Favorable results of auxiliary heterotopic liver transplantation in patients with end-stage chronic liver insufficiency

Auxiliary heterotopic liver transplantation (HLT), which avoids removal of the host liver, may improve the results of liver transplantation in patients with end-stage chronic liver disease. However, the results of HLT have so far been disappointing. In 1986 a program of HLT was started in the University Hospital Rotterdam-Dijkzigt. Eighteen patients with chronic liver failure underwent HLT. Twelve out of 18 (67%) patients were discharged 25 days after transplantation with normal liver function. Six patients died within 3 months after operation due to septic causes. Three months after transplantation ascites was no longer detectable and oesophageal varices had disappeared in all surviving recipients of HLT. The actuarial 3 and 12 months survival rate was 67%. Hepatitis B virus reinfection was seen in all patients. In two patients cirrhosis of the graft developed within one year. These data suggest that HLT in patients with chronic liver failure gives long-term metabolic support and adequate decompression of portal system, and is associated with a morbidity and mortality comparable to that of orthotopic liver transplantation.     

Liver failure is uncommon in adults receiving long-term parenteral nutrition

BACKGROUND: Abnormal liver enzymes and endstage liver disease are reported to occur in 25%-100% and 15%-40% of adult patients receiving long-term parenteral nutrition (PN), respectively. The purpose of this historic cohort study was to investigate the incidence of and possible factors leading to the development of liver disease in our large home PN population. METHODS: All patients on home PN for at least 6 months from July 1991 through June 2002 were eligible. Patients were excluded if they had active malignancy, underlying liver disease, or exposure to a hepatotoxin. The presence of PN-associated liver disease was only considered if test results were elevated on more than 1 occasion over at least 6 or more months. The severity of liver-associated enzymes was based on the degree of elevation and was stratified as mild (<2 times normal), moderate (2-5 times normal), and severe (>5 times normal). Severe liver dysfunction was defined as having all of the following criteria: total bilirubin >3 mg/dL; albumin <3.2 g/dL; and prothrombin time >3 seconds prolonged. A cumulative logit model was used to compare age, gender, underlying disease, PN indication, and PN formulas in patients with normal vs abnormal laboratory test results. RESULTS: Two hundred eight patients received PN for more than 6 months, 36 had exclusion criteria, and 10 could not be analyzed, because of incomplete laboratory test results, leaving 162 in the study group. The average PN duration was 2.14 +/- 2.19 years (maximum, 10.28 years). Abnormal liver tests occurred in 154 patients, with most having a moderate elevation of alkaline phosphatase or aspartate aminotransferase; severe liver dysfunction occurred in 7 patients; 1 patient had completely normal liver enzymes. On average, patients received a PN formula that was high in amino acids (1.45 +/- 0.65 g/kg/d), modest in energy (24.7 +/- 13.4 kcal/kg/d), and in most cases with enough lipid emulsion to meet essential fatty acid requirements (0.28 +/- 0.25 g/kg/d). Only female gender was found to be associated with a greater likelihood of liver failure (p = .02). There was a trend toward a greater amount of total calories, dextrose calories, and duration of PN exposure leading to the development of severe liver dysfunction. CONCLUSIONS: When long-term PN is given with a modest amount of total energy and a minimal amount of lipid emulsion, abnormal liver enzymes are common, but severe liver dysfunction is unusual.     

Parenteral nutrition-associated liver disease in adult and pediatric patients.

There are essentially 3 types of hepatobiliary disorders associated with parenteral nutrition (PN) therapy: steatosis, cholestasis, and gallbladder sludge/stones. Reported prevalence rates of PN-associated liver disease (PNALD) vary greatly, and there are distinct differences between adult and pediatric patients. Various etiologic factors have been evaluated for significance in contributing to PNALD, including enteral feeding history, septic events, bacterial overgrowth, length of intestinal resection, and prematurity/low birth weight. Etiologic factors specifically related to the PN formulation or nutrient intake have also been evaluated, including excessive calorie intake, dextrose-to-lipid ratio, amino acid dose, taurine deficiency, IV fat emulsion (IVFE) dose, carnitine deficiency, choline deficiency, and continuous vs cyclic infusion. Minor increases in serum aminotransferase concentrations are relatively common in patients receiving PN therapy and generally require no intervention. The primary indicator of cholestasis is a serum conjugated bilirubin >2 mg/dL. When a patient receiving PN develops liver complications, it is necessary to rule out all treatable causes and minimize other risk factors. All potential hepatotoxic medications and herbal supplements should be eliminated. Modifications to the PN regimen that may be helpful include reduction of calories, reduction of IVFE dose to <1 g/kg/d, supplementation of taurine in the infant, and use of cyclic infusion. Initiation of even small amounts of enteral nutrition and use of ursodiol may be beneficial in stimulating bile flow. In the long-term PN patient with severe and progressive liver disease, intestinal or liver transplantation may be the only remaining treatment option.     

Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children

BACKGROUND: In children who depend on long-term parenteral nutrition (PN), liver disease is a major complication that may lead to end-stage liver failure requiring liver transplantation. METHODS: This retrospective study investigated the influence of lipid emulsions on cholestasis onset in children receiving long-term total parenteral nutrition (TPN) with lipids. Ten children who presented with a total of 23 episodes of cholestasis, associated in 13 cases with thrombocytopenia, were studied. RESULTS: Changes in the lipid delivery preceded these complications in more than half the cases. The temporary decrease in lipid administration led to normalization of bilirubin in 17 episodes. CONCLUSIONS: These data suggest that lipid supply is one of the risk factors for PN-associated cholestasis. The link between cholestasis and the reticuloendothelial system overload needs to be better understood. Prevention of cholestasis might include the decrease in the lipid load. When cholestasis occurs, lipid supply should be temporarily stopped, especially in the case of associated thrombocytopenia.     

Liver transplantation in acute liver insufficiency: definitive replacement or auxiliary liver?

Orthotopic liver transplantation (OLT) has greatly improved the chances of survival in patients with acute hepatic failure. However, this mode of treatment requires lifelong immunosuppressive medication and negates the potential recovery of the host liver. In theory, auxiliary heterotopic liver transplantation (HLT) offers the diseased host liver a chance to regenerate, so that immunosuppression can be tapered off and eventually stopped. In the University Hospital Rotterdam Dijkzigt OLT and HLT were performed in two patients, with acute and subacute hepatic failure respectively. The patient undergoing OLT recovered quickly but needed a successful re-OLT after a serious rejection episode. The removed diseased liver showed no signs of regeneration at histology. The patient undergoing HLT also recovered well. HIDA scanning as well as liver biopsies of the host liver and the grafted liver 1 and 6 months after transplantation indicated full recovery of the host liver, so that immunosuppression is being tapered off.     

Determinants of hyperhomocysteinemia in patients with chronic liver disease and after orthotopic liver transplantation

BACKGROUND: Homocysteine metabolism may be impaired in chronic liver disease, possibly contributing to fibrogenesis and disease complications. OBJECTIVE: The goal was to investigate the prevalence and determinants of basal and postprandial hyperhomocysteinemia in patients with chronic liver disease and after orthotopic liver transplantation (OLT). DESIGN: This was a cross-sectional study of 323 patients with chronic liver disease (93 with hepatitis, 8 with fatty liver, 168 with cirrhosis, and 54 after OLT) and 25 healthy control subjects. Portohepatovenous gradients of total homocysteine (tHcy) and methionine and postload methionine and tHcy kinetics before and after 10 d of supplementation with folate plus vitamin B-6 were investigated in subgroups. RESULTS: Basal hyperhomocysteinemia was observed in all patient groups (34% of patients with hepatitis, 50% with fatty liver, 54% with cirrhosis, and 52% after OLT). It was more frequently seen in patients with elevated plasma creatinine concentrations and at advanced stages of liver disease. Mean plasma folate was normal in patients with liver disease, but vitamin B-12 was elevated in cirrhosis and vitamin B-6 was low after OLT. There were significant negative associations between tHcy and folic acid or vitamin B-12 concentrations in control subjects and in patients with hepatitis and after OLT. No systematic association between portohepatovenous differences in tHcy and methionine concentrations was found. Cirrhosis was accompanied by impaired methionine clearance. After vitamin supplementation, the area under the tHcy curve improved in cirrhosis at nearly unchanged basal tHcy concentrations. CONCLUSIONS: Basal hyperhomocysteinemia is seen in approximately 50% of patients with cirrhosis and after OLT. Basal tHcy concentrations do not change significantly after supplementation with folate and vitamin B-6, but postprandial Hcy metabolism improves.     

Orthotopic liver transplantation in children

Between 1-1-1982 and 1-1-1988 52 children with an end-stage liver disease were evaluated to determine whether orthotopic liver transplantation (OLT) would be appropriate. 24 children were accepted as candidates in the long term. Twelve were not accepted as potential recipients. The parents of 3 decided not to accept OLT as treatment for their children. Two children died before a suitable donor liver was available, so that OLT was carried out in 11 children. Two of these children needed a second transplant. In 3 children only a part of a donor liver was transplanted. Shortage of donor livers of small size is partly alleviated by using a part of a larger liver. The underlying diseases of the transplanted children were cryptogenic cirrhosis (1x), biliary atresia with a hepatoportoenterostomy (8x) and cirrhosis following neonatal hepatitis (2x). Ten children with OLT are clinically and physically well. Postoperatively a primary graft dysfunction occurred in one child. He was retransplanted. The median waiting time for a donor liver was 5 months. The timing for OLT has to take this in account. In treating children with end-stage liver disease (partial) OLT should be considered.     

肝移植术后营养支持

目的 探讨肝移植术后的营养支持方法。方法 对２例肝移植病人术后的营养方法和营养状况进行了回顾性分析,在术后２～３天内采用全肠外营养（ＴＰＮ）,并辅以人血白蛋白以维持血浆白蛋白水平,在术后第３－４天开始肠内营养（ＥＮ）结合肠外营养（ＰＮ）,并逐渐过渡为完全经口饮食,结果 ２例病人现生活质量均良好,结论 术后应视移植肝功能恢复的程度,适当控制营养供给量,并循序渐进,一旦病人胃肠功能恢复,宜尽早开始ＥＮ     

门脉高压症肝移植的治疗体会及围手术期处理(附23例报告)

目的探讨肝移植在肝硬化门脉高压治疗中的意义。方法回顾性分析本中心23例肝脏移植肝硬化门脉高压症患者的临床资料。结果23例患者中2例死于围手术期并发症，其余均存活，最长37个月，最短2个月，术后并发症发生率42．8％。结论肝移植是目前能从根本上治疗门静脉高压症的有效方法。     

原位肝移植合并重症脓毒症病人的临床研究

目的观察肝移植合并重症脓毒症病人的相关检验和临床指标，旨在总结原位肝移植合并重度脓毒症这一特殊感染人群的ICU治疗经验。方法回顾性分析入住外科ICU术后的56例符合重症脓毒症标准者病人，分成2组：非肝移植组（A组）和肝移植组（B组）。分别在第1天、第3天和第7天记录病人一般情况、血乳酸、器官衰竭个数、APACHEⅡ评分和MODS评分。观察住院28d的存活率和随访情况。结果非肝移植组合并重症脓毒症住院死亡率30％，而在肝移植组则为57．6％。肝移植组第l天血乳酸比非肝移植组明显升高，差异有统计学意义（P〈0．01），随之有所下降，但7d内仍然高于非肝移植组；肝移植组器官衰竭个数比非肝移植组明显增多，差异有统计学意义（P〈0．01）；2组观察期间APACHEⅡ动态评分差异无统计学意义（P〉0．05）；MODS动态评分在肝移植组比非肝移植组明显升高，差异有统计学意义（P〈0．01）。结论原位肝移植合并重症脓毒症住院28d死亡率约是非肝移植组的2倍，值得高度重视。原位肝移植合并重症脓毒症病人更容易合并有多器官功能衰竭且病情较难逆转。肝移植合并重症脓毒症病人判断病情和器官功衰竭程度的轻重，MODS评分优于APACHEⅡ评分。建议改进或者制定器官移植特有的评分标准并且应该加入血乳酸。     

Omega-3-enriched lipid emulsion for liver salvage in parenteral nutrition-induced cholestasis in the adult patient

The intrahepatic cholestasis attributed to parenteral nutrition (PN) in the adult patient is relatively rare and usually occurs in patients receiving long-term PN. This article reports the first case of an adult patient with cholestatic PN-associated liver disease without sepsis who received almost all her nutrition requirements through PN. Administration of an ω-3-enriched lipid emulsion added to the PN regimen reversed cholestasis and demonstrated histologic improvement on serial liver biopsy. The patient had failed to respond to other modalities of treatment for this condition and was deeply jaundiced. Liver biochemistry profiles returned to baseline, and follow-up liver biopsy showed that cholestasis had resolved and that the only residual changes were mild portal inflammation with no histochemical or ultrastructural progression. The PN regimen for the patient was restored to provide total estimated energy requirements and remains the principle source of the patient's nutrition to date.     

Nutrition Support in Liver Transplantation and Postoperative Recovery: The Effects of Vitamin D Level and Vitamin D Supplementation in Liver Transplantation

Vitamin D plays an important role in the arena of liver transplantation. In addition to affecting skeletal health significantly, it also clinically exerts immune-modulatory properties. Vitamin D deficiency is one of the nutritional issues in the perioperative period of liver transplantation (LT). Although vitamin D deficiency is known to contribute to higher incidences of acute cellular rejection (ACR) and graft failure in other solid organ transplantation, such as kidneys and lungs, its role in LT is not well understood. The aim of this study was to investigate the clinical implication of vitamin D deficiency in LT. LT outcomes were reviewed in a retrospective cohort of 528 recipients during 2014–2019. In the pre-transplant period, 55% of patients were vitamin-D-deficient. The serum vitamin D level was correlated with the model for end-stage liver disease (MELD-Na) score. Vitamin D deficiency in the post-transplant period was associated with lower survival after LT, and the post-transplant supplementation of vitamin D was associated with a lower risk of ACR. The optimal vitamin D status and vitamin D supplementation in the post-transplant period may prolong survival and reduce ACR incidence.     

The role of an intravenous fat emulsion composed of fish oil in a parenteral nutrition-dependent patient with hypertriglyceridemia.

Hypertriglyceridemia is a common complication in patients receiving parenteral nutrition (PN). Management typically involves withholding the IV fat emulsion (IVFE) until serum triglyceride levels normalize. In some instances, this practice may predispose patients to the development of essential fatty acid deficiency (EFAD) unless alternative therapies such as oral or topical oils are used. This is especially true in patients unable to tolerate enteral intake. We describe the management of hypertriglyceridemia in a 12-year-old boy dependent on PN who developed EFAD due to prolonged use of fat-free PN. His course was further complicated by PN-associated liver disease. Treatment involved the use of an IVFE derived from fish oils. Within 3 weeks, there was clinical improvement in EFAD and hypertriglyceridemia. The patient's triene:tetraene ratio decreased from 0.207 to 0.044 (normal: 0.013-0.05). Similarly, his serum triglyceride levels decreased from 628 mg/dL to 183 mg/dL (normal: <200 mg/dL). After 2 months of treatment, he was successfully transitioned to enteral feedings; hepatic function normalized, as did the essential fatty acid profile and serum triglycerides levels. This suggests that using fish-oil-based IVFE may be an effective alternative to conventional IVFE in PN-dependent patients whose clinical course is complicated by hypertriglyceridemia.     

生物型人工肝的肝细胞源研究进展

各种原因所致的肝功能衰竭是一种病死率高的并发症。肝移植是治疗肝衰竭最有效的手段。为了替代肝脏移植,以肝细胞为基础的生物型人工肝(BAL)成为目前肝功能衰竭治疗的基础与临床研究的重点和热点。肝细胞是BAL的生物部分,起着核心作用;应用于BAL的肝细胞主要有:原代肝细胞(包括同源的人肝细胞及异种肝细胞)、各种不同来源的肝细胞株、干细胞等。此文就涉及肝细胞源研究的最新进展作简要综述。     

肝移植术后早期营养支持

目的:探讨肝移植术后早期营养支持的方法.方法:对28例肝移植病人术后的营养支持方法和营养状况进行回顾性分析.在术后1～3天内采用肠外营养,术后第4天开始肠内营养结合肠外营养,直至完全肠内营养,第7天过渡为完全经口饮食.结果:多数病人术后营养状态明显改善,除5例病人死于术后并发症外,其余23例生活质量均良好.结论:肝移植术后第1天起就给予肠外营养,一旦病人胃肠功能恢复,宜尽早开始肠内营养,并尽快过渡到完全经口饮食.     

Incorporating biological natural history in simulation models: empirical estimates of the progression of end-stage liver disease.

OBJECTIVE: To develop an empiric natural-history model that can predict quantitative changes in the laboratory values and clinical characteristics of patients with end-stage liver disease (ESLD), to be used to calibrate an individual microsimulation model. METHODS: The authors report the development of a stochastic model that uses cubic splines to interpolate between observed laboratory values over time in a cohort of 1997 patients with ESLD awaiting liver transplantation at the University of Pittsburgh Medical Center. The splines were recursively sampled to provide a stochastic, quantitative natural history of each candidate's disease. RESULTS: The model was able to simulate the types of erratic disease trajectories that occur in individual patients and was able to preserve the statistical properties of the natural history of ESLD in cohorts of real patients. Moreover, the model was able to predict pretransplant survival rates (87% at 1 year), which were statistically similar to rates observed in the authors' local cohort (92%). CONCLUSIONS: Cubic splines can be used to generate quantitative natural histories for individual patients with ESLD and may be useful for developing clinically robust microsimulation models of other diseases.     

Prevalence,Evolution, and Risk Factors for Advanced Liver Fibrosis in Adults Undergoing Intestinal Transplantation

Introduction

Intestinal failure–associated liver disease (IFALD) occurs commonly in intestinal transplant (ITx) candidates receiving parenteral nutrition (PN). The aim of this study is to establish the prevalence and risk factors for advanced liver fibrosis in adults at the time of ITx.

Methods

Retrospective chart review of all ITx was performed in adults between January 2000 and May 2014. Advanced liver fibrosis was defined as stage 3 or stage 4 fibrosis.

Results

Fifty‐three patients met the inclusion criteria. The mean age was 50.6 ± 10.9 years, and the majority were female (60.4%) and Caucasian (67.9%). The mean body mass index was 21.7 ± 3.8 kg/m² and the median duration of PN was 402 (interquartile range: 529) days. Advanced liver fibrosis at the time of ITx was found in 13 patients (24.5%). The multivariate analysis revealed that female gender and white race were significant predictors of advanced liver fibrosis. A total bilirubin >3.0 mg/dL for > a month prior to ITx was associated with an odds ratio of 8.9 for advanced fibrosis at the time of ITx but did not reach statistical significance (P = 0.055).

Conclusion

Close to one‐quarter of the ITx recipients had advanced liver fibrosis. In the current era of improved PN management, our data suggests that previously reported risk factors for IFALD, such as extreme short gut syndrome and PN duration, may have a lesser impact on development of liver fibrosis. A prolonged duration of bilirubin elevation may be associated with advanced liver fibrosis in patients with IFALD, but this requires validation in a larger cohort.     

Acute beriberi following liver transplantation

Patients scheduled for orthotopic liver transplantation (OLT) undergo extensive routine preoperative cardiac assessment. We describe a 32-year-old male who underwent uneventful OLT for endstage liver failure on the basis of chronic hepatitis C and alcoholism. Despite a normal preoperative cardiac workup, the patient developed acute pulmonary edema on the second postoperative day. A diagnosis of beriberi was entertained and confirmed by (1) the thiamine diphosphate effect and (2) the dramatic response to intravenous thiamine. Possible precipitating factors are described. Thiamine, which has no significant toxicity, should probably be routinely supplemented in all patients undergoing OLT, especially those with a previous history of alcohol abuse.     

Long‐Term Fish Oil Lipid Emulsion Use in Children With Intestinal Failure–Associated Liver Disease

Background: Fish oil lipid emulsion (FOLE) and multidisciplinary care for infants with intestinal failure (IF) have been associated with reduced morbidity and mortality due to IF‐associated liver disease (IFALD). With increased survival, a greater proportion of infants with IF are now able to remain on parenteral nutrition (PN) in the long term. The purpose of this study was to examine outcomes in children with IFALD who have required long‐term PN and FOLE therapy due to chronic IF. Materials and Methods: A review of prospectively collected data was performed for children with IFALD who required at least 3 years of PN and FOLE therapy due to chronic IF. Outcomes examined include the incidence of death, transplantation, and essential fatty acid deficiency (EFAD), as well as growth parameters and the biochemical markers of liver disease. Results: Of 215 patients with IFALD treated from 2004–2015, 30 required PN and FOLE therapy for at least 3 years (median, 4.6 years). To date, no patients have died, required transplantation, or developed EFAD. Biochemical markers of liver disease normalized within the first year of therapy with no recurrent elevations in the long term. Weight‐for age and length‐for‐age z scores improved and PN dependence decreased in the first year of therapy, with a stable rate of growth in the long term. Conclusions: Children with IFALD who required long‐term PN and FOLE for chronic IF had no mortality, need for transplantation, EFAD, or recurrence of liver disease in the long term, allowing for continued intestinal rehabilitation.     

肝移植病人围手术期的营养支持

目的:探讨并制订合理有效的营养支持方法,提高肝移植病人对手术的耐受力,促进术后的恢复.方法:对33例肝移植病人围手术期的营养状况和营养支持方法进行回顾性分析.术后早期(1～3天)采用肠外营养(PN),并辅以人血清蛋白和血浆;在术后第4～5天开始肠内营养(EN)结合PN,并逐渐过渡至完全经口饮食.术后使用精氨酸(Arg)辅助治疗7～11天.结果:33例病人接受围手术期营养支持后,除有2例病人分别于术后第10、25天死于急性排斥反应、多器官功能障碍和1例谷丙转氨酶(GPT)升高外,其余病人的血清总蛋白(TP)和清蛋白(ALB)均有不同程度的升高,GPT、总胆红素(T-BIL)和结合胆红素(D-BIL)降至正常范围,其中第7、14和21天检测的TP、ALB、GPT、T-BIL水平与术后第1天比较差异有显著性意义(P＜0.05).T-BIL第3天与术后第1天比也有显著差异(P＜0.05),D-BIL第3、7和21天与术后第1天比差异有显著性意义(P＜0.05).结论:合理的围手术期营养支持可明显促进肝移植病人术后的恢复.