Utilidad del sistema de recirculación de adsorbentes moleculares en la falla hepática: "diálisis hepática" / Usefulness of the molecular adsorbent recirculating system in liver failure: "liver dialysis"

INTRODUCCIÓN. La falla hepática ya sea aguda o crónica reagudizada representa un reto para el clínico ya que sus complicaciones conllevan una gran mortalidad, esto se ve aún más complicado ya que las opciones terapéuticas son limitadas, incluso muchas veces no se puede acceder a un programa de trasplante hepático oportuno que mejore la sobrevida de estos pacientes, es así que se ha desarrollado un sistema de "diálisis" hepática conocido como sistema de recirculación de adsorbentes moleculares el cual hace un efecto de detoxificación para eliminar sustancias que generan una noxa en el cuerpo humano. OBJETIVO. Entender la utilidad del sistema recirculante molecular adsorbente en la falla hepática, conocer sus indicaciones y complicaciones. METODOLOGÍA. Se realizó una revisión de la literatura con un enfoque descriptivo, retrospectivo cualitativo no experimental, de documentos que tratan sobre la utilización del sistema MARS para tratar la falla hepática, con evidencia desde el año 2004 hasta el 2021. La revisión bibliográfica se llevó a cabo en bases de datos como Pubmed, Embase, BVS, Google Scholar y Elsevier. RESULTADOS. Se identificaron 30 artículos que cumplieron criterios de inclusión de un grupo original de 343 artículos revisados. Se ha determinado que la evidencia sobre este sistema está compuesta sobre todo por reportes de caso y son pocos los ensayos controlados aleatorizados que empleen su uso, sin embargo, se ha podido determinar que este sistema es un puente al trasplante renal mientras se estabiliza al paciente en la Unidad de Cuidados Intensivos, disminuye los marcadores de falla hepática. CONCLUSIÓN. En Latinoamérica su uso es casi nulo de ahí la necesidad de entender el mecanismo de este novedoso sistema.

INTRODUCTION. Hepatic failure, whether acute or chronic, represents a challenge for the clinician since its complications entail a great mortality, this is even more complicated since the therapeutic options are limited, even many times it is not possible to access a timely liver transplant program to improve the survival of these patients, Thus, a hepatic "dialysis" system known as molecular adsorbent recirculation system has been developed, which has a detoxification effect to eliminate substances that generate a noxa in the human body. OBJECTIVE. To understand the usefulness of the molecular adsorbent recirculating system in liver failure, to know its indications and complications. METHODOLOGY. A literature review was performed with a descriptive, retrospective qualitative non-experimental qualitative approach, of papers dealing with the use of the MARS system to treat liver failure, with evidence from 2004 to 2021. The literature review was conducted in databases such as Pubmed, Embase, BVS, Google Scholar and Elsevier. RESULTS. Thirty articles were identified that met inclusion criteria from an original group of 343 articles reviewed. It has been determined that the evidence on this system is mainly composed of case reports and there are few randomized controlled trials that employ its use, however, it has been determined that this system is a bridge to renal transplantation while the patient is stabilized in the Intensive Care Unit, decreasing the markers of liver failure. CONCLUSIONS. In Latin America its use is almost null, hence the need to understand the mechanism of this novel system.

Repermeabilización portal intrahepática luego de ligadura de rama derecha de vena porta: reporte de un caso / Intrahepathic portal revascularization following right portal vein ligation: a case report / Repermeabilização portal intra-hepática após ligadura do ramo direito da veia porta: relato de caso

Resumen: La ligadura de una rama de la vena porta constituye un procedimiento con buenos resultados para evitar la falla hepática posoperatoria en caso de hepatectomías extremas al provocar la hipertrofia del hígado contralateral. Sin embargo, la repermeabilización de ésta ha sido demostrada por la presencia de anastomosis porto portales intrahepáticas, pudiendo determinar una disminución de la hipertrofia esperada o necesaria. Como objetivo documentamos un caso clínico de repermeabilización intrahepática de la vena porta, evento no deseado de la hepatectomía en dos tiempos para el tratamiento de metástasis hepáticas bilobares de origen colorrectal y describimos alternativas para evitar o tratar dicha repermeabilización.

Summary: Left or right portal vein ligation to prevent post-operative liver failure in the case of extreme hepatectomy constitutes a procedure with a good prognosis, as it causes contralateral liver hypertrophy. However, its revascularization has been proved by intrahepatic porto-portal anastomoses, which could result in a reduction of the expected or required hypertrophy. The study aims to record a clinical case of intrahepatic revascularization of the portal vein, an unwanted event of the two-stage hepatectomy to treat bilobar hepatic metastasis of colorectal origin, and describe alternatives to avoid or treat such revascularization.

Resumo: A ligadura de um ramo da veia porta é um procedimento com bons resultados para evitar a insuficiência hepática pós-operatória em hepatectomias extremas por causar hipertrofia do fígado contralateral. No entanto, sua repermeabilização tem sido demonstrada pela presença de anastomose porto-portal intra-hepática, que pode determinar diminuição da hipertrofia esperada ou necessária. Como objetivo, documentamos um caso clínico de repermeabilização da veia porta intra-hepática, um evento indesejado de hepatectomia em dois estágios para o tratamento de metástases hepáticas bilobares de origem colorretal, e descrevemos alternativas para evitar ou tratar essa repermeabilização.

Mechanisms Underlying Cell Therapy in Liver Fibrosis: An Overview.

Fibrosis is a common feature in most pathogenetic processes in the liver, and usually results from a chronic insult that depletes the regenerative capacity of hepatocytes and activates multiple inflammatory pathways, recruiting resident and circulating immune cells, endothelial cells, non-parenchymal hepatic stellate cells, and fibroblasts, which become activated and lead to excessive extracellular matrix accumulation. The ongoing development of liver fibrosis results in a clinically silent and progressive loss of hepatocyte function, demanding the constant need for liver transplantation in clinical practice, and motivating the search for other treatments as the chances of obtaining compatible viable livers become scarcer. Although initially cell therapy has emerged as a plausible alternative to organ transplantation, many factors still challenge the establishment of this technique as a main or even additional therapeutic tool. Herein, the authors discuss the most recent advances and point out the corners and some controversies over several protocols and models that have shown promising results as potential candidates for cell therapy for liver fibrosis, presenting the respective mechanisms proposed for liver regeneration in each case.

The Effects of Gestational Alloimmune Liver Disease on Fetal and Infant Morbidity and Mortality.

OBJECTIVES: To evaluate pregnancy outcomes in pedigrees of neonatal hemochromatosis to determine the spectrum of gestational alloimmune liver disease (GALD) in a large cohort. STUDY DESIGN: We prospectively collected data from women with a prior offspring with proven neonatal hemochromatosis between 1997 and 2015 and analyzed pregnancy outcomes. RESULTS: The pedigrees from 150 women included 350 gestations with outcomes potentially related to GALD. There were 105 live-born infants without liver disease, 157 live-born infants with liver failure, and 88 fetal losses. Fetal loss occurred in 25% of total gestations. Ninety-seven pedigrees contained a single affected offspring, whereas 53 contained multiple affected offspring. Analysis of these 53 pedigrees yielded a per-pregnancy repeat occurrence rate of 95%. Notably, the first poor outcome occurred in the first pregnancy in 60% of pedigrees. Outcomes of the 157 live-born infants with liver failure were poor: 18% survived, 82% died. Of the 134 live-born infants with treatment data, 20 received intravenous immunoglobulin with or without double-volume exchange transfusion of which 9 (45%) survived; 14 infants (10%) received a liver transplant of which 6 (43%) survived. CONCLUSIONS: GALD is a significant cause of both fetal loss and neonatal mortality with a high rate of disease recurrence in untreated pregnancies at risk. Poor outcomes related to GALD commonly occur in the first gestation, necessitating a high index of suspicion to diagnose this disorder at first presentation.

Hepatotoxicidad por Amanita lilloi, reporte de primeros casos / Amanita lilloi hepatotoxicity, first cases report

Se presentan dos casos clínicos de intoxicación por A. lilloi, hongos silvestres, que fueron recolectados por quienes los consumieron. Ambas pacientes desarrollaron sintomatología digestiva y evolucionaron a la falla hepática. La consulta tardía retrasó el diagnóstico y el tratamiento, pero igualmente la evolución de ambas pacientes fue favorable.

Two clinical cases of poisoning A. lilloi, wild mushrooms, which were collected by those who consumed themdebe, are presented. Both patients developed gastrointestinal symptoms and progressed to liver failure. The late consultation delayed diagnosis and treatment, but nevertheless the evolution of both patients was favorable.

Influence of plasma exchange on transplantation related immune function in patients with liver failure.

This study aimed to evaluate the influence of plasma exchange (PE) treatment of patients with liver failure on the patient's immune function, including peripheral blood T lymphocytes and cytokines. Patients accepting PE for liver failure from October 2011 to February 2012 were included prospectively in the research group. Peripheral blood samples were collected at set time points. The percentages of T lymphocyte subtypes were detected by flow cytometry using different fluorescence labels including CD3-FITC, CD4-PerCP, CD8-PE, CD25-FITC, and Foxp3-PE. Changes in serum IL-17 concentration were followed by ELISA. In all fifteen patients who accepted PE, the percentages of CD3(+) and CD8(+) T cells increased immediately after the procedure and then reduced gradually. These significant changes were confirmed by statistical analysis (P < 0.05). The percentage of CD4(+) T cells also increased after PE to a certain extent, but failed to show statistical significance. The positive ratio of CD4(+)CD25(+)Foxp3(+) T cells (Treg) increased after the treatment with statistical difference (P < 0.05). The concentration of IL-17 in patient serum increased significantly following PE treatment (P < 0.05). These results demonstrated that T lymphocyte subgroups of patients with liver failure could be influenced after PE treatment, and that cellular immunity could be recovered. PE treatment, therefore, can be viewed as providing reliable protection for the reconstruction of the patient immune system.

Subacute liver failure by pseudocirrhotic metastatic breast cancer infiltration.

Hepatic metastases are common in the clinical course of breast cancer and typically appear as mass lesions. This report describes the case of a 70-year-old woman with a history of breast cancer and no previously known liver disease presenting with the first episode of variceal bleeding and subacute hepatic failure. Imaging studies indicated liver cirrhosis without signs of malignant focal lesions. Comprehensive diagnostic work-up was negative for specific causes of liver disease and provided no evidence for tumor recurrence. Finally transjugular liver biopsy revealed a marked diffuse desmoplastic infiltration by breast cancer cells. Malignant pseudocirrhosis is an unusual pattern of metastatic, tumor spread representing a rare but important differential diagnosis of progressive liver failure. Liver biopsy is the key procedure to establish the diagnosis as imaging studies may mimic cirrhosis.

Liver transplantation with a strongly positive crossmatch: case study and literature review.

A positive crossmatch has been associated with increased risk in liver transplantation. To study the clinical significance of preformed donor-specific human leukocyte antigen antibodies (DSAs) in liver transplantation, we reviewed patients who underwent liver transplantation with a strongly positive flow cytometry crossmatch. DSAs were evaluated with a Luminex solid phase assay. The complement-fixing ability of DSAs was tested with a complement component 1q (C1q) assay. Using an assay correlation between complement-dependent cytotoxicity crossmatch, flow cytometry crossmatch, and DSA results, we reviewed the effects of DSAs on the outcomes of our patients as well as reported cases in the literature. Five of 69 liver recipients had a strongly positive crossmatch: 4 had a positive T cell crossmatch [median channel shift (MCS) = 383.5 ± 38.9], and 5 had a positive B cell crossmatch (MCS = 408.8 ± 52.3). The DSAs were class I only in 1 patient, class I and II in 3 patients, and class II only in 1 patient. Cholestasis, acute rejection, or both were observed in 3 of the 4 patients with a positive T cell crossmatch with an MCS approximately greater than 300. The C1q assay was positive for 3 patients. Two had either persistent cholestasis or early acute rejection. One patient who was treated with preemptive intravenous immunoglobulin had an unremarkable outcome despite a positive C1q result. One of the 2 patients with a negative C1q assay experienced persistent cholestasis and early and recurrent acute rejection; the other had an unremarkable outcome. None of the patients died or lost a graft within the first year of transplantation. Our study suggests that human leukocyte antigen antibody screening, flow cytometry crossmatch MCS levels, DSA mean fluorescent intensity levels, and C1q assays may be useful in assessing the risk of antibody-mediated rejection and timely interventions in liver transplantation.

Albumina humana: usos e abusos / Human albumin: uses and abuses

A relevância da utilização de albumina em pacientes com doença aguda ou crônica permanece controversa. Apesar da importância fisiológica e dos potenciais efeitos benéficos, sua utilização é baseada na prática clínica e não sustentada nas evidências dos estudos clínicos. Resultados promissores de seu uso são confirmados na falência hepática, no infarto cerebral e, talvez, em situações de exceção na reposição volêmica de pacientes críticos.

The relevance of human albumin administration remains controversial. Albumin infusion has not proven to achieve clinical benefit in many acute and chronic disease states with a few exceptions in liver failure, cerebral infarction and may be in acute hypovolemia in the critical patients.

Risk factors for long-term mortality in a large cohort of patients wait-listed for liver transplantation in Brazil.

Liver donor shortage and long waiting times are observed in many liver transplant programs worldwide. The aim of this study was to evaluate the wait list in a developing country, before and after the introduction of the MELD scoring system. In addition, the MELD score ability to predict mortality in this setting was assessed. A single-center retrospective study of patients wait-listed for liver transplantation between 1997 and 2010 was undertaken. There were 1339 and 762 patients on the list in pre-MELD and MELD era, respectively. A competitive risk analysis was performed to assess age, gender, disease diagnosis, serum sodium, MELD, Child-Pugh, ABO type, and body mass index. Also, MELD score predictive ability at 3, 6, 12, and 24 months after list enrollment was evaluated. The overall mortality rates on waiting list were 31.0% and 28.1% (P = 0.16), and the median waiting times were 412 and 952 days (P < 0.001), in pre and MELD eras, respectively. The competitive risk analysis yielded the following significant P values for both eras: HCC (0.03 and <0.001), MELD (<0.001 and 0.002), sodium level (0.002 and <0.001), and Child-Pugh (0.02 and <0.001). The MELD mortality predictions at 3, 6, 12, and 24 months were similar. In conclusion, in a liver transplant program with long waiting times, the MELD system introduction did not improve mortality rate. In either pre and MELD eras, HCC diagnosis, serum sodium, Child-Pugh, and MELD were significant predictors of prognosis. Short- and long-term MELD based mortality predictions were similarly accurate. Strategies for increasing the liver donor pool should be implemented to improve mortality.

Extracorporeal liver support-albumin dialysis with the Molecular Adsorbent Recirculating System (MARS).

Extracorporeal liver support has been a much studied topic throughout the last 50 years. Albumin dialysis as a therapeutic option for patients with acute liver failure or acute decompensation of chronic liver disease was introduced in the mid-nineties. The Molecular Adsorbent Recirculating System (MARS) is based on the concept of albumin dialysis and allows for the removal of protein-bound as well as water-soluble toxins. Besides its role as a sufficient volume expander human serum albumin is an important scavenger for molecules with pathophysiological relevance in liver failure. Albumin dialysis enables the selective regeneration of patient's albumin resulting in an increase of albumin binding capacity. Clinically, an improvement of central and local hemodynamics as well as liver-, brain-, and kidney-functions were observed. Thus, the treatment can contribute to liver regeneration and stabilization of vital organ functions and thus help to bridge patients to liver transplantation or to recovery of native liver function. Proper patient selection is critical for clinical success. Aggressive treatment of infections and sepsis seems to be a decisive pre-requisite for its safe and efficient use. Cautious anticoagulation with heparin is the common standard. Citrate use is recommended for patients prone to bleeding. Today, albumin dialysis MARS is among the best studied liver support methods. It appears as a valuable therapeutic tool for the treatment of various complications of of liver failure, especially hemodynamic instability and hepatic encephalopathy. Further studies will need to help defining the optimal patient selection and technical process parameters such as session length and frequency of treatment.

Immunosuppressive therapy allows recovery from liver failure in children with autoimmune hepatitis.

BACKGROUND & AIMS: Patients with autoimmune hepatitis (AIH) frequently have liver failure (LF) at the time of diagnosis; their response to immunosuppressive therapy has not been thoroughly analyzed. We evaluated the outcomes of children with AIH and LF who received immunosuppressive therapy and analyzed predictors of liver function recovery. METHODS: We collected data from 237 children that had AIH between September 1996 and December 2008; 50 had LF (defined as prothrombin time <50%) and had not received prior treatment. Patients were treated with either 2 mg/kg/day prednisone at doses up to 60 mg/day (n = 13) or 1 mg/kg/day prednisone at doses up to 40 mg/day plus cyclosporine at blood levels of 200 ± 50 ng/mL (n = 37). RESULTS: Of the 50 patients studied, 45 (90%) achieved prothrombin time >50% in a median time of 24 days (range of 4-257 days); 93% of these patients achieved this within the first 90 days of treatment. Two of the 45 patients who responded to immunosuppression required liver transplantation because of complications related to portal hypertension, and 3 died because of infection. Three of the 5 nonresponders received liver transplants - 1 remained on the waiting list, and the other died because of central nervous system bleeding. Infection was the only independently associated significant factor that delayed recovery from LF (odds ratio = 7.7, 95% confidence interval, 1.5-40). Each therapeutic approach had similar efficacy. CONCLUSIONS: Most pediatric patients with AIH recover after LF with immunosuppressive therapy; liver transplantation could be avoided or delayed. Infection was the most frequent cause of morbidity and mortality in these patients.

Current status of stem cell therapy for liver diseases.

Liver failure is one of the main causes of death worldwide and is a growing health problem. Since the discovery of stem cell populations capable of differentiating into specialized cell types, including hepatocytes, the possibility of their utilization in the regeneration of the damaged liver has been a focus of intense investigation. A variety of cell types were tested both in vitro and in vivo, but the definition of a more suitable cell preparation for therapeutic use in each type of liver lesions is yet to be determined. Here we review the protocols described for differentiation of stem cells into hepatocytes, the results of cell therapy in animal models of liver diseases, as well as the available data of the clinical trials in patients with advanced chronic liver disease.

Liver transplantation for subacute hepatocellular failure due to massive steatohepatitis after bariatric surgery.

New therapeutic options for obesity include restrictive bowel surgery and surgery that promotes malabsorption, such as the Fobi-Capella (gastric bypass) and Scopinaro (biliopancreatic diversion) techniques. Complications associated with these procedures, such as hepatocellular failure, have been observed with increasing frequency. Reported here are 3 patients who, 7 to 24 months after bariatric surgery, developed hepatocellular failure, for which liver transplantation was considered to be indicated. Liver transplantation was undertaken in 2 of the patients; the third patient died while waiting for this procedure. We discuss the possible causes of this uncommon and poorly understood complication of surgery for obesity. One possibility is that it might arise as a result of progression of steatohepatitis. An alternative concept is that this complication may be secondary to rapid, massive loss of body weight.

Living donor liver transplantation for children in Brazil weighing less than 10 kilograms.

Infants with end-stage liver disease represent a treatment challenge. Living donor liver transplantation (LDLT) is the only option for timely liver transplantation in many areas of the world, adding to the technical difficulties of the procedure. Factors that affect morbidity and mortality can now be determined, which opens a new era for improvement. We have accumulated an 11-year experience with LDLT for children weighing<10 kg. From October 1995 to October 2006, a total of 222 LDLT in patients<18 years of age were performed; 129 primary LDLT and 7 retransplants (4 LDLT and 3 deceased donor grafts) were performed in 129 infants weighing<10 kg. Forty-seven patients received grafts with graft-to-recipient weight ratio (GRWR) of >4%. Two patients received monosegmental grafts, and 2 patients underwent delayed abdominal wall closure. Portal vein thrombosis occurred in 5.4% of the patients, hepatic artery thrombosis in 3.1%, and both in 1.5%. Among several variables studied, only the bilirubin level at the time of transplantation was associated with increased risk of death (P=0.009). Grafts with GRWR>4% had no negative effect on patient survival. There were 7 retransplants, and 4 patients received a second parental LDLT. Patient survival rates at 1, 3, and 10 years after transplantation were 88.8%, 84.7%, and 82% for all children, and 87.5%, 84.9%, and 84.9% for infants weighing<10 kg. LDLT has results comparable to other modalities of liver transplantation in infants. Monosegment grafts were rarely required in this series, although they may be necessary in patients with lower body weight.