Introduction
Every year, the prevalence of nonalcoholic fatty liver disease (NAFLD) is on the rise, a chronic condition often linked to an unhealthy lifestyle characterized by sedentary behavior and consumption of highly processed, fatty, and low-fiber foods. Additionally, disruptions in the gut microbiome and certain medications can contribute to NAFLD. Notably, individuals with inflammatory bowel disease (IBD) are increasingly diagnosed with NAFLD, often alongside metabolic syndrome. Specific drugs, such as steroids commonly used in IBD treatment, pose a significant risk for inflammation, liver damage, and cirrhosis.
What Is Nonalcoholic Fatty Liver Disease (NAFLD)?
Nonalcoholic fatty liver disease (NAFLD) is a chronic condition characterized by lipid accumulation in liver cells without secondary causes or progressive fibrosis. Triacylglycerol (TG) plays a significant role in this fat buildup. Approximately 30 % of NAFLD patients may progress to nonalcoholic steatohepatitis (NASH), which can lead to organ fibrosis, hepatocellular carcinoma, and cirrhosis. NAFLD typically presents without symptoms and is often detected during routine biochemical tests. Moreover, NAFLD and NASH can heighten the risk of developing hepatocellular carcinoma and intrahepatic cholangiocarcinoma (iCCA).
NAFLD is increasingly prevalent in patients with IBD, a chronic condition marked by periods of flare-up remission. In Crohn’s disease, inflammation can affect any part of the gastrointestinal tract, with changes extending throughout the intestinal wall. In ulcerative colitis, inflammation is continuous and involves the mucosal lining of the colon or rectum.
How Does Steroid Use Increase the Risk of Nonalcoholic Fatty Liver Disease?
The use of corticosteroids, such as Corticosterone, Dexamethasone, Prednisolone, or Cortisone, is widespread across various medical conditions due to their anti-allergic and anti-inflammatory properties. They are employed in treating ailments like HELLP syndrome during pregnancy, dermatological issues, and pain relief during radiotherapy for bone metastases. Additionally, they play a role in managing musculoskeletal disorders, lupus, ulcerative colitis, and Crohn’s disease.
However, steroid therapy often brings about complications, including metabolic and endocrine disorders like obesity, type 2 diabetes, and hyperlipidemia. Furthermore, evidence suggests that corticosteroids can influence the development of NAFLD, inflammation, and the formation of benign liver tumors.
In IBD, the relationship between steroid use and the risk of NAFLD development is debated. While some studies indicate a potential link between early and prolonged steroid therapy and NAFLD onset in IBD patients, others do not confirm this association.
Patients with severe inflammatory bowel disease are at increased risk of developing NAFLD, which can negatively impact the progression of IBD. Various studies revealed that a significant percentage of IBD patients were diagnosed with NAFLD. These patients tended to be old, with high BMI, and had a higher prevalence of comorbidities like diabetes and hypertension. Notably, steroid use emerged as an independent factor contributing to NAFLD prevalence.
Steroids play a pivotal role in the development of NAFLD by directly impacting the liver and adipose tissue. They promote the conversion of preadipocytes and contribute to adipose tissue hyperplasia. Excessive intake of steroids may lead to steatosis and metabolic disorders like hyperinsulinemia, insulin resistance, and hyperglycemia.
However, prolonged exposure to steroid levels and antagonism of the glucocorticoid receptor (GR) can promote steatosis development. GC-GR signaling is crucial for maintaining blood glucose levels, and GCs can impair glucose uptake in skeletal muscle and adipose tissue, potentially leading to insulin resistance. Conversely, steroid treatment may mimic Cushing’s disease, characterized by elevated cortisol levels and insulin resistance, exacerbating metabolic syndrome.
Pathological alterations in GC signaling, such as NR3C1 mutations, may predispose individuals to metabolic disorders. GR polymorphisms may also contribute to GC resistance, disrupting GC signaling at various molecular stages. Additionally, GR located in the intestinal epithelium plays a role in maintaining normal colon homeostasis, and its deletion can alter intestinal barrier function and induce local inflammation, potentially leading to systemic inflammation.
GCs influence the liver's cell energy homeostasis and metabolic pathway, affecting fatty acid uptake, de novo lipogenesis, VLDL lipid export, and fatty acid beta-oxidation. They may contribute to triglyceride accumulation by reducing apolipoprotein B degradation and triacylglycerol hydrolase activity while inhibiting peroxisome proliferator-activated receptor-alpha (PPAR-alpha) transcriptional activity.
Depending on the fatty acid type and quantity, GCs can modulate dietary fatty acid absorption with prednisone and budesonide treatment. These effects on fatty acid uptake appear independent of early gene responses or genes encoding cytokines, proglucagon, and fatty-acid-binding protein (FABP).
What Is the Treatment of Nonalcoholic Fatty Liver?
Due to obesity being a primary cause of nonalcoholic fatty liver disease (NAFLD), managing patients with excess weight should prioritize adopting a healthier lifestyle. If lifestyle changes prove ineffective, pharmacological interventions for obesity may be considered, with bariatric surgery being an option for those who do not respond to prior treatments. A modest reduction in body weight, around three to five percent, has been shown to improve NAFLD parameters by reducing hepatic steatosis. In comparison, a more substantial reduction of seven to ten percent can also benefit nonalcoholic steatohepatitis (NASH). Dietary adjustments involving a reduction in caloric intake by 500 to 1,000 kcal per day and avoidance of foods exacerbating obesity and NAFLD, such as highly processed foods, sugary snacks, and saturated fats, are recommended. Physical activity should be tailored to individual preferences to facilitate long-term lifestyle changes, as it has been associated with improved fatty acid metabolism and insulin sensitivity.
Pharmacological Approaches:
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NAFLD treatment primarily targets insulin resistance, glycemia, and fat metabolism to reduce obesity. Glucagon-like peptide-1 analogs (GLP-1 RAs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), and inhibitors of dipeptidyl peptidase 4 (DPP-4i) have shown promising effects on NAFLD parameters. Additionally, potential future therapeutic options include ASK1 inhibitors, p38 MAPK inhibitors, and agonists of peroxisome proliferator-activated receptor-alpha.
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Bariatric surgery can induce weight loss, leading to improvements in NAFLD parameters and liver enzyme profiles, particularly in patients with morbid obesity. However, it's crucial to consider individual patient characteristics and preferences when determining the most suitable bariatric procedure.
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Probiotic therapy offers another avenue for NAFLD treatment by restoring a healthy gut microbiome and normalizing lipid metabolism. Various probiotic strains have been shown to reduce hepatic enzymes and improve lipid profiles in NAFLD patients, although further research is needed to elucidate their full therapeutic potential. Vitamin E supplementation is also suggested for its antioxidant and anti-inflammatory properties, which can mitigate oxidative stress and inflammation associated with NAFLD progression.
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Physical activity is significant in NAFLD management because it promotes weight loss, reduces adipose tissue, and enhances insulin sensitivity. Resistance training and moderate aerobic exercise have positively impacted abdominal obesity and liver enzyme levels, respectively, underscoring the importance of regular physical activity in NAFLD patients.
Conclusion
Steroid use poses a potential risk for the development and progression of NAFLD, especially in patients with IBD. While the exact mechanisms linking steroid therapy to NAFLD remain less understood, studies suggest that steroids may exacerbate metabolic and endocrine disorders, such as obesity, insulin resistance, and hyperlipidemia, which are known contributors to NAFLD. Clinicians should know and be cautious about steroid prescription, especially in patients with risk factors for metabolic syndrome, and consider regular monitoring for early detection and management of NAFLD in at-risk patients.
