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a pattern of symptoms indicative of some disease
a complex of concurrent things; "every word has a syndrome of meanings"

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(疾患の徴候となる一群の)症徴候,症候群 / (事件・社会的状態などのパターンを示す)徴候形態

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/03/27 13:39:39」(JST)

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Crigler–Najjar syndrome or CNS is a rare disorder affecting the metabolism of bilirubin, a chemical formed from the breakdown of red blood cells. The disorder results in an inherited form of non-hemolytic jaundice, which results in high levels of unconjugated bilirubin and often leads to brain damage in infants.

This syndrome is divided into type I and type II, with the latter sometimes called Arias syndrome. These two types, along with Gilbert's syndrome, Dubin–Johnson syndrome, and Rotor syndrome, make up the five known hereditary defects in bilirubin metabolism. Unlike Gilbert's syndrome, only a few hundred cases of CNS are known.

Type I

This is a very rare disease (estimated at 0.6–1.0 per million live births), and consanguinity increases the risk of this condition (other rare diseases may be present). Inheritance is autosomal recessive.

Intense jaundice appears in the first days of life and persists thereafter. Type 1 is characterised by a serum bilirubin usually above 345 µmol/L (310–755) (whereas the reference range for total bilirubin is 2–14 μmol/L).

No UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) expression can be detected in the hepatic tissue. Hence, there is no response to treatment with phenobarbital^[1] (which causes CYP450 enzyme induction). Most patients (type IA) have a mutation in one of the common exons (2 to 5), and have difficulties conjugating several additional substrates (several drugs and xenobiotics). A smaller percentage of patients (type IB) have mutations limited to the bilirubin-specific A1 exon; their conjugation defect is mostly restricted to bilirubin itself.

Before the availability of phototherapy, these children died of kernicterus (bilirubin encephalopathy) or survived until early adulthood with clear neurological impairment. Today, therapy includes

exchange transfusions in the immediate neonatal period
12h/d phototherapy
heme oxygenase inhibitors to reduce transient worsening of hyperbilirubinemia (although the effect decreases over time)
oral calcium phosphate and carbonate to form complexes with bilirubin in the gut,
liver transplantation before the onset of brain damage and before phototherapy becomes ineffective at later age

Type II

Type II differs from type I in several aspects:

Bilirubin levels are generally below 345 µmol/L (100–430; thus, there is overlap), and some cases are only detected later in life.
Because of lower serum bilirubin, kernicterus is rare in type II.
Bile is pigmented, instead of pale in type I or dark as normal, and monoconjugates constitute the largest fraction of bile conjugates.
UGT1A1 is present at reduced but detectable levels (typically <10% of normal), because of single base pair mutations.
Therefore, treatment with phenobarbital is effective, generally with a decrease of at least 25% in serum bilirubin. In fact, this can be used, along with these other factors, to differentiate type I and II.
The inheritance pattern of Crigler–Najjar syndrome type II has been difficult to determine but is generally considered to be autosomal recessive.^[2]

Differential diagnosis

Neonatal jaundice may develop in the presence of sepsis, hypoxia, hypoglycemia, hypothyroidism, hypertrophic pyloric stenosis, galactosemia, fructosemia, and so on.

Hyperbilirubinemia of the unconjugated type may be caused by

increased production
- hemolysis (e.g., hemolytic disease of the newborn, hereditary spherocytosis, sickle cell disease)
- ineffective erythropoiesis
- massive tissue necrosis or large hematomas
decreased clearance
- drug-induced
- physiological neonatal jaundice and prematurity
- liver diseases such as advanced hepatitis or cirrhosis
- breast milk jaundice and Lucey–Driscoll syndrome
- Crigler–Najjar syndrome and Gilbert syndrome

In Crigler–Najjar syndrome and Gilbert syndrome, routine liver function tests are normal, and hepatic histology usually is, too. There is no evidence for hemolysis. Drug-induced case typically regress after discontinuation of the substance. Physiological neonatal jaundice may peak at 85–170 µmol/L and decline to normal adult concentrations within two weeks. Prematurity results in higher levels.

Research

One 10-year-old girl with Crigler–Najjar syndrome type I was successfully treated by hepatocyte transplantation.^[3]

The homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase (UDPGT), is an animal model for the study of Crigler–Najjar syndrome. Since there is only one enzyme working improperly, gene therapy for Crigler Najjar is a theoretical option which is being investigated.^[4]

Eponym

The condition is named for John Fielding Crigler (b. 1919), an American Pediatrician and Victor Assad Najjar (b. 1914), a Lebanese-American Pediatrician.^[5]^[6]

References

^ Jansen PL (December 1999). "Diagnosis and management of Crigler–Najjar syndrome". European journal of pediatrics 158 (Suppl 2): S89–S94. doi:10.1007/PL00014330. PMID 10603107.
^ Chowdhury, J. R.; Wolkoff, A. W.; Chowdhury, N. R.; Arias, I. M.: "Hereditary jaundice and disorders of bilirubin metabolism." In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. 2. New York: McGraw-Hill (8th ed.) 2001. Pp. 3063–3101.
^ Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, Dorko K, Sauter BV, Strom SC (May 1998). "Treatment of the Crigler–Najjar syndrome type I with hepatocyte transplantation". The New England Journal of Medicine 338 (20): 1422–6. doi:10.1056/NEJM199805143382004. PMID 9580649.
^ Toietta G, Mane VP, Norona WS, Finegold MJ, Ng P, Mcdonagh AF, Beaudet AL, Lee B (March 2005). "Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector". Proceedings of the National Academy of Sciences of the United States of America 102 (11): 3930–5. doi:10.1073/pnas.0500930102. PMC 554836. PMID 15753292.
^ Crigler JF Jr., Najjar VA (February 1952). "Congenital familial nonhemolytic jaundice with kernicterus; a new clinical entity". A.M.A. American Journal of Diseases of Children 83 (2): 259–60. ISSN 0096-8994. PMID 14884759.
^ synd/86 at Who Named It?

External links

Crigler–Najjar Questions and Answers site
Crigler–Najjar association
Info and links related to Crigler–Najjar
[1]
Crigler–Najjar syndrome, type 1 at NIH's Office of Rare Diseases
Crigler–Najjar syndrome, type 2 at NIH's Office of Rare Diseases

UpToDate Contents

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1. クリグラー・ナジャー症候群 crigler najjar syndrome
2. 小児における非抱合型高ビリルビン血症による黄疸の評価 evaluation of jaundice caused by unconjugated hyperbilirubinemia in children
3. 新生児における非抱合型高ビリルビン血症の発症機序および病因 pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn
4. ビリルビン過剰産生によるジルベール症候群および非抱合型ビリルビン過剰産生 gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction
5. 肝酵素および肝機能検査値の異常が認められた患者に対するアプローチ approach to the patient with abnormal liver biochemical and function tests

English Journal

Monogenic diseases that can be cured by liver transplantation.

Fagiuoli S, Daina E, D'Antiga L, Colledan M, Remuzzi G.SourceGastroenterology and Transplant Hepatology, Ospedale Papa Giovanni XXIII, Bergamo, Italy. Electronic address: sfagiuoli@hpg23.it.
Journal of hepatology.J Hepatol.2013 Apr 8. pii: S0168-8278(13)00219-5. doi: 10.1016/j.jhep.2013.04.004. [Epub ahead of print]
While the prevalence of most diseases caused by single-gene mutations is low and defines them as rare conditions, all together, monogenic diseases account for approximately 10 in every 1.000 births according to the World Health Organisation. Orthotopic liver transplantation (LT) could offer a therap
PMID 23578885

Gilbert and Crigler Najjar syndromes: an update of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation database.

Canu G, Minucci A, Zuppi C, Capoluongo E.SourceLaboratory of Clinical Molecular Diagnostics, Institute of Biochemistry and Clinical Biochemistry, Catholic University of Rome, Italy.
Blood cells, molecules & diseases.Blood Cells Mol Dis.2013 Apr;50(4):273-80. doi: 10.1016/j.bcmd.2013.01.003. Epub 2013 Feb 9.
UGT1A1 enzyme defects are responsible of both Gilbert syndrome (GS) and Crigler-Najjar syndrome (CNS). GS depends on a variant TATAA element (which contains two extra TA nucleotides as compared to the wild type genotype) in the UGT1A1 gene promoter resulting in a reduced gene expression. On the cont
PMID 23403257

Increased Reprogramming of Human Fetal Hepatocytes Compared With Adult Hepatocytes in Feeder-Free Conditions.

Hansel MC, Gramignoli R, Blake W, Davila J, Skvorak K, Dorko K, Tahan V, Lee BR, Tafaleng E, Guzman-Lepe J, Soto-Gutierrez A, Fox IJ, Strom SC.AbstractHepatocyte transplantation has been used to treat liver disease. The availability of cells for these procedures is quite limited. Human embryonic stem cells (hESCs) and inducedpluripotent stem cells (hiPSCs) may be a useful source of hepatocytes for basic research and transplantation if efficient and effective differentiation protocols were developed and problems with tumorigenicity could be overcome. Recent evidence suggests that the cell of origin may affect hiPSC differentiation. Thus, hiPSCs generated from hepatocytes may differentiate back to hepatocytes more efficiently than hiPSCs from other cell types. We examined the efficiency of reprogramming adult and fetal human hepatocytes. The present studies report the generation of 40 hiPSC lines from primary human hepatocytes under feeder-free conditions. Of these, 37 hiPSC lines were generated from fetal hepatocytes, 2 hiPSC lines from normal hepatocytes and 1 hiPSC line from hepatocytes of a patient with Crigler-Najjar Syndrome, Type-1. All lines were confirmed reprogrammed and expressed markers of pluripotency by gene expression, flow cytometry, immunocytochemistry, and teratoma formation. Fetal hepatocytes were reprogrammed at a frequency over 50-fold higher than adult hepatocytes. Adult hepatocytes were only reprogrammed with 6 factors, while fetal hepatocytes could be reprogrammed with 3 (OCT4, SOX2, NANOG) or 4 factors (OCT4, SOX2, NANOG, LIN28 or OCT4, SOX2, KLF4, C-MYC). The increased reprogramming efficiency of fetal cells was not due to increased transduction efficiency or vector toxicity. These studies confirm that hiPSCs can be generated from adult and fetal hepatocytes including those with genetic diseases. Fetal hepatocytes reprogram much more efficiently than adult, although both could serve as useful sources of hiPSC-derived hepatocytes for basic research or transplantation.
Cell transplantation.Cell Transplant.2013 Feb 4. [Epub ahead of print]
Hepatocyte transplantation has been used to treat liver disease. The availability of cells for these procedures is quite limited. Human embryonic stem cells (hESCs) and inducedpluripotent stem cells (hiPSCs) may be a useful source of hepatocytes for basic research and transplantation if efficient an
PMID 23394081

Japanese Journal

Gilbert 症候群と血液疾患

丸尾良浩,太田茂
日本小児血液学会雑誌 18(6), 601-608, 2004-12-31
NAID 10014291451

Modulation of organic anion transporting polypeptide 1 and multidrug resistance protein 3 expression in the liver and kidney of Gunn rats

HIGUCHI Kunihiro,KOBAYASHI Yoshinao,KURODA Makoto,TANAKA Yuji,ITANI Toshio,ARAKI Jun,MIFUJI Rumi,KAITO Masahiko,ADACHI Yukihiko
Hepatology research : the official journal of the Japan Society of Hepatology 29(1), 60-66, 2004-05-01
NAID 10018024061

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リンク元	「クリグラー・ナジャー症候群」
関連記事	「syndrome」

「クリグラー・ナジャー症候群」

Crigler–Najjar syndrome
	Classification and external resources
	; Bilirubin
ICD-10	E80.5
ICD-9	277.4
OMIM	218800 606785
DiseasesDB	3176
MedlinePlus	001127
eMedicine	med/476
MeSH	D003414

　　[★]

英: Crigler-Najjar syndrome
同: Crigler-Najjar症候群、クリグラー-ナジャー症候群
関: 黄疸

病因~

グルクロニルトランスフェラーゼの機能欠損。
原因遺伝子は2q37.1に座乗するUGT1A1遺伝子である。この遺伝子がコードするUDP-グルクロノシルトランスフェラーゼ(UDP-glucuronosyltransferase ,UDPGT)は間接ビリルビンにグルクロン酸抱合を行い直接ビリルビンに変換する。
I型ではUDP-グルクロノシルトランスフェラーゼが完全に機能欠損し、II型は活性が低下したものである。

遺伝形式

常染色体優性遺伝

病型

フェノバルビタール投与によりビリルビン濃度の変化により分類される。　　←　　フェノバルビタールによりUDP-グルクロノシルトランスフェラーゼの発現が誘導される、らしい。
I型：フェノバルビタール投与で変化なし。
I型：フェノバルビタール投与でビリルビン低下。

病態

間接ビリルビンが上昇。
I型

生後まもなく間接ビリルビン上昇により核黄疸に至る。
予後不良

II型

UDP-グルクロノシルトランスフェラーゼの活性は正常人の1/10以下であるが、予後良好。

治療

I型：光線療法、肝移植
II型：光線療法、フェノバルビタール、肝移植？

体質性黄疸 (IMD.875)

体質性黄疸	遺伝形式*	ビリルビン型	ビリルビン値	予後
Crigler-Najjar症候群I型	常染色体劣性	間接型(非抱合)	21-31mg/dl	致死的
Crigler-Najjar症候群II型	常染色体劣性		8-18mg/dl	良好
Gilbert症候群	常染色体優性		<6mg/dl	きわめて良好
Dubin-Johnson症候群	常染色体劣性	直接型(抱合)	2-5(-25)mg/dl	きわめて良好
Rotor症候群	常染色体劣性	直接型(抱合)	2-5(-20)mg/dl	きわめて良好
*劣性か優性かについては例外あり

参考

1. CRIGLER-NAJJAR SYNDROME - OMIM

http://omim.org/entry/218800

「syndrome」

　　[★]

n.

症候群

[1] Jansen PL (December 1999). "Diagnosis and management of Crigler–Najjar syndrome". European journal of pediatrics 158 (Suppl 2): S89–S94. doi:10.1007/PL00014330. PMID 10603107.

[2] Chowdhury, J. R.; Wolkoff, A. W.; Chowdhury, N. R.; Arias, I. M.: "Hereditary jaundice and disorders of bilirubin metabolism." In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. 2. New York: McGraw-Hill (8th ed.) 2001. Pp. 3063–3101.

[3] Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, Dorko K, Sauter BV, Strom SC (May 1998). "Treatment of the Crigler–Najjar syndrome type I with hepatocyte transplantation". The New England Journal of Medicine 338 (20): 1422–6. doi:10.1056/NEJM199805143382004. PMID 9580649.

[4] Toietta G, Mane VP, Norona WS, Finegold MJ, Ng P, Mcdonagh AF, Beaudet AL, Lee B (March 2005). "Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector". Proceedings of the National Academy of Sciences of the United States of America 102 (11): 3930–5. doi:10.1073/pnas.0500930102. PMC 554836. PMID 15753292.

[5] Crigler JF Jr., Najjar VA (February 1952). "Congenital familial nonhemolytic jaundice with kernicterus; a new clinical entity". A.M.A. American Journal of Diseases of Children 83 (2): 259–60. ISSN 0096-8994. PMID 14884759.

[6] synd/86 at Who Named It?

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案内

Crigler-Najjar syndrome