Journal of the Pancreas Open Access

Keywords

Pancreas

INTRODUCTION

Multiple terms have been used to describe fat accumulation in the pancreas, such as pancreatic steatosis, fatty pancreas, pancreatic lipomatosis, fatty infiltration, lipomatous pseudohypertrophy of pancreas, and non-alcoholic fatty pancreas (NAFP). Gastroenterologists should be informed of this condition and its clinical correlations. Here, we review the literature regarding this pancreatic condition in terms of epidemiology, characteristics in imaging studies, etiology, clinical significance, and clinical correlation including treatment and prevention. This condition was first reported in 1993 by Ogilvie [1] who revealed that a higher incidence of fatty pancreas was observed in obese compared to lean cadavers (17% vs. 9%, respectively). Up to the present, the true incidence of fatty pancreas was still unclarified, however, there were only two studies from Choi CW et al. [2] and Seppe PS et al. [3] demonstrate as high as 27.8-46% of the patients who underwent EUS evaluation for some other reasons who had the evidence of hyperechogenic pancreas. While Wong VW et al. reported that 16.1% of Hongkong-Chinese population had pancreatic steatosis(cut-off level at higher than 10% of pancreatic fat infiltration which diagnosed by Fat-water MRI technique) [4]. There have subsequently been many clinical and basic science studies published regarded this condition. A PubMed-library based search , restricted to only human studies available in English articles, was carried out for the period between 2005 and December 2014 . The following individual and combined keywords were used: fatty pancreas, pancreatic steatosis, pancreatic fat infiltration, pancreatic lipomatosis, non-alcoholic-fatty pancreas, NAFP. The referenced obtained from the articles’ citations were also reviewed for other potential sources of information. From a total of 958 articles , only 94 related articles were obtained. All the case report and case series, retrospective cohort studies, cross section and prospective studies which all the abstracts and a total of 72 full text manuscripts were reviewed. Figure 1 shows the diagram for demonstration of the review process [5].

CLINICAL PRESENTATION, DIAGNOSIS AND IMAGING STUDIES

Most of the patients who had pancreatic steatosis or fatty pancreas were asymptomatic. They were diagnosed by abnormal imaging studies of the pancreas. Only a handful of case reports presented with pancreatic bulging or mass-like lesion or abnormal pancreatic imaging studies after surgery such as pancreatic transplantation or chemotherapy. There is no gold standard for histopathological diagnosis of fatty pancreas due to limited tissue acquisition and few studies in living patients. Therefore, the diagnosis of pancreatic steatosis mainly depends on noninvasive imaging studies using transabdominal ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and recently, EUS. The typical fatty tissue characteristic revealed by US is diffuse hyperechoic pancreatic parenchyma when compared to the kidneys. However, if the ultrasonographer would conclude that hyperechogenic pancreas found on transabdominal ultrasonography were all fatty pancreas, they might be wrong. Gullo et al. [6] reported , a small study of 9 patients, that none of the patients who had hyperechogenic pancreas from ultrasound was found to have more fat infiltration in the pancreas when using a regular MRI technique( which in the authors opinion it was also not very sensitive). While hypo-attenuation signal intensity of the pancreas when compared to the spleen on a CT scan can also indicate pancreatic fat accumulation. To our knowledge, MRI is considered the most accurate , noninvasive, method to identify fat accumulation in visceral organs, but there are also other techniques which are more sensitive for detection of fat component in the tissue including T2-weighted imaging which shows prominent reduction in signal intensity of the fat replacement of pancreas in opposed - phase MR imaged [7], chemical shift imaging [8], fat-water MRI, and study of iterative decomposition with echo asymmetry and least squares estimation(IDEAL technique)[4-6], a spectral-spatial excitation technique, which combines chemical shift selectivity with simultaneous slice-selective excitation in combination with another technique based on double-echo chemical shift gradient-echo MR provides in- and opposedphase images simultaneously [9]. All these MRI techniques were all developed for early and accurate diagnosis of fat within internal organs. The definitive diagnosis of pancreatic steatosis is histopathology which usually acquired from post mortem or surgical specimens. The histopathology of pancreatic steatosis showed localized or diffused replacement of pancreatic parenchyma by mature adipose tissue[10]. Altinel and Yasuda et al. [11, 12] reported a rare condition of mass-like fat infiltration, which could be missed diagnosis as pancreatic cancer, called Lipomatous pseudohypertrophy of pancreas.

Etiology

More than 90% of population would have less than 5% of fat infiltration in pancreas [13]. The etiology of pancreatic steatosis varies from congenital related to acquired conditions. However, it can be classified into 4 groups: 1) obesity and metabolic syndrome; there are some clinical studies [2-5, 14] regarded the patients who were diagnosed as fatty pancreas from endoscopic ultrasound, MRI or CT scan which demonstrated that high body mass index(BMI) and metabolic syndrome were associated with fatty pancreas (Odd Ratio(OR) 1.05-3.13 while non alcoholic fatty liver showed a 14-fold correlation with pancreatic steatosis [15]. 2) congenital syndromes such as cystic fibrosis, Shwachman–Diamond syndrome(which was a rare autosomal recessive disorders characterized by association of pancreatic exocrine insufficiency ,due to fat infiltration and atrophy, bone marrow dysfunction and skeleton abnormalities) [16-20], and Johanson–Blizzard syndrome(a rare genetic disorder characterized by short stature, mental retardation, pancreatic insufficiency, sensorineural hearing lost, hypoplatic nasal alae, scalp defect and dental abnormalies) [21, 22]. 3) toxic agents and medications such as steroid therapy and gemcitabine chemotherapy which all of these medication related cases were reported case only [23-25] , and 4) other rare causes such as reoviral infection [26], human immunodeficiency virus infection that could cause pancreatic steatosis through a combination of malnutrition-related and viralrelated effects, and chronic hepatitis B infection [27]. A summary of etiologies of pancreatic steatosis are provided in Table 1.

Clinical Impact of Fatty Pancreas

The prevalence of NAFP was reported to be around 16% in Hong Kong Chinese population [4]. There was a statistically significant correlation between NAFP and non-alcoholic fatty liver disease (NAFLD) (odds ratio [OR]=2.22; 95% confidence interval [CI], 1.88–2.57; P<0.001), central obesity (OR = 2.16; 95% CI, 1.85–2.52; P<0.001), age (OR = 1.05; 95% CI, 1.04–1.05; P<0.001), hypertriglyceridemia (OR = 1.32; 95% CI, 1.13–1.55; P=0.01), aspartate aminotransferase and alanine transaminase level elevation (OR = 1.29; 95% CI, 1.13–1.70; P=0.02), and diabetes mellitus (DM) (OR = 1.59; 95% CI, 1.30–1.95; P<0.001). Data suggest that fat accumulation in the pancreas may lead to similar processes as in non-alcoholic steatohepatitis (NASH). Patel et al. demonstrated in 2013 [28] that higher pancreatic fat content correlated with a higher grade of hepatic steatosis in patients with biopsy-proven NAFLD, but did not correlate with body mass index (BMI) or DM. This study also demonstrated no difference in the distribution of fatty content among the pancreatic portions (head, body, and tail). Although pancreatic steatosis was reported as a clinical manifestation of metabolic syndrome (Figure 1), other research indicates that this condition might lead to beta-cell dysfunction, causing DM. There was a significant difference between ethnicities (Hispanic > African American > Caucasian) in the correlation between pancreatic steatosis, which detected by triglyceride droplets in the cytosol of non-adipose cells in the pancreas via positron emission scan, and beta-cell dysfunction and compensatory insulin secretion. This correlations could be used as a predictor for development of type 2 DM (prediabetic state) [29].

Mirarrakhimov [30] proposed that obstructive sleep apnea might predispose individuals to develop fatty pancreas, which correlated with the etiology of metabolic syndrome and DM, and was related to a greater risk of cardiometabolic disease. Apart from metabolic-related changes associated with pancreatic steatosis, patients with NAFP had an increased risk of developing severe, acute pancreatitis when pancreatitis occurred from any cause.

Van Greenen et al. [31] demonstrated a significant correlation between pancreatic steatosis and the CT severity index of pancreatitis.

Mathur et al. published in 2009 [32] a case controlled study of 20 lymph node-negative and 20 lymph nodepositive pancreatic cancer patients whose other factors such as age, BMI, gender, tumor size, resection status, and co-morbidity were matched. The study showed that significantly more patients in the node-positive group than the node-negative group had fatty pancreas (46.4±8.7 vs. 21.4±4.8; P<0.02). Patients in the node positive group also had less fibrosis than node-negative patients (1.7±0.3 vs. 2.7±0.3; P<0.02). The mean survival was also reduced in the node-positive compared to that in the node-negative group (18.9±2.7 months vs. 30.8±4.8 months; P<0.04). The hypothesis was that pancreatic steatosis altered the tumor microenvironment, enhanced tumor spread, and contributed to early death of the pancreatic cancer patients.

Mathur et al. reported in 2007 [33] that the presence of pancreatic fat significantly increased the risk of developing a pancreatic fistula. A subsequent study [34] showed similar results, as did the 2010 study by Gaujoux et al. [35], which concluded that pancreatic fat was a more reliable risk factor for developing pancreatic fistula than soft pancreas.

However, the data regarded natural history of pancreatic steatosis is still unknown due to lack of supportive evidences.

Correlation Between Non-Alcoholic Fatty Liver and Non-Alcoholic Fatty Pancreas

As mentioned above, Erwin-Jan et al. demonstrated a correlation between NAFLD and NAFP (both interlobular fat infiltration and total pancreatic fat) from material collected from 80 patients postmortem. There were some evidence demonstrated that chronically increase in level of plasma nonesterified fatty acid and triglyceride-riched lipoprotein impaired beta cell function and lead to apoptosis(lipotoxicity process) in the animal model, it is still inconclusive in human studies [36]. Since NAFLD is well known and presents clinical concerns [37-41], we summarize the clinical manifestations and clinical significance of these two conditions in Table 2.

TREATMENT AND PREVENTION

Treatment of fatty pancreas depends upon the etiology. If the etiology is identified and found to be correctable, it may help reduce pancreatic fat infiltration. General lifestyle modifications such as weight reduction, exercise, or dietary restrictions can improve patients with metabolic syndrome. However, there is no specific treatment for fatty pancreas. In some particular patients such as the patients who undergo pancreatic surgery, the higher risk of fistula formation should be aware by the surgeon.

CONCLUSION

Pancreatic steatosis is a common, benign pancreatic condition observed in clinical practice. Clinical knowledge of this condition is essential for gastroenterologists to be able to care for their patients. Identification of the exact etiology and correction would help reduce pancreatic fat infiltration.

Future Research

A large cohort study should be conducted to definitively determine the clinical significance of pancreatic steatosis, its correlation with metabolic syndrome and DM, and its association with pancreatic cancer risk. Potential treatments such as lifestyle modification, weight reduction, and medications used in NAFLD should be investigated.

Conflicting Interest

The authors had no conflicts of interest

References

1. Ogilvie RF. The islands of Langerhans in 19 cased of obesity. J Pathol 1933; 37: 473-81.
2. Choi CW, Kim GH, Kang DH, Kim HW, Kim DU, Heo J, Song GA, Park do Y, Kim S. World J Associated factors for a hyperechogenic pancreas on endoscopic ultrasound. Gastroenterol 2010; 16: 4329-34. [PMID: 20818817]
3. Sepe PS, Ohri A, Sanaka S, Berzin TM, Sekhon S, Bennett G, Mehta G, et al. A prospective evaluation of fatty pancreas by using EUS. Gastrointest Endosc 2011; 73: 987-93.
4. Wong VW, Wong GL, Yeung DK, Abrigo JM, Kong AP, Chan RS, et al. Fatty pancreas, insulin resistance, and β-cell function: a population study using fat-water magnetic resonance imaging. Am J Gastroenterol 2014; 109: 589-97. [PMID: 24492753]
5. Hu HH, Kim HW, Nayak KS, Goran MI. Comparison of fat-water MRI and single-voxel MRS in the assessment of hepatic and pancreatic fat fractions in humans. Obesity (Silver Spring) 2010; 18: 841-7.
6. Gullo L, Salizzoni E, Serra C, Calculli L, Bastagli L, Migliori M. Can pancreatic steatosis explain the finding of pancreatic hyperenzymemia in subjects with dyslipidemia? Pancreas 2006; 33: 351-3.
7. Kim HJ, Byun JH, Park SH, Shin YM, Kim PN, Ha HK, Lee MG. Focal fatty replacement of the pancreas: usefulness of chemical shift MRI. AJR Am J Roentgenol. 2007; 188: 429-32. [PMID: 17242252]
8. Li J, Xie Y, Yuan F, Song B and Tang C. Noninvasive Quantification of Pancreatic Fat in Healthy Male Population Using Chemical Shift Magnetic Resonance Imaging: Effect of Aging on Pancreatic Fat Content. Pancreas 2011; 40: 295-9. [PMID: 21178651].
9. Schwenzer NF, Machann J, Martirosian P, Stefan N, Schraml C, Fritsche A, Claussen CD, Schick F. Quantification of pancreatic lipomatosis and liver steatosis by MRI: comparison of in/opposed-phase and spectralspatial excitation techniques. Invest Radiol 2008; 43: 330-7.
10. Smits MM, van Geenen EJ. The clinical significance of pancreatic steatosis. Nat Rev Gastroenterol Hepatol 2011; 8: 169-77. [PMID: 21304475].
11. Altinel D, Basturk O, Sarmiento JM, Martin D, Jacobs MJ, Kooby DA, Adsay NV. Lipomatous pseudohypertrophy of the pancreas: a clinicopathologically distinct entity. Pancreas 2010; 39: 392-7.
12. Yasuda M, Niina Y, Uchida M, Fujimori N, Nakamura T, Oono T, Igarashi H, et al. A case of lipomatous pseudohypertrophy of the pancreas diagnosed by typical imaging. JOP. 2010; 11: 385-8.
13. Lingvay I, Esser V, Legendre JL, Price AL, Wertz KM, Adams-Huet B, Zhang S, Unger RH, Szczepaniak LS. Noninvasive quantification of pancreatic fat in humans. J Clin Endocrinol Metab 2009; 94: 4070-6.
14. Lee JS, Kim SH, Jun DW, Han JH, Jang EC, Park JY, et al. Clinical implications of fatty pancreas: correlations between fatty pancreas and metabolic syndrome. World J Gastroenterol 2009; 15: 1869-75.
15. Al-Haddad M, Khashab M, Zyromski N, Pungpapong S, Wallace MB, Scolapio J, et al. Risk factors for hyperechogenic pancreas on endoscopic ultrasound: a case-control study. Pancreas 2009; 38: 672-5.
16. Feigelson J, Pécau Y, Poquet M, Terdjman P, Carrère J, Chazalette JP, Ferec C. Imaging changes in the pancreas in cystic fibrosis: a retrospective evaluation of 55 cases seen over a period of 9 years. J Pediatr Gastroenterol Nutr 2000; 30: 145-51. [PMID: 10697132].
17. Ruggiero A, Molinari F, Coccia P, Attinà G, Maurizi P, Riccardi R, Bonomo L. MRI findings in Shwachman diamond syndrome. Pediatr Blood Cancer 2008; 50: 352-4. [PMID:17183583]
18. Gana S, Sainati L, Frau MR, Monciotti C, Poli F, Cannioto Z, Comelli M, Danesino C, Minelli A. Shwachman-Diamond syndrome and type 1 diabetes mellitus: more than a chance association? Exp Clin Endocrinol Diabetes 2011; 119: 610-2.
19. Sanklecha M, Balani K . Chronic pancreatic insufficiency-think of Shwachmann Diamond Syndrome. Indian Pediatr. 2012; 49: 417-8. [PMID:22700671]
20. Nakaya T, Kurata A, Hashimoto H, Nishimata S, Kashiwagi Y, Fujita K, Kawashima H, Kuroda M. Young-age-onset pancreatoduodenal carcinoma in Shwachman-Diamond syndrome. Pathol Int 2014; 64: 75-80.
21. Hoffman WH, Lee JR, Kovacs K, Chen H, Yaghmai F. Johanson-Blizzard syndrome: autopsy findings with special emphasis on hypopituitarism and review of the literature. Pediatr Dev Pathol 2007; 10: 55-60. [PMID: 17378628]
22. Godbole K, Maja S, Leena H, Martin Z. Johanson-blizzard syndrome. Indian Pediatr. 2013; 50: 510-2. [PMID:23778732]
23. Makay O, Kazimi M, Aydin U, Nart D, Yilmaz F, Zeytunlu M, Goker E, Coker A. Fat replacement of the malignant pancreatic tissue after neoadjuvant therapy. Int J Clin Oncol 2010; 15: 88-92.
24. Lin WC, Chen JH, Lin CH, Shen WC. Rapidly progressive pancreatic lipomatosis in a young adult patient with transfusion-dependent myelodysplastic syndrome. J Formos Med Assoc 2007; 106: 676-9. [PMID: 17711803]
25. Oliveira NM, Ferreira FA, Yonamine RY, Chehter EZ. Antiretroviral drugs and acute pancreatitis in HIV/AIDS patients: is there any association? A literature review. Einstein (Sao Paulo). 2014; 12: 112-9. [PMID: 24728257]
26. Walters MN, Leak PJ, Joske RA, Stanley NF, Perret DH. Murine infection with reovirus 3. pathology of infection with types 1 and 2. Br J Exp Pathol 1965; 46: 200-12. [PMID: 14286949]
27. Sasaki M, Nakanuma Y, Ando H. Lipomatous pseudohypertrophy of the pancreas in a patient with cirrhosis due to chronic hepatitis B. Pathol Int 1998; 48: 566-8. [PMID: 9701022]
28. Patel NS, Peterson MR, Brenner DA, Heba E, Sirlin C, Loomba R. Association between novel MRI-estimated pancreatic fat and liver histology-determined steatosis and fibrosis in non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2013; 37: 630-9. [PMID: 23383649]
29. Szczepaniak LS, Victor RG, Mathur R, Nelson MD, Szczepaniak EW, Tyer N, et al. Pancreatic steatosis and its relationship to β-cell dysfunction in humans: racial and ethnic variations. Diabetes Care 2012; 35: 2377-83. [PMID: 22968187]
30. Mirrakhimov AE. Nonalcoholic fatty pancreatic disease and cardiometabolic risk: is there is a place for obstructive sleep apnea? Cardiovasc Diabetol 2014; 13: 29. [PMID: 24475948]
31. van Geenen EJ, Smits MM, Schreuder TC, van der Peet DL, Bloemena E, Mulder CJ. Nonalcoholic fatty liver disease is related to nonalcoholic fatty pancreas disease. Pancreas 2010; 39: 1185-90. [PMID: 20871475]
32. Mathur A, Zyromski NJ, Pitt HA, Al-Azzawi H, Walker JJ, Saxena R, Lillemoe KD. Pancreatic steatosis promotes dissemination and lethality of pancreatic cancer. J Am Coll Surg 2009; 208: 989-94. [PMID: 19476877]
33. Mathur A, Marine M, Lu D, Swartz-Basile DA, Saxena R, Zyromski NJ, Pitt HA. .Nonalcoholic fatty pancreas disease. HPB (Oxford) 2007; 9: 312- 8. [PMID: 18345311]
34. Tranchart H, Gaujoux S, Rebours V, Vullierme MP, Dokmak S, Levy P, et al. Preoperative CT scan helps to predict the occurrence of severe pancreatic fistula after pancreaticoduodenectomy. Ann Surg 2012; 256: 139-45. [PMID: 22609844]
35. Gaujoux S, Torres J, Olson S, Winston C, Gonen M, Brennan MF, et al. Impact of obesity and body fat distribution on survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg Oncol 2012; 19: 2908-16. [PMID: 22411205]
36. van Raalte DH, van der Zijl NJ, Diamant M. Pancreatic steatosis in humans: cause or marker of lipotoxicity? Curr Opin Clin Nutr Metab Care 2010; 13: 478-85.
37. Roberts KJ, Storey R, Hodson J, Smith AM, Morris-Stiff G. Pre-operative prediction of pancreatic fistula: is it possible? Pancreatology 2013; 13: 423-8. [PMID: 23890142]
38. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012; 142: 711-25.e6. [PMID: 22326434]
39. Fisher CP, Kierzek AM, Plant NJ, Moore JB. Systems biology approaches for studying the pathogenesis of non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20: 15070-78. [PMID: 25386055]
40. Lonardo A, Ballestri S, Targher G, Loria P. Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2014; 20: 1-22. [PMID: 25327387]
41. Machado MV, Cortez-Pinto H. Non-alcoholic fatty liver disease: What the clinician needs to know. World J Gastroenterol 2014; 20: 12956-80. [PMID: 25278691]