Early-phase prothrombin time-international normalized ratio in acute liver injury indicates the timing of therapeutic intervention and predicts prognostic improvement

Aim

We investigated whether an early-phase prothrombin time-international normalized ratio (PT-INR) is an interventional prognostic indicator for patients with acute liver injury, including acute liver failure.

Methods

This was a multicenter retrospective observational study. We included 595 patients with alanine aminotransferase levels ≥300 U/L due to acute liver injury who were admitted to Kagoshima University Hospital or other collaborative investigation organizations between January 1, 2010, and December 31, 2015. Patients with alanine aminotransferase levels ≥300 U/L and no previous liver disease were defined as having an acute liver injury. Acute liver failure was defined by PT-INR ≥1.5 with or without hepatic encephalopathy in acute liver injury patients. Data were obtained retrospectively from case reports and analyzed.

Results

The PT-INR on day 1 was the most accurate independent prognosis predictor in patients with acute liver injury and acute liver failure. On day 1, the transplant-free survival rates were significantly lower in patients with PT-INR ≥1.3. The transplant-free survival rates were also significantly higher in patients with acute liver injury and acute liver failure, in whom the PT-INR had recovered from ≥1.3 on day 1 to <1.3 by day 8.

Conclusion

Early-phase changes in the PT-INR can predict the prognosis of patients with acute liver injury and acute liver failure. Furthermore, PT-INR ≥1.3 could be an interventional marker, whereas PT-INR <1.3 after 1 week could reflect prognostic improvement.     

Development of a rapid semi-quantitative immunochromatographic assay for serum hepatocyte growth factor and its usefulness in acute liver failure.

Measurement of serum human hepatocyte growth factor (HGF) by enzyme-linked immunosorbent assay (ELISA) is useful for the early diagnosis and prediction of prognosis of patients with acute liver failure (ALF). This ELISA methodology, however, is neither rapid nor convenient for use at the bedside. In this study, we have developed a rapid semi-quantitative immunochromatographic (IC) assay and evaluated its usefulness in assessing patients with acute hepatic injury. Only 100mul of serum is required; the assay can be easily completed in 20min. The values obtained using this novel assay correlated well with the values obtained using the standard ELISA protocol. In addition, the values obtained in the IC assay correlated with clinical course; increased serum HGF levels were associated with an increased frequency of ALF and death. These results indicate that this rapid semi-quantitative IC assay for HGF is useful for the early diagnosis of ALF and prediction of clinical outcome in acute hepatic injury.     

急性肝衰竭的治疗进展

急性肝衰竭(ALF)是一种罕见的危及生命的疾病,病情发展迅速并影响多个器官系统功能,生存率低。早期识别病因及保护重要脏器功能对生存至关重要。近年来,随着人工肝、干细胞移植及肝移植技术不断发展,ALF疗效有明显提高。主要从ALF的病因和累及的主要器官系统两大方面阐述了ALF的治疗,并介绍了人工肝及干细胞移植的最新进展。     

Normotest and abnormal prothrombin in liver transplantation

Abstract: Postoperative changes in coagulation parameters, including the abnormal plasma prothrombin level, were studied in 95 patients who underwent liver transplantation, and the results were compared with the clinical outcome. The patients were classified into four groups: Group I had a satisfactory postoperative course, (n=76), Group II suffered graft failure or death at 31 days or more after transplantation (n=9); Group III suffered graft failure or death from 8 to 30 days after transplantation (n=4); and Group IV suffered graft failure or death within 7 days of transplantation (n=6). The Normotest, which closely reflected liver graft function, showed an increase immediately after transplantation in Group I, II, and III, but showed a marked decrease in Group IV. In patients with severe acute cellular rejection, the plasma level of abnormal prothrombin (desgamma-carboxy prothrombin) was compared with the histology of the liver biopsy specimen. When liver graft function was good after orthotopic transplantation, the Normotest value recovered to the normal range of 70% or more. Subsequently, graft function remained good when the desgamma-carboxy prothrombin level stayed low, whereas acute cellular rejection was indicated by an elevation of des-gamma-carboxy prothrombin. When the Normotest value was lower than 20% for the first 2 days after transplantation, graft failure was likely. Because des-gamma-carboxy prothrombin was not produced by graft with early failure, the des-gamma-carboxy prothrombin level also remained low. Thus, the Normotest value and the des-gamma-carboxy prothrombin level were both useful parameters for assessing hepatic function and rejection after transplantation.     

乙型肝炎病毒相关慢加急性肝衰竭患者肝纤维化、肝功能、病毒学指标及甲胎蛋白水平与预后的关系

目的初步探讨乙型肝炎相关慢加急性肝衰竭(HBV-ACLF)患者血清肝纤维化、肝功能、病毒学指标及甲胎蛋白(AFP)水平与预后的关系。方法根据预后将185例HBV-ACLF患者分为好转组(116例)和无效组(69例),检测血清肝纤维化和肝功能指标、病毒学指标、AFP水平,分析肝纤维化等指标与预后的关系。结果好转组和无效组性别、HBV基因型、HBeAg阳性率、HBV DNA载量、ALT、Alb、CHE比较差异无统计学意义。好转组和无效组平均年龄分别为(43.3±10.1)岁和(48.7±10.1)岁,TBil分别为(295.9±99.6)μmol/L、(355.4±136.8)μmol/L,凝血酶原活动度(PTA)分别为(34.5±7.9)%、(30.4±7.6)%,AFP分别为85(9～4760)ng/L、26(4～529)ng/L,差异皆有统计学意义(P值分别为0.006、0.009、0.0007、0.000),肝纤维化指标中,透明质酸(HA)、Ⅲ型前胶原(PcⅢ)与Ⅳ型胶原(C-Ⅳ)好转组和无效组差异无统计学意义,层粘连蛋白(LN)好转组和无效组分别为657(45～1616)μg/L、306(29～1724)μg/L,差异有统计学意义(P<0.001)。结论血清LN、AFP、TBil、PTA水平、年龄可能对HBV感染慢加急性肝衰竭患者的预后判断有一定意义。     

Aetiology and outcome of acute liver failure

Background:

Acute liver failure (ALF) is a clinical syndrome characterized by the sudden onset of coagulopathy and encephalopathy. The outcome is unpredictable and is associated with high morbidity and mortality. We reviewed our experience to identify the aetiology and study the outcome of acute liver failure.

Methods:

A total of 1237 patients who presented with acute liver failure between January 1992 and May 2008 were included in this retrospective study. Liver transplantation was undertaken based on the King''s College Hospital criteria. Data were obtained from the units prospectively collected database. The following parameters were analysed: patient demographics, aetiology, operative intervention, overall outcome, 30-day mortality and regrafts.

Results:

There were 558 men and 679 women with a mean age of 37 years (range: 8–78 years). The most common aetiology was drug-induced liver failure (68.1%), of which 90% was as a result of a paracetamol overdose. Other causes include seronegative hepatitis (15%), hepatitis B (2.6%), hepatitis A (1.1%), acute Budd–Chiari syndrome (1.5%), acute Wilson''s disease (0.6%), subacute necrosis(3.2%) and miscellaneous (7.8%). Three hundred and twenty-seven patients (26.4%) were listed for liver transplantation, of which 263 patients successfully had the procedure (80.4%). The current overall survival after transplantation was 70% with a median follow-up of 57 months. After transplantation for ALF, the 1-year, 5-year and 10-year survival were 76.7%, 66% and 47.6%, respectively. The 30-day mortality was 13.7%. Out of the 974 patients who were not transplanted, 693 patients are currently alive. Among the 281 patients who died without transplantation, 260 died within 30 days of admission (26.7%). Regrafting was performed in 31 patients (11.8%), the most common indication being hepatic artery thrombosis (11 patients).

Conclusion:

Paracetamol overdose was the most common cause of acute liver failure. Liver transplantation, when performed for acute liver failure, has good long-term survival.     

Experimental research on TECA-I bioartificial liver support system to treat canines with acute liver failure

AIM To evaluate the efficacy and safety of the TECA-Ibloartificial liver support system(BALSS)in treatingcanines with acute liver failure(ALF).METHODS Ten canines with ALF induced by 80% liverresection received BALSS treatment(BALSS group).Blood was perfused through a hollow fiber tube containing1×10~(10) porcine hepatocytes.Four canines with ALF weretreated with BALSS without porcine hepatocytes(controlgroup),and five canines with ALF received drugtreatment(drug group).Each treatment lasted 6 hours.RESULTS BALSS treatment yielded beneficial effects forpartial liver resection-induced ALF canines with survivaland decreased plasma ammonia,ALT,AST and BIL.Therewas an obvious decrease in PT level and increase in PAlevel,and there were no changes in the count oflymphocytes,immunoglobulins(IgA,IgG and IgM)andcomplement(C3 and CA)levels after BALSS treatment.Incontrast,for the canines with ALF in non-hepatocyteBALSS group(control group)and drug group,there wereno significant changes in ammonia,ALT,AST,BIL,PTand PA levels.ALF canines in BALSS group,controlgroup and drug group lived respectively an average timeof 108.0h±12.0h,24.0h±6.0h and 20.4h±6.4h,andthree canines with ALF survived in BALSS group.CONCLUSION TECA-I BALSS is efficacious and safe forALF canines induced by parcial liver resection.     

美国肝病学会急性肝衰竭处置指南要点

1要点 1．1急性肝衰竭（acuteliverfailure,ALF）是发生于无肝病史患者的一种罕见临床症候群,患者因肝功能急剧恶化,表现为意识障碍和凝血功能紊乱。据估计,美国每年大约发生2000例ALF。     

Inappropriate pemoline therapy leading to acute liver failure and liver transplantation

A 36-year-old female, presenting with jaundice, developed acute liver failure requiring orthotopic liver transplantation. On admission, none of the known causative factors for acute hepatitis, including use of drugs, were found to be present. Several days after hospitalization, the patient admitted taking therapy prescribed by a "non-traditional" physician, that she had been using for several years due to overweight and which had recently been modified with the introduction of pemoline. A considerable body of evidence exists in the medical literature showing that pemoline, which is a central nervous system stimulant, has variable hepatotoxic effects, ranging from a mild transient increase of serum transaminases to liver failure, including some lethal cases.     

TECA hybrid artificial liver support system in treatment of acute liver failure

AIM:To assess the efficacy and safety of TECA type hybridartificial liver support system(TECA-HALSS)in providingliver function of detoxification,metabolism and physiologyby treating the patients with acute liver failure(ALF).METHODS:The porcine liver cells(1-2)×10~(10) wereseparated from the Chinese small swine and cultured in thebloreoctor of TECA-BALSS at 37.0℃ and circulated throughthe outer space of the hollow fiber tubes in BALSS.The sixliver failure patients with vadous degree of hepatic comawere treated by TECA-HALSS and with conventionalmedicines.The venous plasma of the patients wasseparated by a plasma separator and treated by charcoaladsorbent or plasma exchange.The plasma circulatedthrough the inner space of the hollow fiber tubes of BALSSand mixed with the patients' blood cells and flew back totheir blood circulation.Some small molecular weightsubstances were exchanged between the plasma andporcine liver cells.Each treatment lasted 6.0-7.0h.Physiological and biochemical parameters were measuredbefore,during and after the treatment.RESULTS:The average of porcine liver cells was(1.0-3.0)×10~(10) obtained from each swine liver using our modifiedenzymatic digestion method.The survival rate of the cellswas 85%-93% by trypan blue stain and AO/PI fluorescentstain.After cultured in TECA-BALSS bioreactor for 6 h,thesurvival rate of cells still remained 70%-85%.At the end ofTECA-HALSS treatment,the levels of plasma NH_3,ALT,TBand DB were significantly decreased.The patients who werein the state of drowsiness or coma before the treatmentimproved their appetite significantly and regainedconsciousness,some petients resumed light physical workon a short period after the trestment.One to two days afterthe treatment,the ratio of PTA increased warkedly.Duringthe treatment,the heart rates,blood pressure,respirationcondition and serum electrolytes(K~ ,Na~ and cr)werestable without thrombosis and bleeding in all the sixpatients.CONCLUSION:TECA-HALSS treatment could be a rapid,safe and efficacious method to provide temporary liversupport for patients with ALF.     

Ratio of circulating follistatin and activin A reflects the severity of acute liver injury and prognosis in patients with acute liver failure

BACKGROUND AND AIM: The activin A-follistatin system is known to play a critical role in hepatocyte regeneration during the repair of liver tissue. However, the relationship between blood levels of these compounds and the severity and prognosis of acute liver injury remains unclear. The aim of this study was to evaluate the clinical significance of circulating activin A and follistatin in patients with acute liver disease. METHODS: Serum activin A and plasma follistatin levels were determined on admission by enzyme-linked immunosorbent assay in 32 patients with acute hepatitis (AH), 23 patients with acute severe hepatitis (ASH) and 16 patients with acute liver failure (ALF). RESULTS: Both serum activin A and plasma follistatin levels were significantly elevated in patients with ASH and ALF when compared with those in patients with AH and normal controls (NC). Although plasma follistatin levels were significantly and positively correlated with serum activin A levels (r = 0.413, P < 0.001), the follistatin and activin A (F/A) ratio showed distinct deviation from NC between AH and ALF patients. The F/A ratio in AH patients was significantly elevated when compared with NC, but was significantly reduced in ALF patients. Furthermore, the F/A ratio in non-surviving ALF patients was significantly lower than that in survivors. Levels of serum activin A and plasma follistatin were significantly and negatively correlated with prothrombin time (PT) and normotest (NT) levels, while the F/A ratio showed significant and positive correlations with PT and NT. CONCLUSIONS: Decreased blood F/A ratio in ALF patients may be a reliable indicator of the severity of acute liver injury and prognosis in ALF.     

儿童急性肝衰竭

儿童急性肝衰竭是一种以肝性脑病、黄疸、凝血障碍和腹水为主要表现的临床综合征,常导致多器官功能障碍,病死率较高,是重症医学面临的救治难题。由于儿童这个群体的特殊性,儿童急性肝衰竭和成人相比在定义、病因以及诊治过程中均有其独特性。近年来随着医学技术的发展,尤其是重症医学的发展使得急性肝衰竭的预后有所改善。儿童肝移植的发展也为儿童急性肝衰竭的治疗提供了更多的机会。     

Imatinib mesylate as a cause of acute liver failure

A 46-year-old patient diagnosed with chronic myeloid leukemia in whom cytogenetic and molecular remission had never been achieved was commenced on Imatinib Mesylate (Gleevec, Novartis Pharmaceuticals Corp., East Hanover, NJ). After 18 months of treatment, she developed abnormal liver function tests and subsequently acute liver failure, requiring transfer to the regional liver unit. The patient proceeded to liver transplantation but later died. The explanted liver had histological features of severe hepatic necrosis. This is the first case described of fatal hepatic necrosis in a patient who has have been on long-term imatinib therapy. This may have implications for long-term use of the drug and emphasizes the need for regular monitoring of liver function.     

异甘草酸镁对D-氨基半乳糖致急性肝衰竭大鼠模型的保护作用

目的探讨异甘草酸镁对D-氨基半乳糖致急性肝衰竭(ALF)大鼠模型的保护作用及其机制。方法 90只SD大鼠随机分为正常组(A组,n=10)、模型组(B组,n=20)、异甘草酸镁低剂量组(C组,n=20)、中剂量组(D组,n=20)和高剂量组(E组,n=20)。A组腹腔内仅注射等量无菌生理盐水,其余4组均一次性腹腔注射10%D-氨基半乳糖。C、D、E 3组在造模30 min后均于尾静脉注射异甘草酸镁注射液(25、50和100 mg/kg)。建模24和48 h后分别取肝组织行HE染色观察肝组织结构的病理变化,收集血清检测各组大鼠肝功能指标[ALT、AST、TBil、白蛋白(Alb)]、促炎症因子[肿瘤坏死因子(TNF)α、白细胞介素(IL)1β、干扰素(IFN)γ]和抑炎症因子[IL-4、IL-10、转化生长因子(TGF)β]水平。计量资料多组间比较采用单因素方差分析,进一步两两比较采用SNK-q检验。结果 5组大鼠的血清ALT、AST、TBil和Alb水平比较差异均有统计学意义(F值分别为74.6、108.9、25.1、58.4,P值均0.05);与A组比较,B组血清ALT、AST和TBil水平显著升高,Alb水平显著降低(P值均0.05);与B组比较,C、D、E 3组ALT、AST、TBil水平显著降低,Alb水平上升,E组变化最明显,差异均有统计学意义(P值均0.05)。5组大鼠的TNFα、IL-lβ、IFNγ、IL-4、IL-10、TGFβ水平比较差异均有统计学意义(F值分别为75.1、58.9、25.4、43.6、66.4、86.8,P值均0.05);与A组比较,B组血清TNFα、IL-lβ、IFNγ、IL-4、IL-10、TGFβ水平显著升高,差异有统计学意义(P值均0.05);与B组比较,C、D、E 3组血清TNFα、IL-1β、IFNγ水平显著降低,IL-4、IL-10、TGF-β水平显著升高,E组变化最明显,差异均有统计学意义(P值均0.05)。结论异甘草酸镁可通过降低促炎因子、升高抗炎因子降低炎症反应,对ALF大鼠具有保护作用。