**2. Pathophysiology of pain in chronic pancreatitis**

The pathophysiology of CP is complex and remains poorly understood, with a number of theories having been put forward. Together with this, understanding of the mechanisms leading to the development of pain has also remained largely theoretical, confounded to a large extent by small and to some degree poorly designed studies, which have at times been contradictory. Furthermore, it is likely that the cause of pain is multi-factorial and may vary during the course of the disease (Bornman PC W J Surg 2003). To date, the most predominant theories regarding genesis of pain in CP have included:

#### **2.1 Morphological pancreatic ductal changes resulting in obstruction and pancreatic ductal and tissue hypertension**

In large duct chronic pancreatitis, changes in the composition of pancreatic fluid occur including an increase in free oxygen radicals and secretion of enzymes and calcium but a concomitant decrease in serine protease inhibitor Kazal type 1 (SPINK1), bicarbonate and citrate. (Sarles H Dig Dis Sci 1986). These changes are followed by precipitation of proteins such as lactoferrin and altered levels of pancreas related secretory stress proteins (including pancreatitis associated protein and pancreatic stone protein) (Singh SM W J Surg 1990; Graf R J Surg Res 2006). Glycoprotein plugs are formed which later become calcified leading to calcific disease with associated parenchymal fibrosis. Calcified protein plugs or calculi damage the ductal epithelium further and contribute to stasis thereby facilitating further stone formation. These changes are believed to begin in the side ducts but progress to involve the main pancreatic duct (PD) with the development of pancreatic duct strictures and obstruction (PDSO) as a consequence of fibrosis or calculi. Ductal hypertension follows with associated dilatation (Nagata A Gatroenteology 1981). Together with ductal hypertension, pancreatic tissue pressure may become elevated, particularly in areas of calcification (Okazaki K Gastroenterology 1986; Manes G Int J Pancreatol 1994; Jalleh RPBr J Surg 1991). The exact mechanism of elevated PTP in CP has not been proven, however it has been speculated that it may be a reflection of obstructed pancreatic side ducts rather than main PD obstruction. This situation may be aggravated by the development of perilobular fibrosis and a fibrotic peripancreatic capsule, resulting in a compartment syndrome like

procedures to address these mechanisms. Resection of diseased pancreatic tissue, in particular inflamed tissue within the head of the pancreas containing altered neural tissue and diseased ducts, considered the "pacemaker of disease" (Beger HG World J Surg 1990) and drainage of the pancreatic ductal system, in order to relieve ductal and parenchymal tissue hypertension. Removal of sufficient pancreatic tissue as to result in effective and durable relief of symptoms must however be balanced against the desire to avoid surgically related morbidity and mortality as well as to prevent post-operative pancreatic functional insufficiency. This has led to the development of less extensive resections and hybrid procedures which attempt to combine the advantages while avoiding the

This chapter will describe the theories around the pathophysiology of pain in chronic pancreatitis, discuss the rationale and indications for surgical intervention and detail the procedures currently available. It will also review the literature guiding the choice of these

The pathophysiology of CP is complex and remains poorly understood, with a number of theories having been put forward. Together with this, understanding of the mechanisms leading to the development of pain has also remained largely theoretical, confounded to a large extent by small and to some degree poorly designed studies, which have at times been contradictory. Furthermore, it is likely that the cause of pain is multi-factorial and may vary during the course of the disease (Bornman PC W J Surg 2003). To date, the most

**2.1 Morphological pancreatic ductal changes resulting in obstruction and pancreatic** 

In large duct chronic pancreatitis, changes in the composition of pancreatic fluid occur including an increase in free oxygen radicals and secretion of enzymes and calcium but a concomitant decrease in serine protease inhibitor Kazal type 1 (SPINK1), bicarbonate and citrate. (Sarles H Dig Dis Sci 1986). These changes are followed by precipitation of proteins such as lactoferrin and altered levels of pancreas related secretory stress proteins (including pancreatitis associated protein and pancreatic stone protein) (Singh SM W J Surg 1990; Graf R J Surg Res 2006). Glycoprotein plugs are formed which later become calcified leading to calcific disease with associated parenchymal fibrosis. Calcified protein plugs or calculi damage the ductal epithelium further and contribute to stasis thereby facilitating further stone formation. These changes are believed to begin in the side ducts but progress to involve the main pancreatic duct (PD) with the development of pancreatic duct strictures and obstruction (PDSO) as a consequence of fibrosis or calculi. Ductal hypertension follows with associated dilatation (Nagata A Gatroenteology 1981). Together with ductal hypertension, pancreatic tissue pressure may become elevated, particularly in areas of calcification (Okazaki K Gastroenterology 1986; Manes G Int J Pancreatol 1994; Jalleh RPBr J Surg 1991). The exact mechanism of elevated PTP in CP has not been proven, however it has been speculated that it may be a reflection of obstructed pancreatic side ducts rather than main PD obstruction. This situation may be aggravated by the development of perilobular fibrosis and a fibrotic peripancreatic capsule, resulting in a compartment syndrome like

disadvantages of each approach.

procedures for the relief of pain.

**ductal and tissue hypertension** 

**2. Pathophysiology of pain in chronic pancreatitis** 

predominant theories regarding genesis of pain in CP have included:

scenario with consequent tissue ischaemia and acidosis. (Karanjia ND Br J Surg 1994). While PDSO with ductal and tissue hypertension have not been consistently demonstrated in CP, nor a definite correlation shown with the development of pain (Novis BH Dig Dis Sc 1985; Manes G Int J Pancreatol 1994; Ugljesic M Int J Pancreatol. 1996; Bornman PC W J Surg 2003), surgical drainage procedures have been documented to reduce pancreatic tissue pressures (PTP), while a significant association between recurrence of pain and subsequent elevation of PTP has been shown. (Ebbehøj N Scand J Gastroenterol. 1990). On the other hand, ductal dilatation has been observed in the absence of ductal obstruction giving rise to the suggestion that dilatation may also be related to parenchymal destruction; this is supported by the association between duct dilatation and pancreatic insufficiency (Jensen AR Scand J Gastroent 1984). Thus, while PDSO is likely an important factor in generating pain, there are likely factors other than main pancreatic duct abnormalities that can also be implicated (Bornman PC W J Surg 2003). Furthermore, the role of side duct obstruction in the genesis of pain has not yet been clearly defined; it may be that side branch disease contributes to the development of an inflammatory mass in the pancreatic head which is recognised as important in driving the disease process (the so called "pacemaker" of disease) (Beger HG World J Surg 1990).

#### **2.2 Interaction between the processes of inflammation and damaged neural structures**

Histological studies have shown that there is invasion of neural tissue by inflammatory cells associated with chronic pancreatitis. This is accompanied by disruptions in the perineural sheaths which expose the internal neural compartments to the inflammatory response (Bockman DE Gastroenterol 1988). In addition, there are increased amounts of pain transmitted substances, pain modulators and nerve growth factors and receptors in enlarged / damaged pancreatic nerve structures, which appear to correlate with the intensity and frequency of pain (Büchler M Pancreas 1992, Zhu ZW Dig Dis Sci 2001,McMahon SP Nat Med 1995,Friess H Ann Surg 1999). Surgical resection of a pancreatic inflammatory mass effectively removes the pain stimulus together with the altered / damaged neural structures.

#### **2.3 Toxin metabolism and generation of excessive oxygen derived free radicals resulting in electrophilic stress and inflammation**

Acinar cells and proliferated islets of Langerhans are known to express cytochrome P450 (CYP) mono-oxygenases which metabolise xenobiotics (substances foreign to a living organism), often utilizing glutathione & catalysed by glutathione transferases. (Foster JR J Pathol 1993). There may however be adverse consequences to these metabolic reactions with the generation of reactive oxygen species (ROS) and toxic xenobiotic metabolites. Prevention of cellular injury relies on defences against ROS and xenobiotic metabolites; these defences include: selenium dependant glutathione peroxidase, glutathione transferases, glutathione and ascorbic acid. These varied properties make the pancreas a versatile yet vulnerable xenobiotic metabolizing organ (Braganza JM JOP 2010; Foster JR. Toxicology of the exocrine pancreas. In: General and applied toxicology 2009). Inhaled xenobiotics (such as cigarette smoke, occupational volatile hydrocarbons and petrochemicals) that pass through the pulmonary circulation represent the biggest threat by striking the pancreas through its rich

The Surgical Management of Chronic Pancreatitis 433

This theory suggests a primary immunological attack on ductal epithelium leading to inflammation and scarring of ductal architecture. This may have specific relevance in

Once inflammation becomes established in CP, patients may enter a phase of stable disease with the histological features of acinar loss, mononuclear cell infiltrate and fibrosis (Shrikhande SV Br J Surg 2003). Subsequent progression to end stage disease is characterised by loss of all secretory tissue, disappearance of inflammatory cells and intense fibrosis. This may be accompanied by loss of pancreatic function together with diminished pain, the so-called "pancreatic burn-out syndrome"; this phenomenon is however not a universal outcome in patients with CP, thereby confounding potential treatment strategies (Girdwood AH J Clin Gastroenterol 1981; Amman RW Gastroenterol

Complications of CP related to inflammation and fibrosis may develop which can alter the

This is common in advanced disease, particularly when there calcification and an inflammatory mass in the head. Obstruction may be transient when related to oedema during acute flaring of disease or more permanent when occurring as a result of a fibrotic

This may be the result of peri-duodenal fibrosis or from the mass effect provided by a

Pancreas related fluid collections or pseudocysts occur in 30-40% of patients with CP and are thought to be the consequence of either ductal obstruction or pancreatic necrosis with ductal disruption (D'Egidio A BJS 1991). Typically cysts communicate with the pancreatic ductal system which shows gross morphological abnormalities. Postnecrotic peripancreatic collections occur only rarely, usually as a consequence of an acute on chronic attack of pancreatitis. Pseudocysts in CP are usually located either near the head when they are mostly intra-pancreatic or in the lesser sac. Pseudocysts in CP are less likely to spontaneously resolve than those associated with acute disease as they have usually matured by the time of presentation and typically communicate with the pancreatic ductal system. Pancreatic ascites occurs when there is rupture of a pseudocyst or duct into the peritoneal cavity (Bornman PC in Hepatobiliary and pancreatic surgery – a companion to

Portal hypertension may develop in up to 10% of patients as a result of venous compression or thrombosis. Splenic vein thrombosis may result in segmental portal hypertension giving rise to gastric and oesophageal varices, although frank variceal bleeding in this setting is

autoimmune pancreatitis. (Cavallini G. Ital J Gastroenterol 1993).

course of disease as well as clinical presentation. These include

stricture or mass effect from an adjacent pseudocyst. .

**3. Development of a pseudocyst / pancreatic ascites** 

**2.5 Primary duct hypothesis** 

1984; Lankisch PG Digestion 1993).

**1. Biliary obstruction** 

**2. Duodenal obstruction** 

specialist surgical practice. 2009).

a. Portal hypertension

**4. Gastro-intestinal bleeding, related to** 

pseudocyst.

arterial supply (Braganza JM Lancet 2011). When the acinar cell's defence mechanisms are insufficient to meet the increased oxidant load from ROS and xenobiotic metabolites, eletrophilic stress results (Braganza JM Digestion 1998; Braganza JM JOP 2010; Foster JR. Toxicology of the exocrine pancreas. In: General and applied toxicology 2009). Dietary insufficiency of micronutrients and ascorbic acid may predispose to this (Braganza JM Digestion 1998). Electrophilic stress in turn results in pancreastasis, the failure of apical exocytosis in the acinar cell (Sanfey H Ann Surg 1984; Leung P Antioxid Redox Signal 2009). Enzymes (both newly synthesised & those stored in zymogen granules) not able to be released apically, are released via the basolateral memebrane into the interstitium, lymphatics and bloodstream (Cook LJ Scand J Gastroenterol 1996). Entrance of enzymes and free radical oxidation products into the interstitium causes mast cell degranulation, resulting in local inflammation, activation of nociceptive axon reflexes and fibrosis. (Cook LJ Scand J Gastroenterol 1996; Braganza JM Digestion 1998). This inflammatory response is potentiated by cytokines produced by the damaged acinar cell as a result of activated signaling cascades caused by the release of ROS. (Leung P Antioxid Redox Signal 2009).

#### **2.4 Fibrosis as a result of pancreatic stellate cell activation in the necrosisinflammation-fibrosis sequence and sentinel acute pancreatitis events**

Pancreatic stellate cells play a central role in the fibrotic process associated with chronic pancreatitis (Stevens T Am J Gastroenterol 2004). This is particularly relevant in the necrosisinflammation-fibrosis sequence, the most widely accepted hypothesis in the pathogenesis of chronic pancreatitis (Bornman PC in Chronic pancreatitis. Hepatobiliary and pancreatic surgery – a companion to specialist surgical practice. 2009). Initially this hypothesis held that fibrosis developed as a stepwise progressive process from recurrent bouts of acute pancreatitis (Comfort MW Gastroenterology 1946; Kloppel G Hepatogastroenterol 1991). An alternative theory suggested that alcohol might be directly toxic to the acinar cell through a change in cellular metabolism (toxic-metabolic theory). Alcohol was purported to produce cytoplasmic lipid accumulation within the acinar cell, leading to fatty degeneration, cellular necrosis and eventual fibrosis (Bordalo O Am J Gastroenterol 1977). More recently the theory of a sentinel acute pancreatitis event (SAPE) has been proposed. This theory hypothesizes that stimulation of the pancreatic acinar cell by alcohol or oxidative stress activates trypsin which results in a sentinel acute pancreatitis event. This is followed by a dual phase chronic inflammatory response, with the early phase characterised by a pro-inflammatory cell infiltrate including macrophages and lymphocytes. Cytokines released during the early phase also attract a later anti-inflammatory cellular infiltrate comprising pro-fibrotic cells, including stellate cells. These cells, once attracted, are activated by lipid peroxidation products (caused by excess ROS) and mast cell degranulation products, and are considered "primed"; continued stimulation by cytokines (in particular TGF-β1) produced by acinar cells, inflammatory cells or the stellate cells themselves as a result of oxidative stress, alcohol or recurrent acute pancreatitis, cause these activated stellate cells to deposit collagen, resulting in fibrosis and the features of chronic pancreatitis (Whitcomb DC Best Pract Res Clin Gastroenterol 2002). The transient formation of fatty acid ethanol esters and the role of macrophages and lymphocytes in pancreatic tissue destruction are also thought to be integral to this process (Pandol SJ Pancreatology 2007). It is suggested that the contractive potential and perivascular location of the stellate cells results in fibrosis that leads to microvascular ischaemia and pain (Wells RG Gastroenterol 1998).
