Гипербилирубинемия в амбулаторных условиях.

[Alon]

Могу Вас успокоить - скрининг в Израиле работает вполне нормально и, насколько я помню, включает в себя и TSH и FreeT4. Dr.Ira просто не первый адресат для получения его результатов (это не ее функция).

В отношении зависимости от времени начала лечения и, грубо говоря, "степени кретинизма" тут все ясно, если я не ошибаюсь, для случаев, когда лечение начинается после 4 недель жизни ( а начало лечения до 4- х недель считается нормальным). А вот в остальном, при своевременном начале лечения, с ясностью есть проблемы, т.е. равенство IQ со здоровыми остается, по-видимому, и в этом случае под вопросом.Тут вы поправите меня, если я не прав.

В отношении "израильского протокола" доктора Иры - забудьте и читайте новые рекомендации ААР - там все довольно ясно написано.

Между прочим, детская консультация, о которой пишет доктор Ира, в Израиле называется "Типат халав", что означает "Капля молока"

[Melnichenko]

"Тут вы поправите меня, если я не прав" - не поправлю, потому что слишком много вводных- тяжесть гипотироза к моменту рождения( коррелирует с уровнем св. Т4 - а его не все страны смотрят), время\ адекватность дозы назначенного тироксина, тщательность контроля в будущем, тщательность соблюдения режима в будущем, регион проживания( иододефицит), социоэкономический статус семьи и пр.



Так что я действительно не знаю, будет ли значимое преимущество для большинства, если лечение будет не позднее 15 дня( Англия) или же приемлем 21 день, или 30 дней...Речь, разумеется, о доношенных.

И, уж кстати о "капле молока" - удивительно, но не анализируется в публикациях факт грудного ( в молоке мамы есть тироксин) \ искусственного вскармливания - имеет ли это значение для врожденного гипотироза( встарь считали, что имеет).

Кроме того, нужны большие усилия по сбору данных обо всех детях-т.е нужны государственные регистры с учетом перчисленных ( и. наверно, забытых еще факторов).

[Alon]

Кстати -



Joanne F. Rovet

Children With Congenital Hypothyroidism and Their Siblings: Do They Really Differ?

Pediatrics 2005; 115: e52-e57.

------------------------------

Abstract



Objective. Although favorable outcome is typically described in follow-up studies of children with congenital hypothyroidism (CH) identified by newborn screening, IQ reductions and persistent cognitive deficits are still reported. These findings are accounted for by disease and treatment variables as well as methodologic factors including choice of comparison group. Although siblings are ideal because they control for genetic and environmental influences, by definition they have different ages when tested, which can also introduce bias. Because we followed children with CH and their siblings over an extended period of time, there were a number of occasions when both groups were tested at the same age. The purpose of this study was to compare the results of children with CH and their unaffected siblings at the same age and with the same test.



Methods. The sample consisted of 42 children with CH detected between 1975 and 1985 and their 42 siblings, all of whom were tested with the McCarthy or Wechsler Intelligence Scale for Children—Revised (WISC-R) intelligence tests. Nineteen pairs of children were evaluated at 6 years with the McCarthy, and 30 pairs of children were evaluated at 7 or 9 years with the WISC-R. Recorded for children with CH were disease etiology, bone age and thyroxine levels at diagnosis, age at onset of treatment, and starting dosage of levothyroxine.



Results. Paired t tests revealed that the CH group scored lower than siblings by 8.1 IQ points on the McCarthy and 6.2 points on the WISC-R. Factors contributing to the size of the CH-sibling IQ difference were (1) the etiology of hypothyroidism, reflecting the larger differences by those with athyreosis or an ectopic gland than dyshormonogenesis, and (2) the starting dosage of levothyroxine, with those initially treated with 8.2 µg/kg per day having smaller CH-sibling differences than those given lower starting doses. There were no effects of bone age, thyroxine levels at diagnosis, or age at treatment onset.



Conclusion. Children with CH treated early in life due to newborn screening may have reduced IQ relative to siblings.

[Tanya G]

Могу Вас успокоить - скрининг в Израиле работает вполне нормально и, насколько я помню, включает в себя и TSH и FreeT4.

Я правильно поняла - помимо исследования ТТГ, в скрининг включено и определение св. Т4? Интересно, сколько же в таком случае закладывается в бюджете Израиля денег на проведение скрининга... Здесь правомерен вопрос - а оценивается ли разумность таких затрат, если лечение все равно начинается поздно?

[Alon]

Bilirubin the beneficent

Pediatrics, Dec, 2004 by Antony McDonagh

To the Editor.--



I wish to add a few corrections and comments to the recent timely review by Sedlak and Snyder on bilirubin, (1) the born-again benignant pigment.





1. It is not true that bilirubin formation is restricted to mammals. This is an obsolete, but frequently repeated, hypothesis that flies in the face of scientific evidence. Bilirubin and its conjugates occur in many noninammals, although they may not be the principle bile pigments excreted in bile. (2) For example, conjugates of bilirubin are excreted in bile in many fish species, and jaundice in fish is not unknown. (3) Bilirubin conjugates are also present in bile of embryonic and adult chickens, (4) and the observation in 1886 by Minkowski and Naunyn (5) that arsine poisoning produced marked jaundice in normal but not hepatectomized geese was a key obsmwation in the elucidation of the physiologic pathway of heme catabolism and the role of the reticuloendothelial system. Similarly, observations on the biosynthesis of bilirubin in ducks were important in elucidating bilirubin-formation pathways in humans. (6) Bilirubin pigments also occur in alligators, snakes, and turtles, (2) and a biliverdin reductase with substantial sequence homology to the human enzyme is present even in the lowly unicellular cyanobacterium Synechocystis. (7) Therefore, the hoary idea that bilirubin occurs uniquely in mammalss is unfounded and should be laid to rest. The puzzle is not so much why mammals make bilirubin but rather why biliverdin reductase evolved and why many animals do without it.



2. Similarly, it is not true that the principle isomer of bilirubin formed in the fetus is bilirubin IX[beta] rather than the IX[alpha] isomer produced postnatally. (1,8) This notion seems to have evolved from an incorrect interpretation of observations that the pre dominant isomer of bilirubin in meconinm and fetal bile is IX[beta]. (9,10) However, the IX[beta] isomer in fetal bile is probably but a small residual fraction of the total amount of bile pigment produced, most of which is the IX[alpha] isomer. The IX[alpha] isomer, being relatively lipophilic, does not accumulate because of its easy egress across the placenta. (9,11) In contrast, the less lipophilic IX[beta] isomer is less likely to diffuse across the placenta but can be excreted relatively easily in bile without the need fur hepatic conjugation. (1,2) Therefore, the fact that the IX[beta] isomer is the principle isomer in fetal bile does not indicate that it is the major isomer made in the fetus. Similarly, the presence of an IX[beta]-specific reductase in the fetus does not mean that the IX[alpha]-specific enzyme is not present or unimportant. Quite the contrary. The IX[alpha]-specific reductase is probably essential, because it facilitates transplacental excretion of bile pigment produced by heme cleavage during fetal life. There is no evidence that heme oxygenase is any less regioselective for the [alpha] bridge of heme in the fetus than it is in adults, where small amounts of the IX[beta] isomer are also reportedly formed. (13,14)



3. Because biliverdin reduction occurs in nonmammals and non-placental mammals and a biliverdin reductase is present in Synechocystis, it is reasonable to assume that biliverdin reductases did not evolve solely to facilitate disposal of bilirubin across the placenta. However, that should not be interpreted to indicate that reduction is unimportant for fetal disposal of bile pigments in mammals. There is much experimental evidence in primates, guinea pigs, and rats that bilirubin IX[alpha] readily crosses the placenta and that reduction of biliverdin to unconjugated bilirubin really does facilitate fetal bile pigment disposal. (11) Striking evidence for bidirectional flux of bilirubin across the placenta comes from the Gunn rat animal model, in which there is a recessive genetic defect in bilirubin conjugation. Heterozygous pups born 10 homozygous jaundiced mothers are icteric at birth but quickly lose their yellow pigmentation. In contrast, humozygous pups born to heterozygous nonjaundiced mothers are anicteric at birth but become jaundiced shortly thereafter. Early reports that bilirubin does not cross the placenta in the rat (15) are not reliable, because they depended on the use of impure radioactive bilirubin prepared by a defective technique, (16) which similarly has led to conflicting results in more recent investigations. (17,18)



4. Although it is true that bilirubin is ]ipophilic, it is hardly correct to describe it as lipid soluble. Just try dissolving some in olive oil. As Brodersen (19) showed, bilirubin does trot dissolve to any significant extent in olive oil or classical lipids. Nevertheless, it does partition readily from aqueous solution to olive oil or octanol. (20)



5. Recycling of bilirubin by biliverdin redoctase reduction of biliverdin is an old idea, It would be significant only if biliverdin is a major product of the reaction of bilirubin with reactive oxygen species. Although formation of soiue biliverdin has been noted under certain conditions, (8) there is much evidence that biliverdin is not formed stoichiometrically and is generally not a major product of the reaction of bilirubin with oxyradicals, dioxygen, or singlet oxygen. The importance of the proposed mechanism in vivo, therefore, must remain speculative. Furthermore, there are other plausible chemical mechanisms for regenerating bilirubin after it intercepts radical reactions that do not require biliverdin reductase reduction. For example, bilirubin undergoes oxygen-dependent free-radical reactions in water at pH 7.4 to 9.0, in which the pigment is regenerated without the intermediacy of biliverdin or enzyme. (21)



6. As known for half a century, bilirubin is a potent antioxidant. However, evidence for its beneficial effects on human health, (1) copious though it may be, remains fuzzy. It is surprising that so few studies have been done in Gunn rats. These animals permit comparative studies on icteric and anicteric littermates differing only in their glucuronosyl transferase (UGT1A1) activities and burden of unconjngated bilirubin. Although rats may be unreliable models for humans, experiments in Gunn rats might provide decisive or quantitative answers to some of the currently unresolved questions on the beneficial effects of bilirubin. Anybody wishing to obtain breeder pairs for starting their own research colony can contact me.



7. Finally, although the antioxidant activity of bilirubin has been known for over half a centurv, credit for the first suggestion that bilirubin might be beneficial should perhaps go to Najib-Farah, (22) who postulated in 1937, albeit for curious reasons, that the pigment forms part of a protective mechanism designed to overcome infection. Even by that date, however, the (probably ineffectual) use of bilirubin in traditional Asian medicines had become well established. (23)



ANTONY McDONAGH, PHD



Division of Gastroenterology



University of California