Christian Thoma

Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: A systematic review

Non-alcoholic fatty liver disease is a serious and growing clinical problem. Despite lifestyle modification, i.e. diet and physical activity, being the recommended therapy, there are currently no systematic evaluations of its efficacy. This review applies a systematic approach to evaluating lifestyle modifications studied to date. Medline (Pubmed), Scopus, and the Cochrane Controlled Trials Register were searched for studies and study groups assessing the effect of diet, physical activity, and/or exercise modification in adult populations with non-alcoholic fatty liver disease. The outcome markers of interest were indicators of steatosis, histological evidence of inflammation and fibrosis, and glucose control/insulin sensitivity. We identified 23 studies for inclusion; seven had control groups, but only six were randomised. Eleven groups received diet-only interventions, two exercise-only, and 19 diet and physical activity/exercise. Studies consistently showed reductions in liver fat and/or liver aminotransferase concentration, with the strongest correlation being with weight reduction. Of the 5 studies reporting changes in histopathology, all showed a trend towards reduction in inflammation, in 2 this was statistically significant. Changes in fibrosis were less consistent with only one study showing a significant reduction. The majority of studies also reported improvements in glucose control/insulin sensitivity following intervention. However, study design, definition of disease, assessment methods, and interventions varied considerably across studies. Lifestyle modifications leading to weight reduction and/or increased physical activity consistently reduced liver fat and improved glucose control/insulin sensitivity. Limited data also suggest that lifestyle interventions may hold benefits for histopathology.

Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss

Background Lifestyle interventions focusing on weight loss remain the cornerstone of non-alcoholic fatty liver disease (NAFLD) management. Despite this, the weight losses achieved in research trials are not easily replicated in the clinic and there is an urgent need for therapies independent of weight loss. Aerobic exercise is not well sustained and the effectiveness of the better tolerated resistance exercise upon liver lipid and mediators of liver lipid has not been assessed. Methods Sedentary adults with clinically defined NAFLD were assigned to 8 weeks of resistance exercise (n=11) or continued normal treatment (n=8). Results 8 weeks of resistance exercise elicited a 13% relative reduction in liver lipid (14.0±9.1 vs 12.2±9.0; p<0.05). Lipid oxidation (submaximal RQ ∆ −0.020±0.010 vs −0.004±0.003; p<0.05), glucose control (−12% vs +12% change AUC; p<0.01) and homeostasis model assessment insulin resistance (5.9±5.9 to 4.6±4.6 vs 4.7±2.1 to 5.1±2.5; p<0.05) were all improved. Resistance exercise had no effect on body weight, visceral adipose tissue volume, or whole body fat mass (p>0.05). Conclusion This is the first study to demonstrate that resistance exercise specifically improves NAFLD independent of any change in body weight. These data demonstrate that resistance exercise may provide benefit for the management for non-alcoholic fatty liver, and the long-term impact of this now requires evaluation.

Cardiac structure and function are altered in adults with non-alcoholic fatty liver disease

BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is associated with a twofold greater risk of developing cardiovascular disease. Despite this, little is known about the effect of NAFLD upon cardiac function, limiting our ability to identify therapeutic strategies. This study aimed to address this by defining the effect of NAFLD on cardiac function, structure, and metabolism. METHODS Nineteen adults with NAFLD were age-, sex-, and BMI-matched to healthy controls without liver or metabolic disease. Cardiac structure and function were assessed using high-resolution cardiac MRI and tagging at 3.0 T. High-energy phosphate metabolism was assessed using (31)P-magnetic resonance spectroscopy to measure the PCr/ATP ratio. RESULTS Adults with NAFLD had significantly thicker left ventricular walls at systole (14 ± 3 vs. 12 ± 2 mm; p <0.01) and diastole (8 ± 1 vs. 7 ± 1 mm; p <0.01) than those without fatty liver and showed decreased longitudinal shortening (14 ± 3 vs. 17 ± 3%; p <0.01). The eccentricity ratio was significantly higher in the NAFLD group (1.1 ± 0.2 vs. 0.9 ± 0.2 g/ml; p <0.01) indicating concentric remodelling. Peak whole wall strain was higher in the NAFLD group (19 ± 2 vs. 17 ± 3%; p <0.01), as was peak endocardial strain (28 ± 4 vs. 22 ± 5%; p <0.01). Cardiac metabolism, measured by PCr/ATP ratio, was not altered in NAFLD (1.8 ± 0.3 vs. 1.9 ± 0.3; p=0.36). CONCLUSIONS Significant changes in cardiac structure and function are evident in adults with NAFLD in the apparent absence of metabolic changes or overt cardiac disease. Clinicians should continue to explore therapies to improve cardiac function as a means to modify the excess risk of cardiovascular disease associated with NAFLD.

Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: a randomized controlled trial

Although lifestyle changes encompassing weight loss and exercise remain the cornerstone of non-alcoholic fatty liver disease (NAFLD) management, the effect of different types of exercise on NAFLD is unknown. This study defines the effect of modified high-intensity interval training (HIIT) on liver fat, cardiac function and metabolic control in adults with NAFLD. Twenty-three patients with NAFLD [age 54±10 years, body mass index (BMI) 31±4 kg/m(2), intra-hepatic lipid >5%) were assigned to either 12 weeks HIIT or standard care (controls). HIIT involved thrice weekly cycle ergometry for 30-40 min. MRI and spectroscopy were used to assess liver fat, abdominal fat and cardiac structure/function/energetics. Glucose control was assessed by oral glucose tolerance test and body composition by air displacement plethysmography. Relative to control, HIIT decreased liver fat (11±5% to 8±2% compared with 10±4% to 10±4% P=0.019), whole-body fat mass (35±7 kg to 33±8 kg compared with 31±9 kg to 32±9 kg, P=0.013), alanine (52±29 units/l to 42±20 units/l compared with 47±22 units/l to 51±24 units/l, P=0.016) and aspartate aminotransferase (AST; 36±18 units/l to 33±15 units/l compared with 31±8 units/l to 35±8 units/l, P=0.017) and increased early diastolic filling rate (244±84 ml/s to 302±107 ml/s compared with 255±82 ml/s to 251±82 ml/s, P=0.018). There were no between groups differences in glucose control. Modified HIIT reduces liver fat and improves body composition alongside benefits to cardiac function in patients with NAFLD and should be considered as part of the broader treatment regimen by clinical care teams. ISRCTN trial ID: ISRCTN78698481.

Hepatic Cholesteryl Ester Accumulation in Lysosomal Acid Lipase Deficiency: Non-Invasive Identification and Treatment Monitoring by Magnetic Resonance

Background & Aims Lysosomal Acid Lipase (LAL) deficiency is a rare metabolic storage disease, caused by a marked reduction in activity of LAL, which leads to accumulation of cholesteryl esters (CE) and triglycerides (TG) in lysosomes in many tissues. We used 1H magnetic resonance (MR) spectroscopy to characterize the abnormalities in hepatic lipid content and composition in patients with LAL deficiency, and in ex vivo liver tissue from a LAL deficiency rat model. Secondly, we used MR spectroscopy to monitor the effects of an enzyme replacement therapy (ERT), sebelipase alfa (a recombinant human lysosomal acid lipase), on hepatic TG and CE content in the preclinical model. Methods Human studies employed cohorts of LAL-deficient patients and NAFLD subjects. Rat experimental groups comprised ex vivo liver samples of wild type, NAFLD, LAL-deficient, and LAL-deficient rats receiving 4 weeks of sebelipase alfa treatment. Hepatic 1H MR spectroscopy was performed using 3T (human) and 7T (preclinical) MRI scanners to quantify hepatic cholesterol and triglyceride content. Results CE accumulation was identified in LAL deficiency in both human and preclinical studies. A significant decrease in hepatic CE was observed in LAL-deficient rats following treatment with sebelipase alfa. Conclusions We demonstrate an entirely non-invasive method to identify and quantify the hepatic lipid signature associated with a rare genetic cause of fatty liver. The approach provides a more favorable alternative to repeated biopsy sampling for diagnosis and disease progression / treatment monitoring of patients with LAL deficiency and other disorders characterised by increased free cholesterol and/or cholesteryl esters.

Exercise Reduces Liver Lipids and Visceral Adiposity in Patients With Nonalcoholic Steatohepatitis in a Randomized Controlled Trial

BACKGROUND & AIMS: Pharmacologic treatments for nonalcoholic steatohepatitis (NASH) are limited. Lifestyle interventions are believed to be effective in reducing features of NASH, although the effect of regular exercise, independent of dietary change, is unclear. We performed a randomized controlled trial to study the effect of exercise on hepatic triglyceride content (HTGC) and biomarkers of fibrosis in patients with NASH. METHODS: Twenty‐four patients (mean age, 52 ± 14 y; body mass index, 33 ± 6 kg/m2) with sedentary lifestyles (<60 min/wk of moderate–vigorous activity) and biopsy‐proven NASH were assigned randomly to groups that exercised (n = 12) or continued standard care (controls, n = 12) for 12 weeks while maintaining their weight. The exercise (cycling and resistance training) was supervised at an accredited sports center and supervised by a certified exercise specialist and recorded 3 times per week on nonconsecutive days. We measured HTGC, body composition, circulating markers of inflammation, fibrosis, and glucose tolerance at baseline and at 12 weeks. RESULTS: Compared with baseline, exercise significantly reduced HTGC (reduction of 16% ± 24% vs an increase of 9% ± 15% for controls; P < .05), visceral fat (reduction of 22 ± 33 cm2 vs an increase of 14 ± 48 cm2 for controls; P < .05), plasma triglycerides (reduction of 0.5 ± 1.0 mmol/L vs an increase of 0.3 ± 0.4 mmol/L for controls; P < .05), and &ggr;‐glutamyltransferase (reduction of 10 ± 28 U/L–1 vs a reduction of 17 ± 38 U/L−1 for controls; P < .05). There were no effects of exercise on liver enzyme levels, metabolic parameters, circulatory markers of inflammation (levels of interleukin 6, tumor necrosis factor‐&agr;, or C‐reactive protein) and fibrosis. CONCLUSIONS: In a randomized controlled trial, 12 weeks of exercise significantly reduced HTGC, visceral fat, and plasma triglyceride levels in patients with NASH, but did not affect circulating markers of inflammation or fibrosis. Exercise without weight loss therefore affects some but not all factors associated with NASH. Clinical care teams should consider exercise as part of a management strategy of NASH, but weight management strategies should be included. Larger and longer‐term studies are required to determine the effects of exercise in patients with NASH. ISRCTN registry.com: ISRCTN16070927.

Phenotypic Characterization of Insulin-Resistant and Insulin-Sensitive Obesity

CONTEXT Whereas insulin resistance and obesity coexist, some obese individuals remain insulin sensitive. OBJECTIVE We examined phenotypic and metabolic factors associated with insulin sensitivity in both muscle and liver in obese individuals. DESIGN AND PARTICIPANTS Sixty-four nondiabetic obese adults (29 males) underwent hyperinsulinemic (15 and 80 mU/m(2) · min)-euglycemic clamps with deuterated glucose. Top tertile subjects for glucose infusion rate during the high-dose insulin clamp were assigned Musclesen and those in the lower two tertiles were assigned Muscleres. Secondarily, top tertile subjects for endogenous glucose production suppression during the low-dose insulin clamp were deemed Liversen and the remainder Liverres. MAIN OUTCOMES MEASURES Clinical and laboratory parameters and visceral, subcutaneous, liver, and pancreatic fat were compared. RESULTS Musclesen and Muscleres had similar body mass index and total fat (P > .16), but Musclesen had lower glycated hemoglobin (P < .001) and systolic (P = .01) and diastolic (P = .03) blood pressure (BP). Despite similar sc fat (P = 1), Musclesen had lower visceral (P < .001) and liver (P < .001) fat. Liversen had lower visceral (P < .01) and liver (P < .01) fat and C-reactive protein (P = .02) than Liverres. When subjects were grouped by both glucose infusion rate during the high-dose insulin clamp and endogenous glucose production suppression, insulin sensitivity at either muscle or liver conferred apparent protection from the adverse metabolic features that characterized subjects insulin resistant at both sites. High-density lipoprotein-cholesterol, 1-hour glucose, systolic BP, and triglycerides explained 54% of the variance in muscle insulin sensitivity. CONCLUSIONS Obese subjects who were insulin sensitive at muscle and/or liver exhibited favorable metabolic features, including lower BP, liver and visceral adiposity. This study identifies factors associated with, and possibly contributing to, insulin sensitivity in obesity.

Non-alcoholic fatty liver disease is associated with higher levels of objectively measured sedentary behaviour and lower levels of physical activity than matched healthy controls

Background and aims Physical activity is a key determinant of metabolic control and is recommended for people with non-alcoholic fatty liver disease (NAFLD), usually alongside weight loss and dietary change. To date, no studies have reported the relationship between objectively measured sedentary behaviour and physical activity, liver fat and metabolic control in people with NAFLD, limiting the potential to target sedentary behaviour in clinical practice. This study determined the level of sedentary behaviour and physical activity in people with NAFLD, and investigated links between physical activity, liver fat and glucose control. Methods Sedentary behaviour, physical activity and energy expenditure were assessed in 37 adults with NAFLD using a validated multisensor array over 7 days. Liver fat and glucose control were assessed, respectively, by 1H-MRS and fasting blood samples. Patterns of sedentary behaviour were assessed by power law analyses of the lengths of sedentary bouts fitted from raw sedentary data. An age and sex-matched healthy control group wore the activity monitor for the same time period. Results People with NAFLD spent approximately half an hour extra a day being sedentary (1318±68 vs1289±60 mins/day; p<0.05) and walked 18% fewer steps (8483±2926 vs 10377±3529 steps/day; p<0.01). As a consequence, active energy expenditure was reduced by 40% (432±258 vs 732±345 kcal/day; p<0.01) and total energy expenditure was lower in NAFLD (2690±440 vs 2901±511 kcal/day; p<0.01). Power law analyses of the lengths of sedentary bouts demonstrated that patients with NAFLD also have a lower number of transitions from being sedentary to active compared with controls (13±0.03 vs15±0.03%; p<0.05). Conclusions People with NAFLD spend more time sedentary and undertake less physical activity on a daily basis than healthy controls. High levels of sedentary behaviour and low levels of physical activity represent a therapeutic target that may prevent progression of metabolic conditions and weight gain in people with NAFLD and should be considered in clinical care.

Citrus pectin and oligofructose improve folate status and lower serum total homocysteine in rats.

Low folate status leads to increased total homocysteine (tHcy) concentration, and this has been associated with an increased risk of several diseases. Many colonic bacteria are capable of synthesizing folate, and certain dietary fibers may enhance this effect. We assessed the ability of non-fermentable (cellulose) and fermentable (citrus pectin and oligofructose) fibers to improve folate status and lower tHcy in rats. Weanling Sprague-Dawley rats were fed a folate-deficient diet with 5% cellulose for four weeks. Rats were then randomly assigned to one of five folate-adequate (400 micrograms/kg diet) test diets for 24 days. Diets were as follows: Basal; Basal + Sulfa Drug (succinylsulfathiazole); Cellulose; Citrus Pectin; and Oligofructose. High-fiber diets were formulated by diluting the basal diet such that the final diets contained 10% of the added fiber. Twenty-one days later, 3H-p-aminobenzoic acid was injected into the cecum, and rats were terminated three days later. Rats receiving the Citrus Pectin diet had significantly higher plasma (p = 0.011), erythrocyte (p = 0.035), and colonic tissue folate concentrations (p = 0.013) and lower tHcy (p = 0.003) than rats given the Cellulose diet. Rats receiving the Oligofructose had significantly higher plasma folate (p < 0.001) and lower tHcy (p = 0.032) concentrations than rats receiving the Cellulose diet. 3H-folate was detected in the livers of all rats except those receiving Sulfa Drug. Our study indicates that Citrus Pectin and Oligofructose, but not Cellulose, can significantly increase indices of folate status in rats and lower tHcy. It also confirms the ability of the large bowel to absorb folate.

Resistance exercise improves autonomic regulation at rest and haemodynamic response to exercise in non-alcoholic fatty liver disease.

Autonomic dysfunction has been reported in patients with NAFLD (non-alcoholic fatty liver disease) and is associated with clinical presentations. To date, there are no therapies to improve autonomic regulation in people with NAFLD. The present study defines the impact of a short-term exercise programme on cardiac autonomic and haemodynamic regulation in patients with NAFLD. A total of 17 patients with clinically defined NAFLD [age, 55±12 years; BMI (body mass index), 33±5 kg/m²; liver fat, 17±9%] were randomized to 8 weeks of resistance exercise or a control group to continue standard care. Resting and submaximal exercise (50% of peak oxygen consumption) autonomic and cardiac haemodynamic measures were assessed before and after the intervention. Resistance exercise resulted in a 14% reduction in HR (heart rate) and 7% lower SBP (systolic blood pressure) during submaximal exercise (16 beats/min, P=0.03 and 16 mmHg, P=0.22). Sympathovagal balance, expressed as LF/HF (low-frequency/high-frequency) ratio of the mean HR beat-to-beat (R-R) interval, was reduced by 37% (P=0.26). Similarly sympathovagal balance of DBP (diastolic blood pressure) and SBP variability decreased by 29% (P=0.33) and 19% (P=0.55), respectively in the exercise group only. BRS (baroreflex sensitivity) increased by 31% (P=0.08) following exercise. The mean R-R interval increased by 23% (159 ms, P=0.09). Parasympathetic regulation was decreased by 17% (P=0.05) and overall sympathovagal balance in BP regulation (LF/HF ratio) increased by 26% (P=0.02) following resistance exercise. Resting haemodynamic measures remained similar between groups. Resistance exercise therapy seems to improve autonomic and submaximal exercise haemodynamic regulation in NAFLD. Further studies are required to define its role in clinical management of the condition.