Case 24

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 18/02/2015

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CASE 24

MM, a 3-year-old white monozygotic twin boy was brought to the emergency department by his mother after suffering from a viral-like illness for nearly 3 weeks. Previously, she had taken MM to the family physician, but he had reassured her that the symptoms would resolve with acetaminophen (Tylenol). At the present time her son is not eating well; his urine output has been diminished for over 24 hours; he is quite listless with sunken eyes, and he is feverish.

This boy is obviously quite sick. All routine blood work is ordered, as is a chest radiograph and urinalysis. An intravenous line is obtained and fluid resuscitation is begun. The laboratory director calls approximately 1 hour later with urgent results. MM’s blood glucose concentration is elevated, and his potassium concentration is low. Urinalysis was positive for glucose. Intravenous administration of insulin and potassium chloride is immediately initiated. Hyperglycemia in a young white child is highly suggestive of type 1A diabetes mellitus (type 1 DM). What would you expect the family history to reveal? Which Class II human leukocyte (HLA/major histocompatibility complex [MHC]) genes confer susceptibility to type 1 DM? What autoantibodies would you measure?

QUESTIONS FOR GROUP DISCUSSION

1. This patient’s clinical history and presentation looks like the typical picture of type 1 immune-mediated diabetes (type 1 DM), an autoimmune disorder resulting from a breakdown in tolerance. What tissue does the immune system target? What is the role of these cells in the normal state?

2. Discuss the evidence that supports a genetic basis for this autoimmune disorder.

3. Discuss the putative environmental factors that have been investigated as triggers for type 1 DM.

4. What are the metabolic complications in type 1 DM? Explain the significance of a decrease in potassium levels and the presence of glucose in the urine. How does the presence of glucose in urine contribute to dehydration?

5. What autoantibodies are detected in the serum of patients in the early stage of the disease, long before clinical symptoms appear? How can this be used to benefit the patient?

6. What is the mainstay of treatment for type 1 DM? Why did patients (in the past) develop anti-insulin antibodies? Why is this not a problem today?

7. Explain why there has been a move toward more frequent injection of short-acting insulin in some individuals.

8. What is the significance of the fact that immunization with hsp60 peptide was associated with a shift from Th1 to Th2 cells specific for this peptide?

9. Explain why CD4+, CD25+ T cells have come under scrutiny in autoimmune disorders.

10. Explain the significance of identifying a patient with type 1A DM who has already been diagnosed with X-linked agammaglobulinemia (see Case 3).

RECOMMENDED APPROACH

Implications/Analysis of Family History

Although we have not been given any family history, disease susceptibility for type 1 DM depends on the degree of genetic similarity that an individual has with the proband. For example, MM’s monozygotic twin, whose genetic makeup is identical to MM, has a 50% risk of also developing type 1 DM. The remaining risk is thought to be due to environmental factors (see Implications/Analysis of Clinical History).

More than 20 different genes have been identified that contribute to type 1 DM disease susceptibility, but the highest predisposing risks are associated with the inheritance of particular groups of class II MHC antigens. Individuals at highest risk for developing type 1 DM are those whose haplotype includes HLA-DR3, DQ2 and HLA-DR4, DQ8. Risk is somewhat lower, but still substantial, for individuals who express HLA-DR3, DQ2 or HLA-DR4, DQ8 (i.e., not both). Close to half of the patients with type 1 DM express all four of these HLA genes. Interestingly, some patterns of HLA-DR/DQ linkage patterns are protective. Given MM’s age when the disease manifested, one would predict that MM (and his twin) would express the HLA genes that have the highest predisposing risk.

Individuals with type 1 DM and their relatives are at increased risk for a number of autoimmune disorders, including celiac disease, Addison’s disease, pernicious anemia, and autoimmune thyroid dysfunction. About 14% of children with type 1 DM (without celiac disease) have IgA anti-tissue transglutaminase (tTG) autoantibodies. These tTG autoantibodies are also present in about 7% of nondiabetic first-degree relatives (without celiac disease). We would expect, therefore, that a family history would reveal autoimmune disorders in immediate or related family members.

Implications/Analysis of Clinical History

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