Noninvasive Marker, Fibrospect II, Overestimates Fibrosis in Hepatitis C-Infected Patients with Chronic Renal Insufficiency

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Liver biopsy is the gold standard for determining liver fibrosis stage, but it is an invasive test with fallibility including sampling error and observer variability. Many non-invasive markers including Fibrospect II, a proprietary formula, have been developed to replace liver biopsy, but their accuracy in patients with chronic renal insufficiency (CRI) is unclear. We aimed to investigate the accuracy of Fibrospect II in chronic hepatitis C (HCV) infected patients with CRI.

The World Health Organization estimates over 185 million people are infected with hepatitis C virus (HCV) worldwide, and up to 4.7 million people have active infection within the United States. Liver fibrosis is an important predictor of disease progression and mortality in HCV infection. While liver biopsy remains the gold standard in determining liver fibrosis stage, it is limited by its invasive nature, sampling error and observer variability. To replace liver biopsy in fibrosis detection, many non-invasive serum markers such as serum Fibrospect II, Hyaluronic acid (HA), aspartate aminotransferase (AST) to platelet ratio (APRI), Fibrotest, Hepascore, and cartilage oligomeric matrix protein (COMP), and radiologic methods such as transient elastography acoustic radiation force impulse imaging and magnetic resonance elastography have been developed. Adoption of these noninvasive markers of fibrosis has been gaining momentum. The most recent joint HCV recommendations from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America, and from the European Association for the Study of the Liver advocate for non-invasive markers and transient elastography as first line tests for liver fibrosis, and to proceed to a liver biopsy only in patients with inconclusive results or when more information is necessary. Fibrospect II score, a proprietary matrix of serum tissue inhibitor of metalloproteinase-1 (TIMP-1) measured by ELISA, alpha-2 macroglobulin (A2M) measured by nephelometry, and HA measured by ELISA, was initially studied in 294 patients with chronic HCV and validated in an external cohort of 402 patients. A Fibrospect II score > 0.36 was associated with significant fibrosis (F2-F4), with 75% accuracy. A more recent study showed the Fibrospect II score to have a sensitivity of 72%, specificity of 74%, positive predictive value (PPV) of 61% and negative predictive value (NPV) of 82% in the detection of significant fibrosis in chronic HCV patients. At our institution, we have noted that the Fibrospect II may have a lower accuracy in predicting the degree of fibrosis in HCV patients with renal insufficiency or renal failure. To investigate this anecdotal observation further, we compared the accuracy of Fibrospect II in estimating hepatic fibrosis in HCV patients with significant renal insufficiency to a control group of HCV patients with normal renal function. Secondly, we also sought to identify the component of the Fibrospect II score that may affect its accuracy in patients with renal dysfunction. Lastly, the study aimed to determine if a hemodialysis (HD) session has any impact on the Fibrospect II scores in non-HCV infected patients who were dialysis-dependent.

This was a combined retrospective and prospective study. Twenty consecutive patients with HCV infection, confirmed by a positive serum HCV RNA, and chronic renal insufficiency (CRI) [defined as glomerular filtration rate (GFR)

For all patients, demographic data and laboratory tests including serum creatinine, calculated GFR per Modification of Diet in Renal Disease (MDRD) method, serum alanine aminotransferase (ALT) and Fibrospect II scores were obtained. MDRD is the methodology utilized to calculate GFR in the electronic medical record at our institution. Histologic data was obtained from the Liver and Pathology databases of the University of Chicago Medicine. Liver biopsies were graded and scored according to the Batts and Ludwig criteria with significant fibrosis defined as F2 – F4 staging. Continuous variables were expressed as means and medians and categorical variables were expressed as percentages. Data was subjected to ANOVA, t-test, chi2 test, area under receiver operating characteristic (AUROC) and regression analysis using Stata 10 software (StataCorp, LP, Texas). A p - value of < 0.05 was deemed significant. The University of Chicago Medicine Institutional Review Board approved this study. All authors had unlimited access to the study data and approved the final manuscript prior to publication.

A total of 48 patients were included in this study. The study group included 20 patients with chronic HCV and CRI (HCV+CRI group), and the control group included 18 HCV-infected patients with normal renal function (HCV group). Ten non-HCV infected patients on HD (HD group) were also studied. There was no significant difference in age or gender distribution amongst the study groups, but the HCV+CRI and the HD groups had significantly lower mean GFR’s at 16.7±13.4 ml/ min and 11.7±6.8 ml/min, respectively, than the HCV group, (p < 0.001). Notably, the mean serum ALT was lower in the HCV+CRI group at 39±24 IU/L than the HCV group at 75±38 IU/L, (p < 0.001). Both the HCV+CRI and HCV groups had a similar distribution of significant fibrosis (Table 1). Causes of renal disease in the HCV+CRI group included hypertensive nephropathy in 50%, diabetic nephropathy in 22% and other causes (focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, membranous glomerulonephritis, post-streptococcus glomerulonephritis, and calcineurin-inhibitor toxicity) in the rest.