Kenneth Cusi, MD, discusses the diagnosis and management of nonalcoholic fatty liver disease (NAFLD), a complication of type 2 diabetes. NAFLD has become more common in recent decades as the risk factors for NAFLD—obesity and type 2 diabetes—have also become more common. Addressing this disease in patients with type 2 diabetes can prevent serious complications, such as cirrhosis and liver cancer.

Q: What is NAFLD? How is NAFLD related to type 2 diabetes?

A: Nonalcoholic fatty liver disease (NAFLD) means fatty liver disease in the absence of alcohol and other causes of fatty liver. NAFLD includes a broad spectrum of diseases.

• In simple fatty liver, also called nonalcoholic fatty liver (NAFL), fat and triglycerides accumulate in the liver but don’t cause inflammation or worsening disease.
• Nonalcoholic steatohepatitis (NASH) is a form of NAFLD associated with inflammation, liver cell death, and often scarring—called fibrosis—of the liver.
• NASH can lead to cirrhosis or chronic liver failure and is a risk factor for liver cancer.

Until recently, we didn’t know much about how common NAFLD is in people with diabetes. Now that we have better ways to assess liver fat, we know that up to about 70 percent of people with type 2 diabetes have NAFLD. My research group just completed a study that found, among people with NAFLD and type 2 diabetes, about half have NASH and about one-third of those with fat in the liver have significant liver fibrosis.

So, NAFLD is a big problem, and health care professionals who care for patients with diabetes are learning more about how to manage it.  

Q: Why should health care professionals be concerned about NAFLD in patients who have type 2 diabetes?

A: Health care professionals should be concerned for a number of reasons. In people who have prediabetes, NAFLD is associated with more insulin resistance and more dyslipidemia—abnormal amounts of fat in the bloodstream. NAFLD also increases the risk of prediabetes progressing to type 2 diabetes.

In people who have NAFLD, type 2 diabetes and being overweight or having obesity are key risk factors for simple fatty liver progressing to NASH and fibrosis, putting these people at a much higher risk of developing cirrhosis and liver cancer. NASH is currently the second-leading cause of liver transplants in the United States, and, if the current trend continues, it will be the leading cause within 5 years.

A significant number of studies also suggest that people with type 2 diabetes and NAFLD have a higher risk of cardiovascular disease.

Q: When and how should health care professionals check for NAFLD and NASH in patients with type 2 diabetes?

A: One important concept is that the liver fat is not the real target of your diagnostic work-up. You're trying to identify scarring of the liver, or fibrosis. You need to think of liver problems at three levels: fat, inflammation, and fibrosis.

First, look at liver enzymes: alanine transaminase (ALT) or aspartate aminotransferase (AST). In 2019, the American Diabetes Association (ADA) Standards of Medical Care in Diabetes started recommending checking for NASH and fibrosis in patients with elevated liver enzymes. That recommendation has been a game changer, and we're beginning to train the next generation of health care professionals to check liver enzymes for signs of NAFLD in the same way that we check urine albumin for signs of diabetic nephropathy.

If a patient has

• ALT below 20 U/L, the patient most likely doesn't have a fatty liver, although ALT levels can become low in advanced cirrhosis.
• ALT above 40 U/L in the setting of obesity and type 2 diabetes, the patient likely has NAFLD and has a high risk for NASH. In test results, the cut-off for normal ALT is 40 U/L, which is actually pretty high. The real normal ALT is 19 U/L in women and 30 U/L in men, and you should use lower cutoffs to begin thinking about problems.
• AST above 26 U/L, or definitely above 30 U/L, the patient is at a higher risk of having liver fibrosis.

You can use online tools to calculate the patient’s Fibrosis-4 (FIB-4) score, which is based on the patient’s age, AST and ALT, and platelet count. The FIB-4 score isn’t very sensitive, but it can help you identify patients with very advanced disease.

You can order an ultrasound to check for fat in the liver. Hepatologists may use elastography tests to check for signs of liver fat and fibrosis. Ultrasound-like tests include vibration-controlled transient elastography (FibroScan), which is the most commonly used in liver clinics, and shear-wave elastography. At university research centers, hepatologists may also be able to order magnetic resonance elastography.

However, we don’t have a good way to diagnose liver inflammation, or NASH, with blood and imaging tests. The bottom line is that a liver biopsy is the only way to conclusively diagnose NASH.

Health care professionals may wonder when to order a liver biopsy or refer a patient to a hepatologist. I would suggest the following tips about when to refer patients to a liver specialist.

• Patients with an ALT in the 40s or above definitely have fat in the liver and are at risk for NASH, especially if they have type 2 diabetes and obesity.
• If the FIB-4 score is 2.67 or higher, the patient is at a high risk of cirrhosis. You’d want to refer patients with a FIB-4 score above 1.7 to a hepatologist as the risk is also much higher.
• Patients with vibration-controlled transient elastography test results above 8.2 kPa should be referred to a hepatologist.
• If you’re not sure about a patient’s risk for NASH, talk with a hepatologist.

Q:  How should health care professionals manage NASH in patients who have type 2 diabetes?

A: The cornerstone of management is knowing that available interventions—weight loss and certain diabetes medicines—can effectively improve NASH. No medicines have yet been approved to treat NASH.

Weight loss can improve NASH. For many patients, losing 7 to 10 percent of their bodyweight will reduce liver inflammation and even reverse fibrosis.  To achieve a gradual weight loss through lifestyle changes, people typically need a structured program that involves regularly seeing a registered dietitian and professionals who can help with behavioral modification and exercise. Bariatric surgery isn’t recommended to treat NASH alone, but in people who have other indications for it, bariatric surgery can lead to weight loss and improve NASH.

Several medicines prescribed to treat type 2 diabetes have also been shown to improve NASH, including

• pioglitazone. This medicine has the best evidence for improving NASH. Practice guidance from the American Association for the Study of Liver Diseases and recommendations from the ADA recognize the possible benefits of pioglitazone for people with NASH.
• glucagon-like peptide-1 (GLP-1) receptor agonists. The LEAN trial, a small study conducted in the United Kingdom, found that the GLP-1 receptor agonist liraglutide improved NASH. A preliminary report suggests that a daily injectable formulation of semaglutide, which is not yet available, can also improve NASH.

While research suggests vitamin E may be an effective treatment for NASH in people without diabetes, there’s still some debate about its safety and whether it increases the risk for prostate cancer and cardiovascular disease.

Health care professionals should also aggressively manage cardiovascular risk factors in patients with type 2 diabetes and NAFLD. Clinical trials have shown that pioglitazone and GLP-1 receptor agonists reduce cardiovascular risk. Don’t stop statins in your patients who have NASH—research suggests that statins are fairly safe in patients with NASH. You should also control patients’ blood pressure and treat obesity to lower cardiovascular risk.

Q: What research is being conducted on the diagnosis and treatment of NAFLD in people who have type 2 diabetes?

A: Major areas of ongoing research include

• the prevalence and burden of NAFLD and NASH in people who have type 2 diabetes.
• new biomarkers and combinations of blood and imaging tests to optimize diagnosis. 
• new medications to treat NASH, including several that are currently in the drug discovery pipeline. For example, the NATIVE study recently presented preliminary data showing that a compound called lanifibranor led to improvements in NASH and fibrosis.

My research group has received an NIDDK grant to support a study that will screen for NAFLD and NASH in primary care and family medicine settings. The study will also offer treatment of NASH fibrosis with a low dose—15 mg—of pioglitazone for a 72-week randomized controlled trial.

Previous studies of pioglitazone in NASH have used higher doses—30 to 45 mg—which were associated with weight gain and other side effects. The 15 mg dose of pioglitazone reduces A1C and improves blood glucose control and blood lipids with fewer side effects. We are optimistic that this lower dose will also improve liver inflammation and damage.

Q: Is there anything else that health care professionals should know about NAFLD and type 2 diabetes?

A: NAFLD and NASH screening should be incorporated into the type 2 diabetes management algorithm, in the same way that neuropathy, retinopathy, nephropathy, and cardiovascular disease screening have been.

There are things you can do today to help improve and possibly reverse NASH in your patients, such as helping patients lose weight and considering diabetes medicines that also improve NASH. Addressing NASH can prevent patients from going into chronic liver failure.

How do you manage NAFLD in your patients who have type 2 diabetes? Tell us below in the comments.