У ашкеназских евреев frequency in these individuals is approximately 1 per 15 population, whereas the disease frequency is 1 per 855 population, поэтому делается ДОродовый скрининг ( в нашей больничной кассе, даже, за бесплатно). Так что, достаточно выяснить, делались ли анализы и каков результат, чтобы исключить Gaucher’s Disease без лишних мучений.Igor Bulatov писал(а): Type I Gaucher’s Disease is the most common genetic disease among jews.
Case 19. Опять кровотечения.
Модераторы: Ren_Yumi, AOkhotin, Pyankov Vasily, Алексей Живов, Alon, dr.Ira
Делай, что должен, и будь, что будет.
Из анализов все понятно, кроме анализа кала на скрытую кровь:-).
Ультазвуковое исследование живота, снимок грудной клетки - зачем, что ищем?
---------------------------
Итак, общий анализ крови - лейкоциты нормальны, включая формулу, гематокрит 28, тромбоциты - норма. PT на этот раз - 36 (INR 3,6), aPTT 48. Электролиты - ничего особенного, non-anion gap acidosis, бикарбонат 16 ммоль\л, фосфор 2.3, АлАТ 267, АсАТ 383, щелочная фосфатаза 383, общий билирубин 1,5 (конъюгированный 0,4), альбумин 2,2. С общем анализе мочи рН 7.0, кровь 1+, глюкоза 3+.
В последующие 72 часа гематокрит упал до 23, общий билирубин стал 3,6 (конъюгированный 0.8 ).
Ультазвуковое исследование живота, снимок грудной клетки - зачем, что ищем?
---------------------------
Итак, общий анализ крови - лейкоциты нормальны, включая формулу, гематокрит 28, тромбоциты - норма. PT на этот раз - 36 (INR 3,6), aPTT 48. Электролиты - ничего особенного, non-anion gap acidosis, бикарбонат 16 ммоль\л, фосфор 2.3, АлАТ 267, АсАТ 383, щелочная фосфатаза 383, общий билирубин 1,5 (конъюгированный 0,4), альбумин 2,2. С общем анализе мочи рН 7.0, кровь 1+, глюкоза 3+.
В последующие 72 часа гематокрит упал до 23, общий билирубин стал 3,6 (конъюгированный 0.8 ).
Всего наилучшего, Алон
Когда посылала на анализы, еще не знала, что конкретно ищу. Искала, откуда может терять кровь и/ или почему нарушено кроветворение.Alon писал(а):Из анализов все понятно, кроме анализа кала на скрытую кровь:-).
Ультазвуковое исследование живота, снимок грудной клетки - зачем, что ищем?
Теперь понятно, что поражена печень.
Сейчас еще раз посмотрела результаты анализов. Гемолиз.
Делай, что должен, и будь, что будет.
Вот, нашла.
Mechanisms of hemolysis in liver disease
EE Morse
Liver disease, particularly alcoholic cirrhosis, is associated with a number of interesting chemical changes which result in structural and metabolic abnormalities of the erythrocyte membrane leading to microscopically observable cell shape changes and hemolytic anemia varying from very mild to potentially lethal. Increase in unesterified serum cholesterol owing to lecithin cholesterol acyl transferase (LCAT) deficiency in cirrhosis leads to expansion of the lipid bilayer and macrocytosis without megaloblastic changes in precursors. Substitutions of phosphatidyl choline (PC) moieties in the erythrocyte lipid bilayer lead to echinocytes (disaturated PC) or to stomatocytes (diunsaturated PC). In some patients, high density lipoprotein (HDL) abnormalities lead to erythrocyte surface changes causing rapid formation of echinocytes. The rapidity and reversibility of these changes suggest blockade of metabolic transport channels critical to the maintenance of erythrocyte membrane shape. Metabolic changes involving vitamin E deficiency leading to lipid peroxidation and pyruvate kinase instability leading to adenosine triphosphate (ATP) reduction have also been invoked to explain hemolysis associated with acute liver damage. The most severe hemolysis in liver disease is associated with acanthocytes (spur cells) and a marked imbalance in cholesterol-phospholipid ratio. These patients usually have hypersplenism, as well as rigid erythrocyte membrane transformations which are irreversible. Any of the other erythrocyte membrane shape changes described appear to be reversible if the liver disease abates, but they too may become irreversible if bits of projecting membrane are repeatedly removed by the macrophages of an enlarged spleen. http://www.annclinlabsci.org/cgi/conten ... t/20/3/169
Но, вряд ли у этого ребенка алкогольный цирроз. Будем искать Liver disease. Кровь на гепатиты пришла?
Mechanisms of hemolysis in liver disease
EE Morse
Liver disease, particularly alcoholic cirrhosis, is associated with a number of interesting chemical changes which result in structural and metabolic abnormalities of the erythrocyte membrane leading to microscopically observable cell shape changes and hemolytic anemia varying from very mild to potentially lethal. Increase in unesterified serum cholesterol owing to lecithin cholesterol acyl transferase (LCAT) deficiency in cirrhosis leads to expansion of the lipid bilayer and macrocytosis without megaloblastic changes in precursors. Substitutions of phosphatidyl choline (PC) moieties in the erythrocyte lipid bilayer lead to echinocytes (disaturated PC) or to stomatocytes (diunsaturated PC). In some patients, high density lipoprotein (HDL) abnormalities lead to erythrocyte surface changes causing rapid formation of echinocytes. The rapidity and reversibility of these changes suggest blockade of metabolic transport channels critical to the maintenance of erythrocyte membrane shape. Metabolic changes involving vitamin E deficiency leading to lipid peroxidation and pyruvate kinase instability leading to adenosine triphosphate (ATP) reduction have also been invoked to explain hemolysis associated with acute liver damage. The most severe hemolysis in liver disease is associated with acanthocytes (spur cells) and a marked imbalance in cholesterol-phospholipid ratio. These patients usually have hypersplenism, as well as rigid erythrocyte membrane transformations which are irreversible. Any of the other erythrocyte membrane shape changes described appear to be reversible if the liver disease abates, but they too may become irreversible if bits of projecting membrane are repeatedly removed by the macrophages of an enlarged spleen. http://www.annclinlabsci.org/cgi/conten ... t/20/3/169
Но, вряд ли у этого ребенка алкогольный цирроз. Будем искать Liver disease. Кровь на гепатиты пришла?
Делай, что должен, и будь, что будет.
Для диагностики гемолиза достаточно данных?
Может peripheral blood smear посмотреть?
Он не может просто терять кровь? За эти 72 часа не было кровотечений? Ему не нужно витамин К срочно вести?
Статью нашла. На 14 страниц. Пойду читать:
http://www.columbia.edu/itc/hs/nursing/ ... isease.pdf
Может peripheral blood smear посмотреть?
Он не может просто терять кровь? За эти 72 часа не было кровотечений? Ему не нужно витамин К срочно вести?
Статью нашла. На 14 страниц. Пойду читать:
http://www.columbia.edu/itc/hs/nursing/ ... isease.pdf
Подведем некоторые итоги. Итак, у ребенка снижена синтетическая функция печени и повышены трансаминазы, что указывает на поражение печени. Острые заболевания печени, конечно, не исключаются (гепатиты А, В,С ЕBV,CMV, лекарства, токсины и пр.), но все-таки выраженность кровоточивости и низкий альбумин указывают скорее на хронический процесс. Об этом же говорит и легкая коагулопатия с носовыми кровотечениями в недалеком прошлом. Кроме этого есть гемолиз и какая-то тубулопатия.
Пока мы думаем о том, что может вызвать хроническое поражение печени у ребенка 9-ти лет, анализы крови, взятые для исключения различных вирусных гепатитов, вернулись нормальными, аутоиммунный гепатит тоже был исключен.
И тут, переходя от строчки к строчке в списке дифдиагнозов хронических заболеваний печени у детей, мы оказались перед группой метаболических заболеваний, одно из которых уже было здесь упомянуто. Давайте чуть расширим этот список.
Пока мы думаем о том, что может вызвать хроническое поражение печени у ребенка 9-ти лет, анализы крови, взятые для исключения различных вирусных гепатитов, вернулись нормальными, аутоиммунный гепатит тоже был исключен.
И тут, переходя от строчки к строчке в списке дифдиагнозов хронических заболеваний печени у детей, мы оказались перед группой метаболических заболеваний, одно из которых уже было здесь упомянуто. Давайте чуть расширим этот список.
Всего наилучшего, Алон
Это правильное замечание. 
Прежде всего надо подумать о недостаточности альфа-1-антитрипсина и болезни Вильсона. Далее можно рассмотреть тирозинемию, уже упомянутую болезнь Гоше и, например, муковисцидоз, хотя вероятность последних низка из-за отсутствия других признаков заболевания.
Уровень альфа-1-антитрипсина оказался нормальным, альфафетопротеин - слегка повышенным (27 ng/mL ,норма от 0 до 6.7 ng/mL), уровень сукцинилацетона в моче - нормальным, медь сыворотки и церулоплазмин - нормальны.
Поскольку диагноз до сих пор отсутствовал, вы решили после соответствующей подготовки (у ребенка склонность к кровотечениям) провести печеночную биопсию.
Анализ биоптата показал макро- и микростеатоз, цирроз.
После чего наконец последовал спасительный звонок из лаборатории - концентрация меди в ткани печени оказалась 527 µg/g (норма от 10 до 35 µg/g), количество меди в суточной моче - 2,085 µg (норма от 3 до 35 µg). Эти данные подтвердили диагноз: болезнь Вильсона.
В дальнейшем из-за развития фульминантной печеночной недостаточности, ребенку была успешно пересажена печень.
Прежде всего надо подумать о недостаточности альфа-1-антитрипсина и болезни Вильсона. Далее можно рассмотреть тирозинемию, уже упомянутую болезнь Гоше и, например, муковисцидоз, хотя вероятность последних низка из-за отсутствия других признаков заболевания.
Уровень альфа-1-антитрипсина оказался нормальным, альфафетопротеин - слегка повышенным (27 ng/mL ,норма от 0 до 6.7 ng/mL), уровень сукцинилацетона в моче - нормальным, медь сыворотки и церулоплазмин - нормальны.
Поскольку диагноз до сих пор отсутствовал, вы решили после соответствующей подготовки (у ребенка склонность к кровотечениям) провести печеночную биопсию.
Анализ биоптата показал макро- и микростеатоз, цирроз.
После чего наконец последовал спасительный звонок из лаборатории - концентрация меди в ткани печени оказалась 527 µg/g (норма от 10 до 35 µg/g), количество меди в суточной моче - 2,085 µg (норма от 3 до 35 µg). Эти данные подтвердили диагноз: болезнь Вильсона.
В дальнейшем из-за развития фульминантной печеночной недостаточности, ребенку была успешно пересажена печень.
Всего наилучшего, Алон
Заключение.
First described in 1913 by Rumpel, Wilson disease is a rare, autosomal recessive disease with an incidence of one in every 30,000 people. The defective gene, ATP7B, located on chromosome 13, is an ATPase that transports copper. Patients with Wilson disease carry two different mutated alleles, one on each chromosome, rendering their genetic defect as compound heterozygotic.
In a healthy person, dietary copper is absorbed via the upper small intestine into the portal circulation. After hepatic extraction for cellular functions, copper is excreted primarily through biliary drainage but is also released into the systemic circulation as ceruloplasmin-bound copper. The ATP7B gene is involved in both steps. With copper transport defective in Wilson disease, copper begins to accumulate in the liver and, subsequently, in the central nervous system and kidneys. Excess copper causes oxidative damage to cell membranes and DNA after the chelating and reducing capacities of intracellular glutathione and metallothionein are saturated. Signs and symptoms of liver failure and neurologic and renal illness ensue.
The age of onset of Wilson disease varies—from 5 to 50 years of age. It can manifest as acute hepatitis, chronic hepatitis with or without cirrhosis, fulminant liver failure, or primarily central nervous system disturbances, such as movement disorders, depression, and psychosis. Direct or slit-lamp examination may reveal Kayser-Fleischer rings, which reflect copper deposition in the Descemet's membrane; 50% of people who have only liver disease—as is the case with most pediatric patients—do not have Kayser-Fleischer rings, however. Other nonspecific but suggestive signs of Wilson disease are non-immune hemolytic anemia and Fanconi renal tubular acidosis.
For lack of a pathognomonic test, the diagnosis of Wilson disease is made by synthesizing information from the medical and family history and physical exam, biochemical and histochemical test results, and, often, liver biopsy findings. When neurologic symptoms are present, Kayser-Fleischer rings are highly suggestive of Wilson disease, although their absence is not exclusionary.
Low serum levels of copper and ceruloplasmin, an elevated 24-hour urine copper level, and increased liver copper content are classic findings in Wilson disease. But—as this case illustrates—too much reliance placed on these tests can be a pitfall in making the diagnosis. The serum copper level may be normal or elevated in the face of acute liver decompensation, as copper is released from injured hepatocytes. Likewise, 5% to 10% of patients have a normal level of ceruloplasmin, because it is an acute-phase reactant that becomes elevated in the presence of chronic inflammation. The ceruloplasmin level can also be falsely elevated if it is measured by an immunologic assay that also detects apoceruloplasmin rather than oxidase activity.
In situations of borderline urine copper content, some authorities have proposed a penicillamine challenge, which enhances copper elimination in these patients, clarifying the diagnosis. Concomitant presence of Coombs-negative hemolytic anemia or Fanconi's renal tubular acidosis (evidenced by non-anion gap acidosis, hypophosphatemia accompanied by phosphaturia, and glycosuria), or both, should also raise the index of suspicion for this disease. Ultimately, as the extent of the coagulopathy permits, liver biopsy (for histologic study, staining for copper, and quantitation of copper [>250 µg/g]) provides the best chance of a definitive diagnosis.
When Wilson disease is diagnosed before the onset of cirrhosis, first-line treatment is copper-chelating agents, such as d-penicillamine, trientine, and tetrathiomolybdate—the choice depending on tolerance of reported adverse effects. Zinc has also been used successfully in children, indirectly reducing copper absorption by inducing synthesis of metallothionein in enterocytes, which preferentially binds copper, thereby blocking its absorption from the diet.
With appropriate pharmacotherapy, hepatic and neurologic dysfunction and KF rings can be reversed. Patients who remain adherent can lead a normal, healthy life. In the setting of end-stage liver disease (because of late diagnosis or nonadherence), liver transplant may be lifesaving; in one series of 21 patients, one-year survival of 87.5% was reported.
Last, siblings of patients must be screened for Wilson disease—initially, with tests of liver function, serum copper and ceruloplasmin, and 24-hour urinary copper content. Haplotype analysis of the patient and his or her parents may be used to determine whether a sibling has inherited the defective copies of ATP7B. In an asymptomatic sibling given a diagnosis of Wilson disease, prompt initiation of a chelating agent may be lifesaving.
A penny for our thoughts? When you confront a presentation of liver disease—acute or chronic—in a child, remember to place Wilson disease in the differential.
----------------------
P.S.
AASLD guideline: A practice guideline on Wilson disease - см. присоединенный файл.
First described in 1913 by Rumpel, Wilson disease is a rare, autosomal recessive disease with an incidence of one in every 30,000 people. The defective gene, ATP7B, located on chromosome 13, is an ATPase that transports copper. Patients with Wilson disease carry two different mutated alleles, one on each chromosome, rendering their genetic defect as compound heterozygotic.
In a healthy person, dietary copper is absorbed via the upper small intestine into the portal circulation. After hepatic extraction for cellular functions, copper is excreted primarily through biliary drainage but is also released into the systemic circulation as ceruloplasmin-bound copper. The ATP7B gene is involved in both steps. With copper transport defective in Wilson disease, copper begins to accumulate in the liver and, subsequently, in the central nervous system and kidneys. Excess copper causes oxidative damage to cell membranes and DNA after the chelating and reducing capacities of intracellular glutathione and metallothionein are saturated. Signs and symptoms of liver failure and neurologic and renal illness ensue.
The age of onset of Wilson disease varies—from 5 to 50 years of age. It can manifest as acute hepatitis, chronic hepatitis with or without cirrhosis, fulminant liver failure, or primarily central nervous system disturbances, such as movement disorders, depression, and psychosis. Direct or slit-lamp examination may reveal Kayser-Fleischer rings, which reflect copper deposition in the Descemet's membrane; 50% of people who have only liver disease—as is the case with most pediatric patients—do not have Kayser-Fleischer rings, however. Other nonspecific but suggestive signs of Wilson disease are non-immune hemolytic anemia and Fanconi renal tubular acidosis.
For lack of a pathognomonic test, the diagnosis of Wilson disease is made by synthesizing information from the medical and family history and physical exam, biochemical and histochemical test results, and, often, liver biopsy findings. When neurologic symptoms are present, Kayser-Fleischer rings are highly suggestive of Wilson disease, although their absence is not exclusionary.
Low serum levels of copper and ceruloplasmin, an elevated 24-hour urine copper level, and increased liver copper content are classic findings in Wilson disease. But—as this case illustrates—too much reliance placed on these tests can be a pitfall in making the diagnosis. The serum copper level may be normal or elevated in the face of acute liver decompensation, as copper is released from injured hepatocytes. Likewise, 5% to 10% of patients have a normal level of ceruloplasmin, because it is an acute-phase reactant that becomes elevated in the presence of chronic inflammation. The ceruloplasmin level can also be falsely elevated if it is measured by an immunologic assay that also detects apoceruloplasmin rather than oxidase activity.
In situations of borderline urine copper content, some authorities have proposed a penicillamine challenge, which enhances copper elimination in these patients, clarifying the diagnosis. Concomitant presence of Coombs-negative hemolytic anemia or Fanconi's renal tubular acidosis (evidenced by non-anion gap acidosis, hypophosphatemia accompanied by phosphaturia, and glycosuria), or both, should also raise the index of suspicion for this disease. Ultimately, as the extent of the coagulopathy permits, liver biopsy (for histologic study, staining for copper, and quantitation of copper [>250 µg/g]) provides the best chance of a definitive diagnosis.
When Wilson disease is diagnosed before the onset of cirrhosis, first-line treatment is copper-chelating agents, such as d-penicillamine, trientine, and tetrathiomolybdate—the choice depending on tolerance of reported adverse effects. Zinc has also been used successfully in children, indirectly reducing copper absorption by inducing synthesis of metallothionein in enterocytes, which preferentially binds copper, thereby blocking its absorption from the diet.
With appropriate pharmacotherapy, hepatic and neurologic dysfunction and KF rings can be reversed. Patients who remain adherent can lead a normal, healthy life. In the setting of end-stage liver disease (because of late diagnosis or nonadherence), liver transplant may be lifesaving; in one series of 21 patients, one-year survival of 87.5% was reported.
Last, siblings of patients must be screened for Wilson disease—initially, with tests of liver function, serum copper and ceruloplasmin, and 24-hour urinary copper content. Haplotype analysis of the patient and his or her parents may be used to determine whether a sibling has inherited the defective copies of ATP7B. In an asymptomatic sibling given a diagnosis of Wilson disease, prompt initiation of a chelating agent may be lifesaving.
A penny for our thoughts? When you confront a presentation of liver disease—acute or chronic—in a child, remember to place Wilson disease in the differential.
----------------------
P.S.
AASLD guideline: A practice guideline on Wilson disease - см. присоединенный файл.
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Последний раз редактировалось Alon Ср июн 27, 2007 12:11 am, всего редактировалось 1 раз.
Всего наилучшего, Алон