“Birds of a Feather Flock Together”: Type 1A Diabetes and Other Autoimmune Disease States

W.E.W. is a 54-year-old white man who has type 1A diabetes, the most common form of type 1 diabetes. Type 1A diabetes is a cellular-mediated autoimmune disease characterized by the production of autoantibodies causing β-cell destruction and subsequent insulin deficiency.¹ 

At age 12 years, he was diagnosed with vitiligo. This autoimmune dermatological process involved mainly his neck, arms, and hands. After repeated medical consultations, he and his family received reassurance, but no treatment was recommended.

At age 14 years, W.E.W. was diagnosed with type 1 diabetes after the onset of polyuria, polydipsia, and weight loss. Because an older brother had been previously diagnosed at age 12 years with type 1 diabetes, his mother diagnosed his diabetes via home urine testing in 1964. Type 1 diabetes was subsequently confirmed via venous blood testing, W.E.W. was hospitalized, and insulin therapy was initiated.

In 1984, W.E.W. was diagnosed with Hashimoto's thyroiditis after experiencing fatigue, poor exercise tolerance, and weight gain. Thyroid peroxidase antibodies were positive, and he was begun on levothyroxine replacement therapy. His presenting symptoms resolved with this treatment. At age 34 years, W.E.W. now had three coexisting autoimmune diseases.

Pertinent family history includes:

• mother with Hashimoto's thyroiditis

• brother with type 1 diabetes

• paternal grandfather with Graves' disease

• suspicion of type 1 diabetes in a paternal great uncle. (This relative died without a definitive diagnosis at age 18 years in 1917, after a 2-month history of weight loss and frequent urination.)

1. How common are other autoimmune diseases in patients with type 1A diabetes?

2. In which patients should health care providers be more vigilant in testing for these other disease states?

3. What symptoms offer clues to other autoimmune disease entities?

This case demonstrates the importance of both the patient's medical history and family history. Many autoimmune diseases have an insidious onset and rarely present as an acute medical problem. Primary care providers often are in the unique position to make the proper diagnoses in patients such as W.E.W. However, because of time constraints, providers may fail to collect all of the patient's medical history and family history or ignore this factual history after obtaining it.

Polyglandular autoimmune (PGA) syndromes are constellations of multiple endocrine gland insufficiencies. Three types are now recognized.^2,3 Type I PGA is rare and presents in childhood. It is associated with candidiasis, hypoparathyroidism, and adrenal failure and is a rare disorder,having sporadic autosomal recessive inheritance. Type III PGA is the co-occurrence of autoimmune thyroid disease with two other autoimmune disorders, including type 1A diabetes, pernicious anemia, or a nonendocrine,organ-specific, autoimmune disorder such as alopecia or vitiligo. Because it does not involve the adrenal cortex, Addison's disease is absent. Type II PGA is the most common and is defined as primary adrenal insufficiency (Addison's disease) with either autoimmune thyroid disease (Hashimoto's thyroiditis) or type 1A diabetes occurring in the same individual. Primary hypogonadism,Graves' disease, myasthenia gravis, pernicious anemia, Parkinson's disease,vitiligo, and celiac disease may also be observed in this syndrome. PGA II occurs primarily in adulthood, usually around the 3rd and 4th decades of life,and is associated with HLA-DR3 and/or HLA-DR4 haplotypes. Its pattern of inheritance is autosomal dominant with variable expressivity.^3,4 

The pathophysiology of PGA II is thought to include an initial genetic susceptibility of the individual, allowing exposure to an autoimmune trigger(environmental or intrinsic factor), which initiates immunological change in specific proteins. These proteins mimic the molecular structure of a self-antigen and start the active production of organ-specific autoantibodies as well as the occurrence of autoimmune activity in the respective organ. This process leads to progressive glandular destruction. Unfortunately, the individual is asymptomatic during this process. Not until extensive organ damage has occurred does overt clinical disease ensue, as autoantibodies react to target tissue-specific antigens.^2,3 

As mentioned above, type 1A diabetes is an autoimmune disease characterized by β-cell destruction and subsequent insulin deficiency. Approximately 85-90% of people with type 1 diabetes test positive for autoantibodies and are deemed to have type 1A. The remaining individuals test negative for autoantibodies and are classified as having idiopathic type 1 diabetes,sometimes called type 1B diabetes.¹  Many type 1A diabetic patients have a personal or family history of other autoimmune diseases, such as Hashimoto's thyroiditis, Addison's disease, pernicious anemia, or vitiligo.⁵ 

The insidious autoimmune process of type 1A diabetes begins long before clinical symptoms occur and a diagnosis is confirmed(Figure 1). More than 90%destruction of the components of the β-cells within the islets of Langerhans occurs before the onset of clinical symptoms. Autoantibodies that have been associated with type 1A diabetes and serve as markers of this process are listed in Table 1.

Because autoimmune diseases tend to occur in both the same person and within the same family, family members with type 1A diabetes are at risk for the following autoimmune disease states: Addison's disease, celiac disease,Graves' disease, Hashimoto's thyroiditis, hypogonadism, myasthenia gravis,pernicious anemia, and vitiligo (Table 2).^6-8 

In patients with autoimmune polyendocrine syndromes with a single disease such as type 1A diabetes or Addison's disease, the prevalence of an additional autoimmune disorder is 30-50 times that in the general population.⁹ Screening should focus on the more common autoimmune disease states(Table 3). Because thyroid disease is the most common, some experts recommend that all patients with type 1A diabetes and their families be screened for autoimmune thyroid disease on a yearly basis. This is definitely indicated if the index case with type 1A diabetes has developed thyroid disease.^10-14 

As noted, these autoimmune markers may precede overt disease states by years and develop either 1) directly, be pathogenic, and cause damage; 2) serve as markers of disease; or 3) both. In T-cell mediated disorders, such as Hashimoto's thyroiditis, the autoantibodies serve as a marker of the disease state. These autoantibodies may be positive before thyroid-stimulating hormone (TSH) tests become abnormal.

The prevalence of these autoantibodies for other diseases varies. Twelve percent of patients with type 1A diabetes have transglutaminase autoantibodies. Thirty-three percent of patients with type 1A diabetes have thyroid antibodies.⁹ The prevalence depends on the age, race, and ethnic origin of the patient.

In addition, certain triggers are associated with the appearance of autoantibodies and specific autoimmune states. For example, one-third of women with type 1A diabetes will develop postpartum thyroiditis. These patients should be monitored closely for the development of autoimmune thyroid disease states. The administration of interferon-α for one medical condition can induce the formation of antibodies to 21-hyhdroxylase and islet cell and thyroid antibodies and lead to a new autoimmune state.⁹ 

Because the signs and symptoms can be subtle, one must be aware of these related disease states and their increased familial incidence(Table 2). Patients with type 1A diabetes and their family members have a 20% risk for developing autoimmune disease. Thyroid disease is the most common autoimmune disease encountered. Fifteen to twenty percent of patients with type 1A diabetes and their parents or siblings have evidence of thyroid autoimmune disease. This is in contrast to 4.5% in the general population.¹⁵ 

Some authorities recommend the periodic screening for thyroid disease and pernicious anemia (intrinsic factor autoantibodies). However, no controlled trials have been published, and these recommendations are level C scientific evidence (expert opinion). In patients with type 1A diabetes whose control becomes unstable without obvious cause, one should consider evaluation for an associated autoimmune process.

These related diseases often coexist in the same patient or family. An awareness of these associations can provide clues in the index patient with type 1 diabetes. When diabetes control deteriorates or unexplained symptoms occur, consider a concomitant autoimmune disease process. Often birds of a feather do flock together.

• A prominent family history of autoimmune disease raises the index of suspicion of an autoimmune process in the index patient.

• A previous autoimmune disease in a given patient increases the chances of another autoimmune disease in that same patient.

• When evaluating new presenting symptoms, one should always rule out an additional autoimmune disease process.

• Primary care providers should review patients' recorded medical history and family history when evaluating patients with new presenting symptoms or complaints. History previously collected and documented in the chart may be overlooked years later.