Obesity has become a significant health issue worldwide, leading to a wide range of medical conditions. Among these, gallbladder disease is a common but often overlooked consequence. Individuals who restrict themselves to very-low-calorie diets may be at increased risk of developing gallstones that require hospitalization or cholecystectomy.
Understanding Gallstones and the Gallbladder
The gallbladder is a small, pear-shaped organ located under the liver. Its primary function is to store bile, a digestive fluid produced by the liver that helps in digesting fats. Gallbladder disease typically involves inflammation, infection, or the formation of gallstones-solid particles that develop from bile cholesterol and bilirubin in the gallbladder.
The Connection Between Low-Calorie Diets and Gallstones
Research has shown a clear link between low-calorie diets, particularly very-low-calorie diets (VLCDs), and the development of gallbladder disease.
Rapid Weight Loss
While weight loss is generally beneficial, rapid weight loss, especially through very low-calorie diets or bariatric surgery, can increase the risk of gallstone formation. Rapid weight loss, either by VLCD or bariatric surgery, is a known risk factor for gallstone formation.
A study published in the International Journal of Obesity followed individuals enrolled in a commercial weight-loss program in 28 Swedish centers between 2006 and 2009. The year-long program restricted participants to either a very-low-calorie diet consisting of 500 calories a day or a low-calorie diet of 1200 to 1500 calories per day. After 3 months, participants gradually returned to normal caloric intake to maintain their weight loss over a 9-month period. Participants were matched with controls based on age, sex, body mass index, and gallstone history. Researchers collected data on participants’ gallstones and cholecystectomies from the Swedish National Patient Register.
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After 1 year, participants in the very-low-calorie group lost an average of 24.5 pounds, compared with 18 pounds for those in the low-calorie group. However, 48 participants in the very-low-calorie group developed gallstones requiring hospitalization or cholecystectomy, compared with 16 participants in the low-calorie group. The researchers conclude that the risk of developing gallstones that required hospitalization or cholecystectomy was 3 times higher for those on a very-low-calorie diet compared with those on a low-calorie diet.
How Low-Calorie Diets Promote Gallstone Formation
Increased risk for gallstone formation during VLCDs could be explained by inadequate fat content of the diet and/or the rapid weight loss associated with VLCDs.
The two most commonly suggested mechanisms for gallstone formation are supersaturation of bile with cholesterol, leading to cholesterol crystallization and stone formation, and the insufficient gallbladder emptying due to impaired motility. Rapid weight loss induced by VLCDs is believed to affect both the mechanisms: Supersaturation is believed to be caused by decreased bile salt levels and increased cholesterol levels, and impaired motility due to reduced gallbladder stimulation because of the low-fat content.
The Importance of Fat Intake
Increased risk for gallstone formation during VLCDs could be explained by inadequate fat content of the diet and/or the rapid weight loss associated with VLCDs. However, as described previously, a fat intake of 7-10 g per day has been reported as a threshold for maintaining an efficient gallbladder emptying.
Other Risk Factors
Obesity often leads to an increase in cholesterol production by the liver. Excess cholesterol can saturate the bile, leading to the formation of cholesterol gallstones. In obese individuals, the gallbladder may not empty completely or as frequently as it should. This can cause bile to become stagnant, increasing the likelihood of gallstone formation. Obesity is often associated with insulin resistance, a condition in which the body’s cells become less responsive to insulin.
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Symptoms and Complications of Gallstones
Acute Cholecystitis: This is the inflammation of the gallbladder, often caused by gallstones blocking the ducts. Symptoms include severe abdominal pain, fever, and nausea. Pancreatitis: Gallstones can block the pancreatic duct, leading to inflammation of the pancreas, a condition known as pancreatitis.
Study: VLCD vs. LCD and Gallstone Risk
A 1-year matched cohort study of consecutively enrolled adults in a commercial weight loss program conducted at 28 Swedish centers between 2006 and 2009 provides further insights. A 3-month weight loss phase of VLCD (500 kcal per day) or LCD (1200-1500 kcal per day) was followed by a 9-month weight maintenance phase. Matching (1:1) was performed by age, sex, body mass index, waist circumference and gallstone history (n=3320:3320).
Key Findings
One-year weight loss was greater in the VLCD than in the LCD group (−11.1 versus −8.1 kg; adjusted difference, −2.8 kg, 95% CI −3.1 to −2.4; P<0.001). During 6361 person-years, 48 and 14 gallstones requiring hospital care occurred in the VLCD and LCD groups, respectively, (152 versus 44/10 000 person-years; hazard ratio, 3.4, 95% CI 1.8-6.3; P<0.001; number-needed-to-harm, 92, 95% CI 63-168; P<0.001). Of the 62 gallstone events, 38 (61%) resulted in cholecystectomy (29 versus 9; hazard ratio, 3.2, 95% CI 1.5-6.8; P=0.003; number-needed-to-harm, 151, 95% CI 94-377; P<0.001). Eighty-two percent of the VLCD group and 78% in the LCD group completed the 1-year program (odds ratio, 1.3, 95% CI 1.2-1.5; P<0.001). After the initial weight loss phase (0-3 months; baseline observation carried forward), weight loss was 12.7 versus 7.9 kg (adjusted mean difference, 4.6, 95% CI 4.4-4.9; P<0.001). After the entire 1-year program, weight loss was 11.1 versus 8.1 kg (adjusted mean difference, 2.8, 95% CI 2.4-3.1; P<0.001; Figure 2). During 6361 person-years of follow-up, 48 gallstones occurred in the VLCD group and 14 in the LCD group (152 versus 44 per 10 000 person-years; conditional hazard ratio, 3.4, 95% CI 1.8−6.3; P<0.001; Figure 3; Table 2). The risk difference was 108 per 10 000 person-years (95% CI 59-157; P<0.001), resulting in a number-needed-to-harm of 92 (95% CI 63-168; P<0.001). Including only participants who did not undergo a cholecystectomy preceding program start (n=3159 in the VLCD group and 3159 in the LCD group), 38 cases of cholecystectomy were performed during 6067 person-years of follow-up, of which 29 were in the VLCD group and 9 in the LCD group (96 versus 30 per 10 000 person-years; conditional hazard ratio, 3.2, 95% CI 1.5-6.8; P=0.003; number-needed-to-harm, 151, 95% CI 94-377; P<0.001; Figure 3; Table 2).
Risk Factors Identified
In multivariable analysis, the risk of developing gallstones requiring hospital care was higher in women than in men, in younger than in older participants, in those with a higher baseline BMI, among those who lost the most weight and in those with a history of gallstones (irrespective of cholecystectomy status; Supplementary Table 2).
Study Conclusions
The absolute risk of gallstones as well as cholecystectomy was found to be low but approximately three times higher in the VLCD than in the LCD group during the 1-year commercial weight loss program. After adjusting for weight loss during the first 3 months, the risk was attenuated but remained higher with VLCD than LCD, suggesting a direct effect of VLCD on gallstone disease.
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Limitations of Previous Studies
Previous studies have investigated the association between VLCD and ultrasonography-assessed gallstone formation, rather than the risk of gallstones as a serious adverse event requiring hospital care and/or cholecystectomy. The majority of these studies were conducted in the late 1980s and early 1990s using VLCDs containing low levels of fat (≈1g per day). In a review of these studies, Everhart reported that 10-25% of VLCD participants developed gallstones, one-third of which were symptomatic. Limitations of these studies were the lack of control groups, small sample sizes and short follow-up (8-36 weeks). Later studies included VLCDs containing higher fat content (12-30 g per day), two of which were randomized controlled trials. None developed systematic gallstones in the high-fat group in either of the studies, suggesting that an adequate fat intake reduces gallstone formation.
Mechanisms of Gallstone Formation During VLCDs
Increased risk for gallstone formation during VLCDs could be explained by inadequate fat content of the diet and/or the rapid weight loss associated with VLCDs. Rapid weight loss, either by VLCD or bariatric surgery, is a known risk factor for gallstone formation. The two most commonly suggested mechanisms for gallstone formation are supersaturation of bile with cholesterol, leading to cholesterol crystallization and stone formation, and the insufficient gallbladder emptying due to impaired motility. Rapid weight loss induced by VLCDs is believed to affect both the mechanisms: Supersaturation is believed to be caused by decreased bile salt levels and increased cholesterol levels, and impaired motility due to reduced gallbladder stimulation because of the low-fat content. However, as described previously, a fat intake of 7-10 g per day has been reported as a threshold for maintaining an efficient gallbladder emptying.
Timing of Gallstone Events
The majority of the gallstones requiring hospital care occurred during the maintenance phase (37/48 in the VLCD group and 8/14 in the LCD group).
Considerations
Whether the benefits of the additional weight loss in the VLCD group are worth the extra risk for gallstones and cholecystectomy may depend on patients' disease and risk factor status, as well as their preferences.
Strengths and Limitations of the Study
The strengths of the current study include the large sample of weight loss participants in a real-life setting, with a direct VLCD and LCD comparison. With the risk of symptomatic gallstones being low, statistical power may become an issue in smaller studies. Our large study made it possible to study the risk of symptomatic gallstones leading to hospitalization and/or cholecystectomy as a serious adverse event to VLCD. The main limitation was the nonrandomized design. Baseline differences in age, sex, BMI, waist circumference and gallstone history were handled by matching. Multivariable adjustment was used for handling remaining baseline imbalances. However, residual confounding may exist. Second, participants had selected and paid for the treatment themselves, possibly limiting generalizability to the wider overweight and obese population. Finally, the National Patient Register contains data on inpatient and nonprimary outpatient visits for gallstones, not visits in primary care, or undetected asymptomatic gallstones. Our results may therefore not be generalizable to mild or asymptomatic gallstones. However, our primary outcomes were gallstones requiring hospital care and cholecystectomies.
Prevention and Management
Given the strong link between obesity and gallbladder disease, managing your weight is one of the most effective ways to prevent this condition.Aim for gradual weight loss rather than rapid dieting. Engage in regular physical activity, such as walking, swimming, or cycling. In some cases, your doctor may prescribe medications that help dissolve gallstones or manage cholesterol levels. If gallstones are causing severe symptoms or complications, surgical removal of the gallbladder, known as a cholecystectomy, may be necessary.
Broader Context: Weight Patterns, Physical Activity, and Gallstone Risk
Introduction to Weight Cycling and Obesity in South Korea
Obesity is a global health concern, not only due to its prevalence but also because of the intense social pressures for weight reduction towards a lean body image. However, sustainable weight management is a challenge for most obese individuals, characterized by weight cycling-defined as intentional weight loss followed by unintentional weight regain-and gradual weight gain. In South Korea, the prevalence of overweight and obesity among adults surged to 36.1% during 2005-2021, reflecting a growing public health issue. Studies among Korean adults have shown an increasing trend of older adults overestimating their weight status, with significant percentages of non-overweight individuals attempting weight loss-15% of men and 25% of women over 60 years old.
Increasing Prevalence of Gallstones
The prevalence of gallstones is increasing worldwide, affecting about 20% of the population in Western countries and 5% in Eastern countries. Obesity not only increases the risk of developing gallstones due to excessive body weight but also through the mechanisms involved in body weight reduction. Previous research has indicated that weight cycling, particularly the intensity and frequency of such fluctuations, can exacerbate the risk of symptomatic gallstones. This association, well-documented in Western populations-who generally have higher rates of obesity, weight cycling, and gallstones-has not been extensively studied in Eastern contexts.
The Role of Physical Activity
Recent shifts in health paradigms suggest that increasing physical fitness and activity may be more beneficial than focusing solely on weight loss for reducing health risks, including mortality and gallstone formation. Indeed, engaging in physical activity is associated with reduced risks of cholecystectomy and gallstone development, suggesting that interventions aimed at promoting physical activity could be particularly effective. However, the specific effects of physical activity in relation to long-term weight patterns on gallstone risk remain largely unexplored.
Study Aim and Data Sources
This study aims to assess the risks of gallstones relative to long-term weight patterns and physical activity using a population-based cohort from the National Health Insurance (NHI) and National Health Screening Program (NHSP) databases in South Korea. These databases provide comprehensive lifestyle and anthropometric data for all insured Korean populations, facilitating a detailed examination of these associations.
Study Population Demographics
Among the 5,062,154 individuals in the study, 31.6% maintained their weight and 27.5% experienced weight cycling over 10 years. Weight changes of 5-20% (gain or loss) were observed in 24.4% and 16.1% of subjects, respectively. Extreme weight changes of more than 20% (gain or loss) were observed in 0.2% and 0.1% of subjects, respectively. Compared to males, females had lower rates of weight maintenance (33.7% for males vs. 28.6% for females) and higher rates of weight cycling (24.5% for males vs. 31.9% for females). Among all groups, weight maintainers had the highest socioeconomic status (SES). Clinical characteristics varied distinctly by weight pattern.
Risk Analysis of Gallstones According to Long-Term Weight Patterns
Both overall and central obesity are correlated with gallstone risk, with a greater risk associated with central obesity, hazard ratio (HR) 1.32 (95% confidence interval [CI], 1.24-1.41) for BMI ≥ 30 kg/m2 and HR 1.58 (95% CI 1.54-1.62) for WC75-100. The association between gallstone risk and overall obesity was stronger in females (HR 1.32 for females compared to 1.14 for males). However, the association between gallstone risk and central obesity was more pronounced in males (HR 1.68 for males compared to 1.54 for females).
The highest gallstone rates were in subjects with either more than 20% weight gain or loss (50.7 per 10,000 person-years for both), followed by those with 5-20% weight loss (38.1 per 10,000), weight cycling (35.3 per 10,000), and the lowest in those with 5-20% weight gain (31.6 per 10,000). After adjusting for covariates, all weight change groups showed increased HRs compared to those who maintained weight.
In the underweight BMI group (< 18.5 kg/m2), an increased risk of gallstones was associated with more than 20% weight loss. For those with a normal BMI (18.5-25.0 kg/m2), any weight change was a risk factor for gallstones. In the overweight category (25.0-29.9 kg/m2), only weight gain was a risk factor. However, for those with obesity (> 30.0 kg/m2), no long-term weight patterns were significantly associated with gallstone risk.
Subgroup Analyses on Gallstone Risks by Sex and Age
Subgroup analyses indicated that the risks associated with different weight patterns varied between males and females. Males primarily showed increased risks with weight loss, while females showed increased risks with weight gain. Weight cycling posed an increased risk for both sexes.
When analyzing HRs according to age at enrollment, younger individuals (under 45 years) displayed the highest risks associated with weight cycling, whereas older individuals (45 years and above) faced the highest risks with more than 20% weight loss. In particular, younger males were most at risk in the weight cycling category, while older males were predominantly at risk in the weight loss category. Notably, weight gain did not significantly affect the risk of gallstones in males. In contrast, females exhibited different patterns: younger females showed the highest risk with more than 20% weight gain, while older females were most at risk with more than 20% weight loss.
Risk Analysis of Gallstones by Physical Activity and Long-Term Weight Patterns
Consistent physical activity reduced the gallstone risk, revealing an HR of 0.92 (95% CI 0.89-0.96) in both males (0.90; 0.86-0.94) and females (0.93; 0.88-0.98). In individuals with consistent physical activity, all weight changers reduced their gallstone risk to levels similar to weight maintainers. Conversely, those with no or intermittent physical activity showed increased risks for all types of weight changes except the 5-20% weight loss group. The most significant risk reductions attributed to regular physical activity were observed in those gaining more than 20% of their weight (61%), followed by those losing more than 20% (17%), those gaining between 5 and 20% (3%), and those experiencing weight cycling (1%), in descending order. The risk reduction by physical activity manifested in both males and females.
Risk Analysis of Covariates Associated with Gallstones
Covariates that increased the risk of gallstones included older age, male sex, low SES, proteinuria, prediabetes or diabetes, abnormal liver function tests, and heavy smoking. In addition, levels of cholesterol, blood pressure (BP), and PP did not show a correlation with the risk of gallstones.
Discussion of the Broader Context
This study demonstrated that the risks associated with gallstones correlate with long-term weight patterns and physical activity. Subjects experiencing weight changes had an increased risk of gallstones compared to those maintaining stable weight, regardless of overall or central obesity. However, consistent physical activity mitigated the gallstone risk associated with weight changes, bringing it to the level of those who maintained their weight.
In this study, weight changers, both weight loss and weight gain as well as weight cycling, heightened the risk of gallstones relative to stable weight, at equivalent levels of obesity. The magnitude of risk varied with the amount of weight change. Subjects with weight changes exceeding 20% exhibited a higher risk compared to those with weight changes between 5% and 20% (increased gallstone risk: 13% vs. 3% for weight gain, and 32% vs. 2% for weight loss, respectively).
While having a low BMI or low WC is associated with a reduced risk of developing gallstones, rapid or excessive weight loss can paradoxically increase the risk of gallstone formation. This is because rapid weight loss triggers several metabolic changes that create a prolithogenic state-a condition that favors the formation of gallstones. During weight loss, the bile cholesterol saturation index increases and gallbladder stasis occurs. Weight gain may also increase gallstone risk, potentially related to a fat-dominant body composition, microbial changes, or dietary factors.
Among the individuals with weight loss or gain, the risk of gallstones was greater in the individuals with severe weight loss (more than 20% of body weight) than severe weight gain (more than 20% of body weight). These results are consistent with previous study, such as one that found the risk of cholecystectomy in women increasing by 14% and 61% with weight gain or loss of more than 5 pounds, respectively, compared to weight maintainers.
Weight cycling presents another independent risk for gallstones, regardless of obesity status. It alters body composition, leading to fat accumulation, muscle loss, and ectopic fat deposition, which can damage the intestinal barrier, increase epithelial permeability, and cause lipotoxicity. Subsequent weight loss following obesity can prime adipose macrophages for enhanced inflammation upon weight regain, potentially worsening glucose tolerance. However, the increased gallstone risk due to weight cycling in this study was only 4%, which is lower compared to 11-51% in Western men and 20-68% in Western women. The lesser impact in Asian populations may be due to less severe weight fluctuations and a lower prevalence of cholesterol stones, although the increasing rates of weight cycling and obesity in recent years suggest that this risk may rise.
This study also revealed demographic differences in gallstone risk: the increased risk associated with weight gain was more pronounced in females and younger individuals, consistent with previous studies. The gallstone risk from weight loss was more distinct in males and older individuals. Weight loss induces a catabolic state through caloric restriction, which significantly elevates the accumulation of excess fat, possibly linked to the gallstone risk, particularly among the elderly. The reasons for linking weight loss and males are not clarified. Weight cycling, despite being more frequent in females, increased the gallstone risk across both sexes but was more significant in younger males. The reasons for sex-predominant gallstone risk by weight patterns need further studies.
An inverse association between physical activity and gallstone was also confirmed in this study. Engaging in regular physical activity more than once per week can reduce the risk of gallstones among individuals with weight changes to the level of weight maintainers. Their protective effects were more substantial in those gaining weight compared to those losing weight or cycling in this study. The risk reduction by physical activity is effective in both sexes consistent with previous studies. Physical activity directly reduces gallstone risk by decreasing biliary cholesterol supersaturation and enhancing gallbladder motility. In addition, it reduces the level of deoxycholic acid by accelerating colonic transit. It is also effective in improving glucose tolerance and reducing insulin levels through the enhancement of glucose utilization.
This study also confirmed that both overall (BMI) and central adiposity obesity (WC) are correlated with gallstone risk, with a greater risk associated with central obesity.
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