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- Husebye, E. S., et al.
(författare)
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Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency
- 2014
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 275:2, s. 104-115
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Forskningsöversikt (refereegranskat)abstract
- Primary adrenal insufficiency (PAI), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow-up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21-hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life-threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow-up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self-adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow-up.
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| 3. |
- Kerkhofs, Tm, et al.
(författare)
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Comparison of Two Mitotane Starting dose Regimens in Patients with Advanced Adrenocortical Carcinoma
- 2013
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 98:12, s. 2281-
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Tidskriftsartikel (refereegranskat)abstract
- Context:Mitotane is the only approved drug for treatment of adrenocortical carcinoma(ACC). Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been compared head-to-head.Objective:To investigate the relationship between mitotane dose and plasma concentration comparing two dosing regimens.Design/Setting:Prospective open-label multicenter trial of a predefined duration of twelve weeks.Patients/Interventions:Forty mitotane-naïve patients with metastatic ACC were assigned to a predefined low- or high-dose regimen by the local investigator. Thirty-two could be evaluated in detail.Main Outcome Measure:Difference in median mitotane plasma levels between both treatment groups.Results:Despite a difference in mean cumulative dose (440±142g versus 272±121g), median maximum plasma levels were not significantly different between the two groups (high-dose 14.3mg/L (6.3-29.7,n=20) versus 11.3mg/L (5.5-20.0,n=12), p=0.235). Ten out of twenty patients on the high-dose regimen reached plasma concentrations ≥14mg/L after 46 days (18-81 days) compared to four of twelve patients on the low-dose regimen after 55 days (46-74 days,p=0.286). All patients who reached 14mg/L at 12 weeks displayed a level ≥4.1 mg/L on day 33 (100% sensitivity). There were no significant differences in frequency and severity of adverse events. Among patients not receiving concomitant chemotherapy mitotane exposure was higher in the high-dose group: 1013±494mg.d/L versus 555±168mg.d/L, p=0.080.Conclusions:The high-dose starting regimen did neither result in significantly different mitotane levels nor in a different rate of adverse events, but concomitant chemotherapy influenced these results. Thus, for mitotane monotherapy the high-dose approach is favorable, whereas for combination therapy a lower dose seems reasonable.
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- Zwermann, O, et al.
(författare)
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Multiple endocrine neoplasia type 1 gene expression is normal in sporadic adrenocortical tumors
- 2000
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Ingår i: European journal of endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 142:6, s. 689-695
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Tidskriftsartikel (refereegranskat)abstract
- Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder with neoplasia of the anterior pituitary, the parathyroid, the endocrine pancreas and other endocrine tissues including the adrenal cortex. The tumor-suppressor gene causing this disease was identified at the gene locus 11q13. We recently reported that adrenocortical carcinomas frequently show loss of heterozygosity (LOH) of 11q13, but do not contain point mutations within the MEN1-coding region. To investigate whether reduced gene expression (for example by mutations within the MEN1 promoter) may contribute to the tumorigenesis of sporadic adrenocortical tumors, 24 adrenocortical specimen were studied by Northern blot analysis. This series included six adrenocortical carcinomas, four cortisol-producing adenomas, six aldosterone-producing adenomas, three endocrine-inactive adenomas and six normal adrenal glands. The presence of LOH of 11q13 was investigated using five polymorphic microsatellite markers (D11S956, PYGM, D11S4939, D11S4946 and D11S987) close to the MEN1 gene. Poly-A mRNA was hybridized with a PCR-generated cDNA probe of the MEN1 gene, a cDNA of the former MEN1 candidate gene phospholipase (PLC) beta3 and a mouse beta-actin cDNA for normalization. LOH of 11q13 was detected in five out of six carcinomas and two inactive adenomas, but in none of the hormone-producing adenomas. Compared with normal adrenals (100+/-6. 5%, mean+/-s.e.m.) MEN1 mRNA in adrenocortical tumors was expressed in similar amounts (carcinomas 109+/-11%, cortisol-producing adenomas 131+/-10%, aldosterone-producing adenomas 113+/-13%, endocrine-inactive adenomas 111+/-2%) with the exception of one adrenocortical carcinoma with low MEN1 mRNA expression (66%). PLCbeta3 mRNA expression showed a variable pattern without reaching significant differences between the groups. We conclude that since mRNA levels were unaltered in the majority of tumors, mutations of the MEN1 gene causing altered gene transcription is unlikely to be a major pathogenic factor of sporadic adrenocortical tumors.
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