Source/Disclosures
Disclosures: Frias reports he receives research support frotm Allergan, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Intercept, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxil, Sanofi and Theracos; serves on advisory boards or is a consultant for 89bio, Altimmune, Axcella Health, Boehringer Ingelheim, Coherus Therapeutics, Echosens, Eli Lilly, Gilead, Intercept, Merck, Novo Nordisk and Sanofi; and is on the speakers bureau for Merck and Sanofi.
December 15, 2020
4 min read
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Diabetes, liver disease epidemics call for early detection, monitoring, lifestyle changes

Source/Disclosures
Disclosures: Frias reports he receives research support frotm Allergan, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Intercept, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxil, Sanofi and Theracos; serves on advisory boards or is a consultant for 89bio, Altimmune, Axcella Health, Boehringer Ingelheim, Coherus Therapeutics, Echosens, Eli Lilly, Gilead, Intercept, Merck, Novo Nordisk and Sanofi; and is on the speakers bureau for Merck and Sanofi.
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The inextricable, well-documented link between the twin epidemics of nonalcoholic fatty liver disease, or NAFLD, and type 2 diabetes has raised alarms in the medical community.

The presentations of NAFLD range from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD has a prevalence of up to 70% among patients with type 2 diabetes. Overweight or obesity and insulin resistance have been strongly linked to NAFLD. The connection between NAFLD and type 2 diabetes is no coincidence, and a growing number of endocrinologists recognize that obesity-related hepatic steatosis is not simply an innocent bystander.

Fatty Liver
Source: Adobe Stock

NAFLD is associated with a twofold to threefold increased risk for developing type 2 diabetes, and type 2 diabetes can exacerbate NAFLD by promoting and accelerating progression to NASH, the more severe form of NAFLD, and fibrosis. In turn, NAFLD may alter the natural history of type 2 diabetes and make the disease more difficult to manage. Because the liver plays such an important role in lipid metabolism and glucose homeostasis, the accumulation of fat in this organ may portend poorer outcomes for people living with type 2 diabetes by elevating their already high risk for cardiovascular disease.

Closer look at NAFLD

NAFLD has become the most common chronic liver disease in the world and affects between 25% and 30% of adults in the United States, with 54% overall prevalence of NAFLD in type 2 diabetes patients estimated by random-effects models. NAFLD is composed of a spectrum of disease severity, ranging from simple steatosis, referred to as nonalcoholic fatty liver (NAFL), to NASH. NAFL is defined as the presence of at least 5% hepatic steatosis without evidence of hepatocellular injury.

Juan Pablo Frias

NASH is the more progressive and clinically important form of NAFLD and includes hepatic steatosis, inflammation and hepatocyte injury/apoptosis, referred to as “ballooning.” NASH may be accompanied by various degrees of fibrosis, from stage 1 to stage 4 (cirrhosis), and more advanced fibrosis is associated with an increased risk for hepatic and extrahepatic morbidity and mortality. About 37% of patients with type 2 diabetes and NAFLD will progress to NASH, with approximately 17% of those having clinically significant hepatic fibrosis. Patients with NASH, particularly those with advanced fibrosis, experience significantly increased mortality due to cirrhosis and hepatocellular carcinoma and extrahepatic complications, primarily CVD.

Identifying patients with NAFLD is important, as is determining whether patients might have advanced fibrosis, which is associated with worse prognosis. This is where noninvasive exams at the point of care are critical for determining if the patient has excess liver fat and is at high risk for advanced fibrosis.

Considering the ongoing obesity epidemic beginning in childhood, the rise in diabetes, and other factors, the prevalence of NAFLD, along with the proportion of those with advanced liver disease, is projected to increase.

Diagnosis and monitoring

Most people with type 2 diabetes may have NAFLD, but the condition is typically undiagnosed because of the asymptomatic nature of the disease, lack of clear consensus regarding screening and follow-up, low awareness about its importance among some health care providers, and the need for liver biopsy to make the diagnosis of NASH.

Liver enzymes, which may be normal in up to 80% of patients with NAFLD, tend to correlate poorly with liver histology and do not differentiate well between NAFL and NASH or stage of fibrosis. Blood-based composite scores, such as FIB-4 index and NAFLD fibrosis score, can be used to determine risk for advanced fibrosis. In addition, having noninvasive imaging is critical for diagnosing NAFLD and helping determine the presence of advanced fibrosis.

FibroScan (Echosens), for example, is an FDA-cleared technology for the diagnosis and monitoring of adult patients as part of an overall evaluation of liver health. Unlike blood tests that measure circulating markers of hepatocyte injury, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) alone, FibroScan directly measures physical properties of the liver. This exam provides reproducible results, allowing diagnosis and monitoring of liver stiffness and liver fat. This represents a cost-effective tool for screening and also identifying potential fibrosis in people with NAFLD.

FAST, a score that combines AST with FibroScan, can be used to noninvasively identify patients at high risk for active fibrotic NASH from among those with high suspicion of NAFLD. This information can support care management across key components of the metabolic syndrome, including obesity, type 2 diabetes and other modifiable CV risk factors, such as hypertension and dyslipidemia, and can be used in determining which patients should be referred for specialty care with a hepatologist.

The FibroScan exam can also be used to rule out the need for further assessment, including an invasive liver biopsy, saving time and resources for people who may not currently require further evaluation. Such noninvasive point-of-care exams, therefore, provide important clinical information that helps dictate the workup and management of patients with NAFLD.

Treatment options

The good news is that fatty liver can be improved without drugs. In fact, NAFLD is reversible if caught in the early stages and accompanied by lifestyle change. In many patients, a 5% to 7% decrease in body weight is associated with a reduction in liver fat and inflammation. Greater reductions in body weight have been shown to reverse fibrosis. Screening and early detection can help to prevent more serious conditions, such as end-stage liver disease or liver cancer.

Lifestyle modifications, weight loss and strict control of metabolic risk factors are currently the most effective treatment. Because disease progression is typically slow, patients with NAFL can be managed well by primary care physicians. NASH patients with indications of advanced liver fibrosis should be referred to specialist care for further assessment. Although finding and managing fibrotic NASH is an important component to addressing liver disease, patients with steatosis alone are also at a greater risk of CV mortality and morbidity than the general population.

The American Diabetes Association recommends maintaining a healthy weight, and regular exercise to reduce the amount of fat in the liver and for better control of blood glucose levels.

Because NAFLD and NASH are so tightly intertwined with obesity, diabetes and lifestyle, a “whole person,” multifactorial approach to patient engagement is needed to support behavioral changes that will result in better outcomes across the comorbid conditions affecting the individual patient. The challenge is that lifestyle changes are not always sustainable or efficient. This is where a comprehensive assessment of liver health, combined with “whole person” strategies to address NAFLD, can help optimize a medication-free and highly effective manner to improve liver health and prevent liver damage.

For more information:

Juan Pablo Frias, MD, FACE, is medical director and a principal investigator of the National Research Institute in Los Angeles. He can be reached at juan.frias@nritrials.com.