Endocrinologists must screen for nonalcoholic fatty liver disease as a complication of type 2 diabetes

Prevalence of nonalcoholic fatty liver disease — and its more severe stage, nonalcoholic steatohepatitis, or NASH, in particular — is increasing in developed countries. The condition has surpassed alcoholism as a cause of cirrhosis and will soon be the primary cause of liver transplantation in the United States, exceeding hepatitis C, according to Kenneth Cusi, MD, FACP, FACE, chief of the division of endocrinology, diabetes and metabolism at University of Florida.

Kenneth Cusi

Cusi, who is an Endocrine Today Editorial Board Member, discussed the pathophysiology, diagnosis and management of NASH ahead of the first symposium on the topic to be held during the American Diabetes Association Scientific Sessions. For the first time in 2019, the ADA began recommending screening for liver fibrosis in patients with type 2 diabetes suspected of having nonalcoholic fatty liver disease.

Why are we seeing a rise in interest in NASH now?

Cusi: Because liver cirrhosis takes about 20 or more years to develop, we are just now beginning to see the consequences of the epidemics of obesity and type 2 diabetes that started worsening in the last 2 to 3 decades. We think the common denominator is insulin resistance.

What obesity does, and it’s worsened by developing type 2 diabetes, is to increase adipose tissue mass. This fat is a “sicker” fat and quite in contrast to that of a lean person. “Sick fat” cannot hold to its excess energy depots and continually releases energy stored in triglycerides into the circulation as free fatty acids. Other body tissues, such as skeletal muscle and the liver, are poorly adapted to deal with that excess flow of free fatty acids and the formation of other toxic lipids in these tissues. They likely impair mitochondrial function and trigger signals that cause inflammation and decrease the response to insulin. This has been broadly labeled as causing cellular “lipotoxicity.” In the liver, this is believed to drive several pathways that promote cirrhosis, although there are likely multiple yet poorly understood mechanisms. In skeletal muscle, excess free fatty acids may exacerbate insulin resistance, and even impair pancreatic beta-cell function worsening insulin secretion, which, taken together, make diabetes much more difficult to control.

There are analogies between NASH and diabetic nephropathy. First, both conditions are preventable with an early diagnosis. Second, there is a long period of time when the patient is asymptomatic and given a false sense of security. And third, early diagnosis is essential as the disease is reversable, unless too late. Thirty years ago, we began measuring albumin in the urine and preventing diabetic nephropathy. Today with NASH, we are where we were 30 years ago before routinely using albumin measurements.

Another analogy is to osteoporosis. We didn’t used to be very concerned about “osteoporosis” unless a patient sustained a fracture — particularly men were perceived as never having osteoporosis — until we had bone densitometers so we could identify it years before it was just too late to prevent fracture. With liver disease, if you diagnose NASH when you have cirrhosis, it’s just too late in the game.

What we want to do now is start an educational campaign to encourage endocrinologists to incorporate NASH as a complication of diabetes in the same way they do nephropathy. In 3 to 5 years, I anticipate that we’re going to routinely screen for NASH in primary care.

How is NASH diagnosed?

Cusi: The bad news today is that we don’t have a simple and reliable blood test like HbA1c to tell us if someone has NASH or not. Instead, we have a multistep strategy.

First, we must identify patients with the highest risk for NASH with fibrosis that also have uncontrolled diabetes or obesity. Second is taking a good patient history to rule out other diagnoses. Those with alcohol abuse, viral hepatitis, hemochromatosis and some other conditions, have fatty liver but not NASH. Third, increased levels of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) can help with diagnosis. Normal ranges are lower than previously thought. Women should have AST equal to or below 19 IU/L and men equal to or below 30 IU/L. Our laboratories say 40 IU/L, but once you hit 40 IU/L, you can be almost certain that you have some degree of liver steatosis. Typically, ALT is going to be 50% higher than AST, except at the very end, when you have cirrhosis and AST begins creeping up.

The next step is imaging. Ultrasound helps to identify fat, but doesn’t quantify it. Ultrasound is not very sensitive, and it’s operator dependent, but we can image liver fat of moderate to severe degree, which indicates hepatic steatosis. This now calls to rule out liver fibrosis, which has been associated with future cirrhosis and increased mortality.

The good news is that we can diagnosis fibrosis by imaging. The most commonly used test by your hepatologist is measuring liver stiffness by transient elastography, or Fibroscan (Echosens). Other ways are shear wave or magnetic resonance elastography. Fibroscan is pretty accurate for advanced disease. A value of at least 8 kPa indicates likely moderate fibrosis; 14 kPa and above usually signals cirrhosis. Although the test is not definitive, it takes about 5 minutes and is not expensive for the patient. It is likely that you can order the test through your electronic medical record system or through consulting your hepatologist.

Finally, once we have a high probability of fibrosis, we consider the need for a liver biopsy. That’s a discussion that depends on many factors, including age of the patient and the probability of having cirrhosis. Biopsy is a personal choice, but definitely it’s the only thing that can diagnose the disease. It is highly motivating for patients to incorporate lifestyle changes that can reverse NASH. If they have advanced disease confirmed in a biopsy, we’re going to talk about the treatments to reverse that.

#
Prevalence of nonalcoholic fatty liver disease — and its more severe stage, nonalcoholic steatohepatitis, or NASH, in particular — is increasing in developed countries.
Adobe Stock

Is lifestyle change the best option for both prevention and treatment?

Cusi: Yes, this is really important because a lot of doctors say, “Well, we don’t have any FDA-approved drugs so there’s nothing to do. Why would I do a biopsy? Why would I do anything?”

That’s the most significant error an endocrinologist, primary care doctor or related health care provider can do because a weight loss of 7% causes significant reduction in liver fat and even inflammation 70% of the time. With at least 10% weight loss, you can reverse inflammation and fibrosis 80% to 90% of the time.

Those are similar percentages when we’re talking about diabetes, too.

Cusi: Right. Patients with NASH have a twofold chance of developing diabetes and two- or threefold higher chance of having “diastolic dysfunction” (also known as heart failure with preserved ejection fraction) and cardiovascular disease. Weight loss of the magnitude mentioned above will prevent or reverse diabetes and improve patients’ cardiometabolic profile, not only liver disease.

The American Association for the Study of Liver Diseases recommends 800 IU per day of vitamin E or pioglitazone in addition to lifestyle changes for patients without diabetes. The ongoing controversy is whether vitamin E may increase the risk for CVD or prostate cancer. For patients with prediabetes or type 2 diabetes, the guidelines say that you may use pioglitazone. There are now three randomized controlled trials in patients with prediabetes or type 2 diabetes that have shown a resolution of NASH of about 50% or 60%, or about a 40% improvement over placebo. However, the most recent trial adding vitamin E to pioglitazone did not show an added benefit when compared with past studies of pioglitazone alone.

Pioglitazone is inexpensive and may also prevent diabetes. It cuts down progression from prediabetes to diabetes by 70%. There are now four large trials in patients with diabetes and prediabetes that have shown reduction in CVD.

Is pioglitazone associated with weight gain?

Cusi: Yes. In our study, we used a maximum dose, 45 mg per day. My recommendation is to start low with the 15-mg dose, which may cause a small 1% amount of weight gain. If it doesn’t cause significant weight gain, and you can see that the patient is tolerating it well, you can increase the dose to 30 mg per day. The weight gain with 30 mg per day is typically 2% to 3% if the patient doesn’t change their diet. If you have a nutritionist and proper integrated care, that should be less. But again, this is the only circumstance where you may gain some weight and reduce the risk for diabetes and CVD. The reason is because adipose tissue recovers metabolically and insulin resistance is reversed.

If I could have everybody lose 10% of body weight, that would be my choice. But the problem with weight loss alone is that the effect on fibrosis is variable, so you need something else to turn off the disease. When we talk about resolution of NASH, we’re referring to reversing the hepatocyte death and associated inflammatory component that we believe drives liver fibrosis and cirrhosis.

What other cautions should we note about pioglitazone?

Cusi: Precipitating heart failure may occur in 1% of patients taking pioglitazone due to undiagnosed heart failure with preserved ejection fraction. However, people with obesity, diabetes and NASH have a two- or threefold higher rate of diastolic dysfunction, which is often undiagnosed. With the combination of edema (seen in 5% to 8% of patients taking pioglitazone) and undiagnosed heart failure with preserved ejection fraction, you’re going to look like you gave the patient heart failure, but there are recent studies that show that pioglitazone improves cardiac function in patients with type 2 diabetes. There was no increase in the rate of heart failure in the IRIS study that demonstrated a reduction in diabetes and CVD in over 3,800 insulin-resistant patients without diabetes treated with pioglitazone and followed for a median of 4.8 years.

In general, pioglitazone has been proven safe. The issue of bladder cancer is fading away as most studies have been negative, but I advise physicians to rule out hematuria with a urinalysis before starting therapy and to repeat that once a year, as the controversy will never be completely settled.

The real pending issue is a higher rate of fractures with thiazolidinediones. We prescribe vitamin D for our patients on pioglitazone to reach a normal level and also calcium for postmenopausal women. We have not seen major bone loss or fractures in our NASH studies; however, in the IRIS study, there was an increased rate with pioglitazone.

What other treatments are in the pipeline for NASH?

Cusi: There are so many agents that I’ve lost count. In the next 2 or 3 years, we’ll have a number of new FDA-approved drugs. There are new insulin sensitizers that attempt to replicate what pioglitazone does without the weight gain. There are agents that modulate receptors in the liver and improve inflammation and fibrosis. There are several FGF21 agents that modify glucose and lipid metabolism. There are more potent GLP-1 receptor agonists, like semaglutide (Ozempic, Novo Nordisk). There are thyroid hormone receptor beta-selective agonists in development that are specific to the liver and have shown some promising results. Again, there’s a laundry list of agents, so there’s a lot of research activity in this field, and we think that several novel treatment approaches will become available in the next 5 years. – by Jill Rollet

For more information:

Kenneth Cusi, MD, can be reached at the University of Florida Division of Endocrinology, Diabetes and Metabolism, 1600 SW Archer Road, Room U-2, PO Box 100226, Gainesville, FL 32610; email: kenneth.cusi@medicine.ufl.edu.

Disclosure: Cusi reports he is a consultant for Allergan, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Coherus, Deuterex, Genentech, Gilead, Merck, Novo Nordisk, Pfizer, Poxel SA and ProSciento, and receives research support from Cirius Therapeutics, Echosens, Eli Lilly and Company, Inventiva Pharma, Janssen Research & Development, Novartis AG, Novo Nordisk and Poxel SA.

Prevalence of nonalcoholic fatty liver disease — and its more severe stage, nonalcoholic steatohepatitis, or NASH, in particular — is increasing in developed countries. The condition has surpassed alcoholism as a cause of cirrhosis and will soon be the primary cause of liver transplantation in the United States, exceeding hepatitis C, according to Kenneth Cusi, MD, FACP, FACE, chief of the division of endocrinology, diabetes and metabolism at University of Florida.

Kenneth Cusi

Cusi, who is an Endocrine Today Editorial Board Member, discussed the pathophysiology, diagnosis and management of NASH ahead of the first symposium on the topic to be held during the American Diabetes Association Scientific Sessions. For the first time in 2019, the ADA began recommending screening for liver fibrosis in patients with type 2 diabetes suspected of having nonalcoholic fatty liver disease.

Why are we seeing a rise in interest in NASH now?

Cusi: Because liver cirrhosis takes about 20 or more years to develop, we are just now beginning to see the consequences of the epidemics of obesity and type 2 diabetes that started worsening in the last 2 to 3 decades. We think the common denominator is insulin resistance.

What obesity does, and it’s worsened by developing type 2 diabetes, is to increase adipose tissue mass. This fat is a “sicker” fat and quite in contrast to that of a lean person. “Sick fat” cannot hold to its excess energy depots and continually releases energy stored in triglycerides into the circulation as free fatty acids. Other body tissues, such as skeletal muscle and the liver, are poorly adapted to deal with that excess flow of free fatty acids and the formation of other toxic lipids in these tissues. They likely impair mitochondrial function and trigger signals that cause inflammation and decrease the response to insulin. This has been broadly labeled as causing cellular “lipotoxicity.” In the liver, this is believed to drive several pathways that promote cirrhosis, although there are likely multiple yet poorly understood mechanisms. In skeletal muscle, excess free fatty acids may exacerbate insulin resistance, and even impair pancreatic beta-cell function worsening insulin secretion, which, taken together, make diabetes much more difficult to control.

There are analogies between NASH and diabetic nephropathy. First, both conditions are preventable with an early diagnosis. Second, there is a long period of time when the patient is asymptomatic and given a false sense of security. And third, early diagnosis is essential as the disease is reversable, unless too late. Thirty years ago, we began measuring albumin in the urine and preventing diabetic nephropathy. Today with NASH, we are where we were 30 years ago before routinely using albumin measurements.

Another analogy is to osteoporosis. We didn’t used to be very concerned about “osteoporosis” unless a patient sustained a fracture — particularly men were perceived as never having osteoporosis — until we had bone densitometers so we could identify it years before it was just too late to prevent fracture. With liver disease, if you diagnose NASH when you have cirrhosis, it’s just too late in the game.

What we want to do now is start an educational campaign to encourage endocrinologists to incorporate NASH as a complication of diabetes in the same way they do nephropathy. In 3 to 5 years, I anticipate that we’re going to routinely screen for NASH in primary care.

How is NASH diagnosed?

Cusi: The bad news today is that we don’t have a simple and reliable blood test like HbA1c to tell us if someone has NASH or not. Instead, we have a multistep strategy.

First, we must identify patients with the highest risk for NASH with fibrosis that also have uncontrolled diabetes or obesity. Second is taking a good patient history to rule out other diagnoses. Those with alcohol abuse, viral hepatitis, hemochromatosis and some other conditions, have fatty liver but not NASH. Third, increased levels of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) can help with diagnosis. Normal ranges are lower than previously thought. Women should have AST equal to or below 19 IU/L and men equal to or below 30 IU/L. Our laboratories say 40 IU/L, but once you hit 40 IU/L, you can be almost certain that you have some degree of liver steatosis. Typically, ALT is going to be 50% higher than AST, except at the very end, when you have cirrhosis and AST begins creeping up.

The next step is imaging. Ultrasound helps to identify fat, but doesn’t quantify it. Ultrasound is not very sensitive, and it’s operator dependent, but we can image liver fat of moderate to severe degree, which indicates hepatic steatosis. This now calls to rule out liver fibrosis, which has been associated with future cirrhosis and increased mortality.

The good news is that we can diagnosis fibrosis by imaging. The most commonly used test by your hepatologist is measuring liver stiffness by transient elastography, or Fibroscan (Echosens). Other ways are shear wave or magnetic resonance elastography. Fibroscan is pretty accurate for advanced disease. A value of at least 8 kPa indicates likely moderate fibrosis; 14 kPa and above usually signals cirrhosis. Although the test is not definitive, it takes about 5 minutes and is not expensive for the patient. It is likely that you can order the test through your electronic medical record system or through consulting your hepatologist.

Finally, once we have a high probability of fibrosis, we consider the need for a liver biopsy. That’s a discussion that depends on many factors, including age of the patient and the probability of having cirrhosis. Biopsy is a personal choice, but definitely it’s the only thing that can diagnose the disease. It is highly motivating for patients to incorporate lifestyle changes that can reverse NASH. If they have advanced disease confirmed in a biopsy, we’re going to talk about the treatments to reverse that.

#
Prevalence of nonalcoholic fatty liver disease — and its more severe stage, nonalcoholic steatohepatitis, or NASH, in particular — is increasing in developed countries.
Adobe Stock

Is lifestyle change the best option for both prevention and treatment?

Cusi: Yes, this is really important because a lot of doctors say, “Well, we don’t have any FDA-approved drugs so there’s nothing to do. Why would I do a biopsy? Why would I do anything?”

That’s the most significant error an endocrinologist, primary care doctor or related health care provider can do because a weight loss of 7% causes significant reduction in liver fat and even inflammation 70% of the time. With at least 10% weight loss, you can reverse inflammation and fibrosis 80% to 90% of the time.

Those are similar percentages when we’re talking about diabetes, too.

Cusi: Right. Patients with NASH have a twofold chance of developing diabetes and two- or threefold higher chance of having “diastolic dysfunction” (also known as heart failure with preserved ejection fraction) and cardiovascular disease. Weight loss of the magnitude mentioned above will prevent or reverse diabetes and improve patients’ cardiometabolic profile, not only liver disease.

The American Association for the Study of Liver Diseases recommends 800 IU per day of vitamin E or pioglitazone in addition to lifestyle changes for patients without diabetes. The ongoing controversy is whether vitamin E may increase the risk for CVD or prostate cancer. For patients with prediabetes or type 2 diabetes, the guidelines say that you may use pioglitazone. There are now three randomized controlled trials in patients with prediabetes or type 2 diabetes that have shown a resolution of NASH of about 50% or 60%, or about a 40% improvement over placebo. However, the most recent trial adding vitamin E to pioglitazone did not show an added benefit when compared with past studies of pioglitazone alone.

Pioglitazone is inexpensive and may also prevent diabetes. It cuts down progression from prediabetes to diabetes by 70%. There are now four large trials in patients with diabetes and prediabetes that have shown reduction in CVD.

Is pioglitazone associated with weight gain?

Cusi: Yes. In our study, we used a maximum dose, 45 mg per day. My recommendation is to start low with the 15-mg dose, which may cause a small 1% amount of weight gain. If it doesn’t cause significant weight gain, and you can see that the patient is tolerating it well, you can increase the dose to 30 mg per day. The weight gain with 30 mg per day is typically 2% to 3% if the patient doesn’t change their diet. If you have a nutritionist and proper integrated care, that should be less. But again, this is the only circumstance where you may gain some weight and reduce the risk for diabetes and CVD. The reason is because adipose tissue recovers metabolically and insulin resistance is reversed.

If I could have everybody lose 10% of body weight, that would be my choice. But the problem with weight loss alone is that the effect on fibrosis is variable, so you need something else to turn off the disease. When we talk about resolution of NASH, we’re referring to reversing the hepatocyte death and associated inflammatory component that we believe drives liver fibrosis and cirrhosis.

What other cautions should we note about pioglitazone?

Cusi: Precipitating heart failure may occur in 1% of patients taking pioglitazone due to undiagnosed heart failure with preserved ejection fraction. However, people with obesity, diabetes and NASH have a two- or threefold higher rate of diastolic dysfunction, which is often undiagnosed. With the combination of edema (seen in 5% to 8% of patients taking pioglitazone) and undiagnosed heart failure with preserved ejection fraction, you’re going to look like you gave the patient heart failure, but there are recent studies that show that pioglitazone improves cardiac function in patients with type 2 diabetes. There was no increase in the rate of heart failure in the IRIS study that demonstrated a reduction in diabetes and CVD in over 3,800 insulin-resistant patients without diabetes treated with pioglitazone and followed for a median of 4.8 years.

In general, pioglitazone has been proven safe. The issue of bladder cancer is fading away as most studies have been negative, but I advise physicians to rule out hematuria with a urinalysis before starting therapy and to repeat that once a year, as the controversy will never be completely settled.

The real pending issue is a higher rate of fractures with thiazolidinediones. We prescribe vitamin D for our patients on pioglitazone to reach a normal level and also calcium for postmenopausal women. We have not seen major bone loss or fractures in our NASH studies; however, in the IRIS study, there was an increased rate with pioglitazone.

What other treatments are in the pipeline for NASH?

Cusi: There are so many agents that I’ve lost count. In the next 2 or 3 years, we’ll have a number of new FDA-approved drugs. There are new insulin sensitizers that attempt to replicate what pioglitazone does without the weight gain. There are agents that modulate receptors in the liver and improve inflammation and fibrosis. There are several FGF21 agents that modify glucose and lipid metabolism. There are more potent GLP-1 receptor agonists, like semaglutide (Ozempic, Novo Nordisk). There are thyroid hormone receptor beta-selective agonists in development that are specific to the liver and have shown some promising results. Again, there’s a laundry list of agents, so there’s a lot of research activity in this field, and we think that several novel treatment approaches will become available in the next 5 years. – by Jill Rollet

For more information:

Kenneth Cusi, MD, can be reached at the University of Florida Division of Endocrinology, Diabetes and Metabolism, 1600 SW Archer Road, Room U-2, PO Box 100226, Gainesville, FL 32610; email: kenneth.cusi@medicine.ufl.edu.

Disclosure: Cusi reports he is a consultant for Allergan, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Coherus, Deuterex, Genentech, Gilead, Merck, Novo Nordisk, Pfizer, Poxel SA and ProSciento, and receives research support from Cirius Therapeutics, Echosens, Eli Lilly and Company, Inventiva Pharma, Janssen Research & Development, Novartis AG, Novo Nordisk and Poxel SA.

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