Case Scenario

A 52-year-old woman was employed as a busy engineer and often traveled for work, frequently ate fast food, and reported having no time for exercise. She had a body mass index of 29 kg per m² and borderline hypertension that she attributed to white coat syndrome. A few years ago, her A1C was high (6.5%), and type 2 diabetes mellitus was diagnosed. Her physician recommended a healthier diet and regular exercise for diabetes management. The patient tried to adhere to the recommendations, but her weight and A1C did not decrease.

Last year, her A1C increased to 7.1%, and her aspartate and alanine transaminase levels increased to nearly 100 U per L (1.67 μkat per L). She agreed to start metformin, be more careful about what she ate, and stop drinking wine with dinner. Three months later, her A1C improved to 6.6%, but her weight and transaminase levels were stable. She had not consumed alcohol, although she admitted to not adhering to a diabetes-friendly diet. She did not have abdominal pain, nausea, or changes in bowel movements. Liver ultrasonography showed hepatic steatosis consistent with non-alcoholic fatty liver disease (NAFLD). Results of tests for other causes of liver dysfunction, including viral hepatitis, were normal. The patient was very concerned that she had liver disease. She insisted on being referred to a hepatologist and was so worried about the possibility of developing cirrhosis that she broke down in tears.

Clinical Commentary

NAFLD is a diagnosis first recognized in the 1980s, with detection increasing as technology advanced during the following decades. NAFLD is defined by a fatty liver with a similar histologic appearance to alcoholic liver disease. The cardinal finding is macrovesicular hepatic steatosis on biopsy. Higher levels of inflammation and fibrosis are linked to worse outcomes.¹ The condition is invariably associated with metabolic syndrome and obesity, with most people having some insulin resistance. The prevalence of NAFLD is estimated to be as high as 30%.² When a biopsy shows inflammation, the condition is called nonalcoholic steatohepatitis (NASH), which has a worse prognosis than NAFLD. Approximately 60% of people with NAFLD who undergo a biopsy are found to have NASH.³ Within the next decade, NAFLD is projected to become the leading cause of liver-related death and disability and the primary diagnosis leading to liver transplantation.³

Elevated transaminase levels and hepatic steatosis on ultrasonography are the hallmarks of NAFLD, especially in people who are obese and have high blood glucose levels.⁴ People with NAFLD are generally not symptomatic, and because liver biopsy is the only definitive way to diagnose and distinguish mild NAFLD from NASH, the true prevalence is unknown. Elevated transaminase levels alone are not diagnostic of NAFLD, and ultrasonography has a 15% false-positive rate for NAFLD, which can lead to significant overdiagnosis if performed on all people with predisposing factors.⁵

EPIDEMIOLOGY

One study that sampled more than 8 million people in 22 Western countries found a prevalence of 25%, mostly among people with obesity (51%), type 2 diabetes (23%), hyperlipidemia (69%), and metabolic syndrome (43%).⁶ Prevalence and poor outcomes increase with age, possibly because of a longer duration of living with the condition and the additive effect of declining hepatic function with age.³ Because many people with NAFLD never seek medical attention or receive a liver biopsy, the prevalence and prognosis of NAFLD and NASH are based on limited, highly selective studies in tertiary care settings and modeling projections.⁶

PROGNOSIS

If 25% of adults have NAFLD, and approximately one-half of them develop NASH as the selective data indicate, the population burden of liver disease could be huge. However, the lack of prospective population-based studies and the scarcity of biopsy evidence make these estimates unreliable.⁶ The prognosis of an individual with NAFLD cannot be accurately predicted because liver disease progresses very slowly (typically over decades), and there is no correlation between ultrasound findings or the extent of increase in transaminase level and outcome.³

One retrospective study in Iceland found that people with NAFLD had a mean survival of 24 years after diagnosis. Although 7% ultimately progressed to cirrhosis, virtually none died of liver-related disease, with more than one-half dying of heart disease.⁷ Other data suggest that only people with symptomatic liver disease or who seek specialty care are likely to be enrolled in clinical studies or undergo biopsies. Others are less likely to progress to cirrhosis or develop serious liver disease.² The most common cause of death in people with NAFLD is vascular disease because NAFLD is a manifestation of metabolic syndrome, a common risk factor for vascular disease.⁵