When you eat may contribute to fatty liver disease as much as what you eat

People who skip breakfast and eat late at night may have an elevated risk of non-alcoholic fatty liver disease (NAFLD), according to research presented this week at the 2016 AASLD Liver Meeting in Boston. This suggests that meal timing and frequency of meals may be modifiable risk factors for fatty liver disease, which can lead to cirrhosis and liver cancer.

NAFLD, and its more severe form non-alcoholic steatohepatitis (NASH), refer to excessive fat accumulation in the liver in the absence of heavy alcohol consumption. With hepatitis B now preventable with a vaccine and hepatitis C treatable with direct-acting antivirals, fatty liver disease is becoming an increasingly important cause of cirrhosis, hepatocellular carcinoma and liver transplantation.

NAFLD is associated with cardiovascular risk factors including obesity, diabetes and metabolic syndrome, and it is becoming more common as the population becomes more overweight.

James Philip Esteban of the Medical College of Wisconsin and colleagues conducted a study to assess whether meal timing and the distribution of calorie consumption over the course of a day affect NAFLD risk.

Circadian rhythms or 'internal clocks' – usually corresponding to a 24-hour day – govern the timing of physiological processes, the researchers noted as background. This involves a central master clock in the brain's suprachiasmatic nucleus as well as peripheral clocks in various organs.

Metabolic pathways in the liver (including carbohydrate, lipid and bile acid metabolism) follow circadian rhythms, enabling the liver to anticipate daily changes in nutrient supply and demand. Meal timing is thought to be an important cue that keeps the liver in phase with a 24-hour day. Meals that are misaligned with circadian rhythms may promote liver steatosis and inflammation, and meal timing has been shown to be an emerging risk factor for obesity and diabetes in animals and humans.

Esteban's team used data from the third US National Health and Nutrition Examination Survey (NHANES III), conducted between 1988 and 1994. NHANES asks participants about demographics, smoking, and consumption of alcohol and caffeinated drinks. Participants undergo physical exams and laboratory testing. They were asked to recall all food and beverage intake during a 24-hour period. Gall bladder ultrasound was used to evaluate liver fat.

This analysis included 9015 adults with complete data and gall bladder ultrasounds. Just over half (53%) were women and 78% were non-Hispanic whites. People with hepatitis B or C, heavy alcohol consumption and use of hepatotoxic medications were excluded.

Cardiovascular and metabolic co-morbidities were common, including metabolic syndrome (22%), diabetes or pre-diabetes (28%), hypertension (27%), obesity (23%) and central obesity based on waist circumference. Ultrasounds showed that 64% had absent, 14% had mild, 15% had moderate and 7% had severe steatosis or liver fat accumulation. Participants were given an NAFLD fibrosis score indicating high (73%), intermediate (21%) or low (6%) probability of having advanced fibrosis.

The 24-hour day was divided into four intervals: 4am to 10am, 10am to 4pm, 4pm to 10pm and 10pm to 4am. The researchers asked about meal times, skipped meals and the amount of calories consumed during each period as a percentage of total daily intake.

Overall, participants consumed about 25% of their daily calories during each of the first three periods and less than 10% during the 10pm-4am period; 23% skipped morning meals, 6% skipped midday meals and 3% skipped evening meals. A quarter ate late-night meals, and they were more likely to be younger, male and black. Whether meals were eaten earlier or later during a given period varied by age, sex and race/ethnicity, as did the percentage of calories consumed during each period.

In a univariate analysis, liver steatosis was significantly associated with older age, male sex, being Mexican-American, being over- or underweight, central obesity, diabetes, hypertension and metabolic syndrome. Advanced fibrosis was associated with older age, being black, being overweight or obese and the same set of co-morbidities. Moderate or light alcohol consumption was actually associated with a lower risk of steatosis and fibrosis, and total calorie intake had a negative or non-significant effect.

In a multivariate analysis that took into account age, sex, race/ethnicity, smoking, alcohol use and total daily calorie consumption, dividing a day's total calories into more meals per day was associated with about a 10% reduction in the likelihood of having severe steatosis or advanced fibrosis per additional meal.

Consuming a greater percentage of daily calories in the morning decreased the likelihood of steatosis by 14% to 21%. Conversely, skipping morning meals (4am-10am) was associated with a 20% increase in the risk of steatosis, while skipping mid-day meals (10am-4pm) raised the odds by 73%. People who ate late-night meals after 10pm had a higher likelihood of steatosis and advanced fibrosis.

"NAFLD is associated with meal timing and temporal distribution of calories, independent of total caloric consumption," the researchers concluded. "Meal timing may be a novel modifiable risk factor for NAFLD and warrants prospective observational, perhaps even interventional, studies."

"Modern society has seen a growing number of people working nights or staying up much later than before, which often upsets 'normal' sleeping and eating patterns," Dr Esteban said in an AASLD press release. "Our study suggests that the chances of developing NAFLD may be reduced by simple modifications to the way that we eat and time our meals, and adherence to a few 'rules of thumb', such as not skipping daytime meals and avoidance of late night meals."

However, he stressed that this analysis only reflects associations between meal patterns and fatty liver disease, and additional research is needed to determine whether there are causal connections.

The analysis assumes that people wake up and eat breakfast in the morning, eat lunch at midday and eat dinner in the evening. Shift work – working outside a typical 9am-5pm schedule – has been associated with a multitude of health problems, but it is unclear whether this applies equally to 'owls' with a naturally late circadian rhythm and 'larks' whose work schedule conflicts with their natural early rhythm.