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Professor of Internal Medicine
Associate Chair for Clinical Trials
Saint Louis University School of Medicine
St Louis, Missouri
Brent A. Neuschwander-Tetri, MD, has disclosed that he has received consulting fees from 89Bio, Alimentiv, Allergan, Allysta, Alnylam, Amgen, Arrowhead, Axcella, Boehringer Ingelheim, Bristol-Myers Squibb, Coherus, Cymabay, Enanta, Fortress, Genfit, Gilead Sciences, High Tide, HistoIndex, Innovo, Intercept, Ionis, LG Chem, Lipocine, Madrigal, MedImmune, Merck, Mirum, NGM, Novo Nordisk, Novus Therapeutics, pH Pharma, Sagimet, and Target RWE; has received funds for research support from Allergan, Bristol-Myers Squibb, Cirius, Enanta, Genfit, Gilead Sciences, Intercept, Madrigal, and NGM; and has ownership interest in HepGene.
When I think about nonalcoholic steatohepatitis (NASH), I think of a liver that is overtaxed from the delivery of too much metabolic substrate, that is, fat and carbohydrates. This can help us to understand (and explain to patients) the relationship among NASH, obesity, and diabetes, and why they occur together so often.
Adipose tissue plays an important role in NASH. Adipose tissue is a great place to store extra energy in the form of triglycerides. However, adipose tissue has limited storage capacity, and when that limit is reached, the tissue becomes stressed and begins to leak out fatty acids. It’s the liver that has to deal with those excess fatty acids in the blood.
The relationship between adipose tissue and the liver in NASH varies among different patients. Some patients will get NASH without much adipose tissue, known as lean NASH, where lipodystrophies can play a role. For whatever reason—genetics, medication—their adipose tissue stores are limited, and even without having a high body mass index, fatty acids that cannot be stored as triglycerides in the adipose tissue have to be dealt with by the liver.
Obesity and the 10%
Many patients with NASH also suffer from obesity. The data are clear that patients who lose 10% of their body weight experience enormous benefit for the liver. This is true even if, after that weight loss, the patient is still obese.
How do we explain that threshold, where the obesity can remain but the liver can benefit? In my assessment, it comes back to the adipose tissue’s capacity to store excess energy as triglycerides. That 10% weight loss helps because it can relieve stress on the adipose tissue such that it is no longer delivering excess fatty acids to the liver—the excess fats that ultimately cause NASH.
Although remaining obese has other problems, including physical impairments with back and knee injuries and the cultural disdain for obesity that our patients suffer with enormously, to me it is encouraging and fascinating that a 10% weight loss can have such profound physiologic benefits for the liver and likely other tissues. It’s as though it brings them back into that range where their adipose tissue is now healthier and not adversely affecting the liver.
Diabetes and Fat
To my mind, diabetes is another manifestation of the inability to safely store fat in adipose tissue. The lipotoxicity that occurs in other tissues causes insulin resistance that leads to dysregulated lipid metabolism throughout the body.
One perspective is that diabetes is actually a disease of lipid metabolism, which promotes dysregulation of blood glucose levels. That is potentially highly relevant to treatment, as diabetes management has been very focused on glycemic control. However, if we do not control glucose the right way, then lipid storage becomes a bigger issue that leads to increased cardiovascular risk. As cardiovascular disease is a major cause of mortality in patients with diabetes and especially in patients with NASH, we do not want to exacerbate cardiovascular risk.
To that end, for patients with type 2 diabetes, I typically recommend newer medications such as sodium glucose co-transporter 2 inhibitors and glucagon-like peptide-1 agonists, which help eliminate glucose from the body and improve metabolism, sometimes even promoting weight loss. These drugs offer an advantage over sulfonylureas, which merely help β cells in the pancreas make more insulin but do not improve cardiovascular and liver health. However, the newer drugs can be cost prohibitive for those without insurance.
How I Explain It to Patients With NASH
In my practice, I bring this pathophysiology right into the clinic and talk to my patients about it. I emphasize the importance of limiting sugar intake, since the fructose in our table sugar and sweetened foods and beverages appears to play a major role in de novo lipogenesis, where the liver turns that sugar into fat.
Patients often do not realize how much sugar is in beverages such as sugar‑sweetened tea or sodas. I explain to them that unless they are running a marathon, their body does not need that sugar for energy, so the liver will have to deal with it by turning it into fat.
I also encourage them to lose weight in a gentle, kind way, acknowledging that for many patients, achieving a 10% weight loss is an enormous challenge. I try to work with my patients and say, “Do the best you can; focus on healthy eating and try to be more active, whatever that means for you and whatever works for you.”
How do you talk to your patients about the complex pathogenesis of NASH? Answer the polling question and join the conversation by posting in the discussion section.