鄒春華，黃濤金，謝勇久，林 爭(zhēng)，王 繹，明 華

老年惡性腫瘤患者甲狀腺功能狀態(tài)及化學(xué)藥物療法對(duì)其的影響

鄒春華，黃濤金，謝勇久，林 爭(zhēng)，王 繹，明 華

目的 探討老年惡性腫瘤患者的甲狀腺功能狀態(tài)及化學(xué)藥物療法(簡(jiǎn)稱(chēng)化療)對(duì)其甲狀腺功能的影響。方法 選取2010-01至2014-02確診的老年惡性腫瘤患者398例，并選擇400例體檢老年人群作為健康對(duì)照組，進(jìn)行甲狀腺激素(thyroid hormone，TH)和促甲狀腺激素(thyroid stimulating hormone，TSH)水平測(cè)定。將激素水平正常，KPS (Karnofsky)評(píng)分>60的老年惡性腫瘤患者分為: 腫瘤治療組132例，腫瘤對(duì)照組 129例。兩組年齡、KPS評(píng)分無(wú)統(tǒng)計(jì)學(xué)差異。腫瘤治療組患者進(jìn)行相應(yīng)化療，觀察治療前及治療后6個(gè)月的TH和TSH水平，腫瘤對(duì)照組僅給予對(duì)癥治療，同期比較兩組TH和TSH水平，分析化療對(duì)老年惡性腫瘤患者甲狀腺功能的影響。結(jié)果 398例老年惡性腫瘤患者的TH、TSH與健康對(duì)照組相比差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。腫瘤治療組患者的TH、TSH與腫瘤對(duì)照組相比，TSH的差異存統(tǒng)計(jì)學(xué)意義(P<0.05)。腫瘤治療組中甲狀腺功能減退(甲減)的比例為7.58%，亞臨床型甲減的比例為23.48%。腫瘤對(duì)照組中甲減的比例為5.65%，亞臨床甲減的比例為5.65%。兩組比較，亞臨床型甲減的發(fā)生率存在統(tǒng)計(jì)學(xué)差異(P<0.05)。結(jié)論 老年惡性腫瘤患者的甲狀腺功能異常發(fā)生率與健康群體比較無(wú)統(tǒng)計(jì)學(xué)差異，化療對(duì)老年惡性腫瘤患者的甲狀腺功能有一定的影響。

惡性腫瘤；老年；甲狀腺激素；甲狀腺功能亢進(jìn)；甲狀腺功能減退

惡性腫瘤嚴(yán)重威脅著人類(lèi)的健康，隨著人口的老齡化，相當(dāng)多的老年惡性腫瘤患者被確診。老年惡性腫瘤患者伴隨的多種疾病、內(nèi)分泌失調(diào)等因素對(duì)治療有一定的影響。甲狀腺是人體的重要內(nèi)分泌器官，TH參與機(jī)體的新陳代謝[1,2]。本研究對(duì)老年惡性腫瘤患者進(jìn)行TH和TSH水平測(cè)定，并就與化療因素相關(guān)的甲狀腺功能進(jìn)行分析，以探討在老年惡性腫瘤患者的甲狀腺功能狀態(tài)。

1 對(duì)象與方法

1.1 對(duì)象 選取2010-01至2014-02確診的老年惡性腫瘤患者 398例，男203例，女195例，平均(72.1±5.1)歲；其中肺癌197例，惡性淋巴瘤 82例，食管癌 14例，胃癌37例，結(jié)腸癌 63例，鼻咽癌5例。選擇400例正常體檢老年人群作為對(duì)照組，男208例，女192例，平均(73.9±4.8)歲。對(duì)有如下病況者進(jìn)行排除：有甲狀腺功能亢進(jìn)(甲亢)或甲狀腺功能減退(甲減)病史、甲狀腺癌、甲狀腺手術(shù)史；近期服用抗甲狀腺藥物、乙胺碘呋酮、糖皮質(zhì)激素；曾進(jìn)行放射性碘治療。398例惡性腫瘤患者中，TH水平正常且KPS評(píng)分>60的老年惡性腫瘤患者261例，此261例患者根據(jù)其意愿分為: 腫瘤治療組132例，男70例，女62例, 65～79歲，平均(73.5±5.6)歲；腫瘤對(duì)照組 129例, 男70例,女59例, 65～78歲，平均(74.7±4.7)歲。其余137例患者存在TH水平異常和(或)KPS評(píng)分≤60，則予以排除。

兩組年齡、KPS評(píng)分差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。腫瘤治療組患者進(jìn)行相應(yīng)化療，觀察治療前及治療后6個(gè)月的TH和TSH水平，腫瘤對(duì)照組僅給予對(duì)癥治療，同期觀察TH和TSH水平。

1.2 方法 抽取研究對(duì)象空腹肘正中靜脈血3 ml，靜置30 min后，常規(guī)離心5 min，分離血清備用。采用化學(xué)發(fā)光法檢測(cè)，嚴(yán)格按儀器操作手冊(cè)，用配套試藥盒，進(jìn)行TH和TSH測(cè)定。

1.3 評(píng)定標(biāo)準(zhǔn) 甲減：血清TH降低伴T(mén)SH升高；亞臨床甲減：血清TH正常，僅存在TSH升高；甲亢：血清TH升高伴T(mén)SH降低；亞臨床甲亢：血清TH正常，僅存在TSH降低。

2 結(jié) 果

2.1 腫瘤患者與正常體檢老年人群比較 腫瘤組游離三碘甲狀腺原氨酸(FT3)、游離甲狀腺素(FT4)、總?cè)饧谞钕僭彼?TT3)、總甲狀腺素(TT4)及TSH與健康對(duì)照組相比差異無(wú)統(tǒng)計(jì)學(xué)意義(表1)。腫瘤組甲狀腺功能異常者45例，其中甲亢7例，亞臨床甲亢7例，甲減13例，亞臨床甲減18例；對(duì)照組甲狀腺功能異常者45例，其中甲亢5例，亞臨床甲亢9例，甲減15例，亞臨床甲減16例。兩組患者甲狀腺疾病異常率比較差別無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。

甲狀腺功能老年腫瘤組(n=398)健康對(duì)照組(n=400)tPTSH(μU/ml)3.78±1.243.65±1.671.250.21FT3(pmol/L)4.45±1.414.63±1.371.830.07FT4(pmol/L17.2±3.6715.8±4.011.470.14TT3(nmol/L)1.96±0.572.03±0.441.940.06TT4(nmol/L)137.04±16.92134.99±13.581.890.06

2.2 治療組與對(duì)照組比較 治療6個(gè)月后,腫瘤治療組與腫瘤對(duì)照組比較，F(xiàn)T3、FT4、TT3、TT4差異無(wú)統(tǒng)計(jì)學(xué)意義。TSH差異存統(tǒng)計(jì)學(xué)意義(P<0.05，表2)。

甲狀腺功能腫瘤治療組(n=132)腫瘤對(duì)照組(n=129)tPTSH(μU/ml)4.05±2.272.59±0.916.79<0.001FT3(pmol/L)4.72±0.994.92±0.571.960.067FT4(pmol/L)16.20±4.1517.10±3.631.840.060TT3(nmol/L)2.36±0.992.57±0.771.8910.118

2.3 對(duì)完成化療的132例分析 經(jīng)檢測(cè)分析顯示，腫瘤治療組中甲減的比例為7.58%，亞臨床型甲減的比例為23.48%，甲亢的比例為1.51%，亞臨床型甲亢的比例為2.27%。腫瘤對(duì)照組中甲減的比例為5.65%，亞臨床甲減的比例為5.65%，甲亢的比例為1.61%，亞臨床甲亢的比例為3.23%。兩組比較，亞臨床型甲減的發(fā)生率存在統(tǒng)計(jì)學(xué)差異(P<0.05)。

3 討 論

本研究通過(guò)對(duì)老年惡性腫瘤患者進(jìn)行TH和TSH水平進(jìn)行測(cè)定，并未發(fā)現(xiàn)老年惡性腫瘤患者的甲狀腺功能與健康對(duì)照組存在統(tǒng)計(jì)學(xué)差異。通過(guò)對(duì)KPS評(píng)分>60分，甲狀腺功能正常老年惡性腫瘤患者進(jìn)行相應(yīng)化療干預(yù)，觀察治療前及治療后TH和TSH水平，分析患者甲狀腺功能。結(jié)果顯示132例可以納入分析的老年惡性腫瘤患者中甲減為7.58%；亞臨床甲減為23.48%；甲亢為1.51%；亞臨床甲亢的為2.27%。顯示老年惡性腫瘤患者進(jìn)行化療干預(yù)后甲狀腺功能異常以亞臨床甲減的患病率最高。老年惡性腫瘤患者進(jìn)行化療干預(yù)后的甲狀腺功能與其對(duì)照組存在統(tǒng)計(jì)學(xué)差異，本研究結(jié)果與Huang等[3]的研究結(jié)論基本一致，說(shuō)明化療對(duì)老年患者甲狀腺功能有一定的影響。

亞臨床甲減癥(又稱(chēng)輕度甲狀腺衰竭)是指血清 TSH水平高于正常值上限,而FT4、FT3在正常范圍，不伴或伴輕微非特異的甲減癥狀[4]。亞臨床甲減主要依賴(lài)于實(shí)驗(yàn)室診斷。近年來(lái)，隨著激素測(cè)定技術(shù)水平的提高，亞臨床甲減的檢出率明顯增高。亞臨床甲減的患病率4%～10%，隨年齡增長(zhǎng)而增高[5]。由于亞臨床甲減病情隱匿，通常沒(méi)有或僅有輕微的臨床癥狀，因此老年人甲減診斷相對(duì)困難，常引起動(dòng)脈粥樣硬化、血脂異常及心功能不全等不良事件，在原本就存在基礎(chǔ)心臟疾病的老年患者這些心血管風(fēng)險(xiǎn)則進(jìn)一步擴(kuò)大，造成很多危害[4,6]。本研究發(fā)現(xiàn)，老年惡性腫瘤患者甲狀腺功能異常的患病率主要以亞臨床甲減為主，進(jìn)行化療干預(yù)后甲狀腺功能異常以亞臨床甲減的患病率最高。

目前認(rèn)為，亞臨床甲減的病因包括自身免疫性甲狀腺疾病，物理性、藥物性或放射性因素?fù)p傷甲狀腺[4]。筆者對(duì)激素水平正常老年惡性腫瘤患者進(jìn)行相應(yīng)化療干預(yù)，對(duì)完成化療可納入的患者進(jìn)行分析，甲狀腺功能異常以亞臨床甲減最高，其亞臨床甲減發(fā)生率為23.48%。筆者認(rèn)為，其原因可能包括藥物性甲狀腺損傷、自身免疫性甲狀腺疾病，即由于較高的藥物濃度或藥物代謝致免疫系統(tǒng)異常，或老年人免疫功能紊亂引起，尚需進(jìn)一步進(jìn)行相關(guān)研究。近年有文獻(xiàn)[7,8]報(bào)告，腫瘤治療相關(guān)性甲減，部分腎細(xì)胞癌患者經(jīng)酪氨酸激酶抑制藥舒尼替尼治療呈現(xiàn)甲減表現(xiàn)，與甲狀腺功能正常的患者比較顯現(xiàn)其生存期延長(zhǎng)。有作者認(rèn)為，甲減是某些抗癌藥物的常見(jiàn)不良反應(yīng)，對(duì)于癌癥患者預(yù)后的有潛在效果[9]。在頭頸部癌的臨床研究中，甲減患者比甲狀腺功能正常的患者表現(xiàn)為較長(zhǎng)的生存期[10]。自發(fā)或故意誘發(fā)的甲狀腺功能減退癥可能與更好的臨床反應(yīng)率和患者生存期延長(zhǎng)相關(guān)。

研究也發(fā)現(xiàn)，在老年惡性腫瘤患者中有出現(xiàn)甲狀腺功能正常的病態(tài)綜合征(euthyroid sicyndrome，ESS，低T3綜合征)約 49例(12.31%)。甲狀腺功能正常的病態(tài)綜合征實(shí)驗(yàn)室檢查示T3減低，血清總T4正?；蜉p度增高，而TSH正常[11]?？紤]系因部分老年惡性腫瘤患者為腫瘤4期并存惡病質(zhì)，可能是機(jī)體的一種保護(hù)性反應(yīng)，而非甲狀腺本身病變，屬非甲狀腺疾病綜合征。

本研究結(jié)果需進(jìn)一步分層分析，追蹤亞臨床甲狀腺功能減退癥是否進(jìn)展為臨床甲狀腺功能減退及甲狀腺功能與腫瘤預(yù)后相關(guān)性。總之，對(duì)老年惡性腫瘤患者進(jìn)行甲狀腺功能檢測(cè)對(duì)指導(dǎo)治療及判斷預(yù)后有一定的意義。

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[6] 陳少華，蔣群湘，楊 坤. 亞臨床甲狀腺功能減退癥與特殊人群[J].中國(guó)醫(yī)師雜志,2013,15(1):138-140.

[7] Sabatier R, Eymard J C, Walz J,etal. Could thyroid dysfunction influence outcome in sunitinib-treated metastatic renal cell carcinoma? [J]. AnnOncol, 2012,23(3):714-721.

[8] Clemons J, Gao D, Naam M,etal. Thyroid dysfunction in patients treated with sunitinib or sorafenib[J]. Clin Genitourin Cancer, 2012, 10(4):225-231.

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(2014-07-17收稿 2014-10-22修回)

(責(zé)任編輯 岳建華)

Thyroid functional status in aged patients with malignant tumors and relationship with chemotherapy

ZOU Chunhua，HUANG Taojin，XIE Yongjiu，LIN Zheng，WANG Yi，and MING Hua.

Department of Oncology, Chengdu Hospital of Sichuan Provincial Corps, Chinese People’s Armed Police Forces, Chengdu 610041, China

Objective To study thyroid functional status of the aged patients with malignant tumors and the relationship between thyroid function with chemotherapy. Methods 398 aged patients with malignant tumors were recruited as the pathological group. At the same time, 400 aged healthg subjects served as the control group. The thyroid hormones (thyroid hormone, TH), and thyrotropin (thyroid stimulating hormone, TSH) levels were measured. The thyroid function in the groups was analyzed and compared. When KPS score is over 60, the aged patients with malignant tumors in normal hormone levels were divided into the observation group (132 cases) and the control group (129 cases).Two groups had no significant difference in the age and KPS score. The patients in the observation group were treated by chemotherapy and TH and TSH levels observed before treatment and 6 moths post-treatment. The patients in the control group were given symptomatic treatment, TH and TSH levels were observed over the same period. We compared thyroid hormone and thyroid hormone levels and analyzed the relationship between thyroid function with chemotherapy in the aged patients with malignant tumor. Results The thyroid hormone and thyroid stimulating hormone in 398 aged patients with malignant tumor were compared with those in the healthy control group, the difference was not statistically significant (P<0.05). The aged patients with malignant tumors in normal hormone levels were divided into the observation group and the control group. In observation group the hypothyroidism (hypothyroidism) ratio was 7.58%, the proportion of subclinical hypothyroidism was 23.48%, hyperthyroidism (hyperthyroidism) ratio was 1.51%, and subclinical hyperthyroidism ratio was 2.27%. In control group, the proportion of hypothyroidism was 5.65%, subclinical hypothyroidism ratio was 5.65%, hyperthyroidism ratio was 1.61% and subclinical hyperthyroidism ratio was 3.23%. In the observation group, the thyroid disease incidence rate was higher. Incidence of subclinical hypothyroidism in the two groups was significantly different (P<0.05). Conclusions The thyroid dysfunction in the aged patients with malignant tumor was not significantly different compared with the health control group. Chemotherapy in the aged patients with malignant tumor harms the thyroid function to some extent. The detection of thyroid function in the aged patients with malignant tumor has clinical significance.

malignant tumor; the aged; thyroid hormone; hyperthyroidism; hypothyroidism

鄒春華，博士，主任醫(yī)師， E-mail: zouchun_hua06@163.com

610041,武警四川總隊(duì)成都醫(yī)院腫瘤科

R730