Mitochondrial neurogastrointestinal encephalomyopathy: Clinical and biochemical impact of allogeneic stem cell transplantation in a Greek patient with one novel TYMP mutation.

We describe the case of a Greek female patient with the Classic form of the ultra- rare and fatal autosomal recessive disorder Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and the impact of allogeneic hematopoietic stem cell transplantation on the biochemical and clinical aspects of the disease. The patient presented at the age of 15 years with severe gastrointestinal symptoms, cachexia, peripheral neuropathy and diffuse leukoencephalopathy. The diagnosis of MNGIE disease was established by the increased levels of thymidine and deoxyuridine in plasma and the complete deficiency of thymidine phosphorylase activity. The novel c.[978dup] (p.Ala327Argfs*?) variant and the previously described variant c.[417 + 1G > A] were identified in TYMP. The donor for the allogeneic hematopoietic stem cell transplantation was her fully compatible sister, a carrier of the disease. The patient had a completely uneventful post- transplant period and satisfactory PB chimerism levels. A marked and rapid decrease in thymidine and deoxyuridine plasma levels and an increase of the thymidine phosphorylase activity to the levels measured in her donor sister was observed and is still present sixteen months post-transplant. Disease symptoms stabilized and some improvement was also observed both in her neurological and gastrointestinal symptoms. Follow up studies will be essential for determining the long term impact of allogeneic hematopoietic stem cell transplantation in our patient.

Postreperfusion Liver Biopsy as Predictor of Early Graft Dysfunction and Survival After Orthotopic Liver Transplantation.

Background: Postreperfusion liver biopsy (PRB) can assess the degree of ischemia/reperfusion injury (IRI) after orthotopic liver transplantation (OLT). The influence of IRI on graft outcomes and overall survival is controversial. Aim: To determine the correlation between the severity of IRI in PRB and overall graft and patient survival and, secondarily, to identify factors on PRB that predict poor graft outcomes. Methods: This is a retrospective analysis of all patients who underwent OLT using donation after brain death (DBD) with PRB. The severity of IRI in PRB was graded. Predictors of IRI were assessed using univariate and multivariate analysis and the Kaplan-Meier with log rank test for the graft and overall survival, respectively. Results: We included 280 OLTs (64.7%). The histopathological assessment of IRI severity was as follows: no IRI (N = 96, 34.3%), mild IRI (N = 65; 23.2%), moderate IRI (N = 101; 36.1%), and severe IRI (N = 18; 6.4%). The incidence rates of initial good graft function (IGGF), primary nonfunction and early allograft dysfunction (EAD) were 32.5%, 3.9%, and 18.6%, respectively. Severe IRI was associated with a lower incidence of IGGF (OR: 0.34, 95% CI 0.12-0.92; P = 0.03). Patients with severe IRI tended to have a higher incidence of EAD (33.2% vs. 18.6, P = 0.23). The cold ischemia time was an independent predictor of severe IRI on the multivariate analysis. Severe IRI was associated with poor 1- and 5-year overall survival rates (67% and 44%, respectively, compared with 84 and 68% in nonsevere IRI). Patients with severe IRI exhibited worse graft and overall survival. Conclusions: Cold ischemia time predicts the development of severe IRI. Patients with severe IRI show worse graft and overall survival and a lower incidence of IGGF, suggesting that histopathological findings could be useful for identifying patients at high risk of worse outcomes after OLT.

Transplantation for EASL-CLIF and APASL acute-on-chronic liver failure (ACLF) patients: The TEA cohort to evaluate long-term post-Transplant outcomes.

Background: The forecast accuracy of the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) and Asian Pacific Association for the Study of the Liver (APASL) acute-on-chronic liver failure (ACLF) criteria in assessing long-term outcomes after liver transplantation (LT) is still unclear, especially when the staging of the two standards is inconsistent. Methods: A retrospective cohort (NCT05036031) including 565 patients from January 2015 to June 2021 was conducted. The 28 and 90 days, 1- and 3-years overall survival (OS) after LT were compared between different grades. Findings: Total of 162 (28.7%) and 230 (40.7%) patients met the ACLF standards. In the EASL-CLIF criteria, the 3-year OS rates were 83·0%, 80·3%, and 69·8% for ACLF1-3, respectively. In the APASL criteria, the 3-year OS rates were 85·7% for APASL ACLF Research Consortium (AARC)-1, similar to ACLF-1. The 3-year OS rates were 84·5% for AARC-2, which were slightly better than ACLF-2. Regarding AARC-3, the 3-year OS rate was 5·8% higher than ACLF-3. For patients who met neither set of criteria for ACLF, the 3-year OS rates were 89·8%. The multivariate analysis showed that alanine aminotransferase >100 U/L, respiration failure, and cerebral failure were independent risk factors for post-LT death. Interpretation: This study provides the first large-scale long-term follow-up data in Asia. Both criteria showed favorable distinguishing ability for post-LT survival. Patients with ACLF had a higher post-LT mortality risk, and ACLF-3 and AARC-3 correlated with significantly greater mortality. Funding: National Natural Science Foundation of China and Science and Technology Commission of Shanghai Municipality.

Restoration of the gut microbiota is associated with a decreased risk of hepatic encephalopathy after TIPS.

Background & Aims: Hepatic encephalopathy (HE) is a major complication after transjugular intrahepatic portosystemic shunt (TIPS) and is primarily influenced by the gut microbiota. We aimed to evaluate alterations in the microbiota after TIPS and the association between such alterations and HE. Methods: We conducted a prospective longitudinal study of 106 patients with cirrhosis receiving TIPS. Faecal samples were collected before and after TIPS, and the gut microbiota was analysed by 16S ribosomal RNA sequencing. Results: Among all patients, 33 developed HE (HE+ group) within 6 months after TIPS and 73 did not (HE- group), and 18 died during follow-up. After TIPS, the autochthonous taxa increased, whereas the potential pathogenic taxa decreased in the HE- group, and the autochthonous taxon Lachnospiraceae decreased in the HE+ group. Furthermore, synergism among harmful bacteria was observed in all patients, which was weakened in the HE- group (p <0.001) but enhanced in the HE+ group (p <0.01) after TIPS. Variations of 5 autochthonous taxa, namely, Coprococcus, Ruminococcus, Blautia, Ruminococcaceae_uncultured, and Roseburia, were negatively correlated with the severity of HE. Notably, increased abundances of Coprococcus and Ruminococcus were protective factors against HE, and the incidences of HE in patients with improved, stable, and deteriorated microbiota after TIPS were 13.3, 25.9, and 68.2%, respectively. Higher total bilirubin level, Child-Pugh score, model for end-stage liver disease score, Granulicatella, and Alistipes and lower Subdoligranulum before TIPS were the independent risk factors for death. Conclusions: Alterations in gut dysbiosis were negatively related to the occurrence and severity of post-TIPS HE, and the pre-TIPS microbiota were associated with death, suggesting the gut microbiota could be a promising potential biological target for screening suitable patients receiving TIPS and prevention and treatment of post-TIPS HE. Lay summary: Alterations in the gut microbiota after transjugular intrahepatic portosystemic shunt (TIPS) and the relationship between such alterations and post-TIPS hepatic encephalopathy (HE) remain unclear. We therefore performed this study and found that after TIPS, restoration of the gut microbiota, mainly characterised by expansion of autochthonous taxa, depletion of harmful taxa, and weakening of synergism among harmful bacteria, was inversely related to the occurrence and severity of post-TIPS HE.

Technical characteristics and quality of grafts in liver procurement from brain-dead donors: A single-center study in Vietnamese population.

INTRODUCTION: Donor liver graft quality plays an especially important role that contributes to the success of organ transplantation. Almost all local and international authors are interested in the techniques and results of transplantation, however, in Vietnam, there have not been any studies that report the results of liver procurement from brain-dead donors from a technical perspective as well as the morphology and function of the transplanted organ. MATERIALS AND METHOD: This study is descriptive cross-section study with analysis of retrospective occurrences of a series of cases of liver procurement from brain-dead donors from March 2010 to March 2020. All cases were proceeded the multiple organ procurement with warm liver dissection and in vivo cannulation and perfusion. RESULTS: The average age of brain-dead donors was 29.7 ± 10.7 (18-69), 92.16% of the harvested organs were of good quality macroscopically; and the rate of anatomical modification was 33.3% that occurred mostly in the left hepatic artery (LHA). Technically, warm dissection was proceeded in majority of cases (98,0%), the graft implantation was performed by this technique with mean cold ischemia time (CIT) of 190,0 ± 100,5 min and WIT of 74,0 ± 39,2 s. There were no complications relating to graft injuries occurring during procurement and no primary liver failure, good results accounted for 94.1% of the total number of transplants postoperatively. CONCLUSION: Multiple organ procurement with warm liver dissection and in vivo cannulation and perfusion was a safe technique and may be effective by avoiding any donor's damages in cold-phase dissection.

Alcohol-associated liver disease: A review on its pathophysiology, diagnosis and drug therapy.

One of the global burdens of health care is an alcohol-associated liver disease (ALD) and liver-related death which is caused due to acute or chronic consumption of alcohol. Chronic consumption of alcohol damage the normal defense mechanism of the liver and likely to disturb the gut barrier system, mucosal immune cells, which leads to decreased nutrient absorption. Therapy of ALD depends upon the spectrum of liver injury that causes fatty liver, hepatitis, and cirrhosis. The foundation of therapy starts with abstinence from alcohol. Corticosteroids are used for the treatment of ALD but due to poor acceptance, continuing mortality, and identification of tumor necrosis factor-alpha as an integral component in pathogenesis, recent studies focus on pentoxifylline and, antitumor necrosis factor antibody to neutralize cytokines in the therapy of severe alcoholic hepatitis. Antioxidants also play a significant role in the treatment but till today there is no universally accepted therapy available for any stage of ALD. The treatment aspects need to restore the gut functions and require nutrient-based treatments to regulate the functions of the gut system and prevent liver injury. The vital action of saturated fatty acids greatly controls the gut barrier. Overall, this review mainly focuses on the mechanism of alcohol-induced metabolic dysfunction, contribution to liver pathogenesis, the effect of pregnancy, and targeted therapy of ALD.

Novel vectors and approaches for gene therapy in liver diseases.

Gene therapy is becoming an increasingly valuable tool to treat many genetic diseases with no or limited treatment options. This is the case for hundreds of monogenic metabolic disorders of hepatic origin, for which liver transplantation remains the only cure. Furthermore, the liver contains 10-15% of the body's total blood volume, making it ideal for use as a factory to secrete proteins into the circulation. In recent decades, an expanding toolbox has become available for liver-directed gene delivery. Although viral vectors have long been the preferred approach to target hepatocytes, an increasing number of non-viral vectors are emerging as highly efficient vehicles for the delivery of genetic material. Herein, we review advances in gene delivery vectors targeting the liver and more specifically hepatocytes, covering strategies based on gene addition and gene editing, as well as the exciting results obtained with the use of RNA as a therapeutic molecule. Moreover, we will briefly summarise some of the limitations of current liver-directed gene therapy approaches and potential ways of overcoming them.

Long Term Survival of Patients Undergoing TIPS in Budd-Chiari Syndrome.

BACKGROUND: There has been significant improvement in understanding the etiology and management of Budd-Chiari Syndrome (BCS). Patients with chronic or acute-on-chronic BCS need radiological interventions in the form of angioplasty, hepatic vein/inferior vena cava stenting or Transjugular Intrahepatic Portosystemic Shunt (TIPS). Data regarding the long term follow up of patients undergoing TIPS is limited. We thus prospectively followed-up BCS patients who underwent TIPS at our center. METHODS: This study included 42 patients with BCS who underwent TIPS with a covered stent between 2004 and 2014. We analyzed the etiology, symptoms, severity, laboratory parameters and imaging pre and post TIPS. All patients underwent surveillance for hepatocellular carcinoma. RESULTS: Patients demographics included 26 males and 16 females with a mean age of 40.5 years (19-68 years). The mean Model for End-Stage Liver Disease score of the entire cohort was 15.38 (range: 9-25). Thirty-four patients were grouped into Rotterdam Class 2 and remaining into Class 3. There was significant improvement in ascites, gastrointestinal bleed, renal function and transaminase levels post TIPS. There were 11 deaths over the follow-up period - 4 within one month, 2 within six months and the rest after 3 years following TIPS. Median duration from clinical presentation to TIPS was 2.1 weeks and median survival till follow-up was 45.5 months (0-130 months). 33/42 patients underwent TIPS prior to 2013, and their median survival till follow-up was 55 months. Six out of eleven deaths that occurred within six months post-TIPS were before 2006; when the technique of TIPS creation was evolving. The cumulative 1 year, 5 years and 10 years OLT-free survival was 86%, 81% and 76%, respectively. Two patients underwent a liver transplant at 4 and 7 years after TIPS. CONCLUSION: Our results validate the role of TIPS in the management of patients with BCS. With the accessibility of TIPS, the requirement for liver transplantation has become rare.

Bioinformatic identification of key genes and pathways that may be involved in the pathogenesis of HBV-associated acute liver failure.

In order to explore the molecular mechanisms behind the pathogenesis of acute liver failure (ALF) associated with hepatitis B virus (HBV) infection, the present study aimed to identify potential key genes and pathways involved using samples from patients with HBV-associated ALF. The GSE38941 array dataset was downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) between 10 liver samples from 10 healthy donors and 17 liver specimens from 4 patients with HBV-associated ALF were analyzed using the Linear Models for Microarray Data package. Gene Ontology and KEGG pathway enrichment analyses of the DEGs were performed, followed by functional annotation of the genes and construction of a protein-protein interaction (PPI) network. Subnetwork modules were subsequently identified and analyzed. In total, 3142 DEGs were identified, of which 1755 were upregulated and 1387 were downregulated. The extracellular exosome, immune response, and inflammatory response pathways may potentially be used as biomarkers of ALF pathogenesis. In total, 17 genes (including CCR5, CXCR4, ALB, C3, VGEFA, and IGF1) were identified as hub genes in the PPI network and may therefore be potential marker genes for HBV-associated ALF.

Natural History of Cirrhosis of Liver after First Decompensation: A Prospective Study in India.

BACKGROUND AND AIMS: As liver cirrhosis is a dynamic condition, it is possible to improve survival in decompensated cirrhosis. Hence, we planned a prospective study to determine the natural history of cirrhosis after first decompensation. METHODS: We enrolled all patients of liver cirrhosis who presented with first episode of decompensation defined by the presence of ascites, either overt or detected by Ultrasonography (UD), Gastroesophageal Variceal Bleeding (GEVB), and Hepatic Encephalopathy (HE). All patients were followed up to death/liver transplant or at least for the period of 1 year. Multivariable Cox proportional hazards regression was used to analyze the risk of failure (death or Orthotopic Liver Transplantation (OLT)). RESULTS: In total of 110 cirrhotic patients (93 males, mean age 50 ± 11 years), the most frequent etiology was alcohol (48%), followed by nonalcoholic steatohepatitis/cryptogenic (26%), hepatitis B (10%), autoimmune hepatitis (7%), and hepatitis C (6%). The distribution of CTP classes was: 4%, 56%, and 41% in class A, B, and C, respectively. Ascites was the most common decompensation found in 88 patients (80%) followed by HE (14%) and GEVB (6%). At 1-year follow up, transplant free survival was 78%, 2 underwent OLT, 4 developed hepatocellular carcinoma, and 24 died. Cumulative incidence of failure (death or OLT) by type of decompensation after 1 year was: 22% overt ascites, 50% GEVB, 28% UD ascites, 20% HE, and 33% ascites and GEVB concomitant. CONCLUSIONS: Patients with UD ascites do not have a negligible mortality rate as compared to overt ascites. Patients with cirrhosis after first decompensation have better transplant free survival with treatment of etiology and complications than previously mentioned in literature.

Long-Term Outcomes of Liver Transplantation for Hepatic Sarcoidosis: A Single Center Experience.

AIM: Hepatic sarcoidosis is a rare indication for orthotopic liver transplantation (OLT). Hence, studies evaluating these patients are scarce. We present a single center experience with OLT for hepatic sarcoidosis in a case-control study. METHODS: A retrospective chart review was performed on 970 patients with OLT at our center, and 13 patients (1.3%) were identified who underwent 14 OLTs for hepatic sarcoidosis. For each case, two controls matched for etiology of liver disease, recipient age (±5 years), and duration since transplant (within 5 years) were selected. RESULTS: For the 13 patients transplanted for sarcoidosis, the median age was 46 years. The majority were women (62%) and African-American (85%). Cholestatic liver disease was the primary manifestation. Portal hypertensive complications were present in 11 patients (84%). The median MELD score at transplantation was 19. Extra-hepatic manifestations were present in ten patients (77%). All patients received whole deceased 14 donor allografts. Six patients remain alive with a median post-OLT follow-up of 8.4 years. The 1-, 3-, 5-, and 10-year patient survival rates were 84.6%, 76.9%, 61.1%, and 51.3%, respectively for the sarcoidosis group and 82.1%, 78.6%, 78.6%, and 61.9%, respectively for the matched PSC/PBC group (P = 0.739). Re-graft free survival for sarcoidosis patients was 84.6%, 76.9%, 61.5%, and 51.3% for 1-, 3-, 5-, and 10-years and for the matched control group re-graft free survival was 78.6% at 1-, 3-, 5-years, and 64.8% at 10-years (P = 0.661). Recurrence of hepatic sarcoidosis was found in 4 patients at 11 days, 112 days, 222 days, and 6.6 years. CONCLUSIONS: Our study depicts the long-term benefit of liver transplantation in patients with end stage liver disease secondary to sarcoidosis. It shows statistically comparable graft and patient survival for such patients when compared to other cholestatic diseases. Disease recurrence, although possible, has not been shown to cause allograft dysfunction.

Management in acute liver failure.

Acute liver failure (ALF) is a rare, potentially fatal complication of severe hepatic illness resulting from various causes. In a clinical setting, severe hepatic injury is usually recognised by the appearance of jaundice, encephalopathy and coagulopathy. The central and most important clinical event in ALF is occurrence of hepatic encephalopathy (HE) and cerebral edema which is responsible for most of the fatalities in this serious clinical syndrome. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a central role in the pathogenesis. The role of newer ammonia lowering agents is still evolving. Liver transplant is the only effective therapy that has been identified to be of promise in those with poor prognostic factors, whereas in the others, aggressive intensive medical management has been documented to salvage a substantial proportion of patients. A small fraction of patients undergo liver transplant and the remaining are usually treated with medical therapy. Therefore, identification of the complications and causes of death in such patients, and use of appropriate prognostic models to identify those who need liver transplant and those who can be managed with medical treatment is a vital component of therapeutic strategy. In this review, we discuss the various pathogenetic mechanisms and treatment options available.

Infections after orthotopic liver transplantation.

Opportunistic infections are a leading cause of morbidity and mortality after orthotopic liver transplantation. Systemic immunosuppression renders the liver recipient susceptible to de novo infection with bacteria, viruses and fungi post-transplantation as well to reactivation of pre-existing, latent disease. Pathogens are also transmissible via the donor organ. The time from transplantation and degree of immunosuppression may guide the differential diagnosis of potential infectious agents. However, typical systemic signs and symptoms of infection are often absent or blunted after transplant and a high index of suspicion is needed. Invasive procedures are often required to procure tissue for culture and guide antimicrobial therapy. Antimicrobial prophylaxis reduces the incidence of opportunistic infections and is routinely employed in the care of patients after liver transplant. In this review, we survey common bacterial, fungal, and viral infections after orthotopic liver transplantation and highlight recent developments in their diagnosis and management.

The Indian National Association for Study of the Liver (INASL) Consensus on Prevention, Diagnosis and Management of Hepatocellular Carcinoma in India: The Puri Recommendations.

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality and healthcare expenditure in patients with chronic liver disease. There are no consensus guidelines on diagnosis and management of HCC in India. The Indian National Association for Study of the Liver (INASL) set up a Task-Force on HCC in 2011, with a mandate to develop consensus guidelines for diagnosis and management of HCC, relevant to disease patterns and clinical practices in India. The Task-Force first identified various contentious issues on various aspects of HCC and these issues were allotted to individual members of the Task-Force who reviewed them in detail. The Task-Force used the Oxford Center for Evidence Based Medicine-Levels of Evidence of 2009 for developing an evidence-based approach. A 2-day round table discussion was held on 9th and 10th February, 2013 at Puri, Odisha, to discuss, debate, and finalize the consensus statements. The members of the Task-Force reviewed and discussed the existing literature at this meeting and formulated the INASL consensus statements for each of the issues. We present here the INASL consensus guidelines (The Puri Recommendations) on prevention, diagnosis and management of HCC in India.

Treprostinil Improves Hepatic Cytochrome P450 Activity during Rat Liver Transplantation.

BACKGROUND: Cytochrome P450 (CYP450) activity is an important indicator of liver graft function. CYP450 activity is altered by pro-inflammatory cytokines, which are associated with ischemia-reperfusion (I/R) injury during orthotopic liver transplantation (OLT). Treprostinil, an FDA-approved prostacyclin analog, ameliorated cold I/R injury during rat OLT. We hypothesized that treprostinil would improve CYP450 activity in liver graft during cold I/R injury post-OLT. METHODS: OLT was performed in syngeneic male Lewis rats with 18 h graft preservation in cold UW solution. Donor and recipients received treprostinil (100 ng/kg/min) or matching placebo for 24 h before and up to 48 h post-OLT. Liver graft mRNA and protein expression of CYP450 isoforms were analyzed by qRT-PCR and Western blot analysis, respectively. The formation rates of 1-hydroxymidazolam and 6ß-hydroxytestosterone, 6-hydroxychlorzoxazone, 2α- and 16α-hydroxytestosterone in liver graft microsomes served as markers for CYP3A, CYP2E1, and CYP2C11 activity, respectively, and were measured by LC-MS. RESULTS: Treprostinil significantly decreased serum ALT and AST levels at 6-48 h after OLT, compared to placebo. The expressions of TNFα and IFNγ mRNA in the liver graft were significantly inhibited in the treprostinil-treated group at 1 h post-reperfusion. Treprostinil restored CYP2E1 protein expression to that of normal liver and significantly improved CYP3A activity to more than two-fold of placebo early post-OLT. CONCLUSIONS: Treprostinil significantly ameliorated hepatic injury, reduced expression of pro-inflammatory cytokines, and improved CYP450 activity in liver graft early post-OLT. These findings suggest that treprostinil has the potential to serve as a therapeutic option to protect liver graft function against I/R injury during clinical OLT.