foto

Dr. A. Boelen

Position
Other
Main activities
Patient care, Research
Specialisation
endocrinology, neonatal screening
Focus of research

Central and peripheral thyroid hormone metabolism during inflammation

Hypothalamus-pituitary-thyroid axis

Key publications
  • van der Spek AH, Surovtseva OV, Jim KK, van Oudenaren A, Brouwer MC, Vandenbroucke-Grauls CMJE, Leenen PJM, van de Beek D, Hernandez A, Fliers E, Boelen A, Regulation of Intracellular Triiodothyronine Is Essential for Optimal Macrophage Function. ENDOCRINOLOGY 2018;159 (5):2241-2252 [PubMed]
  • van der Spek AH, Bloise FF, Tigchelaar W, Dentice M, Salvatore D, van der Wel NN, Fliers E, Boelen A, The Thyroid Hormone Inactivating Enzyme Type 3 Deiodinase is Present in Bactericidal Granules and the Cytoplasm of Human Neutrophils. ENDOCRINOLOGY 2016;157 (8):3293-3305 [PubMed]
  • Heinen CA, Losekoot M, Sun Y, Watson PJ, Fairall L, Joustra SD, Zwaveling-Soonawala N, Oostdijk W, van den Akker ELT, Alders M, Santen GWE, van Rijn RR, Dreschler WA, Surovtseva OV, Biermasz NR, Hennekam RC, Wit JM, Schwabe JWR, Boelen A, Fliers E, van Trotsenburg ASP, Mutations in TBL1X Are Associated With Central Hypothyroidism. J CLIN ENDOCR METAB 2016;101 (12):4564-4573 [PubMed]
  • Heinen CA, de Vries EM, Alders M, Bikker H, Zwaveling-Soonawala N, van den Akker ELT, Bakker B, Hoorweg-Nijman G, Roelfsema F, Hennekam RC, Boelen A, van Trotsenburg ASP, Fliers E, Mutations in IRS4 are associated with central hypothyroidism. J MED GENET 2018;55 (10):693-700 [PubMed]
  • Kwakkel J, Surovtseva OV, de Vries EM, Stap J, Fliers E, Boelen A, A Novel Role for the Thyroid Hormone-Activating Enzyme Type 2 Deiodinase in the Inflammatory Response of Macrophages. ENDOCRINOLOGY 2014;155 (7):2725-2734 [PubMed]
All Publications
Research programmes

Thyroid hormone metabolism and action

Thyroid hormone metabolism and action during illness
Illness of any cause is known to be associated with decreased serum thyroid hormone concentrations and paradoxically low serum TSH, together known as nonthyroidal illness syndrome (NTIS). The functional meaning of NTIS has remained enigmatic. Although the common view was that NTIS results in overall downregulation of metabolism in order to save energy, recent work has shown a more complex picture. Local T3 tissue concentrations in NTIS may be decreased, unaltered or even increased. This differential picture results from marked variation in transcriptional and translational activity of genes involved in thyroid hormone metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. In addition, the illness induced changes appear to be very different during acute or chronic inflammation.
We recently published that type 2 deiodinase, the main T3 activating enzyme, is expressed in macrophages and serves as a local determinant of macrophage function during inflammation. Type 3 deiodinase (D3) is the main T3 inactivating enzyme, converting the thyroid hormones T3 and T4 to their inactive metabolites. Our lab discovered that D3 is expressed in infiltrating murine neutrophils, a type of white blood cell that is key to the innate immune system. As D3 knockout mice show impaired bacterial killing compared to wildtype mice, D3 expression in neutrophils is likely a novel player in the innate immune response. To further unravel these novel roles of deiodinating enzymes in immune functions we will use mouse models, primary cultures and cell lines.
Our previous studies in postmortem human hypothalamus in NTIS showed decreased hypothalamic TRH expression in critical illness, while work by others showed clear effects of iv TRH administration in ICU patients, restoring the HPT axis to a large extent. We aim to perform clinical studies in ICU patients in order to address the clinical relevance of interventions that restore serum thyroid hormone concentrations in protracted critical illness.

Clinical aspects and novel genetic causes of congenital central hypothyroidism
Central hypothyroidism (CeH) is characterized by thyroid hormone (TH) deficiency due to insufficient stimulation of an otherwise normal thyroid gland by thyroid-stimulating hormone (TSH). Central hypothyroidism occurs either isolated, or in combination with other pituitary hormone deficiencies. Well-known genetic causes of isolated central hypothyroidism include mutations in TSHB, TRHR and IGSF1. Using whole-exome sequencing in patients with isolated central hypothyroidism of unknown origin we recently identified two additional and novel genetic causes for CeH. One of these mutations is associated with a unique syndrome of CeH and sensorineural hearing loss. We are now assessing clinical, biochemical and radiological characteristics of the probands and the carriers. Additionally, we focus on the mechanisms involved using cell systems and transgenic mice models.
The laboratory of Endocrinology has hosted the Neonatal Screening Laboratory Amsterdam since the start of the neonatal screening in the Netherlands (1981). A blood sample is taken from every newborn between 72 – 168 hours after birth. The blood is tested in the laboratory for 17 rare diseases. Early detection and treatment of these diseases can prevent or limit serious impairment of the physical and mental development of the child. Congenital hypothyroidism was the first disease to be taken up in the program.

 

Faculty
Dr. A. Boelen

PhD Students
E. Belegri MSc
Drs. Y. Hu MSc
Drs. J.C. Naafs
Drs. K. Stroek MSc

Others
Ing. O.V. Surovtseva

Prof. dr. E. Fliers (Neuroendocrinology)

Other research related activities
  • Membership of medical or scientific committee, European Thyroid Association, educational board
  • Membership of medical or scientific committee, Dutch Endocrine Society, board
  • Membership of medical or scientific committee, Dutch Thyroid Association, secretary board
  • Membership of advisory board / Consultant, Advies Commissie Neonatale sceening CH-AGS
  • Membership of editorial board / Editorship, JOURNAL OF ENDOCRINOLOGY
  • Membership of editorial board / Editorship, ENDOCRINOLOGY
  • Membership of medical or scientific committee, Other, Program Organizing Committee ITC2020
Current research funding
  • AMC
  • ETA European Thyroid Association
  • Innovatiefonds Zorgverzekeraars
  • PerkinElmer
  • RIVM