“Do you want your brisket lean or moist?”
This was the first “hardball” question I fielded at this year’s American College of Gastroenterology (ACG) conference in San Antonio. While I knew the translation of “moist” was “fat-infused,” I could not resist the temptation. And as it turns out, I am not alone. While America’s coastlines are receding its waistlines are mushrooming, fueling a full-fledged public health crisis (a sentiment which is not hyperbolic). According to the latest CDC data, the prevalence of obesity is 39.8% among adults and 18.5% among youth. With this backdrop, it came as no surprise that non-alcoholic fatty liver disease (NAFLD) was a hot topic at this year’s ACG conference.
What’s Your Problem?
The scope of the problem cannot be overstated. In the U.S., NAFLD has ousted both hepatitis C and alcoholic liver disease as the most common cause of chronic liver disease. While overly simplistic, the progression can be thought of as follows: 1) fat deposition in the liver results in an inflammatory state (nonalcoholic steatohepatitis – NASH); 2) Progression/persistence of inflammation leads to scarring and fibrosis; 3) advanced fibrosis leads to a cirrhotic “stiff” liver.
The Miracle Treatment (Sort Of)
Given the epidemic of “fatty liver disease” and its disastrous downstream effects, when an expert expounds on the topic, you sit and you listen (and so I sat and listened). According to consensus, there is a straightforward way to reverse liver fibrosis in NASH patients (thus preventing progression to cirrhosis). That’s the good news. The bad news – it occurs through weight loss (the seemingly unattainable Holy Grail of medicine). The silver lining – you don’t need transformations comparable to those seen on the The Biggest Loser. Indeed, losing ≥10 % of one’s total body weight is predictive of fibrosis regression. However, this remains easier said than done, particularly if the entirety of a patient-doctor interaction is a flippant “you need to lose weight” comment at the end of a visit. With ever shortening clinic slots, most physicians, I would argue, don’t have the time or the training to be effective weight loss “counselors.” Weight loss, as it turns out, is best done through a collaborative multidisciplinary approach.
Teamwork Makes the Dream Work
Collaboration was a recurring theme at this year’s ACG conference (both within and between institutions). This concept is well described in inflammatory bowel disease where cohesive teams of gastroenterologists, nurses, dieticians/nutritionists, and social workers/schedulers have formed outpatient “medical homes” – the end result being reduced ED visits and hospitalizations for their patients. Similar collaborative models have been proposed in NAFLD/NASH where inroads in weight loss could significantly reduce progression to cirrhosis. Pragmatically, this makes sense as obesity is often a multifactorial process driven by endocrine pathology, physical constraints, psychosocial distress, financial constraints, lack of nutritional literacy, etc. With this framework in mind, a multidisciplinary team targeting weight loss might operate as follows:
Primary care/endocrinologist: Transitions patient off sulfonylurea (which is associated with weight gain) in favor of GLP-1 agonist (which is associated with weight loss).
Psychiatrist/psychologist: Offers patient cognitive behavioral therapy and starts patient on bupropion for depression and smoking cessation (with added benefit of weight loss).
Social work: Helps patient enroll patient in a free community exercise program and arranges for physical therapy.
Dietician: Designs a calorie-restricted diet with patient’s food preferences in mind.
Surgeon: Offers bariatric surgery to select patients (which is associated with reduction in liver fibrosis in 34% of patients).
NASH Wars – May the Force be With You
For those still planning to indulge in the “moist” brisket option, further hope may be on the horizon. There is a pharmaceutical arms race building, with companies vying to capture market share. And there is reason for optimism. As highlighted during this year’s ACG conference, there are a handful of NASH therapies currently in Phase 3 clinical trials: elafibranor (RESOLVE IT study), aramchol (ARMOR study), resmetirom (MAESTRO study), obeticholic acid (REGENERATE study), cenicriviroc (Aurora study). Further fanning the competitive flames, on September 27th, Intercept became the first company to file a New Drug Application (NDA) for obethicholic acid for the treatment of NASH patients with fibrosis. This filing came on the heels of interval data from the REGNERATE study which documented ≥1 stage of liver fibrosis improvement with no worsening of NASH at 18 months (however, pruritus was a notable side effect).
Oh, the Places You Will Go
To date, NAFLD/NASH has proven a formidable foe with no knock out punches delivered (à la the success of hepatitis C therapy). That said, no stone is being let unturned. The kitchen sink is being thrown at this malady (including fecal transplant interventions). I suspect a multi-modal multi-agent approach will ultimately be required for success with old-fashioned diet/exercise forming a cornerstone. For now, I am awaiting clinical trial outcomes, popcorn in hand (unbuttered of course).