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北京大学学报（医学版） ›› 2021, Vol. 53 ›› Issue (5): 921-927. doi: 10.19723/j.issn.1671-167X.2021.05.018

• 论著 • 上一篇    下一篇

显著高铁蛋白血症与噬血细胞性淋巴组织细胞增多症的相互关系

高伟波,石茂静,张海燕,吴春波(),朱继红   

  1. 北京大学人民医院急诊科,北京 100044
  • 收稿日期:2019-11-30 出版日期:2021-10-18 发布日期:2021-10-11
  • 通讯作者: 吴春波 E-mail:wuchunbowcb@163.com

Relationship between marked hyperferritinemia and hemophagocytic lymphohistiocytosis

GAO Wei-bo,SHI Mao-jing,ZHANG Hai-yan,WU Chun-bo(),ZHU Ji-hong   

  1. Department of Emergency, Peking University People’s Hospital, Beijing 100044, China
  • Received:2019-11-30 Online:2021-10-18 Published:2021-10-11
  • Contact: Chun-bo WU E-mail:wuchunbowcb@163.com

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摘要：

目的: 探讨显著高铁蛋白血症(marked hyperferritinemia,MHF)与噬血细胞性淋巴组织细胞增多症(hemophagocytic lymphohistiocytosis,HLH)患者的临床特征以及相关性。方法: 回顾性收集北京大学人民医院2017年1月至2018年9月急诊及住院的MHF患者的临床资料,包括患者一般资料,症状体征,血常规、生化、出凝血检测、血清铁蛋白检查,以及自然杀伤(natural killer, NK)细胞活性、可溶性白介素(interleukin, IL)-2受体、骨髓检查等。按是否诊断为HLH分为HLH组和非HLH组,按随访3个月结局分为死亡组与存活组,分别对各组进行比较分析。结果: 123例MHF患者平均年龄为(44.2±17.4)岁,男女比例为1.3 ∶1;常见病因为血液肿瘤、风湿免疫性疾病、铁超载、HLH。随着铁蛋白水平升高,HLH患者比例增加,铁蛋白在10 000~19 999、20 000~29 999、30 000~39 999、40 000~49 999、50 000 μg/L以上时,HLH占比分别为28.8%、40.0%、54.5%、50.0%、50.0%。HLH共46例(37.4%), 继发于肿瘤15例、风湿免疫性疾病14例、感染性疾病2例,不明原因15例。HLH组与非HLH组比较,两组间在年龄、性别、发热、意识障碍、初始铁蛋白、最高铁蛋白、血细胞改变、谷丙转氨酶(alanine aminotransferase, ALT)、谷草转氨酶(aspartate aminotransferase, AST)、总胆红素(total bilirubin,TBIL)、直接胆红素(direct bilirubin DBIL)、甘油三酯(triglyceride, TG)方面差异无统计学意义(P>0.05), 出凝血检测除纤维蛋白原(fibrinogen, Fib)外,差异也无统计学意义(P>0.05),在死亡率方面两组间差异无统计学意义(P>0.05);而在肝、脾、淋巴结肿大,白蛋白(albumin, ALB),Fib方面两组间差异有统计学意义(P<0.05)。死亡组与存活组比较,两组间在年龄,性别,发热,肝、脾、淋巴结肿大,初始铁蛋白,最高铁蛋白,中性粒细胞(neutrophil, Neu),血红蛋白(hemoglobin, Hb),ALT,AST,ALB,TG方面差异无统计学意义(P>0.05),出凝血检测除凝血酶原时间(prothrombin time, PT)外,两组间差异无统计学意义(P>0.05), HLH所占比例两组间差异也无统计学意义(P>0.05),而在意识障碍、血小板计数(platelet, PLT)、PT、TBIL、DBIL方面两组间差异有统计学意义(P<0.05)。结论: 随着铁蛋白水平升高,HLH患者的比例随之增加,但是MHF对于HLH诊断不具有特异性。

关键词: 高铁蛋白血症, 噬血细胞性淋巴组织细胞增多症, 预后

Abstract:

Objective: To investigate the relationship between marked hyperferritinemia (MHF) and hemophagocytic lymphohistiocytosis(HLH). Methods: The clinical data of 123 patients with MHF admitted to Peking University People’s Hospital from January 2017 to September 2018 were collected, including demographics, baseline characteristics, signs and symptoms, blood routine, blood biochemistry, coagulation function parameters, such as prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), d-dimer (D-D), fibrin degradation product (FDP), blood ferritin, natural killer (NK) cell activity, soluble interleukin (IL)-2 receptor and bone marrow examination. According to the diagnosis of HLH, the patients were divided into HLH group and non HLH group. The patients were divided into death group and survival group according to the 3-month follow-up results. The groups were compared and statistically analyzed. Results: In the 123 patients with MHF, the average age was (44.2±17.4) years with a male/female ratio of 1.3 ∶1. The most common causes were hematolo-gic malignancies, rheumatologic and inflammatory disorders, iron overload, and HLH. HLH was enriched as the ferritin increased, and the HLH ratios were 28.8%, 40.0%, 54.5%, 50.0%, 50.0% in ferritin value of 10 000-19 999, 20 000-29 999, 30 000-39 999, 40 000-49 999 μg/L,more than 50 000 μg/L respectively. There were 46 cases of HLH, among which 15 cases were secondary to malignancies,14 cases secondary to rheumatologic disorders, 2 cases secondary to infection, and 15 cases with no clear precipitating cause. There were significant differences between the HLH group and non-HLH group in hepatomegaly, splenomegaly, lymphadenectasis, albumin (ALB), fibrinogen(Fib), P<0.05, and no significant differences in age, gender, fever, disturbance of consciousness, ferritin level on presentation, maximum ferritin level, cytopenia in 2 or more cell lines, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), triglyceride (TG), coagulation parameters (PT, APTT, D-D, FDP, exception of Fib), and mortality rate (P>0.05). There were significant differences between the death group and survival group in disturbance of consciousness, platelet count, PT, TBIL, and DBIL (P<0.05), but no significant differences in age, gender, fever, hepatomegaly, splenomegaly, lymphadenectasis, ferritin level on presentation, maximum ferritin level, neutrophils, hemoglobin, ALT, AST, ALB, TG, coagulation parameters (Fib, APTT, D-D, FDP, exception of PT) and the HLH ratio (P>0.05). Conclusion: HLH was enriched as the ferritin increased, but marked hyperferritinemia was not specific for HLH in adults.

Key words: Hyperferritinemia, Hemophagocytic lymphohistiocytosis, Prognosis

中图分类号: 

  • R557.4

表1

123例显著高铁蛋白血症患者临床特征"

Clinical symptoms and signs Proportion of total cases,n (%) HLH,n (%)
Fever 100 (81.3) 38(38.0)
Splenomegaly 51 (41.5) 29(56.9)
Hepatomegaly 22 (17.9) 15(68.2)
Lymphadenopathy 53 (43.1) 29(54.7)
Disturbance of consciousness 16 (13.0) 6(37.5)
Hemocytopenia (more than 2 lines) 40 (32.5) 14(35.0)
Neu(<1.0×109/L) 25 (20.3) 8(32.0)
Hb(<90 g/L) 49 (39.8) 19(38.8)
PLT(<100×109/L) 86 (69.9) 33(38.4)
Hypertriglyceridemia (≥3.0 mmol/L) 38 (30.9) 17(44.7)
Low fibrinogen (≤1.5 g/L) 25 (20.3) 16(64.0)

表2

5组显著高铁蛋白血症患者HLH发生率"

Ferritin n HLH, n (%)
10 000-19 999/(μg/L) 66 19 (28.8)
20 000-29 999/(μg/L) 20 8 (40.0)
30 000-39 999/(μg/L) 11 6 (54.5)
40 000-49 999/(μg/L) 10 5 (50.0)
≥50 000/(μg/L) 16 8 (50.0)

表3

HLH组与非HLH组的临床参数比较"

Items HLH (n=46) Non-HLH (n=77) P
Age/years, M (P25, P75) 48 (31, 61) 41 (27, 56) 0.178
Male/female, n 22/24 47/30 0.153
Fever, n (%) 38 (82.6) 62 (80.5) 0.774
Splenomegaly, n (%) 29 (63.0) 22 (28.6) 0.000
Hepatomegaly, n (%) 15 (32.6) 7 (9.1) 0.001
Lymphadenopathy, n (%) 29 (63.0) 24 (31.2) 0.001
Disturbance of consciousness, n (%) 6 (13.0) 10 (13.0) 0.993
Initial ferritin/(μg/L), M (P25, P75) 12 558 (6 249, 22 407) 13 901 (10 463, 24 059) 0.386
Ferritin MAX/(μg/L), M (P25, P75) 24 816 (13 528, 41 885) 16 774 (11 909, 29 421) 0.075
WBC/(×109/L), M (P25, P75) 4.6 (2.2, 8.9) 4.3 (2.6, 9.9) 0.824
Neu /(×109/L), M (P25, P75) 3.2 (1.4, 6.6) 2.9 (1.3, 7.7) 0.913
Hb/(g/L), x ?±s 95.8±23.0 96.2±26.8 0.924
PLT/(×109/L), M (P25, P75) 52 (24, 109) 38 (18, 140) 0.453
ALT/(U/L), M (P25, P75) 78 (33, 191) 58 (25, 251) 0.960
AST/(U/L), M (P25, P75) 94 (50, 216) 63 (33, 195) 0.099
LDH/(U/L), M (P25, P75) 779 (505, 1 432) 455 (296, 805) 0.003
ALB/(g/L), x ?±s 29.7±6.6 33.9±6.2 0.001
TG/(mmol/L), M (P25, P75) 2.6 (1.4, 4.1) 2.2 (1.4, 3.2) 0.216
TBIL/(mmol/L), M (P25, P75) 14.0 (10.3, 66.5) 13.3 (9.0, 25.2) 0.387
DBIL/(mmol/L), M (P25, P75) 6.8 (3.1, 47.2) 5.8 (3.1, 14.6) 0.347
Fib/(g/L), M (P25, P75) 2.01 (1.33, 3.65) 2.79 (1.91, 3.62) 0.011
D-D/(μg/L), M (P25, P75) 2247 (853, 5 761) 812 (257, 3 027) 0.002
FDP/(mg/L), M (P25, P75) 19.0 (7.9, 50.3) 7.7 (2.5, 24.0) 0.002
PT/s, M (P25, P75) 12.4 (10.8, 14.7) 12.2 (11.3, 14.0) 0.647
APTT/s, M (P25, P75) 33.2 (29.0, 40.8) 30.9 (28.0, 35.9) 0.044
Mortality, n (%) 7 (15.2) 10 (13.0) 0.729

表4

死亡组与存活组的临床参数比较"

Items Death group (n=17) Survival group (n=106) P
Age/years, M (P25, P75) 57 (30, 75) 44 (29, 56) 0.101
Male/female, n 11/6 58/48 0.441
Fever, n (%) 15 (88.2) 85 (80.2) 0.649
Splenomegaly, n (%) 8 (47.1) 43 (40.6) 0.614
Hepatomegaly, n (%) 5 (29.4) 17 (16.0) 0.320
Lymphadenopathy, n (%) 8 (47.1) 45 (42.5) 0.722
Disturbance of consciousness, n (%) 8 (47.1) 8 (7.5) 0.000
Initial ferritin/(μg/L), M (P25, P75) 11 225 (2 648, 28 526) 13 801(10 209, 22 242) 0.638
Ferritin MAX/(μg/L), M (P25, P75) 22 349 (13 621, 39 473) 18 177 (12 601, 34 026) 0.501
WBC/(×109/L), M (P25, P75) 4.6 (1.1, 15.1) 4.6 (2.7, 8.6) 0.814
Neu /(×109/L), M (P25, P75) 3.3 (0.6, 6.9) 3.2 (1.6, 6.2) 0.981
Hb/(g/L), x ?±s 87.8±22.0 96.4±24.9 0.116
PLT/(×109/L), M (P25, P75) 26 (13, 38) 67 (23, 165) 0.013
ALT/(U/L), M (P25, P75) 68 (27, 252) 56 (26, 162) 0.648
AST/(U/L), M (P25, P75) 117 (39, 642) 65 (36, 151) 0.290
LDH/(U/L), M (P25, P75) 714 (244, 2 479) 492 (294, 761) 0.183
ALB/(g/L), x ?±s 30.6±5.8 32.8±6.7 0.230
TG/(mmol/L), M (P25, P75) 2.2 (1.1, 3.5) 2.4 (1.4, 4.4) 0.199
TBIL/(mmol/L), M (P25, P75) 27.8 (12.2, 111.8) 12.6 (8.4, 27.2) 0.045
DBIL/(mmol/L), M (P25, P75) 17.3 (6.7, 71.3) 5.2 (2.7, 14.8) 0.017
Fib/(g/L), M (P25, P75) 2.34 (1.49, 3.69) 2.57 (1.85, 3.48) 0.504
D-D/(μg/L), M (P25, P75) 1 615 (167, 4 067) 848 (308, 3 146) 0.889
FDP/(mg/L), M (P25, P75) 11.2 (3.8, 32.0) 7.7 (2.8, 23.1) 0.665
PT/s, x ?±s 14.6±3.6 12.6±2.5 0.046
APTT/s, x ?±s 39.2±14.5 32.0±6.2 0.069
HLH ratio, n (%) 7 (41.2) 39 (36.8) 0.729
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