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Journal Club

Journal Club. Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, Chiusano E, John R, Guaraldo V, George LM, Perona M, Dall'Amico D, Parkes AB, Joomun M, Wald NJ . Antenatal thyroid screening and childhood cognitive function.

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Journal Club

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  1. Journal Club Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, Chiusano E, John R, Guaraldo V, George LM, Perona M, Dall'Amico D, Parkes AB, Joomun M, Wald NJ. Antenatal thyroid screening and childhood cognitive function. N Engl J Med. 2012 Feb 9;366(6):493-501. Ludvigsson J, Krisky D, Casas R, Battelino T, Castaño L, Greening J, Kordonouri O, Otonkoski T, Pozzilli P, Robert JJ, Veeze HJ, Palmer J. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med. 2012 Feb 2;366(5):433-42. 埼玉医科大学　総合医療センター　内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田　昌文 Matsuda, Masafumi 2012年2月16日8:30-8:55 ８階　医局

  2. Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted. N Engl J Med 1999;341:549-55.

  3. the Centre for Endocrine and Diabetes Sciences, Cardiff School of Medicine (J.H.L., R.R., A.B.P.); the Department of Child Psychology, St. David’s Hospital (S.C., R.P.); and the Department of Medical Biochemistry, University Hospital of Wales (R.J.) — all in Cardiff, United Kingdom; Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London (J.P.B., L.M.G., M.J., N.J.W.); and Azienda Ospedaliera Ospedale Infantile Regina Margherita– Sant’Anna, Turin, Italy (A.M., E.C., V.G., M.P., D.D.) N Engl J Med 2012;366:493-501.

  4. Background Children born to women with low thyroid hormone levels have been reported to have decreased cognitive function. • Active secretion of thyroid hormone in the fetus does not start until about 18 to 20 weeks’ gestation. • Studies in animals suggest that until fetal hormone secretion begins, the fetus is dependent on circulating free thyroxine (T4) in the mother for growth and development, including central nervous system maturation. • Iodine is essential for free T4 synthesis, and in iodine-deficient populations, an increase in cognitive performance has been observed after iodine supplementation before pregnancy. • High levels of thyrotropinin women during pregnancy have been associated with impaired cognitive development in their offspring.

  5. Methods We conducted a randomized trial in which pregnant women at a gestation of 15 weeks 6 days or less provided blood samples for measurement of thyrotropin and free thyroxine (T4).Women were assigned to a screening group (in which measurements were obtained immediately) or a control group (in which serum was stored and measurements were obtained shortly after delivery). Thyrotropin levels above the 97.5th percentile, free T4 levels below the 2.5th percentile, or both were considered a positive screening result. Women with positive findings in the screening group were assigned to 150 μg of levothyroxine per day. The primary outcome was IQ at 3 years of age in children of women with positive results, as measured by psychologists who were unaware of the group assignments.

  6. Randomization and Follow-up of the Study Participants. about 24% of the women were lost to follow-up

  7. * Plus–minus values are means ±SD. In the screening group, the women were assigned to treatment with levothyroxine. To convert the values for free thyroxine (T4) from picomoles per liter to nanograms per deciliter, divide by 12.87. † Values for thyrotropin and free T4 levels are provided separately for the United Kingdom and Turin because different assays were used (ADVIA Centaur in the United Kingdom and AutoDELFIA in Turin, Italy). ‡ The difference between the screening and control groups was significant (P = 0.009); there were no other significant differences. ¶ Data shown are for the United Kingdom only (parents in Turin were not asked about educational status or age at delivery). ? ? • 基準値 • FT4(遊離サイロキシン) 0.8～1.8ng/dℓ. • TSH(甲状腺刺激ホルモン) 0.5～5.0μIU/mℓ

  8. Thyrotropin and free T4 levels at initial visit (median 12,3 weeks gestation), 6 weeks after starting levothyroxine therapy (median 20,0 weeks gestation) and at about 30 weeks (median 30,1 weeks gestation).

  9. Aspects of child behavior that might affect the evaluation of IQ were assessed with the use of the Child Behavior Checklist (CBCL) 2000 (Achenbach System of Empirically Based Assessment, University of Vermont) and the Behavior Rating Inventory of Executive Function, preschool version (Brief-P), 2003 (Psychological Assessment Resources). Information relating to parental education and maternal psychological status (assessed with the use of the Beck Depression Inventory II [Psychological Corporation]) was also collected. IQ assessments were performed by two psychologists in the United Kingdom and one in Turin.

  10. Figure 2. Relative Risk of an IQ Score below Specified Cutoff Scores in the Screening Group as Compared with the Control Group, According to the Intention to- Treat Analysis. I bars indicate 95% confidence intervals.

  11. Figure 3. Relative Risk of an IQ Score below Specified Cutoff Scores in the Screening Group as Compared with the Control Group, According to the On-Treatment Analysis. A total of 308 women (79%) were found to have complied with treatment (i.e., they had a decrease of at least 10% in the thyrotropin level and an increase of at least 10% in the free thyroxine level). I bars indicate 95% confidence intervals.

  12. Screening was performed and levothyroxine therapy initiated too late in gestation to have a major influence on brain development (up to 20 weeks’ gestation; median, 13 weeks 3 days). ? Current guidelines do not recommend routine antenatal screening for hypothyroidism in pregnancy. Our study provides support for these guidelines

  13. One possible explanation for the lack of benefit of levothyroxine is that the women in the present study had milder hypothyroidism than the women whose offspring were reported to have adverse cognitive outcomes. The previous observational study included women with a mean thyrotropin level of 13.2 mIU per liter, significantly higher than in the treatment groups in the current study, in which the median thyrotropin levels were 3.8 mIU per liter (range, 1.5 to 4.7) in the United Kingdom and 3.1 mIU per liter (range, 1.3 to 4.0) in Italy. Cf. HaddowJE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549-555 Editorial The Debate over Thyroid-Function Screening in Pregnancy Gregory A. Brent, M.D. N Engl J Med 2012; 366:562-563

  14. Results Of 21,846 women who provided blood samples (at a median gestational age of 12 weeks 3 days), 390 women in the screening group and 404 in the control group tested positive. The median gestational age at the start of levothyroxine treatment was 13 weeks 3 days; treatment was adjusted as needed to achieve a target thyrotropin level of 0.1 to 1.0 mIU per liter. Among the children of women with positive results, the mean IQ scores were 99.2 and 100.0 in the screening and control groups, respectively (difference, 0.8; 95% confidence interval [CI], −1.1 to 2.6; P = 0.40 by intention-to-treat analysis); the proportions of children with an IQ of less than 85 were 12.1% in the screening group and 14.1% in the control group (difference, 2.1 percentage points; 95% CI, −2.6 to 6.7; P = 0.39). An on-treatment analysis showed similar results.

  15. Conclusions Antenatal screening (at a median gestational age of 12 weeks 3 days) and maternal treatment for hypothyroidism did not result in improved cognitive function in children at 3 years of age. (Funded by the Wellcome Trust UK and Compagnia di San Paulo, Turin; Current Controlled Trials number, ISRCTN46178175.)

  16. Message 甲状腺検査陽性の妊婦を対象に、甲状腺機能低下症の治療と産児の認知機能の関連を無作為化試験で調査。児の3歳時のIQは、検査とレボチロキシンによる治療を出産前に行った群（390人）で99.2、検査と治療を出産後に行った群（404人）で100.0だった。母親の出産前の甲状腺検査と治療による産児の認知機能改善は見られなかった。 検査が遅すぎた！！！という解釈もあるが 勿論　極端な検査値異常は話は別！

  17. Diabetes Metab. Rev. 14, 3–29 (1998)

  18. Dorota B. Schranz, Åke Lernmark Department of Medicine, University of Washington, Seattle, U.S.A. Diabetes Metab. Rev. 14, 3–29 (1998)

  19. The strongest susceptibility to Type 1 diabetes is with HLA-DQ alleles. Caucasian susceptibility is more strongly associated with DQA1* 0501–DQB1*0201/DQA1*0301–DQB1*0302 than with DRB1*03/DRB1*04. DRB1*03 and DRB1* 04 are in strong linkage disequilibrium with class I molecules B8 and B15, respectively. Conversely, the DRB1*04 allele is in linkage disequilibrium with the DQB1*0302 allele. Negative association with Type 1 diabetes was observed for DQA1*0102–DQB1*0602–DRB1*1501 genotype. The DQB1*0602 allele is probably immunodominant over susceptibility DQB1 alleles and may be protective even among islet cell autoantibody positive first-degree relatives to patients with Type 1 diabetes. Among people with the DQA1*0501–DQB1*0201/DQA1*0301–DQB1*0302 genotype protection may be associated with the DRB1*0403 allele, while the DRB1*0401 allele is susceptible. This negative association may, however, not be detected in all populations. Also, the DQA1*0301–DQB1*0301 haplotype may be protective, in spite of the small sequence differences between this molecule and the susceptible DQA1*0301–DQB1*0302 molecule. The association of the DQ alleles with diabetes is correlated with amino acid residue on the bchainand amino acid residue on the achain. However, these individual amino acids do not solely explain susceptibility or protection. Many individuals develop Type 1 diabetes despite the presence of Asp-57 on the DQ bchain. The presence of negatively charged aspartic acid at position 57 of DQ bis associated with unique peptide binding capacity which may influence disease etiology, pathogenesis or both processes. Diabetes Metab. Rev. 14, 3–29 (1998)

  20. Susceptibility genes for type 1 diabetes Major gene： HLA (IDDM1) b-cell specificity： INS (IDDM2) negative regulator： CTLA4 (IDDM12) SUMO4 (IDDM5) PTPN22

  21. Association of DRB1 alleles with type 1 diabetes Type 1 diabetesControls OR P (n=264) (n=314) DRB1*040533.7% 17.2%2.45 <0.00001 *0901 25.4% 13.1% 2.26 0.0002 *15021.9% 14.6% 0.11 <0.0000001 Kawabata Y et al. Diabetes 51:545-551, 2002

  22. Disease susceptible HLA-haplotypes Japanese DRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9) Caucasians DRB1*0301-DQB1*0201 (DR3) DRB1*0401-DQB1*0302 (DR4)

  23. Different haplotypes are associated with type 1 diabetes in Japanese and Caucasian populations Japanese Caucasian DRB1-DQB1Type 1 diabetes HF1)Type 1 diabetes HF haplotypesusceptibilitysusceptibility DRB1*0405-DQB1*0401susceptible present unknown rare DRB1*0901-DQB1*0303susceptible present unknown rare DRB1*0301-DQB1*0201 unknown rare susceptible present DRB1*0401-DQB1*0302 unknown rare susceptible present DRB1*1501-DQB1*0602protective present protective present • HF: Haplotype frequency, http://square.umin.ac.jp/JSHI/frame.html

  24. High risk genotypes for type 1 diabetes Japanese DRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9) Caucasians DRB1*0301-DQB1*0201 (DR3) DRB1*0401-DQB1*0302 (DR4) Very high risk genotype(Caucasians) DRB1*0301 /0401 (DR3/4)

  25. 23.1 1.0 Kawabata Y et al. Diabetes 51:545-551, 2002 Disease-associated genotypes in Japanese （DRB1*0405 vs. DRB1*0901 haplotype） Odds Ratio DRB1*0405 / DRB1*04052.1 DRB1*0405 / X 2.8 DRB1*0901 /DRB1*0901 DRB1*0901 / Y

  26. High risk genotypes for type 1 diabetes Japanese DRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9) Caucasians DRB1*0301-DQB1*0201 (DR3) DRB1*0401-DQB1*0302 (DR4) Very high risk genotype（Japanese） DRB1*0901 /0901 (DR9/9)

  27. HLA haplotypes associated with type 1 diabetes Japanese DRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9) Caucasians DRB1*0301-DQB1*0201 (DR3) DRB1*0401-DQB1*0302 (DR4) Korean DRB1*0301-DQB1*0201 (DR3) DRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9)

  28. DR9 homozygosity confers susceptibility to type 1 diabetes :homo 20 :hetero Odds ratio 10 1 Japanese Korean Japanese Korean DR4 DR9 Kawabata Y et al. Diabetes 51:545-551, 2002

  29. Susceptibility genes for type 1 diabetes Major gene： HLA (IDDM1) b-cell specificity： INS (IDDM2) negative regulator： CTLA4 (IDDM12) SUMO4 (IDDM5)

  30. 4.1 kb region of IDDM2 Association of INS-VNTR with type 1 diabetes VNTR TH INS IGF2 -23 HphI -596 VNTR Type 1 diabetes susceptibility Class III haplotype Class III - protective Class I haplotype Class I ＋ susceptible

  31. Frequency of class I INS-VNTR tended to be higher in type 1 diabetes than in controls ControlsCasesOdds ratio France1 55% 84% 4.2 UK2 59% 76% 2.2 Japan3 94% 99% 1 Lucassen et al. Nature Genet 4:305, 1993 2 Bennet et al. Nature Genet 9:284, 1995 3 Kawaguchi et al. BBRC233:283, 1997

  32. Susceptibility genes for type 1 diabetes Major gene： HLA (IDDM1) b-cell specificity： INS (IDDM2) negative regulator： CTLA4 (IDDM12) PTPN22 SUMO4 (IDDM5)

  33. NATURE |VOL 423 | 29 MAY 2003 |www.nature.com/nature

  34. Association of CTLA4 with autoimmune diseases (Caucasian populations) Odds ratio (95% CI) Graves’s disease 1.51 (1.31-1.75) Hashimoto thyroiditis 1.45 (1.17-1.80) Type 1 diabetes 1.14 (1.07-1.21) SNP: +6230G>A (rs3087243) Ueda H et al. Nature 2003

  35. Arg620Trp(R620W)of PTPN22 was consistently reported to be associated with autoimmune diseases in Caucasian populations Odds ratio(95%CI) Type 1 diabetes N. American1 1.83 (1.28-2.60) Italian1 2.31 (0.93-5.82) UK2 1.78 (1.54-2.06) Caucasian3 (C/T) 1.7 (1.3-2.3) (T/T) 3.4 (1.3-8.9) Graves's disease2 1.43 (1.17-1.76) RA4 1.74 (1.27-2.38) SLE5 (C/T) 1.37 (1.07-1.75) (T/T) 4.37 (1.98-9.65) 1Nat Genet 36:337, 2004, 2Diabetes 53:3020, 2004, 3Diabetes 54:906, 2005 4Am J Hum Genet 75:330, 2004, 5 Am J Hum Genet 75:504, 2004

  36. SUMO4 SNPs identified by re-sequencing in Japanese 2176bp SUMO4 Exon 6 Exon 7 -504A>G M55V 438C>T MAP3K7IP2 D’: 1.0 for single pair of SNPs estimated by EM algorithm （Haploview v2.03）

  37. SUMO4（M55V）is associated with type 1 diabetes (Japanese and Koreans) Cases Controls OR (95%CI) p (n=541) (n=743) Japanese 59% 50% Koreans 58% 44% 1.46 (1.17-1.83) 0.0008* *Mantel-Haenszel test Noso S et al. Poster #098 Diabetes ( in press)

  38. Meta-analysis Caucasian, Guo et al. 2004 Asian, Guo et al. 2004* UK, Smyth et al. 2005* Canadian, Paterson et al. 2005 Korean, Park et al. 2005 Japanese, Noso et al. 2005 Korean, Noso et al. 2005 0.5 1.0 1.2 1.5 2.0 3.0 0.7

  39. Meta-analysis Caucasian, Guo et al. 2004 UK, Smyth et al. 2005* Canadian, Paterson et al. 2005 Summary OR:1.02 (95%CI: 0.98-1.07) p = 0.25 (NS) Caucasian (n=23,431) Asian, Guo et al. 2004* p value against homogeneity 0.16 (NS) Korean, Park et al. 2005 Japanese, Noso et al. 2005 Korean, Noso et al. 2005 Asian (n=4720) Summary OR:1.29 [95%CI: 1.15-1.44] p = 4.0 x 10-7 Total (n=28,151) 0.5 1.0 1.2 1.5 2.0 3.0 0.7

  40. SUMO4 M55V is associated with type 1 diabetes in Asians, but not in Caucasians. 95%CI （Caucasian) 95%CI （Asian) Meta-analysis Caucasian, Guo et al. 2004 UK, Smyth et al. 2005* Canadian, Paterson et al. 2005 Summary OR:1.02 (95%CI: 0.98-1.07) p = 0.25 (NS) Caucasian (n=23,431) Asian, Guo et al. 2004* Korean, Park et al. 2005 Japanese, Noso et al. 2005 Korean, Noso et al. 2005 Asian (n=4720) Summary OR:1.29 [95%CI: 1.15-1.44] p = 4.0 x 10-7 Total (n=28,151) 0.5 1.0 1.2 1.5 2.0 3.0 0.7 Noso S et al. Poster #098 Diabetes ( in press)

  41. Reasons for apparent differences in susceptibility alleles for type 1 diabetes between Japanese and Caucasian populations Association Reasons for apparent Caucasian Japanese difference HLA yes yesallele difference INS yes yesallele frequency CTLA4 yesrestricted clinical subtype PTPN22 yes unknown allele absent SUMO4 ? yes heterogeneity?

  42. 2009年12月24日 N Engl J Med 2009;361:2143-52 From the Indiana University School of Medicine, Indianapolis (M.D.P., H.R.); the Benaroya Research Institute, Seattle (C.J.G.); the George Washington University Biostatistics Center, Rockville, MD (H.K.-S., P.F.M., J.M.L.); the University of Pittsburgh, Pittsburgh (D.J.B.); the University of California, San Francisco, San Francisco (S.E.G.); Columbia University, New York (R.G.); University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora (P.A.G.); the University of Miami Diabetes Research Institute, Miami ( J.B.M., J.S.S.); the University of Minnesota, Minneapolis (A.M.M.); the University of Texas Southwestern Medical School, Dallas (P.R.); the University of Florida, Gainesville (D.A.S.); Hospital for Sick Children, University of Toronto, Toronto (D.W.); and Stanford University, Stanford, CA (D.M.W.).

  43. The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte–mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes.

  44. Linköping University, Linköping, Sweden (J.L., R.C.); Diamyd Medical, Pittsburgh (D.K.); University Medical Center– University Children’s Hospital, Faculty of Medicine, Ljubljana, Slovenia (T.B.); Hospital de Cruces–University of Basque Country, Barakaldo, Bizkaia, Spain (L.C.); the Department of Paediatrics, Leicester Royal Infirmary, Leicester, United Kingdom ( J.G.); the Diabetes Center for Children and Adolescents, Kinderkrankenhaus auf der Bult, Hannover, Germany (O.K.); Children’s Hospital, University of Helsinki, and Helsinki University Central Hospital, Helsinki (T.O.); University Campus Bio-Medico, Rome (P.P.); Hôpital Necker–EnfantsMalades, Université René Descartes Paris 5, Paris ( J.-J.R); StichtingDiabeter, Rotterdam, the Netherlands (H.J.V.); and the Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle ( J.P.). N Engl J Med 2012;366:433-42.

  45. Background The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.

  46. Methods We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixedmeal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.

  47. Figure 1. Enrollment, Randomization, and Follow-up of the Study Patients. Between August 2008 and November 2009, a total of 469 patients were screened for a fasting C-peptide level above 0.3 ng per milliliter (0.1 nmol per liter) and elevated levels of the 65-kD isoform of glutamic acid decarboxylase (GAD65) autoantibodies, and 334 underwent randomization. Of these patients, 327 made up the intention-to-treat cohort, whose data were used in the primary effectiveness analysis at 15 months.

  48. * Plus–minus values are means ±SD. Baseline characteristics did not differ significantly among the three groups. Data are for the safety population (all enrolled patients) unless otherwise indicated. To convert values for C peptide to nanograms per milliliter, divide by 0.333. To convert values for glucose to milligrams per deciliter, divide by 0.05551. AUC denotes area under the curve, BMI body-mass index, and GAD65 the 65-kD isoform of glutamic acid decarboxylase. † Data regarding BMI percentile were missing for 1 patient each in the two-dose and placebo groups. ‡ Data are for the modified intention-to-treat population. § Data regarding HLA classification were missing for 2 patients in the four-dose group, 1 patient in the two-dose group, and 1 patient in the placebo group. ¶ The Tanner puberty stage ranges from 1 to 5, with higher stages indicating more developed genitalia. Data regarding puberty stage were missing for 2 patients in the four-dose group, 1 patient in the two-dose group, and 3 patients in the placebo group.

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