Obesity, diabetes fuel liver disease epidemic

"We currently recommend that anyone with NAFLD cirrhosis or cirrhosis of unknown etiology who is also obese or had diabetes should receive routine HCC surveillance," said Dr. György Baffy, chief of gastroenterology at the VA Boston Healthcare System. He predicts that "we may soon reach a general conclusion that people with morbid obesity (a body mass index of greater that 40 kg/m²) and poorly controlled diabetes should be considered for liver cancer surveillance even without clear evidence for cirrhosis," he said in an interview. But in general, "HCC occurrence in noncirrhotic liver is so low that surveillance would be rather inefficient."

Despite that, Dr. Baffy admits that the connection between diabetes and HCC may go beyond cirrhosis. "Up to half of all HCC may develop in noncirrhotic livers," he wrote in a recent editorial (Am. J. Gastroenterol. 2012;107:53-5). "It is more difficult to determine the need for HCC surveillance in diabetic patients with noncirrhotic liver or with no established liver disease."

To avoid missing a diagnosis of HCC, Dr. Baffy suggested awareness of the risk factors for advanced background liver disease and for HCC in patients with diabetes: male sex, older age, morbid obesity, poorly controlled and long-standing disease, and coexisting hepatitis C.

"For now, cirrhosis remains the primary indication for implementing HCC surveillance," but the new findings on liver cancer developing in liver disease associated with obesity and diabetes so far provide insufficient evidence to warrant any firm screening recommendations for these patients, Dr. Baffy wrote in another recent article along with Dr. Caldwell and Dr. Elizabeth M. Brunt (J. Hepatology 2012;56:1384-91). "The greater dilemma comes from new evidence that HCC may complicate NAFLD when fibrosis is mild or absent. Observations that diabetes may increase the risk of HCC regardless of the presence of cirrhosis remain a major concern for the 26 million Americans estimated to have diabetes or prediabetes," they wrote. "We may need to contemplate a paradigm shift in liver cancer surveillance, but for now at least, HCC appears to be a rare complication of NAFLD in the complete absence of fibrosis."

In addition, the value of regular cancer surveillance, even in patients with cirrhosis, remains uncertain, just as surveillance for breast cancer and prostate cancer has come under similar criticism. "It gets a little shaky when you look for evidence that [HCC] surveillance led to prolonged survival," said Dr. Caldwell. "You have all the same controversy as breast cancer, but surveillance is even less established for HCC."

Diabetes also linked to HCC spread

Once hepatocellular carcinoma forms in a patient with diabetes, the cancer may act more aggressively, according to studies from the University of Rochester (N.Y.).

A review of 265 consecutive patients treated for hepatocellular carcinoma (HCC) at Rochester’s Wilmot Cancer Center identified 91 (34%) with diabetes at the time of HCC diagnosis. Forty-seven of the 265 patients (18%) had distant metastases at the time of diagnosis. A multivariate analysis that controlled for age and etiologic risk factors showed that patients with diabetes were 10 times more likely to have distant metastases at the time of HCC diagnosis, compared with patients without diabetes, Dr. Aram F. Hezel and his associates reported last year (Cancer Investigation 2012;30:698-702). The analysis showed no statistically significant impact of diabetes on survival rate.

In a second analysis they found that patients with newly diagnosed HCC and diabetes were also significantly more likely to have macrovascular invasion by the HCC.

Dr. Aram Hezel

"We don’t treat patients with HCC differently if they have diabetes or obesity, but our findings show an association between diabetes and greater spread of HCC, more invasive cancer," said Dr. Hezel, an oncologist and director of hepatic and pancreatic cancer research at the Wilmot Cancer Center of the University of Rochester (N.Y.). "We don’t know whether we can treat the diabetes and change the behavior of the cancer by having patients under better control. Are cancers different in patients with diabetes or obesity? Do some metabolic states help push a cancer to more invasive behavior?" he asked in an interview.

"We use liver transplant to treat patients with liver cancer. In early stages of liver cancer the tumor is less likely to spread, so liver transplant can be curative. But if there are patients with a greater propensity for cancer spread at an earlier stage" then the efficacy of transplantation needs reassessment, Dr. Hezel said.

Few proven treatments for NAFLD, NASH, and to prevent HCC

Although diagnosing NAFLD is an important step in identifying patients at risk for NASH, cirrhosis, and liver cancer, interventions with proven benefits for NAFLD are limited. No approved drug treatments exist for NAFLD; lifestyle modification is the standard treatment to reduce steatosis and plasma levels of liver aminotransferases. Reductions in liver fat correlate closely with weight loss, Dr. Cusi, Dr. Lomonaco, and their associates said in a recently published analysis of NAFLD (Drugs 2013; Jan. 11 [Epub ahead of print]). A weight loss of 7%-10% has been linked with a roughly 50% drop in liver fat levels in NAFLD patients, they said. But long-term controlled studies are needed to better assess the impact of lifestyle changes on NAFLD and fatty livers.