SHAHID AZIZ DO, FACOI.

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1 SHAHID AZIZ DO, FACOI. ASSOCIATE CLINICAL PROFESSOR OF GI AND LIVER DISEASE. UT SOUTHWESTERN HEALTH SCIENCE CENTER, DALLAS ADJUNCT CLINICAL ASSISTANT PROFESSOR DEPT OF MEDICINE UNT HEALTH SCIENCE CENTER Characteristics of patients that leads to fibrosis Diseases that lead to fibrosis Stellate cells and fibrosis Inflammatory cascade diagram Histology interface hepatitis What gene leads to hepatic fibrosis? Genetic testing 1

2 3 Billion base pairs 25,000 genes Progression of fibrosis in HCV is highly variable GWAS assays have identified genetic markers that can increase risk for fibrosis Genes that increase risk of fibrosis in HCV: 1. HFE gene SNPs 2. TGPB1 gene SNPs 3. TNFa gene SNPs Genes that increase risk for steatosis/fibrosis: 1. PNPLA3 gene SNPs 2. rs gene SNPs Limitations to develop new treatments for hepatic fibrosis: variable rate of fibrosis progression Afdhal. Genetics of Hepatic Fibrosis: Epidemiology, Progression and Risk Stratification. AASLD Cirrhosis: histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury, which leads to portal hypertension and end-stage liver disease. Afdhalet al. Liver Cirrhosis Seminar. Lancet

3 Freidman et al. Mechanisms of Hepatic Fibrogenesis. Gastroenterology % of patients will progress to advanced fibrosis Individual variability that can be explained 1. Viral 2. Environmental 3. Host related factors 4. Host genetic factors Host genetic factors must account for differing rates of fibrosis progression. These factors include known genes: 1. HFE gene with SNPs: C282Y and H63D 2. TGB1 gene with SNPs: L10P and R25P Afdhal. Genetics of Hepatic Fibrosis: Epidemiology, Progression and Risk Stratification. AASLD HFE gene with SNPs: 1. C282Y 2. H63D TGB1 gene with SNPs 1. L10P 2. R25P TNFa gene with SNPs 1. G308A 3

4 C282Y polymorphism is the first genetic defect associated with increased hepatic fibrosis. SNP mutation C282Y in HFE gene leads to disease state (homozygous C282Y/C282Y) Patients with HCV and C282Y have higher fibrosis score (1.8 vs 2.6) Bonkovsky et al. Iron and HFE or TfR1 mutation as comorbid factors in HCV. J Hepatology Current Liver Fibrosis: Fibrospect score Liver elastography Liver biopsy Future risk for progression of Fibrosis: Signature 7 Genetic markers Patients with 25 yrs of HCV were compared for their variable rates of fibrosis progression: 1. Low rate of progression (Stage 0) 2. High rate of progression (Stage 4) Genome wide scan of 24,823 genes found 361 SNPs. Ranking these SNPs yielded top 7 SNPs. 4

5 154 Caucasian patients Cirrhosis Risk Score < 0.50 Sensitivity 89% Specificity 45% NPV 72% Cirrhosis Risk Score > 0.70 Sensitivity 60% Specificity 77 % PPV 82% 5

6 271 untreated patients with HCV Initial biopsy F0-2 Repeat biopsy done 5 years later CRS scores much higher in patients with fibrosis progression CRS scores even higher in patients who progressed from F0 Marcolongoet al. A seven-gene signature (CRS) predicts liver firbosis in HCV. Hepatology Marcolongoet al. A seven-gene signature (CRS) predicts liver firbosis in HCV. Hepatology CRS associated with both the risk of fibrosis and cirrhosis but not useful to predict HCC or decompensation. Curtoet al. Predicting cirrhosis in patients with HCV with a panel of genetic markers. Pharmocogenticsand Genomics

7 TGB1 gene affected by SNPs TGB1 stimulates synthesis and prevents breakdown of extracellular matrix proteins SNPs: L10P and R25P have been shown to alter the TGB1 secretion. TNFa gene affected by SNP TNFa is proinflammatory and can activate stellate cells. SNP: G308A promoter has been shown to increase fibrosis 2000 patients with HCV Comparing F0 to F4 patients Identified 7 SNPs: RNF7 antioxidant MERTK macrophage clearance of apoptotic cells PNPLA3 steatohepatitis in NAFLD rs steatohepatitis in NAFLD Impaired triglyceride hydrolysis Patinet al. GWAS identifies variants with liver fibrosis progression in HCV patients. EASL Barcelona

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