Thyroid Function Of Adrenal Cushing’s Syndrome And Molecular Mechanism Of Macronodular Adrenal Hyperplasia

BackgroundCortisol-producing adenoma（CPA）and primary bilateral macronodular adrenocortical hyperplasia（PBMAH）are two subtypes of adrenocorticotropic hormone adrenal Cushing’s Syndrome（CS）.Previous studies reported that glucocorticoid excess suppressed thyroid function.Nevertheless,previous finding about changes in thyroid function due to CPA have been inconsistent.This should be explored and studied further.In addition,the clinical manifestation of PBMAH was variable and onset of the disease was slow.Early diagnosis and timely treatment are the difficult problems of PBMAH.Armadillo repeat containing 5（ARMC5）germline mutations have been identified as a genetic cause of PBMAH.Although several foreign studies analyzed the association between genotype and clinical phenotype,there is no report about this in China.Identifying the relationship between genotype and phenotype is helpful to improve the understanding of PBMAH and provide new sight for clinical early screening and timely treatment.ObjectiveTo investigate the association between thyroid function and excessive cortisol secretion in patients with CPA.To assess the prevalence of ARMC5 germline mutations and investigate the correlation between genotype and phenotype in Chinese PBMAH patients.Methods1.94 consecutive patients with CPA,94 patients with nonfunctioning adrenal incidentalomas（NFAIs）and 94 healthy controls（HC）matched for age and sex were included.Thyroid function in the three groups were observed and compared.CPA was divided into four groups according to the quartiles of morning serum cortisol to analyze the relationship between serum cortisol level and thyroid function.Comparisons were conducted before and after adrenalectomy to evaluate the changes in thyroid function of patients with CPA.2.The clinical data,blood sample and adrenal tissue were obtained from 48 patients with PBMAH.ARMC5 sequence was determined by the sanger method.LOH was further investigated by means of microsatellite analysis.The clinical phenotype of PBMAH patients with and without ARMC5 mutations was compared.Results1.Serum total triiodothyronine（TT₃）,total thyroxine（TT₄）,free triiodothyronine（FT₃）,free thyroxine（FT₄）,thyroid stimulating hormone（TSH）levels were significantly lower in the CPA group than in the HC or NFAIs groups（P<0.001）.The prevalence of central hypothyroidism was 12.8%in the CPA group and increased according to serum cortisol quartiles（P for trend=0.025）.According to the stepwise multiple linear regression analysis,serum cortisol was negatively associated with TSH and free T4 levels in the CPA group after adjustment for body mass index（BMI）and age.Thyroid dysfunction was significantly improved after unilateral adrenalectomy,all patients with central hypothyroidism returned to normal.2.This study including 48 patients with PBMAH,and ARMC5-damaging mutation were detected in 29 of 48 patients（60%）.Patients with ARMC5-damaging mutations showed higher midnight serum cortisol levels,larger nodular diameter and higher rate of bilateral adrenalectomy than those without ARMC5 mutations.17 patients carried both germline and additional somatic mutations or LOH.Patients with ARMC5 somatic alterations were younger than those without somatic events.However,there was no significant difference in sex ratio,BMI,blood pressure,serum cortisol levels and adrenal nodule diameter between the two groups.Genetic investigation of relatives showed that ARMC5 germline mutations were found in 5 relatives of the index case.Conclusion1.The prevalence of central hypothyroidism was higher in the CPA group than in HC group.Patients with CPA had lower serum TSH、TT3、TT4、FT3、FT4 levels than those in healthy control.Thyroid hormones levels decreased as the increasing serum cortisol level,suggesting that thyroid dysfunction was mainly affected by hypercortisolism.After unilateral adrenalectomy,thyroid dysfunction was reversible as cortisol were back to normal.2.Patients with PBMAH who carried ARMC5 germline mutation had higher midnight cortisol levels and larger adrenal nodular,and a higher proportion to perform bilateral adrenalectomy.Patients with somatic mutations were younger than those without mutations,and there was no significant difference in phenotypes.Genetic screening of family members of sporadic cases is helpful for early diagnosis and timely treatment.