severe aplastic anemia ( saa ) is a fatal disease characterized by pancytopenia and hypocellular bone marrow .
bone marrow transplantation is the treatment of choice for young patients who have a human leukocyte antigen ( hla ) matched sibling donor .
immunosuppressive treatment ( ist ) with antithymocyte globulin ( atg ) and cyclosporine is an effective therapy for patients who have no suitable donor .
atg exerts its action by depleting clonal suppressor t cells implicated in the pathogenesis of saa123 ) .
the depletion of suppressor t cells by atg could change the b - cell activation12 ) .
there have been rare reports on the association between atg treatment for saa and the development of autoimmune hyperthyroidism4567 ) . because horse atg ( hatg ) is no longer available for the treatment of saa in most countries , rabbit atg ( ratg )
moreover , as ratg has more potent and prolonged suppression of t cells than hatg8 ) , more frequent encounters of autoimmune hyperthyroidism can be anticipated .
we report the rare case of graves disease following ratg treatment for saa in a korean child .
a 12-year - old boy visited chonnam national university hwasun hospital because of petechiae , easy bruising and knee joint pain in december 2007 .
a complete blood count showed white blood cell 1,600/l , hemoglobin 11.7 g / dl , platelets 4,000/l , absolute neutrophil count 940/l , and corrected reticulocyte count 0.89% .
the patient was diagnosed as a saa . as he had no hla - matched sibling , he was treated with ist using ratg ( thymoglobuline , genzyme , cambridge , ma , usa ; 3.5 mg / kg / day for 5 days ) and cyclosporine ( 5 mg / kg / day ) and methylprednisolone ( 2 mg / kg / day for 5 days , then tapered over 30 days ) . while being treated with ist , he developed peripheral neuropathy with pain and tingling sensation in both extremities , requiring a sympathetic nerve block , which relieved symptoms .
twenty - three months after ist with ratg , he complained of mild hand tremors , sweating , weight loss , palpitations and goiter .
subsequent thyroid function tests showed the hyperthyroidism ( free thyroxine , 3.42 ng / dl ; tsh , < 0.01 niu / ml ; triiodothyronine , 3.99 ng / ml ; thyroxine , 17.3 g / dl ) .
autoantibody results were as follows : antimicrosome antibody ( + ) , tsh - binding inhibitory immunoglobulin ( + ) , antithyroglobulin antibody ( - ) , and antinuclear antibody ( - ) .
a tc-99 m pertechnetate thyroid scan showed enlarged thyroid gland with diffuse uptake ( fig .
the patient has been disease free 39 months after ist and 9 months after methimazole treatment
. currently , his blood counts and thyroid function tests are normal , and he has no discomfort from graves disease .
graves disease is an autoimmune disorder characterized by hyperthyroidism , diffuse goiter , ophthalmopathy , and occasionally a dermopathy referred to as pretibial or localized myxedema9 ) . in immune pathogenesis of graves disease ,
b and t cells have a major role in the production of tsh receptor antibodies ( tshr - ab ) that are responsible for the thyroid stimulation and growth .
these activated t cells in turn increase the secretion of tshr - ab from b cells .
the hyperthyroidism and goiter of graves disease are caused by stimulation of the thyroid by tshr - ab9 ) .
it has been suggested that a genetic clonal lack of suppressor t cells may be responsible for the unregulated production of tshr - ab in in vitro studies10 ) .
the pathogenesis of aplastic anemia is thought to be t - cell - mediated destruction of hematopoietic progenitors and stem cells .
a variety of in vitro and in vivo research supported the implication of immune effector cells and cytokines , such as interferon- or tumor necrosis factor-1 ) .
the mechanism action of atg therapy for aplastic anemia is likely complex and multifactorial , but its main mechanism is thought to have immunosuppressive effect by depleting peripheral t cells from the circulation through complement - dependent lysis or activation associated apoptosis11 ) .
atg is manufactured through the immunization of horses or rabbits with thymocytes or t - cell lines , followed by the purification of the igg fraction of the sera from these animals . between hatg and ratg preparations ,
thus , they are dissimilar in inducing activation of t cells , as exemplified in the case of expansion of regulatory t cells11 ) . also , gene expression profiling was markedly different between cells treated with both preparations11 ) .
as a consequence , hatg and ratg would provide different mechanisms of action through multiple modes of immunomodulation . despite the differences mentioned above , hatg and ratg
have generally been used interchangeably in the clinic . however , in a recent randomized , prospective trial , ratg plus cyclosporine compared unfavorably with hatg plus cyclosporine when used as a first - line treatment .
the use of ratg led to a more profound depletion of cd4 + t cells , whereas both preparations resulted in a similar depletion of cd8 + t cells8 ) .
the depletion of suppressor t cells by atg was thought to have a role in the development of many autoimmune disorders3 ) .
interferon- is vital for cell - mediated immunity , inhibition of inappropriate b - cell proliferation and antibody production .
it is secreted by a subset of suppressor t cells to inhibit th2-cells which in turn activate b cells13 ) .
thus , depletion of suppressor t cells and resultant decreased production of interferon- by atg could also allow b - cell activation , which increases the risk of autoimmune disorder .
this was supported by studies showing that interferon- down - regulates tshr - ab production14 ) .
it also attenuated tsh receptor ( the tshr - ab target ) synthesis in graves disease15 ) .
thus , impaired interferon- production can cause derestricted tshr - ab production and increased tsh receptor production , resulting in immune hyperthyroidism .
there are a few reports of graves disease after treatment with atg for saa4567 ) .
three cases have been described occurring 26 , 42 , and 106 months after treatment with antilymphocyte globulin or atg in patients aged 25 , 30 , and 35 years , respectively4 ) . a 62-year - old man developed graves disease and fibrosing alveolitis 15 days after the administration of atg for saa5 ) .
the first case in children was described 6 years after atg in a 10-year - old boy7 ) .
this case represents the first case of possible implication of ratg in the pathogenesis of autoimmune hyperthyroidism .
recently , hatg is no longer available for the treatment of saa in europe , japan , latin america , and korea .
moreover , ratg has more potent and prolonged suppression of t cells than hatg8 ) , and the development of autoimmune hyperthyroidism may be encountered more frequently .
therefore , thyroid function tests should be incorporated in the routine follow - up of saa following ratg treatment .
 antithymocyte globulin ( atg ) is used as an immunosuppressive treatment ( ist ) to deplete clonal suppressor t cells in patients with severe aplastic anemia ( saa ) . 
 the depletion of suppressor t cells by atg may affect the activation of b cells , which results in an increased risk for autoimmune conditions . 
 a 12-year - old boy was diagnosed with idiopathic saa . 
 as he did not have an human leukocyte antigen - matched sibling , he was treated with rabbit atg ( 3.5 mg / kg / day for 5 days ) and cyclosporine . 
 five months later , he became transfusion independent . 
 however , 23 months after ist , he complained of mild hand tremors , sweating , weight loss , palpitations , and goiter . 
 results of thyroid function tests revealed hyperthyroidism ( free thyroxine , 3.42 ng / dl ; thyroid stimulating hormone [ tsh ] , 
 < 0.01 niu / ml ; triiodothyronine , 3.99 ng / ml ) . results of tests for autoantibodies were positive for the antimicrosome antibody and tsh - binding inhibitory immunoglobulin , but negative for the antithyroglobulin antibody and antinuclear antibody . 
 he was treated with methimazole , and his symptoms improved . 
 the patient has been disease free for 39 months after ist and 9 months after methimazole treatment . 
 this case report suggests that although rare , rabbit atg may have implications in the pathogenesis of autoimmune hyperthyroidism . 
 our findings suggest that thyroid function tests should be incorporated in the routine follow - up of saa patients treated with atg . 
Introduction
Case report
Discussion