Subacute Liver Failure Research Articles

Efficacy and limitation of bone marrow transplantation in the treatment of acute and subacute liver failure in rats

Recent reports have shown that bone marrow cells (BMC) retain the potential to differentiate into hepatocytes. Thus, the BMC have been recognized as an attractive source for liver regenerative medicine. However, it has not been clarified whether BMC transplantation can be used to treat liver damage in vivo. In the present study, we explored whether BMC possess therapeutic potential to treat acute and/or subacute liver failure. Fulminant hepatic failure (FHF) was induced by 70% hepatectomy with ligation of the right lobe pedicle (24% liver mass), followed by transplantation of BMC into the spleen. Dipeptidyl peptidase IV-positive (DPPIV(+)) BMC were then transplanted into DPPIV-negative (DPPIV(-)) recipients following hepatic irradiation (HIR) in which 70% of the liver was resected and the remnant liver irradiated. There was no benefit of BMC transplantation towards survival in the FHF model. DPPIV(+) hepatocytes appeared in the liver tissues of the DPPIV(-) HIR model rats, but DPPIV(+) hepatocytes replaced less than 13% of the recipient liver. BMC transplantation may have limitations in the treatment of fulminant or acute liver failure because they do not have sufficient time to develop into functional hepatocytes. Preparative HIR may be beneficial in help to convert the transplanted BMC into host hepatocytes, and provide a survival benefit. Although, However, the precise mechanism warrants further studies.

Influence of the Primary Disease on Rehabilitation Results in the Early Postoperative Period in Patients After Orthotopic Liver Transplantation

Background Rehabilitation after orthotropic liver transplantation (OLT) is a difficult clinical problem due to severe comorbidities and complications. We evaluated the rehabilitation progress in the early postoperative period of patients after OLT depending on the reason for liver transplantation. Materials and Methods We retrospectively evaluated 309 OLT recipients transplanted between 2003 and 2006, including 161 women and 148 men. We analyzed the results of early postoperative rehabilitation measured by the time to full, active, erection upright after surgery. We divided the patients into 5 groups due to etiology of liver failure: group A ( n = 89; mean age, 46.7 years) consisted of patients with liver cirrhosis due to hepatitis B, C, or both; group B ( n = 70; mean age, 43.8 years) included patients with primary biliary cirrhosis and primary sclerosing cholangitis; group C ( n = 44; mean age, 46 years) conprised patients with postalcoholic liver cirrhosis; group D ( n = 23; mean age, 29.7 years) had experienced acute or subacute liver failure; and group E ( n = 83; mean age, 37.4 years) had other reasons of liver failure. All patients were included in an identical rehabilitation program. Results The mean time to full, active, erection upright was dependent on the reason for liver failure. The best result was observed in groups A and E (4.51 and 4.6 days, respectively), medium in groups B and C (5.3 and 5.02, respectively), and worst in group D (8.5 days). The differences between groups A, E, and D were significant. Conclusion The best results were obtained in groups A and E, where full, active, erection upright was achieved at 4.51 and 4.60 days respectively, and worst in group D, where it was achieved on day 8.50. These results need to be taken into account in planning the rehabilitation process for OLT patients. When analyzing the correlation between full, active, erection upright and primary diseases, one of the factors contributing to the delay needs to be assumed to be the inability to develop compensating mechanisms in the cases of acute and subacute hepatic failures, resulting from the sudden development of the disease.

Clinical course and outcomes of drug-induced liver injury: Nimesulide as the first implicated medication

Drug-induced liver injury (DILI) is the most common cause of death from acute liver failure, and accounts for approximately 13% of cases of acute liver failure in the United States. The clinical presentation of DILI covers a wide spectrum, from asymptomatic liver test abnormalities to symptomatic acute liver disease, prolonged jaundice and disability, or overt acute or subacute liver failure. The aim of our study was to evaluate the number of DILI cases admitted to our Unit and to identify the drugs responsible. Thus, we reviewed all clinical records of patients with DILI admitted to our Unit from 1996 to 2006. A database was constructed, reporting demographic, clinical features at onset, laboratory results, suspected drugs and follow-up. Liver damage was defined as hepatocellular, cholestatic or mixed, according to clinical and laboratory data. Forty-six patients were admitted with a diagnosis of DILI. Presentation was jaundice in 22 patients and hepatic failure in 3 (all attributed to nimesulide). Liver damage was of a cytolytic pattern in 19 cases (41%), cholestatic in 15 (33%) and mixed in 12 (26%). Jaundice was found to be higher in nimesulide-induced liver damage compared to other drugs (p=0.007). Three out of 14 patients with nimesulide-induced DILI developed encephalopathy and/or ascites. Time of recovery in the nimesulide group was significantly lower than DILI from other drugs (p<0.001). Non-steroidal anti-inflammatory drugs, psychotropic drugs and antimicrobials are the most common causes of DILI. Nimesulide-induced DILI is usually reversible upon discontinuation of the drug, but occasionally progresses to liver failure.

"Síndrome pequeño para su tamaño", (small-for-size), como complicación de un trasplante hepático con donante vivo adulto relacionado

Although the use of cadaveric split or living donor liver transplantation is a valid option for liver transplants, they have several complications, being the "small-for-size syndrome" one of the most frequent. This entity is mainly due to the incapacity that the graft has to meet the blood drainage demands. We report a 61 year-old patient with sub-acute liver failure, transplanted with a partial liver graft that developed hyperbilirubinemia, ascites and liver function deterioration. A meso-caval shunt was performed, after which the ascites resolved, serum bilirubin normalized and the synthetic function of the liver improved. After one month, a follow-up CT seen showed the absence of blood flow in the shunt, possible due to the reduction of the hyper-perfusion of the liver. The clinical and biochemical condition of the patient continued improving despite the lack of flow through the shunt.

Outcome of liver transplantation in hereditary hemochromatosis

Hereditary hemochromatosis (HH) is a genetic disorder of iron metabolism. It is an uncommon indication for liver transplantation (LT). It has been suggested that patients who undergo LT for cirrhosis related to HH have higher morbidity and mortality from cardiac, infectious and malignant complications. The purpose of this retrospective review was to determine whether these observations hold true in the current era. We analysed the data of 22 patients who had LT for HH from 1996 to 2007 at our center. Thirteen patients had LT for complications of end-stage liver disease, seven for hepatocellular carcinoma (HCC) and two for subacute liver failure. Cofactors promoting liver disease were identified in 15 patients. Ten patients had iron reduction with venesection before transplantation. Patient and graft survival at 1 and 5 years were 80.7%, and 74% respectively. There were seven deaths after a median follow up of 46 months either because of multiorgan failure, or caused by HCC recurrence. Bacterial infections were the commonest cause of morbidity. Patients with HH remain at a higher risk of developing HCC. Infectious complications are common. Iron reduction with preoperative venesection reduces the risk of cardiac and infection complications postoperatively. Improved survival post-LT reflects changes in selection, disease modification through venesection, and improvement in immunosuppression.

Acute aplastic crisis superimposed on drug-induced subacute liver failure: A case report.

急性造血功能停滞是由于多种原因所致的骨髓造血功能停滞.临床表现以贫血、出血为主要特征,疴情凶险,进展快,患者可出现红细胞系统或粒细胞、红细胞、巨噬细胞三系功能重度减低;如不及时治疗可危及生命,积极治疗可于短期内自然康复。

This Month in Gastroenterology

This Month in Gastroenterology

Hepatitis E autochthonous infection in chronic liver disease

Hepatitis E virus is endemic in many parts of the developing world and causes a self-limiting hepatitis in young adults, except in pregnant women and patients with chronic liver disease, where the mortality is high. Locally acquired hepatitis E is increasingly recognized in the developed world. It is caused by hepatitis E virus genotype 3, affects the middle-aged and the elderly, and may be a zoonotic infection from pigs. We present a case of locally acquired hepatitis E infection in a patient with previously undiagnosed cirrhosis, which resulted in subacute liver failure and death. We describe our attempt to trace this infection to a free-range pig farm adjacent to the patient's place of employment. Hepatitis E infection should be considered in the differential diagnosis in patients with decompensated chronic liver disease whatever their age or travel history. When found, the prognosis may be poor.

Orlistat-Associated Adverse Effects and Drug Interactions

Orlistat, an anti-obesity drug, is a potent and specific inhibitor of intestinal lipases. In light of the recent US FDA approval of the over-the-counter sale of orlistat (60 mg three times daily), clinicians need to be aware that its use may be associated with less well known, but sometimes clinically relevant, adverse effects. More specifically, the use of orlistat has been associated with several mild-to-moderate gastrointestinal adverse effects, such as oily stools, diarrhoea, abdominal pain and faecal spotting. A few cases of serious hepatic adverse effects (cholelithiasis, cholostatic hepatitis and subacute liver failure) have been reported. However, the effects of orlistat on non-alcoholic fatty liver disease are beneficial. Orlistat-induced weight loss seems to have beneficial effects on blood pressure. No effect has been observed on calcium, phosphorus, magnesium, iron, copper or zinc balance or on bone biomarkers. Interestingly, the use of orlistat has been associated with rare cases of acute kidney injury, possibly due to the increased fat malabsorption resulting from the inhibition of pancreatic and gastric lipase by orlistat, leading to the formation of soaps with calcium and resulting in increased free oxalate absorption and enteric hyperoxaluria. Orlistat has a beneficial effect on carbohydrate metabolism. No significant effect on cancer risk has been reported with orlistat.Orlistat interferes with the absorption of many drugs (such as warfarin, amiodarone, ciclosporin and thyroxine as well as fat-soluble vitamins), affecting their bioavailability and effectiveness. This review considers orlistat-related adverse effects and drug interactions. The clinical relevance and pathogenesis of these effects is also discussed.

Beneficial drugs for liver diseases

Liver diseases are a major problem of worldwide proportions. However, the number of drugs actually used successfully in humans is very small. In this review some of the most promising/studied drugs utilized for liver diseases were chosen and analysed critically from the basic to the clinical point of view. Antiviral agents are not discussed because excellent reviews have appeared on this topic. The compounds/preparations described herein are, alphabetically: colchicine, corticosteroids, curcumin, glycyrrhizin, interferons (for their antifibrotic properties), Liv 52, nitric oxide, resveratrol, silymarin, sulfoadenosylmethionine, and thalidomide. Colchicine and corticosteroids have been studied extensively in animals and humans; most clinical studies suggest that these compounds are not useful in the treatment of liver diseases. Glycyrrhizin is an herbal medicine with several components that has interesting hepatoprotective properties in patients with subacute liver failure but deserves more prospective controlled trials. Interferon has shown interesting antifibrotic properties in animals and humans; prospective studies on their antifibrotic/fibrolytic activity are required. Curcumin, resveratrol and thalidomide are very attractive newly discovered protective and curative compounds on experimental hepatic diseases. Their mechanism of action is associated with the ability to down-regulate NF-kappaB and to decrease pronecrotic and profibrotic cytokines. Unfortunately, clinical studies are lacking. Sulfoadenosylmethionine and silymarin are also promising drugs utilized mainly in cholestasis but the benefits can be expanded if more controlled trials are performed. The future is to carry out controlled prospective double-blind multicenter studies with the newly discovered drugs with proven beneficial effects on animals. Fundamental hepatobiology should also be encouraged.

Liver Failure in Mitochondrial DNA Depletion Syndrome: The Importance of Serial Neuroimaging in Liver Transplantation Evaluation

Liver Failure in Mitochondrial DNA Depletion Syndrome: The Importance of Serial Neuroimaging in Liver Transplantation Evaluation

Comparison scoring model of severe viral hepatitis and model of end stage liver disease for the prognosis of patients with liver failure in China

To estimate the prognosis of patients with liver failure using a scoring model of severe viral hepatitis (SMSVH) and a model of end stage liver disease (MELD) to provide a scientific basis for clinical decision of treatment. One hundred and twenty patients with liver failure due to severe viral hepatitis were investigated with SMSVH established. Patients with acute, subacute, and chronic liver failure were 40, 46 and 34, respectively. The follow-up time was 6 mo. The survival rates of patients with liver failure in 2 wk, 4 wk, 3 mo and 6 mo were estimated with Kaplan-Meier method. Comparison between SMSVH and MELD was made using ROC statistic analysis. The survival curves of group A (at low risk, SMSVH score <or= 4) and group B (at high risk, SMSVH score >or= 5) were significantly different (The 4-wk, 3-mo, 6-mo survival rates were 94.59%, 54.05%, 43.24% in group A, and 51.81%, 20.48%, 12.05% in group B, respectively, P < 0.001). The survival curves of group C (SMSVH scores unchanged or increased), group D (SMSVH scores decreased by 1) and group E (SMSVH scores decreased by 2 or more) were significantly different .The survival rates of groups C, D and E were 66.15%, 100%, 100% in 2-wk; 40.0%, 91.18%, 100% in 4-wk; 0%, 58.82%, 80.95% in 3-mo and 0%, 38.24%, 61.90% in 6-mo, respectively, P < 0.001). The area under the ROC curve (AUC) of SMSVH scores at baseline and after 2 wk of therapy was significantly higher than that under the ROC curve of MELD scores (0.804 and 0.934 vs 0.689, P < 0.001). SMSVH is superior to MELD in the estimation of the prognosis of patients with severe viral hepatitis within 6 mo. SMSVH may be regarded as a criterion for estimation of the efficacy of medical treatment and the decision of clinical treatment.

Formal Heparin Anticoagulation Protocol Improves Safety of Charcoal-Based Liver-assist Treatments

Extracorporeal devices have had limited effectiveness in liver failure due to consequences of inadequate anticoagulation. The purpose of this study was to evaluate an anticoagulation protocol developed for Liver Dialysis Unit (LDU) treatments. Twelve patients underwent 19 LDU treatments for acetaminophen overdose (n = 1), subacute liver failure (n = 1), and refractory encephalopathy in cirrhosis (n = 10). The initial 6 patients (group 1) were treated according to the manufacturer's recommendations. The subsequent 6 patients (group 2) were treated using a formal heparin anticoagulation protocol that included 2000 units in prime solution and 30 units/kg induction, activated clotting time (ACT) measurements, and heparin administered by dose-response curve to maintain 300-second ACT. Protamine reversal was used. Treatments were well tolerated and equally effective in both groups. Adequate (ACT > or = 250 seconds) and therapeutic (ACT 250-350 seconds) anticoagulation was maintained more consistently in group 2 (90.9% vs 50.0%, p < 0.0001; and 77.4% vs 45.8%, p < 0.001). There was less consumption of fibrinogen (12.1% vs 43.3%, p < 0.005) and platelets (13.8% vs 29.9%, p < 0.05) and a trend for less blood product used (8.3 vs 15.8 units/patient, p = 0.13) and fewer complications (16.7% vs 66.7%, p = 0.15) in group 2. Anticoagulation using ACT monitoring, heparin dose-response curves, and a target ACT of 300 seconds improves the safety of LDU treatments.

ABO‐incompatible deceased donor liver transplantation with the use of antigen‐specific immunoadsorption and anti‐CD20 monoclonal antibody

In patients with fulminant liver failure requiring emergency liver transplantation, the only donor organ that becomes available may be ABO incompatible. The risk of graft failure because of antibody-mediated acute rejection is high, but can be reduced by various means. We reported a deceased donor ABO-incompatible liver allograft recipient who was treated with antigen-specific immunoadsorption in combination with anti-CD20 monoclonal antibody and conventional plasmapheresis and immunosuppression. The patient was a 33-yr-old male with blood group A who presented with subacute liver failure of unknown aetiology and received a blood group AB liver graft. Pretransplant he underwent plasmapheresis and received one dose of rituximab. The immunosuppressive regimen consisted of methylprednisolone, tacrolimus and mycophenolate mofetil. Despite regular post-operative plasmapheresis sessions, anti-B antibody titres increased. Antigen-specific immunoadsorption with depletion of anti-B antibodies was performed from day nine to day 17. Thereafter, anti-B IgM and IgG antibody titres remained low. After one month the patient was reoperated with hepaticojejunostomy because of bile duct necrosis and with reconstruction of a stenotic hepatic artery. A mild rejection was successfully treated with methylprednisolone four months post-transplant. At six months post-transplant there was a stricture of the biliary-enteric anastomosis, but the graft was well functioning. We conclude that antigen-specific immunoadsorption can be an important adjuvant therapy to control recipient anti-A/B antibody levels and prevent acute rejection in ABO-incompatible deceased donor liver transplantation.

Cost-effectiveness of pharmacotherapy for autoimmune hepatitis

In > 80% of patients with autoimmune hepatitis, steroid therapy alone or in combination with azathioprine results in disease remission. Treatment response results in reversal of fibrosis and excellent long-term survival in many patients, whereas untreated patients may expect a 10-year survival of < 30%. The use of azathioprine monotherapy (2 mg/kg/day) has gained widespread acceptance in maintaining remission in clinical practice. Although all patients with autoimmune hepatitis may not need treatment, particularly those with mild disease, alternative strategies are required in patients who have failed to achieve remission on standard therapy of steroids with or without azathioprine, or patients with azathioprine-induced drug toxicity. In such circumstances, the use of salvage therapy in the form of ciclosporin, tacrolimus or mycophenolate mofetil may be warranted. Liver transplantation is the treatment of choice for patients who present with subacute liver failure or decompensated cirrhosis. Salvage therapy results in an exponential rise in cost with each increment in therapeutic escalation. As an alternative to standard therapy, it has also been suggested that novel therapies such as ciclosporin, tacrolimus or mycophenolate mofetil be initiated to achieve remission. However, a > 10-fold cost differential exists between the charges associated with more potent immunosuppression and standard therapy. Therefore, in evaluating novel immunosuppression in autoimmune hepatitis, it behoves clinicians not only to consider end points pertaining to efficacy, but also end points pertaining to cost-effectiveness. Moreover, the exact role of pharmacogenomics and genotyping of thiopurine methyltransferase in patients with autoimmune hepatitis needs to be fully defined.

Terbinafine-induced hepatic failure requiring liver transplantation

Drug-induced liver disease accounts for about 50% of acute or subacute liver failure in the United States. United Network of Organ Sharing (UNOS) data suggest 8%-20% of liver transplantation in this country per year is for fulminant liver failure due to drugs. Even though the most common medication implicated in acute liver injury is acetaminophen (75%), there are numerous other drugs that are responsible for acute and chronic liver injury. A variety of antifungal medications are known to cause a wide range of liver injury from a mild hepatocellular-cholestatic injury pattern to acute/subacute liver failure. Terbinafine is one of the antifungals that have been associated with such liver injuries. We report a case of terbinafine-induced severe liver failure requiring liver transplantation.

Orlistat (Xenical)-induced subacute liver failure

Thurairajah, Prem H.a; Syn, Wing-Kina; Neil, Desley A.H.b; Stell, Davida; Haydon, Geoffreya Author Information

Herbal Medicines for Liver Diseases

Herbal medicines have been used in the treatment of liver diseases for a long time. A number of herbal preparations are available in the market. This article reviews four commonly used herbal preparations: (1) Phyllanthus, (2) Silybum marianum (milk thistle), (3) glycyrrhizin (licorice root extract), and (4) Liv 52 (mixture of herbs). Phyllanthus has a positive effect on clearance of HBV markers and there are no major adverse effects; there are no data from randomized controlled trials on clinically relevant outcomes, such as progression of chronic hepatitis to cirrhosis and/or liver cancer, and on survival. Silymarin does not reduce mortality and does not improve biochemistry and histology among patients with chronic liver disease; however, it appears to be safe and well tolerated. Stronger neominophagen C (SNMC) is a Japanese preparation that contains 0.2% glycyrrhizin, 0.1% cysteine, and 2% glyceine. SNMC does not have antiviral properties; it primarily acts as an anti-inflammatory or cytoprotective drug. It improves mortality in patients with subacute liver failure and improves liver functions in patients with subacute hepatic failure, chronic hepatitis, and cirrhosis with activity. SNMC does not reduce mortality among patients with cirrhosis with activity. SNMC may prevent the development of hepatocellular carcinoma in patients with chronic hepatitis C, however, prospective data are lacking. Liv 52, an Ayurvedic hepatoprotective agent, is not useful in the management of alcohol-induced liver disease. Standardization of herbal medicines has been a problem and prospective, randomized, placebo-controlled clinical trials are lacking to support their efficacy. The methodological qualities of clinical trials of treatment with herbal preparations are poor. The efficacy of these herbal preparations need to be evaluated in rigorously designed, larger randomized, double-blind, placebo-controlled multicenter trials.

Liver failure

Liver failure is a rare but life-threatening condition affecting a multitude of other organ systems, most notably the brain and kidneys, following severe hepatocellular injury. Liver failure may develop in the absence ('acute') or presence ('acute-on-chronic') of liver disease with substantial differences in pathophysiology and therapeutic options. Within the last 12 months substantial progress has been made in identifying patients who will potentially benefit from extracorporeal support of their failing liver. In addition to traditional 'static' laboratory tests to assess liver function, the significance of 'dynamic' tests, such as indocyanine green clearance, has been better defined, and these tests are becoming more easily available. Transplantation remains the treatment of choice for fulminant, acute and subacute liver failure with predicted unfavorable outcome according to King's College or Clichy criteria, most notably in the absence of pre-existing liver disease, and should be performed before extrahepatic complications emerge. Encouraging results have been obtained with the use of support systems in patients with acute and acute-on-chronic liver failure in relatively small patient collectives, making well-conducted randomized trials a necessity to define their role in this high-risk population. Current (pre)clinical data suggest that programmed cell death is an important mechanism for the pathogenesis of acute and acute-on-chronic liver failure and, thus, antiapoptotic strategies are promising pharmacologically. Although mortality remains high, substantial progress has been made in 2004 regarding the understanding of pathophysiology, and the monitoring and support of the patient presenting with a failing liver.

Late complications of NASH: a challenge for hepatologists

Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, Hall P, Khan M, George J. Data on the long-term outcome of nonalcoholic steatohepatitis (NASH)-associated cirrhosis are few, and most reports describe cases of cryptogenic cirrhosis associated with risk factors for NASH but without histologic definition. In this prospective cohort study, we describe the long-term morbidity and mortality of 23 patients with NASH-associated cirrhosis defined by strict clinicopathologic criteria. Outcomes were compared with 46 age- and gender-matched patients with cirrhosis from chronic hepatitis C virus (HCV) infection: 23 untreated and 23 nonresponders to antiviral therapy. During follow-up (mean, 84 months; median, 60 months; range, 5–177 months), 9 of the 23 NASH-associated cirrhosis cases developed liver-related morbidity (8 ascites and/or encephalopathy, 1 variceal bleeding). The probability of complication-free survival was 83, 77, and 48% at 1, 3, and 10 years, respectively, and the cumulative probability of overall survival was 95, 90, and 84% at 1, 3, and 10 years, respectively. Five deaths were from liver failure, 1 from a non-liver-related cause. By multivariate analysis, bilirubin ( P =0.02) and platelet ( P =0.04) were independent predictors of complication-free survival; bilirubin ( P =0.05) was the only predictor for overall survival. After controlling for these factors, there was no difference in complication-free or overall survival between the NASH-cirrhosis cohort and either group of HCV-cirrhosis. However, 8 cases of liver cancer occurred in the HCV-cirrhosis groups compared with none among NASH cases. In conclusion, liver failure is the main cause of morbidity and mortality in NASH-associated cirrhosis. The prognosis is either similar or less severe than HCV-cirrhosis, except that HCC appears less common. [Abstract reproduced by permission of Hepatology 2003;38:420–427].