Significant Improvement In Fibrosis Research Articles

Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing, and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Preclinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGFβ pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support the clinical development of antivirals for the treatment of patients with RDEB and potentially other fibrotic diseases.

#3650 LINACLOTIDE IS PROTECTIVE AGAINST RENAL ISCHEMIA-REPERFUSION INJURY

Abstract Background and Aims Renal ischemia-reperfusion injury is associated with delayed graft function and poor long-term graft survival following transplantation. Linaclotide is a guanylate cyclase C (GC-C) receptor agonist that increases intracellular cGMP concentrations and promotes intestinal transport capacity by activating the GC-C receptor. Since CKD is a deficiency of cGMP in the kidney, increasing cGMP in the kidney by linaclotide would suppress fibrosis, protecting the kidney. Method An AKI rat model of unilateral nephrectomy plus contralateral ischaemia (30 min) and impaired reperfusion (up to 14 days) was used. Linaclotide was administered before and after surgery for 2 weeks, and blood and renal tissue samples were collected to determine its effect on renal function and whether it was protective against the progression of CKD. Results In the I/R injury+ group, creatinine levels were lower in the linaclotide-treated group than in the non-treated group. Sirius red staining showed significant improvement in fibrosis. The hydroxyproline content of kidneys was determined by the basic hydroxyproline method. RNA seq showed that genes down-regulated in I/R injury+ were the oxidative stress markers SOD3 and Gpx1. The expression of genes down-regulated in I/R injury+ was up-regulated to a degree similar to that in I/R injury- by treatment with linaclotide. These data suggest that linaclotide may ameliorate renal fibrosis by suppressing renal dysfunction through its antioxidant effects. Conclusion The antioxidant effect of linaclotide was found to suppress the decrease in renal function caused by I/R. We would like to apply this finding to human renal transplantation in the future to prevent renal function deterioration due to I/R.

Efficacy and Safety of a Botanical Formula Fuzheng Huayu for Hepatic Fibrosis in Patients with CHC: Results of a Phase 2 Clinical Trial.

Background Hepatitis C virus (HCV) is a common cause of progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma worldwide. Despite the availability of effective direct-acting antivirals, patients often have significant hepatic fibrosis at the time of diagnosis due to delay in diagnosis and comorbidities which promote fibrogenesis. Thus, antifibrotic agents represent an attractive adjunctive therapy. Fuzheng Huayu (FZHY), a traditional Chinese medicine botanical formulation, has been used as an antifibrotic agent in chronic HBV infection. Our aim was to assess FZHY in patients with HCV infection and active viremia. Method We randomized 118 patients with active viremia from 8 liver centers in the U.S. to receive oral FZHY (n = 59) or placebo (n = 59) for 48 weeks. Efficacy was assessed by histopathologic changes at the end of therapy. A subset of biopsies was further analyzed using qFibrosis to detect subtle changes in fibrosis in different zones of the hepatic lobules. Results FZHY was well tolerated and safe. Patients with baseline Ishak fibrosis stages F3 and F4 had better response rates to FZHY than patients with baseline F0–F2 (p=0.03). qFibrosis zonal analysis showed significant improvement in fibrosis in all zones in patients with regression of the fibrosis stage. Conclusions FZHY produced antifibrotic effects in patients with baseline Ishak F3 and F4 fibrosis stages. Reduction in fibrosis severity was zonal and correlated with the severity of inflammation. Based on its tolerability, safety, and efficacy, FZHY should be further investigated as a therapy in chronic liver diseases because of its dual anti-inflammatory and antiibrotic properties. Lay Summary. This is the first US-based, multicenter and placebo-controlled clinical trial that shows statistically significant reduction in fibrosis in patients with active HCV using an antifibrotic botanical formula. This has important implications as there is an immediate need for effective antifibrotic agents in treating many chronic diseases including NASH that lead to scarring of the liver. With artificial intelligence-based methodology, qFibrosis, we may provide a more reliable way to assess the FZHY as a therapy in chronic liver diseases because of its dual anti-inflammatory and antifibrotic properties.

Hepatic fibrosis changes in patients with chronic hepatitis C infection who respond to direct-acting antivirals.

BACKGROUND: Clearance of hepatitis C virus (HCV) can potentially slow or reverse liver fibrosis and cirrhosis. Studies of fibrosis changes after treatment with direct-acting antivirals (DAAs) are limited.OBJECTIVES: We aimed to assess the impact of DAAs on fibrosis in HCV treatment responders.DESIGN: Retrospective cohort study.SETTING: Tertiary care centers.PATIENTS AND METHODS: This study included adult patients who received DAA treatment for HCV (naïve and experienced) from June 2015 to January 2019 who were treatment responders. Biochemical and hematological data and noninvasive fibrosis markers were recorded at baseline and follow-up.MAIN OUTCOME MEASURES: Aspartate aminotransferase/platelet ratio index (APRI), fibrosis-4 score (FIB-4) and liver stiffness measurements (LSM) at baseline and follow-up.SAMPLE SIZE AND CHARACTERISTICS: 172 HCV treatment responders, mean (SD) age 54.1 (14.1) and body mass index 28.8 (6.5) kg/m2 at baseline; 96 (55.8%) were females.RESULTS: Fifty-eight (33.7%) patients were HCV treatment-experienced. Most patients were genotype 4 (n=125, 73%) and the mean follow-up was 141 (57.9) weeks. Compared with baseline, changes in alanine aminotransferase (P<.001), aspartate aminotransferase (P<.001), and albumin (P=.01) were statistically significant. Changes in LSM (15.09 kPa [11.4] vs. 10.19 kPa [7.4], P<.001), APRI (0.81 [0.7] vs. 0.34 [0.2], P<.001), and FIB-4 (1.99 [1.4) vs.1.35 [0.9], P<.001), and AST/ALT ratio (0.86 [0.32] vs. 0.95 [0.41], P=.015) were statistically significant. Differences in many of the same parameters were statistically significant between patients with low fibrosis (F0-F1) (n=59, 34.3%) and significant fibrosis (≥F2) (n=113, 65.7%).CONCLUSIONS: Our findings confirm that clearance of HCV with DAAs is associated with significant improvement in fibrosis as assessed by noninvasive liver fibrosis measures, which supports the concept of post-treatment fibrosis regression. Long follow-up studies are needed to assess the impact on morbidity and mortality.LIMITATIONS: Absence of histological correlation with these noninvasive scores. No assessment of fibrosis changes based on HCV geno-type or treatment regimen.CONFLICT OF INTEREST: None.

Clinical Role of Oral Vitamin C and E Therapy in Skin and Hair Disorders

Clinical Role of Oral Vitamin C and E Therapy in Skin and Hair Disorders

S1058 Impact of Hepatitis C Treatment With Direct-Acting Antiviral Agents on Liver Stiffness Using Vibration-Controlled Transient Elastography and Fibrosis-4 Scores: A Prospective Study in the U.S. Veteran Population

INTRODUCTION: Successful treatment of chronic Hepatitis C (CHC) is measured by sustained viral response (SVR) at 12 and/or 24 weeks after treatment with Direct Acting Antiviral Agents (DAAs). We assessed for improvement in liver stiffness following CHC treatment using vibration controlled transient elastography (VCTE) and Fibrosis 4 Score (Fib-4). METHODS: This was a prospective cohort study conducted by the GI Dept. at Dayton Veterans Affair Medical Center (VAMC). Stages for Liver Stiffness Measurement (LSM) obtained by VCTE were:F0 ≤ 6 kPa, F1–F2 = 6.1–9.4 kPa, F3 = 9.5–12.4 kPa and F4 (cirrhosis) ≥12.5 kPa. Stages for Fib-4 scores were:F0–F1 < 1.45, F2–F3 = 1.45–3.25, ≥ F4 (advanced fibrosis) > 3.25. Veterans who underwent SVR 12 and/or 24 after treatment with DAAs and had a pre-treatment LSM between January 1, 2014 and December 31, 2017 were included. Veterans who met the inclusion criteria and consented to a 2 year post SVR follow up VCTE were enrolled. Exclusion criteria were BMI > 32, co-existing Hepatitis B, poor quality VCTE, incomplete study values, and death. 204 patients were enrolled and 64 were included in analysis. RESULTS: CHC treatment with DAAs showed statistically significant improvement in fibrosis. For VCTE, median LSM was 11.85 kPa (IQR/M 3–27%) and 6.40 kPa (IQR 3–28%) [P < 0.001] before and after DAA treatment. Median Fib-4 scores were 2.08 and 1.41 before and after DAA treatment [p=< 0.001]. LSM from VCTE showed 76.9% (95% CI = 58.0%–89.0%, N0 = 26, N1 = 20) of patients at stage F4 had at least 1 stage improvement and 50% (95% CI = 32.1%–67.9%, N0 = 26, N1 = 13) showed 2 stage improvement. Fib-4 showed 73.3% (95% CI = 48.1%–89.1%; N0 = 15, N1 = 11) with 1 stage improvement and 6.7 % (95% CI = 1.2–29.8%; N0 = 15, N1 = 1) with 2 stage improvement. When all stages of fibrosis were included, 1 stage improvement was noted in 78.1% of patients on LSM (95% CI = 65.7–87.1%) and 62.5% of patients on Fib-4 score (CI = 48.4%–74.8%). There were no differences in variables such as BMI, alcohol use, underlying diabetes, statin use, pre-treatment fibrosis stage, viral load or genotype between those who had 1 stage improvement in fibrosis vs those who did not. 31 of 45 (68.9%, 95% CI = 53.2%–81.4%) had concordant findings on VCTE and Fib-4 score and 14 patients did not. CONCLUSION: Successful CHC treatment with DAAs results in fibrosis improvement by at least 1 stage as measured by VCTE and Fib-4. This improvement occurs regardless of variables such as BMI, presence of diabetes, or alcohol use.

Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis.

Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]. PAT-505 is a potent, selective, noncompetitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a Stelic Mouse Animal Model of nonalcoholic steatohepatitis (NASH), PAT-505 treatment resulted in a small but significant improvement in fibrosis with only minor improvements in hepatocellular ballooning and hepatic inflammation. In a choline-deficient, high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning, or inflammation. These data demonstrate that inhibiting autotaxin is antifibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH.

Review of current and potential future pharmacological treatments in nonalcoholic steatohepatitis.

Review of current and potential future pharmacological treatments in nonalcoholic steatohepatitis.

1273 OBESITY-INDUCED NAFLD: IDENTIFICATION OF TRANSCRIPTIONAL MASTER REGULATORS CONTROLLING METABOLIC AND INFLAMMATORY RESPONSES TO HIGH FAT DIET IN LIVER AND ADIPOSE TISSUE

Material and Methods: C57BL/6 mice, fed a high-fat diet (HFD) for 24 weeks, were confirmed to result in NASH, and devided into four groups for additional 24 weeks treatment. HFD group was fed HFD for 48 weeks, UDCA group was fed with HFD for 24 weeks, and then HFD+UDCA at a dose of 20mg/(kg.d) via gavages for additional 24 weeks, PUFA group was fed with HFD for 24 weeks, and then HFD+PUFA at a dose of 70mg/(kg.d) via gavages for following 24 weeks, and UDCA+PUFA group was fed with HFD for 24 wk, followed by HFD+UDCA+PUFA for 24 weeks. At the end of the experiment, body weight, serum biochemical index, and hepatopathologic changes by CRN scoring system were examined. Results: Liver showed hypertrophic and yellowish color change and all mice developed steatohepatitis after 24-week-HFD. The mean CRN scores by their liver histology as follows: 2.9±0.3 in steatosis, 2.65±0.7 in lobular inflammation, 1.8±0.4 in ballooning and 1.9±0.3 in fibrosis. After additional 24 weeks of HFD, only fibrosis score was increased significantly to 2.4±0.3. Treatment with UDCA and/or PUFA reduced liver/body weight ratio. Compared with the HFD group, significant improvement of steatosis was noted only in the UDCA group. Lobular inflammation was improved significantly both in UDCA and UDCA+PUFA groups compared with the HFD group. However, significant improvement of fibrosis was seen only in the UDCA+PUFA group. Conclusion: UDCA might play a role in the improvement of steatosis and lobular inflammation. Co-treatment of UDCA and PUFA reduces inflammation and finally fibrosis. For clinical application for NASH, UDCA and PUFA co-administration can be beneficial to prevent progression into cirrhosis.

Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct.

Chronic obstruction of the common bile duct may cause hepatic fibrosis and secondary biliary cirrhosis. We studied liver-biopsy specimens from 11 patients with chronic stenosis of the common bile duct due to chronic pancreatitis; all the patients had undergone liver biopsy before or at the time of surgical biliary decompression and underwent a subsequent liver biopsy for various clinical reasons. The patients were followed as part of a prospective study of 501 patients who had been treated for chronic pancreatitis. Two pathologists, who were unaware of the sequence of specimens, graded fibrosis on a scale of 0 (none) to 3 (cirrhosis). The 11 patients were all men. Chronic pancreatitis was due to alcohol abuse in 10 of the men; 1 had idiopathic disease. The median age at diagnosis was 38 years. The median interval between the first and second liver biopsies was 2.5 years (range, 0.3 to 9.0). The two patients who had restenosis of the biliary anastomosis were excluded from the analysis of fibrosis. In the group of nine patients without restenosis, the second specimen showed significant improvement in fibrosis (P=0.01). The fibrosis improved by two grades in two patients and by one grade in four patients; in three patients, the grade did not change. The pathologists agreed on the grading of specimens from 10 of the 11 patients. In patients with chronic pancreatitis and stenosis of the common bile duct, liver fibrosis may regress after biliary drainage.

Clinical significance of serum hyaluronic acid as a fibrosis marker in chronic hepatitis C patients treated with interferon-alpha: histological evaluation by a modified histological activity index scoring system.

The aim of the present study was to investigate the histological changes effected by interferon (IFN) treatment and to evaluate the clinical significance of serum hyaluronic acid (HA) as a marker of fibrosis. Forty-nine patients with chronic hepatitis C treated with IFN-alpha were divided into three groups according to the existence of viraemia: sustained complete responders (CR), complete responders with relapse (PR) and non-responders (NR). Needle biopsy sections of the liver taken before and at the end of IFN treatment were assessed according to the modified histological activity index (HAI) scoring system. Serum fibrosis markers, including HA, were measured at needle biopsies. Biopsies of CR at the end of treatment showed a significant improvement in fibrosis and necroinflammatory scores. More significant correlation was observed between fibrosis scores and serum levels of HA before IFN treatment (r = 0.607, P < 0.0001) than those between fibrosis scores, on the one hand, and peptide of type III procollagen (PIIIP; r = 0.531, P = 0.0004) or type IV collagen 7S domain (type IV-C; r = 0.241, P = 0.1062) on the other. Moreover, serum HA levels fell significantly in patients in whom fibrosis improved (P = 0.011). This is the first paper describing the advantages of the modified HAI scoring system over others in estimating the effect of IFN-alpha; the results also indicate that serum HA can be useful in monitoring liver fibrosis in chronic hepatitis C patients treated with IFN-alpha.