Liver at 50% Greater Risk in Diabetes

Although the liver is often overlooked in diabetes, even newly-diagnosed cases carry a substantial risk of serious hepatic damage, researchers found....

According to Gillian Booth, MD, MSc, of St. Michael's Hospital in Toronto, in a population-based study, newly-diagnosed diabetes was associated with a near doubling in the rate of liver cirrhosis, liver failure, or liver transplant compared with people in the general population who did not have diabetes.


After adjusting for important contributors to liver disease, the association remained significant with a 77% increased risk for newly-diagnosed diabetes patients (95% confidence interval 68% to 86%).

"The negative impact of diabetes on the retinal, renal, nervous, and cardiovascular systems is well recognized, yet little is known about its effect on the liver," they wrote.

According to Kenneth Cusi, MD, who has been studying this condition at the University of Texas Health Science Center in San Antonio, although much still remains to be discovered about the mechanisms and cause of the link between diabetes and liver disease, nonalcoholic steatohepatitis (NASH) is almost certainly involved.

"Steatosis is known to arise in relationship to insulin resistance in obesity, and most people with the condition do have some degree of glucose abnormality.... The two seem to 'feed on each other'."

Unlike with eye disease, cardiovascular disease, and kidney disease, guidelines for diabetes care don't recommend screening for liver disease.

"However, when the liver fails," Booth's group cautioned in the paper, "there is no equivalent form of management, such as hemodialysis or retinal photocoagulation."

They suggested that liver disease "may be appropriate for addition to the list of target-organ conditions related to diabetes," with annual screening by means of a blood test, such as for the liver enzyme alanine aminotransferase.

But the sensitivity of blood tests and even ultrasound aren't great for identifying fatty liver disease that is the precursor to more serious liver problems and liver biopsy is not a feasible screening method, Cusi noted.

Also, it would first have to be shown that preventive measures such as weight loss and glycemic and lipid control are effective in diabetes, as they are in isolated fatty liver without diabetes, the researchers said.

To expand evidence for the link, the researchers retrospectively examined the administrative databases of the universal healthcare system in the province of Ontario from 1994 through 2006.

They compared 438,069 adults with newly diagnosed diabetes and an age-, sex-, and regionally-matched control group of 2,059,708 individuals without known diabetes. Preexisting liver or alcohol-related disease were cause for exclusion.

During a median of 6.4 years of follow-up, serious liver disease -- liver cirrhosis, liver failure, or liver transplant -- developed in 2,463 newly-diagnosed diabetes cases and 5,902 controls.

Thus, unadjusted liver disease incidence was 92% higher with diabetes (8.19 per 10,000 person-years with diabetes and 4.17 without it).

This difference remained significant across mutually-adjusted patient subgroups by age, gender, urban versus rural residence, and income level.

Diabetes appeared to have the most pronounced link with liver and the least with liver transplantation.

Hypertension and obesity didn't appear to entirely account for the relationship with diabetes. The risk of serious liver disease in nondiabetic individuals with preexisting hypertension or obesity was elevated but less so than among those with diabetes.

But the researchers cautioned that it is difficult to separate out the effects of these related conditions.

"Although our findings and those of the U.S. study [which found elevated chronic NASH risk in veterans with diabetes] edge forward the idea that diabetes may be harmful to the liver, the question remains of whether this effect extends beyond the metabolic syndrome," they wrote.

Another question that remains to be answered is causality.

Booth's group pointed out that hepatic fat content rises in parallel with insulin resistance and glucose dysregulation and that diabetes as a complication of cirrhosis typically doesn't arise until cirrhosis reaches an advanced stage.

However, they noted, they couldn't rule out the pre-existence of subclinical liver disease before study entry.

HbA1clevels correlate strongly to future diabetes, cardiovascular risk

An ancillary study to the ARIC (Atherosclerosis Risk in Communities) study supports the most recent (2010) ADA risk categories of hemoglobin (Hb) A1c in identifying future risk of developing diabetes and macrovascular and microvascular disease. The data were presented by Elizabeth Selvin, PhD.
The ADA now recommends the use of HbA1c for the diagnosis of diabetes and identification of persons at increased risk for diabetes. The ADA defines an HbA1c of 5.7% to less than 6.5% as “high risk” for the future development of diabetes.
In this analysis, 11,092 participants from ARIC, a large community-based epidemiologic study, without cardiovascular disease or diabetes at baseline had HbA1c measured from stored whole blood samples obtained between 1990 and 1992. Participants were followed for 15 years.
“In individuals with an A1c of 5.7% to less than 6.5%, which is the group identified as high risk for the development of diabetes and other complications, we see a very high risk of the subsequent development of diabetes. We can also see that individuals in that range are at risk for kidney disease, CHD [coronary heart disease], and stroke,” said Selvin, assistant professor of epidemiology and medicine at Johns Hopkins in Baltimore.
Compared with the reference population with an HbA1c level of 5% to less than 5.7%, those in the high-risk category of 5.7% to less than 6.5% had more than triple the risk of diagnosed diabetes, a 60% increase in the risk of CHD, a 56% increase in the risk of stroke, a 62% increased risk of end-stage renal disease, and a 42% increase in all-cause mortality, all adjusted for age, sex, race, and other potential confounders.
These risks were even greater in the cohort with HbA1c levels of 6.5% or greater at baseline.
“The vast majority of individuals with HbA1c greater than 6.5% will subsequently be diagnosed with diabetes during follow-up, and they’re at very high risk of kidney disease and have almost 4 times the risk of developing end-stage renal disease compared to those people in the normal range, and a 2-fold increased risk of developing CHD or stroke or dying during follow-up,” she said.
More than 20% of the group with HbA1c values of 5.7% to less than 6.5% and almost 80% of those with values of 6.5% or greater developed diabetes within 10 years.