Adrenocorticotropic hormone deficiency

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Adrenocorticotropic hormone deficiency
Other namesACTH Deficiency, Isolated adrenocorticotropic hormone deficiency, Isolated ACTH Deficiency.
Adrenocorticotropic hormone.JPG
Adrenocorticotropic hormone (ACTH), structure
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Fatigue, anorexia, weight loss, hypoglycemia, muscle weakness, nausea, vomiting, and hypotension. [1]
Complications Adrenal crisis [2]
Causes Autoimmune processes, congenital etiologies, and physical trauma. [3]
Diagnostic method Morning serum cortisol levels, [4] Insulin tolerance testing, and ACTH stimulation test [2]
Differential diagnosis Congenital adrenal hyperplasia, Addison's disease, and Secondary adrenal insufficiency. [1]
Treatment Glucocorticoids. [2]

Adrenocorticotropic hormone deficiency is a rare disorder characterized by secondary adrenal insufficiency with minimal or no cortisol production and normal pituitary hormone secretion apart from ACTH. [3] ACTH deficiency may be congenital or acquired, and its symptoms are clinically similar to those of glucocorticoid deficiency. Symptoms consist of weight loss, diminished appetite, muscle weakness, nausea, vomiting, and hypotension. Low blood sugar and hyponatremia are possible; however, blood potassium levels typically remain normal because affected patients are deficient in glucocorticoids rather than mineralocorticoids because of their intact renin-angiotensin-aldosterone system. ACTH may be undetectable in blood tests, and cortisol is abnormally low. [1] Glucocorticoid replacement therapy is required. With the exception of stressful situations, some patients with mild or nearly asymptomatic disease may not require glucocorticoid replacement therapy. [2] As of 2008 about two hundred cases have been described in the literature. [5]

Contents

Signs and symptoms

Adrenocorticotropic hormone deficiency has a variety of clinical manifestations and can be fatal if left untreated. Clinical manifestations of adrenocorticotropic hormone deficiency are similar to those of primary adrenal insufficiency, except for cutaneous hyperpigmentation and electrolyte disturbances. [2]

Adrenocorticotropic hormone deficiency is characterized by nonspecific symptoms such as fatigue, anorexia, unintentional weight loss, and hypoglycemia. Pale skin may contribute to patients' diminished appearance and aid in differentiating between primary and secondary adrenal insufficiency. Secondary adrenal insufficiency is not associated with a lack of aldosterone, so symptoms and signs of mineralocorticoid deficiency, such as salt craving, postural hypotension, and electrolyte abnormalities, are typically absent. [2]

Patients with adrenocorticotropic hormone deficiency typically do well during non-stressful periods until an intervening event triggers an acute adrenal crisis. This life-threatening illness is characterized by extreme fatigue, acute abdominal pain, nausea, vomiting, diarrhea, fever, severe hypotension, and hypoglycemia, and may be irreversible if not treated promptly. [2]

Causes

The most common causes of adrenocorticotropic hormone deficiency appear to be related to the pituitary gland and include autoimmune processes, congenital etiologies, and physical trauma. [3] It can occur on its own or as a component of a pluriglandular auto-immune syndrome. After a head injury, isolated ACTH deficiency has been reported in association with diabetes mellitus and benign intracranial hypertension. [6]

Adrenocorticotropic hormone deficiency can be associated with lymphocytic hypophysitis and selective destruction of corticotrophs. This almost always manifests during pregnancy or after childbirth. [6] Patients with lymphocytic hypophysitis or a deficiency in Adrenocorticotropic hormone have been found to have antibodies against a 22 kDalton pituitary protein, which lends support to this theory. [2]

Post-traumatic ACTH deficiency is usually associated with other pituitary defects; however, persistent or transient post-traumatic Adrenocorticotropic hormone deficiency has been reported. Adrenocorticotropic hormone deficiency can also be part of an atypical Sheehan's syndrome, be linked to an empty sella, and appear after brain tumor radiation therapy. [2]

A few instances of acquired adrenocorticotropic hormone deficiency have been linked to autoimmune diseases, such as autoimmune thyroid disease, anti-pituitary antibodies in the serum, such as anti-corticotroph antibodies, and hypophysitis caused by anti-programmed death 1 or anti-programmed death ligand 1 antibodies. This strongly suggests that the development of acquired adrenocorticotropic hormone deficiency is influenced by autoimmune etiology. [7]

Genetics

It is thought that congenital adrenocorticotropic hormone deficiency is extremely rare. A few cases with onsets ranging from the perinatal period to the early teen years have been described. [3]

TBX19 is involved in corticotropic cell differentiation and proliferation, and TBX19 mutations account for over 60 percent of neonatal cases of adrenocorticotropic hormone deficiency. [8]

The TBX19 gene, formerly known as TPIT, encodes a T-box transcription factor found in pituitary cells that express proopiomelanocortin. TBX19 is required for these cells' terminal differentiation and the expression of the POMC gene. TBX19 is found on chromosome 1q24.2, and its primary transcript consists of 8 exons. [8]

Due to the dual role of α-MSH in regulating food intake and hair pigmentation, a defect in proopiomelanocortin (POMC) or its cleavage enzyme, prohormone convertase, results in defects in POMC-derived peptides (e.g., ACTH, MSH) and consequently, Adrenocorticotropic hormone deficiency. Furthermore, the phenotype associated with a defect in POMC should include obesity, altered hair pigmentation, and ACTH deficiency. Other candidate genes include CRH and CRH receptor type 1, but no mutations in these genes have been linked to a lack of adrenocorticotropic hormone. [2]

Diagnosis

Morning serum cortisol levels are typically the first step in the diagnostic work-up, but this test is only significant if values are extremely low, adrenal insufficiency is almost certain with values below 3 μg/dl, or it can be excluded with values in the upper half of the normal range. Cortisol levels above 19 g/dl almost always rule out adrenal insufficiency. Intermediate values necessitate additional testing. [4]

Insulin tolerance testing is widely regarded as the gold standard for assessing the entire hypothalamic-pituitary-adrenal axis. [2]

A high-dose ACTH stimulation test directly evaluates the adrenal secretory reserve, which can be compromised not only in primary adrenal insufficiency but also in long-term ACTH deficiency. [2] This test may not detect recent onset or less severe forms of secondary adrenal insufficiency, and a normal cortisol response does not rule out secondary adrenal insufficiency, so insulin tolerance testing may be required to confirm the diagnosis. [9]

A low-dose ACTH stimulation test has been suggested as a sensitive test for secondary adrenal insufficiency diagnosis. [10] When compared to insulin tolerance testing [11] and the high-dose ACTH test, this test allows for a more accurate identification of patients with secondary adrenal insufficiency. [12]

Blood chemistry tests may reveal mild hypoglycemia, hyponatremia, normal-to-high potassium levels, slight anemia, lymphocytosis, and eosinophilia. [2] Hypercalcemia can occur in rare cases resulting from increased intestinal absorption as well as decreased renal excretion of calcium caused by glucocorticoid deficiency. [13] TSH is usually mildly elevated since cortisol has no physiological inhibitory effect on TSH. [14]

Differential diagnosis

Differential diagnosis of Adrenocorticotropic hormone deficiency includes Congenital adrenal hyperplasia, Addison's disease, and Secondary adrenal insufficiency. [1]

Plasma ACTH levels when off glucocorticoid replacement therapy are the best parameter for differential diagnosis, as levels in primary adrenal insufficiency are generally above 100 pg/ml and low-normal in secondary adrenal insufficiency. [2]

Treatment

Replacement doses of glucocorticoids are required for treatment. Except for stressful events, some patients with mild, near-asymptomatic disease may not require glucocorticoid replacement therapy. Mineralocorticoids are generally not required to be administered because their production is maintained. [2]

Glucocorticoid replacement dose must be increased when supervising stressful events such as illnesses, trauma, fever, and major surgical or diagnostic procedures. Vomiting, diarrhea, or other causes of poor intestinal absorption necessitate the administration of intravenous hydrocortisone. [2]

Acute adrenal crisis requires intravenous administration of 100 mg hydrocortisone immediately, followed by 100–200 mg over the next 24 hours and large volumes of saline while under continuous cardiac monitoring. [15]

Special populations

In the neonatal period, adrenocorticotropic hormone deficiency is a potentially fatal condition. [8] TBX19 is involved in the differentiation and proliferation of corticotropic cells, and TBX19 mutations account for 65% of neonatal onset adrenocorticotropic hormone deficiency, which can result in 25% neonatal mortality if not treated. [16]

Low cortisol causes hypoglycemia, prolonged cholestatic jaundice, and seizures in the neonatal period, families frequently have a history of neonatal death. [17]

Cognitive impairment is one of the most serious outcomes of undiagnosed adrenal crises and inadequately adjusted hydrocortisone treatment in adrenocorticotropic hormone deficiency caused by TBX19 mutations. To avoid brain damage, early diagnosis, close clinical monitoring in specialized centers, and multiple therapeutic education sessions for parents are critical. [8]

See also

Related Research Articles

<span class="mw-page-title-main">Adrenal gland</span> Endocrine gland

The adrenal glands are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which produces steroid hormones and an inner medulla. The adrenal cortex itself is divided into three main zones: the zona glomerulosa, the zona fasciculata and the zona reticularis.

<span class="mw-page-title-main">Adrenocorticotropic hormone</span> Pituitary hormone

Adrenocorticotropic hormone is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress. Its principal effects are increased production and release of cortisol and androgens by the cortex and medulla of the adrenal gland, respectively. ACTH is also related to the circadian rhythm in many organisms.

<span class="mw-page-title-main">Cushing's syndrome</span> Symptoms from excessive exposure to glucocorticoids such as cortisol

Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, a round red face due to facial plethora, a fat lump between the shoulders, weak muscles, weak bones, acne, and fragile skin that heals poorly. Women may have more hair and irregular menstruation. Occasionally there may be changes in mood, headaches, and a chronic feeling of tiredness.

<span class="mw-page-title-main">Proopiomelanocortin</span> Mammalian protein found in Homo sapiens

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.

<span class="mw-page-title-main">Addison's disease</span> Endocrine disorder

Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adrenal glands, causing adrenal insufficiency. Symptoms generally come on slowly and insidiously and may include abdominal pain and gastrointestinal abnormalities, weakness, and weight loss. Darkening of the skin in certain areas may also occur. Under certain circumstances, an adrenal crisis may occur with low blood pressure, vomiting, lower back pain, and loss of consciousness. Mood changes may also occur. Rapid onset of symptoms indicates acute adrenal failure, which is a clinical emergency. An adrenal crisis can be triggered by stress, such as from an injury, surgery, or infection.

Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary. This is most often as a result of a pituitary adenoma or due to excess production of hypothalamus CRH that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing's syndrome, when excluding Cushing's syndrome from exogenously administered corticosteroids. The equine version of this disease is Pituitary pars intermedia dysfunction.

<span class="mw-page-title-main">Congenital adrenal hyperplasia</span> Medical condition

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. Most of these disorders involve excessive or deficient production of hormones such as glucocorticoids, mineralocorticoids, or sex steroids, and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults. It is one of the most common autosomal recessive disorders in humans.

<span class="mw-page-title-main">Adrenal insufficiency</span> Medical condition

Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids, mineralocorticoids, and androgens. These hormones are important in regulating blood pressure, electrolytes, and metabolism as a whole. Deficiency of these hormones leads to symptoms ranging from abdominal pain, vomiting, muscle weakness and fatigue, low blood pressure, depression, mood and personality changes to organ failure and shock. Adrenal crisis may occur if a person having adrenal insufficiency experiences stresses, such as an accident, injury, surgery, or severe infection; this is a life-threatening medical condition resulting from severe deficiency of cortisol in the body. Death may quickly follow.

Corticotropes are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulating hormone (MSH). These cells are stimulated by corticotropin releasing hormone (CRH) and make up 15–20% of the cells in the anterior pituitary. The release of ACTH from the corticotropic cells is controlled by CRH, which is formed in the cell bodies of parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and passes to the corticotropes in the anterior pituitary via the hypophyseal portal system. Adrenocorticotropin hormone stimulates the adrenal cortex to release glucocorticoids and plays an important role in the stress response.

<span class="mw-page-title-main">Lipoid congenital adrenal hyperplasia</span> Medical condition

Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia (CAH). It arises from defects in the earliest stages of steroid hormone synthesis: the transport of cholesterol into the mitochondria and the conversion of cholesterol to pregnenolone—the first step in the synthesis of all steroid hormones. Lipoid CAH causes mineralocorticoid deficiency in affected infants and children. Male infants are severely undervirilized causing their external genitalia to look feminine. The adrenals are large and filled with lipid globules derived from cholesterol.

Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasia (CAH) resulting from a mutation in the gene CYP17A1, which produces the enzyme 17α-hydroxylase. It causes decreased synthesis of cortisol and sex hormones, with resulting increase in mineralocorticoid production. Thus, common symptoms include mild cortisol deficiency, ambiguous genitalia in men or amenorrhea at puberty in women, and hypokalemic hypertension. However, partial (incomplete) deficiency often has inconsistent symptoms between patients, and affected women may be asymptomatic except for infertility.

<span class="mw-page-title-main">Congenital adrenal hyperplasia due to 21-hydroxylase deficiency</span> Medical condition

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is a genetic disorder characterized by impaired production of cortisol in the adrenal glands.

<span class="mw-page-title-main">Metyrapone</span> Chemical compound

Metyrapone, sold under the brand name Metopirone, is a medication which is used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome (hypercortisolism). It is part of the steroidogenesis inhibitor class of drugs.

<span class="mw-page-title-main">ACTH receptor</span> Mammalian protein found in Homo sapiens

The adrenocorticotropic hormone receptor or ACTH receptor also known as the melanocortin receptor 2 or MC2 receptor is a type of melanocortin receptor (type 2) which is specific for ACTH. A G protein–coupled receptor located on the external cell plasma membrane, it is coupled to Gαs and upregulates levels of cAMP by activating adenylyl cyclase. The ACTH receptor plays a role in immune function and glucose metabolism.

The ACTH test is a medical test usually requested and interpreted by endocrinologists to assess the functioning of the adrenal glands' stress response by measuring the adrenal response to adrenocorticotropic hormone or another corticotropic agent such as tetracosactide or alsactide (Synchrodyn). ACTH is a hormone produced in the anterior pituitary gland that stimulates the adrenal glands to release cortisol, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and aldosterone.

<span class="mw-page-title-main">Adrenal crisis</span> Medical condition

Adrenal crisis, also known as Addisonian crisis or Acute adrenal insufficiency, is a serious, life-threatening complication of adrenal insufficiency. Hypotension, or hypovolemic shock, is the main symptom of adrenal crisis, other indications and symptoms include weakness, anorexia, nausea, vomiting, fever, fatigue, abnormal electrolytes, confusion, and coma. Laboratory testing may detect lymphocytosis, eosinophilia, hyponatremia, hyperkalemia, hypoglycemia, and on occasion, hypercalcemia.

Hypoadrenocorticism in dogs, or, as it is known in people, Addison's disease, is an endocrine system disorder that occurs when the adrenal glands fail to produce enough hormones for normal function. The adrenal glands secrete glucocorticoids such as cortisol and mineralocorticoids such as aldosterone; when proper amounts of these are not produced, the metabolic and electrolyte balance is upset. Mineralocorticoids control the amount of potassium, sodium, and water in the body. Hypoadrenocorticism is fatal if left untreated.

<span class="mw-page-title-main">Adrenal gland disorder</span> Medical condition

Adrenal gland disorders are conditions that interfere with the normal functioning of the adrenal glands. Your body produces too much or too little of one or more hormones when you have an adrenal gland dysfunction. The type of issue you have and the degree to which it affects your body's hormone levels determine the symptoms.

Late onset congenital adrenal hyperplasia (LOCAH), also known as nonclassic congenital adrenal hyperplasia, is a milder form of congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol synthesis that leads to variable degrees of postnatal androgen excess.

<span class="mw-page-title-main">Generalized glucocorticoid resistance</span> Medical condition

Generalized glucocorticoid resistance or Chrousos syndrome is a rare genetic disorder that can run in families or be sporadic. It is characterized by partial or generalized target-tissue insensitivity to glucocorticoids.

References

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