The use of genomic approaches to diagnostics and treatment, along with concepts involving manipulation of the gut microbiome, open up promising avenues into more personalized, precision approaches to treating non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Experts discussed some of the research in these fields on Sunday at the ALD and NAFLD SIG Program.
Frank Lammert, MD, of Saarland University Medical Center in Homburg, Germany, spoke about several genetic susceptibility markers for liver diseases. There are now a number of genetic tests that clinicians can consider when treating a patient with unknown or known chronic liver diseases, he said; these include the HFE gene which is related to hemochromatosis, the ATP7B gene and Wilson disease; several genes associated with fatty liver disease including PNPLA3, and the SERPINA1 gene and alpha1-antitrypsin deficiency.
Patients who are homozygous for the HFE p.C282Y gene not only have an increased risk of hemochromatosis, but for liver disease in general. In one large meta-analysis, homozygous individuals had an odds ratio for any liver disease of 3.9 (95% CI, 1.9-8.1) compared to those who aren’t homozygous. The odds of developing fatty liver disease (OR, 10.0 [95% CI, 2.1-53.0]) and hepatocellular carcinoma (OR, 11.1 [95% CI, 3.7-34.5]) are even higher with this genotype.
A study in Iceland, where much of the population has undergone full genome sequencing, common ABCB4 polymorphisms were shown to significantly raise the risk of chronic liver diseases. One genotype raised the risk of cirrhosis by more than five-fold. “ABCB4 variants set patients on the highway to liver disease,” Dr. Lammert said.
The PNPLA3 gene can also do so, he said, particularly with the p.I148M risk variant. Individuals with this genotype have 70% higher liver fat content, a 3.5-fold increased risk of steatohepatitis, and increased risk for both cirrhosis and HCC, Dr. Lammert said.
“Can we use this info in clinics? It’s difficult,” he added, since the sensitivity is too low. Certain PNPLA3 genotypes do carry high negative predictive value, however, which could be useful to nearly rule out the risk of developing HCC in some patients.
Interestingly, that same gene is associated with the degree of success of lifestyle interventions in NAFLD. In one study, the reduction of liver fat contents after a lifestyle intervention was dependent both on BMI and on PNPLA3 genotype. “Those with risk genotypes are more likely to lose liver fat with intervention,” Dr. Lammert said, meaning the riskier genotypes in terms of disease development actually confer benefit once intervention is used.
“We all hope that genetically tailored recommendations for fatty liver disease might come soon,” he said.
Another potential of precision medicine in this field lies with the modification of the gut microbiome. Changes in the gut microbiota are associated with ALD and NAFLD, and thus targeting these changes could offer a new avenue of therapy.
Many “good” bacteria are decreased in alcohol-dependent patients, and if these patients are abstinent for only a few weeks these bacteria largely return. “Microbiome changes are very reversible, they are very dynamic, at least in the pre-cirrhotic state,” said Bernd Schnabl, MD, of the University of California, San Diego.
Targeting the microbiome could involve several approaches. First, pre- and probiotics have been tested in several double-blind randomized trials of non-cirrhotic NAFLD and NASH patients. These trials found generally positive results, including improvements in transaminases, reductions in serum IL-6, and reductions in hepatic steatosis. The issue with the trials, though, is that there is a wide range of bacteria used. “It’s very hard to reproduce these trials,” Dr. Schnabl said, adding that it is also unclear if the approaches could be translated into daily clinical practice. For future trials, he said, standardized approaches to pre- and probiotics would allow for a better path toward actually helping patients.
There is some conflicting evidence regarding the use of antibiotics. A study of paromomycin failed to show improvement in liver function tests, while another of rifamixin did show such improvement in patients with both NAFLD and NASH. There is some preliminary evidence that fecal microbiota transplantation could also treat NAFLD.
There are also precision microbiome approaches that hold promise, Dr. Schnabl said. For example, fexaramine, an FXR agonist, only affects intestinal epithelial cells. In a mouse study, the agent dramatically inhibited ethanol-induced liver injury.
“Modulation of ALD/NAFLD/NASH-associated dysbiosis represents an attractive target for therapy,” Dr. Schnabl said. Though both untargeted and precision approaches hold promise, he added that better specific targets in liver disease still need to be defined.