Cystic fibrosis patients on cystic fibrosis transmembrane conductance regulator modulators have a reduced incidence of cirrhosis.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators significantly improve pulmonary function in patients with cystic fibrosis (CF) but the effect on hepatobiliary outcomes remains unknown. We hypothesized that CF patients on CFTR modulators would have a decreased incidence of cirrhosis compared to patients not on CFTR modulators or on ursodiol. AIM: To investigate the effect of CFTR modulators on the development of cirrhosis in patients with CF. METHODS: A retrospective analysis was performed using Truven MarketScan from January 2012 through December 2017 including all patients with a diagnosis of CF. Patients were excluded if they underwent a liver transplantation or if they had other etiologies of liver disease including viral hepatitis or alcohol use. Subjects were grouped by use of CFTR modulators, ursodiol, dual therapy, or no therapy. The primary outcome was development of cirrhosis. Kaplan-Meier curves estimated the incidence of cirrhosis and log-rank tests compared incidence curves between treatment groups. RESULTS: A total of 7201 patients were included, of which 955 (12.6%) used a CFTR modulator, 529 (7.0%) used ursodiol, 105 (1.4%) used combination therapy, and 5612 (74.3%) used neither therapy. The incidence of cirrhosis was 0.1% at 1 year and 0.7% at 4 years in untreated patients, 5.9% and 10.1% in the Ursodiol group, and 1.0% and 1.0% in patients who received both therapies. No patient treated with CFTR modulators alone developed cirrhosis. Patients on CFTR modulators alone had lower cirrhosis incidence than untreated patients (P = 0.05), patients on Ursodiol (P < 0.001), and patients on dual therapy (P = 0.003). The highest incidence of cirrhosis was found among patients treated with Ursodiol alone, compared to untreated patients (P < 0.001) or patients on Ursodiol and CFTR modulators (P = 0.01). CONCLUSION: CFTR modulators are associated with a reduction in the incidence of cirrhosis compared to other therapies in patients with CF.

Coagulopathy, Bleeding Events, and Outcome According to Rotational Thromboelastometry in Patients With Acute Liver Injury/Failure.

BACKGROUND AND AIMS: Patients with acute liver injury or failure (ALI/ALF) experience bleeding complications uncommonly despite an abnormal hemostatic profile. Rotational thromboelastometry (ROTEM), which assesses clot formation in whole blood, was used to determine the nature of abnormal hemostasis and whether it contributes to bleeding events, illness severity, or survival. APPROACH AND RESULTS: A total of 200 patients were recruited from sites of the ALF Study Group. Blood collected daily for up to 5 days was analyzed using ROTEM delta devices. Consistent with standard laboratory evidence of hypocoagulability (median international normalized ratio = 2.9 and platelet count = 144 × 109 /L), patients frequently exhibited ROTEM parameters outside the normal range (73% and 62% had abnormalities in clot formation from extrinsic and intrinsic clotting cascades, respectively); however, measures of clot stability were generally normal. Eighteen patients (9%) experienced bleeding events, in whom clot initiation, assembly, and firmness were more severely deranged than patients without bleeding. Abnormal ROTEM parameters were more frequently observed in patients with non-acetaminophen ALI/ALF than those with acetaminophen ALI/ALF (clot initiation [P < 0.001], assembly [P = 0.02], firmness at 10 minutes [P = 0.05], and maximal firmness [P = 0.06]). Patients with more severe systemic complications (high-grade hepatic encephalopathy and need for renal replacement therapy) also had a higher incidence of abnormal ROTEM parameters. Finally, more hypocoagulable ROTEM parameters (clot initiation (P = 0.005), stiffness at 10 minutes (P = 0.05), and maximal stiffness by fibrin assembly (P = 0.004)) were observed in patients who died or underwent liver transplantation than those who survived with their native liver. CONCLUSIONS: In patients with ALI/ALF, abnormal ROTEM parameters are frequent and proportional to disease severity. Whether the increased bleeding risk associated with abnormal ROTEM indicates hemostatic failure or is a proxy for disease severity requires additional study.

Outcomes of hepatitis C virus seropositive donors to hepatitis C virus seronegative liver recipients: A large single center analysis.

INTRODUCTION AND OBJECTIVES: The success of direct-acting antivirals (DAA) has transformed the management of hepatitis C virus (HCV) infection and has led to the expansion of the deceased donor organ pool for liver transplantation. MATERIAL AND METHODS: We present a single center retrospective review of liver transplantations performed on HCV-seronegative recipients from HCV-seropositive organs from 11/2017 to 05/2020. HCV nucleic acid testing (NAT) was performed on HCV-seropositive donors to assess active HCV infection. RESULTS: 42 HCV-seronegative recipients underwent a liver transplant from a HCV-seropositive donor, including 21 NAT negative (20 liver, 1 simultaneous liver kidney transplant) and 21 NAT positive liver transplants. Two (9.5%) HCV antibody positive/NAT negative recipients developed HCV viremia and achieved sustained virologic response with DAA therapy. The remaining patients with available data (19 patients) remained polymerase chain reaction (PCR) negative at 6 months. 20 (95%) of HCV antibody positive/NAT positive recipients had a confirmed HCV viremia. 100% of patients with available data (15 patients) achieved SVR. Observed events include 1 mortality and graft loss and equivalent rates of post-transplant complications between NAT positive and NAT negative recipients. CONCLUSIONS: HCV-seropositive organs can be safely transplanted into HCV-seronegative patients with minimal complications post-transplant.

Cannabis use may reduce healthcare utilization and improve hospital outcomes in patients with cirrhosis.

INTRODUCTION AND OBJECTIVES: Previous studies reveal conflicting data on the effect of cannabis use in patients with cirrhosis. This research evaluates the impact of cannabis on hepatic decompensation, health care utilization, and mortality in patients with cirrhosis. MATERIAL AND METHODS: A retrospective analysis of the State Inpatient Database (SID) was performed evaluating patients from Colorado and Washington in 2011 to represent pre-cannabis legalization and 2015 to represent post-cannabis legalization. Multivariable analysis was performed to study the impact of cannabis on the rate of admissions with hepatic decompensations, healthcare utilization, and mortality in patients with cirrhosis. RESULTS: Cannabis use was detected in 370 (2.1%) of 17,520 cirrhotics admitted in 2011 and in 1162 (5.3%) of 21,917 cirrhotics in 2015 (p-value <0.001). On multivariable analysis, cirrhotics utilizing cannabis after its legalization experienced a decreased rate of admissions related to hepatorenal syndrome (Odds Ratio (OR): 0.51; 95% Confidence Interval (CI): 0.34-0.78) and ascites (OR: 0.73; 95% CI: 0.63-0.84). Cirrhotics with an etiology of disease other than alcohol and hepatitis C had a higher risk of admission for hepatic encephalopathy if they utilized cannabis [OR: 1.57; 95% CI: 1.16-2.13]. Decreased length of stay (-1.15 days; 95% CI: -1.62, -0.68), total charges (-$15,852; 95% CI: -$21,009, -$10,694), and inpatient mortality (OR: 0.68; 95% CI: 0.51-0.91) were also observed in cirrhotics utilizing cannabis after legalization compared to cirrhotics not utilizing cannabis or utilizing cannabis prior to legalization. CONCLUSION: Cannabis use in patients with cirrhosis resulted in mixed outcomes regarding hospital admissions with hepatic decompensation. A trend towards decreased hospital utilization and mortality was noted in cannabis users after legalization. These observations need to be confirmed with a longitudinal randomized study.

Management of hepatic hydrothorax and effect on length of stay, mortality, cost, and 30-day hospital readmission.

BACKGROUND AND AIM: Cirrhosis-related complications are associated with high inpatient mortality, cost, and length of stay. There is a lack of multi-centered studies on interventions for hepatic hydrothorax and its impact on patient outcomes. The aim of this study was to determine the effect of performing thoracentesis for hepatic hydrothorax on hospital length of stay, mortality, cost, and 30-day readmission. METHODS: A retrospective analysis of the Nationwide Inpatient Sample between 2002 and 2013 and Nationwide Readmission Database during 2013 was performed including patients with a primary diagnosis of hydrothorax or pleural effusion and a secondary diagnosis of cirrhosis based on International Classification of Disease 9 codes. Univariate and multivariate analyses were performed to determine the effect of thoracentesis on patient outcomes during their hospital stay. RESULTS: Of the 37 443 patients included from the Nationwide Inpatient Sample, 26 889 (72%) patients underwent thoracentesis. Thoracentesis was associated with a longer length of stay (4.56 days, 95% confidence interval [CI]: 2.40-6.72) and higher total cost ($9449, 95% CI: 3706-15 191). There was no significant difference in inpatient mortality between patients who underwent thoracentesis compared with those who did not. Of the 2371 patients included from the Nationwide Readmission Database, 870 (33%) were readmitted within 30 days. Thoracentesis was not a predictor of readmission; however, transjugular intrahepatic portosystemic shunt (odds ratio: 4.89, 95% CI: 1.17-20.39) and length of stay (odds ratio: 1.02, 95% CI: 1.001-1.05) on index admission were predictors of readmission. CONCLUSION: When considering treatment for hepatic hydrothorax, many factors should contribute to determining the best intervention. While performing thoracentesis may provide immediate relief to symptomatic patients, it should not be considered a long-term intervention given that it increases hospital cost, was associated with longer length of stays, and did not improve mortality.

Paracentesis in cirrhotics is associated with increased risk of 30-day readmission.

AIM: To determine the readmission rate, its reasons, predictors, and cost of 30-d readmission in patients with cirrhosis and ascites. METHODS: A retrospective analysis of the nationwide readmission database (NRD) was performed during the calendar year 2013. All adults cirrhotics with a diagnosis of ascites, spontaneous bacterial peritonitis, or hepatic encephalopathy were identified by ICD-9 codes. Multivariate analysis was performed to assess predictors of 30-d readmission and cost of readmission. RESULTS: Of the 59597 patients included in this study, 18319 (31%) were readmitted within 30 d. Majority (58%) of readmissions were for liver related reasons. Paracentesis was performed in 29832 (50%) patients on index admission. Independent predictors of 30-d readmission included age < 40 (OR: 1.39; CI: 1.19-1.64), age 40-64 (OR: 1.19; CI: 1.09-1.30), Medicaid (OR: 1.21; CI: 1.04-1.41) and Medicare coverage (OR: 1.13; CI: 1.02-1.26), > 3 Elixhauser comorbidity (OR: 1.13; CI: 1.05-1.22), nonalcoholic cirrhosis (OR: 1.16; CI: 1.10-1.23), paracentesis on index admission (OR: 1.28; CI: 1.21-1.36) and having hepatocellular carcinoma (OR: 1.21; CI: 1.05; 1.39). Cost of index admission was similar in patients readmitted and not readmitted (P-value: 0.34); however cost of care was significantly more on 30 d readmission ($30959 ± 762) as compared to index admission ($12403 ± 378), P-value: < 0.001. CONCLUSION: Cirrhotic patients with ascites have a 33% chance of readmission within 30-d. Younger patients, with public insurance, nonalcoholic cirrhosis and increased comorbidity who underwent paracentesis are at increased risk of readmission. Risk factors for unplanned readmission should be targeted given these patients have higher healthcare utilization.

Acute Liver Failure from Tumor Necrosis Factor-α Antagonists: Report of Four Cases and Literature Review.

BACKGROUND: Tumor necrosis factor-α antagonists (anti-TNF-α) have been associated with drug-induced liver injury. However, cases of anti-TNF-α-associated acute liver failure have only been rarely reported. AIMS: To identify cases of anti-TNF-α-associated acute liver failure and evaluate patterns of liver injury and common characteristics to the cases. METHODS: The United States Acute Liver Failure Study Group database was searched from 1998 to 2014. Four subjects were identified. A PubMed search for articles that reported anti-TNF-α-associated acute liver failure identified five additional cases. RESULTS: The majority of individuals affected were female (eight of nine cases). Age of individual ranged from 20 to 53 years. The most common anti-TNF-α agent associated with acute liver failure was infliximab (n = 8). The latency between initial drug exposure and acute liver failure ranged from 3 days to over a year. Of the nine cases, six required emergency LT. Liver biopsy was obtained in seven cases with a preponderance toward cholestatic-hepatitic features; none showed clear autoimmune features. CONCLUSIONS: Anti-TNF-α-associated acute liver failure displays somewhat different characteristics compared with anti-TNF-α-induced drug-induced liver injury. Infliximab was implicated in the majority of cases. Cholestatic-hepatitic features were frequently found on pre-transplant and explant histology.

Safety, tolerability, and pharmacokinetics of l-ornithine phenylacetate in patients with acute liver injury/failure and hyperammonemia.

Cerebral edema remains a significant cause of morbidity and mortality in patients with acute liver failure (ALF) and has been linked to elevated blood ammonia levels. l-ornithine phenylacetate (OPA) may decrease ammonia by promoting its renal excretion as phenylacetylglutamine (PAGN), decreasing the risk of cerebral edema. We evaluated the safety, tolerability, and pharmacokinetics of OPA in patients with ALF and acute liver injury (ALI), including those with renal failure. Forty-seven patients with ALI/ALF and ammonia ≥60 µM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (<75 µg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] µg/mL), and increased to target levels in all but one who received 20 g every 24 hours (150 [100] µg/mL). Plasma [PAGN] increased, and conversion of PA to PAGN became saturated, with increasing OPA dose. Urinary PAGN clearance and creatinine clearance were linearly related (r = 0.831, P < 0.0001). Mean ammonia concentrations based on the area under the curve decreased to a greater extent in patients who received 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting. CONCLUSION: OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, leading to ammonia excretion in urine as PAGN in proportion to renal function. Randomized, controlled studies of high-dose OPA are needed to determine its use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003-1013).

Rotational Thromboelastometry or Conventional Coagulation Tests in Liver Transplantation: Comparing Blood Loss, Transfusions, and Cost.

INTRODUCTION: Orthotopic liver transplantation (OLT) can be associated with significant bleeding requiring multiple blood product transfusions. Rotational thromboelastometry (ROTEM) is a point-of-care device that has been used to monitor coagulation during OLT. Whether it reduces blood loss/transfusions during OLT remains controversial. MATERIALS AND METHODS: We aim to compare ROTEM with conventional coagulation tests (aPTT, PT, INR, platelet count, fibrinogen) to guide transfusion of platelets, cryoprecipitate, and fresh frozen plasma (FFP) during OLT over 3 years. Thirty-four patients who had transfusions guided by ROTEM were compared to 34 controls who received transfusions guided by conventional coagulation tests (CCT). Intraoperative blood loss, type/ amount of blood products transfused, and direct costs were compared between the two groups. RESULTS: The ROTEM group had significantly less intra-operative blood loss (2.0 vs. 3.0 L, p = 0.04) and fresh frozen plasma (FFP) transfusion (4 units vs. 6.5 units, p = 0.015) compared to the CCT group (2.0L vs. 3.0L, p = 0.04). However, total number of patients transfused cryoprecipitate was increased in ROTEM (n = 25;73%) as compared to CCT (n = 19; 56%), p = 0.033. The direct cost of blood products plus testing was reduced in the ROTEM group ($113,142.89 vs. $127,814.77). CONCLUSION: In conclusion implementation of a ROTEM-guided transfusion algorithm resulted in a reduction in intra-operative blood loss, FFP transfusion and a decrease in direct cost during OLT. ROTEM is a useful and safe point of care device in OLT setting.

HBV-Associated Acute Liver Failure After Immunosuppression and Risk of Death.

BACKGROUND & AIMS: Acute liver failure (ALF) caused by hepatitis B virus (HBV) infection can occur after immunosuppressive treatment and be fatal, although it might be preventable. We aimed to characterize the causes, clinical course, and short-term outcomes of HBV-associated ALF after immune-suppressive therapy, compared with patients with HBV-associated ALF without immunosuppression (control subjects). METHODS: We performed a retrospective multicenter study of 156 consecutive patients diagnosed with HBV-associated ALF (22 with a solid or blood malignancy) enrolled in the Acute Liver Failure Study Group registry from January 1998 through April 2015. We collected data on results of serologic and hepatic biochemistry analyses, grade of hepatic encephalopathy, Model for End-Stage Liver Disease score, and King's College criteria. We also collected data on clinical features, medical therapies, and complications in the first 7 days following study enrollment. Logistic regression was used to identify factors associated with transplant-free survival at 21 days in HBV-associated ALF (the primary outcome). RESULTS: Among patients with HBV-associated ALF, 28 cases (18%) occurred after immunosuppressive therapy (15 patients received systemic corticosteroids and 21 received chemotherapy); and 128 cases did not (control subjects, 82%). Significantly greater proportions of patients with HBV-associated ALF after immunosuppression were nonwhite persons, and had anemia or thrombocytopenia than controls (P < .02 for all). The serologic profile of HBV infection, severity of liver failure (based on MELD score), and complications (hepatic encephalopathy or need for mechanical ventilation, vasopressors, or renal replacement therapy) were similar between the groups (P > .17 for all). Factors associated with 21 day transplant-free survival were increased MELD score (odds ratio ∼OR, 0.894 (95% confidence interval 0.842-0.949 per increment), requirement for mechanical ventilation (OR 0.111(0.041-0.300), and immunosuppressive therapy (OR 0.274(0.082-0.923)). CONCLUSIONS: Within a cohort study of patients with HBV-associated ALF, 18% had received immunosuppressive therapy. Significantly smaller proportions of patients with HBV-associated ALF after immunosuppression survive beyond 21 days than patients with HBV-associated ALF who did not receive immunosuppression. Patients undergoing chemotherapy should be screened for HBV infection and given appropriate antiviral therapies to reduce preventable mortality.

Impact of Recipient and Donor Obesity Match on the Outcomes of Liver Transplantation: All Matches Are Not Perfect.

There is a paucity of literature examining recipient-donor obesity matching on liver transplantation outcomes. The United Network for Organ Sharing database was queried for first-time recipients of liver transplant whose age was ≥18 between January 2003 and September 2013. Outcomes including patient and graft survival at 30 days, 1 year, and 5 years and overall, liver retransplantation, and length of stay were compared between nonobese recipients receiving a graft from nonobese donors and obese recipient-obese donor, obese recipient-nonobese donor, and nonobese recipient-obese donor pairs. 51,556 LT recipients were identified, including 34,217 (66%) nonobese and 17,339 (34%) obese recipients. The proportions of patients receiving an allograft from an obese donor were 24% and 29%, respectively, among nonobese and obese recipients. Graft loss (HR: 1.27; 95% CI: 1.09-1.46; p = 0.002) and mortality (HR: 1.38; 95% CI: 1.16-1.65; p < 0.001) at 30 days were increased in the obese recipient-obese donor pair. However, 1-year graft (HR: 0.83; 95% CI: 0.74-0.93; p = 0.002) and patient (HR: 0.84; 95% CI: 0.74-0.95; p = 0.007) survival and overall patient (HR: 0.93; 95% CI: 0.86-1.00; p = 0.042) survival were favorable. There is evidence of recipient and donor obesity disadvantage early, but survival curves demonstrate improved long-term outcomes. It is important to consider obesity in the donor-recipient match.

Pretransplant Locoregional Therapy for Hepatocellular Carcinoma: Evaluation of Explant Pathology and Overall Survival.

BACKGROUND AND OBJECTIVES: Liver transplant is an important treatment option for patients with hepatocellular carcinoma (HCC) within Milan criteria. We sought to determine the rate of complete tumor necrosis after bridging therapy. METHODS: The medical records of all 178 patients undergoing liver transplantation between January 1, 2008 and July 31, 2015 were reviewed. Response to therapy by imaging was based on mRECIST criteria (1). RESULTS: Sixty-three (35%) patients had HCC. Forty-three (68%) were treated with at least one bridging therapy and 14 (22%) were diagnosed incidentally. Eighteen (42%) underwent TACE and 25 (58%) underwent ablation. Twenty (80%) patients who underwent ablation and nine (60%) who underwent TACE had complete response based on imaging. Viable tumor was identified in explant pathology in 32 patients (74%). The presence or absence of viable tumor was not associated with overall survival. CONCLUSION: Rates of viable tumor based on pathologic analysis in the hepatic explant were high after bridging therapy, but not associated with worse outcome. We conclude that serial bridging to achieve complete pathologic tumor response is not needed prior to transplant for HCC, and presence of complete response by imaging is adequate. Further studies are needed to determine if cancer cells that appear viable are alive.

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study.

BACKGROUND: Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction-without prior advanced liver disease-that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively. OBJECTIVE: To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers. DESIGN: Prospective observational cohort study. (ClinicalTrials .gov: NCT00518440). SETTING: 31 liver disease and transplant centers in the United States. PATIENTS: Consecutively enrolled patients-without prior advanced liver disease-with ALF (n = 2070). MEASUREMENTS: Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013). RESULTS: Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period. LIMITATIONS: The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers. CONCLUSION: Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study. PRIMARY FUNDING SOURCE: National Institutes of Health.

Radiofrequency Wire Recanalization of Chronically Thrombosed TIPS.

Radiofrequency (RF) guide wires have been applied to cardiac interventions, recanalization of central venous thromboses, and to cross biliary occlusions. Herein, the use of a RF wire technique to revise chronically occluded transjugular intrahepatic portosystemic shunts (TIPS) is described. In both cases, conventional TIPS revision techniques failed to revise the chronically thrombosed TIPS. RF wire recanalization was successfully performed through each of the chronically thrombosed TIPS, demonstrating initial safety and feasibility in this application.

Collagen immunostains can distinguish capsular fibrous tissue from septal fibrosis and may help stage liver fibrosis.

Core-needle biopsy remains essential for diagnosis of cirrhosis; however, evaluation of fibrosis in such biopsies is often challenging due to the fragmented nature of cirrhotic liver specimens. It is also common to see portions of liver capsules present in the biopsy which adds to the diagnostic challenge. The distinction between capsular/subcapsular fibrous tissue and septal fibrosis is critical to avoid potential overstaging of liver fibrosis. We compared the differential immunostaining in liver capsular and septal areas for collagens III, IV, V, VI, vitronectin, laminin, Orcein, and Trichrome in 15 whole sections of explanted cirrhotic livers and 5 simulated liver biopsies. Collagens III, IV, V, VI, Trichrome, and Orcein show distinct staining patterns in capsular fibrous tissue and septal fibrosis. Collagen IV shows strong diffuse septal staining and consistently weak to negative capsular staining. Collagens III and VI stain similar to IV for septal fibrosis, whereas collagen V, Trichrome, and Orcein show strong staining in both areas. Collagen IV, possibly with III or VI in addition to the routine Trichrome and hematoxylin and eosin stain, is useful in differentiating capsular fibrous tissue from septal fibrosis on challenging and fragmented liver biopsies.

Current approach to down-staging of hepatocellular carcinoma prior to liver transplantation.

PURPOSE OF REVIEW: Orthotopic liver transplantation is currently the best curative treatment for hepatocellular carcinoma within conventional Milan criteria. Recent data have suggested that modest expansion of tumor size limits could still preserve acceptable long-term recurrence-free survival. Down-staging of hepatocellular carcinoma initially exceeding conventional criteria for transplantation provides a unique perspective on tumor biology in that those with more favorable tumor biology are more likely to be successfully down-staged and do well after transplantation. This article reviews the principles and published data on down-staging of hepatocellular carcinoma prior to orthotopic liver transplantation. RECENT FINDINGS: Several groups have examined the use of loco-regional therapy such as chemoembolization and radiofrequency ablation for tumor down-staging before Orthotopic liver transplantation. According to the latest results from the University of California, San Francisco involving 61 patients with hepatocellular carcinoma exceeding Milan criteria but meeting specific criteria for tumor size and number, 70% were successfully down-staged to within Milan criteria by an intention-to-treat analysis, with no posttransplant recurrence and a 4-year posttransplant survival of 92%. SUMMARY: Strictly defined upper limits of tumor size and number for patient inclusion, as well as criteria for response to loco-regional therapy, are essential in achieving excellent posttransplant outcome following tumor down-staging.

Preoperative evaluation of patients with liver disease.

Patients with end-stage liver disease often undergo surgery for indications other than liver transplantation. These patients have an increased risk of morbidity and mortality that is related to their underlying liver disease. Assessments of surgical risk provide a basis for discussion of risks and benefits, treatment decision making, and for optimal management of patients for whom surgery is planned. The most useful indicators of surgical risk are indices that predict advanced disease, such as the Child-Turcotte-Pugh score, or those that predict prognosis, such as the Model for End-stage Liver Disease score. Careful preoperative risk assessment, patient selection, and management of various manifestations of advanced disease might decrease morbidity and mortality from nontransplant surgery in patients with liver disease.

Case report: fulminant hepatic failure involving duloxetine hydrochloride.

BACKGROUND AND AIMS: Duloxetine hydrochloride was approved by the Food and Drug Administration in August 2004 for the treatment of major depressive disorder and diabetic peripheral neuropathic pain. Initial product labeling contained a precaution regarding the risk for increases in liver function test results. Recently, postmarketing research has revealed episodes of cholestatic jaundice and increases in transaminase levels to greater than 20 times normal in patients with chronic liver disease. METHODS: In this case report, we describe a patient with non-Hodgkin's lymphoma in remission and depression treated with duloxetine and mirtazapine. RESULTS: Approximately 6 weeks after increasing her duloxetine dose from 30 to 60 mg daily, she became jaundiced and presented with fulminant hepatic failure. Liver function tests immediately before initiating duloxetine were not available, although the patient carried no prior history of chronic liver disease. A complete work-up for alternate causes failed to reveal another explanation for the patient's clinical presentation. A liver biopsy examination showed histologic changes of subacute injury and the patient's clinical course was consistent with drug-induced liver injury. Despite aggressive measures, the patient's condition deteriorated and the decision was made to withdraw care. CONCLUSIONS: This report shows a case of fulminant hepatic failure and death involving duloxetine use. Given recent reports of severe hepatotoxicity associated with the use of duloxetine in patients with pre-existing liver disease, further investigation into the safety of this compound is warranted.

The use of selected nutrition supplements and complementary and alternative medicine in liver disease.

Almost all patients with liver disease, especially advanced liver disease, have some evidence of malnutrition, including mineral/vitamin deficiency. A major health trend in the United States has been the significant growth in the use of complementary and alternative medicine (CAM), including nutrition supplements and herbal agents. In the 1990s, the United States government created the National Center for Complementary and Alternative Medicine (NCCAM), as well as the Office on Dietary Supplements, to extend our knowledge in these areas. CAM users are often highly educated and frequently use CAM therapy for chronic diseases, including chronic liver disease. Indeed, most studies suggest that patients with chronic liver disease frequently use nutrition supplements and CAM agents in addition to their traditional medicines. The purpose of this review is to provide an update on the role of nutrition supplements and herbals in liver disease. This article will focus mainly on 7 selected agents (vitamin E, zinc, magnesium, S-adenosylmethionine, betaine, silymarin, and glycyrrhizin), for which there have been not only in vitro and animal studies but also human clinical trials, and we will review both potential efficacy and safety issues.