Widespread Liver Disease Missed in Patients With Type 2 Diabetes

Mitchel L. Zoler, PhD

January 25, 2021

Dr Christos S. Mantzoros

Mounting evidence of strikingly high prevalence rates of fatty liver disease, advanced fibrosis, and cirrhosis among patients with type 2 diabetes has led to calls for heightened awareness and screening to identify these patients and target treatments to reduce their risk for irreversible liver damage.

Among these calls is a pending statement from the Endocrine Society, the American Association of Clinical Endocrinologists, the American Gastroenterology Association, and other groups on what the growing appreciation of highly prevalent liver disease in patients with type 2 diabetes (T2D) means for assessing and managing patients. Publication of the statement is expected by spring 2021, said Christos S. Mantzoros, MD, DSc, PhD, chief of endocrinology for the Veterans Affairs Boston Healthcare System and a representative from the Endocrine Society to the statement-writing panel.

This upcoming "Call to Action" from these groups argues for a "need to collaborate across disciplines, and work together on establishing clinical guidelines, and creating new diagnostics and therapeutics," said Mantzoros in an interview.

"Over time, it is becoming clearer that management of NAFLD [nonalcoholic fatty liver disease]/NASH [nonalcoholic steatohepatitis] requires a multidisciplinary panel of doctors ranging from primary care practitioners, to endocrinologists, and hepatologists. Given that the nature of the disease crosses scientific discipline boundaries, and that the number of patients is so large (it is estimated that about one in four U.S. adults have NAFLD), not all patients can be treated at the limited number of hepatology centers.

"However, not all stakeholders have fully realized this fact, and no effort had been undertaken so far by any professional society to develop a coordinated approach and clinical care pathway for NAFLD/NASH. The 'Call to Action' meeting can be considered as a starting point for such an important effort," said Mantzoros, who is also a professor of medicine at Harvard Medical School and director of the human nutrition unit at Beth Israel Deaconess Medical Center, both in Boston.

Dramatic Prevalence Rates in Patients With T2D

Results from two independent epidemiology reports, published in December 2020, documented steatosis (the fatty liver of NAFLD) in 70%-74% of unselected U.S. patients with T2D, advanced liver fibrosis accompanying this disease in 6%-15%, and previously unrecognized cirrhosis in 3%-8%.

One of these reports analyzed 825 patients with T2D included in the National Health and Nutritional Examination Survey of 2017-2018 run by the Centers for Disease Control and Prevention. All these patients, selected to be representative of the overall U.S. adult population with T2D, underwent transient elastography to identify steatosis and fibrosis, the first U.S. National Health Survey to run this type of population-based survey. The results showed an overall steatosis prevalence of 74% with grade 3 steatosis in 58%, advanced liver fibrosis in 15%, and cirrhosis in 8%, reported the team of Italian researchers who analyzed the data.

The second study focused on a single-center series of 561 patients with T2D who also underwent screening by transient elastography during 2018-2020 and had no history of NAFLD or other liver disease, or alcohol abuse. The imaging results showed a NAFLD prevalence of 70%, with 54% of the entire group diagnosed with severe steatosis, severe fibrosis in 6%, and cirrhosis in 3%. Among the 54% of patients with severe steatosis, 30% also had severe liver fibrosis. About 70% of the 561 patients assessed came from either the family medicine or general internal medicine clinics of the University of Florida, Gainesville, with the remaining 30% enrolled from the center's endocrinology/diabetes outpatient clinic.

Dr Kenneth Cusi

Neither report documented a NASH prevalence, which cannot receive definitive diagnosis by imaging alone. "This is the first study of its kind in the U.S. to establish the magnitude of [liver] disease burden in random patients with T2D seeking regular outpatient care," wrote the University of Florida research team, led by Kenneth Cusi, MD, professor and chief of the university's division of endocrinology, diabetes, and metabolism. Their finding that patients with T2D and previously unknown to have NAFLD had a 15% prevalence of moderate or advanced liver fibrosis "should trigger a call to action by all clinicians taking care of patients with T2D. Patient and physician awareness of the hepatic and extrahepatic complications of NASH, and reversing current diagnosis and treatment inertia will be the only way to avert the looming epidemic of cirrhosis in patients with diabetes."

"Endocrinologists don't 'see' NAFLD and NASH" in their patients with T2D " because they don't think about it," Mantzoros declared.

"Why is NASH underdiagnosed and undertreated? Because many physicians aren't aware of it," agreed Cusi during a talk in December 2020 at the 18th World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease (WCIRDC). "You never find what you don't look for."

"Endocrinologists should do the tests for NASH [in patients with T2D], but we're all guilty of not doing it enough," Tracey McLaughlin, MD, an endocrinologist and professor of medicine at Stanford (Calif.) University, commented during the WCIRDC.

These prevalence numbers demand that clinicians suspect liver disease "in any patient with diabetes, especially patients with obesity who are older and have components of metabolic syndrome," said Mantzoros. "We need to screen, refer the most advanced cases, and treat the early- and mid-stage cases."

How to Find NASH

Both the American Diabetes Association and the European Association for the Study of Diabetes call for routine screening of patients with T2D, starting with a check of liver enzymes, such as ALT, but no clear consensus exists for the specifics of screening beyond that. Mantzoros, Cusi, and other experts agree that the scheme for assessing liver disease in patients with T2D starts with regular monitoring of elevations in liver enzymes including ALT. Next is noninvasive ultrasound assessment of the extent of liver fibrosis inferred from the organ's stiffness using transient elastography. Another frequently cited initial screening tool is the Fibrosis-4 (FIB-4) score, which incorporates a patient's age, platelet count, and levels of ALT and a second liver enzyme, AST.

"There is more consensus about FIB-4 and then elastography, but some people use tests other than FIB-4. Unfortunately there is no perfect diagnostic test today. A top priority is to define the best diagnostic test," said Mantzoros, who is leading an effort to try to refine screening using artificial intelligence.

"FIB-4 is simple, easy, and well validated," commented Cusi during the WCIRDC last December. "FIB-4 and elastography should get you pretty close" to identifying patients with T2D and significant liver disease.

But in a recent editorial, Cusi agreed on the need for "more reliable tests for the diagnosis of NASH and advanced fibrosis in patients with T2D. Significant work is being done in the field to validate novel and more sophisticated fibrosis biomarkers. Future studies will help us enter a new era of precision medicine where biomarkers will identify and target therapy to those with more active disease at risk for cirrhosis," he wrote.

"The ultimate goal is to diagnose fibrosis at an early stage to prevent people from developing cirrhosis," Cusi said in a recent written statement. "We're trying to identify these problems before they're unfixable. Once someone has cirrhosis, there isn't a whole lot you can do."

Pioglitazone Remains the Best-Documented Treatment

Perhaps some of the inertia in diagnosing NAFLD, NASH, and liver fibrosis in patients with T2D is dissatisfaction with current treatment options, although several proven options exist, notably weight loss and diet, and thiazolidinedione (TZD) pioglitazone. But weight loss and diet pose issues for patient compliance and durability of the intervention, and many clinicians consider pioglitazone flawed by its potential adverse effects.

"When we don't have an established treatment for something, we tend to not measure it or go after it. That's been true of liver disease" in patients with T2D, said Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif., during the WCIRDC.

Treatment with pioglitazone has resolved NASH in about a third of patients compared with placebo, prevented fibrosis progression, and cut cardiovascular disease events, noted Cusi during the WCIRDC.

"Pioglitazone is used in only 8% of patients with T2D, or less, but we need to use it more often because of its proven efficacy in patients with T2D and NASH" said Mantzoros. "The problem is that pioglitazone has side effects, including weight gain and fluid retention, that makes it less attractive unless one thinks about the diagnosis of NASH."

Others highlight that the adverse effects of pioglitazone have been either misunderstood, or can be effectively minimized with careful dosing.

Dr Ralph A. DeFronzo

"The data with the TZDs are much stronger than the data from anything else. TZDs have gotten a bad name because they also work in the kidney and enhance fluid reabsorption. We use modest dosages of pioglitazone, 15 mg or 30 mg a day, to avoid excess fluid retention," Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio, said during the WCIRDC. "The best drug for NASH is pioglitazone. No other drug beats it" based on current data, DeFronzo asserted.

Other strategies include the potential to pair pioglitazone with other interventions that can blunt a weight-gain effect. One intriguing combination would combine pioglitazone with a GLP-1 receptor agonist, a drug class that can produce significant weight loss. Results from a phase 2 study showed promise for semaglutide (Rybelsus) in treating patients with NASH.

Getting the Name Right

Another factor that may be keeping NAFLD and NASH from achieving a higher profile for patients with T2D are those names, which focus on what the diseases are not – nonalcoholic – rather than what they are.

A series of recent publications in both the endocrinology and hepatology literature have called for renaming these disorders either "metabolic (dysfunction)–associated fatty liver disease (MALFD)", or "dysmetabolism-associated fatty liver disease (DALFD)".

"The names NAFLD and NASH indicate absence of alcohol as a cause, but the disease is also characterized by the absence of other causes, such as autoimmune disorders or hepatitis. The names were coined when we did not know much about these diseases. We now know that it is dysmetabolism that causes these conditions, and so we need to adopt a new, more accurate name," explained Mantzoros, who has published support for a name change.

While many agree, some have raised concerns as to whether a name change now is premature. A group of hepatologists recently published a rebuttal to an immediate name change, saying that, "although we are in agreement that metabolic fatty liver disease may more accurately and positively reflect the relevant risk factors better than the age-old term nonalcoholic fatty liver disease, the term still leaves a great deal of ambiguity. A name change will be appropriate when informed by a new understanding of the molecular basis of the disease entity, insights that fundamentally change risk stratification, or other important aspects of the disease. We may be on the cusp of this, but we are not there yet."

Mantzoros agreed, but for somewhat different reasons.

"We need to be careful and deliberate, because there is a significant body of knowledge and a lot of data from clinical trials collected using the old definitions. We need to find an appropriate time frame for a [name] transition. We need to find a nice and robust way to productively bridge the old to the new," he said. "We also need new diagnostic criteria, and new therapies. A new name and definition will facilitate progress."

Mantzoros been a shareholder of and consultant to Coherus and Pangea, he has been a consultant to AstraZeneca, Eisai, Genfit, Intercept, Novo Nordisk, P.E.S., and Regeneron, and has received travel support from the Metabolic Institute of America and the California Walnut Commission. Cusi has been a consultant to and has received research funding from numerous drug companies. McLaughlin is a consultant to January AI. Handelsman has been a consultant to numerous drug companies. DeFronzo received research grants from AstraZeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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