**3. Chronic pancreatitis complications and their management**

### **3.1 Pancreatic cancer**

Since the first report by Rocca et al. in 1987 for an increased incidence of pancreatic cancer (PC) in patients with CP, several epidemiological studies have identified that CP, mainly tropical and hereditary pancreatitis, is a major risk factor for pancreatic cancer development. Augustine et al. reported that PC is affecting 8.3% of patients with CP with a roughly 100-fold higher incidence compared to patients without tropical pancreatitis. Younger patients are affected and have a worse outcome. In hereditary CP due to multiple PRSS1 mutations the lifetime risk for PC is 40–55% by the age of 70. Possible explanations for the increased neoplastic transformation risk are the onset of CP at younger age and its long duration. Various risk factors for PC development have been described, of which smoking is the major one. In a recent study, Hao et al. (2017) suggest that age at the onset of CP (hazard ratio, 1.05) and a > 60 pack-year smoking history (hazard ratio, 11.83) are PC risk factors. CP as an inflammatory disease is associated with higher cell turnover with/ without DNA damage, progressing to oncogenic mutations in K-ras, p16 and p53 promoting metaplasia and neoplastic degeneration. Another well-known PC risk factor is diabetes mellitus. Ethanol and its metabolites are supposed to activate pancreatic stellate cells over-proliferation. They play a role in tumor progression and chemotherapy resistance. Moreover, cholecystokinin receptors are abnormally over-produced. Clinical features may mimic those of CP in early stages. When symptoms such as obstructive jaundice, pain, weight loss and worsening of diabetes appear, all of which are specific for malignancy, this generally indicates that the disease is at an advanced stage. The most investigated biomarker for malignancy prediction is CA 19–9 with 96.5–100% specificity. Based on metabolic biomarkers, Mayerle et al. (2018) introduce a novel approach for differential diagnose between CP and PC with an accuracy of 90% and a negative predictive value of 99.9%. Other promising markers are plasma micro-RNAs, monoclonal antibody PAM4, CD1D, which require further investigation. For the imaging diagnosis of PC, a CT scan is the technique of choice. Endoscopic ultrasound (EUS) could detect small pancreatic tumors in CP patients at a highest sensitivity compared to the available imaging and has the potential to detect early stage PC. The most appropriate cancer treatment (surgery, chemotherapy, radiation) depends on disease proliferation, defining the cancer as resectable, locally advanced or metastatic [144–149].

#### **3.2 Pseudocysts**

Pancreatic pseudocysts are common complication in CP with a frequency of 20–40%. The majority of patients are with alcoholic (70–80%) or idiopathic

**47**

*Up-To-Date View on the Clinical Manifestations and Complications of Chronic Pancreatitis*

etiology of CP (6–16%). The outcome of pseudocysts is assessed 6 weeks after acute episode occurring. In 40% of the pseudocysts there is a spontaneous resolution, another 40% of pseudocysts remain asymptomatic and in 20% of pseudocysts complications are observed (infection, rupture, bleeding, splenic vein thrombosis). Treatment is required if patients are symptomatic, if complications or obstruction of the stomach, duodenum or bile duct occur. Drainage of chronic pseudocysts may be performed by surgical, endoscopical or percutaneous approach. In asymptomatic pseudocysts with size above 5 cm, due to high possibility of complications, an endoscopical or surgical treatment is recommended. Percutaneous drainage should be avoided where possible. In chronic pseudocysts the endoscopical procedure is the treatment of choice due to lower mortality rate, improved quality of life and less length of hospitalization stay. Depending on size and localization, two endoscopic techniques are performed. A transpapillary approach should be considered in small pseudocysts with communication with the main pancreatic duct. The transmural approach (cystogastrostomy) is similar to the management of walled-off necrosis. It is more successful under echoendoscopic guidance. Double-pigtail plastic stents for at least 2 months are used for pseudocyst drainage. If a malignant genesis of the pseudocyst is suspected, surgery should

In 1920 Hirschfeldt first reported splenic vein thrombosis (SVT) as a pancreatitis consequence. Secondary involvement of the splenic vein endothelium by a nearby inflammation, compression by a pseudocyst or enlarged retroperitoneal/ pancreatic lymph nodes or initial injury could result in a splenic vein thrombosis and obstruction. The incidence of SVT in patients with CP is 1.5–41.6%. Sinistral portal hypertension and collateral development resulting in gastric and/or esophageal varices are major risk factor for bleeding. Splenomegaly is reported in 42–54% of patients. Most patients are asymptomatic. Clinical features include gastrointestinal bleeding in 12.3% of cases and abdominal pain. SVT is diagnosed primary by contrast-enhanced CT scan and/or upper endoscopy. Venous phase angiography is the gold standard confirmatory test, which could verify obstruction and collaterals routes. Based on the widely available CT scan most patients nowadays are diagnosed asymptomatic. The SVT management depends on existing symptoms including hypersplenic syndrome and history of variceal bleeding, which might require splenectomy with venous collateral outflow elimination and further variceal decompression. Gastric varices should be treated endoscopically by sclerotherapy,

The duodenal obstruction is a rare complication in CP patients (1%) due to the anatomical relationship between the duodenum and the head of the pancreas. However, when analyzing operated patients with CP, the incidence of duodenal obstruction is higher—12%. Two types of obstruction are observed—transients during acute pancreatitis episodes and fixed by pseudocyst compression (discussed above) or fibrosclerotic process. Paraduodenal or groove pancreatitis is a rare clinic-pathological focal type of CP. The reported incidence of groove pancreatitis in resected CP patients ranges between 2.7 and 24.5%. It was first described by Becker in 1973 as a segmental pancreatitis. In 2004 Adsav and Zamboni unify the previously described terms under paraduodenal pancreatitis. The proposed pathophysiological mechanisms comprise functional/

*DOI: http://dx.doi.org/10.5772/intechopen.84738*

follow [148, 150–156].

**3.3 Splenic vein thrombosis**

gastric banding [148, 157–162].

**3.4 Duodenal obstruction**

*Up-To-Date View on the Clinical Manifestations and Complications of Chronic Pancreatitis DOI: http://dx.doi.org/10.5772/intechopen.84738*

etiology of CP (6–16%). The outcome of pseudocysts is assessed 6 weeks after acute episode occurring. In 40% of the pseudocysts there is a spontaneous resolution, another 40% of pseudocysts remain asymptomatic and in 20% of pseudocysts complications are observed (infection, rupture, bleeding, splenic vein thrombosis). Treatment is required if patients are symptomatic, if complications or obstruction of the stomach, duodenum or bile duct occur. Drainage of chronic pseudocysts may be performed by surgical, endoscopical or percutaneous approach. In asymptomatic pseudocysts with size above 5 cm, due to high possibility of complications, an endoscopical or surgical treatment is recommended. Percutaneous drainage should be avoided where possible. In chronic pseudocysts the endoscopical procedure is the treatment of choice due to lower mortality rate, improved quality of life and less length of hospitalization stay. Depending on size and localization, two endoscopic techniques are performed. A transpapillary approach should be considered in small pseudocysts with communication with the main pancreatic duct. The transmural approach (cystogastrostomy) is similar to the management of walled-off necrosis. It is more successful under echoendoscopic guidance. Double-pigtail plastic stents for at least 2 months are used for pseudocyst drainage. If a malignant genesis of the pseudocyst is suspected, surgery should follow [148, 150–156].

### **3.3 Splenic vein thrombosis**

*Pancreatitis*

25, 31, 32, 122, 138–143].

**3.1 Pancreatic cancer**

in improved insulin secretion and glucose tolerance during meals. Adequate oral enzyme replacement affects steatorrhea, prevents malnutrition and metabolic complications. In patients with severe malnutrition, insulin therapy is a first-line of choice because of the anabolic effect of insulin. The association of low levels of vitamin D and poor glycemic control draws attention to the need to normalize vitamin status in patients with type 3c DM. Diagnosis and monitoring of DM should be consistent with the endocrinology societies guidelines. Annually screening for type 3c DM by fasting glucose and HbA1c is of a great importance in patients with CP regardless the grade of pathological structural changes [18, 20,

**3. Chronic pancreatitis complications and their management**

cancer as resectable, locally advanced or metastatic [144–149].

Pancreatic pseudocysts are common complication in CP with a frequency of 20–40%. The majority of patients are with alcoholic (70–80%) or idiopathic

Since the first report by Rocca et al. in 1987 for an increased incidence of pancreatic cancer (PC) in patients with CP, several epidemiological studies have identified that CP, mainly tropical and hereditary pancreatitis, is a major risk factor for pancreatic cancer development. Augustine et al. reported that PC is affecting 8.3% of patients with CP with a roughly 100-fold higher incidence compared to patients without tropical pancreatitis. Younger patients are affected and have a worse outcome. In hereditary CP due to multiple PRSS1 mutations the lifetime risk for PC is 40–55% by the age of 70. Possible explanations for the increased neoplastic transformation risk are the onset of CP at younger age and its long duration. Various risk factors for PC development have been described, of which smoking is the major one. In a recent study, Hao et al. (2017) suggest that age at the onset of CP (hazard ratio, 1.05) and a > 60 pack-year smoking history (hazard ratio, 11.83) are PC risk factors. CP as an inflammatory disease is associated with higher cell turnover with/ without DNA damage, progressing to oncogenic mutations in K-ras, p16 and p53 promoting metaplasia and neoplastic degeneration. Another well-known PC risk factor is diabetes mellitus. Ethanol and its metabolites are supposed to activate pancreatic stellate cells over-proliferation. They play a role in tumor progression and chemotherapy resistance. Moreover, cholecystokinin receptors are abnormally over-produced. Clinical features may mimic those of CP in early stages. When symptoms such as obstructive jaundice, pain, weight loss and worsening of diabetes appear, all of which are specific for malignancy, this generally indicates that the disease is at an advanced stage. The most investigated biomarker for malignancy prediction is CA 19–9 with 96.5–100% specificity. Based on metabolic biomarkers, Mayerle et al. (2018) introduce a novel approach for differential diagnose between CP and PC with an accuracy of 90% and a negative predictive value of 99.9%. Other promising markers are plasma micro-RNAs, monoclonal antibody PAM4, CD1D, which require further investigation. For the imaging diagnosis of PC, a CT scan is the technique of choice. Endoscopic ultrasound (EUS) could detect small pancreatic tumors in CP patients at a highest sensitivity compared to the available imaging and has the potential to detect early stage PC. The most appropriate cancer treatment (surgery, chemotherapy, radiation) depends on disease proliferation, defining the

**46**

**3.2 Pseudocysts**

In 1920 Hirschfeldt first reported splenic vein thrombosis (SVT) as a pancreatitis consequence. Secondary involvement of the splenic vein endothelium by a nearby inflammation, compression by a pseudocyst or enlarged retroperitoneal/ pancreatic lymph nodes or initial injury could result in a splenic vein thrombosis and obstruction. The incidence of SVT in patients with CP is 1.5–41.6%. Sinistral portal hypertension and collateral development resulting in gastric and/or esophageal varices are major risk factor for bleeding. Splenomegaly is reported in 42–54% of patients. Most patients are asymptomatic. Clinical features include gastrointestinal bleeding in 12.3% of cases and abdominal pain. SVT is diagnosed primary by contrast-enhanced CT scan and/or upper endoscopy. Venous phase angiography is the gold standard confirmatory test, which could verify obstruction and collaterals routes. Based on the widely available CT scan most patients nowadays are diagnosed asymptomatic. The SVT management depends on existing symptoms including hypersplenic syndrome and history of variceal bleeding, which might require splenectomy with venous collateral outflow elimination and further variceal decompression. Gastric varices should be treated endoscopically by sclerotherapy, gastric banding [148, 157–162].

#### **3.4 Duodenal obstruction**

The duodenal obstruction is a rare complication in CP patients (1%) due to the anatomical relationship between the duodenum and the head of the pancreas. However, when analyzing operated patients with CP, the incidence of duodenal obstruction is higher—12%. Two types of obstruction are observed—transients during acute pancreatitis episodes and fixed by pseudocyst compression (discussed above) or fibrosclerotic process. Paraduodenal or groove pancreatitis is a rare clinic-pathological focal type of CP. The reported incidence of groove pancreatitis in resected CP patients ranges between 2.7 and 24.5%. It was first described by Becker in 1973 as a segmental pancreatitis. In 2004 Adsav and Zamboni unify the previously described terms under paraduodenal pancreatitis. The proposed pathophysiological mechanisms comprise functional/

anatomical obstruction of papilla minor, Brunner's gland hyperplasia around papilla minor, heterotopic intraduodenal pancreatic tissue or ductal variation. Two types paraduodenal pancreatitis are defined–cystic and solid. The cystic type is common with localization in the submucosa or lamina propria. The size may reach 10 cm, resulting in a bile duct obstruction. The solid type is rare and includes sheet-like and mass-like subtypes. According to several retrospective studies, the risk groups for paraduodenal pancreatitis development are middleaged men with alcohol consumption. Acute manifestation complains include postprandial abdominal pain (90–100%), nausea and vomiting (20%), gastric outlet syndrome. Chronic manifestations are weight loss (90%) and jaundice (20%). Perforation, bleeding, malignant degeneration of heterotopic pancreas are reported rare complications. EUS and MRCP are the preferred imaging methods for diagnostic evaluation. Treatment is based on a stepwise approach: (1) conservative treatment (analgesics, infusions, PPI, PERT, enteral nutrition, somatostatin analogues); (2) endoscopic treatment; (3) surgery (Whipple procedure, pancreaticoduodenectomy, suprapapillar duodenal resection in isolated duodenal dystrophy, palliative gastrojejunostomy) [8, 148, 163–170].

### **3.5 Biliary obstruction**

The incidence of distal common bile duct obstruction in patients with advanced chronic predominantly calcific pancreatitis with frequent acute episodes ranges from 3 to 46%. Pseudocysts are considered more as a risk factor than as a cause. Patients may be asymptomatic or with various spectrum of complains and complications—pain, jaundice (transient or persistent for longer than 1 month), cholangitis and even sepsis, long-term risk of secondary biliary cirrhosis. Hyperbilirubinemia and twofold elevation of alkaline phosphatase levels for more than a month are used as reliable laboratory markers for common bile duct obstruction. CT scan provides information for the structural changes with high specificity and sensitivity. Based on the Caroli and Nora criteria, most patients with common bile duct stricture and CP are classified as type I and III. The treatment of choice depends on presence and severity and duration of symptoms; suspected malignant degeneration. To prevent progression to secondary biliary cirrhosis in patients with progressively increased alkaline phosphatase levels or persistent/with frequent relapses hyperbilirubinemia, endoscopic biliary stenting with self-expanding metal stents or multiple plastic stents or surgical procedures (pancreaticoduodenectomy, choledochojejunostomy, choledochoduodenostomy, hepaticojejunostomy) are required [148, 171–173].

#### **3.6 Pseudoaneurysm**

Pancreatic pseudoaneurysm as a rare life-threatening chronic pancreatitis complication occurs in 10% of patients, most often in those with pseudocysts. The pseudoaneurysm represents fibrous tissue containing hematoma and is mainly induced by enzymatic autodigestion or eroding of the nearby vessels, most frequent affecting the splenic artery. Most patients are asymptomatic, however, the first clinical manifestation might be bleeding caused by pseudoaneurysm rupture into gastrointestinal tract or other adjacent anatomic structures—peritoneal cavity, retroperitoneum, biliopancreatic ducts (hemosuccus pancreaticus). Shock and multiorgan failure further complicate the rupture. The mortality rate is about 40% and higher (90–100%) if pseudoaneurysm remains untreated. Worst outcome results have been shown in patients with pseudoaneurysm localization in the pancreas head. Angiography is the diagnostic tool of choice. Patients are nowadays treated

**49**

*Up-To-Date View on the Clinical Manifestations and Complications of Chronic Pancreatitis*

surgical, endovascular, by angioembolization and/or by percutaneous ultrasonographically guided thrombin injection. Treatment in diagnosed asymptomatic

In about 50% of patients chronic inflammation, gene predisposition and alcohol intake as a key cause change the pancreatic juice composition with pancreatic stone protein levels reduction, leading to formation of a nucleus with calcium deposition layers and later formation of a stone. The pancreatic duct stones are classified according to their number, localization and density to single or multiple calculi; stones in the pancreatic head, body and/or tail; localized in the main pancreatic duct, side-branches and/or parenchyma; radiopaque positive (the majority of cases), negative or mixed stones. The main pathological consequence is the duct obstruction with upstream dilatation, followed by ductal hypertension, which results in pain episodes, exocrine insufficiency due to reduce pancreatic juice flow into duodenum and impaired quality of life. Pancreatic duct stones are diagnosed by ERCP, CT or MRCP. However, MRCP is superior to ERCP for diagnosis as MRCP is a non-invasive alternative with no complications, providing detailed information about duct system and stone formations. Calculi removal could be performed by extracorporeal shock wave lithotripsy (ESWL), endoscopic techniques and surgery. According to the European Society of Gastrointestinal Endoscopy guidelines, first-line therapy for painful uncomplicated CP is ESWL combined or not with ERCP followed by spontaneous expulsion or endoscopic extraction of less than 3 mm fragments. However, ESWL should be performed in centers with ESWL expertise. Best results from endoscopic techniques are observed in patients with early stages of CP with infrequent pain attacks, when calculi are less than 5 mm and have head localization with upstream main pancreatic duct dilatation. Alcohol and tobacco cessation improve the long-lasting results. Endoscopic techniques include ERCP followed by pancreatic sphincterotomy; stone retrieval with a balloon, Dormia basket and/or forceps; dilatation and stent placement; mechanical lithotripsy. Endoscopy procedures together with ESWL improve the success to up to 90%. Direct visualization by pancreatoscopy followed by intraductal lithotripsy (Spyglass system) might be a future procedure of choice but today its use is limited. Surgery should be performed in patients with large or multiple calculi and strictures, after unsuccessful prior endoscopy or ESWL procedures, as well as in those

With disease progression, patients with CP report for impaired overall quality of life. Many studies are conducted to investigate the contributing factors, leading to low QoL. Pain significantly correlates with overall health status, physical and mental subscales. Researchers emphasize the role of severity in contrast to pain frequency and pathophysiology. A large study of Machiado et al., including 1024 CP patients, highlights constant pain as well as inability due to pain, smoking status and concomitant co-morbidities to worsen significantly QoL with negative influence on both physical and mental domains, leading to worsened social and family status and health resource utilization. Other assumed factors, which importance differs among the literature data, are disease duration, young age, women, tobacco and alcohol intake, underweight, pancreatic structural changes DM, PEI, prior endoscopic or surgical treatments. Psychologically conditioned disturbances

*DOI: http://dx.doi.org/10.5772/intechopen.84738*

patients is recommended [174–179].

**3.7 Pancreatic duct stones**

with no pain relief [8, 180–183].

**4. Quality of life**

*Up-To-Date View on the Clinical Manifestations and Complications of Chronic Pancreatitis DOI: http://dx.doi.org/10.5772/intechopen.84738*

surgical, endovascular, by angioembolization and/or by percutaneous ultrasonographically guided thrombin injection. Treatment in diagnosed asymptomatic patients is recommended [174–179].

#### **3.7 Pancreatic duct stones**

*Pancreatitis*

**3.5 Biliary obstruction**

required [148, 171–173].

**3.6 Pseudoaneurysm**

anatomical obstruction of papilla minor, Brunner's gland hyperplasia around papilla minor, heterotopic intraduodenal pancreatic tissue or ductal variation. Two types paraduodenal pancreatitis are defined–cystic and solid. The cystic type is common with localization in the submucosa or lamina propria. The size may reach 10 cm, resulting in a bile duct obstruction. The solid type is rare and includes sheet-like and mass-like subtypes. According to several retrospective studies, the risk groups for paraduodenal pancreatitis development are middleaged men with alcohol consumption. Acute manifestation complains include postprandial abdominal pain (90–100%), nausea and vomiting (20%), gastric outlet syndrome. Chronic manifestations are weight loss (90%) and jaundice (20%). Perforation, bleeding, malignant degeneration of heterotopic pancreas are reported rare complications. EUS and MRCP are the preferred imaging methods for diagnostic evaluation. Treatment is based on a stepwise approach: (1) conservative treatment (analgesics, infusions, PPI, PERT, enteral nutrition, somatostatin analogues); (2) endoscopic treatment; (3) surgery (Whipple procedure, pancreaticoduodenectomy, suprapapillar duodenal resection in isolated duodenal

The incidence of distal common bile duct obstruction in patients with advanced chronic predominantly calcific pancreatitis with frequent acute episodes ranges from 3 to 46%. Pseudocysts are considered more as a risk factor than as a cause. Patients may be asymptomatic or with various spectrum of complains and complications—pain, jaundice (transient or persistent for longer than 1 month),

cholangitis and even sepsis, long-term risk of secondary biliary cirrhosis.

Hyperbilirubinemia and twofold elevation of alkaline phosphatase levels for more than a month are used as reliable laboratory markers for common bile duct obstruction. CT scan provides information for the structural changes with high specificity and sensitivity. Based on the Caroli and Nora criteria, most patients with common bile duct stricture and CP are classified as type I and III. The treatment of choice depends on presence and severity and duration of symptoms; suspected malignant degeneration. To prevent progression to secondary biliary cirrhosis in patients with progressively increased alkaline phosphatase levels or persistent/with frequent relapses hyperbilirubinemia, endoscopic biliary stenting with self-expanding metal stents or multiple plastic stents or surgical procedures (pancreaticoduodenectomy, choledochojejunostomy, choledochoduodenostomy, hepaticojejunostomy) are

Pancreatic pseudoaneurysm as a rare life-threatening chronic pancreatitis complication occurs in 10% of patients, most often in those with pseudocysts. The pseudoaneurysm represents fibrous tissue containing hematoma and is mainly induced by enzymatic autodigestion or eroding of the nearby vessels, most frequent affecting the splenic artery. Most patients are asymptomatic, however, the first clinical manifestation might be bleeding caused by pseudoaneurysm rupture into gastrointestinal tract or other adjacent anatomic structures—peritoneal cavity, retroperitoneum, biliopancreatic ducts (hemosuccus pancreaticus). Shock and multiorgan failure further complicate the rupture. The mortality rate is about 40% and higher (90–100%) if pseudoaneurysm remains untreated. Worst outcome results have been shown in patients with pseudoaneurysm localization in the pancreas head. Angiography is the diagnostic tool of choice. Patients are nowadays treated

dystrophy, palliative gastrojejunostomy) [8, 148, 163–170].

**48**

In about 50% of patients chronic inflammation, gene predisposition and alcohol intake as a key cause change the pancreatic juice composition with pancreatic stone protein levels reduction, leading to formation of a nucleus with calcium deposition layers and later formation of a stone. The pancreatic duct stones are classified according to their number, localization and density to single or multiple calculi; stones in the pancreatic head, body and/or tail; localized in the main pancreatic duct, side-branches and/or parenchyma; radiopaque positive (the majority of cases), negative or mixed stones. The main pathological consequence is the duct obstruction with upstream dilatation, followed by ductal hypertension, which results in pain episodes, exocrine insufficiency due to reduce pancreatic juice flow into duodenum and impaired quality of life. Pancreatic duct stones are diagnosed by ERCP, CT or MRCP. However, MRCP is superior to ERCP for diagnosis as MRCP is a non-invasive alternative with no complications, providing detailed information about duct system and stone formations. Calculi removal could be performed by extracorporeal shock wave lithotripsy (ESWL), endoscopic techniques and surgery. According to the European Society of Gastrointestinal Endoscopy guidelines, first-line therapy for painful uncomplicated CP is ESWL combined or not with ERCP followed by spontaneous expulsion or endoscopic extraction of less than 3 mm fragments. However, ESWL should be performed in centers with ESWL expertise. Best results from endoscopic techniques are observed in patients with early stages of CP with infrequent pain attacks, when calculi are less than 5 mm and have head localization with upstream main pancreatic duct dilatation. Alcohol and tobacco cessation improve the long-lasting results. Endoscopic techniques include ERCP followed by pancreatic sphincterotomy; stone retrieval with a balloon, Dormia basket and/or forceps; dilatation and stent placement; mechanical lithotripsy. Endoscopy procedures together with ESWL improve the success to up to 90%. Direct visualization by pancreatoscopy followed by intraductal lithotripsy (Spyglass system) might be a future procedure of choice but today its use is limited. Surgery should be performed in patients with large or multiple calculi and strictures, after unsuccessful prior endoscopy or ESWL procedures, as well as in those with no pain relief [8, 180–183].
