Endocrine Abstracts (2008) 16 PL6

Graves' ophthalmopathy: problems solved and new questions to be answered

Wilmar M Wiersinga


Academic Medical Center, Amsterdam, The Netherlands.


Graves’ ophthalmopathy (GO) remains the most enigmatic presentation of thyroid autoimmunity. Although many issues regarding its pathogenesis and management have been solved, they are still outnumbered by unresolved open questions.

Pathogenesis: Orbital fibroblasts (OF) have been recognized as the primary target cells of the autoimmune attack. Cytokine-induced excessive secretion of glycosaminoglycans and differentiation of a subset of OF into adipocytes cause swelling of extraocular muscles and orbital fat, explaining in a mechanistic sense symptoms and signs of GO. The nature of the autoantigen on OF remains elusive, although the TSH receptor is favoured over others (like the IGF-1 receptor). Attempts to develop a suitable experimental animal model are still unsuccessful.

Clinical presentation: Graves’ hyperthyroidism (GH) and GO apparently belong to the same disease entity, as the majority of GH patients have subclinical GO and euthyroid GO patients have TSH receptor autoantibodies. Why not all GH patients develop overt GO remains (apart from smoking) poorly understood; also why not all euthyroid GO patients develop overt GH. Whereas unilateral GO frequently evolves into bilateral GO many cases remain strictly unilateral for unknown reasons. Most patients have increased muscle and fat volumes, but some have only increased muscle or fat volume, probably indicating various phenotypes with different immunopathogenesis.

Management: It matters for the eyes whether the patient is euthyroid and how euthyroidism is restored, although controversy continues on the benefit of total thyroid ablation. There is broad agreement that immunosuppression is indicated only in active GO, and that iv pulses of methylprednisolone are most effective. Anticytokine treatment (rituximab) is promising, but in its early stages. Combination treatment might be more efficaceous than monotherapy.

Prevention: Discontinuation of smoking constitutes primary, secondary and tertiary prevention. Determinants of progression from mild to more severe GO are incompletely understood, and hamper effective intervention (with selenium?) to halt progression.

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