Although the co-existence of dual thyroid TSAb and TBAb has been well documented , its pattern in the presence of hepatitis C and its modulation by interferon treatment has rarely been reported previously . The present case highlights the population of thyroid autoantibodies whose evolution is significantly influenced in the presence of hepatitis C and interferon. It was highly likely that the initial diagnosis of hypothyroidism was the result of TSH blocking activity resulting in the biochemical expression of hypothyroidism. In the absence of further information at the time of diagnosis, it was hard to confirm this hypothesis. However, in favour of this diagnosis was the absent/negligible nuclear uptake in the thyroid scan, the presence of a normal-size thyroid on ultrasound and the absence of any thyroid auto-antibodies. Although excessive thyroxine can affect thyroid uptake scan appearance, in the presence of a normal (non-suppressed) TSH level, it is very likely that the uptake scan reflects the activity of TBAbs.
The development of GO is a fascinating feature that must closely involve the presence of TRAb. Although the pathogenesis of GO remains undetermined, TSAb is one of the major contributors in inducing the inflammatory process in the orbital fat and ocular muscles resulting in swelling and congestion of the orbit . In addition, recent case reports suggested an association between hepatitis C infection and GO [8, 9]. Hypothetically, prior to the development of GO, there must have existed an equilibrium between these two sub-classes of thyroid antibodies, albeit unbalanced in favour of TBAb, just sufficient to elicit the hypothyroidism but with enough stimulating activity to participate in the development of GO. In the presence of interferon as an immuno-modulator, the equilibrium then shifted in favour of TSAb and hence the progressive thyrotoxic biochemical profile with marked nuclear uptake. It was conceivable but unlikely that this shift was spontaneous and coincidental because his thyroid status was stable in the intervals following interferon therapy. This would have been further bolstered if his thyroid parameters were available in the period preceding hepatitis C treatment. These changes appeared permanent as the hypothyroidism moderated compared to before treatment. Despite the mildly elevated TSH level, no thyroxine was required 3 years after the completion of interferon therapy. This is underlined by the newly equilibrated antibody profile at the end of treatment, with both TS- and TB-Ab subclass activities being normal. These were not performed further in the convalescing period. Interestingly, the relatively higher TS-Ab activity did not further compound the ophthalmopathy.
The management of GO in this case was both challenging and difficult, involving plentiful of discussion with the patient and his spouse. As mentioned, the addition of interferon may aggravate the GO which in turn may be further exacerbated by the evolving TSAb, potentially precipitating an ophthalmic crisis and loss of vision . On the other hand, independent treatment with immunosuppressants such as glucocorticoid, calcineurin inhibiting agents or methotrexate can potentially lead to fulminant hepatic necrosis and failure. After much deliberation and risk estimation, the GO was monitored closely with visual acuities and color charts weekly, tapering to monthly as the condition remained progressively stable. Although the natural history of this condition is unknown in this setting and to be safe, orbital irradiation and decompressive surgery were also consulted and made readily available. Fortunately, his ophthalmic condition did not deteriorate.
The underlying pathogenesis of this swinging antibody profile is unknown. Although the prevalence of hypothyroidism in the setting of hepatitis C and interferon is not uncommon, this rare type of hypothyroidism often goes unsuspected unless there are other indicators such as ophthalmopathy. The antibodies switching to the TSH receptors must be modulated, evolving from blocking to predominantly stimulating. It is both a relief and fascination that GO failed to progress as TSAb has been suggested to initiate and stimulate orbital adipogenesis . Recent studies were able to further investigate the inhibitory and stimulatory nature of these antibodies. In fact monoclonal antibodies with both stimulating and block activities were recently developed. Plausibly the relevant B cells are selected to alter the variable regions of the immunoglobulins to specifically affect the critical areas for TSH receptors stimulation and blockade, particularly region M22 and 5C9 of the TSH autoantibodies [11, 12]. It must be noted however that the switching between hyper- and hypothyroid phases of Graves' disease can occur independent of hepatitis C infection and interferon therapy 
In HCV infection, there is also an increased secretion of IFN-γ and chemokine ligand 10 (CXCL10) generally as well as by thyrocytes . The high CXCL10 level is higher in patients who develop thyroid disease, especially hypothyroidism in the setting of hepatitis C. It is possible that the endo-, exo-genous interferon and CXCL 10 combine to modify the immune response. The elevated CXCL10 level has also been implicated in GO recently . These factors may add to the aforementioned mechanisms to result in the complex immuno-chemical cascade representative of this case. This is purely speculative however and this observed immune phenomenon remains poorly understood. It adds to the spectrum of thyroid diseases in the presence of hepatitis C and in particular its modulation by interferon therapy .