Management of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is progressively becoming the most common liver disease in the United States. Thirty percent of people in the United States have non-alcoholic fatty liver disease. The confirmation of diagnosis of non-alcoholic fatty liver disease is when there is excessive fat buildup in the liver, also known as hepatic steatosis. Diagnostics to confirm this diagnosis can be done with a range of tests. Starting with less invasive of an ultrasound, transient elastography, cat scan, magnetic resonance imaging (MRI), to most invasive of a liver biopsy. Laboratory tests, such as liver function tests (LFT’s), that include: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels which indicate liver damage and disorders, lipid profile, complete blood count, fasting glucose test, and hemoglobin A1C (HgA1C), can be performed, but are not confirmative of a diagnosis. These laboratory tests are not always abnormal in a patient with non-alcoholic fatty liver disease.

Background

Researchers and experts do not fully understand the why some patients accumulate fat in the liver compared to others. Therefore, there is not a definitive pharmacological treatment for non-alcoholic fatty liver disease. The best option for patients with this diagnosis is to manage their associative risk factors to the disease. Researchers believe that non-alcoholic fatty liver disease is becoming so prevalent due its association and increase of obesity and diabetes in the United States as well (Arab et al., 2014). Managing obesity is best seen with exercise and dietary regimens and managing diabetes with pharmacological and dietary regimens, as well. Obesity, diabetes, and non-alcoholic fatty liver disease puts the patient at cardiovascular disease risk as well. Prevention of cardiovascular risk, based off of studies, have shown to prevent and improve non-alcoholic fatty liver disease as well.

The goal of the literature review is to examine the best management options for non-alcoholic fatty liver disease that is evidenced based.  A consolidative analysis will take place of current literature within the last five years. Many research articles, as evidenced within this review, examine what the best management plan is for non-alcoholic fatty liver disease since there is no clear-cut treatment option.

Literature Review

Eslami, Merat, Malekzadeh, Nasseri-Moghaddam, Aramin, 2013, performed a study with the main focus validating the beneficial and harmful effects of statin medications on non-alcoholic fatty liver disease. This study describes that treatment is unavailable in non-alcoholic fatty liver disease, but goes on to describe how statin medications can decrease elevated liver function tests or keep them low if they were never elevated to begin with and in result, help cure the disease in patients. The researchers believed that the intervention, of statins, may work by minimizing the intrahepatic cholesterol and influence the abnormal lipid metabolism that has been seen in patients diagnosed with non-alcoholic fatty liver disease.

From randomized clinical trials, statins were given to patients and compared to either no intervention or given a placebo. Imaging studies followed in order to evaluate the effectiveness of the drug versus no drug. A decrease in liver function tests appeared to be superior in participants who were given a statin when compared to the control group. Although, it was resulted on diagnostic imaging that simvastatin, a statin medication, when evaluated against a placebo had no effects on disease management. Atorvastatin, another statin medication, compared to fenofibrate (a non-statin lipid-lowering drug) likewise had no differences when comparing ultrasound reports. When the two results were joined into one, atorvastatin compared to be a more beneficial drug to fenofibrate.

The following year, Arab et al., 2014, conducted a study using the Delphi method to gather data on evidence-based management of non-alcoholic fatty liver disease. Thirteen experts of the disease process received a survey of seventeen open-ended specific questions that providers are consistently challenged with during the management of non-alcoholic fatty liver disease. The experts underwent three rounds where a level of agreement in the first round was 93.8% and then 100% the second and third rounds. The seventeen open-ended questions consisted of the following interventional categories for management: diet and weight loss, physical exercise, weight loss medications, bariatric surgery, insulin-sensitizing medications, hypolipidemic medications, and antioxidants.

The relationship between diet and weight loss was agreed to be recommended to all patients with non-alcoholic fatty liver disease. A caloric restriction of 25-30 kilocalories per kilogram per day was found to best assist with gradual weight loss. Dramatic weight loss was shown to correlate with progressive liver fibrosis and portal inflammation. Appropriate diet with at least thirty minutes of physical exercise at least three times a week was beneficial for the patient by reducing the risk of cardiovascular disease. Physical exercise in relation to liver enzymes had a significant normalization of levels, regardless of weight loss. Medications for weight loss had contraindicative results of not being fit to solely manage or treat NAFLD. One drug, orlistat was recommended to be used in combination with nutritional and exercise programs. Due to high risk of cardiovascular adverse events, the weight loss drug sibutramine was not recommended.

The importance of cardiovascular disease, in conjunction with non-alcoholic fatty liver disease, was further studied by Targher et al., 2013.  Four hundred participants who previously had been diagnosed with type 2 diabetes were selected to be followed over a ten-year period.  All participants were deemed free from atrial fibrillation during initial baseline assessment. Any participant who had a history of atrial fibrillation, atrial flutter, or taking an antiarrhythmic drug were excluded from the study. An ultrasound was also done at based line to confirm diagnosis of NAFLD. Out of the 400 participants, the number that met the clinical criteria to be diagnosed with NAFLD were 281. At that time, the remaining 281 participants underwent annual review, with the use of a twelve lead electrocardiogram and diagnosed with atrial fibrillation by a cardiologist when appropriate.  At the ten-year completion, the study identified 10.5% of type 2 diabetic participants were diagnosed with NAFLD and atrial fibrillation respectively (Targher et al., 2013).

Individualization of the indication of bariatric surgery was recommended by Arab et al., 2014. The effects of bariatric surgery long term had not been studied. Though it possibly could play a part in weight loss for obese patients, per researchers, and complications of bariatric surgery may occur depending on the patient and place of operation. Three year later, Cazzo, Pareja, and Chaim, 2017, conducted a meta-analysis study of ninety-one individuals correlating bariatric surgery and non-alcoholic fatty liver disease. Different surgical techniques of bariatric surgery were taken into consideration when conducting the study. Overall, research showed that weight loss generated by bariatric surgery, improved or resolved entirely NAFLD in the bulk of individuals. Cazzo, Pareja, and Chaim, 2017, conclude that illimitable amount of patients with NAFLD are lean and overweight, but morbid obese patients with NAFLD are the patients who would benefit the most from bariatric surgery induced weight loss.  In 2016, a control clinical trial was conducted utilizing twenty-four Sprague Dawley rats.  The rates were randomly placed in sets of eight and identified as Sham or Roux-en-Y gastric bypass (RYGM) surgery group and compared to eight placed in the lean control group.  To maintain obese rats, they were fed a high fat diet throughout the study.  The rats were assessed ninety days’ post-surgery for insulin resistance, hepatic steatosis, triglyceride levels, endoplasmic reticulum (ER) stress and apoptosis.  There was a significant difference between the groups and the RYGM group had decreased their baseline weight by 20% and showed increased insulin sensitivity (Mosinski et al., 2016).

Insulin-sensitizing medications, act by improving the sensitivity of peripheral tissues to insulin, which results in decreased circulating insulin levels. Insulin-sensitizing medications, such as Metformin, were not recommended for regular use to prevent insulin resistance in non-alcoholic fatty liver disease. Unless, these medications were used in patients who were already diagnosed insulin-resistant. In which case, Metformin, helped with insulin resistance, but continued to not show any improvement in NAFLD. A verdict was able to be reached that reinforced the importance of lifestyle changes of diet and exercise within these patients. (Arab et al., 2014).

As found in the research done by Eslami et al., 2013 on statin use in non-alcoholic fatty liver disease patients, Arab et al., 2014 verified further that regular use of statins in the NAFLD patient is not supported. Statin use for the management of lowering lipid profile results in the NAFLD patient, despite the fact, can be used to support reduction of risk factors associated. Del Ben et al., 2017, studied NAFLD in 605 patients with cardio-metabolic disorders and the use lipid-lowering medications. It was proven in this study, the use of lipid-lowering medications, such as statins, was highly under prescribed to patients at all levels of cardiovascular disease. Fifty percent of patients who had an indication for statin use were not prescribed any. A correlation of under prescribing was found in patients with NAFLD as a major consideration. Even though statin use for the treatment of NAFLD is still an ongoing debate with no clear evidence-based results, some studies have shown improvement of liver function tests as others have not. Nevertheless, Del Ben et al., 2017 recommends their use for management of cardiovascular risk in the NAFLD patient.

Antioxidant use, such as vitamin E, has been shown to be beneficial in nondiabetic patients who’ve had biopsy diagnosed non-alcoholic fatty liver disease. Reversal effects of the liver have taken place with discontinuation of vitamin E suggesting that long-term use is needed in order to be used as management of NAFLD (Arab et al., 2014). Similarly, Eslamparast, Eghtesad, Poustchi, and Hekmatdoost, 2015, concluded that Vitamin E is recommended in adults who are without diabetes. This study also agreed with Arab et al., 2014 that studies completed to evaluate and support long term effects of vitamin E and non-alcoholic fatty liver disease are lacking. The literature goes on to reveal that vitamin E does not yield greater outcomes for NAFLD management when compared to diet and exercise.

Dietary supplementation advances, as evidenced by studies conducted and released in literature, have shown to be beneficial. Green tea extract, in a study conducted in mice, proved to have beneficial effects on obesity, components of metabolic syndrome, and liver steatosis. Studies in humans are needed as the next step in furthering the green tea extract advancement. Anti-oxidative, anti-inflammatory, and anti-fibrotic properties of coffee are to blame for the hepatoprotective response. Among the NAFLD patients, coffee consumption has been associated with a decreased in the risk of fibrosis and a lower risk of developing type two diabetes (Eslamparast, Eghtesad, Poustchi, & Hekmatdoost, 2015).

In addition to green tea extract and coffee, the benefits of probiotics were also studied, utilizing the method of a double-blind, randomized, controlled clinical trial.  Seventy-two participants, diagnosed with NAFLD were selected, and placed into a group of thirty-six who ate 300 grams a day of probiotic yogurt and the thirty-six participants placed in the control group ate 300 grams a day of conventional yogurt. Upon concluding the study, after an eight-week interval, there was no noted change, of the controlled group, in their serum liver enzymes, glucose or lipid levels at their baseline.  However, the probiotic group showed reductions in their serum liver levels of aspartate aminotransferase and alanine aminotransferase (Nabavi, et al, 2014). These results show improvement in the serum indicators for liver disease and damage.

Multiple types of diets have been used by patients to promote their health. A study done by, Mohseni et al., 2016 evaluated the adherence to the Mediterranean diet pattern in seventy-five patients with NAFLD. Mohseni et al., 2016 and Eslamparast et al., 2015 both concluded diets that included unsaturated fats and excluded saturated fats were beneficial for patients with NAFLD. The development of NAFLD was prevented by unsaturated fats reducing the oxidation of low-density lipoprotein (LDL), serum levels of LDL and cholesterol totals. Body fat accumulation was also shown to decrease. It is evident, according to Mohseni et al., 2016, that dietary modifications are efficient in reducing the metabolic risk factors of chronic diseases, including non-alcoholic fatty liver disease.

In addition to studying types of diets, studies have also been completed to review eating styles and behaviors.  A retrospective cohort study, comparing participants who ate before bedtime and participants who did not, was completed in the year 2016. Nishi, et al., 2016, chose participants with a median age of forty-eight years old and who were free of a history of stroke, coronary heart disease, chronic kidney disease, liver cancer, liver fibroids, anemia, chronic viral hepatitis, alcoholic liver disease or anemia and were not treated with corticosteroids. The results showed a significant increase in NAFLD in participants who ate before bedtime, when compared to those who did not.

A cross sectional study of self-reported eating habits was completed by Lee et al., (2016) during routine medical exams. The subject sample consisted of 7,917 Korean adults without a medical history of a positive hepatitis B surface antigen (HBsAg positive), a positive hepatitis C antibody (HCV Ab positive), liver cirrhosis, hepatocellular carcinoma, elevated liver enzymes, or elevated gamma-glucronyl transpeptidase. Also incorporated in the exclusions were participants who had been taking medicine due to a liver disease or had a history of alcohol consumption of more than 20 grams per day for participants under the age of twenty and those who didn’t comply with questionnaires and ultrasonography.  The results were reported that faster eating groups showed an increased proportion of participants with advanced grade NAFLD. Lee et al., 2016, describe that faster eating habits may not directly affect NAFLD, but recommend the importance of education to patients regarding eating speeds. Education should include how slower eating speeds can prevent overeating, which may lead to obesity.

Endothelial nitric oxide synthase (eNOS) function in patients with hepatic steatosis, the first stage of non-alcoholic fatty liver disease and steatohepatitis, the second stage, was investigated in as study completed by Persico et al., 2017. It is already known that NAFLD is related to insulin resistance and insulin resistance is responsible for endothelial dysfunction. Two groups, steatosis and steatohepatitis, were divided out of the fifty-four patients enrolled in the study. Clinical, laboratory tests, and liver biopsies were taken to evaluate the eNOS function in platelets and liver samples taken. The early stage, simple steatosis, was correlated with a worse eNOS impairment when compared to steatohepatitis. Endothelial damage and deterioration of endothelial regulatory mechanisms serve as the pathophysiological foundation of cardiovascular disease. Persico et al., 2017 supports the other literature texts in this review by breaking down the damage done by NAFLD and reinforcing the need to manage and maintain risk factors such as cardiovascular disease and diabetes.

One cohort study was reviewed in regards to the accuracy of liver marker when diagnosing the presence of steatosis.  Three hundred and twenty-four liver biopsies were performed and assessed for steatosis.  Steatosis was then categorized into levels classified as none, mild, moderate or severe.  Five biomarkers were used to measure fatty liver index, NAFLD liver fat score, hepatic steatosis index, visceral adiposity index and triglyceride X glucose index (Fedchuk et al., 2014).  Reported findings state 81% were diagnosed with fatty liver as they showed bright red patterns on liver ultrasounds and only 5% did not have steatosis.  In addition, all of the fatty liver markers displayed were accurate in estimating the presence of any steatosis (Fedchuk et al., 2014).

Another cohort study was completed in 2016 with fifty-seven patients who had biopsy proven non-alcoholic fatty liver disease and the union with gut dysbiosis. Following liver biopsies, patients were asked to give a stool sample, genomic DNA was isolated and then the sample was frozen. The study spanned from October 2012 to September 2013 and excluded hepatitis infections, alcohol consumption, cirrhosis, bariatric surgery, ingestion of steatosis inducing drugs, other chronic liver diseases and antibiotic use within the preceding two months (Boursier et al., 2016).  The findings report an increase level of bacteroides in non-alcoholic steatohepatitis (the second stage of NAFLD) patients and ruminococcus bacteria was higher with fibrosis. “Recent animal studies have placed the gut microbiota as a potentially important player in the pathogenesis of NAFLD” (Boursier et al., 2016). Although the results were obtained after liver biopsy, the results are a promising indicator for future diagnostics.

Method

Relevant articles for the purpose of this literature review were obtained using the State University of New York Polytechnic Institute of Technology, Cayan Library electronic database. CINAHL Plus with Full Text and Ebsco Clinical Ebook Collection were the primary databases utilized. Google Scholar was also utilized as an additional search.

The key terms used to reach this literature review were fatty liver disease, non-alcoholic fatty liver disease, management of fatty liver disease, literature review, treatment of fatty liver disease, bariatric surgery for fatty liver disease, diet for non-alcoholic fatty liver disease, lifestyle modifications for NAFLD. The literature search was restricted to peer-reviewed articles printed in the English language. The search was also restricted to published articles between the years of 2012 and 2017. An overwhelming total of twenty-two articles were found and reviewed for relevance to main focus of this literature review. Fifteen of those articles were chosen that focused on managing the risk factors associated with non-alcoholic fatty liver disease. A final analysis of the fifteen articles was performed to compare the results (see Appendix A).

Results

Through comparison and contrast of findings, the results of the literature review support current evidence based practice for treating and reducing the risk of non-alcoholic fatty liver disease.  At this time current, evidence-based, treatment is weight loss, healthy diet, exercise, lowering cholesterol, controlling diabetes, protecting the liver, and avoidance of alcohol (Mayo Clinic, 2017).   Identified risk factors include, but are not limited to: obesity, elevated weight, diabetes, increased cholesterol and triglycerides, and poor eating habits. Upon review, the fifteen articles selected and identified in appendix A, can be subdivided into four categories that align and support current treatment.  There are six articles supporting diet and nutrition, with two referencing weight management through surgical means, four identifying the use cholesterol reducing medications and the impact on cardiovascular disease, one addresses the need of “good” bacterial levels within the body, and two demonstrates the importance of diagnostics associated with NAFLD.

Diet and Nutrition

Excess weight and fat can influence multiple risk factors of non-alcoholic fatty liver disease.  Poor diet and a sedentary lifestyle with a lack of exercise can not only increase weight but can also increase cholesterol and triglyceride levels.  In addition, it can also cause insulin resistance, which causes the pancreas to increase insulin production to maintain regular blood sugar levels and can lead to the development of diabetes (Johns Hopkins, nd).  In response to these concerns, research studies have addressed the potential impact of vitamin supplements, weight reduction surgery and eating habits.

Research done, by Arab et al., 2014, concluded that Vitamin E and pioglitazone in nondiabetic patients was a beneficial pharmacological therapy with biopsy proven steatohepatitis. Eslamparast et al., 2015 suggests that antioxidants, anti-inflammatory and insulin sensitizer dietary supplements have also shown beneficial effects.  Mohseni et al., 2016 concluded that diet modifications were significant and effective in reducing risk factors of chronic disease and the study conducted by Abulnaja and El Rabey, 2015, of barley bran consumption demonstrated a significant decrease in overall organ weights.

The diet modifications that were identified included the Mediterranean diet. Consisting of lean sources of protein (fish and poultry) versus red meats and increased consumption of legumes, whole grains, fruits and vegetables. Red wine is also acceptable within this diet type, provided it is consumed in moderation (Mohseni et al., 2016). Eating styles, which include eating before bed and speed of food consumption, also indicate an association to non-alcoholic fatty liver disease.  Subjects who ate before going to bed had a significant increase in NAFLD when compared to individuals who did not. When participants eating times were compared, there was also a correlation between an increased eating speed and an increase in the total body mass index (Nishi et al., 2016 & Lee et al., 2016).

Two studies indicate a benefit of bariatric surgery to reduce weight and obesity.  Both studies indicate this surgical measure, as beneficial as it, protected the liver against high fat density and improved the stage of NAFLD (Cazzo et al., 2017 & Mosinski et al., 2016).  However, authors of both articles indicate the need for further studies to show overall effectiveness.  The information in regards to bariatric surgery remains conflicting since rapid weight loss has also been identified as a NAFLD risk factor.

Medications

Increased cholesterol and triglycerides are significant in non-alcoholic fatty liver disease.  The fats inside the liver impair its metabolic ability to break down fats and produce energy.  Eslami et al., 2013, concluded that atorvastatin was superior to non-statin fenofibrate and research completed by Del Ben et al., 2017, demonstrated an underuse of prescribed statins with cardiovascular patients diagnosed with NAFLD. These results are of particular interest when compared with research analysis that found people diagnosed with NAFLD had increased eNOS dysfunction which can lead to a higher risk of cardiovascular disease. The study completed by Targher et al., 2013 showed that of 400 diabetic participants, 10.5% developed atrial fibrillation over a ten-year span. Making the correlation between NAFLD and cardiovascular disease and evidenced based risk factor. These increased risks of cardiovascular disease and gap in prescribed statins is alarming and produce evidence for the need of future implementation and further research.

Bacteria

Limited information is available in regard to normal body bacteria, also known as “good bacteria” and its effects on non-alcoholic fatty liver disease and the function of the liver.  However; Nabavi et al., 2014, completed a study that indicated a lowering of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels when eating probiotic yogurt.  This information is valuable as AST indicates levels of liver damage and ALT assists in diagnosing liver disorders. Though the study completed by Boursier et al, 2016 was done post diagnosis of NAFLD, it suggests that further studies are needed to prove that probiotic use as a preventative measure for NAFLD is evidenced-based.

Diagnostics

         The only way to diagnose non-alcoholic fatty liver disease with complete certainty is by performing a liver biopsy.  However, studies have shown a correlation with biomarkers and diagnosis.  One example is a research study that used multivariate analysis which resulted in showing an increased amount of bacteroides with NASH and increased amount of ruminococcus with fibrosis (Boursier et al., 2016).  This is supported by the fact that bacteroides have an increased presence in the intestinal tract of a person who consumes a diet high in animal fat. Nonetheless, the increased presence of ruminococcus is not readily explainable. Another study utilized five steatosis biomarkers with 324 liver biopsies and determined that all the fatty liver markers “displayed an acceptable accuracy in estimating the presence of steatosis of any amount vs. no steatosis” (Fedchuk et al., 2014).  The results of the study completed by Nabavi et al, 2014, also supports the use of diagnostics through the use of serum levels to assess AST and ALTs.

Conclusion

In conclusion, fifteen articles were selected to perform a literature review to examine the best management options for non-alcoholic fatty liver disease that is proven to be evidence based.  Articles were referenced over the past five years and included various methods of research.  Studies support the ongoing best standards of practice, with focus being on decreasing risk factors and prevention, with the most prevalent being obesity.  Education of treatment and ongoing medical care needs to be reinforced to decrease the severity in non-alcoholic fatty liver disease.  The current recommendations include follow up visits with a primary care provider every six months for assessment of body weight, body mass index, serum liver and serum metabolic testing.  In addition, an annual liver and abdominal ultrasound should be obtained to monitor disease progression which may result in a gastroenterologist referral (Mayo Clinic, 2017).

The studies included in the literature review, readily identified the need for ongoing research as current treatment options are pharmaceutically limited and treatment requires behavior modifications.  In addition to this challenge, the importance of effective treatment of non-alcoholic fatty liver disease is supported by it becoming the fastest growing liver disease, with 30% of the United States population being afflicted.  Although research continues in this area the primary approach for treating non-alcoholic fatty liver disease is education and reducing previously identified risk factors.

References

Abulnaja, K. & El Rabey, H. (2015).  The efficiency of barley (hordeum vulgare) bran in

ameliorating blood and treating fatty heart and liver in male rats. Evidence-Based

Complementary and Alternative Medicine. Retrieved from: 

http://eds.a.ebscohost.com.sunypoly.idm.oclc.org/eds/pdfviewer/pdfviewer?vid=12&sid=

6f1f7e23-fc8b-4541-8e7b-dbb232a3272b%40sessionmgr4010

Arab, J. P., Candia, R., Zapata, R., Muñoz, C., Arancibia, J. P., Poniachik, J., … Riquelme,

A. (2014). Management of nonalcoholic fatty liver disease: An evidence-based clinical practice review. World Journal of Gastroenterology: WJG, 20(34), 12182–12201. http://doi.org/10.3748/wjg.v20.i34.12182

Boursier, J., Mueller, O., Barrett, M., Machado, M., Fizanne, L., Araujo-Perez, F., Guy, C., Seed,

P., Rawls, J., David, L., Hunault, G., Oberti, F., Cales, P., & Die, A. (2016). The severity

of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the

metabolic function of the gut microbiota. Hepatology. 63(3). 764-765. Retrieved from:

http://onlinelibrary.wiley.com/doi/10.1002/hep.28356/full

Cazzo, E., Pareja, J. C., & Chaim, E. A. (2017). Nonalcoholic fatty liver disease and bariatric                              surgery: a comprehensive review. Sao Paulo Medical Journal = Revista Paulista De  Medicina, 135(3), 277-295. doi:10.1590/1516-3180.2016.0306311216

Del Ben, M., Baratta, F., Polimeni, L., Loffredo, LAverna, M., Violo, F., & Angelico, F. (2017).                      Under-prescription of statins in patient with non-alcoholic fatty liver disease. Nutrition, Metabolic, & Cardiovascular Diseases, 27, 161-167.

Eslami L, Merat S, Malekzadeh R, Nasseri-Moghaddam S, Aramin H. (2013). Statins for                                      non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Of Systematic Reviews, (12), doi:10.1002/14651858.CD008623.pub2

Eslamparast, T., Eghtesad, S., Poustchi, H., & Hekmatdoost, A. (2015). Recent advances

in dietary supplementation, in treating non-alcoholic fatty liver disease. World Journal

of  Hepatology, 7(2), 204–212. http://doi.org/10.4254/wjh.v7.i2.204

Fedchuk, L, Nascimbeni, F., Pais, R, Charlotte, F., Housset, C., & Ratziu, V. (2014).

Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty

liver disease. Alimentary Pharmacology and Therapeutics. 40(10). 1209-1222. Retrieved from:http://onlinelibrary.wiley.com/doi/10.1111/apt.12963/full

Johns Hopkins Medicine. (n.d.). Digestive weight loss center. Retrieved from:

http://www.hopkinsmedicine.org/digestive_weight_loss_center/conditions/fatty_liver_dis

ease.html

Lee, S., Ko, B., Gong, Y., Han, K., Duck Han, A., Yoon, Y., Park, S., Kim, J., & Mantzoros, C.

(2016).  Self‑reported eating speed in relation to non‑alcoholic fatty liver disease in

adults.  European Journal of Nutrition. 55: 327-333.  Retrieved from: 

http://eds.a.ebscohost.com.sunypoly.idm.oclc.org/eds/pdfviewer/pdfviewer?vid=8&sid=3

1208938-49a8-415a-8b80-b491b4b152a3%40 sessionmgr 4010

Mayo Clinic. (2017). Nonalcoholic fatty liver disease treatment.  Retrieved from:

http://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/diagnosis

-treatment/treatment/txc-20211616

Mohseni, F., Farhangi, M. A., Farajnia, S., Khoshbaten, M., Ajorlou, E., & Kakaei, F. (2016).

Adherence to Mediterranean Nutrition Pattern in Patients with Non-Alcoholic Fatty Liver Disease: Relationship with Metabolic Risk Factors and -UCP2 -866G/A Gene Polymorphisms.  Current Topics in Nutraceutical Research, 14(1), 49-57.

Mosinski, J., Pagadala, M., Mulya, A., Juang, H., Dan, O., Shimizu, H., Ratayyah, E., Paj, R.,

Schauer, P., Brethauer, S. & Kirwan, J. (2016). Gastric bypass surgery is protective from

high-fat diet-induced non-alcoholic fattyliverdisease and hepatic endoplasmic reticulum

stress. Acta Physiologica. 217(2). 141-151. Retrieved from: 

http://eds.b.ebscohost.com.sunypoly.idm.oclc.org/eds/pdfviewer/pdfviewer?vid=2&sid=2

482fc6b-9352-41f0-8220-37300dd23ead%40 session mgr 103

Nabavi, S., Rafraf, M., Somi, M, Homayouni-Rad, A., & Asghari-Jafarabadi, M. (2014). Effects

of probiotic yogurt consumption on metabolic factors in individuals with nonalcoholic

fattyliver disease. Journal of Dairy Science. 97(12). 7386-7393.  Retrieved from:

http://eds.b.ebscohost.com.sunypoly.idm.oclc.org/eds/detail/detail?vid=2&sid=09794972

-5edd-471d-a204-bc92477066bf%40sessionmgr103&bdata=JnNpdGU9ZWRzLWxpdm

U%3d#AN=99683034&db=bth

Nishi, T., Babazono, A., Toshiki, M., Imatoh, T. & Une, H. (2016). Effects of eating fast and

eating before bedtime on the development of nonalcoholic fatty liver disease. Population

Health Management. 19(4). 279-283.  Retrieved from: 

http://eds.a.ebscohost.com.sunypoly.idm.oclc.org/eds/pdfviewer/pdfviewer?vid=6&sid=9

472d5db-9bc7-448b-8406-482b9b73661b%40sessionmgr4010

Persico, M., Masarone, M., Damato, A., Ambrosio, M., Federico, A., Rosato, V., &  Vecchione, C. (2017). Non-alcoholic fatty liver disease and eNOS dysfunction in               humans. BMC Gastroenterology, 17(1), 35. doi:10.1186/s12876-017-0592-y

Targher, G., Valbusa, F., Bonapace, S., Bertolini, L., Zenari, L., Rodella, S., Zoppini, G.,

Mantovani, W., Barbieri, E., & Byrne, C. (2013).  Non-Alcoholic Fatty Liver Disease Is

Associated with an Increased Incidence of Atrial Fibrillation in Patients with Type 2

Diabetes. PLOS ONE. 8(2). 1-9. Retrieved from:

http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0057183&type=print

able

Appendix A

Research Question:		Best management options for non-alcoholic fatty liver disease that is evidenced based
In Text Citation	Source	Main Findings	Method	Subjects
(Abulnaja, K. & El Rabey, H. 2015)	Evidence-Based Complementary and Alternative Medicine	The mean relative value of all organs was increased as a result of feeding rats of G2 on fat rich diet and 2% cholesterol for 8 weeks, compared with the negative control. The concurrent supplementation with the two doses of barley bran in G3 and G4 significantly decreased all organs’ relative weights compared with the positive control group.	Clinical control group	24 male albino lab rats First group (G1) is untreated control group and was fed basal lipid rich diet Second group (G2) was fed 2% cholesterol in the lipid rich diet to induce hypercholesterolemia and considered as the positive control group Third group (G3) was fed 2% cholesterol and co-treated with 5% barley bran for 8 weeks Fourth group (G4) was fed 2% cholesterol and co-treated with 10% barley bran seed powder for 8 weeks.
(Arab et al., 2014)	World Journal of Gastroenterology	Using Delphi technique, all patients with NAFLD were assessed using a three-focused approach that contemplates the risks of developing advanced liver disease, T2DM, and CV events. Consensus supporting lifestyle change, such as exercise and diet changes, in patient with NAFLD. Only considering that Vitamin E and pioglitazone in nondiabetic patients beneficial as pharmacological therapies with biopsy proven steatohepatitis (progressive type) in non-alcohol form of fatty liver disease.	Group of 13 experts who received a survey of 17 specific, open ended questions that faced providers during the treatment of NAFLD. The Delphi methodology was used to gathering data. This method is known to be good for consensus building in scenarios where evidence-based recommendations are not well established.	13 experts
(Boursier, J., Mueller, O., Barret, M., Machado, M., Fizanne, L., Araujo-Perez, F., Guy, C., Seed, P., Rawls, J., David, L., Hunault, G., Oberti, F., Cales, P., & Die, A. 2016)	Hepatology	Bacteroides were significantly increased in NASH and F≥2 patients Prevotella abundance was decreased. Ruminococcus was significantly higher in F≥2 patients. By multivariate analysis, Bacteroides were independently associated with NASH and Ruminococcus with F≥2 fibrosis.	Cohort study	Fifty-seven patients with NAFLD that was biopsy-proven
(Cazzo, Pareja, & Chaim, 2017)	Sao Paulo Medical Journal	This study revealed that induced weight loss from bariatric surgery either improved or completely resolved steatosis, steatohepatitis, and fibrosis in the majority of patients.	Meta-analysis	91 individuals
(Del Ben et al., 2017)	Nutrition, Metabolism, & Cardiovascular Diseases	Study shows that prescriptions of statins are underused and should improve for patients with cardiovascular risks in patients with NAFLD. Study results shows that 50% of these patients with indication for statin use do not receive any type of cholesterol lowering medication.	605 patients were studied using multiple methods based on which part of the study was being conducted. Serum cholesterol and triglycerides results used enzymatic colorimetric method. Liver steatosis was defined based off of Hamaguchi criteria. Cardiovascular risks and LDL targets were established according to ESC/EAS guidelines. Statistical analysis completed by SPSS statistical software version 18.0 for Windows. Variables that were continuous were tested using the Kolmogorov-Smirnov test for normality. T-test/Mann-Whitney/Kruskall-Wallis tests were performed for analysis of variance for group comparison on normally distributed variables.	605 patients
(Eslami, Merat, Malekzadeh, Nasseri-Moghaddam, Aramin, 2013)	Cochrane Database Of Systematic Reviews	In a trial of NAFLD, there was no great difference in atorvastatin versus fenofibrate (non-statin lipid-lowering drug) in plasma liver enzymes or ultrasound findings. Simvastatin versus placebo, also did not show a great difference. Once these outcomes were combined, atorvastatin showed to be superior to fenofibrate.	Randomized clinical trials using Mantel-Haenszel method	653 records identified. Of the 653, 41 records identified for further assessment. Within the 41 records, 6 randomized clinical trials were identified and from the 6 only 2 were identified eligible for inclusion for the review.
(Eslamparast, Eghtesad, Poustchi, & Hekmatdoost, 2015)	World Journal of Hepatology	Exploration of dietary supplements that are considered to have an antioxidant, anti-inflammatory, and/or insulin sensitizer properties and their role in NAFLD management.	Content analysis	7 Antioxidant agents 3 Anti-inflammatory agents 4 Insulin sensitizers and lipid lowering agents
(Fedchuk, L, Nascimbeni, F., Pais, R, Charlotte, F., Housset, C., & Ratziu, V. 2014)	Alimentary Pharmacology and Therapeutics	Metabolic alterations were common and full-blown metabolic syndrome was present in half of the cases. Of 296 patients, 241 (81%) had a liver ultrasound showing a bright liver pattern which was diagnostic of fatty liver. Only 5% of patients did not have steatosis, mild steatosis was detected in 39% and moderate/severe steatosis in the remaining 57% of cases. One hundred and seventy-one patients (53%) had NASH, 76 patients (24%) had advanced fibrosis (stage 3–4) and 38 (12%) had advanced NASH on liver biopsy. All the fatty liver markers displayed an acceptable accuracy in estimating the presence of steatosis of any amount versus. no steatosis.	Cohort study Five steatosis biomarkers were measured: fatty liver index (FLI), NAFLD liver fat score (NAFLD-LFS), hepatic steatosis index (HSI), visceral adiposity index (VAI) and triglyceride × glucose (TyG) index.	Three hundred and twenty-four consecutive liver biopsies were included and histological steatosis was categorized as none (<5%), mild (5–33%), moderate (33–66%) and severe (>66%).,
(Lee, S., Ko, B., Gong, Y., Han, K., Duck Han, A., Yoon, Y., Park, S., Kim, J., & Mantzoros, C. 2016)	European Journal of Nutrition	Faster eating groups had increased proportion of NAFLD with an advanced grade in Korean adults. Subjects with BMI < 25 kg/m2 and increased eating times also had increased proportion of NAFLD. Is possible that obesity is overwhelming the effects of eating times on NAFLD.	Cross sectional study	Study sample included 7,917 subjects. Exclusion of participants included subjects with: medical history of HBs Ag positive, HCV Ab positive, liver cirrhosis, hepatocellular carcinoma, elevated liver enzymes, elevated gamma-glucronyl transpeptidase, participants who had been taking medicine due to a liver disease or persons who reported drinking more than 20 g of alcohol per day and those under the age of 20 and those who did not comply with ultrasonography and questionnaires.
(Mohseni et al., 2016)	Current Topics in Nutraceutical Research	The components of a Mediterranean diet pattern and metabolic risk factors of NAFLD showed a strong relationship. From a gene-nutrient interaction between GG genotype – UCP2 -866G/A gene polymorphisms and dietary meat intakes this study concluded that modifications of diet appeared to be significant and effective in reducing risk factors of chronic diseases.	Data analysis completed by SPSS statistical software package version 16. Kolmogorov-Smirnov test completed for normality of variables distributions. For comparison between groups of discrete and continuous variables a Chi-square test, along with sample t-test or one-way ANOVA test were completed. Semi-quantitative food-frequency questionnaire (FFQ), including 168 food items with specified serving sizes commonly used.	75 patients
(Mosinski, J., Pagadala, M., Mulya, A., Juang, H., Dan, O., Shimizu, H., Ratayyah, E., Paj, R., Schauer, P., Brethauer, S. & Kirwan, J. 2016)	Acta Physiologica	The RYGB group lost 20% of their baseline weight, with significant weight loss differences between the groups. Overall food intake was not different between the Sham and RYGB groups throughout the study and the RYGB animals became significantly more insulin sensitive compared to the Sham group.	Controlled clinical trial	24 male Sprague Dawley rats were randomized to Sham (N = 8) or Roux-en-Y gastric bypass (RYGB) surgery (N = 8) and compared to Lean controls (N = 8).
(Nabavi, S., Rafraf, M., Somi, M, Homayouni-Rad, A., & Asghari-Jafarabadj, M. 2014)	Journal of Dairy Science	Detected no statistically significant differences between the 2 groups in terms of serum liver enzymes or glucose and lipid levels at baseline. Probiotic yogurt consumption resulted in reductions of 4.67, 5.42, 4.1, and 6.92% in serum levels of ALT, AST, TC, and LDL-C, respectively, compared with these variables in the conventional yogurt group.	Double-blind, randomized, controlled clinical trial	72 subjects selected with NAFLD. (33 males and 39 females. Ages 23 – 63 years old. The intervention group (n = 36) consumed 300 g/d of probiotic yogurt containing Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12 The control group (n = 36) consumed 300 g/d of conventional yogurt for 8 wk.
(Nishi, T., Babazono, A., Toshiki, M., Imatoh, T. & Une, H. 2016)	Population Health Management	Subjects who habitually ate before bedtime had significant increase in NAFLD. Those who did not eat fast but did eat before bed, and who had both behaviors were identified as being at increased risk of NAFLD.	Retrospective cohort study	The authors selected 2254 insurance beneficiaries whose FLI was <30, who were not diagnosed with stroke, coronary heart disease, chronic kidney disease, liver cancer, liver fibroids, anemia, chronic viral hepatitis, alcoholic liver disease or anemia and were not treated with corticosteroids. Median age 48 years with 60% being female.
(Persico et al., 2017)	BMC Gastroenterology	NAFLD patients, in this study, have significant eNOS dysfunction. In which, can be contributing to the higher risk of cardiovascular disease. The early stage, simple steatosis, was associated with a worse eNOS impairment when compared to steatohepatitis.	Statistical analysis completed using Statistical Program for Social Sciences (SPSS) version 16.0 for Macintosh. Student t-test/Mann-Whitney U test completed on continuous variables in order to compare them. For comparison of categorical variables the Chi-square with Yates correction or Fisher-exact test were completed.	54 (38 males, 16 females) patients
(Targher, G., Valbusa, F., Bonapace, S., Bertolini, L., Zenari, L., Rodella, S., Zoppini, G., Mantovani, W., Barbieri, E., & Byrne, C. 2013)	PLOS ONE	At the 10 year completion 281 (70.2%) participants met the clinical criteria for diagnosis of NAFLD and 119 (29.8%) patients did not. During the 10 years of follow-up, 42 patients developed incident AF with a cumulative incidence of 10.5%.	Random sample	400 participants with type 2 diabetes, who were free from atrial fibrillation (AF) at baseline were followed for 10 years.