Chronic pancreatitis

Alexandra M. Koenig, Kai Bachmann and Jakob R. Izbicki

Summary

Chronic pancreatitis (CP) is a widespread disorder with enormous personal and socioeconomic impact. This inflammatory disease is characterised by the progressive conversion of pancreatic parenchyma to fibrous tissue, predominantly in the head of the gland, with consecutive endocrine and exocrine insufficiency. Consumption of alcohol and nicotine abuse are the leading causes in the progress of the disease. The aim of therapy is primarily pain relief, improvement in the quality of life and treatment of complications. Surgical intervention encompasses drainage procedures, surgical resections or the combination of both.

Duodenum-preserving resection of the pancreatic head combines the highest safety of all surgical procedures with the maximum efficacy.

Definition

Chronic pancreatitis is a benign inflammatory disease, characterised by an irreversible loss of pancreatic parenchyma, leading to exocrine insufficiency with maldigestion and in advanced stages finally endocrine insufficiency.

Although the lost function can be replaced with pancreatic enzymes and management of diabetes mellitus, the most challenging symptom is pain.

Ammann et al. suggested that acute pancreatitis and chronic alcoholic pancreatitis are different stages of the same disease.¹^,² Chronic pancreatitis represents the persistent damage after episodes of severe acute pancreatitis.³^,⁴

The classification of CP as an separate disease was described in 1946 by Comfort et al.⁵ Since then, different classifications of CP have been presented. According to the Marseille Classification, CP is characterised by histological changes, persisting after the aetiologic agent has been removed.⁶ The Cambridge Classification (1983) defined CP as an ongoing inflammatory disease characterised by irreversible structural changes associated with abdominal pain and permanent loss of function.

In the Marseille–Rome classification of 1988 obstructive chronic pancreatitis, chronic inflammatory pancreatitis (with loss of exocrine parenchyma and replacement by fibrosis) and the chronic calcifying pancreatitis were described.

Recently, a new classification of CP has been suggested. Probable CP is characterised by a typical history and one or more of the following criteria: recurrent or persistent pseudocysts, ductal alterations, endocrine insufficiency (abnormal glucose tolerance test) or pathological secretin test. Definite CP is characterised by a typical history and at least one of the following criteria: typical histology from an adequate surgical specimen, moderate or marked ductal alterations, pancreatic calcification, marked exocrine insufficiency defined as steatorrhea, normalised or markedly reduced by enzyme substitution.⁷

Incidence

Chronic pancreatitis is a disease with high personal and socioeconomic impact. The prevalence of CP is 10–30 per 100 000 population and it affects about 8 new patients per 100 000 population per year in the USA.⁸^,⁹ Autopsy series suggest a higher prevalence of 0.04–5%.

Aetiology

Chronic pancreatitis is a highly complex process that begins with episodes of acute pancreatitis and progresses to end-stage fibrosis at different rates in different people due to different mechanisms. The most frequent causes are excess alcohol consumption (70–90%),⁹ cholelithiasis, autoimmune or individual genetic predisposition and anatomical variants such as pancreas divisum (Box 14.1).

Box 14.1 Aetiology of chronic pancreatitis

In up to 20% of patients the reasons or predisposing factors are not identifiable. The peak presentation of the disease occurs in patients between 35 and 55 years of age. Long-term consumption of alcohol is associated with an increased risk of developing CP. The precise level of daily alcohol intake at which patients are at risk for developing CP has not been clearly recognised, but it is estimated at 60–80 g per day, although individual sensitivity to the toxic effects of alcohol varies. Women are at greater risk, as are non-Caucasians when compared to their Caucasian counterparts. High caloric intake of protein and fat, smoking and lack of vitamins and trace elements have been described as additional predisposing risk factors.

Clinical course

Recurrent episodes of abdominal pain is the main symptom of CP, leading to inability to work, early retirement and addiction to analgesics. Severe pain attacks are the leading causes for hospitalisation. In most patients, pain is characterised as deep, penetrating, radiating to the back, and mostly worse after meals. Pain is frequently nocturnal, usually felt centrally in the epigastric region or subcostally with radiation to the back or shoulder tip, and is often eased by leaning forward or lying down to one side with knees pulled up, the so-called ‘jack-knife’ position. Ammann et al. described two different types of pain. The first, type A, is characterised by recurrent bouts of short-term, relapsing pain episodes. Type B pain is characterised as prolonged and persistent, and it is associated with secondary complications of CP such as pseudocysts or biliary obstruction. The natural course of CP is characterised by a consecutive loss of pancreatic parenchyma by fibrosis leading to exocrine insufficiency with diarrhoea, steatorrhoea, malnutrition and weight loss. In advanced stages, patients may present with endocrine insufficiency (diabetes mellitus). The clinical course and histomorphological changes that characterise the disease are extremely variable. Overall, life expectancy is shortened by 10–20 years. The mortality is increased 3.6-fold compared with a population without CP. The annual treatment costs are approximately $17 000 per patient.

The inflammation leads to progressive and irreversible loss of functional parenchyma and replacement with fibrotic tissue. The ductal system displays strictures of the bile duct, and duodenal stenosis ¹⁰ or the formation of pancreatic pseudocysts. Furthermore, CP can result in intraductal or parenchymal calcifications of the pancreas.

Besides pain, and exocrine/endocrine malfunction, mechanical complications occur in CP. The process of continuing organ destruction cannot be interrupted by abstinence from alcohol consumption. Despite thousands of reports that have been published in the last few decades dealing with this disease, the pathogenesis and pathophysiology of CP are poorly understood and the clinical course is unpredictable.¹¹

The natural course is that most patients with long-standing CP will become pain free due to a progressive ‘burning out’ of the organ.¹²^,¹³ Episodes of pain may occur less frequently, whereas endocrine and exocrine insufficiency commonly worsens. The pancreatic parenchyma is irreversibly converted to fibrous tissue with associated diabetes and steatorrhoea.¹⁴

At the time of onset of CP, 8% of patients have at least a moderate degree of endocrine insufficiency, whereas in long-term follow-up approximately 80% have endocrine insufficiency.¹⁵^,¹⁶ Studies have shown that it takes 10–20 years of a progressive inflammatory process to cause exocrine insufficiency by destroying the pancreatic parenchyma.¹⁷^,¹⁸

Ten years after onset of CP, 50–93% of patients with CP still suffer from abdominal pain.¹⁹

At least 50–68% of patients with CP need surgery for management of complications or for intractable pain.²⁰ Although spontaneous relief occurs, the effects of chronic pain can have lasting repercussions including depression, opiate addiction, unemployment and social alienation exacerbated by the stigma of alcoholism.

Reduction of alcohol intake does not influence the course of pain in chronic alcoholic pancreatitis, but continued alcohol abuse is associated with significantly lower survival rates. Patients that stop drinking may get some improvement in exocrine function.²¹ Endocrine insufficiency does not alter the course of pain. For the individual patient, the course of the disease is unpredictable.^21–23

Pathophysiological findings and pain mechanisms in chronic pancreatitis

Despite the advances in our understanding of pathophysiology there is still no therapy directed toward the inflammatory process that leads to the regression of the disease. Therefore, symptom control is the primary aim of treatment. Several theories about the course of pain have been proposed but it is extremely multifactorial and variable between patients.

Alcohol consumption is the leading cause of CP in western countries (70–90%).⁷

The acinar cells are directly damaged by alcohol. A change in microcirculatory perfusion and alterations in epithelial permeability lead to an imbalance in the pancreatic juice, and decreased fluid or bicarbonate secretion. Parenchymal necrosis of the pancreas may induce perilobular fibrosis that leads to intralobular fibrosis, ductal obstruction and periductal inflammation. Altered amounts of lithostatin in the pancreatic juice can lead to formation of protein plugs and stones in ducts and ductules.²⁴

Pathomorphological findings in CP such as inflammatory infiltration of the pancreatic tissue, fibrosis, atrophy of the acinar cells, calcifications, pancreatic duct strictures and pseudocysts can affect focal segments of the gland, or be a diffuse finding throughout the whole organ.

Histomorphologically different forms of CP can be distinguished.

Calcifying CP

The most common form (calcifying CP) is characterised by recurrent bouts of acute pancreatitis with abdominal pain and development of intraductal calculi, protein plugs and parenchyma calcifications. These alterations of various degrees in different stages of the disease lead to pancreatic duct stenosis and consecutively to prestenotic duct dilatation. Additionally, epithelial alterations, inflammatory periductal infiltrations, parenchymal atrophy, necrosis and fibrosis can be found.²⁵

Obstructive CP is often painless and caused by blockage of the main pancreatic duct due to tumour or an inflammatory process (post-acute pancreatitis) that leads to atrophy of the pancreatic tissue and prestenotic duct dilatation. No alteration of the ductal epithelium is found.²⁶ Pancreatic duct stones are uncommon. Periductal fibrosis and inflammatory infiltration are mainly found around the larger ducts and in the pancreatic head. Diffuse fibrotic changes occur throughout the organ without lobular topography. Pancreatic main-duct stenosis may be caused by papillary stenosis (tumour) or inflammation, duodenal diverticula, pancreatic tumours, congenital or acquired duct abnormalities (pancreas divisum), or rarely by traumatic pancreatic duct injuries. Small-duct pancreatitis is an extremely rare form of CP that is defined as main duct diameter ≤ 3 mm, with fibrous and inflammatory tissue.²⁷

Autoimmune pancreatitis

Autoimmune pancreatitis is characterised by the absence of typical risk factors for developing CP or hereditary factors. In the past this subtype was named primary inflammatory sclerosis of the pancreas, non-alcoholic duct destructive pancreatitis or lymphoplasmacytic sclerosing pancreatitis.28–30 The term autoimmune pancreatitis was introduced by Yoshida et al. in 1995.³¹ Autoimmune pancreatitis can present with a focal event or with multiple lesions. Pseudocysts and caliculi are rarely found. Four histological features are characteristic of autoimmune pancreatitis. Lymphoplasmacytic infiltration, consisting of lymphocytes and plasma cells (often with high levels of IgG4), macrophages, neutrophils and eosinophils result in an intestinal fibrosis.³² Additionally, periductal inflammation and periphlebitis can lead to luminal strictures or obliterative venulitis, respectively. Obstructive jaundice is caused by an effect on the common bile duct that may extend to the gallbladder and biliary tree. An increased level of IgG4 is a sensitive marker.³³ Autoimmune pancreatitis is associated with other autoimmune disorders such as ulcerative colitis, Crohn’s disease, primary sclerosing cholangitis, Sjörgren’s syndrome, lymphocytic thyroiditis and primary biliary cirrhosis.³⁴

Hereditary CP

Hereditary chronic pancreatitis (HCP) is a rare form with an incidence of approximately 3.5–10 per 100 000 inhabitants.³⁵ The morphological findings in HCP are irregular sclerosis with focal, segmental or diffuse destruction of the parenchyma. Different mutations have been detected to be associated with HCP, most commonly R122H, an N291 mutation of the PRSS1 gene, and mutations of the CFTR and SPINK1 genes.³⁶ The risk of developing pancreatic cancer is increased in HCP with PRSS1 mutation as compared with the normal population and chronic alcoholic pancreatitis.

Rare reasons for CP besides pancreatic duct obstruction due to tumours, strictures, diverticula and anatomical variations like pancreas divisum or annular pancreas are trauma and genetic mutation.