Reversibility of liver failure secondary to metastatic breast cancer by vinorelbine and cisplatin chemotherapy

Purpose: The development of liver metastases from breast cancer is associated with a very poor prognosis, estimated at 4 months median survival. Since treatment with many chemotherapeutic agents is relatively contraindicated, we assessed the safety, tolerability and potential efficacy of combination chemotherapy with vinorelbine and cisplatin (ViP). Method: Pilot study in 11 patients with histologically confirmed breast carcinoma, radiological evidence of liver metastases and serum bilirubin greater than 1.5 times the upper limit of normal. Patients received up to six cycles of cisplatin (75 mg/m 2) every 21 days and vinorelbine (20 mg/m 2) on days 1 and 8 of every 21-day cycle. Measurement of liver lesions was performed on CT scan every 8 weeks into treatment. Results: The most frequently reported adverse event was myelosuppression. Other adverse effects included nausea, vomiting and mild neurotoxicity. Two patients died after one treatment with ViP, one of whom suffered an intracerebral haemorrhage that was possibly treatment-related. Improvement in liver function tests was observed in 10 patients, and mean time to normalization of bilirubin levels was 36 days. Partial responses were documented radiologically in 7 out of 11 patients treated. Median overall survival from trial entry was 6.5 months (range 11-364 days), with one patient alive 13 months from trial entry. Conclusion: Normalization of liver function is possible with ViP treatment of metastatic breast cancer, offering the potential to prolong survival. Phase II clinical trials of this regimen in this patient group should include measurement of quality of life in order to assess risk versus benefit.

Acute liver failure in children : a regional experience

Objective: To review the outcome of acute liver failure (ALF) and the effect of liver transplantation in children in Australia. Methodology: A retrospective review was conducted of all paediatric patients referred with acute liver failure between 1985 and 2000 to the Queensland Liver Transplant Service, a paediatric liver transplant centre based at the Royal Children's Hospital, Brisbane, that is one of three paediatric transplant centres in Australia. Results: Twenty-six patients were referred with ALF. Four patients did not require transplantation and recovered with medical therapy while two were excluded because of irreversible neurological changes and died. Of the 20 patients considered for transplant, three refused for social and/or religious reasons, with 17 patients listed for transplantation. One patient recovered spontaneously and one died before receiving a transplant. There were 15 transplants of which 40% (6/15) were < 2 years old. Sixty-seven per cent (10/15) survived > 1 month after transplantation. Forty per cent (6/15) survived more than 6 months after transplant. There were only four long term survivors after transplant for ALF (27%). Overall, 27% (6/22) of patients referred with ALF survived. Of the 16 patients that died, 44% (7/16) were from neurological causes. Most of these were from cerebral oedema but two patients transplanted for valproate hepatotoxicity died from neurological disease despite good graft function. Conclusions: Irreversible neurological disease remains a major cause of death in children with ALF. We recommend better patient selection and early referral and transfer to a transplant centre before onset of irreversible neurological disease to optimize outcome of children transplanted for ALF.

Long-term growth and anthropometry after childhood liver transplantation

Objectives: To describe longitudinal height, weight, and body mass index changes up to 15 years after childhood liver transplantation. Study design: Retrospective chart review of patients who underwent liver transplant from 1985-2004 was performed. Subjects were age <18 years at transplant, survived ≥5 years, with at least 2 recorded measurements, of which one was ≥5 years post-transplant. Measurements were recorded pre-transplant, 1, 5, 10, and 15 years later. Results: Height and weight data were available in 98 and 104 patients, respectively; 47% were age <2 years at transplant; 58% were Australian, and the rest were from Japan. Height recovery continued for at least 10 years to reach the 26th percentile (Z-score -0.67) 15 years after transplant. Australians had better growth recovery and attained 47th percentile (Z-score -0.06) at 15 years. Weight recovery was most marked in the first year and continued for 15 years even in well-nourished children. Growth impaired and malnourished children at transplant exhibited the best growth, but remained significantly shorter and lighter even 15 years later. No effect of sex or age at transplant was noted on height or weight recovery. Post-transplant factors significantly impact growth recovery and likely caused the dichotomous growth recovery between Australian and Japanese children; 9% (9/98) of patients were overweight on body mass index calculations at 10-15 years but none were obese. Conclusions: After liver transplant, children can expect ongoing height and weight recovery for at least 10-15 years. Growth impairment at transplant and post-transplant care significantly impact long-term growth recovery. Copyright © 2013 Mosby Inc. All rights reserved.

Body composition and components of energy expenditure in children with end-stage liver disease

Background: Better understanding of body composition and energy metabolism in pediatric liver disease may provide a scientific basis for improved medical therapy aimed at achieving optimal nutrition, slowing progression to end-stage liver disease (ESLD), and improving the outcome of liver transplantation. Methods: Twenty-one children less than 2 years of age with ESLD awaiting liver transplantation and 15 healthy, aged-matched controls had body compartment analysis using a four compartment model (body cell mass, fat mass, extracellular water, and extracellular solids). Subjects also had measurements of resting energy expenditure (REE) and respiratory quotient (RQ) by indirect calorimetry. Nine patients and 15 control subjects also had measurements of total energy expenditure (TEE) using doubly labelled water. Results: Mean weights and heights were similar in the two groups. Compared with control subjects, children with ESLD had higher relative mean body cell mass (33 ± 2% vs 29 ± 1% of body weight, P < 0.05), but had similar fat mass, extracellular water, and extracellular solid compartments (18% vs 20%, 41% vs 38%, and 7% vs 13% of body weight respectively). Compared with control subjects, children with ESLD had 27% higher mean REE/body weight (0.285 ± 0.013 vs 0.218. ± 0.013 mJ/kg/24h, P < 0.001), 16% higher REE/unit cell mass (P < 0.05); and lower mean RQ (P < 0.05). Mean TEE of patients was 4.70 ± 0.49 mJ/24h vs 3.19 ± 0.76 in controls, (P < 0.01). Conclusions: In children, ESLD is a hypermetabolic state adversely affecting the relationship between metabolic and non-metabolic body compartments. There is increased metabolic activity within the body cell mass with excess lipid oxidation during fasting and at rest. These findings have implications for the design of appropriate nutritional therapy.

Value of total body potassium in assessing the nutritional status of children with end-stage liver disease

Malnutrition is a common problem in children with end-stage liver disease (ESLD), and accurate assessment of nutritional status is essential in managing these children. In a retrospective study, we compared nutritional assessment by anthropometry with that by body composition. We analyzed all consecutive measurements of total body potassium (TBK, n = 186) of children less than 3 years old with ESLD awaiting transplantation found in our database. The TBK values obtained by whole body counting of 40K were compared with reference TRK values of healthy children. The prevalence of malnutrition, as assessed by weight (weight Z score < -2) was 28%, which was significantly lower (chi-square test, p < 0.0001) than the prevalence of malnutrition (76%) assessed by TBK (< 90% of expected TRK for age). These results demonstrated that body weight underestimated the nutritional deficit and stressed the importance of measuring body composition as part of assessing nutritional status of children with ESLD.

Growth hormone resistance and somatomedins in children with end-stage liver disease awaiting transplantation

Background: The success of orthotopic liver transplantation as treatment for end-stage liver disease has prompted investigation of strategies to maintain or improve nutrition and growth in children awaiting transplantation, because malnutrition is an adverse prognostic factor. The purpose of this study was to evaluate the effect of recombinant human growth hormone therapy on body composition and indices of liver function in patients awaiting transplant. Methods: The study was designed as a placebo- controlled, double-blind, crossover trial. Patients received 0.2 U/kg growth hormone, subcutaneously, or placebo daily for 28 days during two treatment periods, separated by a 2-week washout period. Ten patients (mean age, 3.06 ± 1.15 years; range, 0.51-11.65 years, five men), with extrahepatic biliary atresia (n = 8) or two with Alagille's syndrome (n = 2), with end-stage liver disease, completed the trial while awaiting orthotopic liver transplantation. Height, weight, total body potassium, total body fat, resting energy expenditure, respiratory quotient, hematologic and multiple biochemical profile, number of albumin infusions, insulin-like growth factor-1 and 1, growth hormone binding protein (GHBP), and insulin-like growth factor binding protein-1 (IGFBP-1) and insulin-like growth factor binding protein (IGFBP-3) were measured at the beginning and end of each treatment period. Results: Growth hormone treatment was associated with a significant decline in serum bilirubin (-34.6 ± 16.5 μmol/l vs. 18.2 ± 11.59 μmol/l; p < 0.02) but there was no significant effect on any anthropometric or body composition measurements, or on any biochemical or hematologic parameters. Conclusions: These children with end-stage liver disease displayed growth hormone resistance, particularly in relation to the somatomedin axis. Exogenous growth hormone administration may be of limited value in these patients

Nutritional support in children with end-stage liver disease : a randomized crossover trial of a branched-chain amino acid supplement

Malnutrition is common in children with end-stage liver disease (ESLD) awaiting orthotopic liver transplantation (OLT), and nutritional support is assuming an important role in preoperative management. To evaluate preoperative nutritional therapy, 19 children (median age 1.25 y) with ESLD awaiting OLT were prospectively studied. Two high-energy, isoenergetic and isonitrogenous nutritional formulations delivered nasogastrically were compared: a branched-chain amino acid (BCAA)-enriched semielemental formulation and a matched standard semielemental formulation. Twelve of 19 patients completed a randomized controlled study before OLT and 10 of 19 completed a full crossover study. Improvements in weight and height occurred during the BCAA supplements, with no statistical change on the standard formulation. Significant increases in total body potassium, midupper arm circumference, and subscapular skinfold thickness occurred during the BCAA supplements, whereas no significant changes occurred during the standard formulation period. Significantly fewer albumin infusions were required during the BCAA supplement. These findings suggest that BCAA-enriched formulas have advantages over standard semielemental formulas in improving nutritional status in children with ESLD. and are deserving of wider application and study.

The nature of malnutrition in children with end-stage liver disease awaiting orthotopic liver transplantation

To evaluate malnutrition in chronic liver disease, and its relationship to nutrient deficiencies and hepatic dysfunction. 27 children with end-stage liver disease were studied. Mean protein-energy intakes were 70% of recommended daily intakes. The patients were underweight and stunted with reduced mean triceps and subscapular skinfold thicknesses and midupper arm circumference. Mean total body potassium was only 63 ± 18% of that expected for age and sex. Deficiency of essential fatty acids (32%), and low concentrations of fat-soluble vitamins (A, 92%; E, 32%), iron (32%), zinc (42%), and selenium (13%) were common. Serum ammonia concentrations were raised in all patients, and increased methionine, tyrosine, and glutamic acid, and reduced glutamine concentrations were noted. There was no correlation between the degree of malnutrition and the degree of liver synthetic function, the degree of cholestasis, or the degree of liver injury. We suggest that potentially correctable factors in addition to liver failure (eg, inadequate absorbed intake) were important determinants of malnutrition in these patients.

Liver transplantation in children: Experience with the development of an Australian pilot programme. The Queensland Liver Transplantation Programme

Children with end-stage liver disease now form a major sub-group of patients considered suitable for liver transplantation (ltp), and enjoy better survival statistics after transplantation than do adults. Since June 1984, a paediatric ltp programme has been developed in Brisbane with an initial working relationship and ongoing close links with two USA centres (Pittsburgh, and the UCLA Medical Center). Fourteen children with end-stage liver disease have been referred to the Queensland Liver Transplantation Programme for formal assessment. Following frank, informed discussion with their parents, 10 of these children were offered the option of ltp. During the transition stage, two infants with biliary atresia were referred to UCLA at their parents' request and, subsequently, eight children aged from 9 months to 6 years have been placed on a transplant candidacy list in Brisbane. A donor procurement team with access to a Queensland Government jet has been available to cover all mainland States except Western Australia. Six of the children have now had orthotopic ltp (two children at the UCLA Medical Center; four children at the Royal Children's Hospital, Brisbane). One UCLA patient died with a non-functioning graft, and one Brisbane patient died 5 weeks post-transplant with rejection, hepatic artery thrombosis and sepsis. The other four children are alive and well, three with normal liver function and one with unexplained intrahepatic cholestasis, during the 1-20 month follow-up to date. Three further children have died of their liver disease without a donor of an appropriate blood group and size being found, and one patient still awaits a suitable donor. The experience of these authors suggests that ltp is a major advance in the treatment of paediatric liver disease, and that the procedure can be carried out successfully in Australia with initial results comparable with leading overseas centres. The procedure requires the full array of services of a major paediatric tertiary care facility, an intensive team effort with awareness of the special needs of children, and a widespread procurement capability. A major problem for Australia is the procurement of sufficient numbers of optimal paediatric donor livers.

Transplantation of human amnion epithelial cells reduces hepatic fibrosis in immunocompetent CCl4-treated mice

Chronic liver injury and inflammation lead to hepatic fibrosis, cirrhosis, and liver failure. Embryonic and mesenchymal stem cells have been shown to reduce experimental liver fibrosis but have potential limitations, including the formation of dysplastic precursors, tumors, and profibrogenic cells. Other stem-like cells may reduce hepatic inflammation and fibrosis without tumor and profibrogenic cell formation. To test this hypothesis we transplanted human amnion epithelial cells (hAEC), isolated from term delivered placenta, into immunocompetent C57/BL6 mice at week 2 of a 4-week regimen of carbon tetrachloride (CCl4) exposure to induce liver fibrosis. Two weeks following hAEC infusion, intact cells expressing the human-specific markers inner mitochondrial membrane protein and human leukocyte antigen-G were found in mouse liver without evidence of host rejection of the transplanted cells. Human albumin, known to be produced by hAEC, was detected in sera of hAEC-treated mice. Human DNA was detected in mouse liver and also spleen, lungs, and heart of some animals. Following hAEC transplantation, CCl4-treated animals showed decreased serum ALT levels and reduced hepatocyte apoptosis, compared to controls. hAEC-treated mouse liver had lower TNF-α and IL-6 protein levels and higher IL-10 compared to animals given CCl4 alone. Compared to CCl4 controls, hAEC-treated mice showed fewer activated collagen-producing hepatic stellate cells and less fibrosis area and collagen content. Reduced hepatic TGF-β levels in conjunction with a twofold increase in the active form of the collagen-degrading enzyme matrix metalloproteinase-2 in hAEC-treated mice compared to CCl4 controls may account for the reduction in fibrosis. hAEC transplantation into immunocompetent mice leads to cell engraftment, reduced hepatocyte apoptosis, and decreased hepatic inflammation and fibrosis.

The Queensland liver transplant programme: The first two years

Orthotopic liver transplantation began in Brisbane in January 1985. During the first two years of the programme an assessment committee evaluated 55 patients (38 adults, 17 children). Patients were either accepted for transplantation, rejected as unsuitable or deferred for elective reassessment. All of the 10 adults who were rejected for transplantation because they had 'too advanced' disease died within four months of assessment. Six children who were accepted for transplantation died before a suitable donor liver could be found. In the first two years, 21 orthotopic liver transplantations were performed on 18 patients (adults, 13 patients; children, five patients). Fifteen of 21 grafts were procured from within Queensland. Twelve (67%) patients are alive at three to 23 months and all have been discharged from hospital. Deaths in adults were due to sepsis (three patients), aspiration pneumonitis (one patient), rejection and hepatic artery thrombosis (one patient) and the recurrence of a hepatocellular carcinoma five months after discharge from hospital (one patient). Two patients underwent a second transplantation procedure because of chronic rejection at four months and at 11 months, respectively, after the initial operation. One patient received a second transplant for primary graft failure at four days after the operation. A scoring system which considered the presence of pre-operative patient factors, such as coma, ascites, malnutrition and previous abdominal surgery, partly predicted the operative blood loss and patient survival. In conclusion, orthotopic liver transplantation is being performed in Australia with survival rates that are comparable with those of established overseas units.