James W. Williams

Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon α2b and ribavirin: An open-label series

Background. Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is universal. We aimed to evaluate the efficacy and safety of pegylated interferon (PEG-IFN) and ribavirin (RIB) in the treatment of post-OLT HCV recurrence. Methods. Thirty-seven patients with recurrent HCV after OLT were screened and began treatment. Nineteen patients have completed therapy. PEG-IFN was started at a dose of 0.5 &mgr;g/kg per week and titrated toward a maximum dose of 1.5 &mgr;g/kg per week. RIB was started at a dose of 400 mg per day and titrated toward a maximum of 1000 mg per day, as tolerated. Therapy continued for 1 year after HCV replication was undetectable by reverse transcriptase-polymerase chain reaction and was discontinued if there was no virologic clearance at 48 weeks. Results. Twelve patients (63%) completed the combination regimen. Therapy was discontinued in seven (37%) patients. Seven patients (37%) had undetectable viral load at the end of treatment. Of those, five patients (26%) had sustained viral response 6 months after discontinuation of therapy. Five patients (26%) had no virologic response. Necro-inflammatory score declined from 5.22 to 2.89 (P =0.05) in nonresponders versus 6.8 to 2.6 (P <0.01) in responders. Fibrosis stage did not change in either group. Genotype 1-infected patients had a lower likelihood of attaining end of treatment or sustained viral response (P <0.05 for both). Conclusions. Post-OLT HCV recurrence can be safely treated with PEG-IFN and RIB. Bone marrow toxicity, depression, and rejection are limiting factors that require aggressive management. There was short-term histologic benefit to the use of this regimen, even in those patients without viral clearance.

Natural History of Post-Liver Transplantation Hepatitis C: A Review of Factors That May Influence Its Course

Our aim was to assess long‐term survival in patients transplanted for HCV‐related end‐stage liver disease (ESLD) and evaluate potentially modifiable predictors of survival. We performed a retrospective analysis of adult liver transplants (LT) at our institution for HCV‐related ESLD since the programs inception. Pertinent demographic, clinical, and biochemical information was retrieved from electronic medical records and histological data from 990 per‐protocol liver biopsies were collected. Three hundred eighty LT were performed at our institution during the study period, 206 patients were transplanted for HCV‐related ESLD; 6 died within 30 days of transplantation and were not included. The remaining 200 recipients (DDLT 168 LDLT 32) constituted the evaluable population. The demographics were as follows: 150 males, median age 53 years; median donor age 39 years; hepatocellular carcinoma (HCC) in 26%. Overall 1‐, 5‐, and 7‐year survival: 95%, 81%, and 79%; median survival 43 months, mortality 15%. Significant HCV recurrence (HAI ≥6 and/or fibrosis ≥2) was present in 49%, “early recurrence” (within 1 year of LT) in 30.5% and biopsy‐proven acute rejection was present in 27%. Factors with a significant negative impact on patient survival included: fibrosis stage ≥2 at 12‐month biopsy, advanced donor age, history of HCC and early acute rejection. Survival was similar regardless of the donor type (DDLT vs. LDLT). Early and aggressive HCV recurrence has a very heavy toll on patient survival. Prompt recognition and treatment of “rapid fibrosers” may impart benefit. As has been described before, avoidance of rejection and selection of young donors for HCV‐positive recipients will also improve survival in this population. On the basis of our findings, LDLT is a good option for HCV‐positive recipients. Liver Transpl 15:1872–1881, 2009.

Impact of Subclinical Inflammation on the Development of Interstitial Fibrosis and Tubular Atrophy in Kidney Transplant Recipients

Our aim was to study the impact of subclinical inflammation on the development of interstitial fibrosis and tubular atrophy (IF/TA) on a 1‐year protocol biopsy in patients on rapid steroid withdrawal (RSW). A total of 256 patients were classified based on protocol biopsy findings at months 1 or 4. Group 1 is 172 patients with no inflammation, group 2 is 50 patients with subclinical inflammation (SCI), group 3 is 19 patients with subclinical acute rejection (SAR) and group 4 is 15 patients with clinical acute rejection (CAR). On the 1‐year biopsy, more patients in group 2 (SCI) (34%, p = 0.004) and group 3 (SAR) (53%, p = 0.0002), had an IF/TA score > 2 compared to group 1 (control) (15%). IF/TA was not increased in group 4 (CAR) (20%). The percent with IF/TA score > 2 and interstitial inflammation (Banff i score > 0) was higher in group 2 (16%, p = 0.004) and group 3 (37%, p < 0.0001) compared to group 1 (3%). In a multivariate analysis, patients in groups 2 or 3 had a higher risk of IF/TA score > 2 on the 1‐year biopsy (OR 6.62, 95% CI 2.68–16.3). We conclude that SCI and SAR increase the risk of developing IF/TA in patient on RSW.

Hepatic steatosis in hepatitis C virus genotype 3 infection: Does it correlate with body mass index, fibrosis, and HCV risk factors?

Hepatic steatosis is a recognized feature of hepatitis C viral infection, particularly in genotype 3. The demographics and the associations contributing to moderate to severe steatosis in genotype 3 are not very well studied. The aim of this study is to determine the demographics and association of steatosis with fibrosis, obesity, diabetes, lipid levels, and risk factors among patients with hepatitis C virus (HCV) genotype 3. Two hundred ninety-three consecutive HCV patients (genotype 1, n = 218; genotype 2, n = 43; genotype 3, n = 32) at our institution were studied retrospectively. Demographic information such as height, weight, genotype, risk factors, serum cholesterol and triglyceride, and liver biopsy was collected. Steatosis was graded using the Brunt classification. HCV genotype 3-infected patients were younger (P < 0.04) and had lower serum cholesterol levels (P < 0.02) compared to nongenotype 3 patients. Moderate to severe steatosis was more prevalent in HCV genotype 3 patients (P < 0.001) with intravenous drug abuse as a risk factor (P = 0.04). Genotype 3 was the independent predictor of steatosis in all patients. There was no statistical association between grade of steatosis and body mass index, fibrosis, necroinflammation, or hyperlipidemia when only HCV genotype 3 patients were included in the multivariate logistic model. Hepatic steatosis is a feature of genotype 3. Patients with HCV genotype 3 are younger and have lower serum cholesterol levels. Genotype 3 is the independent predictor for steatosis in HCV patients. HCV genotype 3 patients with moderate to severe steatosis are more likely to have intravenous drug use as a risk factor.

Living Donor Liver Transplantation for Hepatitis C-Related Cirrhosis: No Difference in Histological Recurrence When Compared to Deceased Donor Liver Transplantation Recipients

The question of possible earlier and more aggressive recurrence of hepatitis C virus (HCV) infection after living donor liver transplantation (LDLT) compared to deceased donor liver transplantation (DDLT) remains unanswered. To address this issue we retrospectively reviewed virological, histological, and clinical data in 67 patients (52 DDLT and 15 LDLT) who underwent liver transplant for their HCV‐related cirrhosis since April 2001. Our data indicate that there is no statistical difference between LDLT and DDLT groups in mean age, Child‐Turcotte‐Pugh score, model for end‐stage liver disease score, and gender distribution. The mean follow‐up was 749 ± 371 days in LDLT and 692 ± 347 days in DDLT. The predominant genotype in the LDLT and DDLT are genotype 1 (LDLT, 91%; DDLT, 70%). All patients with histologically confirmed recurrent HCV had detectable HCV‐RNA in serum. The histological recurrence rate of hepatitis C was 58% at 4 months, 90% at 1 year, and 100% at 2 years in LDLT patients vs. 71% at 4 months, 94% at 1 year, and 95% at 2 years in DDLT patients (not significant) Comparison of the activity of inflammation and fibrosis score at all time points failed to show a statistical difference. Kaplan‐Meier survival analysis showed similar patient and graft survival rates between the 2 groups. Our data indicate that histological recurrence of HCV is an early event and virtually universal 2 years posttransplantation, regardless of modality of donor procurement. Liver Transpl 12:560–565, 2006.

Hepatitis C Virus Quasi-Species Dynamics Predict Progression of Fibrosis after Liver Transplantation

BACKGROUNDnThe dynamics of hepatitis C virus (HCV) quasi species in the E2 region may correlate with the course of infection after orthotopic liver transplantation (OLT).nnnMETHODSnThirty-four patients who underwent transplantation for HCV-related cirrhosis were studied. Serum and liver samples were available before OLT and at 1 week, 4 months, and 1 year after OLT. Patients were divided into group 1 (Knodell/Ishak fibrosis stage [FS] at 1 year, <2) and group 2 (FS at 1 year, > or =2). Complexity was estimated by the number of bands in a single-strand conformational polymorphism assay, whereas diversity was measured by Shannon entropy (SE) and median mobility shift (MMS) values derived from the heteroduplex mobility assay. Diversity dynamics were measured at transmission (before OLT vs. 1 week after OLT) and after OLT (1 week after OLT vs. 1 year after OLT).nnnRESULTSnComplexity was higher in group 1 patients than in group 2 patients before OLT (P<.02) and at 1 week after OLT (P<.04). Diversity decreased in group 1 at transmission, as measured by either SE (P<.01) or MMS (P<.04). However, diversity increased in this group after OLT, as measured by SE (P<.03) or MMS (P<.02). FS at 1 year after OLT correlated with transmission changes, as measured by SE (r=0.642, P<.0001) and MMS (r=0.443, P<.04), and with post-OLT changes (for SE: r=-0.583, P<.01; for MMS: r=-0.536, P<.01).nnnCONCLUSIONSnHCV complexity and diversity in the E2 region correlated with the severity of recurrence of HCV infection after OLT. Increased diversity of quasi species at transmission correlated with a higher FS at 1 year. However, increased diversity of quasi species in the post-OLT period correlated with a lower FS at 1 year. The dynamics of HCV quasi species in patients who undergo transplantation are predictive of outcome.

Vitamin A toxicity: When one a day doesn't keep the doctor away

Vitamin A toxicity has been reported to cause severe liver disease and, occasionally, liver failure. Herein we present the case of a 60‐year‐old male with symptoms of muscle soreness, alopecia, nail dystrophy, and ascites. He continued to deteriorate with the development of refractory ascites, renal insufficiency, encephalopathy, and failure to thrive. A liver biopsy demonstrated presence of Ito cells and vacuolated Kupffer cells without the presence of cirrhosis. His clinical history revealed ingestion of large doses of vitamin A. His worsening clinical situation ruled out the possibility of a transjugular intrahepatic portosystemic shunt. The patient underwent orthotopic liver transplantation with resolution of symptoms. Vitamin A toxicity should be considered in the differential diagnosis of noncirrhotic portal hypertension. In conclusion, liver transplantation is a valid option if no improvement occurs in spite of cessation of the medication. Liver Transpl 12:1888–1891, 2006.

Interobserver Agreement in Hepatitis C Grading and Staging and in the Banff Grading Schema for Acute Cellular Rejection: The “Hepatitis C 3” Multi-Institutional Trial Experience

CONTEXTnEstablishing adequate interobserver agreement is crucial not only for standardization of patient care but also to ensure validity of findings in multi-institutional trials.nnnOBJECTIVEnTo evaluate interobserver agreement in assessing chronic hepatitis C (HCV) and acute cellular rejection (ACR) among 17 hepatopathologists involved in the Hepatitis C 3 trial.nnnDESIGNnThe trial is a randomized multicenter (17 institutions) study involving 312 patients undergoing transplantation for HCV. Patients are randomized to 3 treatment arms. For final data analysis, all biopsy specimens are reviewed by a central pathologist (G.J.N.). Recurrence of HCV is evaluated according to the Batts and Ludwig schema. The 1997 Banff schema is used to evaluate ACR. To assess interobserver agreement, hematoxylin-eosin-stained sections from 11 liver biopsy specimens (6 HCV and 5 ACR) were sent by the central pathologist to 16 local pathologists from 13 institutions. Statistical analysis was performed on raw ACR/HCV data as well as data grouped according to clinically significant primary endpoint cutoffs.nnnRESULTSnStatistically significant agreement was found among all participating pathologists (P < .001). On kappa analysis, the degree of agreement was rated moderate for HCV grade and stage and ACR global grading (kappa = 0.30, 0.33, and 0.37, respectively). Interobserver agreement was weaker for rejection activity index scoring of ACR (kappa = 0.15). A stronger degree of agreement was found when scores were grouped based on endpoint cutoffs (kappa = 0.76 almost perfect for HCV and 0.62 substantial for ACR).nnnCONCLUSIONSnAn overall statistically significant interobserver agreement was found among 17 pathologists using the 1997 Banff schema and the Batts and Ludwig schema.

Primary biliary cirrhosis and systemic amyloidosis, a new association

Amyloidosis is a heterogeneous group of disorders characterized by the extracellular deposition of proteins in an abnormal fibrillar pattern with pathognomonic applegreen birefringence under polarized light when stained with Congo red (1). Historically, these have been classified as “primary” or “secondary” amyloidosis. Primary amyloidosis (AL) represents the most common form of systemic amyloid deposition in the Western world and is typically associated with immunocyte dyscrasias such as multiple myeloma, lymphomas, macroglobulinemia, and “benign” monoclonal gammopathies (2). Secondary amyloidosis (AA) is associated with longstanding infectious or noninfectious inflammatory disorders and, less frequently, neoplastic disorders. Associated disorders include adult rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Reiter’s syndrome, systemic lupus erythematosus, systemic sclerosis, tuberculosis, leprosy, Castleman’s disease, bronchiectasis, cystic fibrosis, osteomyelitis, heroin abuse, psoriasis, inflammatory bowel disease, and Whipple’s disease (1, 2). Despite a strong association with chronic inflammatory disorders and AA, an extensive literature review did not reveal a previously reported association between primary biliary cirrhosis (PBC) and AA. In this case review, we report the first association of these two entities.

Capsule retention in a patient with eosinophilic gastroenteritis mimicking diaphragm disease of the small bowel

tion of anemia, abdominal bloating, and weight loss. He had been diagnosed with eosinophilic gastroenteritis (EGE) in childhood. He had no history of current or past nonsteroidal anti-inflammatory drug (NSAID) use. Computed tomography enterography (CTE) did not reveal any small-bowel abnormalities. Video capsule endoscopy was significant for ulcerated stenoses similar to diaphragm disease (● Fig. 1), and the test was complicated by capsule retention. At antegrade double-balloon enteroscopy (DBE), multiple ulcerated stenoses were present (● Fig. 2). Small-bowel biopsies revealed ulceration (● Fig. 3a), partial villous atrophy and eosinophilic infiltration (> 50/HPF) (● Fig. 3b), consistent with EGE. Following initiation of prednisone, the patient had resolution of symptoms and eosinophilia. Segmental resection of 6 inches of ileum was performed for capsule retrieval. Multiple diaphragms were present on surgical pathology (● Fig. 4), without mucosal or serosal eosinophilia. Diaphragm disease is a disorder characterized by ulcerated small-bowel stenoses in patients with a history of NSAID use [1]. In the past, most cases were diagnosed at laparotomy, but an increasing number of cases are now diagnosed on capsule endoscopy and DBE [2,3]. As radiologic imaging studies (CTE) have a low sensitivity for detection of diaphragms, patients undergoing capsule endoscopy are at risk of retention. Interestingly, not all cases of diaphragm disease are related to NSAID use. In a prior case report of diaphragm disease, NSAID use was ruled out by history and objective testing for salicylates [4]. The term cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) has been coined to refer to ulcerated small-bowel strictures, in the absence of an obvious etiology [5]. In a series of 10 patients with diaphragm disease, three had mucosal eosinophilia (> 20/HPF), and satisfied the clinical criteria for EGE [6]. Circumferential ulcerated lesions, similar to diaphragm disease, have also been reported in equines with EGE [7]. Although small-bowel eosinoCapsule retention in a patient with eosinophilic gastroenteritis mimicking diaphragm disease of the small bowel