Preventive Effect of High-Dose Digestive Enzyme Management on Development of Nonalcoholic Fatty Liver Disease after Pancreaticoduodenectomy: A Randomized Controlled Clinical Trial.

2020-12
Journal of the American College of Surgeons 231(6)
- Koya Yasukawa
- Akira Shimizu
- Takahide Yokoyama
- Koji Kubota
- Tsuyoshi Notake
- Hitoshi Seki
- Akira Kobayashi
- Yuji Soejima

PubMed: 32927075
DOI: 10.1016/j.jamcollsurg.2020.08.761

Study Design

Type: Randomized Controlled Trial (RCT)
Population: 80 patients (39 normal-dose, 41 high-dose) undergoing elective pancreaticoduodenectomy
Methods: parallel-group, nonblinded, multicenter study; patients randomly assigned to normal-dose or high-dose digestive enzyme treatment within 1 week after surgery
Blinding: Open-label
Duration: within 1 year
Funding: Unclear

Background

Nonalcoholic fatty liver disease (NAFLD) is a complication of pancreaticoduodenectomy (PD). We conducted a randomized clinical trial to determine if high-dose digestive enzymes prevented the development of NAFLD after PD.

Study design

This parallel-group, nonblinded, multicenter study enrolled patients undergoing elective PD at Shinshu University School of Medicine, from June 2011 to April 2017. Patients were randomly assigned to receive normal-dose (Excelase: 3.0 g/day [Meiji Seika Pharma Holdings Co, Ltd]) or high-dose digestive enzyme treatment (Excelase: 3.0 g/day; Pancreatin g/day; Berizym g/day; and Toughmac-E g/day) within 1 week after surgery. Because patients in the control group switched interventions upon receiving a diagnosis of NAFLD, intention-to-treat analysis was used. The primary endpoint was incidence of NAFLD within 1 year, and the secondary endpoints were the incidences of NAFLD at 1, 3, 6, and 12 months and the rate of improvement in NAFLD with high-dose transfer in the control group. The secondary analysis comprised assessment of risk factors for the development of NAFLD.

Results

Eighty-four patients were randomly assigned (42 per group), 80 of whom were finally analyzed (39 normal-dose, 41 high-dose). The incidence of NAFLD was significantly lower in the high-dose (8 of 41) compared with the normal-dose (25 of 39) patients (p < 0.001). Multivariate analysis identified normal-dose (odds ratio [OR] 14.65, p < 0.001), total protein ≤ 6.5g/dL (OR 9.01, p = 0.018), pre-albumin ≤ 22.0 mg/dL (OR 7.71, p = 0.018), and pancreatic function diagnostic test ≤ 70% (OR 6.66, p = 0.009) as independent risk factors. There were no adverse effects. The model was accurate (c-index = 0.92) and reliable (Hosmer-Lemeshow test p = 0.32).

Conclusions

High-dose administration of digestive enzymes significantly reduced the onset of NAFLD after PD compared with normal-dose administration. Registration number: UMIN000005595 (http://www.umin.ac.jp/ctr/).

Research Insights

Pancreatin→Improved Nonalcoholic Fatty Liver Disease
The secondary endpoints were the incidences of NAFLD at 1, 3, 6, and 12 months and the rate of improvement in NAFLD with high-dose transfer in the control group.
Effect
Neutral
Effect size
Small
Dose
3.0 g/day
Pancreatin→Reduced Nonalcoholic Fatty Liver Disease Incidence
The incidence of NAFLD was significantly lower in the high-dose (8 of 41) compared with the normal-dose (25 of 39) patients (p < 0.001).
Effect
Beneficial
Effect size
Large
Dose
3.0 g/day

Adverse Events Reported

Pancreatin→adverse events
There were no adverse effects.
Finding
No significant difference
Significant
No
Pancreatin→Overall tolerability
There were no adverse effects.
Finding
Reported