Albumin administration in patients with cirrhosis: Current role and novel perspectives

Mortality in cirrhosis is mostly associated with the development of clinical decompensation, characterized by ascites, hepatic encephalopathy, variceal bleeding, or jaundice. Therefore, it is important to prevent and manage such complications. Traditionally, the pathophysiology of decompensated cirrhosis was explained by the peripheral arterial vasodilation hypothesis, but it is currently understood that decompensation might also be driven by a systemic inflammatory state (the systemic inflammation hypothesis). Considering its oncotic and nononcotic properties, albumin has been thoroughly evaluated in the prevention and management of several of these decompensating events. There are formal evidence-based recommendations from international medical societies proposing that albumin be administered in individuals with cirrhosis undergoing large-volume paracentesis, patients with spontaneous bacterial peritonitis, those with acute kidney injury (even before the etiological diagnosis), and those with hepatorenal syndrome. Moreover, there are a few randomized controlled trials and meta-analyses suggesting a possible role for albumin infusion in patients with cirrhosis and ascites (long-term albumin administration), individuals with hepatic encephalopathy, and those with acute-on-chronic liver failure undergoing modest-volume paracentesis. Further studies are necessary to elucidate whether albumin administration also benefits patients with cirrhosis and other complications, such as individuals with extraperitoneal infections, those hospitalized with decompensated cirrhosis and hypoalbuminemia, and patients with hyponatremia.     

Intravenous albumin infusion is an effective therapy for hyponatraemia in cirrhotic patients with ascites.

The treatment of moderate to severe hyponatraemia in patients with decompensated liver disease is unsatisfactory. We report our preliminary experience using intravenous infusion of albumin to treat this condition. Three patients with cirrhosis, ascites, and hyponatraemia responded satisfactorily to treatment; one patient with fulminant hepatitis B did not respond. Intravenous albumin infusion is a safe and effective therapy for patients with cirrhosis complicated by hyponatraemia. Its main role may be in preparing patients for surgery, particularly liver transplantation.     

脐带间充质干细胞经肝动脉灌注治疗失代偿期肝硬化患者

目的 观察人脐带间充质干细胞治疗失代偿期肝硬化患者的有效性.方法 失代偿期乙型肝炎肝硬化患者10例,经肝动脉灌注人脐带间充质干细胞2×107个.比较患者在移植前及移植后1、4、8、12、24周肝功能以及临床病情的变化情况.结果 随访过程中,患者乏力、尿少、水肿症状在第1～2周即明显缓解,食欲较术前明显增加,腹水消退快,...     

Early administration of branched-chain amino acid granules

The effect of malnutrition on survival in patients with decompensated liver cirrhosis has not been well defined. Nutritional intervention with branched-chain amino acid (BCAA) can increase serum albumin concentration in patients with decompensated cirrhosis but its effects on survival are unclear. The BCAA to tyrosine ratio (BTR) is a surrogate marker (the normal range of BTR is between 4.41 and 10.05, and a Fischer's ratio of 1.8 corresponds to a BTR of 3.5) in patients with decompensated liver cirrhosis, and BCAA inhibits hepatic carcinogenesis in patients with compensated cirrhosis. This review discusses data regarding the effect of early administration of BCAA granules based on the ratio of BCAA to BTR on prognosis in patients with cirrhosis.     

Management of ascites in patients with end-stage liver disease

Ascites is the most common complication in patients with decompensated cirrhosis. Approximately 50% of patients with compensated cirrhosis will develop ascites over a 10-year period. This occurrence is an important milestone in the natural history of end-stage liver disease because only 50% of patients survive 2 to 5 years (depending on the cause of cirrhosis) after its onset. Salt restriction and diuretics are the mainstays of therapy, and these measures are effective in approximately 90% of patients. Large-volume paracentesis or transjugular intrahepatic portosystemic shunt can be used in patients with refractory ascites as either a bridge to transplant or as palliation. Cirrhotic patients with ascites should be carefully monitored for the development of bacterial peritonitis, and those at greatest risk should receive antibiotic prophylaxis. When spontaneous bacterial peritonitis is suspected, prompt diagnostic paracentesis followed by broad-spectrum antibiotics and albumin infusion can be life saving. Orthotopic liver transplantation should be considered in all patients with decompensated liver disease with or without ascites.     

Phase 1 human trial of autologous bone marrow-hematopoietic stem cell transplantation in patients with decompensated cirrhosis

AIM： TO evaluate safety and feasibility of autologous bone marrow-enriched CD34^＋ hematopoietic stem cell Tx through the hepatic artery in patients with decompensated cirrhosis.
METHODS： Four patients with decompensated cirrhosis were included. Approximately 200 mL of the bone marrow of the patients was aspirated, and CD34^＋ stem cells were selected. Between 3 to 10 million CD34^＋ cells were isolated. The cells were slowly infused through the hepatic artery of the patients.
RESULTS： Patient 1 showed marginal improvement in serum albumin and no significant changes in other test results. In patient 2 prothrombin time was decreased; however, her total bilirubin, serum creatinine, and Model of End-Stage Liver Disease （MELD） score worsened at the end of follow up. In patient 3 there was improvement in serum albumin, porthrombin time （PT）, and MELD score. Patient 4 developed radiocontrast nephropathy after the procedure, and progressed to type 1 hepatorenal syndrome and died of liver failure a few days later. Because of the major side effects seen in the last patient, the trial was prematurely stopped.
CONCLUSION： Infusion of CD34^＋ stem cells through the hepatic artery is not safe in decompensated cirrhosis. Radiocontrast nephropathy and hepatorenal syndrome could be major side effects. However, this study does not preclude infusion of CD34^＋ stem cells through other routes.     

Efficacy and safety of albumin infusion for overt hepatic encephalopathy: A systematic review and meta-analysis

Background and AimsThe efficacy and safety of albumin infusion for treatment and prevention of overt hepatic encephalopathy (OHE) among cirrhosis patients remained controversial. We performed a systematic review and meta-analysis to evaluate the benefit of albumin infusion for the treatment and prevention of OHE.MethodsWe performed a systematic search of 4 electronic databases up to 31st January 2021. The primary outcome was the resolution of OHE. Secondary outcomes were inpatient mortality and albumin-associated adverse events. We assessed the pooled odds’ risk, pooled mean differences, 95% confidence interval and heterogeneity using Review Manager Version 5.3.ResultsA total of 12 studies (2,087 subjects) were identified. Among cirrhosis patients with OHE, albumin infusion was associated with a lower pooled risk of OHE (OR=0.43, 95%CI: 0.27, 0.68; I²=0%). Among patients without baseline OHE, albumin infusion was associated with a lower pooled risk of developing OHE (OR=0.53, 95%CI: 0.32, 0.86; I²=62%). Albumin infusion was associated with a lower pooled risk of inpatient mortality (OR=0.36, 95%CI: 0.21, 0.60; I²=0%).ConclusionWell-powered randomized trials are required to confirm the benefits of albumin infusion for the prevention and treatment of overt hepatic encephalopathy among decompensated cirrhosis patients.     

Clinical comparison of branched-chain amino acid (l-Leucine, l-Isoleucine, l-Valine) granules and oral nutrition for hepatic insufficiency in patients with decompensated liver cirrhosis (LIV-EN study).

This multicenter study compared the effects of branched-chain amino acid granules (Livact((R)) Granules, LIV) and an enteral nutrient for chronic hepatic failure (Aminoleban((R)) EN, EN) on serum albumin in patients with decompensated liver cirrhosis. This study enrolled "patients with decompensated liver cirrhosis associated with hepatic encephalopathy who were suffering from hypoalbuminemia in spite of adequate food intake," a condition for which both drugs are indicated. Enrolled patients were randomized to the two groups according to the central registration method. This study continued for 24 weeks. Selected foods were supplied to each patient in principle so that caloric and protein intakes were standardized between the two groups. A total of 281 patients were enrolled. LIV was not inferior to EN concerning the primary efficacy endpoint changes in serum albumin.     

Sofosbuvir plus velpatasvir treatment for hepatitis C virus in patients with decompensated cirrhosis: a Japanese real-world multicenter study

Background

Real-world data on the efficacy and safety of sofosbuvir plus velpatasvir (SOF/VEL) treatment for patients with hepatitis C virus (HCV)-related decompensated cirrhosis are limited in Japan.

Methods

A total of 190 patients with compensated (108) or decompensated (82) cirrhosis who initiated direct-acting antiviral (DAA) treatment between February 2019 and August 2019 were enrolled. Sustained virologic response (SVR) was defined as undetectable serum HCV-RNA at 12 weeks after the end of treatment (EOT).

Results

The SVR12 rates were 92.6% in patients with compensated cirrhosis and 90.2% in patients with decompensated cirrhosis (p = 0.564), and the treatment completion rates were 98.1% and 96.3%, respectively (p = 0.372). In patients with decompensated cirrhosis, 3 patients discontinued treatment and 2 patients died because of liver-related events. In patients with decompensated cirrhosis with SVR12, 50% of patients with Child–Pugh class B at baseline showed improvement to class A at SVR12, and 27% and 9% of patients with Child–Pugh class C at baseline showed improvement to class B and class A at SVR12, respectively. Patients who achieved SVR12 showed elevated serum albumin levels at the EOT, which were further elevated at SVR12, but no elevated serum albumin levels after the EOT were observed in patients with baseline serum albumin levels less than 2.8 g/dl.

Conclusions

Real-world efficacy of SOF/VEL treatment for patients with decompensated cirrhosis was similar to Japanese phase 3 study, although treatment discontinuation and death related to liver disease occurred. In patients with poor hepatic reserve, whether it improves continuously after viral clearance requires further evaluation.

     

Evidence for altered hepatic gluconeogenesis in patients with cirrhosis using in vivo 31-phosphorus magnetic resonance spectroscopy

BACKGROUND AND AIMS: Alterations in gluconeogenesis in the diseased liver can be assessed non-invasively using magnetic resonance spectroscopy by measuring changes in phosphomonoester resonance which contains information regarding several metabolites, including the phosphorylated intermediates of the gluconeogenic pathway. METHODS: 31P magnetic resonance spectroscopy was used to determine changes in phosphomonoesters following bolus infusions of 2.8 mmol/kg L-alanine in five patients with functionally compensated cirrhosis and in five patients with functionally decompensated cirrhosis. RESULTS: Compared with six healthy volunteers, baseline phosphomonoester values were elevated by 35% (p<0.05) in the compensated cirrhosis group and by 57% (p<0.01) in the decompensated cirrhosis group. Following alanine infusion, phosphomonoesters in healthy volunteers increased by 46% from baseline values (p<0.01), in patients with compensated cirrhosis by 27% (p<0.02) but those with decompensated cirrhosis showed no increase from baseline. There was a reduction in the percentage of inorganic phosphate signal in all subjects. CONCLUSIONS: By analysing changes in phosphomonoester and inorganic phosphate resonances it is possible to discern clear metabolic differences between healthy volunteers and patients with cirrhosis of varying severity using magnetic resonance spectroscopy. Those patients with functionally decompensated cirrhosis have higher percentage baseline phosphomonoester values but the absence of phosphomonoester elevation following L-alanine infusion suggests that they are unable to mount a significant metabolic response with a progluconeogenic stimulus.     

肝硬化顽固性腹水的治疗现状

顽固性腹水是肝硬化失代偿期常见严重并发症之一,其发生机制较为复杂,对患者生活质量和预后影响极大。及时、正确、有效地治疗腹水对肝硬化患者尤为重要。近年对顽固性腹水的治疗提出了许多新的方法和途径,本文就其治疗现状,包括基础治疗、利尿剂的应用、改善肝肾血液循环、大量放腹水联合白蛋白输注等作一概述。     

A prospective and comparative cohort study on efficacy and drug resistance during long-term lamivudine treatment for various stages of chronic hepatitis B and cirrhosis

Background and Aims: A prospective , non‐randomized cohort study on long‐term lamivudine treatment , comparing efficacy, drug resistance, and prognosis for various stages of chronic hepatitis B virus (HBV)–related liver disease was performed to elucidate the significance and indication of lamivudine for individual patients at each stage of disease. Methods: A total of 158 cases consisting of 87 chronic hepatitis, 28 compensated cirrhosis, and 43 decompensated cirrhosis, with serum HBV‐DNA > 5 log₁₀ copies/mL and with elevated alanine aminotransferase (ALT) over twice the upper normal limit or complications of hepatic insufficiency, were administered 100 mg of lamivudine daily and monitored for HBV markers, biochemistry, and prognosis. Results: Lamivudine reduced HBV‐DNA and ALT equally in all groups. Serum albumin, prothrombin time (%), and platelet count increased in all groups. The increased margin of albumin was the highest in the decompensated cirrhosis and higher in the compensated cirrhosis than the chronic hepatitis groups. Cumulative incidence of virologic breakthrough was 16%, 42%, 49%, and 53% at 12, 24, 36, and 48 months, respectively, and the strongest predictive factor for lamivudine resistance was persistent HBV‐DNA at 3 months. Ascites, encephalopathy, and jaundice improved in the majority of patients with decompensated cirrhosis. On the other hand, hepatic failure developed or deteriorated in 10 patients after virologic breakthrough, and nine of them had decompensated cirrhosis. Conclusions: Lamivudine was effective in reducing HBV‐DNA and improving hepatic reserve at all stages and was most beneficial and significant for decompensated cirrhosis. Meanwhile, close monitoring of viral load and immediate rescue treatment for lamivudine resistance is necessary to prevent hepatic failure in decompensated cirrhosis.     

Clinical value of increased serum creatinine concentration as predictor of short-term outcome in decompensated cirrhosis

BACKGROUND: The purpose of this study was to assess whether serum creatinine concentration alone or associated with other biological parameters was an independent predictor of short-term mortality in patients with decompensated cirrhosis. METHODS: A total of 212 consecutive episodes of decompensated cirrhosis in patients admitted to the hospital between January 1999 and December 2001 were reviewed retrospectively. Depending on a serum creatinine concentration equal to or greater than 1.5 mg/dL at the time of admission, patients were divided into decompensated cirrhosis with renal failure (101 episodes in 59 patients, aged 69.8 +/- 10 years) and without renal failure (111 episodes in 61 patients, aged 64.5 +/- 13 years). Outcome (alive, death) during the episode of decompensation of liver disease and outcome at 90 days after admission were assessed. RESULTS: Differences in the frequency of variables according to outcome in the overall episodes of decompensated cirrhosis with and without renal failure showed significant differences between patients who died and those who were alive both at hospital discharge and at 90 days in serum bilirubin, Child-Pugh score, MELD (model for end-stage liver disease) score, and serum creatinine levels. In the multivariate analysis, serum creatinine was not an independent predictor of outcome. The prediction accuracy according to the area under the ROC (receiver operating characteristic) curve was greater for the MELD scale than for serum creatinine. CONCLUSIONS: Serum creatinine concentration is a parameter that should be included in the prognostic assessment of patients with decompensated cirrhosis, but should be combined with other specific parameters of liver function, such as bilirubin, albumin, and the international normalized ratio (INR) for prothrombin time.     

骨髓干细胞肝动脉移植治疗失代偿期肝硬化87例

目的观察骨髓干细胞肝动脉移植治疗失代偿期肝硬化的疗效,为失代偿期肝硬化的临床治疗提供新思路和新方法。方法选择我院感染科的失代偿期肝硬化住院患者87例,年龄27～65岁,平均年龄46.7±8.3岁,其中乙型肝炎肝硬化67例,丙型肝炎肝硬化2例,原发性胆汁性肝硬化8例,酒精性肝硬化9例,原因不明性肝硬化1例。87例失代偿期肝硬化患者在无菌条件下,抽取骨髓200ml,分离纯化骨髓干细胞。在局部麻醉下,将分离的骨髓干细胞经肝动脉移植入肝脏。观察患者移植后第4周的临床疗效、症状改善情况及术后的不良反应。结果在移植后第4周,患者血浆白蛋白由31.5±5.1g/L升高到33.9±6.0g/L（P〈0.01）;凝血酶原时间由17.4±5.6s下降到15.8±4.7s（P〈0.01）;天门冬氨酸氨基转移酶、总胆红素和甲胎蛋白水平在移植前后无差异性变化（P〉0.05）;胸水消失10例,腹水消失23例,腹胀减轻17例,下肢浮肿消退21例。术中术后未发生严重并发症。结论骨髓干细胞肝动脉移植治疗失代偿期肝硬化有较好的近期疗效,且安全可靠、不良反应小,值得临床进一步研究。     

肝动脉超选灌注自体骨髓干细胞治疗失代偿期乙型肝炎肝硬化的临床研究

目的 分析肝动脉超选灌注自体骨髓干细胞对失代偿期乙型肝炎(乙肝)肝硬化患者的疗效及安全性.方法 选择失代偿期乙肝肝硬化患者20例,从髂后上棘抽取骨髓,体外分离纯化骨髓源性干细胞,通过肝动脉超选注入肝脏,在移植后2、4、8、12周复查肝功能,观察实验室指标变化及不良反应情况.同时选取常规治疗的失代偿期乙肝肝硬化患者20例...     

Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B

The prognosis of decompensated cirrhosis resulting from chronic hepatitis B is poor, and the benefits of treatment with interferon are outweighed by serious side effects and by the risk of fatal exacerbation of disease activity. Lamivudine rapidly reduces hepatitis B virus (HBV)-DNA in serum to undetectable levels. We have treated 35 patients with chronic hepatitis B and decompensated cirrhosis with lamivudine 100 mg or 150 mg orally once daily. Pretreatment, all were positive for HBV-DNA in serum. Ten had Child-Pugh class B and 25 had Child-Pugh class C liver disease. Seven patients underwent liver transplantation within 6 months of treatment initiation, 5 patients died within 6 months, and 23 patients were treated for at least 6 months (mean = 19 months). In a majority of these 23 cases, there was a slow but marked improvement in liver function, which was most apparent after 9 months of treatment, with a decrease in serum bilirubin from 67 +/- 13 to 30 +/- 4 micromol/L (P <.05, baseline vs. 9 months), an increase in serum albumin from 27 +/- 1 to 34 +/- 1g/L (P <.05), and a decrease in Child-Pugh score from 10.3 +/- 0.4 to 7.5 +/- 0.5 (P <.05). Three patients developed resistance to lamivudine because of a mutation in the YMDD motif, but liver function did not deteriorate. We conclude that inhibition of viral replication with lamivudine results in a significant improvement of liver function in patients with decompensated HBV cirrhosis, but the long-term benefits remain uncertain.     

Prognostic Factors in Compensated and Decompensated Cirrhosis

There are an increasing number of studies that evaluate predictive factors, mostly of death, in cirrhosis. These are different depending on the presence of compensated or decompensated cirrhosis. In compensated cirrhosis the main event to predict is decompensation. The degree of portal hypertension as determined by the hepatic venous pressure gradient (HVPG) and serum albumin levels are the most relevant predictors of decompensation. Since HVPG determination is obtained through an invasive procedure, recent studies have examined alternative non-invasive methods to establish the presence of clinically significant portal hypertension. In decompensated cirrhosis the main event to predict is death and “further decompensation”, the event that most commonly occurs prior to death. The Child and MELD scores are the most important predictors of death in decompensated disease. Child score continues to be a useful stratifying tool in all patients with cirrhosis. Specific predictive factors in each type of clinical decompensation are discussed.     

原发性胆汁性肝硬化失代偿期的临床特征

目的了解原发性胆汁性肝硬化(PBC)失代偿期的临床特征。方法回顾性分析204例PBC患者(包括代偿期113例,失代偿期91例)的人口统计学、实验室检查、临床表现及预后模型积分等,研究失代偿期PBC的临床特征,并且与乙型肝炎肝硬化失代偿期(乙肝组,51例)、丙型肝炎肝硬化失代偿期(丙肝组,20例)、酒精性肝硬化失代偿期(ALD组,51例)患者的临床特征进行比较。统计学处理采用t检验、方差分析及χ2检验。结果 (1)PBC失代偿期患者往往高龄,血细胞计数、血脂水平、白蛋白、胆碱酯酶及凝血酶原活动度明显降低,国际标准化比值、总胆红素及直接胆红素水平显著升高,Child-Pugh分级、终末期肝病模型、Mayo等模型积分均明显升高(P<0.05)。(2)与乙肝、丙肝及ALD组失代偿期肝硬化相比,PBC失代偿期患者女性比例较多,血清碱性磷酸酶显著升高,凝血酶原时间延长较少,更常见瘙痒症状(与ALD、丙肝组相比,P<0.05),上消化道出血发生率较高(与乙肝、丙肝组相比,P<0.05),更常合并干燥综合征、骨质疏松,但肝细胞癌发生率较低。结论 PBC多发于中老年女性,与其他病因所致肝硬化失代偿期患者相比,失代偿期PBC有一些显著不同的临床特征。     

Hepatocyte transplantation in rats with decompensated cirrhosis

Hepatocyte transplantation improves the survival of laboratory animals with experimentally induced acute liver failure and the physiological abnormalities associated with liver-based metabolic deficiencies. The role of hepatocyte transplantation in treating decompensated liver cirrhosis, however, has not been studied in depth. To address this issue, cirrhosis was induced using phenobarbital and carbon tetrachloride (CCL(4)) and animals were studied only when evidence of liver failure did not improve when CCL(4) was held for 4 weeks. Animals received intrasplenic transplantation of syngeneic rat hepatocytes (G1); intraperitoneal transplantation of syngeneic rat hepatocytes (G2); intraperitoneal transplantation of a cellular homogenate of syngeneic rat hepatocytes (G3); intraperitoneal transplantation of syngeneic rat bone marrow cells (G4); or intrasplenic injection of Dulbecco's modified Eagle medium (DMEM) (G5). After transplantation, body weight and serum albumin levels deteriorated over time in all control (G2-G5) animals but did not deteriorate in animals receiving intrasplenic hepatocyte transplantation (G1) (P <.01). Prothrombin time (PT), total bilirubin, serum ammonia, and hepatic encephalopathy score were also significantly improved toward normal in animals receiving intrasplenic hepatocyte transplantation (P <. 01). More importantly, survival was prolonged after a single infusion of hepatocytes and a second infusion prolonged survival from 15 to 128 days (P <.01). Thus, hepatocyte transplantation can improve liver function and prolong the survival of rats with irreversible, decompensated cirrhosis and may be useful in the treatment of cirrhosis in humans.