G. Novelli

Fractal and Fourier analysis of the hepatic sinusoidal network in normal and cirrhotic rat liver

The organization of the hepatic microvascular network has been widely studied in recent years, especially with regard to cirrhosis. This research has enabled us to recognize the distinctive vascular patterns in the cirrhotic liver, compared with the normal liver, which may explain the cause of liver dysfunction and failure. The aim of this study was to compare normal and cirrhotic rat livers by means of a quantitative mathematical approach based on fractal and Fourier analyses performed on photomicrographs and therefore on discriminant analysis. Vascular corrosion casts of livers belonging to the following three experimental groups were studied by scanning electron microscopy: normal rats, CCl4‐induced cirrhotic rats and cirrhotic rats after ligation of the bile duct. Photomicrographs were taken at a standard magnification; these images were used for the mathematical analysis. Our experimental design found that use of these different analyses reaches an efficiency of over 94%. Our analyses demonstrated a higher complexity of the normal hepatic sinusoidal network in comparison with the cirrhotic network. In particular, the morphological changes were more marked in the animals with bile duct‐ligation cirrhosis compared with animals with CCl4‐induced cirrhosis. The present findings based on fractal and Fourier analysis could increase our understanding of the pathophysiological alterations of the liver, and may have a diagnostic value in future clinical research.

Pediatric Acute Liver Failure With Molecular Adsorbent Recirculating System Treatment

BACKGROUND The prognosis of pediatric acute liver failure (PALF) has been significantly improved by emergency orthotopic liver transplantation (OLT). Since 2004, the molecular adsorbent recirculating system (MARS) has been proposed as a bridging procedure. The aim of our study was to assess its efficacy in children with PALF. PATIENTS AND METHODS Since 1999 we performed treatment of 39 fulminant hepatic failure (FHF) cases with MARS. Since September 2004 we treated 6 pediatric patients with FHF who were of mean age 10.6 years (range, 3-15 years) including 4 females and 2 males. In 3 cases the cause of FHF was unknown; in 2 cases, it was induced by paracetamol overdose; and in 1, by acute hepatitis B virus. Inclusion criteria were: bilirubin >15 mg/dL; creatinine >or=2 mg/dL; encephalopathy grade >II; and International normalized ratio (INR) >2.5. Other estimated parameters were: AST and ALT serum levels, lactate, and urine volume. Neurological status was monitored using the Glasgow Coma Scale (GCS). Continuous MARS treatment was performed in all patients with a kit change every 8 hours. Intensive care unit (ICU) treatment was applied to optimize regeneration and to prevent cardiovascular complications. RESULTS We observed a significant improvement among levels of bilirubin (P< .009), ammonia (P< .005), creatinine (P< .02), GCS (P< .002), and predictive criteria and as Sequential Organ Failure Assessment (SOFA) and Pediatric End-Stage Liver Disease (PELD). Three children underwent OLT: 1 died after 5 days due to primary nonfunction and 2 children are alive after a median follow-up of 14 months. In 2 children the MARS treatment led to resolution of clinical status without liver transplantation. One child died before OLT due to sepsis and multiorgan failure. CONCLUSIONS We concluded that application of the MARS liver support device in combination with experienced ICU management contributed to improve the clinical status in children with PALF awaiting liver transplantation.

Cytokine Level Modifications: Molecular Adsorbent Recirculating System Versus Standard Medical Therapy

INTRODUCTION Acute-on-chronic liver failure (ACLF) is a systemic inflammatory reaction, which is characterized by a predominantly proinflammatory cytokine profile, causing the transition from stable cirrhosis to ACLF. The aim of the present study was to evaluate the changes in several cytokines associated with inflammatory liver disease and liver regeneration among 15 ACLF patients treated with the Molecular Adsorbent Recirculating System (MARS) compared with 15 patients treated with standard medical therapy (SMT). The subjects showed various disease etiologies but similar values for Model End-stage Liver Disease scores. METHODS In the MARS group, 15 (10 male and 5 female) patients were treated with MARS (Gambro). The number of MARS applications was nine; the length of applications was 8 hours. In the SMT group; 15 (10 male and 5 female) patients were treated with SMT. The patients were monitored for 30 days from inclusion with a survival follow-up at 3 months. Statistical results were calculated with SPSS14.0 (SPSS Inc, Chicago, Ill). A P < .07 was considered significant. RESULTS In the MARS group, we observed significant changes in the levels of Interleukin (IL)-6, IL-1, IL-10, and tumor necrosis factor (TNF)-alpha in association with improved hepatocyte growth factor. Patient survival at 3 months was 60%. The SMT group showed only a significant change in TNF-alpha (P = .03). Patient survival at 3 months was 30%. CONCLUSION The MARS liver support device corrected pathophysiologies of ALF and may be used to enhance spontaneous recovery or as a bridge to transplantation.

Clinical Results of Treatment of Postsurgical Endotoxin-Mediated Sepsis With Polymyxin-B Direct Hemoperfusion

We evaluated the possibility of preventing the evolution of endotoxin-mediated sepsis in severe septic shock using early treatment of critical endotoxemia with polymyxin-B direct hemoperfusion (PMX-DHP). Thirty-eight postsurgical patients who fulfilled at least 2 criteria for systemic inflammatory response syndrome were stratified on the basis of the value of the endotoxin activity assay. Seventeen patients who demonstrated high risk of endotoxin activity (>or=0.6) received standard therapy plus PMX-DHP every 24 hours to lower the endotoxin activity level to less than 0.4, and the remaining 21 patients with endotoxin activity levels less than 0.6 received standard therapy only. Seven patients required 2 courses of PMX-DHP therapy, 8 required 3 courses, and 2 required 4 courses. After treatment, mean arterial pressure increased, from 69.00 mm Hg to 81.35 mm Hg (P < .01); heart rate decreased, from 105.40 bpm to 78.12 bpm (P < .01); white blood cell count decreased, from 20,700 cells/mm(3) to 9740 cells/mm(3) (P < .01); arterial oxygen tension-fraction of inspired oxygen ratio increased, from 273.82 to 305.82 (P < .01); and Sequential Organ Failure Assessment score decreased, from 7 to 4 (P < .01). Length of stay was longer for transplant recipients (16 days) than for other surgical patients (8(1/2) days). All patients survived to 28-day follow-up, and 15 of 16 patients (94%) had survived at 60-day follow-up. Despite the small number of patients included in the study, the encouraging results suggest that PMX-DHP is a useful therapeutic strategy for lowering sepsis-related mortality.

Combined Liver-Kidney Transplantation in Polycystic Disease: Case Reports

Polycystic disease causes a progressive decrease in renal function and liver degeneration. The progression of the disease evolves separately between organs and transplantation options vary: simultaneous or sequential liver-kidney transplantation or single-organ transplantation. From September 2006 to June 2007 3 combined liver kidney transplantations (CLKT) were performed for polycystic disease with end-stage renal disease: 2 with polycystic liver disease, and 1 with hepatic failure due to congenital hepatic fibrosis. The widest dimensions of the polycystic liver of 50 and 60 cm diameter were due to extensive cystic degeneration. We performed 1 simultaneous CLKT and 2 sequential transplantations: 1 liver after kidney, and 1 kidney after liver. At present all patients are alive with 100% graft function. Median creatinine level at discharge was 0.9 mg/dL (ranges, +/-0.2). Good liver graft function was reported in all 3 cases. Transplant benefit in polycystic liver-kidney disease has been already demonstrated; conservative surgical options may result in a high incidence of complications in highly involved polycystic livers. Delaying transplantation results in a more difficult surgical technique, a higher rate of postoperative complications, and a disturbance of optimal graft retrieval because of the worse preoperative condition of the patients.

Giant hemangiomas of the liver: surgical strategies and technical aspects

The incidence of hemangiomas is 2-7% in the general population. We evaluated more than 300 patients with hepatic hemangiomas. Surgical removal of hepatic hemangiomas was performed in 48 cases due to uncertain diagnosis (2 cases), intractable symptoms (26 cases), size increase (18 cases), and liver failure in 2 cases that were treated by hepatic transplantation. In all, 26 patients underwent enucleation of hemangiomas or segmentectomies, while the remaining 20 patients underwent right lobectomies or left lateral segmentectomies. Blood transfusions were required in four cases (including two liver transplants); mean post-resection hospital stay was 6.3 days. We observed no perioperative mortality and only two cases of major morbidity (bile leaks not requiring reoperation). Our experience confirms that, after adequate patient selection, surgical treatment of hepatic hemangiomas is a very effective therapeutic choice with no mortality and low morbidity.

Management of Sepsis During MARS Treatment in Acute on Chronic Liver Failure

INTRODUCTION The aim of our study was a 30-day follow-up of the use of early detection of endotoxin by the endotoxin activity assay (EAA) for patients with acute liver failure superimposed on chronic liver disease (AoCLF) and treated with polymyxin-B hemoperfusion-based (PMX-DHP) treatment and albumin dialysis in the molecular adsorbent recirculating system (MARS). MATERIALS AND METHODS From February 2008 to July 2010, we evaluated 10 AoCLF patients experiencing systemic inflammatory response syndrome (SIRS) in association with suspected infection and an EAA-positive test (>0.60). These patients awaiting liver transplantation (OLT) showed similar Model End-Stage Liver Disease (MELD) scores (range, 19-25) and encephalopathy grade ≤ 2. Five patients received therapy to remove endotoxins with PMX-DHP with MARS treatment for liver failure (group A); the other 5 patients received MARS treatment only (group B). RESULTS Two PMX-DHP treatments were performed in 4 group A patients (average EA=0.66 [range, 0.61-0.70]) and 3 treatments for 1 patient (EA=0.92). All 5 subjects underwent an average of 4 MARS treatments (range, 3-5). At the end of therapy, the median EA level was 0.42 (range, 0.37-0.48). As reported in the literature, we achieved a significant improvement in liver and kidney functions using MARS. Measurements of lactate, interleukin (IL)-6, and tumor necrosis factor (TNF)-α were significantly improved among patients treated with the extracorporeal therapies. At 30 days of observation, all 5 patients treated with MARS plus PMX-DHP are alive. In group B, a mean of 7.5 MRAS treatments were performed. We observed an improvement in hemodynamic and liver functions with reduced levels of proinflammatory cytokines and lactates in 4 patients. One patient showed no improvement in clinical status with the development of sepsis and subsequent multiorgan failure after 24 days. CONCLUSION The possibility of an early diagnosis using the EAA in AoCLF patients could prevent the progression of the sepsis cascade. The use of PMX-DHP and MARS in these patients, could lead to resolution of clinical status in a short time.

Hemodynamic Improvement as an Additional Parameter to Evaluate the Safety and Tolerability of the Molecular Adsorbent Recirculating System in Liver Failure Patients

BACKGROUND The molecular adsorbent recirculating system (MARS) is an extracorporeal acute liver failure (ALF) support system method using albumin-enriched dialysate to remove albumin-bound toxins. PATIENTS AND METHODS Since 1999 we performed 2027 MARS treatments in 191 patients: 39 fulminant hepatic failure (FHF), 16 primary nonfunction (PNF), 21 delayed function (DF), 94 acute-on-chronic liver failure (AoCHF), 7 post-hepatic resection, and 14 intractable pruritus. RESULTS We divided the complications by the AoCHF versus the ALF populations. Among 83 ALF patients, we observed worsening of hemodynamic parameters in 16 patients: 3 with PNF, 2 with DF without retransplantation, 9 with FHF, and 2 after hepatic resection. Among 94 AoCHF patients, 42 showed hemodynamic instability requiring intensive care unit support. Our study did not note significant adverse effects (1.8%), except for infections and hemorrhage from the central venous catheter not due to MARS treatment. The thrombocytopenia was controlled through administration of platelets before the start of treatment when a patient showed a level under 30,000 mm(3). CONCLUSION Our results confirmed that nonbiological hepatic support by MARS was safe and tolerable.

Simultaneous pancreas-kidney transplantation: a single-center experience and prospective analysis.

In patients with end-stage chronic kidney disease (CKD) and type 1 diabetes mellitus (DM 1), simultaneous pancreas-kidney (SPK) transplantation is currently considered the gold standard therapy. The aim of this study was to analyze and report the long-term clinical outcomes of the 23 SPK transplantations performed at our institution over an 84-month period (January 1, 2000 to December 31, 2006). A prospective analysis of these patients included donor, recipient, and transplantation characteristics. The only requirements for transplantation were blood group compatibility and a negative cross-match. Bladder drainage via pancreaticoduodenocystostomy was performed in all of the patients. Due to a pulmonary embolus 1 patient (4.3%) died at 2 months. The actuarial patient survival rates at 3 months and 1, 3, and 5 years were 95.6%. Causes for the renal graft loss were chronic allograft nephropathy in 3 cases (13%) and death of the patient in 1 case (4.3%). The actuarial censored renal allograft survival rates at 3 months and at 1 year were 100%, and at 3 and 5 years were 91.3%. Causes for the renal graft loss were chronic rejection in 1 case (4.3%) and patient death in 1 case (4.3%). The actuarial censored pancreatic allograft survival rates at 3 months and at 1 and 3 years were 100%, and at 5 years was 95.6%. The results of this work add further evidence that SPK is the gold standard therapy for selected patients with end-stage CKD due to DM 1.

Primary Nonfunction: Timing Retransplantation Versus Hemodynamic Parameters and Kidney Function

BACKGROUND Patients with acute liver failure (ALF) show an aggravated hyperdynamic circulation. We evaluated potential changes in systemic hemodynamics and improved kidney function induced by the molecular adsorbent recirculating system (MARS) in a group of patients with primary nonfunction (PNF). PATIENTS AND METHODS In the intensive care unit we treated 18 patients with PNF (6 females and 12 males) after orthotopic liver transplantation (OLT) of overall mean age 47.8 years (range, 28-60 years). Continuous MARS treatment was performed on all patients with a kit change every 8 hours during a mean of 10 days (range, 1-20 days). Double-lumen catheter type veno-venous access was used for the blood supply. The blood flow rate was 150 to 250 mL/min, depending on the hemodynamic situation of the patient. Blood passed through an albumin nonpermeable, high flux dialysis membrane. During MARS treatment we monitored the hemodynamic condition, using a series of parameters: heart rate (HR), mean arterial pressure (MAP), cardiac index (CI), systemic vascular resistance index (SVRI), and pulmonary vascular resistance index (PVRI) before (baseline value) as well as after 1 hour (T1), 3 hours (T2), and the end of treatment (T3). RESULTS There was a progressive decrease in positive inotropic support (dobutamine, norepinephrine) and significant improvement in hemodynamic parameters, such as MAP (P< .01), PVRI/SVRI/V(mean) (P< .002), and KARI (P< .01). The improved kidney functions were shown by significant improvements in serum creatinine (P< .03), urea (P< .02), and urine volume (P< .005). Eleven patients were alive: 6 with OLT and 5 without OLT. Seven patients died: 4 after OLT and 3 before OLT due to multiorgan failure. CONCLUSIONS The MARS device significantly improved the hemodynamic parameters and kidney function that also determine patient survival in ALF (61.1%) with PNF while awaiting retransplantation presumably by removal of certain vasoactive substances.