Natural History Of Subclinical Hypothyroidism And The Lipid-lowering Effect Of Levothyroxine

Background:Subclinical hypothyroidism(SCH),characterized as a state of elevated thyrotropin(TSH)with normal levels of serum free thyroxine(FT4),has become a common thyroid disease among adults.SCH can be classified to 2 types according to serum TSH levels,which is defined as mild when TSH levels are no more than 10 mIU/L or severe when TSH levels are more than 10 mIU/L.Age,sex,initial TSH levels and thyroid peroxidase antibodies(TPOAb)status may influence thyroid function.However,when referring to the natural history of"mild" SCH,there is no sufficient data about it.The clinical significance of SCH varies widely,including increasing risk of cardiovascular disease(CVD),depression and cognitive impairment.There is no doubt that we should control the adverse consequences of SCH.It is widely agreed that L-thyroxine is necessary for severe SCH patients.However,controversy exists for mild SCH patients.The essential reason is that the possible adverse outcome,in other words,the benefits of treatment,is not clear.Thus,we urgently need to clarify the natural history of mild SCH to lend reference to therapeutic strategy making.We aimed to investigate the natural history of mild SCH in a Chinese population,and tried to find some novol predictive factors.Then,considered the relationship of SCH,dyslipidemia and CVD,we performed a meta-analysis to clarify the lipid-lowering effect of levothyroxine(L-T4)in patients with SCH.Methods:1 SubjectsThis was a prospective community-based cohort study conducted in the rural area of Shandong Province,China.The study population was derived from the REACTION study.A total of 11000 subjects participated the survey,of whom 10795 subjects had results of thyroid function tests,and 1088 subjects meet the diagnostic criteria of mild SCH,Finally 505 subjects completed the survey and were enrolled in our analysis.2 Data CollectionHeight,weight and blood pressure were measured by specific investigators in line with a standard protocol.Every participant was inquired to complete a standard questionnaire,which contained the imformation about name,sex,age,medical history,family medical history,drug history and so on.All participants provided fasting bloodsamples.An oral glucose tolerance test was performed if the participants had no previous diagnosis of diabetes.Thyroid function test,including TSH,free triiodothyronine.FT4 and TPOAb,was measured using chemiluminescent procedures.The ARCHITECT ci16200 Integrated System(Abbott)were used to determine the serum lipids profile(including low-density lipoprotein cholesterol,high-density lipoprotein cholesterol,total cholesterol and triglycerides),liver function(including aspartate aminotransferase and alanine aminotransferase)and creatinine.3 Statistical analysesAll statistical analyses in part one were performed using SPSS Statistical Analysis System.We part two we use STATA to perform meta-analysis.To analyze the variables related to the transition from SCH to OH or euthyroidism,logistic regression models were used.We used random-effect model for meta-analysis,and tested publication bias,heterogeneity,subgroup analysis and meta regression.Results:1.1 Prevalence of mild SCH and outcomes at the end of follow-up At baseline,thyroid function tests were performed on 10795 subjects among 11000 participants,and 1088 subjects meet the criteria of mild SCH.The prevalence of mild SCH was 10.1%.Of 505 subjects with baseline mild SCH,43.8%(n = 221)had persistent SCH.49.7%(n = 251)had normalization of thyroid function,and 3.4%(n =17)had OH at the end of follow-up.1.2 Baseline characteristics of the study populationWe classified subjects with mild SCH into 3 groups according to the outcomes of thyroid function(euthyroidism,SCH or OH)at the end of the follow-up.Compared to patients who would revert to euthyroidism,patients with persistent SCH were significantly older and had higher TSH and lower FT3 and FT4 levels.Additionally,patients with OH had higher TSH than euthyroidism group and significantly lower baseline FT4 levels and a higher positive rate of TPOAb than the other two groups.1.3 Regression modelMild SCH patients with serum TC levels of 5.20-6.20 mmol/L or higher than 6.20 mmol/L had greater risks of developing OH than those with TC below 5.20 mmol/L(OR = 5.769 and 15.676,p=.048 and.006,respectively).Similarly,the incidence of developing OH was higher for those with positive TPOAb than patients with negative TPOAb(OR = 7.007,p=.009).On the other hand,patients aged older than 60 years had a lower likelihood of reversion than those aged 50 years or younger(OR =.487,p =.012).Those with creatinine between 62.31-70.80 mmol/L or higher than 70.80 mmol/L were less likely to normalize their thyroid function than those with creatinine of 57.10 mmol/L or lower(OR =.529 and.350,p=.031 and.004,respectively).Additionally,patients with TSH of 7.00 mlU/L or higher also were less likely to revert to euthyroidism(OR=.192,p<.001).2 Meta-analysis of lipid-lowering effect of L-T4Twelve trials,with 940 participants,were eligible for analysis.Compared with the control group,levothyroxine substitution yielded an improved mean reduction in TC(-0.29,[-0.42 to-0.16])and LDL-C(-0.22,[-0.36 to-0.09]),and no significant effects were found in HDL-C(-0.04.[-0.08 to 0.01])or triglycerides(-0.04,[-0.08 to 0.00]).Trials in which only patients with mild SCH(thyrotropin<10 mlU/L)were enrolled showed equivalent effects.The lowering effects were weaker,but still significant,in long-term treatment(>6 months)compared with short-term treatment(?6 months)for TC(-0.19[-0.35,-0.03]vs.-0.50[-0.68,-0.31],p= 0.047)and LDL-C(-0.09[-0.16,-0.02]vs.-0.46[-0.68,-0.25],p =0.006).Conclusion:1.Our present study demonstrated that nearly half of mild SCH patients revert to euthyroidism.In mild SCH patients,TPOAb and TC seem to be important predictors of progression to OH,whereas high baseline TSH or creatinine were negative correlated with reversion to euthyroidism.The prognostic value of TC and creatinine in mild SCH and the possible mechanism involved should be considered.2.Levothyroxine treatment has clear benefits on TC and LDL-C in SCH patients,as well as in patients with mild SCH.