Bariatric Nutritional Intervention in Obese Patients with Compensated Liver Cirrhosis: A Four-Year Prospective Study

Obesity and malnutrition have been associated with a worse prognosis in patients with chronic liver disease. In recent decades, the proportion of overweight or obese patients with chronic liver diseases has increased even in cohorts on the waiting list for transplantation [1], and obesity has been identified as an independent risk factor for de novo liver disease, progressive liver fibrosis and cirrhosis, and adverse outcomes among patients with established cirrhosis [2, 3]. Moreover, malnutrition is also common in cirrhotic patients [4] and it is associated with ascites, hepatorenal syndrome, longer hospitalisations, higher healthcare costs, and higher mortality [4, 5]. According to the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines, nutritional therapy should be an integral part of the management of cirrhotic patients [6], since specialized nutrition counseling is related to improved survival in patients with liver cirrhosis [7]. Hence, obesity constitutes a major risk factor for the complication development in cirrhosis and weight loss should be an important goal for these patients [8].

Bariatric medicine aims at providing comprehensive care to patients with obesity and related conditions by helping them achieve and maintain a healthy weight by promoting changes in diet and lifestyle, as well as providing medical or surgical interventions when appropriate. Such an approach is the application of the Mediterranean diet (MEDD). The effect of this diet on patients with nonalcoholic fatty liver disease (NAFLD) and, in particular nonalcoholic steatohepatitis (NASH), has been widely studied [9, 10]. MEDD is a dietary pattern characterized by a high content of antioxidants and fiber, a balanced lipid profile with a focus on olive oil, moderate consumption of poultry, eggs, and dairy products and a low content of simple sugars, and processed and red meat. Cumulative data from seven interventional and five observational studies suggest that MEDD has beneficial effects on body weight, insulin sensitivity and hepatic steatosis, as well as fibrosis [11‐20].

This prospective study aimed to evaluate the effects of a bariatric nutritional intervention based on the Mediterranean diet on anthropometric (e.g., body weight) and biochemical parameters in obese patients with compensated liver cirrhosis.

The main findings of the current study are a positive outcome on weight control accompanied by an improved biochemical profile in obese patients with compensated cirrhosis that have followed a bariatric nutritional intervention based on the principles of the Mediterranean diet combined with close medical monitoring.

To date, the data on the possible health benefits of MEDD in patients with liver cirrhosis are very limited [26, 27]. This is the first prospective follow-up study, to our knowledge, investigating the role of the Mediterranean diet in obese patients with compensated liver cirrhosis using an extensive array of anthropometric, biochemical, and hematological indices.

The worldwide prevalence of obesity has been tripled over the last 40 years and is, respectively, very high in patients with compensated cirrhosis [3]. Since obesity has been identified as an independent risk factor for a worse clinical outcome in cirrhosis, ESPEN strongly recommends the application of a nutritional intervention aiming for beneficial effects of weight loss in obese cirrhotic patients [3, 6]. The majority of clinical trials, to date, have been performed in NAFLD and have shown improved steatosis and insulin sensitivity [28, 29]. In a meta-analysis of eight randomized controlled trials, patients achieving ≥ 5% weight loss showed improvement in hepatic steatosis while a ≥ 7% weight loss improved histological disease activity in NASH. However, most of these trials performed intensive lifestyle interventions that were plagued by weight gain after completion, since weight loss goals were achieved by less than 50% of the participants. Furthermore, most patients in these studies did not suffer from liver cirrhosis [30].

In the current study, patients with cirrhosis achieved an average weight loss of 17.3% at 12 months and managed to preserve an average weight loss of 15.7% at the end point of the study. Interestingly, after 12 months, a proportional increase in individuals with low adherence to the diet was observed only in the cirrhosis group (P). This can be explained if taken into consideration the demographic data of the two groups; cirrhotic patients were by a significant percentage from rural and semi-urban areas and more prone to incorrect eating habits due to culture and lifestyle, combined with the mild physiological deterioration of their health due to the disease. The controls were mainly from urban areas, with a stronger motivation to change their appearance and maintain the effect. This is still higher than a weight loss of > 5%–10% recommended by the European Association for the Study of the Liver guidelines for cirrhotic patients with BMI > 30 kg/m² [31]. The applied intervention aimed at limiting the fatty infiltration of the liver and avoiding alcohol consumption, which were reinforced by regular surveillance and control. The improvement of liver enzymes values of cirrhotic patients corroborates with previous studies regarding the contribution of MEDD to the improvement of liver enzymes and contribute to the argument regarding the safety of the proposed lifestyle intervention [15, 20, 32]. Interestingly, during the four-year intervention, all cirrhotic patients (n = 62) remained in the compensated state despite that a percentage of 5–7% of patients with compensated cirrhosis is expected to transit to the decompensated state per year [33].

The duration of our study also provides useful insights into weight loss maintenance. Compared to baseline, cirrhotic patients had lost on average 18 ± 1.6 kg in 12 months after enrollment (p < 0.05) while they only regained 8.8% of the initial weight loss at the end of the follow-up period. Interestingly, obese control subjects continued to lose weight throughout the study period, despite the decline in diet adherence, resulting in an average loss of 26.2 ± 1.8 kg (p < 0.05). The majority of clinical trials studying lifestyle interventions have a duration of six to twelve months [34, 35]. Our long-term study indicates that a prolonged dietary intervention, based on MEDD is attainable in patients with early compensated cirrhosis and can result in maintained significant weight loss without major drop-out risks.

Sarcopenia, the combination of dynapenia (low muscle strength) and myopenia (low muscle mass), is one of the most common complications in advanced liver disease, even in obese cirrhotic patients [36]. Although sarcopenia was not assessed in the current study, one of the main goals of the designed individualized nutritional plans was adequate protein intake (15–20% of the daily macronutrient intake). No trials or intervention studies on the protein requirements of well-nourished compensated cirrhotic patients are available to our knowledge. Interestingly, HGS measurements exhibited a continuous increase in the first 12 months (31.1 ± 1.1 kg → 34 ± 1.2 kg, p < 0.05) and stabilized during the subsequent time points of the study, indicating increase or, at least, conservation of muscle strength, which is crucial for protecting from or improving sarcopenia.

Potential changes in the concentration of circulating cytokines in the cirrhotic patients were also assessed at three months from baseline. The results indicated a significant decrease in the concentration of IL-6 (p < 0.001), IL-8 (p < 0.05), and IL-10 (p < 0.05). Acute and chronic liver diseases are considered cytokine-driven as several proinflammatory cytokines (IL-1α, IL-1β, tumor necrosis factor-alpha (TNF- α), and IL-6) are critically involved in inflammation, steatosis, fibrosis, and cancer, as well as complication development [37]. Taken together with the fact that key inflammatory markers have been consistently associated with obesity and the risk of adverse outcomes in obesity-related diseases [38, 39], it is clear that obesity may be a further factor contributing to the systemic inflammation and, thus, cirrhosis progression. Unsurprisingly, previously published data have shown that obesity may be a risk factor for disease progression in cirrhosis [40, 41]. In a recent meta-analysis of 76 papers, an association of weight loss with reduction of IL-6 was established [42]. Our preliminary data show a decrease in proinflammatory cytokines in patients with cirrhosis during the first three months of dietary intervention. These data would need to be confirmed in further larger studies with follow-up cytokine measurements at longer intervals, investigating whether weight loss, in particular by means of following a MEDD, may be related to delaying cirrhosis progression.

Diet adherence was interpreted by a nutrition specialist (ZK) based on the questionnaires filled in by the subjects. The majority of the participants in both groups exhibited a very good level of adherence to the suggested nutritional programs for the first 12 months of the study (82.3% of the patient and 88.6% of the control group, respectively, had a score of 6–9 points), with the control group sustaining a high dietary adherence level for a longer period of time. These observations, along with previous reports, support the advantage of MEDD on adherence over most of other prescribed hypocaloric diets on adherence [29]. The variety of foods and flavors involved in the MEDD favors the achievement of the treatment objectives, especially in the long-term, which is potentially crucial in the case of chronic diseases.

Our study has several limitations. Ideally, an additional control group consisting of obese cirrhotic patients undergoing no intervention would be required. However, ethical issues were raised regarding leaving obese patients untreated while there were also concerns that patients residing in Crete were likely to follow a MEDD to some extent anyway, which could render comparisons difficult. Second, the cirrhotic and control groups had comparable gender distribution but the former were significantly older than the latter, which may have biased our findings. Another limitation of our study pertains to the fact that the cirrhosis group was heterogeneous with regard to the etiology of liver disease. The composition of our cirrhosis cohort, comprising mainly viral hepatitis patients, is consistent with that of other cirrhosis cohorts from southern Europe. Although there is no compelling reason to believe that the etiology of cirrhosis is contingent on the final study outcome, with increasing obesity and NASH rates, it seems reasonable to expect that future research would focus on the potential benefits of the Mediterranean diets on NASH patients with cirrhosis. An inherent limitation of our study was the disparity in the distribution of obesity severity between the study and control groups. This divergence stemmed from the notable challenge of enrolling a sufficient number of healthy obese participants, leading us to include a slightly younger age group with lower BMI values in the control cohort. Consequently, the degree of obesity among controls was less pronounced. It is important to emphasize, however, that statistically significant disparities were evident in both age and body type changes between the control and cirrhotic patient groups throughout the study stages (Mann–Whitney U = 706.00, p < 0.001 for age; χ² = 278.13, b.e. = 28, p < 0.001 for control body type changes; χ² = 123.38, b.e. = 28, p < 0.001 for cirrhotic patient body type changes). Third, a follow-up of patients and controls after the end of the intervention could provide insight into whether dietary modifications and its benefits may be maintained. Our data, however, provide strong evidence in support of the integration of dietary advice to the medical management of cirrhotic patients in general and those with obesity in particular [6]. Another limitation of our study is the absence of quantitative assessment of physical activity levels among participants. Although we inquired about physical activity during our monthly meetings and found no significant changes or unusual reports throughout the study, the absence of objective quantification remains a constraint. Future studies should include a more thorough investigation of participant physical activity. Hepatic steatosis was diagnosed using ultrasound scans due to the unavailability of methods such as controlled attenuation parameters at our institution. As conventional ultrasound scans may have limitations in sensitivity for diagnosing or excluding hepatic steatosis, particularly in cases of mild steatosis (< 30%), we cannot rule out that some participants may have had undetected mild steatosis. Lastly, we have no data on whether our suggested long-term intervention could be followed by the majority of obese cirrhotic patients or if an intervention based on the Mediterranean diet could be applicable in countries with different dietary habits. Therefore, although a clear beneficial effect of the nutritional intervention on the health outcomes of the subjects is demonstrated in our study, further and larger-scale studies are needed in order to establish the Mediterranean diet as a bariatric tool in the treatment of obese cirrhotic patients as well as other obesity-related comorbidities.

In conclusion, our findings suggest that a nutritional intervention based on the principles of the Mediterranean diet can be safely recommended to attain weight loss and improve biochemical and anthropometric outcomes in obese patients with compensated cirrhosis. Further prospective studies are warranted to assess the potential benefits of the Mediterranean diet in obese patients with compensated liver cirrhosis and its potential role as a non-pharmacological treatment in this population.