Abstract：
OBJECTIVE: The role of histamine in advanced chronic liver disease (ACLD) is poorly understood. We investigated plasma histamine levels across ACLD stages and their prognostic value.
METHODS: We included patients with evidence of ACLD, defined by portal hypertension (hepatic venous pressure gradient [HVPG] ≥6 mmHg) and/or a liver stiffness measurement by transient elastography ≥10 kPa, who underwent HVPG measurement between 2017 and 2020. Acute-on-chronic liver failure (ACLF) and/or liver-related death were defined as composite endpoint.
RESULTS: Of 251 patients, 82.5% had clinically significant portal hypertension (median HVPG: 17 mmHg [interquartile range (IQR) 12-21]) and 135 patients (53.8%) were decompensated at baseline. Median plasma histamine was 8.5 nmol/L (IQR: 6.4-11.5), 37.1% of patients showed elevated values (>9.9 nmol/L). Histamine levels did not differ significantly across Child-Turcotte-Pugh (CTP) stages nor strata of model for end-stage liver disease (MELD) or HVPG. Histamine levels correlated with markers of circulatory dysfunction (i.e. sodium, renin and aldosterone). During a median follow-up of 29.2 months, 68 patients developed ACLF or liver-related death. In univariate as well as in multivariate analysis (adjusting for age, sex, HVPG as well as either MELD, clinical stage, and serum albumin or CTP and serum sodium), elevated histamine levels remained associated with the composite endpoint. CTP-based multivariate model adjusted sub-distribution hazard ratio (asHR): 1.010 (95% CI: 1.004-1.021), p < .001; MELD-based multivariate model asHR: 1.030 (95% CI: 1.017-1.040), p < .001.
CONCLUSIONS: High levels of histamine were linked to circulatory dysfunction in ACLD patients and independently associated with increased risks of ACLF or liver-related death. Further mechanistic studies on the link between histamine signalling and development of hyperdynamic circulation and ACLF are warranted.
METHODS: We included patients with evidence of ACLD, defined by portal hypertension (hepatic venous pressure gradient [HVPG] ≥6 mmHg) and/or a liver stiffness measurement by transient elastography ≥10 kPa, who underwent HVPG measurement between 2017 and 2020. Acute-on-chronic liver failure (ACLF) and/or liver-related death were defined as composite endpoint.
RESULTS: Of 251 patients, 82.5% had clinically significant portal hypertension (median HVPG: 17 mmHg [interquartile range (IQR) 12-21]) and 135 patients (53.8%) were decompensated at baseline. Median plasma histamine was 8.5 nmol/L (IQR: 6.4-11.5), 37.1% of patients showed elevated values (>9.9 nmol/L). Histamine levels did not differ significantly across Child-Turcotte-Pugh (CTP) stages nor strata of model for end-stage liver disease (MELD) or HVPG. Histamine levels correlated with markers of circulatory dysfunction (i.e. sodium, renin and aldosterone). During a median follow-up of 29.2 months, 68 patients developed ACLF or liver-related death. In univariate as well as in multivariate analysis (adjusting for age, sex, HVPG as well as either MELD, clinical stage, and serum albumin or CTP and serum sodium), elevated histamine levels remained associated with the composite endpoint. CTP-based multivariate model adjusted sub-distribution hazard ratio (asHR): 1.010 (95% CI: 1.004-1.021), p < .001; MELD-based multivariate model asHR: 1.030 (95% CI: 1.017-1.040), p < .001.
CONCLUSIONS: High levels of histamine were linked to circulatory dysfunction in ACLD patients and independently associated with increased risks of ACLF or liver-related death. Further mechanistic studies on the link between histamine signalling and development of hyperdynamic circulation and ACLF are warranted.
摘要：
目的：组胺在晚期慢性肝病（ACLD）中的作用知之甚少。我们调查了ACLD阶段的血浆组胺水平及其预后价值。
方法：我们纳入了有ACLD证据的患者，由门脉高压（肝静脉压力梯度[HVPG]≥6mmHg）和/或瞬时弹性成像≥10kPa的肝脏硬度测量定义，在2017年至2020年之间进行了HVPG测量。急性慢性肝衰竭（ACLF）和/或肝脏相关死亡被定义为复合终点。
结果：在251名患者中，82.5％患有临床上显着的门静脉高压症（HVPG中位数：17mmHg[四分位距（IQR）12-21]），基线时失代偿的患者为135例（53.8％）。血浆组胺中位数为8.5nmol/L（IQR：6.4-11.5），37.1％的患者显示升高的值（>9.9nmol/L）。在Child-Turcotte-Pugh（CTP）阶段和终末期肝病（MELD）或HVPG模型的各个阶段，组胺水平都没有显着差异。组胺水平与循环功能障碍的标志物相关(即钠，肾素和醛固酮)。在29.2个月的中位随访期间，68例患者发生ACLF或肝脏相关死亡。在单变量和多变量分析中(调整年龄，性别,HVPG以及MELD，临床分期,和血清白蛋白或CTP和血清钠)，组胺水平升高仍然与复合终点相关.基于CTP的多变量模型调整后的子分布风险比(asHR):1.010(95%CI:1.004-1.021),p<.001；基于MELD的多变量模型asHR：1.030（95%CI：1.017-1.040），p<.001。
结论：高水平的组胺与ACLD患者的循环功能障碍有关，并且与ACLF或肝脏相关死亡的风险增加独立相关。有必要对组胺信号传导与高动力循环和ACLF的发展之间的联系进行进一步的机理研究。
方法：我们纳入了有ACLD证据的患者，由门脉高压（肝静脉压力梯度[HVPG]≥6mmHg）和/或瞬时弹性成像≥10kPa的肝脏硬度测量定义，在2017年至2020年之间进行了HVPG测量。急性慢性肝衰竭（ACLF）和/或肝脏相关死亡被定义为复合终点。
结果：在251名患者中，82.5％患有临床上显着的门静脉高压症（HVPG中位数：17mmHg[四分位距（IQR）12-21]），基线时失代偿的患者为135例（53.8％）。血浆组胺中位数为8.5nmol/L（IQR：6.4-11.5），37.1％的患者显示升高的值（>9.9nmol/L）。在Child-Turcotte-Pugh（CTP）阶段和终末期肝病（MELD）或HVPG模型的各个阶段，组胺水平都没有显着差异。组胺水平与循环功能障碍的标志物相关(即钠，肾素和醛固酮)。在29.2个月的中位随访期间，68例患者发生ACLF或肝脏相关死亡。在单变量和多变量分析中(调整年龄，性别,HVPG以及MELD，临床分期,和血清白蛋白或CTP和血清钠)，组胺水平升高仍然与复合终点相关.基于CTP的多变量模型调整后的子分布风险比(asHR):1.010(95%CI:1.004-1.021),p<.001；基于MELD的多变量模型asHR：1.030（95%CI：1.017-1.040），p<.001。
结论：高水平的组胺与ACLD患者的循环功能障碍有关，并且与ACLF或肝脏相关死亡的风险增加独立相关。有必要对组胺信号传导与高动力循环和ACLF的发展之间的联系进行进一步的机理研究。
