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]
| Adrenocorticotropic hormone deficiency | |
|---|---|
| Other names | ACTH Deficiency, Isolated adrenocorticotropic hormone deficiency, Isolated ACTH Deficiency. |
 | |
| Adrenocorticotropic hormone (ACTH), structure | |
| Specialty | Endocrinology  |
| 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] |
Signs and symptoms
editAdrenocorticotropic 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
editThe 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
editIt 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
editMorning 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
editDifferential 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
editReplacement 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
editIn 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
editReferences
edit- ^ a b c d "Symptoms, Causes, Treatment". National Organization for Rare Disorders. February 11, 2015. Retrieved November 11, 2023.
- ^ a b c d e f g h i j k l m n o p Andrioli, Massimiliano; Giraldi, Francesca Pecori; Cavagnini, Francesco (October 30, 2006). "Isolated corticotrophin deficiency". Pituitary. 9 (4). Springer Science and Business Media LLC: 289–295. doi:10.1007/s11102-006-0408-5. ISSN 1386-341X. PMID 17077949. S2CID 12553579. Retrieved November 10, 2023.
- ^ a b c d Kamoun, Mahdi; Kacem, FatenHadj; Charfi, Nadia; Mnif, MounaFeki; Akid, Faouzi; Mnif, Fatma; Naceur, BasmaBen; Rekik, Nabila; Mnif, Zainab; Abid, Mohamed (2013). "Isolated adrenocorticotropic hormone deficiency due to probable lymphocytic hypophysitis in a woman". Indian Journal of Endocrinology and Metabolism. 17 (7). Medknow: S107–S110. doi:10.4103/2230-8210.119521. ISSN 2230-8210. PMC 3830271. PMID 24251125.
- ^ a b LK, Nieman (2003). "Dynamic evaluation of adrenal hypofunction". Journal of Endocrinological Investigation. 26 (7 Suppl). J Endocrinol Invest: 74–82. ISSN 0391-4097. PMID 14604069. Retrieved November 12, 2023.
- ^ Syriou, Vassiliki; Moisidis, Anestis; Tamouridis, Nikolaos; Alexandraki, Krystallenia; Anapliotou, Margarita (October 15, 2008). "Isolated adrenocorticotropin deficiency and flexion contractures syndrome". Hormones. 7 (4). Springer Science and Business Media LLC: 320–324. doi:10.14310/horm.2002.1213. ISSN 1109-3099. PMID 19121993. Retrieved November 11, 2023.
- ^ a b Orme, S. M.; Belchetz, P. E. (1991). "Isolated ACTH deficiency". Clinical Endocrinology. 35 (3). Wiley: 213–217. doi:10.1111/j.1365-2265.1991.tb03524.x. ISSN 0300-0664. PMID 1660365. S2CID 31834655. Retrieved November 11, 2023.
- ^ Fujita, Yasunori; Bando, Hironori; Iguchi, Genzo; Iida, Keiji; Nishizawa, Hitoshi; Kanie, Keitaro; Yoshida, Kenichi; Matsumoto, Ryusaku; Suda, Kentaro; Fukuoka, Hidenori; Ogawa, Wataru; Takahashi, Yutaka (February 19, 2021). "Clinical Heterogeneity of Acquired Idiopathic Isolated Adrenocorticotropic Hormone Deficiency". Frontiers in Endocrinology. 12. Frontiers Media SA. doi:10.3389/fendo.2021.578802. ISSN 1664-2392. PMC 7933588. PMID 33679614.
- ^ a b c d Charnay, Théo; Mougel, Gregory; Amouroux, Cyril; Gueorguieva, Iva; Joubert, Florence; Pertuit, Morgane; Reynaud, Rachel; Barlier, Anne; Brue, Thierry; Saveanu, Alexandru (February 15, 2023). "A novel TBX19 gene mutation in patients with isolated ACTH deficiency from distinct families with a common geographical origin". Frontiers in Endocrinology. 13. Frontiers Media SA. doi:10.3389/fendo.2022.1080649. ISSN 1664-2392. PMC 9987334. PMID 36890856.
- ^ Dorin, Richard I.; Qualls, Clifford R.; Crapo, Lawrence M. (August 5, 2003). "Diagnosis of Adrenal Insufficiency". Annals of Internal Medicine. 139 (3). American College of Physicians: 194–204. doi:10.7326/0003-4819-139-3-200308050-00009. ISSN 0003-4819. PMID 12899587. S2CID 38462457. Retrieved November 11, 2023.
- ^ DICKSTEIN, GABRIEL; SHECHNER, CARMELA; NICHOLSON, WENDELL E.; ROSNER, ITZHAK; SHEN-ORR, ZILA; ADAWI, FAYAD; LAHAV, MICHAL (1991). "Adrenocorticotropin Stimulation Test: Effects of Basal Cortisol Level, Time of Day, and Suggested New Sensitive Low Dose Test*". The Journal of Clinical Endocrinology & Metabolism. 72 (4). The Endocrine Society: 773–778. doi:10.1210/jcem-72-4-773. ISSN 0021-972X. PMID 2005201. Retrieved November 11, 2023.
- ^ Thaler, Leonard M.; Blevins, Lewis S. (1998). "The Low Dose (1-μg) Adrenocorticotropin Stimulation Test in the Evaluation of Patients with Suspected Central Adrenal Insufficiency". The Journal of Clinical Endocrinology & Metabolism. 83 (8). The Endocrine Society: 2726–2729. doi:10.1210/jcem.83.8.5039. ISSN 0021-972X. PMID 9709938.
- ^ Tordjman, Karen; Jaffe, Anat; Trostanetsky, Yana; Greenman, Yona; Limor, Rona; Stern, Naftali (May 19, 2000). "Low-dose (1 μg) adrenocorticotrophin (ACTH) stimulation as a screening test for impaired hypothalamo–pituitary–adrenal axis function: sensitivity, specificity and accuracy in comparison with the high-dose (250 μg) test". Clinical Endocrinology. 52 (5). Wiley: 633–640. doi:10.1046/j.1365-2265.2000.00984.x. ISSN 0300-0664. PMID 10792344. S2CID 72291146. Retrieved November 11, 2023.
- ^ Vasikaran, S. D.; Tallis, G. A.; Braund, W. J. (1994). "Secondary hypoadrenalism presenting with hypercalcaemia". Clinical Endocrinology. 41 (2). Wiley: 261–264. doi:10.1111/j.1365-2265.1994.tb02540.x. ISSN 0300-0664. PMID 7923833. S2CID 21508041. Retrieved November 11, 2023.
- ^ Hangaard, J; Andersen, M; Grodum, E; Koldkjaer, O; Hagen, C (1996). "Pulsatile thyrotropin secretion in patients with Addison's disease during variable glucocorticoid therapy". The Journal of Clinical Endocrinology & Metabolism. 81 (7). The Endocrine Society: 2502–2507. doi:10.1210/jcem.81.7.8675567. ISSN 0021-972X. PMID 8675567.
- ^ Dineen, Rosemary; Thompson, Christopher J; Sherlock, Mark (2019). "Adrenal crisis: prevention and management in adult patients". Therapeutic Advances in Endocrinology and Metabolism. 10. SAGE Publications: 204201881984821. doi:10.1177/2042018819848218. ISSN 2042-0188. PMC 6566489. PMID 31223468.
- ^ Kardelen Al, Aslı Derya; Poyrazoğlu, Şükran; Aslanger, Ayça; Yeşil, Gözde; Ceylaner, Serdar; Baş, Firdevs; Darendeliler, Feyza (2019). "A Rare Cause of Adrenal Insufficiency — Isolated ACTH Deficiency Due to TBX19 Mutation: Long-Term Follow-Up of Two Cases and Review of the Literature". Hormone Research in Paediatrics. 92 (6): 395–403. doi:10.1159/000506740. ISSN 1663-2826. PMID 32344415.
- ^ Couture, C.; Saveanu, A.; Barlier, A.; Carel, J. C.; Fassnacht, M.; Flück, C. E.; Houang, M.; Maes, M.; Phan-Hug, F.; Enjalbert, A.; Drouin, J.; Brue, T.; Vallette, S. (March 1, 2012). "Phenotypic Homogeneity and Genotypic Variability in a Large Series of Congenital Isolated ACTH-Deficiency Patients with TPIT Gene Mutations". The Journal of Clinical Endocrinology & Metabolism. 97 (3). The Endocrine Society: E486–E495. doi:10.1210/jc.2011-1659. ISSN 0021-972X. PMID 22170728.
Further reading
edit- Nussey, S. S.; Soo, Shlu-Ching; Gibsonf, S.; Gout, I.; White, A.; Bain, M.; Johnstone, A. P. (1993). "Isolated congenital ACTH deficiency: a cleavage enzyme defect?". Clinical Endocrinology. 39 (3). Wiley: 381–385. doi:10.1111/j.1365-2265.1993.tb02381.x. ISSN 0300-0664. PMID 8222301. S2CID 9832686. Retrieved November 10, 2023.
- Vallette-Kasic, Sophie; Brue, Thierry; Pulichino, Anne-Marie; Gueydan, Magali; Barlier, Anne; David, Michel; Nicolino, Marc; Malpuech, Georges; Déchelotte, Pierre; Deal, Cheri; Van Vliet, Guy; De Vroede, Monique; Riepe, Felix G.; Partsch, Carl-Joachim; Sippell, Wolfgang G.; Berberoglu, Merih; Atasay, Begüm; de Zegher, Francis; Beckers, Dominique; Kyllo, Jennifer; Donohoue, Patricia; Fassnacht, Martin; Hahner, Stefanie; Allolio, Bruno; Noordam, C.; Dunkel, Leo; Hero, Matti; Pigeon, B.; Weill, Jacques; Yigit, Sevket; Brauner, Raja; Heinrich, Juan Jorge; Cummings, Elizabeth; Riddell, Christie; Enjalbert, Alain; Drouin, Jacques (2005). "Congenital Isolated Adrenocorticotropin Deficiency: An Underestimated Cause of Neonatal Death, Explained byTPITGene Mutations". The Journal of Clinical Endocrinology & Metabolism. 90 (3). The Endocrine Society: 1323–1331. doi:10.1210/jc.2004-1300. ISSN 0021-972X. PMID 15613420.
- Kyllo, Jennifer H.; Collins, Malia M.; Vetter, Kimberly L.; Cuttler, Leona; Rosenfield, Robert L.; Donohoue, Patricia A. (March 29, 1996). "Linkage of congenital isolated adrenocorticotropic hormone deficiency to the corticotropin releasing hormone locus using simple sequence repeat polymorphisms". American Journal of Medical Genetics. 62 (3). Wiley: 262–267. doi:10.1002/(sici)1096-8628(19960329)62:3<262::aid-ajmg11>3.0.co;2-i. ISSN 0148-7299. PMID 8882784. Retrieved November 11, 2023.
- STEINBERG, ARTHUR; SHECHTER, F. R.; SEGAL, H. I. (1954). "TRUE PITUITARY ADDISON'S DISEASE—A PITUITARY UNITROPIC DEFICIENCY (FIFTEEN-YEAR FOLLOW-UP)*". The Journal of Clinical Endocrinology & Metabolism. 14 (12). The Endocrine Society: 1519–1529. doi:10.1210/jcem-14-12-1519. ISSN 0021-972X. PMID 13211787. Retrieved November 11, 2023.