Fibrosing Cholestatic Hepatitis Research Articles

Fibrosing cholestatic hepatitis as a variant of the course of hepatotropic viruses’ infection

Fibrosing cholestatic hepatitis is a special variant of infectious hepatitis, with a rapid progressive deterioration of liver function, and usually results in immunosuppression. It has also been reported in patients with immunocompetent status having viral hepatitis B and C. Fibrosing cholestatic hepatitis is diagnosed based on the histological examination of the liver tissue, which reveals severe damage to hepatocytes with pronounced ballooning over a weak inflammatory reaction, pericellular and perisinusoidal fibrosis, and intracellular and tubular cholestases. Analysis of the literature confirms the authors’ assumption that pathological changes in the liver, described as fibrosing cholestatic hepatitis, can develop in different conditions under the influence of various infectious agents. Despite the availability of effective antiviral therapy for hepatitis B and C, the outcomes of fibrosing cholestatic hepatitis are often unfavorable, particularly in cases not associated with solid-organ transplantation. Currently, because of the emergence of numerous drugs that selectively act on the immune system and the development of new areas of medicine such as hematology, rheumatology, oncology, transplantology, and infectious diseases, doctors in these specialties increasingly encounter severe liver damage in patients receiving specific therapy. The authors believe that doctors who do not work at liver transplantation centers underestimate the possibility of fibrosing cholestatic hepatitis development in patients with viral hepatitis B and C, in the clinic of infectious and internal diseases.

Hepatitis C viremic lung transplantation to aviremic recipients: Comprehensive outcomes and post-transplant viremia.

Direct-acting antiviral (DAA) therapy has revolutionized solid organ transplantation by providing an opportunity to utilize organs from HCV-viremic donors. Though transplantation of HCV-viremic donor organs into aviremic recipients is safe in the short term, midterm data on survival and post-transplant complications is lacking. We provide a midterm assessment of complications of lung transplantation (LT) up to 2 years post-transplant, including patient and graft survival between HCV-viremic transplantation (D+) and HCV-aviremic transplantation (D-). This is a retrospective cohort study including 500 patients from 2018 to 2022 who underwent LT at our quaternary care institution. Outcomes of patients receiving D+ grafts were compared to those receiving D- grafts. Recipients of HCV antibody+ but PCR- grafts were treated as D- recipients. We identified 470 D- and 30 D+ patients meeting inclusion criteria. Crude mortality did not differ between groups (p=.43). Patient survival at years 1 and 2 did not differ between D+ and D- patients (p=.89, p=.87, respectively), and graft survival at years 1 and 2 did not differ between the two groups (p=.90, p=.88, respectively). No extrahepatic manifestations or fibrosing cholestatic hepatitis (FCH) occurred among D+ recipients. D+ and D- patients had similar rates of post-transplant chronic lung allograft rejection (CLAD) (p=6.7%vs. 12.8%, p=.3), acute cellular rejection (60.0%vs. 58.0%, p=.8) and antibody-mediated rejection (16.7%vs. 14.2%, p=.7). There is no difference in midterm patient or graft survival between D+ and D-LT. No extrahepatic manifestations of HCV occurred. No differences in any type of rejection including CLAD were observed, though follow-up for CLAD was limited. These results provide additional support for the use of HCV-viremic organs in selected recipients in LT.

HCV eradication does not protect from fibrosis progression in patients with fibrosing cholestatic hepatitis after liver transplantation

IntroductionHepatitis C virus (HCV) may recur after liver transplantation (LT) in the severe form of fibrosing cholestatic hepatitis (FCH). The prognosis dramatically improved by the use of direct acting antivirals (DAAs). The aim of the present study was to describe the change in histological features of FCH after virological eradication. MethodsFrom the ANRS CUPILT cohort we included 17 patients who presented FCH and at least two graft biopsies, one before DAA-treatment and one after. A single expert pathologist, blinded for clinical outcome, retrospectively confirmed the diagnosis of FCH and progression of fibrosis. ResultsDiagnosis of FCH was made after a median [IQR] 6.0 [3.1–11.8] months after LT, and the median interval between diagnosis and onset of treatment was 1.2 [0.7–6.1] months. The rate of viral eradication was 94.1%. The median delay between the pre-treatment and the treatment biopsies was 12.5 [11.1–20.0] months. Between the end of treatment and the second biopsy, the delay was 5.3 [0.6–7.4] months. Fibrosis stage worsened in 10 patients (58.8%); 6 patients had cirrhosis (35.3%). Chronic rejection appeared in 4 (23.5%) patients. ConclusionOur results suggest that, despite viral eradication in patients presenting FCH after LT, fibrosis progression was observed in half of patients. This should encourage monitoring fibrosis progression despite HCV cure.

Ultrashort Duration Prophylaxis for Hepatitis C Donor Positive to Recipient Negative Simultaneous Kidney/Pancreas Transplants.

Recent clinical trials have successfully used a strategy of hepatitis C virus (HCV) D+ (donor nucleic acid test [NAT] positive)/R– (recipient NAT negative) kidney and/or pancreas transplants followed by 8 to 12 wk of pangenotypic direct-acting antiviral (DAA) therapy.1,2 Translating these trials into real-world practice has revealed limitations. One concern is a delay in timely access to DAAs for these newly transplanted immunosuppressed patients. This early HCV viremia has been associated with abnormal liver function, acute fibrosing cholestatic hepatitis, and development of de novo donor-specific antibodies.3,4 Utilization of abbreviated regimens may obviate the need for insurance approval and delay in therapy. We have previously shown a low transmission rate of 4% with a prophylactic perioperative 7-d DAA regimen ( ±ezetimibe) for “kidney-only” transplants.5 Ezetimibe, a cholesterol-lowering drug, was used, as it has been shown to restrict HCV entry in hepatocytes in a humanized mouse model.6 Here, we present our early experience using the same strategy for simultaneous kidney/pancreas transplants (SKPT), where the risk of transmission is conceivably higher because of a cumulative higher HCV load delivered with dual-organ transplantation. Data were collected via an ethics board-approved prospective registry (REgistry for the study of ORgan transplants froM HEPatitis C infected donors)5 with informed consent for all participants. Of 12 eligible SKPT candidates, 10 (83%) agreed to accept HCV NAT+ SKPT offers. Inclusion criteria included (1) a de novo transplant; (2) a calculated panel reactive antibody ≤50%; (3) an absence of synthetic liver dysfunction; and (4) an absence of HIV, HCV, and hepatitis B. The primary outcome was donor HCV transmission at 90 d posttransplant. Secondary outcomes included posttransplant organ function, development of de novo donor-specific antibodies, and acute rejection. Patients were screened with HCV NAT at day 7, 14, 28, and 90 posttransplant. All subjects received an initial dose of sofosbuvir/velpatasvir (SOF/VEL) with ezetimibe on day 0 ≤6 h before transplant and then daily for a total of 7 d. Proton pump inhibitors were not initiated early posttransplant to avoid a known drug–drug interaction and reduced absorption of SOF/VEL. Immunosuppression included induction with rabbit antithymocyte globulin followed by maintenance tacrolimus, mycophenolate, and steroids. The protocol mandated initiation of full-course DAA therapy in the case of 2 consecutive positive NATs. Of the 10 candidates, 4 received HCV NAT+ SKPT at a median of 4.7 mo post consent. Summary characteristics of these 4 patients are presented in Table 1. All patients had immediate graft functions of both transplanted organs. At a median follow-up of 7 mo posttransplant, all patients maintained excellent graft functions. All subjects remained negative for HCV at all monitored time points, including at 90 d posttransplant, resulting in an HCV transmission rate of 0%. One patient had acute kidney injury because of biopsy-proven thrombotic microangiopathy at 1 mo posttransplant that improved with conversion of tacrolimus to belatacept. No other major adverse events were recorded at the most recent follow-up. TABLE 1. - Selected donor and recipient characteristics of study cohort Recipient characteristics Variable N 4 Age (y, mean ± SD) 41 ± 13 Male sex 3 (75%) African American race 2 (50%) Blood type A 1 (25%) B 1 (25%) O 2 (50%) Median total wait time (mo, range) 5.3 (4–31) Postenrollment wait time (mo, range) 4.7 (3.6–5.8) Cold ischemia time (h, mean ± SD) 9 ± 1 Donor characteristics Donor age (y, mean, mean ± SD) 27 ± 1 Donor KDPI (%, mean ± SD) 28 ± 9 Donor corrected KDPIa (%, mean ± SD) 7 ± 6 Donor terminal creatinine (mg/dL, mean ± SD) 1.0 ± 0.1 Selected outcomes Delayed graft function 0 (0%) Time of follow-up (mo, range) 7.3 (4.4–10.7) ALT at 3 mo posttransplant (IU/L, mean ± SD) 67 ± 22 Lipase at 3 mo posttransplant (U/L, mean ± SD) 15 ± 11 GFR at 3 mo posttransplant (mean ± SD) 77 ± 25 Most recent GFR (mean ± SD) 87 ± 14 Acute rejection 0 (0%) De novo donor-specific antibody at 3 mo posttransplant 0 (0%) aKDPI recalculated after exclusion of hepatitis C as a contributing factor.ALT, alanine aminotransferase; GFR, glomerular filtration rate (mL/min/1.73 m2); KDPI, Kidney Donor Profile Index. This early experience suggests that ultrashort duration 7-d perioperative DAA prophylaxis with SOF/VEL can be successfully used for patients with SKPT. These data are limited by a small sample size, a single-center design, and an absence of donor virological data.

Liver Tumor Post Liver Transplantation for Hepatitis C Cirrhosis: An Unusual Cause

Question: A 60-year-old African American man with a history of hepatitis C virus (HCV) cirrhosis underwent orthotopic liver transplantation in 2009. The explant showed chronic HCV with mild activity and cirrhosis (grade 2, stage 4) without evidence of malignancy. The post-transplant course was complicated by recurrent HCV treated 5 years later with simeprevir and sofosbuvir with a sustained viral response. However, the patient developed fibrosing cholestatic hepatitis with rapid progression to fibrosis and portal hypertension demonstrated by small varices and ascites. A liver biopsy in August 2010 revealed mild to moderated inflammatory activity and incipient bridging fibrosis grades 2–3, stages 2–3. Due to worsening renal function and new-onset proteinuria, the dose of the calcineurin inhibitor was reduced and mycophenolate mofetil was added. He was lost to follow-up from 2014 to 2016. Magnetic resonance imaging in February 2017 for screening showed numerous masses in the liver with arterial enhancement and incomplete but progressive washout, some with an enhancing capsule (Figure A–C). At the time, his laboratory tests showed excellent graft function. What is the diagnosis and strategy for treatment? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. Given the history of HCV infection and transplantation, there was concern for hepatocellular carcinoma. An ultrasound-guided core biopsy showed a vascular tumor positive for CD34 and negative for pancytokeratin and CK7, consistent with epithelioid hemangioendothelioma (HEHE) (Figure D-F). Low-power image on with hematoxylin and eosin staining (Figure D) shows upper core with normal liver, and lower core with replacement by vascular lesion (black arrow) with hemorrhage (thick black arrows). Figure E shows high power image with multiple diminutive vascular channels replacing liver parenchyma (black arrowheads), and Figure F with vascular channels replacing liver parenchyma on CD34 stain (black arrows). Figures A-C demonstrate HEHE lesions as target shaped lesion on a T1-weighted volumetric interpolated breath-hold examination sequence (Figure A), with largest lesion in a postcontrast sequence (Figure B), and multiple lesions seen on venous phase sequence (Figure C). Retransplantation was considered; however, given the indolent nature of the lesions, he was referred to oncology and interventional radiology for treatment. He did not make those appointments, and the latest blood tests in August 2020 showed stable graft function with no decompensation. He developed dementia and has not been able to follow-up with further imaging. HEHE was first described in 1984 and is a rare indolent malignant tumor with unclear etiology with vague presentations including abdominal discomfort, nausea, and vomitting.1Ishak K.G. Sesterhenn I.A. Goodman M.Z.D. et al.Epithelioid hemangioendothelioma of the liver: A clinicopathologic and follow-up study of 32 cases.Hum Pathol. 1984; 15: 839-852Crossref PubMed Scopus (382) Google Scholar HEHE rarely involves the vasculature, causing Budd–Chiari Syndrome, veno-occlusive disease, and portal hypertension. At diagnosis, extrahepatic involvement is reported in 36.6% of patients involving lungs, regional lymph nodes, and peritoneum.2Mehrabi A. Kashfi A. Fonouni H. et al.Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy.Cancer. 2006; 107: 2108-2121Crossref PubMed Scopus (343) Google Scholar Although the etiology is unknown, reported associations include oral contraceptive use, alcohol consumption, liver trauma, sarcoidosis, Crohn’s disease, viral hepatitis, and vinyl chloride or asbestos exposure.2Mehrabi A. Kashfi A. Fonouni H. et al.Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy.Cancer. 2006; 107: 2108-2121Crossref PubMed Scopus (343) Google Scholar Treatment options include a combination of liver resection, transarterial chemoembolization, liver transplantation, and the possible addition of chemotherapy.2Mehrabi A. Kashfi A. Fonouni H. et al.Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy.Cancer. 2006; 107: 2108-2121Crossref PubMed Scopus (343) Google Scholar,3Brahmbhatt M. Prenner S. Bittermann T. Liver transplantation for hepatic epithelioid hemangioendothelioma is facilitated by exception points with acceptable long-term outcomes.Transplantation. 2020; 104: 1187-1192Crossref PubMed Scopus (13) Google Scholar HEHE should be considered in the differential diagnosis of de novo liver masses after liver transplantation.

The Impact of Treatment Delay on Hepatitis C Liver Transplant Outcomes

Background: Direct-acting antivirals for the treatment of hepatitis C virus (HCV) have improved outcomes in liver transplant recipients (LTRs). However, the timing of HCV treatment and approach to treating rejection have not been well described. Additionally, pharmacists’ roles in these comprehensive areas have not been investigated. Methods: This single-center, retrospective, cohort review compared 1-year graft and patient survival between HCV-positive and HCV-negative LTRs. Secondary endpoints included 1-year rejection rates, HCV sustained virologic response and time to HCV treatment. Results: Ninety-two HCV Nucleic Acid Amplification Test (NAT)-positive LTRs were matched 1:1 to HCV-seronegative LTRs. One-year graft and patient survival were similar between groups. HCV-positive LTRs were more likely to experience biopsy-proven acute rejection (BPAR), and despite treatment with pulse steroids, there was no impact on graft survival or occurrence of fibrosing cholestatic hepatitis (FCH). Time to HCV treatment was 5.4–6.4 months post-transplant, with no treatment failures or impact on graft or patient survival. Conclusions: No difference was seen in graft survival at 1 year between HCV-positive and HCV-seronegative LTRs. Delayed time to treatment of HCV and treatment of rejections in the HCV-positive cohort did not impact outcomes. However, pharmacist-driven protocols could ensure more efficient initiation of HCV treatment in the future.

Systematic review: hepatitis C viraemic allografts to hepatitis C-negative recipients in solid organ transplantation.

Given the success of direct-acting antivirals (DAAs) in treating hepatitis C (HCV), interest is growing in utilizing solid organs from allografts with active HCV to expand donor availability. To review post-transplant outcomes and patient survival in HCV-negative recipients receiving solid organ transplants (SOT) from viraemic, that is, HCV+/NAT+ (nucleic acid testing) allografts. A literature search was conducted on PubMed and EMBASE from 01/01/2007 to 4/17/2021 for articles matching eligibility criteria. Two authors independently screened titles and abstracts. Disagreements were solved by a third independent reviewer. Methodological quality assessment was done using a modified Newcastle-Ottawa scale (NOS). Data synthesis was done qualitatively using median, ranges and percentages. Thirty-five studies were included (or 852 SOTs): 343 kidney, 233 heart, 204 liver, and 72 lung transplants from viraemic allografts. Of the recipients eligible for sustained virological response at 12weeks (SVR12) calculation, 100% achieved cure from HCV. No deaths/graft failures were reported to be related to HCV transmission. Seven SOT recipients had viral relapse, with all seven patients treated successfully. Four patients developed fibrosing cholestatic hepatitis with complete resolution post-treatment. Transplanting viraemic organs into uninfected individuals can become the standard of care for patients who do not have contraindications to DAAs.

Outcomes of hepatitis C virus nucleic acid testing positive donors in aviremic recipients with delayed direct-acting antiviral initiation.

The use of allografts from hepatitis C virus (HCV) Nucleic Acid Testing (NAT)+ donors into HCV NAT- recipients has been reported to be efficacious in a handful of studies. However, these studies have not reflected real-world practice where the initiation of direct-acting antivirals (DAA) is dependent on insurance coverage. A single-center, retrospective chart review of HCV NAT- recipients who underwent solid organ transplantation (SOT) from a HCV NAT+ donor between April 1, 2019 and May 27, 2020 was conducted. Sixty-one HCV NAT- patients underwent SOT with a HCV NAT+ organ, with 59 transplant recipients included for evaluation: 22 kidney (KT), 18 liver (LiT), 10 heart (HT), nine lung (LuT). HCV transmission occurred in 100% of recipients. Average time to DAA initiation was POD 46.3 ± 25 days. SVR12 was achieved in 98% (56/57; two patients ineligible for analysis). Treatment failure occurred in one LuT on glecaprevir/pibrentasvir with P32del and Q80K mutations. No patients developed fibrosing cholestatic hepatitis. Two patients died, secondary to anastomotic complication (LuT) and pulmonary embolism (HT). Clinically significant rejection was diagnosed and treated in two HT (one patient with ACR2 and one with ACR2/pAMR2) and one LiT (RAI 5/9). Six patients (10.2%) had documented adverse effects attributed to DAA therapy, primarily gastrointestinal.

Updated View on Kidney Transplant from HCV-Infected Donors and DAAs.

Background: The discrepancy between the number of potential available kidneys and the number of patients listed for kidney transplant continues to widen all over the world. The transplant of kidneys from hepatitis C virus (HCV)-infected donors into HCV naïve recipients has grown recently because of persistent kidney shortage and the availability of direct-acting antiviral agents. This strategy has the potential to reduce both waiting times for transplant and the risk of mortality in dialysis. Aim: We made an extensive review of the scientific literature in order to review the efficacy and safety of kidney transplant from HCV-viremic donors into HCV naïve recipients who received early antiviral therapy with direct-acting antiviral agents (DAAs). Results: Evidence has been rapidly accumulated on this topic and some reports have been published (n = 11 studies, n = 201 patients) over the last three years. Various combinations of DAAs were administered—elbasvir/grazoprevir (n = 38), glecaprevir/pibrentasvir (n = 110), and sofosbuvir-based regimens (n = 53). DAAs were initiated in a range between a few hours before renal transplant (RT) to a median of 76 days after RT. The sustained virological response (SVR) rate was between 97.5% and 100%. A few severe adverse events (SAEs) were noted including fibrosing cholestatic hepatitis (n = 3), raised serum aminotransferase levels (n = 11), and acute rejection (n = 7). It remains unclear whether the AEs were related to the transmission of HCV, the use of DAAs, or kidney transplant per se. It appears that the frequency of AEs was greater in those studies where DAAs were not given in the very early post-kidney transplant phase. Conclusions: The evidence gathered to date encourages the expansion of the kidney donor pool with the adoption of HCV-infected donor organs. We suggest that kidney transplants from HCV-viremic kidneys into HCV-uninfected recipients should be made in the context of research protocols. Many of the studies reported above were externally funded and we need research generating “real-world” evidence. The recent availability of pangenotypic combinations of DAAs, which can be given even in patients with eGFR < 30/min/1.73 m2, will promote the notion that HCV-viremic donors are a significant resource for kidney transplant.

Impact of Transplanting Hepatitis C Nucleic Acid Testing Positive (NAT+) Donors to Hepatitis C Virus NAT- Cardiothoracic Recipients

<h3>Purpose</h3> The purpose of this study is to assess the clinical impact of utilizing HCV NAT+ donors in aviremic heart (HT) and lung (LT) transplant recipients. <h3>Methods</h3> A single-center, retrospective chart review was conducted on patients who received a HT or LT between 4/1/19-5/27/20. HCV antibody - and NAT- recipients of a HCV NAT+ graft were included in the analysis. <h3>Results</h3> Nineteen HCV NAT- patients underwent cardiothoracic transplantation (CT) with a HCV NAT+ organ (10 HT and 9 LT) and were included for evaluation; 47.4% male, average age 58 ± 7.9 years, 73.7% white. HCV transmission occurred in 100% of recipients. Average time to direct acting antiviral (DAA) initiation was 46 ± 20.7 days after transplant. SVR12 was achieved in 93.3% (14/15; 4 patients have not completed 12-week follow up post DAA completion). Treatment failure occurred in 1 LT patient with P32del mutation on glecaprevir/pibrentasvir, requiring alternative therapy (sofosbuvir/velpatasvir/voxilaprevir and ribavirin). 84.2% of patients developed post-transplant liver dysfunction. No patients developed fibrosing cholestatic hepatitis. Two patients died, 1 due to anastomotic complication (LT) and 1 due to pulmonary embolism (HT). De novo donor specific antibodies were present in 1 HT and 2 LT recipients, developing 4 days and a median of 137.5 (56-219) days post-transplant, respectively. Clinically significant rejection was identified and treated in 1 HT patient (ACR2). No episodes of rejection were identified in LT recipients. Five patients (26.3%) had documented DAA related adverse effects, including gastrointestinal, fatigue, orthostatic hypotension, and nail discoloration. <h3>Conclusion</h3> A high SVR12 rate was achieved in HCV NAT donor +/recipient - CT, who were initiated on DAA therapy after insurance approval. These results are reflective of real-word experience for patients not included in clinical trials. Few reported clinically significant episodes of rejection or DAA adverse effects occurred.

S2599 Successful Treatment of Fibrosing Cholestatic Hepatitis With Sofosbuvir and Velpatasvir in an Immunocompromised Patient After Chemotherapy for Diffuse Large B-Cell Lymphoma With Concurrent HIV and Hepatitis C

S2599 Successful Treatment of Fibrosing Cholestatic Hepatitis With Sofosbuvir and Velpatasvir in an Immunocompromised Patient After Chemotherapy for Diffuse Large B-Cell Lymphoma With Concurrent HIV and Hepatitis C

Should My Patient Accept a Kidney from a Hepatitis C Virus-Infected Donor?

The availability of direct-acting antiviral (DAA) agents that reliably offer cure rates exceeding 95% for patients with CKD and patients with ESKD infected with hepatitis C virus (HCV) (1) has had a significant effect on the retrieval and allocation of kidneys from HCV-infected donors. Presented with increasing numbers of kidney offers from viremic donors, the transplant community has studied the feasibility of using these kidneys in an effort to increase access to kidney transplantation. Many transplant centers are now routinely performing transplants from HCV-viremic donors into HCV-positive recipients and initiating DAA treatment early after transplantation with excellent outcomes (2,3). This approach has translated into shorter waitlist times, increased access to transplantation, and a potential decrease in long-term morbidity and mortality for this patient population (2⇓⇓–5). In the context of studies demonstrating the safety and efficacy of the DAAs in kidney recipients (2,3,6,7), there has been increased interest in transplanting kidneys from HCV-positive donors into uninfected recipients. Agreeing to accept a kidney from a Public Health Service increased risk, HCV-infected donor requires informed consent at the time of listing, and in this context, many patients are being presented with this option and often seek advice and recommendations from their nephrologist. Understanding the pertinent literature on this topic will enable the nephrologist to actively participate in this decision and offer valuable guidance. Following the discovery of HCV and the availability of an ELISA to identify anti-HCV antibody, many cases of transmission of HCV with kidney transplantation were reported (8,9). Adverse consequences of transmission at the time of transplantation with resulting de novo HCV infection in the setting of intense immunosuppression included an aggressive form of fibrosing cholestatic hepatitis (FCH) and an immune complex injury to the allograft resembling …

2278 Rapidly Progressive Hepatitis C After Liver Transplantation Treated With Glecaprevir/Pibrentasvir

INTRODUCTION: Hepatitis C recurrence following liver transplantation occurs in all patients with chronic HCV infection who have detectable serum HCV RNA levels prior to transplant. Less than 10% of these patients develop an acute and severe phenotype called fibrosing cholestatic hepatitis, which often involves fibrosis, rapid graft loss and decreased survival. The introduction of direct-acting antiviral agents (DAAs) have changed the paradigm of treatment of these patients. CASE DESCRIPTION/METHODS: A 62-year-old woman with a medical history of hepatitis C infection, hepatocellular carcinoma status post orthotropic liver transplantation, diabetes mellitus and hypertension who was hospitalized for fatigue and elevated liver chemistries following her liver transplantation. Laboratory tests showed a white cell count 6.67 × 103/μL, creatinine 1.1 mg/dL, aspartate aminotransferase 592 U/L, alanine aminotransferase 504U/L, alkaline phosphatase 312 U/L, bilirubin 3.5 mg/dL, albumin 2.9 g/dL. Acute hepatitis work up showed a positive hepatitis C virus antibodies with genotype 1B, with a viral load of 80 million IU/mL HCV RNA. HBsAg, HBc IgG, HBc IgM, and hepatitis A virus IgM were negative. Evaluation for Epstein-Barr virus, cytomegalovirus and herpes simplex virus were negative. Ultrasound of the abdomen revealed that the liver is normal in size, echotexture and contours. No focal hepatic lesions. Normal hepatic blood flow. The patient underwent liver biopsy that showed lymphocytic portal inflammation with frequent lobular apoptosis consistent with active chronic hepatitis C (MHAI: 5-6/18). Mild portal fibrosis (ISHAK FIBROSIS STAGE: 1/6) and minimal evidence of acute t cell-mediated rejection (rejection activity index: 1/9). During the patient hospitalization her liver chemistries significantly worsened and peaked to aspartate aminotransferase 740 U/L, alanine aminotransferase 511U/L, alkaline phosphatase 312 U/L, bilirubin 3.5 mg/dL. We decided to start the patient on Glecaprevir/Pibrentasvir for acute and severe hepatitis. Fourteen days after starting Glecaprevir/Pibrentasvir, the patient viral load decreased to 782 IU/mL HCV RNA and normalized liver chemistries with AST19 and ALT 27. The patient denied any adverse events due to the treatment. DISCUSSION: To our knowledge, this is the first case report of treating early and aggressive form of HCV recurrence with Glecaprevir/Pibrentasvir. The dramatic improvement of the patient suggest that DAA might be safe and effective in this situation.

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

IntroductionDiagnosis of severe hepatitis C recurrence is based on analytical and histological criteria but there is little information about their correlation. AimTo assess the accuracy of laboratory criteria for the diagnosis of fibrosing cholestatic hepatitis (FCH). Patients and methodsRetrospective 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. ResultsSeventy 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). DiscussionAnalytical 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 B virus preS/S gene mutations and their clinical implications

Hepatitis B virus (HBV) infection remains a major health problem worldwide. HBV is one of the smallest enveloped DNA viruses, and also one of the principal pathogens causing acute and chronic hepatitis. Hepatitis B surface antigen (HBsAg) is a hallmark for the diagnosis of HBV infection, and the quantification of serum HBsAg is regarded as a reliable marker of disease progression and predictor of the outcome. However, the mutations in the preS/S genomic region can occur in HBV DNA sequences from the patients with chronic HBV infection, including genetic recombination, base pair deletion, and point mutations. These variants carrying the modified surface antigen may induce immune escape or occult HBV infection (OBI). Furthermore, the preS/S variants may be the cause of fulminant hepatitis (FH) and fibrosing cholestatic hepatitis (FCH). The mutations in the preS/S region would increase the difficulty of preventing and treatment of HBV infection. In this review, we summarized the prevalence of the mutations in the preS/S region and their effect for the diagnosis or progression of HBV infection.

Successful Treatment of Fibrosing Cholestatic Hepatitis in a HIV-HCV Coinfected Patient, in the Absence of Liver Transplantation

Successful Treatment of Fibrosing Cholestatic Hepatitis in a HIV-HCV Coinfected Patient, in the Absence of Liver Transplantation

Long-term Survival After Successful Use of Dose-Adjusted Sofosbuvir and Ribavirin for Treatment of Fibrosing Cholestatic Hepatitis C With Severe Renal Impairment After Liver Transplantation

Long-term Survival After Successful Use of Dose-Adjusted Sofosbuvir and Ribavirin for Treatment of Fibrosing Cholestatic Hepatitis C With Severe Renal Impairment After Liver Transplantation

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.

Retrospective analysis of post-transplant liver biopsies – From diagnosis to therapy – Can we guide further? Experience from a tertiary care center in India

Background and Aim: Post-transplant liver biopsies form a critical part of management of complications arising post-transplant. The objective of this study was to analyze the Indian experience in pathologic diagnosis of liver biopsies after orthotopic liver transplantation (OLT) with special emphasis on cases presenting with intrahepatic cholestasis (IHC). Type, incidence, and timing of major complications were analyzed. All cases with IHC were retrospectively analyzed with clinical inputs to look for cryptic clues in subclassifying such cases. Materials and Methods: Forty-five post-transplant liver biopsies from 39 OLT patients were retrospectively analyzed from May 2015 to May 2016. All biopsies were stained with hematoxylin and eosin and Masson's Trichrome, and other stains were performed as required. Results: The number of liver biopsies performed for each patient ranged from 1 to 3. The timing of these biopsies varied from 5 days to >4 years post-transplant. Of the 39 patients who underwent post-transplant liver biopsies, most common etiology of a liver transplant was hepatitis C virus (HCV)-related chronic liver disease in 66.6% cases. The common complications post-transplant were acute cellular rejection (ACR) (33.3%), biliary stricture (13.3%), HCV recurrence (11.1%), plasma cell hepatitis (4.4%), chronic hepatitis (4.4%), IHC (22.2%), and others. On analysis of post transplant biopsy cases with IHC, we found that patients with high baseline HCV RNA levels had recurrences presenting only with prominent IHC without fibrosis and ballooning of hepatocytes. These changes might represent early stages of fibrosing cholestatic hepatitis (FCH). Conclusions: This study evaluated the types, incidence, and timing of major complications occurring after OLT. ACR remains major complication following transplant. The presence of IHC on biopsy, especially in HCV-positive patients, should prompt anti-HCV therapy even if other features of FCH were not found.

Ledipasvir and Sofosbuvir +/- Ribavirin in Post-hepatic Transplant Patients Reinfected with Genotype 1 Hepatitis C at a Large Academic Medical Center

Introduction: Hepatitis C (HCV) is the leading etiology of liver transplantation in the U.S. However, HCV re-infection in the transplanted liver is almost universal. Newer treatments options, including ledipasvir/sofosbuvir (L-S), have shown significant improved sustained virologic response (SVR) in non-transplant patients. However, data is limited on the use of L-S in post liver transplant patients. The purpose of this study was to assess the response to L-S in such patients at a single center institution. Methods: A retrospective study of all post liver transplant patient's with Genotype 1 Hepatitis C receiving L-S with/without ribavirin at a large academic medical center. There were sixteen total liver transplant patients who were treated with L-S. Nine patients also received weight based ribivirin. Two patients had stage IV fibrosis and three had stage III fibrosis. The primary end points of this study were to assess both virologic response and SVR at weeks 4 and 12. Results: Our analysis showed that 11/16 patients had an undetectable viral load after just 4 weeks of treatment. All patients achieved SVR-4 and SVR-12. One patient developed fibrosing cholestatic hepatitis while on treatment. Three patients after achieving SVR-12, developed acute cellular rejection despite maintaining adequate calcineurin inhibitor levels. They were treated successfully with steroids and by changing their immunosuppression regimen from cyclosporine to tacrolimus. These three patients maintained an undetectable viral load. All patients tolerated the treatment well with notable side effects of sleep disturbances and fatigue noted in patients taking ribavirin as well. No patients discontinued the treatments. No immunosuppression dose adjustments were required except in the three patients who developed rejection after completion of HCV treatment. Conclusion: This study shows promising results in post liver transplant HCV patients, who are treated with L-S even in traditionally difficult to treat populations. Treatment length and the addition of ribavirin did not appear to have an effect on the response as all patients achieved SVR although the small sample size likely biases these results. Larger prospective studies are needed to validate these results and further stratify treatment duration and efficacy for patients with advanced fibrosis, previous treatment failure etc. Future studies may be needed to determine if cyclosporine regimens should be changed to FK506 based regimens prior to HCV treatment.Table 1: Patient CharacteristicsTable 2: Results