Obesity, Weight Gain Linked to Fibrosis Progression in NAFLD

Obesity and weight gain are independently associated with an increased risk for fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD), a large cohort study has found. Weight loss was negatively associated with fibrosis progression.

“This association remained significant after adjustment for confounders including baseline BMI [body mass index], indicating that weight change per se is an independent risk factor for fibrosis progression. Higher BMI at baseline was also positively associated with APRI [aspartate aminotransferase to platelet ratio index] progression,” the researchers write.

The study, by Yejin Kim, MHS, Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea, and colleagues, was published online July 15 in Clinical Gastroenterology and Hepatology.

The researchers analyzed data from 40,700 adults who received comprehensive annual or biennial examinations as part of the Kangbuk Samsung Health Study. They included participants with fatty liver, as evidenced on abdominal ultrasonography, who had undergone a health examination between 2002 and 2016 and who had had two or more follow-up visits through the end of 2016. Patients were followed for a median of 6 years.

The authors explain that they used APRI score to assess fibrosis progression because it is noninvasive and the formula includes neither BMI nor age. The study’s primary endpoint was the development of intermediate to high probability of advanced fibrosis, as assessed by APRI.

The researchers first adjusted for age and sex, and later adjusted for center, year of screening examination, smoking status, alcohol consumption, regular exercise, education level, BMI, diabetes history, cardiovascular disease history, and hypertension history. A second model also adjusted for homeostatic model assessment of insulin resistance (HOMA-IR) and high-sensitivity C-reactive protein (hsCRP).

There were 275,421.5 person-years of follow-up, during which 5454 patients with low APRI progressed to intermediate or high APRI.

When stratified into quintiles by weight change, those with the greatest weight loss (-43.4 to -2.3 kg) had a significantly reduced risk for progression (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.62 – 0.74), compared with those whose weight was stable. Similarly, patients with small degrees of weight loss (-2.2 to -0.6 kg) had a reduced risk for progression (HR, 0.86; 95% CI, 0.78 – 0.94).

By contrast, any weight gain appeared to increase progression risk. Specifically, those who gained a smaller amount of weight (0.7 to 2.1 kg) showed a 17% risk increase (HR, 1.17; 95% CI, 1.07 – 1.28), and those who gained more (2.2 to 26.5 kg) had a 71% increased risk (HR, 1.71; 95% CI, 1.58 – 1.85).

These associations were not mediated by inflammation or insulin resistance after adjustment for HOMA-IR and hsCRP.

Compared with those whose baseline BMI was from 18.5 to 22.9 kg/m2, the HRs for APRI progression were as follows: 1.67 (95% CI, 0.74 – 3.73) for BMI of <18.5 kg/m2; 1.13 (95% CI, 1.02 – 1.26) for BMI of 23 – 24.9 kg/m2; 1.41 (95% CI, 1.28 – 1.55) for BMI of 25 – 29.9 kg/m2; and 2.09 (95% CI, 1.86 – 2.36) for BMI of ≥ 30. All values were determined after adjusting for age, sex, health center, year of screening examination, smoking status, alcohol consumption, exercise, education, diabetes history, cardiovascular disease history, and hypertension history. These associations remained significant after adjustments for HOMA-IR and hsCRP.

“When the impact of weight change on APRI worsening was compared with that of other metabolic factors, increasing quintiles of weight change, triglyceride, uric acid, and HOMA-IR and decreasing quintiles of high-density lipoprotein cholesterol were associated with increased risk of APRI worsening in a dose-response manner (all P for trend <.001), with weight change showing the greatest magnitude of association among the metabolic factors evaluated,” the authors explain.

The associations of both weight change and BMI with APRI progression were still seen in patients with NAFLD who had no history of diabetes or cardiovascular disease.

“Although the mechanisms underlying the association between excessive adiposity or fat gain and the fibrosis progression are not yet fully understood, insulin resistance and inflammation are thought to be involved,” the researchers write. “However, after adjustment for HOMA-IR and hsCRP, the association between obesity, weight gain, and fibrosis progression remained significant. Multiple other factors, including oxidative stress and lipotoxicity, have also been implicated in fibrosis progression.”

Study limitations include the use of ultrasonography to diagnose NAFLD. Although liver biopsy is considered the gold standard, it is not be feasible in a large, low-risk population, and abdominal ultrasound is acceptable, the authors say. Also, although APRI “has demonstrated a reasonable utility as a noninvasive method for the prediction of histologically confirmed advanced fibrosis…there are no currently available longitudinal data to support the use of worsening noninvasive fibrosis markers as an indicator of histologic progression of fibrosis stage over time.”

The study was conducted among fairly healthy young and middle-aged Koreans and may not be generalizable to those of other ages, or to groups in which comorbidities are more prevalent, or to other racial or ethnic groups.

“In this large cohort study of young and middle-aged adults with NAFLD, obesity and weight gain were significantly and independently associated with an increased risk of developing fibrosis progression. Strategies for maintaining a healthy weight and preventing weight gain may help reduce fibrosis progression and its associated consequences in individuals with NAFLD,” the researchers conclude.

MRI Monitors Liver Fat Response to Bariatric Surgery

Quantitative chemical shift-encoded magnetic resonance imaging (CSE-MRI) is an effective, noninvasive way to monitor liver fat levels over time after bariatric surgery, a study published today in Radiology reports.

Common in obese people, nonalcoholic fatty liver disease (NAFLD) can progress to fibrosis, cirrhosis, and cancer. Although weight loss can reduce the extent of NAFLD, biopsy has been the only possible method of assessing the long-term impact of weight loss on hepatic steatosis.

B. Dustin Pooler, MD, an adjunct assistant professor at the University of Wisconsin School of Medicine and Public Health and a radiologist at Madison Radiologists, S.C., in Madison, Wisconsin, and colleagues used the noninvasive MRI technique to measure average liver proton density fat fraction (PDFF) in 50 patients before bariatric surgery and at several points during the year afterward. They compared this MRI biomarker with postsurgical changes in body mass index (BMI), weight, and waist circumference.

The study cohort, which included 43 women and seven men and was recruited from 2010 to 2015 from medical centers at the University of California San Diego and the University of Wisconsin-Madison, had a mean age of 51.0 years and a mean BMI of 44.9 kg/m2.

Presurgical preparation entailed a very low-calorie diet of 600 to 900 calories per day, started at a mean of 2.6 weeks before surgery. Bariatric procedures included gastric banding (n = 2), gastric bypass (n = 28), gastric sleeve (n = 19), and gastric plication (n = 1). PDFF was assessed presurgically before and after the diet, and along with anthropomorphic measurements was assessed at 1, 3, and 6 months after surgery.

Liver fat content began to normalize early during the low-calorie diet and soon after surgery, suggesting metabolic disturbances of NAFLD begin to correct rapidly in response to the caloric deficit of the presurgical diet even before substantial weight loss.

Overall, 32 (64%) of 50 study participants saw their liver fat normalized and an estimated 90% reached that goal by 42 weeks. Six to 10 months postsurgery, patients’ mean PDFF had returned to the normal range of < 5%, falling from 18.1% to 4.9%, with a mean estimated time to normalization of 22.5 weeks.

Mean BMI fell to 34.5 kg/m2 (mean decrease 10.4), and the cohort’s final mean weight of 91.6 kg represented am overall reduction of 29.9 kg. The final mean waist circumference of 110.9 cm represented a mean decrease of 21.3 cm. All reductions were statistically significant (P < .0001)

Rohit Loomba, MD, director of the NAFLD Research Center at the University of California San Diego and chair of the NAFLD Special Interest Group for the American Association for the Study of Liver Diseases, told Medscape Medical News the findings are an important contribution to the field of liver study.

“Previously the MOZART trial conducted by our group demonstrated the role of MRI-PDFF in assessing treatment response in [nonalcoholic steatohepatitis; NASH] trials. This excellent study clearly extends those findings to examine longitudinal changes in liver fat by MRI-PDFF specifically after bariatric surgery,” said Loomba, who was not involved in the research.

Loomba noted that further studies are needed to examine longitudinal changes that might suggest progressive NAFLD, including biomarkers of fibrosis and inflammation.

Earlier this year, Duke University researchers confirmed MRI’s utility for detecting NAFLD, but concluded it was not sufficiently accurate to replace biopsy in distinguishing between NAFLD and its more advanced relative, nonalcoholic steatohepatitis.

Interestingly, whereas initial PDFF level strongly predicted both rate of liver fat change and time to normalization, body anthropometrics did not predict either outcome. “Decreases in liver fat content were only weakly correlated with starting weight and the amount of overall weight loss, suggesting possible utility in monitoring liver fat with MRI following bariatric surgery, independent of monitoring weight loss,” Pooler and colleagues write.

They suggest that PDFF measurements could also help identify appropriate candidates for bariatric surgery as a result of this robust association between liver fat reduction and pretreatment steatosis levels.

According to the authors, their study is the first longitudinal analysis of changes in liver fat over time in a bariatric surgery population.

Obscure Asthma Drug Shows Promise for Treating Diabetes

A little-used asthma drug called amlexanox may potentially be repurposed to treat type 2 diabetes, according to findings from a small proof-of-concept study published in the July issue of Cell Metabolism.

Results showed that using the drug for 12 weeks was linked to significantly reduced HbA1c in some patients with obesity, type 2 diabetes, and nonalcoholic fatty-liver disease (NAFLD).

“The overall significant reduction in HbA1c over this relatively short trial indicates that amlexanox can benefit some patients with type 2 diabetes. The reduction in HbA1c is on the order of a [dipeptidyl peptidase-4] DPP-4 inhibitor when given alone over the same time period,” commented first author Elif Oral, MD, director of the MEND Obesity and Metabolic Disorder Program at the University of Michigan, Ann Arbor.

Researchers also looked at baseline inflammation, which revealed an interesting finding: people with higher levels of inflammation responded better.

“Among drug-treated patients, there seemed to be a greater degree of inflammation in responders compared with nonresponders. This is interesting, since we know that inflammatory pathways drive up expression of the targets of amlexanox,” Dr Oral said.

Amlexanox inhibits two enzymes: IKKƐ and TBK1. Studies in mice have shown that inhibiting these enzymes improves weight, insulin resistance, fatty liver, and inflammation.

Another intriguing result: responders showed over 1100 gene changes, and these changes were found only in this group.

“The drug response was characterized by a unique and dramatic molecular signature of gene-expression changes, consistent with what was seen in mouse models, in which expression of energy-expenditure genes were increased. We’re still investigating the importance and significance of these gene-expression changes,” Dr Oral added.

Amlexanox Developed in Japan to Treat Allergies and Asthma

Amlexanox was developed in Japan in the 1980s to treat asthma and allergic rhinitis. However, it requires thrice-daily dosing and was never introduced to the United States, because of heavy competition from more popular medications like montelukast, which can be taken once a day. Even in Japan, the prescription rate was very low, and therefore amlexanox was discontinued this year for commercial reasons.

However, its exact mechanism of action has never been fully investigated. It was not until Dr Oral and colleagues screened 150,000 chemicals, looking for inhibitors of IKKƐ and TBK1, that they hit upon amlexanox as a potential antidiabetes drug.

They first tested amlexanox in mice and did an open-label safety study in humans. Both the animal and human trials pointed to fat tissue as an important target for amlexanox.

So researchers next tested amlexanox in a randomized double-blind placebo controlled study that included 42 obese individuals with type 2 diabetes and NAFLD. Participants were randomized to 12 weeks of 50-mg amlexanox three times daily or placebo.

About one-third of participants showed a robust response to amlexanox, with reductions in HbA1c of ≥ 0.5% percentage points or more, which was significantly different from placebo (= .05). Responders also showed significant decreases in fructosamine, a marker for shorter-term glucose control (= .024).

Similar to results in mice, at 2 to 4 weeks responders showed a transient increase in IL-6, followed by decreased fasting glucose and improved insulin sensitivity. A subgroup of responders with NAFLD showed improvement in fatty liver.

Responders also had higher levels of baseline inflammation than nonresponders or placebo patients, including higher levels of CRP, which correlated with the amount of reduction in HbA1c. And analyses of fat biopsies showed they also had higher baseline activation of genes involved in inflammation.

Fat biopsies also replicated findings from the open-label study in humans, showing responders treated with amlexanox had higher expression of genes involved in energy expenditure and “browning” of fat.

Seven patients in the amlexanox group developed a rash at 4 weeks, which resolved within 2 weeks using local treatment. No other adverse events attributable to amlexanox occurred. This is consistent with the long-term safety profile in Japan, in which about 5% of patients developed rash, Dr Oral pointed out.

“We don’t understand the mechanism for why participants with more underlying inflammation responded better. However, previous work has shown that TBKI and IKKƐ are upregulated in the setting of more inflammation. So it is possible that inflammation oversensitizes the pathway that the drug targets,” she explained.

More Studies Planned

The team is now planning a longer 6-month prospective, randomized study in humans that will test whether individuals with elevated CRP and higher levels of fat inflammation at baseline have better responses to amlexanox.

They also plan another trial in humans that will test amlexanox in combination with mirabegron (Myrbetriq, Astellas Pharma), a pure beta agonist used to treat overactive bladder. The idea is to see whether amlexanox can restore catecholamine sensitivity.

Future studies will also determine the optimal safe dose and dosing regimen for amlexanox.

“If we can really prove that those patients with higher inflammation will respond better with this drug, it will be the first time that such an observation will be made, which is exciting. It’s another way of customizing therapy for patients,” Dr Oral stressed.

The group is currently looking for ways to partner with companies and investors, but currently none are involved.

Treatment with pegbelfermin for 12 weeks improved lipid profile in adults with obesity, type 2 diabetes and a predisposition for nonalcoholic fatty liver disease, or NAFLD, according to findings from a phase 2 study published in Obesity.

Treatment with pegbelfermin for 12 weeks improved lipid profile in adults with obesity, type 2 diabetes and a predisposition for nonalcoholic fatty liver disease, or NAFLD, according to findings from a phase 2 study published in Obesity.

Brent A. Neuschwander-Tetri, MD, a professor of internal medicine, division of gastroenterology and hepatology at the Saint Louis University School of Medicine in St. Louis, and colleagues conducted the study with a randomized, double-blind, placebo-controlled design across 12 weeks. Pegbelfermin (Bristol-Myers Squibb), which is a polyethylene glycol-modified recombinant human fibroblast growth factor 21 analogue, was assessed for how well it is tolerated and how it affected HbA1c, lipids, adiponectin and biomarkers for liver fibrosis, NAFLD and nonalcoholic steatohepatitis (NASH).

Researchers analyzed data from 120 adults with obesity and type 2 diabetes from 15 sites in the U.S. and Canada, enrolled between July 2014 and September 2015.

Researchers randomly assigned participants to one of five groups based on the size of dosage of pegbelfermin: 1 mg daily (n = 24; 46% women; mean age, 55 years); 5 mg daily (n = 24; 54% women; mean age, 55 years); 20 mg daily (n = 24; 37% women; mean age, 56 years); 20 mg weekly (n = 24; 50% women; mean age, 55 years) and placebo (n = 24; 42% women; mean age, 58 years).

After 12 weeks of treatment, there was no difference in HbA1c levels across the cohort, regardless of dosage of pegbelfermin. There were no between-group differences for body weight, fasting plasma insulin, C-peptide or insulin sensitivity. However, the researchers noted that the 20 mg weekly group experienced a mean decrease in fasting plasma glucose (P = .028) vs. placebo, whereas researchers observed an increase in whole-body insulin sensitivity in the 20 mg per day group vs. placebo group based on the Matsuda index (P = .033). The 20 mg per day group also exhibited improved levels of HDL cholesterol (P = .015) and triglycerides (P = .037).

“The improvements in HDL and triglycerides observed in the 20 mg/d treatment group are consistent with findings from clinical trials of other [fibroblast growth factor 21] analogs,” the researchers wrote. “These findings, if confirmed in subsequent studies, could be of clinical significance, as a lipid-lowering agent could reduce the overall cardiovascular risk of patients with obesity and [type 2 diabetes].”

The researchers also noted that adiponectin levels increased in the 1 mg per day (P = .043), 5 mg per day (P = .011), 20 mg per day (P = .002) and 20 mg per week (P = .034) groups vs. placebo.

Additionally, reports of adverse events were relatively stable throughout the treatment groups and the placebo group. The researchers noted that injection-site bruising, other injection-site reactions and diarrhea were the most commonly reported adverse events.

“These results suggest that pegbelfermin is generally safe, well-tolerated and associated with improvement in liver-related biomarkers and multiple metabolic parameters in patients with obesity and [type 2 diabetes] who have a high prevalence of fatty liver and who are at risk for developing NASH,” the researchers wrote. – by Phil Neuffer

Diabetes risk persists in metabolically healthy adults without NAFLD

Among metabolically healthy adults with overweight or obesity, researchers observed an association between BMI and diabetes risk independent of nonalcoholic fatty liver disease, according to findings published in Obesity.

“Our findings indicate that excess adiposity is not a harmless condition and can induce the development of diabetes, even in [nonalcoholic fatty liver disease]-free subjects without any metabolic abnormalities,” Yoosoo Chang, MD, PhD, of the Center for Cohort Studies at Total Healthcare Center, Kangbuk Samsung Hospital and Sungkyunkwan University School of Medicine in Seoul, South Korea, and colleagues wrote.

Chang and colleagues analyzed data from 74,509 adults considered to bemetabolically healthy at baseline, defined in this study as adults without insulin resistance or any criteria for metabolic syndrome except for large waist circumference (31,221 men). Adults were participants in the Kangbuk Samsung Health Study, a cohort of Korean adults who underwent comprehensive annual or biennial exams with at least one follow-up visit between March 2005 and December 2013; exams included blood draws and abdominal ultrasounds.

During a mean follow-up period of 4.1 years, 472 adults developed diabetes (incidence rate, 1.5/1,000 person-years). Researchers found that, as BMI increased, the incidence of diabetes also increased in a dose-response manner, independent of the presence of nonalcoholic fatty liver disease (NAFLD).

In adults with overweight but without NAFLD, the HR incident diabetes vs. adults of normal weight was 1.29 (95% CI, 1-2.16) after multivariable adjustment; HR for those with obesity and without NAFLD was 1.57 (95% CI, 1.14-2.16). For adults with NAFLD and overweight, the adjusted HR for incident diabetes rose to 1.9 (95% CI, 0.95-3.8); the HR for those with obesity and NAFLD was 2.57 (95% CI, 1.32-5.02).

“Even in strictly selected metabolically healthy men and women, we observed a strong association between BMI and incident diabetes that was independent of NAFLD,” the researchers wrote. “Also, our study demonstrates that overweight and obesity both independently affect the risk of diabetes in a dose-response manner.” – by Regina Schaffer