十一、亚临床甲减
2010年中国十城市流行病学调查显示，我国成人亚临床甲减患病率为16.7%[6]。国际报道亚临床甲减患病率为5%～10%，患病率随年龄增长而增高，女性多见[1-2，5，30]。
亚临床甲减一般不具有特异的临床症状和体征，诊断主要依赖实验室检查。是指仅有血清TSH水平升高，TT4和FT4水平正常。根据TSH水平，亚临床甲减可分为两类：轻度亚临床甲减，TSH＜10mIU/L；重度亚临床甲减，TSH ≥10mIU/L。其中，轻度亚临床甲减占90%。
诊断亚临床甲减时要排除其他原因引起的血清TSH增高：①TSH测定干扰：被检者存在抗TSH自身抗体可以引起血清TSH测定值假性增高。②甲状腺功能正常病态综合征的恢复期：血清TSH可以增高至5～20mIU/L，机制可能是机体对应激的一种调整。③20%的中枢性甲减：患者表现为轻度TSH增高（5～10mIU/L）。④肾功能不全：10.5%的终末期肾病患者有TSH增高，可能与TSH清除减慢、过量碘摄入、结合于蛋白的甲状腺激素丢失有关。⑤糖皮质激素缺乏：可以导致轻度TSH增高。⑥生理适应：暴露于寒冷9个月，血清TSH升高30%～50%。需2～3个月重复测定TSH及FT4、TT4水平，TSH升高且FT4、TT4正常，方可诊断亚临床甲减[31]。
本病的主要危害：①发展为临床甲减：英国Whickham前瞻性研究证实，单纯甲状腺自身抗体阳性、单纯亚临床甲减、甲状腺自身抗体阳性合并亚临床甲减每年发展为临床甲减的发生率分别为2%、3%和5%；我国学者随访100例未接受甲状腺激素治疗的亚临床甲减患者5年，29%仍维持亚临床甲减；5%发展为临床甲减；其余66%患者甲状腺功能恢复正常。Logistic回归分析显示，初访时TSH＞6 mIU/L（OR=3.4），甲状腺自身抗体阳性（OR=5.3），原碘缺乏补碘至碘超足量（OR=8.0）是亚临床甲减患者甲状腺功能不易恢复正常的影响因素[32]。美国一项前瞻性队列研究，对459例65岁以上亚临床甲减患者随访2年，发现56%仍维持亚临床甲减，35%甲状腺功能恢复正常，9%进展为临床甲减或应用L-T4替代治疗；分析发现，基线TSH＞7mIU/L及TPOAb阳性者甲状腺功能不易恢复正常，而TSH＞10mIU/L者更容易进展为临床甲减或应用L-T4替代治疗，年龄和性别对甲状腺功能的自然转归无明显影响[33]。②血脂代谢异常及其导致的动脉粥样硬化：部分学者认为，亚临床甲减是缺血性心脏病发生的危险因素，可以引起脂类代谢紊乱和心脑血管疾病。“鹿特丹研究”发现，亚临床甲减与高血压、血脂异常、高血糖等因素一样是缺血性心脏病的独立危险因素，其与主动脉粥样硬化和心肌梗死的相对危险度分别为1.9和3.1[34]；一项包含17项队列研究的荟萃分析发现，50岁以下亚临床甲减患者发生卒中的风险是甲状腺功能正常者的3.32倍[35]；亚临床甲减患者血清中与动脉粥样硬化相关的microRNA表达谱发生变化；亚临床甲减总胆固醇水平高于甲状腺功能正常者，且高总胆固醇血症发生率高于正常人，与TSH水平呈正相关[36-37]。多项随机对照临床试验发现，L-T4 替代治疗可以降低亚临床甲减患者血清总胆固醇及低密度胆固醇的水平[38-41]。所以，从亚临床甲减的角度防治心脑血管疾病是一个被关注的问题。③代谢综合征及非酒精性脂肪肝：日本一项大规模流行病学调查（N=11 498）发现，与甲状腺功能正常的女性相比，亚临床甲减的女性患代谢综合征的风险增加了1.7倍[42]。韩国一项横断面研究表明，血清TSH水平与非酒精性脂肪肝的患病率呈正相关。我国的一项前瞻性病例及对照研究同样发现，与甲状腺功能正常者相比，亚临床甲减患者随访5年后非酒精性脂肪肝的发病风险明显增高；在校正腰围、血脂、血糖等因素后，亚临床甲减仍然是非酒精性脂肪肝的独立危险因素[43]。④妊娠期亚临床甲减可能影响后代的神经智力。⑤对认知的影响：Pasqualetti G等对13项相关研究进行荟萃分析，在总人群中并未发现亚临床甲减与认知障碍的相关性，但是在75岁以下的人群中分析发现，亚临床甲减者的认知能力明显降低，痴呆的发生风险比甲状腺功能正常者增加了81%[44]。⑥其他：a.糖尿病视网膜病变：亚临床甲减可能是糖尿病视网膜病变的危险因素。b.胃动力的改变：亚临床甲减患者更容易出现胃动力障碍及相关的上消化道症状，给予L-T4 替代治疗后上述情况得以改善。
亚临床甲减的治疗：①替代治疗的获益：目前尚缺乏高质量（多中心、足够样本量、分层随机分组）的随机对照临床试验对替代治疗的获益进行评价，目前的结论大多来自回顾性的观察性研究或样本量较小的临床试验。a.对冠心病及其危险因素的影响：“硬终点事件”方面，替代治疗可降低患者冠心病的发生风险，Whickham研究也提示替代治疗可降低全因死亡率；“危险因素”方面，替代治疗可改善颈动脉内中膜厚度，可影响动脉粥样硬化性斑块中固有免疫因子的水平从而使斑块稳定性增加，可改善血液的高凝状态，可改善内皮细胞功能，对总胆固醇及低密度脂蛋白胆固醇的影响如前所述。b.对心脏功能的影响：替代治疗可改善心脏收缩和舒张功能并降低患者心力衰竭的发生风险，可部分逆转左室重构，可改善心脏的生物能量代谢状态。c.对肾功能的影响：可改善慢性肾疾病患者的肾功能。d.对甲减相关症状、生活质量、认知及情绪障碍均未见明显改善。②替代治疗的建议：重度亚临床甲减（TSH≥10mIU/L）患者，建议给予L-T4 替代治疗；治疗的目标和方法与临床甲减一致。为避免L-T4 过量导致心律失常和骨质疏松，替代治疗中要定期监测血清TSH。轻度亚临床甲减（TSH＜10mIU/L）患者，如果伴有甲减症状、TPOAb阳性、血脂异常或动脉粥样硬化性疾病，应予L-T4 治疗，不伴有上述情况的患者，定期监测TSH的变化。70岁以上的老年亚临床甲减患者的治疗目前存在争议。老年重度亚临床甲减患者推荐给予治疗，而老年轻度亚临床甲减患者，由于缺乏大规模的多中心前瞻性研究，其临床获益存在不确定性，因此应密切随访观察，治疗应谨慎选择。
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