title: The Natural History of Subclinical Hyperthyroidism in Graves' Disease: The Rule of Thirds.
abstract: There is little information regarding the natural history of subclinical hyperthyroidism (SH) due to Graves' disease (GD).
  
  
  
  A prospective analysis was conducted of patients with SH due to GD between 2007 and 2013 with at least 12 months of follow-up. SH was diagnosed if serum thyrotropin (TSH) was below the laboratory reference range (0.4-4.0 mIU/L) and when thyroid hormones were normal. GD was confirmed by either a raised TSH receptor antibody (TRAb) level or uniform uptake on Technetium scan.
  
  
  
  Forty-four patients (89% female, 16% current smokers, and 5% with active Graves' orbitopathy) were diagnosed with SH due to GD. Over the follow-up period (median 32 months), approximately one third (34%) of the cohort progressed to overt hyperthyroidism, one third (34%) normalized their thyroid function, slightly less than one third (30%) remained in the SH state, while one person became hypothyroid. Multivariate regression analysis showed that older age and positive antithyroid peroxidase (TPO) antibody status had a positive association with risk of progression to overt hyperthyroidism, with hazard ratios of 1.06 ([confidence interval (CI) 1.02-1.10], p < 0.01) per year and 10.15 ([CI 1.83-56.23], p < 0.01), respectively, independent of other risk factors including, smoking, TRAb levels at diagnosis, and sex.
  
  
  
  A third each of patients with SH due to GD progress, normalize, or remain in the SH state. Older people and those with positive anti-TPO antibodies have a higher risk of progression of the disease. These novel data need to be verified and confirmed in larger cohorts and over longer periods of follow-up.
authors.affiliation: 1 Department of Endocrinology, Queen Elizabeth Hospital , Gateshead, United Kingdom .|2 Newcastle Magnetic Resonance Centre, Newcastle University , Newcastle, United Kingdom .
authors.forename: Sviatlana
authors.initials: S
authors.lastname: Zhyzhneuskaya
authors.affiliation: 1 Department of Endocrinology, Queen Elizabeth Hospital , Gateshead, United Kingdom .
authors.forename: Caroline
authors.initials: C
authors.lastname: Addison
authors.affiliation: 1 Department of Endocrinology, Queen Elizabeth Hospital , Gateshead, United Kingdom .
authors.forename: Vasileios
authors.initials: V
authors.lastname: Tsatlidis
authors.affiliation: 1 Department of Endocrinology, Queen Elizabeth Hospital , Gateshead, United Kingdom .|3 Institute of Cellular Medicine, Newcastle University , Newcastle, United Kingdom .
authors.forename: Jolanta U
authors.initials: JU
authors.lastname: Weaver
authors.affiliation: 1 Department of Endocrinology, Queen Elizabeth Hospital , Gateshead, United Kingdom .|4 Institute of Genetic Medicine, Newcastle University , Newcastle, United Kingdom .
authors.forename: Salman
authors.initials: S
authors.lastname: Razvi
mesh_terms: D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood; D018450:Disease Progression; D005260:Female; D006111:Graves Disease / Q000097:blood / Q000175:diagnosis* / Q000276:immunology; D049970:Graves Ophthalmopathy / Q000097:blood / Q000175:diagnosis* / Q000276:immunology; D006801:Humans; D006980:Hyperthyroidism / Q000097:blood / Q000175:diagnosis* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011989:Receptors, Thyrotropin / Q000276:immunology; D012720:Severity of Illness Index; D013960:Thyroid Function Tests
chemical_list: D001323:Autoantibodies; D011989:Receptors, Thyrotropin