Chronic pancreatitis affects over 250,000 people in the US and millions worldwide. It is associated with chronic debilitating pain, pancreatic exocrine failure, and high risk of pancreatic cancer and usually progresses to diabetes. Treatment options are limited and ineffective. We developed a new potential therapy, wherein a pancreatic ductal infusion of 1%–2% acetic acid in mice and nonhuman primates resulted in a nonregenerative, near-complete ablation of the exocrine pancreas, with complete preservation of the islets. Pancreatic ductal infusion of acetic acid in a mouse model of chronic pancreatitis led to resolution of chronic inflammation and pancreatitis-associated pain. Furthermore, acetic acid–treated animals showed improved glucose tolerance and insulin secretion. The loss of exocrine tissue in this procedure would not typically require further management in patients with chronic pancreatitis because they usually have pancreatic exocrine failure requiring dietary enzyme supplements. Thus, this procedure, which should be readily translatable to humans through an endoscopic retrograde cholangiopancreatography (ERCP), may offer a potential innovative nonsurgical therapy for chronic pancreatitis that relieves pain and prevents the progression of pancreatic diabetes.
Mohamed Saleh, Kartikeya Sharma, Ranjeet Kalsi, Joseph Fusco, Anuradha Sehrawat, Jami L. Saloman, Ping Guo, Ting Zhang, Nada Mohamed, Yan Wang, Krishna Prasadan, George K. Gittes
Submitter: Ihsan Ekin Demir | ekin.demir@tum.de
Authors: Elke Demir and Helmut Friess
Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
Published February 12, 2021
We read with great interest the article by Saleh et al. on “chemical pancreatectomy” for chronic pancreatitis (CP) and the related commentary. We feel that, for a balanced discussion of this intriguing technique, a more clinical perspective on the translatability of the technique is necessary.
In CP, the crucial clinical problems include abdominal pain, maldigestion and malabsorption (due to exocrine dysfunction), diabetes, and the risk for recurrent attacks of (acute on chronic) pancreatitis.
The proposed technique of chemical ablation of exocrine tissue is not a treatment for CP, but rather an acceleration of the natural course, i.e. rapid induction of a pancreatic exocrine “burnout”.
What has found no mention in the manuscript is the risk of acute pancreatitis (within the first 48 hours) due to the ductal acetic acid infusion procedure. The authors noted that a “local inflammation” was indeed observed in the pancreas. This may be clinically threatening especially when performed as part of an ERCP, which itself bears the risk for post-intervention acute pancreatitis (i.e. post-ERCP pancreatitis). Therefore, testing this procedure as part of clinical trials will be problematic from a medical and ethical perspective.
Furthermore, the long-term impact of acetic acid on the main pancreatic duct (which can in theory react to this treatment with strictures), or in the bile duct system, which communicates with the pancreatic duct, also remains unknown.
Moreover, pain data from the nonhuman primates are missing in the paper, which is important for drawing conclusions on the impact of the suggested procedure on the most severe symptom of human CP. Besides, one has to consider that acetic acid itself is a nociceptive trigger for sensory neurons [1,2].
The authors also do not consider that CP can be treated in an organ-sparing manner via surgery as well. Indeed, many CP cases exhibit the inflammation mostly in the pancreatic head, and partial or complete removal of only the pancreatic head as part of a duodenum-preserving pancreatic head resection or Whipple’s procedure, leaving the pancreatic body and tail in situ, is a very effective method for pain control, and for preserving both exocrine and endocrine function [3,4]. In centers with experience in pancreatic surgery, these surgical procedures can be done safely with almost zero mortality [3]. One aspect that also needs consideration are the long-term “nutritional” consequences of such an acute, complete chemical ablation of the pancreatic exocrine function. Indeed, in such a scenario of complete exocrine ablation, patients will probably be prone to severe deficiency of fat-soluble vitamins (D, A, E, K) and trace minerals (e.g. selenium, zinc), even with high-dose enzyme (pancreatin) supplementation [5,6].
Collectively, while the study of the authors point out an interesting ablative effect of acetic acid on the exocrine compartment, the proposed method is embedded in a network of several critical medical and ethical issues, including induction of an acute on chronic pancreatitis, vitamin deficiency, and acute exacerbation of pain. These aspects, which suggest a very long way until clinical application, need to be taken into account for future efforts of translation.
References
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