Jack R. Wall

Susceptibility genes in Graves' ophthalmopathy: searching for a needle in a haystack?

The variety of clinical presentations of eye changes in patients with Graves’ disease suggests that complex interactions between genetic, environmental, endogenous and local factors influence the development/severity of Graves’ ophthalmopathy (GO). At present, the role of genetic factors in the development of GO remains unknown. Based on small case‐control association studies with candidate genes, several susceptibility loci in GO have been proposed. These are human leucocyte antigen (HLA, 6p21·3), cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4, 2q33), tumour necrosis factor (TNF, 6p21·3), interferon‐γ (IFN‐γ, 12q14), intercellular adhesion molecule‐1 (ICAM‐1, 19p13), and thyroid stimulating hormone receptor gene (TSH‐R, 14q31). Unfortunately, these results were either not confirmed or require replication in larger studies. There are many reasons for the lack of reproducibility of association studies in GO, including poor characterization of the studied groups and small sample sizes, which may result in both false positive and negative results. Thus, the genetic background of GO remains to be elucidated in future research. However, the possibility that GO may be a genetically heterogeneous disorder, or that the development of GO may be predominantly influenced by environmental factors such as cigarette smoking, can not be disregarded.

The ocular muscle cell is a target of the immune system in endocrine ophthalmopathy.

The exact pathogenic mechanism of thyroid-associated ophthalmopathy (TAO) remains unclear, and extensive studies on this disorder have resulted in often conflicting data. Well-known technical difficulties including the limited access to orbital tissues from patients with active and early disease, lack of an animal model and poor reproducibility of some of the immunological techniques used are in part responsible for this confusing situation. Despite this there is considerable evidence for eye muscle (EM) tissue involvement in the autoimmune reactions of TAO. Although the primary EM antigen(s) recognized by immunocompetent cells and autoantibodies has not been definitely identified, some good candidates, among them a membrane antigen of 64 kD which is also expressed in the thyroid, have been partially characterized. While it is unclear which component of the autoimmune reaction against EM-humoral or cell mediated-plays the more important role, autoantibodies seem to be responsible at least in part for the clinical features of the eye disorder. On the other hand, the orbital connective tissue (OCT) cells, especially the fibroblasts surrounding the EM fibers, seem to be extremely sensitive to stimulation by cytokines and other soluble proteins and immunoglobulins released in the course of an immune reaction in the muscle cells. Fibroblasts secrete large amounts of glycosaminoglycans and also participate in maintaining the autoimmune reaction. It seems likely that the EM is the main and primary target of the orbital autoimmune process whereas inflammation of the OCT is probably secondary.

Antibodies targeting the calcium binding skeletal muscle protein calsequestrin are specific markers of ophthalmopathy and sensitive indicators of ocular myopathy in patients with Graves disease

We have identified several eye muscle antigens and studied the significance of the corresponding serum autoantibodies in patients with Graves’ disease. Of these antigens, only calsequestrin is expressed more in eye muscle than other skeletal muscles, which could explain at least partly the specific involvement of eye muscle in patients with Graves’ disease. Earlier, we found a modest relationship between anti‐calsequestrin antibodies and ophthalmopathy, but in that study we used calsequestrin prepared from rabbit heart muscle and measured antibodies by immunoblotting. We have reinvestigated the prevalences of anti‐calsequestrin antibodies in larger groups of well‐characterized patients with thyroid autoimmunity with and without ophthalmopathy and control patients and healthy subjects, using standard enzyme‐linked immunosorbent assay incorporating highly purified rabbit skeletal muscle calsequestrin, which has a 97% homology with human calsequestrin, as antigen. Anti‐calsequestrin antibodies were detected in 78% of patients with active congestive ophthalmopathy, in 92% of those with active inflammation and eye muscle involvement, but in only 22% of patients with chronic, ‘burnt out’ disease. Tests were also positive in 5% of patients with Graves’ hyperthyroidism without evident ophthalmopathy (two patients) and one patient with ‘watery eyes’ but no other clear signs of congestive ophthalmopathy and IgA nephropathy and no known thyroid disease, but in no patient with Hashimoto’s thyroiditis, toxic nodular goitre, non‐toxic multi‐nodular goitre or diabetes, or age‐ and sex‐matched healthy subjects. In serial studies of all 11 patients with Graves’ hyperthyroidism who had active ophthalmopathy at the time of the first clinic visit, or developed eye signs during the first 6 months, and positive anti‐calsequestrin antibodies in at least one sample, anti‐calsequestrin antibodies correlated with the onset of ocular myopathy in six patients. Antibodies targeting calsequestrin appear to be specific markers for ophthalmopathy and sensitive indicators of the ocular myopathy subtype of ophthalmopathy in patients with thyroid autoimmunity. However, these results must be considered preliminary until a large prospective study of patients with newly diagnosed Graves’ hyperthyroidism, in which serum levels of calsequestrin antibodies are correlated with clinical changes and orbital eye muscle and connective tissue/fat volumes, has been carried out.

Pathogenesis of thyroid-associated ophthalmopathy: does autoimmunity against calsequestrin and collagen Xiii play a role?

Thyroid-associated ophthalmopathy (TAO), or thyroid eye disease, is a complex inflammatory disorder of the eye that, as its name implies, is associated with thyroid disease. TAO can be divided into three subtypes: ocular myopathy, congestive myopathy and mixed congestive and myopathic ophthalmopathy. Although the precise pathophysiology of TAO remains unclear it is likely to reflect an autoimmune reaction involving sensitized T-cells and autoantibodies directed against a thyroid and orbital tissue shared antigen. One well studied candidate in this immune reaction is the thyroid-stimulating hormone receptor (TSH-r), expressed in the orbital fibroblast and pre adipocyte. In our studies of TAO, we have investigated the nature and significance of antibodies targeting other eye muscle and orbital connective tissue (OCT) antigens. Our findings suggest that autoimmunity against the eye muscle antigen calsequestrin and the OCT antigen collagen XIII plays a role in the pathogenesis of TAO. We propose that ocular myopathy and chronic eyelid retraction are due to autoimmunity against skeletal muscle calsequestrin in the extraocular and eyelid muscles, respectively. This may be initiated in the thyroid where calsequestrin expression is upregulated, possibly due to a stimulatory effect of TSH-r antibodies. We also propose that congestive ophthalmopathy results from a reaction against the TSH-r or collagen XIII in orbital fibroblast cell membranes. Further insight into the role of eye muscle and OCT antigens in the pathogenesis of TAO may allow for the development of new therapies to treat the eye disorder and reduce patient morbidity.

Antibodies against Calsequestrin and Type XIII Collagen are Good Markers for Chronic Upper Eyelid Retraction

Purpose: Chronic upper eyelid retraction is a common manifestation of thyroid-associated ophthalmopathy (TAO) but can occur as a dominant feature of ophthalmopathy in patients with Graves’ hyperthyroidism and in association with Hashimotos thyroiditis in the absence of other eye signs except mild proptosis. Methods: We measured antibodies against calsequestrin, flavoprotein (Fp), G2s, and collagen XIII in an enzyme-linked immunosorbent assay (ELISA) in 15 patients with chronic upper eyelid retraction. Results: Calsequestrin antibodies were detected in 67% of patients with upper eyelid retraction, Fp antibodies in 47%, G2s antibodies in 20%, and collagen XIII antibodies were detected in 40% of these patients at the first visit. These prevalences were significantly greater than normal for calsequestrin and collagen XIII, but not for Fp and G2s antibodies. On follow-up, calsequestrin antibodies were detected in two more patients, for an overall prevalence of 80%. Levels of the four antibodies remained fairly constant over the study period and generally correlated with the presence and severity of upper eyelid signs. Conclusions: These findings support the notion that autoimmune attack against calsequestrin and collagen XIII in the levator palpebrae superioris (LPS) muscle may play a role in the pathogenesis of upper eyelid retraction and that lid retraction may be the dominant feature of ophthalmopathy in patients with Hashimotos thyroiditis and non-autoimmune thyroid disease. Because calsequestrin is an intracellular protein, the corresponding autoantibodies probably do not initiate LPS muscle inflammation but may contribute to its damage. The mix of antibodies against calsequestrin and collagen XIII may shed light on the diverse presentations found in thyroid-associated ophthalmopathy.

Relationship between thyroid dysfunction and chronic kidney disease in community-dwelling older adults

OBJECTIVES Renal function has been shown to be influenced by thyroid status in animal models and human studies. We aimed to assess the cross-sectional association between thyroid hormones and function with prevalence of chronic kidney diseases (CKD) in older adults. STUDY DESIGN 1571 Blue Mountains Eye Study participants aged ≥ 60 years were analyzed in 2002-4. Thyroid dysfunction was defined using serum thyrotropin (TSH) screen, followed by serum free T4 (FT4) assessment. Baseline biochemistry including serum creatinine was measured. Moderate CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2). RESULTS After adjusting for age, sex, receipt of pension payment, body mass index, smoking, hypertension and diabetes, persons with any thyroid dysfunction (hyperthyroidism or hypothyroidism) had 84% higher likelihood of having CKD, odds ratio, OR, 1.84 (95% confidence intervals, CI, 1.03-3.31). Participants in the highest versus lowest quartile (reference) of serum TSH and FT4 had a significantly greater odds of prevalent CKD, OR 1.82 (95% CI 1.22-2.71), and OR 1.64 (95% CI 1.10-2.45), respectively. Similarly, among participants not receiving treatment for their thyroid dysfunction (n=1329), those in the third and fourth quartiles of serum TSH had significantly greater odds of having prevalent CKD, OR 1.83 (95% CI 1.15-2.92) and OR 1.96 (95% CI 1.23-3.13), respectively, Ptrend=0.001. Significant associations were not observed between type of thyroid dysfunction (hyperthyroidism or hypothyroidism) and prevalent CKD. CONCLUSIONS Increasing serum TSH was associated with a greater likelihood of prevalent CKD among older adults, independent of the influence of age, diabetes and hypertension.

T-Cell–Mediated Immunity in Thyroid-Associated Ophthalmopathy

Thyroid-associated ophthalmopathy (TAO) is considered to be an autoimmune inflammatory disorder of the extraocular muscles and the orbital fat/connective tissue. Recent studies analyzing T cells infiltrating retrobulbar tissues generated important insights into the immunopathogenesis of TAO. The present review focuses on advances in our understanding of mechanisms responsible for the autoimmune inflammation in TAO, especially T cell migration to the inflammatory site, T cell activation by autoantigens and costimulatory signals and their cytokine profile. The elucidation of these processes might lead to the development of novel therapeutic strategies directed against autoreactive T cells.

Five-year incidence and progression of thyroid dysfunction in an older population

Background: Very few studies have assessed both the incidence and progression of thyroid dysfunction in a single older population‐based cohort. In this study, we aimed to assess the 5‐year incidence, progression and risk factors for development of thyroid dysfunction in an older Australian population.

Current concepts in Graves’ disease

Graves’ disease is the most common cause of hyperthyroidism in the developed world. It is caused by an immune defect in genetically susceptible individuals in whom the production of unique antibodies results in thyroid hormone excess and glandular hyperplasia. When unrecognized, Graves’ disease impacts negatively on quality of life and poses serious risks of psychosis, tachyarrhythmia and cardiac failure. Beyond the thyroid, Graves’ disease has diverse soft-tissue effects that reflect its systemic autoimmune nature. Thyroid eye disease is the most common of these manifestations and is important to recognise given its risk to vision and potential to deteriorate in response to radioactive iodine ablation. In this review we discuss the investigation and management of Graves’ disease, the recent controversy regarding the hepatotoxicity of propylthiouracil and the emergence of novel small-molecule thyroid-stimulating hormone (TSH) receptor ligands as potential targets in the treatment of Graves’ disease.

Type 2 diabetes does not predict incident thyroid dysfunction in the elderly

Thyroid dysfunction was assessed in an older population-based cohort with type 2 diabetes. Among type 2 diabetes subjects, 7.1% had incident thyroid dysfunction versus 3.8% in those without diabetes (odds ratio 1.97, 95% confidence interval 0.88-4.38). Screening of thyroid dysfunction in older diabetes subjects is not supported by these findings.