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SYMPTOMS TO DIAGNOSIS GREGORY W. RUTECKI, MD, Section Editor SAMUEL P. WILES, MD MATTHEW KICZEK, DO GREGORY W. RUTECKI, MD Department of Pulmonary and Critical Care, Department of Diagnostic Radiology, Department of Internal Medicine, Cleveland Clinic Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

A paraneoplastic and acid-base disturbance

NOTE: The scenario presented here is partly ■■ ASSESSING ACID-BASE DISORDERS based on cases reported elsewhere by Martínez- Valles et al1 and Fernández-Rodríguez et al.2 What type of acid-base disorder does this 1patient have? 55-year-old man is admitted to the hos- □□ Metabolic A pital with generalized malaise, paresthe- □□ sias, and severe hypertension. He says he had □□ Metabolic experienced agitation along with weakness on □□ exertion 24 hours before presentation to the emergency department, with subsequent on- The patient has . set of paresthesias in his lower extremities and A 5-step approach perioral area. If a patient has an acid-base disorder, one He is already known to have mild chronic should use a 5-step process to characterize it obstructive pulmonary disease, with a ratio of (Table 2).3 forced expiratory volume in 1 second (FEV1) 1. Acidosis or alkalosis? The patient’s ar- A 55-year-old to forced vital capacity (FVC) of less than terial pH is 7.5, which is alkalemic because it smoker with COPD 70% and an FEV1 85% of predicted. In addi- is higher than 7.44. tion, he was recently diagnosed with , 2. Metabolic or respiratory? The primary presents resistant hypertension requiring maximum process in our patient is overwhelmingly met- with malaise, doses of 3 agents (a channel blocker, abolic, as his partial pressure of carbon diox- paresthesias, an angiotensin-converting enzyme inhibitor, ide (Pco2) is slightly elevated, a direction that and a loop diuretic), and hyperlipidemia. would cause acidosis, not alkalosis. and severe He is a current smoker with a 30-pack-year 3. The anion gap (the con- hypertension: smoking history. He does not use alcohol. His centration minus the sum of the and family history is noncontributory. concentrations) is normal at 8 What is the cause? His blood pressure is 190/110 mm Hg de- mmol/L (DRG:HYBRiD-XL Immunoassay spite adherence to his 3-drug regimen. His oxy- and Clinical Chemistry Analyzer, reference gen saturation is 94% on room air, respiratory range 8–16). rate in the low 30s, and pulse 110 beats/minute. 4. Is the disturbance compensated? We He has normal breath sounds, normal S1 and have determined that this patient has a meta- S2 with an S4 gallop, bilateral lower-extremity bolic alkalemia; the question now is whether edema, truncal obesity, and abdominal striae. there is any compensation for the primary dis- Electrocardiography shows tachycardia with turbance. In metabolic alkalosis, the Pco may in- first-degree atrioventicular block. Chest radi- 2 ography shows an opacity in the right middle crease by approximately 0.6 mm Hg (range 0.5–0.8) above the nominal normal level of lung field. Initial laboratory results and those 40 mm Hg for each 1-mmol/L increase in bi- from 1 year ago are shown in Table 1. carbonate above the nominal normal level of doi:10.3949/ccjm.86a.18014 25 mmol/L.4 If the patient requires oxygen,

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mm Hg, and in fact it is 51 mm Hg, which is TABLE 1 within the normal range of expected compen- Laboratory results on presentation sation (47.5–52 mm Hg). Therefore, yes, he is and 1 year earlier compensating for the primary disturbance. 5. In , is there a delta Current 1 year Reference Test levela earlier range gap? As our patient has metabolic alkalosis, not acidosis, this question does not apply in Sodium (mmol/L) 144 135 136–144 this case. Potassium (mmol/L) 2.8 4.0 3.7–5.1 Chloride (mmol/L) 96 100 97–105 ■■ WHICH TEST TO FIND THE CAUSE? Bicarbonate (mmol/L) 40 28 22–30b Which is the best test to order next to Serum (mg/dL) 1.2 1.2 0.58–0.96 2determine the cause of this patient’s hypo- (mg/dL) 28 19 7–21 kalemic metabolic alkalosis? (mg/dL) 197 74–99 □□ Serum magnesium level Calcium and magnesium Normal □□ Spot chloride Arterial blood gases □□ Renal ultrasonography □□ 24-hour urine collection for sodium, pH 7.50 7.34 7.35–7.45 potassium, and chloride Pco (mm Hg) 51 40 34–46c 2 The first step in the algorithm for hypokale- Pao (mm Hg) 75 76 85–95 2 mic metabolic alkalosis (Figure 1) is to obtain Bicarbonate (mmol/L) 40 22–26 a spot urine chloride measurement. If this val- a Abnormal results are shown in bold. ue is low, the hypokalemic metabolic alkalosis b For acid-base problem-solving, a value of 25 mmol/L is considered normal. is volume-responsive; if it is high, the distur- c For acid-base problem-solving, a value of 40 mm Hg is considered normal. bance is volume-independent. The patient’s loop diuretic is withheld for An algorithmic the calculation may be unreliable, however, as 12 hours and a spot urine chloride is obtained, hypoxemia may have an overriding influence which is reported as 44 mmol/L. This high approach on respiratory drive. value suggests that a volume-independent can arrive Patients with chronically high Pco levels hypokalemic­ metabolic alkalosis is present 2 with potassium depletion. at the cause such as those with chronic obstructive pulmo- nary disease can become accustomed to high As for the other answer choices: of hypokalemic carbon dioxide levels and lose their hyper- Serum magnesium. Though hypomagne- metabolic capnic respiratory drive. Giving oxygen sup- semia can cause hypokalemia due to lack of plementation is thought to decrease respira- inhibition of renal outer medullary potassium alkalosis with tory drive in these patients, so that they will channels and subsequent increased excretion hypertension breathe slower and retain more carbon diox- of potassium in the apical tubular membrane, ide. There is some degree of respiratory com- it is not independently associated with acid- pensation for metabolic alkalosis that occurs base disturbances.5 by breathing less, though it is limited overall— Renal ultrasonography gives information even in very alkalotic patients, breathing less about structural disease but is of lim-

results in CO2 retention, which, by displacing ited utility in identifying the cause of hypoka- O2 molecules in the alveoli, will in turn result lemic metabolic alkalosis. in hypoxia. The brain then senses the hypoxia A 24-hour urine collection is unnec- and makes one breathe faster, thereby limiting essary in this setting and would ultimately this compensation. result in delay in diagnosis, as spot urine This patient’s serum bicarbonate level is chloride is a more efficient means of rap- 40 mmol/L, or 15 mmol/L higher than the idly distinguishing volume-responsive vs nominal normal level. If he is compensat- volume-independent causes of hypokalemic 6 ing, his Pco2 should be 40 + (15 × 0.6) = 49 metabolic alkalosis.

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TABLE 2 ‘Rules of 5’ for acid-base problem-solving 1 Determine the arterial pH pH < 7.38 is acidemic, pH > 7.42 is alkalemica Normal pH does not rule out an acid-base disorder

2 If the arterial pH is abnormal, determine pH Pco2 HCO3 whether the primary process is respiratory, a High — metabolic, or both Respiratory acidosis Low Metabolic acidosis Low — Low Mixed respiratory and metabolic acidosis Low High Low Respiratory alkalosis High Low — Metabolic alkalosis High Variesb High Mixed respiratory and metabolic alkalosis High Low High 3 Calculate the anion gap Anion gap = sodium – (chloride + bicarbonate) If serum is low, add 2.5 mmol/L to the anion gap for every 1 g the serum albumin is below normal

4 Check the degree of compensation Pco2 and bicarbonate should increase or decrease together (respiratory or metabolic) Normal levels: bicarbonate 25 mmol/L, Pco2 40 mm Hg

Acute respiratory acidosis: For every 10-mm Hg increase in Pco2, bicarbonate should increase by 1 mmol/L Chronic respiratory acidosis (> 48 hours): For every 10-mm Hg

increase in Pco2, bicarbonate should increase by 4 mmol/L Metabolic acidosis: For every 1-mmol/L decrease in bicarbonate ,

Pco2 should decrease by 1.3 mm Hg

Acute respiratory alkalosis: For every 10-mm Hg decrease in Pco2, bicarbonate should decrease by 2 mmol/L Chronic respiratory alkalosis (> 48 hours): For every 10-mm Hg

decrease in Pco2, bicarbonate should decrease by 5 mmol/L Metabolic alkalosis: For every 1-mmol/L increase in bicarbonate ,

Pco2 may increase by 0.6 mm Hg 5 If the patient has metabolic acidosis with Delta gap = change in anion gap / change in bicarbonate an elevated anion gap, assess for ‘delta gap’ ([anion gap – 10] / [24 – bicarbonate]) (whether the decrease in bicarbonate = the increase > 1: Additional metabolic alkalosis in anion gap) 1: No additional disturbance present < 1: Additional non-anion gap metabolic acidosis present a Acidosis and alkalosis refer to acid-base disturbances with determined metabolic or respiratory etiologies. Alkalemia and acidemia refer to disturbances in blood pH prior to determination of the underlying metabolic/respiratory cause. b Pco 2 in metabolic alkalosis may vary depending on the clinical context, as compensation for metabolic alkalosis requires decreased respiratory drive, which may be influenced by other factors (ie, hypoxia).

Pco2 = partial pressure of carbon dioxide

Adapted from Mani S, Rutecki GW. A patient with altered mental status and an acid-base disturbance. Cleve Clin J Med 2017; 84(1):27–34. Copyright © 2017 The Cleveland ClinicFoundation. All rights reserved.

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Metabolic acidosis pH < 7.4 Bicarbonate < 22 mmol/L

Anion gap ≥ 12 mmol/L Anion gap < 12 mmol/L

Osmolar gap present Osmolar gap absent High urine ammonium Low urine ammonium Urine osmolal gap > 200 mEq/La Urine osmolal gap < 40 mEq/L

Methanol Gut-mediated Renal-mediated (l-lactate and d-lactate) Loss of bicarbonate-rich intestinal Ethylene and fluids with intact renal tubular (intrinsic or drug-induced) Diabetic generation of ammonia Ureteral diversions , renal failure Posthypocapnia recovery Oxyproline (from acetaminophen)

a Urine osmolal gap = measured minus the calculated urine osmolality, where calculated urine osmolality = (2[Na+] + 2[K+]) + (urine urea nitrogen [mg/dL]/2.8) + (urine glucose [mg/dL]/18).27

Metabolic alkalosis pH ≥ 7.44 Bicarbonate > 30 mmol/L

Hypokalemia (Potassium < 3.4 mmol/L)

Low spot urine chloride High spot urine chloride (≥ 20 mmol/L) (< 20 mmol/L)

Loss of gastric fluid (vomiting or Hypertension present Hypertension absent gastric suction) Hyperaldosteronism (primary or secondary) Bartter syndrome Recovery from hypercapnia Cushing disease or syndrome Gitelman syndrome Diuretics (after withholding) Licorice Severe potassium depletion (villous Adipsic hypernatremia adenoma) Liddle syndrome Diuretics (measured during diuretic 11-, 17-, and 21-hydroxylase deficiencies effect) Diuretics (measured during diuretic effect)

Figure 1. Algorithms for determining causes of metabolic acid-base disturbances.

■■ IS HIS HYPERTENSION SECONDARY? than primary. It is of recent onset. The pa- IF SO, WHAT IS THE CAUSE? tient’s family history is noncontributory, and his hypertension is resistant to the use Several features of this case suggest that the of maximum doses of 3 antihypertensive patient’s hypertension is secondary rather agents.

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TABLE 3 and values in hypokalemic metabolic alkalosis with high urine chloride Renin and aldosterone Elevated blood pressure Normotensive High renin, high aldosterone, Renal artery stenosis Bartter syndrome normal ratio of plasma aldosterone concentration Renin-secreting tumor Gitelman syndrome (PAC) to Diuretics Severe potassium depletion (PRA) (villous adenoma) Diuretics Low renin, high aldosterone, Primary hyperaldosteronism high PAC–PRA ratio Low renin, low aldosterone, Licorice normal PAC–PRA ratio Cushing disease or syndrome Hydroxylase deficiencies Liddle syndrome

Which of the following causes of second- Additional diagnostic testing: 3ary hypertension is not commonly asso- Plasma renin and plasma aldosterone ciated with hypokalemia and metabolic At this juncture, the differential diagnosis for alkalosis? this patient’s potassium depletion, metabolic □□ Hyperaldosteronism alkalosis, high urine chloride, and hyperten- Several sion has been narrowed to primary or second- □□ Liddle syndrome features □□ Cushing syndrome ary hyperaldosteronism, surreptitious miner- □□ Renal parenchymal disease alocorticoid ingestion, Cushing syndrome, suggest □□ Chronic licorice ingestion licorice ingestion, Liddle syndrome, or one of that his the 3 hydroxylase deficiencies (11-, 17-, and Renal parenchymal disease is a cause of resis- 21-) (Figure 1). hypertension tant hypertension, but it is not characterized by Although clues in the history, physical ex- is secondary metabolic alkalosis, hypokalemia, and elevated amination, and imaging may suggest a specific 7 rather than urine chloride, while the others listed here— cause of his abnormal laboratory values, the hyperaldosteronism, Liddle syndrome, Cushing next step in the diagnostic workup is to mea- primary syndrome, and chronic licorice ingestion—are.­ sure the plasma renin and aldosterone levels Other common causes of resistant hyperten- (Table 3). sion without these metabolic abnormalities include obstructive sleep apnea, alcohol abuse, ■■ HYPERALDOSTERONISM and nonadherence to treatment. While treatment of hypertension with Hyperaldosteronism is associated with loop diuretics can result in hypokalemia and 4which of the following patterns of renin metabolic alkalosis due to the effect of these and aldosterone values? drugs on potassium reabsorption in the loop of Henle, the patient’s hypokalemia persisted □□ High renin, high aldosterone, normal after this agent was withdrawn.8 ratio of plasma aldosterone concentration Causes of hypokalemic metabolic alkalosis (PAC) to plasma renin activity (PRA) with and without hypertension are further de- □□ Low renin, low aldosterone, normal lineated in Figure 1. PAC–PRA ratio

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□□ Low renin, high aldosterone, high sterone antagonist (spironolactone or eplere- PAC–PRA ratio none in the case of bilateral disease) or surgery □□ High renin, low aldosterone, low (unilateral disease).9,11,12 PAC–PRA ratio Secondary hyperaldosteronism The pattern of low renin, high aldosterone, Secondary hyperaldosteronism should be sus- and high PAC–PRA ratio is associated with pected when plasma renin and aldosterone hyperaldosteronism. levels are both elevated with a PAC–PRA ra- Primary hyperaldosteronism tio less than 10. Primary hyperaldosteronism is one of the most This pattern is most commonly seen with common causes of resistant hypertension and diuretic use but can also be a consequence of renal artery stenosis or, rarely, a renin-secret- is underappreciated, being diagnosed in up to 13 20% of patients referred to hypertension spe- ing tumor. Renal artery stenosis is a com- cialty clinics.7 Potassium levels may be nor- mon finding in patients with hypertension mal, likely contributing to its lack of recogni- undergoing cardiac catheterization, which is not surprising as more than 90% of such ste- tion in this target population. 7 Primary hyperaldosteronism should be sus- noses are atherosclerotic. Renin-secreting pected in patients who have a plasma aldo- tumors are exceedingly rare, with fewer than 100 cases reported in the literature, and are sterone PAC–PRA ratio greater than 20 with 13 elevated plasma aldosterone concentrations more common in younger individuals. (> 15 ng/dL). Our patient has low-normal aldosterone Persistently elevated aldosterone levels in and plasma renin the setting of elevated plasma volume is proof On further testing, this patient’s plasma aldo- that aldosterone secretion is independent of sterone level is 2.55 ng/dL (normal < 15 ng/ the renin-angiotensin-aldosterone axis, and dL), his plasma renin activity is 0.53 ng/mL/ therefore is autonomous (secondary to adre- hour (normal 0.2–2.8 ng/mL/hour), and his nal tumor or hyperplasia). Further testing in PAC–PRA ratio is therefore 4.81. Primary hyper- the form of oral salt loading, saline infusion, or The categories discussed thus far have in- aldosteronism fludrocortisone (a sodium-retaining steroid) cluded primary and secondary hyperaldoste- administration is thus required to confirm in- is one of the ronism, which typically do not present with appropriate, autonomous aldosterone secre- low to normal levels of both renin and aldo- 9 most common tion. sterone. Surreptitious mineralocorticoid use causes After establishing the diagnosis of primary could present in this manner, but is unlikely hyperaldosteronism, one should determine in this patient, whose medications do not in- of resistant the subtype (ie, due to an adrenal carcinoma, clude fludrocortisone. hypertension unilateral hypersecreting adenoma, or uni- The low-normal values thus lead to con- lateral or bilateral hyperplasia). Further test- and is under­ sideration of a third category: apparent min- ing includes adrenal computed tomography eralocorticoid excess. Diseases in this category appreciated (CT) to rule out adrenal carcinomas, which such as Cushing disease or adrenocorticotrop- are suspected with adenomas larger than 4 ic hormone (ACTH) excess are character- cm. Though part of the diagnostic workup, ized by increases in corticosteroids so that the CT as a means of confirmational testing alone potassium depletion, metabolic alkalosis, and does not preclude the possibility of bilateral hypertension are not a consequence of renin adrenal hyperplasia in some patients, even in and aldosterone but rather the excess cortico- the presence of an adrenal adenoma. For this steroids.14 reason, adrenal venous sampling is required to definitively determine whether the condition Causes of apparent is due to a hypersecreting adrenal adenoma or mineralocorticoid excess unilateral or bilateral hyperplasia.9,10 There are several possible causes of mineralo- Treatment of primary hyperaldosteronism corticoid excess associated with hypertension depends on the subtype of the disease and in- and hypokalemic metabolic alkalosis not due volves salt restriction in addition to an aldo- to renin and aldosterone.

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Chronic licorice ingestion in high vol- TABLE 4 umes is one such cause and is thought to result in inhibition of 11B-hydroxysteroid Effects of hypercortisolism dehydrogenase or possibly cortisol oxidase by licorice’s active component, glycyrrhetinic Organ system Manifestation acid. This inhibition results in an inability to Cardiovascular Hypertension, thromboembolism, convert cortisol to cortisone. The cortisol ex- cardiomyopathy cess binds to mineralocorticoid receptors, and acting like aldosterone, results in hyperten- Metabolic Glucose intolerance/diabetes, hyperlipidemia, obesity sion and hypokalemic metabolic alkalosis as well as feedback inhibition of renin and aldo- Reproductive Menstrual irregularities, hirsutism, sterone levels.15 changes in libido, virilization Partial hydroxylase deficiencies, though Dermatologic Easy bruisability, striae, skin atrophy, rare, should also be considered as a cause of hyperpigmentation, oily skin hypokalemic metabolic alkalosis, hyperten- sion, and, potentially, hirsutism and clito- Musculoskeletal Proximal muscle wasting, osteopenia/ romegaly in women. They can be diagnosed osteoporosis with elevated levels of 17-ketosteroids and de- Neuropsychiatric Psychosis, emotional lability, depression, hydroepiandrosterone , both of which, anxiety, sleep apnea in excess, may act on aldosterone receptors in a manner similar to cortisol.16 Immunologic function Increased susceptibility to fungal and Liddle syndrome, a rare autosomal domi- bacterial infection, opportunistic infec- nant condition, may also present with sup- tions pressed levels of both renin and aldosterone. Ophthalmologic Glaucoma, cataracts, central serous chorio­ In contrast to the disorders of nonaldoste- retinopathy, hypertensive retinopathy rone mineralocorticoid excess, however, the sodium channel defect in Liddle syndrome is characterized by a primary increase in so- dium reabsorption in the collecting tubule produce effects similar to that of aldosterone and potassium wasting. The resultant volume on acid-base and balance and 19 expansion leads to suppressed renin and al- blood pressure. dosterone levels and hypertension with low The increase in blood pressure that is as- potassium and elevated bicarbonate concen- sociated with elevated plasma levels of cor- trations.17 tisol is not attributable solely to its effect Liddle syndrome is commonly diagnosed on mineralocorticoid receptors, however. in childhood but may go unrecognized due The pathogenesis is multifactorial and not to occasional absence of hypokalemia at pre- fully understood, but it also is thought to sentation. Potassium-sparing diuretics such as involve increased peripheral vascular sen- amiloride or triamterene are the mainstays of sitivity to adrenergic agonists, increased 18 treatment. hepatic production of angiotensinogen, Hypercortisolism results in hypokalemic as well as direct and indirect cardiotoxic metabolic alkalosis through the effect of ex- effects via metabolic and electrolyte aber- cess cortisol on mineralocorticoid receptors, rations.20 Other common effects and mani- similar to what occurs in chronic licorice ingestion. Under normal conditions, 11B- festations of hypercortisolism are listed in hydroxysteroid dehydrogenase converts cor- Table 4. tisol to cortisone and is the rate-limiting step Rates of cardiovascular and all-cause mor- in the mineralocorticoid action of cortisol. tality are increased in patients with long-term When plasma cortisol levels are in excess, hypercortisolism, even after plasma concen- however, the enzyme is saturated so that its trations of cortisol are normalized.21 action is insufficient, resulting in cortisol Figure 2 shows the cascade of the hypo- binding to mineralocorticoid receptors to thalamic-pituitary-adrenal axis.

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2 of the aforementioned tests should be per- formed, as 1 normal result may not be suffi- Hypothalamus cient to exclude the diagnosis.22,23 A 24-hour urinary cortisol collection and overnight dexamethasone suppression test are obtained. His 24-hour urinary free cortisol level is elevated at 6,600 µg (normal 4–100), CRH and suppression testing with 8 mg of dexa- methasone (a form of “high-dose” testing) demonstrates only an 8% decline in serum cortisol levels. Cortisol should generally drop more than 90%. Morning serum cortisol concentration is Anterior less than 5 µg/dL (140 nmol/L) in most pa- pituitary tients with Cushing disease (ie, a pituitary tu- mor), and is usually undetectable in normal ACTH-secreting tumor ACTH subjects. Only about 50% of neuroendocrine ACTH-secreting tumors will suppress with ACTH this test. Adrenal The patient’s clinical presentation, in con- cortex junction with his diagnostic testing, are thus consistent with Cushing syndrome.

Cortisol ■■ CUSHING SYNDROME Cushing syndrome is most often exogenous or iatrogenic, ie, a result of supraphysiologic doses of glucocorticoids used to treat a variety of inflammatory, autoimmune, and neoplastic Target tissues conditions. Figure 2. The hypothalamic-pituitary-adrenal axis. Endogenous Cushing syndrome, on the other hand, is rare, with an estimated preva- CRH = corticotropin-releasing hormone; ACTH = adrenocorticotropic hormone lence of 0.7 to 2.4 cases per million per year. ACTH-dependent causes account for 80% of ■■ TESTING FOR HYPERCORTISOLISM endogenous Cushing syndrome cases, with IN OUR PATIENT ACTH-secreting pituitary adenomas (Cush- ing disease) accounting for 75% to 80% and Given the patient’s clinical presentation ectopic ACTH secretion accounting for 15% and laboratory and imaging findings with to 20%. Less than 1% of cases are due to tu- normal plasma renin and aldosterone levels, mors that produce corticotropin-releasing a workup for suspected hypercortisolism is hormone (CRH). initiated. ACTH-independent Cushing syndrome Initial diagnostic testing for hypercorti- is diagnosed in 20% of endogenous cases solism depends on the degree of clinical sus- and is most commonly caused by a unilateral picion. In those with low probability of the adrenal tumor. Rare causes of ACTH-inde- disease, testing should consist of 1 of the fol- pendent disease include adrenal carcinoma, lowing, as a single negative test may be suf- McCune-Albright syndrome, and adrenal ficient to rule out the disease: hyperplasia.24 • 24-hour urinary cortisol levels • Overnight dexamethasone suppression The patient’s ACTH is high testing To determine whether this is an ACTH-de- • Late-night salivary cortisol measurements. pendent or independent process, the next step In those with a high index of suspicion, is to order an ACTH level. His ACTH level is

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Figure 3. Computed tomography of the chest depicting biopsy-proven small-cell carcinoma (arrows).

high at 107 pg/mL (normal < 46 pg/mL), con- ■■ ACTH-SECRETING firming the diagnosis of ACTH-dependent TUMORS Cushing syndrome. To find out if this ACTH-dependent pro- Cushing syndrome due to ectopic ACTH cess is due to a pituitary adenoma, magnetic 5 secretion is most commonly attributed to Severe cases resonance imaging (MRI) of the pituitary is which of the following tumors? obtained but is normal. of Cushing □□ Small-cell lung carcinoma Large masses (> 6 mm) strongly suggest □□ Pancreatic carcinoma syndrome Cushing disease, but these tumors are often □□ Medullary thyroid carcinoma small and may be missed even with more ad- are often □□ Gastrinoma vanced imaging techniques. Corticotropin- attributable secreting adenomas arising from normal cells Severe cases of Cushing syndrome are often to ectopic in the pituitary retain some sensitivity to glu- attributable to ectopic ACTH secretion due cocorticoid negative feedback and CRH stim- to an underlying malignancy, most commonly ACTH secretion ulation, and thus high-dose dexamethasone small-cell lung carcinoma or neuroendocrine suppression testing in conjunction with CRH tumors of pulmonary origin. Other causes in- stimulation testing can be used to differentiate clude pancreatic and thymic neuroendocrine Cushing disease from ectopic ACTH secre- tumors, gastrinomas, and medullary thyroid tion.24,25 Both of these tests have poor diagnos- carcinoma.25,26 tic accuracy, however, and thus inferior petro- Because most ACTH-producing tumors sal sampling remains the gold standard for the are intrathoracic, initial imaging in cases of diagnosis of Cushing disease. suspected ectopic ACTH secretion should Given this patient’s history of smoking focus on the chest, with CT the usual first and a right hilar pulmonary opacity on chest choice. Octreotide scintigraphy can also radiography, inferior petrosal sampling was be useful in localizing disease, as many neu- deferred in favor of CT of the chest, which roendocrine tumors express somatostatin showed a right consolidative lung lesion (Fig- receptors. Specialized positron-emission to- ure 3). Subsequent CT-guided fine-needle bi- mography scans may also be helpful in tumor opsy demonstrated a small-cell carcinoma. identification.24

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■■ TREATMENT OF CUSHING SYNDROME ■■ DISCUSSION DUE TO ECTOPIC ACTH SECRETION The differential diagnosis for hypokalemia is broad and relies on information obtained dur- Which of the following is most appropri- ing the history and physical examination, fol- 6ate medical therapy for suppression of cor- lowed by interpretation of selected laboratory tisol secretion in Cushing syndrome due to results. Myriad pathologies in diverse organ ectopic ACTH secretion? systems, eg, , renal tubular acidosis, □□ Spironolactone and adrenal disease, may be responsible for □□ Dexamethasone a low serum potassium. Further categorizing □□ Somatostatin potassium depletion on the basis of an associ- □□ Estrogen ated acid-base disturbance, such as metabolic □□ Ketoconazole alkalosis, allows one to use an algorithmic ap- proach that can identify specific etiologies re- , hypokalemia, hypertension, sponsible for both the potassium and the acid- psychiatric disturbances, venous thrombo- base disturbances. embolism, and systemic infections appear to Using the spot urine chloride in the set- be common in ectopic ACTH syndrome and ting of hypokalemic metabolic alkalosis with often correlate with the degree of hypercor- or without hypertension can narrow the dif- tisolemia. Severe Cushing syndrome due to ferential diagnosis and allow additional clini- ectopic ACTH secretion is an emergency re- cal findings to guide clinical problem-solving quiring prompt control of cortisol secretion. and decision-making, even for conditions not First-line treatments include steroidogen- commonly encountered in routine medical esis inhibitors (ketoconazole, metyrapone, practice. etomidate, mitotane) and glucocorticoid re- Obtaining renin and aldosterone mea- ceptor antagonists (mifepristone). High-dose surements in patients with potassium deple- spironolactone and eplerenone can also be tion, metabolic alkalosis, high urine chloride used to treat the hypertension and hypokale- excretion, and hypertension permits further mia associated with mineralocorticoid recep- categorization into 3 clinical groups: elevated tor stimulation. Definitive treatment involves aldosterone and renin (secondary hyperaldo- surgical resection, chemotherapy, or radio- steronism), elevated aldosterone and low re- therapy when applicable.24,25 nin (primary hyperaldosteronism), or appar- After confirmation of the diagnosis, the ent mineralocorticoid excess wherein neither patient is prescribed ketoconazole and spi- renin nor aldosterone are responsible for the ronolactone, with substantial improvement. syndrome. He subsequently is started on combination The patient in our case had apparent min- chemotherapy and radiation therapy for his eralocorticoid excess as a consequence of an small-cell lung carcinoma. ACTH-producing small-cell carcinoma. ■ ■■ REFERENCES doi:10.1681/ASN.2007070792 6. Rose BD. Metabolic alkalosis. In: Clinical Physiology of Acid-Base and 1. Martínez-Valles MA, Palafox-Cazarez A, Paredes-Avina JA. Severe Electrolyte Disorders. 4th ed. New York, NY: McGraw-Hill, Health hypokalemia, metabolic alkalosis and hypertension in a 54 year Professions Division; 1994:515. old male with ectopic ACTH syndrome: a case report. Cases J 2009; 7. Calhoun DA, Jones D, Textor S, et al; American Heart Association 2:6174. doi:10.4076/1757-1626-2-6174 Professional Education Committee. Resistant hypertension: diag- 2. Fernández-Rodríguez E, Villar-Taibo R, Pinal-Osorio I, et al. Severe nosis, evaluation, and treatment: a scientific statement from the hypertension and hypokalemia as first clinical manifestations in American Heart Association Professional Education Committee of ectopic Cushing’s syndrome. Arq Bras Endocrinol Metabol 2008; the Council for High Blood Pressure Research. Circulation 2008; 52(6):1066–1070. pmid:18820819 117(25):e510–e526. doi:10.1161/CIRCULATIONAHA.108.189141 3. Mani S, Rutecki GW. A patient with altered mental status and an 8. Koeppen BM, Stanton BA. Physiology of diuretic action. In: Renal acid-base disturbance. Cleve Clin J Med 2017; 84(1):27–34. Physiology. 5th ed. Philadelphia, PA: Elsevier Inc; 2013:167–178. doi:10.3949/ccjm.84a.16042 9. Blumenfeld JD, Sealey JE, Schlussel Y, et al. Diagnosis and treatment 4. Adrogué HJ, Madias NE. Secondary responses to altered acid-base of primary hyperaldosteronism. Ann Intern Med 1994; 121(11):877– status: the rules of engagement. J Am Soc Nephrol 2010; 21(6):920– 885. pmid:7978702 923. doi:10.1681/ASN.2009121211 10. Kempers MJ, Lenders JW, van Outheusden L, et al. Systematic re- 5. Huang CL, Kuo E. Mechanism of hypokalemia in magnesium defi- view: diagnostic procedures to differentiate unilateral from bilateral ciency. J Am Soc Nephrol 2007; 18(10):2649–2652. adrenal abnormality in primary aldosteronism. Ann Intern Med

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