Stuart Brink

Genetic Prediction of Nonresponse to Hepatitis B Vaccine

In previous studies of the antibody response to hepatitis B vaccine in 598 subjects who received a full course of vaccination, we observed a bimodal response, with about 14 percent producing less than approximately 1000 radioimmunoassay (RIA) units. An analysis of the major histocompatibility complex (MHC) HLA and complement types of 20 of the subjects with the lowest responses indicated a greater-than-expected number of homozygotes for the extended or fixed MHC haplotype [HLA-B8, SC01, DR3]. This finding suggested that the lack of a normal response was a recessive MHC-linked trait. In this study, we prospectively vaccinated five homozygotes and nine heterozygotes for this haplotype in the expectation that the homozygotes would produce much lower levels of antibody than the heterozygotes. When the antibody response was assessed two months after the third injection, four of the five homozygotes had produced very low levels (approximately 1000 units or less) of antibody (mean, 467 RIA units; range, less than 8 to 1266), whereas all nine heterozygotes produced more than 2500 RIA units (mean, 15,608; range, 2655 to 28,900) (P less than 0.01). We conclude that the usual response to hepatitis B surface antigen is due to the presence of a dominant immune-response gene in the MHC and that a low response is due to the absence of such a gene and the presence on both chromosomes of MHC haplotypes (such as [HLA-B8, SC01, DR3]) that indicate such a response.

Differential Sensitivity to β-Cell Secretagogues in “Early,” Type I Diabetes Mellitus

The insulin secretory response to various β-cell secretagogues was studied in four children (ages 11,11, 12, and 10 yr) in “early” stages or remission of type I diabetes mellitus. One child was an anti-islet antibody positive monozygotic twin of a type I diabetic subject, two children had impaired glucose tolerance and elevated levels of la-positive T-cells, and the fourth was in remission (off insulin) of type I diabetes 6 mo after immunotherapy. The peak first-phase (0–10 min) insulin increment after intravenous (i.v.) glucose was negligible in each patient, whereas the peak responses to i.v. glucagon, tolbutamide, arginine, and oral glucose ranged between 10% and 43% of median responses in normal control subjects. The rank order of response to a variety of secretagogues was remarkably similar in all four subjects: i.v. arginine > i.v. glucagon > oral glucose > i.v. tolbutamide > i.v. glucose. These studies indicate that a “functional” β-cell defect, namely a complete loss of response to i.v. glucose and a partial loss to other secretagogues, exists in type I diabetic patients before complete β-cell destruction. This alteration in β-cell responsiveness probably underlies our prior observation of slowly progressive loss of i.v.-glucose-induced insulin release in islet cell antibody-positive siblings of type I diabetic subjects.

Specific Association of HLA-DR4 With Increased Prevalence and Level of Insulin Autoantibodies in First-Degree Relatives of Patients With Type I Diabetes

First-degree relatives of patients with insulin-dependent (type I) diabetes (n = 264 from 106 families) were evaluated with HLA typing and determination of competitive insulin autoantibodies (CIAAs) and islet cell autoantibodies (ICAs). The levels of CIAAs in 30 relatives exceeded our upper limit of normal (≥39 nU/ml), and 30 had high-titer ICAs (≥40 Juvenile Diabetes Foundation units [JDF U]). Eleven of the HLA-typed relatives developed diabetes during follow-up. Twenty-three percent (28 of 123) of the relatives with at least one HLA-DR4 allele were CIAA+ (CIAA ≥39 nU/ml) versus 4% (6 of 141) among DR4− relatives (P < 0.0001). Twenty-one of 22 of the highest CIAA values were all in the DR4+ group (DR4+ vs. DR4−, P = 0.003, Wilcoxons rank-sum test). HLA-DR3 did not correlate with the level of CIAAs, and neither DR3 nor DR4 correlated with titer of ICAs measured in JDF U. We conclude that, in first-degree relatives of patients with type I diabetes, there is a striking association with HLA-DR4 in both the prevalence of relatives exceeding the normal CIAA range and in the level of CIAAs. These data suggest that a gene on HLA-DR4 haplotypes contributes to the level of anti-insulin autoimmunity, and we hypothesize that DR4-associated diabetes susceptibility, distinct from DR3-associated susceptibility, may be secondary to this influence.

Progressive Autoimmune Beta Cell Insufficiency: Occurrence in the Absence of High-Risk HLA Alleles DR3, DR4

In a prospective screening program for type I diabetes mellitus, we identified a unique family in which several members (mother and three siblings) expressed an unusual set of HLA-DR alleles (DR2+, DR3/4−) and were in different phases of immunologically mediated islet beta cell dysfunction. Immunologic and/or clinical manifestations of type I diabetes were absent in all siblings not sharing both HLA haplotypes in common with the proband. This article illustrates: the clinical utility of prospective family screening for predictive markers, such as islet cell antibodies, progressive autoimmune beta cell destruction can occur in the absence of the “high-risk” alleles HLA-DR3 and DR4, and HLA identity with the proband, rather than specific HLA alleles, i.e., presence of DR3, DR4 and absence of DR2, is an essential factor.

A restriction fragment of the C2 gene is a unique marker for C2 deficiency and the uncommon C2 allele C2*B (a marker for type 1 diabetes).

There are three common C2 protein alleles in caucasians, C2*C, C2*B, and C2*Q0, with allele frequencies of 0.96, 0.03, and 0.01, as well as Sst I RFLP variants of 2.75, 2.7, 2.65, 2.55, and 2.4 kb, with frequencies of 0.017, 0.533, 0.358, 0.017, and 0.075. Thus, C2*C is informatively split by the RFLP. Of 94 nonrandomly ascertained caucasian complotypes, 77 contained C2*C, four contained C2*Q0, and 13 had C2*B. None of the C2*C-containing complotypes carried the 2.75 kb Sst I fragment and all of the complotypes with C2*B or C2*Q0 carried it. All of the C2*Q0 alleles were associated with C4A*4, C4B*2 in the complotype S042 as previously reported. C2*B was usually (9/13) in the complotype SB42, occasionally (1/13 each) in SB45, SB41, SB(4,3)0, and SB31. Thus, the association of the C2 2.75-kb fragment was with C2*B and C2*Q0, not with C4A*4, C4B*2, or even C4A*4 alone. The complotype SC42 was associated with the 2.65-kb Sst I fragment in four of five instances and in a single example with the 2.7-kb fragment. C2*B and C2*Q0 possibly had a common evolutionary ancestor complotype which carried the 2.75-kb Sst I fragment, and BF*S, C4A*4, and C4B*2. C2*B (particularly as the haplotype HLA-Bw62, SB42, DR4) is associated with type 1 diabetes but C2*Q0 is protective.

ISPAD Clinical Practice Consensus Guidelines 2014. Sick day management in children and adolescents with diabetes.

Stuart Brinka, Dipesalema Joelc, Lori Laffeld, Warren Wei Rhen Leee, Birthe Olsenf, Helen Phelang and Ragnar Hanasb aNew England Diabetes and Endocrinology Center (NEDEC), Waltham, MA, USA; bDepartment of Pediatrics, NU Hospital Group Uddevalla, and The Sahlgrenska Academy, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden; cBotswana-Baylor Children’s Clinical Centre of Excellence, Princess Marina Hospital, Gaborone, Botswana; dJoslin Diabetes Center, Harvard Medical School, Boston, USA; eGrowth and Diabetes Centre, Singapore, Singapore; fDepartment of Pediatrics, Glostrup University Hospital, Copenhagen, Denmark and gJohn Hunter Children’s Hospital, Newcastle, New South Wales, Australia

Promoting Excellence in the Care of Pediatric Endocrine Diseases in the Developing World

On behalf of the Global Pediatric Endocrinology and Diabetes group, the authors provide a perspective on the rights of a child as enshrined in the United Nations Convention on the Rights of the Child (1989) concerning the care of pediatric endocrine disorders and diabetes mellitus, throughout the world, with particular reference to care in resource-constrained settings. In this article, we define the spectrum of health care needs of the child with an endocrine disorder and how they may be addressed, in terms of education, research, and development of sustainable programs for improved health outcomes. We emphasize the responsibilities of medical communities, the pharmaceutical industry, and relevant governments in promoting and supporting such concepts.

Diabetes in Children and Adolescents: Basic Training for Healthcare Professionals in Developing Countries∗∗Based on the Changing Diabetes in Children (CDiC) Sub-Saharan African collaborative initiative of NovoNordisk, Roche Diagnostics and ISPAD

Abstract Type 1 diabetes mellitus is the most common of all the pediatric and adolescent endocrine disorders despite its overall relative rarity in the developing world where infectious diseases and malnutrition are rampant. Diabetes is often not even considered so death at diagnosis occurs in more than 90% of youngsters all too often. Diabetes symptoms can be subtle, masquerade or co-exist with HIV/AIDS and many other overwhelming infections such as (cerebral) malaria, gastroenteritis, parasitic infestation and sepsis. When health care professionals and even parents are aware of symptoms such as dehydration with concomitant enuresis or excess urination, or even simpler questions such as ants at the site of urination, then training to question the possibility of diabetes allows appropriate confirmation, insulin and fluid management and recognition of diabetic ketoacidosis. Once diagnosed, costs of insulin as well as blood glucose testing can be overwhelming but new initiatives by ISPAD working with pharmaceutical and medical industry initiatives as well as health ministries and private donations can raise awareness, offer education for health care workers, general physicians and pediatricians and drastically cut DKA rates. Earlier diagnosis means less morbidity and mortality and lower health care costs. Ongoing treatment strategies, group education and support for health profesionals as well as patients and their families all work together successfully to improve diabetes diagnosis and ongoing care incrementally as outlined in this chapter.