Chapter 56. Chronic Pancreatitis

Chronic pancreatitis is an inflammatory and fibrosing disease of the exocrine pancreas characterized by irreversible morphological changes and permanent loss of function. The apparent incidence of chronic pancreatitis has increased approximately fourfold over the past several decades, likely due a broadening of its definition and the inclusion of patients with earlier-stage disease. The natural history of chronic pancreatitis is unpredictable. Affected individuals typically suffer a pattern of persistent or recurrent attacks of pain along with progressive pancreatic exocrine insufficiency. Symptoms may also result from extension of the disease process to adjacent organs and vascular structures. In later stages, pancreatic endocrine insufficiency may develop. Decision making in the management of chronic pancreatitis must be individualized to the specific anatomic and pathological circumstances, taking into account the extent of local expertise in various diagnostic and therapeutic modalities as well as the fact that there is a relative paucity of high-quality data on the clinical effectiveness of surgical and medical interventions. Optimal management is facilitated by a multidisciplinary approach that includes surgical, endoscopic, and radiological expertise in addition to nutrition, endocrinology, pain management, and psychosocial support.

Pancreatitis is thought to have its origin as an autodigestive disease initiated by inappropriate activation of pancreatic zymogens. The terms acute pancreatitis and chronic pancreatitis are often used to draw the temporal distinction between an isolated episode and a more persistent illness associated with progressive loss of pancreatic function. In fact, pancreatitis represents a far more heterogeneous clinical entity than can be captured by these two simple descriptors. A number of international conferences have been held in order to develop uniform terminology to characterize the spectrum of morphology seen in acute and chronic pancreatitis.

According to the Marseille-Rome classification of 1988, the term acute pancreatitis is used to refer to single or repeated episodes of abdominal pain associated with a range of potentially reversible pancreatic lesions including pancreatic edema, necrosis, and hemorrhage, as well as peripancreatic fluid collections, necrosis, and pseudocysts. Chronic pancreatitis is used to refer to recurrent or persistent abdominal pain that is associated with irreversible and ongoing inflammatory destruction of exocrine parenchyma and, eventually, islets. In practice, however, the distinction between acute and chronic pancreatitis is rarely made based on tissue sampling, and there is no consensus on the definition of irreversible morphological change.1 It is also acknowledged that certain forms of chronic pancreatitis can occur in the absence of pain.

The Marseille-Rome classification further divides chronic pancreatitis into several morphological subtypes that may coexist in the same patient. Chronic obstructive pancreatitis is characterized by exocrine atrophy and is associated with duct stenosis caused by tumors, pseudocyst, or scarring from prior acute pancreatitis. Chronic calcifying pancreatitis is characterized by intraductal calcifications and protein plugs, and is often associated with atrophy, stenotic ducts, and areas of acute inflammation or pseudocyst. Chronic inflammatory pancreatitis consists of dense infiltration of mononuclear inflammatory cells. Retention cysts and pseudocysts, seen in both calcifying and obstructive forms, may also become infected. Fibrosis may develop in the absence of symptoms.

Chronic pancreatitis lacks a simple unifying theory of disease pathogenesis. The precise mechanism by which any specific agent or circumstance induces pancreatitis remains obscure. Excessive alcohol ingestion has been associated with chronic pancreatitis ever since the term was introduced by Comfort in 1946.2 However, the precise relationship between alcohol and chronic pancreatitis remains poorly understood. Alcohol ingestion in and of itself does not lead to pancreatitis in experimental animals. Chronic pancreatitis in humans occurs in the absence of significant alcohol usage, and, in fact, it is only a small percentage (fewer than 5%) of alcoholics that develop pancreatic disease.3,4 Acute and chronic forms of pancreatitis have been found to share common risk factors including exposure to toxic agents other than alcohol, and acute pancreatitis clearly has the potential to evolve into chronic disease. However, repeated episodes of acute pancreatitis do not invariably lead to chronic pancreatitis, and chronic pancreatitis may present without prior acute attacks. As with alcohol, most individuals exposed to the other toxic substances associated with pancreatitis do not develop the chronic form of the disease.

For these reasons, the concept of identifying risk modifiers rather than etiologies or causes of chronic pancreatitis may be more appropriate in classifying the disease particularly when making decisions regarding patient management. Far from being merely a “drunkard's disease,” chronic pancreatitis should be attributed to a variety of genetic, environmental, anatomic, immunologic, and other poorly understood susceptibility factors that interact to initiate and perpetuate the pathology. The TIGAR-O system (Table 56-1) proposed by Whitcomb4 is a framework that allows various risk factors associated with the disease to be logically organized into categories: Toxic or metabolic, Idiopathic, Genetic, Autoimmune, Recurrent acute, and Obstructive. The TIGAR-O system implies that chronic pancreatitis is not a uniform disease with one etiology and a single common pattern of presentation. Instead, there is a diversity of etiologic risk factors that contributes to a spectrum of pathological and functional derangements, clinical features, and natural history.

Toxic or Metabolic

The majority of patients with chronic pancreatitis (55–80%) will report significant alcohol intake over the years prior to diagnosis. A relationship between dose and duration of alcohol use has been repeatedly documented, and there appears to be a threshold level for the risk of pancreatitis at approximately 50 gm (four drinks) per day.5 Several mechanisms have been proposed to account for pancreatic injury including alterations in pancreaticobiliary secretory flow, ductal plugging, and direct toxic action on acinar cells. Chronic pancreatitis in the setting of alcohol use is associated with pancreatic calcification and ductal stone formation, but none of the proposed mechanisms is convincingly supported experimentally, and the hypotheses are not mutually exclusive. Several other toxic agents have been identified as risk factors for pancreatitis. Included among these is tobacco, which has been shown to confer increased risk of chronic pancreatitis independent of alcohol use.6 Several medications have been implicated in acute pancreatitis but probably do not play a role in the chronic form of the disease. Similarly, hypercalcemia (eg, associated with hyperparathyroidism) and various forms of hyperlipidemia (eg, hypertriglyceridemia) are linked to acute but not chronic pancreatitis. So-called tropical chronic pancreatitis, described in children living in developing parts of the world, is thought to be either due to a dietary toxin or to an unidentified micronutrient deficiency.

Idiopathic

About 20% of patients with chronic pancreatitis have no clinically obvious risk factor. It is suspected that a great many of these idiopathic cases will ultimately prove to harbor yet unidentified genetic or molecular derangements that explain the process. In recent years, many patients previously considered to be idiopathic recurrent acute and chronic pancreatitis have been found to carry mutations, polymorphisms, or splice variants of the gene associated with cystic fibrosis. Recent evidence also suggests that polymorphisms in genes associated with oxidative stress and xenobiotic metabolism may be more prevalent in patients with what is now characterized as idiopathic disease.7 Thus, as new genetic associations that predispose to the development of chronic pancreatitis become recognized, the percentage of patients with truly idiopathic disease will decrease.

Genetic

Hereditary pancreatitis was first characterized in 1952 as early onset of chronic pancreatitis clustering in family members without other risk factors.8 At least half of hereditary pancreatitis kindreds have been found to carry germline mutations in the cationic trypsinogen (PRSS1) gene.3,4,9 The arginine-to-histidine (R122H) substitution is the most common defect. Hereditary pancreatitis has an autosomal dominant pattern of inheritance, with a high degree of penetrance. Cationic trypsinogen is produced in the pancreatic acinar cells and, upon cleavage by duodenal enteropeptidase, forms trypsin. Trypsin is a protease that acts to hydrolyze dietary proteins and plays the key role in both initial activation of other pancreatic zymogens (including trypsinogen itself) and in their subsequent proteolytic inactivation. Trypsin encoded by pancreatitis-associated PRSS1 mutations is unusually stable and resists autolytic inactivation, predisposing to premature and extended activation of trypsin within the pancreatic parenchyma.10 Mutations in other genes such as anionic trypsinogen (PRSS2) or the calcium-sensing receptor (CASR) have also been reported in some cases of hereditary pancreatitis, although in many other kindreds, the responsible gene has not yet been identified.11 Other gene associations with hereditary or otherwise idiopathic chronic pancreatitis will undoubtedly emerge over the next several years. Recently, for example, inactivating mutations in the gene encoding for the trypsin-degrading enzyme chymotrypsin C have been identified in a German cohort.12

Another genetic disorder associated with pancreatic pathology is cystic fibrosis (CF), a disease linked to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.9,13–15 CFTR is a chloride ion channel involved in water, chloride, and bicarbonate secretion by epithelial cells such as those lining the gastrointestinal tract and respiratory system. In the pancreas, CFTR is localized to centroacinar and proximal lobular duct cells.16 Over 90% of CF patients are pancreatic insufficient, and, while severe pancreatic fibrosis is common, acute pancreatitis is rare.17 However, a subset of patients with otherwise idiopathic recurrent acute and chronic pancreatitis has been noted to have borderline abnormalities in functional tests for cystic fibrosis such as sweat chloride content. These patients harbor at least an eightfold increase in CF-associated CFTR mutations on a single allele. Various other CFTR mutations, polymorphisms, and splice variants not associated with classical pulmonary manifestations of CF are also frequently identified in patients with recurrent acute and chronic pancreatitis. The CFTR gene shows autosomal recessive inheritance with incomplete penetrance, and thus a family history of CF or pancreatic disease is usually absent in CFTR-associated pancreatitis. The mechanism of CFTR-associated pancreatitis is thought to involve the viscous, low-volume, low-bicarbonate containing pancreatic fluid secretion leading to duct sludge and enzyme hyperconcentration, enhancing the potential for intraglandular enzyme activation.

Mutations and polymorphisms in other genes may also modify susceptibility to chronic pancreatitis. Pancreatic serine protease inhibitor Kazal type 1 (SPINK1) is a natural protease inhibitor that localizes with trypsinogen within zymogen granules. SPINK1 binds to and inhibits activated trypsin, thus serving as a “buffer” of sorts against inappropriate early trypsinogen activation. Mutations of the SPINK1 gene (notably N34S) appear to increase the risk of recurrent acute and chronic pancreatitis, particularly in patients who harbor two mutated alleles.3,4,9 A single mutated SPINK1 allele appears to increase the risk of alcohol-associated pancreatitis and tropical pancreatitis.

Autoimmune

Autoimmune chronic pancreatitis (AIP), also known as lymphoplasmocytic sclerosing pancreatitis, is characterized by diffuse glandular enlargement and infiltration with CD4 or CD8-positive lymphocytes and IgG4-positive plasma cells.3,4,18,19 The exact immunologic etiology is unknown, although circulating antibodies with homology both to a peptide sequence associated with a protein from Helicobacter pylori (infection with which is associated with various autoimmune disorders including AIP) and to a protein highly expressed in pancreatic acinar cells have recently been found in over 90% of patients.20 Inflammatory infiltrates are particularly concentrated in duct rather than acinar zones, however, and thus a duct-origin autoantigen has been postulated. Notably, diffused ductal narrowing rather than dilation is usually observed. Initially described predominately in young men, AIP has been increasingly recognized as a cause of biliary obstruction and pseudotumor in older individuals.21 Most patients report little in the way of pain, and prior attacks of acute pancreatitis are unusual. It has been associated with serologic elevation of IgG4 levels in about two-thirds of patients and with other autoimmune conditions in approximately 20%, including Crohn's disease, ulcerative colitis, Sjögren's syndrome, primary biliary cirrhosis or primary sclerosing cholangitis.18,21

Recurrent and Severe Acute Pancreatitis

Recurrent episodes, or even a single severe episode of, acute pancreatitis may lead to chronic pancreatitis, but the basis for progression is poorly understood. Patients with prior episodes of necrosis appear to be at particular risk for developing chronic disease. In many cases, progression may be due to postpancreatic ductal scarring, persistent activation of pancreatic stellate cells, and neuroplasticity leading to hyperalgesia.

Obstructive

Post-traumatic duct strictures, or obstruction associated with tumors including cystic neoplasms, neuroendocrine lesions, and pancreatic adenocarcinoma have been associated with pancreatic pathology consistent with chronic pancreatitis, although these patients are often asymptomatic. Chronic pancreatitis has also been associated with anomalous anatomic variations in the pancreatic ductal system, most notably pancreasdivisum, and it has been postulated that relative obstruction to pancreatic flow through the dorsal duct and minor papilla predisposes to recurrent acute and chronic pancreatitis. The evidence supporting the association to chronic pancreatitis in particular is largely circumstantial and may reflect referral bias22 but pancreas divisum may be a contributing factor in the presence of certain genetic risk factors (Fig. 56-1). Some cases of chronic pancreatitis are attributed to sphincter of Oddi dysfunction, although rigorous evidence to support this association is also lacking.

Progress in elucidation of the pathogenesis of chronic pancreatitis has been hampered by the lack of a suitable experimental model that adequately recapitulates the features of the disease seen in humans.23 However, existing evidence suggests a number of useful conceptual frameworks that may help guide efforts to treat patients with chronic pancreatitis. Traditional theories of the pathogenesis of acute pancreatitis include the toxic-metabolic or oxidative stress hypotheses, in which normal acinar cell processing and release of zymogens are disrupted by a toxic or oxidative stressor, and the ductal obstruction hypothesis that proposes a mechanical role for ductal plugs and stones causing disruption of the integrity of the acinar cell (common in alcoholic and tropical disease). In certain situations, notably autoimmune disease, pancreatitis may begin not in the acinar cell but in the duct cell, triggered by the development of an as-yet-unidentified autoantigen on the duct epithelium. Recently, attention has focused on understanding the mechanism of pancreatic fibrosis, the central histological feature that characterizes the evolution from acute disease to chronic pancreatitis. One attractive hypothesis is that a sentinel acute pancreatitis event (SAPE) primes the pancreas for fibrogenesis.23 According to the SAPE concept, local inflammatory cytokines released during acute pancreatitis activate circulating macrophages that infiltrate the gland as well as resident pancreatic stellate cells, myofibroblast-like cells that are normally quiescent. During the subsequent healing phase, anti-inflammatory mediators (particularly anti-inflammatory cytokines such as tumor growth factor beta [TGF-β]) drive stellate cells and tissue macrophages to synthesize and deposit fibrogenic matrix proteins. The pancreatic parenchyma may return to normal after a mild self-limited episode. However, the damage may not completely resolve after a severe attack, particularly if there has been significant tissue necrosis. Thus, following the SAPE, the local pancreatic environment may be permanently altered by the persistent presence of anti-inflammatory and profibrogenic cell populations that are perpetually activated by ongoing toxic-metabolic, oxidative, or mechanical stress. The pancreas then becomes subject to repeated cycles of inflammation and progressive fibrosis.

A comprehensive mechanistic explanation for pain, often the most debilitating symptom of chronic pancreatitis, also remains elusive.23 One hypothesis is that pain results from capsular stretch associated with ductal or organ hypertension. This hypothesis is supported by the favorable results of surgical or endoscopic ductal drainage in patients with chronic pancreatitis associated with dilated pancreatic ducts, and the success of surgical resection in other selected patient populations. An alternative, and possibly complementary, hypothesis is that the pain represents a neuropathy caused by repeated inflammatory insults and damage to retroperitoneal sensory nerves.23–25 Recent evidence demonstrating neuroplasticity in nociceptive dorsal root ganglia in chronic inflammatory states, with evidence of upregulation of nociceptors such as TRPV1 by proteolytic enzymes such as trypsin26 supports this theory.

As in acute pancreatitis, pain in chronic pancreatitis typically localizes to the left upper quadrant or epigastric region, often radiating around or into the back. The pattern of pain is variable. Some patients experience recurrent attacks of moderate to severe pain interspersed with periods of relative or complete quiescence. In others, the pain may be persistent and lead to significant incapacitation and chronic disability. During acute exacerbations, the pain may be increased by food intake and is frequently associated with nausea and vomiting.

Weight loss and malnutrition are common, due to both decreased intake as well as exocrine insufficiency with consequent malabsorption of protein and fat. Exocrine insufficiency is usually obvious in patients with classical steatorrhea (loose, bulky bowel movements that may be greasy, sticky, oily, or foul-smelling), but these symptoms are obscured by narcotic-associated constipation.

Endocrine insufficiency typically occurs late in the course of disease, often after exocrine insufficiency has appeared, and usually not before about 90% of the pancreatic parenchyma has been replaced by fibrosis. Diabetes is more common in patients with alcohol-associated chronic calcifying pancreatitis with 80% of these individuals demonstrating endocrine insufficiency within 10 years of the development of severe exocrine insufficiency.27 For unclear reasons, there is a relative sparing of islet cells until late in the course of the disease. Histologically, pancreatic islets are seen to persist within areas of extensive fibrotic replacement of exocrine tissue (Fig. 56-2). Because diabetes of chronic pancreatitis is associated with indiscriminate destruction of all cell types within the islets of Langerhans, counter-regulatory glucose control may be considerably more labile than in either type I or type II diabetes. Less is known regarding the natural history of nonalcohol-associated chronic pancreatitis but the risk of diabetes appears to be lower.27 Both endocrine and exocrine insufficiency occur later and less frequently in patients with chronic pancreatitis associated with gene mutations than those without gene mutations.28

On occasion, the initial manifestation of chronic pancreatitis will be related to extrapancreatic complications such as intestinal or biliary obstruction due to compression by a pseudocyst, and gastrointestinal hemorrhage due to blood lost into the pancreatic duct (hemosuccus pancreaticus) or due to rupture of pseudoaneurysm into a pseudocyst or to splenomesenteric vein thrombosis.

The diagnosis is usually suspected based on an appropriate clinical history and is confirmed by imaging studies. Laboratory investigation is of limited value. Acute exacerbation of abdominal pain may be paralleled by a transient increase in serum amylase or lipase, but these may be normal with progressive destruction of acinar cell mass. Elevation of liver function tests, particularly serum bilirubin and alkaline phosphatase, may indicate the presence of bile duct obstruction.

The diagnosis of chronic pancreatitis is usually confirmed by imaging studies, most commonly computed tomography (CT). CT findings depend on the morphologic type of chronic pancreatitis, the duration of disease, and the presence of complications. In the early phases of chronic pancreatitis, ductal or parenchymal changes may be rather subtle, but as the disease advances, progressive and irreversible changes in organ architecture are readily apparent. Chronic pancreatitis associated with toxic-metabolic or genetic risk factors, and idiopathic chronic pancreatitis may demonstrate calcifications either focally or scattered throughout the organ. There may be evidence of acute inflammatory changes or focal areas of enlargement associated with areas of dense calcifications, particularly in the pancreatic head (Fig. 56-3); this so-called “inflammatory head mass” appears to be more common in European than American cohorts.29 There may be evidence of segmental or diffuse pancreatic ductal dilation related to stricture formation, and pseudocyst formation and evidence of extrapancreatic complications such as duodenal or biliary obstruction, or splenomesenteric vein thrombosis (Fig. 56-4). In autoimmune pancreatitis, calcifications are almost uniformly absent and the pancreas is usually diffusely enlarged although a focal mass-forming variant is occasionally encountered.18 In obstructive forms of chronic pancreatitis, the pancreatic duct is dilated upstream of the area of stenosis and the acinar parenchyma appears atrophic. Although CT can readily confirm the clinical suspicion of chronic pancreatitis, it rarely provides sufficient information for therapeutic decision making.

Pancreatic ductography complements CT imaging and is generally considered essential in planning intervention. Endoscopic retrograde cholangiopancreatography (ERCP) has long served as a gold standard of sorts in mapping duct pathology and offers endotherapeutic options including sphincterotomy and stent placement (Fig. 56-5). Magnetic resonance cholangiopancreatography (MRCP) is less invasive and provides image quality that rivals ERCP; the addition of secretin stimulation further enhances duct visualization and allows some assessment of pancreatic exocrine function (Fig. 56-6).30 Anatomic ductal anomalies such as pancreas divisum are readily defined by ERCP or MRCP, as are dominant focal duct strictures that might be amenable to endoscopic stenting or surgical drainage procedures. MR imaging integrates information regarding parenchymal and ductal involvement and may be particularly helpful when the disease is regionally heterogeneous and architecturally complex.

It is not difficult to establish the diagnosis of chronic pancreatitis in its advanced stages, when classical clinical symptoms are present or when imaging studies demonstrate obvious abnormalities such as strictures, ductal dilation, or pancreatic calcifications. Recognition of disease in its earlier stages presents more of a challenge. A 1983 conference held in Cambridge categorized chronic pancreatitis as equivocal, mild, moderate, or marked and established criteria (Table 56-2) according to combinations of features seen in the main and side branch pancreatic ducts on CT and ductograms.1,31,32 Although this consensus approach has proven useful over the years, there continues to be a subset of patients with symptoms suspicious for chronic pancreatitis but in whom imaging studies are negative. Some of these patients may suffer from functional abdominal pain disorders rather than pancreatic disease.33 Others may have early forms of chronic pancreatitis. Consensus workshops by the Japan Pancreas Society (1995 and 2001) continue to address the ongoing challenge of so-called “minimal change” disease in the context of evolving imaging and diagnostic modalities.

Endoscopic ultrasound (EUS) appears to be valuable in evaluation of the suspicious pancreatic mass and in characterizing cystic lesions of the pancreas.34 EUS generally adds little to the evaluation of chronic pancreatitis in its advanced stages but has potential applicability in early stage, minimal change disease where other imaging modalities fail to establish the diagnosis.3,35–37 EUS appears to be more sensitive than ERCP or MRCP in detecting early parenchymal fibrosis and subtle ductal changes occurring in early forms of chronic pancreatitis. Various systems using up to 11 different parenchymal and ductal endosonographic criteria (Table 56-3) to diagnose chronic pancreatitis have been proposed.38 There is however, no gold standard grading system or agreement on the threshold number of abnormalities that must be present for the diagnosis of chronic pancreatitis. Because of this, the value of EUS in making an early diagnosis of chronic pancreatitis, remains uncertain. EUS may have more practical utility in cases of suspected autoimmune pancreatitis. Surgical interventions may be avoided in some of these patients that present with a mass-forming variant by EUS-directed core needle biopsy demonstrating the pathognomonic lymphoplasmacytic infiltrate39 and thus ruling out malignancy.

Functional testing to demonstrate pancreatic exocrine insufficiency is occasionally helpful, although from a practical standpoint, the condition is usually clinically obvious. Symptoms of steatorrhea, postprandial gaseous distension, or progressive weight loss despite adequate caloric intake are all suggestive of exocrine insufficiency. Quantification of fecal fat content or measurement of fecal human elastase (FE-1) levels can confirm the diagnosis and can be used to monitor efficacy of enzyme supplementation and surgical intervention.40 Unfortunately, these studies are most reliable in those patients in whom the diagnosis is clinically obvious. They are of questionable accuracy in the setting of patients with more subtle symptoms where objective documentation of exocrine insufficiency might be most needed.

Elevation in fasting serum glucose or glycosylated hemoglobin (HgA1c) suggests pancreatic diabetes. Functional evaluation (eg, formal oral glucose or arginine-tolerance testing) for pancreatic endocrine insufficiency may be helpful in patients prior to pancreatic resection, particularly if autologous islet transplantation is under consideration.

In patients with suspected autoimmune pancreatitis, measurement of serum immunoglobulin G levels, particularly IgG4, is indicated. Other markers of autoimmune disease include rheumatoid factor, antinuclear antibody, C-reactive protein (CRP), or erythrocyte sedimentation rate, although these are less specific.19

The role of genetic testing in patients with idiopathic or suspected hereditary pancreatitis is controversial.41 It may be most reasonable to screen for PRSS1 mutations in patients with a strong family history of pancreatitis because of the autosomal dominant inheritance and the high risk of development of pancreatic cancer; a risk that is further dramatically elevated by tobacco use. However, hereditary pancreatitis patients without PRSS1 mutations may have the same elevated risk of cancer, and there is no evidence that screening by serial imaging studies leads to earlier diagnosis or improved prognosis of pancreatic cancer. Identification of CFTR or SPINK1 gene mutations may be useful in selected circumstances; for example, patients with idiopathic pancreatitis may feel reassured by having an “explanation” for their disease. However, in the absence of therapy directed at the specific functional defects associated with these mutations, the clinical value of gene testing is debatable.

Cessation of potential inciting agents such as alcohol may reduce the intensity or frequency of attacks. Avoidance of high-fat foods and tobacco use may also be of value. Occasionally, patients are unable to tolerate oral food intake for extended periods of time, in which case nutritional support by an enteral route that minimizes pancreatic stimulation (eg, via nasojejunal or gastrojejunal tube) or by a parenteral approach may be required. Pancreatic enzyme replacement is used to treat steatorrhea and other symptoms of exocrine insufficiency. Enteric-coated preparations are most useful in this setting.42 Various formulations differ in lipase, protease, and amylase content and enzyme replacement therapy should be titrated to effect.42,43 Patients must be carefully instructed to time enzyme ingestion appropriately in relation to meals to optimize mixing.

In certain circumstances, medical therapy may alter the intensity or frequency of exacerbations of chronic pancreatitis. For example, some patients with early, small duct, or minimal change disease appear to benefit from high doses of noncoated enzyme preparations.42 The presence of activated enzymes within the duodenum has been shown to decrease cholecystokinin-mediated stimulation of the pancreas. Noncoated enzyme preparations must be protected from destruction by gastric acid suppression therapy; trials that instead utilize enteric-coated delayed release enzyme formulations showed no benefit.42,43 Several randomized trials suggest that a five-component antioxidant regimen reduces the frequency and intensity of painful episodes.44 Patients with autoimmune pancreatitis confirmed by elevated IgG4 levels or tissue biopsy may be treated with an 8-week tapering course of corticosteroids.21

The major reason patients with chronic pancreatitis seek medical attention is unrelenting or frequently relapsing pain. Pain, more than any other feature, accounts for intractability and overall loss of quality of life. While in some patients, the intensity of pain may burnout as the disease reaches its end stage, this natural history is highly variable and may take years, if it occurs at all. Thus, a conservative, watch-and-wait approach is rarely acceptable. Pharmacotherapy for pain should begin with nonsteroidal anti-inflammatory medications, but if more powerful agents are needed, propoxyphene or tramadol may be used prior to escalating to more aggressive pharmacotherapy. Long-acting narcotics supplemented by short-acting narcotic formulations for breakthrough pain may be more effective than short-acting agents alone. Unfortunately, narcotic dependency is a common consequence of the use of these agents. Psychosocial supports such as counseling are essential to successful longitudinal management of chronic pain. Variable results have been reported with the use of long-acting somatostatin analogues. Occasionally, tricyclic antidepressants or gabapentin may be useful. Alternatives such as placement of infusion pumps for intrathecal delivery of narcotics have been anecdotally successful.45

Neurolysis may be considered in patients who have failed medical management and who do not appear to have favorable anatomic circumstances amenable to endoscopic or surgical intervention. The most common neurolytic procedure is celiac plexus block, which can be performed under radiological or endoscopic guidance. The initial approach involves injection of a combination of steroids and a local anesthetic into the celiac ganglion. If temporary relief if obtained, this is followed by permanent neurolysis with 100% alcohol injection. Results of celiac plexus block in chronic pancreatitis have been mixed, but transient improvement (typically no more than 6 months) may be of benefit in selected patients.36,46 Splanchnicectomy, usually performed by a thoracoscopic approach, has also been used, but similar to other forms of neurolysis, permanent resolution of pain is unusual.47

Therapeutic endoscopic intervention may be considered in patients with obstructive and inflammatory disease. Lithotripsy of pancreatic duct stones and pancreatic duct stent placement has been reported in several small retrospective series. Technical success can be reliably achieved in appropriately selected patients (eg, manageable stone size and local density sufficiently close to the working end of the scope and without intervening duct stricture). However, the effectiveness of endotherapy over time is often less than 50% with respect to improvement in pain or reduction in frequency of attacks. Multiple procedures are often necessary, recurrence of strictures and stones is frequent, and the substantial fraction of patients that fail generally require surgical intervention (Fig. 56-7).48,49 Long-term presence of stents within the pancreatic duct may worsen inflammatory ductal strictures, although most series find a few patients who achieve durable pain relief following removal of stents. Patients who are suitable for endotherapy are usually also candidates for surgical intervention, provided there are no medical contraindications to operation. The two randomized trials (Table 56-4) to date that directly compared surgical therapy to endoscopic stenting reported long-lasting superiority of the surgical approach with respect to pain relief, quality of life, over time, and other endpoints.50,51

Surgical therapy for chronic pancreatitis is usually reserved for patients with symptoms that are otherwise intractable to pharmacotherapy and other therapeutic approaches. In over 90% of patients, the main indication for operation is pain. Occasionally, an operation is performed to relieve biliary or gastrointestinal obstruction, to internally drain a symptomatic pseudocyst, or for vascular complications of chronic pancreatitis such as gastric variceal hemorrhage secondary to splenic vein thrombosis.

A number of pancreatic operations have been developed over several decades of international effort. These operations generally involve either ductal drainage, parenchymal resection, or some combination of resection and ductal drainage. The choice of operation depends on anatomic morphology. In many patients, the disease appears to be driven predominantly by pathology within the pancreatic head, sometimes considered the “pacemaker” of chronic pancreatitis, particularly in those with a sizable inflammatory mass in this region of the organ. Others present more diffuse disease involving extensive areas of stricture and dilation of the main pancreatic duct or its ductal tributaries. Occasionally, disease appears limited to the body or tail. Operations on the pancreas may be technically demanding and carry significant risks of postoperative morbidity and mortality. Although in appropriately selected patients, the immediate results may be excellent, long-term success (durable pain relief) is achieved in at most 85% of patients at 5 years of follow-up. Alternatives for surgical intervention are best individualized and considered in the context of the most frequently encountered clinical and anatomic scenarios.

Large-Duct Disease

Large-duct chronic pancreatitis is characterized by enlargement of the main pancreatic duct lumen to a diameter exceeding 7–8 mm. Ductal dilation is often diffuse along the length of the organ, but there may be one or more intervening areas of ductal stricture. In many patients, calcific deposits (stones) may be evident on imaging studies within the main or secondary ducts.

Puestow described a procedure to provide enteric drainage to a diffusely dilated main pancreatic duct, with the goal of achieving pain relief by duct decompression. In its initial description, the Puestow procedure consisted of a longitudinal unroofing of the dilated pancreatic duct in the body and neck of the gland, and also involved resection of the pancreatic tail.52 A long segment longitudinal pancreaticojejunstomy was then constructed to establish enteric drainage. A modification reported by Partington and Rochelle in 1960 eliminated the distal pancreatectomy. Lateral pancreaticojejunostomy is now thus referred to as either a (modified) Puestow or Partington-Rochelle procedure53 and continues to be commonly used for disease characterized by a diffusely dilated main pancreatic duct with no significant biliary obstruction and no mass in the pancreatic head.

Lateral Pancreaticojejunostomy— Technique

Midline or transverse upper abdominal incisions provide acceptable exposure for this procedure. The dissection is begun by incising the peritoneal lining adjacent to the lateral border of the second portion of the duodenum, extending laterally to release the hepatic flexure of the right colon. Using electrocautery, the retroperitoneal attachments lateral and posterior to the duodenum are divided to widely mobilize the duodenum and posterior aspect of the head of the pancreas (Kocher's maneuver). This dissection is carried inferiorly to free the third portion of the duodenum from the base of the transverse mesocolon, effectively exposing the head of the pancreas and anterior surface of the duodenum from the pylorus to the level of the superior mesenteric vessels. Exposure of the anterior surface of the pancreatic body and tail requires access to the lesser sac, which is entered by dividing the gastrocolic omentum or by separating the avascular plane of attachment from the transverse colon and mesocolon. Next, the gastroduodenal artery (GDA) is identified at its supraduodenal origin from the common hepatic artery and traced across the head of the pancreas. The GDA is then suture ligated at both the superior and inferior border of the head of the pancreas in an effort to prevent intraoperative hemorrhage during incision of the pancreatic head and main pancreatic duct during the dissection as well as postoperative bleeding at the site of the pancreaticojejunostomy. The anterior surface of the pancreas is then carefully examined to confirm the presence of main duct dilation and the absence of suspicious mass lesions or unanticipated inflammatory changes in the head of the gland. The dilated pancreatic duct is usually visible by direct inspection or palpation of the anterior surface of the pancreas but can also be accessed by means of a fine needle and low-volume syringe. The duct can also be localized using intraoperative ultrasound, but this is usually not necessary. The pancreatic duct is then incised longitudinally along its full length using electrocautery. This ductotomy should extend across the neck into the head of the organ where the GDA traverses the pancreas, and should extend laterally as far as possible along the length of the tail so that the entire segment of dilated duct is unroofed. The pancreaticojejunal anastomosis is performed in Roux-en-Y fashion using a 40–50 cm defunctionalized jejunal limb. Using a linear gastrointestinal stapler, the proximal jejunum is divided at the apex of a mesojejunal vascular arcade of suitable mobility, typically at least 20–30 cm distal to the ligament of Treitz, although the precise distance is probably unimportant. The distal staple line is inverted using a series of 3-0 silk sutures placed in a Lembert fashion which are tied (but not cut) and then held by a fine clamp that facilitates later positioning of the pancreatic anastomosis. Intestinal continuity is then re-established by a handsewn or stapled enteroenterostomy such that the intestinal conduit is approximately 60 cm in length. The Roux limb is then advanced through the transverse mesocolon either to the right or left of the middle colic vessels. A longitudinal jejunostomy is made to correspond to the pancreatic ductotomy. The pancreaticojejunostomy is handsewn with a running absorbable suture (eg, 4-0 double-armed polyglyconate or polydioxanone suture), which, according to surgeon preference, may be additionally reinforced by an outer later of interrupted nonabsorbable suture (Fig. 56-8). After completion of the anastomosis, the distance between the pancreaticojejunostomy and the enteroenterostomy should measure at least 40 cm to prevent reflux of enteric contents up to the anastomosis.

Lateral Pancreaticojejunostomy— Outcomes

Results of the Partington-Rochelle procedure in appropriately selected patients are generally favorable. In most series, 75–80% of patients with diffusely dilated main pancreatic ducts (>7 mm) and no dominant inflammatory mass, have achieved durable pain relief over 5–10 years of follow-up.52,54–57 Compared to other major pancreatic operations, perioperative morbidity is low, and because no pancreatic parenchyma is removed, endocrine and exocrine functions are generally preserved relative to preoperative levels. Failure of lateral pancreaticojejunostomy is usually due to inappropriate patient selection (underappreciated extent of disease with the presence of significant fibrosis in the pancreatic head), or ongoing fibrosis with the progressive development of neuropathic pain.

Chronic Pancreatitis with a Dominant Pancreatic Head Mass

Lateral pancreaticojejunostomy has limited applicability in patients without diffuse main duct dilation. Multiple groups have reported that an isolated drainage procedure in patients with complex inflammatory changes in the pancreatic head, body, or tail results in poor clinical outcome with quick recurrence of symptoms of pain and progression to exocrine insufficiency. For patients with an inflammatory mass, extensive calcifications or duct stones in the pancreatic head, results appear to be better either with pure resectional or with hybrid resection and drainage procedures. There are four procedures being used in a great frequency today. These include pancreaticoduodenectomy (Whipple procedure, with or without pyloric preservation) and three forms of duodenum-preserving pancreatic head resection (DPPHR): the Beger procedure, the Berne procedure, and the Frey procedure.

The outcomes associated with these procedures have been compared in several randomized trials enrolling small numbers of patients with head predominant morphology. None of these studies has demonstrated any one of the techniques to be clearly superior to others (Table 56-5). There are no measurable differences in outcomes compared, the numbers in the trials are small and the metrics used to evaluate the outcomes are variable and imperfect.58–61 As a result, no consensus opinion among pancreatic experts about which procedure is the best in any given clinical situation has emerged. In recent years, European surgeons have tended to favor a duodenum-preserving approach and American surgeons have tended to favor pancreaticoduodenectomy. One recent survey of American surgeons who were members of the Pancreas Club found that of 59 surgeons surveyed, only 34 had ever performed DPPHR and that only 23 US surgeons continue to perform these procedures on a regular basis.62

In spite of the lack of data supporting the relative superiority of any given procedure, we do believe that each has specific applicability to certain subtypes of head predominant morphology. A reasonable approach is to tailor the procedure to the anatomic morphology seen on the preoperative axial imaging and ductography. Patients with a dominant head mass and a dilated main pancreatic duct but no biliary dilation, may be best served by a Frey procedure (limited duodenum-preserving resection of the pancreatic head with extended lateral pancreaticojejunostomy). Patients with a dominant head mass without main duct dilation and no biliary obstruction may be better suited for the Berne modification of the Beger procedure (limited duodenum-preserving resection of the pancreatic head without extension of the lateral pancreaticojejunostomy toward the tail). Patients with biliary obstruction or imaging characteristics more suspicious for the presence of malignancy should probably undergo pancreaticoduodenectomy rather than any form of DPPHR.

Pancreaticoduodenectomy—Technique

The early primary objective in the pancreaticoduodenectomy is making an efficient determination of whether or not the pathology allows safe resection. This typically involves a thorough manual examination of the abdomen to rule out metastatic cancer and then a rapid exposure of the pancreatic neck superiorly and inferiorly in an effort to assess the operator's ability to free the hepatic artery, superior mesenteric vein, and superior mesenteric artery from the pathology in the pancreatic head safely. Pancreaticoduodenectomy may be performed through a midline laparotomy or bilateral subcostal incision. Careful inspection and palpation of the peritoneal surfaces and liver is performed first, with frozen-section biopsy obtained of any suspicious lesions. Small areas of fat necrosis or fibrosis from prior attacks of pancreatitis are easily mistaken for metastatic deposits. The base of the transverse mesocolon should be inspected for evidence of foreshortening or inflammatory involvement that may herald a difficult or dangerous dissection in the vicinity of the superior mesenteric vessels, and to confirm the absence of otherwise unsuspected tumor extension. The hepatic flexure of the colon is mobilized by freeing the lateral retroperitoneal attachments using the electrocautery, an extended Kocher maneuver is performed, and the lesser sac is then entered by separation or division of the gastrocolic omentum, as described in the previous section. The mass in the head of the gland is palpated and determined to be safely free from the superior mesenteric vein (SMV) at the inferior border of the neck of the pancreas by preliminary dissection of the plane anterior to the SMV posterior to the neck of the pancreas. Attention is then turned to the supraduodenal region. A cholecystectomy is performed, and the portal dissection is initiated by isolating the common bile duct (CBD) at the level of the cystic duct stump. The bile duct is carefully freed from the anterolateral surface of the portal vein and secured temporarily with a vessel loop. The common hepatic artery is usually found anteromedially to the portal vein, and it should be carefully isolated with a vessel loop and preserved. The lateral, free edge of the gastrohepatic ligament at the foramen of Winslow should be carefully inspected and palpated for an accessory or replaced right hepatic artery, which, if present, should also be isolated and protected during the subsequent resection. The GDA is isolated at its origin from the common hepatic artery and secured temporarily with a vessel loop. The continued presence of pulsatile flow in the proper hepatic artery after temporary occlusion of the GDA should be assured, both to confirm the vascular anatomy and to ensure that there is no stenosis in the proximal common hepatic artery or celiac trunk due to atherosclerotic plaque. Preliminary dissection of the plane anterior to the portal vein is begun. These measures demonstrate that there is no evidence of unresectable cancer and that the pancreatic head can be removed without concern for undue injury to the blood supply of the small intestine and liver.

At this point, technical resectability of the pancreatic head has been assured (Fig. 56-9). The GDA is divided between clamps and is doubly tied or suture ligated. The common hepatic duct is divided just proximal to the cystic duct entry, and bile flow is controlled with a small bulldog clamp. The right gastric artery is divided between suture ligatures. For a standard pancreaticoduodenectomy, the greater omentum is divided to a point on the greater curvature of the stomach in the vicinity of the junction of the right and left gastroepiploic arteries. The lesser omentum is divided at the level of the incisura of the lesser curvature of the stomach, and the descending branch of the left gastric artery is carefully secured. The stomach is then divided with two firings of a linear gastrointestinal stapler. The lesser curve staple line is inverted with silk Lembert sutures. For pyloric-preserving pancreaticoduodenectomy, the duodenum is divided using a stapler approximately 2 cm distal to the pyloric ring. The ligament of Treitz is taken down with electrocautery, being certain to avoid injury to the inferior mesenteric vein. The proximal jejunum is divided approximately 15 cm distal to the ligament of Trietz with a linear gastrointestinal stapler. The distal staple line is oversewn with interrupted Lembert sutures, initially left long to use for traction and positioning of the limb during the reconstruction. The short mesojejunal vessels of the proximal segment are carefully isolated and secured close to the mesenteric border of the jejunum using fine nonabsorbable ligatures, surgical clips, or an electrosurgical vessel-sealing device. This dissection is continued proximally to the duodenojejunal junction, and then the proximal jejunum is advanced into the supracolic compartment by passing it under the superior mesenteric vessels. At this point blunt dissection is used to complete development of a tunnel between the neck of the pancreas and the SMV or portal vein. The superior and inferior pancreatic vascular arcades are then ligated on either side of the planned transection site at the neck of the pancreas using nonabsorbable suture. The neck is then divided with electrocautery. Gentle retraction of the pancreatic head, distracting it from the right lateral wall of the SMV or portal vein, helps to expose small venous tributaries from the uncinate process, which should then be carefully controlled with fine ties or suture ligatures. The first jejunal venous tributary may be quite large and is easily injured during this dissection. The uncinate branches from the superior mesenteric artery (SMA) are then divided sequentially between clamps with great care to preserve the integrity of the SMA. The specimen is then oriented and submitted for pathological examination.

The reconstruction begins with the pancreaticojejunostomy (Fig. 56-10). The jejunum is advanced through the transverse mesocolon either to the right or left of the middle colic vessels according to surgeon's preference. Several techniques of pancreaticojejunostomy have been described. One commonly used approach is a two-layer method that is begun by placing a posterior row of interrupted nonabsorbable sutures between the pancreatic capsule and the seromuscular layer at the antimesenteric aspect of the jejunum. A small enterotomy is then made with bovie cautery across from the site of the main pancreatic duct at the pancreatic neck. An inner layer of four to eight interrupted fine absorbable monofilament sutures is used to secure the pancreatic duct to the intestinal wall at the enterotomy in a duct-to-mucosa fashion. An anterior row of interrupted nonabsorbable suture is then used to secure the anterior pancreatic capsule to the anterior serosa at the antimesenteric border of the jejunal limb. The duct-to-mucosa anastomosis may also be performed over a 5F pediatric feeding tube, which can then be exteriorized through the jejunal limb using a Witzel-type closure. The choledochojejunostomy is then constructed at a site approximately 15 cm distal to the pancreaticojejunostomy. A small enterotomy is made at the antimesenteric border of the jejunal limb at this location. The choledochojejunostomy is also performed in a duct-to-mucosa fashion, either with a single layer of interrupted absorbable monofilament suture or, if the bile duct is dilated, using absorbable continuous suture. The pancreaticobiliary limb is then secured to the transverse mesocolon using interrupted sutures and any potential gap through which herniation may occur is closed. The retroperitoneal space at the level of the ligament of Treitz is also closed. Gastric continuity is reestablished by means of an antecolic loop gastrojejunotomy performed at a site sufficiently distal to the transverse mesocolon closure to prevent angulation of the afferent limb. A Hofmeister-type configuration is typically used, wherein the lesser curvature half of the gastric transection line is oversewn and the anastomosis is performed to the greater curvature half. The jejunal limb is oriented with the afferent limb toward the lesser curvature, efferent limb to the greater curvature. A two-layered anastomosis is preferred, with an outer layer of nonabsorbable interrupted seromuscular Lembert sutures and an inner continuous absorbable Connell-style layer. The abdomen is then irrigated with saline or dilute antibiotic solution and the abdominal wall closed. No closed suction peritoneal drains are necessary.

Beger Procedure—Technique

Duodenum-preserving pancreatic head resection was first described by Beger in 1972. The operation evolved from the premise that a pancreaticoduodenectomy was unnecessarily radical for benign pathology and that a more limited resection preserving the duodenum would avoid some of the adverse sequelae associated with pancreaticoduodenectomy such as delayed gastric emptying and insulin-dependent diabetes.63 The procedure is performed through a midline laparotomy or bilateral subcostal incision. As at the start of the pancreaticoduodenctomy, the gastrocolic ligament is separated or divided, the transverse mesocolon is mobilized off the head of the pancreas and duodenum, and a wide Kocher maneuver is performed. A cholecystectomy is performed. The GDA is isolated and divided. A tunnel is then created between the pancreatic neck and superior mesenteric vein or portal vein. The pancreatic neck is divided at this location and the pancreatic head manually rotated out of the retroperitoneum so that the cut edge faces up into the midline wound. The cystic duct is cannulated with a Bakes dilator and the CBD manually palpated in the head of the pancreas. Electrocautery is then used to core out the head of the gland with care taken to leave a rim of pancreas attached to the duodenum and to leave the bile duct intact within that rim (Fig. 56-11). The specimen is submitted to pathology for frozen-section examination to confirm the absence of malignancy. Pancreaticoenteric drainage is then reestablished by means of a two-sided Roux-en-Y pancreaticojejunostomy (Fig. 56-12). A Roux limb of jejunum is fashioned and advanced into the supracolic compartment through the transverse mesocolon as described for the lateral pancreaticojejunostomy. A two-layered handsewn duct to mucosa pancreaticojejunostomy is constructed at the neck margin as done for a typical pancreaticoduodenectomy with the exception that the anastomosis is sited closer to the mesenteric margin of the jejunum. The jejunal limb is then laid such that the antimesenteric border of the limb faces the midline wound. A second long pancreaticojejunostomy is constructed here by opening the border of the jejunal limb contralateral to the first pancreaticojejunostomy at the neck for a distance appropriate to include the entire length of the proximal pancreatic rim. This pancreatic margin is then secured to the long longitudinal enterotomy by means of a single layer of interrupted nonabsorbable suture. Intestinal continuity is then reestablished by means of a jejunojejunostomy performed as described earlier for the lateral pancreaticojejunostomy. The abdomen is irrigated and closed. No closed suction drains are necessary.

Beger Procedure versus Pancreaticoduodenctomy—Outcomes

Beger has recently reviewed his three-decade experience with DPPHR for chronic pancreatitis presenting with an inflammatory mass in the pancreatic head. His perioperative results demonstrate very reasonable rates of morbidity and mortality and an impressive improvement in pancreatic pain. His pancreatic fistula rate is reported as 3.3%, the rate of delayed emptying reported is 1.5%, and perioperative mortality rate is 0.7% in 603 consecutive patients. Late outcomes reported in this series demonstrated 91.3% of patients are free of pain at a median follow-up of 5.7 years.64 There have been two randomized trials that have attempted to compare outcomes from DPPHR to those achieved with pylorus-preserving pancreatoduodenectomy (PPPD). The most widely cited is by Buchler and colleagues and has been recently represented with long-term results. In this study 40 patients with chronic pancreatitis and a dominant focus in the pancreatic head were randomized to PPPD or DPPHR. The initial paper reported 6-month outcomes. This demonstrated a statistical advantage to DPPHR with regard to pain (75% of patients undergoing DPPHR were pain free at 6 months vs 40% of patients undergoing PPPD) and weight gain (average weight gain for those undergoing DPPHR was 4.1 kg whereas that for those undergoing PPPD was 1.9 kg).65 Length of hospital stay, perioperative morbidity and perioperative mortality rates were statistically identical. The authors of this study have recently presented their long-term results. At median follow-up of 7 years, the early advantages of the DPPHR were no longer evident with patients in each group having identical health-related quality of life scores, identical pain scores, and identical rates of exocrine and endocrine insufficiency. The other randomized comparison again studied only 40 patients for 12 months. This study demonstrated statistically identical rates of pain relief but a slight statistical advantage in terms of scores seen on a general assessment of health-related quality of life for patients undergoing DPPHR relative to those undergoing PPPD.58

Frey Procedure—Technique

The disadvantage of the DPPHR as described by Beger is that it does not address disease (either diffuse parenchymal fibrosis with side branch disruption or stricturing with upstream dilation of the main pancreatic duct) that may coexist in the pancreatic body and tail. Late failures of the Beger procedure have been attributed to poor drainage of the pancreatic body and tail. In an effort to overcome this, and in large part to avoid the certain exocrine and endocrine insufficiency that comes with the near-total pancreatectomy pioneered by one of his early mentors, Frey and colleagues developed a procedure that combines a duodenum-preserving pancreatic head resection with a hybrid resection or drainage procedure at the pancreatic body and tail (referred to as a local resection of the pancreatic head with longitudinal pancreaticojejunostomy or LR-LPJ) (Fig. 56-13). In this procedure, no tunnel is created behind the pancreatic neck. Instead the entire length of the pancreas is exposed anteriorly. The GDA is ligated. The gallbladder is removed. The cystic duct is cannulated using a Bakes dilator and the bile duct is identified in its course through the head of the pancreas by palpating the dilator. The pancreatic head is then excavated down to the level of the portal vein with care taken to leave a rim of tissue surrounding the bile duct at the duodenal margin. From this cavity an extensive longitudinal unroofing of the pancreatic duct through the body and tail is made using electrocautery. If the duct is not dilated in the tail, then the body and tail may simply be excavated as done at the pancreatic head (Fig. 56-14). Pancreaticoenteric drainage is then accomplished by means of a lateral pancreaticojejunostomy covering the entire excavation cavity, typically constructed using a Roux-en-Y jejunal limb sewn to the pancreatic capsule in one or two layers.

Frey Procedure versus Beger Procedure—Outcomes

In various reports including small randomized trials, the results of LR-LPJ appear similar to those reported for the Beger DPPHR, with postoperative mortality less than 1% and morbidity reported as 19–32%.60,66 Excellent pain relief is obtained in about 75% of patients and the change in postoperative pain scores and rates of postoperative exocrine and endocrine insufficiency are identical over follow-up as long as 9 years. A small prospective randomized trial compared LR-LPJ to PPPD with an average length of follow-up of 2 years. Postoperative morbidity was significantly higher in the PPPD group (53 vs 17% for the LR-LPJ group). Although there was similar improvement in pain symptoms, the LR-LPJ group demonstrated a statistically better overall quality of life as assessed by a general assessment of health-related quality of life.67 The long-term results of the study were published in 2008 with a median follow-up of 7 years. At that length of follow-up, there were no statistical differences with regard to the improvement in pain, health-related quality of life or the incidence of exocrine or endocrine insufficiency.68

Berne Procedure—Technique and Outcomes

There has been one further modification of the Beger DPPHR made in recent years. The Berne procedure adopts the technical safety advantage of the Frey LR-LPJ that comes by avoiding transaction of the neck of the pancreas off the portal vein. In this modification as in the Beger DPPHR, no lateral pancreaticojejunostomy is performed. The anterior surface of the mass in the head is palpated and then cored out by electrocautery. A Roux limb is then sewn to the residual pancreatic rim at this location. One randomized trial comparing the Berne modification to the standard Beger DPPHR showed rough equivalence of outcomes with these procedures.59

Small Duct Disease or Diffuse Sclerosis

In many instances, as the disease progresses there will be no dominant focus of ductal obstruction and no dominant mass. Instead the morphology of the disease is characterized by diffuse calcification and/or diffuse fibrosis with atrophy of the pancreatic parenchyma. In these cases the pancreatic remnant may be quite small and will have a uniform firm consistency. Patients with this morphology of disease present a particular challenge, as there is no discrete target for either endoscopic or surgical intervention. Those manifesting intractable pain syndromes have had, until very recently, few and imperfect options for surgical management. These have included total or near-total pancreatectomy procedures that have traditionally been avoided due to the significant morbidity associated with profound postoperative exocrine and endocrine insufficiency. Autologous islet transplantation may mitigate the diabetic consequences of total pancreatectomy. Another alternative for small duct disease is the V-shaped or wedge pancreatectomy described by Izbicki.69

Total Pancreatectomy with Autologus Islet Transplantation—Technique

Total pancreatectomy is performed as either an en bloc resection of the pancreatic head, body, and tail or, more commonly, in a staged fashion with a left pancreatectomy followed by a head resection (pancreaticoduodenectomy) allowing initial islet processing on the body and tail specimen. The isolation process relies on enzymatic and mechanical mechanisms to dissociate the islets from surrounding acinar tissue and fibrosis. Depending on the proximity of the islet isolation facilities and the efficiency of the process, infusion of the islet preparation into the portal circulation may be performed during the same anesthetic or postoperatively (usually the same day) under radiological guidance.70 Briefly, the resected pancreas is cooled to 4°C in an organ-preserving solution (eg, University of Wisconsin Solution). The pancreas is then transected at the neck of the gland and the pancreatic duct cannulated. The ductal system is then perfused with a cold solution of the purified digestive enzyme collagenase. The gland is sectioned, and then physically shaken in a small digestion chamber at 37°C until the acinar tissue is separated from the endocrine tissue. The islets are then partially purified from the acinar debris by gradient density centrifugation on a cold dextrose gradient. The islets are washed and resuspended in an albumin-rich transplant medium or cultured. The islets are transplanted by direct injection into portal circulation with access to the portal circulation being achieved under ultrasound-guided percutaneous placement of a transhepatic portovenous catheter in interventional radiology or by direct operative cannulation of the portal vein.

Autologus Islet Transplantation—Outcomes

The first human autologous islet transplant was performed at the University of Minnesota in 1977 and since that time several hundred procedures have been reported from Minnesota, Miami, Cincinnati, Leicester, and other emerging centers.71 Taken together, the results from these institutions suggest that in a highly selected group of patients, complete pain relief (without the use of narcotics) can be achieved in approximately 50–60% of patients but that there is a significant rate of recidivism of pain after 1 year of follow-up. Insulin-independence is initially achieved in 40–50% of patients but there is a steady decline in islet function that continues even at 10 years of follow-up. Although reports of assessment of quality of life after total pancreatectomy with autologous islet transplantation suggests that the procedure compares favorably to either total pancreatectomy without islet transplantation or to continue nonoperative management of pain, direct evidence supporting this approach over alternatives in appropriately matched controls is lacking. Total pancreatectomy with autologous islet transplantation is costly and requires a high degree of technical expertise that is difficult to replicate. The indications for islet autotransplantation are controversial and the overall safety and efficacy of the procedure have not been fully validated outside a handful of centers. Questions regarding the long-term viability of the islets and adverse impact on the surrounding liver parenchyma have been raised. Pathologic analysis of liver tissue that has been explanted following islet transplant has demonstrated that the transplanted islets typically migrate across the liver sinusoids and reside in the liver parenchyma. It has also been noted that the transplanted islets exhibit some degree of peri-islet fibrosis in the liver. There have been no reports of chronic hepatic fibrosis or cirrhosis in patients receiving autologous islets but the concern exists. It must be emphasized that complete long-term insulin independence is achieved only in a relatively small minority of patients after islet autotransplantation and that pain is persistent or recurrent in about half of patients even after total pancreatectomy.72 Currently, the strongest arguments in favor of total pancreatectomy and islet autotransplantation can perhaps be made in the setting of a limited subset of patients with hereditary pancreatitis, who otherwise carry a significant long-term risk of developing pancreatic cancer. When a more traditional surgical operation (resection or drainage) is also possible in this setting, decision making must be highly individualized (Fig. 56-15).

Izbicki Procedure—Technique and Outcomes

An alternative to total pancreatectomy (with or without islet autotransplantation) that may yield similar rates of pain relief yet preserve islet function is the V-shaped longitudinal pancreatic resection introduced by Izbicki and colleagues for patients with small duct disease and diffuse fibrosis. In this procedure the entire pancreas is excavated along the trajectory of the main pancreatic duct from the pancreatic head (as with the Frey procedure) across the body and tail of the organ. Pancreaticoenteric drainage is established by Roux-en-Y lateral pancreaticojejunostomy similar to the Puestow and Frey procedures. The short-term results of the Izbicki procedure compare favorably to those reported in the Minnesota and Cincinnati series of autologous islet transplantation, although the patient populations are not matched.61

Chronic pancreatitis is a relapsing inflammatory process that results in a variable degree of parenchymal destruction and fibrotic change in the pancreas with consequent clinical manifestations typically including characteristic abdominal pain, exocrine and endocrine insufficiency. A single unifying model for the pathogenesis of chronic pancreatitis remains elusive, although recent basic and clinical research has identified a number of gene mutations, immunologic conditions, environmental toxins, and anatomic anomalies that alone and together confer risk of developing chronic pancreatitis. The morphology of pathological change seen in the gland at the time that patients present for treatment varies significantly from one patient to the next. A myriad of endointerventional and surgical procedures have been developed over time and are now applied in the treatment of the disease. Both the endoscopic and surgical procedures used are technically demanding and carry substantial risk of morbidity. While there is substantial retrospective, case-series evidence demonstrating the utility of these approaches in well-selected patients, high-level evidence comparing the efficacy of the interventions in large series is lacking. For all of these reasons, chronic pancreatitis is often best managed in experienced centers in which multidisciplinary teams collaborate to individualize treatment in the context of established local expertise with various medical, endoscopic, and surgical therapies.