Wednesday, March 30, 2016

Merck to Present New Findings from Chronic Hepatitis C Clinical Development Programs at The International Liver Congress 2016

Merck to Present New Findings from Chronic Hepatitis C Clinical Development Programs at The International Liver Congress 2016
Presentations Include Results from Phase 3 Study Evaluating ZEPATIER™ (elbasvir and grazoprevir) Compared to Sofosbuvir-Containing Regimen, and Results from Studies in Difficult-to-Treat Populations

KENILWORTH, N.J.--()--Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced the planned presentations of data from the company’s broad chronic hepatitis C virus (HCV) clinical development programs at the upcoming International Liver Congress™ 2016. Clinical data from trials evaluating ZEPATIER™ (elbasvir and grazoprevir) 50mg/100mg tablets will be featured, including the Phase 3 C-EDGE Head-to-Head trial comparing ZEPATIER to a regimen of sofosbuvir with peginterferon alfa and ribavirin (RBV), and the Phase 3 C-EDGE IBLD and C-EDGE CO-STAR studies evaluating ZEPATIER in underserved patients with historically difficult-to-treat conditions. In addition, data from trials evaluating Merck’s chronic HCV candidates MK-3682B (grazoprevir/MK-84081/MK-36822) and MK-8408 monotherapy will be presented. ZEPATIER – Merck’s once-daily, fixed-dose combination tablet indicated with or without RBV for the treatment of chronic HCV genotype (GT) 1 or GT4 infection in adults – was approved by the U.S. Food and Drug Administration (FDA) on Jan. 28, 2016. The International Liver Congress™ 2016 is scheduled to take place at the Fira Barcelona Gran Via, Barcelona, Spain from April 13-17, 2016.
“We continue to build on the data that supported the recent U.S. FDA approval of ZEPATIER with additional studies that provide clinical evidence about ZEPATIER in multiple patient populations”
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“We continue to build on the data that supported the recent U.S. FDA approval of ZEPATIER with additional studies that provide clinical evidence about ZEPATIER in multiple patient populations,” said Dr. Eliav Barr, vice president, infectious diseases, Merck Research Laboratories. “Merck remains committed to the fight against chronic hepatitis C through our ongoing clinical programs exploring diverse patient groups and areas of unmet need.”
At The International Liver Congress™ 2016, key data presentations will include:
  • New data from the Phase 3 C-EDGE clinical trial program, evaluating ZEPATIER (elbasvir and grazoprevir) (with or without RBV), across multiple HCV genotypes (1, 4 and 6) and diverse patient populations, including those who are historically difficult-to-treat, over a 12-week treatment duration.
Thursday, April 14:
  • C-EDGE Head-to-Head (H2H): Efficacy and Safety of Elbasvir and Grazoprevir Compared With Sofosbuvir/Pegylated Interferon/Ribavirin: A Phase 3 Randomized Controlled Trial (Oral presentation, Abstract #PS002, 4:15 p.m.-4:30 p.m. CEST)
  • C-EDGE CO-STAR: Favorable Impact of Elbasvir and Grazoprevir on Health-Related Quality of Life in Treatment-Naïve HCV-Infected Persons Who Inject Drugs Receiving Opioid Agonist Therapy (Poster presentation, Abstract #THU-225, 8:00 a.m.-6:00 p.m. CEST)
Saturday, April 16:
  • C-EDGE IBLD: Efficacy and Safety of Elbasvir/Grazoprevir (EBR/GZR) in Subjects With Chronic Hepatitis C Virus Infection and Inherited Blood Disorders (IBLD) (Poster presentation, Abstract #SAT-128, 8:00 a.m.-6:00 p.m. CEST)
  • C-EDGE TN: Final SVR24 Data From the Phase 3 C-EDGE Treatment-Naïve (TN) Study of Elbasvir (EBR)/Grazoprevir (GZR) in Patients With Chronic HCV Genotype 1, 4 or 6 Infection (Poster presentation, Abstract #SAT-266, 8:00 a.m.-6:00 p.m. CEST)
  • C-EDGE CO-STAR: Risk of Reinfection Following Successful Therapy With Elbasvir and Grazoprevir in Persons Who Inject Drugs (PWID) Receiving Opioid Agonist Therapy (OAT) (Poster presentation, Abstract #SAT-163, 8:00 a.m.-6:00 p.m. CEST)
Additional Presentations of Interest
Thursday, April 14:
  • In a 5-Day Monotherapy Trial, MK-8408 Demonstrates Potent Antiviral Activity and Improved Resistance Profile in HCV Patients With Genotypes 1, 2, and 3 Infections (Poster presentation, Abstract #THU-222, 8:00 a.m.-6:00 p.m. CEST)
Saturday, April 16:
  • High Efficacy of an 8-Week 3-Drug Regimen of Grazoprevir/MK-8408/MK-3682 in HCV Genotype 1, 2 and 3-Infected Patients: SVR24 Data From the Phase 2 C-CREST 1 and 2 Studies (Poster presentation, Abstract #SAT-139, 8:00 a.m.-6:00 p.m. CEST)
  • C-SWIFT Retreatment Final Results: Highly Successful Retreatment of GT1-Infected Patients With 12 Weeks of Elbasvir/Grazoprevir Plus Sofosbuvir and Ribavirin After Failure of Short-Duration All-Oral Therapy (Poster presentation, Abstract #SAT-148, 8:00 a.m.-6:00 p.m. CEST)
  • Cost Effectiveness of Elbasvir (EBS, MK-8742)/Grazoprevir (GZR/MK-5172) Use in Treatment-Naïve and Treatment-Experienced Patients With Hepatitis C Virus (HCV) Genotype 1 Infection and Chronic Kidney Disease (CKD) in the United States (Poster presentation, Abstract #SAT-141, 8:00 a.m.-6:00 p.m. CEST)
  • Sustained Virologic Response Among Patients With Genotype 1 Hepatitis C and Treated With Interferon-Free Direct-Acting Antiviral Regimens (Poster presentation, Abstract #SAT-217, 8:00 a.m.-6:00 p.m. CEST)
  • Characteristics and Prevalence of Chronic Kidney Disease Among Patients With Hepatitis C Who Are Treated With Interferon-Free Direct-Acting Antiviral Regimens (Poster presentation, Abstract #SAT-109, 8:00 a.m.-6:00 p.m. CEST)
For more information, including a complete list of abstract titles at the meeting, please visit:
Selected Safety Information about ZEPATIER (elbasvir and grazoprevir)
ZEPATIER is not for use in patients with moderate or severe hepatic impairment (Child Pugh B or C). ZEPATIER is also not for use with organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors (e.g., atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cyclosporine), strong cytochrome P450 3A (CYP3A) inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s Wort), and efavirenz. If ZEPATIER (elbasvir and grazoprevir) is administered with ribavirin (RBV), healthcare professionals should refer to the prescribing information for RBV as the contraindications, warnings and precautions, adverse reactions and dosing for RBV also apply to this combination regimen.
Elevations of alanine transaminase (ALT) to greater than 5 times the upper limit of normal (ULN) occurred in 1% of subjects, generally at or after treatment week 8. These late ALT elevations were typically asymptomatic and most resolved with ongoing or completion of therapy. Healthcare professionals should perform hepatic lab testing on patients prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, additional hepatic lab testing should be performed at treatment week 12.
Patients should be instructed to consult their healthcare professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces. Healthcare providers should consider discontinuing ZEPATIER if ALT levels remain persistently greater than 10 times ULN. ZEPATIER should be discontinued if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or international normalized ratio.
The concomitant use of ZEPATIER with certain drugs may lead to possible clinically significant adverse reactions from greater exposure to ZEPATIER or concomitant drugs. Coadministration of ZEPATIER is not recommended with certain strong CYP3A inhibitors (e.g., ketoconazole or the cobicistat-containing regimens of elvitegravir/cobicistat/emtricitabine/tenofovir [disoproxil fumarate or alafenamide]). Healthcare professionals should not exceed atorvastatin 20mg/daily or rosuvastatin 10mg/daily when given with ZEPATIER. If ZEPATIER is given with fluvastatin, lovastatin or simvastatin, healthcare professionals should give the lowest statin dose necessary and closely monitor for statin-associated adverse events. If ZEPATIER and tacrolimus are coadministered, frequent monitoring of tacrolimus whole blood concentrations, changes in renal function and tacrolimus-associated adverse events is recommended.
The concomitant use of ZEPATIER and certain drugs may cause significant decrease of elbasvir and grazoprevir plasma concentrations, which may lead to reduced therapeutic effect of ZEPATIER and possible development of resistance. Coadministration of ZEPATIER is not recommended with moderate CYP3A inducers (e.g., nafcillin, bosentan, etravirine, modafinil).
In subjects receiving ZEPATIER for 12 weeks, the most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache and nausea. In subjects receiving ZEPATIER with RBV for 16 weeks, the most commonly reported adverse reactions of moderate or severe intensity (greater than or equal to 5%) were anemia and headache.

About ZEPATIER™ (elbasvir and grazoprevir) 50mg/100mg Tablets
ZEPATIER is a fixed-dose combination product containing elbasvir, a hepatitis C virus (HCV) NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor, and is indicated with or without ribavirin (RBV) for treatment of chronic HCV genotype (GT) 1 or GT4 infection in adults. The dosing regimens and durations for treatment with once-daily ZEPATIER for chronic HCV GT1 or GT4 infection in patients with or without cirrhosis, HIV-1 co-infection or renal impairment are as follows:
  • Twelve weeks of treatment with ZEPATIER is recommended for: GT1a-infected patients who are treatment-naïve or who failed prior treatment with peginterferon alfa plus RBV (PegIFN/RBV-experienced) without baseline NS5A resistance-associated polymorphisms (amino acid positions 28, 30, 31 or 93); GT1b-infected patients who are treatment-naïve or PegIFN/RBV-experienced; and GT4-infected patients who are treatment-naïve.
  • Twelve weeks of treatment with ZEPATIER in combination with RBV is recommended for GT1a- or GT1b-infected patients who failed prior treatment with PegIFN/RBV + a HCV NS3/4A protease inhibitor (PI) (boceprevir, simeprevir or telaprevir). For GT1a-infected PegIFN/RBV/PI-experienced patients with one or more baseline NS5A resistance-associated polymorphisms, the optimal ZEPATIER-based treatment regimen and duration of therapy has not been established.
  • Sixteen weeks of treatment with ZEPATIER in combination with RBV is recommended for: GT1a-infected patients who are treatment-naïve or PegIFN/RBV-experienced with baseline NS5A resistance-associated polymorphisms; and GT4-infected patients who are PegIFN/RBV-experienced.
For patients with chronic HCV GT1a infection, testing for the presence of NS5A resistance-associated polymorphisms is recommended prior to starting treatment with ZEPATIER to determine the optimal dosage regimen and duration.

CDL March Issue The Liver in Systemic Disease: Rheumatic and connective tissue disorders

Clinical Liver Disease is an official digital educational learning resource from the American Association for the Study of Liver Diseases. Visitors are able to view videos, access full text articles, and download files in either HTML or PDF formats.

Clinical Liver Disease© The American Association for the Study of Liver Diseases

Volume 7, Issue 3 Pages 45 - 67, March 2016

Special Issue: Emerging Liver Scholars, Consultations in Hepatology, Ethics in Clinical Liver Disease, Integrated Health and The Liver in Systemic Disease
The latest issue of Clinical Liver Disease is available on Wiley Online Library

Emerging Liver Scholars
The Liver in Systemic Disease
Guest Edited by John O'Grady, MD
Rheumatic and connective tissue disorders (pages 64–67)
Deepak Joshi
Article first published online: 29 MAR 2016 | DOI: 10.1002/cld.536
Watch a video presentation of this article

Guest Edited by William Sanchez, MD
Noninvasive evaluation of nonalcoholic fatty liver disease (pages 45–47)
Benjamin Renelus and Temitope Foster
Article first published online: 29 MAR 2016 | DOI: 10.1002/cld.538
Watch a video presentation of this article

Consultations in Hepatology
Guest Edited by Mary Rinella, MD
Elevated creatinine in a patient with cirrhosis (pages 48–52)
Heather L. Klavan and Brett E. Fortune
Article first published online: 29 MAR 2016 | DOI: 10.1002/cld.534
Watch a video presentation of this article
Watch the interview with the author

Unexplained ascites (pages 53–56)
Ruben Hernaez and James P. Hamilton
Article first published online: 29 MAR 2016 | DOI: 10.1002/cld.537
Watch a video presentation of this article
Watch the interview with the author

Ethics in Clinical Liver Disease
Guest Edited by Andrew Aronsohn, MD
Ethical review of the responsibilities of the patient advocate in living donor liver transplant (pages 57–59)
Rebecca Hays and Arthur J. Matas
Article first published online: 29 MAR 2016 | DOI: 10.1002/cld.533
Watch a video presentation of this article
Watch the interview with the author

Integrated Health
Guest Editor by Felix Stickel, MD
 Drug-induced liver injury in the United States: A review of multi-ingredient supplements (pages 60–63)
Elizabeth Zheng and Victor Navarro
Article first published online: 29 MAR 2016 | DOI: 10.1002/cld.535
Watch a video presentation of this article
Watch the interview with the author

New Travel Horizons: Hepatitis C Tourism From China

China Real Time Report

New Travel Horizons: Hepatitis C Tourism From China
Chinese people in the past have gone to the U.S. to for cancer treatment and have snatched up cold medicine and painkillers on trips to Japan. Chinese now go overseas for another medical purpose: curing their liver diseases.
In October, Ms. Sun boarded a plane to New Delhi with the help of a Shanghai-based company. It was a first trip outside China. She came back with three months’ worth of Gilead Sciences’ blockbuster drug Sovaldi, which is still in the testing stage in China. She says she now tests negative for hepatitis C.
Continue reading....

Chinese Market Offers New Life to Many Drugs
By finding local partners in China, global drugmakers have chance to make money on drugs that have fallen short elsewhere

Thursday, March 24, 2016

Canada’s uneven response to hep C

Erasing hepatitis C: Is Canada doing enough?

More work needed to screen baby boomers at higher risk of carrying the disease, ensure antiviral drugs reach patients, say UAlberta researchers.

By Bryan Alary on March 23, 2016

Michael Houghton’s “race” started 35 years ago in a San Francisco-area lab where he was part of the team that first identified hepatitis C. In those days, the early 1980s, scientists knew the virus existed—patients were getting sick because of blood transfusions—but it was labelled for what it wasn’t: “non-A” or “non-B” hepatitis. “It ended up taking seven years—a lot of false leads, a lot of frustration,” remembers Houghton, now Canada Excellence Research Chair in Virology at the University of Alberta.
One of the major challenges with hepatitis C is many people don’t know they are carriers for years—sometimes decades—after becoming infected, often learning of their diagnosis after showing symptoms of liver damage. The new antivirals are so expensive that in many cases provincial pharmacare programs only cover patients with more pronounced symptoms. “It’s almost like we’re going to wait until you get very sick before we treat you. That’s never ideal,” says Houghton. “The treatment cures hep C, not liver cancer, and that’s a very real risk when you delay treatment.”
 Continue reading....

Wednesday, March 23, 2016

A Focus on Hepatitis C: Novel Therapeutic Regimens

A Focus on Hepatitis C: Novel Therapeutic Regimens
In the second part of this three-part series, Dr William Balistreri continues his discussion of hepatitis C with a review of new antiviral agents and novel therapeutic strategies.
Medscape Gastroenterology, March 22, 2016

Antivirals for HCV

Novel therapeutic strategies directed against HCV are based on a cocktail of DAAs that are most commonly used in fixed-dose combinations and constructed on the basis of their synergistic mechanisms of action. They are highly effective against the entire spectrum of HCV genotypes and patient populations.

The currently or soon to be available antiviral agents are outlined below and include NS3/4A protease inhibitors, which act by interrupting the HCV life cycle; NS5A inhibitors, which block the HCV replication complex and the assembly and release of HCV particles; nucleotide inhibitors, which cause HCV synthesis chain termination; and nonnucleoside inhibitors, which block HCV replication.

  • Simeprevir—an oral NS3/4A protease inhibitor;
  • Paritaprevir—an NS3 protease inhibitor, combined with low-dose ritonavir;
  • Asunaprevir—an NS3 protease inhibitor;
  • Grazoprevir (GZR)—an NS3/4A protease inhibitor;
  • Ledipasvir (LDV)—an NS5A inhibitor;
  • Daclatasvir (DCV)—a pangenotypic NS5A replication complex inhibitor;
  • Elbasvir (EBR)—an NS5A replication complex inhibitor;
  • Velpatasvir (VEL)—a pangenotypic inhibitor of the NS5A protein;
  • Ombitasvir—an NS5A inhibitor;
  • Sofosbuvir (SOF)—a uridine nucleotide analogue and a pangenotypic, selective inhibitor of NS5B polymerase; and
  • Dasabuvir—a nonnucleoside NS5B polymerase inhibitor.
Continue reading part two; A Focus on Hepatitis C: Novel Therapeutic Regimens
Part 1 focused on prevalence, screening methods, and access and barriers to care.

Serum Level of Thyroid Hormones in Patients with Chronic Hepatitis C Virus Infection

Serum Level of Thyroid Hormones in Patients with Chronic Hepatitis C Virus Infection

Download as PDF (Size:1143KB) ePub, PP. 126-134
OJEMD> Vol.6 No.3, March 2016
DOI: 10.4236/ojemd.2016.63017

Mohamed Abdel-Fattah El-Feki, Nilly Helmy Abdalla, Mohamed Ibrahim Atta, Ahmed Amin Ibrahim 

Internal Medicine Department, Faculty of Medicine, Beni Suef University, Beni Suef, Egypt.

Objective: There are clinical and laboratory associations between thyroid and liver diseases. Hepatitis C virus (HCV) is known to be responsible for both hepatic and extrahepatic diseases. The most frequent and clinically important endocrine extrahepatic diseases are thyroid disorders and type 2 diabetes mellitus. We aim to study the relationship between the serum level of thyroid hormones (THs) and the severity of liver disease in patients with chronic hepatitis C virus (CHC) infection.

Methods: 60 patients with CHC infection were selected for the study. They were divided into two groups: with or without liver cirrhosis. Those with liver cirrhosis were further subdivided according to the Child-Turcotte-Pugh scoring system. Serum levels of free T3 (FT3), free T4 (FT4) and TSH were measured to all patients.

Results: There was decrease in the FT3 and FT4 levels and increase in the TSH levels in patients with CHC with cirrhosis when compared to patients with CHC without cirrhosis.

Conclusion: Thyroid profile abnormalities were seen in cirrhotic HCV patients when compared to non-cirrhotic patients. The abnormalities in the serum level of THs (decreased FT3, FT4, and increased TSH) are strongly associated with the severity of liver damage and advancing of the child score.

Hepatitis C Virus, Thyroid Hormones, Liver Cirrhosis

Full text article
Download as PDF

Clinical trials of DAAs against HCV suggest cure often took place before the end of treatment

More cost-effective cure for hepatitis C may be close
Loyola researchers predict cure using reduced drugs through tailored regimen
Loyola University Health System

The cost of treating hepatitis C virus (HCV) could be cut up to 50 percent if mathematical models are used to predict when patients can safely stop taking direct-acting antiviral (DAA) medication, according to a new study by researchers at Loyola University Health System and Loyola University Chicago.

An estimated 170 million people have the blood-borne infection worldwide, which is a major cause of chronic liver disease. The recent approval of DAAs has led to a revolution in the treatment of HCV, but the high cost of DAAs limits access to treatment in America and abroad.

"Recent clinical trials of DAAs against HCV suggest that cure of the infection often took place before the end of treatment," said Harel Dahari, PhD, assistant professor at Loyola University Chicago Stritch School of Medicine.

"Treatment currently is standardized to be given for a set period of time, not tailored to the patient," said Scott Cotler, MD, FCO, hepatology division director for Loyola and Stritch professor. "In many cases, this may result in the prolonged use of expensive drugs with essentially no additional positive effect."

Using more frequent blood testing to determine HCV levels, Loyola researchers were able to identify when a cure was reached and predict when therapy could be discontinued. This modeling could allow for individualized treatment to achieve optimal results while reducing drug duration and cost.

"This is the first time this approach has been tested in hepatitis C patients undergoing DAA treatment," Dr. Dahari said. "This initial study is very encouraging."

The lead authors, Drs. Dahari, Laetitia Canini, PhD, Susan L. Uprichard, PhD, and colleagues examined the test results of 58 chronic-HCV patients being treated with the widely used DAA drug sofosbuvir, combined with daclatasvir, simeprevir or ledipasvir, in three French referral centers. HCV was measured before treatment (called baseline), at day two, every other week, end of treatment and then 12 weeks after end of treatment. Mathematical modeling was used to predict the duration of treatment need to achieve a cure.

"The use of early viral-kinetic analysis has the potential to individualize duration of DAA therapy with a projected cost savings of 16 to 20 percent per 100 treated persons and up to 50 percent in about 40 percent of patients," Dr. Dahari and colleagues wrote. "Shorter regimens with low pill burdens, and few adverse effects, could improve patient adherence in difficult to treat populations."
The study, published in the Journal of Hepatology, is titled "HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with declatasvir, simeprevir or ledipasvir."

Other authors of the study include collaborators from Germany (Frederik Graw), Brazil (Evaldo S.A. Araújo), and France (Guillaume Penaranda, Emilie Coquet, Laurent Chiche, Aurelie Riso, Christophe Renou, Marc Bourliere, and Philippe Halfon - as senior author).

The U.S. Centers for Disease Control (CDC) recommends that Baby Boomers (born 1945-1965), be tested for HCV. For undetermined reasons, people born during this era are five times more likely to be infected than other adults. The CDC reports that a one-time test of every Baby Boomer would find 800,000 new cases and prevent 120,000 deaths.

Loyola's researchers and board-certified hepatologists, or liver disease experts, have developed effective, nationally recognized treatment plans for hard-to-treat and advanced cases of hepatitis B, hepatitis C and hepatocellular carcinoma. Additionally, the team is skilled in treating all aspects of liver disease, including cirrhosis and acute liver failure. Loyola has a highly successful liver transplant program. 

Read more:

Tuesday, March 22, 2016

Michigan Medicaid now approving coverage of popular Hepatitis-C Drug

Michigan Medicaid now approving coverage of popular Hepatitis-C Drug
(NEWSCHANNEL 3) - Michigan Medicaid is now starting to approve coverage of a popular but expensive Hepatitis-C drug. This comes just one month after ...

Updated - Anthem Sues Express Scripts For A Bigger Slice Of Drug Savings

Updated - Anthem Sues Express Scripts For A Bigger Slice Of Drug Savings
Alison Kodjak

Updated March 22, 20167:43 AM ET
Published March 21, 20163:16 PM ET

The battle over drug prices escalated Monday when health insurance giant Anthem Inc. sued Express Scripts, a manager of drug benefits, to get a bigger share of savings on prescription medicines.

Anthem is looking for a change in its contract with Express Scripts, which handles drug benefits for 80 million people. The insurer says it's overpaying for pharmaceuticals and not benefiting from rebates the pharmacy benefit manager has negotiated with drugmakers.

Document: View The Complaint, here....

Monday, March 21, 2016

Metabolic Disorder Largest Risk Factor of Hepatocellular Carcinoma

Jason Hoffman, PharmD, RPh
March 21, 2016

Metabolic Disorder Largest Risk Factor of Hepatocellular Carcinoma

Among US Medicare recipients, metabolic disorders contribute more to the incidence of hepatocellular carcinoma (HCC) incidence than any other risk factor, including hepatitis C virus (HCV) infection, alcohol, and smoking, a study published in the journal Cancer has shown.1

The incidence of HCC has been increasing in the United States for many decades. Because the incidence of HCV infection has been declining and the prevalence of metabolic disorders has been rising, researchers hypothesized that the proportion of HCC attributable to certain risk factors may be changing.

For the study, researchers analyzed data from 10 708 patients with HCC diagnosed between 2000 and 2011 and included in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. These patients were compared with 332 107 cancer-free controls.

Results showed that 32% of HCC cases were attributable to metabolic disorders, 20.5% to HCV infection, 13.4% to alcohol, 9% to smoking, 4.3% to hepatitis B virus (HBV) infection, and 1.5% to genetic disorders.

Researchers found that the impact of risk factors on the incidence of HCC varied by race/ethnicity and sex. HCC was more likely to be attributable to metabolic disorders among Hispanics and whites, while HCV had the largest effect among blacks and Asians.

Further, the study demonstrated that HCC cases attributed to metabolic disorders increased by approximately 10%, while HCC cases attributable to alcohol-related disorders and HCV infection remained stable.


1. Makarova-Rusher OV, Altekruse SF, McNeel TS, et al. Population attributable fractions of risk factors for hepatocellular carcinoma in the United States [published online ahead of print March 21, 2016]. Cancer. doi:10.1002/cncr.29971.

Article Source

FDA approves expanded use of Roche hepatitis C virus RNA test as aid in diagnosis

FDA approves expanded use of Roche hepatitis C virus RNA test as aid in diagnosis

INDIANAPOLIS, March 21, 2016 /PRNewswire/ -- Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today that it has received approval from the U.S. Food and Drug Administration (FDA) for its hepatitis C virus (HCV) quantitative RNA test to be used as an aid in the diagnosis of HCV infection for certain patient populations. Results from the COBAS AmpliPrep/COBAS TaqMan HCV Test, v2.0 can now be used to confirm an active hepatitis infection, in addition to providing an accurate measurement of how much virus is in a patient's blood, to help a physician determine the best course of treatment. This expanded use for the test saves a physician time in making a treatment decision and helps improve patient care.

"Hepatitis C can be a silent killer, but with several highly effective new antiviral drugs on the market, there is a very high cure rate," said Alan Wright, MD, MPH, chief medical officer at Roche Diagnostics. "That's why the CDC recommends HCV testing for persons at risk for infection and for everyone born between 1945 and 1965. But a positive HCV antibody test alone does not indicate an active infection. So it's critical for physicians to diagnose an active infection by detecting the presence of hepatitis C virus RNA."
The Roche test is the first quantitative HCV RNA test to be approved for use as an aid in diagnosis for active HCV infection. This expanded indication is in addition to its approved use as a viral load test to help physicians assess a patient's response to antiviral therapy. Roche HCV viral load tests have also been used to establish the treatment efficacy of direct-acting antiviral treatment regimens recently approved by the FDA. The COBAS AmpliPrep/COBAS TaqMan HCV Test, v2.0 is part of Roche's expanding portfolio of diagnostic tests to diagnose, confirm and manage hepatitis C infection.
About the test
The COBAS AmpliPrep/COBAS TaqMan HCV Test, v2.0 represents the latest innovation in Roche's virology test portfolio. The dual-probe PCR assay is intended for use in the management of patients with chronic HCV, in conjunction with clinical and laboratory markers of infection, and as an aid in diagnosis for individuals with antibody evidence of HCV infection with evidence of liver disease, individuals suspected to be actively infected with HCV antibody evidence, and individuals at risk for HCV infection with antibodies to HCV. Detection of HCV RNA indicates that the virus is replicating and therefore is evidence of active infection. The test is an in vitro nucleic acid amplification test for the detection and quantitation of hepatitis C virus RNA genotypes 1 to 6 in human EDTA plasma or serum. It can be used to predict the probability of sustained virologic response (SVR) early during a course of antiviral therapy and to assess viral response to antiviral treatment (response-guided therapy), as measured by changes of HCV RNA levels.
The real-time polymerase chain reaction (PCR)-based HCV test is designed for use on Roche's fully automated COBAS AmpliPrep/COBAS TaqMan System, an established platform for viral load monitoring of multiple infectious diseases that improves workflow in testing laboratories. The system can be combined with the cobas p 630 instrument, which provides an integrated pre-analytical primary tube handling solution.

Sunday, March 20, 2016

Type 2 Diabetes in Non-Alcoholic Fatty Liver Disease and Hepatitis C Virus Infection-Liver: The “Musketeer” in the Spotlight

Int. J. Mol. Sci. 2016, 17(3), 355; doi:10.3390/ijms17030355

Type 2 Diabetes in Non-Alcoholic Fatty Liver Disease and Hepatitis C Virus Infection—Liver: The “Musketeer” in the Spotlight
Stefano Ballestri 1, Fabio Nascimbeni 2,3, Dante Romagnoli 2, Enrica Baldelli 3, Giovanni Targher 4 and Amedeo Lonardo 2,*
1 Operating Unit Internal Medicine, Pavullo General Hospital, Azienda USL Modena, ViaSuore di San Giuseppe Benedetto Cottolengo, 5, Pavullo, 41026 Modena, Italy
2 Outpatient Liver Clinic and Operating Unit Internal Medicine, NOCSAE, Azienda USL Modena, Via P. Giardini, 1355, 41126 Modena, Italy
3 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via P. Giardini, 1355, 41126 Modena, Italy
4 Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126 Verona, Italy
* Correspondence: Tel.: +39-059-396-1807; Fax: +39-059-396-1322
Academic Editor: Giovanni Tarantino

Received: 16 February 2016 / Accepted: 2 March 2016 / Published: 9 March 2016

Abstract: The pathogenesis of type 2 diabetes (T2D) involves chronic hyperinsulinemia due to systemic and hepatic insulin resistance (IR), which if uncorrected, will lead to progressive pancreatic beta cell failure in predisposed individuals. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty (simple steatosis and steatohepatitis) and non-fatty liver changes (NASH-cirrhosis with or without hepatocellular carcinoma (HCC)) that are commonly observed among individuals with multiple metabolic derangements, notably including visceral obesity,  insulin resistance (IR) and type 2 diabetes (T2D).

Hepatitis C virus (HCV) infection is also often associated with both hepatic steatosis and features of a specific HCV-associated dysmetabolic syndrome. In recent years, the key role of the steatotic liver in the development of insulin resistance (IR) and type 2 diabetes (T2D) has been increasingly recognized. Thus, in this comprehensive review we summarize the rapidly expanding body of evidence that links type 2 diabetes (T2D) with NAFLD and HCV infection.

For each of these two liver diseases with systemic manifestations, we discuss the epidemiological burden, the pathophysiologic mechanisms and the clinical implications. To date, substantial evidence suggests that NAFLD and HCV play a key role in T2D development and that the interaction of T2D with liver disease may result in a “vicious circle”, eventually leading to an increased risk of all-cause mortality and liver-related and cardiovascular complications. Preliminary evidence also suggests that improvement of NAFLD is associated with a decreased incidence of T2D. Similarly, the prevention of T2D following HCV eradication in the era of direct-acting antiviral agents is a biologically plausible result. However, additional studies are required for further clarification of mechanisms involved.

epidemiology; cirrhosis; clinical implications; direct acting antivirals; fibrosis; insulin resistance; hepatocellular carcinoma; NASH; pathophysiology

1. Introduction
1.1. Definitions

Type 2 diabetes (T2D) identifies the more prevalent category of diabetes mellitus and is due to a progressive insulin secretory defect in the background of insulin resistance (IR) [1]. T2D is typically found in obese and overweight middle-aged individuals though the age of its initial manifestation has now been observed shifting towards adolescents and even children [2].
Non-alcoholic fatty liver disease (NAFLD) describes a cluster of hepatic disorders predominantly (though not exclusively) characterized by fatty changes with or without ballooning degeneration and fibrosis (i.e., simple steatosis, steatohepatitis (NASH) and advanced fibrosis), which may evolve into cirrhosis (NASH-cirrhosis will typically lose fatty changes) and hepatocellular carcinoma (HCC); NAFLD is commonly observed in insulin-resistant, dysmetabolic individuals without excessive alcohol consumption and other competing etiologies of liver disease [3,4]. There is now compelling evidence that NAFLD is a multisystem disease associated with a wide range of extra-hepatic manifestations, notably including, among others, IR, dysglycemia and premature atherosclerosis [5,6].
Hepatitis C virus (HCV) is a small enveloped RNA virus belonging to the genus Flaviviridae, of which six different genotypes are recognized and which is transmitted via the parenteral route [7]. In several countries there have been two major HCV epidemics. The first one (mostly sustained by genotype 1 HCV) took place in the 1960s as a result of HCV being transmitted via medical procedures. The second one (predominantly due to genotype 3 HCV) occurred in the 1980s owing to needle-sharing practices among intravenous illicit drug users [7].
The natural course of HCV infection is variable and modulated by the interaction of host and viral factors. Of concern, the chronicity rate following acute infection approximates 85%, giving way to dreadful sequelae, such as chronic hepatitis, cirrhosis, end-stage liver failure and HCC [7]. Similarly to NAFLD, HCV infection is increasingly identified as a systemic disease which may be conducive to metabolic disorders (including IR and T2D) and premature atherosclerosis [8].
1.2. Epidemiology and Burden of Type 2 Diabetes
The world prevalence of T2D was estimated to be 6.4% in 2010 and is projected to rise to 7.7% in 2030 [9]. Recent estimates of T2D prevalence in the main five European countries (France, Germany, Italy, Spain and UK) ranged from 4.8% in Italy to 8.9% in Germany, with rates increasing steadily over the past two decades in all these countries. Of concern, in these European countries the total direct medical costs of T2D in 2010 were estimated to range from 5.45 billion euros in Spain to 43.2 billion euros in Germany, with hospitalizations due to T2D-related complications accounting for the greatest proportion of these costs [10]. In the USA, T2D now affects up to 8%–10% of adults in the general population in whom it increases up to four-fold the risk of major cardiovascular events and is the leading cause of blindness, chronic kidney failure and non-traumatic lower extremity amputations [11]. In 2007, T2D posed on society a cost as high as 174 billion dollars in the USA [12]. Of concern, this already alarming prevalence of T2D is predicted to be increasing in all age groups, making it urgent for clinicians, researchers and health authorities to gain a better understanding of the pathophysiology of T2D aimed at preventing the further spread of its disastrous pandemic [13].
1.3. Liver and Type 2 Diabetes: Historical Overview
In the past, clinicians and pathologists viewed the hepatic fatty changes as a histological correlate of the coexistence of T2D and obesity (the so-called “diabesity”) [14], a conclusion which has been fully supported by contemporary studies [15]. Stated otherwise, the liver was essentially regarded as a target organ affected by either concurrent or pre-existent “diabesity”.
More recently, however, this perspective has been fully overturned. Several studies have now exhaustively proven that hepatic steatosis precedes the development of T2D and Metabolic Syndrome (MetS) in a large proportion of cases [16,17,18]. In tandem, epidemiological evidence has also suggested that HCV infection almost doubles the risk of incident T2D compared to both HBV infection and virus-free individuals [19]. This is of outstanding interest given that HCV infection is a systemic disease [20] that often exhibits hepatic histological changes of variable severity, including hepatic steatosis, which makes it conceptually similar to NAFLD [7,21]. Excitingly, a cure for HCV has recently become available with direct acting antivirals [22,23,24].
Collectively, all the above findings support the notion that there is a causal, bi-directional link between NAFLD and T2D [25]; that HCV infection is a diabetogenic condition [19]; and that T2D is potentially preventable by curing NAFLD [26] and HCV infection [27].
1.4. Aim of the Review and Evidence Acquisition
The liver, the skeletal muscle and the pancreas are the anatomic basis of IR and they have collectively been alluded as the “three musketeers” [28]. Along with these three organs, the adipose tissue is the “fourth musketeer” which is implicated in the pathogenesis of IR (Figure 1) [29]. Over the last decade, the liver has been put in the spotlight of research and our group has been gaining particular interest in the association between the steatotic liver and risk of incident T2D. Accordingly, the main purpose of this article was to review data linking T2D with either NAFLD or HCV infection. For each of these two liver diseases, we will discuss systematically the epidemiological burden, the pathophysiologic mechanisms and the clinical implications.

Figure 1. The “four musketeers” fighting for maintaining glucose homeostasis. Under normal conditions, muscle and pancreas improve glycemic control. However, an expanded adipose tissue will usually lead to dysglycemia. Similarly, fatty changes occurring in the liver will result in the development of insulin resistance. Hence, this review article puts the liver in the spotlight.
In order to retrieve pertinent articles, the PubMed database was extensively searched for reports published through 31 January 2016. To this end, we used the following keywords “nonalcoholic fatty liver disease” or “NAFLD” combined with “insulin resistance”, “type 2 diabetes” or “diabetes”. The same keywords were used to identify those articles in which “insulin resistance”, “type 2 diabetes” or “diabetes” were combined with either “HCV” or “hepatitis C virus”.

The selection of articles was performed based on agreement among the authors. Cross-references were taken in consideration based on the authors’ judgment.

 2. NAFLD and Type 2 Diabetes
2.1. Epidemiology
The wide spectrum of the extra-hepatic manifestations and correlates of NAFLD includes cardiovascular diseases (CVD), chronic kidney disease, colorectal cancer, obstructive sleep apnea syndrome, psoriasis, endocrine disorders, notably including IR/T2D, thyroid dysfunction, polycystic ovarian syndrome and osteoporosis (Figure 2) [5,6,30,31,32,33,34,35,36]. Epidemiological data fully support a bi-directional relationship between NAFLD and T2D [25]. Stated otherwise, NAFLD is associated with established T2D in cross-sectional studies and precedes the development of T2D in follow-up studies [3,16,18].
Figure 2. The spectrum of extra-hepatic manifestations and correlates of both non-alcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection: type 2 diabetes is a shared feature. This figure illustrates the concept that NAFLD and HCV infection are two systemic diseases whose spectrum of clinical manifestations tends to overlap significantly. Type 2 diabetes is a feature shared among the various pathologic conditions included in the NAFLD clinical spectrum [5,6,30,31,32,33,34,35,36] as well as in the clinical spectrum of chronic HCV infection [8,37,38].
2.1.1. NAFLD as a “Manifestation” of Type 2 Diabetes
A consistent body of epidemiological evidence supports the conclusion that NAFLD is strongly associated with T2D and that T2D is a major modifier of the epidemiological features of NAFLD [3,39]. For example, the prevalence of NAFLD (assessed by ultrasonography) is approximately 25%–30% in the general adult population, and men outnumber women by 20% to 40%. In patients with T2D, the prevalence of NAFLD is considerably higher (occurring in up to 75% of these patients), and, remarkably, T2D abrogates sex differences among patients with NAFLD [3,39]. The prevalence of NAFLD in patients with T2D ranges widely from 45% to 75% in large hospital-based studies and from 30% to 70% in population-based studies; this wide inter-study variability is largely due to differences in the ethnicity, population characteristics and criteria adopted for the diagnosis of diabetes [39]. The prevalence of histologically diagnosed NASH, i.e., the more rapidly progressive form of NAFLD [40], is estimated to occur in 2%–3% of the general adult population [6]; conversely, it ranges from 56% to 76% in hospital-based studies [41,42] and from 22% to 83% in outpatient cohort-based studies among individuals with T2D [15,43,44]. Notably, a recent study reported a high prevalence of NAFLD (76%) and NASH (56%) in obese T2D patients with normal serum aminotransferase levels [42]. The finding that many T2D patients with NAFLD have fairly normal serum transaminase concentrations is not reassuring given that NASH, advanced fibrosis and even cirrhosis may occur in such patients with “normal” serum aminotransferases [39,45,46]. Taken together, these studies suggest that the “normal” range of serum liver enzymes needs to be lowered to capture more NAFLD cases.
 2.1.2. NAFLD as a Precursor of Type 2 Diabetes
Accumulating data from observational prospective studies indicate that NAFLD (as diagnosed by serum liver enzymes or imaging) is strongly associated with an increased incidence of both T2D and MetS [3,45]. Two large meta-analytic studies have provided further evidence for a strong association between NAFLD and increased risk of incident T2D [17,18]. The first of such meta-analyses, published by Musso et al., [17] found an approximately two-fold increased risk of incident T2D among patients with NAFLD. The second one, recently published by our group, confirmed that NAFLD was associated with an almost two-fold increased risk of developing both T2D and MetS over a median period of five years. Worryingly, our meta-analysis is first in suggesting that the risk of developing MetS was much higher in those in whom NAFLD was identified by ultrasonography compared to those in whom NAFLD was identified based on abnormal liver enzymes [18]. In agreement with these findings, a retrospective cohort study by Sung et al. [47] showed that individuals in whom ultrasonography-assessed NAFLD developed or worsened over five years had a marked increase in T2D risk, suggesting that more severe NAFLD is associated with a higher risk of incident T2D [47]. Conversely, individuals in whom NAFLD resolved over five years did not show an increased T2D risk [47]. Similarly, a recent retrospective study reported a strong and independent association between NAFLD improvement and reduced incidence of T2D [48]. Moreover, another recent study has shown that non-overweight individuals with NAFLD had a substantially increased risk of incident T2D compared with both overweight and non-overweight NAFLD-free individuals [49]. Finally, the Multi-Ethnic Study of Atherosclerosis [50] has shown that NAFLD, assessed by computed tomography, was associated with an increased risk of incident T2D independent of common risk factors of T2D.
To date, there is a paucity of published data regarding the association between biopsy proven-NAFLD and the risk of incident T2D or MetS. In a retrospective cohort of 129 Swedish adults with histologically confirmed NAFLD and elevated liver enzymes, the baseline prevalence of T2D was 8.5% and approximately 80% of cases developed T2D (58%) or pre-diabetes (20%) at the end of a 14-year follow-up period [51].
In conclusion, a large body of epidemiological evidence supports the notion that the prevalence of NAFLD is remarkably increased in patients with T2D and that NAFLD is closely associated with an increased risk of incident T2D and MetS.

 2.2. Pathophysiology
The pathogenic mechanisms linking NAFLD and T2D encompass a complex cross-talk among different organ systems, notably including the gut and the nervous system further to the previously alluded “four musketeers”: the adipose tissue, the skeletal muscle, the liver and the pancreas.

 2.2.1. Remodeling of White Adipose Tissue
Excess visceral adiposity is a key factor in connecting NAFLD and T2D. The expansion of white adipose tissue (WAT) is associated with hypoxia and adipocytes necrosis [52,53,54,55]. The former causes the release of hypoxia inducible factor 1α (HIF1α), while adipocytes necrosis induces infiltration and M1-polarization of macrophages, thus producing WAT dysfunction, inflammation and fibrosis [53,55,56,57,58,59,60,61,62]. Such a WAT remodeling causes a dysregulation of multiple endocrine and lipid storage functions [54,62]. Dysfunctional WAT, in its turn, is associated with an imbalanced cytokine release, i.e., over-production of multiple pro-inflammatory adipocytokines, such as tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1/C-C chemokine receptor-2 (MCP-1/CCR-2), and reduction of adiponectin, which contribute to worsen local and systemic metabolic derangements [62,63,64,65,66,67,68,69,70,71,72]. Increased interstitial fibrosis in WAT limits adipose tissue expandability [52,53,62]. Reduction in lipid storage capacity also contributes to ectopic lipid accumulation in the liver, skeletal muscles and pancreas where lipotoxicity triggers multiple pathways that hinder insulin signaling [53,62,73,74]. All of these mechanisms may contribute to the development of IR in the adipose tissue with its inherent failure to suppress adipose lipolysis that results in an overflow of free fatty acids (FFAs) to the liver [74].
2.2.2. Role of Skeletal Muscle and Brown Adipose Tissue
Muscle IR, due to intra-myocellular lipid accumulation, occurs early in the course of T2D. It has been suggested that intra-myocellular diacylglycerol (DAG) accumulation activates protein kinase C-θ (PKCθ), which impairs insulin signaling, impeding muscle glucose uptake and leading to increased delivery of glucose to the liver, where it becomes substrate for hepatic de-novo lipogenesis (DNL) [74,75,76,77]. Accordingly, it has recently been shown that skeletal muscle steatosis is associated with NAFLD [78].
The myokines, i.e., cytokines produced by the skeletal muscle, have been recently identified as another piece in the interplay linking NAFLD to T2D. Irisin is produced by the skeletal muscle in response to physical exercise and exerts beneficial metabolic effects by recruiting brown adipose tissue (BAT) and triggering thermogenesis [79,80]. Evidence has recently shown that BAT is recruitable post-natally within either WAT or skeletal muscle [81,82,83,84,85]. BAT, through the expression of uncoupling C protein-1 (UCP-1), generates heat and regulates energy expenditure, lipid and glucose metabolism [81,86,87]. For these reasons, both irisin and BAT could be potential targets for the treatment of obesity-related complications. Interestingly, low levels of irisin have been associated with NAFLD and T2D in humans, thus confirming the important role of this myokine in the regulation of energy homeostasis and preservation of a healthy metabolism [88,89,90].
 2.2.3. Intrahepatic Fat Accumulation, Hepatic Insulin Resistance and Hepatokines
In NAFLD, steatogenesis results mainly from increased hepatic esterification of FFAs originating from dysfunctional/inflamed WAT (60%), DNL (25%) and diet (15%) [91,92]. Increased lipolysis drives hepatic lipid synthesis through esterification of FFAs and stimulates hepatic gluconeogenesis [92,93,94], thus promoting hepatic IR [74,95]. Muscle IR increases glucose delivery to the liver, thus enhancing DNL. Moreover, dietary monosaccharides, particularly fructose, directly promotes hepatic lipogenesis by increasing sterol regulatory element binding protein 1c (SREBP1c), carbohydrate-responsive element-binding protein (chREBP), peroxisome proliferator-activated receptor (PPAR)-γ coactivator 1-β, and liver X receptor expression [74,96,97,98,99,100,101].
The resulting intrahepatic ectopic storage of lipids has been specifically associated with hepatic IR [74,102]. However, hepatic triglyceride accumulation per se is not always harmful. Experimentally, the inhibition of diacylglycerol acyltransferase 2 (DGAT2), an enzyme devoted to hepatocyte triglyceride biosynthesis, decreases hepatic steatosis, but increases markers of lipid peroxidation/oxidant stress, hepatic lobular necro-inflammation and fibrosis [103]. Several lines of evidence support that intrahepatic diacylglycerol (DAG), via activation of PKCε, and ceramides, by impairing Akt2 action and inducing endoplasmic-reticulum stress and mitochondrial dysfunction, are the two major lipid mediators of hepatic IR [74,102,104,105,106,107,108,109,110,111,112,113,114]. Also intracellular localization of lipids in the liver matters [102]. A common single-nucleotide polymorphism of patatin-like phospholipase domain-containing protein 3 (PNPLA3), a lipid droplet protein with triglyceride lipase activity, has been strongly associated with NAFLD, but not with IR [114,115,116,117,118,119,120]. This dissociation between hepatic steatosis and IR is likely due to the accumulation of metabolically inert polyunsaturated triacylglycerols in lipid droplets caused by the PNPLA3 I148M variant [114,121,122]. Other underlying mechanisms clearly implicated in the development of hepatic IR and in the progression of NAFLD are low-grade chronic inflammation, elevated production of reactive oxygen species, activation of unfolded protein response and endoplasmic-reticulum stress, activation of Jun N-terminal kinase (JNK)-1, increased hepatocyte apoptosis and lipo-autophagy [25,92,102,123,124,125,126,127].
Finally, the liver releases several endocrine mediators, the so-called hepatokines, able to impact glucose metabolism, insulin action and secretion. Fetuin-A, which is abundantly secreted by steatotic hepatocytes, mediates IR by inhibiting the insulin receptor, reducing adiponectin expression, and enhancing WAT inflammation and dysfunction, and is independently associated with T2D development [128,129,130,131,132]. More recently, also fetuin-B has emerged as a potentially major player in T2D pathogenesis. Indeed, in their seminal study, Meex et al. [133], have shown that 32 hepatokines are differently secreted in steatotic versus non-steatotic hepatocytes. By inducing inflammation and IR in macrophages and skeletal muscles, these changes in the secretory products may contribute to the development of metabolic dysfunction in other cell types. These authors have identified higher levels of fetuin-B in the altered hepatokine secretory profile of steatotic livers in obese patients, and have also experimentally demonstrated that fetuin-B impairs insulin sensitivity in myotubes and hepatocytes and causes glucose intolerance in mice [133]. Fibroblast growth factor (FGF)-21 acts as a potent activator of glucose uptake and inhibitor of WAT lipolysis, recruits BAT and is associated with obesity, NAFLD and T2D [134,135,136,137,138,139,140]. Finally, serpinB1 increases pancreatic β-cell proliferation and its deficiency leads to maladaptive β-cell proliferation in IR [141,142].

 2.2.4. Gut-Liver Axis
Compelling evidence links gut microbiota, intestinal barrier integrity and NAFLD. Dysbiosis and impaired gut permeability favor the occurrence of endotoxemia and toll like receptor (TLR) 4-mediated inflammation, thereby contributing to the development of IR and other metabolic complications in obese individuals [143,144,145]. Other interactions between the gut and the liver may occur through the production of multiple gut hormones and the entero-hepatic circulation of bile acids that activate farnesoid X receptor in the liver [26].
Although further research is needed, these findings underline the importance of NAFLD as a precursor for the development of hepatic and systemic IR. However, the presence of long-standing IR per se is not sufficient to lead to the development of T2D. Gluco-lipotoxicity and genetic factors are additional requirements, which induce T2D through the development of pancreatic β-cell failure [25,74,146].
2.3. Clinical Implications
2.3.1. NASH and Fibrosis
Several studies have shown that T2D patients with NAFLD are at a high risk of NASH and cirrhosis [39,147,148,149]. Data from cross sectional studies [15,150,151,152,153] and longitudinal retrospective studies with sequential liver biopsies [154,155,156] clearly indicate that T2D strongly predicts fibrosis severity and progression in NAFLD patients. Consistently, two studies have demonstrated that poor glycemic control was associated with an increased risk of fibrosis in NASH [157,158].
Interestingly, one study showed that T2D and IR were strongly associated with NASH and severe fibrosis in patients with normal serum liver enzymes [159]. This finding provides further evidence to the clinical wisdom that “normal” serum liver enzyme levels are not a sufficient reason for excluding from liver biopsy those “high-risk” patients in whom advanced liver disease is strongly suggested by non-invasive evaluation. To this end, transient elastography and semi-quantitative ultrasound or non-invasive clinical scores (such as the US-FLI, the NAFLD fibrosis or the Fib4 scores) may be used in most patients with T2D [39,45,160,161].
 2.3.2. Cirrhosis and Hepatocellular Carcinoma
Many studies have reported T2D as an established risk factor for cirrhosis [162,163] and HCC [164,165,166]. Worryingly, a significant proportion of NAFLD patients with HCC have no evidence of cirrhosis [164], implying that they have escaped the normal surveillance strategies implemented in patients with cirrhosis of viral or alcoholic origin, and thus are diagnosed too late to receive radical treatment [167,168].
The presence of NAFLD among patients with T2D is also an important risk factor of increased all-cause and cause-specific mortality. Patients with T2D have an increased mortality risk from cirrhosis of any aetiology [39]. Accordingly, a recent cohort study showed that, compared to the age- and sex-matched general population, patients with T2D had a two- to three-fold higher risk of dying of non-viral and non-alcoholic chronic liver disease, largely attributable to NAFLD [169]. Consistently, a recent Scottish national retrospective cohort study reported that T2D was associated with an increased risk of hospital admissions or deaths for all common chronic liver diseases and, among them, NAFLD had the strongest association with T2D [170]. In agreement, a retrospective USA cohort study on 132 NAFLD patients found that T2D patients with NAFLD were at risk for the development of poor clinical outcomes, such as increased all-cause and liver-related mortality or morbidity after adjusting for potential confounding factors [162]. Finally, NAFLD was associated with a two-fold increased risk of all-cause mortality (mainly due to malignancy (33%), liver-related complications (19%) or ischemic heart disease (19%)) in a cohort study of 337 T2D patients followed-up for a mean period of 11 years [171].
 2.3.3. Atherosclerosis
Accumulating evidence indicates that NAFLD is strongly associated not only with liver-related morbidity or mortality, but also with an excess risk of CVD, which is the most common cause of death in T2D [39]. Several studies have reported a strong association between NAFLD and early subclinical or advanced atherosclerosis among patients with and without T2D [172]. These findings have been further confirmed by multiple prospective studies that showed an increased risk of fatal and non-fatal CVD events in patients with and without T2D, independently of several cardiometabolic risk factors [39,172,173,174]. The association between NAFLD and risk of CVD mortality has been further supported by a milestone meta-analysis [17], although some recent follow-up studies are conflicting [172,175].
Emerging evidence also indicates that NAFLD is independently associated with the development of microvascular diabetic complications, i.e., chronic kidney disease and advanced diabetic retinopathy [5].
Collectively, the above-mentioned studies convincingly show that T2D is strongly associated with an increased risk of progressive NAFLD and an excess risk of overall and cause-specific mortality, including not only liver-related but also CVD-related mortality. These findings fully support careful monitoring and screening for NAFLD and/or advanced fibrosis among patients with T2D.

3. HCV and Type 2 Diabetes
3.1 Epidemiology
3.1.1. HCV and Diabetes: A Non-chance Association
The notion that cirrhosis is a potentially diabetogenic condition dates back to as early as 1906 [176]. More recently, such a view was confirmed in the pre-HBV and pre-HCV age [177]. It was more than 20 years ago that Allison et al., [178] by comparing the rates of T2D among cirrhotic patients undergoing evaluation for liver transplantation, showed that T2D prevalence was 50% in patients with HCV-related versus 9% in those with non-HCV-related cirrhosis. Since that pioneering report, this topic has developed into a major line of research and, at the time of this writing, more than 1340 articles can be retrieved [179].
3.1.2. The Burden
Licensing of oral direct acting antivirals (DAA), which deliver sustained virological response (SVR) rates >90%, has led to the revolutionary expectation that HCV infection will possibly be the first chronic viral infection totally eradicated [22]. However, such an inference is premature and, for the time being, HCV still infects from 150,000,000 to 185,000,000 people worldwide, namely up to 2.8% of the world population [180,181]. Moreover, in developing countries, the case-finding and management have not improved in tandem, suggesting that continued refinement of epidemiology, cost-utility models and targeted diagnostic strategies remain an unmet need [182]. Worldwide, chronic HCV infection remains a significant public health burden, given that it can lead to cirrhosis in approximately 15% to 20% of those infected within 20 years, resulting in end-stage liver disease and HCC [182]. In Europe, although the iatrogenic HCV transmission was enormously reduced over the last 20 years, transmission related to intravenous recreational drug use is on the increase, especially in Eastern Europe, and the high HCV prevalence in the migrant populations is a challenge [183]. Moreover, HCV-related morbidity and mortality are projected to increase in Europe until 2030 [183]. In the USA, up to 35% of patients on the liver-transplant waiting list are infected with HCV, and global HCV-associated mortality estimates approximate 500,000 deaths per year [184,185].
3.1.3. Extra-Hepatic Manifestations of HCV Infection: Type 2 Diabetes
The clinical spectrum of chronic HCV infection is not limited to liver disease but also includes major extra-hepatic conditions, affecting eyes, salivary glands, skin, kidneys, genital tract, endocrine, neurologic, cardiovascular and immune systems (Figure 2) [8,37,38].
Among the extra-hepatic manifestations of HCV, a mutual and bi-directional relationship connects T2D with HCV infection. HCV infection is more common in patients with T2D than in those without T2D and, conversely, T2D abounds among patients with chronic HCV infection [177]. That said, however, the usual clinical scenario depicts a vignette in which, in predisposed individuals, HCV infection precedes and accelerates the development of new-onset T2D by approximately 10 years [38,186]. This finding suggests that HCV infection observed in T2D patients does not result from the risk of HCV infection associated with medical procedures in the highly medicalized T2D population but is the primary event which may adversely affect the subsequent development of T2D [187].
3.1.4. Heterogeneity in the Distribution of HCV and Type 2 Diabetes and Differential Features of Hepatitis C-Associated Dysmetabolic Syndrome and MetS
There are 170,000,000 individuals with T2D worldwide, namely the same number of individuals with HCV infection [177]. However, HCV infection has undergone epidemiological diffusion in certain age groups and geographical areas as a result of specific lifestyle risk behaviors or transmission via medical practices, whereas T2D reaches its zenith among 45-to-64 year old individuals, particularly in obese and sedentary individuals [177]. Stated otherwise, the epidemiological distribution of HCV infection and T2D does not identify the same geographical areas and groups of individuals. Accordingly, screening campaigns to identify either HCV infection among T2D patients or T2D among those with HCV infection are not justifiable at this time and more accurate strategies are needed in screening selected cohorts of individuals [188].
Finally, it should be pointed out that while T2D is a prominent feature of the MetS which is bi-directionally associated with NAFLD [3], HCV infection is also associated with a specific hepatitis C-associated dysmetabolic syndrome (HCADS), which was first described by Lonardo et al. [189].
Table 1 schematically compares the main features of the MetS with those of the HCADS [3,7,168,190,191,192,193].
 3.2.1. HCV Increases T2D Risk via Insulin Resistance
Consistent with the development of new-onset T2D observed in the setting of NAFLD, HCV promotes a state of IR that leads, over time, to pancreatic beta-cell dysfunction, eventually culminating in the irreversible damage of such cells and the development of overt T2D [177].
 3.2.2. IR Associated with HCV: Antigens, Sites and Determinants
HCV antigens, such as the core protein, play a key role in determining post-receptor defects causing IR by interfering with the AKT signaling pathway via cytokines (such as TNF-α and interleukin-6) and the suppressors of cytokine signaling [194,195,196,197]. Strong evidence suggests that the site of IR is not only hepatic but also extra-hepatic [198], predominantly in the skeletal muscle, correlates with subcutaneous, rather than visceral adiposity, and is independent of liver fat content [199]. These findings conflict with the notion that HCV predominantly infects hepatocytes and suggest that either HCV-infected hepatocytes release a soluble mediator capable of inducing IR in skeletal muscles [38] or, alternatively, that HCV directly infects myocytes. This latter hypothesis appears to be conceptually sustainable based on the findings of a recent case-control study, which provided evidence for a significant association between inclusion body myositis and HCV infection [200].
3.2.3. T2D in the Setting of the HCADS
T2D is not the only metabolic disease observed in the setting of HCV infection. Over time, several features of what is now alluded to as the HCADS have been increasingly identified. For example, hepatic steatosis, which is one of such features, was first identified as a distinct disease entity [7,21,201]. Data comparing hepatic steatosis due to varying viral (HIV-related) and non-viral (NAFLD) steatogenic disorders suggest that IR is a prominent feature specifically associated with HCV infection [202].
Over time, several features have been added to the initial description of the HCADS [203,204,205], which, presently, is deemed to characterize hyperuricemia, reversible hypocholesterolemia, IR, hypertension and visceral obesity [189]. Collectively, these dysmetabolic disorders may best be interpreted as a Darwinian survival strategy favoring the survival of HCV at the expenses of the host’s metabolism [189]. The finding of expanded visceral adipose tissue in patients with HCV infection is consistent with the hepatic and extra-hepatic origin of IR discussed above and prompts further research as to the potential ability of HCV infection to localize directly within adipocytes [206,207].
3.3. Clinical Implications
3.3.1. Risk of Fibrosis
A consistent body of evidence supports the notion that T2D is closely associated with fibrosis in the setting of chronic HCV infection [188]. More recently, a large study conducted in USA in approximately 10,000 patients with hepatitis C found that age, sex, race, HCV genotype, HIV co-infection, alcohol abuse, antiviral therapy and T2D were independently associated with the risk of cirrhosis [208]. Moreover, a recent meta-analysis of 14 studies, involving 3659 participants with HCV infection, reported a significant association between IR and advanced hepatic fibrosis among patients with HCV genotype 1 infection but not among those with HCV genotype 3 [209]. These findings are consistent with those of previous studies reporting that IR was strongly associated with HCV genotypes 1 and 4 [210,211].
3.3.2. Risk of Hepatocellular Carcinoma
Population-based studies fully support T2D being as an emerging risk factor for HCC [192]. In a recent meta-analysis, Dyal et al., [193] have reported that concurrent T2D is strongly associated with an increased risk of HCC among chronic HCV patients. It may be argued, however, that, in these patients, T2D may either be a proxy of more advanced metabolic derangement which leads to excess fibrosis via NASH or that T2D per se exposes these individuals to higher risk of developing HCC via increased oxidative stress and hormonal changes (e.g., IR, increased IGF-1 and activation of the renin-angiotensin-aldosterone system) [193,212,213].
An Italian study conducted in 163 consecutive HCV-positive patients with cirrhosis followed-up for a median period of 10.7 years found that HCV genotype 1b was strongly associated with a higher risk of developing HCC [214].
Further studies are needed to control accurately for all viral and host’s confounders, such as genotype, obesity and ethnicity, given that an improved understanding of HCC risk factors may provide specific areas of targeted interventions to reduce HCC risk in chronic HCV patients [193].
3.3.3. Risk of Atherosclerosis
The strong association between HCV infection and T2D development is one of the most important mechanisms that may lead to accelerated atherogenesis in chronic HCV patients [215]. Three studies showed that HCV infection is a strong risk factor for carotid subclinical atherosclerosis [216,217,218]. Consistent with the notion that HCV infection is a systemic disease, the risk of major CVD events is higher in patients with HCV infection than in HCV-negative controls, independently of traditional CVD risk factors and other potential confounding variables [219,220]. In a recent meta-analysis conducted on 22 studies, Petta et al. [191] showed that patients with chronic HCV infection had an increased risk of CVD-related morbidity and mortality, especially those with T2D and hypertension. On these grounds, all chronic HCV patients should be non-invasively screened for atherosclerosis [215].
4. Conclusions
Among the “four musketeers” fighting for controlling glucose homeostasis, the liver is now in the spotlight of basic, epidemiological and clinical investigations (Figure 1). Indeed, by reviewing the role of HCV and NAFLD in the development of T2D, we found that there is a substantial body of evidence indicating that the liver plays a pathogenic role in T2D development and that the close inter-connections connecting T2D with liver disease may result in a “vicious circle” eventually leading to an excess risk of liver-related and CVD complications (Figure 3).

Figure 3.
Non-alcoholic fatty liver disease, hepatitis C virus infection and type 2 diabetes: the “vicious circle”.
The liver plays a pathogenic role in the development of type 2 diabetes both in the context of non-alcoholic fatty liver disease and hepatitis C virus infection through the development of systemic and hepatic insulin resistance, partly mediated by the release of multiple pro-inflammatory cytokines, diabetogenic hepatokines and reactive oxygen species. If left uncorrected, insulin resistance will eventually lead to progressive pancreatic beta cell failure in predisposed individuals. Moreover, the strong interconnection between type 2 diabetes and liver disease may result into a “vicious circle” [25] eventually leading to liver disease progression with an excess risk of liver-related, i.e., cirrhosis and hepatocellular carcinoma (HCC), and cardiovascular complications, i.e., atherosclerosis.

NAFLD and HCV infection are two multisystem diseases whose spectrum of clinical manifestations, seemingly as a result of their sharing hepatic steatosis and IR as prominent features (Figure 2) [205], tends to overlap more and more. Basic research is very active in the arena of NAFLD pathophysiology and extrapolation of notions from the NAFLD to the HCV research field appears to be justified and potentially fruitful [21].
However, several questions remain largely unanswered. For instance: is NAFLD treatment able to reduce the development of T2D and its major complications? Based on preliminary evidence [47,48] one may be tempted to answer affirmatively, though this remains to be fully proven by studies ad hoc. Does T2D impair SVR in the era of new direct-acting antivirals? While T2D was associated with a lower SVR rate following interferon-based therapy [7], regimens based on new direct-acting antiviral agents do not appear to be affected by coexisting T2D [221]. Moreover, whether HCV eradication may also have an impact on the future morbidity and mortality due to T2D is a clinically relevant and biologically plausible outcome. However, further studies with new direct-acting antivirals are needed to ultimately settle this issue [27].
In the meantime, it is important to underline that lifestyle changes are the mainstay of treatment for all patients with NAFLD and T2D [173,222]. It has been reported that a combination of educational, behavioral and motivational strategies may help patients with NAFLD in achieving lifestyle changes [223,224,225]. Preliminary evidence also suggests that body weight reduction may improve liver histology in those patients in whom HCV infection is associated with hepatic steatosis [226]. However, future studies are required to better define effective weight loss strategies in these patients.
Giovanni Targher is supported in part by grants from the University School of Medicine of Verona. We are indebted to Ms. Elisa Gibertini for her helping us as a graphic artist.
Author Contributions

Amedeo Lonardo conceived the idea of this article, wrote the first draft of Chapters 1 and 4, the Table and, with Dante Romagnoli, Chapter 3; Amedeo Lonardo also drew the figures in collaboration with Giovanni Targher and Fabio Nascimbeni; Stefano Ballestri and Fabio Nascimbeni wrote the first draft of Abstract and Chapter 2; Giovanni Targher and Enrica Baldelli contributed to the discussion and reviewed the manuscript. All the Authors took part in the bibliographic research, discussed, edited and approved the final version of the article.
Conflicts of Interest
Stefano Ballestri, Fabio Nascimbeni, Enrica Baldelli, Giovanni Targher and Amedeo Lonardo have nothing to disclose. Dante Romagnoli serves as a consultant for AbbVie.
The following abbreviations are used in this manuscript:
C-C chemokine receptor-2
coronary heart disease
carbohydrate-responsive element-binding protein
cardiovascular disease
direct acting antivirals
diacylglycerolacyltransferase 2
de-novo lipogenesis
fatty acids
fibroblast growth factor 21
farnesoid X receptor
hepatocellular carcinoma
hypoxia inducible factor 1α
hepatitis C virus
insulin resistance
monocyte chemoattractant protein-1
metabolic syndrome
patatin-like phospholipase domain-containing protein 3
peroxisome proliferator–activated receptor γ
reactive oxygen species
sterol regulatory element binding protein 1c
type 2 diabetes
toll-like receptor 4
tumor necrosis factor α
uncoupling protein-1
white adipose tissue
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