New management options for end-stage chronic liver disease and acute liver failure: potential for pediatric patients

The management of children with end-stage chronic liver disease and acute liver failure mandates a multidisciplinary approach and intense monitoring. In recent years, considerable progress has been made in developing specific and supportive medical measures, but studies and publications have mainly concerned adult patients. Therapeutic approaches to complications of end-stage chronic liver disease and acute liver failure (e.g. refractory ascites, hepatorenal syndrome, encephalopathy, and cerebral edema) that may be applied to children are reviewed in this article.Mild-to-moderate ascites should be managed by modest salt restriction and oral diuretic therapy in the first instance. Large volume paracentesis associated with colloid volume expansion and diuretic therapy may be effective for acute relief. Treatment of hepatorenal syndrome type 1 with vasopressin analogs (terlipressin) is recommended prior to liver transplantation in order to improve renal function. Prevention and treatment of chronic hepatic encephalopathy are directed primarily at controlling the events that may precipitate hepatic encephalopathy and at reducing ammonia generation and increasing its detoxification or removal. In addition to reduction of gut ammonia production using non-absorbable disaccharides such as lactulose and/or antibacterials such as neomycin, sodium benzoate may be used on a long-term basis to prevent, stabilize, or improve hepatic encephalopathy. The management of hepatic encephalopathy in acute liver failure is considerably more unsatisfactory; treatment is aimed at preventing brain edema and intracranial hypertension. Extracorporeal liver support devices are now used commonly in critically ill children with acute renal failure, advanced hepatic encephalopathy, cerebral edema, intracranial hypertension, and severe coagulopathy. Continuous renal replacement therapy could potentially help support patients until liver transplantation is performed or liver regeneration occurs. The Molecular Adsorbent Recirculating System (MARS or albumin dialysis) is the liver support system most frequently used worldwide in adults and appears to offer distinct advantages over hepatocyte-based systems.There are no specific medical therapies or devices that can correct all of the functions of the liver. Apart from a few metabolic diseases presenting with severe liver dysfunction for which specific medical therapies may preclude the need for liver transplantation, liver transplantation still remains the only definitive therapy in most instances of end-stage chronic liver disease and acute liver failure. Future research should focus on gaining a better understanding of the mechanisms responsible for liver cell death and liver regeneration, as well as developments in hepatocyte transplantation and liver-directed gene therapy.     

Review article: the current management of acute liver failure

Aliment Pharmacol Ther 31 , 345–358

Summary

Background Acute liver failure is a devastating clinical syndrome with a persistently high mortality rate despite critical care advances. Orthotopic liver transplantation (OLT) is a life‐saving treatment in selected cases, but effective use of this limited resource requires accurate prognostication because of surgical risks and the requirement for subsequent life‐long immunosuppression. Aim To review the aetiology of acute liver failure, discuss the evidence behind critical care management strategies and examine potential treatment alternatives to OLT. Methods Literature review using Ovid, PubMed and recent conference abstracts. Results Paracetamol remains the most common aetiology of acute liver failure in developed countries, whereas acute viral aetiologies predominate elsewhere. Cerebral oedema is a major cause of death, and its prevention and prompt recognition are vital components of critical care support, which strives to provide multiorgan support and ‘buy time’ to permit either organ regeneration or psychological and physical assessment prior to acquisition of a donor organ. Artificial liver support systems do not improve mortality in acute liver failure, whilst most other interventions have limited evidence bases to support their use. Conclusion Acute liver failure remains a truly challenging condition to manage, and requires early recognition and transfer of patients to specialist centres providing intensive, multidisciplinary input and, in some cases, OLT.     

Personal view: current role of artificial liver support devices

Enthusiasm for liver support devices, particularly cell-based biological systems and albumin dialysis, increased over the last decade and there has been considerable clinical activity both within and without the construct of clinical trials. Most data have been generated on patients with acute liver failure or in patients with decompensation of chronic liver disease, often referred to as acute-on-chronic liver failure. In acute liver failure liver, liver support devices are more realistically being used as a 'bridge' to liver transplantation rather than to transplant-free survival. In acute-on-chronic liver failure the clinical objective of attaining clinical stability with treatment appears more achievable. The so-called bioartificial liver device, based on porcine hepatocytes, is the most extensively evaluated biological device. A sizeable clinical trial failed to demonstrate efficacy, but secondary analyses suggest it would be unwise to assume futility had been established with this device. Molecular adsorbent recirculating system leads the way in the non-biological category in terms of the number of patients treated, but data from large clinical trials are not yet available. One of the strongest conclusions of this review is that the amount of high-quality data available on liver support devices dramatically understates the effort and money that have been expended in their assessment. It is very clear that randomized controlled trials are mandatory to establish clinical efficacy, but it is less clear how the ideal trial should be constructed.     

MARS人工肝治疗肝衰竭的临床探讨

目的 探讨肝衰竭病人MARS人工肝治疗的最佳时机、治疗次数、每次治疗时间及疗效。方法 将接受MARS治疗的肝衰竭病人152例,按MARS治疗的次数分为单次MARS治疗组42例,多次MARS治疗组印例,内科治疗对照组50例。观察MARS治疗前后临床症状的改变,对比分析MARS治疗前及治疗6,7,8h的相关实验室数据。比较单次MARS治疗组、多次MARS治疗组和对照组的生存率,以及死亡病例的特点。结果 MARS人工肝治疗能有效改善肝衰竭病人的临床症状。明显提高病人的生存率（P〈0．05）,无明显合并症者治疗效果好,连续多次的MARS治疗病人的预后可得到进一步的改善。出现多个并发症时．无论MARS人工肝治疗还是内科加强治疗,病死率均明显增加。MARS治疗时间6,7。8h在毒索的清除上无显著性差异（P〈0．05）。结论 MARS治疗时机应尽量选择早期无并发症时,特别危重的病人应进行多次MARS人工肝治疗,间歇期不应过长（24-48h）。每次MARS治疗的时间以6h为宜．     

背驮式原位肝移植2例

目的 总结背驮式原位肝移植治疗终末期肝病的临床经验。方法 回顾性分析2例肝炎后肝硬变患行背驮式原位肝移植手术治疗的临床资料。结果 死亡1例，存活1例。术后并发症包括腹腔内出血1例，肝后下腔静脉扭曲狭窄1例，急性排斥反应1例，肺部感染、呼吸功能衰竭1例，均给予相应的治疗。结论 肝移植手术是终末期肝病的有效治疗手段。术后应积极预防各种并发症的发生，了解各种并发症的发生时间和症状有助于早期诊断，并采取各项积极正确的治疗措施。     

The management of acute liver failure

Acute liver failure (ALF) is a relatively uncommon but dramatic clinical syndrome with high mortality rates, in which a previously normal liver fails within days or weeks. Paracetamol overdose remains the major cause of ALF in the UK, while viral hepatitis is the commonest cause world-wide. Cerebral oedema is the leading cause of death in patients with ALF. Despite advances in intensive care and the development of new treatment modalities, ALF remains a condition of high mortality best managed in specialist centres. Orthotopic liver transplantation is the only new treatment modality that has made a significant impact in improving outcome. Bioartificial liver support systems and hepatocyte transplantation are new promising treatment options that may change the management of ALF in the future.     

人工肝支持系统治疗肝衰竭术后并发下肢深静脉血栓形成的处理策略

目的明确人工肝支持系统(ALSS)治疗肝衰竭(LF)病人术后并发下肢深静脉血栓形成的处理策略。方法回顾性分析2019年1月至2021年9月安徽医科大学第一附属医院收治的经ALSS治疗的肝衰竭病人216例，选择有临床症状并经彩     

人工肝支持系统在肝移植围手术期应用及护理

目的：探讨人工肝支持系统在肝移植围手术期应用的护理。方法：对10例肝功能衰竭患者给予39次人工肝支持治疗，治疗过程中严格执行各项操作规程，做好治疗前的各项准备工作，加强治疗过程中的监护及治疗间隙的护理。结果：经人工肝支持治疗后，患者高胆红素血症下降，尿量逐渐增多，电解质紊乱及酸碱失衡均得以纠正，一般情况得到改善，6例肝昏迷逆转，10例均成功进行肝移植。结论：人工肝支持系统作为肝移植嗣手术期的治疗，能明显延长肝功能衰竭患者的生存天数，赢得了宝贵的待肝时间，从而使人工肝在临床应用中取得了突破性的进展。而完善的护理是治疗成功的基础。     

人工肝支持系统治疗肝功能衰竭216例

目的观察人工肝支持系统治疗肝功能衰竭的疗效。治疗肝功能衰竭216例．并与214例常规治疗对照。结果72．7％，对照组为60．3％，54．7％，治疗组优于对照组。结论竭疗效优于常规治疗。方法使用人工肝支持系统联合常规治疗方法治疗组的有效率为96．3％（208／216），存活率为人工肝支持系统联合内科常规方法治疗肝功能衰     

Advances in extracorporeal detoxification by MARS dialysis in patients with liver failure

Although liver transplantation has become standard procedure for patients with liver failure, a number of issues in the management of these patients remains to be addressed. Alternative approaches have been tested, such as hepatocytes containing liver-support systems and filtration devices. However, the replacement of detoxification has been difficult, as the majority of toxins accumulating in liver failure is albumin-bound. Albumin dialysis (MARS system) is characterized by the specific removal of albumin-bound toxins through an innovative membrane transport. In particular, the albumin acts as a specific molecular adsorbent that is regenerated on line in a recycling system. Nowadays MARS represents the most frequently used liver support system. This treatment has been shown to remove albumin-bound molecules, such as bilirubin, bile acids, aromatic amino acids and copper. The removal of these toxins is clinically accompanied with an improvement of liver, cardiovascular and renal functions and hepatic encephalopathy. In several trials MARS was found to improve the clinical situation in patients with acute exacerbation of chronic liver failure and acute hepatic failure, but also in hepatorenal syndrome and primary graft non function or chronic rejection after liver transplantation. In summary, a critical analysis of the literature confirms that MARS device can be a safe therapeutic choice to achieve a better clinical outcome, and, sometimes, a survival advantage in patients with liver failure, even if a multi-center randomized trial is the only reliable way to enforce today's results. Further advances in the MARS components will definitively state whether albumin dialysis may represent the future in the field of artificial liver devices.     

人体原位肝移植三例报告

目的 报告3例肝移植的治疗经验，探讨肝移植的手术技术与疗效。方法 2例原发性肝癌合并门静脉高压病人、1例终末期胆道病合并胆汁性肝硬化病人均施行同种异体原住肝移植术。供肝采用Uw液原位灌注，快速切取。肝移植方式采用背驮式原位肝移植术。2例肝癌病人术前1周开始服用抗乙肝病毒药物拉米呋啶，并进行一个疗程化疗；术后免疫抑制治疗采用环孢素A、激素和／或晓悉联合应用。术后分别在30d、60d、90d按5-FuAB(5-Fu 阿霉素 顺铂)方案进行化疗。例3病人术前积极子肝肾功能堆护及人工肝支持。结果 例1肝移植术中供肝立即发挥功能，病人术半随即清醒。术后第9d发生轻度急性排斥反应，用甲基强的松龙冲击后控制。追踪随访9个月生活质量良好；例2肝移植术中供肝立即发挥功能，病人在术后1h内清醒。术后第11d发生轻度急性排斥反应，用甲基强的松龙冲击后控制。随访至今患者生活学习行如常人，生活质量良好；例3肝移植术中供肝立即发挥功能，术后死于急性肾功能衰竭。结论(1)精细的手术操作和完善的麻醉配合是确保手术成功的关键；(2)手术后的严密观察、正确及时处理并发症以及围手术期良好的综合支持治疗是确保患者术后能否长期存活的重要条件；(3)大肝癌在未发生远处转移而存在肝功能衰竭表现时，肝移植是唯一能够挽救病人生命，获得良好生活质量的外科治疗手术。     

Medical management of chronic liver diseases (CLD) in children (part II): focus on the complications of CLD, and CLD that require special considerations

Treatment of the causes of many chronic liver diseases (CLDs) may not be possible. In this case, complications must be anticipated, prevented or at least controlled by the best available therapeutic modalities. There are three main goals for the management of portal hypertension: (i) prevention of the first episode of variceal bleeding largely by non-selective β-adrenoceptor antagonists, which is not generally recommended in children; (ii) control of bleeding by using a stepwise approach from the least to most invasive strategies; (iii) and prevention of re-bleeding using bypass operations, with particular enthusiasm for the use of meso-Rex bypass in the pediatric population. Hepatic encephalopathy management also consists of three main aspects: (i) ruling out other causes of encephalopathy; (ii) identifying and treating precipitating factors; and (iii) starting empiric treatment with drugs such as lactulose, rifaximin, sodium benzoate, and flumazenil. Treatment of mild ascites and peripheral edema should begin with the restriction of sodium and water, followed by careful diuresis, then large-volume paracentesis associated with colloid volume expansion in severe cases. Empiric broad spectrum antimicrobial therapy should be used for the treatment of spontaneous bacterial peritonitis, bacterial and fungal sepsis, and cholangitis, after taking appropriate cultures, with appropriate changes in therapy after sensitivity testing. Empirical therapies continue to be the standard practice for pruritus; these consist of bile acid binding agents, phenobarbital (phenobarbitone), ursodeoxycholic acid, antihistamines, rifampin (rifampicin), and carbamazepine. Partial external biliary diversion can be used in refractory cases. Once hepatorenal syndrome is suspected, treatment should be initiated early in order to prevent the progression of renal failure; approaches consist of general supportive measures, management of concomitant complications, screening for sepsis, treatment with antibiotics, use of vasopressin analogs (terlipressin), and renal replacement therapy if needed. Hepatopulmonary syndrome and portopulmonary hypertension are best managed by liver transplantation. Provision of an adequate caloric supply, nutrition, and vitamin/mineral supplements for the management of growth failure, required vaccinations, and special care for ensuring psychologic well-being should be ensured. Anticoagulation might be attempted in acute portal vein thrombosis. Some CLDs, such as extrahepatic biliary atresia (EHBA), Crigler-Najjar syndrome, and Indian childhood cirrhosis, require special considerations. For EHBA, Kasai hepatoportoenterostomy is the current standard surgical approach in combination with nutritional therapy and supplemental fat and water soluble vitamins, minerals, and trace elements. In type 1 Crigler-Najjar syndrome, extensive phototherapy is the mainstay of treatment, in association with adjuvant therapy to bind photobilirubin such as calcium phosphate, cholestyramine, or agar, until liver transplantation can be carried out. Treating Indian childhood cirrhosis with penicillamine early in the course of the disease and at doses similar to those used to treat Wilson disease decreases the mortality rate by half. New hopes for the future include extracorporeal liver support devices (the molecular adsorbent recirculating system [MARS?] and Prometheus?), hepatocyte transplantation, liver-directed gene therapy, genetically engineered enzymes, and therapeutic modalities targeting fibrogenesis. Hepapoietin, a naturally occurring cytokine that promotes hepatocyte growth, is under extensive research.     

肝巨噬细胞与肝纤维化研究进展

肝纤维化是由各种病因所致慢性肝损伤的修复反应,其持续进展可发展为肝硬化甚至肝细胞癌,最终导致肝功能衰竭。目前,肝纤维化尚无有效治疗方法。肝巨噬细胞在肝内炎症反应、纤维化的进展和消退方面发挥关键作用,已成为抗肝纤维化的重要治疗靶细胞。主要就肝巨噬细胞在肝纤维化过程中的作用进行综述,以期能够为肝纤维化治疗提供思路。     

Emergency adult living donor right lobe liver transplantation for fulminant hepatic failure

Fulminant hepatitis is fatal in most cases and timely liver transplantation is the only effective treatment. This study evaluates the survival outcomes of patients who underwent living-donor liver transplantation (LDLT) using right lobe liver grafts for fulminant liver failure due to hepatitis B infection. Nine cases of adult right lobe LDLT were performed in our department from September 2002 to August 2005 and the clinical and following-up data were reviewed. According to the pre-transplant Child-Pugh-Turcotte classification, the nine patients were classified as grade C. The model for end-stage liver disease (MELD) score of these patients ranged from 16 to 42. The principal complications before transplantation included abnormal renal function, hepatic coma of different degrees and alimentary tract hemorrhage. The main complications after transplantation included pulmonary infection in two cases, acute renal failure in three cases and transplantation-related encephalopathy in one case. No primary failure of vascular or biliary complications occurred. The one-year survival rate was 55.6%. There were no serious complications or deaths in donors. In general, it is extremely difficult to treat fulminant hepatitis by conservative regimen, particularly, in cases with rapid progression. Emergency adult living-donor liver transplantation is an effective treatment for fulminant hepatitis patients and is relatively safe for donors.     

生物人工肝应用及开发

人工肝可改善机体内环境，临床有望用于辅助治疗肝功能不全、肝衰竭以及相关肝脏疾病。生物人工肝是临床应用的发展方向。本文简要介绍生物人工肝的应用和注册进展，分析目前生物人工肝存在的问题并探讨其应用前景。     

Review article: current management of alcoholic liver disease

Alcoholic liver disease, including acute alcoholic hepatitis and alcoholic cirrhosis, is a major cause of morbidity and mortality in the Western world. Abstinence remains the cornerstone of management of all forms of alcoholic liver disease. Recent research, which has elucidated the mechanisms of alcohol-induced liver injury, offers the prospect of advances in the management of alcoholic liver disease. We review the most recent data on the efficacy of treatment of acute alcoholic injury, including nutritional support, corticosteroids, anti-inflammatory agents and antioxidants, and agents that are directed against the progression to fibrosis, such as colchicines, propylthiouracil and antioxidants. Although these therapies offer a tantalizing glimpse into a future that may include therapies that directly alter the process of injury and repair in the liver, none has been shown consistently to improve the course of alcoholic liver damage. Consequently, liver transplantation remains an ultimate option for selected patients with liver failure due to chronic alcoholic liver damage.     

Non-alcoholic fatty liver disease in the metabolic syndrome

Non-alcoholic fatty liver disease (NAFLD) is often associated with features of the metabolic syndrome, carrying an increased risk to develop non-alcoholic steatohepatitis (NASH), the inflammatory form of liver steatosis. Epidemiological data confirm that obesity, diabetes, hypertension and hyperlipidemia are frequently found in NAFLD and worsen its prognosis because of increased risk of fibrotic evolution, eventually leading to liver cirrhosis. Recent studies confirm the close relationship between the metabolic syndrome and liver steatosis, and further support the detrimental role of oxidative stress and lipid peroxidation, which are pathophysiological processes present in both conditions. Novel diagnostic tools and life style modifications together with targeted therapeutic actions are urgently needed for the management of liver dysfunction in course of metabolic syndrome.     

解剖性肝切除为基础的精准肝切除治疗肝恶性肿瘤25例分析

目的 探讨解剖性肝切除为基础的精准肝切除对肝恶性肿瘤的治疗效果.方法 选取高州市中医院2012年10月至2013年12月期间的肝恶性肿瘤患者25例,所有患者都以解剖性精准肝切除术治疗.对患者的手术时间、手术中出血量以及术后并发症发生情况进行分析.结果 所有患者均成功完成了精准肝切除术,平均手术时间为（364.5±36.8） min,术中平均出血量（110.9±36.7） ml;共有7例患者出现术后并发症,发生率为28.0％,其中肝衰竭和腹腔渗血患者1例、肺部感染3例、腹腔脓肿2例、切口感染1例,所有并发症患者经过治疗均痊愈.结论 解剖性肝切除是精准肝切除的基础和前提,患者的手术时间、术中平均出血量以及术后并发症发生等情况令人满意,具有安全、可行性.     

Nutritional support of patients with severe hepatic failure

The pathophysiology, etiology, and metabolic alterations of severe hepatic failure and nutritional support of patients with this condition are reviewed. Hepatic failure encompasses a broad range of acute and chronic processes; complications may be fatal or quite minimal. Cirrhosis refers to all types of chronic diffuse liver disease. While hepatocytes regenerate in cirrhotic patients, eventually the parenchymal and vascular architecture of the liver is disrupted, leading to a syndrome of hepatic insufficiency. Normal metabolic processes deteriorate, and serum amino acid imbalances and fat intolerance may develop. Aromatic amino acids, which are normally catabolized by the liver, accumulate in the serum, and branched-chain amino acid deficiencies develop as these amino acids are broken down for energy by peripheral muscle. Hepatic encephalopathy often develops in these patients. Successful nutritional support of the patient with severe hepatic failure depends on correction of the specific metabolic abnormalities occurring. Parenteral nutrition with Hepatamine (American McGaw), a product with more branched-chain amino acids and less aromatic amino acids than other amino acid solutions, is useful in patients with altered serum amino acid profiles who develop hepatic encephalopathy. Patients in whom factors other than altered amino acids are primary causes of encephalopathy may not respond to Hepatamine. Enteral nutritional products with amino acid compositions similar to Hepatamine [Hepatic-Aid II (McGaw), Travasorb-Hepatic (Travenol Laboratories)] may be used in patients with encephalopathy, but they must be supplemented to provide complete nutrition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Use of artificial liver support

Artificial liver support is used to remove toxic substances accumulating in the circulation of patients with fulminant hepatic failure. Charcoal haemoperfusion with infusion of prostacyclin (PGI2) to prevent platelet damage has become a routine treatment and has led to improved survival. In 76 patients treated 29 (38%) survived to leave hospital and of these 31 patients were treated when in Grade III coma and 20 (65%) survived. Charcoal haemoperfusion also reduced the incidence of cerebral oedema which is a major cause of death in fulminant hepatic failure. Most episodes (congruent to 80%) of cerebral oedema can be managed using the osmotic agent mannitol. In a complete liver support system both protein-bound and compounds of a middle relative molecular mass as well as water soluble compounds should be removed. An albumin-coated resin has been developed to remove these compounds and in preliminary clinical studies it has been shown to have good blood compatibility and satisfactory adsorption properties. The importance of combined systems has been confirmed in studies on the removal of inhibitors of brain Na+K+-ATPase, where both resin and charcoal columns removed significant amounts of the inhibitory activity.