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Three in 10 of your diabetic patients may have liver fibrosis



– For every 10 of your adult patients with type 2 diabetes, three are likely to have moderate to severe liver fibrosis, according to Kenneth Cusi, MD, FACP, FACE.

“If in the last 10 patients, you didn’t diagnose anybody with fibrosis, you probably missed it,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “The question is, How are we going to tackle this problem? My academic goal is that we incorporate screening for NASH [nonalcoholic steatohepatitis], or for fibrosis more specifically, in the same way we do for retinopathy or nephropathy, because we do have a way to treat it.”

Dr. Kenneth Cusi, University of Florida, Gainesville Doug Brunk/Frontline Medical News
Dr. Kenneth Cusi
Dr. Cusi, chief of the division of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, predicted that obesity will become the No. 1 cause of liver transplantation. “It’s a real epidemic; you’re not seeing it because the inflexion of obesity happened just 2 decades ago,” he said. “Patients with diabetes face the greatest risk of fatty liver and of fibrosis. Untreated, it’s the equivalent of having macroalbuminuria. If you do nothing and they don’t die of cardiovascular disease, they’re going to have a good chance of getting fibrosis.”

As part of the large population-based Rotterdam study of individuals aged 45 years and older, researchers found that liver stiffness of 8 kPa or more by transient elastography was present in 5.6% of the study participants and was strongly associated with steatosis and diabetes (Hepatology. 2016;63:138-47). According to Dr. Cusi, individuals who have steatosis without diabetes face a 5%-10% risk of fibrosis, while those with steatosis and diabetes face a 15%-20% risk.

“It’s well established in a number of studies that if you have fibrosis, you’re at high risk not only of cirrhosis, but also of hepatocellular carcinoma,” he said. “The key thing is not detecting fat, which is not really the target. The target is if there’s fibrosis or not.” Three ways to assess for fibrosis include MR elastography, transient elastography (which is the most commonly used), and fibrosis marker panels.

Liver fibrosis likely starts with adipose tissue dysfunction, said Dr. Cusi, who authored a review on the pathophysiology of interactions between adipose tissue and target organs in obesity and the resulting clinical implications for the management of nonalcoholic steatohepatitis (Gastroenterology. 2012;142[4]:711-25.e6).

“When you have insulin-resistant, sick adipose tissue, that leads to the accumulation of fat in the liver,” he said. “Steatosis happens in about 70% of patients who are obese and have type 2 diabetes. The dilemma is how to know who is going down the path to fibrosis. Even if you get people who are matched for BMIs [body mass indexes] between 30 and 35 kg/m2, there is a spectrum in which some individuals have very insulin-resistant adipose tissue and others less so. I would say that 1 out of 10 are metabolically healthy, and we don’t understand exactly why.”

In a recent cross-sectional analysis of 352 healthy individuals, Dr. Cusi and his associates found that intrahepatic triglyceride (IHTG) accumulation is strongly associated with adipose tissue insulin resistance, supporting the current theory of lipotoxicity as a driver of IHTG accumulation (Hepatology. 2017;65[4]:1132-44). The researchers observed that once IHTG accumulation reaches about 6%, skeletal muscle insulin resistance, hypertriglyceridemia, and low HDL cholesterol become fully established.

“The next question is, How does this correlate with NASH?” Dr. Cusi said. “Our take is that there is a threshold effect. Once you have a critical amount of triglycerides in your liver, some individuals are going to activate pathways that are harmful. NASH is not something exclusive to individuals who are obese. Lean people can also develop NASH. The key feature is insulin resistance, not metabolic syndrome. Once you develop a fatty liver, your chances of NASH are comparable to that of an obese individual. The paradox is that lean individuals get a fatty liver, but when they get a fatty liver, they are at risk for NASH and for fibrosis.”

Why lean individuals develop NASH is not fully understood, but Dr. Cusi said he suspects that the problem develops at the mitochondrial level.

Results from an unpublished animal model in which mice were fed a high–trans-fat diet for 24 weeks showed that the mice developed steatosis by week 8 and NASH by week 24. The mice had an increase in the tricarboxylic acid (TCA) cycle, which is typical of the NASH period, as well as an increase in ceramides.

“Perhaps a unifying hypothesis would be that the development of NASH is linked to inflammation and to insulin signaling,” Dr. Cusi said. “Not surprisingly, it had a number of effects on the mitochondria, and in this animal model it decreases the TCA.” He noted that the biology of fibrosis remains unknown in humans. “What we have been familiar with is the high-triglyceride, low-HDL pattern,” he said. “If you look at how that correlates with the amount of liver fat, it is basically a threshold effect. Once you have steatosis, you don’t see much worse dyslipidemia, which is typical of these patients.”

Recently published guidance from the American Association for the Study of Liver Diseases on the diagnosis and management of nonalcoholic fatty liver disease (NAFLD) suggests that patients require a weight loss of 3%-5% to improve steatosis, but a loss of 7%-10% to improve most histologic features of NASH, including fibrosis (Hepatology. 2018;67[1]:328-57). Exercise alone may prevent or reduce steatosis, but its ability to improve other aspects of liver histology remains unknown. Bariatric surgery can be considered in otherwise eligible obese individuals with NAFLD or NASH. The procedure’s impact on fibrosis is unknown.

The AASLD practice guideline notes that metformin is not recommended for treating NASH in adult patients, but pioglitazone improves liver histology in patients with and without type 2 diabetes with biopsy-proven NASH.

“Pioglitazone has had the greatest benefit in terms of treatment effect, compared to placebo,” Dr. Cusi said. “It’s a generic drug; at the VA [Veterans Affairs], it costs 8 cents per tablet. I think that pioglitazone will be to NASH what metformin has been to type 2 diabetes. The most common side effect is weight gain, typically between 4 and 9 lb. Risks and benefits should be discussed with each patient. It should not be used for NAFLD without biopsy-proven NASH.”

The guideline goes on to say that it’s currently premature to consider GLP-1 (glucagonlike peptide–1) agonists for treating liver disease in patients with NAFLD or NASH. Meanwhile, vitamin E at 800 IU has been shown to improve liver histology in nondiabetic adults with NASH, but the risks and benefits should be discussed with each patient. Vitamin E is not recommended for NASH in diabetic patients, NAFLD without a liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.

The AASLD practice guideline also states that the best evidence for using SGLT2 (sodium-glucose cotransporter–2) inhibitors in NAFLD comes from animal studies, which report a reduction in steatosis with and without weight loss. Clinical studies reporting a reduction in steatosis are limited. There are positive observational studies with a reduction in alanine aminotransferase and some studies that have shown a reduction in liver fat. “For me, the best option is to tailor treatment to the pathophysiology of the disease,” Dr. Cusi said. “You reduce fat by weight loss in some way, or you change the biology of fat with a thiazolidinedione.”

Dr. Cusi reported that he has received grant support from the Burroughs Wellcome Fund, the American Diabetes Association, and the National Institutes of Health.

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