Efficiency of Double Plasma Molecular Absorption System on the Acute Severe Cholestatic Hepatitis.

BACKGROUND: Cholestasis may lead to hepatic cirrhosis and a longer hospital stay. A part of the patients with cholestasis requires liver transplantation. However, most of the treatment efficiency of cholestatic hepatitis (CH) is not satisfactory. For the patients with severe CH after artificial liver support, there was a lack of systemic evaluation on the treatment efficiency of double plasma molecular absorption system (DPMAS) for acute severe CH. OBJECTIVE: We aim to investigate the treatment efficiency of DPMAS on acute severe CH. METHODS: This retrospective study involved 309 cases diagnosed with acute severe CH admitted to the First Affiliated Hospital, Zhejiang University. We compared the prognosis of patients received standard medical therapy (SMT) and SMT + DPMAS. Besides, the effects of DPMAS on total bilirubin (TBIL) and prothrombin time (PT) were investigated. RESULTS: DPMAS could significantly reduce the requirements for liver transplantation in the CH patients. After DPMAS therapy, significant decline was noticed in the TBIL, direct bilirubin (DBIL), total bile acid, and cholesterol. The baseline ratio of neutrophil showed significant elevation in the patients received 4 or more DPMAS compared with those received less DPMAS. CONCLUSIONS: DPMAS could significantly eliminate the necessity of liver transplantation. The artificial liver support system should be conducted to bring down the bilirubin level and the ratio of cases with severe conditions. In general, DPMAS should be preferred as an artificial liver support therapy for the patients with acute severe CH.

Ductular reaction and hepatocyte ballooning identify patients with fibrosing cholestatic hepatitits after liver transplantation.

INTRODUCTION: Diagnosis of severe hepatitis C recurrence is based on analytical and histological criteria but there is little information about their correlation. AIM: To assess the accuracy of laboratory criteria for the diagnosis of fibrosing cholestatic hepatitis (FCH). PATIENTS AND METHODS: Retrospective analysis of prospectively collected data form HCV positive patients who underwent liver transplantation (LT) between 2000 and 2014 in two European university hospitals. Patients were classified according to laboratory criteria such as FCH, cholestatic hepatitis (CH) and non-cholestatic acute hepatitis (NCAH). Histological characteristics were also evaluated. RESULTS: Seventy patients with acute HCV recurrence within the first year after LT with an available liver biopsy were included in the study. Most patients were male (70%) with a median age of 58 years (50-64) and infected with genotype 1b (71.4%). Median time from LT to diagnosis of recurrence was 2.96 months (2.1-5.3). Thirty-nine patients were classified as FCH, 21 as CH and 10 as NCAH. Marked hepatocyte ballooning and ductular reaction were associated with the presence of FCH with an OR of 4.66 (p=0.047) and 20.58 (p=0.025), respectively. Considering liver biopsy as the gold standard, the sensitivity, specificity, positive and negative predictive values of the analytical criteria were 0.8, 0.5, 0.3 and 0.9, respectively. However, correlation between histological and analytical criteria was poor (k=0.033). DISCUSSION: Analytical criteria may be used to rule out the presence of FCH, but a biopsy is mandatory to confirm the diagnosis. Ductular reaction and hepatocyte ballooning were independent predictors of FCH.

Hepatitis C virus intrinsic molecular determinants may contribute to the development of cholestatic hepatitis after liver transplantation.

Cholestatic hepatitis C (CHC) is a severe form of hepatitis C virus (HCV) infection recurrence that leads to high graft loss rates early after liver transplantation (LT). To investigate the pathogenic mechanisms of CHC, we analysed HCV quasispecies in CHC patients compared to a control group (mild hepatitis C recurrence) by deep pyrosequencing. At the time of LT, NS5B quasispecies complexity was similar between the two groups but, after LT, it decreased more sharply in CHC patients than in the control group. Interestingly, the major variant before LT propagated efficiently and remained as the dominant sequence after LT in 62 % of CHC patients versus 11 % of controls (P=0.031). Sequence analysis of the complete non-structural region in a limited number of patients revealed a potential 12 aa signature specific to the CHC group. These data suggest that intrinsic molecular determinants in the circulating HCV quasispecies may provide a fitness advantage, contributing to the development of CHC.

Evaluation of multikinase inhibitor LDN193189 induced hepatotoxicity in teleost fish Poecilia latipinna.

Currently, scientists show keen interest in the drugs that inhibit multiple kinases, LDN193189, being an example. It combats certain cancers in vitro as well as in vivo, making it a prerequisite for researchers to study the toxic potential of this drug in animal models. As most of the drugs metabolized by liver cause hepatic injury, LDN193189-induced hepatotoxicity was examined using a teleost fish, Poecilia latipinna. As a prelude, calculation of LD50 showed a value of 95.22 mg/kg body weight and three doses were decided based on it for further evaluations. All these groups were tested for antioxidant enzyme levels and were significantly raised for mid- and high-dose group. Similar trend was recorded for ALP, AST, and ALT levels. Furthermore, some key indicators of drug metabolism in liver were tested for their expression in response to LDN193189 treatment. Among these, Cyt-C, CYP3A4, CYP1B1 and CYP1A1 were elevated in mid- and high dose, except CYP21A1, which declined remarkably. Moreover, histological profile of the liver reflected high degree of inflammation due to drug treatment, but this was found only at high dose. In summary, LDN193189, at 2.5 mg/kg body weight, did not cause any adverse hepatotoxicity, rendering it safe for use as an anti-proliferative agent - an activity for which it has already shown promising results in the same animal model. The low-dose group previously studied for its anti-proliferative property showed no adverse effect in liver, whereas the mid- and high dose induced moderate or severe hepatotoxicity in P. latipinna.

Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments.

The Italian compassionate use of sofosbuvir observational cohort study for the treatment of recurrent hepatitis C: clinical and virological outcomes.

Direct antivirals are available for treating recurrent hepatitis C (RHC). This study reported outcomes of 424 patients with METAVIR F3-F4 RHC who were treated for 24 weeks with sofosbuvir/ribavirin and followed for 12 weeks within the Italian sofosbuvir compassionate use program. In 55 patients, daclatasvir or simeprevir were added. Child-Pugh class and model of end stage liver disease (MELD) scores were evaluated at baseline and 36 weeks after the start of therapy. The sustained viral response (SVR) was 86.7% (316/365) in patients who received sofosbuvir/ribavirin and 98.3% (58/59) in patients who received a second antiviral (P < 0.01). In patients treated with sofosbuvir/ribavirin, a significant difference in SVR was observed between patients diagnosed with METAVIR F4 (211/250; 84.4%), METAVIR F3 (95/105; 90.5%) and fibrosing cholestatic hepatitis (10/10; 100%) (P = 0.049). A significant association was found between patients who worsened from Child-Pugh class A and who experienced viral relapse (4/26 vs. 8/189, P = 0.02). In patients with a baseline MELD score <15, a significant association was found between maintaining a final MELD score <15 and the achievement of SVR (187/219 vs. 6/10, P = 0.031). This real-world study indicates that sofosbuvir/ribavirin treatment for 24 weeks was effective, and the achievement of SVR was associated with a reduced probability of developing worsening liver function.

Real-world experience with daclatasvir plus sofosbuvir ± ribavirin for post-liver transplant HCV recurrence and severe liver disease.

Optimizing therapy of post-transplant HCV recurrence remains important, especially in advanced liver disease. We evaluated daclatasvir (DCV) plus sofosbuvir (SOF), with or without ribavirin (RBV), in patients with post-liver transplant recurrence in a real-world European cohort at high risk of decompensation or death within 12 months. Recommended treatment was DCV 60 mg plus SOF 400 mg once daily for 24 weeks; RBV use/shorter treatment duration was at physicians' discretion. Patients (N = 87) were 70% male, 93% white, and mostly infected with HCV genotypes 1b (48%), 1a (32%), or 3 (9%); 37 (43%) had cirrhosis (16 decompensated), five had fibrosing cholestatic hepatitis. Sustained virologic response at post-treatment week 12 (SVR12) was 94% (80/85) in a modified intention-to-treat analysis: 95% (58/61) without RBV and 92% (22/24) with RBV, with no virologic failures. SVR12 was 100% (80/80) in an as-observed analysis excluding five nonvirologic failures. Four patients (5%) discontinued therapy for adverse events (AEs); 16 (18%) experienced serious AEs. One patient died on treatment and five during follow-up. Most AEs were associated with advanced liver disease and unrelated to therapy. No clinically significant drug-drug interactions were observed. DCV + SOF ± RBV was well tolerated and achieved high SVR12 (94%) in patients with post-transplant HCV recurrence, including patients with severe liver disease.

A jaundiced bodybuilder Cholestatic hepatitis as side effect of injectable anabolic-androgenic steroids.

The use of anabolic steroids is prevalent in recreational athletes. This case report describes a young amateur bodybuilder who was referred to our outpatient clinic with jaundice and loss of appetite due to cholestatic hepatitis. Additional tests including a liver biopsy made it likely that the hepatitis was caused by the injectable anabolic steroid trenbolone enanthate. Cholestatic hepatitis may not be limited to the use of oral anabolic-androgenic steroids, as is widely assumed. Therefore, and because of other side effects, the recreational use of all forms of anabolic steroids should be discouraged.

Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease.

BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

Increased hepatic progenitor cell response and ductular reaction in patients with severe recurrent HCV post-liver transplantation.

OBJECTIVES: Post-liver transplant (LT) hepatitis C virus (HCV) patients may develop allograft cirrhosis and rarely fibrosing cholestatic hepatitis (FCH), while others have a stable course. Hepatic progenitor cells (HPC) may be implicated in liver injury and fibrogenesis through ductular reaction (DR). We studied HPC response and DR in three distinct post-LT patterns of HCV: stable recurrence, allograft cirrhosis, and FCH. METHODS: We identified 52 patients with untreated recurrent HCV and longitudinal liver biopsies (20 stable/23 cirrhosis/9 FCH) and eight healthy controls. Archived liver biopsy specimens for three time points (LT; initial recurrence; and clinical outcome) were stained for cytokeratin-7. Manual HPC counts and DR quantification using image analysis were performed. RESULTS: HCV counts and DR at LT did not differ across groups. At initial recurrence, HPC expansion occurred only in patients who developed cirrhosis, while prominent DR was present in those who developed FCH vs. stable and controls (p < 0.05). At outcome biopsies, HPC response and DR were increased in cirrhosis and FCH vs. stable and controls (p < 0.05). HPC response and DR did not differ in stable vs. CONCLUSIONS: These findings suggest that an altered HPC response assessed by cytokeratin-7 stain after LT may predict severity of HCV recurrence.

Hepatic involvement in congenital cytomegalovirus infection - infrequent yet significant.

Congenital cytomegalovirus (cCMV) infection can reside in many organ systems; however, the virus has a particular predilection towards inhabiting the reticuloendothelial system, especially the liver. Specific studies focusing only on hepatic involvement in infants with cCMV are lacking. We report our experience with a large cohort of infants treated in our hospital clinic due to cCMV and hepatic involvement. Hepatic involvement was defined either as hepatitis (elevated alanine transaminases (ALT) >80 units/L without cholestatic disease) or cholestatic disease (elevated ALT >80 units/L combined with direct bilirubin >2 mg/dL). During the study period, 198 infants were diagnosed with symptomatic cCMV in our clinic. Hepatic involvement was observed in 13 infants (6.6%); 7 (3.5%) with hepatitis and 6 (3%) with cholestatic disease. Maternal primary infection with cytomegalovirus during pregnancy was diagnosed in 7 (53.8%) of the 13 infants, nonprimary in 3 (23.1%) and unknown in 3 (23.1%). Among these 13 infants, central nervous system (CNS) involvement was observed in 11 (84.6%) and hearing impairment in 7 (53.8%). Treatment with an antiviral agent was initiated in all cases. Gradual improvement of hepatic enzymes and cholestasis was observed over a prolonged period. We found that the incidence of hepatic involvement in infants with cCMV is much less frequent than previously reported. The hepatic involvement in these infants may manifest in two different ways, and thus, a high index of suspicion and a stepwise approach will help in correctly diagnosing these infants. Antiviral treatment due to CNS involvement is warranted and prognosis is excellent.

Treating fibrosing cholestatic hepatitis C with sofosbuvir and ribavirin: a matched analysis.

BACKGROUND: Fibrosing cholestatic hepatitis (FCH) is an uncommon but potentially fatal complication of recurrent hepatitis C (HCV) in liver transplant recipients. METHODS: We matched the treatment outcomes of 10 liver transplant recipients who developed FCH with those of 10 recipients with recurrent HCV without FCH treated with sofosbuvir and ribavirin. RESULTS: Baseline mean alanine transaminase, aspartate transaminase, alkaline phosphatase, and total bilirubin were 186 U/L, 197 U/L, 243 U/L, and 6.7 mg/dL, respectively, in the FCH recipients and 82 U/L, 60 U/L, 110 U/L, and 0.99 mg/dL, respectively, in non-FCH recipients. The sustained viral response in FCH and non-FCH recipients was 40% and 80%, respectively. One-yr patient and graft survival rates were 90% and 80%, respectively, in FCH recipients, and 100% in non-FCH recipients. Seven FCH and six non-FCH recipients were treated for anemia with blood transfusion and/or erythropoietin growth factors. CONCLUSION: Our results suggest that the use of sofosbuvir and ribavirin is effective and tolerable in liver transplant recipients treated for recurrent FCH. There is a trend of lower sustained viral response, patient survival, and graft survival in the FCH recipients.

Successful treatment of fibrosing cholestatic hepatitis with pegylated interferon, ribavirin and sofosbuvir after a combined kidney-liver transplantation.

Fibrosing cholestatic hepatitis (FCH) is a classical but rare and severe form of recurrent hepatitis C virus (HCV) after liver transplantation. Classical anti-HCV therapy, that is pegylated-interferon (peg-interferon) and ribavirin, has been shown to have limited efficacy in treating FCH. Herein, we report on the first case of successful use of peg-interferon, ribavirin, plus sofosbuvir to treat HCV-induced FCH in a combined liver-kidney transplant patient. Antiviral therapy was given for 24 weeks. HCV clearance occurred within 4 weeks after starting therapy and was maintained until 4 weeks after the end of therapy. Antiviral tolerance was good. We conclude that the use of sofosbuvir-based anti-HCV therapy can be successfully used to treat FCH after a liver or combined kidney-liver transplantation.

Interferon-free antiviral treatment of chronic hepatitis C in the transplant setting.

Interferon-based regimens with first-generation protease inhibitors have a limited efficacy and an unfavorable safety profile. Combination therapies with two or more second-generation direct-acting antivirals plus/minus ribavirin revolutionized treatment strategies in patients chronically infected with hepatitis C virus. In this rapidly evolving era, patients in the transplant setting benefit from interferon-free treatment regimens. Scientific societies can barely keep up with this development, making it necessary to update the clinical guidelines by the American and European Associations for the Study of Liver Diseases within short periods. This review presents and discusses the currently available data of the use of interferon-free treatment in the setting of liver transplantation. However, costs, different reimbursement strategies, and health-care options cannot be answered by guidelines and recommendations from scientific societies. Further investigator-initiated trials are needed to individualize treatment concepts.

Safe and effective treatment with daclatasvir and asunaprevir in a liver transplant recipient with severe cholestatic hepatitis C.

Severe cholestatic hepatitis C (SCH) is a unique variant of recurrent hepatitis C that occurs after liver transplantation. Unfortunately, the prognosis of SCH is poor, and interferon (IFN) therapy has been reported to not improve the prognosis. We herein report a case of progressive SCH with acute cellular rejection (ACR) and bacterial infection, which was successfully treated using IFN-free therapy with daclatasvir and asunaprevir. A 43-year-old man was diagnosed with SCH and mild ACR at day 48 after liver transplantation, and IFN-free therapy with daclatasvir and asunaprevir was started. Although he experienced catheter-related bacteremia on the first day, the IFN-free therapy was safely continued, which immediately caused his liver function to improve. His bilirubin levels decreased from 11.1 to 2.1 mg/dL and serum hepatitis C virus RNA levels became undetectable after 4 weeks of the treatment. This case indicates that IFN-free therapy for progressive SCH with acute cellular rejection and bacterial infection is safe and effective, and may improve the outcomes of hepatitis C virus positive transplant recipients.

Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience.

BACKGROUND & AIMS: Protease inhibitors (PI) with peginterferon/ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge. METHODS: This cohort study included 37 liver transplant recipients (male, 92%, age 57 ± 11 years), treated with boceprevir (n=18) or telaprevir (n=19). The indication for therapy was HCV recurrence (fibrosis stage ≥F2 (n=31, 83%) or fibrosing cholestatic hepatitis (n=6, 16%). RESULTS: Eighteen patients were treatment-naive, five were relapsers and fourteen were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and fifteen tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (p=0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (p=0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (p=0.24). Treatment was discontinued in sixteen patients (treatment failures (n=11), adverse events (n=5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n=34, 92%), treated with erythropoietin and/or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8 ± 1.1-fold and 3.4 ± 1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2 ± 1.5-fold with boceprevir and 23.8±18.2-fold with telaprevir. CONCLUSIONS: Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections require close monitoring.

Uncommon gastrointestinal complications of enteric fever in a non-endemic country.

Enteric fever is a systemic illness with varying presentation. It is an important infectious disease in developing countries and also in industrialized countries where many migrants reside. Enteric fever can result in complications in different organ systems and delay in identification and prompt treatment can be fatal. The important gastrointestinal complications of enteric fever include hepatitis, intestinal ulcers, bleeding and bowel perforation. We report three relatively uncommon complications of enteric fever in Qatar, a non-endemic country, ileal ulcer presenting with hematochezia; duodenal ulcer with polyserositis, cholestatic hepatitis and bone marrow suppression; enteric fever related peritonitis.

Multisystemic Disease in a Child and Successful Recovery With Antiviral Treatment.

Cytomegalovirus (CMV), a member of the Herpesviridae family, typically causes asymptomatic infections or mild mononucleosis-like syndromes in immunocompetent individuals. However, severe manifestations are well-documented in immunocompromised populations. This case report presents a previously healthy seven-year-old girl with a rare and complex presentation of primary CMV infection leading to severe multiorgan involvement, hepatosplenomegaly, cholestasis, bicytopenia, and a prolonged disease course. The patient's condition prompted an exhaustive diagnostic investigation, ruling out other potential causes. The diagnosis was confirmed by positive CMV IgM and IgG antibodies and a significantly elevated CMV DNA viral load. Treatment with intravenous ganciclovir resulted in a remarkable recovery. The case underscores the importance of considering CMV as a potential etiology of hepatitis, even in immunocompetent children, and the challenges of diagnosing complicated CMV infections. While guidelines for treating CMV in immunocompetent individuals are lacking, this report suggests that antiviral therapy may be beneficial in severe cases. Further research is needed to establish clear treatment protocols for such instances. This report contributes to the limited body of literature on severe CMV-induced hepatitis in immunocompetent children, emphasizing the need for heightened clinical awareness and timely interventions to prevent progression to acute liver failure.

Viral Hepatitis B Reactivation With Delayed Cholestatic Effect Secondary to Acalabrutinib.

One significant complication of hepatitis B virus includes reactivation (HBVr) in the context of the use of immunosuppressive agents, such as corticosteroids and rituximab, among others. Limited data exist on the topic of HBVr risk in the context of tyrosine kinase inhibitors for which there is no strong guidance recommendation. We describe the clinical characteristics, diagnostic challenges, and the clinical course of a single patient with recurrent mantle cell lymphoma who developed HBVr after treatment with acalabrutinib, a Bruton tyrosine kinase inhibitor.