Pancreatology 13 (2013) 629e630
Contents lists available at SciVerse ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Case report
Evidence of pancreatic neuropathy and neuropathic pain in hereditary chronic pancreatitis Elke Tieftrunk a, Ihsan Ekin Demir a, Peter Simon b, Helmut Friess a, Güralp O. Ceyhan a, * a b
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany Department of Internal Medicine A, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 April 2013 Received in revised form 26 May 2013 Accepted 27 May 2013
Increased neural density and neural hypertrophy are characteristic features of pancreatic neuropathy in chronic pancreatitis. Here, we present the extraordinary case of prominent pancreatic neuropathy in a 21-year-old female patient with hereditary chronic pancreatitis and intractable pain who underwent total pancreatectomy. The histopathological analysis demonstrated remnant pancreatic tissue which was only composed of prominent intrapancreatic nerves and fibrosis, without any visible remaining functional pancreatic parenchyma. These histological alterations, including nerve hypertrophy and increased neural density, are known for different aetiologies of chronic pancreatitis, e.g. alcoholic, idiopathic and tropic pancreatitis. However, this is the first report of a patient with hereditary chronic pancreatitis demonstrating the characteristic features of pancreatic neuropathy and neuropathic pain. Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Neuropathy Neuropathic pain Hereditary pancreatitis Chronic pancreatitis Neuroplasticity
1. Introduction A 21-year-old woman with hereditary chronic pancreatitis/CP presented to our clinic in August 2012 with total exocrine and endocrine pancreatic insufficiency and persistent severe upper abdominal pain, asking for potential therapeutic options. 2. Case description The first episode of acute pancreatitis occurred at the age of 6, recurring up to 6 a year, often requiring inpatient stay due to severe pain. In 2003, at the age of 12, she was diagnosed with pancreas divisum, with subsequent several stenting trials of the pancreatic duct. In 2005, she underwent a pancreatico-jejunostomy (Partington-Rochelle operation), but without any pain relief. After the operation, the episodes of acute pancreatitis were recurring up to once a month, and at that time oral replacement therapy with pancreatic enzymes was initiated. In 2006, a mutation analysis, which was performed during genetic counselling, showed a R122C-mutation on the cationic trypsinogen (PRSS1) gene, confirming the diagnosis of hereditary pancreatitis. In 2007, due to ongoing severe abdominal pain, a duodenum-preserving pancreatic head resection (Beger’s procedure) was performed as an additional
* Corresponding author. Tel.: þ49 89 4140 5091; fax: þ49 89 4140 4870. E-mail address: [email protected] (G.O. Ceyhan).
attempt to provide pain relief. In the following 3 years, the frequency of pancreatitis episodes was diminished to 1e2 times a year, becoming more responsive to non-opioid analgesics. However, in 2009, the patient developed severe frequent flatulence and dyspepsia, and in 2010 she was diagnosed with diabetes mellitus, requiring insulin therapy. Careful review of the pain history revealed that her pain “pattern” has remained the same over the years, varying only in intensity and duration. Each episode of acute pancreatitis started with having the feeling of a fist in the epigastrium for several hours with increasing intensity. This feeling was followed by neuropathic pain-like sensations including burning in the skin, starting in the epigastrium and reaching the umbilicus. This resembled the typical feeling of a belt that gets tighter in the upper abdomen and intraabdominal pain radiating in the back which was of pressure-like and burning character. When she presented to our clinic, the patient was taking tilidin (50 mg p.o. 4/day), without any significant pain relief. Preoperative magnetic resonance imaging (MRI) showed atrophic pancreatic tissue, without any discernible pancreatic duct (Fig. 1A). Due to intractable upper abdominal pain and already existing total endo- and exocrine insufficiency, a pancreatectomy was indicated. This was performed in August 2012. Intraoperatively, the remaining pancreatic tissue appeared like a hard clump of dense tissue without the typical lobular appearance of the pancreas. Histopathological examination of the resected remaining pancreas revealed that the tissue contained nearly no exocrine parenchyma
1424-3903/$ e see front matter Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pan.2013.05.009
630
E. Tieftrunk et al. / Pancreatology 13 (2013) 629e630
Fig. 1. Neuroplasticity in a 21-year-old female patient with hereditary chronic pancreatitis. A. Preoperative MRI scan demonstrating the atrophic pancreatic tissue without discernible pancreatic duct. The arrow indicates the anastomosed bowel loop, * indicates the remaining pancreatic head. B,C. Immunohistochemical staining of the resected tissue with the neuroplasticity marker GAP-43 demonstrates the large number of hypertrophic nerves (stained brown) embedded in fibrotic tissue.
but was composed of an enormously increased number of hypertrophic nerves embedded in vast areas of fibrosis (Fig. 1B and C). Importantly, all these hypertrophic nerves were strongly immunoreactive for the neuroplasticity marker growth-associatedprotein-43 (GAP-43, Fig. 1B and C). The neuropathic pain score evaluated by painDETECT questionnaire dropped from a preoperative score of 13 (a neuropathic origin could not be excluded) to 2 after 6 months after our operation [1].
pathways and neurons supplying the pancreas may shed light on the mechanisms of the extreme neuroplasticity as also seen in this extraordinary case of hereditary CP. In summary, this is the first report of a patient with hereditary CP demonstrating the characteristic features of intrapancreatic neuropathy and associated pancreatic neuropathic pain. Therefore, pain of neuropathic origin should be routinely considered in the treatment of patients with hereditary CP and intractable abdominal pain.
3. Discussion Conflicts of interest Owing to large case studies, neural hypertrophy and increased neural density have been recognized as typical features of pancreatic neuropathy in CP and pancreatic cancer which are directly associated with the degree of pain sensation [2]. These alterations could be demonstrated for CP of different aetiologies, including alcoholic, idiopathic or biliary CP. However, so far, neuropathy was not reported for hereditary pancreatitis. Looking at the extent of these neuropathic alterations, generation of pancreatic neuropathy seems to be a common feature of CP, independent of the underlying aetiology. This observation suggests a common pathophysiological pathway leading to these prominent nerve alterations, which might be triggered by severe inflammatory processes, resulting in replacement of pancreatic tissue by stromal structures like nerves. Mechanisms of pancreatic neuropathy are largely unknown, and particularly the deciding question as to why the fibrotic tissue is associated with the selective hypertrophy and sprouting of nerves remains to be answered. In fact, the tissue microenvironment in CP was shown to contain increased amounts of neurotrophic factors like nerve growth factor (NGF), neurturin and artemin [3e5]. However, the trophic effect of such neurotrophic factors is not limited to neural structures, as NGF and Artemin were detected to be pro-angiogenic in endothelial cells and breast cancer [6,7]. Therefore, attributing pancreatic neuropathy solely to the increased neurotrophic factor content of chronically inflamed pancreatic tissue may indeed be an oversimplification. Looking at the extent of neuroplasticity as seen in this case, it is plausible to assume that neurons supplying the pancreas (e.g. in dorsal root ganglia or sympathetic ganglia) have to be driven to sprout into the pancreas. Therefore, investigation of trophic signals within extrinsic neural
None. Financial disclosures None. Acknowledgements We are grateful to our patient for allowing us to learn from her case history. References [1] Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin 2006;22:1911e20. [2] Ceyhan GO, Bergmann F, Kadihasanoglu M, Altintas B, Demir IE, Hinz U, et al. Pancreatic neuropathy and neuropathic painea comprehensive pathomorphological study of 546 cases. Gastroenterology 2009;136. 177e186 e171. [3] Ceyhan GO, Demir IE, Maak M, Friess H. Fate of nerves in chronic pancreatitis: neural remodeling and pancreatic neuropathy. Best Pract Res Clin Gastroenterol 2010;24:311e22. [4] Demir IE, Wang K, Tieftrunk E, Giese NA, Xing B, Friess H, et al. Neuronal plasticity in chronic pancreatitis is mediated via the neurturin/GFRalpha2 axis. Am J Physiol Gastrointest Liver Physiol 2012;303:G1017e28. [5] Ceyhan GO, Bergmann F, Kadihasanoglu M, Erkan M, Park W, Hinz U, et al. The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis. Gut 2007;56:534e44. [6] Cantarella G, Lempereur L, Presta M, Ribatti D, Lombardo G, Lazarovici P, et al. Nerve growth factor-endothelial cell interaction leads to angiogenesis in vitro and in vivo. Faseb J 2002;16:1307e9. [7] Kim H, Li Q, Hempstead BL, Madri JA. Paracrine and autocrine functions of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brain-derived endothelial cells. J Biol Chem 2004;279:33538e46.
Contents lists available at SciVerse ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Case report
Evidence of pancreatic neuropathy and neuropathic pain in hereditary chronic pancreatitis Elke Tieftrunk a, Ihsan Ekin Demir a, Peter Simon b, Helmut Friess a, Güralp O. Ceyhan a, * a b
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany Department of Internal Medicine A, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 April 2013 Received in revised form 26 May 2013 Accepted 27 May 2013
Increased neural density and neural hypertrophy are characteristic features of pancreatic neuropathy in chronic pancreatitis. Here, we present the extraordinary case of prominent pancreatic neuropathy in a 21-year-old female patient with hereditary chronic pancreatitis and intractable pain who underwent total pancreatectomy. The histopathological analysis demonstrated remnant pancreatic tissue which was only composed of prominent intrapancreatic nerves and fibrosis, without any visible remaining functional pancreatic parenchyma. These histological alterations, including nerve hypertrophy and increased neural density, are known for different aetiologies of chronic pancreatitis, e.g. alcoholic, idiopathic and tropic pancreatitis. However, this is the first report of a patient with hereditary chronic pancreatitis demonstrating the characteristic features of pancreatic neuropathy and neuropathic pain. Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Neuropathy Neuropathic pain Hereditary pancreatitis Chronic pancreatitis Neuroplasticity
1. Introduction A 21-year-old woman with hereditary chronic pancreatitis/CP presented to our clinic in August 2012 with total exocrine and endocrine pancreatic insufficiency and persistent severe upper abdominal pain, asking for potential therapeutic options. 2. Case description The first episode of acute pancreatitis occurred at the age of 6, recurring up to 6 a year, often requiring inpatient stay due to severe pain. In 2003, at the age of 12, she was diagnosed with pancreas divisum, with subsequent several stenting trials of the pancreatic duct. In 2005, she underwent a pancreatico-jejunostomy (Partington-Rochelle operation), but without any pain relief. After the operation, the episodes of acute pancreatitis were recurring up to once a month, and at that time oral replacement therapy with pancreatic enzymes was initiated. In 2006, a mutation analysis, which was performed during genetic counselling, showed a R122C-mutation on the cationic trypsinogen (PRSS1) gene, confirming the diagnosis of hereditary pancreatitis. In 2007, due to ongoing severe abdominal pain, a duodenum-preserving pancreatic head resection (Beger’s procedure) was performed as an additional
* Corresponding author. Tel.: þ49 89 4140 5091; fax: þ49 89 4140 4870. E-mail address: [email protected] (G.O. Ceyhan).
attempt to provide pain relief. In the following 3 years, the frequency of pancreatitis episodes was diminished to 1e2 times a year, becoming more responsive to non-opioid analgesics. However, in 2009, the patient developed severe frequent flatulence and dyspepsia, and in 2010 she was diagnosed with diabetes mellitus, requiring insulin therapy. Careful review of the pain history revealed that her pain “pattern” has remained the same over the years, varying only in intensity and duration. Each episode of acute pancreatitis started with having the feeling of a fist in the epigastrium for several hours with increasing intensity. This feeling was followed by neuropathic pain-like sensations including burning in the skin, starting in the epigastrium and reaching the umbilicus. This resembled the typical feeling of a belt that gets tighter in the upper abdomen and intraabdominal pain radiating in the back which was of pressure-like and burning character. When she presented to our clinic, the patient was taking tilidin (50 mg p.o. 4/day), without any significant pain relief. Preoperative magnetic resonance imaging (MRI) showed atrophic pancreatic tissue, without any discernible pancreatic duct (Fig. 1A). Due to intractable upper abdominal pain and already existing total endo- and exocrine insufficiency, a pancreatectomy was indicated. This was performed in August 2012. Intraoperatively, the remaining pancreatic tissue appeared like a hard clump of dense tissue without the typical lobular appearance of the pancreas. Histopathological examination of the resected remaining pancreas revealed that the tissue contained nearly no exocrine parenchyma
1424-3903/$ e see front matter Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pan.2013.05.009
630
E. Tieftrunk et al. / Pancreatology 13 (2013) 629e630
Fig. 1. Neuroplasticity in a 21-year-old female patient with hereditary chronic pancreatitis. A. Preoperative MRI scan demonstrating the atrophic pancreatic tissue without discernible pancreatic duct. The arrow indicates the anastomosed bowel loop, * indicates the remaining pancreatic head. B,C. Immunohistochemical staining of the resected tissue with the neuroplasticity marker GAP-43 demonstrates the large number of hypertrophic nerves (stained brown) embedded in fibrotic tissue.
but was composed of an enormously increased number of hypertrophic nerves embedded in vast areas of fibrosis (Fig. 1B and C). Importantly, all these hypertrophic nerves were strongly immunoreactive for the neuroplasticity marker growth-associatedprotein-43 (GAP-43, Fig. 1B and C). The neuropathic pain score evaluated by painDETECT questionnaire dropped from a preoperative score of 13 (a neuropathic origin could not be excluded) to 2 after 6 months after our operation [1].
pathways and neurons supplying the pancreas may shed light on the mechanisms of the extreme neuroplasticity as also seen in this extraordinary case of hereditary CP. In summary, this is the first report of a patient with hereditary CP demonstrating the characteristic features of intrapancreatic neuropathy and associated pancreatic neuropathic pain. Therefore, pain of neuropathic origin should be routinely considered in the treatment of patients with hereditary CP and intractable abdominal pain.
3. Discussion Conflicts of interest Owing to large case studies, neural hypertrophy and increased neural density have been recognized as typical features of pancreatic neuropathy in CP and pancreatic cancer which are directly associated with the degree of pain sensation [2]. These alterations could be demonstrated for CP of different aetiologies, including alcoholic, idiopathic or biliary CP. However, so far, neuropathy was not reported for hereditary pancreatitis. Looking at the extent of these neuropathic alterations, generation of pancreatic neuropathy seems to be a common feature of CP, independent of the underlying aetiology. This observation suggests a common pathophysiological pathway leading to these prominent nerve alterations, which might be triggered by severe inflammatory processes, resulting in replacement of pancreatic tissue by stromal structures like nerves. Mechanisms of pancreatic neuropathy are largely unknown, and particularly the deciding question as to why the fibrotic tissue is associated with the selective hypertrophy and sprouting of nerves remains to be answered. In fact, the tissue microenvironment in CP was shown to contain increased amounts of neurotrophic factors like nerve growth factor (NGF), neurturin and artemin [3e5]. However, the trophic effect of such neurotrophic factors is not limited to neural structures, as NGF and Artemin were detected to be pro-angiogenic in endothelial cells and breast cancer [6,7]. Therefore, attributing pancreatic neuropathy solely to the increased neurotrophic factor content of chronically inflamed pancreatic tissue may indeed be an oversimplification. Looking at the extent of neuroplasticity as seen in this case, it is plausible to assume that neurons supplying the pancreas (e.g. in dorsal root ganglia or sympathetic ganglia) have to be driven to sprout into the pancreas. Therefore, investigation of trophic signals within extrinsic neural
None. Financial disclosures None. Acknowledgements We are grateful to our patient for allowing us to learn from her case history. References [1] Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin 2006;22:1911e20. [2] Ceyhan GO, Bergmann F, Kadihasanoglu M, Altintas B, Demir IE, Hinz U, et al. Pancreatic neuropathy and neuropathic painea comprehensive pathomorphological study of 546 cases. Gastroenterology 2009;136. 177e186 e171. [3] Ceyhan GO, Demir IE, Maak M, Friess H. Fate of nerves in chronic pancreatitis: neural remodeling and pancreatic neuropathy. Best Pract Res Clin Gastroenterol 2010;24:311e22. [4] Demir IE, Wang K, Tieftrunk E, Giese NA, Xing B, Friess H, et al. Neuronal plasticity in chronic pancreatitis is mediated via the neurturin/GFRalpha2 axis. Am J Physiol Gastrointest Liver Physiol 2012;303:G1017e28. [5] Ceyhan GO, Bergmann F, Kadihasanoglu M, Erkan M, Park W, Hinz U, et al. The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis. Gut 2007;56:534e44. [6] Cantarella G, Lempereur L, Presta M, Ribatti D, Lombardo G, Lazarovici P, et al. Nerve growth factor-endothelial cell interaction leads to angiogenesis in vitro and in vivo. Faseb J 2002;16:1307e9. [7] Kim H, Li Q, Hempstead BL, Madri JA. Paracrine and autocrine functions of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brain-derived endothelial cells. J Biol Chem 2004;279:33538e46.
