Inventing Engineered Organoids for end-stage liver failure patients.

End-stage liver disease (ESLD) is a term used clinically in reference to a group of liver diseases with liver transplantation as the choice of treatment. Due to the limitations of liver transplantation, alternative treatments are needed. The use of primary human hepatocytes represents a valid alternative treatment, but the limitations related to hepatocyte quality, viability, function, conservation, and storage need to be overcome. Transplanted hepatocytes have only been followed for 6-9 months. Therefore, long-term causes of failures are not yet established, including rejection, apoptosis, or other causes. Other alternative therapies to replace liver transplantation include plasmapheresis, hemodiafiltration, and artificial livers. Unfortunately, these methods are highly limited due to availability, high cost, anaphylaxis reaction, development-deposition of immune-complexes, and restricted functionality. Liver organoids, which utilize stem cells instead of 'impractical' adult hepatocytes, may be a solution for the development of a complex bioartificial liver. Recent studies have explored the benefits of differentiating mature hepatocytes from stem cells inside a bioreactor. When the use of human-induced Hepatocytes (hiHeps) was investigated in mouse and pig models of liver failure, liver failure markers were decreased, hepatocyte function indicated by albumin synthesis improved, and survival time increased. Bioartificial liver treatment may decrease the infiltration of inflammatory cells into liver tissue by down-regulating pro-inflammatory cytokines.

TRMU deficiency: A broad clinical spectrum responsive to cysteine supplementation.

TRMU is a nuclear gene crucial for mitochondrial DNA translation by encoding tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase, which thiolates mitochondrial tRNA. Biallelic pathogenic variants in TRMU are associated with transient infantile liver failure. Other less common presentations such as Leigh syndrome, myopathy, and cardiomyopathy have been reported. Recent studies suggested that provision of exogenous L-cysteine or N-acetylcysteine may ameliorate the effects of disease-causing variants and improve the natural history of the disease. Here, we report six infants with biallelic TRMU variants, including four previously unpublished patients, all treated with exogenous cysteine. We highlight the first report of an affected patient undergoing orthotopic liver transplantation, the long-term effects of cysteine supplementation, and the ability of the initial presentation to mimic multiple inborn errors of metabolism. We propose that TRMU deficiency should be suspected in all children presenting with persistent lactic acidosis and hypoglycemia, and that combined N-acetylcysteine and L-cysteine supplementation should be considered prior to molecular diagnosis, as this is a low-risk approach that may increase survival and mitigate the severity of the disease course.

Clinical translation of bioartificial liver support systems with human pluripotent stem cell-derived hepatic cells.

There is currently a pressing need for alternative therapies to liver transplantation. The number of patients waiting for a liver transplant is substantially higher than the number of transplantable donor livers, resulting in a long waiting time and a high waiting list mortality. An extracorporeal liver support system is one possible approach to overcome this problem. However, the ideal cell source for developing bioartificial liver (BAL) support systems has yet to be determined. Recent advancements in stem cell technology allow researchers to generate highly functional hepatocyte-like cells from human pluripotent stem cells (hPSCs). In this mini-review, we summarize previous clinical trials with different BAL systems, and discuss advantages of and potential obstacles to utilizing hPSC-derived hepatic cells in clinical-scale BAL systems.

Long-Term Fish Oil Lipid Emulsion Use in Children With Intestinal Failure-Associated Liver Disease [Formula: see text].

BACKGROUND: Fish oil lipid emulsion (FOLE) and multidisciplinary care for infants with intestinal failure (IF) have been associated with reduced morbidity and mortality due to IF-associated liver disease (IFALD). With increased survival, a greater proportion of infants with IF are now able to remain on parenteral nutrition (PN) in the long term. The purpose of this study was to examine outcomes in children with IFALD who have required long-term PN and FOLE therapy due to chronic IF. MATERIALS AND METHODS: A review of prospectively collected data was performed for children with IFALD who required at least 3 years of PN and FOLE therapy due to chronic IF. Outcomes examined include the incidence of death, transplantation, and essential fatty acid deficiency (EFAD), as well as growth parameters and the biochemical markers of liver disease. RESULTS: Of 215 patients with IFALD treated from 2004-2015, 30 required PN and FOLE therapy for at least 3 years (median, 4.6 years). To date, no patients have died, required transplantation, or developed EFAD. Biochemical markers of liver disease normalized within the first year of therapy with no recurrent elevations in the long term. Weight-for age and length-for-age z scores improved and PN dependence decreased in the first year of therapy, with a stable rate of growth in the long term. CONCLUSIONS: Children with IFALD who required long-term PN and FOLE for chronic IF had no mortality, need for transplantation, EFAD, or recurrence of liver disease in the long term, allowing for continued intestinal rehabilitation.

Fallo hepático por intoxicación con producto casero elaborado con anís estrellado y anís verde en lactante de 4 meses / Liver failure secondary to poisoning by a homemade product made of star and green anise in a 4-month-old infant

Las intoxicaciones en edad pediátrica representan una causa frecuente de consulta en urgencias hospitalarias. Los productos elaborados con hierbas pueden resultar tóxicos para el lactante. Se han descrito ampliamente las propiedades neurotóxicas del anís estrellado (Illicium verum), producto clásicamente empleado para el tratamiento del cólico del lactante. La presentación de fallo hepático agudo por consumo de infusiones elaboradas con hierbas de anís es excepcional en nuestro entorno. Se describe el caso de un lactante de 4 meses con hipertransaminasemia, coagulopatía grave, hipoglucemia no cetósica, acidosis metabólica moderada y síntomas neurológicos con crisis convulsivas y nistagmo. Tras descartar etiología infecciosa, metabólica y autoinmune y realizar una anamnesis cuidadosa, la familia refería haber administrado al paciente durante los últimos dos meses una infusión diaria con anís estrellado y anís verde (Pimpinella anisum). Es de gran importancia resaltar el grave riesgo de administrar infusiones de hierbas caseras en el lactante (AU)

Intoxications in pediatric age represent a frequent cause of visit to the hospital emergency unit. Herb-made products can be toxic for the infant. The neurotoxic properties of the star anise (Illicium verum) have been widely described, although it is a classic product used to treat the infantile colic. Hepatic failure due to the consumption of anise herb elaborated infusions is presented as an exceptional finding in our environment. A case of a 4-month-old infant with hypertransaminasemia, severe coagulopathy, non ketotic hypoglycemia, moderated metabolic acidosis and neurologic symptoms such as seizures and nistagmus is described. After discarding infectious, metabolic and autoimmune etiology and through a meticulous anamnesis, the family referred having administered in the last two months a daily star anise and green anise (Pimpinella anisum) infusion to the patient. It is important to emphasize the serious risk of administering homemade herb infusions to infants (AU)

Hepato- and nephroprotective activities of a Nigerian local king tuber oyster mushroom, Pleurotus tuberregium (higher Basidiomycetes), in chemically induced organ toxicities in rats.

Chronic kidney disease, end-stage renal failure, and liver diseases are increasing worldwide and constitute a huge burden on health care costs, with attendant high morbidity and debility. Despite advances in modern medicine, there are still no licensed drugs that satisfactorily restore lost kidney or hepatic functions. In this study the chemoprotective effects of the hot aqueous extract of a local edible oyster mushroom, Pleurotus tuberregium (APTR), was evaluated in experimental liver and kidney toxicities. The effect of APTR on carbon tetrachloride (CCl4)- and paracetamol (PCM)-induced hepatotoxicity in rats was investigated by determining serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Short-term oral treatment with APTR (100 and 250 mg/kg) significantly reduced (P < 0.05) the increased concentrations of AST, ALT, and ALP induced in both PCM and CCl4 models of liver toxicity. APTR (100 and 250 mg/kg) decreased the mean serum AST concentrations by as much as 73.00% and 99.37%, respectively, in PCM-treated rats. Nephroprotection was assessed by determining the serum concentrations of creatinine and urea, as well as antioxidant enzymes, in kidney tissue homogenates after a repeated high dose of gentamicin. APTR (100 and 250 mg/kg) produced a significant decrease (P < 0.05) in the escalated serum concentrations of creatinine and urea by as much as 48.36% and 41.53%, respectively, compared to control. Similarly, levels of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase in kidney tissue were increased in a dose-related manner in groups that received oral APTR supplementation. The results of this study suggest that the consumption of our local edible mushroom, P. tuberregium, could, in addition to its high nutritive value, protect the liver and kidneys from oxidative damage caused by drugs and toxicants such as CCl4 and high doses of gentamicin and PCM.

Experience of Treatments of Amanita phalloides-Induced Fulminant Liver Failure with Molecular Adsorbent Recirculating System and Therapeutic Plasma Exchange.

Ingestion of the mushroom containing Amanita phalloides can induce fulminant liver failure and death. There are no specific antidotes. Blood purifications, such as molecular adsorbent recirculating system (MARS) and therapeutic plasma exchange (TPE), are potential therapies. However, the extent to which these technologies avert the deleterious effects of amatoxins remains controversial; the optimal intensity, duration, and initiation criteria have not been determined yet. This study aimed to retrospectively observe the effects of MARS and TPE on nine patients with A. phalloides-induced fulminant liver failure. The survival rate for the nine patients was 66.7%. Both TPE and MARS might remove toxins and improve liver functions. However, a single session of TPE produced immediately greater improvements in alanine aminotransferase (-60% vs. -16.3%), aspartate aminotransferase (-47.6% vs. -15.4%), and total bilirubin (-37.3% vs. -17.1%) (compared with the values of pretreatment, all p < 0.05) than MARS compared with MARS. Early intervention may be more effective than delayed therapy. Additionally, the presence of severe liver failure and renal failure indicated worse outcome. Although these findings are promising, additional case-controlled, randomized studies are required to confirm our results.

Expert beliefs regarding novel lipid-based approaches to pediatric intestinal failure-associated liver disease.

OBJECTIVE: To determine expert beliefs regarding the probability of intestinal failure-associated liver disease (IFALD) with novel lipid-based approaches (lipid minimization/ω-3 lipids) in managing IFALD to facilitate Bayesian analyses of clinical trials of these therapies. STUDY DESIGN: Structured interviews were conducted using a validated approach to belief elicitation with 60 intestinal failure (IF) experts from across North America. Participants were asked to estimate, in an average population of infants referred for management of IF with early IFALD, the probability of advanced IFALD at 3 months following referral in each of 3 scenarios: (1) conventional lipid, (2) ω-3 lipids, and (3) lipid minimization. Probability distributions of the risk of advanced IFALD with each strategy were developed. Distributions of the elicited treatment effect for the novel approaches, relative to conventional lipid, were calculated. RESULTS: Median duration of experience of participants managing patients with IF was 8.5 (range, 2-35) years. The median probability of advanced IFALD using conventional lipid was 32.5%; ω-3 lipids, 17.5%; and lipid minimization, 13%. The median of the elicited treatment effects relative to conventional lipid was a relative risk of 0.53 for the ω-3 lipid and 0.45 for lipid minimization. CONCLUSIONS: There was consistent expert opinion that the novel lipid-based approaches are superior to conventional therapy, with similar estimates of treatment efficacy for the 2 approaches. The distributions of the elicited treatment effects can be used as prior distributions in Bayesian analyses of clinical trials of these novel strategies.

Bone disease in patients awaiting liver transplantation. Has the situation improved in the last two decades?

In recent years, there has been speculation about the possibility of a reduction in the incidence of fractures after liver transplantation (LT) because of changes in the characteristics of candidates and the use of different immunosuppressive therapies. We analyzed the characteristics of LT candidates (CTC) and compared them with historical data from a group of LT candidate patients (HTC). Data from 60 CTC patients consecutively included in a screening program of metabolic bone disease were compared with data from 60 HTC patients prospectively evaluated between 1992 and 1993. In all patients, we analyzed the clinical and laboratory characteristics, bone mineral density (BMD) dual-energy X-ray absorptiometry, and skeletal fractures. Patients in the CTC group were older than patients in the HTC group. The CTC group had lower femoral neck T scores. No differences were observed between groups in the proportion of patients with osteoporosis (22 vs. 30 %, p = ns) or fractures (36 vs. 33 %, p = ns). The percentage of patients with normal BMD decreased from 38 to 20 %. 25(OH)D values were low in both groups. Only 7.5 % of the CTC patients received calcium and/or vitamin D supplementation. The prevalence of fractures among CTC patients was similar to that seen two decades ago. At present, candidates for LT are older and have lower femoral bone mass. Vitamin D deficiency remains frequent; however, calcium and/or vitamin D supplementation is uncommon.

[Nutrition in intensive care medicine: Part 2: special nutritional problems]. / Ernährung in der Intensivmedizin : Teil 2: spezielle Ernährungsprobleme.

Therapy of intensive care patients is often complicated by co-morbidities or complex systemic disorders such as sepsis. The necessity to generate an individualized nutritional regime has gained in importance in recent years as this essential part of supportive care has a direct impact on the prognosis of the patient. In the present article a special focus is put on particular questions of nutritional aspects of intensive care patients. The current guidelines and study data on disorders relevant in intensive care medicine, such as acute or chronic renal and liver failure, acute respiratory distress syndrome and sepsis are presented and discussed. Another focus is the establishment of an adequate nutritional regime for patients after operations or suffering from multiple trauma.

Therapeutic hypothermia: implications for acute care practitioners.

The use of therapeutic hypothermia (TH) in acute care medicine has evolved over the past 2 centuries, and its use over the past decade has increased in emergency departments, intensive care units, and operating rooms. Therapeutic hypothermia has several potential clinical applications based on its putative mechanisms of action. It appears to improve oxygen supply to ischemic areas of the brain and decreases intracranial pressure. Mild-to-moderate TH (33 degrees C +/- 1 degrees C) after resuscitation from cardiac arrest is neuroprotective, and also acts on the cardiovascular system with evidence of a decrease in heart rate and increase in systemic vascular resistance. Therapeutic hypothermia decreases cardiac output by 7% for each 1 degrees C decrease in core body temperature, but maintains the stroke volume and the mean arterial pressure. Despite a growing amount of data, this life-saving technique is underutilized in hospitals worldwide. The purpose of this comprehensive review is to show the evolution and the clinical use of TH as it pertains to acute care practitioners.

A hyperbaric oxygen therapy approach to heat stroke with multiple organ dysfunction.

Here in we report the case of a patient who displayed a classic heat stroke with multiple organ dysfunction and hypercoagulable state resistant to conventional whole body cooling and antipyretic therapy, and necessitating the use of hyperbaric oxygen therapy (HBOT) to rescue him from death. A 49-year-old male laborer, suffering from heat stroke syndromes (e.g., hyperpyrexia, seizure and coma, and hypotension), was admitted to an emergency unit of a medical center hospital. The patient displayed multiple organ dysfunction with rhabdomyolysis, hepatic, renal, respiratory, and cerebral dysfunction, and disseminated intravascular coagulation (DIC). Both hyperpyrexia and multiple organ dysfunction were resistant to conventional treatment measures. HBOT was adopted to rescue the patient from heat stroke-induced death. Before HBOT, analyses of serum revealed hypercoagulable state or DIC as well as signs of rhabdomyolysis, and renal and hepatic failure. In addition, pulmonary edema, coma, hypotension, and hyperpyrexia occurred. HBOT was used successfully to combat these syndromes and to rescue the patient from heat stroke death. This case suggests that HBOT is useful for treatment of heat stroke with multiple organ dysfunction.

Nutrition of critically ill horses.

Nutritional supplementation is becoming the standard of practice in equine medicine, although there are minimal data on nutritional support in critically ill horses and its association or effect on morbidity and mortality or length of hospital stay. Horses can be fed orally and when that is not possible, intravenously or parenterally. Enteral feeding is less expensive, more physiologic, improves immunity, and is easier and safer. This article reviews available information on the development of a nutritional plan for critically ill horses, and describes methods for and complications of enteral and parenteral feeding.

[Liver failure a la Eastern Europe]. / Májelégtelenség kelet-európai módra.

The use of valeriana was underplayed at the beginning of the 20th century because of its addictive and side effects. The 38-year-old woman, mother of a 20-month-old child from Eastern Europe, was treated with liver insufficiency and vascular, parenchymal decompensated cirrhosis needing plasmapheresis for the first time in our hospital. In case history, abusus of aethyl-alcohol and valeriana was found to be as toxic agent which was treated as the etiologic factor of the liver disease and liver failure. After intensive and conservative treatment her status was stabilised, during the follow-up she had no signs and symptoms, the laboratory results tend to be in normal range. Half year after her hospitalization intensive care treatment was necessary abroad due to gastric bleeding. In the background the histology of gastric biopsy taken during gastroscopic examination showed gastric sigillocellular carcinoma in our hospital. Total gastrectomy, omentectomy, lymphadenectomy were performed, the tumor was removed and she received cytostatic treatment. The use of valeriana and aethyl-alcohol is supposed to have a potential effect on tumorgenesis and on the increase of toxicity.

Adjuvant therapeutic plasma exchange in liver failure: assessments of clinical and laboratory parameters.

BACKGROUND: Therapeutic plasma exchange (TPE) seems to be an effective approach for clearing toxins, immune-mediated antigens, and other particles from the circulation. The aim of this study was to analyze the positive effects of TPE on clinical and biochemical parameters of liver failure. PATIENTS AND METHODS: Between January 2001 and March 31, 2005 individuals (men/women, 17/14; median age, 42.7+/-15.8 y) with acute and chronic liver failure who underwent a total of 113 TPEs (median session 3.7) were retrospectively reviewed. TPE was performed using the Fresenius AS-TEC 204 cell separator (Fresenius AG, Germany). The indication for TPE was severe coagulopathy (prothrombin time >20 s), severe hepatic encephalopathy, hyperbilirubinemia, and candidacy for liver transplantation. All patients were examined before and immediately after the last TPE session. RESULTS: When compared with baseline, there was significant improvement in hepatic encephalopathy stage (from median score 3.0 to 1.0, P=0.001), serum prothrombin time (from median 26.0 to 20.0 s, P=0.003), aminotransferases (P<0.001), and total bilirubin levels (from median 35.0 to 23.3 mg/dL, P<0.001) after TPE. Thirteen of the thirty-one individuals (41.9%) died in the hospital. The mean follow-up period of 18 survival patients was 35.9+/-5.6 months and 10 of those survived (55.6%, 10/18). No serious adverse effect of TPE was observed in any of the patients during or after completion of TPE. Only 6 patients experienced minor transfusion reactions. CONCLUSIONS: TPE seems to be effective in improving hepatic encephalopathy stage and liver tests in individuals with acute and chronic liver failure. The data suggest that TPE is safe and tolerable in such individuals, however, overall survival remains poor despite TPE.