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