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Non-alcoholic fatty liver disease (NAFLD) refers to a spectrum of progressive liver conditions in the absence of significant alcohol consumption. Bland steatosis occurs when intrahepatic triglycerides accumulate in hepatocytes, which may progress to non-alcoholic steatohepatitis (NASH) if accompanied by inflammation.1 In 10–25% of patients, steatosis advances to hepatic fibrosis, cirrhosis, and end-stage liver disease. In addition, the likelihood of cardiovascular disease is increased when NAFLD occurs, and consequently, these patients have an increased risk of overall and liver-specific mortality.2, 3 NAFLD has emerged as one of the most widespread liver diseases in western societies, with prevalence estimates ranging up to 50% and even higher in diabetics.4 This variation is based on differences in screening and detection strategies as well as genetic and environmental risk factors.5, 6 For instance, overweight, type 2 diabetes7 as well as genetic predisposition, such as the patatin-like phospholipase domain containing 3 (PNPLA3) variant p.I148M, are all implicated in fatty liver manifestation.8, 9 Specifically, carriers of the PNPLA3 risk allele carry a more than twofold increased steatosis risk10 as well as an increased likelihood of developing fibrosis, cirrhosis, and hepatocellular carcinoma.11, 12 Currently, treatment options for NAFLD are limited and no accepted standard pharmacotherapy exists. According to AASLD guidelines, reduction of body weight of at least 3–5% through a hypocaloric diet alone or together with increased physical activity has been recommended to reduce steatosis.1 Lifestyle intervention studies, specifically diet alone (such as, low-fat or low-carbohydrate diets) or combined with physical activity, have shown potential in ameliorating hepatic steatosis.13, 14 Specifically, preliminary data suggests that a protein-enriched dietary intervention reduces hepatic steatosis in obese patients.15 However, the majority of studies have employed serum surrogate markers,16 semiquantitative ultrasonography,17 elaborate computer tomography, or magnetic resonance imaging.18 Only few studies have used liver biopsy, the “gold standard” for assessing histological changes in hepatic steatosis,19, 20 which carries a risk of bleeding and is affected by sampling errors.21, 22 The use of non-invasive and risk-free techniques to diagnose and monitor hepatic steatosis is highly sought after.23 As such, non-invasive techniques are increasingly being evaluated. During ultrasound-based vibration-controlled transient elastography (VCTE), the attenuation of low-frequency ultrasound waves by liver tissue can be measured. The controlled attenuation parameter (CAP) quantifies liver fat (while simultaneously detecting liver stiffness).24 VCTE is the most widely validated technique for the detection of liver fibrosis, as documented by the new European Association for the Study of the Liver (EASL) recommendations on non-invasive tests for the evaluation of liver diseases.25 Until now, no study has compared CAP at baseline and at follow-up in combination with a dietary intervention. The aim of this study was to monitor patients with hepatic steatosis receiving a short-term hypocaloric high-fiber, high-protein diet with the primary outcome of improving liver fat, as quantified with CAP. We hypothesized that this 14-day low-calorie diet would significantly reduce CAP and therefore hepatic steatosis. The primary outcome of this study was the effect of the dietary intervention on liver fat contents as measured by CAP. Secondary outcomes included changes in body composition, liver stiffness measurements (LSM), serum lipid concentrations, and cardiovascular risk profile. At the Department of Medicine II of Saarland University Medical Center (Homburg, Germany), we quantified CAP and LSM, and determined body composition. Patients were included in the study if they had a CAP≥215 dB/m at baseline and were excluded from observation if they had any of the following: harmful alcohol intake based on the AUDIT questionnaire,26 histologically defined liver cirrhosis or LSM≥13 kPa,27 pregnancy, cardiac pacemaker, or stage IV or V chronic kidney disease.28 Written informed consent was obtained from each participant. The study protocol complies with the ethical guidelines of the Declaration of Helsinki as reflected in a priori approval by the Saarland Ethics Committee (Ärztekammer des Saarlandes, ref. 271/11). Fasted blood samples were collected for routine analysis of liver function tests and serum lipids: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), gamma-glutamyl transferase (γ-GT), pseudocholinesterase (PChE), triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol as well as uric acid, glucose, HbA1c, and kidney function tests. Fatty liver index (FLI), which is based on BMI, WC, γ-GT, and TG, was calculated according to Bedogni et al.:29   Variables were tested for correlation using the Spearman’s rank coefficient rs. Contingency tables were used to assess for associations between categorical variables. Parameter changes after the dietary intervention are reported as absolute and relative frequencies. Comparisons between two and three unpaired groups were conducted using the Mann–Whitney U and Kruskal–Wallis tests, respectively. The Wilcoxon-signed ranks tests were used for comparisons between two paired groups. Both linear univariate and multivariate regression analysis were employed to detect the influence of baseline variables on absolute CAP changes. We also carried out subgroup analyses assessing for sex-specific differences, patients with and without type 2 diabetes, and comparing CAP responders (defined by CAP reduction) with CAP non-responders (defined by CAP increase). Of 60 patients, 49 (81.7%) demonstrated a decrease in median CAP of 15.9% (50 dB/m, P<0.001) and were defined as CAP responders (see Statistical analysis). Of these, 10 patients (20.4%) showed resolution of steatosis, i.e., they presented with CAP<215 dB/m after the dietary intervention. Interestingly, 11 demonstrated a median CAP increase of 3.4% (9 dB/m, P=0.003) after the 14-day intervention despite improvements in body composition, thus we classified them as CAP non-responders. Compared to responders, non-responders were mostly women (72.7 vs. 46.9%, P>0.05), younger (51 vs. 56 years, P>0.05), had a higher baseline BMI (32.2 vs. 31.2 kg/m2, P>0.05) and a lower baseline CAP (262 vs. 308 dB/m, P=0.001). When comparing genetic variation, all five homozygous PNPLA3 mutation carriers with two prosteatogenic p.148M alleles were responders. Reductions in CAP between patients with a weight reduction ≥5 and <5% were similar (14.9 and 11.4%, both P<0.001). Table 5 summarizes within and between group changes. Overall, 14 (23.3%) patients had a previous diagnosis of type 2 diabetes. When compared to non-diabetics, these patients were older, had higher serum glucose concentrations and higher baseline CAP, but CAP reductions did not differ between the two groups (Table 6). Overall, glucose levels decreased significantly by 7.1% (P<0.001). A positive change in systolic and diastolic blood pressure of −5.6 and −4.5% (both P≤0.001) was observed. The median reductions of key parameters assessed during the study are summarized in Figure 3. The aims herein were to simultaneously and non-invasively monitor liver and body fat composition in patients with NAFLD participating in a short-term dietary program, and to avail of CAP to assess dynamic changes in liver fat. After a 14-day hypocaloric high-fiber, high-protein diet, an absolute CAP reduction of 47 dB/m and a relative decrease of 14.0% were achieved. This was accompanied by a significant weight loss of 4.6%, of which almost two-thirds (61.9%) was loss of body fat mass. To our knowledge, this is the first study to monitor rapid changes in hepatic steatosis using CAP, which represents a patient-friendly non-invasive tool. The results are in line with previous smaller studies using other methodologies to assess changes of liver phenotypes after dietary interventions. According to the AASLD guidelines, a reduction of body weight of at least 3–5% through a hypocaloric diet alone or together with increased physical activity is recommended for ameliorating steatosis.1 Colles et al.32 studied a very low-calorie diet (680 kcal/day) for 12 weeks in 32 morbidly obese patients. Body weight was reduced by 10.6% (14.8 kg), and liver volume assessed by computer tomography decreased by 18.7% (0.56 l). Interestingly, after 2 weeks, 80% of the overall decrease in liver volume was detected, whereas body weight improved steadily throughout.32 We did not observe a significant association between the extent of weight loss and improvement of liver phenotypes, as reported by others,18, 33 which might be related to less drastic changes in body fat mass (Figure 3). Some of the previously reported studies compared overall weight loss and BMI reductions only rather than compartmental changes of body composition. As the interventions were significantly longer, they may have resulted in greater changes of fat mass and corresponding liver-specific effects.18, 33 In addition to CAP reductions and weight loss, the dietary modification assessed herein also resulted in metabolic improvements, particularly those related to the metabolic syndrome. Besides the expected reduction in triglycerides, the reduction of LDL cholesterol levels by 33 mg/dl after 14 days is remarkable, especially in comparison to a meta-analysis of 174,000 patients, which reported a decrease of 42.5 mg/dl after 1 year of statin therapy.34 Another meta-analysis on dietary fiber reported a reduction of LDL cholesterol of 2.21 mg/dl for each 1 g of soluble fiber per day,35 which is reflected in our study with a daily intake of 14 g soluble fiber. HDL cholesterol levels decreased, which has previously been reported during acute weight loss, however HDL subsequently increased in the weight maintenance phase.36, 37, 38 Brinton et al.39 suggested that the reduction in HDL cholesterol might be associated with lower HDL apolipoprotein transport rates, and Aminian et al.40 observed a decrease in lipoprotein lipase activity by up to 50% during caloric restriction. Once weight stabilized, HDL cholesterol metabolism reversed and led to increased HDL cholesterol concentrations above the pre-intervention levels.40 The diet given to patients as part of a specifically designed weight loss program contains ingredients known to be potentially beneficial for the liver, including omega-3 polyunsaturated fatty acids,41 l-carnitine,42 choline,43 β-glucan,44 inulin,45 and taurine.46 A limitation of this study is that we were unable to determine if, and to what extent, these ingredients contributed to the overall effects of liver fat reduction, as compared to the overall effects of the caloric restriction and concomitant weight reduction. Moreover, the significant improvements observed after 14 days do not afford the opportunity to evaluate the liver-specific long-term effects of the diet. Although several key parameters of the metabolic syndrome improved, we did not specifically assess the effect of the diet on insulin resistance. Shen et al.47 studied the effect of a lifestyle modification program in NAFLD patients and observed that patients who carry the PNPLA3 mutation p.I148M showed a better response as compared to patients with wild-type alleles.47 Although, the current data on genetic associations in our study are hampered by sample size, we also note that hepatic response was observed in all homozygous carriers of the PNPLA3 risk allele, which should be further evaluated as personalized biomarker for a response to the dietary regimen. Recent recommendations from a joint AASLD–FDA workshop pointed out that the use of elastography in subjects with NASH has not been explored in great detail, and that non-invasive measures should be included as secondary or exploratory endpoints in current trials.48 Our study results illustrate that CAP might represent a reliable alternative for monitoring hepatic steatosis in research and clinical settings.23, 49 In conclusion, the 14-day hypocaloric high-fiber, high-protein diet reduced CAP, and hence hepatic steatosis simultaneously to improvements in parameters of the metabolic syndrome. We demonstrated that improvements in hepatic fat contents can be observed after a couple of weeks only, which highlights the possibility for dynamic short-term modulation of liver fat. Whether such a program provides long-term benefits for these patients should be substantiated, but extent and rate of liver fat reduction set the benchmark for pharmacological treatment. Regardless, CAP provides a convenient and patient-friendly method to assess lipid turnover during lifestyle and dietary interventions to combat NAFLD.  Guarantor of the article: F. Lammert, MD, PhD. Specific author contributions: After designing the study by A. Arslanow, F. Lammert, and C. S. Stokes; A. Arslanow, M. Teutsch, and H. Walle recruited patients; A. Arslanow collected the data and together with F. Lammert and C. S. Stokes analyzed the data and drafted the manuscript, which was then critically revised by all authors. The final draft submitted has been approved by all authors. Financial support: This work was supported, in part, by Bodymed, which awarded an unrestricted grant to Saarland University (A. Arslanow and F. Lammert). M. Teutsch is employed by and H. Walle is a stockholder of Bodymed. Bodymed did not have any influence on study design and data analysis; the work was independent of the financial support. C. S. Stokes and F. Grünhage have nothing to declare. Potential competing interests: None. The authors thank all patients for taking part in this study as well as Agathe Buchheit, Silke Schirra, Marita Lieblang, and Beate Linnebach for collecting blood samples. Anita Arslanow is grateful to the European Association for the Study of the Liver (EASL) for the travel bursary to attend the International Liver Congress 2015. The results were, in part, presented at the 50th Annual Meeting of EASL in Vienna 2015, acknowledged with an EASL prize for the best poster presentation, and published in abstract form in the JOURNAL OF HEPATOLOGY, Vol. 62, Suppl. 2, p. S738. This work is part of the PhD thesis of Anita Arslanow.

Short-Term Hypocaloric High-Fiber and High-Protein Diet Improves Hepatic Steatosis Assessed by Controlled Attenuation Parameter