Chapter 8: Disorders of the Adrenal Cortex

The adrenal cortex produces three classes of corticosteroid hormones: glucocorticoids (e.g., cortisol), mineralocorticoids (e.g., aldosterone), and adrenal androgen precursors (e.g., dehydroepiandrosterone [DHEA]) (Fig. 8-1). Glucocorticoids and mineralocorticoids act through specific nuclear receptors, regulating aspects of the physiologic stress response as well as blood pressure and electrolyte homeostasis. Adrenal androgen precursors are converted in the gonads and peripheral target cells to sex steroids that act via nuclear androgen and estrogen receptors.

Disorders of the adrenal cortex are characterized by deficiency or excess of one or several of the three major corticosteroid classes. Hormone deficiency can be caused by inherited glandular or enzymatic disorders or by destruction of the pituitary or adrenal gland by autoimmune disorders, infection, infarction, or iatrogenic events such as surgery or hormonal suppression. Hormone excess is usually the result of neoplasia, leading to increased production of adrenocorticotropic hormone (ACTH) by the pituitary or neuroendocrine cells (ectopic ACTH) or increased production of glucocorticoids, mineralocorticoids, or adrenal androgen precursors by adrenal nodules. Adrenal nodules are increasingly identified incidentally during abdominal imaging performed for other reasons.

The normal adrenal glands weigh 6–11 g each. They are located above the kidneys and have their own blood supply. Arterial blood flows initially to the subcapsular region and then meanders from the outer cortical zona glomerulosa through the intermediate zona fasciculata to the inner zona reticularis and eventually to the adrenal medulla. The right suprarenal vein drains directly into the vena cava, while the left suprarenal vein drains into the left renal vein.

During early embryonic development, the adrenals originate from the urogenital ridge and then separate from gonads and kidneys at about the sixth week of gestation. Concordant with the time of sexual differentiation (seventh to ninth week of gestation, Chap. 10), the adrenal cortex starts to produce cortisol and the adrenal sex steroid precursor DHEA. The orphan nuclear receptors SF1 (steroidogenic factor 1; encoded by the gene NR5A1) and DAX1 (dosage-sensitive sex reversal gene 1; encoded by the gene NR0B1), among others, play a crucial role during this period of development, as they regulate a multitude of adrenal genes involved in steroidogenesis.

Production of glucocorticoids and adrenal androgens is under the control of the hypothalamic-pituitary-adrenal (HPA) axis, whereas mineralocorticoids are regulated by the renin-angiotensin-aldosterone (RAA) system.

Glucocorticoid synthesis is under inhibitory feedback control by the hypothalamus and the pituitary (Fig. 8-2). Hypothalamic release of corticotropin-releasing hormone (CRH) occurs in response to endogenous or exogenous stress. CRH stimulates the cleavage of the 241–amino acid polypeptide proopiomelanocortin (POMC) by pituitary-specific prohormone convertase 1 (PC1), yielding the 39–amino acid peptide ACTH. ACTH is released by the corticotrope cells of the anterior pituitary and acts as the pivotal regulator of adrenal cortisol synthesis, with additional short-term effects on mineralocorticoid and adrenal androgen synthesis. The release of CRH, and subsequently ACTH, occurs in a pulsatile fashion that follows a circadian rhythm under the control of the hypothalamus, specifically its suprachiasmatic nucleus (SCN), with additional regulation by a complex network of cell-specific clock genes. Reflecting the pattern of ACTH secretion, adrenal cortisol secretion exhibits a distinct circadian rhythm, starting to rise in the early morning hours prior to awakening, with peak levels in the morning and low levels in the evening (Fig. 8-3).

Diagnostic tests assessing the HPA axis make use of the fact that it is regulated by negative feedback. Glucocorticoid excess is diagnosed by employing a dexamethasone suppression test. Dexamethasone, a potent synthetic glucocorticoid, suppresses CRH/ACTH by binding hypothalamic-pituitary glucocorticoid receptors and, therefore, results in downregulation of endogenous cortisol synthesis. Various versions of the dexamethasone suppression test are described in detail in Chap. 5. If cortisol production is autonomous (e.g., adrenal nodule), ACTH is already suppressed and dexamethasone has little additional effect. If cortisol production is driven by an ACTH-producing pituitary adenoma, dexamethasone suppression is ineffective at low doses but usually induces suppression at high doses. If cortisol production is driven by an ectopic source of ACTH, the tumors are usually resistant to dexamethasone suppression. Thus, the dexamethasone suppression test is useful to establish the diagnosis of Cushing’s syndrome and to assist with the differential diagnosis of cortisol excess.

Conversely, to assess glucocorticoid deficiency, ACTH stimulation of cortisol production is used. The ACTH peptide contains 39 amino acids but the first 24 are sufficient to elicit a physiologic response. The standard ACTH stimulation test involves administration of cosyntropin (ACTH 1-24), 0.25 mg IM or IV, and collection of blood samples at 0, 30, and 60 min for cortisol. A normal response is defined as a cortisol level >20 μg/dL (>550 nmol/L) 30–60 min after cosyntropin stimulation. A low-dose (1 μg cosyntropin IV) version of this test has been advocated; however, it has no superior diagnostic value and is more cumbersome to carry out. Alternatively, an insulin tolerance test (ITT) can be used to assess adrenal function. It involves injection of insulin to induce hypoglycemia, which represents a strong stress signal that triggers hypothalamic CRH release and activation of the entire HPA axis. The ITT involves administration of regular insulin 0.1 U/kg IV (dose should be lower if hypopituitarism is likely) and collection of blood samples at 0, 30, 60, and 120 min for glucose, cortisol, and growth hormone (GH), if also assessing the GH axis. Oral or IV glucose is administered after the patient has achieved symptomatic hypoglycemia (usually glucose <40 mg/dL). A normal response is defined as a cortisol >20 μg/dL and GH >5.1 μg/L. The ITT requires careful clinical monitoring and sequential measurements of glucose. It is contraindicated in patients with coronary disease, cerebrovascular disease, or seizure disorders, which has made the short cosyntropin test the commonly accepted first-line test.

Mineralocorticoid production is controlled by the RAA regulatory cycle, which is initiated by the release of renin from the juxtaglomerular cells in the kidney, resulting in cleavage of angiotensinogen to angiotensin I in the liver (Fig. 8-4). Angiotensin-converting enzyme (ACE) cleaves angiotensin I to angiotensin II, which binds and activates the angiotensin II receptor type 1 (AT1 receptor [AT1R]), resulting in increased adrenal aldosterone production and vasoconstriction. Aldosterone enhances sodium retention and potassium excretion, and increases the arterial perfusion pressure, which in turn regulates renin release. Because mineralocorticoid synthesis is primarily under the control of the RAA system, hypothalamic-pituitary damage does not significantly impact the capacity of the adrenal to synthesize aldosterone.

Similar to the HPA axis, the assessment of the RAA system can be used for diagnostic purposes. If mineralocorticoid excess is present, there is a counter-regulatory downregulation of plasma renin (see below for testing). Conversely, in mineralocorticoid deficiency, plasma renin is markedly increased. Physiologically, oral or IV sodium loading results in suppression of aldosterone, a response that is attenuated or absent in patients with autonomous mineralocorticoid excess.

ACTH stimulation is required for the initiation of steroidogenesis. The ACTH receptor MC2R (melanocortin 2 receptor) interacts with the MC2R-accessory protein MRAP, and the complex is transported to the adrenocortical cell membrane, where it binds to ACTH (Fig. 8-5). ACTH stimulation generates cyclic AMP (cAMP), which upregulates the protein kinase A (PKA) signaling pathway. Inactive PKA is a tetramer of two regulatory and two catalytic subunits that is dissociated by cAMP into a dimer of two regulatory subunits bound to cAMP and two free and active catalytic subunits. PKA activation impacts steroidogenesis in three distinct ways: (1) increases the import of cholesterol esters; (2) increases the activity of hormone-sensitive lipase, which cleaves cholesterol esters to cholesterol for import into the mitochondrion; and (3) increases the availability and phosphorylation of CREB (cAMP response element binding), a transcription factor that enhances transcription of CYP11A1 and other enzymes required for glucocorticoid synthesis.

Adrenal steroidogenesis occurs in a zone-specific fashion, with mineralocorticoid synthesis occurring in the outer zona glomerulosa, glucocorticoid synthesis in the zona fasciculata, and adrenal androgen synthesis in the inner zona reticularis (Fig.  8-1). All steroidogenic pathways require cholesterol import into the mitochondrion, a process initiated by the action of the steroidogenic acute regulatory (StAR) protein, which shuttles cholesterol from the outer to the inner mitochondrial membrane. The majority of steroidogenic enzymes are cytochrome P450 (CYP) enzymes, which are either located in the mitochondrion (side chain cleavage enzyme, CYP11A1; 11β-hydroxylase, CYP11B1; aldosterone synthase, CYP11B2) or in the endoplasmic reticulum membrane (17α-hydroxylase, CYP17A1; 21-hydroxylase, CYP21A2; aromatase, CYP19A1). These enzymes require electron donation via specific redox cofactor enzymes, P450 oxidoreductase (POR), and adrenodoxin/adrenodoxin reductase (ADX/ADR) for the microsomal and mitochondrial CYP enzymes, respectively. In addition, the short-chain dehydrogenase 3β-hydroxysteroid dehydrogenase type 2 (3β-HSD2), also termed Δ4,Δ5 isomerase, plays a major role in adrenal steroidogenesis.

The cholesterol side chain cleavage enzyme CYP11A1 generates pregnenolone. Glucocorticoid synthesis requires conversion of pregnenolone to progesterone by 3β-HSD2, followed by conversion to 17-hydroxyprogesterone by CYP17A1, further hydroxylation at carbon 21 by CYP21A2, and eventually, 11β-hydroxylation by CYP11B1 to generate active cortisol (Fig.  8-1). Mineralocorticoid synthesis also requires progesterone, which is first converted to deoxycorticosterone by CYP21A2 and then converted via corticosterone and 18-hydroxycorticosterone to aldosterone in three steps catalyzed by CYP11B2. For adrenal androgen synthesis, pregnenolone undergoes conversion by CYP17A1, which uniquely catalyzes two enzymatic reactions. Via its 17α-hydroxylase activity, CYP17A1 converts pregnenolone to 17-hydroxypregnenolone, followed by generation of the universal sex steroid precursor DHEA via CYP17A1 17, 20 lyase activity. The majority of DHEA is secreted by the adrenal in the form of its sulfate ester, DHEAS, generated by DHEA sulfotransferase (SULT2A1).

Following its release from the adrenal, cortisol circulates in the bloodstream mainly bound to cortisol-binding globulin (CBG) and to a lesser extent to albumin, with only a minor fraction circulating as free, unbound hormone. Free cortisol is thought to enter cells directly, not requiring active transport. In addition, in a multitude of peripheral target tissues of glucocorticoid action, including adipose, liver, muscle, and brain, cortisol is generated from inactive cortisone within the cell by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) (Fig. 8-6). Thereby, 11β-HSD1 functions as a tissue-specific prereceptor regulator of glucocorticoid action. For the conversion of inactive cortisone to active cortisol, 11β-HSD1 requires nicotinamide adenine dinucleotide phosphate (NADPH [reduced form]), which is provided by the enzyme hexose-6-phosphate dehydrogenase (H6PDH). Like the catalytic domain of 11β-HSD1, H6PDH is located in the lumen of the endoplasmic reticulum, and converts glucose-6-phosphate (G6P) to 6-phosphogluconate (6PGL), thereby regenerating NADP+ to NADPH, which drives the activation of cortisol from cortisone by 11β-HSD1.

In the cytosol of target cells, cortisol binds and activates the glucocorticoid receptor (GR), which results in dissociation of heat shock proteins (HSP) from the receptor and subsequent dimerization (Fig.  8-6). Cortisol-bound GR dimers translocate to the nucleus and activate glucocorticoid response elements (GRE) in the DNA sequence, thereby enhancing transcription of glucocorticoid-regulated genes (GR transactivation). However, cortisol-bound GR can also form heterodimers with transcription factors such as AP-1 or NF-κB, resulting in transrepression of proinflammatory genes, a mechanism of major importance for the anti-inflammatory action of glucocorticoids. It is important to note that corticosterone also exerts glucocorticoid activity, albeit much weaker than cortisol itself. However, in rodents, corticosterone is the major glucocorticoid, and in patients with 17-hydroxylase deficiency, lack of cortisol can be compensated for by higher concentrations of corticosterone that accumulates as a consequence of the enzymatic block.

Cortisol is inactivated to cortisone by the microsomal enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) (Fig. 8-7), mainly in the kidney, but also in the colon, salivary glands, and other target tissues. Cortisol and aldosterone bind the mineralocorticoid receptor (MR) with equal affinity; however, cortisol circulates in the bloodstream at about a thousandfold higher concentration. Thus, only rapid inactivation of cortisol to cortisone by 11β-HSD2 prevents MR activation by excess cortisol, thereby acting as a tissue-specific modulator of the MR pathway. In addition to cortisol and aldosterone, deoxycorticosterone (DOC)(Fig.  8-1) also exerts mineralocorticoid activity. DOC accumulation due to 11β-hydroxylase deficiency or due to tumor-related excess production can result in mineralocorticoid excess.

Aldosterone synthesis in the adrenal zona glomerulosa cells is driven by the enzyme aldosterone synthase (CYP11B2). The binding of angiotensin II to the AT1 receptor causes glomerulosa cell membrane depolarization by increasing intracellular sodium through inhibition of sodium potassium (Na⁺/K⁺) ATPase enzymes as well as potassium channels. This drives an increase in intracellular calcium by opening of voltage-dependent calcium channels or inhibition of calcium (Ca²⁺) ATPase enzymes. Consequently, the calcium signaling pathway is triggered, resulting in upregulation of CYP11B2 transcription (Fig. 8-8).

Analogous to cortisol action via the GR, aldosterone (or cortisol) binding to the MR in the kidney tubule cell dissociates the HSP–receptor complex, allowing homodimerization of the MR, and translocation of the hormone-bound MR dimer to the nucleus (Fig.  8-7). The activated MR enhances transcription of the epithelial sodium channel (ENaC) and serum glucocorticoid-inducible kinase 1 (SGK-1). In the cytosol, interaction of ENaC with Nedd4 prevents cell surface expression of ENaC. However, SGK-1 phosphorylates serine residues within the Nedd4 protein, reduces the interaction between Nedd4 and ENaC, and consequently, enhances the trafficking of ENaC to the cell surface, where it mediates sodium retention.

(See also Chap. 5) Cushing’s syndrome reflects a constellation of clinical features that result from chronic exposure to excess glucocorticoids of any etiology. The disorder can be ACTH-dependent (e.g., pituitary corticotrope adenoma, ectopic secretion of ACTH by nonpituitary tumor) or ACTH-independent (e.g., adrenocortical adenoma, adrenocortical carcinoma, nodular adrenal hyperplasia), as well as iatrogenic (e.g., administration of exogenous glucocorticoids to treat various inflammatory conditions). The term Cushing’s disease refers specifically to Cushing’s syndrome caused by a pituitary corticotrope adenoma.

Epidemiology

Cushing’s syndrome is generally considered a rare disease. It occurs with an incidence of 1–2 per 100,000 population per year. However, it is debated whether mild cortisol excess may be more prevalent among patients with several features of Cushing’s such as centripetal obesity, type 2 diabetes, and osteoporotic vertebral fractures, recognizing that these are relatively nonspecific and common in the population.

In the overwhelming majority of patients, Cushing’s syndrome is caused by an ACTH-producing corticotrope adenoma of the pituitary (Table 8-1), as initially described by Harvey Cushing in 1912. Cushing’s disease more frequently affects women, with the exception of prepubertal cases, where it is more common in boys. By contrast, ectopic ACTH syndrome is more frequently identified in men. Only 10% of patients with Cushing’s syndrome have a primary, adrenal cause of their disease (e.g., autonomous cortisol excess independent of ACTH), and most of these patients are women. Overall, the medical use of glucocorticoids for immunosuppression, or for the treatment of inflammatory disorders, is the most common cause of Cushing’s syndrome.

Etiology

In at least 90% of patients with Cushing’s disease, ACTH excess is caused by a corticotrope pituitary microadenoma, often only a few millimeters in diameter. Pituitary macroadenomas (i.e., tumors >1 cm in size) are found in only 5–10% of patients. Pituitary corticotrope adenomas usually occur sporadically but very rarely can be found in the context of multiple endocrine neoplasia type 1 (MEN 1) (Chap. 29).

Ectopic ACTH production is predominantly caused by occult carcinoid tumors, most frequently in the lung, but also in thymus or pancreas. Because of their small size, these tumors are often difficult to locate. Advanced small-cell lung cancer can cause ectopic ACTH production. In rare cases, ectopic CRH and/or ACTH production has been found to originate from medullary thyroid carcinoma or pheochromocytoma, the latter co-secreting catecholamines and ACTH.

The majority of patients with ACTH-independent cortisol excess harbor a cortisol-producing adrenal adenoma; intratumor mutations, i.e., somatic mutations in the PKA catalytic subunit PRKACA, have been identified as cause of disease in 40% of these tumors. Adrenocortical carcinomas may also cause ACTH-independent disease and are often large, with excess production of several corticosteroid classes.

A rare but notable cause of adrenal cortisol excess is macronodular adrenal hyperplasia with low circulating ACTH, but with evidence for autocrine stimulation of cortisol production via intraadrenal ACTH production. These hyperplastic nodules are often also characterized by ectopic expression of G protein–coupled receptors not usually found in the adrenal, including receptors for luteinizing hormone, vasopressin, serotonin, interleukin 1, catecholamines, or gastric inhibitory peptide (GIP), the cause of food-dependent Cushing’s. Activation of these receptors results in upregulation of PKA signaling, as physiologically occurs with ACTH, with a subsequent increase in cortisol production. A combination of germline and somatic mutations in the tumor-suppressor gene ARMC5 have been identified as a prevalent cause of Cushing’s due to macronodular adrenal hyperplasia. Germline mutations in the PKA catalytic subunit PRKACA can represent a rare cause of macronodular adrenal hyperplasia associated with cortisol excess.

Mutations in one of the regulatory subunits of PKA, PRKAR1A, are found in patients with primary pigmented nodular adrenal disease (PPNAD) as part of Carney’s complex, an autosomal dominant multiple neoplasia condition associated with cardiac myxomas, hyperlentiginosis, Sertoli cell tumors, and PPNAD. PPNAD can present as micronodular or macronodular hyperplasia, or both. Phosphodiesterases can influence intracellular cAMP and can thereby impact PKA activation. Mutations in PDE11A and PDE8B have been identified in patients with bilateral adrenal hyperplasia and Cushing’s, with and without evidence of PPNAD.

Another rare cause of ACTH-independent Cushing’s is McCune-Albright syndrome, also associated with polyostotic fibrous dysplasia, unilateral café-au-lait spots, and precocious puberty. McCune-Albright syndrome is caused by activating mutations in the stimulatory G protein alpha subunit 1, GNAS-1 (guanine nucleotide binding protein alpha stimulating activity polypeptide 1), and such mutations have also been found in bilateral macronodular hyperplasia without other McCune-Albright features and, in rare instances, also in isolated cortisol-producing adrenal adenomas (Table 8-1; Chap. 36).

Clinical manifestations

Glucocorticoids affect almost all cells of the body, and thus signs of cortisol excess impact multiple physiologic systems (Table 8-2), with upregulation of gluconeogenesis, lipolysis, and protein catabolism causing the most prominent features. In addition, excess glucocorticoid secretion overcomes the ability of 11β-HSD2 to rapidly inactivate cortisol to cortisone in the kidney, thereby exerting mineralocorticoid actions, manifest as diastolic hypertension, hypokalemia, and edema. Excess glucocorticoids also interfere with central regulatory systems, leading to suppression of gonadotropins with subsequent hypogonadism and amenorrhea, and suppression of the hypothalamic-pituitary-thyroid axis, resulting in decreased thyroid-stimulating hormone (TSH) secretion.

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. 8-9), 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 observed (Fig.  8-9) 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.

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 may also occur. Even after cure, long-term health may be affected by persistently impaired health-related quality of life and increased risk of cardiovascular disease and osteoporosis with vertebral fractures, depending on the duration and degree of exposure to significant cortisol excess.

Diagnosis

The most important first step in the management of patients with suspected Cushing’s syndrome is to establish the correct diagnosis. Most mistakes in clinical management, leading to unnecessary imaging or surgery, are made because the diagnostic protocol is not followed (Fig. 8-10). This protocol requires establishing the diagnosis of Cushing’s beyond doubt prior to employing any tests used for the differential diagnosis of the condition. In principle, after excluding exogenous glucocorticoid use as the cause of clinical signs and symptoms, suspected cases should be tested if there are multiple and progressive features of Cushing’s, particularly features with a potentially higher discriminatory value. Exclusion of Cushing’s is also indicated in patients with incidentally discovered adrenal masses.

A diagnosis of Cushing’s can be considered as established if the results of several tests are consistently suggestive of Cushing’s. These tests may include increased 24-h urinary free cortisol excretion in three separate collections, failure to appropriately suppress morning cortisol after overnight exposure to dexamethasone, and evidence of loss of diurnal cortisol secretion with high levels at midnight, the time of the physiologically lowest secretion (Fig.  8-10). Factors potentially affecting the outcome of these diagnostic tests have to be excluded such as incomplete 24-h urine collection or rapid inactivation of dexamethasone due to concurrent intake of CYP3A4-inducing drugs (e.g., antiepileptics, rifampicin). Concurrent intake of oral contraceptives that raise CBG and thus total cortisol can cause failure to suppress after dexamethasone. If in doubt, testing should be repeated after 4–6 weeks off estrogens. Patients with pseudo-Cushing states, i.e., alcohol-related, and those with cyclic Cushing’s may require further testing to safely confirm or exclude the diagnosis of Cushing’s. In addition, the biochemical assays employed can affect the test results, with specificity representing a common problem with antibody-based assays for the measurement of urinary free cortisol. These assays have been greatly improved by the introduction of highly specific tandem mass spectrometry.

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.  8-10). 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. 8-11), 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.

For ACTH-dependent cortisol excess (Chap. 5), 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. These tests exploit the fact that most pituitary corticotrope adenomas 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.  8-10). 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.  8-10), 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 cortisol-lowering agents should be used prior to IPSS.

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.

TREATMENT

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.

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 8-3). 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 8-3) 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 aldosterone-producing adenomas usually measure <2 cm in diameter.

A rare cause of aldosterone excess is glucocorticoid-remediable aldosteronism (GRA), which is caused by a chimeric gene resulting from cross-over of promoter sequences between the CYP11B1 and CYP11B2 genes that are involved in glucocorticoid and mineralocorticoid synthesis, respectively (Fig.  8-1). 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.

Other rare causes of mineralocorticoid excess are listed in Table 8-3. 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.  8-7). 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. 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.  8-1). 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.  8-7), and thereby decreasing receptor internalization and degradation. The constitutively active ENAC drives hypokalemic hypertension, resulting in an autosomal dominant disorder termed Liddle’s syndrome.

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.

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.

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. 8-12). The accepted screening test is concurrent measurement of plasma renin and aldosterone with subsequent calculation of the aldosterone-renin ratio (ARR) (Fig.  8-12); 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 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 8-4).

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.  8-12). 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.

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.

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.  8-12). 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.

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.  8-12). 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 blocker amiloride (5–10 mg bid).

In patients with normal adrenal morphology and family history of early-onset, severe hypertension, a diagnosis of GRA should be 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.

The diagnosis of nonaldosterone-related mineralocorticoid excess is based on documentation of suppressed renin and suppressed aldosterone in the presence of hypokalemic hypertension. This testing is best carried out by employing urinary steroid metabolite profiling by gas chromatography/mass spectrometry (GC/MS). An increased free 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 irregular steroid secretion pattern in a DOC-producing adrenocortical carcinoma (Fig.  8-12). If the GC/MS profile is normal, then Liddle’s syndrome should be considered. It is very sensitive to amiloride treatment but will not respond to MR antagonist treatment, because the defect is due to a constitutively active ENaC.

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, α- and β-adrenergic, luteinizing hormone, vasopressin V1, and interleukin 1 receptors) have been identified in some sporadic cases of macronodular adrenocortical hyperplasia.

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 cortisol- or aldosterone-producing adrenocortical adenoma or a pheochromocytoma associated with catecholamine excess (Table 8-5). 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 8-5).

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?

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. 8-13). Furthermore, autonomous cortisol and aldosterone secretion resulting in Cushing’s syndrome or primary aldosteronism, respectively, require exclusion. Adrenal incidentalomas 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.

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.  8-11). 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, whereas most malignant lesions appear lobulated and inhomogeneous. Pheochromocytoma and adrenomyelolipoma may also exhibit lobulated and inhomogeneous features. 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.

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.

Adrenal masses associated with confirmed hormone excess or suspected malignancy are usually treated surgically (Fig.  8-13) 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 peri- and 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.

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 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.

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.

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.

Tumor staging at diagnosis (Table 8-6) 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. 8-14) 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.  8-14). 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.

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.

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 ≥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 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 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.

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 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.

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. 29) (Table 8-7). APS1, also termed APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal 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 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.

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 (Table 8-7); 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 8-7) 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.  8-5), and factors involved in redox regulation (NNT) and DNA repair (MCM4, CDKN1C).

Secondary adrenal insufficiency is the consequence of dysfunction of the hypothalamic-pituitary component of the HPA axis (Table 8-8). Excluding iatrogenic suppression, the overwhelming majority of cases are caused by pituitary or hypothalamic tumors or their treatment by surgery or irradiation (Chap. 5). 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 8-8). Mutations in the ACTH precursor POMC or in factors regulating pituitary development are genetic causes of ACTH deficiency (Table  8-8).

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 8-9). 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 8-9). 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 8-9), if exogenous glucocorticoids are stopped abruptly. However, patients will appear clinically cushingoid as a result of the preceding overexposure to glucocorticoids.

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. 8-15). Conversely, in secondary adrenal insufficiency, the skin has an alabaster-like paleness due to lack of ACTH secretion.

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.

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).

Diagnosis

The diagnosis of adrenal insufficiency is established by the short cosyntropin test, a safe and reliable tool with excellent predictive diagnostic value (Fig. 8-16). 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 (Fig.  8-3). 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.

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.  8-16). 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, very-long-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 trauma, should be carefully explored, particularly in patients with no obvious MRI lesion.

TREATMENT

(See also Chap. 10) 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.  8-1). Invariably, patients affected by CAH exhibit glucocorticoid deficiency. Depending on the exact step of enzymatic block, they may also have excess production of mineralocorticoids or deficient production of sex steroids (Table 8-10). 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 8-10).

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.  8-1), 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.

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.

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 rest tumors (Fig. 8-17). 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.

TREATMENT