Mueataz A. MahyoubpersName, Mohamed ElhoumedpersName, Abdulfatah Hassan MaqulpersName, Maged AlmezgagipersName, Mustafa AbbaspersName, Yang JiaopersName, Jinhai WangpersName, Mohammed AlnaggarpersName, Ping ZhaopersName, Shuixiang HepersName (2023date). “Fatty infiltration of the pancreas: a systematic concept analysis.” Frontiers in Medicinetitle·j.
Object of study — fatty infiltration of the pancreasterm·dom
Research question — what is known of the nomenclature, causes, diagnosis, consequences and treatment of fatty infiltration of the pancreasterm·dom
Contribution — adopts the single term fatty infiltration of the pancreasterm·dom to make reporting consistent
phenomenon · claim-type · cross-domain-transfer · mechanism · claim-relation · replication-status · limitation — grounded in the full text| phenomenon | a common pancreatic fat disorder that is frequently overlooked — “FIP is a common yet frequently overlooked disorder that requires increased attention and investigation to comprehend its clinical significance.” | |
| claim-type | existence — “During the last decade, pancreatic fat infiltration has been established as a risk factor for various disorders, including type 2 diabetes mellitus (T2DM), pancreatitis, pancreatic fistula (PF), metabolic syndrome (MS), and pancreatic duct adenocarcinoma (PDAC) ( 1 ).” | |
| method — evidence | — “This review is presented in a detailed narrative format for accessibility to clinicians and medical students.” | |
| object of study — evidence | — “Fatty infiltration of the pancreas (FIP) has been recognized for nearly a century, yet many aspects of this condition remain unclear.” | |
| research question — evidence | — “This review article covers key aspects of FIP, including nomenclature and definition of pancreatic fat infiltration, history and epidemiology, etiology and pathophysiology, clinical presentation and diagnosis, clinical consequences, and treatment.” | |
| contribution — evidence | — “To address this issue, this review adopts the term “fatty infiltration of the pancreas” (FIP) to promote consistency in reporting and facilitate communication between healthcare professionals.” | |
| mechanism | tissue hypoxia Hypertension may cause lasting tissue hypoxia, leading to lipid accumulation and islet dysfunction. — “Consequently, HTN may contribute to persistent tissue hypoxia, leading to lipid accumulation and pancreatic islet dysfunction.” | mechanisms[0] |
| mechanism | chronic ischemia Chronic ischemia damages the pancreas and leads through chronic pancreatitis to FIP. — “Therefore, chronic ischemia caused pancreatic damage, limited cell necrosis, and the formation of a reaction zone, which led to chronic pancreatitis and, ultimately, FIP.” | mechanisms[1] |
| builds-on | Khoury et al. — “A research study by Khoury et al. developed a simplified scoring system to identify the presence of FIP.” | claim_relations[0] |
| sense | FIP - once reported as caused by T2DM, now found to be associated with its development — “Although old studies have reported T2DM as the cause of FIP ( 5 , 33 ), recent studies have found that FIP is associated with T2DM development ( 34 , 35 ).” | senses[0] |
| relation | Fatty infiltration of the pancreas —same-as→ FIP — Fatty infiltration of the pancreas (FIP) has been recognized for nearly a century, yet many aspects of this condition remain unclear. — “Fatty infiltration of the pancreas (FIP) has been recognized for nearly a century, yet many aspects of this condition remain unclear.” | concept_edges[0] |
| weight | Fatty infiltration of the pancreas —same-as→ FIP — 0.9 — “Fatty infiltration of the pancreas (FIP) has been recognized for nearly a century, yet many aspects of this condition remain unclear.” | concept_edges[0] |
| relation | peri-pancreatic fat —same-as→ extra-lobular fat — Notably, FIP excludes peri-pancreatic fat, also called extra-lobular fat ( 2 , 3 ). — “Notably, FIP excludes peri-pancreatic fat, also called extra-lobular fat ( 2 , 3 ).” | concept_edges[1] |
| weight | peri-pancreatic fat —same-as→ extra-lobular fat — 0.85 — “Notably, FIP excludes peri-pancreatic fat, also called extra-lobular fat ( 2 , 3 ).” | concept_edges[1] |
| relation | pancreatic steatosis —same-as→ fatty pancreas — The lack of clear differentiation between triglyceride accumulation in acinar cells, beta cells, or intra-pancreatic adipose cell infiltration has led to various synonyms, such as pancreatic steatosis, pancreatic lipomatosis, or fatty pancreas, to describe all forms of pancreatic fat accumulation outlined in Table 1 . — “The lack of clear differentiation between triglyceride accumulation in acinar cells, beta cells, or intra-pancreatic adipose cell infiltration has led to various synonyms, such as pancreatic steatosis, pancreatic lipomatosis, or fatty pancreas, to describe all forms of pancreatic fat accumulation outlined in Table 1 .” | concept_edges[2] |
| weight | pancreatic steatosis —same-as→ fatty pancreas — 0.7 — “The lack of clear differentiation between triglyceride accumulation in acinar cells, beta cells, or intra-pancreatic adipose cell infiltration has led to various synonyms, such as pancreatic steatosis, pancreatic lipomatosis, or fatty pancreas, to describe all forms of pancreatic fat accumulation outlined in Table 1 .” | concept_edges[2] |
| effect direction | Obesity —causes→ chronic low-grade inflammation — increases — “Obesity induces chronic low-grade inflammation, increasing pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α).” | concept_edges[3] |
| relation | Obesity —causes→ chronic low-grade inflammation — Obesity induces chronic low-grade inflammation, increasing pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). — “Obesity induces chronic low-grade inflammation, increasing pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α).” | concept_edges[3] |
| weight | Obesity —causes→ chronic low-grade inflammation — 0.7 — “Obesity induces chronic low-grade inflammation, increasing pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α).” | concept_edges[3] |
| effect direction | low-calorie diet —causes→ pancreatic fat content — reduces — “In humans, a study involving 11 individuals with T2DM revealed that a low-calorie diet significantly reduced pancreatic fat content (FIP) by creating a negative energy balance, implying its relevance to T2DM-associated pancreatic fat ( 41 ).” | concept_edges[4] |
| relation | low-calorie diet —causes→ pancreatic fat content — In humans, a study involving 11 individuals with T2DM revealed that a low-calorie diet significantly reduced pancreatic fat content (FIP) by creating a negative energy balance, implying its relevance to T2DM-associated pancreatic fat ( 41 ). — “In humans, a study involving 11 individuals with T2DM revealed that a low-calorie diet significantly reduced pancreatic fat content (FIP) by creating a negative energy balance, implying its relevance to T2DM-associated pancreatic fat ( 41 ).” | concept_edges[4] |
| weight | low-calorie diet —causes→ pancreatic fat content — 0.7 — “In humans, a study involving 11 individuals with T2DM revealed that a low-calorie diet significantly reduced pancreatic fat content (FIP) by creating a negative energy balance, implying its relevance to T2DM-associated pancreatic fat ( 41 ).” | concept_edges[4] |
| replication | not-applicable | |
| limitation | No reliable biomarker for FIP exists; diagnosis rests on histopathology and imaging. — “Currently, there is no reliable biomarker for diagnosing FIP, and histopathology and imaging remain the primary diagnostic methods.” | limitations[0] |
| limitation | How FIP promotes pancreatic fistula is unknown. — “The exact mechanism by which FIP promotes PF development is unknown.” | limitations[1] |
finding · quantity · variable · definition · key-term — grounded in the full text| finding | FIP carried a relative risk of 2.37 for metabolic syndrome. — “The presence of FIP was significantly correlated with a higher incidence of MS, with a relative risk of 2.37 (95% CI: 2.07–2.71; P < 0.001), indicating a 137% increased likelihood of developing metabolic syndrome in individuals with FIP ( 20 ).” | content_tags.findings[0] |
| finding | FIP was significantly associated with pancreatic fistula across 11 studies. — “A meta-analysis of 11 studies involving 2484 individuals found that FIP was significantly associated with the occurrence of the PF (OR = 3.75; 95% CI: 1.64, 8.58; P = 0.002; I 2 = 78).” | content_tags.findings[1] |
| quantity | 33% — — “A meta-analysis of 11 studies involving a total of 12,675 individuals reported an FIP prevalence of 33% (95% CI: 24%−41%) ( 20 ).” | content_tags.quantities[0] |
| quantity | 1.81 — — “FIP was independently associated with an increased hazard ratio of 1.81 for incident T2DM.” | content_tags.quantities[1] |
| key-terms | fatty infiltration of the pancreas, pancreatic steatosis, T2DM, NAFLD, metabolic syndrome, pancreatic fistula, PDAC, lipotoxicity, obesity, MRI |
| concept | FIP — the presence of one or more of the following features: (1) inter-lobular fat, which is the presence of cells containing fat between pancreatic lobules; (2) lipid droplets within pancreatic acinar cells or islets; (3) pancreatic acinar-to-adipocyte trans-differentiation; and (4) fat replacement of dead pancreatic acinar cells — “FIP is defined by the presence of one or more of the following features: (1) inter-lobular fat, which is the presence of cells containing fat between pancreatic lobules; (2) lipid droplets within pancreatic acinar cells or islets; (3) pancreatic acinar-to-adipocyte trans-differentiation; and (4) fat replacement of dead pancreatic acinar cells.” | concepts[0] |
| concept | Fatty infiltration of the pancreas — not defined in this paper's own words; the build-up of fat within the pancreas — “Fatty infiltration of the pancreas (FIP) has been recognized for nearly a century, yet many aspects of this condition remain unclear.” | concepts[1] |
| concept | inter-lobular fat — the presence of cells containing fat between pancreatic lobules — “FIP is defined by the presence of one or more of the following features: (1) inter-lobular fat, which is the presence of cells containing fat between pancreatic lobules; (2) lipid droplets within pancreatic acinar cells or islets; (3) pancreatic acinar-to-adipocyte trans-differentiation; and (4) fat replacement of dead pancreatic acinar cells.” | concepts[2] |
| concept | peri-pancreatic fat — not defined in this paper's own words; fat lying around rather than within the pancreas — “Notably, FIP excludes peri-pancreatic fat, also called extra-lobular fat ( 2 , 3 ).” | concepts[3] |
| concept | extra-lobular fat — not defined in this paper's own words; another name the paper gives for peri-pancreatic fat — “Notably, FIP excludes peri-pancreatic fat, also called extra-lobular fat ( 2 , 3 ).” | concepts[4] |
| concept | pancreatic steatosis — not defined in this paper's own words; one name in use for fat accumulation in the pancreas — “The lack of clear differentiation between triglyceride accumulation in acinar cells, beta cells, or intra-pancreatic adipose cell infiltration has led to various synonyms, such as pancreatic steatosis, pancreatic lipomatosis, or fatty pancreas, to describe all forms of pancreatic fat accumulation outlined in Table 1 .” | concepts[5] |
| concept | fatty pancreas — not defined in this paper's own words; another name in use for fat accumulation in the pancreas — “The lack of clear differentiation between triglyceride accumulation in acinar cells, beta cells, or intra-pancreatic adipose cell infiltration has led to various synonyms, such as pancreatic steatosis, pancreatic lipomatosis, or fatty pancreas, to describe all forms of pancreatic fat accumulation outlined in Table 1 .” | concepts[6] |
| concept | lipotoxicity — characterized by adverse implications for cellular functionality and metabolic processes — “The build-up of ectopic fat has the potential to give rise to a phenomenon termed lipotoxicity, characterized by adverse implications for cellular functionality and metabolic processes.” | concepts[7] |
| concept | NAFLD — a condition with excessive fat build-up in hepatocytes — “NAFLD is a condition with excessive fat build-up in hepatocytes and is prevalent in approximately 30% of the general population.” | concepts[8] |
| concept | Hemochromatosis — a genetic disorder that causes systemic iron overload due to reduced hepcidin or hepcidin-ferroprotein binding levels, leading to iron accumulation in parenchymal cells in the liver, pancreas, and heart — “Hemochromatosis is a genetic disorder that causes systemic iron overload due to reduced hepcidin or hepcidin-ferroprotein binding levels, leading to iron accumulation in parenchymal cells in the liver, pancreas, and heart ( 47 ).” | concepts[9] |
| concept | Obesity — not defined in this paper's own words; excess body fat — “Obesity induces chronic low-grade inflammation, increasing pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α).” | concepts[10] |
| concept | chronic low-grade inflammation — not defined in this paper's own words; persistent mild inflammatory activity — “Obesity induces chronic low-grade inflammation, increasing pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α).” | concepts[11] |
| concept | low-calorie diet — not defined in this paper's own words; a diet giving less energy than the body uses — “In humans, a study involving 11 individuals with T2DM revealed that a low-calorie diet significantly reduced pancreatic fat content (FIP) by creating a negative energy balance, implying its relevance to T2DM-associated pancreatic fat ( 41 ).” | concepts[12] |
| concept | pancreatic fat content — not defined in this paper's own words; the amount of fat in the pancreas — “In humans, a study involving 11 individuals with T2DM revealed that a low-calorie diet significantly reduced pancreatic fat content (FIP) by creating a negative energy balance, implying its relevance to T2DM-associated pancreatic fat ( 41 ).” | concepts[13] |
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Fatty infiltration of the pancreasterm·dom: a systematic concept analysis Abstract Fatty infiltration of the pancreasterm·dom (FIPterm·dom) has been recognized for nearly a century, yet many aspects of this condition remain unclear. Regular literature reviewsterm·mth on the diagnosis, consequences, and management of FIPterm·dom are crucial. This reviewterm·mth article highlights the various disorders for which FIPterm·dom has been established as a risk factor, including type 2 diabetes mellitus (T2DMterm·key), pancreatitis, pancreatic fistulaterm·key (PF), metabolic syndrometerm·key (MS), polycystic ovary syndrome (PCOS), and pancreatic duct adenocarcinoma (PDACterm·key), as well as the new investigation tools. Given the interdisciplinary nature of FIPterm·dom research, a broad range of healthcare specialists are involved. This reviewterm·mth article covers key aspects of FIPterm·dom, including nomenclature and definition of pancreatic fat infiltration, history and epidemiology, etiology and pathophysiology, clinical presentation and diagnosis, clinical consequences, and treatment. This reviewterm·mth is presented in a detailed narrative format for accessibility to clinicians and medical students.
1. Introduction Pancreatic fat infiltration was first reported in the scientific literature almost a century ago; however, despite the extensive research on FIPterm·dom, much about this condition remains unknown. It is, therefore, imperative to regularly reviewterm·mth the literature on pancreatic fat infiltration, with a particular emphasis on the diagnosis, consequences, and management of the disease.
During the last decade, pancreatic fat infiltration has been established as a risk factor for various disorders, including type 2 diabetes mellitus (T2DMterm·key), pancreatitis, pancreatic fistulaterm·key (PF), metabolic syndrometerm·key (MS), and pancreatic duct adenocarcinoma (PDACterm·key) ( 1 ).
In addition, the lack of consensus on the terminology used to describe this condition has led to confusion and inconsistent reporting of research findings. To address this issue, this reviewterm·mth adopts the term “fatty infiltration of the pancreasterm·dom” (FIPterm·dom) to promote consistency in reporting and facilitate communication between healthcare professionals. Given the interdisciplinary nature of FIPterm·dom research, this reviewterm·mth encompasses a broad range of healthcare specialists, including gastroenterologists, endocrinologists, radiologists, general practitioners, and others.
This reviewterm·mth focuses on key aspects of FIPterm·dom, such as history and epidemiology, etiology, pathophysiology, clinical presentation and diagnosis, clinical consequences, and treatment, aiming to accelerate research progress and translate findings into routine clinical practice. To ensure accessibility for clinicians and medical students, the information is presented in a detailed narrative format.
2. Nomenclature and definition of pancreatic fat infiltration Pancreatic fat is commonly present in humans, with an average weight of 9.7 ± 6.5 g, constituting about 3% of the pancreas' weight in thin individuals. Normal pancreatic fat makes up ~5.5% of the pancreas' weight, primarily consisting of triglycerides (47%), free fatty acids (10%), and total cholesterol (4%). Oleic and palmitic acids are the main triglyceride components, while palmitic and stearic acids are the major free fatty acids ( 2 ).
FIPterm·dom is defined by the presence of one or more of the following features: (1) inter-lobular fatterm·dom, which is the presence of cells containing fat between pancreatic lobules; (2) lipid droplets within pancreatic acinar cells or islets; (3) pancreatic acinar-to-adipocyte trans-differentiation; and (4) fat replacement of dead pancreatic acinar cells. Notably, FIPterm·dom excludes peri-pancreatic fatterm·dom, also called extra-lobular fatterm·dom ( 2 , 3 ).
The lack of clear differentiation between triglyceride accumulation in acinar cells, beta cells, or intra-pancreatic adipose cell infiltration has led to various synonyms, such as pancreatic steatosisterm·dom, pancreatic lipomatosis, or fatty pancreasterm·dom, to describe all forms of pancreatic fat accumulation outlined in Table 1 .
Nomenclature and definition of pancreatic fat infiltration ( 2 , 3 ).
3. History and epidemiology FIPterm·dom was first described by Oligvie in 1933, who noted that the presence of pancreatic fat was higher in obese individuals (17%) than in those who were thin (9%) ( 6 ). In 1926, a biometric analysis was conducted to measure the average pancreatic weight in mature human individuals. It was found that FIPterm·dom is more prevalent in overweight individuals than in those of normal weight. In adults, the average weight of the pancreas is positively correlated with normal body weight in both males and females, with a stronger correlation observed in females ( 18 ). In 1978, a significant description of FIPterm·dom was completed when 394 cadavers were studied, and it was observed that the proportion of pancreatic fat tends to increase with age ( 19 ).
The epidemiology of FIPterm·dom in the general population needs to be better established. FIPterm·dom prevalence varies significantly based on the ethnicity of the population and the diagnostic criteria used (see Table 2 ). A meta-analysis of 11 studies involving a total of 12,675 individuals reported an FIPterm·dom prevalence of 33% (95% CI: 24%−41%) ( 20 ).
Prevalence of FIPterm·dom by different methodologies in different countries and ethnic groups.
4. Etiology and pathophysiology of FIPterm·dom There are various etiologies associated with FIPterm·dom ( Figure 1 ), which can be broadly classified into 11 categories: Suggested underlying mechanisms of fatty infiltration of the pancreasterm·dom (FIPterm·dom) and its role in type 2 diabetes mellitus (T2DMterm·key) and pancreatic cancer (PD) development. (1) Suggested underlying mechanisms of FIPterm·dom. Insulin resistance reduces cellular responsiveness to insulin, leading to impaired glucose uptake, particularly in muscle and adipose tissue. Various factors contribute to its development, including genetic predisposition, obesityterm, a sedentary lifestyle, and dietary habits. In individuals with insulin resistance in muscle, glucose uptake by muscle cells is diminished, causing a significant portion of dietary carbohydrates to be redirected toward the liver ( 21 ). Excess glucose in the liver undergoes de novo lipogenesis (DNL) to be converted into fatty acids and then triglycerides, contributing to hepatic fat build-up. Additionally, when dietary carbohydrate intake exceeds immediate energy demands, surplus glucose is converted into fatty acids through hepatic DNL, further promoting hepatic lipid deposition. Over time, the progressive build-up of fat in the liver may lead to fatty liver disease. In fatty liver disease, the liver's production of triglycerides is elevated, leading to an increase in plasma very-low-density lipoprotein (VLDL) triglycerides. If subcutaneous adipose tissue cannot adequately store the excess triglycerides, excess ectopic fat accumulates in various tissues, including the pancreas ( 22 ). Notably, pancreatic fat build-up occurs through one or more of the following patterns: (1) inter-lobular fatterm·dom, characterized by the existence of adipose-laden cells positioned amidst pancreatic lobules; (2) lipid droplets residing within pancreatic acinar cells or islets; (3) pancreatic acinar-to-adipocyte trans-differentiation, denoting the intricate process of acinar cell conversion into adipocytes; and (4) adipose replacement of deceased pancreatic acinar cells. Obesityterm induces chronic low-grade inflammationterm·dom, increasing pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). This inflammation leads to higher levels of triglycerides, free fatty acids, cholesterol, and total fat accumulation in the pancreas. Additionally, obesityterm disrupts the balance of cytokines by reducing the production of the spleen's anti-inflammatory cytokine interleukin-10 (IL-10) ( 23 ). These imbalances contribute to FIPterm·dom, PDO, and pancreatic duct obstruction. (2) Suggested underlying mechanisms of FIPterm·dom in T2DMterm·key. The build-up of ectopic fat has the potential to give rise to a phenomenon termed lipotoxicityterm, characterized by adverse implications for cellular functionality and metabolic processes. Specifically, within the pancreatic milieu, the manifestation of lipotoxicityterm assumes a pivotal role in inducing impediments to both insulin secretion and overall cellular performance. Notably, lipotoxicityterm's ramifications extend to the emergence of insulin resistance upon ectopic fat accrual within the pancreatic tissue, thereby fostering a pro-inflammatory milieu in these domains. The confluence of lipotoxicityterm, insulin resistance, and localized inflammatory responses collectively perturbs the intricate glucose metabolism homeostasis, thereby initiating disruptions conducive to the genesis of glucose metabolic irregularities. These perturbations, in essence, denote anomalies in regulating blood glucose levels. As temporal progression ensues, these perturbations can evolve into the etiopathological basis of T2DMterm·key. Furthermore, the build-up of fat within pancreatic endocrine cells also emerges as a relevant factor potentially contributing to the failure of beta cells and, consequently, assuming a pronounced role in the pathogenesis of T2DMterm·key ( 2 ). (3) Suggested the underlying mechanisms of FIPterm·dom in pancreatic cancer (PC) development. FIPterm·dom plays a pivotal role in promoting PC development. This process involves the secretion of adipokines, including adiponectin and leptin, which drive carcinogenesis through various mechanisms. Increased fat content reduces adiponectin levels and increases leptin levels, contributing to a higher risk of aggressive PC. Adiponectin typically promotes apoptosis and inhibits the availability of growth factors, while leptin activates JAK2 and causes phosphorylation of STAT3, leading to increased transcriptional upregulation of genes involved in angiogenesis, inflammation, anti-apoptosis, repression of interferon-inducible genes, and cell migration and invasion. FIPterm·dom also leads to the release of pro-inflammatory chemokines and cytokines, fostering a chronically inflamed tumor microenvironment. This environment further supports the progression of PC by influencing cell transition, inflammation, and fibrosis development. Pro-inflammatory signaling, particularly involving cytokines like IL-6, produced by cancer-associated fibroblasts and PC cells, encourages tumor cell invasion and migration. In addition to adipokine secretion, FIPterm·dom contributes to the dysregulation of cytokines in the tumor microenvironment. The presence of anti-inflammatory cytokines like IL-10 might be an immune response to combat cancer, while pro-inflammatory cytokines and chemokines fuel inflammation and cell transition. The nutrient-deprived tumor microenvironment resulting from FIPterm·dom can lead to dysfunction in regulatory immune cells that would otherwise promote the apoptosis of developing PC cells. This impaired apoptosis may create a cycle where surviving intra-pancreatic CD8 + T cells downregulate key enzymes, ultimately aggravating the accumulation of harmful long-chain fatty acids, which can lead to lipotoxicityterm. The build-up of lipophilic toxins in pancreatic adipose tissue further exacerbates this process, potentially driving PC development ( 24 ).
4.1. Demographic determinants The prevalence of FIPterm·dom exhibits an age-dependent pattern, with higher rates observed among the middle-aged and elderly populations, as reported in previous studies ( 19 , 25 , 26 ). Notably, the onset of the fifth decade appears to be a critical time point when an increase in pancreatic fat fraction is commonly observed ( 27 ). Furthermore, it has been demonstrated that middle-aged men are at a higher risk of developing FIPterm·dom than their younger counterparts ( 8 ). FIPterm·dom also increases in middle-aged and elderly women compared to young women, and the risk ratio was 6.60 (95% CI: 0.92–47.49) and 19.11 (95% CI: 2.57–142.28), respectively. Post-climacteric women have a higher risk of FIPterm·dom than pre-climacteric women ( 28 ). The cause of age-related pancreatic fat build-up is unclear, but atherosclerosis and reduced blood flow may contribute ( 29 ). FIPterm·dom is more prevalent in individuals of East/Southeast/South Asian heritage, less common in Black African individuals, and intermediate in European or Latin American individuals ( 30 ).
4.2. Obesityterm and metabolic factors Adipose tissue is an endocrine organ that communicates with other organs in the body and contains adipocytes and other tissue cells. When body weight increases, adipose tissue storage capacity is exceeded, leading to a relocation of fat in non-adipose organs, such as the liver, skeletal muscle, and pancreas ( 21 ). In obesityterm, a hormonal microenvironment disorder causes an increase in macrophage infiltration into fat tissue. This leads to a chronic low-inflammatory state characterized by pro-inflammatory cytokine release and fat accumulation in distal organ tissues ( 23 , 31 ). In animal studies, obese mice with leptin insufficiency had a higher pancreas weight. They exhibited greater intra-lobular and total pancreatic fat contentterm and elevated levels of pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β).
Additionally, pancreatic tissue triglyceride composition was significantly higher in the progeny of obese dams than in the progeny of thin dams, indicating that exposure to an obesogenic environment shortly after birth can lead to FIPterm·dom. The study revealed a previously unknown fatty pancreatic phenotype associated with obesityterm, which suggests that maternal obesityterm can program a pancreatic phenotype similar to non-alcoholic fatty liver disease (NAFLDterm·dom) ( 32 ). Obesityterm and insulin resistance play essential roles in pancreatic adipocyte infiltration, which can lead to FIPterm·dom ( 22 ). Although old studies have reported T2DMterm·key as the cause of FIPterm·dom ( 5 , 33 ), recent studies have found that FIPterm·dom is associated with T2DMterm·key development ( 34 , 35 ). FIPterm·dom can often be cured by reducing weight ( 36 ).
4.3. Diet Diet may play a pivotal role in initiating FIPterm·dom in experimental animal models. In a rat model, prolonged exposure to a high-fat diet resulted in adipose tissue build-up within pancreatic acinar cells, triggering a cascade culminating in tissue fibrosis and injury ( 37 ). Similar observations were made in mice fed a high-fat diet, which displayed FIPterm·dom characteristics and MS markers, including insulin resistance ( 38 ). The impact of high-fat diets on pancreatic physiology appears to involve intricate interactions between saturated and unsaturated fatty acids along with overall fat content. This suggests that dietary fats' specific composition and quantity influence pancreatic impairment ( 39 ). Oleic acid, an unsaturated fatty acid, emerged as a determinant influencing individual variations in pancreatic triglyceride accumulation, underscoring the significance of dietary fat composition ( 40 ).
In humans, a study involving 11 individuals with T2DMterm·key revealed that a low-calorie dietterm significantly reduced pancreatic fat contentterm (FIPterm·dom) by creating a negative energy balance, implying its relevance to T2DM-associated pancreatic fat ( 41 ). A trial comparing Mediterranean (rich in unsaturated fats) and low-fat diets among individuals with abdominal obesityterm or dyslipidemia, including T2DMterm·key cases, reported significantly lower FIPterm·dom prevalence with the Mediterranean diet ( 42 ). These findings underscore the potential of diet to influence pancreatic fat contentterm and metabolic health, particularly in individuals with T2DMterm·key.
A prospective study involved three distinct cohorts, totaling 120,877 US women and men, all of whom were initially free from chronic illnesses and not obese. The follow-up periods extended from 1986 to 2006, 1991 to 2003, and 1986 to 2006. In each successive 4-year interval, participants exhibited an average weight gain of 3.35 lbs, ranging from the 5th to the 95th percentile (−4.1 to 12.4 lbs). When examining augmented daily servings of individual dietary constituents, the alteration in weight over 4 years was most notably linked to the consumption of potato chips (1.69 lb), potatoes (1.28 lb), sugar-sweetened beverages (1.00 lb), unprocessed red meats (0.95 lb), and processed meats (0.93 lb). Considering obesityterm's established association with a significant risk for FIPterm·dom, it is plausible that meat consumption may contribute to the development of FIPterm·dom ( 43 ).
4.4. Non-alcoholic fatty liver disease NAFLDterm·dom is a condition with excessive fat build-up in hepatocytes and is prevalent in approximately 30% of the general population. FIPterm·dom has been increasingly recognized as a condition that can occur with NAFLDterm·dom. A study that included post-mortem material from 80 patients found that total pancreatic fat is a major determinant of the presence of NAFLDterm·dom. Specifically, intra-lobular pancreatic adipose build-up was associated with non-alcoholic steatohepatitis (NASH), as reported in a prior investigation ( 22 ). Furthermore, a study that employed transabdominal ultrasonography (TUS) to assess the relationship between NASH and FIPterm·dom found that over 50% of individuals with NASH exhibited concurrent FIPterm·dom. FIPterm·dom was observed at various stages in 51.2% of NASH patients and 14% of normal individuals ( 44 ). In another prospective study, it was observed that nearly 80% of NASH patients also developed FIPterm·dom. Hepatic steatosis, in particular, was significantly associated with FIPterm·dom ( 45 ).
Moreover, a retrospective study used proton density fat fraction (PDFF) and MRIterm·key to evaluate the extent of pancreatic fat in individuals with NAFLDterm·dom confirmed by biopsy. The average MRI-PDFFs for the liver and pancreas were 18.7% and 5.7%, respectively. T2DMterm·key patients had a significantly higher association (12.2% vs. 4.8%) than non-T2DM patients ( 46 ).
A systematic reviewterm·mth and meta-analysis found that FIPterm·dom was associated with a more than 2.5-fold higher co-prevalence of NAFLDterm·dom and a substantial positive correlation between pancreatic and liver fat content in an uncorrected analysis of healthy individuals ( 13 ).
4.5. Hemochromatosisterm·dom Hemochromatosisterm·dom is a genetic disorder that causes systemic iron overload due to reduced hepcidin or hepcidin-ferroprotein binding levels, leading to iron accumulation in parenchymal cells in the liver, pancreas, and heart ( 47 ). In the pancreas, this can cause function dysregulation, fibrosis, and tissue replacement with fat ( 48 ). Studies have shown a correlation between hemochromatosisterm·dom and fat accumulation in the pancreas, which may contribute to the development of FIPterm·dom ( 49 – 51 ).
4.6. Virus FIPterm·dom has been associated with hepatitis B, reovirus, and HIV. An autopsy report revealed that a 52-year-old Japanese woman with cirrhosis caused by chronic hepatitis B also had FIPterm·dom, indicating a possible correlation between chronic hepatitis B or extensive hepatic lesions and FIPterm·dom ( 52 ). An animal study found that after the third week of reovirus infection, there was a fatty replacement of some necrotic tissue in the pancreas, suggesting a potential relationship between reovirus and FIPterm·dom ( 34 ). HIV has also been linked to FIPterm·dom, which can directly harm the pancreas ( 34 , 52 ).
4.7. Alcohol consumption Studies suggest that long-term alcohol intake can contribute to the development of FIPterm·dom. An animal study found that alcohol consumption in the long term promotes pancreatic cholesteryl ester build-up and induces FIPterm·dom ( 53 ). Furthermore, a human histopathological examination has observed fat storage in pancreatic acinar cells in patients who consume more than 30 g/day of ethanol ( 54 ). Another study reported that alcohol consumption of more than 14 g/week can lead to FIPterm·dom ( 34 , 48 ).
4.8. Drug use Abnormal lipid metabolism induced by Cushing syndrome or steroid therapy has been identified as a contributing factor to the development of FIPterm·dom. A case report study demonstrated a significant association between the administration of cortisone or its analogs and the occurrence of FIPterm·dom in affected patients ( 48 ). FIPterm·dom is frequently observed in individuals with HIV-1 undergoing antiretroviral therapy ( 55 ).
During the HAART era, FIPterm·dom has become a prevalent clinical consequence. Reports have indicated that changes in body composition occur with the introduction of HIV protease inhibitors (HAARTs). These changes involve a seemingly increased redistribution of fat, including a relative increase in abdominal fat with peripheral lipoatrophy. These changes caused peripheral lipoatrophy and increased circulating lipids, leading to excess fatty acids deposited in pancreatic cells ( 56 ).
According to an animal study, Rosiglitazone leads to FIPterm·dom by increasing pancreatic bulk, fat entrapment, acinar degeneration, and the invasion of inflammatory cells ( 57 ). A clinical case report study of an individual with pancreatic head malignancy found total fat substitution of the pancreas following a chemoradiotherapy regimen that included Gemcitabine and radiotherapy after excluding the fatty replacement in the pancreatic bed before the therapy; hence, Gemcitabine may cause FIPterm·dom ( 58 ).
4.9. Pancreatic duct obstruction PDO has been investigated concerning FIPterm·dom. Post-mortem and case report studies have reported an association between PDO due to intraductal calculus or pancreatic cancer and the development of FIPterm·dom ( 33 , 59 , 60 ). However, an animal study showed that simple closure of the pancreatic duct only resulted in fibrosis and not FIPterm·dom due to insufficient inflammatory cell infiltration. These findings were reversed with pancreatic juice drainage, indicating that more arterial occlusion was necessary to induce FIPterm·dom ( 61 ). Therefore, chronic ischemia caused pancreatic damage, limited cell necrosis, and the formation of a reaction zone, which led to chronic pancreatitis and, ultimately, FIPterm·dom.
4.10. Genetic predisposition Several genetic abnormalities have been identified as causing FIPterm·dom, among other conditions. FIPterm·dom is a late-stage pancreatic disease observed in individuals with cystic fibrosis, and it is primarily caused by a deficiency or malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in the pancreatic duct epithelium (PDE) ( 62 ). The CFTR protein functions as a chloride and bicarbonate channel on the apical surface of epithelial cells, including those in the pancreas. CFTR malfunction leads to reduced bicarbonate secretion from the PDE, causing an acidic small intestine environment, thickened mucus production, and PDO, ultimately resulting in FIPterm·dom ( 63 ).
In Western countries, Schwachman-Diamond syndrome (SDS) ranks second in prevalence among exocrine pancreatic genetic disorders, following cystic fibrosis. The disorder is commonly associated with exocrine pancreatic dysfunction, which can lead to the development of FIPterm·dom ( 64 , 65 ).
Johanson-Blizzard syndrome is an uncommon genetic disorder associated with exocrine pancreatic insufficiency (EPI) ( 66 ). This disorder is distinguished by congenital EPI, which stems from histological variances in the pancreatic buds during embryonic development and can lead to uneven fatty infiltration ( 67 , 68 ). Radiological examination of the pancreas in non-diabetic children with carboxyl-ester lipase (CEL) gene mutations revealed structural changes indicating fat build-up. It confirmed previous research on EPI in CEL-mediated disease in all mutant carriers over 5 years old ( 69 ).
A recent study on twins found that the impact of hereditary factors on FIPterm·dom detected by CT was limited. Upon controlling for various factors, the statistical significance of the association with FIPterm·dom was exclusively detected in monozygotic twins but not in dizygotic twins ( 70 ).
4.11. Severe malnutrition The severe malnutrition condition of kwashiorkor may play a role in the development of FIPterm·dom, according to a case report study of an 11-year-old boy who presented with clinical and pathological features of kwashiorkor for over 2 years and was diagnosed with FIPterm·dom ( 34 ). Therefore, kwashiorkor may contribute to the development of FIPterm·dom.
5. Diagnosis of FIPterm·dom Many patients with FIPterm·dom may not display any noticeable symptoms, and diagnosis often relies on conducting investigative tests, which are summarized in Table 3 . Two types of investigative tests for FIPterm·dom are available: invasive and non-invasive.
Summary of diagnostic tests of FIPterm·dom ( 71 , 72 ).
5.1. Invasive test 5.1.1. Histopathology Histopathology is the gold standard for diagnosing FIPterm·dom ( 77 ). FIPterm·dom is characterized by adipocyte infiltration and intracellular fat deposition in acinar and islet cells ( Figure 2 ). Collecting a pancreatic biopsy after surgery has limited indications and cannot be widely adopted due to the low frequency of pancreatic surgery among those at risk for FIPterm·dom. Endoscopic ultrasonography fine needle aspiration (EUS-FNA) biopsy can also be used. Nonetheless, it carries a significant risk of complications and is only considered ethical when differentiating between malignant and benign localized pancreatic tumors ( 2 ). The build-up of fat in the pancreas can be either homogeneous or heterogeneous. Heterogeneous FIPterm·dom is classified into Category 1A (35%), which involves the head, not the uncinate process or the peribiliary area. Category 1B (35%) involves the head, neck, and body but spares the uncinate and peribiliary areas. Category 2A (12%) involves the head and uncinate process but spares the peribiliary area. Finally, Category 2B (18%) involves the entire pancreas replacement but spares the peribiliary area ( 77 ).
(A) The histopathology of FIPterm·dom. (B) The histopathology of a normal pancreas. Courtesy of Prof. Vasquez E. and Dr. Angelico G., Anatomical Pathological Department, University of Catania, Catania, Italy ( 78 ).
5.2. Non-invasive tests 5.2.1. Biomarker Currently, there is no reliable biomarker for diagnosing FIPterm·dom, and histopathology and imaging remain the primary diagnostic methods. However, a meta-analysis study suggests a modest positive correlation between FIPterm·dom and triglycerides (TG) and a modest negative correlation between FIPterm·dom and high-density lipoprotein cholesterol (HDL-C) among lipid metabolism markers. Additionally, several glucose metabolic biomarkers have shown a significant link to FIPterm·dom, including glycated hemoglobin (HbA1c), fast insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and fast glucose. HbA1c may be a useful marker for FIPterm·dom diagnosis as it is stable, not affected by changes in activity or exercise, and does not require fasting before testing. The pathophysiology of FIPterm·dom is likely influenced by underlying inflammation. Inflammatory markers, such as high-sensitivity C-reactive protein (CRP) and plasminogen activator inhibitor-1 (PAI1), have minor connections with the contents of pancreatic fat. The liver produces CRP, an acute-phase protein, in response to the pro-inflammatory cytokine IL6. While CRP is a well-known inflammation index, it is not a valid and precise biomarker for FIPterm·dom. CRP affects plasminogen activator inhibitor 1, a protein that helps coordinate fibrinolysis ( 20 ).
5.2.2. Ultrasonography Two ultrasound modalities, TUS and EUS, can detect FIPterm·dom, each with advantages and disadvantages. TUS is quick, cheap, and safe ( 79 ), but it is insensitive to mild to moderate FIPterm·dom and may not always visualize the pancreas, especially in obese patients ( 80 ). EUS offers detailed imaging of the pancreas and the ability to collect FNA/B, but it is a riskier procedure than TUS. However, both modalities are operator-dependent, and comparing pancreatic echogenicity to hepatic or nephrotic echogenicity is subjective ( 81 ).
In TUS, a hyperechogenic pancreas is a diagnostic sign of FIPterm·dom ( Figure 3 ), but fibrosis or fibro-lipomatosis can also cause a similar sign ( 82 ). Various methods have been used to identify FIPterm·dom in TUS, including comparing the pancreas' echogenicity to other organs such as the liver, renal parenchyma, spleen, and retroperitoneal adipose tissue ( 45 ).
FIPterm·dom on TUS. The pancreas has increased echogenicity compared to the spleen and kidney ( 80 ). P, pancreas; S, spleen; K,kidney.
Researchers have used the spleen as a comparison organ in EUS to quantify the degree of FIPterm·dom. They used the ImageJ software to estimate the midpoint value of pancreatic brightness at the adipose surrounding the liver on both the transverse and longitudinal scans. This stratum of adipose tissue is located between an anterior abdominal muscle stratum and an anterior liver surface, and the results are used to calculate the pancreas–liver index ( 83 ).
Another study adapted the previous TUS method to evaluate FIPterm·dom by assessing the entire pancreas using gray-scale imaging on a body cross-section ( 80 ). The body of the pancreas was considered to have corrected echogenicity if it had less echogenicity than the retroperitoneal adipose in the region of a superior mesenteric artery (SMA), while the splenic vein (SV) and PD were completely demarcated. The first degree of FIPterm·dom occurs when the pancreas has echogenicity similar to that of fatty tissue in the region of the SMA, with a uniform, raised echogenicity and a flat abdominal contour, while the SV, SMA, and PD are clearly visible. The second degree of FIPterm·dom is linked to elevated echogenicity, a darker background in the dorsal part of the pancreas, indistinct borders of the SV and PD, and an almost imperceptible region of the SMA. In some cases, the abdominal contour of the pancreas appears wavy and may exceed the usual limit of visibility. The third degree of FIPterm·dom is characterized by worsened ultrasonic wave propagation of the pancreas, allowing only its abdominal portion to be visible, often with a clear external waviness, while the SV, SMA, or PD are not visible. The second and third degrees of FIPterm·dom may entail a reciprocal invasion of the hyperechogenic fatty lobes of the pancreas and the hypoechogenic fatty tissue encircling it, also referred to as interference ( 84 ).
5.2.3. Computed tomography CT is commonly used for imaging abdominal organs and is an excellent option for visualizing the pancreas due to its widespread availability, fast acquisition time, and routine use by clinicians ( 85 ).
Although no agreed-upon diagnostic criteria exist for FIPterm·dom on CT, researchers have used various techniques, such as measuring pancreatic attenuation through non-enhanced CT images with three regions of interest (ROIs) on the head, body, and tail of the pancreas.
The theory is that fat accumulation in visceral organs decreases Hounsfield units (HU), making fat visible on CT if there is more pancreatic inter-lobular fatterm·dom ( Figure 4 ). The attenuation within the ROI can be standardized by adipose attenuation (less than −30 HU) using histogram analysis to obtain a percentile of adipose attenuation values ( 86 ).
FIPterm·dom on CT ( 98 ).
Studies have shown a good correlation ( r = 0.67) between CT and histologic measurements of FIPterm·dom. The variance in CT attenuation between the pancreas and the spleen has also been used to assess FIPterm·dom. Other volumetric histography research has revealed an average pancreatic fat contentterm of 27.9 cm 3 and an average fat-to-parenchyma ratio of 0.69. This technique evaluates individual pixel values to quantify FIPterm·dom ( 87 ).
5.2.4. Magnetic resonance spectroscopy (MRS) Magnetic resonance spectroscopy (MRS) is the preferred non-invasive method for pancreatic fat assessment ( Figure 5 ). However, using MRS requires manually arranging a voxel (typically 2.0 × 1.0 × 1.0 cm, for example, 2.0 cm 3 ) to encompass more pancreatic tissue while avoiding the major PD and blood vessels ( 7 ).
FIPterm·dom assessment using MRIterm·key and MRS. Regions of interest are highlighted on magnetic resonance imaging (MRIterm·key) (OP series with a 70° pulse angle and TE = 2.4 ms) and the corresponding magnetic resonance spectroscopy (MRS). (A) Kidney and subcutaneous tissue measurements; (B) liver and pancreas measurements; and (C) the liver MRS spectral map, which shows a range of water and fat peaks ( 89 ).
MRS presents several technical challenges. Prolonged acquisition times result from the essential requirement for precise local shimming to attain the best possible magnetic field uniformity. Furthermore, when aiming to obtain spectra from small voxels, there is a need for substantial signal averaging during the acquisition process. This increases vulnerability to cardiac motion artifacts from nearby pulsatile vessels and respiratory motion artifacts. Visceral or peritoneal fat outside the pancreas typically contaminates the voxels, lowering shim quality and causing large changes in recorded spectra ( 88 ).
However, longer acquisition times can lead to patient discomfort, resulting in patient movements. MRS is operator-dependent and susceptible to noise-induced errors due to the low-fat content in the intra-lobular pancreas. The reproducibility and replicability of pancreatic MRS assessments have been flawed and inferior to those observed in the liver ( 89 ).
5.2.5. Chemical shift MRIterm·key MR scanning techniques offer the advantage of setting quantitative data throughout an entire scanned region. However, quicker acquisition times can limit pancreatic fat measurement. Chemical shift imaging (CSI) is a technique that helps overcome this limitation by acquiring an imaging signal at two or more echo times, which allows for contrasting the chemical shift between the primary fat and water peaks ( 90 ).
Fat content estimation can be achieved through the subtraction of the “in-phase” image, which depicts the constructive interaction between fat and water, from the “out-of-phase” image, which represents their destructive interaction ( 27 , 91 , 92 ). This technique offers more sophisticated assumptions about fat distribution within the pancreas, surrounding viscera, and other tissues, which may be investigated with faster acquisition times.
5.2.6. Proton density fat fraction mapping PDFF MRIterm·key is currently the most advanced method for estimating fat content via MRIterm·key ( Figure 6 ), but it has limitations. PDFF sequences are designed to evaluate hepatic fat, and further advancements are needed to accurately quantify pancreatic fat contentterm. The complexity of the pancreatic fat spectrum has been examined, and current in vivo spectra may be susceptible to contamination from extra-lobular fatterm·dom. Surgical samples for ex vivo pancreatic MRS could be a feasible alternative, although they are likely to contain a significant amount of extra-lobular fatterm·dom, particularly in cases of fatty infiltration ( 93 ).
The assessment of pancreatic fat contentterm using a proton density fat fraction (PDFF) map, with the position of three regions of interest (ROIs) indicated by red circles. The ROIs are located in the pancreatic head (A) , pancreatic body (B) , and pancreatic tail (C) ( 93 ).
5.2.7. The new FIPterm·dom diagnostic tool A research study by Khoury et al. developed a simplified scoring system to identify the presence of FIPterm·dom. The scoring system is based on the presence of obesityterm, hyperlipidemia, and fatty liver, each of which is assigned a score of 1, resulting in a maximum score of 3. The scoring system has demonstrated high accuracy and specificity, with a receiver operating characteristic (ROC) value of 0.77 and a specificity range of 82.1%−98.4%. Patients with a score of 1 have a low probability of having FIPterm·dom, whereas those with a score of 2 or more have a higher likelihood ( 94 ).
6. Classification of FIPterm·dom By EUS, the pancreatic adipose tissue classification system was initially established based solely on pancreatic echogenicity ( 95 , 96 ). Nonetheless, the current assessment version now encompasses an evaluation of the pancreatic parenchyma and the clarity of the PD border ( Figure 7 ).
Fatty infiltration of the pancreasterm·dom on EUS ( 97 ). (a) Iso-dense image of the normal pancreas (arrow) with the spleen (arrowhead). (b) High-density image of fatty infiltration of the pancreasterm·dom (arrow) with the spleen (arrowhead). (c) Iso-dense image of the normal liver (arrow) with the right kidney (arrowhead). (d) High-density image of fatty liver (arrow) with the right kidney (arrowhead).
Grade I pancreatic fat is hypoechoic or isoechoic compared to the spleen, with a well-defined major PD and “salt and pepper” specks visible in the pancreatic parenchyma.
Grade II pancreatic fat is described as having more than 80% of the parenchyma hyperechoic compared to the spleen, with a well-identified major PD and salt and pepper specks visible in the pancreatic parenchyma.
Grade III pancreatic fat has more than 80% more hyperechoic parenchyma than the spleen, with relatively unclear major PD borders and salt and pepper pancreatic parenchyma ( 5 ).
Grade IV pancreatic fat is where the pancreas cannot be distinguished from nearby fat, the major PD boundaries are intensely unclear, and salt and pepper specks in the parenchyma of the pancreas are intensely fuzzy. Grades I and II indicate a normal pancreas, while grades III and IV indicate FIPterm·dom ( 5 ).
7. Clinical consequences of FIPterm·dom The clinical consequences of FIPterm·dom are summarized in Figure 8 .
Clinical consequences of FIPterm·dom.
7.1. FIPterm·dom and acute pancreatitis It has been established that FIPterm·dom directly impacts the pancreatic parenchyma and is linked with parenchymal damage in acute pancreatitis, specifically in the adipose tissue enveloping the acinar cells of the pancreas ( 99 , 100 ). A human study revealed that deceased adipocytes were surrounded by an area of necrotic parenchyma, with the most severe damage observed near the dead adipose tissue. This peri-fat acinar necrosis, characterized by the presence of macrophages (CD68-positive), is an antemortem event and was found to be more common in patients with acute pancreatitis, especially those with severe forms of the disease, compared to controls. It was also the most frequently observed type of necrosis in post-mortem samples. Another type of necrosis observed was isolated acinar necrosis, which occurs in pancreatic parenchyma away from the adipose tissue. However, this type of necrosis was significantly less common than peri-fat acinar necrosis in severe acute pancreatitis. The presence of FIPterm·dom contributes to increased morbidity and mortality in patients with severe acute pancreatitis ( 101 ).
7.2. FIPterm·dom and MS MS is a growing clinical and societal concern worldwide due to changing lifestyles characterized by high-calorie, high-fat diets and low physical activity levels. A recent study revealed that the group with FIPterm·dom had a significantly higher prevalence of MS than the control group, along with a greater number of MS markers ( P < 0.05). Furthermore, FIPterm·dom showed a strong association with MS, as evidenced by four studies involving 611 individuals with FIPterm·dom, of whom 265 had MS, compared to 2,051 non-FIP individuals, of whom 361 had MS. The presence of FIPterm·dom was significantly correlated with a higher incidence of MS, with a relative risk of 2.37 (95% CI: 2.07–2.71; P < 0.001), indicating a 137% increased likelihood of developing metabolic syndrometerm·key in individuals with FIPterm·dom ( 20 ).
In addition, a prospective study demonstrated that patients with FIPterm·dom were over three times more likely to receive an MS diagnosis than those without FIPterm·dom (OR 3.13, P = 0.004). This study also explored the relationship between FIPterm·dom and increasing MS risk factors and whether a higher BMI could largely explain the correlation between FIPterm·dom and MS. The findings revealed that each additional MS risk factor, such as BMI >30 kg/m 2 , T2DMterm·key, HTN, or hyperlipidemia, increased the risk of FIPterm·dom by 37% ( 5 ).
7.3. FIPterm·dom and cardiovascular diseases FIPterm·dom has been implicated in the development of cardiovascular diseases (CVD), including atherosclerosis. FIPterm·dom has been found to occur not only in individuals with general obesityterm but also in those without established pancreatic disease. It has been strongly associated with diabetes and severe widespread atherosclerosis ( 102 , 103 ). FIPterm·dom has been linked to a higher prevalence of carotid artery plaques and increased vascular rigidity in individuals who are not overweight. Nonetheless, no significant associations were found in obese individuals ( 104 ).
Studies have also shown that FIPterm·dom is linked with augmented epicardial adipose tissue and aortic intima-media thickness, which are markers of clinical atherosclerosis. FIPterm·dom was strongly associated with a 3-fold increased risk of developing aortic intima-media thickness and a 16-fold increased risk of developing epicardial adipose tissue ( 105 ). Furthermore, FIPterm·dom has been correlated with the severity of coronary artery stenosis in individuals with T2DMterm·key, suggesting that it may be a predictor of coronary artery stenosis in this population. A higher incidence of complex coronary artery lesions was found in patients with acute coronary syndrome (ACS) and FIPterm·dom. A significant and independent positive correlation was observed between FIPterm·dom and the Syntax (SX) score, a well-established angiographic scoring system considering lesion characteristics and coronary anatomy ( 106 ).
The pathophysiological mechanisms underlying the association between FIPterm·dom and coronary atherosclerosis involve the secretion of pro-inflammatory factors by adipose tissue in the pancreas, consequently resulting in endothelial dysfunction and metabolic abnormalities. The severity of fat accumulation in the pancreas has also been correlated with the severity of coronary arteriosclerosis. These findings suggest that FIPterm·dom may be a potential contributor to CVD, particularly in individuals who are not overweight ( 107 ).
7.4. FIPterm·dom and HTN HTN is a significant global health issue associated with the risk of heart, brain, kidney, and other organ disorders, and it is the leading cause of death worldwide.
A study involving 55 non-diabetic human pancreas donors revealed that donors with a history of HTN had higher pancreatic fat and islet fat content, regardless of gender. These findings suggest that a previous history of HTN may independently contribute to increased pancreatic fat contentterm and islet fat content ( 108 ). HTN is known to cause small vessel constriction and a reduction in microvascular density, leading to decreased tissue perfusion ( 109 ). Hypoxia and hypoxia-inducible factors have been linked to alterations in lipid metabolism and intracellular lipid accumulation in cultured cells and organs such as the liver and pancreatic islets ( 110 , 111 ). Consequently, HTN may contribute to persistent tissue hypoxia, leading to lipid accumulation and pancreatic islet dysfunction.
On the other hand, a meta-analysis study reported a 67% increased risk of HTN associated with FIPterm·dom ( 13 ). However, a prospective study showed a non-statistically significant trend toward an association between HTN and FIPterm·dom ( 5 ). In a cross-sectional retrospective study involving 65 children with NAFLDterm·dom, FIPterm·dom was 1.28 times more likely to cause HTN (OR 1.28, 95% CI: 1.01–1.62) when examining potential risk factors for HTN in children with NAFLDterm·dom ( 112 ).
7.5. FIPterm·dom and T2DMterm·key T2DMterm·key is projected to become the sixth leading cause of mortality by 2030, with obesityterm and physical inactivity being significant contributors to its development, and it is crucial to understand their impact on the pancreas and associated morbidity.
The build-up of ectopic fat in non-adipose tissues, such as the pancreas, due to metabolic overload of adipose tissue may result in lipotoxicityterm, insulin resistance, and inflammation, leading to glucose metabolic disturbances and T2DMterm·key. The build-up of fat in pancreatic endocrine cells plays a crucial role in the pathogenesis of T2DMterm·key ( 113 ). FIPterm·dom has been implicated in the pathogenesis of T2DMterm·key, even independent of NAFLDterm·dom, with evidence suggesting that it may be associated with beta-cell failure independent of insulin resistance ( 114 , 115 ). However, other studies have reported that NAFLDterm·dom patients with FIPterm·dom have increased insulin resistance, impaired glucose parameters, and higher rates of prediabetes and diabetes than those with NAFLDterm·dom alone ( 116 ). In an animal study, pancreatic fat build-up was observed before the onset of hyperglycemia in obese Zucker diabetic fatty mice ( 117 ). A cross-sectional study also reported a significantly higher prevalence of T2DMterm·key in FIPterm·dom patients compared to non-FIP patients (12% vs. 5%) ( 7 ).
In some studies, pancreatic fat contentterm, measured by various methods such as MRS, MRIterm·key, and CT, is higher in individuals with T2DMterm·key than in non-diabetic subjects. However, some studies using CT or post-mortem examinations have reported no difference in pancreatic fat contentterm, and the discrepancies in findings are due to differences in measurement accuracy ( 116 ).
A meta-analysis study revealed that individuals with FIPterm·dom had a 108% higher risk of developing T2DMterm·key. Another meta-analysis of six studies showed that individuals with FIPterm·dom had a significantly increased relative risk of developing T2DMterm·key (RR 2.08; 95% CI: 1.44–3.00; P = 0.001). Some studies have also reported a significant association between FIPterm·dom, insulin resistance, and beta-cell dysfunction ( 20 ).
Recently, a 10-year prospective cohort study involving 631 participants found that those with FIPterm·dom had a significantly higher incidence of T2DMterm·key than those without FIPterm·dom (33.3% vs. 10.4%; P < 0.001). FIPterm·dom was independently associated with an increased hazard ratio of 1.81 for incident T2DMterm·key. Furthermore, the risk of developing incident T2DMterm·key was significantly increased by 7% for every 1% increase in pancreatic fat, with a hazard ratio of 1.07 ( 35 ).
However, recent studies have shown that T2DMterm·key may be reversible with bariatric surgery and dietary energy intake restriction, which can improve beta-cell activity and reduce pancreatic fat contentterm.
The role of FIPterm·dom, particularly the first-phase insulin response, may be crucial in glucose metabolism and beta-cell failure, and different susceptibility thresholds to pancreatic fat build-up may be determinants of beta-cell dysfunction ( 118 ).
7.6. FIPterm·dom and PF Pancreaticoduodenectomy (PDE) is currently the preferred treatment for pancreatic cancer. However, one of the most significant complications of PDE is PF. Early detection and management of potential risk factors for PF are crucial. FIPterm·dom has been identified as a significant risk factor for PF ( 119 ). Studies have shown that patients with PF have significantly greater intra-lobular, inter-lobular, and total pancreatic fat than non-PF patients.
Moreover, the risk of PF becomes considerable when the percentage of fatty infiltration exceeds 10% ( 26 , 119 ). In a retrospective study, 40 patients with PF and 40 without PF were selected and matched for age, sex, pancreatic pathology, surgeon, and type of surgery. Compared to non-PF patients, those with PF demonstrated a considerable increase in intra-lobular, inter-lobular, and total pancreatic fat contentterm ( P < 0.001). An inverse correlation was observed between PF and fibrosis, blood vessel density ( P < 0.001), and a small PD. A soft pancreatic texture is also deemed a risk factor for PF formation, potentially owing to augmented fat build-up, which can impede anastomosis and heighten the likelihood of perioperative pancreatitis ( 120 , 121 ).
A meta-analysis of 11 studies involving 2484 individuals found that FIPterm·dom was significantly associated with the occurrence of the PF (OR = 3.75; 95% CI: 1.64, 8.58; P = 0.002; I 2 = 78). Overall, the evidence suggests that FIPterm·dom is a critical risk factor for PF and should be carefully managed during PDE to reduce the incidence of PF ( 119 ). The exact mechanism by which FIPterm·dom promotes PF development is unknown. Nonetheless, researchers propose that a soft pancreas is more susceptible to ischemia and damage during restoration, and the exocrine function can worsen tissue damage ( 122 ).
7.7. FIPterm·dom and pancreatic transplantation Pancreatic transplantation has become increasingly successful, and as a result, the number of individuals awaiting pancreatic transplantation has risen. FIPterm·dom is an essential criterion in determining the viability of donor pancreata for transplantation. Although many pancreas from overweight donors can be transplanted successfully, certain transplant surgeons avoid using the pancreas with significant FIPterm·dom since the surgery is technically more challenging. However, a more objective measurement could help avoid discarding suitable organs for transplant. In the case of pancreatic transplantation, the presence of pancreatic lobules with associated ducts and blood arteries loosely separated from the primary pancreas recommends that all cut-away fatty pancreatic tissue be ligated to prevent pancreatic leaks and bleeding after transplantation. Careful hemostasis after fat removal minimizes the chance of hematoma leading to infection, especially when anticoagulation is indicated, even minor anticoagulation. To prevent fat necrosis, octreotide should be administered prior to revascularization and continued until the pancreatitis is resolved, rather than late after surgery. Flushing and cooling should be used to maximize graft preservation and avoid autolysis ( 78 ).
7.8. FIPterm·dom and PDACterm·key PDACterm·key is a highly lethal cancer worldwide ( 123 , 124 ). The late presentation and lack of early-stage biomarkers make early identification of PDACterm·key challenging. Additionally, the retroperitoneal location of the pancreas facilitates the spread of PDACterm·key to nearby organs and blood vessels, and non-specific features further complicate early detection ( 125 ).
PDACterm·key typically arises from precursor lesions such as acinar-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasia (IPMN), mucinous cystic neoplasia, and atypical flat lesions ( 126 , 127 ). The most common genetic alteration in PDACterm·key is the KRAS mutation, which is detected in more than 90% of cases and is an early event in low-grade PanIN 1A lesions ( 126 ). Obesityterm is a significant risk factor for PDACterm·key ( 128 , 129 ), and increased pancreatic adiposity contributes to PDACterm·key development from FIPterm·dom ( 130 ). Animal studies have shown that obesityterm and hyperlipidemia enhance FIPterm·dom, leading to the progression of N-nitrosobis(2-oxopropyl)amine (BOP)-induced PDACterm·key and the upregulation of adipocytokines and cell proliferation-related genes in the pancreas ( 131 ). Thus, local adipocytokine production from adipose tissues in an adipose tissue-rich milieu is linked to the development of PDACterm·key.
PanIN, which affects small pancreatic ducts, may contribute to localized pancreatitis and promote the development of neoplasms. FIPterm·dom is linked to the development of PanIN, and it is the most significant risk factor for precancerous pancreatic lesions, according to a retrospective study with an odds ratio of 17.86 [4.94–88.12], independent of age and diabetes status ( 132 ).
A case–control study of patients who had surgical intervention for PDACterm·key found that increased pancreatic fat enhanced PDACterm·key propagation and mortality. Fat-induced aberrant local cytokine production and toxic fatty acids have been shown to play a role in tumor proliferation, invasion, and angiogenesis ( 133 ). Additionally, persistent overproduction of reactive oxygen species can cause and accelerate mutagenesis alterations that contribute to the development and progression of PDACterm·key ( 134 ). These mechanisms and the generation of growth factors by adipocytes are likely to hasten the spread of cancer cells to the lymphatics and local lymph nodes. FIPterm·dom affects the tumor microenvironment, accelerates tumor progression, and leads to the early death of individuals with PDACterm·key ( 135 ).
7.9. The new clinical consequences of FIPterm·dom Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder impacting women during their reproductive years ( 136 ). Osman et al. found that FIPterm·dom was identified in 38.0% of patients with PCOS, significantly higher than the 12.0% of FIPterm·dom cases detected in healthy controls ( 1 ). On the other hand, a recent study on adolescents did not find a relationship between FIPterm·dom and PCOS ( 137 ). Notably, Osman et al. found that age was independently associated with the development of FIPterm·dom in PCOS patients, suggesting that the metabolic interactions between PCOS and FIPterm·dom may take longer to become evident in younger patients. The complex connection between FIPterm·dom and PCOS reveals the intersection of metabolic and endocrine issues. Ongoing research could transform our grasp of these conditions and lead to innovative treatments.
8. Treatments of FIPterm·dom Until recently, there was no conventional treatment for FIPterm·dom. However, lifestyle modifications such as weight loss, a healthy diet, and regular exercise have shown promise in reversing FIPterm·dom by lowering calorie intake. Studies conducted on animal and human models have demonstrated the efficacy of weight loss through bariatric surgery in reversing FIPterm·dom and its clinical consequences, including T2DMterm·key.
Pharmacological therapy for FIPterm·dom has also been investigated in animal studies, with oral hypoglycemic medications such as metformin, dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), and thiazolidinediones showing promise in managing FIPterm·dom in patients with T2DMterm·key. Metformin, a first-line anti-diabetic medication, has been found to improve lipid metabolism and directly affect insulin secretion in pancreatic islets by reducing oxidative stress. It can also reduce visceral fatty tissue by improving insulin resistance and suppressing compensatory beta-cell hyperplasia resulting from a high-fat diet ( 138 ).
In animal studies, Troglitazone administration significantly increased pancreatic weight and protein content, effectively preventing or reversing inflammatory cell infiltration, pancreatic fatty replacement, and fibrosis in T2DMterm·key mouse models. Pancreatic lipase inhibition through tetrahydrolipstatin decreased the severity of acute inflammation of the pancreas, fat apoptosis, pancreatic failure, and mortality in obese mice with FIPterm·dom. Moreover, the combined use of Sitagliptin and Telmisartan, two anti-diabetic medications, showed efficacy in managing FIPterm·dom and preventing the progression from lipotoxicityterm to severe pancreatic disease in mice. Berberine and cinnamic acid, components of a novel Japanese drug known as the “Jiaotai Pill,” were found to inhibit lipid accumulation in pancreatic beta-cell cultures by lowering lipogenesis and boosting lipid oxidation ( 139 ).
In obese rats, Sandostatin (a somatostatin analog) downregulated the expression of an adipose differentiation-associated protein in the pancreas, reducing pancreatic fatty deposition, lipid dysregulation, and insulin resistance and ameliorating pancreatic damage ( 140 ).
Although these findings hold promise for FIPterm·dom treatment, further long-standing interventional research is necessary to establish the mortality benefit, improvement in glycemic management, and incidence of pancreatitis and pancreatic cancer for prospective therapeutic options.
9. Conclusion FIPterm·dom is a common yet frequently overlooked disorder that requires increased attention and investigation to comprehend its clinical significance. Early detection and understanding of FIPterm·dom may aid in developing and strengthening management strategies, leading to improved patient clinical outcomes. Recent studies suggest a higher prevalence of FIPterm·dom in patients with PCOS, with age being independently associated with its development. This highlights the intriguing crossroads of metabolic and endocrine dysfunction. Early screening for FIPterm·dom may facilitate early detection of PDACterm·key, the lethal clinical consequence of FIPterm·dom. However, there are currently no suitable biomarkers for FIPterm·dom detection, and diagnosis relies on histopathology and imaging. A simplified scoring system developed by Khoury et al. has demonstrated high accuracy and specificity in identifying the presence of FIPterm·dom. Management guidelines for FIPterm·dom are yet to be established and require further research.
Author contributions MAM, ME, YJ, and PZ contributed to the conception of the reviewterm·mth. MAM conceived the study subject and made substantive revisions to the important content of the manuscript, and he was the major contributor to the writing of the manuscript. AM, MA, MAlm, and MAM provided suggestions and technical support, revised important manuscript sections, and assisted in the literature search. JW, MAln, PZ, and SH critically reviewed the manuscript. All authors contributed to the article and approved the submitted version.