The Impact of Intermittent Fasting on Non-Alcoholic Fatty Liver Disease in Older Adults: A Review of Clinicaltrials.gov Registry

Introduction

Non-alcoholic fatty liver disease (NAFLD) is an escalating and concerning global health issue, and its incidence has undergone a substantial rise in the recent past. A recent meta-analysis study estimated that by the year 2040, more than 50% of the adult population would be diagnosed with NAFLD.¹ NAFLD refers to the accumulation of hepatic steatosis in individuals who consume little or no alcohol.² It encompasses a continuum of hepatic disorders spanning from uncomplicated fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH), the latter holding the potential to advance to cirrhosis and, in more severe cases, hepatocellular carcinoma (HCC).³ The exact pathophysiology of NAFLD is complex and multifactorial, involving a combination of genetic, metabolic, and environmental factors.⁴ Resistance to insulin is a key characteristic of NAFLD;⁵ this induces heightened lipolysis within adipose tissue, consequently amplifying the transportation of free fatty acids to the liver, precipitating hepatic steatosis⁶ Over an extended duration, hepatic steatosis may advance to NASH, characterized by inflammatory processes, hepatocellular damage, and fibrotic changes, potentially culminating in cirrhosis and the development of HCC.⁷ NAFLD is often asymptomatic in its early stages and is incidentally detected during routine blood tests or imaging studies.^8,9 Numerous factors can increase the risk of developing NAFLD. Obesity, especially visceral adiposity, is a significant risk factor for NAFLD, due to its propensity to cause insulin resistance and a rise in the release of free fatty acids from adipose tissue.^10,11 NAFLD is also associated with several other risk factors, including metabolic syndrome, dyslipidemia, and Type 2 diabetes.^12,13 Other risk factors include a sedentary lifestyle, poor diet, rapid weight loss and polycystic ovary syndrome (PCOS).^14–16 Various researchers have reported that fasting may lead to improvements in liver function, potentially indicating a reduction in liver fat accumulation or inflammation.^17–20 Additionally, total cholesterol levels, which are known to be associated with NAFLD, may also improve during this fasting period.

The management of NAFLD involves a combination of lifestyle modifications, pharmacotherapy, and addressing the underlying risk factors.²¹ A recommended method for the management of the disease is losing weight by exercising, changing diet, and changing behaviour.²² Liver histology is reported to improve when losing >10% of total body weight, and the risk of disease progression decreases.²³ As part of the management of NAFLD, it is recommended that a patients follow a well-balanced and calorie-restricted diet. This diet should emphasize a reduction in the intake of refined carbohydrates, saturated fats, and added sugars, while consuming more healthy fats, wholegrains, fruits and vegetables, and lean proteins.^17,24

Moreover, numerous pharmacological agents have undergone scrutiny in the pursuit of effective interventions for the management of NAFLD. Although there is no specific FDA-approved medication for NAFLD, some medications have shown promise in certain situations. For example, NASH patients taking vitamin E, particularly those without diabetes, have been reported to show improved liver histology, although its long-term safety and efficacy need further evaluation.^25–27 Studies on Pioglitazone, a thiazolidinedione, have shown that it can lead to improvements in liver histology in patients with concurrent diabetes and NASH.^28–30 However, its utilization should be cautiously weighed, taking into account potential adverse effects such as an increase in weight, retention of fluid, and a greater risk of heart failure.^29,31 Other pharmacological interventions, including statins, ursodeoxycholic acid, and obeticholic acid, are currently under investigation for their potential therapeutic role in the management of NAFLD.^32,33 Furthermore, incretin mimetics (glucagon-like peptide-1 (GLP-1) receptor agonists), have been reported to be a potentially valuable therapeutic option for patients with fatty liver disease, NAFLD in particular.^34,35 They reduce the accumulation of fat in the liver, as well as inflammation and fibrosis in these patients.^36,37

Numerous researchers have explored the impact of IF on NAFLD utilizing both animal models and human participants. Findings from animal studies have demonstrated that IF possesses the capacity to mitigate hepatic steatosis, inflammatory responses, and fibrosis across a spectrum of NAFLD animal models.^38–40 Promising results have also been published on how IF can positively impact NAFLD. A clinical study by Badran et al conducted with 98 NAFLD patients demonstrated that IF led to significant and noteworthy improvements in the ultrasonographic, biochemical, and anthropometric parameters associated with NAFLD, particularly in the early phases of the condition and among individuals at risk of developing diabetes.¹⁹ Another study by Faris et al found that Ramadan IF induced significant but subtle changes in liver function tests with aspartate transaminase, alkaline phosphatase and bilirubin demonstrating minor yet noteworthy enhancements, and gamma glutamyl transpeptidase exhibiting a more moderate improvement.¹⁸

Intermittent fasting holds paramount importance for older patients as it offers a multifaceted approach to addressing common age-related health challenges. It can improve metabolic health by enhancing insulin sensitivity and aiding weight management, crucial factors in preventing and managing conditions like diabetes and cardiovascular disease.^41,42 This study will review and assess the impact of IF on NAFLD in older adults using data extracted from the ClinicalTrials.gov registry.

Methods

Search Strategy

On April 12th, 2023, ClinicalTrials.gov was searched for relevant studies, using the single search term “NAFLD” for the disease/condition, in conjunction with “intermittent fasting”.

Review Search Results

The identification of relevant clinical trials was based on the following inclusion and exclusion criteria: the inclusion criteria included NAFLD clinical trials that used IF as an observational measure, and other clinical trials were excluded.

Extracted Data

Data such as study title, study status, study type, intervention details, and outcome were extracted from the database.

Results

Number of Studies Returned by the Search

On April 12th, 2023, a total of 1304 clinical trials related to NAFLD were identified in the ClinicalTrial.gov registry. Only five studies included IF as an intervention.

Characteristics of the Clinical Trials

These five clinical trials examined mainly NAFLD along with obesity, diabetes mellitus, insulin resistance and gut microbiota. They included a total of 325 participants. The full details are shown in Table 1.

Table 1 Characteristics of the Clinical Trials (from ClinicalTrials.gov 12.04.2023)

Outcome Measures

Most of the clinical trials focused on taking basic measurements such as liver fat content, visceral adipose tissue content, dietary intake, body weight, blood glucose, fasting blood glucose, HbA1c levels, liver enzymes levels, total cholesterol, and triglyceride. The full list is provided in Table 2.

Table 2 Outcome Measures with NAFLD Using if

Discussion

NAFLD is a prevalent liver disorder marked by excessive accumulation of fat in the liver, without excessive alcohol intake. NAFLD has a close link to obesity, insulin resistance, dyslipidemia, and other components of metabolic syndrome, and it has been subject to thorough investigation through clinical trials. In recent times, there has been a burgeoning interest in evaluating the prospective influence of IF on NAFLD, prompting the utilization of diverse approaches and methodologies to scrutinize IF’s impact on this ailment. Lifestyle modifications play a crucial role in the management of NAFLD.¹⁸ IF is a dietary regimen characterized by alternating periods of fasting and feeding. It encompasses diverse patterns such as time-restricted feeding, alternate day fasting, and periodic fasting practices, such as those observed during Ramadan.^43,44

The main premise of IF is to create periods of energy restriction, which can lead to changes in metabolism and cellular responses, and potentially impact the development and progression of NAFLD.⁴⁵ The mechanisms through which IF may impact NAFLD are complex and yet to be understood in full, but scholars have proposed a number of potential mechanisms. One of the most prominent of these is through improved glucose homeostasis and sensitivity to insulin. Intermittent fasting can induce changes in insulin signaling pathways, leading to improved insulin sensitivity, reduced hepatic gluconeogenesis, and increased glucose uptake in peripheral tissues, which may help to reduce hepatic fat accumulation. A study conducted by Gnanou et al demonstrated that Ramadan fasting in young, healthy individuals positively influences glucose homeostasis maintenance, accompanied by a reduction in adiponectin levels and significant weight loss.⁴⁶ Another study on 27 healthy male participants found that IF practiced during Ramadan yielded favorable effects by enhancing insulin sensitivity, as well as promoting beneficial outcomes related to weight and fat reduction.²⁰ The key factor underlying the metabolic alterations in adipose tissue during fasting is most likely a decrease in insulin signaling. Another potential mechanism is the modulation of lipid metabolism.⁴⁷ IF can lead to changes in lipid metabolism, including increased lipolysis, reduced lipogenesis, and increased β-oxidation of fatty acids, which can lead to a decrease in hepatic fat content.^48,49 Additionally, IF can affect the gut microbiota, leading to changes in bile acid metabolism, which can impact lipid metabolism and hepatic steatosis.⁵⁰ Furthermore, IF has been shown to induce autophagy.⁵¹ The activation of autophagy, which results in the reduction of hepatic triglyceride levels and improved liver function, holds potential as a therapeutic approach for treating NAFLD through the use of autophagy regulators.^51–53 Moreover, IF has been shown to modulate oxidative stress and inflammation,⁵⁴ which are both key contributors to the pathogenesis of NAFLD.⁵⁵ Furthermore, IF has demonstrated its capacity to modulate oxidative stress and liver inflammation. A small body of research has indicated that IF may diminish indicators of oxidative stress, including reactive oxygen species (ROS) and malondialdehyde (MDA), while concurrently augmenting the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the liver. This, in turn, has the potential to alleviate oxidative stress.^56,57 In addition, it has been shown that fasting during can decrease hepatic inflammation by reducing the levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and by increasing the levels of anti-inflammatory cytokines such as interleukin-10 (IL-10).^58,59

Conclusion

The studies in this review demonstrate that IF positively affects NAFLD through a number of different physiological pathways. These include improved insulin sensitivity and glucose homeostasis, modulation of lipid metabolism, induction of autophagy, modulation of oxidative stress and inflammation, and modulation of gut microbiota. However, it should be noted that the mechanisms underlying the effects of IF on NAFLD are complex and may involve other pathways as well.

However, it is crucial to acknowledge that the clinical evidence for IF in the context of NAFLD remains relatively sparse. Many of the existing studies are small in scale and lack long-term follow-up, making it challenging to draw decisive conclusions about its safety and efficacy. Additionally, the outcomes of these studies can vary widely depending on the specific fasting regimen employed, making it difficult to establish standardized guidelines for NAFLD management. Future research should be conducted to fully clarify the underlying mechanisms and to determine the optimal regimen of IF for the management of NAFLD. It should be noted that patients are strongly advised to consult with a healthcare professional before engaging in IF.