Need For Orthotopic Liver Transplantation Research Articles

Elevated Liver Fibrosis Progression in Isolated PSC Patients and Increased Malignancy Risk in a PSC-IBD Cohort: A Retrospective Study.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (CU), and rarely with Crohn's disease (CD). Various long-term analyses show different rates of cancer and the need for orthotopic liver transplantation (OLT) in patients with isolated PSC and with concomitant IBD, respectively. However, data on the detailed course of PSC with or without IBD are limited. We aimed to analyze the clinical disease course of PSC patients without IBD compared to PSC patients with UC and CD, respectively. A retrospective data analysis of patients with isolated PSC (n = 41) and of patients with concomitant IBD (n = 115) was performed. In detail, PSC disease characteristics including occurrence of dominant stenoses, liver cirrhosis, OLT and malignancy, as well as the temporal course of PSC activity and disease progression, were analyzed. A multivariable Cox regression model and a Fine-Gray competing risk model were further used for the independent risk factor analysis of cirrhosis development and OLT. Patients with isolated PSC were significantly older at first diagnosis than patients with PSC-IBD (39 vs. 28 years, p = 0.02). A detailed analysis of the course of PSC revealed a faster PSC progression after initial diagnosis in isolated PSC patients compared to PSC-IBD including significantly earlier diagnosis of dominant stenoses (29 vs. 74 months, p = 0.021) and faster progression to liver cirrhosis (38 vs. 103 months, p = 0.027). Patients with isolated PSC have a higher risk of developing cirrhosis than patients with PSC-IBD (Gray's test p = 0.03). OLT was more frequently performed in male patients with isolated PSC compared to males with coincident IBD (48% (n = 13) vs. 33% (n = 25), p = 0.003). Colorectal carcinoma was significantly more often diagnosed in patients with PSC-IBD than in isolated PSC (8.7% vs. 0%, p = 0.042). Patients with isolated PSC seem to have a different clinical course of disease than PSC patients with concomitant IBD characterized by a more pro-fibrotic disease course with earlier onset of liver cirrhosis and dominant stenosis but with less malignancy. These data may be interpreted as either a more progressive disease course of isolated PSC or a later diagnosis of the disease at an advanced disease stage. The different clinical courses of PSC and the underlying mechanisms of the gut-liver axis need further attention.

S3069 Lifesaving but Tiresome Treatment for Tyrosinemia Type 1

Introduction: Tyrosinemia type I (HT1) is a rare autosomal recessive condition caused by a genetic mutation disrupting proper functioning of the fumarylacetoacetate hydrolase (FAH) enzyme, the terminal enzyme in the tyrosine catabolism pathway. The below case exemplifies the difficulty for adherence as children transition to adulthood of the standard therapy that prolongs life and decreases need for orthotopic liver transplantation (OLT). Case Description/Methods: A 23-year-old male with known tyrosinemia type I presents with progressively worsening back, lower extremity, and abdominal pain over the last six months. He had been lost to follow-up from Genetics clinic for the last ten years. He adhered to nitisinone therapy and diet modifications until around five years ago. The patient was admitted to the hospital for neurological crises due to non-adherence to HT1 therapy. On admission, vital signs were stable and his physical exam significant for mild tenderness of abdomen at RUQ and tenderness in the lumbar and thoracic region of back. Pertinent lab findings were albumin of 3.2, alkaline phosphatase of 356. AST, ALT, Bili, CBC, BMP WNL. Amino acid panel found tyrosine level of 62. AFP level of 188. MRI Abdomen with and without contrast found cirrhotic liver morphology, developing portal hypertension (borderline enlarged spleen, collateral vasculature, but no ascites), and a lesion of hepatic segment 8 measuring 2.3cm x 1.4cm in diameter. Patient was planned to be restarted on nitisinone with pending further evaluation of liver lesion. (Figure) Discussion: The above case demonstrates a patient with the rare genetic disorder Tyrosinemia type 1 with non-adherence to nitisinone and diet modification therapies. The presentation of neurological crises and abdominal pain with development of hepatomas/hepatocellular carcinoma (HCC) is typical for untreated or non-adherent patients with HT1. Nitisinone has been shown to be highly effective for this condition with 4-year survival rates of 94% compared to 29% of diet modification alone. Prior to nitisinone therapy, most patients required OLT. Despite the clear benefits, recent evidence is finding increasing non-adherence as patients grow older into adolescence and adulthood. This is consistent with adherence problems with early diagnosis chronic diseases with long-term therapies. More research is needed to elucidate major barriers for non-compliance and to refine guidelines regarding frequency of follow-up and monitoring of serum AFP to screen for HCC and encourage compliance.Figure 1.: MRI Abdomen with contrast with findings of a hepatic lesion on segment 8.

Pathophysiological, Molecular and Therapeutic Issues of Nonalcoholic Fatty Liver Disease: An Overview.

Nonalcoholic Fatty Liver Disease (NAFLD) represents the leading cause of liver disease in developed countries but its diffusion is currently also emerging in Asian countries, in South America and in other developing countries. It is progressively becoming one of the main diseases responsible for hepatic insufficiency, hepatocarcinoma and the need for orthotopic liver transplantation. NAFLD is linked with metabolic syndrome in a close and bidirectional relationship. To date, NAFLD is a diagnosis of exclusion, and liver biopsy is the gold standard for diagnosis. NAFLD pathogenesis is complex and multifactorial, mainly involving genetic, metabolic and environmental factors. New concepts are constantly arising in the literature promising new diagnostic and therapeutic tools. One of the challenges will be to better characterize not only NAFLD development but overall NAFLD progression, in order to better identify NAFLD patients at higher risk of metabolic, cardiovascular and neoplastic complications. This review analyses NAFLD epidemiology and the different prevalence of the disease in distinct groups, particularly according to sex, age, body mass index, type 2 diabetes and dyslipidemia. Furthermore, the work expands on the pathophysiology of NAFLD, examining multiple-hit pathogenesis and the role of different factors in hepatic steatosis development and progression: genetics, metabolic factors and insulin resistance, diet, adipose tissue, gut microbiota, iron deposits, bile acids and circadian clock. In conclusion, the current available therapies for NAFLD will be discussed.

Hepatocyte transplantation: Consider infusion before incision.

Human hepatocyte transplantation is undergoing study as a bridge, or even alternative, to orthotopic liver transplantation (OLT). This technique has undergone multiple developments over the past thirty years in terms of mode of delivery, source and preparation of cell cultures, monitoring of graft function, and use of immunosuppression. Further refinements and improvements in these techniques will likely allow improved graft survival and function, granting patients higher yield from this technique and potentially significantly delaying need for OLT.

The role of TIPS in the management of liver transplant candidates.

Transjugular intrahepatic portosystemic shunt (TIPS) implantation is used for treatment of several complications in patients with liver cirrhosis. Recent studies have identified a survival benefit for patients on the waiting list after TIPS implantation, but the optimal time point for TIPS implantation prior to orthotopic liver transplantation (OLT) has not been established. This study retrospectively assessed patients undergoing TIPS implantation before or after listing for OLT at the Medical University of Vienna. n = 98 patients with TIPS on the waiting list between January 1993 and December 2013 were identified (n = 73 (74.5%) pre-listing TIPS, n = 25 (25.5%) post-listing TIPS). A matched control group at the time of OLT without TIPS (n = 60) was included. More patients with post-listing TIPS (28.0%, 7/25) showed clinical improvement and went off-list than patients with pre-listing TIPS (8.2%, 6/73, p = .0119). A similar proportion of patients with pre-listing TIPS (19.2%, 14/73) and post-listing TIPS (20.0%, 5/25) died on the OLT waiting list. Transplant surgery time was similar in patients with and without TIPS: 348(±13) vs. 337(±10) minutes (p = .5139). Estimated 1-year post-transplant survival was similar across all groups (pre-listing TIPS: 76.2%, post-listing TIPS: 86.0%, no TIPS: 91.2%, log-rank p = .1506). TIPS should be considered in all liver transplant candidates, since it can obviate the need for OLT and optimize bridging to OLT.

Early nitisinone treatment reduces the need for liver transplantation in children with tyrosinaemia type 1 and improves post‐transplant renal function

Tyrosinaemia type 1 (HT1) is a rare disorder of tyrosine metabolism leading to liver failure and hepatocellular carcinoma. Treatment previously consisted of dietary restriction and orthotopic liver transplantation (OLT) but was transformed by the introduction of nitisinone in 1992. We describe the impact of nitisinone on the outcome and need for OLT in a single centre. A retrospective analysis was performed of patients treated for HT1 at Birmingham Children's Hospital from 1989-2009. Thirty eight patients were treated during the study period. Prior to 1992 6/7 (85.7%) underwent OLT compared to 7/31 (22.6%) after 1992 (p = 0.004) when nitisinone treatment was available. Furthermore, nitisinone-treated patients proceeding to OLT started treatment at a median age of 428 (86-821) days compared to 52 (2-990) days in those who did not (p = 0.004). Pre-OLT calculated glomerular filtration rate (cGFR) was similar in both groups but nitisinone prevented early decline after OLT (pre-nitisinone median 99.8 to 45.8ml/min/1.73m2, p = 0.02 versus nitisinone-treated group median 104.3 to 89.9ml/min/1.73m2, p = 0.5). Urinary protein:creatinine ratio (PCR) fell post-OLT to within the normal range for those treated with nitisinone but remained elevated in those not treated with nitisinone. Tubular reabsorption of phosphate (TRP) was normal or near normal in both groups pre-OLT and post-OLT. Hypertension was commoner and more severe in those not treated with nitisinone. Nitisinone reduces the need for OLT particularly when started early. For those progressing to OLT the use of prior nitisinone therapy results in a preservation of their subsequent renal function.

MMP‐2 is a disease‐modifying gene in primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts, frequently necessitating orthotopic liver transplantation (OLT), often accompanied by inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) are associated with fibrotic diseases caused by the involvement in tissue remodelling. To evaluate the contribution of MMP-2 and -9 promoter polymorphisms to disease severity in PSC, as assessed by death or need for OLT. Matrix metalloproteinase-2 (-1306 C/T) and -9 (-1562 C/T) gene promoter polymorphisms were analyzed in 132 PSC patients. Follow-up was from onset PSC until death, OLT or end of follow-up. Twenty-year cumulative incidence (CI) of death or OLT for PSC patients with MMP-2 CT genotype was 86.5% compared to 52.8% for CC genotype (P = 0.030) and reached 100% at 11.3 years for TT genotype. In patients with IBD, CIs were similar: 20-years CI of death or OLT for MMP-2 CT genotype was 86.0% compared to 49.0% for CC genotype and 100% at 11.3 years for TT genotype. Patients without IBD showed a similar trend in 20 years CI for MMP-2 CT (77.8%) compared to CC (57.8%) and CI for TT genotype reached 100% at 9.3 years. Multivariate analysis showed, along with age at diagnosis, a stepwise increase in hazard ratio for MMP-2 T-allele polymorphism for death or OLT. MMP-9 genotype was not associated with disease severity in PSC. Matrix metalloproteinase-2 C to T-1306 gene promoter polymorphism in PSC is an independent risk factor for disease severity as reflected by the need for OLT or disease progression leading to mortality.

P91 Nitisinone treatment reduces the need for liver transplantation in children with tyrosinaemia type 1 and is associated with improved post-transplant renal tubular function

IntroductionTyrosinaemia Type 1 (TT1) is a disorder of tyrosine metabolism which may lead to liver failure and a high risk of hepatocellular carcinoma (HCC). Treatment previously consisted of dietary restriction...

Paracetamol induced hepatotoxicity

Aim: To identify the clinical and biochemical risk factors associated with outcome of paracetamol induced significant hepatotoxicity in children. Methods: Retrospective case notes review of those with paracetamol overdose admitted...

Neuroregulation of the neuroendocrine compartment of the liver.

Liver progenitor cells as well as hepatic stellate cells have neuroendocrine features. Progenitor cells express chromogranin-A and neural cell adhesion molecule, parathyroid hormone-related peptide, S-100 protein, neurotrophins, and neurotrophin receptors, while hepatic stellate cells express synaptophysin, glial fibrillary acidic protein, neural cell adhesion molecule, nestin, neurotrophins, and their receptors. This phenotype suggests that these cell types form a neuroendocrine compartment of the liver, which could be under the control of the central nervous system. We recently showed that the parasympathetic nervous system promotes progenitor cell expansion after liver injury, since selective vagotomy reduces the number of progenitor cells after chemical injury in the rat. Similarly, after transplantation, which surgically denervates the liver, human livers that develop hepatitis have fewer progenitor cells than native, fully innervated livers with similar degrees of liver injury. There is also accumulating experimental evidence linking the autonomic system, in particular the sympathetic nervous system (SNS), with the pathogenesis of cirrhosis and its complications. Recently, it has been shown that hepatic stellate cells themselves respond to neurotransmitters. Moreover, inhibition of the SNS reduced fibrosis in carbon tetrachloride-induced liver injury. In view of the denervated state of transplanted livers, it is very important to unravel the neural control mechanisms of regeneration and fibrogenesis. Moreover, since there is a shortage of donor organs, a better understanding of the mechanisms of regeneration could have therapeutic possibilities, which could even obviate the need for orthotopic liver transplantation.

Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and optimal timing

Background/Aims : The aim of our study was to evaluate the proportion of patients with severe alcoholic cirrhosis who would need orthotopic liver transplantation (OLT) and to determine the optimal delay to evaluate an abstinent patient for transplantation. Methods : Survival without OLT, improvement in liver function and need for OLT were studied in all patients admitted in 1997 for a first episode of Child–Pugh C alcoholic cirrhosis. Results : Twenty-six percent (19/74) of patients died during the initial hospitalization. The cumulative survival rates after 6 months and 1, 2 and 3 years were 56, 36, 35 and 24%, respectively. One liver transplantation (1.3%, 95% confidence interval 0.0–3.9) was performed for persisting liver failure despite abstinence. Improvement of the Child–Pugh score was observed within 3 months in 66% of the abstinent patients. OLT was indicated in four patients without liver improvement despite abstinence, but was contraindicated in three. Conclusions : Only a few patients with severe alcoholic cirrhosis undergo OLT, since most of them do not stop drinking and/or die soon, and those becoming abstinent often improve their liver function. OLT should be considered when improvement in liver function is lacking after 3 months of abstinence.

The use of the King's college hospital criteria (KCHC) on adminssion to predict mortality or the need for orthotopic liver transplantation (OLT) in patients referenced to emory university hospital (EUH) for fulminant hepatic failure (FHF)

The use of the King's college hospital criteria (KCHC) on adminssion to predict mortality or the need for orthotopic liver transplantation (OLT) in patients referenced to emory university hospital (EUH) for fulminant hepatic failure (FHF)

The use of the King's college hospital criteria (KCHC) on adminssion to predict mortality or the need for orthotopic liver transplantation (OLT) in patients referenced to emory university hospital (EUH) for fulminant hepatic failure (FHF)

The use of the King's college hospital criteria (KCHC) on adminssion to predict mortality or the need for orthotopic liver transplantation (OLT) in patients referenced to emory university hospital (EUH) for fulminant hepatic failure (FHF)

Use and outcome of liver transplantation in acetaminophen-induced acute liver failure.

Once defined clinical criteria are fulfilled in acetaminophen-induced hepatotoxicity, prognosis without orthotopic liver transplantation (OLT) may be very poor. In the present study, we examined the application and outcome of OLT in 548 patients admitted to a single center between 1990 and 1996. Four hundred twenty-four (77%) of the patients studied did not fulfill transplantation criteria, and 396 of these (93%) survived. The majority of the 28 nonsurvivors (7%) in this group fulfilled two of three combined criteria, and the finding of a high APACHE III score could be used as an indicator for the need for OLT. Of the 56 patients (45%) not listed, in only a small proportion was this caused by psychiatric reasons, and in the majority, it was a consequence of the rapid development of multiple organ failure and cerebral edema. This also applied to 24 (35%) of the 68 listed patients in whom the rapidity of clinical deterioration, reflected in increasing APACHE III scores, was such that even with the prompt availability of donor organs, OLT was not possible. In the final event, only 44 (35%) of those who fulfilled criteria underwent OLT, of whom 33 (75%) survived to leave the hospital. Survival was greatest in those receiving unreduced grafts, and markers of early graft function differed significantly between survivors and nonsurvivors. Liver transplantation is an effective treatment in a relatively small number of patients with acetaminophen-induced hepatotoxicity, and for a substantial proportion, transplantation was never an option because of the rapidity of clinical deterioration. APACHE III scoring may be of value in decision making and in better defining patients in clinical trials.