Abstract
Excess adiposity is associated with fat accumulation within the liver, and non-alcoholic steatohepatitis (NASH) is highly prevalent in bariatric patients. Elevated alanine aminotransferase (ALT) is associated with prevalent NASH. Weight loss currently has the most supporting evidence for improving liver enzyme levels, compared with other therapies. Weight loss was shown to be associated with improvements in liver enzymes and improvements of nonalcoholic fatty liver disease. In adults with severe and complicated obesity undergoing a milk-based meal replacement programme, there was an initial unanticipated rise in ALT in the first 2 weeks, followed by a gradual overall reduction by 24 weeks.
Introduction
Obesity represents a significant challenge in the prevention of chronic diseases and poses a global public health threat. In addition to increasing the risk of the development of type 2 diabetes, hypertension, and dyslipidaemia, excess body weight also has an adverse effect on the liver. Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH), is the most common cause of abnormally high levels of alanine aminotransferase (ALT). NAFLD and NASH are highly prevalent amongst patients with obesity, and approximately 50% of people affected by obesity have elevated levels of ALT and co-existing NAFLD. Elevated ALT is an independent predictor of prevalent NAFLD, and there is a significant association between elevated ALT and NASH and liver fibrosis.
Alanine aminotransferase (ALT) is an enzyme found mainly in the cytosol of hepatocytes, with much higher levels of ALT activity demonstrable in the liver than in other tissues. Most interventions to reduce body weight in patients who are overweight or obese tend to lead to improvements in NAFLD. For example, after bariatric surgery improvements in NASH and reductions in ALT have been described after 12 months. Conversely, patients with severe obesity undergoing omega loop gastric bypass had a significant increase in ALT whereas those undergoing sleeve gastrectomy or Roux-en-Y gastric bypass had a reduction in ALT. More severe deteriorations in NAFLD after bypass bariatric surgery have also been described but are the exception rather than the rule. Weight loss interventions based on either increased physical activity, dietary restriction or a combination of the two, have been shown to reduce ALT in meta-analyses. However, intensive caloric restriction such as with a very low-calorie diet has been associated with increased ALT in one study.
The underlying mechanistic basis for the heterogeneity in the hepatic physiological response to weight loss interventions has not previously been determined. Nor have previous studies examined serial changes in ALT over time in bariatric patients after initiation of a dietary weight loss intervention. While no substitute for quantifying steatosis with radiological imaging or spectroscopy, changes in liver enzymes could yield valuable insights into the mechanistic basis for improvements in metabolic health with dietary restriction.
Given the societal pressure to lose weight and the public health implications of obesity, the use of weight loss agents has risen over time. To ensure the safe use of these agents, it is important to monitor serum liver enzymes. This allows the early detection and prompt management of potential liver injuries in adults.
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The Interplay Between Liver Enzymes and Weight Loss
The relationship between liver enzymes and weight loss is complex and multifaceted. While weight loss is generally considered beneficial for improving liver health, particularly in individuals with NAFLD or NASH, the specific effects on liver enzyme levels can vary depending on the method of weight loss, individual characteristics, and underlying liver conditions. Weight loss currently has the most supporting evidence for improving liver enzyme levels, compared with other therapies.
Weight Loss and Reduction in ALT Levels
Most interventions to reduce body weight in patients who are overweight or obese tend to lead to improvements in NAFLD. Weight loss was shown to be associated with improvements in liver enzymes and improvements of nonalcoholic fatty liver disease. A landmark study showed that losing 10% of one’s body weight can reduce liver fat, resolve inflammation, and potentially improve scarring. That meta-analysis and other studies confirmed that weight loss by behavioral programs, medications, or weight-loss surgery can successfully treat NASH.
Several studies have demonstrated that weight loss, achieved through various means, can lead to a reduction in ALT levels.
Lifestyle Interventions: Weight loss interventions based on either increased physical activity, dietary restriction or a combination of the two, have been shown to reduce ALT in meta-analyses. A study found that maintenance of weight loss and exercise in overweight patients with liver disease results in a sustained improvement in liver enzymes, serum insulin levels, and quality of life. Improvements in serum alanine aminotransferase (ALT) levels were correlated with the amount of weight loss.
Bariatric Surgery: After bariatric surgery improvements in NASH and reductions in ALT have been described after 12 months.
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Transient Increases in ALT During Weight Loss
Intensive caloric restriction such as with a very low-calorie diet has been associated with increased ALT in one study. In adults with severe and complicated obesity undergoing a milk-based meal replacement programme, there was an initial unanticipated rise in ALT in the first 2 weeks, followed by a gradual overall reduction by 24 weeks.
A study showed that mild, transient increases in ALT and AST values can be observed immediately after an LCD in women, but not in men.
The Role of Diet Composition
The composition of the diet during weight loss may also influence liver enzyme levels. For example, a milk-based meal replacement programme led to an initial rise in ALT, followed by a gradual reduction. We used milk as the basis for our meal replacement programme for several reasons. It is a relatively low-cost alternative to commercially produced meal replacement supplements, which can be prohibitively cost ineffective. Whey proteins in milk have been shown to attenuate muscle loss and to preserve muscle fibre protein synthesis during very low calorie diets. In men with obesity, milk has been shown to reduce appetite, dietary intake and body weight, as well as improving glucose and fat metabolism.
Weight Loss Methods and Their Impact on Liver Enzymes
Managing obesity involves lifestyle changes such as exercise and diet modifications, as well as pharmacological treatments including appetite suppressants, lipolysis inhibitors, and glucagon-like peptide 1 receptor agonists. Non-prescription drugs, dietary supplements, and traditional herbal medicines are also commonly used for body weight control due to their perceived effectiveness and convenience.
Lifestyle Modifications
Diet and exercise are the first line of treatment. At least 150 minutes of heart-pumping activity per week is recommended. While it’s not clear which diet is best, those that emphasize vegetables and whole foods, such as the Mediterranean diet, are good options.
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A study investigated the longer term effect of a lifestyle intervention involving weight loss and increased physical activity on liver biochemistry, fasting insulin levels, and HRQL in overweight patients with liver disease. The effect of subsequent weight maintenance or weight regain on these biochemical, metabolic, and quality of life parameters was determined.
Pharmacological Interventions
If sufficient weight loss is not attainable with lifestyle modifications, weight loss surgery, such as gastric sleeve or gastric bypass, can be considered. There are currently no FDA-approved medications specifically for NASH, but medications that promote weight loss may be helpful.
The Role of Weight Loss Agents
The use of dietary supplements as a strategy for weight control has become more common. The United States Food and Drug Administration (US FDA) issued a warning about the risk of severe liver injury associated with weight loss agents including dietary supplements and weight loss medications.
Elevated liver enzymes were associated with the use of weight loss agents in men and young participants, and the number of weight loss agent types used was also associated with increased risk. Elevated liver enzymes were associated with the use of traditional medicine and dietary supplements in men, and with weight loss medication use in young participants.
Specific Weight Loss Agents and Liver Enzyme Elevation
The association between the use of traditional herbal medicines and elevated liver enzymes was significant in men. Specific ingredients for traditional herbal medicine were not identified in the KNHANES database we used; however, Kim et al. reported frequently studied traditional medicines for obesity from 2015 to 2019 in Korea, and most frequently studied herbs were Ephedrae herba and Glycyrrhizae radix, and the herbal formulas were taeeumjowi-tang (taiyindiaowei-tang), bangpungtongsung-san (fangfengtongsheng-san), and yanggyeoksanhwa-tang (lianggesanhuo-tang). Products containing ephedra or ephedrine alkaloids, which are often marketed for weight loss in Asian countries, have been linked to adverse liver-related events, including acute and autoimmune hepatitis.
The use of dietary supplements has been significantly associated with men and younger individuals. Garcinia cambogia extract and green tea extract are frequently used as dietary supplements for reducing body fat, particularly among Korean university students.
Factors Influencing the Relationship
Several factors can influence the relationship between liver enzymes and weight loss, including:
- Baseline Liver Health: Patients with pre-existing liver conditions, such as NAFLD or NASH, may experience different responses to weight loss interventions compared to those with healthy livers.
- Sex Differences: A study showed that mild, transient increases in ALT and AST values can be observed immediately after an LCD in women, but not in men. Male sex was significantly associated with an higher risk of death or liver transplantation in patients with liver injury induced by traditional Chinese medicine. Women generally have a 1.5-1.7 times higher risk of drug-related adverse events. Furthermore, women were more susceptible to DILI than men, which might be explained by sex differences in pharmacokinetics including factors such as body weight, body fat composition, and hormonal effects.
- Age: Participants aged less than 40 years old using weight loss agents showed increased risks of elevated liver enzymes, and significant associations were found between elevated liver enzymes and the use of weight loss medications with prescription and supplements.
- BMI: Increased point estimates of ORs were observed in participants with a BMI < 25 kg/m2, neither stratum showed a statistically significant increase in elevated liver enzymes.
Clinical Implications and Monitoring
Given the potential for both beneficial and adverse effects of weight loss on liver enzyme levels, careful monitoring is essential. The AGA recommends that the initial target weight loss be 10 percent of baseline weight at a rate of 1 to 2 lb (0.45 to 0.90 kg) per week.
Monitoring Liver Enzyme Levels
To ensure the safe use of weight loss agents, monitoring serum liver enzymes is important. This allows the early detection and prompt management of potential liver injuries in adults.
Protecting the Liver
Individuals with NASH must also protect the liver from any other causes of liver inflammation. This means abstaining from alcohol and making sure you are vaccinated against the hepatitis A and hepatitis B viruses.