THEME OF THE LECTURE:
CHRONIC PANCREATITIS
Plan of the lecture:
1. Etiology and Pathomorphology of chronic pancreatitis
2. Classification of chronic pancreatitis
3. Clinical picture of chronic pancreatitis
4. Diagnosis of chronic pancreatitis
5. Differential diagnosis of chronic pancreatitis
6. Treatment of chronic pancreatitis
CHRONIC PANCREATITIS
PATHOPHYSIOLOGY
Aetiology
Alcohol is the major cause and the history is usually of > 150 g/day for more than 5 years. Less than 20% of heavy drinkers develop chronic pancreatitis and it is unclear why this is so, but there may be a diet rich in fat in those that do develop chronic pancreatitis. A preceding history of recurrent episodes of acute pancreatitis is not usually present. A tropical form of the disease is described which may be associated with protein malnutrition and intraductal stones. Familial and other inherited causes also occur (Table 1) although in up to 30%, the cause is obscure. It is unclear what initiates and perpetuates the chronic inflammation and fibrosis that develop within the pancreas. One theory is that a diet rich in lipid increases protein secretion by the pancreas. This may cause precipitation of these proteins in pancreatic ducts resulting in partial obstruction, which, when associated with toxic metabolites from alcohol, initiates the process. Another proposal is that chronic pancreatitis is a result of recurrent episodes of acute pancreatitis.
Causes of chronic pancreatitis
Pathogenesis
Grossly, the pancreas may be enlarged or atrophic, with or without cysts or calcifications. The ducts may be dilated, irregular, or strictured. Essential pathologic features include irregular and patchy loss of acinar and ductal tissue, chronic inflammation, ductal changes, and fibrosis.
Several important pathogenic theories have been developed, including the following: (1) oxidative stress; (2) toxic-metabolic; (3) stone and duct obstruction; and (4) necrosis-fibrosis. The premise of the oxidative stress hypothesis is that reactive by-products of hepatic mixed function oxidase activity damage the pancreas through chronic reflux of bile into the pancreatic duct. The toxic-metabolic theory is that alcohol is directly toxic to the acinar cell through a change in intracellular metabolism. This metabolic effect results in pancreatic lipid accumulation, fatty degeneration, cellular necrosis, and eventual widespread fibrosis. Proponents of the stone and duct obstruction theory have postulated that alcohol increases the lithogenicity of pancreatic juice, leading to stone formation. Chronic contact of the stones with duct epithelial cells produces ulceration and scarring. Eventually, atrophy and fibrosis result from chronic obstruction of the acini. The necrosis-fibrosis theory differs from other theories in that it emphasizes that acute and chronic pancreatitis represents a spectrum of disease. Inflammation from acute pancreatitis leads to scarring and extrinsic compression of the pancreatic ductules. Obstruction results in stasis, atrophy, and stone formation.
Discoveries about hereditary pancreatitis have supported the necrosis-fibrosis sequence. The genetic defect of hereditary pancreatitis produces recurrent acute pancreatitis beginning in early childhood, almost invariably leading to chronic pancreatitis in early adulthood. A major advance in understanding the underlying cellular mechanisms of pancreatic fibrogenesis is in the primary role of pancreatic stellate cells. Stimulated by alcohol and oxidative stress, activated stellate cells migrate to the periacinar areas to deposit collagen and fibronectin. Stellate cells are also stimulated by specific cytokines, many of which are emitted during the inflammatory phase of acute pancreatitis. Transforming growth factor beta 1 has received considerable attention as an important mediator of pancreatic fibrosis. The sentinel acute pancreatitis event hypothesis for CP pathogenesis incorporates many of these discoveries. Its major premise is that an episode of acute pancreatitis, the sentinel event, produces an inflammatory milieu, setting the stage for the attraction of collagen-secreting stellate cells.
Epidemiology
· n population studies, males are affected more commonly than females (6.7 vs 3.2 per 100,000 population);
· Differences in the hospitalization rates of patients with chronic pancreatitis exist with respect to sex. Rates in males peak at age 45-54 years and then decline; female rates reach a plateau, which remains stable after age 35 years;
Sex differences with respect to etiology also exist. Alcohol-induced illness is more prevalent in males, idiopathic and hyperlipidemic-induced pancreatitis is more prevalent in females, and equal sex ratios are observed in chronic pancreatitis associated with hereditary pancreatitis
Predisposing factors
The proposed pathologic mechanisms of chronic pancreatitis are as follows:
· Intraductal plugging and obstruction (eg, ETOH abuse, stones, tumors);
· Direct toxins and toxic metabolites: These act on the pancreatic acinar cell to stimulate the release of cytokines, which stimulate the stellate cell to produce collagen and to establish fibrosis. Cytokines also act to stimulate inflammation by neutrophils, macrophages, and lymphocytes (eg, ETOH, tropical sprue);
· Oxidative stress (eg, idiopathic pancreatitis);
· Necrosis-fibrosis (recurrent acute pancreatitis that heals with fibrosis);
· Ischemia (from obstruction and fibrosis), which is important in exacerbating or perpetuating disease rather than in initiating disease;
· Autoimmune disorders: Chronic pancreatitis has been found in association with other autoimmune diseases, such as Sjögren syndrome, primary biliary cirrhosis, and renal tubular acidosis.
Classification
Three groups have been described:
1. chronic calcified pancreatitis – fibrosis, intraductal protein plugs and stones result in ductal injury; alcohol is the major cause.
2. chronic obstructive pancreatitis – obstruction of the main duct with proximal, uniform, ductal dilatation and subsequent atrophy and fibrosis; this is much less common and is due to either an intraductal tumour or a stricture.
3. chronic inflammatory pancreatitis – fibrosis and a mononuclear infiltrate associated with conditions such as Sjogren’s syndrome and primary sclerosing cholangitis.
Table 1. Classification
|
Cronic calcifield panreatitis |
Chronic obstructive pancreatitis |
Chronic inflammatory pancreatitis |
|
Fibrosis, intraductal protein plugs and stones result in ductal injury; alcohol is the major cause |
Obstruction of the main duct with proximal, uniform, ductal dilatation and subsequent atrophy and fibrosis; this is much less common and is due to either an intraductal tumour or a stricture |
Fibrosis and a mononuclear infiltrate associated with conditions such as Sjogren’s syndrome and primary sclerosing cholangitis |
CLINICAL FEATURES
The three important features of chronic pancreatitis are pain, steatorrhoea resulting from exocrine dysfunction and diabetes mellitus resulting from endocrine dysfunction.
Pain. The pain is usually located in the upper abdomen but is poorly localised. It is described as a boring, deep pain which may radiate to the back and is worsened after meals. It may be nocturnal. Its severity is not proportional to steatorrhoea and correlates poorly with loss of exocrine function or structural abnormality. The pain is the most difficult problem to treat and can be frustrating for both the patient and the physician.
Steatorrhoea. Lipase secretion has to be reduced to less than 10% of normal for steatorrhoea to develop and consequently this is a symptom which develops when the disease is advanced. Fat-soluble vitamins (A, D, E and K) are rarely sufficiently malabsorbed to cause symptoms. Stools are passed 2-3 times per day, are pale and may contain droplets of oil.
Diabetes. For overt diabetes to develop, more than 80% of the gland needs to be affected, which means that diabetes is also usually a late complication. However, abnormalities in the glucose tolerance test are detectable much earlier. The vast majority of patients will describe a heavy, sustained alcohol drinking habit and only rarely will there be a significant family history or associated medical history. Examination is usually normal although a mass may be palpable when a pseudocyst or cancer has developed. The spleen may be enlarged when the splenic vein has thrombosed.
Diagnosis
The triad of pain, steatorrhoea and diabetes is unlikely to occur until late in the disease and patients more usually present with pain. There may be no signs of chronic liver disease as this too only develops in one-fifth of heavy drinkers. Simple blood tests are not usually helpful although there may be diabetes or at least an impaired glucose tolerance test. Serum lipase and amylase elevation is unusual and only tends to occur if the pancreatic duct is blocked or there is a pseudocyst. An obstructive pattern in the liver profile may occur if stricturing of the CBD has developed. The important differential diagnoses include peptic ulcer, biliary tract disease, mesenteric ischaemia and gastric or pancreatic malignancy, and appropriate investigation is necessary to exclude these.
Pancreatic function tests
A number of tests are available to assess endocrine pancreatic function. Some tests quantify enzyme production, measured following intubation of the duodenum and stimulation of the pancreas either by hormones or a test meal, while other tests quantify production of metabolites of reactions catalysed by pancreatic enzymes (Table 2).
Table 2 Tests of exocrine pancreatic function
As a group, the tests have similar drawbacks in that they require accurate intubation of the duodenum and all depend on complete sample collection. The other major drawback is that a significantly abnormal test frequently does not develop until late in the condition when diagnostic uncertainty is often much less. They are of no use in monitoring the condition.
Laboratory Studies
· Blood tests
Serum amylase and lipase levels may be slightly elevated in chronic pancreatitis; high levels are found only during acute attacks of pancreatitis. In the later stages of chronic pancreatitis, atrophy of the pancreatic parenchyma can result iormal serum enzyme levels, because of significant fibrosis of the pancreas, resulting in decreased concentrations of these enzymes within the pancreas.
While low concentrations of serum trypsin are relatively specific for advanced chronic pancreatitis, they are not sensitive enough to be helpful in most patients with mild-to-moderate disease.
Laboratory studies to identify causative factors include serum calcium and triglyceride levels.
When common etiologies are not found, research protocols are available to test for genetic mutations in cationic trypsinogen and CFTR.
· Fecal tests
Because maldigestion and malabsorption do not occur until more than 90% of the pancreas has been destroyed, steatorrhea is a manifestation of advanced chronic pancreatitis, and neither qualitative nor quantitative fecal fat analysis can detect early disease.
Assays of fecal chymotrypsin and human pancreatic elastase 1 have the same limitations but are useful in confirming advanced chronic pancreatitis with exocrine insufficiency.
· Pancreatic function tests
Direct tests: These tests are the most sensitive and can be used to detect chronic pancreatitis at its earliest stage; however, they are somewhat invasive, labor intensive, and expensive.
Determination in duodenal aspirates: Intubation of the duodenum usually is performed with a Dreiling tube, which allows for separate aspiration of gastric and duodenal contents. The methodology varies depending on the specific laboratory; however, exogenous secretin with cholecystokinin (CCK) is used to achieve maximal stimulation of the pancreas. The output of pancreatic bicarbonate, protease, amylase, and lipase then is measured in the duodenal aspirates. This test currently only is available in specialized centers. While the greatest sensitivity can be obtained in prolonged infusions of secretagogue to uncover a decreased pancreatic secretory reserve, it is impractical for general clinical use. Determination in pancreatic juice: This test generally is performed in conjunction with an endoscopic retrograde cholangiopancreatography (ERCP). The pancreatic duct is freely cannulated, an exogenous secretagogue is administered as above, and the pancreatic juice then is aspirated out of the
duct as it is produced. The output of pancreatic bicarbonate, protease, amylase, and lipase are measured.
Indirect tests: Noninvasive tests of pancreatic function have been developed for detecting chronic pancreatitis. In principle, these tests work via oral administration of a complex substance that is hydrolyzed by a specific pancreatic enzyme to release a marker substance. The intestine absorbs the marker, which then is measured in the serum or urine. These tests are capable of detecting moderate-to-severe chronic pancreatitis. The presence of renal, intestinal, and liver disease may interfere with the accuracy of these tests. Neither currently is freely available in the United States.
· Diagnosis of chronic pancreatitis requires morphologic abnormalities to appear on imaging procedures. Although advances in technology have improved the ability to detect these changes, most imaging procedures cannot depict early chronic pancreatitis because the structural changes they rely on are associated with moderate-to-advanced disease.
· Abdominal radiography: Pancreatic calcifications, often considered pathognomonic of chronic pancreatitis, are observed in approximately 30% of cases. Paired anteroposterior (AP) and oblique views are preferred because the vertebral column otherwise could obscure small flecks of calcium. The calcifications form within the ductal system—initially in the head, and later in the body and tail, of the gland. Calcium deposition is most common with alcoholic pancreatitis, hereditary pancreatitis, and tropical pancreatitis; however, it is rare in idiopathic pancreatitis.
· Computed tomography (CT) scanning: CT scanning, demonstrated in the images below, has the advantage of providing images of the pancreas of which interpretation is relatively intuitive. Although it excels at depicting the morphologic changes of advanced chronic pancreatitis described above, the subtle abnormalities of early-to-moderate chronic pancreatitis are beyond its resolution, and a normal finding on this study does not rule out chronic pancreatitis. This study is indicated to look for complications of the disease and is useful in planning surgical or endoscopic intervention. The sensitivity and the specificity of CT scan are 80% and 85%, respectively.
Endoscopic retrograde cholangiopancreatography: ERCP, demonstrated in the image below, provides the most accurate visualization of the pancreatic ductal system and has been regarded as the criterion standard for diagnosing chronic pancreatitis. Conversely, one limitation of ERCP is that it cannot be used to evaluate the pancreatic parenchyma, and histologically proven chronic pancreatitis has been documented in the setting of normal findings on pancreatogram. Pancreatograms can be interpreted and classified according to several schemes, such as the Cambridge criteria. A comparison of ERCP scoring with direct pancreatic function tests demonstrated good correlation. However, pancreatography tended to show significantly more severe changes. The problems with ERCP are that it is invasive, expensive, requires complete opacification of the pancreatic duct to visualize side branches, and carries a risk (operator-dependent) of pancreatitis.
Endoscopic ultrasonography: Studies suggest that endoscopic ultrasonography (EUS) may be the best test for imaging the pancreas but requires a highly skilled gastroenterologist.
TREATMENT
It is important to try to minimise disease progression and this is best done by total alcohol avoidance particularly in those in whom alcohol is the cause.
Pain
Analgesia requirement should be titrated against need but often spirals upwards to considerable opiate requirement and subsequent addiction. Care should be taken in controlling associated side-effects such as constipation which can lead to abdominal pain inappropriately attributed to the pancreas. Pancreatic enzyme supplementation is usually used and may be helpful as may an anti-oxidant cocktail given daily. Coeliac axis nerve block may lead to temporary improvement in pain but frequently symptoms recur. Surgery including partial resections and drainage procedures may be helpful in the most severe cases but it is difficult to obtain controlled data for these procedures. Resection of tissue including endocrine cells results in brittle diabetes which is difficult to manage.
Steatorrhoea
Dietary enzyme supplementation usually controls this. Lipase inactivation by gastric acid may result in more than the expected 30 000 units of lipase per meal estimated to be required to prevent steatorrhoea. Gelatin capsules and acid suppression therapy may help.
Diabetes
This is often brittle and wide fluctuations in blood glucose are seen with exogenous insulin.
Complications
Pseudocysts may occur in up to 25% of patients with chronic pancreatitis and if they are of significant size require drainage either surgically or endoscopically. Bleeding may occur into a pseudocyst or there may be erosion into surrounding vessels. Splenic vein thrombosis may occur resulting in gastric and oesophageal varices. Pancreatic cancer is more common in patients with chronic pancreatitis and represents the major differential diagnosis when obstructive jaundice occurs with a stricture of the CBD. Differentiation between the two conditions is difficult and serum markers (CA 19-9), CT and biopsy may all be necessary to confirm the diagnosis.
