Factors contributing to nonalcoholic fatty liver disease (NAFLD) and fat deposition after pancreaticoduodenectomy: A retrospective analysis

Abstract Aim Nonalcoholic fatty liver disease (NAFLD) can occur due to various reasons after pancreaticoduodenectomy (PD). This study examined the risk and perioperative determinants of NAFLD and fat deposition after PD. Methods A total of 101 patients who had undergone computed tomography 6 months after PD were included. We compared perioperative factors between patients who developed NAFLD and those who developed fatty deposits after PD. Results In the NAFLD group, pancreatic cancer was significantly more prevalent among patients who developed postoperative NAFLD (p = 0.024) and had a lower postoperative body mass index (BMI; p = 0.008). Multivariate analysis revealed that pancreatic carcinoma (hazard ratio [HR] 4.42, 95% confidence interval [CI] 1.118–17.442, p = 0.034) and lower postoperative BMI (HR 0.51, 95% CI 0.274–0.954, p = 0.0355) were risk factors for fatty liver. Pancreatic leakage (p = 0.024) and postoperative BMI (p = 0.002) were significantly lower in the fat deposition group than those in the NAFLD group. Multivariate analysis also revealed that a lower postoperative BMI was a risk factor for fat deposition (HR 0.56, 95% CI 0.523–0.982, p = 0.042). Moreover, multivariate analysis revealed that the fat deposition group had significantly lower pancreatic leakage than the NAFLD group (HR 7.944, 95% CI 1.993–63.562, p = 0.049). Conclusion The findings of this study suggest that postoperative BMI and pancreatic cancer are associated with a higher risk of NAFLD after PD, possibly because of pancreatic exocrine insufficiency and impaired fat absorption.


| INTRODUC TI ON
Nonalcoholic fatty liver disease (NAFLD) is a pathological manifestation of fatty liver disease in the absence of a clear history of alcohol consumption. It is broadly classified into progressive nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver (NAFL), with the latter showing little or no disease progression. 1 In 1980, Ludwig et al. 2 defined NASH as a set of pathological findings similar to those of alcoholic hepatitis that steadily progress from cirrhosis to liver failure despite the absence of alcohol use. The development of NAFLD associated with lifestyle-related diseases, such as dyslipidemia and diabetes mellitus, is influenced by environmental and genetic factors. 3 After gastrointestinal surgery, hyponutrition and various metabolic abnormalities may occur, possibly leading to the development of secondary NAFLD. After total gastrectomy, physiological digestive processes in the stomach are lost, and digestive and absorption disorders may develop due to the lack of gastric acid and pepsin, decreased secretion of gastrointestinal hormones, and impaired pancreatic exocrine secretion. 4 NAFLD can occur after pancreaticoduodenectomy (PD) at a reported frequency of 15%-40% due to various reasons. [5][6][7][8] Various risk factors have been reported for the development of NAFLD after PD, including pancreatic cancer, high preoperative HbA1c and CA19-9 levels, pancreas resection volume, pancreatic stiffness, female sex, pancreatic leakage, postoperative pancreatic exocrine insufficiency, and postoperative impaired intake and diarrhea. 6,7,[9][10][11][12] To the best of our knowledge, no studies have investigated the risk factors for fat deposition after PD, which may precede but not necessarily lead to NAFLD. In this study, we examined the risk and perioperative determinants of NAFLD and fat deposition after PD at our institution.

| Surgical procedures
The surgical procedure performed for all patients was subtotal stomach-preserving PD (SSPPD) via the modified Child method. 13 Pancreatic duct jejunal mucosal anastomosis was performed. No pancreatic duct stent was placed in patients with main pancreatic duct dilatation. For patients with a soft pancreas without main pancreatic duct dilation, a 5-Fr pancreatic duct stent (Sumitomo Bakelite) was placed in the jejunum as a lost stent. No external stent was used for pancreatoenterostomy. No external bile fistulas were found, and no jejunostomy or gastrointestinal tube was required. Only one patient required the placement of a closed suction drain from the left side to the dorsal pancreatic jejunal anastomosis. Drinking water and oral nutrition were initiated on the first postoperative day, whereas food intake was initiated on the third postoperative day. The drain was removed after checking it, and the amylase level on the third postoperative day was measured. If no postoperative problems developed, the patient was discharged on the seventh postoperative day. No prescriptions for pancreatic enzyme supplementation, such as LapaCreon® (Eisai Co., Ltd.) or Berizym® (Shionogi & Co., Ltd.), were required.

| Definition of NAFLD
The presence of NAFLD was determined through plain CT performed 6 months after PD. Liver and spleen attenuation values were measured on unenhanced CT images and presented in Hounsfield units to quantify the development of NAFLD. Each region of interest (ROI) was a round area of 1.0 cm 2 . We considered the mean value of four ROIs at different sections of the liver as a measure of the degree of liver attenuation ( Figure 1). To measure spleen attenuation, a single ROI was used, and NAFLD was defined as a liver-to-spleen attenuation ratio 14 of <0.9.
Next, we defined fat deposition as the stage preceding NAFLD as follows. The difference between the preoperative liver-to-spleen attenuation ratio and the 6-month postoperative liver-to-spleen attenuation ratio was calculated. Cases with a difference of 0.10 or more were considered to have a tendency toward fat deposition and were classified into the fat deposition group.

| Statistical analysis
All statistical analyses were performed using SPSS version 26.0 for Windows (IBM). Continuous variables were expressed as mean ± standard deviation (SD). Statistically significant differences were determined using the paired t-test or Mann-Whitney U-test.
Categorical variables were analyzed using the χ 2 test or Fisher's test, as appropriate. Risk factors associated with the development of NAFLD and pre-NAFLD were analyzed using univariate and multivariate analyses. Results were considered statistically significant at a p value of <0.05.

| Background of the enrolled patients
The total number of patients enrolled herein was 101. The male-tofemale ratio was 57:44; the median age was 72 years (interquartile range: 35-87 years); the median surgery duration was 233.0 min (123-507 min); the median blood loss was 631.0 mL (54-3146 mL); and the median postoperative hospital stay was 12.0 days (6-59 days). Fourteen patients (13.9%) had ISGPF Grade B POPF. All patients were able to start drinking water the day after surgery, and all patients were able to start eating on the third postoperative day. The surgical procedures performed were SSPPD in 83 cases, SSPPD + portal vein resection in nine cases, SSPPD + hepatectomy in one case, PD in two cases, and laparoscopic SSPPD in six cases.

| Examination for NAFLD
Only one patient had NAFLD preoperatively. Six months after surgery, NAFLD was identified in 12 patients (11.9%), only one of whom had preoperative NAFLD. The male-to-female ratio was 1:2, and the diseases were pancreatic cancer in 10 cases, cholangiocarcinoma in one case, and serous cyst neoplasm in one case.
Pancreatic cancer was significantly more prevalent among patients with postoperative NAFLD (p = 0.024). SSPPD was performed in 11 cases and PD in one case. Complications included bile leakage in two cases, anastomotic stenosis in one case, and SSI in one case.  There was no pancreatic leakage in the NAFLD group; however, the difference in the incidence of this complication between the NAFLD and non-NAFLD groups was not statistically significant (p = 0.149). The time-lapse until drain removal was shorter in the NAFLD group (5.8 days) than in the non-NAFLD group (9.9 days); however, the difference in this parameter between the two groups was not statistically significant (p = 0.295). No significant differences in blood loss volume, surgery duration, and diagnosis were observed between the NAFLD and non-NAFLD groups. The NAFLD group had a lower postoperative BMI than the non-NAFLD

| Examination for fat deposition
Thirty-four patients in the fat deposition group had a difference of

| DISCUSS ION
In the present study, we investigated postoperative NAFLD and fat deposition after PD and identified pancreatic cancer and low postoperative BMI as risk factors for postoperative NAFLD. We also found that patients with postoperative fatty deposits had a low incidence of pancreatic leakage and lower postoperative BMIs.
The main difference between post-PD NAFLD and the usual NAFLD is that the former occurs without insulin resistance, 6 a TA B L E 3 Comparison of clinical data between the fat deposition and nonfat deposition groups. phenomenon for which several mechanisms have been postulated.
The first mechanism is impaired pancreatic exocrine function, which has been reported in 65.5% of PD cases. 16 In pancreatic cancer, the lesion obstructs the pancreatic duct, causing caudal chronic pancreatitis and associated pancreatic atrophy, which in turn leads to decreased pancreatic exocrine function. Impaired pancreatic exocrine function results in fatty stools, and impaired fat absorption enhances the conversion of carbohydrates to fat in the liver. 9 Neurogenic diarrhea associated with superior mesenteric artery (SMA) plexus dissection may also cause fat malabsorption and exacerbate NAFLD. 9 The second possible mechanism is the presence of endotoxins that induce hepatic dysfunction. creatic enzyme secretion. 20 The incidence of zinc deficiency after PD, in which a portion of the duodenum and proximal jejunum is resected, has been reported to be 68%. 21 Therefore, after PD, malnutrition develops in close association with exocrine dysfunction, diarrhea, infection, and zinc deficiency, resulting in NAFLD.
In our study, pancreatic cancer was significantly more frequently observed in the NAFLD group compared to the non-NAFLD group.
Additionally, pancreatic leakage was significantly more frequently observed in the fat deposition group compared to the nonfat deposition group. Although not significant, no cases of pancreatic exocrine leakage were observed in the NAFLD group, suggesting that the pancreatic exocrine function was impaired; thus, pancreatic leakage did not occur. Hence, the above findings imply that decreased pancreatic exocrine function is associated with the pathogenesis of fat deposition. Patients in the NAFLD and fat deposition groups had lower postoperative BMIs, suggesting that impaired fat digestion and absorption due to impaired pancreatic exocrine function was the underlying cause and was significantly involved in the pathogenesis of hepatic fat deposition. All 12 patients who developed NAFLD after PD were included in the fat deposition group. Therefore, the new concept of fat deposition that we proposed in this study definitely reflects the process of postoperative NAFLD transition after PD.
Moore et al. 22 reported that the incidence of pancreatic exocrine insufficiency after pancreatectomy varied depending on the surgical technique used, with PD, DP, and central resection accounting for 43%, 12%, and 5% of cases, respectively. In case of pancreatic head tumors, caudal pancreatic atrophy occurs; however, in most cases, the pancreatic tissue in the head of the organ is normal during caudal pancreatectomy and pancreatic function is thought to be preserved.
Pancrelipase delayed-release capsules (CREON), as a treatment option for pancreatic exocrine insufficiency, has been reported to be effective in decreasing the frequency of defecation, improving the absorption rate of fat and increasing the post-pancreatectomy body weight. 23,24 Improvements in NAFLD after pancreatectomy have been reported to contribute to the prognosis of patients, 25 especially those with pancreatic cancer. 26 Our study suggests that CREON should be administered prophylactically to patients with pancreatic cancer after PD. In our study, pancreatic cancer was also a risk factor for NAFLD, and CREON should be administered after PD for pancreatic cancer. In addition, patients who do not develop pancreatic leakage may have impaired pancreatic exocrine function, and CREON administration may be considered as a NAFLD prophylaxis in such patients.
This study has several limitations. First, this was a single-center retrospective study; therefore, its relevance may be considered primarily exploratory. Hence, a large-scale multicenter study is desirable to demonstrate the reproducibility of the results of this study.
Second, NAFLD is a quickly changing pathology that depends on the patient's condition and the passage of time. In our study, we used CT values obtained 6 months after PD; however, study data may vary if the period changes. Third, parameters such as pancreatic exocrine function and zinc levels were not evaluated. Future studies are needed to evaluate the post-PD pancreatic exocrine function and clarify its relationship with fat deposition.
In conclusion, our findings suggest that postoperative BMI and pancreatic cancer are associated with a higher risk of postoperative NAFLD after PD, which may result from pancreatic exocrine insufficiency with impaired fat absorption.

AUTH O R CO NTR I B UTI O N S
HI, HY, RF, ST, MM, EN, and HM performed the surgical procedures and postoperative management.

ACK N OWLED G M ENTS
The authors would like to thank Enago for the English language review.

FU N D I N G I N FO R M ATI O N
Not available.

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors declare no conflicts of interest for this article.

E TH I C A L A PPROVA L
The protocol for this research project was approved by a suitably constituted ethics committee of Tokai University in November 2022, approval no. 22R-186, and the study was conducted per the principles of the Declaration of Helsinki. Informed consent was obtained from all participants or their guardians.