**2.5 Primary duct hypothesis**

432 New Advances in the Basic and Clinical Gastroenterology

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).

ischaemia and pain (Wells RG Gastroenterol 1998).

**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 This theory suggests a primary immunological attack on ductal epithelium leading to inflammation and scarring of ductal architecture. This may have specific relevance in autoimmune pancreatitis. (Cavallini G. Ital J Gastroenterol 1993).

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 1984; Lankisch PG Digestion 1993).

Complications of CP related to inflammation and fibrosis may develop which can alter the course of disease as well as clinical presentation. These include

#### **1. Biliary obstruction**

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 stricture or mass effect from an adjacent pseudocyst. .

#### **2. Duodenal obstruction**

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

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

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 specialist surgical practice. 2009).

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

#### a. Portal hypertension

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

The Surgical Management of Chronic Pancreatitis 435

foolhardy to offer surgical intervention with it's attached risk of morbidity and even mortality in patients whose symptoms might be controlled by medical means, it seems equally unreasonable to persist with a conservative approach in anticipation of pain relief, delaying surgery until narcotic addiction has developed and the outcomes from surgery may be worse (Warshaw AL gastroenterol 1984). In the absence of good evidence to guide decision making, it seems most appropriate that the decision regarding timing of surgery be individualized on a patient to patient basis. Surgical intervention should be performed only once an adequate trial of medical therapy has failed to control symptoms and the patient has

Patients referred for surgery for relief of intractable symptoms of CP should be evaluated by experienced clinicians working in a high volume, multi-disciplinary environment. All other treatment options should have been exhausted or considered not appropriate. Cross sectional imaging should be conducted to clearly delineate pancreatic morphology and detect local complications or features suggestive of neoplastic disease. The presence of portal hypertension, particularly as a result of portal or superior mesenteric vein thrombosis should be noted, as this may preclude surgical intervention (Bornman PC S Afr Med J 2010). With careful patient selection and modern surgical strategies, surgery may offer effective

In considering intervention for complications of CP, the clinical picture is paramount in decision making. Biliary obstruction may be asymptomatic, detected only biochemically or during imaging for other indications. In addition, there may be transient jaundice as a result of oedema during acute flares of the disease. The above are not indications for intervention. It must be remembered that once the biliary system has been entered, either percutaneously, endoscopically or surgically, this once sterile system should be considered contaminated with the risk of sepsis developing should obstruction recur in the future. On the other hand, persistent biliary obstruction of sufficient duration may result in secondary biliary cirrhosis, atrophy and deterioration in hepatic function. (Abdallah A HPB 2007). Obstruction longer than 4 weeks should arouse concern and warrants intervention. Decompression by means of endoscopic stenting should only be considered as a temporary bridge to surgery, in acute cholangitis or where patient factors preclude surgery (Bornman PC S Afr Med J 2010). Duodenal obstruction on the other hand typically represents either advanced fibrosis or a clinically significant pseudocyst, neither of which are likely to resolve before progression or further complications develop. Intervention is therefore indicated. Pseudocysts in CP are less likely to resolve than their acute counterparts and thus more often require drainage. The indications for drainage are the presence of symptoms or complications. Although size alone is not a criterion for intervention, cysts larger than 6cm are more likely to be symptomatic and require treatment (Bornman PC S Afr Med J 2010). Percutaneous procedures are generally not favoured for these lesions due to an increased risk of failure, introducing sepsis or creating an external fistula. Endoscopic drainage is associated with a success rate of 65-95% and a low complication rate and is preferred to surgery due to its less invasive nature. (Beckingham IJ Br J Surg 1997). Strict morphological criteria are required however, relating to cyst maturity, intra-luminal bulging, wall thickness (less than 10mm) and vascularity, particularly in the presence of portal hypertension. To this end, careful cross sectional imaging and endoscopic ultrasound are important adjuncts in assessing patients for this modality of treatment. Transmural drainage may be transduodenal or transgastric depending on the best route into the cyst while transpapillary drainage is an

pain relief in over 90% of patients at 5 year follow up (Beger HG Ann Surg 1989).

been counseled regarding the risks and benefits of both modalities.

uncommon (Bornman PC in Hepatobiliary and pancreatic surgery – a companion to specialist surgical practice. 2009).

b. Pseudoaneurysms

Enzyme rich fluid collections may erode into vascular structures resulting in false aneurysms with bleeding into the cyst and pancreatic duct, peritoneum or retroperitoneum.
