Autoimmunity and the Endocrine System
Classification of autoimmune thyroid disease
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Autoimmune hyperthyroidism
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Graves’ disease
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Autoimmune thyroiditis
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Hashimoto’s thyroiditis
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Post-partum thyroiditis
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Atrophic thyroiditis
Graves’ disease
Presentation
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Usually presents with thyrotoxicosis and a diffusely enlarged thyroid gland.
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Often accompanied by exophthalmos and occasionally by thyroid acropachy.
Immunogenetics
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Strong female predominance—F:M = 7:1.
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Disease runs in families and it is associated with HLA-A1 B8 DR3, although less strongly than some other autoimmune diseases.
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In Asians the disease has been associated with HLA-Bw35 and Bw46.
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Strong association of exophthalmos with HLA-DR3.
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There is a weak association with polymorphisms of CTLA-4 and PTPN22 (a T-cell regulatory gene, lymphocyte-specific tryrosine phosphatase).
Immunopathology
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The disease has been associated with aberrant MHC class II expression on thyrocytes, which is thought to play a role in the induction of the autoimmune response.
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There is predominant CD4+ T-cell infiltration of the thyroid gland.
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Exophthalmos may be due to an autoantibody directed to unknown antigens expressed on retro-orbital connective tissue, probably fibroblasts or fat cells, leading to a localized inflammatory response, with plasma-cell infiltrate and consequent hypertrophy and hyperplasia.
Autoantibodies
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Patients with Graves’ disease have elevated levels of the following.
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Antibodies to thyroid peroxidase (present in 50-80%) and antibodies to thyroglobulin (20-40%).
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Antibodies that compete with the binding of thyroid-stimulating hormone (TSH) (TBII, 50-80%). These autoantibodies are directly involved in the pathogenic process.
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Presence of TSI and TBII correlate with risk of relapse and of neonatal hyperthyroidism if present in pregnancy.
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Exophthalmos may be due to a separate autoantibody directed against yet unknown antigens or due to antibodies to autoantigens that are common to both the thyroid gland and the orbits.
Immunotherapy
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Treatment of the thyrotoxicosis does not involve immunotherapy.
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Eye disease may require treatment with steroids, ciclosporin, or irradiation to control the inflammatory process. Rituximab is now being used. Surgical intervention may be required.
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125I ablation of the thyroid to control the thyrotoxicosis may be associated with a flare-up of the eye disease, and pretreatment with steroids may be helpful.
Hashimoto’s thyroiditis
Presentation
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Patients are usually hyperthyroid initially and then progress to hypothyroidism as fibrosis of the gland occurs.
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There is usually a goitre.
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It is the most common cause of hypothyroidism.
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Hashimoto’s thyroiditis also tends to occur in families with other thyroid disease or autoimmune disease, and has a predilection for older females.
Immunogenetìcs
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Association of DR5 with goitrous Hashimoto’s disease.
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DR3 and DR4 are also associated.
Immunopathology
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There is an acute inflammatory thyroiditis, accompanied by a lymphocytic infiltrate of the gland of unknown aetiology.
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Lymphocytic infiltrate comprises all types of cells and may result in germinal centre formation within the gland. These may play a key role in the production of autoantibodies and cytokines.
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Increased HLA class II antigen expression on infiltrating lymphocytes and thyrocytes in affected glands.
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An increased number of helper and cytotoxic T cells are found with decreased suppressor T-cell numbers.
Autoantibodies
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Anti-thyroid peroxidase antibodies will be present in 80-95% of patients, usually at extremely high titres (higher than in Graves’ disease).
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Autoantibodies to multiple other thyroid antigens, including thyroglobulin, can be detected.
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Up to 20% of patients may have antibodies (stimulatory or blocking) directed at the TSH receptor.
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Anti-TPO assays should be incorporated in main biochemistry analysers as part of thyroid profiles.
Immunotherapy
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No immunotherapeutic manoeuvres are used.
Subacute thyroiditis syndromes
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These include transient thyroiditis syndromes such as granulomatous thyroiditis (de Quervain’s syndrome) and post-partum thyroiditis.
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Patients are initially hyperthyroid but may become transiently hypothyroid in recovery before the euthyroid state is restored.
Immunopathology
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de Quervain’s thyroiditis may be caused by viral infections (mumps, measles, adenovirus, EBV, Coxsackievirus, and echovirus) which lead to an acute painful thyroiditis.
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No single agent has been unequivocally linked to the disease.
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Anti-thyroid antibodies against thyroglobulin and thyroid peroxidase are present (usually in low titres) in 10-50% of patients with de Quervain’s thyroiditis.
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Post-partum thyroiditis usually occurs within 3 months of delivery and is usually painless.
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It appears to be common (1-11% of pregnant women).
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It is associated with HLA-DR5.
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Complement-fixing anti-TPO antibodies are present in the majority of patients and the titre correlates with disease severity.
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The presence of such antibodies during or after pregnancy in otherwise well women has a predictive value of subsequent thyroid dysfunction.
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Immunotherapy
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No immunotherapeutic manoeuvres are used.
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Primary hypothyroidism and sporadic goitre
Primary hypothyroidism
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This may well be caused by previous occult thyroiditis, leading eventually to presentation with overt hypothyroidism years later.
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There may be a lymphocytic infiltrate of the gland with marked fibrosis.
Autoantibodies
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80% of patients will have antibodies to thyroid peroxidase, and a lower proportion will have antibodies to thyroglobulin.
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Some cases may have antibodies that block the TSH-R, preventing normal function.
Immunotherapy
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No immunological treatments are used.
Sporadic goitre
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This has been associated with stimulating autoantibodies to the IGF1-R, in the absence of other antibodies, leading to glandular growth.
Thyroid disease and other symptoms
Arthropathy
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Both hypo- and hyperthyroidism can be a cause of significant joint pain.
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Therefore detection of thyroid antibodies in a patient with joint pain may be significant and should not be ignored.
Urticaria
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Occult hypo- or hyperthyroidism has also been associated with the development of urticaria, although the reasons are unclear.
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Unfortunately, the urticaria does not always settle when the thyroid abnormality is treated.
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The association appears to be with thyroid peroxidase antibodies.
Anti-thyroid antibodies in euthryoid patients
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The wider use of autoantibody testing has led to the detection of antithyroid antibodies in fit euthyroid patients.
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The Wickham Community Survey has demonstrated that a significant number of these patients go on to develop overt thyroid disease subsequently.
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Therefore the detection of such antibodies in asymptomatic patients should lead to a high index of suspicion for thyroid disease and a low threshold for requesting thyroid function tests when the patient re-presents with symptoms.
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It may be worth screening the thyroid function annually.
Association with other autoimmune disease
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Autoimmune thyroid disease is strongly associated with pernicious anaemia and vice versa.
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Therefore gastric parietal cell antibodies may be detected in patients with thyroid disease.
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Such patients should be monitored for the subsequent development of B12 deficiency.
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Thyroid disease may be accompanied by Addison’s disease, in addition to pernicious anaemia (Schmidt’s syndrome/type II autoimmune polyglandular syndrome (APS)).
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Generally, patients and family members of a patient with Graves’ disease are more likely to have other autoimmune disease (e.g. type I diabetes, lupus erythematosus, chronic active hepatitis, coeliac disease, dermatitis herpetiformis, Sjögren’s syndrome) than the general population.
Autoantibodies to thyroxine
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May be seen in para-proteinaemic states (Waldenström’s macroglobulinaemia).
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Cause hypothyroidism.
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Interfere with assays for free thyroxine (FT4).
Amiodarone and thyroid function
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Amiodarone-induced thyroid disease is more common in women and in individuals who are positive for antibodies to TPO.
Classification of diabetes mellitus
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There are four types of diabetes.
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There is considerable clinical overlap, although type II does not have an immunological basis.
Type I diabetes (insulin-dependent)
Presentation
Patients may present with symptoms related to an elevated blood sugar, or a raised fasting blood sugar level may be an isolated finding.
Immunogenetics
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Males and females are almost equally affected, unlike other autoimmune diseases.
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Twin concordance for IDDM is only 30-70%.
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Major susceptibility gene is in HLA region, accounting for 40-60% of risk.
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Genotyping has shown that DQA1*0301, DQB1*0302, DQA1*0501, and DQB1*0201 are strongly associated with type Ia.
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DQA1*0102 and DQB1*0602 protect against the development of diabetes.
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CTLA-4 and PTPN22, the interleukin-2 receptor (CD25), interferon-induced helicase, and a number of other genes (including some of unidentified function) are also associated with increased susceptibility to type I diabetes.
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Other specific loci have been associated with the shared risk of developing coeliac disease with diabetes, although the effects are small. The greatest risk appears to be with CCR5.
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At least 17 other genetic loci contribute to susceptibility including polymorphisms in the promoter of the insulin gene.
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Tenfold increased risk of developing diabetes in family members.
Immunopathology
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A disease characterized by immunological destruction of the islets of Langerhans in the pancreas, with subsequent insulinopenia.
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There is a seasonal fluctuation in the presentation.
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It has been postulated that there is an initial viral infection, leading to subsequent autoimmune damage in a genetically susceptible host.
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Viruses that have been proposed include Coxsackievirus, reovirus, mumps, influenza, rubella, and cytomegalovirus.
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In the early stages of the disease there is a lymphocytic infiltrate, predominantly of CD8+ T cells but with small numbers of other types too.
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Islet β-cells are particularly susceptible to damage by TNF-α.
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As diabetes has been described in a patient with X-linked agammaglobulinaemia, T cells are more important than autoantibodies in causing diabetes.
Autoantibodies
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GAD autoantibodies.
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β-cell-specific antibodies have been detected that recognize glutamic acid decarboxylase (GAD).
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This antigen occurs in both nerve and pancreas in two isoforms (65kDa and 67kDa) encoded by separate genes.
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Autoantibodies against this antigen have also been described in the stiff-person syndrome (see Chapter 5).
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Primary target in type Ia diabetes appears to be the 65kDa protein, and antibodies to this are found in up to 80% of newly presenting IDDM.
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Antibodies to GAD-67 are also found.
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There is sequence homology between GAD and a Coxsackievirus antigen.
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GAD autoantibodies may be found in first-degree relatives.
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Insulinoma-associated protein 2 autoantibodies (IA2).
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IA2 antibodies are found in 58% of type I diabetics at first diagnosis.
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They appear later than GAD and insulin antibodies but strongly predict progression to diabetes.
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Zinc transporter (ZnT8) autoantibodies.
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60-80% of newly diagnosed type I diabetics have antibodies to ZnT8.
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They may be the only autoantibody detectable in patients negative for GAD, IA-2, and insulin antibodies.
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They appear early in the process and are lost quickly after the onset of diabetes.
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Polymorphisms of the gene for ZnT8 are associated with Type II diabetes.
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Insulin autoantibodies (IAA).
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Insulin antibodies appear first in children developing diabetes.
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As insulin antibodies develop in patients treated with insulin, they cannot be used as diagnostic markers once insulin has been commenced.
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Islet cell autoantibodies (ICA).
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ICA also recognize cell types in the islets other than the insulin-producing β-cells.
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ICA are not involved in the autoimmune destruction, but are merely a marker of the disease process (secondary autoantibodies).
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With the identification of more specific markers, the role of ICA in diagnosis is uncertain.
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Antibodies are present in 65-85% of newly presenting IDDM, but disappear within 1-2 years.
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