Alison Jazwinski

Elevated serum CK18 levels in chronic hepatitis C patients are associated with advanced fibrosis but not steatosis

Summary.  Cytokeratin‐18 (CK‐18) is a major intermediate filament protein in liver cells. The M30 fragment of CK‐18 has been identified as a useful marker of apoptosis associated with fibrosis and steatosis in nonalcoholic steatohepatitis (NASH). We sought to assess the relationship of this marker and steatosis in a cohort of adult patients with chronic hepatitis C. The study cohort included sera from 267 treatment‐naïve chronic hepatitis C (CHC) patients and 100 healthy controls with normal alanine aminotransferase (ALT). Biopsies from CHC patients were assessed for METAVIR fibrosis stage, Histology Activity Index (HAI) inflammation score and steatosis grade by expert histopathologists. The M30 fragment of CK‐18 was quantified by ELISA. Wilcoxon Rank Sum, Spearman Correlation and Linear Regression tests were performed for statistical analysis. Median CK‐18 levels were higher in CHC patients compared to controls (411 vs 196 U/L, P < 0.0001). Fibrosis stage was associated with increasing serum CK‐18 levels (P = 0.015) and CK‐18 levels were higher for F2–F4 vs F0–F1 (500 vs 344 U/L; P = 0.001). There was no association between CK‐18 and increasing steatosis grade 1, 2 or 3 (460.7 vs 416.8 vs 508.3 U/L; P = 0.35) and presence or absence of steatosis (445.3 vs 365.8 U/L; P = 0.075). Fibrosis stage was independently associated with serum M30 in a multivariable linear regression model (P = 0.03). CK‐18 levels were higher in CHC compared to healthy controls and associated with hepatic fibrosis. There was no difference in CK‐18 M30 levels between CHC patients with and without steatosis. Although apoptosis may still contribute to hepatitis C virus (HCV)‐mediated steatosis, our results suggest that serum CK‐18 will not be a clinically useful test for identifying significant steatosis in CHC.

Immune reconstitution syndrome in a patient with disseminated histoplasmosis and steroid taper: maintaining the perfect balance.

Immune reconstitution syndrome (IRS) is an increasingly common condition that has been described in immunosuppressed individuals once immune function is restored. In this case, we describe a patient who had a renal transplant and subsequently developed pulmonary histoplasmosis. His course was also complicated by the development of a clinical syndrome that was originally attributed to thrombocytopenic thrombotic purpura (TTP). When he did not improve with plasmapheresis and high dose prednisone, a bone marrow biopsy revealed disseminated histoplasmosis and administration of prednisone was rapidly tapered. While on 5 mg of prednisone, he developed an inflammatory syndrome characterised by haemoptysis and respiratory distress, full work‐up with pathology was consistent with immune reconstitution syndrome. Treatment for IRS consists of continuing treatment for the underlying infection and consideration of administering anti‐inflammatory medication for supportive care. This syndrome should be considered in patients who develop worsening inflammatory symptoms while receiving appropriate treatment for their fungal infection in the setting of restoration of immune function.

Emerging therapies in hepatitis C: dawn of the era of the direct-acting antivirals.

The HCV viral life cycle provides targets for drug development at virtually every step, and many new drugs aimed at these targets are currently being developed. Clinical practice takes a major step forward this year with the arrival of telaprevir and boceprevir, which will be added to the current standard of care of pegIFNα/RBV. Patients will need to be monitored closely and counseled extensively, and clinicians will need to learn the new response-guided therapy algorithms with these therapies. Although there remains work to be done in the field of HCV, these therapies will allow many more patients the opportunity to eradicate HCV infection.

Predictors of consent to pharmacogenomics testing in the IDEAL study

Introduction Pharmacogenomic testing is important in developing individualized therapeutic approaches. In the phase 3 IDEAL (Individualized Dosing to Assess Optimal Pegylated Interferon Therapy) clinical trial, a subset of patients receiving peginterferon and ribavirin for treatment of chronic hepatitis C agreed to provide blood samples for genetic testing. Genome-wide association studies subsequently identified associations between IL28B polymorphism and sustained virologic response, and ITPA polymorphism and ribavirin-associated anemia. Objective To characterize the groups of patients who accepted or declined pharmacogenomic testing in the IDEAL study. Methods Clinical and demographic factors and treatment outcomes were compared at all sites that had approved pharmacogenomic testing. Differences between patients who consented to and declined pharmacogenomic testing were analyzed using Student’s t-test and &khgr;2-test. Results In total, 109 of 118 sites participated in the pharmacogenomic substudy, and 1674 of 2949 (57%) patients enrolled at these sites consented to pharmacogenomic testing. More patients treated in academic medical centers than in community centers (60 vs. 52%, P<0.001) provided consent. More men than women (58 vs. 54%, P=0.04) consented to pharmacogenomic testing. There was no significant difference in pharmacogenomic participation between patients from different racial groups, including whites and African Americans (58 vs. 54%, P=0.07). Treatment outcomes were also similar according to pharmacogenomic participation. Conclusion In the IDEAL study, patient consent to pharmacogenomic testing did not introduce selection bias. Treatment at an academic center and male sex were associated with higher rates of pharmacogenomic testing consent. Efficacy and safety outcomes were similar in patients who accepted and declined pharmacogenomic testing.

The Genetics of Virologic Response

The field of medicine is changing rapidly, and the future holds the potential to “personalize” treatment by determining the genome of both patients and pathogens to administer the appropriate therapies. Within the field of hepatology, multiple genetic discoveries have led to new insights into the biology of hepatitis C (HCV) infection and improved ability to predict an individual patient’s response to therapy. Major discoveries in this area include the finding of SNPs near the IL28B gene that are related to sustained virologic response (SVR) and rapid virologic response (RVR) in patients with genotype 1, spontaneous clearance of HCV after acute infection, and SVR in those patients with genotypes 2 and 3 that do not achieve an RVR. Additionally, the IL28B polymorphisms add insight into the variation of treatment response among different ethnicities, and this finding is estimated to explain approximately half of the difference in treatment response rates between patients of African-American and European-American background. Additional genetic findings including variation in the IL-6 haplotype, differences in MHC allele expression, and polymorphisms that lead to increased steatosis and insulin resistance have also provided new insights into differences in response to treatment for hepatitis C.

IL28B: Implications for Clinical Practice

The discovery of genetic variants near the gene for IL28B has provided new insight into the biology of hepatitis C infection and response to treatment with pegylated interferon alpha and ribavirin. Patients that carry the favorable CC genotype for SNP rs12979860 or TT genotype for SNP rs8099917 are more likely to spontaneously clear the virus after acute infection and to respond to therapy with pegylated interferon alpha and ribavirin. IL28B genotype may also have a relationship with the natural history of chronic hepatitis and has implications for organ allocation in liver transplantation. Now that the protease inhibitors telaprevir and boceprevir have improved the response rates to hepatitis c treatment, the applicability of IL28B genotyping in clinical practice is limited. However, further understanding of the mechanism underlying the relationship between IL28B and treatment response is likely to provide valuable insight into the pathophysiology of hepatitis c infection and response to therapy.