Fatty Pancreas: An Underappreciated Intersection of the Metabolic Profile and Pancreatic Adenocarcinoma

Abstract

Although the prevalence of pancreatic cancer is increasing, treatment strategies remain limited, and success is rare. A growing body of evidence links pancreatic cancer to pre-existing metabolic disorders, including, but not limited to, type 2 diabetes mellitus and obesity. An infrequently described finding, fatty pancreas, initially described in the context of obesity in the early 20th century, appears to be at the crossroads of type 2 diabetes and obesity on the one hand, and the development of pancreatic cancer on the other. Similarly, other conditions of the pancreas, such as intrapancreatic mucinous neoplasms, also seem to be related to diabetes while increasing the subsequent risk of pancreatic cancer. In this review, the author explores the diagnostic criteria for, and prevalence of, fatty pancreas and the potential link to other pancreatic conditions, including pancreatic cancer. Diagnostic limitations, and areas of controversy are also addressed, as are potential therapeutic approaches to fatty pancreas intended to reduce the subsequent risk of pancreatic cancer.

Case Synopsis

A 68-year-old man was in his usual state of health, when a routine medical appointment revealed an alkaline phosphatase of 146 IU/L (normal: 37–107); a value 2 months earlier was 80. Other liver tests were normal, and an HbA1c was 5.9%. Of note, triglycerides were 51 mg/dL (normal: <150 mg/dL), total cholesterol was 169 mg/dL, high-density lipoprotein-cholesterol was 59 mg/dL, and low-density lipoprotein-cholesterol 100 mg/dL. His active medical problems included lumbar disk disease. He was not receiving any routine prescription medications and sparingly used nonsteroidal anti-inflammatories for low back pain. Family history was significant for type 1 diabetes (mother), coronary disease (father, brother, and a male cousin). An 84-year-old brother has pancreatic cancer. There is no other family cancer history. The patient is a nonsmoker and drank minimally. On examination he was overweight (body mass index 28) and normotensive. No organomegaly was noted. On repeat testing, alkaline phosphatase remained elevated (207 IU/L) and gamma-glutamyl transferase was elevated at 174 IU/L (normal: 0–55). Serological tests for viral hepatitis, autoimmune hepatitis, and sarcoidosis were normal. Computed tomography revealed a normal liver and a fatty pancreas. Fibroscan suggested fatty liver. Magnetic resonance imaging (MRI) showed pancreatic cysts, confirmed as intraductal papillary mucinous neoplasms on magnetic resonance cholangiopancreatography. These were side-branch cysts, and were 2 mm in diameter. A fatty pancreas was not evident on MRI. Although this patient did not meet the criteria for metabolic syndrome, he did manifest several components (borderline obesity and HbA1c).

Introduction

A recent article in the New York Times, entitled “Pancreatic Cancer, and Why We Can't Stop It,”¹ illustrates a level of the increasing prevalence and public awareness of this usually rapidly progressive neoplasm. Five-year survival remains <10%, and three-fourth of patients will die within a year of diagnosis. Although several theories involving a variety of factors have been advanced to explain this poor prognosis, it remains a fact that the prevalence is increasing and there is a clear association with pre-existing type 2 diabetes (in distinction to the pancreoprivic diabetes that may result after treatment for pancreatic cancer or chronic pancreatitis), suggesting that metabolic derangements may increase risk.

One of the goals of this report to provide an understanding of a largely unrecognized metabolic (and inflammatory) predisposition to pancreatic cancer. We will see how components of the metabolic syndrome are associated with increased risk of pancreatic cancer. The author has reviewed the literature, but does not intend an exhaustive literature review. The objective of this report is to outline areas of clarity and those of uncertainty to guide future investigators and clinicians. In particular, this review addresses pancreatic lesions well-known to gastroenterologists and hepatologists, specifically fatty pancreas and mucinous cysts, and their link to pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive form of pancreatic cancer and is known to occur in the setting of diabetes. As reported by Aggarwal et al., 68% of patients diagnosed with PDAC had concurrent diabetes, whereas diabetes prevalence in other cancers ranged from 15% to 21% (P < 0.001).² Pancreatic cancer has a higher incidence in populations with diabetes³; for patients with PDAC who also have diabetes, diabetes is diagnosed <24 months before the diagnosis of PDAC in 74%–88% of patients.⁴ This has been referred to as “dual causality,” that is, type 2 diabetes mellitus (t2dm) is a risk factor for PDAC, and PDAC is a cause of diabetes. The mechanisms for this association are unclear, as are the diagnostic criteria to distinguish “traditional” t2dm from diabetes occurring as an early consequence of PDAC (thus excluding postpancreatectomy diabetes).⁵

The insulin-acinar axis was described in 1899 when it was observed that exocrine pancreatic acinar tissue in proximity to islets of Langerhans appeared more robust than more distant acini.⁶ As reported by Andersen et al.,⁵ insulin is released from β-cells into the intrapancreatic circulation feeding acinar and ductal cells. Islet proximity allows high levels of hormones to reach these cells, exerting “proxicrine” effects on insulin and IGF-1 receptors, potentially promoting survival and proliferation of transformed ductal or acinar cells. Thus, hyperinsulinemia from insulin resistance may contribute to the observed increased risk of PDAC in type 2 diabetes and obesity.⁵ Poor glycemic control has been associated with increased concentrations of advanced glycation end products, which activate a receptor called receptor for advanced glycation end products (RAGE)⁷; this receptor also binds cytokines and agonists implicated in the etiology of inflammation and cancer.⁷ Hyperglycemia has been proposed to promote tumorigenesis in cultured pancreatic ductal epithelial cells by activating transforming growth factor-β signaling.⁸

Whence Fatty Pancreas?

Reports in the early 20th century commented on pancreatic weights; however, many of these studies had small numbers of subjects, had disproportionate numbers of malnourished or diabetic subjects. Schaefer addressed these shortcomings in a report from the Mayo Clinic where pancreases from >200 patients were studied, including men and women; the correlation between pancreas weight and body weight was slightly greater in women.⁹ In 1933, Ogilvie described enlarged fatty pancreases in obese individuals, and coined the phrase fatty pancreas; this finding was present in 17% of obese compared with 9% of lean cadavers.¹⁰ Olsen subsequently confirmed that pancreatic lipomatosis was correlated with age and weight, and was potentially reversible: predictably, the degree of lipomatosis was less in patients with long terminal illness.¹¹ These findings were limited to observations obtained from cadavers, and limited also by the fragility of the pancreas after death. Recent studies using contemporary imaging have described fatty pancreas (also known as pancreatic steatosis, pancreatic lipomatosis, fatty infiltration, lipomatous pseudohypertrophy of the pancreas, and nonalcoholic fatty pancreas)¹²; data obtained by endoscopic ultrasound (EUS) suggest a wide range of prevalence: between 38.7 (Korean¹³), 27.8 (United States, race not specified¹⁴), and 25.9% of patients (Iranian¹⁵) have fatty pancreas, comparison magnetic resonance imaging (MRI) studies of Hong Kong–Chinese reveal a prevalence of 16.1%.¹⁶ The latter studies were based on patients, which biases results in ways that are disease dependent. Actual results may vary as exemplified by a population-based study in China, which found a prevalence of 2.7%.¹⁷ Furthermore, the impact of age, gender, and ethnicity remains to be defined.^18,19 In addition to metabolic syndrome and its individual criteria leading to fatty pancreas (the focus of this article) other etiologies include congenital syndromes such as cystic fibrosis, toxins, and medications such as steroid and gemcitabine therapy, human immunodeficiency virus, and chronic hepatitis B. The reader is referred elsewhere for a more thorough discussion of these other etiologies.¹² In general, the discussion of fatty pancreas is compromised by the lack of definitive diagnostic criteria.²⁰ Although there have been attempts at developing computerized scoring systems quantitatively assessing the degree of fat infiltration,^21,22 none has yet been validated in clinical practice.

In a recent study, Tirkes et al. reported on a cohort of patients evaluated in a pancreatic disease clinic who underwent magnetic resonance cholangiopancreatography (MRCP) and observed that pancreatic fat correlated with visceral fat; this correlation was particularly evident in patients with chronic pancreatitis and type 2 diabetes.²³ A recent meta-analysis by Sreedhar et al. confirmed the association of pancreatic cancer or premalignant lesions with intrapancreatic fat deposition.²⁴

Taylor in Newcastle, Great Britain, has promoted the “Twin Cycle Hypothesis,” which postulates that chronic dietary calorie excess first leads to accumulation of intrahepatic fat with secondary development of pancreatic fat deposition. Since the liver is “downstream” from the pancreas, this spillage is thought to reflect fat carried in circulating triglycerides (R. Taylor, pers. comm.). These self-reinforcing cycles between liver and pancreas eventually cause metabolic inhibition of insulin secretion after meals and onset of hyperglycemia. When examined with serial MRIs, organ fat accumulation has been reversed with low calorie diets. Lipid reversal begins in the liver and subsequently includes the pancreas, accompanied by normalization of beta cell function and sustained reversal of diabetes.^25,26

Based on postmortem data, van Geenen et al. reported a strong correlation between nonalcoholic fatty liver disease (NAFLD) and nonalcoholic fatty pancreas.²⁷ Although possibly related to circulating triglycerides, other investigators feel the evidence is inconclusive.²⁸ Information regarding the relationship of triglycerides to fatty pancreas is provided for completeness since our subject had normal triglycerides.

Obstructive sleep apnea, related with metabolic syndrome also may predispose to fatty pancreas.²⁹ A variety of studies support a correlation between fatty pancreas and NAFLD. Higher pancreatic fat content is related to the degree of hepatic steatosis in patients with biopsy-proven NAFLD.³⁰ Fatty pancreas is also associated with beta-cell dysfunction,³¹ and appears to be more common in lymph node-positive as compared with lymph node-negative patients with pancreatic cancer.³²

Although fatty pancreas and fatty liver are often associated, a recent study found that 68% of cases of fatty pancreas had fatty liver, whereas 97% of cases of fatty liver had fatty pancreas, suggesting an independence of these two lesions.³³ Other studies also showed a lack of correlation.^34,35 In addition, hepatic fat is intracellular, whereas pancreatic fat is related to adipocyte infiltration.³⁶ Fat loss in pancreas and liver were not correlated after bariatric surgery although both organs lost fat.³⁷

Original descriptions of fatty pancreas were in the context of obesity and pancreatic hypertrophy. Accumulation of pancreatic fat results from at least two independent mechanisms: (i) fat accumulation associated with obesity and type 2 diabetes, also called “fatty infiltration,” or “nonalcoholic fatty pancreas disease”; and (ii) “fatty replacement” occurring as the result from the replacement of dead acinar cells with adipocytes. Major conditions contributing to fatty replacement include congenital diseases (cystic fibrosis,³⁸ Shwachman–Diamond syndrome,^39,40 Johanson–Blizzard syndrome⁴¹), reovirus infection,⁴² iron overload either congenital (hemochromatosis⁴³) or acquired (transfusion^44,45 or malnutrition^46,47).

There is also controversy over the definition of fatty pancreas, independent of the etiology. Most criteria to date are based on radiographic imaging in vivo. Some define fatty pancreas as a pancreas with more fat than the spleen,⁴⁸ some use a threshold of >10.4% fat content,⁴⁹ whereas others use a cutoff of >6.2%.⁵⁰ Some definitions are subjective with no numeric value. This inconsistency reflects the different methods used to establish a diagnosis, but also underscores the lack of a standard limits accurate and reproducible methodology for quantifying fatty pancreas and the risk of metabolic and malignant disease and for monitoring evolution of the pancreatic lesion over time.

Diagnosis of Fatty Pancreas in Vivo

It is only recently that studies have correlated imaging and histology of intrapancreatic fat.⁵¹ Although a major limitation is that pancreatic histological samples are usually obtained in a pathological context, a wide variety of imaging techniques are available for determining intrapancreatic fat.

Ultrasound

Although ultrasound is inexpensive, noninvasive, and has no radiation exposure, it is hard to see entire pancreas with transabdominal ultrasound (TUS) due to its location and supervening bowel gas. It is thus considered inaccurate for the diagnosis of intrapancreatic fat.

Traditionally, pancreatic echogenicity has been compared with that of liver, kidney, and spleen⁵²; a fatty pancreas is one that is comparatively hyperechoic. Despite these limitations, a Chinese study using TUS reported that 16% of otherwise healthy volunteers reportedly had fatty pancreas.⁵³ Similarly, in a study of 256 Chinese subjects with metabolic syndrome, TUS of the pancreas was superior to that of the liver for detecting fat deposits.⁵⁴ In response to the possible shortcomings of TUS, EUS has emerged as an approach to diagnose and grade fatty pancreas; Sepe et al. have proposed an EUS grading system.¹⁴ This proposal has been limited by the lack of tissue sampling or comparative studies with computed tomography (CT) or MRI. This technique is also more expensive and invasive than TUS.

Computed tomography

Adipose tissue shows characteristic attenuation on noncontrast CT scanning. Navina et al. have reported that a reasonable correlation (0.677, P = 0.01) exists between CT and histological estimates of intrapancreatic fat; it is unclear if intrapancreatic fat is evenly distributed or has a predilection for the head or tail.⁵¹ Although noncontrast CT is available and relatively inexpensive, it has limitations when used to assess pancreatic fat: a mass can mimic fatty change, pancreatic fat reflects adipocytes and pancreatic tissue, and the attenuation range for fat is based on adipose tissue measurements.⁵²

Magnetic resonance imaging/magnetic resonance cholangiopancreatography

Compared with CT scanning, MRI has superior soft tissue resolution and identifies intrapancreatic fat by discriminating between fat and water protons,⁵⁵ but needs further study and validation to define an accurate diagnostic cutoff value for intrapancreatic fat. MRCP is not so widely used to evaluate pancreatic fat, but rather ductal architecture. It should be further clarified that although it is relatively easy to make the diagnosis of fatty pancreas on CT scanning by simple measurement of Hounsfield units of the pancreas and comparing with other organs, MRI determination requires quantification software that, although usually done for liver studies, is not routinely done for pancreas.

Elastography

Pancreatic specialized elastography (an estimate of tissue stiffness in response to an applied mechanical force (compression or shear wave)) is being developed and can be performed by either transabdominal or endoscopic techniques. Elastography incorporates strain and shear wave techniques. The latter can only be performed by the transabdominal approach, whereas strain elastography is more accurate imaging the body, but not the head or tail, of the pancreas.⁵⁶ A recent study comparing MRI, MRCP, ultrasound, and elastography in pancreata in patients with cystic fibrosis reported that MRI was superior to ultrasound and shear wave elastography.⁵⁷ Most clinicians are familiar with the widely used Fibroscan (Echosens, Waltham, MA) used to evaluate liver fibrosis; this device uses shear wave technology only.

Other Pancreatic Lesions That Lead to an Increased Risk of Pancreatic Cancer

Intraductal papillary mucinous neoplasms (IPMN) of the pancreas is a term that was first coined in the 1990s to refer to papillary growths within the pancreatic ductal system with thick mucin secretion and a risk for malignant transformation.⁵⁸ Although the prevalence of IPMN has risen since the early reports, this may reflect new diagnostic techniques.⁵⁹ The World Health Organization has divided cystic mucin-producing neoplasms of the pancreas into two classifications: IPMN and mucinous cystic neoplasms (MCN).⁵⁹ MCN and other rare pancreatic cystic conditions are beyond the scope of this article and are addressed elsewhere.⁶⁰ Although mucinous lesions have variable neoplastic potential, serous lesions (serous cystadenomas) are almost always benign and will not be considered in this study.⁶⁰ IPMN can be classified as main duct or branch duct; the latter comprise pancreatic cysts that communicate with the main pancreatic duct. Although a variety of pathological descriptions have been made of IPMN (beyond the scope of this review), the relationship to pancreatic cancer is related to size and location of the cysts and clinical features such as pain or jaundice.⁵⁹

Various international groups have proposed guidelines to aid in the management of patients with mucin-producing cystic lesions.⁶¹ The European Study Group on Cystic Tumours of the Pancreas recommends surgical removal for dilated main pancreatic duct, a large cyst, or evidence of cyst-related obstructive jaundice.⁶²

The International Association of Pancreatology published consensus guidelines in 2006 focusing on IPMNs and MCNs. MCNs often have ovarian-type stroma and have been postulated to arise from ovarian rests in the pancreas, in comparison with IPMNs that arise from pancreatic ducts. These guidelines consider branch duct IPMNs to be nominally less dangerous (in terms of malignant transformation) than main duct IPMNs. They are more likely to be multifocal and difficult to distinguish from main duct IPMNs.⁶³ At this time, these guidelines represent consensus opinion, and are not yet accepted as “evidence-based.”⁶⁴

In 2010, the American College of Radiology (ACR) published a “White Paper” addressing the management of incidental findings on abdominal CT; they pointed out that the frequency of detection of pancreatic cysts ranged between almost 3% by CT scanning to almost 20% by MRI.⁶⁵ These authors focused on size of cyst (<3 cm supporting nonsurgical management) as well as characterizing the cyst as mucinous. They also supported the role of MRI as the preferred modality. An updated White Paper in 2017 proposed an algorithm based on size of the cyst at initial imaging evaluation as well as age of the patient; the follow-up interval ranged between 1 and 2 years based on these characteristics.⁶⁶ This suggests that all lesions are considered to have malignant potential.

The American Gastroenterological Association (AGA) published a technical review in 2015 addressing the diagnosis and management of asymptomatic neoplastic pancreatic cysts. They also supported MRI as the preferred imaging modality. Patients with concerning features on MRI should be evaluated by EUS and fine needle aspiration. Follow-up every 1–2 years is recommended for patients who are surgical candidates with a benign-appearing MRI.⁶¹

Although there is a general consensus that MRI is the preferred imaging modality, there is wide disagreement about the period of surveillance, both the duration as well as the frequency of imaging. As might be expected in a field where the imaging technology and understanding of the natural history of identified lesions are both proceeding rapidly and in parallel, there have been attempts to reconcile these published recommendations. Nakamura et al. point out that the major focal points of these guidelines are when to operate and how to follow up nonresected lesions.⁶⁷

Similarly, Xu et al. attempt to compare the AGA guidelines, the 2010 ACR guidelines, and the 2012 Fukuoka guidelines from the standpoint of differing levels of sensitivity and specificity and recognize that each of them will have a certain number of missed cancers; therefore, it is important for clinicians to determine the acceptable rate of false-positives who may undergo unnecessary, risky surgery to prevent a true-positive not being treated definitively in a timely manner.⁶⁸

Other Factors Contributing to the Development of Fatty Pancreas and Pancreatic Cancer

Genetics

Although the risk of PDAC is strongly linked clinically and epidemiologically to long-standing type 2 diabetes and chronic pancreatitis, there is little overlap in the genetic basis of susceptibility. All three conditions are characterized by genetic heterogeneity.⁵ The study of genetic predisposition has been impacted as well as a result of an implied selection bias through the recruiting and collecting specimens from patients with poor survival.⁵

Age

Pancreatic fat content increases with age and peaks in the third and fourth decades; after the sixth decade, pancreatic parenchymal content declines and, as a result, the ratio of fat to parenchyma increases later in life.²¹

Enterobiome

Some very interesting recent study from a multicenter group based in New York and Chapel Hill, NC, suggests a microbial influence. Pushalkar et al.⁶⁹ reported that the cancerous pancreas harbors a more abundant microbiome compared with normal pancreas in mice and humans, and that select bacteria are preferentially increased in the tumorous pancreas compared with gut. Microbial ablation with oral antibiotics in a murine model of pancreatic oncogenesis protected against pancreatic cancer development, whereas transfer of bacteria from hosts bearing pancreatic cancer reversed this protection. It appeared that selective bacterial ablation allowed an immunogenic reprogramming of the tumor microenvironment and promoted T cell activation and improved checkpoint-targeted immunotherapy, suggesting that the microbiome has potential as a therapeutic target.⁶⁹ More recent study from the same consortium suggest a role for gut fungi; human and mouse models of pancreatic cancer have a roughly 3000-fold increase in fungi compared with normal pancreatic tissue, with particular enrichment in Malassezia species. These investigators propose a role in tumor pathogenesis for the activation of mannose-binding lectin and the complement cascade.⁷⁰

Previous studies have suggested an association between variations of the salivary microbial profile and pancreatic cancer and chronic pancreatitis; no causation was implied, but rather the use of salivary studies as a noninvasive marker of pancreatic disease.⁷¹

Generalized inflammation

As indicated previously, poor glycemic control has been associated with RAGE activation⁷; in mouse models, RAGE activation leads to obesity and a proinflammatory profile.⁷² In humans, obesity, particularly visceral adiposity, carries a strong association with pancreatic cancer.⁷³ Compared with the perigonadal fat depot, the mesenteric (peripancreatic depot) adipose tissue showed an enhanced proinflammatory response to a high-fat high-calorie diet.⁷⁴ In a mouse model, this diet accelerates the progression of pancreatic intraepithelial neoplasia.⁷⁵

A recent review from investigators at University of California, Los Angeles, proposes that visceral adipose tissue inflammation is a strong promoter of PDAC growth and progression in a mouse model of PDAC and diet-induced obesity.⁷⁶ Similarly, Mizuno et al. reported that visceral adiposity based on CT data was correlated with MRI-documented pancreatic cystic lesions; adiponectin was also positively associated with the prevalence of pancreatic lesions.⁷⁷

Treatment

Currently, there is no consensus guideline regarding treatment of fatty pancreas since it is only recently recognized as a clinical entity. If it is assumed to be in analogy with fatty liver disease, fatty pancreas may be reversible.²⁰

Weight loss

Successful bariatric surgery results in reduced insulin resistance, pancreatic fat volume, and pancreatic fatty acid uptake all decreased in association with weight loss.⁷⁸

Exercise

Heiskanen et al.⁷⁹ studied health middle aged men (n = 28) and prediabetic or diabetic middle aged men and women (n = 26), who were then randomized to either moderate or high intensity exercise. After 2 weeks of exercise, either moderate- or high-intensity, all groups showed decreased pancreatic fat, as well as subcutaneous and visceral fat, with negligible effect on weight or body mass index.⁷⁹

Diabetes medications

Diabetic medications may have different impacts in pancreatic cancer patients with diabetes. A multicenter consortium (the International Pancreatic Cancer Case–Control Consortium) reported on data derived from >8000 patients with pancreatic adenocarcinoma. Patients with diabetes of more than two decades' duration had a 30% excess risk for pancreatic cancer. Treatment with “oral antidiabetic” medications (not otherwise specified but likely sulfonylureas and metformin based on the time frame of the study) may decrease the risk of pancreatic cancer, whereas insulin therapy had an inconsistent duration–risk relationship.⁸⁰ A meta-analysis published by Zhou et al. suggested metformin has a survival benefit in pancreatic cancer patients with diabetes⁸¹; this analysis was retrospective and evaluated the use of metformin in patients with concurrent diabetes and pancreatic cancer. Metformin may also reduce the risk of pancreatic cancer in patients with diabetes.^82,83 Animal models suggest that metformin may enhance the effect of gemcitabine⁸⁴; this effect may be heterogeneous within a tumor and reflect tumor architecture.⁸⁵ Current guidelines for diabetes management warn of the risk of pancreatitis and/or pancreatic cancer with use of dipeptidyl peptidase-4 (DPP-4) inhibitor agents and GLP-1 receptor agonists, which have otherwise been very popular based on glucose and weight control and cardiovascular benefit. These warnings are based, in part, on an analysis of the United States Food and Drug Administration's database of reported adverse events; use of sitagliptin or exenatide increased the odds ratio for reported pancreatitis sixfold; pancreatic cancer was similarly more commonly reported.⁸⁶ However, recent analyses based on cardiovascular outcome trials tell a different story. El Aziz et al. reported an increased risk of pancreatitis but not cancer with DPP-4 agents but not GLP-1 agonists.⁸⁷ Pinto et al. showed no effect of GLP-1 agonists on pancreatic cancer.⁸⁸ Monami et al. reported no effect on pancreatic cancer but an increased risk of gallstones.⁸⁹ Nevertheless, based on current regulatory approvals, practitioners might choose to avoid these medications in patients with a history of pancreatitis or pancreatic cancer.

As intimated earlier, there are sparse studies evaluating treatment options for fatty pancreas in humans. However, animal models of fatty pancreas show promise with sitagliptin and telmisartan,⁹⁰ troglitazone,⁹¹ and berberine and cinnamic acid.⁹²

Summary

In conclusion, fatty pancreas appears to be a significant underappreciated risk factor for the subsequent development of pancreatic cancer. Given the increasing prevalence of obesity, type 2 diabetes, and pancreatic cancer, clinicians might be well advised to consider undiagnosed fatty pancreas in their patients, particularly those with fatty liver. Unfortunately, imaging every obese patient or those with type 2 diabetes for underlying fatty pancreas is not feasible. However, a low threshold of suspicion should be reserved, particularly for those with abnormal liver tests or a family history of pancreatic cancer.

In addition to identifying those individuals with fatty pancreas, several unanswered questions remain: Is it possible to have a consistent quantitative definition of fatty pancreas that can be used to identify patients? Does an improved metabolic milieu, either through lifestyle changes, that is, exercise or weight loss, or medication, reduce the prevalence of fatty pancreas, and potentially the risk of pancreatic cancer? What is the role of inflammatory cytokines, and is this a potential avenue for therapeutic intervention? There are tantalizing suggestions that microbial changes may play a role in tumorigenesis, and other studies suggesting that microbial changes may serve as early markers of malignancy. Is there a relationship between fatty pancreas and mucinous pancreatic cysts, which themselves serve as a marker for pancreatic cancer risk? There is clear documentation of the link between visceral adiposity and intrapancreatic fat and pancreatic cancer, and visceral adiposity and pancreatic cystic lesions. There is little documentation of a link between fatty pancreas and pancreatic cystic lesions; whether this represents radiographic or biological limitations is unclear. Our case had both findings, each uncovered by a different imaging modality.

Footnotes

Acknowledgments

This material is the result of study supported with resources and the use of facilities at the VA Northern California Health Care System. The author acknowledges the expert assistance of Ms. Alba Scott, MILS, without whose efforts this article would not have been possible. The author appreciates the efforts of Jon A. Green, MD, PhD, and Ann Manheimer, for critically reading the article.

Disclaimer

The contents do not represent the view of the United States Department of Veterans Affairs or the United States Government.

Author Disclosure Statement

No conflicting financial interests exist.

Funding Information

No funding was received for this article.

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