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Josep Oriola, Tomás Lucas, Irene Halperin, Mireia Mora, Ma José Perales, Cristina Alvarez-Escolá, de Miguel-Novoa Paz, Gonzalo Díaz Soto, Isabel Salinas, María Teresa Julián, Izaskun Olaizola, Ignacio Bernabeu, Mónica Marazuela, and Manuel Puig-Domingo

Objective

Most cases of familial isolated pituitary adenomas with mutated aryl hydrocarbon receptor-interacting protein (AIP:HGNC:358) gene develop somatotropinomas. They are characterised by an aggressive clinical phenotype including early age at diagnosis, large tumours and frequent invasiveness. There is little information on AIP gene mutations' prevalence in isolated somatotropinomas characterised by poor response to somatostatin analogue treatment. The aim of this study was to investigate the prevalence of AIP mutations in non-familial cases of somatotropinomas with poor response to conventional treatment.

Design and methods

Fifty patients with acromegaly (22 males/28 females, age 51±18 years) and 60 controls were included in this study performed at eight University Hospitals in Spain. None had family history of pituitary adenomas or other endocrine tumors. All patients failed to respond to conventional treatment including surgery and somatostatin analogues. Some patients received adjuvant radiotherapy and most cases required pegvisomant (PEG) treatment for normalisation of IGF1. AIP analysis was performed in DNA extracted from peripheral leucocytes, using standardised PCR protocol in which the coding regions of exons 1, 2, 3, 4, 5 and 6 were amplified. Possible deletions/duplications were studied using multiplex ligation-dependent probe amplification.

Results

Sequence changes of potential different significance that could be considered as mutations or variations of unknown significance (VUS) of the AIP gene were found in four patients (8%). In two cases, two different mutations previously described were found: p.Arg9Gln and p.Phe269Phe. Two other VUS were also found: c.787+24C>T in intron 5 and c.100-18C>T in intron 1. Age at diagnosis ranged from 21 to 50 years old, and in all patients, the tumor was a macroadenoma depicting IGF1 normalisation under PEG treatment.

Conclusions

AIP germline mutations show a low, but non-negligible, prevalence in non-familial acromegaly patients with tumors resistant to treatment with somatostatin analogues.

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María Teresa Julián, Guillem Pera, Berta Soldevila, Llorenç Caballería, Josep Julve, Carlos Puig-Jové, Rosa Morillas, Pere Torán, Carmen Expósito, Manel Puig-Domingo, Esmeralda Castelblanco, Josep Franch-Nadal, Kenneth Cusi, Didac Mauricio, and Nuria Alonso

Objective: To investigate the prevalence and risks factors associated with the presence of significant liver fibrosis in subjects with nonalcoholic fatty liver disease (NAFLD) with and without type 2 diabetes mellitus (T2D).

Design and methods: This study was part of a population-based study conducted in the Barcelona metropolitan area among subjects aged 18-75 years old. Secondary causes of steatosis were excluded. Moderate-to-advanced liver fibrosis was defined as a liver stiffness measurement (LSM) ≥ 8.0 kPa assessed by transient elastography.

Results: Among 930 subjects with NAFLD, the prevalence of moderate-to-advanced liver fibrosis was higher in subjects with T2D compared those without (30.8% vs. 8.7%). By multivariable analysis, one of the main factors independently associated with increased LSM in subjects with NAFLD was atherogenic dyslipidemia, but only in those with T2D. The percentage of subjects with LSM ≥ 8.0 kPa was higher in subjects with T2D and atherogenic dyslipidemia than in those with T2D without atherogenic dyslipidemia, both for the cut-off point of LSM ≥8.0 kPa (45% vs 24%, p=0.002) and 13 kPa (13% vs 4%, p=0.020). No differences were observed in the prevalence of LSM ≥8.0 kPa regarding glycemic control among NAFLD-diabetic subjects.

Conclusions: Factors associated with moderate-to-advanced liver fibrosis in NAFLD are different in subjects with and without T2D. Atherogenic dyslipidemia was associated with the presence of moderate-to-advanced liver fibrosis in T2D with NAFLD but not in non-diabetic subjects. These findings highlight the need for an active search for liver fibrosis in subjects with T2D, NAFLD and atherogenic dyslipidemia.