4 Autoimmunity and the endocrine system

Graves’ disease

Hashimoto’s thyroiditis

Subacute thyroiditis syndromes

Primary hypothyroidism and sporadic goitre

Thyroid disease and other symptoms

Classification of diabetes mellitus

Type I diabetes (insulin-dependent)

Immunological complications of insulin therapy

Crow–Fukase syndrome (POEMS syndrome; Takatsuki syndrome)

Classification of adrenal insufficiency

Addison’s disease

Classification of autoimmune polyglandular syndromes (APS/APGS)

Type I APS (autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED))

Type II APS (Schmidt’s syndrome) and type III APS

IPEX syndrome

Cushing’s syndrome

Pernicious anaemia

Premature ovarian failure, gonadal autoimmunity, and immunological infertility

Pituitary autoimmunity

Parathyroid autoimmunity

Vitiligo and alopecia

Graves’ disease

Autoimmune thyroiditis

Hashimoto’s thyroiditis

Post-partum thyroiditis

Atrophic thyroiditis

Often accompanied by exophthalmos and occasionally by thyroid acropachy.

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).

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.

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.

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.

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.

DR3 and DR4 are also associated.

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 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.

Patients are initially hyperthyroid but may become transiently hypothyroid in recovery before the euthyroid state is restored.

Post-partum thyroiditis usually occurs within 3 months of delivery and is usually painless.

There may be a lymphocytic infiltrate of the gland with marked fibrosis.

Some cases may have antibodies that block the TSH-R, preventing normal function.

Therefore detection of thyroid antibodies in a patient with joint pain may be significant and should not be ignored.

Unfortunately, the urticaria does not always settle when the thyroid abnormality is treated.

The association appears to be with thyroid peroxidase antibodies.

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.

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.

Cause hypothyroidism.

Interfere with assays for free thyroxine (FT4).

There is considerable clinical overlap, although type II does not have an immunological basis.

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.

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.

Insulinoma-associated protein 2 autoantibodies (IA2).

Zinc transporter (ZnT8) autoantibodies.

Insulin autoantibodies (IAA).

Islet cell autoantibodies (ICA).

Autoantibodies have also been described to a number of other putative target antigens although the relevance of these is yet to be determined.

Presence of autoantibodies is helpful in distinguishing type I and type II diabetes.

Screening of first-degree relatives for GAD and insulin antibodies may be valuable in identifying those at risk of developing diabetes.

The optimal screening profile for autoimmunity in type I diabetes has not been defined. It is likely that ICA will be replaced by an automated screen of GAD, IA-2, insulin antibodies, and possibly ZnT8 (although no commercial assays are yet available for this autoantigen).

The more autoantibodies that are present, the higher the risk of developing diabetes.

For patients though to have type II diabetes, the presence of autoantibodies is predictive of the need for insulin therapy.

The aim is to prevent damage to the islets, as presentation with overt diabetes clearly represents the endstage of the disease when insufficient islet tissue remains.

Studies of immunotherapy are aided by the existence of a mouse model (NOD mouse).

Aggressive therapy with corticosteroids, azathioprine, ciclosporin, tacrolimus (FK506), and anti-thymocyte globulin (ATG) has been tried with some success in newly presenting patients and has staved off the requirement for insulin for some time.

Many monoclonal antibodies and polyclonal antibodies that are directed against the T cell, including Campath^®-1, anti-CD4, anti-CD8, anti-CD45, are immunosuppressive and have been shown to prevent the onset of diabetes in pre-diabetic NOD mice.

Anti-CD3 mAbs are able to reverse diabetes in new-onset diabetic NOD.

Initial clinical trials in humans are promising with moderate loss of β-cell function during and after therapy.

Tolerance induction using parenterally administered GAD and heat shock protein p277 peptide has been successfully used in mice. The oral route has also been used.

Clinical trials using Hsp p277, GAD, and insulin are under way in newly diagnosed patients.

Cytokine-based immunotherapy has been tried.

Early insulin treatment may also assist by β-cell rest, and perhaps by decreasing MHC class II expression, although the role of this in diabetes is controversial.

Other potential therapies include MHC class II blockade with peptides.

Pancreatic islet cell transplantation is now being undertaken.

In children, there is strong association with coeliac disease: all children with type Ia diabetes need regular endomysial/tTG antibodies checking (recommended annually).

The manufacturing process for human insulin is capable of altering the tertiary structure of the molecule in a way that can render it immunogenic.

Other agents used to alter the pharmacokinetics of the drug, such as zinc and protamine, may also contribute.

Reactions may include local or generalized urticaria and, very rarely, severe systemic reactions.

Both immediate and late reactions may occur.

Insulin oedema is non-immunological.

Oral antihistamines and the inclusion of 1–5mg hydrocortisone in the syringe with the insulin may be helpful.

Desensitization may be possible, but should only be attempted where severe reactions that compromise diabetic control are occurring.

Development of antibodies to protamine in diabetics may lead to major systemic reactions if intravenous protamine is used to reverse anticoagulation with heparin (e.g. after cardiac bypass surgery).

IgE antibodies have been documented.

Insulin resistance due to anti-insulin antibodies has also been reported in ataxia telangiectasia.

This is seen in Japan (possible genetic basis) and in association with myeloma (paraprotein with specificity for insulin).

Clinical features include the following.

Plasma cell dyscrasia (IgG or IgA)—invariably λ light chain:

May be due to elevated IL-6 and IL-1 levels.

Elevated VEGF.

Check serum immunoglobulins, electrophoresis, and immunofixation.

Treatment is with steroids and alkylating agents (cyclophosphamide).

Bone marrow transplantation has been used successfully.

Anti-VEGF MAb (bevacizumab) may be beneficial in some cases but can cause severe capillary leak syndrome.

Tuberculosis (most common worldwide)

Malignancy

Sarcoidosis

Haemochromatosis

Haemorrhage (post-partum)

Thrombosis (anti-phospholipid syndrome)

Infections (fungi, viruses)

Genetic causes include X-linked adrenoleucodystrophy, congenital adrenal hypoplasia, familial glucocorticoid deficiency, triple A syndrome, and Kearns–Sayre syndrome.

Findings include pigmentation, postural hypotension, hyponatraemia, and an absent response to ACTH stimulation test (Synacthen^® test).

There is a strong association with autoimmune ovarian disease and therefore females with Addison’s should also be checked for the presence of ovarian antibodies and other features of the autoimmune polyglandular syndrome (APS)); see sections on types I, II, and III APS, pp.180–182).

The MICA-5.1 allele is an additional major independent determinant of Addison’s disease.

Polymorphisms in CTLA4 and the Class II transactivator (CIITA) have been associated with autoimmune Addison’s disease.

It has been suggested that Addison’s disease is a Th2 disease.

Autoantibodies are rarely found in normal individuals or in first-degree relatives. They may be found in small numbers of patients with other autoimmune endocrine diseases (1.7% type diabetics)

21 hydroxylase (21OH; CYP21A2) has been identified as the major autoantigen which is localized to the endoplasmic reticulum of zona glomerulosa cells.

17 α-hydroxylase (CYP17), expressed in adrenal gland and gonads, and P450scc (CYP11A1), expressed in adrenals, gonads, and placenta, can also be the target of autoantibodies in autoimmune Addison’s disease.

Autoantibodies are normally detected by indirect immunofluorescence on adrenal sections. This detects mainly antibodies to CYP21A and CYP17.

First sign is often chronic Candida infection.

This is generally followed by autoimmune hypoparathyroidism and Addison’s disease.

At least two of these three features should be present for diagnosis.

Other autoimmune disease may be present:

It forms part of the spectrum of chronic mucocutaneous candidiasis (see Chapter 1).

There is no strong HLA linkage, although several reports have suggested a link to HLA-A28.

APS type 1 is the result of mutations of the recessive autosomal autoimmune regulator element (AIRE) gene localized on chromosome 21q22.3 (autosomal recessive).

Equal male and female incidence.

Autoantibodies to 21OH, 17OH, and/or P450scc are found.

Antibodies to tryptophan hydroxylase (an endogenous intestinal antigen) have been described in patients with gastrointestinal complications.

Autoantibodies to interferon (particularly interferon-omega) have been described.

Other disease-specific autoantibodies will be found.

AIRE gene.

Pernicious anaemia, chronic active hepatitis, vitiligo, and hypogonadism may also occur.

Peak age of onset is 20–30 years of age.

Females are more commonly affected than males (2:1).

Abnormal cellular immune function may occur.

Autosomal dominant and recessive patterns of inheritance have been identified.

There is an association with HLA-B8, DR3, and certain subtypes including DQA1*0501, DRB1*0301, and DQB1*0201.

This syndrome is also associated with polymorphism of the MHC class I chain-related A (MICA) gene.

Non-endocrine autoimmune disease may also occur, for example, myasthenia gravis.

Vitiligo and alopecia may also be present.

There is a very strong female predominance and an association with HLA-DR3.

Presentation is in infancy with enteropathy, IDDM, and thyroiditis.

It is an X-linked condition.

The gene defect (FOXP3) has been localized to Xp11.23–13.3.

BMT/SCT has been used as a treatment.

Patients often have prematurely grey hair and blue eyes.

Increased risk of both gastric carcinoma and carcinoid tumours.

Females are more commonly affected than males.

More common in people with blood group A.

Increased incidence in family members.

Strong association with other endocrine autoimmune disease such as autoimmune thyroiditis, IDDM, and adrenalitis.

Vitamin B₁₂ deficiency is a consequence of the loss of intrinsic factor producing gastric parietal cells in the corpus of the stomach afflicted by autoimmune gastritis.

Pathological lesion of autoimmune gastritis, also known as type A chronic atrophic gastritis, is restricted to the parietal-cell-containing corpus of the stomach, sparing the gastric antrum.

Gastric lesion is characterized by chronic inflammatory (mainly lymphocytic) infiltrate in the submucosa.

Advanced lesions are characterized by intestinal metaplasia with replacement of resident parietal and zymogenic cells of gastric glands by mucus-secreting cells.

Intrinsic factor antibody (IgA isotype) secreted on to the gastric lumen by local lymphoid cells is likely to contribute to the deficiency of intrinsic factor by complexing with intrinsic factor and preventing the absorption of the intrinsic factor–vitamin B₁₂ in the terminal ileum.

Progression to overt pernicious anaemia may span 20–30 years.

Intrinsic factor antibodies:

Patients who have vitamin B₁₂ deficiency should be given replacement intramuscular vitamin B₁₂ (given initially in high doses with supplemental potassium, having checked that other haematinics, especially iron, are adequate and then 3 monthly).

Erroneous treatment of patients with folic acid may not only mask the anaemia caused by vitamin B₁₂ deficiency but can permit the development of irreversible neurological damage.

Asymptomatic GPC antibody positive patients with normal MCV and B₁₂ should be monitored annually for development of B₁₂ deficiency, especially if other family members have PA.

GPC antibody positive patients should be screened for autoimmune thyroid disease.

20% of these are associated with Addison’s disease, but the remainder are not associated with APS.

Steroid cell antibodies are directed at 17α-hydroxylase and P450 side-chain-cleavage enzyme.

Another target enzyme appears to be 3β-hydroxysteroid dehydrogenase, which may be a more sensitive and specific marker of premature ovarian failure.

Antibodies have been described against the follicle-stimulating hormone (FSH) receptor and other unidentified surface receptors in premature ovarian failure, although this still appears to be controversial.

Screening of patients with premature ovarian failure should include a search for ovarian-, adrenal-, and steroid-cell antibodies by indirect immunofluorescence.

React with steroid-producing cells of the adrenal cortex, syncytiotrophoblasts, Leydig cells of the testis, and the theca interna/granulosa cell layer of the ovary.

Associated with type I APS.

The target antigens are 17α-hydroxylase (CYP17) and P450 side-chain-cleavage enzyme (CYP11A1).

Steroid-cell antibodies are found in 15% of Addison’s patients without hypogonadism, but in >80% with hypogonadism.

They rarely disappear and infertility is usually lifelong.

ZP3, the primary sperm receptor, has been identified as a target antigen in an experimental mouse system.

Antibodies against spermatozoa, causing agglutination or immobilization, have also been described.

It is not now thought that these antibodies play a major role in the genesis of the infertility, as they may also be detected in 12% of fertile women.

Target antigens are unknown at present, but a possible target is the prolactin-secreting cell.

Antibodies may also be detected against vasopressin-producing cells, associated with autoimmune diabetes insipidus.

A lymphocytic hypophysitis associated with pituitary failure has been found in young women during or after pregnancy. This may be associated with pituitary-reactive autoantibodies.

Care needs to be taken to exclude a rare presentation of Wegener’s granulomatosis.

Pituitary antibodies may also be found in some patients with Sheehan’s syndrome (pituitary infarction).

Treatment with immunosuppressive drugs (corticosteroids, azathioprine) has been used.

They recognize the external domain of the calcium-sensing receptor and are associated with CMC and APS.

Antibodies to mitochondria of parathyroid chief cells have been described.

Blocking antibodies to the PTH receptor have been described in secondary hyperparathyroidism of renal failure.

Detection is by immunofluorescence on parathyroid sections, but normal mitochondrial and antinuclear antibodies must be excluded first using a standard multiblock slide, as these will interfere with the detection of parathyroid antibodies.

It can also occur in association with inflammatory diseases.

Multiple susceptibility gene loci have been identified, including PTPN22 (generalized vitiligo), IL-2RA, and MHC Class I and Class II (DRB1, DQA1). Mutations (SNPs) have been identified in the NALP1 gene.

High levels of IL-1β expression are found.

Target antigen of the immune response is tyrosinase and antibodies are present in most patients.

This enzyme is an important target antigen in melanoma, and patients with vitiligo and melanoma who have detectable antibodies do better than those without.

Anti-tyrosinase antibodies are only found in patients with type II APS, but not type I APS or sporadic vitiligo.

Specific treatment is rarely successful: topical tacrolimus and UVA or UVB therapy may be tried.

There is no conclusive evidence for autoantibodies to the hair follicles, although this would not preclude a T-cell-mediated disease process.