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Early-onset obesity in father linked to increased potential for liver disease in child

April 01, 2008

A history of early-onset paternal obesity increases the odds of elevated liver enzyme levels in offspring and points to the potential for a genetic link between obesity and liver disease, according to a study in Gastroenterology, the official journal of the American Gastroenterological Association (AGA) Institute.

This new study found that participants with paternal early-onset obesity had higher serum alanine aminotransferase (ALT) levels than those without paternal obesity. These results showed that children with fathers who were defined as clinically obese at an early age were more likely to have increased liver enzyme levels, an indicator of liver disease. A secondary analysis, excluding obese offspring, produced a strengthened connection between paternal early-onset obesity and elevated serum ALT levels, demonstrating that the link between obesity in the father and elevated serum ALT levels in the offspring is independent of the child's body mass index (BMI) and persists among non-obese children. No relationship between maternal early-onset obesity and ALT levels was found.

Serum ALT levels are a marker of liver disease in the general population. Previous studies have shown that obesity is an important correlate of elevated serum ALT levels, and according to the National Health and Nutrition Examination Survey (NHANES), up to 7 percent of the adult U.S. population has unexplained elevated serum ALT levels. These elevated levels are potentially due to nonalcoholic fatty liver disease (NAFLD), which is now considered to be the most common cause of serum ALT elevations in the U.S. population and is associated with obesity. Elevated serum ALT levels and NAFLD can lead to inflammation of the liver (hepatitis), scarring of the liver (cirrhosis) and liver cancer, a potentially deadly condition.

"Serum ALT elevations and NAFLD are more prevalent than ever in the U.S., though we don't know specifically what's causing the increase. Our results point to a genetic connection between early-onset paternal obesity and increased ALT levels," said Caroline S. Fox, MD, MPH, the senior author of the study and medical officer with the Framingham Heart Study, Framingham, MA. "These findings show that familial factors may play a role in elevated serum ALT levels in the general population." The Framingham Heart Study is a prospective, community-based, family study supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH).

Dr. Fox and her colleagues from the NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) evaluated participants of the NHLBI's Framingham Heart Study for their research, using a well-characterized, large community-based sample with detailed clinical examination data available. Both parents had to have been participants in the Framingham Heart Study for the child to qualify. Researchers evaluated 1,732 offspring cohort participants, with an average age of 42 years and an even split of male and female patients. Parental obesity was defined as a BMI of 30 or more on at least two occasions during the follow-up of the original cohort. Early-onset parental obesity was defined as the twenty-fifth percentile of the age at the first obesity among the obese fathers and mothers (41 years in men and 45 years in women).

Serum ALT and serum aspartate aminotransferase (AST) levels were measured on fasting morning samples using standard methodology and were categorized as "elevated" based on traditional cut-off levels: serum ALT and AST ≥ 30 IU/L in men and ≥ 19 IU/L in women. BMI was defined as weight (kilograms) divided by square of the height (meters). The first analysis of data reported that offspring with paternal early-onset obesity were more likely to have elevated ALT levels compared to those without paternal obesity. Data specifically reflected a multivariable model odds ratio of 1.75 (1.06-2.89) at a confidence interval of 95 percent and a statistically significant p-value of 0.03. The study found no correlation between parental obesity and serum AST levels.

A secondary analysis excluded children who themselves were clinically obese to assess whether the findings were independent of offspring obesity. The overall results were relatively unchanged, but the connection between early-onset obesity in the father and elevated serum ALT in the child was strengthened in this review.

"This study is the first to look at the connection between parental early-onset obesity and elevated serum ALT levels in their children using objective clinical measurements of parental BMI instead of self-reports," said Rohit Loomba, MD, of NIDDK's Liver Diseases Branch and first author of the study. "Though we are looking at a very specific, community-based sample in our work, the results suggest an association between elevated serum ALT levels and early-onset paternal obesity. Additional studies are needed to assess whether this connection suggests a genetic predisposition to developing liver disease in larger populations."

Previous studies have reported that there is a familial clustering of factors that may predispose a person to the development of liver diseases. Future studies may evaluate the relations of potential candidate genes, elevated ALT levels and NAFLD and work to determine whether individuals with early-onset parental obesity and elevated serum ALT levels are at a higher risk of developing liver disease. In addition, future studies will evaluate whether the results of this study, which was conducted in a Caucasian population, apply to individuals in other ethnic groups.

American Gastroenterological Association