1726 REVIEW ARTICLE

Pancreatic Steatosis: An Emerging Clinical Entity

REVIEW ARTICLE

Resham Ramkissoon, MD1 and Timothy B. Gardner, MD, MS1

Pancreatic steatosis is an emerging clinical entity whose pathophysiology, natural history, and long-term
complications are poorly characterized in the current literature. Epidemiological and prospective studies have
described prevalence rates between 16% and 35%. Although the natural history is not well known, there are strong
associations with obesity, metabolic syndrome, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Ectopic
fat accumulation of the pancreas can cause chronic, low-grade inflammation from adipocytokine imbalances that
involve beta cells and acinar cells. This mechanism can lead to pancreatic endocrine and exocrine dysfunction and
initiate carcinogenesis. Although it is associated with morbid conditions, pancreatic steatosis may be amendable to
treatment with a healthy diet, less meat consumption, exercise, and smoking cessation. Pancreatic steatosis should
factor into clinical decision-making and prognostication of patients with pancreatic and systemic disease. This review
seeks to describe the pathophysiology, natural history, diagnosis, and complications of this emerging clinically
relevant entity.
Am J Gastroenterol 2019;114:1726–1734. https://doi.org/10.14309/ajg.0000000000000262

INTRODUCTION mellitus (T2DM) and atherosclerosis (9). These publications

The increasing prevalence of obesity has become a global epi- demonstrated the early interest surrounding obesity and its
demic. The World Health Organization estimates approxi- effect on the pancreas.
mately 3.5 million deaths occur yearly from obesity. Obese
individuals live in a state of chronic, low-grade inflammation
NOMENCLATURE
through heightened actions of tumor necrosis factor alpha and
Many terms are used to describe the “accumulation of fat” in the
interleukin (IL)-6. Steatosis is a phenomenon correlating
pancreas: pancreatic steatosis, fatty pancreas, pancreatic lip-
strongly with obesity and insulin resistance, where non-
omatosis, fatty replacement, fatty infiltration, nonalcoholic fatty
esterified fatty acids (NEFAs) deposit in nonadipose tissues
pancreas disease (NAFPD), and lipomatous pseudohypertrophy
(1–3). Nonalcoholic fatty liver disease (NAFLD) is a well-
(LPH). A Nature Review by Smits and van Geenen (10) asserts
known clinical entity of ectopic fat accumulation within hep-
that pancreatic steatosis is the best description of general fat ac-
atocytes. The pathophysiology, diagnosis, and natural history
cumulation in the pancreas from any etiology. Like pancreatic
of NAFLD is thoroughly studied and described in the current
steatosis, fatty pancreas is a less-common general term describing
literature (4,5). Steatosis of the pancreas is a finding docu-
all forms of fat accumulation in the pancreatic parenchyma. Fatty
mented a century ago but is not well characterized, yet it may
replacement is a term describing conditions resulting in acinar
be as clinically important as NAFLD. Enhancing our un-
cell death (viral infections, chemotherapy, or ductal ligation)
derstanding of pancreatic steatosis has important implications;
leading to replacement of the pancreatic parenchyma with adi-
there is a potential link between primary pancreatic endocrine
pocytes, an essentially irreversible process (11–13). Fatty in-
and exocrine dysfunction as well as pancreatic cancer. The goal
filtration is an older term describing adipocyte infiltration into the
of this review is to describe the current understanding of
pancreatic parenchyma, without replacement, which is related to
pancreatic steatosis including its pathophysiology, natural
obesity (14,15).
history, and diagnosis.
NAFPD is a newer term reserved for the subtype of pancreatic
steatosis associated with obesity and metabolic syndrome. Unlike
HISTORICAL CONTEXT fatty replacement, NAFPD is reversible with weight loss and/or
The concept of pancreatic steatosis was first described in 1926 pharmacotherapy (14,16–24). Pancreatic lipomatosis is another
based on correlations between pancreatic weight, pancreatic fat less-common general term describing fatty replacement in-
content, and body weight of cadavers (6). One decade later, volving the exocrine tissue and fatty infiltration (10). LPH is in-
a study found a greater pancreatic fat percentage in obese voked when the pancreas is enlarged, uniformly or focally,
cadavers compared with lean cadavers (7). Almost 40 years because of fat replacement. LPH can be considered a variant of
later, autopsy studies found higher pancreatic fat content cor- pancreatic steatosis with pseudotumor formation by fat that is
related with increasing age and obesity (8). Individuals who had difficult to distinguish from pancreatic adenocarcinoma without
.25% pancreatic fat also had higher rates of type 2 diabetes histology (10,12,21,25). Pancreatic steatosis has been used to

1
Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. Correspondence: Resham Ramkissoon, MD.
E-mail: resham.a.ramkissoon@hitchcock.org.
Received October 1, 2018; accepted March 12, 2019; published online May 23, 2019

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 Pancreatic Steatosis 1727

describe pancreas enlargement but is not always related to obesity pancreas (35). Another study examined the relationship between
(26,27). This is consistent with the assertion by Smits and van pancreatic steatosis and nonalcoholic steatohepatitis (NASH),
Geenen that pancreatic steatosis is the best, overarching term for finding approximately 50% of patients with NASH have con-
pancreatic fat accumulation. current pancreatic steatosis (11). Overall, NAFLD was the

REVIEW ARTICLE
strongest predictor for pancreatic steatosis (odds ratio 14, P ,
PREVALENCE 0.002) (37).
There are limited epidemiological studies documenting the true Other important risk factors for pancreatic steatosis are obe-
global prevalence of pancreatic steatosis. A systemic review and sity, followed by existing metabolic syndrome, T2DM, and dys-
meta-analysis involving .12,000 individuals yielded a preva- lipidemia (11,33–35,37–43). Lifestyle factors such as sedentary
lence rate of 33% (95% confidence interval 24%–41%). Meta- habits, smoking, alcohol use, and frequent meat consumption
regression argues that NAFPD prevalence is independent of age (frequency not specified) were also associated with pancreatic
and sex, however, is associated with hypertension, T2DM, and steatosis (30). Apart from medical comorbidities, there is a scar-
metabolic syndrome. Body mass index (BMI) and waist cir- city of literature on long-term mortality outcomes of patients with
cumference were not associated with NAFPD, suggesting these pancreatic steatosis, and future prospective studies are needed to
measures are not a reliable proxy for NAFPD. This suggests further our understanding.
individual differences in “metabolic phenotype” exist among
obese individuals. Furthermore, the absence of pancreatic DIAGNOSIS
steatosis, before bariatric surgery, can be a screening feature of There are no widely accepted diagnostic criteria for pancreatic
“metabolic phenotypes” and prevent low-risk patients from steatosis based on imaging or severity score of fat accumulation.
a having potentially unneeded surgery (28). The gold standard for assessing pancreatic fat is histology
Nine of 11 studies in this systematic review were conducted in (37,44,45), which will show more adipocytes within the pancre-
Asian populations, raising the concern for phenotypic variations atic parenchyma (46). Singh et al. (28) recommends the cutoff for
and biases (28). Other studies in Asian populations agree with this normal pancreatic fat content should be 6.2%. This cutoff was
review, finding prevalence rates between 16% and 35% (29,30). determined by meta-regression of mean pancreatic fat content in
The prevalence of pancreatic steatosis in hospitalized pediatric healthy volunteers plus 2 SDs. Could this cutoff indicate that
patients is 10% (31), concurring with the increasing prevalence of a small degree (,6.2%) of pancreatic steatosis is normal? Out of
childhood obesity and NAFLD (32). A study by Weng et al. (33) individuals who have NAFPD, it is still unknown how to define
examined .4000 Asian subjects, finding a smaller prevalence of the fraction of individuals who develop nonalcoholic steatopan-
NAFPD of 11.1%. In addition, this study finds a higher incidence creatitis (NASP). Could the cutoff of 6.2% indicate a threshold for
of NAFPD with age and in men younger than 55 years. Two transition to a disease entity such as NASP? Future prospective
different studies demonstrate men have a greater risk of de- studies following individuals with different percentages of pan-
veloping pancreatic steatosis independent of age (34,35). Ethnic creatic steatosis are needed to determine this natural history of
differences in prevalence exist with pancreatic steatosis; there is pancreatic steatosis.
higher pancreatic triglyceride content in obese Hispanics than Some studies use computer-generated techniques for organ fat
obese African Americans (36). quantification, but these have not been validated through real-
Most epidemiological studies of pancreatic steatosis are con- world experience (16,47,48). Morphometric analysis is an ob-
ducted in Asian populations. More studies in different pop- jective, computerized technique which calculates the amount of
ulations, especially those with high rates of obesity, would be pancreatic fat within a field on histology. This technique can be
valuable in understanding the global prevalence of pancreatic protocolized to grade pancreatic steatosis based on histology but,
steatosis. Future comparisons between studies may be challeng- like the previous techniques, requires validation in clinical
ing because clear definitions have not been outlined regarding practice (40). Distributions of pancreatic fat accumulation are
imaging, biochemical studies, nomenclature, and etiology. frequently uneven based on radiology studies (48). This leads to
However, the previous meta-regression recommends that 6.2% errors in sampling and histological grading when attempting to
should be the cutoff for normal pancreatic fat content (28). classify and diagnose pancreatic steatosis. Furthermore, obtain-
ing routine biopsies is not a clinically validated approach for an
RISK FACTORS initial diagnostic test and carries significant risk.
In assessing the prevalence of pancreatic steatosis, several risk Computed tomography (CT) is a preferred imaging technique
factors have been identified. Age seems to be an important risk for visualizing abdominal organs. CT without contrast is pre-
factor for pancreatic steatosis because epidemiological studies in ferred for the evaluation of pancreatic fat because contrast is
Asian patients found a positive correlation between age and absorbed by the normal parenchyma between areas of fatty
NAFPD (33,34). Yet, pancreatic steatosis in the pediatric pop- deposits, misleading readers to suspect a solid lesion (49). The
ulation should not go unrecognized (31). Men also seem to have severity of steatosis can be measured with CT using Hounsfield
a greater risk for pancreatic steatosis than women (33–35). In the units; however, cutoff thresholds are not established (50). Mag-
study by Weng et al., men younger than 55 years had a higher netic resonance imaging (MRI) is an imaging technique with
incidence of pancreatic steatosis compared with women of similar higher resolution and is used to diagnose pancreatic steatosis.
age. There was no gender predilection, however, in individuals Proton magnetic resonance spectroscopy (1H-MRS) is the gold
older than 55 years. standard for noninvasive quantification of pancreatic fat content.
One of the primary associations and risk factors with pan- Several studies indicate its diagnostic accuracy is comparable with
creatic steatosis is NAFLD. A study of 293 patients with pan- histology and biochemical markers (17,39,51). A newer technique
creatic steatosis found a 67.9% concurrence rate with NAFLD and known as 3D Iterative Decomposition with Echo Asymmetry and
a 96.4% negative predictive value of NAFLD with a normal Least Squares Estimation (IDEAL)-MRI is studied comparatively

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 1728 Ramkissoon and Gardner

with 1H-MRS. Images are obtained faster with 3D IDEAL-MRI cytosine-cytosine-adenosine-adenosine-thymidine (CCAAT)
with less signal contamination, making this technique possibly enhancer binding protein-a, and CCAAT enhancer binding
better than the gold standard for fat quantification of small, ret- protein-b which inhibit differentiation of preadipocytes into
roperitoneal organs such as the pancreas (52,53). mature adipocytes. Poor preadipocyte differentiation perpetuates
REVIEW ARTICLE

Transabdominal ultrasonography is an inexpensive technique triglyceride “spillover” and mishandling. This continuous cycle
that is readily available with minimal risk and cost. However, will lead to worsening adipocytokine imbalances and chronic,
results can be operator dependent, and visualization of the pan- low-grade inflammation (5,63).
creas can be challenging in obese patients. Magnetic resonance Inflammation and lipid mishandling are the key factors that
elastography (MRE) is an imaging technique that can provide lead to the release of NEFAs, ectopic fat deposition, and pan-
a quantitative assessment of the stiffness of biological tissues. The creatic steatosis. Adipocytokine-mediated inflammation con-
retroperitoneal location, size, shape, and heterogeneity of the tributes to oxidative stress on the pancreas, leading to beta cell and
pancreas make the use of ultrasound challenging, which is why acinar cell dysfunction and apoptosis, followed by endocrine and
elastography will enhance the ability to differentiate between exocrine insufficiency (5,64). NEFAs reduce insulin-stimulated
pancreatic vs surrounding fat (54). This is performed by reading glucose uptake, glycogen synthesis, and glucose oxidation, which
magnetic resonance-generated shear waves from soft tissues. all contribute to overstimulation and “burnout” of beta cells. This
MRE is a recently well-established technique for evaluating fi- further contributes to endocrine dysfunction (65).
brosis, inflammation, and edema of tissues. MRE is the most The higher volumes of pancreatic fat in pancreatic steatosis are
accurate, noninvasive test for assessing hepatic fibrosis and cor- associated with extensive pancreatic necrosis and multisystem
relates well with histological staging of fibrosis (55,56). Like the organ failure in the individuals with acute pancreatitis (66).
liver, MRE may be a technique for quantifying stiffness of the Furthermore, obese individuals are at greater risk of increased
pancreas and a noninvasive technique for diagnosing chronic severity and death from acute pancreatitis (57,67,68). Obesity-
pancreatitis and pancreatic cancer. Studies in healthy volunteers related etiologies of pancreatitis include cholelithiasis, malig-
confirm interobserver reliability and reproducibility between nancy, hyperlipidemia, or medications, but pancreatic steatosis is
subjects (54). No comparative studies, however, have focused on an under-recognized cause. Just as NAFLD can develop into
MRE examinations in patients with solely pancreatic steatosis. NASH, so can NAFPD progress into NASP (37,61). NASP is not
Endoscopic ultrasonography (EUS) overcomes the visual and a diagnosis used in clinical practice, but there is a large body of
anatomic barriers of transabdominal ultrasound with the added literature that supports its clinical significance (62).
availability of a biopsy; however, this carries procedural risks. There is promising work describing the pathogenesis of
Elastography via EUS is developed to complement EUS in the chronic, low-grade inflammation related to ectopic fat accumu-
assessment of pancreatic tumors and lymph nodes that are hard lation in nonadipose tissues (5). The pathophysiology of NAFLD
to reach. Added techniques to EUS elastography such as strain and NASH has been investigated extensively and, given the close
ratio and strain histograms add dynamic quantification of organ association between NAFLD and NAFPD, similar in vitro studies
stiffness in a region of interest. Strain histograms can be analyzed could be conducted to elucidate the pathophysiology of pancre-
and programmed to differentiate between benign and malignant atic steatosis.
tissue. Strain histograms can be predictive of exocrine in-
sufficiency in chronic pancreatitis and correlate well with histo- ENDOCRINE DYSFUNCTION
pathology (57). The Japanese Society of Medical Ultrasonics has Obesity is a significant risk factor for T2DM and is associated with
published clinical practice guidelines for elastography of the pancreatic steatosis. The global epidemic of obesity may explain
pancreas. The guidelines describe high precision of evaluating the increasing incidence and prevalence of T2DM (69), with
tumors, chronic pancreatitis, and pancreatic fibrosis that will only pancreatic steatosis as the causal link between these 2 diseases. It
improve with continued technological advancement (58). is therefore important to investigate the effects obesity has on the
These ultrasound techniques cannot differentiate between fat pancreas, specifically relating to fatty infiltration.
accumulations within the endocrine or exocrine tissue. On seeing Studies in animal models showed high-fat diets are a risk
pancreatic steatosis by any imaging technique, this should gen- factor for oxidative stress, beta-cell apoptosis, and pancreatic
erally be described as architecturally agnostic pancreatic steatosis steatosis (P , 0.05) (70). Mouse models with metabolic syndrome
that cannot be attributed to existing endocrine or exocrine dys- develop insulin resistance, NAFLD, and pancreatic steatosis
function without biopsy or biochemical studies. when fed prolonged, high-fat diets (38). This supported a later
finding that fat accumulation in pancreatic parenchyma leads to
PATHOPHYSIOLOGY AND CONSEQUENCES impairment in beta-cell function (71).
The pathophysiology and consequences of pancreatic steatosis The next step would be to translate these findings from animal
begin with obesity. Adipose tissue is a metabolically active en- models to human subjects. A study evaluating the utility of MRS
docrine organ that is involved in homeostasis (59,60). Excess found that pancreatic fat content correlated with worsening
calorie intake will result in adipocyte hypertrophy and hyper- glycemic control (42). Another study of .8000 Asian subjects
plasia. Once at critical mass, triglycerides will “spillover” into the showed an association between T2DM and pancreatic steatosis
surrounding tissue, causing alterations in the microenvironment using ultrasonography (41). Biochemical studies support the
from ectopic fat deposit. This phenomenon is studied in the liver, connection between pancreatic steatosis and T2DM; trending
muscle, heart, and kidney (5). In response to changes in extra- pancreatic steatosis and beta-cell function in men showed
cellular homeostasis, there is an influx of macrophages and re- a higher pancreatic fat content in diabetic compared with non-
lease of adipocytokines (IL-6, IL-1b, tumor necrosis factor alpha, diabetic individuals (P 5 0.032). Pancreatic fat content correlated
leptin, and serum amyloid A) (5,16,61,62). This causes the negatively with beta-cell function parameters (P , 0.05), and this
downregulation of peroxisome proliferator-activated receptor-g, was worse in nondiabetic men (P , 0.01) (53). Therefore,

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 Pancreatic Steatosis 1729

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Figure 1. Pathogenesis and pathophysiology of pancreatic steatosis. A pathophysiology map starting from obesity that describes the pathogenesis of
NAFPD and proposed mechanisms leading to diseases of the pancreas. This includes endocrine dysfunction, exocrine dysfunction, and pancreatic
malignancy. C/EBPa, CCAAT enhancer-binding protein a; C/EBPb, CCAAT enhancer-binding rotein b; IL, interleukin; NAFPD, nonalcoholic fatty pancreas
disease; NASP, nonalcoholic steato-pancreatitis; NEFA, nonesterified fatty acid; PPARg, peroxisome proliferator-activated receptor g.

pancreatic fat infiltration is an independent factor leading to Americans and greater suppression of beta-cell function
endocrine dysfunction. Multiple studies found similar results parameters compared with whites with similar levels of pancre-
when examining pancreatic fat content, finding negative corre- atic triglycerides (65). These studies indicate a significant asso-
lations between pancreatic fat content and beta-cell function in ciation between pancreatic steatosis and pancreatic endocrine
prediabetic men (34,39). dysfunction with ethnic predispositions. The mechanistic path-
The concept of glucose and free fatty acid “crosstalk” is way of this association remains unclear, and further studies are
a reported phenomenon in which NEFAs stimulate insulin se- needed to determine how this occurs.
cretion. This directly causes hyperinsulinemia leading to insulin
resistance. Interestingly, this process occurs in diabetic and EXOCRINE DYSFUNCTION
nondiabetic patients (65,72,73). Furthermore, there is an ethnic The earliest manifestations of exocrine dysfunction in pancreatic
predilection as Hispanic individuals may be more susceptible to steatosis are deficits in enzyme secretion; however, the time
the “crosstalk” phenomenon. Obese Hispanic individuals had course and clinical significance are yet to be determined. Pan-
greater pancreatic triglycerides compared with African creatic steatosis is the second leading cause of pediatric pancreatic

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 1730 Ramkissoon and Gardner

Table 1. Nomenclature of pancreatic “fat accumulation” Table 2. Clinical features of pancreatic steatosis

Nomenclature Definition Clinical features Pancreatic steatosis

REVIEW ARTICLE

Pancreatic steatosis The best general term for “fat accumulation” in Physical examination findings • Higher age (8,30)
the pancreas (10) • Male sex (33–35)
• Obesity and/or higher BMI (.25
Fatty pancreas A general term for “fat accumulation” in the
kg/m2) (1,2,17,30,34,35,39,41–43)
pancreas (10)
• Larger waist circumference
NAFPD A subtype of pancreatic steatosis related to (11,30,34,35,39,41)
obesity and metabolic syndrome that is • Elevated blood pressures (30,34,43)
reversible (14,16–24)
Historical findings • History of smoking (30)
Pancreatic lipomatosis A term used to describe fatty replacement of • Frequent meat consumption (33)
exocrine tissues and fat infiltration (10) Comorbidities and associated • Metabolic syndrome (10,30,35,43)
Fatty infiltration Adipocyte infiltration into the pancreas related conditions • T2DM (9,11,17,34,41)
to obesity that is reversible (15,20) • NAFLD (10,41,43,52,95)
• NASH (11)
Fatty replacement Irreversible replacement of pancreatic tissue
• Atherosclerosis (9)
with fat, often resulting from acinar cell death • Steatorrhea and malabsorption
(11,13,21) (26,75–79),a
LPH A variant-associated enlargement of the • Chronic pancreatitis (80)
pancreas by a pseudotumor made of fat, • Pancreatic ductal adenocarcinoma (87)
histologically distinct from an organ lipoma • Pancreatic intraepithelial neoplasia (88)
(10,12,21,25) Laboratory findings • Elevated fasting and postprandial
plasma glucose (30,34,53)
LPH, lipomatous pseudohypertrophy; NAFPD, nonalcoholic fatty pancreas
disease.
• Elevated hemoglobin A1c (53)
• Elevated total cholesterol
(30,34,35,43)
insufficiency and coexists with syndromes that consistently result • Hypertriglyceridemia (30,34,35)
in exocrine dysfunction including cystic fibrosis, Shwachman- • Elevated LDL (30,43)
• Lower HDL (30,34,35)
Diamond syndrome, and Johanson-Blizzard syndrome (74).
• Higher ALT and AST (30,34,35)
Since Dupont authored this publication in 1989, few studies on
• Higher GGT (30,35)
exocrine insufficiency and pancreatic steatosis have been pub-
lished, apart from some case reports (21,26,75–79). Patients with Ultrasound (endoscopic/ • Hyperechoic pancreatic parenchyma
endocrine dysfunction in these cases developed symptoms of transcutaneous) (10,37)
• EUS of such patients will have normal
malabsorption. Complete fatty replacement was seen on imaging
caliber biliary ducts (77)
studies; however, histology was unavailable. Additionally, a case
• Normal ERCP (77)
series describes patients with chronic pancreatitis who had EUS
findings demonstrating pancreatic steatosis and intraductal CT • Hypointensities similar in density to
pancreatic calculi. This series implicates pancreatic steatosis as retroperitoneal adipose tissues (10)
the primary cause of chronic pancreatitis and ductal stones (80). MRI • T1-weighted and T2-weighted images
The oxidative stress resulting from fat accumulation leads to will show hyperintensities similar to
acinar cell apoptosis and exocrine insufficiency. Furthermore, the surrounding fat within the
hypertrophied pancreatic adipocytes enact a paracrine effect on pancreatic parenchyma when
acinar cells, decreasing their exocrine function (10). These compared with a normal liver (10)
mechanisms are based on in vitro studies and require in vivo Histology • Increased pancreatic adipocytes,
studies for development. which can be either heterogeneous or
There is a significant correlation between the degree of fatty homogeneous (46)
infiltration into the pancreatic parenchyma and pancreatitis se-
verity, supporting the pathophysiology that more fat deposition ALT, alanine aminotransferase; AST, aspartate aminotransferase; CT, computed
tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS,
leads to more inflammation (10).
endoscopic ultrasonography; GGT, gamma-glutamyl transferase; HDL, high-
density lipoprotein; LDL, low-density lipoprotein; MRI, magnetic resonance
imaging; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic
MALIGNANCY
steatohepatitis; T2DM, type 2 diabetes mellitus.
Obesity is a known risk factor for pancreatic cancer (81–86). The a
Steatorrhea is finding that was found in case reports of patients with exocrine
increased pancreatic fat accumulation is hypothesized to play insufficiency likely caused by pancreatic steatosis.
a role in the progression from NAFPD and NASP to pancreatic
cancer. This theory is supported by a study showing high-fat diets
increase the risk of pancreatic cancer in animal models and examining the histopathology of patients with pancreatic stea-
humans (16). Specifically, there is a direct association between tosis, pancreatic cancer, and healthy controls (87,88). Pancreatic
pancreatic fat infiltration and the incidence of pancreatic ductal cancer is one of the most lethal cancers in the world with few
adenocarcinoma and intraepithelial neoplasia from 2 studies clinical tools for early detection. Retrospective studies report

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 Pancreatic Steatosis 1731

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Figure 2. Imaging studies displaying pancreatic steatosis. (a) CT of the abdomen showing hypointensities within the pancreatic parenchyma, similar in
intensity to the retroperitoneal fat, which represents fatty infiltration. (b) T2-weighted MRI showing intensities within the pancreatic parenchyma, which is
a higher intensity compared with the liver and spleen, representing fatty infiltration. (c) Transcutaneous ultrasound of the pancreas showing a heterogenous,
hypoechoic parenchyma (94). (d) Radial endoscopic ultrasound image demonstrating fatty infiltration of the pancreas (arrows) in a patient with CFRT-
related pancreatic disease.

a high prevalence of NAFPD in patients with pancreatic malignancy There is no consensus on the pathogenesis of pancreatic car-
(odds ratio 18.027, 95% confidence interval 7.288–44.588). EUS, the cinoma in the setting of pancreatic steatosis; however, 2 studies
most sensitive test for pancreatic fat, may be a necessary screening suggest a possible mechanism: the combination of metabolic
tool for pancreatic malignancy in patients with NAFPD (89). syndrome, oxidative stress/inflammation, and adipocytokine

Figure 3. Histology of pancreatic steatosis. Histology of pancreatic steatosis showing numerous adipocytes (red arrows) within the pancreatic parenchyma
at 350 (a) and 3100 (b).

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 1732 Ramkissoon and Gardner

imbalances precipitates pancreatic carcinoma (90,91) (Figures prevented or reversed inflammatory cell infiltration, fatty re-
1–3). The increased mass of adipocytes in pancreatic steatosis placement, and fibrosis based on histology (14). Pancreatic lipase
initiates carcinogenesis, which is propagated by low-grade in- inhibition (with Orlistat) in mice reduces the severity of acute
flammation from adipocytokine imbalances. The chronic pancreatitis, fat necrosis, organ failure, and mortality in obese
REVIEW ARTICLE

proinflammatory state created by diffuse pancreatic adipocytes mice with pancreatic steatosis (18). Furthermore, combining
puts patients at risk for recurrent pancreatitis, which is a prime sitagliptin and telmisartan demonstrates efficacy in controlling
risk factor for pancreatic adenocarcinoma (10). pancreatic steatosis and avoiding progression to morbid pan-
A case-control analysis examined patients with known pan- creatic disease from lipotoxicity in mice (19). In vitro studies with
creatic adenocarcinoma undergoing planned tumor resection. berberine and cinnamic acid (components of a new medication in
Pancreatic fat was correlated with markers of severe disease which Japan; the “Jiaotai Pill”) in pancreatic beta cell cultures showed
included lymph node involvement, tumor size, and mean sur- inhibition of lipid accumulation by decreasing lipogenesis and
vival. They found that “node-positive” patients had more pan- promoting lipid oxidation (20). These animal and in vitro studies
creatic fat and reduced mean survival, suggesting pancreatic provide a foundation for further studies into pharmacotherapy
steatosis promotes dissemination, tumor spread, and lethality in for individuals with pancreatic steatosis.
pancreatic cancer (92). More prospective cohort studies with No consensus guidelines exist for the treatment of pancreatic
long-term follow-ups are needed to establish the timing and steatosis because it is an entity needing more recognition and
causal link between pancreatic steatosis and primary pancreatic investigation to understand its clinical significance. Based on
malignancy. these data for potential treatment options, more long-term
interventional studies should be conducted to assess the mortality
TREATMENT benefit, improvement in glycemic control, and the incidence of
Early treatment of NAFLD and NASH is important because the pancreatitis and pancreatic neoplasia.
inflammation leads to hepatocyte apoptosis, fibrosis, and even-
tually cirrhosis. Management is geared toward reducing com-
pounding liver injury and reducing fat burden of the liver through CONCLUSION
weight loss, healthy dieting, and exercise (93). These lifestyle Pancreatic steatosis is an entity that is emerging into clinical
modifications may also benefit patients with pancreatic steatosis relevance. Since the 1920s, physicians queried the relationship
because it is a reversible process by reducing calorie intake (15). In between obesity and a fatty pancreas. Epidemiological studies
addition, frequent meat consumption (frequency not specified) is have described high prevalence rates and increased risk with age,
associated with a greater risk of pancreatic steatosis (30). Weng male sex, and Hispanic ethnicity. More studies should be con-
et al. (33) examined other lifestyle factors, including regular ex- ducted with representative populations with high rates of obesity
ercise and smoking, and found a nonsignificant trend between including young and old people. There are many invasive and
pancreatic steatosis and sedentary habits as well as smoking (P 5 noninvasive tools to diagnose pancreatic steatosis including
0.071 and 0.794, respectively). 1H-MRS, 3D IDEAL-MRI, and EUS elastography. These highly
The impact of weight loss on pancreatic steatosis after bariatric accurate tests are predictive of histology, and there are guidelines
surgeries has been studied in animal and human models. Mouse that exist in Japan for the use of MR and EUS elastography.
models of “obesity-induced pancreatopathy” demonstrated Sedentary lifestyles, obesity, and metabolic syndrome all
pancreatic adipocyte infiltration and what they describe as contribute to the “spillover” of triglycerides from adipocytes. The
“exocrine tissue lesions of pancreatopathy” (acinar duct meta- resulting adipocytokine imbalances lead to chronic, low-grade
plasia, fibrosis, and iron deposits) by quantitative MRI, MR inflammation that is implicated as a cause of beta-cell and acinar
elastography, and histology. These findings were reversible in cell apoptosis. In vitro studies, which have been performed ex-
mouse models after vertical sleeve gastrectomy and/or Roux-en- tensively for NAFLD, are needed to characterize the pathophys-
Y anastomosis (22). Bariatric surgery in obese humans that iology of pancreatic steatosis and the proposed differences in
resulted in weight loss has the following benefits after 6 months: “metabolic phenotype.” The increased mass of adipocytes, ac-
decreased pancreatic fat volume, decreased fatty acid uptake, and companied by oxidative stress, can be an initiator of malignancy.
improved beta cell function parameters (23). Specifically, there Obesity and fat accumulation in the pancreas have a direct effect
was a 40% reduction in pancreatic lipid content by positron on the increased severity of pancreatitis and pancreatic necrosis,
emission tomography and CT, agreeing with the 44% reduction and an increase in the progression and lethality of pancreatic
observed in other studies (17,24). Interestingly, the degree of adenocarcinoma as well.
pancreatic fat reduction did not correlate with reductions in total According to the World Health Organization, obesity will lead
body weight or waist circumference, again suggesting differences to millions of deaths every year and pancreatic steatosis may be
in individual “metabolic phenotype” (28). Glucose-dependent the entity that leads to “obesity-related” complications such as
insulinotrophic peptide is a hormone that has been implicated in endocrine dysfunction, exocrine dysfunction, and, one of the
regulating adiposity in rodents (23) and may have a role in this most lethal disease known to man, pancreatic cancer. Enhancing
mechanism. Fatty replacement caused by diseases such as he- our understanding of this condition may unearth some pre-
mochromatosis and cystic fibrosis may not have the same benefit ventable causes of death and ways of potentially screening for and
(10), which is consistent with the nomenclature described by treating this condition. There is enough evidence that pancreatic
Smits and van Geenen. (10) (Tables 1 and 2). steatosis can be treated with weight loss and reducing high-calorie
Studies in mouse models have demonstrated a role for drug intake, and a role for frequent exercise and smoking cessation.
therapy in patients with pancreatic steatosis. Troglitazone ad- Further clinical and basic research is needed to elucidate the
ministered to mouse models for T2DM causes a significant in- pathophysiology, long-term complications, and effective treat-
crease in pancreatic wet weight, protein content, and completely ment strategies for this condition.

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 Pancreatic Steatosis 1733

CONFLICTS OF INTEREST 24. Steven S, Hollingsworth KG, Small PK, et al. Weight loss decreases excess
Guarantor of the article: Resham Ramkissoon, MD. pancreatic triacylglycerol specifically in type 2 diabetes. Diabetes Care
2016;39:158–65.
Specific author contributions: All authors have made substantial
25. Altinel D, Olca Basturk, Sarmiento JM, et al. Lipomatous
contributions, participated in the drafting and revision of the article, pseudohypertrophy of the pancreas: A clinicopathological distinct entity.

REVIEW ARTICLE
and gave final approval of the version to be published. R.R. and T.G. Pancreas 2010;39:392–7.
assume the final direct responsibility for the manuscript. 26. Lozano M, Navarro S, Pérez-Ayuso R, et al. Lipomatosis of the pancreas:
Financial support: There were no funding sources for this An unusual cause of massive steatorrhea. Pancreas 1988;3:580–2.
27. Yang DM, Kim HC, Ryu JK, et al. Sonographic appearance of focal fatty
publication. infiltration of the pancreas. J Clin Ultrasound 2010;38:45–7.
Potential competing interests: None. 28. Singh RG, Yoon HD, Wu LM, et al. Ectopic fat accumulation in the
pancreas and its clinical relevance: A systematic review, meta-analysis,
and meta-regression. Metab Clin Exp 2017;69:1–13.
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