Objective To investigate the causes of hypoglycemia and the features of clinical indices in patients with liver cirrhosis and diabetes mellitus. Methods A total of 50 patients with liver cirrhosis and diabetes mellitus who were admitted to Beijing YouAn Hospital,Capital Medical University,from January 2017 to June 2019 were enrolled as subjects,among whom 25 patients with one hypoglycemic event were enrolled as experimental group and 25 patients without hypoglycemia were enrolled as control group. Hepatic and renal function,fasting blood glucose,glycosylated hemoglobin,and Child-Pugh class were evaluated for both groups,and the time period and possible causes of hypoglycemia were analyzed. The independent samples t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups,and the chi-square test was used for comparison of categorical data between two groups. Results Compared with the control group,the experimental group had significantly lower levels of fasting blood glucose [6. 10( 3. 45 ～ 8. 96) mmol/L vs 8. 12( 6. 18 ～12. 59) mmol/L,Z =-2. 687,P = 0. 007],cholinesterase [3009. 00( 1788. 50 ～ 4439. 50) U/L vs 4936. 00( 4051. 00 ～ 6740. 50) U/L,Z =-3. 095,P = 0. 002),albumin( 32. 02 ± 7. 07 g/L vs 35. 89 ± 5. 49 g/L,t = 2. 161,P = 0. 036),and glycosylated hemoglobin( 6. 97± 1. 64 mmol/L vs 8. 04 ± 1. 78 mmol/L,t = 2. 047,P = 0. 047). Among the patients in the experimental group,36% had Child-Pugh class B cirrhosis and 36% had Child-Pugh class C cirrhosis,and among the patients in the control group,56% had Child-Pugh class A cirrhosis and 40% had Child-Pugh class B cirrhosis; there was a significant difference in Child-Pugh class between the two groups( χ2=8. 786,P = 0. 012). Most of the patients with liver cirrhosis and diabetes mellitus experienced hypoglycemia in the fasting state in the morning and in the daytime,with the main causes of excessive insulin( 44%) and insufficient food intake or calorie supplementation( 40%),and some patients experienced fasting asymptomatic hypoglycemia( 16%). Conclusion Blood glucose monitoring and management should be taken seriously for patients with liver cirrhosis and diabetes mellitus in clinical practice,in order to reduce the occurrence of hypoglycemia.
按照UDCA治疗应答情况，637例患者中436例发生完全应答，201例为应答不良。性别分布中，完全应答组与应答不良组分布无统计学意义(P值均＞0.05)，基线存在肝硬化的患者UDCA应答率更高(78.9% vs 71.1%，P=0.032)，生化指标中，TBil、AST、ALP、TBA和TC在两组间存在统计学差异(P值均＜0.001)。免疫指标中，应答不良组IgA、IgM水平及抗Gp210阳性率均较高(P值均＜0.05)。预后风险评分中，应答不良组MRS、Globe评分、UK-PBC评分均高于完全应答组(P值均＜0.001)(表 2)。
表
2
UDCA治疗完全应答与应答不良患者基线指标及风险评分差异
Table
2.
Differences of baseline characteristics and risk scores between PBC with complete response and poor response to UDCA treatment
根据IgM预测UDCA应答不良的最佳临界值将患者分为IgM≥1.5×ULN及IgM＜1.5×ULN两组，性别分布、年龄、肝硬化占比在两组中比较差异均无统计学意义(P值均＞0.05)；IgM≥1.5×ULN组AST、ALP、TC显著高于IgM＜1.5×ULN组(P值均＜0.05)；IgM≥1.5×ULN组IgG水平及抗Gp210阳性率显著高于IgM＜1.5×ULN组(P值均＜0.001)。IgM≥1.5×ULN组经过UDCA治疗后发生应答不良患者显著高于IgM＜1.5×ULN组(38.3% vs 27.1%，P=0.003)(表 5)。
表
5
不同IgM水平PBC患者基线临床特征及UDCA疗效比较
Table
5.
Comparison of baseline characteristics and the outcome of UDCA treatment between PBC with different levels of IgM
UDCA是PBC治疗的一线药物，可显著改善部分PBC患者非肝移植存活率[11-12]，但仍有30%~40%的患者对UDCA治疗无应答，本研究中显示UDCA完全应答率为68.4%，对于这部分患者需要及时联合一种或两种二线药物来改善胆汁淤积以预防疾病进展[13]。UDCA治疗可能影响IgM水平，研究[14]发现UDCA能够显著降低细菌CpG诱导的总IgM和IgM-AMA的产生，但对IgG-AMA的水平却无影响。IgM与肝硬化相关症状和肝脏相关事件的发生关系密切，在UDCA联合苯扎贝特治疗过程中，不论ALP及GGT下降与否，当IgM水平持续异常时，患者的预后均较差，其生存期显著低于IgM水平正常化的患者，治疗过程中IgM水平的逐步正常化可能提示预后较好[15]。对于UDCA不完全应答的PBC患者，在给予联合利妥昔单抗治疗后，IgM水平随着肝功能指标的好转而逐步下降[16]。IgM正常化可作为长期预后的预测指标，但初始IgM正常患者IgM水平的变化情况及预测因素尚缺乏研究。在本研究中，UDCA治疗基线IgM平均水平为2.76 g/L，IgM升高的占比为56.0%，在UDCA完全应答组与应答不良组之间，基线IgM水平存在显著性差异(P=0.034)，进一步分析IgM升高与IgM正常组患者的临床特征及在UDCA治疗1年后的疗效差异，发现IgM正常组UDCA应答率高于IgM升高组(71.8% vs 65.8%)，但两组差异无统计学意义(P=0.108)，通过ROC曲线分析获得IgM预测UDCA治疗1年后应答不良风险的最佳临界值(1.5×ULN)，按最佳临界值进行分组后，结果显示IgM＜1.5×ULN组的PBC患者发生UDCA应答率显著高于IgM≥1.5×ULN组(72.9% vs 61.7%, P=0.003)，IgM≥1.5×ULN组发生UDCA应答不良风险是前者的1.416倍(95%CI: 1.129~1.776)，因此基线IgM水平可能有助于预测PBC治疗应答。
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