By Peter G. Traber, M.D.
With over 40% of Americans classified as obese and millions of others overweight, it’s well-known that obesity is a risk factor for heart disease, but few realize that it can also cause life-threatening liver disease.
As many as 25 million adults in the U.S. suffer from non-alcoholic steatohepatitis (NASH), where fat globules accumulate in liver cells, leading to cell death and the development of inflammation. With years of chronic inflammation, scar tissue begins to form and cause liver fibrosis. When fibrosis is severe, it becomes cirrhosis, which can result in liver failure.
The only cure for NASH cirrhosis at this time is a liver transplant. NASH is soon to surpass hepatitis C as the number one cause of liver transplants in the U.S.
NASH has been called a “hidden epidemic.” Millions of people are at risk, yet people with the disease show no symptoms until the very late stages. Diagnosing the disease is also difficult as it can take decades to progress to advanced fibrosis and cirrhosis, and it can only be diagnosed with an invasive and painful liver biopsy.
While there is a lot we don’t know about NASH, there are many things we do know. For example, we know that weight loss is one of the most effective ways to reverse the effects of early NASH. In a recent clinical study, patients who lost at least 10% of their body weight had reductions in their fatty liver disease, with 90% having complete resolution of early NASH.
More research is being done every day to understand and treat NASH, pushing ahead on two fronts: enabling doctors to diagnose the disease, and giving them a way to treat it.
Non-invasive tests are for us to diagnose and track the progression of NASH without performing a liver biopsy. Physical assessment of the liver using imaging technology seems particularly promising, such as using advanced ultrasound techniques -- acoustic radiation force impulse imaging (ARFI) and real-time shear wave elastography (SWE) -- and magnetic resonance elastography (MRE) and multi-parametric MRI. Developing a blood test for specific biomarkers, a “liquid biopsy,” would be a boon for diagnosis. Unfortunately, research has yet to establish that what’s found in the blood is reflective of what’s in the liver. There are also a number of potential approaches being developed to test actual liver function, which involve a tagged compound and then measuring how well the liver metabolizes it. Research has shown a strong correlation between the results of these tests and the extent of a person’s liver damage.
Even more important than diagnosis is research on potential treatments. While weight loss and exercise are proven effective in reversing early NASH, such regimens won’t work for everyone, especially since NASH generally doesn’t show symptoms until the late stages of the disease. The agents currently in clinical development can be roughly grouped into four major categories:
Diabetic/lipid. Because insulin resistance, and often overt diabetes, is a consistent feature of NASH, multiple anti-diabetic drugs have been evaluated in NASH, mostly with early stages of fibrosis.
Bile acids/ farnesoid X receptor (FXR) pathway. Bile acids and other agents that activate FXR are attractive since they affect multiple pathways that may be involved in NASH pathogenesis.
Anti-apoptotic. Apoptosis (programmed cell death) of hepatocytes and stellate cells has been implicated in the pathogenesis of NASH.
Anti-inflammatory/anti-fibrotic. Inflammation of the liver leads to fibrogenesis, so agents that affect inflammation or fibrosis are anticipated to be effective drugs in NASH.
The results of multiple clinical trials over the next few years will clarify the effectiveness of potential therapies and targeting pathways. Overall, NASH and liver fibrosis represent an enormous public health problem with roots in obesity. There should be a continual focus on increasing awareness and developing non-invasive diagnostic methods and effective treatments.
Dr. Peter Traber is chief executive officer, chief medical officer and president of Galectin Therapeutics and posts regularly on NASH on the CEO Perspectives blog.