ketendoКлиническая и экспериментальная тиреоидологияClinical and experimental thyroidology1995-54722310-3787Endocrinology Research Centre10.14341/ket10303ketendo-10303Research ArticleОбзоры литературыReview of literatureВторичный гипотиреоз у взрослых: диагностика и лечениеSecondary hypothyroidism in adults: diagnosis and treatmenthttps://orcid.org/0000-0001-9205-8979КиеняТатьяна АлександровнаKieniaTatiana A.

MD

tatyana2336@yandex.ruhttps://orcid.org/0000-0003-1500-1586МоргуноваТатьяна БорисовнаMorgunovaTatiana B.

к.м.н.

MD, PhD

tanmorgun@mail.ruhttps://orcid.org/0000-0002-2504-7468ФадеевВалентин ВикторовичFadeyevValentin V.

д.м.н., профессор, член-корр. РАН

MD, PhD, Professor

walfad@mail.ru<p>ФГАОУ ВО Первый Московский государственный медицинский университет им. И.М. Сеченова Минздрава России (Сеченовский Университет)</p>Россия<p>I.M. Sechenov First Moscow State Medical University (Sechenov University)</p>Russian Federation2019031020191526472Copyright &#x00A9; Киеня Т.А., Моргунова Т.Б., Фадеев В.В., 20192019Киеня Т.А., Моргунова Т.Б., Фадеев В.В.Kienia T.A., Morgunova T.B., Fadeyev V.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.cet-endojournals.ru/jour/article/view/10303

Вторичный гипотиреоз – редкая патология, при диагностике и лечении которой возникает ряд вопросов и трудностей. Выделяют казуистически редко встречающуюся врожденную и приобретенную формы данного заболевания. Основными причинами вторичного гипотиреоза у взрослых являются опухоли гипоталамо-гипофизарной области и состояния после оперативного и лучевого воздействия на эту область. Гормонально активные и неактивные макроаденомы гипофиза служат причиной развития приобретенного вторичного гипотиреоза более чем в 50% случаев. При лучевой терапии опухолей головного мозга развитие вторичного гипотиреоза возможно спустя годы после проведенного лечения. Как и при первичном гипотиреозе, клинические проявления вторичного гипотиреоза неспецифичны. Диагностика и лечение данного заболевания зачастую осложняются его сочетанием с недостаточностью других тропных гормонов. Основу диагностики вторичного гипотиреоза составляют анамнестические данные и лабораторные показатели – одновременное определение концентрации св.Т4 и ТТГ. Содержание св.Т4 на сегодняшний день также используют как основной маркер адекватности дозы L-Т4 при лечении вторичного гипотиреоза. Результаты недавно проведенных работ позволяют оптимизировать заместительную терапию при вторичном гипотиреозе, однако до настоящего времени остается неизученным вопрос использования дополнительных биохимических маркеров для оценки адекватности заместительной терапии.

Secondary hypothyroidism is a rare disease. There is a number of questions and difficulties in diagnosis and management of this condition. There are two forms of secondary hypothyroidism: congenital (casuistic seldom) and acquired. The main causes of secondary hypothyroidism in adults are tumors of the hypothalamic-pituitary region and the state after surgical and radiation effects on this area. Hormonally active and inactive pituitary macroadenomas cause the development of acquired secondary hypothyroidism in more than 50% of cases. The development of secondary hypothyroidism is possible years after the radiotherapy of brain tumors. As well as in case of primary hypothyroidism, the clinical manifestations of secondary hypothyroidism are non-specific. Diagnosis and management of this pathology is often complicated by its combination with the deficiency of other tropic hormones. The diagnosis of secondary hypothyroidism is based on anamnestic data and laboratory tests - the simultaneous determination of the levels of fT4 and TSH. The level of fT4 today is also used as the main marker of the adequacy of the dose of L-T4 in the treatment of secondary hypothyroidism. The results of recent studies help us to optimize replacement therapy in secondary hypothyroidism. However, the use of additional biochemical markers to assess the adequacy of replacement therapy remains unexplored.

вторичный гипотиреоздиагностикалевотироксинзаместительная терапияоценка адекватности терапииsecondary hypothyroidismdiagnosislevothyroxinereplacement therapyassessment of the adequacy of therapyReferencesPrice A, Weetman AP. Screening for central hypothyroidism is unjustified. BMJ. 2001;322(7289):798. doi: https://doi.org/10.1136/bmj.322.7289.798.Price A, Weetman AP. Screening for central hypothyroidism is unjustified. BMJ. 2001;322(7289):798. doi: https://doi.org/10.1136/bmj.322.7289.798.Feldt-Rasmussen U, Klose M. Central hypothyroidism and its role for cardiovascular risk factors in hypopituitary patients. Endocrine. 2016;54(1):15-23. http://doi.org/10.1007/s12020-016-1047-x.Feldt-Rasmussen U, Klose M. Central hypothyroidism and its role for cardiovascular risk factors in hypopituitary patients. Endocrine. 2016;54(1):15-23. http://doi.org/10.1007/s12020-016-1047-x.Yamada M, Mori M. Mechanisms related to the pathophysiology and management of central hypothyroidism. Nat Clin Pract Endocrinol Metab. 2008;4(12):683-694. doi: https://doi.org/10.1038/ncpendmet0995.Yamada M, Mori M. Mechanisms related to the pathophysiology and management of central hypothyroidism. Nat Clin Pract Endocrinol Metab. 2008;4(12):683-694. doi: https://doi.org/10.1038/ncpendmet0995.Asakura Y, Tachibana K, Adachi M, et al. Hypothalamo-pituitary hypothyroidism detected by neonatal screening for congenital hypothyroidism using measurement of thyroid-stimulating hormone and thyroxine. Acta Paediatr. 2002;91(2):172-177. doi: http://doi.org/10.1111/j.1651-2227.2002.tb01691.x.Asakura Y, Tachibana K, Adachi M, et al. Hypothalamo-pituitary hypothyroidism detected by neonatal screening for congenital hypothyroidism using measurement of thyroid-stimulating hormone and thyroxine. Acta Paediatr. 2002;91(2):172-177. doi: http://doi.org/10.1111/j.1651-2227.2002.tb01691.x.Nebesio TD, McKenna MP, Nabhan ZM, Eugster EA. Newborn screening results in children with central hypothyroidism. J Pediatr. 2010;156(6):990-993. doi: http://doi.org/10.1016/j.jpeds.2009.12.011.Nebesio TD, McKenna MP, Nabhan ZM, Eugster EA. Newborn screening results in children with central hypothyroidism. J Pediatr. 2010;156(6):990-993. doi: http://doi.org/10.1016/j.jpeds.2009.12.011.Kempers MJ, Lanting CI, van Heijst AF, et al. Neonatal screening for congenital hypothyroidism based on thyroxine, thyrotropin, and thyroxine-binding globulin measurement: potentials and pitfalls. J Clin Endocrinol Metab. 2006;91(9):3370-3376. doi: http://doi.org/10.1210/jc.2006-0058.Kempers MJ, Lanting CI, van Heijst AF, et al. Neonatal screening for congenital hypothyroidism based on thyroxine, thyrotropin, and thyroxine-binding globulin measurement: potentials and pitfalls. J Clin Endocrinol Metab. 2006;91(9):3370-3376. doi: http://doi.org/10.1210/jc.2006-0058.Gonc EN, Yordam N, Ozon A, et al. Endocrinological outcome of different treatment options in children with craniopharyngioma: a retrospective analysis of 66 cases. Pediatr Neurosurg. 2004; 40(3):112-119. doi: http://doi.org/10.1159/000079852.Gonc EN, Yordam N, Ozon A, et al. Endocrinological outcome of different treatment options in children with craniopharyngioma: a retrospective analysis of 66 cases. Pediatr Neurosurg. 2004; 40(3):112-119. doi: http://doi.org/10.1159/000079852.Beck-Peccoz P, Rodari G, Giavoli C, Lania A. Central hypothyroidism – a neglected thyroid disorder. Nat Rev Endocrinol. 2017;13(10):588-598. doi: http://doi.org/10.1038/nrendo.2017.47.Beck-Peccoz P, Rodari G, Giavoli C, Lania A. Central hypothyroidism – a neglected thyroid disorder. Nat Rev Endocrinol. 2017;13(10):588-598. doi: http://doi.org/10.1038/nrendo.2017.47.Constine LS, Woolf PD, Cann D, et al. Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med. 1993; 328(2):87-94. doi: http://doi.org/10.1056/NEJM199301143280203.Constine LS, Woolf PD, Cann D, et al. Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med. 1993; 328(2):87-94. doi: http://doi.org/10.1056/NEJM199301143280203.Snyder PJ, Fowble BF, Schatz NJ, et al. Hypopituitarism following radiation therapy of pituitary adenomas. Am J Med. 1986;81(3): 457-462. doi: http://doi.org/10.1016/0002-9343(86)90299-8.Snyder PJ, Fowble BF, Schatz NJ, et al. Hypopituitarism following radiation therapy of pituitary adenomas. Am J Med. 1986;81(3): 457-462. doi: http://doi.org/10.1016/0002-9343(86)90299-8.Grunenwald S, Caron P. Central hypothyroidism in adults: better understanding for better care. Pituitary. 2015;18(1):169-175. doi: http://doi.org/10.1007/s11102-014-0559-8.Grunenwald S, Caron P. Central hypothyroidism in adults: better understanding for better care. Pituitary. 2015;18(1):169-175. doi: http://doi.org/10.1007/s11102-014-0559-8.Littley MD, Shalet SM, Beardwell CG, et al. Radiation induced hypopituitarism is dose-dependent. Clin Endocrinol (Oxf). 1989; 31(3):363-373. doi: http://doi.org/10.1111/j.1365-2265.1989.tb01260.x.Littley MD, Shalet SM, Beardwell CG, et al. Radiation induced hypopituitarism is dose-dependent. Clin Endocrinol (Oxf). 1989; 31(3):363-373. doi: http://doi.org/10.1111/j.1365-2265.1989.tb01260.x.Rose SR, Lustig RH, Pitukcheewanont P, et al. Diagnosis of hidden central hypothyroidism in survivors of childhood cancer. J Clin Endocrinol Metab. 1999;84(12):4472-4479. doi: http://doi.org/10.1210/jcem.84.12.6097.Rose SR, Lustig RH, Pitukcheewanont P, et al. Diagnosis of hidden central hypothyroidism in survivors of childhood cancer. J Clin Endocrinol Metab. 1999;84(12):4472-4479. doi: http://doi.org/10.1210/jcem.84.12.6097.Fernandez-Rodriguez E, Bernabeu I, Castro AI, Casanueva FF Hypopituitarism after traumatic brain injury. Endocrinol Metab Clin North Am. 2015;44(1):151-159. doi: http://doi.org/10.1016/j.ecl.2014.10.012.Fernandez-Rodriguez E, Bernabeu I, Castro AI, Casanueva FF Hypopituitarism after traumatic brain injury. Endocrinol Metab Clin North Am. 2015;44(1):151-159. doi: http://doi.org/10.1016/j.ecl.2014.10.012.Krewer C, Schneider M, Schneider HJ, et al. Neuroendocrine disturbances one to five or more years after traumatic brain injury and aneurysmal subarachnoid hemorrhage: data from the German database on hypopituitarism. J Neurotrauma. 2016; 33(16):1544-1553. doi: http://doi.org/10.1089/neu.2015.4109.Krewer C, Schneider M, Schneider HJ, et al. Neuroendocrine disturbances one to five or more years after traumatic brain injury and aneurysmal subarachnoid hemorrhage: data from the German database on hypopituitarism. J Neurotrauma. 2016; 33(16):1544-1553. doi: http://doi.org/10.1089/neu.2015.4109.Faje A. Hypophysitis: evaluation and management. Clin Diabetes Endocrinol. 2016;2:15. doi: http://doi.org/10.1186/s40842-016-0034-8.Faje A. Hypophysitis: evaluation and management. Clin Diabetes Endocrinol. 2016;2:15. doi: http://doi.org/10.1186/s40842-016-0034-8.Alexopoulou O, Beguin C, De Nayer P, Maiter D. Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients. Eur J Endocrinol. 2004;150(1):1-8. doi: http://doi.org/10.1530/eje.0.1500001.Alexopoulou O, Beguin C, De Nayer P, Maiter D. Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients. Eur J Endocrinol. 2004;150(1):1-8. doi: http://doi.org/10.1530/eje.0.1500001.Neumann S, Raaka BM, Gershengorn MC. Constitutively active thyrotropin and thyrotropin-releasing hormone receptors and their inverse agonists. Methods Enzymol. 2010;485:147-160. doi: http://doi.org/10.1016/B978-0-12-381296-4.00009-9.Neumann S, Raaka BM, Gershengorn MC. Constitutively active thyrotropin and thyrotropin-releasing hormone receptors and their inverse agonists. Methods Enzymol. 2010;485:147-160. doi: http://doi.org/10.1016/B978-0-12-381296-4.00009-9.Barbesino G, Sluss PM, Caturegli P. Central hypothyroidism in a patient with pituitary autoimmunity: evidence for TSH-independent thyroid hormone synthesis. J Clin Endocrinol Metab. 2012;97(2):345-350. doi: http://doi.org/10.1210/jc.2011-1591.Barbesino G, Sluss PM, Caturegli P. Central hypothyroidism in a patient with pituitary autoimmunity: evidence for TSH-independent thyroid hormone synthesis. J Clin Endocrinol Metab. 2012;97(2):345-350. doi: http://doi.org/10.1210/jc.2011-1591.Hashimoto K. The etiology of isolated thyroid stimulating hormone deficiency. Intern Med. 1998;37(3):231-232. doi: http://doi.org/10.2169/internalmedicine.37.231.Hashimoto K. The etiology of isolated thyroid stimulating hormone deficiency. Intern Med. 1998;37(3):231-232. doi: http://doi.org/10.2169/internalmedicine.37.231.Persani L. Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab. 2012;97(9): 3068-3078. doi: http://doi.org/10.1210/jc.2012-1616.Persani L. Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab. 2012;97(9): 3068-3078. doi: http://doi.org/10.1210/jc.2012-1616.Beck-Peccoz P, Persani L. Variable biological activity of thyroid-stimulating hormone. Eur J Endocrinol. 1994;131(4):331-340. doi: http://doi.org/10.1530/eje.0.1310331.Beck-Peccoz P, Persani L. Variable biological activity of thyroid-stimulating hormone. Eur J Endocrinol. 1994;131(4):331-340. doi: http://doi.org/10.1530/eje.0.1310331.Persani L. Hypothalamic thyrotropin-releasing hormone and thyrotropin biological activity. Thyroid. 1998;8(10):941-946. doi: http://doi.org/10.1089/thy.1998.8.941.Persani L. Hypothalamic thyrotropin-releasing hormone and thyrotropin biological activity. Thyroid. 1998;8(10):941-946. doi: http://doi.org/10.1089/thy.1998.8.941.Beck-Peccoz P, Amr S, Menezes-Ferreira MM, et al. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. N Engl J Med. 1985;312(17):1085-1090. doi: http://doi.org/10.1056/NEJM198504253121703.Beck-Peccoz P, Amr S, Menezes-Ferreira MM, et al. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. N Engl J Med. 1985;312(17):1085-1090. doi: http://doi.org/10.1056/NEJM198504253121703.Persani L, Ferretti E, Borgato S, et al. Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J Clin Endocrinol Metab. 2000;85(10):3631-3635. doi: http://doi.org/10.1210/jcem.85.10.6895.Persani L, Ferretti E, Borgato S, et al. Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J Clin Endocrinol Metab. 2000;85(10):3631-3635. doi: http://doi.org/10.1210/jcem.85.10.6895.Toft AD. Thyroxine therapy. N Engl J Med. 1994;331(3):174-180. doi: http://doi.org/10.1056/NEJM199407213310307.Toft AD. Thyroxine therapy. N Engl J Med. 1994;331(3):174-180. doi: http://doi.org/10.1056/NEJM199407213310307.Atmaca H, Tanriverdi F, Gokce C, et al. Do we still need the TRH stimulation test? Thyroid. 2007;17(6):529-533. doi: http://doi.org/10.1089/thy.2006.0311.Atmaca H, Tanriverdi F, Gokce C, et al. Do we still need the TRH stimulation test? Thyroid. 2007;17(6):529-533. doi: http://doi.org/10.1089/thy.2006.0311.Gupta V, Lee M. Central hypothyroidism. Indian J Endocrinol Metab. 2011;15(Suppl 2):S99-S106. doi: http://doi.org/10.4103/2230-8210.83337.Gupta V, Lee M. Central hypothyroidism. Indian J Endocrinol Metab. 2011;15(Suppl 2):S99-S106. doi: http://doi.org/10.4103/2230-8210.83337.Ormston BJ, Cryer RJ, Garry R, et al. Thyrotrophin-releasing hormone as a thyroid-function test. Lancet. 1971;2(7714):10-14. doi: http://doi.org/10.1016/s0140-6736(71)90005-5.Ormston BJ, Cryer RJ, Garry R, et al. Thyrotrophin-releasing hormone as a thyroid-function test. Lancet. 1971;2(7714):10-14. doi: http://doi.org/10.1016/s0140-6736(71)90005-5.Mehta A, Hindmarsh PC, Stanhope RG, et al. Is the thyrotropin-releasing hormone test necessary in the diagnosis of central hypothyroidism in children. J Clin Endocrinol Metab. 2003;88(12): 5696-5703. doi: http://doi.org/10.1210/jc.2003-030943.Mehta A, Hindmarsh PC, Stanhope RG, et al. Is the thyrotropin-releasing hormone test necessary in the diagnosis of central hypothyroidism in children. J Clin Endocrinol Metab. 2003;88(12): 5696-5703. doi: http://doi.org/10.1210/jc.2003-030943.Hartoft-Nielsen ML, Lange M, Rasmussen AK, et al. Thyrotropin-releasing hormone stimulation test in patients with pituitary pathology. Horm Res. 2004;61(2):53-57. doi: http://doi.org/10.1159/000075239.Hartoft-Nielsen ML, Lange M, Rasmussen AK, et al. Thyrotropin-releasing hormone stimulation test in patients with pituitary pathology. Horm Res. 2004;61(2):53-57. doi: http://doi.org/10.1159/000075239.Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-1751. doi: http://doi.org/10.1089/thy.2014.0028.Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-1751. doi: http://doi.org/10.1089/thy.2014.0028.de Carvalho GA, Paz-Filho G, Mesa Junior C, Graf H. Pitfalls on the replacement therapy for primary and central hypothyroidism in adults. Eur J Endocrinol. 2018;178(6):R231-R244. doi: http://doi.org/10.1530/EJE-17-0947.de Carvalho GA, Paz-Filho G, Mesa Junior C, Graf H. Pitfalls on the replacement therapy for primary and central hypothyroidism in adults. Eur J Endocrinol. 2018;178(6):R231-R244. doi: http://doi.org/10.1530/EJE-17-0947.Persani L, Brabant G, Dattani M, et al. 2018 European Thyroid Association (ETA) guidelines on the diagnosis and management of central hypothyroidism. Eur Thyroid J. 2018;7(5):225-237. doi: http://doi.org/10.1159/000491388.Persani L, Brabant G, Dattani M, et al. 2018 European Thyroid Association (ETA) guidelines on the diagnosis and management of central hypothyroidism. Eur Thyroid J. 2018;7(5):225-237. doi: http://doi.org/10.1159/000491388.Koulouri O, Auldin MA, Agarwal R, et al. Diagnosis and treatment of hypothyroidism in TSH deficiency compared to primary thyroid disease: pituitary patients are at risk of under-replacement with levothyroxine. Clin Endocrinol (Oxf). 2011;74(6):744-749. doi: http://doi.org/10.1111/j.1365-2265.2011.03984.x.Koulouri O, Auldin MA, Agarwal R, et al. Diagnosis and treatment of hypothyroidism in TSH deficiency compared to primary thyroid disease: pituitary patients are at risk of under-replacement with levothyroxine. Clin Endocrinol (Oxf). 2011;74(6):744-749. doi: http://doi.org/10.1111/j.1365-2265.2011.03984.x.Ferretti E, Persani L, Jaffrain-Rea ML, et al. Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab. 1999;84(3):924-929. doi: http://doi.org/10.1210/jcem.84.3.5553.Ferretti E, Persani L, Jaffrain-Rea ML, et al. Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab. 1999;84(3):924-929. doi: http://doi.org/10.1210/jcem.84.3.5553.Slawik M, Klawitter B, Meiser E, et al. Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine. J Clin Endocrinol Metab. 2007;92(11): 4115-4122. doi: http://doi.org/10.1210/jc.2007-0297.Slawik M, Klawitter B, Meiser E, et al. Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine. J Clin Endocrinol Metab. 2007;92(11): 4115-4122. doi: http://doi.org/10.1210/jc.2007-0297.Agha A, Walker D, Perry L, et al. Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients. Clin Endocrinol (Oxf). 2007;66(1):72-77. doi: http://doi.org/10.1111/j.1365-2265.2006.02688.x.Agha A, Walker D, Perry L, et al. Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients. Clin Endocrinol (Oxf). 2007;66(1):72-77. doi: http://doi.org/10.1111/j.1365-2265.2006.02688.x.Гаврилова Т.А., Моргунова Т.Б., Фадеев В.В. Вторичный гипотиреоз: современные подходы к диагностике и лечению // Медицинский совет. – 2017. – №3. – С. 64-67. [Gavrilova TA, Morgunova TB, Fadeev VV. Secondary hypothyroidism: current approaches to diagnosis and treatment. Meditsinskii sovet. 2017;(3): 64-67. (In Russ.)] doi: http://doi.org/10.21518/2079-701X-2017-3-64-67.Гаврилова Т.А., Моргунова Т.Б., Фадеев В.В. Вторичный гипотиреоз: современные подходы к диагностике и лечению // Медицинский совет. – 2017. – №3. – С. 64-67. [Gavrilova TA, Morgunova TB, Fadeev VV. Secondary hypothyroidism: current approaches to diagnosis and treatment. Meditsinskii sovet. 2017;(3): 64-67. (In Russ.)] doi: http://doi.org/10.21518/2079-701X-2017-3-64-67.Doin FC, Rosa-Borges M, Martins MR, et al. Diagnosis of subclinical central hypothyroidism in patients with hypothalamic-pituitary disease by Doppler echocardiography. Eur J Endocrinol. 2012;166(4):631-640. doi: http://doi.org/10.1530/EJE-11-0907.Doin FC, Rosa-Borges M, Martins MR, et al. Diagnosis of subclinical central hypothyroidism in patients with hypothalamic-pituitary disease by Doppler echocardiography. Eur J Endocrinol. 2012;166(4):631-640. doi: http://doi.org/10.1530/EJE-11-0907.

The authors declare that there are no conflicts of interest present.