Cellular therapy for liver disease Huebert, Robert C; Rakela, Jorge
Mayo Clinic proceedings,
03/2014, Letnik:
89, Številka:
3
Journal Article
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Regenerative medicine is energizing and empowering basic science and has the potential to dramatically transform health care in the future. Given the remarkable intrinsic regenerative properties of ...the liver, as well as widespread adoption of regenerative strategies for liver disease (eg, liver transplant, partial hepatectomy, living donor transplant), hepatology has always been at the forefront of clinical regenerative medicine. However, an expanding pool of patients awaiting liver transplant, a limited pool of donor organs, and finite applicability of the current surgical approaches have created a need for more refined and widely available regenerative medicine strategies. Although cell-based therapies have been used extensively for hematologic malignant diseases and other conditions, the potential application of cellular therapy for acute and chronic liver diseases has only more recently been explored. New understanding of the mechanisms of liver regeneration and repair, including activation of local stem/progenitor cells and contributions from circulating bone marrow-derived stem cells, provide the theoretical underpinnings for the rational use of cell-based therapies in clinical trials. In this review, we dissect the scientific rationale for various modalities of cell therapy for liver diseases being explored in animal models and review those tested in human clinical trials. We also attempt to clarify some of the important ongoing questions that need to be addressed in order to bring these powerful therapies to clinical translation. Discussions will cover transplant of hepatocytes and liver stem/progenitor cells as well as infusion or stimulation of bone marrow-derived stem cells. We also highlight tremendous scientific advances on the horizon, including the potential use of induced pluripotent stem cells and their derivatives as individualized regenerative therapy for liver disease.
Liver transplantation (LT) is a life-saving treatment for patients with acute liver failure (ALF). Currently, there are few detailed data regarding long-term outcomes after LT for ALF. We combined ...prospective data from the Acute Liver Failure Study Group (ALFSG) Registry with those of the Scientific Registry of Transplant Recipients (SRTR) to assess outcomes among consecutive patients with ALF listed for LT. Cohort analysis of detailed pretransplantation data for patients listed for LT for ALF in the ALFSG Registry between January 1998 and October 2018 matched with transplantation-related data from the SRTR. Primary outcomes were 1- and 3-year post-LT patient survival. Secondary outcome was receipt of LT; independent associations with successful receipt of LT were determined using multivariable logistic regression. Of 624 patients with ALF listed for LT, 398 (64%) underwent LT, 100 (16%) died without LT, and 126 (20%) recovered spontaneously. Among LT recipients, etiologies included seronegative/indeterminate (22%), drug-induced liver injury (18%), acetaminophen overdose (APAP; 16%), and viral hepatitis (15%). The 1- and 3-year post-LT patient survival rates were 91% and 90%, respectively. Comparing those dying on the waiting list versus with those who received LT, the former had more severe multiorgan failure, reflected by increased vasopressor use (65% vs. 22%), mechanical ventilation (84% vs. 57%), and renal replacement therapy (57% vs. 30%; p < 0.0001 for all). After adjusting for relevant covariates, age (adjusted odds ratio aOR 1.02, 95% confidence interval CI 1.00-1.04), APAP etiology (aOR 2.72, 95% CI 1.42-5.23), requirement for vasopressors (aOR 4.19, 95% CI 2.44-7.20), Grade III/IV hepatic encephalopathy (aOR 2.47, 95% CI 1.29-4.72), and Model for End-Stage Liver Disease (MELD) scores (aOR 1.05, 95% CI 1.02-1.09; p < 0.05 for all) were independently associated with death without receipt of LT. Post-LT outcomes for ALF are excellent in this cohort of very ill patients. The development of multiorgan failure while on the transplantation list and APAP ALF etiology were associated with a lower likelihood of successful receipt of LT.
Sarcopenia, or loss of skeletal muscle mass, is associated with increased mortality and morbidity in liver transplant (LT) candidates. Six‐minute walk distance (6MWD) and health‐related quality of ...life (HRQOL) as assessed by short form 36 scores (SF‐36) also impact clinical outcomes in these patients. This study explored the relationship between the sarcopenia, 6MWD, and HRQOL in LT candidates. Sarcopenia was evaluated based on skeletal muscle mass index (SMI) quantified from abdominal computed tomography. Patients were followed until death, removal from the wait list or the end of the study period. Two hundred and thirteen patients listed for LT were included. The mean SMI, 6MWD and mean gait speed were 54.3 ± 9.7, 370.5 m and 1 m/s, respectively. Sarcopenia was noted in 22.2% of LT candidates. There was no correlation between sarcopenia, 6MWD, and SF‐36 scores. The 6MWD, but not sarcopenia, was an independent predictor of mortality (hazard ratio = 2.1 0.9–4.7). In summary, sarcopenia did not emerge as a significant predictor of waitlist mortality and also failed to correlate with either functional capacity or HRQOL in LT candidates. In patients with ESLD awaiting LT, 6MWD appears to be a more useful prognostic indicator than the presence of sarcopenia.
There has been a growing interest in identifying prognostic biomarkers that alone or with available prognostic models (King's College Criteria, KCC; MELD and ALFSG Prognostic Index) would improve ...prognosis in acute liver failure (ALF) patients being assessed for liver transplantation. The Acute Liver Failure Study Group (ALFSG) has evaluated 15 potential prognostic biomarkers: serum AFP; apoptosis-associated proteins; serum actin-free Gc-globulin; serum glycodeoxycholic acid; sRAGE/RAGE ligands; plasma osteopontin; circulating MBL, M-, L-, H-ficolin and CL-1; plasma galectin-9; serum FABP1; serum Lct2; miRNAs; factor V; thrombocytopenia, and sCD163. The ALFSG also has reported on 4 susceptibility biomarkers: keratins 8 and 18 (K8/K18) gene variants; polymorphisms of genes encoding putative APAP-metabolizing enzymes ( UGT1A1 , UGT 1A0 , UGT 2B15 , SULT1A1 , CYP2E1 , and CYP3A5 ) as well as CD44 and BHMT1 ; single nucleotide polymorphisms (SNPs) of genes associated with human behavior, rs2282018 in the arginine vasopressin ( AVP ) gene and rs11174811 in the AVP receptor 1A gene. Finally, rs2277680 of the CSCL16 gene in HBV-ALF patients. In conclusion, we have reviewed the prognostic and susceptibility biomarkers studied by the ALFSG. We suggest that a better approach to predicting the clinical outcome of an ALF patient will require a combination of biomarkers of pathogenic processes such as cell death, hepatic regeneration, and degree of inflammation that could be incorporated into prognostic models such as KCC, MELD or ALFSG PI.
Background
The etiology of acute liver failure (ALF) remains one of the most important factors in determining prognosis and predicting outcomes. In a significant proportion of ALF cases, however, the ...etiology remains unknown and is categorized as indeterminate ALF (IND‐ALF). In this study, we summarize findings from patients with IND‐ALF from 32 transplant centers across the United States, and we compare laboratory, prognostic, and outcome data for patients with IND‐ALF.
Methods
Between 1998 and 2019, 3364 adult patients with ALF or acute liver injury (ALI) from 32 liver transplant centers were enrolled in the ALFSG registry. The primary clinical outcome of interest was 21‐day transplant‐free survival (TFS).
Results
Of the 3364 patients enrolled in the ALFSG registry, 3.4 % (n = 114) were adjudicated as true indeterminate. On multivariate analysis, patients with a lower bilirubin, lower INR, lack of use of mechanical ventilation and no clinical features of coma at baseline had a higher odds ratio of transplant free survival. The number of deaths were similar between patients with true‐IND ALF versus patients with indeterminable ALF (29.8% vs. 27.2%), with almost half of the patients requiring liver transplant (42.1% vs. 45.7%).
Conclusion
We illustrate the poor prognoses that true‐IND‐ALF and indeterminable ALF carry and the need for emergency liver transplantation in most cases.
In the FAQ page of this software, it recommends not switching from version 2: “The gnomAD v2 call set contains fewer whole genomes than v3 but also contains a very large number of exomes that ...substantially increase its power as a reference in coding regions. ...gnomAD v2 is still our recommended dataset for most coding regions analyses” (https://gnomad.broadinstitute.org/faq#should-i-switch-to-the-latest-version-of-gnomad). ExAC (r0.3_GRCh38: 60,706 unrelated individuals from 17 disease-specific and population genetic studies, excluding individuals affected by a severe pediatric disease) 1000G (20130502_GRCh38: integrated set of SNPs, indels, MNPs, long insertions and deletions, copy number variations, and other types of structural variations discovered and genotyped in 2,504 unrelated individuals), and Mayo Clinic Biobank (funded by a Mayo Clinic initiative for Individualized Medicine to assist investigators throughout the institution in obtaining “normal” samples to serve as controls for their patient populations, 982 whole genome samples) Furthermore, as explained in our study, we divided 26 patients into the following 2 groups: 8 patients who survived spontaneously from their acute liver failure (ALF) episode of indeterminate etiology and 18 patients with the same diagnosis who died or underwent liver transplant. See PDF Given the small cohort size of our pilot study, we intend to expand our study to a larger population with ALF of indeterminate etiology and compare their variants distribution with patients with ALF associated with viral hepatitis, ALF associated with drug-induced liver injury, and autoimmune ALF.
It is unclear whether the current antiviral treatment for chronic hepatitis C virus (HCV) infection results in complete elimination of the virus, or whether small quantities of virus persist. Our ...study group comprised 17 patients with chronic HCV who had sustained virological response (SVR) after interferon/ribavirin treatment. Serum and peripheral blood mononudear cells were collected 2 to 3 times at 3- to 6-month intervals starting 40 to 109 months (mean, 64.2 +/- 18.5 months) after the end of therapy. In addition, lymphocyte and macrophage cultures were established at each point. In 11 patients, frozen liver tissue samples were available from follow-up biopsies performed 41 to 98 months (mean, 63.6 +/- 16.7 months) after therapy. Presence of HCV RNA was determined by sensitive reverse-transcriptase polymerase chain reaction, and concentration of positive and negative strands was determined by a novel quantitative real-time reverse transcriptase polymerase chain reaction. Only 2 of 17 patients remained consistently HCV RNA negative in all analyzed compartments. HCV RNA was detected in macrophages from 11 patients (65%) and in lymphocytes from 7 patients (41%). Viral sequences were also detected in 3 of 11 livers and in sera from 4 patients. Viral replicative forms were found in lymphocytes from 2 and in macrophages from 4 patients. In conclusion, our results suggest that in patients with SVR after therapy, small quantities of HCV RNA may persist in liver or macrophages and lymphocytes for up to 9 years. This continuous viral presence could result in persistence of humoral and cellular immunity for many years after therapy and could present a potential risk for infection reactivation.
Acute liver failure associated with Garcinia cambogia use Corey, Rebecca; Werner, K. Tuesday; Singer, Andrew ...
Annals of hepatology,
2016, 2016 Jan-Feb, 2016-01-00, 20160101, 2016-01-01, Letnik:
15, Številka:
1
Journal Article
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AbstractMillions of Americans regularly use herbal supplements, but many are unaware of the potential hidden dangers. Numerous supplements have been associated with hepatotoxicity and, indeed ...dietary/herbal supplements represent an increasingly common source of acute liver injury. We report a case of acute liver failure requiring liver transplantation associated with the use of Garcinia cambogia, a supplement widely promoted for weight loss. When patients present with acute hepatitis or liver failure from an unknown etiology, a careful history of supplement use should be performed.
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