End-of-Year NASH News
Fatty liver disease (FLD) and non-alcoholic steatohepatitis (NASH) are increasing in prevalence worldwide, creating a major global public health crisis. To adequately educate patients, practitioners and policy makers, there is a need to collect, curate and share relevant information. NASH News, published on behalf of the Global Liver Institute’s NASH Council, intends to meet that need and to facilitate collaboration across the emerging NASH community on a monthly basis.
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Getting Beyond the Biopsy: Our Top Challenge for 2019
GLI sees one of our most important roles in the rapidly-evolving field of NASH as keeping the community focused on addressing the most impactful issues with a unified voice. Amidst the flurry of drug development research, epidemiology, population profiles and landscape assessments the one key barrier to success for the field is reliance on liver biopsy and the timeline for validation and adoption of non-invasive tests (NIT) for diagnosis, staging, and treatment response measurement. To patients, and to an increasing number of non-hepatologists who are becoming aware that fatty liver disease is something that they need to diagnose and manage in their patients today, a five to ten year goal for replacement of liver biopsy with one or more NITs is unacceptable.
The liver biopsy, an invasive diagnostic procedure, has long been considered the “gold standard” in diagnosis and management of non-alcoholic steatohepatitis despite limitations of sampling errors and patient burdens of cost, time, and risk. Despite ongoing initiatives in the U.S and Europe by individual companies and research consortia, regulatory pressure, clinical inertia, and health system procurement processes together cause estimates of replacement of biopsies by validated NITs to necessitate close to a decade of further development.
As a patient-driven advocacy organization with expertise in leveraging both policy and communications to advance liver health, GLI is uniquely poised to create a sense of urgency and catalyze action to reduce the time for acceptance and adoption. Stay tuned for more information throughout 2019.
From Park City, Utah to Paris, France and many, many cities in between, GLI CEO Donna Cryer has traveled and made presentations at 17 conferences in 2018 to audiences ranging from investors and payers to researchers and clinicians to ensure that the patient voice is front and center shaping conversations around fatty liver disease, NASH, and obesogenic cancers.
Rounding out the year Mrs. Cryer moderated a panel at the 14th Annual Personalized Medicine Coalition Conference at Harvard Medical School, participated on a panel at the National Comprehensive Cancer Network Patient Advocacy Summit at the National Press Club both on the topic of ensuring that the promise of new treatments in liver disease reach the full diversity of liver patients equitably and had her views on the Liver Meeting 2018 featured in MD Magazine. She discussed the focus on fatty liver and NASH, the need for more non-hepatologists to attend, and the emphasis on the lack of a non-invasive biomarker in diagnosing and grading NASH.
GLI held an in-person NASH Policy Workgroup meeting on Tuesday, December 4 at the GLI DC office attended by representatives of more than 15 NASH Council members to develop a NASH policy agenda for 2019. A report on the meeting will be available for NASH Council members.
Future NASH Council Policy Workgroup meetings will be held monthly by phone and quarterly in person. For more information on this workgroup, or on the Lifestyle Intervention and Clinical Workflow workgroups, please contact us at firstname.lastname@example.org.
NASH Patient Insights
GLI interviewed Tony and Betsy Villiotti, a patient and caregiver team. Both are 2018 GLI Advanced Advocacy Academy (A3) trainees. Tony was diagnosed in 2005 with NAFLD and received a liver transplant in March of this year with Betsy beside him every step of the way.
If you could change one thing about how the healthcare system treats patients, what would you change?
T: In retrospect, I wish I had been given a roadmap that laid out all the possible outcomes when I was diagnosed with fatty liver. ...I did not know that it could lead to cirrhosis and don’t believe I was told of that possibility. [I think that] doctors should do a better job explaining possible outcomes.
What do you most want people to know about life with liver disease?
T: As a patient proceeds through the spectrum of liver disease, [they often] have the power to make lifestyle changes that affect the progression of the disease. Make the effort to learn about how nutrition can affect your disease. A patient should also know that there are likely to be many twists in the road. Situations will pop up, seemingly out of nowhere. Most prominent is hepatic encephalopathy (HE), but ascites, edema, and other conditions can arise. Be prepared for that eventuality.
What challenges you the most, from a patient and caregiver perspective?
T: ...My biggest challenge during my disease progression was diet. I come from a large Italian family where holidays, weekends, and any other excuse we could come up with centered around food. [Our] view was that a fat child was a happy child. We were big consumers of white bread, red meat and pasta. Between that and my enjoyment of Italian food, it was very hard to change my diet. I eventually came up with a rule that if I liked something it probably wasn’t good for me. Exercise was also difficult as I was frequently tired and had to really push myself to stay active. Post-transplant, my challenge has been to continue eating smaller and healthier meals.
B: One of the biggest challenges I had as a caregiver was knowing what foods were affecting my husband’s disease. I did talk to nutritionists, but… [they] did not have information that was specific to liver disease and cirrhosis. After the second time he was hospitalized for HE, I finally talked with a nutritionist well-versed in liver disease. I was also unaware of the many side effects that can occur with liver disease. It was important that I paid special attention to any behavior changes in my husband even though he made a valiant effort to hide them from me. In hindsight, I realize I may have missed mild episodes of HE, blaming it [instead] on dehydration.
What inspires or motivates both of you?
T: In 2008, I met the family of a teenager who had liver and lung cancer and passed away. What [I’ll} never forget from meeting that family was their child’s motto: “Life isn’t about how many breaths you take; it is about what you do with those breaths.” I kept coming back to this after my transplant and it inspired me and motivated me to form a non-profit, NASH Education, [with the mission to] increase the awareness of NAFLD and NASH. My target is the person who has the same knowledge, which was none, that I had when I was diagnosed with fatty liver in 2005.
B: Now that my husband has been successfully transplanted in March 2018, I am inspired by him and his effort to spread the word about NAFLD and NASH.
As a caregiver, what would you want to say to those who might be in your position?
B: I would tell someone in my position to seek out a nutritionist for diet advice that specializes in liver disease. I was surprised that too much protein can trigger HE. I thought I was helping my husband avoid malnutrition...turns out I was pushing him over the edge to HE. I would also tell them that they need to accept the new normal. Liver disease can cause a person to sleep more, not want to socialize and at times be irritable. All this can be overwhelming, so it is important to keep up with YOUR social life, find a good friend you can vent to, and, most importantly, take care of your health. Also, keep the faith and know there are better days ahead after transplant.
AASLD The Liver Meeting Highlights
At this year’s AASLD The Liver Meeting, Dr. Arun Sanyal was given the Distinguished Achievement Award for his research in NAFLD and NASH treatments as well as the creation of the Liver Forum. We are also proud to have Dr. Sanyal as a founding member of the GLI NASH Council. In accepting the award, Dr. Sanyal emphasized that while current pharmacology solutions hold great potential, the NASH community must look at the disease as a whole and address how it affects more than just the liver. He called for an examination into the full biology of NASH and its progression, and the need to determine why lifestyle interventions are not working. Sanyal urged listeners to focus on the need for non-invasive biomarkers, an investigation into the biological causes of NASH, as well as health policy changes within government.
Dr. Alina Allen of Mayo Clinic presented findings that NAFLD is the driver for an increased obesity-related cancer risk. The risk ratios for liver, uterus, stomach, pancreas, and colon cancer are all significantly higher for obese patients with NAFLD.
A team of researchers from University of California, San Francisco shared results from their study examining the effects of weight loss surgery before liver transplantation in obese patients. Their conclusions suggest that careful selection of qualified patients should be chosen for weight loss surgery to decrease the risk of post-transplant diabetes, hypertension, and recurrence of NAFLD.
A retrospective study analyzing 10 years of data conducted by Dr. Shil Patel from CarePoint Health Medical Center has shown an increase in number of patients, cost of care, length of stay, and mortality rates in NAFLD cases.
NASH Fact of the Month
Concurrent conditions are often seen in NASH patients: more than 70% are obese, up to 75% have type 2 diabetes, and anywhere from 20-80% have hyperlipidemia. However, not having these conditions does not guarantee that an individual will not develop NAFLD or NASH.
Source: Chopra, S. (2018, Oct.). Patient Education: NAFLD, including NASH (Beyond the Basics). Retrieved from: https://www.uptodate.com/contents/nonalcoholic-fatty-liver-disease-nafld-including-nonalcoholic-steatohepatitis-nash-beyond-the-basics.
NASH patients in phase 2b of a clinical trial focusing on diabetic patients for MSDC-0602K showed an improvement in liver enzymes as well as glycemic control.
Genentech and Jecure Therapeutics
Genentech acquired Jecure and its portfolio of NLRP3 inhibitors for NASH treatment. Controlling this pathway has shown promising results in preventing harmful inflammation that can result in NASH.
HTD1801 received a Fast Track designation by the FDA after a successful Phase 1 clinical trial. The drug targets insulin resistance, oxidative stress, and normalization of lipid and glucose metabolism, among other conditions.
A proof-of-concept model has established the potential for larazotide to facilitate a treatment by using it in combination with other NASH drugs. It reduces intestinal permeability, a known abnormality associated with liver disease, specifically NASH. Larazotide permits more effective absorption of the medication.
Novartis and Pfizer
Novartis and Pfizer announced a clinical development collaboration to create a potential new combination therapy for NASH. Novartis plans on combining tropifexor, a Farnesoid X receptor agonist, with multiple Pfizer drugs, including inhibitors of ACC, DGAT2 and KHK.
LiverMultiScan’s cT1 metric has shown positive results indicating its ability to successfully detect and monitor resolution of NASH in clinical trials, permitting treatment efficacy assessments.
TARGET PharmaSolutions announced that Gilead joined as the sixth pharmaceutical company to partner in TARGET-NASH, a longitudinal observational study.
Research & Studies
There are two pathways that are inactivated in obesity due to the oxidative hepatic environment; one of them is STAT-1, and this inactivation leads to the development of NASH, as seen in mice models. The other pathway is STAT-3, which is associated with the development of HCC.
Two types of the interleukin protein have been identified as part of the inflammatory and fibrotic pathway in mice livers. Blocking the mechanisms associated with creating these proteins, which are type-3 cytokines, results in delayed hepatic fibrosis.
Two new microRNAs have been identified as treatment targets in mice livers, mi-R221/222. Deletion of these microRNAs has resulted in decreased hepatic fibrosis, inflammation, and lipid content.
A prospective study of more than 500,000 Chinese adults found those with diabetes or high blood sugar levels are associated with a higher risk of liver cancer and major chronic liver diseases.
Current smokers were found to have higher risk for incident NAFLD in both men and women, and smoking pack-years were correlated with an increased risk for more advanced NAFLD.
NAFLD was found to be associated with coronary plaques, even non-calcified plaques. This means that patients diagnosed with NAFLD should have their heart health monitored closely.
A study has concluded that a metabolically unhealthy status has a greater impact on the fibrosis levels of NASH than obesity. Patients that were metabolically unhealthy and not obese had higher levels of liver damage than those who were just obese.
Even after adjusting for multiple confounders, researchers found that men who consumed more animal protein, or more meat in general, were associated with a higher incidence of NAFLD. This shifts the focus from limiting carbohydrate or fat intake to examining the effect of changing meat intake.
While there are shared NAFLD mechanisms between males and females, certain disease pathways appear to be specific to each gender. Using a big data analysis method called mergeomics, Dr. Xia Yang found inflammatory, lipid, and insulin-related pathways more strongly associated with NAFLD in male mice, a possible explanation for increased severity of metabolic dysfunction in males.
Researchers have found a statistically significant link between psoriasis and increased incidence of NAFLD, suggesting that those with psoriasis should be screened for liver disease.
Breastfeeding is associated with better maternal outcomes. Recent research shows that longer lactation duration is also associated with lower incidence of NAFLD in women. Additionally, infants born to obese mothers have different gut microbes that may be initiate disease pathways resulting in higher rates of obesity and fatty liver disease later in life.
NASH In The News
Daily Express reports that Malaysia is now the fattest country in Asia and half its population is either overweight or obese. According to the article, “Along with obesity comes obesity-related diseases such as fatty liver. The big concern about fatty liver is that it can be a silent killer.”
According to NutraIngredients.com, NAFLD patients are found to have lower levels of omega 3 in their livers, which can lead to further steatosis. In Europe, an omega 3 supplement has shown significant increases in omega 3 levels within the NAFLD patients’ livers. It is set to become available in selected European markets in 2019.
Reported on Helio In the Journals Plus, researchers have called upon pediatricians to screen for NAFLD and NASH in children with type 2 diabetes.
Parade Magazine, with a readership of 54.1 million, quoted Dr. Tamar Taddei from Yale on How to Keep Your Liver Healthy.
Terms to Know
Ascites: build-up of fluid in the abdominal area, causing swelling. Often caused by liver cirrhosis
Edema: excess build-up of fluid in the body’s tissues, resulting in swelling. Can also be caused by liver cirrhosis.
microRNA: cellular RNA component that prevents production of certain proteins by binding to the messenger RNA that codes for the protein.