratings correspond globally to sensitivity and speci-pressure should be consistently below 160/90 mmHg. Classically, ficity rates as follows: ++, <85%; +++, 85–95%; and ++++, >95%. blood pressure has been controlled by α-adrenergic blockers (oral phenoxybenzamine, 0.5–4 mg/kg of body weight). Because patients are volume-constricted, liberal salt intake and hydration are necessary to avoid severe orthostasis. Oral prazosin or intravenous phentolamine can be used to manage paroxysms while adequate alpha blockade is awaited. Beta blockers (e.g., 10 mg of propranolol three or four times per day) can then be added. Other antihypertensives, such as calcium channel blockers or angiotensin-converting enzyme inhibitors, have also been used effectively.


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InternalMed_Harrison. Surgery should be performed by teams of surgeons and anesthesiologists with experience in the management of pheochromocytomas. Blood pressure can be labile during surgery, particularly at the outset of intubation or when the tumor is manipulated. Nitroprusside infusion is useful for intraoperative hypertensive crises, and hypotension usually responds to volume infusion. Minimally invasive techniques (laparoscopy or retroperitoneoscopy) have become the standard approaches in pheochromocytoma surgery. They are associated with fewer complications, a faster recovery, and optimal cosmetic results. Extra-adrenal abdominal and most thoracic pheochromocytomas also can also be removed endoscopically. Postoperatively, catecholamine normalization should be documented. An adrenocorticotropic hormone test should be used to exclude cortisol deficiency when bilateral adrenal cortex–sparing surgery has been performed.


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InternalMed_Harrison. About 5–10% of pheochromocytomas and paragangliomas are malignant. The diagnosis of malignant pheochromocytoma is problematic. The typical histologic criteria of cellular atypia, presence of mitoses, and invasion of vessels or adjacent tissues are insufficient for the diagnosis of malignancy in pheochromocytoma. Thus, the term malignant pheochromocytoma is restricted to tumors with distant metastases, most commonly found by nuclear medicine imaging in lungs, bone, or liver—locations suggesting a vascular pathway of spread. Because hereditary syndromes are associated with multifocal tumor sites, these features should be anticipated in patients with germ-line mutations of 2331 RET, VHL, SDHD, or SDHB. However, distant metastases also occur in these syndromes, especially in carriers of SDHB mutations.


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InternalMed_Harrison. Treatment of malignant pheochromocytoma or paraganglioma is challenging. Options include tumor mass reduction, alpha blockers for symptoms, chemotherapy, and nuclear medicine radiotherapy. The first-line choice is nuclear medicine therapy for scintigraphically documented metastases, preferably with 131I-MIBG in 200-mCi doses at monthly intervals over three to six cycles. Averbuch’s chemotherapy protocol includes dacarbazine (600 mg/m2 on days 1 and 2), cyclophosphamide (750 mg/m2 on day 1), and vincristine (1.4 mg/m2 on day 1), all repeated every 21 days for three to six cycles. Palliation (stable disease to shrinkage) is achieved in about one-half of patients. Other chemotherapeutic options are sunitinib and temozolomide/ thalidomide. The prognosis of metastatic pheochromocytoma or paraganglioma is variable, with 5-year survival rates of 30–60%.


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InternalMed_Harrison. Pheochromocytomas occasionally are diagnosed in pregnancy. Endoscopic removal, preferably in the fourth to sixth month of gestation, is possible and can be followed by uneventful childbirth. Regular screening in families with inherited pheochromocytomas provides an opportunity to identify and remove asymptomatic tumors in women of reproductive age. About 25–33% of patients with a pheochromocytoma or paragan glioma have an inherited syndrome. At diagnosis, patients with inherited syndromes are a mean of ∼15 years younger than patients with sporadic tumors. Neurofibromatosis type 1 (NF1) was the first described pheochromocytoma-associated syndrome (Chap. 118). The NF1 gene functions as a tumor suppressor by regulating the Ras signaling cascade. Classic features of neurofibromatosis include multiple neurofibromas, café au lait spots, axillary freckling of the skin, and Lisch nodules of the iris (Fig. 407-2). Pheochromocytomas occur in only ∼1% of these patients


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InternalMed_Harrison. FIGURE 407-2 Neurofibromatosis. A. MRI of bilateral adrenal pheochromocytoma. B. Cutaneous neurofibromas. C. Lisch nodules of the iris.


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InternalMed_Harrison. D. Axillary freckling. (Part A from HPH Neumann et al: Keio J Med 54:15, 2005; with permission.) 2332 and are located predominantly in the adrenals. Malignant pheochromocytoma is not uncommon. The best-known pheochromocytoma-associated syndrome is the autosomal dominant disorder multiple endocrine neoplasia type 2 (MEN2) (Chap. 408). Both types of MEN2 (2A and 2B) are caused by mutations in RET (rearranged during transfection), which encodes a tyrosine kinase. The locations of RET mutations correlate with the severity of disease and the type of MEN2 (Chap. 408). MEN2A is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism; MEN2B also includes MTC and pheochromocytoma as well as multiple mucosal neuromas, marfanoid habitus, and other developmental disorders, though it typically lacks hyperparathyroidism. MTC is found in virtually all patients with MEN2, but pheochromocytoma occurs in only ∼50% of these patients. Nearly all pheochromocytomas in


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InternalMed_Harrison. disorders, though it typically lacks hyperparathyroidism. MTC is found in virtually all patients with MEN2, but pheochromocytoma occurs in only ∼50% of these patients. Nearly all pheochromocytomas in MEN2 are benign and located in the adrenals, often bilaterally (Fig. 407-3). Pheochromocytoma may be symptomatic before MTC. Prophylactic thyroidectomy is being performed in many carriers of RET mutations; pheochromocytomas should be excluded before any surgery in these patients. Von Hippel–Lindau syndrome (VHL) is an autosomal dominant disorder that predisposes to retinal and cerebellar hemangioblastomas, which also occur in the brainstem and spinal cord (Fig. 407-4). Other important features of VHL are clear cell renal carcinomas, pancreatic neuroendocrine tumors, endolymphatic sac tumors of the inner ear, cystadenomas of the epididymis and broad ligament, and multiple pancreatic or renal cysts.


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InternalMed_Harrison. The VHL gene (among other genes) encodes an E3 ubiquitin ligase that regulates expression of hypoxia-inducible factor 1. Loss of VHL is associated with increased expression of vascular endothelial growth factor (VEGF), which induces angiogenesis. Although the VHL gene can be inactivated by all types of mutations, patients with pheochromocytoma predominantly have missense mutations. About 20–30% of patients with VHL have pheochromocytomas, but in some families the incidence can reach 90%. The recognition of pheochromocytoma as a VHL-associated feature provides an opportunity to diagnose retinal, central nervous system, renal, and pancreatic tumors at a stage when effective treatment may still be possible.


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InternalMed_Harrison. The paraganglioma syndromes (PGLs) have been classified by genetic analyses of families with head and neck paragangliomas. The susceptibility genes encode subunits of the enzyme succinate dehydrogenase (SDH), a component in the Krebs cycle and the mitochondrial electron transport chain. SDH is formed by four subunits (A–D). Mutations of SDHB (PGL4), SDHC (PGL3), SDHD (PGL1), and SDHAF2 (PGL2) predispose to the PGLs. The transmission of the disease in carriers of SDHB and SDHC germ-line mutations is autosomal dominant. In contrast, in SDHD and SDHAF2 families, only the progeny of affected fathers develop tumors if they inherit the mutation. PGL1 is most common, followed by PGL4; PGL2 and PGL3 are rare. Adrenal, extra-adrenal abdominal, and thoracic pheochromocytomas, which are components of PGL1 and PGL4, are rare in PGL3 and absent in PGL2 (Fig. 407-5). About one-third of patients with PGL4 develop metastases.


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InternalMed_Harrison. FIGURE 407-3 Multiple endocrine neoplasia type 2. A, B. Multifocal medullary thyroid carcinoma shown by MIBG scintigraphy (A) and operative specimen (B). Arrows demonstrate the tumors; arrowheads show the tissue bridge of the cut specimen. C–E. Bilateral adrenal pheochromocytoma shown by MIBG scintigraphy (C), CT imaging (D), and operative specimens (E). (From HPH Neumann et al: Keio J Med 54:15, 2005; with permission.)


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InternalMed_Harrison. FIGURE 407-4 Von Hippel–Lindau disease. A. Retinal angioma. All subsequent panels show findings on MRI: B–D. Hemangioblastomas of the cerebellum (B) in brainstem (C) and spinal cord (D). E. Bilateral pheochromocytomas and bilateral renal clear cell carcinomas F. Multiple pancreatic cysts. (Parts A and D from HPH Neumann et al: Adv Nephrol Necker Hosp 27:361, 1997. © Elsevier. Part B from SH Morgan, J-P Grunfeld [eds]: Inherited Disorders of the Kidney. Oxford, UK, Oxford University Press, 1998. Part F from HPH Neumann et al: Contrib Nephrol 136:193, 2001. © S. Karger AG, Basel.)


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InternalMed_Harrison. FIGURE 407-5 Paraganglioma syndrome. A patient with the SDHD W5X mutation and PGL1 underwent incomplete resection of a left carotid body tumor. A. 18F-DOPA positron emission tomography demonstrating tumor uptake in the right jugular glomus, the right carotid body, the left carotid body, the left coronary glomus, and the right adrenal gland. Note the physiologic accumulation of the radiopharmaceutical agent in the kidneys, liver, gallbladder, renal pelvis, and urinary bladder. B and C. CT angiography with three-dimensional reconstruction. Arrows point to the paraganglial tumors. (From S Hoegerle et al: Eur J Nucl Med Mol Imaging 30:689, 2003; with permission.) 2334 Familial pheochromocytoma (FP) has been attributed to hereditary, germ-line mutations even in patients without a known family history. mainly adrenal tumors in patients with germ-line mutations in the A first step is to search for clinical features of inherited syndromes genes TMEM127, MAX, and SDHA. Transmission is also


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InternalMed_Harrison. history. mainly adrenal tumors in patients with germ-line mutations in the A first step is to search for clinical features of inherited syndromes genes TMEM127, MAX, and SDHA. Transmission is also autosomal and to obtain an in-depth, multigenerational family history. Each dominant, and mutations of MAX, like those of SDHD, cause tumors of these syndromes exhibits autosomal dominant transmission with only if inherited from the father. variable penetrance, but a proband with a mother affected by paraganglial tumors is not predisposed to PLG1 (SDHD mutation carrier). GUIDELINES FOR GENETIC SCREENING OF PATIENTS WITH Cutaneous neurofibromas, café au lait spots, and axillary freckling PHEOCHROMOCYTOMA OR PARAGANGLIOMA suggest neurofibromatosis. Germ-line mutations in NF1 have not In addition to family history, general features suggesting an inher-been reported in patients with sporadic pheochromocytomas. Thus,ited syndrome include young age, multifocal tumors, extra-adrenal NF1 testing


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InternalMed_Harrison. to family history, general features suggesting an inher-been reported in patients with sporadic pheochromocytomas. Thus,ited syndrome include young age, multifocal tumors, extra-adrenal NF1 testing need not be performed in the absence of other clinicaltumors, and malignant tumors (Fig. 407-6). Because of the relatively features of neurofibromatosis. A personal or family history of MTC or high prevalence of familial syndromes among patients who present an elevation of serum calcitonin strongly suggests MEN 2 and shouldwith pheochromocytoma or paraganglioma, it is useful to identify prompt testing for RET mutations. A history of visual impairment or


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InternalMed_Harrison. Percentages of germ-line mutations in pheochromocytoma susceptibility genes


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InternalMed_Harrison. FIGURE 407-6 Mutation distribution in the VHL, RET, SDHB, SDHC, SDHD, and NF1 genes in 2021 patients with pheochromocytomas and paragangliomas from the European-American Pheochromocytoma-Paraganglioma Registry based in Freiburg, Germany, as updated on March 1, 2014. A. Correlation with age. The bars depict the frequency of sporadic (spor) or various inherited forms of pheochromocytoma in different age groups. The inherited disorders are much more common among younger individuals presenting with pheochromocytoma. Patients with mutations in the TMEM127, MAX, and SDHA genes are not included, since they contribute <1% in decades 4–7 only. B–F. Germ-line mutations according to multiple (B), extra-adrenal retroperitoneal (C), thoracic (D), and malignant (E) pheochromocytomas and head and neck paragangliomas (F). (Data from the Freiburg International Pheochromocytoma and Paraganglioma Registry, 2014.) tumors of the cerebellum, kidney, brainstem, or spinal cord suggests the possibility of


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InternalMed_Harrison. paragangliomas (F). (Data from the Freiburg International Pheochromocytoma and Paraganglioma Registry, 2014.) tumors of the cerebellum, kidney, brainstem, or spinal cord suggests the possibility of VHL. A personal and/or family history of head and neck paraganglioma suggests PGL1 or PGL4.