Chronic pancreatitis

Chronic pancreatitis is the progressive and permanent destruction of the pancreas resulting in exocrine and endocrine insufficiency and, often, chronic disabling pain. The etiology is multifactorial. Alcoholism plays a significant role in adults, whereas genetic and structural defects predominate in children. The average age at diagnosis is 35 to 55 years. Morbidity and mortality are secondary to chronic pain and complications (e.g., diabetes, pancreatic cancer). Contrast-enhanced computed tomography is the radiographic test of choice for diagnosis, with ductal calcifications being pathognomonic. Newer modalities, such as endoscopic ultrasonography and magnetic resonance cholangiopancreatography, provide diagnostic results similar to those of endoscopic retrograde cholangiopancreatography. Management begins with lifestyle modifications (e.g., cessation of alcohol and tobacco use) and dietary changes followed by analgesics and pancreatic enzyme supplementation. Before proceeding with endoscopic or surgical interventions, physicians and patients should weigh the risks and benefits of each procedure. Therapeutic endoscopy is indicated for symptomatic or complicated pseudocyst, biliary obstruction, and decompression of pancreatic duct. Surgical procedures include decompression for large duct disease (pancreatic duct dilatation of 7 mm or more) and resection for small duct disease. Lateral pancreaticojejunostomy is the most commonly performed surgery in patients with large duct disease. Pancreatoduodenectomy is indicated for the treatment of chronic pancreatitis with pancreatic head enlargement. Patients with chronic pancreatitis are at increased risk of pancreatic neoplasm; regular surveillance is sometimes advocated, but formal guidelines and evidence of clinical benefit are lacking.     

Can plasma human pancreatic polypeptide be used to detect diseases of the exocrine pancreas?

Plasma concentrations of human pancreatic polypeptide (HPP) parallel exocrine pancreatic secretion in response to stimulation with cholecystokinin. We determined prospectively the relationships among fasting HPP level, integrated HPP response to infusion of cholecystokinin, and output of trypsin and also the sensitivity, specificity, and predictive values of the fasting HPP level in the diagnosis of exocrine pancreatic disease. Our study group consisted of 19 patients with acute pancreatitis, 17 with chronic pancreatitis, and 25 with ductal adenocarcinoma of the pancreas and 27 control subjects. In the control patients and those with chronic pancreatitis, significant correlations were detected between HPP level and output of trypsin (P less than 0.001) in response to infusion of cholecystokinin and between fasting HPP and integrated HPP levels (P less than 0.004); no correlation was detected between HPP level and steatorrhea. The sensitivity, specificity, and negative and positive predictive values of the fasting HPP level for detection of either chronic pancreatitis or pancreatic cancer were similar and approximated 0.88, 0.67, 0.88, and 0.66, respectively. The HPP concentration had no value in detecting acute pancreatitis. Because the fasting HPP level has a high degree of negative predictability and is simpler to measure than the integrated HPP level or the output of trypsin, it may be a useful test in patients suspected of having either chronic pancreatitis or pancreatic cancer. A fasting HPP level of 125 pg/ml or greater could be used to exclude chronic pancreatitis or pancreatic cancer, but the finding of a value of less than 125 pg/ml necessitates use of other diagnostic tests for reliable determination of the presence of these diseases.     

Elevated fasting cholecystokinin levels in pancreatic exocrine impairment: evidence to support feedback regulation

Previous studies have suggested that intraduodenal protease suppression of pancreatic exocrine secretion may be mediated through cholecystokinin (CCK) release. Our study compares basal plasma immunoreactive CCK concentrations in normal human subjects with those obtained in patients with chronic pancreatitis. Fasting plasma samples were collected from 18 normal subjects and from 18 patients with chronic pancreatitis. Eight patients had mild to moderate pancreatic exocrine impairment, and 10 had severe exocrine insufficiency. Venous plasma immunoreactive CCK concentrations were measured with two distinct peptide region-specific antibodies. Basal plasma CCK concentration in controls was 14.3 +/- 1.3 fmol/ml (mean +/- SEM), a value significantly less than that obtained in all patients with chronic pancreatitis, 30.1 +/- 4.0 fmol/ml (p less than 0.001). Patients with mild to moderate impairment had a fasting plasma CCK concentration of 32.8 +/- 7.9 fmol/ml (vs. control p less than 0.01), and those with severe disease 27.9 +/- 3.6 fmol/ml (vs. control p less than 0.001). In five patients with mild to moderate impairment of exocrine function and pancreatic extract-responsive abdominal pain, there was a 39 +/- 11% decrease in basal CCK levels during extract therapy (p less than 0.05). Results of this study indicate that pancreatic exocrine impairment is associated with elevated basal CCK levels, which may reflect a failure to provide feedback downmodulation of CCK release.     

Current advances in the management of chronic pancreatitis

Chronic pancreatitis is characterized by irreversible destruction of pancreatic parenchyma and its ductal system resulting from longstanding inflammation, leading to fibrosis and scarring due to genetic, environmental, and other risk factors. The diagnosis of chronic pancreatitis is made based on a combination of clinical features and characteristic findings on computed tomography or magnetic resonance imaging. Abdominal pain is the most common symptom of chronic pancreatitis. The main aim of treatment is to relieve symptoms, prevent disease progression, and manage complications related to chronic pancreatitis. Patients who do not respond to medical treatment or not a candidate for surgical treatment are usually managed with endoscopic therapies. Endoscopic therapies help with symptoms such as abdominal pain and jaundice by decompression of pancreatic and biliary ducts. This review summarizes the risk factors, pathophysiology, diagnostic evaluation, endoscopic treatment of chronic pancreatitis, and complications. We have also reviewed recent advances in endoscopic retrograde cholangiopancreatography and endoscopic ultrasound-guided therapies for pancreatic duct obstruction due to stones, strictures, pancreatic divisum, and biliary strictures.     

Surgical treatment of pancreatitis: review of a series.

In this review of the surgical experience with pancreatitis, 55 patients had acute relapsing pancreatitis associated with gallstones and 47 had chronic pancreatitis of alcoholic, idiopathic, or familial causation. The severity of pancreatitis associated with gallstones could not be correlated with results of preoperative biochemical tests; only one-third of patients were found to have stones within the biliary ductal system; and postoperative mortality (5%) could not be correlated with the severity of pancreatic inflammation or the timing of surgical intervention. Postoperative observations have revealed that all but four of the patients have remained asymptomatic. With regard to the patients with alcoholic, idiopathic, or familial disease who had significant pancreatic ductal dilatation or obstruction, ductal drainage procedures with or without resection benefited 80%. In the absence of ductal dilatation or obstruction, major resective surgery benefited 50% of patients. Continuing alcohol abuse limited the effectiveness of any operative procedure, and diabetes occurred more often after major resective procedures.     

A prospective multiyear study of the course of chronic recurrent pancreatitis

It was established during observation over time (within the period from 10 to 12 years) that the overwhelming majority of patients with chronic cholecystopancreatitis and primary chronic pancreatitis progressed to a different degree to enzyme-secreting pancreatic failure according to the pancreozymine tests. At the same time in 2/5 of all the cases, enzyme-secreting failure turned out substantial by the end of the indicated period. During the years of prospective studies, every tenth patient with chronic pancreatitis developed secondary diabetes mellitus. The degree of pancreatic enzyme secretion and carbohydrate metabolism abnormalities depended on the number of disease exacerbations suffered by the patient. Secondary gastroduodenal ulcers occurred in 27 out of 647 patients observed over time, and all the cases were associated with a considerable reduction of pancreatic bicarbonate secretion (according to the secretin test). Pancreatogenous pleural exudate was recorded in 1.4% of all the cases of chronic pancreatitis. During the observation period, 16 out of the 647 patients died from chronic pancreatitis associated with progressive exocrine pancreatic failure and malabsorption.     

Evidence of primary beta-cell destruction by T-cells and beta-cell differentiation from pancreatic ductal cells in diabetes associated with active autoimmune chronic pancreatitis

OBJECTIVE: Diabetes associated with autoimmune chronic pancreatitis (ACP) is a subtype of diabetes that is responsive to corticosteroid treatment of progressive endocrine and exocrine dysfunction. However, little is known about pathological changes of islet and exocrine pancreas in ACP. RESEARCH DESIGN AND METHODS: We examined pancreatic specimens obtained on biopsy from four diabetic men with ACP (mean [range]: age 62 years [48-78], duration of ACP 3 months [1-5], duration of diabetes 1 month [0-3]) morphologically, immunohistochemically, and morphometrically. RESULTS: The pancreatic specimens in all cases exhibited inflammatory cell infiltration surrounding ductal cells and extensive fibrosis. Some islets were infiltrated with mononuclear cells with disrupted beta-cells. The subsets of T-cells infiltrated to the islets were mainly CD8(+). Islet beta-cell volume was decreased; the mean percentage area of beta-cells in the islets in four cases with ACP were 16% (range 13-20) (P = 0.0015 vs. type 2 diabetic patients, 48% [27-73], n = 8; P = 0.0002 vs. nondiabetic control subjects, 58% [39-77], n = 7). Preserved ductal cells were surrounded predominantly by CD8(+) or CD4(+) T-cells. Some cytokeratin 19-positive ductal cells contained insulin and glucagon, representing upregulated differentiation of islet cells from ductal cells. Insulin promoter factor-1 (IPF-1) was hyperexpressed in insulin-containing ductal cells. CONCLUSIONS: Diabetes associated with ACP is caused by T-cell-mediated mechanisms primarily involving islet beta-cells as well as pancreatic ductal cells. In ACP, ductal islet precursor cells were associated with IPF-1 hyperexpression, suggesting a critical role of IPF-1 on islet cell differentiation and eventual beta-cell restoration.     

Pancreatic diabetes mellitus

Diabetes mellitus caused by pancreatic exocrine disease is a unique clinical and metabolic form of diabetes. The diagnosis of pancreatic diabetes caused by chronic pancreatitis may be elusive because it is occasionally painless and often not accompanied by clinical malabsorption until after hyperglycemia occurs. Diabetic patients with pancreatic calcification or clinically demonstrable pancreatic exocrine dysfunction will manifest the unique aspects of pancreatic diabetes described herein. Like other forms of diabetes, the primary hormonal abnormality in pancreatic diabetes is decreased insulin secretion. Patients with this disorder are unique in that they have low glucagon levels that respond abnormally to several physiological stimuli, blunted epinephrine responses to insulin-induced hypoglycemia, and malabsorption. In addition, they often have concomitant alcohol abuse with hepatic disease and poor nutrition. These characteristics result in increased levels of circulating gluconeogenic amino acids, decreased insulin requirements, a resistance to ketosis, low cholesterol levels, an increased risk of hypoglycemia while on insulin therapy, and the clinical impression of brittle diabetes. Retinopathy occurs at a rate equal to that of insulin-dependent diabetes but may be less severe in degree. Other complications of pancreatic diabetes have been less well studied but may be expected to be seen more frequently as these patients survive longer. The characteristics of pancreatic diabetes suggest that a conservative approach be taken in regard to intensive insulin therapy and tight blood glucose control.     

EUS-guided celiac block and neurolysis

Abdominal pain related to pancreatic cancer or chronic pancreatitis can be a disabling and difficult symptom to treat for patients, their families, and physicians. Pharmacologic therapy with nonsteroidal anti-inflammatory drugs is usually ineffective. Opiate analgesics may not be well tolerated and can lead to dependence. Endoscopic ultrasound-guided celiac plexus block offers a potential adjunct treatment for pain control.     

内镜下诊断与治疗慢性胰腺炎17例

目的 探讨内镜下诊断和治疗慢性胰腺炎的价值。方法 对17例慢性胰腺炎均行内镜下逆行胰胆管造影术(ERCP)，并对部分胰管狭窄患者施行塑料支架放置引流术(ERPD)或鼻胰管引流术(ENPD)，对部分胰管内结石行内镜下胰管括约肌切开术(EPS)并行网篮取石。结果 有8例胰管狭窄者放置塑料支架，平均引流时间为276d。5例胰管结石中2例行EPS后网篮取出结石，3例行鼻胰管引流术后手术取出。结论 ERCP可作为有条件医院检查慢性胰腺炎的常规手段，是治疗部分慢性胰腺炎安全有效的方法。     

Trial of the combined use of trental and solcoseryl in treating patients with chronic pancreatitis

The effect of combined use of pentoxifylline and solcoseryl was studied in 35 patients with chronic pancreatitis. General clinical findings were studied in parallel with the time course of pancreatic exocrine (trypsin) and endocrine (insulin, C-peptide) function. The blood level of gastrin and changes in intestinal function using 131I-lipids were also studied. The incorporation of both drugs in multimodality therapy made a positive therapeutic effect, resulting in a decrease in the pain syndrome and dyspeptic symptoms. At the same time some favorable shifts in pancreatic and GI tract function were noted. Possible mechanisms of a positive therapeutic effect were discussed. A conclusion was made that the incorporation of pentoxifylline and solcoseryl in multimodality therapy of chronic pancreatitis was clinically justified and determined pathogenetically.     

Predictive factors for pancreatic cancer in patients with chronic pancreatitis in association with K-ras gene mutation

BACKGROUND AND STUDY AIMS: Chronic pancreatitis is considered to be a predisposing factor for pancreatic ductal adenocarcinoma (PAC). The purpose of this study was to examine the prognostic value of a finding of mutated (K- ras) gene in predicting the development of PAC in patients with chronic pancreatitis. PATIENTS AND METHODS: The pancreatic duct brushings of 146 patients with chronic pancreatitis were examined in order to identify K- ras gene mutations. A total of 112 patients were followed up (median duration 42 months) using clinical evaluation, serum CA19 - 9 levels, and imaging studies. RESULTS: One or more K- ras mutations were found in 57 of the 146 patients with chronic pancreatitis (39 %). Patients harboring K- ras mutations had a higher incidence of persistent alcohol consumption ( P = 0.041) and of prior rupture of the main pancreatic duct ( P = 0.040). A finding of nuclear atypia in brushing cytology was also more common in patients with K- ras mutation ( P = 0.048). Out of the 112 patients who were followed up, PAC occurred in four of the 44 patients who had a K- ras mutation, but in none of the 68 patients with the wild genotype ( P = 0.022). PAC occurred in three of the 25 patients who did not have pancreatic calcifications ( P = 0.034) and in four of the 54 patients who had demonstrated exocrine insufficiency, but in none of the 58 patients with preserved exocrine function ( P = 0.051). Using stepwise logistic regression, the absence of calcifications, the presence of exocrine insufficiency, and the presence of K- ras mutation were identified as independent predictive factors for cancer development in all patients with chronic pancreatitis. CONCLUSIONS: K- ras gene mutations occur in chronic pancreatitis and are associated with evolution towards PAC. The absence of pancreatic calcifications and the presence of exocrine insufficiency were identified as additional predictive factors for the development of PAC.     

Hereditary pancreatitis in a young adult: Acute to chronic

This report investigates an unusual case of recurrent pancreatitis. A 22-year-old female was admitted to the emergency room for severe abdominal pain, nausea, and weight loss. She reported having these symptoms since she was a toddler. The clinician ordered fecal pancreatic elastase-1, fat-soluble vitamins, molecular studies, and imaging of the pancreas by computed tomography. The screening test result for fecal pancreatic elastase-1 revealed severe pancreatic exocrine insufficiency, and the concentrations of fat-soluble vitamins were also low. Imaging showed scattered calcifications in the pancreas. These findings supported a diagnosis of chronic pancreatitis. Due to the rarity of chronic pancreatitis in young adults, molecular studies were performed. The patient was found to be homozygous for a mutation in the SPINK1 gene, which is associated with hereditary pancreatitis. This case report discusses hereditary pancreatitis and highlights data on the utilization of fecal pancreatic elastase-1 to assess pancreatic exocrine insufficiency.     

Chronic Pancreatitis: Ultrasound, Computed Tomography, and Magnetic Resonance Imaging Features

Chronic pancreatitis is a progressive, irreversible inflammatory and fibrosing disease of the pancreas with clinical manifestations of chronic abdominal pain, weight loss, and permanent pancreatic exocrine and endocrine insufficiency. In the United States, a long history of heavy alcohol consumption is the most common cause of chronic pancreatitis. This review discusses the different modalities such as computed tomography, transabdominal and endoscopic ultrasound, magnetic resonance imaging/magnetic resonance cholangiopancreatography, and endoscopic retrograde cholangiopancreatography available to image chronic pancreatitis, along with their advantages and limitations. In addition, topics such as groove pancreatitis and autoimmune pancreatitis are examined, along with a discussion of distinguishing chronic pancreatitis from pancreatic adenocarcinoma.     

Floating pancreatic duct concrements in chronic pancreatitis. Pain relief by endoscopic removal

This report describes 3 patients with chronic relapsing pancreatitis, floating pancreatic duct concrements between 4 and 6 mm in diameter, moderate to advanced ductal changes, and repeated severe attacks of pain during acute relapses over a period of several months. Immediate relief of pain was achieved in all 3 patients by endoscopic papillotomy aimed at widening the main pancreatic duct and subsequent extraction or spontaneous passage of pancreatic duct concrements. On the basis of our experience with the patients presented here, endoscopic papillotomy widening the main pancreatic duct may be useful in some patients with chronic pancreatitis and floating pancreatic duct concrements.     

Is pancreatic diabetes (type 3c diabetes) underdiagnosed and misdiagnosed?

Exocrine pancreatic insufficiency is frequently associated with diabetes, with high prevalence in both insulin-dependent or insulin-independent patients. Exocrine pancreatic failure has often been perceived as a complication of diabetes. In contrast, recent clinical observations lead to the notion that nonendocrine pancreatic disease is a critical factor for development rather than a sequel to diabetes. The incidence of diabetes caused by exocrine pancreatic disease appears to be underestimated and may comprise 8% or more of the general diabetic patient population. Nonendocrine pancreas disease can cause diabetes by multiple mechanisms. Genetic defects have been characterized, resulting in a syndrome of both exocrine and endocrine failure. Regulation of beta-cell mass and physiological incretin secretion are directly dependent on normal exocrine function. Algorithms for diagnosis and therapy of diabetes should therefore address both endocrine and exocrine pancreatic function.     

Dysregulation of mannose-6-phosphate–dependent cholesterol homeostasis in acinar cells mediates pancreatitis

Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood. Here, we show that the mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene encoding a key enzyme in the M6P pathway disrupted acinar cell cholesterol turnover, causing accumulation of nonesterified cholesterol in lysosomes/autolysosomes, its depletion in the plasma membrane, and upregulation of cholesterol synthesis and uptake. We found similar dysregulation of acinar cell cholesterol, and a decrease in GNPTAB levels, in both WT experimental pancreatitis and human disease. The mechanisms mediating pancreatic cholesterol dyshomeostasis in Gnptab^–/– and experimental models involve a disordered endolysosomal system, resulting in impaired cholesterol transport through lysosomes and blockage of autophagic flux. By contrast, in Gnptab^–/– liver the endolysosomal system and cholesterol homeostasis were largely unaffected. Gnptab^–/– mice developed spontaneous pancreatitis. Normalization of cholesterol metabolism by pharmacologic means alleviated responses of experimental pancreatitis, particularly trypsinogen activation, the disease hallmark. The results reveal the essential role of the M6P pathway in maintaining exocrine pancreas homeostasis and function, and implicate cholesterol disordering in the pathogenesis of pancreatitis.     

Symptomatic diabetes mellitus in patients with chronic recurrent pancreatitis

Out of 279 patients with chronic recurrent cholepancreatitis 34 (12.2%) developed secondary diabetes mellitus. The secondary genesis of the diabetes was suggested in view of its origin in the presence of chronic pancreatitis and absence of hereditary predisposition, concomitant diseases promoting diabetes onset. The frequency of pancreatitis exacerbations and the degree of pancreatic exocrine insufficiency correlate with the occurrence of symptomatic diabetes. Diminished blood levels of insulin and C-peptide, inhibited response to pancreozymin registered in the patients may be indicative of symptomatic diabetes onset. Ketoacidosis was recorded in 9 patients, diabetic retinopathy in no patients. Ten patients out of 34 patients with chronic pancreatitis with secondary diabetes, 9 of which had episodes of ketoacidosis, received insulin. The sequence chronic cholecystitis-pancreatitis-diabetes was discussed in detail.     

Duodenal stricture: a complication of chronic fibrocalcific pancreatitis

Over the past 10 years, one of us (M.C.A.) has treated 92 patients who required operation for symptoms associated with alcohol-induced chronic fibrocalcific pancreatitis. Four of these patients had duodenal obstruction. All four had had lateral pancreaticojejunostomy to relieve pancreatic ductal obstruction and associated chronic abdominal pain; three of the four also required biliary diversion for stenosis of the intrapancreatic portion of the common bile duct. Each duodenal stricture required reoperation and gastrojejunostomy to bypass the site of obstruction. A review of the English language literature revealed that duodenal obstruction in patients with chronic fibrocalcific pancreatitis is uncommon, only 58 previous cases having been reported. All of those patients had pancreatic ductal obstruction, and more than half had concomitant distal biliary stenosis. Two thirds of the duodenal obstructions were treated by gastroenterostomy, and one third were resected. Duodenal obstruction in patients with chronic pancreatitis and biliary stricture appears to reflect an advanced form of the disease. Combined lateral pancreaticojejunostomy and biliary diversion has emerged as the preferred surgical procedure for this problem. Careful preoperative assessment for evidence of duodenal stenosis also is needed in this group of patients, and gastroenterostomy is indicated in appropriate cases.     

Replacement therapy with pancreatic enzymes and the principle of reversible regulation of the enzyme-secreting activity of the pancreas

In patients suffering from chronic pancreatitis (outside exacerbation) with initial enzyme-secretory pancreatic failure, the two-week intake of pancreatin as a replacement therapy brought about a decrease of the enzyme-secretory activity of the patient's own pancreas paralleled by the lowering of diurnal steatorrhea. This was confirmed by repeated pancreozymine tests. These data confirm the concept of a reverse relation between pancreatic enzymatic secretion and the concentration of the enzymes in the duodenal contents. Combined administration of pancreatin and calcium gluconate led to the preservation of the degree of steatorrhea by the enzymatic preparation. At the same time its inhibitory effect on the activity of the own pancreas was prevented. The effect of calcium gluconate is accounted for from the standpoint of the role Ca2+ plays in the maintenance of the function of the exocrine part of the pancreas. The combination with calcium gluconate is indicated in the clinical use of replacement therapy with preparations of pancreatic enzymes in patients with chronic pancreatitis.