Why does hyperpigmentation occur in Addison's disease

Adrenal insufficiency and adrenal incidentalomas

introduction

This review article deals with primary adrenal insufficiency (Addison's disease) and adrenal incidentaloma with the associated clarification of pheochromocytoma, hypercortisolism (Cushing's syndrome) and primary hyperaldosteronism (Conn's syndrome).

Primary adrenal insufficiency

Primary adrenal insufficiency is defined as the failure of the adrenal glands to produce a sufficient amount of glucocorticoids and / or mineralocorticoids [1]. It is a potentially life-threatening disease, which was first described by Thomas Addison in 1855, with the cardinal symptoms weakness, fatigue, anorexia / weight loss, abdominal pain, orthostatic hypotension, salt craving and characteristic hyperpigmentation [2]. The primary adrenal insufficiency, also known as Addison's disease, was fatal until 1949, since it was only from this point in time that glucocorticoids could be synthesized and used for the treatment of this disease. Primary adrenal insufficiency must be differentiated from secondary and tertiary adrenal insufficiency, which are often simply referred to as central adrenal insufficiency. Secondary adrenal insufficiency is usually the result of a pituitary disease with reduced ACTH (adrenocorticotropic hormone) secretion, or the result of a reduced response of the adrenal glands to ACTH (e.g. in the case of genetically determined ACTH resistance). Tertiary adrenal insufficiency results from a reduced synthesis or effect of CRH (corticotropine releasing hormone or corticotropin releasing factor, CRF) and / or ADH (antidiuretic hormone or vasopressin) from the hypothalamus with a consequent reduced release of ACTH from the anterior pituitary gland (note: also ADH stimulates ACTH secretion). While central (secondary and tertiary) adrenal insufficiency usually "only" shows a significant glucocorticoid deficiency, primary adrenal insufficiency usually shows deficiency symptoms of glucocorticoids, mineralocorticoids (aldosterone) and androgens (e.g. dehydroepindrosterone [DHEA], which is found in the liver metabolized to DHEA sulfate [DHEA-S]).

Regarding the epidemiology of primary adrenal insufficiency, this disease has a prevalence of around 100 to 140 cases per million population, and an estimated incidence of 4 to 6 per million per year in European and Western countries. The incidence of this disease has increased over the past few decades. Women are more frequently affected than men, although the disease occurs at any age, but preferably between the ages of 30 and 50.

In developed countries, 80 to 90% of all primary adrenal insufficiency can be traced back to autoimmune adrenalitis, with around half of these patients also suffering from other autoimmune diseases as part of a polyglandular autoimmune syndrome (e.g. Hashimoto's thyroiditis, type 1 diabetes mellitus, autoimmune gastritis, vitiligo , Hypoparathyroidism, etc.). In most cases of this autoimmune adrenalitis, 21-hydroxylase antibodies can be detected, which are often detectable years before the disease manifests and represent a sufficient diagnostic criterion for the autoimmune genesis of primary adrenal insufficiency. While tuberculosis as the cause of primary adrenal insufficiency is becoming increasingly rare in Western countries, there are numerous other causes that can lead to adrenal gland destruction, such as: B. bleeding during sepsis, metastases, surgery or medication (e.g. azole antimycotics). Among the numerous, but extremely rare, genetic causes of primary adrenal insufficiency is v. a. highlight adrenoleukodystrophy, which is an X-linked disease with v. a. neurological symptoms, but adrenal insufficiency can be the first disease manifestation.

The clinical symptoms of patients with primary adrenal insufficiency include various, mostly relatively unspecific, symptoms and laboratory changes (Table 1), although the hyperpigmentation can be very characteristic and pronounced. This is due to the fact that ACTH and melanocyte-stimulating hormone (MSH) and the related metabolites / fragments originate from a single precursor molecule, namely proopiomelanocortin (POMC). a. is stimulated on areas of the skin exposed to pressure; typically z. B. on hands / elbows / skin folds, but also buccal oral mucosa. The initial diagnosis of primary adrenal insufficiency is a major clinical challenge, as many patients are only correctly diagnosed years (often> 10 years) after the first symptoms (the most common misdiagnoses are psychiatric or gastrointestinal diseases). It is not uncommon for primary adrenal insufficiency to manifest itself as a potentially life-threatening "Addison's crisis" B. triggered by stressful situations such as operations, trauma, or infections.

Diagnosis

Diagnostic work-up for primary adrenal insufficiency is recommended in acutely ill patients who suffer from otherwise unexplainable symptoms / complaints that are considered suggestive of primary adrenal insufficiency: volume deficiency, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or , especially in children, hypoglycemia [1]. In the case of pronounced symptoms, however, if adrenal insufficiency is suspected (suspicion of Addison's crisis), appropriate therapy (e.g. 100 mg hydrocortisone iv [Solu-Cortef®]) should be given. In such cases, serum / plasma should be taken before therapy is initiated for a determination of cortisol / ACTH is recommended. However, unambiguous detection (or exclusion) of adrenal insufficiency by determining cortisol in the serum alone in the morning (6:00 to 10:00) is only insufficiently possible, with a cortisol value of less than 5 µg / dL (50 ng / ml or 140 nmol / L ) is a clear indication of adrenal insufficiency. However, this is only possible under the condition that no exogenous glucocorticoids are administered (cave: exogenous glucocorticoids can suppress the endogenous cortisol and ACTH levels, not only with oral or iv injections, but also, for example, sometimes with joint infiltration or nasal sprays or transdermal application; cave: in contrast to hydrocortisone [= cortisol], many synthetic glucocorticoids are only partially measured by common cortisol assays, whereby dexamethasone is not detected by common assays). At which morning cortisol level primary adrenal insufficiency can be ruled out is controversial, with the relevant serum cortisol limit values ​​in the range of> 10.3 to 17 µg / dL (103 to 170 ng / mL or 285 to 480 nmol / L) are located. However, the preferred and recommended gold standard test for suspected primary adrenal insufficiency is the ACTH short test (cosyntropin short test). In this test, after a basal serum cortisol value has been taken, the i. v. Injection of 250 µg ACTH (1 ampoule Synacthen®) with another serum cortisol determination after 30 (or 60) min. An increase in the cortisol value to> 18 µg / dL (> 500 nmol / L or 180 ng / mL) is considered as proof for a sufficient adrenal function. This test is clinically very well tolerated and can be carried out at any time of the day, regardless of the diet [3, 4]. If the cortisol level after ACTH stimulation is insufficient, plasma ACTH should be determined for further differential diagnosis of adrenal insufficiency. If the plasma ACTH value is more than twice the upper limit of the reference range, this finding indicates the presence of primary adrenal insufficiency, whereas low ACTH values ​​are indicative of central adrenal insufficiency. In the course of the investigation of primary adrenal insufficiency, a simultaneous determination of plasma renin and aldosterone is recommended in order to diagnose a mineralocorticoid deficiency, which is characterized by increased renin with (inappropriately) low aldosterone. When primary adrenal insufficiency is beginning, the mineralocorticoid deficiency can be predominant (or even the only sign), as autoimmunological damage to the adrenal gland is often initially v. a. affects the outer zona glomerulosa.

After the diagnosis of primary adrenal insufficiency is confirmed, an etiological evaluation should always be performed. In this regard, the 21-hydroxylase antibodies should initially be determined which, if positive, provide practical evidence of autoimmune adrenalitis (Addison's disease), in which case diagnostic investigations should also be carried out with regard to other autoimmune diseases / endocrinopathies (e.g. Hashimoto's thyroiditis) , Type 1 diabetes mellitus, etc.). In male adolescents / children, negative 21-hydroxylase antibodies should be investigated for adrenoleukodystrophy by determining long-chain fatty acids, and 17-hydroxyprogesterone should also be determined in children in order to rule out adrenogenital syndrome (AGS), in which the age of 17 -Hydroxyprogesterone would be increased. Imaging (ieL computed tomography [CT]) of the adrenal glands should be carried out in the case of negative 21-hydroxylase antibodies in order to e.g. B. to detect infiltrative processes or metstasis as the cause of primary adrenal insufficiency. In selected cases, the clinical symptoms and / or family history can of course point to one of the rare, v. a. genetic, may be indicative of the causes of primary adrenal insufficiency.

Initiation of therapy

All patients with primary adrenal insufficiency should receive glucocorticoid therapy. In principle, a hydrocortisone dose of 15 to 25 mg (e.g. 1 tablet Hydrocortone® contains 20 mg hydrocortisone; bioavailability approx. 96%), divided into 2 or 3 doses per day, is recommended. Due to the relatively short plasma half-life of hydrocortisone (approx. 90 min), repeated administration on one day is recommended (note: the biological and therefore clinically relevant half-life of hydrocortisone approx. 8–12 h). The largest dose of Hydrocortone (approx. 50 to 75% of the daily dose) should be given in the morning after getting up. With 2 doses per day, the second dose should be given about 2 hours after lunch (or about 2 p.m. to 3 p.m.), and with 3 doses per day, the second dose should be given at lunch and the third dose early To be taken in the evening, but at least 4 to 6 hours before bed rest. A frequently used “standard” dosage of hydrocortisone is therefore 15 mg (3/4 tablet) in the morning and 5 mg (1/4 tablet) in the afternoon, or 10 mg (1/2 tablet) in the morning, 5 mg (1/4 tablet) ) at noon and 5 mg (1/4 tablet) in the early evening / afternoon (note: in some countries 15 to 25 mg daily, cortisone acetate 20 to 35 mg daily is used instead of hydrocortisone). In the case of limited patient compliance with regard to taking hydrocortisone several times a day and / or inadequate treatment response with regard to z. B. Quality of life or ability to work, instead of hydrocortisone, therapy with prednisolone (Aprednislon® or Prednisolon®) 3 to 5 mg daily, divided into 1-2 doses (e.g. 5 mg daily in the morning). Dexamethasone (Fortecortin®) should not be used to treat primary adrenal insufficiency due to potential Cushingoid side effects. There are also newer glucocorticoid preparations z. B. “dual-release-hydrocortisone” (trade name: Plenadren®), a hydrocortisone preparation which, due to its pharmacokinetics, only has to be given once a day [5]. In addition to glucocorticoid substitution, in the case of primary adrenal insufficiency and proven aldosterone deficiency, therapy with fludrocortisone (1 Astonin-H-Tablet® contains 0.1 mg fludrocortisone, i.e. a synthetic aldosterone analogue with a plasma half-life of approx. 200 min and a biological, i.e. clinically relevant half-life from approx. 18 to 36 h) in a once-daily morning dose of usually 0.05 to 0.2 mg per day. Therapy with DHEA, which is available as a dietary supplement without a prescription in many countries (currently with a prescription in Austria), can be used in premenopausal women with primary adrenal insufficiency and reduced or absent libido, depression, anxiety and listlessness (despite adequate glucocorticoid and mineralocorticoid therapy) administered at a dose of 25 to 50 mg daily in the morning.

Therapy management and controls

Therapy control with, if necessary, dose adjustment in patients with primary adrenal insufficiency is based on a. on a clinical assessment, and there should be at least annual check-ups by a doctor with appropriate endocrinological expertise. In glucocorticoid therapy, v. a. to find a dose that includes both an over-substitution, which z. B. can lead to weight gain, insomnia and edema, as well as an underdose, which z. B. can lead to nausea, loss of appetite, weight loss, lethargy and hyperpigmentation, avoid as much as possible. A detailed patient history including z. B. Daily and work routine as well as general well-being etc. are important (e.g. through questionnaires such as the AddiQol: Questionnaire on the quality of life of Addison patients), whereby attention should also be paid to blood pressure, glucose metabolism and the development of osteoporosis. A serum cortisol determination for therapy monitoring is generally not recommended. In certain situations e.g. B. in the case of suspended malabsorption, however, a serum cortisol determination (possibly also a daily profile) can be helpful for determining the dose (note: otherwise the glucocorticoids are practically completely absorbed enterally). After taking hydrocortisone, the serum cortisol values ​​peak after approx. 1 hour, although some authors recommend determining cortisol approx Cortisol) (note: in one study, a value of more than 402 nmol / L [approx. 14.5 µg / dL or 145 ng / mL] was found for the 2-hour cortisol value after taking hydrocortone 3 times a day as an indicator of over-substitution indicated) [6]. A plasma ACTH determination is also not recommended for therapy control, since the ACTH often remains elevated despite adequate substitution therapy (due to a disturbed feedback mechanism) (caution: ACTH normalization is not the therapy goal). Finding the dose taking body weight into account appears sensible, with the physiological, endogenous cortisol production being around 5–8 mg / m2 per day corresponds to a hydrocortisone dose of approx. 15 to 25 mg per day. In practice, there should also be extensive patient training, with patients receiving a standard dose of z. B. 20 mg hydrocortisone daily. With special daily routines z. On stressful days (e.g. intense physical activity), administer 25 to 30 mg daily (i.e. 5 to 10 mg more than usual). In febrile illnesses, the hydrocortisone doses should be doubled (> 38 ° C) or tripled (> 39 ° C) until recovery (usually an increased substitution dose for 2–3 days, then the standard dose taken again). Every patient should also have an emergency ID card and an emergency kit for self-injection of glucocorticoids, e.g. B. Hydrocortisone 100 mg i.p. m. or s. c. in acute situations (such as gastrointestinal infections) to prevent an Addison crisis. For small operations, hydrocortisone should be increased to 25 to 75 mg daily for 1–2 days (alternatively, 100 mg hydrocortisone iv shortly before anesthesia and then double the oral hydrocortisone standard dose for 1 day), and for major operations (or trauma or severe illness with ICU stay) should (preoperatively) hydrocortisone 100 mg i.v. v. are administered, with subsequently 200 mg hydrocortisone as a perfusor over 24 h (alternatively 50 mg hydrocortisone bolus iv every 6 h) and subsequent gradual dose reduction and switch to peroral hydrocortisone depending on the clinic (i.e. on the next day e.g. only 100 mg hydrocortisone iv per day; and then or immediately, if the course is good, possibly double the oral hydrocortisone standard dose for 1–2 days and then the standard dose again) (Cave: iv dosages refer to hydrocortisone ie e.g. Solu-Cortef®, whereas when prednisolone is administered ie Soludacortin® or Prednisolut® would only be about 1/4 to 1/5 of the dose of hydrocortisone needed).In addition, in such acute / stressful situations, sufficient fluids with electrolytes / glucose should always be supplied, and it should be borne in mind that, in contrast to prednisolone, hydrocortisone has a relatively strong mineralocorticoid effect (40 mg hydrocortisone have about the same mineralocorticoid as 0.1 mg fludrocortisone; Note: If fludrocortisone is not available, more hydrocortisone can be administered in exceptional situations, e.g. temporarily, in order to achieve a corresponding mineralocorticoid effect). Regarding the therapy control of the fludrocortisone medication, in addition to the anamnesis regarding z. B. hunger for salt v. a. to control blood pressure (ideally measured while sitting and standing), serum electrolytes and renin (target range: high normal renin level). During stays in extremely hot climates with increased sweating, the dose of fludrocortisone can be temporarily increased, and in hypertensive patients the dose of fludrocortisone can be reduced a little on a trial basis. If antihypertensive therapy is necessary, v. a. Angiotensin Converting Enzyme (ACE) inhibitors or angiotensin II blockers to counteract the vasoconstrictive effects of the often high angiotensin II (cave: mineralocorticoid receptor [MR] blockers such as spironolactone or eplerenone are contraindicated in patients with primary adrenal insufficiency). With regard to DHEA therapy, which is only even considered in premenopausal women (in men, the androgens of the adrenal cortex only play a comparatively minor role), an evaluation should be made about 6 months after the start of therapy to determine whether there is a subjective improvement in the symptoms (e .g . Libido, depression, listlessness), because only in this case a continuation of the therapy is recommended. Dose adjustment of the DHEA therapy is carried out in the controls by measuring the morning serum DHEA-S (without taking DHEA in the morning), with a mean normal value given as the target value for premenopausal women.

During the (at least) annual check-ups, patients with autoimmune adrenalitis should also regularly evaluate the occurrence of other endocrinopathies such as B. thyroid diseases (Hashimoto's thyroiditis), diabetes mellitus, hypogonadism (especially ovarian insufficiency), celiac disease and autoimmune gastritis with vitamin B12 deficiency. Therefore, at least the following parameters should be determined in the annual check-ups: TSH, T4 (and T3), HbA1c, blood count and vitamin B12 as well as, if necessary, transglutaminase antibodies and total IgA level. Hypothyroidism in primary adrenal insufficiency should only really be assessed and treated after glucocorticoid substitution has been initiated, since on the one hand TSH often declines after glucocorticoid substitution and thyroid hormone substitution also stimulates the breakdown / metabolism of glucocorticoids and can even worsen the adrenal insufficiency in some cases (due to increased adrenal insufficiency) 11-β-hydroxysteroid dehydrogenase 2 expression with increased metabolism of cortisol into the inactive cortisone). Some authors also recommend taking bone density measurements every 3 to 5 years. Women should definitely be informed about the increased risk of premature ovarian insufficiency and, if necessary, further evaluated and, if necessary, treated (e.g. with the help of assisted reproductive medicine). In this context, it should also be mentioned that if a pregnancy occurs, of course (!) The substitution therapy must be continued and a check-up should be carried out at least once per trimester. Here v. a. In the last trimester, an increased glucocorticoid requirement (approx. 5–10 mg hydrocortisone more) can be expected, and the substitution therapy should be increased at birth as in major surgery (e.g. hydrocortisone 100 mg iv at induction of labor; thereafter every 6 to Hydrocortisone 50 to 100 mg iv again up to birth 8 h; in the 1–2 days after birth double the standard oral hydrocortisone dose [e.g. 40 mg daily] and then reduce it again to the single standard dose [7]. With regard to pregnancy, it should also be noted that hydrocortisone is inactivated / metabolized in the placenta, and that progesterone has an anti-mineralocorticoid effect, which is often well balanced by an increased hydrocortisone dose with regard to the mineralocorticoid effect, but sometimes an increase the fludrocortisone dose may be necessary (cave: renin is physiologically increased during pregnancy and is therefore not well suited for therapy control in pregnant women; the cortisol-binding globulin [CBG] is also increased during pregnancy with consequently higher serum cortisol values).

Adrenal incidentaloma

Adrenal incidentalomas are adrenal masses larger than (or at least) 1 cm. H. detected in the context of imaging diagnostics that were not performed on the basis of a suspected adrenal disease or staging examination in the case of a known malignancy [8, 9]. The prevalence of adrenal incidentalomas in such CT examinations is about 4 to 5% with a clear age-dependency, i.e. H. well below 1% in 20 to 30 year olds and approx. 5 to 10% in over 70 year olds [8–14]. An adrenal incidentaloma can have a wide variety of entities, whereby in most cases (approx. 80 to 85%) it is an endocrinologically inactive adrenal adenoma (cortisol-producing adenoma approx. 5–10%, pheochromocytoma approx. 3–5%, aldosterone-producing Adenoma approx. 2%), but the prevalence figures in the literature (presumably due to differently selected study populations) vary significantly (see Table 2 for the possible entities of an adrenal incidentaloma). In patients with an adrenal incidentaloma and no known malignancy, the prevalence of a malignant tumor or metastasis is shown in a very well-founded review with a prevalence for adrenocortical carcinoma of 1.9% (0.8 to 3.0%) and for metastases given as 0.7% (0.0 to 1.4%) [15, 16]. With specially selected study populations and v. a. In patients with previously known malignancies, the prevalence of malignant lesions (mostly metastases) is of course much higher.

In practice, when diagnosing an adrenal incidentaloma, two main questions arise: 1. Is it a malignant tumor? and 2. Is the adrenal incidentaloma endocrinically active?

Diagnostic evaluation and imaging in adrenal incidentaloma

Native CT (without contrast agent) is primarily recommended as imaging for the clarification of an adrenal incidentaloma [13, 14]. Other (more expensive) imaging procedures such as According to various guidelines / recommendations, e.g. contrast medium CT, MRT or PET / (CT) should only be used in exceptional cases, whereby MRI has become increasingly important as an alternative imaging (without radiation exposure!) [11–14, 17 ]. In people under 40 years of age and pregnant women, MRI is even recommended as the primary imaging method [13].

When assessing the adrenal gland CT, v. a. the size and the density (which is given in Hounsfield units [HU]) are used to assess dignity. Adrenal masses in patients without previously known malignancies that are smaller than 1.0 cm (and therefore, strictly speaking, are not classic incidentalomas at all due to their size) do not need to be further clarified per se [12, 14]. Characteristic of a typical benign adrenal incidentaloma is a size smaller than 4 cm, a low density (≤10 HU; in the CT image, darker structures have a lower density) and a homogeneous structure. According to the guideline of the European Society of Endocrinology, no further imaging should be performed for homogeneous adrenal incidentalomas with a size of less than 4 cm and a density of ≤10 HU [13, 14]. This recommendation is based on a. that such incidentalomas have an extremely low risk of malignancy and, of course, radiation exposure from a CT scan can induce a malignancy [15, 18, 19]. If a cyst or adrenal myelolipoma is diagnosed, which is characterized by very low density values ​​(e.g. HU less than −20 to −40), no radiological follow-up should be carried out (regardless of size) [12]. If the adrenal incidentaloma cannot be clearly assigned in the initial imaging with regard to the dignity and shows no hormonal activity, there are basically three options for further action, which should best be discussed / decided on an interdisciplinary basis: 1.) Immediately another / another Imaging, 2.) Imaging control in 6–12 months or 3.) Immediate surgery. In cases of unclear dignity and / or a size of> 4 cm, radiological follow-up is often recommended after 6–12 months. If there is an increase in size of the maximum diameter of> 20% (but at least 5 mm) in the follow-up, the operation is recommended. If the size increases by 10–20%, another imaging should be done in 6–12 months. If there is no significant growth (<10%) in the follow-up, no further imaging should be performed. It should be It should also be noted that adrenocortical carcinomas usually have a growth rate of over 2 cm per year and have a very poor prognosis [8, 11, 20]. In the case of adrenal incidentalomas larger than 4 cm, the further procedure must be individually designed, although the guidelines of the European Society of Endocrinology do not specify a definitive cut-off for an indication of surgery [13]. However, the larger the incidentaloma, the sooner an operation should be performed.

Clarification by means of a biopsy (fine needle biopsy), which, like any operation, may only be carried out after excluding a pheochromocytoma (!), Is only carried out in exceptional cases in patients with a history of extra-adrenal malignancies if 1.) the adrenal tumor is hormonally inactive, 2 .) the adrenal gland tumor is not conclusively classified as benign according to the imaging, and 3.) if the result of the biopsy would influence further therapy [13]. If there is a high suspicion of an operable adrenocortical carcinoma, the operation and not the biopsy should be performed with the risk of tumor spreading [13].

Hormonal work-up for adrenal incidentalomas

Every adrenal incidentaloma must be diagnosed for pheochromocytoma and hypercortisolism (Cushing's syndrome). In patients with arterial hypertension and / or inexplicable hypokalaemia, a clarification for primary hyperaldosteronism should also be carried out. A determination of sex hormones (i.e. DHEAS, androstenedione, 17-hydroxyprogesterone, as well as testosterone in women and estradiol in men and postmenopausal women) is only possible if the morphology of the incidentaloma is unclear or suspicious for malignancy and if the clinical picture is appropriate, e.g. B. pronounced virilization / hirsutism recommended. In the case of bilateral adrenal incidentalomas, it should be borne in mind that v. a. the prevalence of z. B. metastases or infiltrative processes is higher, and many authors recommend in bilateral adrenal incidentalomas always a clarification for AGS by determining the 17-hydroxyprogesterone. If the initial endocrinological investigation is normal, the endocrinological hormone examinations should not be repeated in the follow-up unless there are clinical signs of endocrinological activity or a worsening of co-morbidities such as B. arterial hypertension or type 2 diabetes mellitus [13].

In the following chapters, the endocrinological investigations for pheochromocytoma, hypercortisolism and primary hyperaldosteronism are dealt with. In this context it should be noted that the term incidentaloma is strictly speaking only to be used for adrenal masses that are accidental, i.e. H. without suspicion of adrenal pathology, are detected on imaging, whereas adrenal tumors such. B. be diagnosed in a clinically indicated investigation for an adrenal hormone excess does not correspond to the strict definition of an incidentaloma [13]. In the following sections, however, the diagnosis and therapy of pheochromocytoma, hypercortisolism and primary hyperaldosteronism is presented as comprehensively as possible, whereby not only adrenal incidentaloma patients are dealt with here.

Pheochromocytoma workup

Pheochromocytomas are tumors of chromaffin cells of the adrenal medulla, while paragangliomas are derived from extraadrenal chromaffin cells. The clinical symptoms can be very heterogeneous, whereby the clinical triad of headache, sweating and palpitation can only be observed in approx. 10% of the patients. Pheochromocytoma patients are not always hypertensive, but can also be symptomatic due to orthostatic hypotension (see Table 3 for the symptoms / clinical features of pheochromocytoma) [21]. The clinical significance of pheochromocytomas is v. a. that they are often undiagnosed during lifetime and that, according to historical studies, they are usually fatal if left untreated.

With regard to the pheochromocytoma investigation, either the fractionated metanephrines (i.e. separate determination of metanephrine and normetanephrine) can be determined in the plasma or in the acidified 24-hour urine collection [22, 23]. Whether the determination is carried out in plasma or in the acidified 24-hour urine can be freely chosen, although many centers prefer the determination in plasma for reasons of practicality. The metanephrines and normetanephrines are metabolites of adrenaline and noradrenaline, which are basically formed continuously (and not depending on the sometimes episodic exocytotic catecholamine release) by the tumors through the membrane-bound enzyme catecholamine O ‑ methyltransferase (COMT) [ 24]. About half of all pheochromocytomas produce a mix of noradrenaline and adrenaline, while the other half almost exclusively produce noradrenaline or noradrenaline and dopamine (Note: Paragangliomas almost exclusively produce noradrenaline or noradrenaline and dopamine; in extremely rare cases only dopamine, which is together with its metabolite Methoxytyramine should therefore only be measured in exceptional cases) [24]. Laboratory diagnostics naturally play a decisive role in pheochromocytoma (but also hyperaldosteronism / hypercortisolism) diagnostics, which is why the diagnostic clarification including the reference ranges should always be carried out with a view to or taking into account the local conditions of the respective laboratory.

In principle, it would be optimal for the determination of the plasma metanephrine and / or normetanephrine if the blood sample is taken after lying down for at least 30 minutes. As this is often difficult to do organizationally, from a pragmatic point of view, an initial determination of the plasma metanephrine / normetanephrine can also be carried out while sitting. Since the metanephrine / noremetanephrine values ​​in the plasma are generally higher when sitting than when lying down, a pheochromocytoma can be ruled out in the case of "negative" metanephrines / normetanephrines while sitting. On the other hand, if the plasma metanephrines / normetanephrines are elevated while sitting, the test should be repeated after at least 30 minutes while lying down in order to minimize false positive results. False positive test results with increased metanephrines / normetanephrines can also be caused by stress (e.g. clarification in the context of an acute illness) as well as medication (e.g. tricyclic antidepressants) or luxury foods (nicotine or coffee). In principle, the procedure should be such that in the case of a positive test in which the plasma metanephrine and / or normetanephrine is increased but less than 3 times above the upper limit range, the test should be repeated under optimal conditions (e.g. lying down and without previous smoking). If the metanephrines and normetanephrines are then in the normal range, a pheochromocytoma can be ruled out. If the plasma metanephrines / normetanephrines are still (slightly) elevated, a clonidine inhibition test should be carried out (alternatively, some authors recommend a combination of chromogranin A and 24 h urinary metanephrines). In a clonidine inhibition test, which is carried out in a lying position, after the initial blood sample to determine normetanephrine and noradrenaline, 300 µg clonidine (300 µg per 70 kg body weight; e.g. 2 tablets Catapresan® 0.15 mg) is administered orally, and after a further 180 minutes while lying down, another determination of normetanephrine (should drop over 40% from the initial value) and norepinephrine (should drop over 50%). However, if the metanephrines and / or normetanephrines are 3 times or more above the upper limit range after a single blood sample (even under suboptimal) conditions (or a determination in acidified 24-hour urine), the biochemical diagnosis of a pheochromocytoma can in principle be accepted as safe and secure, and further imaging tests should be performed. In the case of very large (e.g. over 5 cm) or bilateral pheochromocytomas (in addition to the initial imaging, which was usually a CT), a 123Iodine MIBG (Metaiodbenzylguanidine) Scintigraphy can be carried out in order to detect any metastases that may be present. If the metastasis is already known (e.g. metastases can already be seen in the CT), a 18F-FDG PET / CT recommended as preferred imaging. Incidentally, malignancy in pheochromocytoma is defined by the presence of metastasis (approx. 10–17% of all pheochromocytomas or parangangliomas are malignant).

When diagnosing a pheochromocytoma, genetic testing should always be considered (offered), since approximately every third patient has a genetic mutation predisposed to a pheochromocytoma (e.g. multiple endocrine neoplasia type 2; neurofibromatosis type 1 ; von-Hippel-Lindau syndrome; etc). A sequential genetic test is carried out depending on the available findings (e.g. depending on the localization, presence of metastases, dominance of either norametanpherine or metanephrine, symptoms of a syndrome, etc.) (see also reference [22]).

Clarification of hypercortisolism

The classic Cushing syndrome still had a very high mortality rate in 1952, when there was no effective therapy, because the median survival at that time was 4.6 years. Even today, active Cushing's syndrome still has a significantly increased mortality, which is 1.7 to 4.8 times higher than that of the general population. The most common causes of death in Cushing patients are cardiovascular diseases, venous thromboses (thromboembolism) and infections.

When evaluating hypercortisolism (Cushing's syndrome), a 1 mg dexamethasone inhibition test is generally recommended in every patient with an adrenal incidentaloma [8–11, 13, 15–17, 25]. 1 mg of dexamethasone (Fortecortin®) is administered between 23:00 and 24:00 and the serum cortisol is determined the next morning between 8:00 and 9:00 in order to evaluate whether the cortisol can be suppressed accordingly. With regard to the cut-off, there are inconsistent information in the literature with values ​​from 1.8 µg / dL (18 ng / mL, 50 nmol / L) to 5 µg / dL (50 ng / mL, 138 nmol / L). In contrast to the Endocrine Society Guidelines for Hypertcortislism [25], many experts recommend a cut-off of 5 µg / dL (50 ng / mL, 138 nmol / L) in adrenal incidentaloma patients, as everyone with adrenal incidentaloma (!) is tested, d. H. also patients without any other clinical indication of hypercortisolism (note: otherwise hypercortisolism clarification only if there is justified clinical suspicion!). A related A pragmatic approach for patients with adrenal incidentaloma was recommended by the European Society of Endocrinology [13]: if the cortisol after 1 mg dexamethasone is less than 1.8 µg / dL (18 ng / mL, 50 nmol / L), hypercortisolism can be ruled out, Values ​​of 1.8 µg / dL (18 ng / mL, 50 nmol / L) to 5 µg / dL (50 ng / mL, 138 nmol / L) are classified as “possible autonomous cortisol secretion”, and cortisol values ​​above 5 µg / dL (50 ng / mL, 138 nmol / L) as a positive test and thus referred to as “autonomous cortisol secretion” [11, 13, 26, 27].

For the final diagnosis of hypercortisolism, however, 2 positive test results are generally required, so that if the dexamethasone inhibition test is positive, a second test should be carried out for confirmation. Here comes z. B. the midnight salivary cortisol (caution: this test is only recommended for confirmation, but not as a screening test for adrenal incidentaloma; cut-off 0.145 µg / dL [1.45 ng / mL, 4 nmol / L]; at least 2 measurements recommended) , the free cortisol in the 24 h urine collection (cut-off is the respective upper reference range of the assay; at least 2 measurements recommended), or the 48 h (2 mg / day) dexamethasone inhibition test (starting at 9:00 a.m. every 6 h 0.5 Administer mg dexamethasone; cut-off for cortisol after 48 h: 1.8 µg / dL (18 ng / mL, 50 nmol / L)) in question. For a more detailed description of the investigation of hypertcortisolism and the influencing factors to be taken into account (caution: e.g. stress or acute illnesses increase cortisol and can lead to false positive results), I refer to the relevant guidelines [25, 28]. However, it should at least be noted that various drugs could have an influence on cortisol and B. when taking oral contraceptives by increasing the CBG, the cortisol in the serum is regularly increased (note: the determination of the free and non-CBG-bound cortisol in the 24-hour urine collection is then particularly helpful). If hypercortisolism is confirmed (2 positive tests), the plasma ACTH should also be determined (at the latest) in order to verify the genesis of the hypercortisolism, since in adrenal hypercortisolism the ACTH is expected to be low / suppressed.

A biochemically verified hypercortisolism is not to be equated with a classic Cushing's syndrome, which in the majority of cases is caused by a pituitary adenoma secreting ACTH. The "Cushing Clinic", which is caused by an ACTH-secreting pituitary adenoma and (often to a much greater extent) by an ectopic Cushing syndrome in z. B. small cell lung cancer is caused, is often much stronger and v. a. more specifically than in patients with adrenal incidentalomas and biochemical hypercortisolism. Therefore, the term “subclinical Cushing's syndrome” is often used for patients who have a biochemically verified hypercortisolism with adrenal incidentaloma, but no classic and v. a. have specific signs of hypercortisolism (e.g. facial plethora [redness], tendency to bruise / bleeding, proximal myopathy, striae if more than 1 cm wide and livid / reddish). The clinical assessment of the patient also plays an important role here in order to differentiate between subclinical and classic Cushing's syndrome.

Primary hyperaldosteronism workup

The clinical significance of primary aldosteronism is v. a. That patients with this disease, compared to patients with essential arterial hypertension, have a significantly increased cardiovascular risk, which is also due to the effects of aldosterone excess that are independent of blood pressure. For this reason, the guidelines on primary hyperaldosteronism also recommend relatively broad indications for clarification in this regard (Tab. 4; [29]). When investigating primary hyperaldosteronism, the determination of plasma aldosterone and renin with calculation of the aldosterone to renin quotient is recommended [29]. If this aldosterone to renin quotient is in the normal range, primary hyperaldosteronism can be ruled out. The cut-off values ​​for the aldosterone to renin quotient depend on the laboratory methodology and the specified concentration units, whereby the most frequently used cut-offs (the concentration units for calculating the quotient are given in brackets) are: 3.7 ( for aldosterone in ng / dL and renin in mU / liter), 5.7 (for aldosterone in ng / dL and renin in ng / liter), 91 (for aldosterone in pmol / liter and renin in mU / liter) and 144 ( for aldosterone in pmol / liter and renin in ng / liter) (Note: The absolute level of the aldosterone value is also taken into account by some authors and so a minimum value of 6–15 ng / dL [170 to 420 pmol / L] is sometimes used. demanded for a pathologically increased aldosterone to renin quotient). If this quotient is in the normal range, primary hyperaldosteronism can be ruled out and, as a rule, no further checks of the aldosterone to renin quotient have to be carried out.

In the case of an increased aldosterone to renin quotient, a so-called confirmation test must be connected to confirm the diagnosis, in which it is evaluated whether the aldosterone secretion is influenced by influencing factors such as e.g. B. Saline exposure can be sufficiently influenced. There are basically 4 confirmation tests to choose from: i. v. Saline exposure test, oral saline exposure test, fludrocortisone suppression test and captopril test. These tests are considered to be equivalent, although in practice v. a. the i. v. Has established a saline exposure test. In this test, 2 liters of physiological saline solution are infused over 4 hours and then the plasma aldosterone is determined in order to evaluate whether the saline exposure also sufficiently suppresses the aldosterone. An aldosterone value after salt exposure <5 ng / dL (140 pmol / liter) excludes primary hyperaldosteronism, whereas a value of> 10 ng / dL (280 pmol / liter) confirms primary hyperaldosteronism and a value of 5 to 10 ng / dL (140 to 280 nmol / liter) represents a "gray area" (cave: take different assays and laboratory methods into account!). Some authors also recommend a cortisol determination at the beginning and at the end of the salt load test in order to evaluate whether a stress load (reflected by a significantly higher cortisol compared to the initial value at the end of the test; caution: e.g. full bladder) due to an ACTH-triggered increase in aldosterone influenced the test result. For patients with a clear laboratory constellation, i. H. In the case of hypokalaemia, renin suppressed below the detection limit, and plasma aldosterone above 20 ng / dL (550 pmol / liter), a confirmatory test can exceptionally be dispensed with.

A major difficulty in the diagnosis of primary hyperaldosteronism is v. a. in the various influencing factors on the aldosterone and renin values ​​(e.g. medication, body position, laboratory analysis, etc.), and an exact description of the entire diagnosis and the influencing factors to be taken into account would by far exceed the scope of this article. Basically, blood samples for aldosterone and renin determination should be done in the morning after sitting for 5–15 minutes and with (at least approximately) a balanced potassium balance (cave: hypokalaemia suppresses aldosterone secretion). MR blockers such as spironolactone and eplerenone (as well as the diuretics amiloride and triamterene) should be discontinued for at least 4 weeks before the blood sample is taken. Of course, it would be optimal not to take antihypertensive drugs (with a potential impact on aldosterone and renin) during testing, but for reasons of practicality, the guidelines recommend that other drugs (such as beta blockers, which mainly suppress renin, and ACE- Inhibitors that mainly increase renin) do not necessarily have to be discontinued. However, this can sometimes be necessary if the findings are unclear. For this purpose, these drugs (e.g. beta-blockers) should be paused for 2 weeks and, if necessary, a switch to e.g. B. takes calcium channel blockers and / or alpha blockers that have little effect on aldosterone and renin.

As soon as the biochemical diagnosis of hyperaldosteronism is confirmed, the subtype investigation of primary hyperaldosteronism (i.e. the differentiation between unilateral or bilateral aldosterone hypersecretion) begins. Surgical adrenalectomy can only be planned for young patients under 35 years of age, with spontaneous hypokalaemia, pronounced aldosterone elevation and unilateral adrenal tumors. In patients under 20 years of age with a family history of primary aldosteronism or stroke under 40 years of age, genetic tests should be carried out with regard to hereditary forms of aldosteronism (e.g. familial aldosteronism type 1 or 3). In all other patients, selective adrenal vein sampling is recommended in order to differentiate between unilateral and bilateral aldosterone hypersecretion, because there is a high prevalence of endocrine-disrupted adrenal adenomas, the a. increases with age (cave: this examination requires sufficient experience and corresponding case numbers!). There are different protocols for this examination, but it is preferably performed under a continuous infusion of cosyntropin (ACTH) (50 µg cosyntropin per hour starting 30 minutes before the procedure). The aim of this infusion is to v. a. cause continuous (and non-fluctuating) aldosterone secretion and also stimulate cortisol secretion from the adrenal glands to evaluate successful adrenal vein catheterization. As part of these examinations, blood is taken from both adrenal veins (caution: especially the right adrenal vein, which opens directly into the inferior vena cava, is sometimes difficult to catheterize) and from a peripheral vein (e.g. cubital or iliacal) to remove cortisol and to determine aldosterone. A successful adrenal vein catheterization exists with a cortisol quotient of the adrenal to peripheral vein of more than 5 to 1, whereby the use of rapid assays for intraprocedural cortisol measurement can increase the rate of successful catheterizations. With regard to the measured values ​​in the adrenal veins, due to dilution effects, the aldosterone values ​​on both sides are not compared, but the aldosterone to cortisol quotients on both sides, since dilution effects due to inflows from other non-adrenal vessels are taken into account by using "cortisol corrected values" . A ratio of the aldosterone to cortisol quotient of both adrenal veins of at least 4: 1 indicates lateralization, while a quotient of less than 3: 1 excludes unilateral aldosterone hypersecretion and a quotient of 3: 1 to 4: 1 represents a gray area (cave: es will other cut-off values ​​recommended if cosyntropin is not used). The determination of a lateralization is of course of great importance for the therapy planning (only patients with lateralization can be treated surgically), whereby such an examination should only be carried out at experienced centers and only makes sense if the patient also has one Does not reject surgery a priori or is suitable for surgery. It should also be noted that carcinomas that produce aldosterone (just like cortisol) are rare and are almost always over 4 cm in size, with a morphology that is often suspicious of malignancy. There is also the rare entity of an aldosterone plus cortisol secreting adenoma.

Therapy of the adrenal incidentaloma

In the case of hormonally (endocrine) inactive adrenal incidentalomas, laparoscopic adrenalectomy is primarily recommended if there is an indication for surgery (due to size, growth or morphology), although in exceptional cases (e.g.> 10 cm large incidentaloma or locally invasive malignancy suspected of being) Incidentaloma), an open adrenalectomy may also be indicated [11]. Special preoperative and postoperative endocrinological treatment (e.g. perioperative glucocorticoid substitution) is not necessary in the case of unilateral adrenalectomy of an endocrine-disrupted adrenal incidentaloma if the findings are otherwise normal [30]. However, some authors recommend an endocrinological check-up approx. 1–2 months after the operation in order to evaluate the need for glucocorticoid replacement on the basis of the clinic and laboratory [11]. In this regard, in some (few) centers, even for endocrinologically inactive incidentalomas after a unilateral adrenalectomy, low-dose glucocorticoid substitution is prescribed until the first endocrinological check-up [11, 31].

Pheochromocytoma therapy

If a non-metastatic pheochromocytoma is diagnosed, a minimally invasive laparoscopic or retroperitoneoscopic complete adrenalectomy is recommended, with large tumors (e.g. over 6 cm) also an open operation should be performed. With certain constellations (e.g. hereditary pheochromocytomas, small tumors with already contralateral complete adrenalectomy), a partial adrenalectomy should be performed in order to avoid adrenal insufficiency. About a third to a half of an adrenal gland is roughly necessary for adequate adrenal function. Preoperatively, therapy with an alpha blocker must be carried out for at least 7‑ (10) to 14 days. Phenoxybenzamine (Dibenzyran®) is mainly used, which should be initiated with a usual starting dose of 10 mg 1-0-1 daily (an alternative would be, for example, doxazosin [Supressin®] starting with 2 mg / day). Phenoxybenzamine should then be titrated up to a target dose of 1 mg / kg / day preoperatively, depending on the clinical situation / blood pressure (e.g. increase by approx. 10 mg / day; caution: watch out for orthostatic dysregulation). The aim is to normalize the blood pressure and heart rate preoperatively, whereby attention should also be paid to an adequate supply of electrolytes and fluids, as there is often a vasoconstrictive volume deficit, which can lead to hypotension after therapy. If alpha-blocker therapy is inadequate, calcium channel blockers are also recommended (e.g. amlodipine). Beta-blocker therapy can be indicated for tachycardia control, but should only be initiated after adequate alpha-blocker therapy, since otherwise paradoxical increases in blood pressure could be induced (caution: predominant vasoconstriction due to insufficient alpha-blockade). Postoperatively, v. a. Regular monitoring of blood pressure, heart rate and blood sugar (caution: risk of hypoglycaemia) should be carried out in the first 24 to 48 hours. a. the postoperative hypotension responds very well to volume administration. Approx.A follow-up examination should be carried out 2–4 weeks after the adrenalectomy in order to biochemically verify the successful resection of the pheochromocytoma (e.g. determination of the plasma metanephrine). Thereafter, (at least) annual endocrinological checks are recommended for life. In the case of known mutations / syndromes, however, “personalized” procedures are sometimes recommended for pheochromocytoma patients with regard to diagnosis, therapy and follow-up of the pheochromocytoma [22]. In malignant / metastatic pheochromocytoma, surgical therapy is primarily recommended; other therapy options are also one 131Iodine MIBG and chemotherapy (preferably as part of a clinical study).