Системные и метаболические эффекты гормона роста у детей с различными вариантами низкорослости тема диссертации и автореферата по ВАК РФ 14.00.03, доктор медицинских наук Волеводз, Наталья Никитична

• Волеводз, Наталья Никитична
• доктор медицинских наук
• 2005

Оглавление диссертации доктор медицинских наук Волеводз, Наталья Никитична

ВВЕДЕНИЕ 4

ГЛАВА I. Обзор литературы: «Системные и метаболические эффекты гормона роста у детей с различными вариантами 10 низкорослости - современное состояние проблемы»

ГЛАВА II. Материалы и методы исследования

ГЛАВА III. Национальный регистр больных соматотропной ^ недостаточностью в Российской Федерации

3.1. Создание Национального регистра больных с соматотропной недостаточностью

3.2. Распространенность соматотропной недостаточности в Российской Федерации

4.2. Дефицит ГР с наличием или отсутствием изменений со стороны гипоталамо-гипофизарной области у детей

7.2. Низкорослость, обусловленная длительным применением глюкокортикоидов (ревматические заболевания)

ГЛАВА IV. Врожденная недостаточность гормона роста у детей

4.1. Изолированный дефицит ГР и множественный дефицит гормонов ^ аденогипофиза

ГЛАВА V. Приобретенная недостаточность гормона роста у детей

5.1. Клинико-гормональная характеристика пациентов после удаленной краниофарингиомы

5.2 Влияние заместительной терапии р-ГР на ростовые параметры у ^^ пациентов после удаленной краниофарингиомы

5.3. Дефицит ГР при других случаях приобретенной недостаточности ГР

ГЛАВА VI. Факторы, определяющие эффективность лечения р- ^^ ГР детей с соматотропной недостаточностью

6.1. Влияние различных доз р-ГР на эффективность лечения детей с соматотропной недостаточностью

6.2. Влияние пубертата на эффективность лечения детей с соматотропной недостаточностью

6.3. Влияние возраста начала заместительной терапии р-ГР на показатели конечного роста детей с соматотропной недостаточностью

ГЛАВА VII. Терапия р-ГР у пациентов с другими формами 121 низкорослости

7.1. Синдром Шерешевского-Тернера

ГЛАВА VIII. Инсулиноподобный фактор роста - 1 и его связывающий белок - 3 у детей с различными вариантами 130 низкорослости

ГЛАВА IX. Состояние костной ткани у детей с соматотропной недостаточностью

9.1. Влияние дефицита ГР и заместительной терапии р-ГР на минеральную массу и минеральную плотность костной ткани у детей с соматотропной недостаточностью

9.2. Влияние терапии р-ГР на содержание биохимических маркеров костного метаболизма и фосфорно-кальциевый обмен у детей с 144 соматотропной недостаточностью

ГЛАВА X. Состояние жирового обмена у детей с различными ^^ вариантами низкорослости

10.1. Индекс массы тела у детей с соматотропной недостаточностью и его динамика на фоне заместительной терапии р-ГР

10.2. Содержание жировой и тощей массы в организме у детей с соматотропной недостаточностью и его динамика на фоне 157 заместительной терапии р-ГР

10.3. Исследование липидов в сыворотке крови у детей с различными вариантами низкорослости и их динамика на фоне заместительной 163 терапии р-ГР

ГЛАВА XI. Исследование сердечно-сосудистой системы у детей с соматотропной недостаточностью

11.1. Электрокардиографическое исследование у детей с ^^ соматотропной недостаточностью

11.2. Эхокардиографическое исследование у детей с с соматотропной ^^ недостаточностью

ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ

ВЫВОДЫ

Введение диссертации (часть автореферата) на тему «Системные и метаболические эффекты гормона роста у детей с различными вариантами низкорослости»

АКТУАЛЬНОСТЬ ИССЛЕДОВАНИЯ

Рост ребенка является одним из критериев здоровья развивающегося организма. Поэтому различные его нарушения могут возникать при множестве заболеваний эндокринного и соматического характера.

Наиболее выраженная задержка роста отмечается при соматотропной недостаточности, как изолированной, так и в сочетании с выпадением тропной функции других гормонов гипофиза. Исследования последних лет свидетельствуют о значительной гетерогенности клинической картины этого состояния в зависимости от этиологии и типа дефицита ГР. Кроме того, низкорослость может быть проявлением хромосомных аномалий (синдром Шерешевского-Тернера, Синдром Нунан, Сильвера-Рассела и др.), внутриутробной задержки роста, хронических соматических заболеваниях (ревматические болезни, хроническая почечная недостаточность и др.)

Отставание в росте, даже носящее временный характер, может неблагоприятно сказываться на показателях конечного роста, приводить к низкорослости. Низкий рост становится зачастую серьезной психологической проблемой и причиной социальной дезадаптации (Burman P. et al. 1995, Erfurth Е. et al. 1999). Помимо низкорослости, недостаточность ГР сопровождается целым рядом метаболических нарушений: гиперхолестеринемией, снижением мышечной массы и толерантности к физическим нагрузкам, остеопенией, нарушением углеводного обмена, изменением иммунного статуса (Salomon et al. 1989, Gilbney et al. 1999, Kann et al. 1998). Эти метаболические нарушения ведут к повышению заболеваемости, ранней инвалидизации и смертности взрослых пациентов с соматотропной недостаточностью. Однако, изменения в обменных процессах вследствие дефицита ГР начинают формироваться уже в детском возрасте (Saggese et al. 1996, Boot et al. 2002). Поэтому их изучение, анализ динамики указанных параметров под влиянием заместительной терапии р-ГР приобретают особую актуальность.

Разработка генно-инженерного метода получения р-ГР произвела настоящую революцию в лечении детей с различными формами низкорослости. Появилась возможность постоянной заместительной терапии у больных соматотропной недостаточностью, которая позволяет не только достичь нормального роста, но и контролировать метаболические нарушения вследствие дефицита ГР, что значительно снижает смертность и инвалидизацию этих пациентов от сердечно-сосудистых осложнений и костных переломов (Bulow et al. 2000, Colao et al. 2001).

Еще совсем недавно сведения о больных, с соматотропной* недостаточностью в Российской Федерации носили разрозненный характер. Существенным шагом на пути оптимизации помощи больным явилось создание Национального регистра больных гипофизарной карликовостью, позволяющего получить объективную информацию о распространенности заболевания, проводить систематический учет детей с дефицитом ГР, определять потребность в препарате (р-ГР) для осуществления централизованных его закупок, проводить мониторинг эффективности и безопасности его применения. Помимо этого, создание регистра существенно расширяет возможности всесторонней научной оценки данного заболевания.

В отечественной практике исследования эффективности и безопасности длительного применения р-ГР при дефиците ГР (как врожденном, так и приобретенном) и других формах низкорослости (синдром Шерешевского-Тернера, ревматические заболевания) до сих пор не проводилось. Остается не ясным его влияние на липидный обмен, показатели костного метаболизма, сердечно-сосудистую систему. Не оптимизированы дозировки и схемы применения, критерии эффективности лечения и его безопасности при различных вариантах низкорослости.

В последнее время все более пристальное внимание исследователей во всем мире направлено на изучение возможности применения р-ГР при других формах низкорослости, не связанных с первичным дефицитом ГР, - хромосомных аномалиях, ревматических болезнях, хронической почечной недостаточности и дрю (Rosenfeld et al. 1998, Czernichow et al. 1998). Однако, ввиду неясности прогноза роста, высокой стоимости лечения и возможного риска возникновения серьезных осложнений, такие работы носят разрозненный и подчас противоречивый характер. Поэтому даже отдельные наблюдения и исследования на небольших выборках больных представляют огромный научно-практический интерес и могут служить основой для разработки новых показаний к применению препаратов р-ГР.

Несмотря на то, что роль ГР, как одного из центральных регуляторов костного метаболизма, известна давно, надежных критериев для оценки костной плотности у детей с дефицитом ГР до сих пор нет. Использование стандартных возрастных нормативов дает зачастую искаженные результаты. В то же время объективная оценка состояния плотности кости необходима для правильной тактики ведения больных с соматотропной недостаточностью (Boot et al. 2002, Saggese et al. 1996).

В то время как у взрослых пациентов с дефицитом ГР исследования жирового обмена давно уже носят широкомасштабный характер, работ, посвященных изучению липидного статуса у детей, сравнительно немного. Своевременная коррекция его нарушений в детском возрасте позволяет существенно улучшить отдаленный прогноз и качество жизни этих больных.

Ведущая роль сердечно-сосудистых заболеваний как одной из главных причин смертности больных с дефицитом ГР диктует необходимость всестороннего изучения состояния сердечно-сосудистой системы на всех возрастных этапах пациентов с соматотропной недостаточностью и, в частности, детей.

Таким образом, перспективными направлениями в изучении соматотропной недостаточности у детей являются исследования белкового, жирового, углеводного обмена, состояния костной ткани и сердечно-сосудистой системы, а также влияние на них заместительной терапии р-ГР. Требуются дальнейшие проспективные исследования для оценки лечения, проводимого в детском возрасте, на показатели смертности и инвалидности взрослых пациентов с дефицитом ГР. Другим важным направлением научного поиска является изучение механизмов задержки роста при различных патологических состояниях, не связанных с недостаточностью соматотропной функции гипофиза, и оценка возможности применения р-ГР для ее коррекции.

ЦЕЛЬ ИССЛЕДОВАНИЯ

Изучить ростстимулирующую эффективность и безопасность применения р-ГР и его системные и метаболические эффекты при различных вариантах низкорослости.

ЗАДАЧИ ИССЛЕДОВАНИЯ

1. Провести эпидемиологическое исследование распространенности соматотропной недостаточности в Российской Федерации на основе Национального регистра больных с дефицитом ГР.

2. Провести комплексное клинико-антропометрическое и гормональное исследование пациентов с различными вариантами соматотропной недостаточности: органическим и идиопатическим дефицитом ГР, изолированным и множественным дефицитом гормонов аденогипофиза до и на фоне лечения р-ГР, определить характер становления пубертата и достижения конечного роста у этих детей.

3. Исследовать секрецию гормона роста и ростовых факторов, антропометрические и гормональные показатели и оценить эффективность и безопасность применения р-ГР при синдроме Шерешевского-Тернера.

4. Оценить возможности применения р-ГР для коррекции низкорослости, обусловленной длительной глюкокортикостероидной терапией.

5. Исследовать содержание инсулиноподобного фактора роста -1 (ИФР-1) и связывающего белка-3 (ИФРСБ-3) у детей с различными вариантами низкорослости и их динамику на фоне лечения р-ГР у детей с соматотропной недостаточностью.

6. Оценить диагностическую значимость различных способов измерения минеральной плотности кости у детей с соматотропной недостаточностью. Изучить влияние заместительной терапии р-ГР на минеральную массу и плотность костной ткани у детей с дефицитом ГР.

7. Исследовать показатели жирового обмена у детей при различных вариантах низкорослости, оценить показатели массы тела, особенности липидного профиля до и на фоне лечения р-ГР.

8. Исследовать особенности морфо-функционального состояния сердечно-сосудистой системы у детей с дефицитом ГР до и на фоне лечения р-ГР.

НАУЧНАЯ НОВИЗНА ИССЛЕДОВАНИЯ

Впервые в России создан Национальный регистр больных с соматотропной недостаточностью, проведено клинико-эпидемиологическое исследование распространенности гипофизарного нанизма в российской популяции.

На большом клиническом материале впервые была проведена оценка эффективности и безопасности длительного лечения р-ГР и выявлены особенности ростового эффекта терапии р-ГР у детей с различными вариантами низкорослости.

Оценены факторы, оказывающие влияние на эффективность и безопасность лечения р-ГР при соматотропной недостаточности. Показан дозозависимый эффект терапии р-ГР у детей с дефицитом ГР и избыточной массой тела.

Дана характеристика становления пубертата и достижения конечного роста при соматотропной недостаточности. Показано, что длительная заместительная терапия р-ГР в препубертатном возрасте позволяет достичь социально приемлемого роста. Впервые в отечественной практике продемонстрирована возможность эффективного использования р-ГР при лечении низкорослости у детей с синдромом Шерешевского-Тернера.

Впервые доказана эффективность и безопасность терапии р-ГР у детей с ревматическими заболеваниями. Впервые в отечественной клинической практике изучено влияние дефицита ГР на состояние костной ткани у детей с соматотропной недостаточностью и проведен анализ ее изменений на фоне заместительной терапии р-ГР.

Доказана диагностическая значимость объемной минеральной плотности кости и необходимость определения проекционной минеральной плотности кости с учетом костного возраста, как наиболее объективных показателей для оценки состояния костной ткани у детей с соматотропной недостаточностью. Проанализированы показатели массы тела и жирового обмена у детей с различными формами низкорослости. Показана гетерогенность пациентов с дефицитом ГР по ИМТ и липидному профилю в зависимости от варианта низкорослости, а также доказано благоприятное влияние заместительной терапии р-ГР на эти показатели.

Впервые проанализированы показатели структуры и функции сердца у детей с соматотропной недостаточностью до и на фоне лечения р-ГР. Показано, что у детей с соматотропной недостаточностью размеры сердца снижены относительно хронологического возраста, а заместительная терапия р-ГР приводит к увеличению всех морфометрических показателей в соответствии с увеличением антропометрических параметров.

ПРАКТИЧЕСКАЯ ЗНАЧИМОСТЬ ИССЛЕДОВАНИЯ

На основании данных Регистра, получены достоверные сведения о распространенности соматотропной недостаточности в Российской Федерации, а результаты клинико-эпидемиологического анализа могут быть использованы в сфере здравоохранения и позволят обоснованно планировать расходы на обследование и уточнить истинную потребность в лечении р-ГР. Работа с Регистром специалистов на местах способствует унификации методов диагностики соматотропной недостаточности, что повышает качество медицинской помощи.

Доказан положительный рост-стимулирующий эффект терапии р-ГР при отсутствии серьезных побочных явлеиий как при соматотропной недостаточности, так и при других вариантах низкорослости, не связанных с дефицитом ГР. Для своевременного выявления потери костной массы и возможной дальнейшей ее коррекции дополнен алгоритм обследования пациентов с соматотропной недостаточностью и обоснована необходимость проведения остеоденситометрии у этих больных. Доказана необходимость оценки показателей остеодеиситометрии не только по возрастным нормативам, но и с учетом костного возраста пациентов.

Доказана значимость ИМТ, трансформированного в показатели БОБ, как наиболее объективного критерия степени ожирения, учитывающего не только рост и вес больных, но и их возраст.

Обоснована целесообразность динамического контроля показателей липидного профиля у детей с дефицитом ГР для определения степени риска развития у них ранних сердечно-сосудистых осложнений. Даны практические рекомендации для назначения р-ГР при ревматических заболеваниях. Продемонстрирована эффективность терапии р-ГР у девочек с синдромом Шерешевского-Тернера.

АПРОБАЦИЯ РАБОТЫ

Материалы диссертации обсуждены и одобрены Ученым Советом ГУ ЭНЦ РАМН (2004); на Всероссийских съездах эндокринологов (2000, 2001, 2002, 2003), на съездах московских эндокринологов (1999, 2000), на конференциях эндокринологов и педиатров-эндокринологов (Уфа, Челябинск, Санкт-Петербург, Томск, Саратов, Самара), на Российской научно-практической конференции «Заболевания гипоталамо-гипофизарпой системы» (Москва, 2001), IX конгрессе педиатров России (Москва, 2004), III Всеросийской научно-практической конференции «Актуальные проблемы нейроэндокринологии» (Москва, 2003), IV Всероссийском конгрессе эндокринологов (Санкт-Петербург, 2001), XI съезде педиатров России (Москва, 2004). Постерные доклады представлены на международных конгрессах и ежегодных съездах Европейского Общества педиатров-эндокринологов (ESPE): в Монреале (Канада, 2001), в Любляне (Словения, 2003), в Базеле (Швейцария, 2004), Международных симпозиумах «Гормон роста и факторы роста в эндокринологии» (Мальта, 2001, Женева, 2004, Афины, 2005).

ПУБЛИКАЦИИ

По материалам диссертации опубликовано 33 научные работы, из них 18 - в отечественной и 15 - в зарубежной печати.

СТРУКТУРА И ОБЪЕМ ДИССЕРТАЦИИ

Диссертация состоит из введения, обзора литературы, описания материалов и методов, 9 глав результатов собственных исследований, обсуждения полученных результатов, а также выводов, практических рекомендаций, и списка использованной литературы (678 источников). Диссертация изложена на 283 страницах машинописного текста, имеет 49 рисунков и 51 таблицу.

Заключение диссертации по теме «Эндокринология», Волеводз, Наталья Никитична

выводы

1. Распространенность соматотропной недостаточности в РФ составляет 7,5 на 100 ООО детского населения. Соматотропная недостаточность чаще встречается у мальчиков -9,7 на 100 ООО, чем у девочек - 5,1 на 100 000.

2. При врожденной соматотропной недостаточности у детей на фоне лечения р-ГР получена значительная прибавка в росте: за первый год - 10,4±2,3 см, за 2 год -8,21±1,55 см, за 3 год - 6,96±1,89см (средняя прибавка за 3 года лечения составила 25,57±6,9 см). В дальнейшем ежегодная прибавка в росте уменьшается, оставаясь выше среднепопуляционной для данного возраста.

3. Адекватная терапия р-ГР детей с соматотропной недостаточностью позволяет достичь нормального средне-популяционного роста. Решающими факторами ростового прогноза являются возраст, статус половой зрелости ребенка, степень низкорослости в начале лечения, адекватность используемой дозы р-ГР.

4. Применение р-ГР у детей с приобретенным дефицитом ГР (после удаления краниофарингиомы) позволяет добиться повышения темпов роста и нормализации липидного обмена, что ведет к улучшению их весо-ростовых показателей при отсутствии развития значимых побочных эффектов и повышения частоты рецидивов опухоли.

5. При синдроме Шерешевского-Тернера низкорослость не обусловлена снижением секреции ГР, однако терапия р-ГР позволяет увеличить скорость роста. Степень повышения скорости роста при синдроме Шерешевского-Тернера зависит от возраста начала терапии и адекватности дозы.

6. Степень снижения минеральной плотности костной ткани у детей с соматотропной недостаточностью значительно варьирует в зависимости от метода его расчета: минеральная плотность костной ткани, рассчитанная по хронологическому возрасту была значительно снижена (остеопороз выявлен у 56%, остеопения - у 33%). При пересчете на костный возраст остеопороз диагностирован у 36%, остеопения — у 47% детей. Показатели объемной минеральной плотности кости с учетом ее реального размера значительно превышают показатели проекционной минеральной плотности как по хронологическому, так и по костному возрасту: остеопения выявлена у 67% детей, остеопороза не было.

7. На фоне заместительной терапии р-ГР и интенсивного роста костей у детей с соматотропной недостаточностью происходит значительное повышение содержания общей и костной фракции щелочной фосфатазы, остеокальцина в сыворотке крови, что свидетельствует о повышении активности остеобластов и процессов остеосинтеза. Увеличение концентрации в сыворотке крови маркера костной резорбции (С-концевых телопептидов) на фоне заместительной терапии ГР указывает на активацию процессов резорбции. Это свидетельствует о сопряженности процессов костного ремоделирования на фоне лечения р-ГР детей с соматотропной недостаточностью. Костная фракция щелочной фосфатазы является прогностическим маркером ростового эффекта, так как имеется прямая корреляционная зависимость между этим показателем и ускорением роста.

8. Через два года терапии р-ГР у детей с соматотропной недостаточностью на фоне постоянного роста минеральная плотность костей позвоночника достоверно увеличивается (на 7%) по отношению к исходной, хотя и не достигает нормальных значений. При этом имеет место снижение минеральной плотности кости в первые 6 месяцев лечения.

9. Лечение р-ГР детей с соматотропной недостаточностью в первые 6 месяцев терапии р-ГР приводило к снижению индекса массы тела во всех группах, независимо от исходного веса больных. Наиболее значимое его снижение отмечалось у пациентов с ожирением. В дальнейшем у пациентов с ожирением сохранялся достигнутый уровень массы тела, тогда как у пациентов с нормальным и недостаточным весом индекс массы тела постепенно нарастал.

10. На фоне лечения р-ГР у детей с соматотропной недостаточностью соотношение жировой и тощей массы существенно меняется в пользу последней. Абсолютное содержание жировой ткани резко уменьшается в первые 6 месяцев, а в последующие 18 месяцев не претерпевает значительных изменений. Абсолютное содержание тощей массы достоверно нарастает на протяжении всего срока 2-летней терапии р-ГР.

11. У детей с соматотропной недостаточностью гиперхолестеринемия выявлена у 58%: погранично-высокий уровень общего холестерина (5,2-6,2 ммоль/л) у 26 % детей и высокий (> 6,2 ммоль/л) - у 32 % детей. Более значимое повышение общего холестерина и Л1Ш11 отмечалось у пациентов с множественным дефицитом гормонов аденогипофиза. При соматотропной недостаточности содержание холестерина и ЛПНП было выше, чем при идиопатической низкорослости и синдроме

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Шерешевского-Тернера. Заместительная терапия р-ГР у детей с соматотропной недостаточностью приводит к снижению уровней холестерина, ЛПНП и, таким образом, оказывает антиатерогенный эффект.

12. У детей с соматотропной недостаточностью размеры сердца относительно хронологического возраста ребенка значительно снижены. Длительная заместительная терапия р-ГР приводит к увеличению всех функциональных и морфометрических показателей сердца в соответствии с увеличением роста, что свидетельствует об анаболическом эффекте ГР на миокард.

ПРАКТИЧЕСКИЕ РЕКОМЕНДАЦИИ

1. У детей с подтвержденной соматотропной недостаточностью целесообразно проведение магнитно-резонансной томографии. При выявлении структурных нарушений гипоталамо-гипофизарной области необходимо исследование функции всех тропных гормонов гипофиза для исключения их дефицита и назначения больным адекватной заместительной терапии.

2. Всем пациентам с приобретенным дефицитом ГР после удаления краниофарингиомы, вне зависимости от ростовых показателей, необходимо лечение р-ГР в дозе 0,03 мг/кг/сут для предотвращения дальнейшего отставания в росте и коррекции метаболических нарушений.

3. Низкорослость, обусловленная длительным применением глюкокортикостероидов при соматических заболеваниях, может быть скомпенсирована назначением р-ГР.

4. Всем пациенткам с синдромом Шерешевского-Тернера показано лечение р-ГР в дозе 0,05 мг/кг/сут при снижении ЗББ роста до -2 и менее, рассчитанного по нормам для больных с синдромом Шерешевского-Тернера.

5. Всем больным с соматотропной недостаточностью рекомендуется исследование минеральной плотности костной ткани с учетом костного возраста методами двухэнергетической ренгеновской абсорбциометрии с целью выявления ранних проявлений остеопенического синдрома.

6. Для обеспечения достижения пика костной массы и профилактики остеопороза и костных переломов всем пациентам с соматотропной недостаточностью показано продолжение терапии р-ГР даже после закрытия зон роста.

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