摘要
目的通过回顾性分析IHP临床特点和相关因素分析,探讨IHP早期诊疗、减少误诊及并发症方法。
方法收集广西医科大学第一附属医院1994年12月到2009年9月确诊的44例IHP住院患者的临床资料,采用Wilcoxon秩和检验、Bivariate Correlation过程、多分类Logistic回归分析或Ordinal过程法等统计学方法对患者的临床特征、实验室检查、诊断与误诊、治疗及转归等情况进行回顾性分析。
结果:本研究显示:1患者平均发病年龄为22.1±14.5岁;误诊率为95.5%,其中15例(34.9%)被误诊为癫痫发作史,25例(58.1%)诊为低钙血症,未能明确IHP;中位数病程为30月。2 2.1临床症状以手足搐搦和癫痫发作多见。发现脑钙化26例,21例EEG异常,6例白内障。2.2低血钙38例,高血磷40例;治疗后患者血钙明显升高(P=0.000);治疗后血磷明显降低(P=0.000);治疗前后血钙磷乘积无明显差异(P=0.125);30例24小时尿钙低于正常值,24例24小时尿磷低于正常值。2.3因素分析:癫痫发作为大脑钙化程度的预测因子(P=0.041);颅内钙化为癫痫发作的危险因素(b=1.168,OR=3.216, P=0.006);癫痫发作(b=2.719,OR=15.162,P=0.014)、病程(b=-0.024,OR=0.977,P=0.025)为EEG异常的主要因素。2.4相关性及回归分析:血钙与血磷相为负相关关系(r=-0.388,P=0.009);血磷与血钙磷乘积为正相关关系(r=0.801,P=0.000);血钙标准化回归系数为0.628(P=0.000),血磷标准化回归系数为1.045(P=0.000),即血磷对血钙磷乘积升高贡献率血磷较血钙大。颅内钙化与智力障碍及癫痫发作正相关关系(r=0.408,P=0.01;r=0.457,P=0.003)。脑电图异常与癫痫发作为正相关关系(r=0.329,P=0.05)。发病年龄与血钙磷乘积为负相关关系(r=-0.494,P=0.001)。
3.治疗方案均采用钙剂联合维生素D或其衍生物治疗、促进排磷和低磷饮食。
结论1 IHP多见于青少年儿童,误诊率高、病程长、脑钙化发生率高。2低血钙、高血磷和低尿钙磷是IHP临床特征;血钙、血磷与血钙磷乘积均为正相关关系,但血磷对血钙磷乘积升高贡献率大于血钙;脑钙化与智力障碍、与癫痫发作呈正相关关系;发病年龄与血钙磷乘积为负相关关系。脑钙化为癫痫发作的主要危险因素。
Objective Through the retrospective analysis of clinical characteristics and related factors,aim to explore the early diagnosis and treatment to reduce the misdiagnosis and complications of the IHP.
Methods clinical data of of characteristics,laboratory findings, diagnosis and misdiagnosis,treatment and prognosis of 44 hospitalized patients diagnosed of IHP from December 1994 to September 2009 in first affiliated hospital of Guangxi Medical University were collected and were retrospectively analyzed by statistical methods such as wilcoxon rank sum test,bivariate correlation process,multi-category or ordinal logistic regression analysis,etc.
Results The study showed:1 the average age of onset were 22.1±14.5years;Misdiagnosis rate was 95.5%,15 cases misdiagnosed as epilepsy history,25 misdiagnosed as hypocalcemia;median duration was 30 months.2 2.1 clinical manifestations of tetany and seizures more common,40 cases were misdiagnosed as Tetany,seizures in 19 cases.26 cases have cerebral calcification,EEG abnormalities in 21 cases,cataract in 6 cases.2.2 38 cases in low blood calcium,40 cases in hyperphosphatemia,serum calcium after treatment was significantly higher than pre-treatment(P=0.000) ; After treatment serum phosphate was significantly lower than before treatment(P=0.000);blood calcium-phosphorus product before and after treatment was not significantly different ( P = 0.125 );24-hour urine calcium of 30 cases below the normal,24 cases below the normal 24-hour urine phosphorus.2.3 Factor Analysis:Epilepsy fat as a predictor of brain calcification (P=0.041);Cerebral calcification was a risk factor of epilepsy ( b =1.168,OR=3.216,P =0.006);Seizures (b =2.719 ,OR = 15.162,P = 0.014 ),duration ( b = -0.024,OR =0.977,P =0.025) as risk factors for abnormal EEG.2.4 Correlation and regression analysis: Calcium and phosphorus was a negative correlation (r = -0.388 , P=0.009), Phosphorus and blood calcium and phosphorus product was a positive correlation (r=0.801,P=0.000),the standardized regression coefficient of calcium was 0.628(P=0.000),phosphorus standardized regression coefficient was 1.045(P=0.000),namely,the contribution rate of phosphorus on calcium-phosphorus product increases is larger than the calcium;Brain calcification and mental retardation was a positive correlation (r=0.408,P=0.01),Cerebral calcification and epilepsy was a positive correlation(r=0.457,P=0.003),Age of onset and blood calcium and phosphorus product was negative correlation (r=-0.494,P=0.001),EEG abnormalities and seizures was a positive correlation (r =0.329, P = 0.05).3 Treatment programs were using calcium and vitamin D or derivatives thereof,treatment,promotion of exclusive phosphorus and low phosphorus diet.
Conclusion 1 the high rate of misdiagnosis and delay long course,the high incidence of brain calcification in IHP,and more common in young children.2 Hypocalcemia,hyperphosphatemia,and low urinary calcium and phosphorus are the clinical features of IHP;Serum calcium and phosphorus in IHP patients exist a negative correlation,Serum calcium,phosphorus and blood calcium-phosphorus product exists a straight-line relationship,And the contribution rate of phosphorus to the rise of blood calcium-phosphorus product was large than calcium.Cerebral calcification and mental retardation as a positive correlation;cerebral calcification and epilepsy and mental retardation exist positive relationship,Age of onset and calcium-phosphorus product exist a negative correlation,cerebral calcification was a risk factor for epileptic seizures.
引文
1廖二元,莫朝晖,主编.内分泌学.第2版[M].北京:人民卫生出版社,2007,11:719-732.
2方定华.原发性甲状旁腺机能减低的脑电图与CT所见的关系.中华神经精神科杂志,1991,24,304-306.
3 Parvari R,Diaz GA,Hershkovitz E.Parathyroid Development and the Role of Tubulin Chaperone E.Horm Res.2006,67(1):12-21.
4 DeGroot LJ,Jameson JL.Endocrinology.4th ed.Philadophia,W.B.S-aunders,2001, 1131-115。
5 A.Lienhardt,M.Bai,J-P Lagarde,et al.Aactivating mutations of the calciumsensing receptor:management of hypocalcemia.J Clin Endocrinol Metabol,2001,86,5313-5323.
6 C.Beterle,N.A.Greggio,M.Volpato.Autoimmune Polyglandular syndrome type1.J Clinic Endocrinol Metabol,1998,83,1049-1055.
7 Tomonobu Hasegawa,Yukihiro Hasegawa,Taiji Aso,et al.HDR syndrome(Hy- poparathyroidism,Sensorineural deafness,Renal dysplasia) associated w-ith del(10)(p13).Am J Med Genet,1997,73,416-418.
8 Ruti Parvari,Eli Hershkovitz,Adam Kanis,et al.Homozygosity and l- inkagedisequilibrium mapping of the syndrome of congenital hypoparathyroidism,growth and mental retardation,and dysmorphism to 1-M interval on chromosome Iq42-43.AmJ Hum Genet,1998,63,163-169.
9 Nakamura Y,Matsumoto T,Tamakoshi A,et al.Prevalence of idiopathic hypoparathyroidism and pseudohypoparathyroidism in Japan.J Epidemiol,2000,10:29-33.
10刘秋华,黄勤,黄新等.特发性甲状旁腺功能减退症l3例误诊及文献复习[J].临床误诊误治,2007,4,20(4):54-55.
11刘秋华,谈驰,王新.特发性甲状旁腺机能减退症5例误诊分析及181例误诊病例文献复习[J].医学临床研究,2007,24(1):143-144.
12黄进能.特发性甲状旁腺机能减退症误诊为原发性癫痫8例分析[J].中国误诊学杂志,2008,10,8(28):6916-6917.
13刘焕.特发性甲状旁腺功能减退症误诊6例分析[J].中国误诊学杂志,2009,9(15):3643-3644.
14 Fredman TH.Idiopathic hypoparathyroidism with extensive brain calcification and persistent neurologic dysfuction[J].Neurology,1987,37(2):307-309.
15史轶蘩.协和内分泌和代谢学[M].北京:科学出版社,1999:1478-1490.
16 Kowdley KV,Coull BM,Orwoll ES.Cognitive impairment and intracranial calcification in chronic hypoparathyroidism.Am J Med Sci,1999,317:273-277.
17 Basetepe M,Jüpper H.GNAS locus and pseudohypothyroidism[J].Horm Res,2005,63(1):65-74.
18陈文彬,潘祥林,主编.诊断学,第7版[M].北京:人民卫生出版社,2008:388-389.
19 Parathyroid disorders and diseases altering calcium metabolism.Oxford Textbook of Medicine 4th edition[M].Oxford University Press,2004:230-241.
20 Brown EM,MacLeod RJ.Extracellular calcium sensingand extraeellular calcium signaling [J].Physiol Rev,2001,81:239-297.
21 Brown EM,Chattopadhyay N,Vassilev PM,et a1.The calcium-sensing receptor(CaR) permits Ca2+ to function as a versatile extracellular first messenger[J].Recent Prog Horm Res,1998,53:257-280;discussion 280-281.
22李同芬,巩若箴,吕京光,等.特发性甲状旁腺功能减退的脑CT表现(附13例分析)[J].医学影像学杂志,2004,14(2):96-97.
23懂可辉,李丽林,李鸿培.甲状旁腺机能减退的神经系统及脑CT表现:附24例报告[J].北京医学,1999.21(3):137.
24 Sachs C,Sjoberg HE,EricBon K,et a1.Basal ganglia calcification on CT:relation to hypoparathroidism[J].Neurology,1982,32(7):779-782.
25 Kowdley KV.Coull BM.Orwoll RS.Cognitive impairment and in tracranial calcifications in chronic hypoparathyroidism[J].Am J Med Sci,1999,317(5):273-277.
26 Benke T,Karner E,Seppi K,et a1.Subacute dementia and imaging correlates in a ease of Fahr’s disease.J Neurol Neurosurg Psyehiatry,2004,75(8):1163-1165.
27 Sieberer M,Haltenhof H,Haubitz B,et al.Basal ganglia calcification and psychosis in 22q11.2 deletion syndrome[J].Eur Psychiatry,2005,20(8):567.
28郗红艳,袁栋才.特发性甲状旁腺功能减退误诊为癫痫1例分析[J].中国误诊学杂志,2008,8(10):2385-2386.
29 DeGroot LJ,Jameson JL.Endocrinology.4th ed.Philadophia,W.B.S- aunders,2001,1131-1153.
30慢性肾脏病骨代谢及其疾病的临床实践指南-指南5-慢性肾脏病患者磷结合剂的应用[J].中国血液净化,2006,5(3):165-168.
31 Endo I,Matsumoto T,Fukumoto S.Hypoparathyroidism update pathophysiology and classitication of parathyroidism[J].Clin Calcium,2007,17(8):1175-1181.
32 Horwitz MJ,Stewart AF.Hypoparathyroidism:is it time for replacement therapy?[J].J Clin Endocrinol Metab,2008,93(9):3307-3309.
33 Nawrot I,Wo niewicz B,ToIboczko T,et al.Allotransplantation of cultured parathyroid p- rogenitor cells without immunosuppression:clinical results[J].Transplantation,2007,83 (6):734-740.
34 Moskalenko V,Ulrichs K,Kerscher A,et al.Preoperative evaluation of microencapsulated human parathyroid tissue aids selection of the optimal bioartificial graft for human parathyroid allotransplantation[J].Transplant,2007,20(8):688-696.
35 Lee S,Hong SW,Choi HS,et al.Experimental parathyroid hormone gene therapy using ?31 integrase[J].Endocr J,2008,55(6):1033-1041.
1张梅邬,敏辰,金坚.PTH融合蛋白研究进展[J].生物技术通报,2009,(3):25-28.
2 KEUTMANN HT,SAUER MM,HENDY GN,et al.Complete amino acid sequence of human parathyroid hormone[J].Biochemistry,1978,17(26) :5723-5729.
3 Marx UC,Alderman K,Bayer P.J Biochem Biophys Res Commun ,2000,267(1):213-220.
4王莹,郄建坤,程卯生,等.甲状旁腺激素构效关系的研究进展[J].中国新药杂志,2007,16(24):2017-2020.
5 John,Reidhaar-Olson,Robyn M,et al.Molecular and Cellular Endocrinology,2000,160:135-147.
6 Silva IV,Blaisdell CJ,Guggino SE,et al.PTH regulates expression of CIC-5 chloride channel in the kidney.Am J Physiol Renal Physiol,2000,278(2):F238-F245.
7 Brommage R,Hotchkiss CE,Lees CJ,et al.Daily treatment with human recombinant parathyroid hormone-(1-34),LY333334,for 1 year increases bone mass in ovariectomized monkeys.J Clin Endocrinol Metab,1999,84(10):3757-63.
8 Fujita T,Inoue T,Morii H,et al.Effect of an intermittent weekly dose Of human parathyroid hormone(1-34) on osteoporosis:a randomized double-masked prospective study using three dose levels.Osteoporos Int,1999,9(4):296-306.
9 Holzer G,Majeska RJ,Lundy MW,et al.Parathyroid hormone enhances fracture healing.A preliminary report.Clin Orthop,1999,(366):258-63.
10 Dubin NH,Monahan LK,Yu-Yahiro JA,et al.Serum concentrations of steroids,parathyroid hormone,and calcitonnin in postmenopausal womenduring the year following hip fracture:effect of location of fracture and age.J Gerontol A Biol Sci Med Sci,1999,54(9):M467-M473.
11 Juppner H,Abou-Samra AB,Freeman MW,et al.Science,1991 ,254(5034):1024-1026.
12 Juppner HW,Gardella TJ,Brown EM,et al.Parathyroid hormone and para-Thyroid hormone-related peptide in the regulation of calcium horme-Ostasis and bone development[A].in:DeGroot LL,Jameson JL,eds.Endoc-rinology[M].4th ed,vol 2,Philadelphia:Elsevier,2000:969-998.
13 Miao D,He B,Andrew CK,et al.Parathyroid hormone is essential for normal fetal bone formation[J].Clin Invest,2002,109(9):1173.
14 Tonn O,Kriegbaum S,Braitmaier A,et al.Expression-level dependent activation of recombinant human parathyroid hormone/parathyroid hormone-related peptide receptor:effect ofhuman parathyroid hormone (1-34)(1-31)and (28-48)[J].Recept signal Transduct Res,2000,20(223): 133.
15 Fujita T,Meguro T,Fukuyama R,et al.New signaling pathway for parathyroid hormone and cyclic AMP action on extracellular-regulated kinase and cell proliferation in bone cells.Checkpoint of modulation by cyclic AMP[J].J Biol Chem,2002,21,277(25):22191-22200.
16 ko JK,Choi KH,Kim IS,et al.Inducible RGS2 is a cross-talk regulator for parathyroid hormone signaling in rat osteoblast-like UMR106 cells[J].Biochem Biophys Res Commun,2001,287(4):1025-1033.
17 Spumey RF,Flanery PJ,Gamer SC,et al.Anabolic effect of a G protein-Coupled receptor kinase inhibitor expressed in osteoblast[J].J Clin Invest,2002,109(10):1361-1371.
18 Goold CP,Usdin TB,Hoare SR,et al.Regions in rat and human parathyroid hormone(PTH) 2 receptors controlling rceptor interaction with PTH and with antagonist ligands[J].J Pharmacol Exp Ther,2001,299(2):678-690.
19 Hoare SR,Rubin DA,Juppner H,et al.Endocrinology,2000,141(9):3080-3086.
20 BANERJEE S SEL M H,SUL MAN G,et al.Synthesis and characterization of novel biotinylated carboxyl-terminal parathyroid hormone peptides that specifically crosslink to the CPTH-receptor[J].Peptides,2006 ,27(12):3352-3362.
21 Divieti P,Inomate N,Chapin K,et al.Receptors for the carboxylterminal region of PTH(1-84) are highly expressed in osteocytic cells[J].Endocrinology, 2001,142(2):916-925.
22 Inomata N,Akiyama M,Kubota N,et at.Endocrinology,1995 ,136(11):4732-4740.
23 Guillen C,Martine P,de Gortazar AR,et al.Both N-and C-terminal domains of parathyroid hormone-related protein increase interleukin-6 by nuclear factor-kappa B activation in osteoblastic cells[J].J boil Chem,2002,277:28109-28117.
24 Horwood NJ,Udagawa N,Elliott J,et al.Interleukin 18 inhitits osteoc-last formation via T cell production of granulocyte macrophage colony-stimulating factor[J].J clin Invest,1998,101:595-603.
25 VAD R,NAFSTAD EI,DAHL LA,et al.Engineering of a Pichia pastoris expression system for secretion of high amounts of intact human parathyroid hormone[J].Biotechnology,2005,116(3):251-260.
26 BR INGHURST FR,POTTS JT JR Bone collagen synthesis in vitro:structure activity relations among parathyroid hormone fragments and analogs [J].Endocrinology,1981,108(1):103-108.
27 GENSURE RC,GARDELLA TJ,JUPPNER H Parathyroid hormone and parathyroithyroid hormone-relate peptide,and their receptors[J].Biochem Biophys Res Commun,2005,328(3):666-678.
28 Nishida S,Yoahiki S,Takahashi HE,et al.Increased bone formation byintermittent parathyroid hormone administration is due to the stimulation of proliferation and differentiation of osteoprogenitor cells in bone marrow[J].Bone,1994,15(6):717-723.
29 Leaffer D,Sweeney M,Kelleman L,et al.Modulation of osteogenic cell ultrastructure by RS-23581,an analog of human parathyroid hormone (PTH)-related peptide-(1-34),and bovine PTH-(1-34)[J].Endocrinology,1995,136(8):3624-3631.
30 Billiard J,Grewal SS,Lukaesko L,et al.Hormonal control of insulin like growth factor gene transcription in human osteoblasts:dual actions of cAMP-dependent protein kinase on CCAAT/enhancer-binding protein delta[J].J Biol Chem,2001,276(33):31238-31246.
31 Jika RL,Weinstein RS,Bellido T,et al.Increased bone formation by prevention of osteoblast apoptosis with parathyroidhormne[J].J Clin Invest,1999,104(4):439-446.
32 May L G,Gay CV.Multiple G-protein involvement in parathyroid hormone regulation of acid production by osteoclasts[J].J Cell Biochem,1997,64(1):161-170.
33 Uy HL,Guise TA,De La,et al.Effects of parathyroid hormone (PTH)-related protein and PTH on osteoclasts and osteoclast precursors in vivo [J].Endocrinology,1995,136(8):3207-3212.
34 Ma YL,Cain RL,Halladay DL,et al.Catabolic effects of continuous human PTH(1-38)in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation[J]. Endocrinology,2001,142(9):4047-4054.
35 Huang YF,Harrison JR,Lorenzo JA,et al.Parathyroid hormone induces interleukin-6 heterogeneous nuclear and messenger RNA expression in murine calvarial organ cultures[J].Bone,1998,23(4):327-332.
36 Quinn CO,Rajakumar RA,Agapova OA.Parathyroid hormone induces rat interstitial collagenase mRNA through Ets-1 facilitated by cyclic AMP response element-binding protein and Ca(2+)/calmodulin-dependent protein kinase II in osteoblastic cells[J].J Mol Endocrinol,2000,25(1): 73-84.
37 Onyia JE,Miles RR,Yang X,et a1.In vivo demonstration that human parathyroid hormone 1-38 inhibits the expression of osteoprotegerin in bone with the kinetics of an immediate early gene[J].JBone Miner Res,2000,15(5):863-871.
38 Ma YL,Cain RL,Halladay DL,et al.Catabolic effects of continuous human PTH(1-38)in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene—associated bone formation[J].Endocrinology,2001,142(9):4047-4054.
39 Ma YF,Jee W SS,Ke HZ,et al.Human parathyroid hormone(1-38) restores cancello us boneto the immobilized,osteopenic proximal tibial,metaphyssis in rats[J].J Bone M ineral Res,1995,10(3):496.
40 GARDELLA TJ,AXELORD D,RUB N D,et al.Mutational analysis of the recaptor-activating region of human parathyroid hormone[J].J Biol Chem ,1991,266(20):13141-13146.
41 SHIMIZU M,CARTER PH,GARDELLA TJ.Autoactivation of type-1 parathyroid hormone receptors containing a tethered ligand[J].J Biol Chem,2000,275(26):19456-19460.
42 REIDHAAR-OLSON JF,DAV IS RM,DE SOUZA-HART JA,etal.Active variants of human parathyroid hormone(1-34) with multiple amino acid substitutions [J].Mol Cellular Endocrin,2000,160(1/2):135-147.
43 BERG C,NEUMEYER K,KIRKPATR ICK P.Teriparatide[J].Nat Rev Drug Discov,2003,2(4):257-258.
44 Kneissel M,Boyde A,Gasser JA,et al.Bone tissue and its mineralization inaged estrogen-depleted rats after long-time intermittent treatment with parathyroid hormone(PTH)analog SDZPTS893 or human PTH(1-34).Bone, 2001,28:237-250.
45 JAMES F,WHITFIELD.Parathyroid hormone:A novel tool fortreating bone marrow depletion in cancer patients caused by chemotherapeutic drugs and ionizing radiation[J].Cancer Lett,2006,244(1):8-15.
46 Martin TJ,Quinn J M W,Gillespie MT,et al.Mechanisms involved in skeletal anabolic therapies.Ann N Y Acad Sci,2006,1068:458-470.
47 Riggs B L.Formation-stimulating regimens other than sodium fluo- ride.Am J Med,1993,95:62.
48 Fujita T,Inoue T,Morii H,et al.Effect of an intermittent weekly dose of human parathyroid hormone(1-34)osteoporosis: a randomized double-masked prospective study using three dose levels[J].Osteoporos Int,1999,9(4):296-306.
49 Neer RM,Arnaud CD,Zanchetta JR,et al.Effect of parathyroid hormone(1-34)on fractures and bone mineral density in postmenopausal women with osteoporosis[J].N Engl J Med,2001,344(19):1434-1441.
50许多荣,余学清,方荸荠.甲状旁腺激素在体外对破骨细胞分化及骨重吸收能力的影响[J].中华肾脏病杂志,2005,21(4):186-190.
51 Thomas T.Intermittent parathyroid hormone therapy to increase bone formation.Joint Bone Spine.2006,73(3):262-269.
52 Locklin RM,Khosla S,Riggs BL,et al.Mechanisms of biphasic anabolic and catabolic effects of parathyroid hormone(PTH)on bone cells.Bone,2001,28Suppl:S80.
53 Pfutzner A,Flacke F,Pohl R,et al.Pilot study with technosphere/ PTH(1-34)-a new approach for effective pulmonary delivery of parathyroid hormone(1-34)[J].Horm Metab Res,2003,35(5):319-323.
54 Ettinger B,San Martin J,Crans G,et al.Differential effects of teriparatide on BMD after treatment with raloxifene or alen- dronate[J].J Bone Miner Res,2004,19(5):745-751.
55 Finkelstein JS,Hayes,Hunzelman JL,et al.The effects of parathyroid hormone,alendronae,or both in men with osteoporosis[J].N Engl J Med,2003,349(6):1216-1226.
56 Deal C.The use of intermittent human parathyroid hormone as a treatment for osteoporosis[J].Curr Rheumatol Rep,2004,6(1):49-58.