Microcirculatory disturbance in acute liver injury

Abstract

Microcirculatory disturbance is thought to be involved in the pathogenesis of acute liver injury (ALI). The current study examined the pathophysiologic role of hepatic microcirculatory disturbance in patients with ALI and in mouse models of ALI. Using serum aminotransferase (ALT)/lactate dehydrogenase (LDH) ratio as a hypoxic marker, 279 patients with ALI were classified into the low ALT/LDH ratio (ALT/LDH ≤1.5) and high ALT/LDH ratio group (ALT/LDH >1.5). In the low ALT/LDH ratio group, serum ALT, LDH, fibrinogen degradation products and prothrombin time-international normalized ratio were increased relative to the high ALT/LDH ratio group. Histologically, hepatic expression of tissue factor (TF) and hypoxia-related proteins was enhanced in the low ALT/LDH ratio group, and this was accompanied by sinusoidal fibrin deposition. Sinusoidal hypercoagulation and intrahepatic hypoxia was also analyzed in two different mouse models of ALI; Concanavalin A (ConA) mice and Galactosamine/tumor necrosis factor (TNF)-α (G/T) mice. Serum ALT/LDH ratio in ConA mice was significantly lower compared with G/T mice. Pimonidazole staining revealed the upregulation of hypoxia-related proteins in ConA mice. Recombinant human soluble thrombomodulin improved liver damage in ConA mice in association with reduced sinusoidal hypercoagulation and intrahepatic hypoxia. The present study provides evidence that serum ALT/LDH ratio aids in the identification of patients with ALI and intrahepatic hypoxia as a result of microcirculatory disturbance. The results facilitate the improved understanding of the pathogenesis of ALI, thereby offering a novel therapeutic strategy against ALI, which arises from sinusoidal hypercoagulation.

Transcatheter Arterial Steroid Injection Therapy Improves the Prognosis of Patients with Acute Liver Failure

“…We strati ed patients with ALF into high-LDH and low-LDH subgroups based on their serum ALT/LDH ratio. The high-LDH subgroup had serum ferritin elevation, microcirculatory disturbance, and subsequent intrahepatic hypoxia [20]. In this study, we analyzed the effectiveness of TASIT for ALF in high-and low-LDH subgroups and found that TASIT improved the prognosis and increased PT% in ALF in the high-LDH, but not in the low-LDH, subgroup.…”

“…The normal ranges of ALT and LDH in this facility were 6-30 and 119-229 U/L, respectively. To focus on the degree of elevation, we set up an index calculated by the following formula: ALT/LDH ratio = (serum ALT−ULN)/(serum LDH−ULN) (ULN: upper limit of normal) as described previously [20].…”

“…Microcirculatory disturbance and consequent massive hypoxic hepatocyte damage occurred in some patients with ALF. As we had previously shown that the serum ALT/LDH ratio could identify these patients [20], we strati ed them into a high-LDH subgroup (ALT/LDH ratio ≤ 1.5) with hepatic microcirculatory disturbance and a low-LDH subgroup (ALT/LDH ratio > 1.5) (Table 1). The TASIT group had signi cantly higher serum AST, ALT, LDH, and ferritin than the no TASIT group, and this was also the case in both LDH subgroups and the all population.…”

“…We have previously reported that at least some ALI patients develop microcirculatory disturbance and subsequent intrahepatic hypoxia. A serum ALT/LDH ratio ≤ 1.5 re ects intrahepatic hypoxia and correlates with the etiology and clinical manifestations of ALI [20]. However, it is not clear whether the pathogenesis might affect the therapeutic response to TASIT.…”

Transcatheter arterial steroid injection therapy improves the prognosis of patients with acute liver failure

“…The high-LDH subgroup had serum ferritin elevation, microcirculatory disturbance, and subsequent intrahepatic hypoxia. [20] In this study, we analyzed the effectiveness of TASIT for ALF in high- and low-LDH subgroups and found that TASIT improved the prognosis and increased PT% in ALF in the high-LDH, but not in the low-LDH, subgroup. Serum ferritin concentrations increase in acute hepatitis, and the source of ferritin is thought to be damaged hepatocytes.…”