Showing papers by "David E. Kleiner published in 2012"

Nonalcoholic Fatty Liver Disease: Pathologic Patterns and Biopsy Evaluation in Clinical Research

Abstract: Nonalcoholic fatty liver disease (NAFLD) results in histologically complex specific and nonspecific injury patterns. In clinical research of NAFLD, the liver biopsy evaluation provides a wealth of information on the architectural arrangement and severity of a variety of histologic changes, including steatosis, inflammation, cellular injury, and fibrosis. This information is summarized as an overall diagnostic category, such steatosis or steatohepatitis and the severity of the injury can be graded and staged. Histopathologic disease classification in NAFLD is related to but separate from evaluation of individual histologic lesions. The patient population under study may affect the prevalence of histologic findings and in particular, pediatric patients with NAFLD may show a higher prevalence of zone 1 steatosis and periportal fibrosis as compared with adult populations. For the purposes of clinical research, it is important to provide the pathologist with biopsies that are adequate to classify the disease process as well as to grade and stage the changes. A current understanding of NAFLD pathologic classification, as well as nuances of grading and staging, is presented in this review.

Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B.

Abstract: Summary Background Adefovir and tenofovir are nucleotide analogues used as long-term therapy of chronic hepatitis B. Side effects are few, but prolonged and high-dose therapy has been associated with proximal renal tubular dysfunction (RTD). Aim To assess the incidence of RTD during long-term nucleotide therapy of chronic hepatitis B. Methods A total of 51 patients being treated at the Clinical Center, National Institutes of Health were studied. Diagnosis of RTD required de novo appearance of at least three of five features: hypophosphataemia, hypouricaemia, serum creatinine elevation, proteinuria or glucosuria. Results Among 51 patients treated for 1–10 (mean 7.4) years with adefovir (n = 42), tenofovir (n = 4) or adefovir followed by tenofovir (n = 5), 7 (14%) developed RTD. Time to onset ranged from 22 to 94 (mean 49) months with an estimated 10-year cumulative rate of 15%. All seven had low urinary percent maximal tubular reabsorption of phosphate (<82%). Patients with RTD were older (58 vs. 44 years; P = 0.01) and had lower baseline glomerular filtration rates (82 vs. 97 cc/min; P = 0.08) compared to those without; but did not differ in other features. Six patients with RTD were switched to entecavir, all subsequently had improvements in serum phosphate (2.0–3.0 mg/dL), creatinine (1.6–1.1 mg/dL), uric acid (2.7–3.8 mg/dL) and proteinuria. Conclusions Renal tubular dysfunction develops in 15% of patients treated with adefovir or tenofovir for 2–9 years and is partially reversible with change to other antivirals. Monitoring for serum phosphate, creatinine and urinalysis is prudent during long-term adefovir and tenofovir therapy.

Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma.

Abstract: Ipilimumab is a fully human monoclonal antibody which blocks cytotoxic T-lymphocyte antigen-4, an immune checkpoint molecule that down-regulates pathways of T-cell activation. Ipilimumab has demonstrated a statistically significant improvement in overall survival in two randomized controlled phase III trials of patients with metastatic melanoma. A main complication of ipilimumab therapy is the development of inflammatory events which can occur in various organs, including the liver (i.e., hepatitis). Hepatic injury is a concern because it can develop with little warning and may potentially be severe. We analyzed liver biopsy findings in 4 cases of ipilimumab treatment-related hepatitis and compared them to a fifth, previously reported case. All 5 patients had a histologic pattern of injury that was similar to what is observed with acute viral and autoimmune hepatitis; however, the findings are not specific and require clinicopathologic correlation. Pathologic evidence of hepatitis resolved in all 5 patients with appropriate immunosuppressive therapy. Although a relatively uncommon adverse event with ipilimumab, patients should be monitored at regular intervals for biochemical/pathological evidence of hepatitis.

Liver regeneration signature in hepatitis B virus (HBV)-associated acute liver failure identified by gene expression profiling.

Abstract: Introduction The liver has inherent regenerative capacity via mitotic division of mature hepatocytes or, when the hepatic loss is massive or hepatocyte proliferation is impaired, through activation of hepatic stem/progenitor cells (HSPC). The dramatic clinical course of acute liver failure (ALF) has posed major limitations to investigating the molecular mechanisms of liver regeneration and the role of HSPC in this setting. We investigated the molecular mechanisms of liver regeneration in 4 patients who underwent liver transplantation for hepatitis B virus (HBV)-associated ALF.

Acute Liver Injury due to Flavocoxid (Limbrel), a Medical Food for Osteoarthritis: A Case Series

Abstract: Background Flavocoxid is a prescription medical food that is used to treat osteoarthritis. It is a proprietary blend of 2 flavonoids, baicalin and catechins, which are derived from the botanicals Scutellaria baicalensis and Acacia catechu, respectively. Objective To describe characteristics of patients with acute liver injury suspected of being caused by flavocoxid. Design Case series. Setting Drug-Induced Liver Injury Network Prospective Study ongoing at multiple academic medical centers since 2004. Patients Four adults with liver injury. Measurements Clinical characteristics, liver biochemistry values, and outcomes. Results Among 877 patients enrolled in the prospective study, 4 had liver injury suspected to have been caused by flavocoxid. All were women; ages ranged from 57 to 68 years. All developed symptoms and signs of liver injury within 1 to 3 months after initiating flavocoxid. Liver injury was characterized by marked elevations in levels of alanine aminotransferase (mean peak, 1268 U/L; range, 741 to 1540 U/L), alkaline phosphatase (mean peak, 510 U/L; range, 286 to 770 U/L), and serum bilirubin (mean peak, 160.7 µmol/L [9.4 mg/dL]; range, 34.2 to 356 µmol/L [2.0 to 20.8 mg/dL]). Liver biochemistry values decreased to the normal range within 3 to 12 weeks after flavocoxid was stopped, and all patients recovered without experiencing acute liver failure or chronic liver injury. Causality was adjudicated as highly likely in 3 patients and as possible in 1 patient. Limitation The frequency and mechanism of liver injury could not be assessed. Conclusion Flavocoxid can cause clinically significant liver injury, which seems to resolve within weeks after cessation.

Hydrogen-1 MR Spectroscopy for Measurement and Diagnosis of Hepatic Steatosis

Abstract: OBJECTIVE. Hydrogen-1 MR spectroscopy (1H-MRS) is gaining acceptance as a noninvasive technique for assessment of hepatic steatosis, and the findings have been found to correlate closely with histopathologic grade. The aims of this study were to validate 1H-MRS performed with a 3-T MRI system for quantifying hepatic steatosis and to determine threshold values of 1H-MRS proton density fat fraction corresponding to standard histopathologic grade in patients undergoing diagnostic liver biopsy. SUBJECTS AND METHODS. We conducted a prospective cross-sectional liver MRS study with 52 subjects undergoing diagnostic liver biopsy. The diagnostic accuracy of 1H-MRS was evaluated with receiver operating characteristic curves. RESULTS. The diagnostic accuracy of 1H-MRS for hepatic steatosis was high with an area under the receiver operating characteristic curve of 0.94 (95% CI, 0.88–1.0). Results were similar for three 1H-MRS measurements obtained at different locations in the liver, for two independent pathologists,...

A 25-Year Study of the Clinical and Histologic Outcomes of Hepatitis C Virus Infection and Its Modes of Transmission in a Cohort of Initially Asymptomatic Blood Donors

Abstract: Background.A total of 738 volunteer blood donors who were positive for anti–hepatitis C virus (HCV) were assessed for risk factors and outcomes for up to 15 years within the study and up to 54 years from the estimated onset of infection. Methods.A third-generation recombinant immunoblot assay (RIBA) was performed to distinguish true from false anti-HCV reactivity. Findings of HCV polymerase chain reaction classified subjects as having chronic HCV infection or as having recovered. Liver biopsy specimens were staged by Ishak fibrosis score and graded by histologic activity index. Results.Of 738 anti-HCV–positive subjects, 469 (64%) had positive RIBA results, 217 (29%) had negative results, and 52 (7%) had indeterminate results. Primary independent risk factors were injection drug use (odds ratio [OR], 35.0; P < .0001), blood transfusion (OR, 9.9; P < .0001), and intranasal cocaine use, including 79 “snorters” who repeatedly denied injection drug use or blood transfusion (OR, 8.5; P < .0001). Classification and regression tree and random forest analyses confirmed these risk factors. A total of 384 RIBA-positive donors (82%) were HCV RNA positive; of these, liver biopsy specimens from 185 (48%) showed no fibrosis in 33%, mild fibrosis in 52%, bridging fibrosis in 12%, and cirrhosis in 2% a mean duration of 25 years after infection. Analysis of 63 repeat biopsy specimens showed that 8% progressed ≥2 Ishak stages over 5 years (mean progression, 0.06 Ishak stages/year). Conclusions.Injection drug use and blood transfusion before 1990 are dominant risk factors for HCV acquisition; intranasal cocaine use may be a surreptitious route of parenteral spread. After a mean of 25 years of HCV infection, histologic outcomes were relatively mild: 85% had no or mild fibrosis, and only 2% had cirrhosis. Nearly one-fifth spontaneously recovered.

Randomised clinical trial: the benefit of combination therapy with adefovir and lamivudine for chronic hepatitis B.

Abstract: Summary Background Combination antiviral therapy holds the promise of increasing response rates while decreasing antiviral resistance, but has yet to be shown to be beneficial or necessary in chronic hepatitis B. Aim To evaluate the benefit of combination therapy with adefovir and lamivudine versus adefovir alone in maintaining virological, biochemical and histological responses. Methods Patients with chronic hepatitis B with and without previous lamivudine therapy were randomised to receive adefovir alone (10 mg/daily) or adefovir and lamivudine (100 mg/daily) for up to 192 weeks. Study endpoints were (i) maintained virological (HBV DNA <500 copies/mL), biochemical and histological response, (ii) loss of HBeAg and (iii) loss of HBsAg. Results A total of 41 patients were enrolled, including 31 HBeAg -positive and 31 treatment-naive subjects. 30 patients remained on assigned therapy at 192 weeks. The percentage of patients achieving a combined maintained response was higher in the combination than the monotherapy arm, both at week 48 (59% vs. 26%, P = 0.06) and 192 (68% vs. 31%, P = 0.03). At week 192, 76% of the combination vs. 36% of the monotherapy group had loss of HBeAg (P = 0.03). One patient receiving adefovir cleared HBsAg. Adefovir resistance developed in 6 of 19 (32%) monotherapy but none of 22 combination treated patients (P = 0.03). Conclusions Extended combination therapy with lamivudine and adefovir is associated with a high rate of long-term virological and biochemical response. Adefovir monotherapy appears to be less effective mainly because of poor initial response and the ultimate development of antiviral resistance (www.Clinical. Trials.gov NCT00023309).

Inverse relationship of interleukin-6 and mast cells in children with inflammatory and non-inflammatory abdominal pain phenotypes

Abstract: AIM: To investigate interleukin-6 (IL-6), mast cells, enterochromaffin cells, 5-hydroxytryptamine, and substance P in the gastrointestinal mucosa of children with abdominal pain. METHODS: Formalin-fixed paraffin-embedded gastrointestinal biopsy blocks from patients (n = 48) with non-inflammatory bowel disease (irritable bowel syndrome and functional abdominal pain) and inflammatory bowel disease were sectioned and stained for IL-6, mast cells, enterochromaffin cells, 5-hydroxytryptamine, and substance P. All children had chronic abdominal pain as part of their presenting symptoms. Biopsy phenotype was confirmed by a pathologist, blinded to patient information. Descriptive statistics, chi-square, and independent sample t tests were used to compare differences between the inflammatory and non-inflammatory groups. RESULTS: The cohort (n = 48), mean age 11.9 years (SD = 2.9), 54.2% females, 90% Caucasian, was comprised of a non-inflammatory (n = 26) and an inflammatory (n = 22) phenotype. There was a significant negative correlation between substance P expression and mast cell count (P = 0.05, r = -0.373). Substance P was found to be expressed more often in female patient biopsies and more intensely in the upper gastrointestinal mucosa as compared to the lower mucosa. There were significantly increased gastrointestinal mucosal immunoreactivity to IL-6 (P = 0.004) in the inflammatory phenotype compared to non-inflammatory. Additionally, we found significantly increased mast cells (P = 0.049) in the mucosa of the non-inflammatory phenotype compared to the inflammatory group. This difference was particularly noted in the lower colon biopsies. CONCLUSION: The findings of this study yield preliminary evidence in identifying biomarkers of undiagnosed abdominal pain in children and may suggest candidate genes for future evaluation.

Acute Liver Injury due to Flavocoxid (Limbrel), a Medical Food for Osteoarthritis

Abstract: This case series describes 4 adults who developed symptoms and signs of liver injury within 3 months after initiating flavocoxid—a proprietary prescription medical food used to treat osteoarthritis...