Mohammed Rela

Lessons from look-back in acute liver failure? A single centre experience of 3300 patients.

BACKGROUND & AIMS Acute liver failure (ALF) is a rapidly progressive critical illness with high mortality. Complex intensive care unit (ICU) protocols and emergency liver transplantation (ELT) are now often available, but rarity and severity of illness have limited its study and evidence-base for care. We reviewed patients treated over a 35-year period at a specialist high-volume ICU, quantifying changes in disease aetiology, severity and evolution of ICU support and ELT use and outcome. METHODS Review of adult patients admitted during the period 1973-2008, with acute liver dysfunction and coagulopathy with overt hepatic encephalopathy (ALF) and those without (acute liver injury; ALI). RESULTS 3305 patients fulfilled inclusion criteria, 2095 with ALF. Overall hospital survival increased from 30% in 1973-78 to 76% in 2004-08; in ALF from 17% to 62% (both p<0.0001). In ALF patients treated without ELT, survival rose from 17% to 48% (p<0.0001); in those undergoing ELT (n=387) from 56% in 1984-88 to 86% in 2004-08 (p<0.01). Coincident with drug sales-restriction, paracetamol-related admissions fell significantly. Viral admissions fell from 56% to 17% of non-paracetamol cases (p<0.0001). Admission markers of liver injury severity fell significantly and the proportion of patients with intracranial hypertension (ICH) fell from 76% in 1984-88 to 20% in 2004-08 (p<0.0001). In those with ICH, mortality fell from 95% to 55% (p<0.0001). CONCLUSIONS The nature and outcome of ALF have transformed over 35 years, with major improvements in survival and a fall in prevalence of cerebral oedema and ICH, likely consequent upon earlier illness recognition, improved ICU care, and use of ELT.

Pregnancy outcome after liver transplantation: A single‐center experience of 71 pregnancies in 45 recipients

Infertility is common in women with end‐stage liver disease. Successful liver transplant (LT), however, can restore childbearing potential. Controversy exists regarding the most appropriate immunosuppressive regimen and timing of conception following LT. We report the outcomes of a review of all pregnancies occurring following LT at Kings College Hospital, London, from 1988 to 2004. Seventy‐one pregnancies were recorded in 45 women. Tacrolimus (60%) and cyclosporin A (38%) were the predominant primary immunosuppressive agents used. Median age at conception was 29 years (range, 19–42), with a median time from LT to conception of 40 months (range, 1–111). There were 50 live births, and no maternal or fetal deaths related to pregnancy. There were no graft losses. Median gestation was 37 weeks (range, 24–42) with a median birth weight of 2,690 g (range, 554–4,260). Caesarean section was performed in 40% of pregnancies. Complications included pregnancy‐induced hypertension in 20%, preeclampsia in 13%, acute cellular rejection in 17%, and renal impairment in 11%. There was no statistically significant difference in complication rates observed between immunosuppressive groups. Pregnancies occurring within 1‐year posttransplant had an increased incidence of prematurity, low birth weight, and acute cellular rejection compared to those occurring later than 1 year. In conclusion, this study confirms that favorable outcomes of pregnancy post‐LT can be expected for the majority of patients. However, delaying pregnancy until after 1‐year post‐LT is advisable, since doing so maybe associated with a lower risk of prematurity. Liver Transpl 12:1138–1143, 2006.

Outcome after wait-listing for emergency liver transplantation in acute liver failure: A single centre experience

BACKGROUND/AIMS Though emergency liver transplantation (ELT) is an established treatment for severe acute liver failure (ALF), outcomes are inferior to elective surgery. Despite prioritization, many patients deteriorate, becoming unsuitable for ELT. METHODS We examined a single-centre experience of 310 adult patients with ALF registered for ELT over a 10-year period to determine factors associated with failure to transplant, and in those patients undergoing ELT, those associated with 90-day mortality. RESULTS One hundred and thirty-two (43%) patients had ALF resulting from paracetamol and 178 (57%) from non-paracetamol causes. Seventy-four patients (24%) did not undergo surgery; 92% of these died. Failure to transplant was more likely in patients requiring vasopressors at listing (hazard ratio 1.9 (95% CI 1.1-3.6)) paracetamol aetiology (2.5 (1.4-4.6)) but less likely in blood group A (0.5 (0.3-0.9)). Post-ELT survival at 90-days and one-year increased from 66% and 63% in 1994-1999 to 81% and 79% in 2000-2004 (p<0.01). Four variables were associated with post-ELT mortality; age >45 years (3 (1.7-5.3)), vasopressor requirement (2.2 (1.3-3.8), transplantation before 2000 (1.9 (1.1-3.3)) and use of high-risk grafts (2.3 (1.3-4.2). CONCLUSIONS The data indicate improved outcomes in the later era, despite higher level patient dependency and greater use of high-risk grafts, through improved graft/recipient matching.

A prospective randomised trial of bile duct reconstruction at liver transplantation: T tube or no T tube?

A prospective randomised study of end-to-end bile duct reconstruction with or without T-tube drainage during orthotopic liver transplantation (OLT) was undertaken in 60 patients well matched for age, sex, aetiology of liver disease, operative blood loss, cold ischaemic time, preoperative serum bilirubin level and Child-Pugh score. Significant biliary complications in the T tube group occurred in five patients and included bile duct stricture (n=2), bile leak/peritonitis (n=1) and cholangitis (n=2). Bile duct strictures occurred in six patients in the no T tube group (P>0.05, NS). Hepatic artery stenosis was identified in one patient from each group in association with a biliary stricture. Biliary complications in both groups were associated with a prolonged graft cold ischaemic time (P<0.01). As no significant difference was noted in the number of early and late biliary complications between the two groups, the routine use of a T tube has been discontinued.

The development of new density gradient media for purifying human islets and islet-quality assessments

Successful islet transplantation is dependent on the quality and quantity of islets infused. Islets are purified on density gradients, but procedures currently used have limited capacity for pancreatic digests, islet yield, and viability. We aimed to improve islet purification with a modified gradient medium. Biocoll was diluted in University of Wisconsin solution to create linear density gradients of 1.065 to 1.095 g/mL. Properties of islets purified from 22 human pancreas digests with modified medium were compared with 15 preparations using standard medium. The modification increased the capacity of gradients for pancreatic digests from 20 to 60 mL, islet yield increased from 218,000 to 435,318 per isolation, and viability increased from 65.4% to 92.1%. Islet fractions contained greater than 95% of recovered insulin. Islets showed good physiologic responses to secretagogues and restored normoglycemia in streptozotocin-induced diabetic severe combined immunodeficiency disease mice. The new medium enhances yield, purity, and viability of human islet preparations for clinical islet transplantation.

Safety and efficacy of combined use of sildenafil, bosentan, and iloprost before and after liver transplantation in severe portopulmonary hypertension†

Portopulmonary hypertension (PPHTN) represents a constrictive pulmonary vasculopathy in patients with portal hypertension. Liver transplantation (LT) may be curative and is usually restricted to patients with mild‐to‐moderate disease severity characterized by a mean pulmonary artery pressure (mPAP < 35 mm Hg). Patients with severe disease (mPAP > 50 mm Hg) are usually excluded from transplantation. We describe a patient with severe PPHTN, initiated on sequential and ultimately combination therapy of prostacyclin, sildenafil, and bosentan (PSB) pretransplantation and continued for 2 years posttransplantation. Peak mPAP on PSB therapy was dramatically reduced from 70 mm Hg to 32 mm Hg pretransplantation, and continued therapy facilitated a further fall in mPAP to 28 mm Hg posttransplantation. The pulmonary vascular resistance index fell from 604 to 291 dyne second−1 cm−5. The perioperative mPAP rose to 100 mm Hg following an episode of sepsis and fell with optimization of PSB therapy. In conclusion, this is the first reported patient with severe PPHTN using this combination of vasodilator therapy as a bridge to LT and then as maintenance in the posttransplantation phase. This regimen may enable LT in similar patients in the future, without long‐term consequences. Liver Transpl 14:287–291, 2008.

Liver transplantation in patients over 60 and 65 years: An evaluation of long‐term outcomes and survival

With increased demand for liver transplantation (LT), outcomes of older recipients have been subjected to greater scrutiny, as previous studies have demonstrated poorer survival outcomes. Outcomes of 77 patients aged > 65 yr (group 1) who underwent transplantation between 1988 and 2003 at Kings College Hospital, London, were compared with all recipients aged between 60 and 64 yr (group 2, n = 137) and 202 time‐matched control patients with chronic liver disease aged between 18‐59 yr (group 3). Patient survival at 30‐days for groups 1, 2, and 3 were 99%, 94%, and 94%, respectively (P = not significant [NS]). At 1‐yr, survival in the 3 groups was 82%, 86%, and 83%, respectively (P = NS), and at 5‐yr patient survival was comparable (73%, 80%, and 78%, respectively) (P = NS). Episodes of acute cellular rejection (ACR) were fewer in the older cohorts (43% vs. 45% vs. 61%, P = 0.0016), although there was no significant difference identified in the numbers of patients in each group who experienced ACR (P = 0.16). A similar but nonsignificant trend was identified for rates of chronic rejection among the groups. In conclusion, these data suggest that survival of patients over 60 and 65 yr undergoing LT is satisfactory, at least in the first 5‐yr posttransplantation. In addition, patients over 65 yr experience less rejection, with good graft survival. Thus, LT should not be denied to patients >65 yr on the basis of age alone, once a comprehensive screen for comorbidity has been undertaken. Liver Transpl 13:1382–1388. 2007.

Liver transplantation for Wilson's disease: long-term results and quality-of-life assessment.

Background. Wilson’s disease associated with severe liver disease is effectively cured by orthotopic liver transplantation (OLT). However, there are also anecdotal reports of improved or resolved neurologic symptoms after OLT in patients with stable or normal liver function. Side effects with conventional chelating agents are common, and it has been suggested that OLT should be considered in patients with severe progressive neurologic symptoms. However, the decision to apply this therapeutic modality to a subgroup of patients without significant liver disease is a quality-of-life issue. Methods. Long-term follow-up and quality-of-life data were obtained prospectively for 24 patients who underwent OLT between 1988 and 2000 for Wilson’s disease associated with severe liver disease. In long-term survivors, quality of life was assessed using the 36-Item Short Form 36 Health Survey Questionnaire. Results. One patient who had multiorgan failure before OLT died within 24 hr of surgery and two patients died within 1 year because of immunosuppressant-related complications. There have been no deaths or graft loss in patients who have undergone transplantation since 1994, and after a median follow-up of 92 months, all survivors have satisfactory graft function (5-year patient and graft survival, 87.5%), with quality-of-life scores (assessed in 86% of survivors) comparable to age- and sex-matched controls from the general population. Conclusions. The authors’ results suggest that liver transplantation can be safely performed in patients with Wilson’s disease, with excellent long-term results and quality of life. Further study of the utility of liver transplantation in the management of patients with severe neurologic symptoms is justified.

Late cellular rejection in paediatric liver transplantation : aetiology and outcome

Background. Acute cellular rejection, though mostly encountered during the first 3 months after liver transplant, may occur later on. Clinical features and outcome of children experiencing late cellular rejection (LCR) have not been described to date. Patients and Methods. A total of 20 children who developed acute rejection 6 months or more after liver transplant were studied for history of early rejection, levels of immunosuppression, causes of low immunosuppression, viral infections, signs of autoimmunity, and HLA mismatch. All liver biopsies were reviewed. Fifteen patients with no history of LCR were randomly selected as controls. Results. Of 20 children 5 were appropriately immunosuppressed, although 15 were not. Causes of low immunosuppression were: unknown (seven), poor compliance (three), posttransplant lymphoproliferative disease, (two), hepatocellular carcinoma recurrence (one), tuberculosis (one), gastroenteritis (one). Of 20 patients early rejection occurred in 13 and cytomegalovirus infection in 5. At last follow‐up 10 children have persistent graft dysfunction, of whom 5 have progressed to de novo autoimmune hepatitis, 2 to chronic rejection, one has persistent graft dysfunction with recurrent cytomegalovirus activation, one has hepatic artery thrombosis and one is likely to have persistent poor compliance. None of the 15 controls developed de novo autoimmune hepatitis or any other form of persistent graft dysfunction at the time of last follow‐up. Conclusion. Late cellular rejection in children is usually due to low or decreased immunosuppression and is associated with long‐term complications. Prompt intervention to correct inadequate immunosuppression and careful follow‐up of the other patients to identify other treatable conditions is essential.

Systematic review and validation of prognostic models in liver transplantation

A model that can accurately predict post–liver transplant mortality would be useful for clinical decision making, would help to provide patients with prognostic information, and would facilitate fair comparisons of surgical performance between transplant units. A systematic review of the literature was carried out to assess the quality of the studies that developed and validated prognostic models for mortality after liver transplantation and to validate existing models in a large data set of patients transplanted in the United Kingdom (UK) and Ireland between March 1994 and September 2003. Five prognostic model papers were identified. The quality of the development and validation of all prognostic models was suboptimal according to an explicit assessment tool of the internal, external, and statistical validity, model evaluation, and practicality. The discriminatory ability of the identified models in the UK and Ireland data set was poor (area under the receiver operating characteristic curve always smaller than 0.7 for adult populations). Due to the poor quality of the reporting, the methodology used for the development of the model could not always be determined. In conclusion, these findings demonstrate that currently available prognostic models of mortality after liver transplantation can have only a limited role in clinical practice, audit, and research. (Liver Transpl 2005;11:814–825.)