INTRODUCTION
The alarming increase in rates of obesity, diabetes, and other metabolic diseases over the past few decades is exerting a huge burden on the health care systems and on patients with gastrointestinal and liver diseases who present to gastroenterology and hepatology clinics. Indeed, obesity is a significant risk factor for diverse gastrointestinal, pancreatic, and liver diseases (Figure 1).1 There is no escaping the impact of obesity in hepatology practice. Obesity is a global epidemic; it is important to note that the World Health Organization has different body mass index (BMI) criteria in Asian populations (World Health Organization (2000). The Asia-Pacific perspective: redefining obesity and its treatment. https://apps.who.int/iris/handle/10665/206936) in part due to differences in the interplay of BMI, percentage body fat, and subsequent health risk relative to Western populations. In this World Health Organization classification for Asian populations, overweight is defined by a BMI of 23–24.9 kg/m2 (compared to 25–29.9 in Western populations) and obesity by BMI ≥ 25 kg/m2 (compared to ≥30).
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FIGURE 1: Gastrointestinal and hepatic morbidity associated with obesity. Figure adapted from ref.
1 Abbreviations: GERD, gastroesophageal reflux disease; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease.
Treating obesity when patients present to gastroenterology and hepatology clinics has the potential to significantly impact morbidities due to obesity, type 2 diabetes, or prediabetes and their associated cardiovascular factors that are more likely to lead to mortality than the gastrointestinal or liver disease itself.2 This is also relevant after liver transplantation (LT), when weight gain can be severe, and obesity increases the risk of de novo diabetes and posttransplant metabolic syndrome, along with downstream complications—cardiovascular disease, renal disease, and allograft steatohepatitis.3 Frequently, primary care providers may be uncomfortable prescribing medications for obesity and/or metabolic syndrome out of concern for the patients’ liver function, requiring the hepatologist to step in and either guide the primary care provider or intervene themselves. Experienced dietitians provide individualized weight loss recommendations that result in modest success,4 yet some patients will only have access to or heed the advice of a physician. Thus, knowledge in weight management is critical to guide the needed weight loss, going beyond simply telling a patient to lose weight; such instruction is almost invariably unsuccessful. A deeper discussion on diet/calorie restriction and exercise is fruitful, and there is no greater incentive than the threat to organ viability, which can be leveraged by the hepatologist emphasizing efforts to lose weight.
Obesity is inextricably linked to steatotic liver disease (SLD, previously referred to as NAFLD). An algorithm for risk stratification in patients with SLD was developed, making specific recommendations regarding the application of lifestyle interventions, including diet, the introduction of liver-directed pharmacotherapy in the presence of fibrosis stage 2–4, and concomitantly treating the diabetes, which includes the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) as well as incretin receptor agonists.5 Obesity, however, is also a significant risk factor for the development and progression of many liver diseases, not just SLD. Weight loss in patients with more advanced liver disease risks potentially worsening nutritional status and liver dysfunction. This review focuses on the impact of obesity on liver disease and the management of obesity within hepatology clinics.
UNDERSTANDING BASIC OBESITY-LIVER INTERACTIONS
The pathophysiological mechanisms leading to obesity in SLD are complex and involve interplay between numerous genetic (eg, patatin-like phospholipase domain-containing 3 gene, TM6SF2, etc.) and environmental factors, which promote the development of both SLD and metabolic comorbidities, as well as liver-related mortality.6 A key contributor to weight gain is the imbalance between energy intake and expenditure. Normal energy metabolism is characterized by periodic shifts between glucose and fatty acid (FA) oxidation, depending on fuel availability.7 In the normal fasted state, serum insulin levels decrease, thereby releasing the insulin-mediated suppression of lipolysis in adipose tissue. This results in a steady supply of FAs which are used as the major fuel source during fasting. In the post-prandial state, meal-induced insulin secretion facilitates the transport of glucose into intracellular compartments, where glucose is the preferred fuel source. The ability to preferentially use available biofuel for energy generation is denoted as metabolic flexibility and is associated with normal weight. In contrast, metabolic inflexibility is the inability to readily use FAs during fasting and is associated with weight gain, irrespective of the presence of other metabolic comorbidities.8,9 Moreover, as skeletal muscle is the principal organ in whole-body energy expenditure, loss of muscle quality and quantity synergize with reduced metabolic flexibility to promote weight gain. Disruption of the human gut microbiome is an emerging regulator of both obesity and SLD. The human gut microbiome represents a diverse ecosystem within the human gut containing more than 100 trillion microbes. The synergistic relationship between the gut microbiome and the host is central to several key physiological processes that include energy regulation, nutrient harvesting, fermentation of nondigestible fibers, immune and inflammatory responses. Perturbations in these processes have been linked to both SLD and obesity.10 The predominant bacterial flora in the gut microbiome are Firmicutes and Bacteroides, while phyla such as Actinobacteria, Pseudomonadota (previously known as Proteobacteria), and Verrucomicrobiota are also commonly found within the gut microbiome.11 In obesity, significant decreases in Akkermansia, Faecalibacterium, Oscillibacter, and Alistipes genera are noted, with increases in Lactobacillus reuteri.12 Chronic alcohol ingestion also increases Lactobacilli and Bifidiobacteria. Dysbiosis results in the altered production of microbiota-derived metabolites that significantly alter normal functions, involving intestinal development and function, micronutrient synthesis, and host energy and drug metabolism, increase microbial nutrient extraction, worsen insulin sensitivity, promote lipogenesis, and modulate chronic inflammation.13
The portal vein provides a direct connection for gut microbiota metabolites to the liver and facilitates bidirectional communication between the two. In SLD, dysbiosis promotes low-grade noninfectious chronic hepatic inflammation and can promote disease progression. Furthermore, metagenomic-based approaches have demonstrated the correlation between increases in Bacteroides and decreases in Provetellaceae and Erysipelotrichaceae with increased fibrosis severity.14 In SLD and cholestatic liver disease, the dysbiosis is also able to modify the bile acid profile, leading to higher fecal levels of unconjugated cholic acid and chenodeoxycholic acid, and higher serum 7alpha C4 suggesting increased hepatic bile acid synthesis; it has been hypothesized that this suggests a role of microbiota in hepatic injury and disease progression.15 The human microbiome, thus, exerts effects on chronic liver diseases and disease progression through mechanisms that target the liver directly (ie, bile acid composition, activation of pro-fibrosis pathways), as well as indirectly by promoting weight gain and obesity. A meta-analysis addressing the utilization of prebiotics and probiotics to alter the microbiome has shown metabolic benefits, including reduced body weight, improved glucose control, and lower liver enzymes.16 Dietary fiber was independently associated with more weight loss in obese individuals following a calorie-restricted diet.17 Since fiber is an effective pre-biotic that helps restore the microbiome, there is little downside to the addition of dietary fiber to any weight loss regimen.
Adipokines are peptide hormones normally produced by healthy adipose tissue and have insulin-sensitizing actions. Obesity is associated with an aberrant adipokine milieu, and adipokines have a role in the pathophysiologic processes of chronic liver disease.18 Adiponectin has anti-steatotic, anti-inflammatory, and antifibrotic activity, and adiponectin is reduced in obesity. Leptin and galectin-3 are frequently elevated in obesity, have pro-inflammatory and pro-fibrogenesis activity, and galectin-3 also induces cell apoptosis. These and other adipokines and inflammatory markers associated with obesity have an influence on liver injury that may be additive to the inflammatory injury of chronic liver diseases (Table 1).
TABLE 1 -
Adipokines in obesity and liver-related effects
|
Normal metabolic effects |
Normal liver effects |
Obesity relationship |
Cirrhosis relationship |
| Adiponectin |
Increased insulin sensitivity and decreased inflammation |
Decreased steatosis, decreased inflammation, and decreased fibrosis
Reduced connective tissue growth factor |
Decreased |
Increased adiponectin levels (increases with cholestasis and worse liver function) |
| Leptin |
Increased inflammation |
Increased inflammation and increase fibrosis |
Increased (subcutaneous > visceral adipose) |
Discordant data |
| Galectin |
Increases inflammation, cell death, and angiogenesis |
Pro-fibrotic, Increased inflammation, Increased uptake lipoxidation end products
Increased cell death |
Increased (visceral > subcutaneous adipose) |
Increase in galectin levels (increases with worse liver function) |
| Resistin |
Increases insulin resistance and inflammation |
Increased fibrogenesis, induces increased cytokine release/inflammation. Suppressed apoptosis, increased lipid uptake, downregulates LDL receptor, and increased lipogenesis |
Increased (visceral > subcutaneous adipose) |
Increase in resistin levels (increases with worse liver function) |
| Visfatin |
|
Increased glucose, fibrosis, and inflammation |
Increased (visceral=subcutaneous adipose) |
Most studies suggest decreased Visfatin levels (1 study: increases with worse liver function) |
THE ROLE OF OBESITY IN THE PROGRESSION OF CHRONIC LIVER DISEASES
While obesity is inextricably linked to SLD, it also affects the natural history and progression of other chronic liver diseases and cirrhosis. It has been shown to increase rates of hepatic decompensation events, the development of acute-on-chronic liver failure, infection, and in-hospital mortality in patients with cirrhosis, and increased liver transplant waitlist mortality.19–22 Acute hepatic decompensation is associated with a marked pro-inflammatory state; obesity compounds systemic inflammation as adipose tissue stores and releases many cytokines (such as TNF-alpha, IL-1 and 16, etc.) and increases the risk of acute-on-chronic liver failure.19 Obesity is also a risk factor for the development of sarcopenia in patients with cirrhosis, as similar pro-inflammatory cytokines increase skeletal muscle breakdown.23
In patients with chronic liver disease in the absence of cirrhosis, obesity and its consequent pro-inflammatory state can increase the risk and rate of progression of advanced fibrosis compared to those without obesity.24 Additionally, other chronic liver diseases can co-exist with SLD and also affect disease progression. The following sections describe the effects of obesity in specific chronic liver diseases.
Alcohol-associated liver disease
While steatosis in SLD is related to lipid accumulation, alcohol has a direct effect on hepatocytes.25 Obesity and SLD are often cofactors in worsening fibrosis in patients with alcohol-associated cirrhosis through similar pro-inflammatory pathways, microbiome dysbiosis, and shared genetic predispositions (specifically, the I148M variant of the patatin-like phospholipase domain-containing 3 gene, which impacts lipid droplet formation in hepatocytes) that accelerate fibrosis progression25 and also impacts results of treatment for hepatic steatosis based on a systematic review.26
Obesity impacts liver disease even among nonheavy drinkers [which is now defined by the Met-ALD (metabolic and alcohol overlap) category]. In a cross-sectional, community-based study that included 2629 current drinkers in the Framingham Heart Study, diverse alcohol use measures were positively associated with at-risk metabolic dysfunction-associated steatohepatitis, based on Fibroscan-aspartate aminotransferase score > 0.35 (90% sensitivity) or ≥ 0.67 (90% specificity). In this community-based cohort, obesity and metabolic syndrome were also found to be risk factors for liver fibrosis and steatohepatitis among nonheavy alcohol drinkers, defined as < 14 drinks per week for women or < 21 for men.27
Independent of SLD, in patients who drink alcohol, a BMI ≥ 25 kg/m2 in women and ≥ 27 kg/m2 in men has been shown to increase the development of steatosis, alcohol-associated hepatitis, and cirrhosis.28 Additionally, obesity and alcohol use (defined in this study as 4 d/week for 1 y) have been linked to a 7-fold increased risk of developing HCC.29 Fortunately, alcohol abstinence, regardless of BMI, can reverse steatosis and prevent disease progression.
HCV
Steatosis is documented in patients with HCV with traditional metabolic risk factors, including obesity and insulin resistance, resulting in overlapping SLD. HCV also has a direct effect on lipid metabolism, leading to triglyceride accumulation in hepatocytes and subsequent steatosis through the inhibition of proteins required for the export of VLDL. This is seen in genotype 3 HCV, where steatosis is common even in the absence of risk factors.30 Daily intake of fructose-enriched foods (not fruit) has been linked to severe liver fibrosis in patients with HCV.31 Similar to the pathophysiology of SLD with oxidative stress and cytokine-mediated injury, steatosis (whether directly or indirectly related to HCV itself) contributes to fibrosis progression in HCV. Prior to the advent of direct-acting antivirals for the treatment of HCV, steatosis severity on index biopsy was shown to be an independent predictor of both fibrosis severity and progression in patients with HCV independent of genotype 3 status.32 Additionally, steatosis resolved with antiviral treatment in genotype 3 HCV but not genotype 1 HCV.
In the “interferon era,” obesity was a negative predictor of sustained virologic response in HCV.33 Although obesity does not affect direct-acting antiviral therapy, a large VA cohort of nearly 12,000 patients found 52% of patients had gained weight (up to 32 lbs) 2 years after achieving sustained virologic response.34 Another study showed that 47% of patients had ongoing steatosis post-sustained virologic response with 6.25% having advanced fibrosis as measured by transient elastography.35 Current guidelines recommend follow-up for only those with advanced fibrosis; however, this needs to be placed in the context of risk factors for SLD, including obesity, and further follow-up is likely warranted.
HBV
SLD is present in up to 30% of patients with chronic HBV. Logically, given the effects of obesity on fibrosis progression in SLD, one would assume the same deleterious effects in patients with HBV; however, conflicting data exist. A prospective study of 2903 men with HBV found that excess body weight increased the risk of HCC and liver-related mortality.36 In contrast, a large meta-analysis comprising 17,955 patients found no difference in HCC, mortality, or the incidence of HBsAg seroconversion in patients with chronic HBV with and without fatty liver, though this did not specifically assess obesity, and there was high heterogeneity.37 A meta-analysis of 13,262 matched patients from that cohort showed that those with chronic HBV and fatty liver had lower rates of HCC, cirrhosis, mortality, and higher HBsAg seroconversion rates. Thus, deleterious effects associated with obesity may not directly impact the consequences of steatosis in patients with HBV.
Paradoxically, the latter association would suggest that SLD could have a beneficial or protective effect on chronic HBV. While the mechanism of such protection is unknown, 1 hypothesis is that the metabolic stress and inflammatory state associated with SLD may activate innate and adaptive immunity that had been previously suppressed by HBV, and thereby eliminate the virus and delay fibrosis progression.37 Proposed mechanisms of such protection include (a) the role of saturated FAs in upregulating pathways (Toll-like-receptor, myeloid differentiation) to inhibit HBV replication;38 (b) increased expression of certain receptors in steatotic hepatocytes that induce apoptosis, thereby increasing seroconversion to anti-Hbs positive;39 and (c) decreased expression of HBsAg as a direct effect of steatosis within the cytoplasm of HBV-infected hepatocytes.39 Further studies are required to validate these hypotheses.
Cholestatic & autoimmune liver diseases
There is limited data on the effect of obesity and concomitant fatty liver disease on the natural history and progression of cholestatic and autoimmune liver diseases. A small study of patients with primary biliary cholangitis (PBC) found that the disease was more severe in overweight patients (BMI ≥ 25 kg/m2), with higher degrees of steatosis and steatohepatitis being associated with more severe fibrosis and biliary duct damage.40 However, in a larger study of nearly 49,000 patients with PBC, obesity was associated with a decrease in PBC-related mortality.41 Other studies have also found that SLD has no effect on the severity or course of PBC and vice-versa.42,43 Conversely, obesity in patients with primary sclerosing cholangitis has been associated with increased fibrosis at presentation and progression.44 However, further studies in both cholestatic diseases as well as autoimmune hepatitis are needed.
MANAGEMENT OF OBESITY FROM THE HEPATOLOGY CLINIC
The literature reviewed above shows that obesity is a risk factor for the progression of fibrosis in most chronic liver diseases. Logically, weight loss can only help the liver and overall health, irrespective of the type of liver disease. Weight loss and exercise in those who are overweight have shown improvement in liver enzymes and quality of life.45 Obesity should be considered a risk factor in the progression of any chronic liver disease, not just SLD, and subsequently evaluated and treated.
Obesity poses unique challenges in both nontransplant and transplant hepatology settings. Aggressive weight management is imperative in mitigating disease progression and major adverse liver and cardiovascular outcomes in patients with obesity with liver disease. Prevention and/or management of the inevitable weight gain experienced after LT is of paramount importance. At a minimum, detailed information to the referring provider regarding obesity should be included in consult letters or the electronic medical records that are often accessible to equip the provider with methods for intervention. Helpful advice includes emphasizing the safety and preference for the use of all noninsulin diabetic regimens with a focus on the agents benefiting weight loss, the absence of contraindications to weight loss procedures, the benefits of anti-lipid agents, including statins, etc. Relying on the patient to navigate the management of obesity or weight loss alone or with other providers can be hit and miss. Thus, hepatologists should be prepared to manage obesity in the hepatology clinic if needed.
Education on lifestyle tactics
Lifestyle interventions are the quintessential cornerstone in the management of obesity. These comprise the implementation of structured dietary and physical activity programs to facilitate weight loss while avoiding sarcopenia, frailty, and clinical decompensation.46 In the absence of cirrhosis and in patients with compensated cirrhosis, closely monitored weight loss through exercise and moderate caloric restriction has been deemed safe, with no associated clinical decompensations or adverse outcomes.47 However, special care is necessary in decompensated patients and in those with pre-existing sarcopenia to prevent further decline in muscle mass or the development of frailty, ascites, and HE.47,48 As a result, in the pre-transplant setting, before prescribing calorie restriction and exercise, a thorough nutritional assessment should be conducted in collaboration with an experienced dietitian. Validated tools, such as the Royal Free Hospital-Nutritional Prioritizing Tool, or Liver Diseases Undernutrition Screening Tool, should be used.46 In addition, baseline and ongoing assessment for sarcopenia and frailty through simple, repeatable, imaging-based measurements and tests such as handgrip strength and liver frailty index should be carried out.46,49 Based on the nutritional status and severity of liver disease, a personalized target weight, total daily caloric and protein intake goals, and an appropriate exercise regimen should be determined. A slow and progressive weight loss goal of 10% (minimum 5%) in patients with obesity is optimal as it is associated with the improvement of metabolic abnormalities, liver histological activity, and portal hypertension across several etiologies of chronic liver disease.50,51
In terms of macronutrient content, data supports the use of the Mediterranean Diet in patients with obesity with chronic liver disease, given its efficacy in promoting weight loss, improving insulin resistance and noninvasive markers of hepatic fibrosis,52 as well as favorable outcomes on cardiovascular risk53 and cancer risk.54 As many patients cannot sustain a specific “diet,” it is advisable to address their individual diet requirements. In the absence of cirrhosis and sarcopenia, moderate calorie restriction (reduction of ~500–800 kcal/day or ≤ 30% of previous caloric intake) can be safely targeted in patients with obesity, with protein consumption of at least 1.2 g/kg adjusted body weight per day to prevent loss of muscle mass and promote satiety. Adjusted body weight is calculated as ideal body weight + (0.4 × [actual body weight − ideal body weight]). In the presence of superimposed sarcopenia, a minimum protein intake of 1.5 g/kg adjusted body weight per day should be targeted; with increasing physical activity, up to 1.8 g/kg/day protein is safely tolerated.46,47 Calorie goals for weight loss will vary among individuals. A rough guide is outlined in Figure 2. It is imperative to educate the patient that weight loss in the first 2–6 weeks will be more notable and results from fluid shift/loss, glycogen utilization, and muscle alterations rather than fat loss. Fat loss takes longer and should be a slow, consistent process over months (as reviewed in55). Increasing the metabolic rate (with exercise) during this time will help avoid the expected plateau in weight loss. Weighing oneself regularly is associated with successful weight loss and less weight regain.56 Referral for psychologic assessment of overeating and behavioral therapy may be considered in appropriate circumstances.
FIGURE 2: Lifestyle prescription for management of obesity.
Physical activity in patients with chronic liver disease and compensated cirrhosis confers numerous benefits, including increased skeletal muscle mass and reduced body fat, reduction in liver fat content, improved ammonia and glucose homeostasis, and improved health-related quality of life.47,57 Many of these benefits are independent of weight loss. Before initiating an exercise regimen, a safety check should be conducted, paying heed to liver-specific considerations (eg, surveillance and management of varices in cirrhosis, evaluation for HE, etc.), cardiopulmonary status (in patients with a history of cardiovascular, metabolic, or renal disease hoping to pursue higher than moderate-intensity training) and physical comorbidities (eg, fall risk).47,57 Once initiated, patients should be guided to “start low, progress slowly, and be alert for symptoms”, in keeping with the graded staircase approach promoted by the American College of Sports Medicine. This generally starts with a 5–10 minute warm-up, includes a 10–40 minute exercise phase containing aerobic and resistance components, and ends with 5–10 minutes of flexibility and balance training. A reasonable overall target is moderate-intensity aerobic activity of 150 minutes per week (750 MET-min per week, where one MET minute is the amount of energy expended during a minute while at rest and moderate-intensity activities are associated with 3–6 MET), incorporating resistance training on 2 or more days.57 Resistance training is indicated in patients at risk of sarcopenia.47 Education on the role of exercise in assisting with weight loss and, more importantly, associated improved metabolism, cardiovascular and musculoskeletal health, and the maintenance of weight loss will improve expectations and outcomes.58
Patients with decompensated cirrhosis are at elevated risk of suffering adverse outcomes and sarcopenia. As a result, weight loss recommendations must be taken with caution in this population.59 In settings where weight loss must be prescribed(eg, listing for LT), there should be consumption of 1.2–1.5 g protein/kg adjusted body weight per day, depending on the absence or presence of concomitant sarcopenia.49 With regards to exercise, safety and efficacy data evaluating moderate-to-vigorous intensity exercise are limited in this population. However, the safety of both institutional and home-based combined exercise and dietary regimens in patients with decompensated cirrhosis has been outlined.60,61 Additionally, Zamora-Valdes et al illustrated benefits in ~75% of patients with obesity on the waiting list for LT with BMI ≥ 35 kg/m2, including those with decompensated cirrhosis. The patients who pursued aggressive lifestyle management using a low-calorie diet (1200–1400 kcal/day for women; 1400–1600 kcal/day for men) and exercise (up to 30–40 min/day of physical activity, mainly walking), safely and successfully achieved weight loss goals (mean weight loss: −21 ± 12.8 kg) before transplant. Of these, ~25% maintained weight loss at 3 years posttransplant.62
It is imperative that positive lifestyle changes continue in the posttransplant period to mitigate the inevitable weight gain conferred by adverse effects of immunosuppressants, concurrent use of insulin, reversal of the catabolic state of cirrhosis, increased appetite, sedentary lifestyle, insulin resistance and interruption of the satiation feedback loop secondary to denervation of the liver.3 Krasnoff et al demonstrated that a combined aerobic exercise and low-fat dietary counseling intervention in liver transplant recipients improved exercise capacity, lowered body fat, and increased lean body mass.63 A more recent evaluation of a 12-week telehealth-delivered diet and exercise program in liver transplant recipients revealed weight loss (−1.3 kg; 95% CI: −2.3, −0.3), reduction in waist circumference (−1.9 cm; 95% CI: −3.8, −0.1), with associated reduction in metabolic syndrome severity scores and triglyceride levels, despite a 23% drop-out rate.64 These results favor the implementation of lifestyle interventions aimed at weight loss across the peri-transplant period, with the support of experienced dietitians and physical therapists.
Therapeutics
The success rate of patients to lose enough weight, with diet and exercise, to produce a meaningful sustained clinical and/or histological response is relatively low. A meta-analysis of nontransplant patients who were initially successful in losing a significant amount of weight showed that these changes are usually transient, as most patients gain weight after 1 year of follow-up.65 This underscores the importance of supplementing positive changes to diet and exercise with pharmacological agents that facilitate sustained weight loss and improve SLD.
Several anti-obesity medications such as orlistat, phentermine/topiramate, and naltrexone/bupropion can lead to weight loss and can be used in chronic liver disease and compensated cirrhosis as well as posttransplantation (noting immunosuppression interaction with orlistat66), but the scarcity of data for long-term use in general limits their use in clinical practice.67
Dietary supplements marketed for weight loss will come up frequently in conversations with patients. A full review is beyond the scope of this article, but the effectiveness of the majority of these compounds remains to be determined. Weight loss experienced with some of the leading agents (0.75–3.5 kg difference, with coexisting diet and exercise regimes) reaches statistical significance in some studies, whereas most other marketed agents have either no data or nonsignificant differences.68 Given that some of these supplements (eg, Green tea extract, Hoodia, Herbalife, Hydroxycut) have been associated with liver toxicity, they should be used cautiously.
Glucagon-like peptide-1 (GLP-1) receptor agonists cause significant weight loss in a dose-dependent fashion.69 A systematic review and meta-analysis showed that in 8 trials conducted in 468 patients, treatment with liraglutide, exenatide, or dulaglutide was associated with reduced transaminases, intrahepatic adipose, and visceral fat.70 Moreover, semaglutide was recently demonstrated to improve individual histological features of metabolic dysfunction-associated steatohepatitis in a phase 2 multi-national clinical trial.71 GLP-1 receptor agonism has a wide array of beneficial metabolic effects, such as improvements in insulin resistance, hypertension, and cardiovascular disease. Additional benefits may be seen in alcohol use disorder, where GLP-1 agonism is shown to reduce alcohol craving and intake,72 and GLP-1 receptor gene variation may have a role in alcohol dependence.73 The combination of agonists of the GLP-1 receptor and glucose-dependent insulinotropic polypeptide receptor is promising for the treatment of obesity74 and may benefit in SLD, but more data is needed. Experimental studies also show reduced hepatic fibrosis in mouse models of steatohepatitis,75 as documented, for example, with the experimental GLP-1/2-Fc fusion compound,76 and the reduction in hepatic fibrosis in both mouse models of steatohepatitis and in humans with overweight, or obesity and type 2 diabetes with the experimental dual incretin agonist, cotadutide.77
Understanding the difference between various GLP-1 receptor agonists may help in the choice of these agents, as they seem to be the leading choices given both weight loss and liver-specific benefits (Table 2). Chemical modulation of the structure of GLP-1 led to the development of agents with far greater half-life than the parent compound GLP-1, with its half-life of 2–3 minutes. Modifications to the structure include the removal of the site of degradation by dipeptidyl-peptidase 4 in GLP-1 and the addition of amino acids to the GLP-1, leading to the short-acting agents, exenatide and lixisenatide, which are associated with half-lives of ~3 hours. Furthermore, molecular alterations lead to agents administered daily or weekly administration through a subcutaneous route. The modifications include covalent conjugation with larger molecules such as human albumin (albiglutide), IgG4 Fc domain (dulaglutide), encapsulation into microspheres (exenatide once-weekly), the addition of C-16 or C-18 FA chains leading to non-covalent binding to albumin (liraglutide and semaglutide, respectively).78
TABLE 2 -
The single, dual, and triple incretin analogs or agonists approved (in bolded text) or in development
| Incretin agonists |
Single |
Dual |
Triple |
| Receptor target(s) |
GLP-1 |
GLP-1/GIP |
GLP-1/glucagon |
GLP-1/GIP/glucagon |
| Administration |
| SQ daily multiple |
Exenatide
|
— |
— |
— |
| SQ daily single |
Lixisenatide, liraglutide
|
— |
Cotadutide |
— |
| SQ weekly |
Albiglutide, dulaglutide, exenatide 1/w
Semaglutide
|
Tirzepatide
|
BI 456906
Mazdutide (IBI362; LY3305677) |
Retatrutide (LY3437943) |
| Oral daily |
Semaglutide
Danuglipron |
— |
— |
— |
Abbreviations: GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1 receptor agonists; SQ, subcutaneous.
Finally, an oral formulation of semaglutide was based on co-formulation with sodium N-[8-(2 hydroxy-benzoyl) amino caprylate with circulating levels and biological efficacy, including reduction in glycosylated hemoglobin and induction of nausea similar to that of subcutaneous semaglutide.79 In the future, it is anticipated that oral small molecule GLP-1 receptor agonists will also be available with the added advantage that no interval will be required between drug intake and meal.80 All these medications, either approved or in development, are peptides, with the exception of the small molecules, danuglipron and orforglipron. The vast literature has generally documented beneficial effects on body weight and glycosylated hemoglobin in patients with type 2 diabetes as well as effects on body weight in nondiabetic overweight or obese participants.
SGLT-2i treat maladaptive glucose reabsorption in patients with type 2 diabetes mellitus and have shown promise for the treatment of SLD in non-histology–based clinical trials.81 While the degree of weight loss with SGLT-2i is modest compared to GLP-1 receptor agonist or dual GLP-1/glucose-dependent insulinotropic polypeptide compounds, SGLT-2i has been demonstrated to improve metabolic flexibility and FA oxidation.82 In addition to the treatment of diabetes, SGLT-2i has beneficial effects on cardiovascular disease, diastolic heart failure, and renal function that make them attractive medications in patients with SLD despite the modest impact on weight.
The efficacy of assessing liver-related effects and, where reported, the adverse effects (AEs) of diverse agents targeting obesity are summarized briefly in Table 3.70,75,83–91 Most AEs were of mild to moderate severity; gastrointestinal disorders (nausea, vomiting, dyspepsia, diarrhea) or asymptomatic hypoglycemia were the most common AEs with GLP-1 receptor agonists, whereas urogenital infections, including urinary tract infections, balanoposthitis, and vaginitis, were the common AEs of SGLT-2i. In addition, concern for weight regain once these medications are stopped emphasizes the need for a solid foundation in lifestyle and behavioral changes to sustain weight loss.
TABLE 3 -
Liver-related studies with GLP-1 and SGLT-2i agents
| GLP-1 agents |
Control |
# RCTs/ total patient # |
Summary of results on liver end points |
Reference |
| Exenatide and liraglutide |
Metformin, gliclazide, sitagliptin, insulin, or placebo |
6/406 (NAFLDa with T2DM in 87%) |
Significant improvement in liver fat fraction with GLP1-RA; exenatide improved ALT and AST; liraglutide increased adiponectin |
82 |
| Exenatide, liraglutide |
Pioglitazone, SGLT-2, or DPP4 inhibitors |
26/946 (NAFLD)a |
Reductions in ALT with all 4: pioglitazone, SGLT-2 and DPP4 inhibitors, and GLP-1 agonists; pioglitazone and GLP-1 agonists reduced hepatic steatosis with numerical trends with pioglitazone and DPP4 inhibitors; |
86 |
| Exenatide, liraglutide |
Placebo, gliclazide, insulin, and pioglitazone + metformin |
8/396 (NAFLDa with T2DM in 67%) |
Reductions in the LFC, ALT, and GGT compared to controls |
81 |
| liraglutide, semaglutide, dulaglutide |
2 placebos, and 2 open-labels |
4/406 (NAFLDa, with 58% T2DM) |
Reduced overall NAFLD activity score, compared with placebo and improvement of hepatic fibrosis by ≥1 Kleiner point and lobular inflammation |
89 |
| Exenatide, semaglutide, liraglutide, dulaglutide |
Metformin, insulin, placebo,or standard of care |
8/615 |
Improvement in ALT, AST, and GGT and reduction in LFC |
83 |
| 5 liraglutide, 2 exenatide, 1 dulaglutide |
Sitagliptin (DPP4), insulin, or placebo |
8/468 (NAFLDa plus DM2) |
GLP-1 RA significantly decreased ALT, AST, and intrahepatic adipose; no effect on FIB-4 index (3 trials) |
68 |
| liraglutide, semaglutide, and dulaglutide |
4 SGLT-2 inhibitors (dapagliflozin, empagliflozin, ipragliflozin, tofogliflozin), vitamin E (α-tocopherol and δ- tocotrienol), pioglitazone |
27/3416 (NAFLD)a |
NMA: evidence for the efficacy of vitamin E, pioglitazone, SGLT-2 inhibitors, and GLP-1 RA in treating NAFLD
Highest SUCRA rankings:
Liraglutide in decreasing CAP and ELF scores and increasing the resolution of NASH.
Pioglitazone in decreasing LFC and fibrosis scores
Tofogliflozin in decreasing keratin-18,
Dapagliflozin in decreasing the GGT level.
Semaglutide in decreasing levels of ALT and AST. |
87 |
| Exenatide, liraglutide, dulaglutide (8 trials) |
SGLT-2 (29 trials) and DPP4 (3 trials) inhibitors |
40/13134 patients with obesity |
SGLT-2 inhibitors and GLP-1 agonists have a beneficial effect on hepatic parameters (AST, ALT, GGT, and FIB-4) in obesity |
88 |
| Exenatide, liraglutide, dulaglutide (8 trials) |
SGLT-2 (4 trials) and DPP4 (3 trials) inhibitors |
12/647 (NAFLD)a |
No drug class had a significant effect on AST or bilirubin; SGLT-2 but not GLP-1 RA and DPP4 had a significant effect on ALT; both SGLT-2 and GLP-1 RA but not DPP4 reduced GGT; GLP-1 RA reduced FIB-4; other classes were not tested |
88 |
| Semaglutide, liraglutide, |
Pioglitazone, vitamin E, placebo |
9/1482 (NAFLD)a |
GLP-1 RA were as effective as pioglitazone and vitamin E for NAFLD activity score (steatosis, lobular inflammation, and ballooning necrosis); pioglitazone ranked first (OR for improvement 1.58) and GLP-1 RA (OR 1.56) second for fibrosis |
84 |
| Exenatide, semaglutide, liraglutide, dulaglutide |
5 SGLT-2 inhibitors: dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and empagliflozin |
37/3172 (NAFLD)a |
On NMA, GLP-1 RA seem more effective than SGLT-2 inhibitors in reducing liver enzymes, liver fat, anthropometric measurements, and improving blood lipids and glycemic parameters |
85 |
aNAFLD (population would have been largely represented by MASLD).
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CAP, controlled attenuation parameter; DPP4, dipeptidyl-peptidase inhibitor-4; ELF, enhanced liver fibrosis; FIB-4, fibrosis-4; GGT, gamma-glutamyl transferase; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; LFC, liver fat content; MASLD, metabolic dysfunction-associated steatotic liver disease; NMA, network meta-analysis; RA, receptor agonists; RCT, randomized controlled trial; SGLT-2, sodium-glucose cotransporter-2; SUCRA, Surface Under the Cumulative RAnking; T2DM, type 2 diabetes mellitus.
BARIATRIC SURGERY IN PATIENTS WITH OBESITY WITH CHRONIC LIVER DISEASE
Bariatric surgery (BS) for the management of obesity is a well-established practice with innumerable studies proving its effectiveness for weight loss and metabolic improvement. The benefits have also been proven in the setting of chronic liver disease, specifically SLD, with improvement in histologic and clinical end points.92 Endoscopic weight management procedures93 are promising as less invasive procedures, and there is evidence that endoscopic sleeve gastroplasty improves steatosis and markers of fibrosis in patients with NAFLD(metabolic associated steatotic liver disease),94,95 but more data is needed relating to liver-specific outcomes.
With advanced liver diseases such as cirrhosis or portal hypertension, the data on BS is less well-established. Small studies in patients with limited portal hypertension have demonstrated the safety and effectiveness of endoscopic96 and surgical bariatric procedures ([with the large majority being sleeve gastrectomy [SG]),97,98 including long-term (10 y) liver-related benefits such as lack of progression to decompensation.99
Obesity not only contributes to liver disease and progression, but it can also limit access to transplantation and prolong wait times for patients with end-stage liver disease (ESLD).100 Most transplant centers have BMI cutoffs ranging from 40 to 45 kg/m2. Although this patient population has not been found to have increased graft loss or mortality, they do have increased short-term morbidity.101 Patients with obesity who undergo LT tend to have increased operative times, blood loss, hospital length of stay, surgical site infections, overall infections, wound dehiscence, biliary complications, and metabolic syndrome-related complications.102 For these reasons, weight loss for patients with obesity with ESLD is highly recommended. Treatment options include diet, exercise, and BS. However, these approaches can be limited in this malnourished and chronically ill cohort, requiring diligent nutritional follow-up. In carefully selected patients, BS may be the best option.
BS has been proven to be safe and effective in carefully selected patients with ESLD,103,104 resulting in long-term, durable weight loss and improvement or resolution of metabolic comorbidities of obesity such as diabetes, hypertension, dyslipidemia, and obstructive sleep apnea.105 This is important as the development of metabolic syndrome in post-liver transplant patients results in a higher risk of major cardiovascular events.3 In this patient population, SG is the BS of choice compared to Roux-en-Y gastric bypass for several reasons, including the ease of performing the surgery, shorter operative times (ideal for this high-risk population),106 and preservation of the gastrointestinal tract, which is important for future LT, biliary reconstruction and access for any endoscopic procedures to the biliary tree. Roux-en-Y gastric bypass is a malabsorptive procedure that can also affect the absorption of immunosuppressants after LT; this is not an issue with SG.
The optimal timing to perform SG in patients with ESLD remains unclear.103,104 SG has been successfully performed pre-LT, simultaneously with transplant (BS-LT), and delayed after LT. Pre-LT endoscopic weight loss procedures have been performed in small studies107,108 with successful short-term weight loss but increased complications, including refractory vomiting and weight regain, if transplantation is not timely.
Undergoing pre-LT BS can help facilitate eligibility for well-compensated patients with cirrhosis who otherwise would not be LT candidates. Thus, SG before LT was superior to medical weight loss in sustained weight loss and reducing the incidence of diabetes, hypertension, as well as recurrent and de novo SLD after transplantation.109 Similar results in multiple small studies show durable long-term weight loss with resolution of type 2 diabetes.110 However, the selection of medically appropriate patients is vitally important as the risk of 30-day mortality in patients with decompensated cirrhosis undergoing BS is 16.7%.111 There are no consensus guidelines regarding patient selection; however, eligibility criteria would depend on the severity of liver disease and careful assessment of risk:benefit. Proposed criteria have included a Child-Pugh score ≤ 9, a Model for End-Stage Liver Disease score < 15–20, and an International normalized ratio ≤ 2.5.109 Relative contraindications to pre-LT BS include moderate or severe coagulopathy or thrombocytopenia, severe hypoalbuminemia, and the presence of decompensation from portal hypertension.
Simultaneous BS-LT is another option for the obese liver transplant candidate. The benefit lies in the single operative intervention. The disadvantage is that it adds another level of complexity to an already extremely complex surgery, with a higher risk of potential complications. However, studies have shown that patients who undergo BS-LT do not have an increased risk of graft loss or mortality.112,113 In a study by Zamora-Valdes et al comparing patients with obesity who underwent LT alone versus BS-LT, the BS-LT group had more effective and durable long-term weight loss as well as lower prevalence of hypertension, insulin resistance, and hepatic steatosis.62
Obesity and metabolic syndrome are common long-term complications after LT. Undergoing BS after LT is an option when diet and exercise have failed. In a meta-analysis of 8 studies114 involving 96 patients in whom the most frequent bariatric procedure was SG, the surgery was safe with low mortality [0.6% (0.02–0.13)], significant improvement in BMI [31.02 (25.96–36.09) kg/m2 and percent excess weight loss [44.08 (27.90–60.26) kg] at 12 months, as well as improvement of hypertension and diabetes in 61% and 45%, respectively, while preserving allograft function. There have been differing reports on the length of operative time in these patients. In a matched case-control series of patients with laparoscopic SG with and without prior LT, there were similar operative times and postoperative morbidity in both groups, but longer lengths of stay in the prior LT group.115 Other groups have reported longer operating times and increased short-term morbidity and mortality.116,117 This may be related to re-operative surgery having an increased risk of adhesions. Complications reported with BS after LT have included surgical site infections, bleeding, fascial dehiscence, dysphagia, malnutrition, and bile leak.116,118
The bulk of the evidence suggests BS, particularly SG, could be considered in select patients with obesity before, during, or after LT to promote weight loss and improve metabolic comorbidities. However, careful patient selection and timing of the surgery are crucial for optimal outcomes.
SUMMARY AND CONCLUSION
Obesity weighs heavily in the hepatology clinics. Weight loss presents innumerable challenges, particularly in patients with chronic disease. Balancing the risks and benefits of interventions will require multidisciplinary team input. Close collaboration is necessary with dietitians, exercise specialists, endocrinology and bariatric specialists along with the primary care team to ensure each patient is equipped with needed coaching, support, and therapeutics to maximize their success at improving their liver disease and, importantly, their overall health and longevity. Ultimately, these goals should start in the hepatology clinic.
CONFLICTS OF INTEREST
Kymberly D. Watt owns stock in Johnson & Johnson, Madrigal, and Viking. She has other interests with Intercept. Sonali Paul received grants from W.L. Gore, Intercept, and TARGET. Mohammad Siddiqui consults and received grants from Novo Nordisk. He consults for Sagimet. He advises AMRA Medical. Michael Camilleri consults for Kallyope, with fee to his employer, Mayo Clinic. He owns stock in Phenomix. The remaining authors have no conflicts to report.
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