Crosstalk between non-alcoholic fatty pancreas disease and metabolic dysfunction-associated steatotic liver disease: Immunometabolic interactions and clinical implications

Abstract

Non-alcoholic fatty pancreas disease (NAFPD) is a recognized but insufficiently studied clinical disease. The clinical and pathophysiological links between NAFPD and other metabolic diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD), are still largely unknown. Both conditions are considered to be manifestations of systemic metabolic syndrome, which indicates common developmental pathways. Although NAFPD and MASLD are closely related through common immunometabolic pathways, they also have differences that are reflected in clinical observations. A recent study by Heymann et al published in World Journal of Gastroenterology showed no direct correlation between the degree of pancreatic steatosis and the severity of steatohepatitis or liver fibrosis, indicating a need for further study of the complex immunometabolic interactions that mediate the relationship between these organs.

Key Words: Non-alcoholic fatty pancreas disease; Metabolic dysfunction-associated steatotic liver disease; Obesity; Steatosis; Fatty degeneration; Lipids; Triglycerides

Core Tip: Non-alcoholic fatty pancreas disease and metabolic dysfunction-associated steatotic liver disease are two distinct conditions caused by common metabolic disturbances, but with different pathogenesis. Despite their frequent co-occurrence, the degree of pancreatic steatosis may not directly correlate with the severity of liver fibrosis or inflammation, as demonstrated in recent studies. A key difference in their pathogenesis is linked to the structure and function of the cells in these organs. Understanding these differences is critical for developing organ-specific approaches to diagnosis and treatment.

This editorial refers to " Pancreatic steatosis is not associated with advanced steatohepatitis or fibrosis in metabolic dysfunction-associated steatotic liver disease" by Heymann et al, 2025; https://doi.org/10.3748/wjg.v31.i47.114651

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INTRODUCTION

Despite a considerable history of investigation, pancreatic steatosis remains less studied than non-alcoholic fatty liver disease (NAFLD), now classified under the updated terminology as metabolic dysfunction-associated steatotic liver disease (MASLD)[1-3]. Both NAFLD/MASLD and non-alcoholic fatty pancreas disease (NAFPD) are regarded as organ-specific manifestations of metabolic syndrome. However, the precise nature of their interrelationship is still being elucidated. On the one hand, their pathogenetic similarity is beyond doubt, as evidenced by the high frequency of co-occurrence of these diseases. On the other hand, data regarding the correlation in the severity of organ involvement are conflicting. For example, it has been shown that combined pancreatic steatosis and hepatic steatosis were detected in 67.9% of patients, while fatty pancreas with normal liver was detected in 29.9% of patients, and fatty liver without pancreatic steatosis was found in only four (2.2%) patients[4]. Another study involving postmortem analysis of 80 patients confirmed an association between NAFLD and pancreatic steatosis. In that study, the total fat content in the pancreas was a significant predictor of NAFLD, and the presence of intralobular fat in the pancreas was linked to non-alcoholic steatohepatitis (NASH)[5]. On the other hand, a recent study by Heymann et al[6] published in World Journal of Gastroenterology showed no direct correlation between the degree of pancreatic steatosis and the severity of steatohepatitis or liver fibrosis. This is consistent with the results of another recent study comparing pancreatic obesity with NAFLD, which found no significant correlation between liver biopsy results and the degree of pancreatic steatosis assessed by computed tomography (CT)[7]. Another study showed that in patients with NAFLD, increased fat content in the pancreas was associated with hepatic steatosis, but hepatic fibrosis was inversely proportional to fat content in the pancreas[8]. These findings indicate that parallels between the two diseases cannot be drawn automatically. A more profound, analytical approach to understanding their pathogenesis and clinical connections is required.

IMMUNOMETABOLIC INTERACTIONS AND CLINICAL IMPLICATIONS

Despite shared etiological factors, the pathogenesis of these diseases differs due to the unique cellular architecture, functions, and microenvironment of each organ. The pathogenesis of MASLD is well-established and has traditionally been described by the classical “two-hit” model, although a more comprehensive “multiple parallel hits” model is now widely accepted[9-11]. The first “hit” in the classical model is lipid accumulation or steatosis. Insulin resistance plays a central role in the development of steatosis[12]. Increased lipolysis in adipose tissue leads to excessive free fatty acids in the liver[13,14]. In hepatocytes, β-oxidation of free fatty acids is impaired and de novo lipogenesis, i.e., synthesis of fatty acids from carbohydrates, is increased. This leads to the accumulation of lipids in the form of triglycerides in lipid droplets in liver cells[15]. Simultaneously, the export of lipids in the form of very-low-density lipoproteins is impaired[16-18]. The imbalance between lipid influx, synthesis, utilization and export leads to lipid accumulation in hepatocytes[17]. The accumulation of lipids in the form of lipid droplets is thought to be an important contribution of the liver to the metabolic defense of other organs. In this case, the liver “takes on” the burden of lipid load, protecting other organs and tissues from the excess of toxic free fatty acids. Lipid accumulation is followed by a second “hit” that includes inflammation and disease progression into NASH[10]. Accumulated lipids, especially toxic species such as saturated fatty acids and ceramides, cause oxidative stress in mitochondria and peroxisomes[19,20]. This activates pro-inflammatory pathways, leading to the release of inflammatory cytokines and chemokines that recruit immune cells[21-25]. Further damage and apoptosis of hepatocytes stimulate the activation of hepatic stellate cells, which begin to actively synthesize extracellular matrix components, which promotes fibrosis and the disease can progress to cirrhosis and sometimes to hepatocellular carcinoma[26].

The pathogenesis of NAFPD is less studied, but it has been established that it is also based on insulin resistance. The peculiarities of damage to this organ are associated with its unique functions in metabolism, different from those of the liver. Under the action of excess free fatty acids and hypertriglyceridemia, triglycerides accumulate not only in adipocytes, but also in acinar cells, which, unlike hepatocytes, are not evolutionarily adapted for fat storage[27-31]. Fat infiltration manifests itself in two ways: Both intralobular and interlobular in the form of lipid inclusions in the cytoplasm of acinar and endocrine cells, as well as in adipocytes, which are formed in the process of replacing apoptotic cells. Adipocytes can also originate from the transdifferentiation of acinar cells themselves[27,29,32]. Lipid accumulation contributes to lipotoxicity. Toxic lipids disrupt intracellular signaling and mitochondrial function in acinar cells, which suppresses the synthesis and secretion of digestive enzymes (amylase, lipase, trypsin) and results in decreased exocrine function of the organ. Lipotoxicity also fosters local inflammation, as evidenced by experimental data showing that obese mice with pancreatic fat accumulation exhibit elevated levels of pro-inflammatory cytokines [interleukin-1β, tumor necrosis factor alpha (TNF-α)][28]. Furthermore, pancreatic stellate cells, the main source of fibrosis, become activated[33]. Notably, these same cells can also serve as a source of ectopic adipocytes, thereby worsening fat infiltration. However, the precise mechanisms and sequence of events linking lipotoxicity, inflammation, and the development of fibrosis in the pancreas remain largely unclear.

Pancreatic steatosis is recognized as an independent risk factor for the development of both acute pancreatitis and its complications and chronic pancreatitis[34,35]. Pancreatic steatosis triggers a series of metabolic stress processes at the molecular level, which pave the way for malignant transformation[36]. In addition, steatosis is considered an independent risk factor for pancreatic cancer[37-39], especially in obese and diabetic patients. In addition to exocrine dysfunction, endocrine dysfunction may be the most important consequence of NAFPD. Chronic inflammation and fibrosis can affect the islets of Langerhans, exacerbating insulin resistance and contributing to the development of diabetes mellitus by the mechanism of “pancreatogenic diabetes”[31,40]. Pancreatogenic diabetes is known as type 3c diabetes mellitus (although this name is not universally accepted) and is characterized by impaired insulin secretion due to damage to the β-cells of the islets of Langerhans, which occurs against a background of previous disease of the exocrine part of the pancreas[41,42]. Pancreatogenic diabetes is quite common and according to some data can occur in 5%-10% of patients[43,44]. The most frequent causes of type 3c diabetes are chronic pancreatitis (accounting for approximately 80% of cases), pancreatic ductal adenocarcinoma, hemochromatosis, cystic fibrosis, and previous pancreatic surgery[41,43]. It is important to note that there is no consensus on whether simple pancreatic steatosis contributes to the development of diabetes mellitus. On the one hand, patients with newly diagnosed type 2 diabetes have been found to have significantly higher degrees of hepatic steatosis[45]. On the other hand, it has been shown that fatty infiltration of the pancreas itself is not an independent predictor of incident type 2 diabetes[46]. Studies show that pancreatic steatosis impairs β-cell function only in people with a high genetic risk of developing diabetes[47]. A recent study of pancreatic tissue showed that the islets of Langerhans contain large amounts of fat deposits. Interestingly, neuroendocrine/islet cells most often showed diffuse fat accumulation (more than 75% of cells), while less than 25% of acinar cells contained lipid droplets[48]. The accumulation of lipid droplets in human islet cells increases with age and is particularly pronounced in type 2 diabetes mellitus[49].

Several mechanisms of β-cell damage in pancreatic steatosis have been proposed[50]. Direct lipotoxicity leads to impaired secretory granulogenesis and apoptosis of β-cells[27]. Unlike hepatocytes, β-cells do not have physiological mechanisms for the safe storage of excess lipids, which makes them particularly vulnerable. Animal studies have shown that a high-fat diet induces significant accumulation of triacylglycerides and infiltration of adipocytes into the exocrine tissue of the pancreas in mice, with the degree of lipid accumulation in the pancreas exceeding that in the liver. This pancreatic lipid accumulation is accompanied by a shift in fatty acid composition, characterized by a general depletion of saturated fatty acids and an enrichment of monounsaturated oleic acid (18:1n-9) in both triacylglycerols and phospholipids. These findings suggest that adipocyte infiltration of the pancreas and the associated alteration of the local fatty acid microenvironment may create conditions conducive to β-cell dysfunction in the islets of Langerhans via mechanisms of lipotoxicity[27]. Another mechanism involves indirect damage to β-cells through fibrosis and inflammation[51,52]. On the other hand, pancreatic steatosis, as previously noted, is heterogeneous and may not involve β-cell damage. In this regard, NAFPD may not be the cause, but rather a marker of severe systemic insulin resistance and visceral obesity, which themselves lead to β-cell depletion. Treatment of diabetes mellitus leads to a reduction in fat accumulation in the pancreas, and the higher the degree of remission of type 2 diabetes mellitus, the lower the amount of fat in the pancreas[53].

In summary, MASLD and NAFPD share a common etiology: Insulin resistance and systemic lipotoxicity. Obesity, dyslipidemia, and elevated circulating free fatty acids are universal risk factors that concurrently affect both the liver and the pancreas. However, the differences in their pathogenesis arise directly from the fundamental distinctions in these organs’ functions. Unlike hepatocytes, pancreatic cells are not evolutionarily adapted for fat storage. MASLD exacerbates insulin resistance, as the liver, affected by steatosis and inflammation, itself produces pro-inflammatory cytokines and contributes to increased systemic insulin resistance[54-56]. This, in turn, creates an adverse metabolic environment for the pancreas, potentially accelerating the development of NAFPD. Conversely, NAFPD can impair glucose tolerance, since pancreatic damage from inflammation and fibrosis may lead to islet of Langerhans injury, β-cell dysfunction, and ultimately, diabetes mellitus. Diabetes itself is a major risk factor for both the development of MASLD and its progression to cirrhosis. It is important to note that endocrine disorders in MASLD and NAFPD are not limited to insulin resistance and diabetes mellitus, but are also associated with thyroid dysfunction, which is also clinically significant[57-59]. Consequently, hepatic and pancreatic steatosis are not so much in a causal relationship with one another, but rather represent parallel consequences of a single underlying systemic metabolic defect[60].

Furthermore, in contrast to MASLD, the diagnosis of NAFPD is less standardized, and reliable non-invasive biomarkers to assess the degree of pancreatic steatosis, inflammation, and fibrosis are lacking. A key pathomorphological feature is the heterogeneous distribution of fat deposits within pancreatic tissue[61]. Notably, fat accumulation occurs more frequently in the head of the pancreas than in its body or tail[62]. Given this non-uniform pattern, fat infiltration in the pancreas is described using various terms, such as “pancreatic steatosis”, “fatty infiltration of the pancreas”, or “intra-pancreatic fat deposition”, “non-alcoholic fatty pancreas disease”, “fatty replacement of pancreas”, etc.[32]. This very terminological variability explains why the available clinical data in the literature are often contradictory.

In addition to terminological uncertainty, NAFPD diagnosis is also not standardized. Histological examination is difficult due to the technical complexity of the procedure. In this regard, imaging methods are of greatest importance, among which quantitative magnetic resonance imaging (MRI) methods, such as proton density fat fraction mapping and proton magnetic resonance spectroscopy (¹H-MRS), are considered the standard for non-invasive assessment of pancreatic steatosis[63-66]. However, its widespread use in routine practice is limited by its high cost and availability. CT, although widely available, is less accurate for assessing low degrees of steatosis and involves radiation exposure. Ultrasound is also used, but its diagnostic value is lower. The pancreas is located deep in the abdominal cavity, which makes it difficult to examine with ultrasound. In addition, pancreatic fibrosis also manifests as hyperechogenicity and cannot be differentiated by ultrasound[67]. It is important to note that the diagnostic criteria and thresholds for pancreatic steatosis are currently not standardized, and the choice of method depends on the clinical context: MRI studies suggest various thresholds, CT often uses the ratio of pancreatic and spleen density, and ultrasound uses a gradation based on echogenicity compared to the kidney and retroperitoneal tissue[68-73].

In addition to instrumental diagnostic methods, active research is underway to identify serum biomarkers for NAFPD. Indicators reflecting lipid metabolism disorders and inflammation in the pancreas appear promising. The role of high-density lipoproteins, fatty acid binding protein-1, as well as profiles of specific lipid mediators and microRNAs are being studied[74,75]. A recent study showed that reduced levels of circulating microRNAs miR-21-3p and miR-320a-5p are specific biological markers that negatively correlate with excessive fat accumulation in the pancreas regardless of ethnicity and may serve as a potential indicator of the risk of metabolic disorders associated with pancreatic steatosis[76]. Metabolomics studies have revealed a specific association between pancreatic steatosis and the bile acid conjugates taurodeoxycholate and sulfolithocholic acid[77,78]. Inflammatory markers such as TNF-α, cluster of differentiation 163, leptin, and lipocalin-2 show a direct and pancreas-specific association with pancreatic fat accumulation, indicating the role of immune inflammation in pathogenesis[79-81]. However, none of these candidates has yet been validated for clinical use. The development of a reliable, affordable biomarker or panel of biomarkers capable of differentiating simple steatosis from steatopancreatitis and fibrosis remains a critical unresolved challenge, paving the way for disease screening and monitoring.

Similar diagnosis, organ-specific treatment of NAFPD is currently under active investigation. Lifestyle modification is the cornerstone of treatment. Low-calorie diets and regular aerobic exercise are known to be effective in reducing visceral obesity and steatosis in both organs[82,83]. Pharmacotherapy of NAFPD is a complex and still unresolved task[84]. Of significant interest are new classes of drugs such as glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and, most notably, sodium-glucose cotransporter type 2 inhibitors[85-88]. Classic glucose-lowering drugs (metformin, sulfonylureas, thiazolidinediones) have conflicting or negative results[86]. In newly diagnosed diabetes, for example, metformin reduces fat accumulation in the liver but not in the pancreas[89]. Statins (atorvastatin, simvastatin) have demonstrated the ability to reduce fat accumulation in the pancreas and reduce endoplasmic stress in the pancreas in preclinical studies, but there are no known reliable clinical data on their use in NAFPD[90,91]. In addition, it is likely necessary to develop a standardized treatment regimen for patients with comorbid MASLD and NAFPD. When liver fibrosis is predominant, drugs with antifibrotic potential are relevant. When pancreatogenic diabetes develops, it is important to monitor exocrine function and provide enzyme replacement therapy.

CONCLUSION

It is important to note that although NAFPD is an actively studied disease, many aspects of it are still unknown to clinicians. The exact epidemiological data in different populations, including the prevalence of the disease among children and elderly patients, are unclear, as are the clinical links between NAFPD and other diseases and how other metabolic diseases affect the progression of NAFPD. Thus, NAFPD and NAFLD/MASLD are closely intertwined but pathogenetically and clinically distinct manifestations of systemic metabolic syndrome. Their comorbidity indicates particularly severe metabolic dysfunction and is associated with a worse clinical prognosis. The key tasks for the near future are to standardize the diagnosis of NAFPD (through the introduction of quantitative imaging methods and the search for specific biomarkers) and to develop comprehensive, individualized patient management strategies. These strategies should combine effective systemic interventions (lifestyle modification, therapy targeting lipid metabolism, correction of lipotoxicity and inflammation) with future organ-specific methods aimed at protecting the acinar and islet cells of the pancreas from lipotoxicity. Such an integrated approach will improve outcomes in this complex category of patients.