Management of patient with abdominal pain

DISEASES OF THE PANCREAS IN FAMILY DOCTOR PRACTICE. MANAGEMENT OF PATIENTS WITH INTESTINAL DISORDERS IN OUTPATIENT CLINICS. CELIAC DISEASE. THE ROUTE OF THE PATIENT. PROPHYLACTIC MEDICAL EXAMINATION. MEDICAL AND LABOR EXPERTISE. PRINCIPLES RATIONAL NUTRITION.

CHRONIC PANCREATITIS

Chronic pancreatitis is commonly defined as a continuing, chronic, inflammatory process of the pancreas, characterized by irreversible morphologic changes. This chronic inflammation can lead to chronic abdominal pain and/or impairment of endocrine and exocrine function of the pancreas.

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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

Table 2. Causes of Pancreatic Exocrine Insufficiency

Alcohol, chronic alcoholism

Idiopathic pancreatitis

Cystic fibrosis

Hypertriglyceridemia

Severe protein-calorie malnutrition with hypoalbuminemia

Tropical pancreatitis (Africa, Asia)

Pancreatic and duodenal neoplasms

Pancreatic resection

Gastric surgery

Subtotal gastrectomy with Billroth I anastomosis

Subtotal gastrectomy with Billroth II anastomosis

Truncal vagotomy and pyloroplasty

Gastrinoma (Zollinger-Ellison syndrome)

Hereditary pancreatitis

Traumatic pancreatitis

Abdominal radiotherapy

Hemochromatosis

Shwachman's syndrome (pancreatic insufficiency and bone marrow dysfunction)

Trypsinogen deficiency

Enterokinase deficiency

Isolated deficiencies of amylase, lipase, or proteases

a₁-Antitrypsin deficiency

The cause of chronic pancreatitis usually is metabolic in nature. The proposed pathologic mechanisms of chronic pancreatitis are as follows:

Intraductal plugging and obstruction - Eg, ethanol (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; 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.
Secondary forms of autoimmune chronic pancreatitis are associated with primary biliary cirrhosis, primary sclerosing cholangitis, and Sjögren syndrome.
While alcohol greatly influences the understanding of its pathophysiology because it is the most common etiology (60-70%), approximately 20-30% of cases are idiopathic and 10% of cases are due to rare diseases.

Autoimmune pancreatitis is a more recently described entity. Clinical characteristics include symptomatic or asymptomatic, diffuse enlargement of the pancreas, diffuse and irregular narrowing of the main pancreatic duct, increased circulating levels of gamma globulin, the presence of autoantibodies, and a possible association with other autoimmune diseases. Fibrosis with lymphocytic infiltration is seen on pathology. The disorder is associated with elevated immunoglobulin G4 (IgG4) concentrations.

In a study of 51 patients with autoimmune pancreatitis, Kawa et al suggested that a strong link exists between pancreatic stone formation and the recurrence of autoimmune pancreatitis and that following several recurrences, this disease may develop into chronic pancreatitis. In the study, the authors found that during a long-term follow-up period, 21 patients suffered a recurrence of the condition and 9 of the 51 patients developed pancreatic stones

The investigators also found that the stones developed more frequently in the recurrence group (7 [33%] of 21 patients) than in the other patients (2 [7%] of 30 patients). In addition, within a group of 175 patients with ordinary chronic hepatitis, 13 patients were found to have high serum concentrations of IgG4.

Excessive alcohol consumption is the most common cause of pancreatitis, accounting for about 60% of all cases.

In the affected gland, alcohol appears to increase protein secretion from acinar cells while decreasing fluid and bicarbonate production from ductal epithelial cells. The resulting viscous fluid results in proteinaceous debris becoming inspissated within the lumen, causing ductular obstruction, upstream acinar atrophy, and fibrosis. GP2, which is secreted from the acinar cell and is homologous to a protein involved in renal tubular casts, is an integral component of these ductal plugs.

Lithostathine (formerly called pancreatic stone protein), which also is produced by acinar cells, accounts for about 5% of secretory protein and inhibits the growth of calcium carbonate crystals. Abnormal lithostathine S1, whether inherited or acquired through trypsin digestion, appears to play a role in stone formation; it is insoluble at the neutral pH of pancreatic juice and is the major constituent of pancreatic stones.

A competing theory suggests that the persistent demands of metabolizing alcohol (and probably other xenobiotics, such as drugs, tobacco smoke, environmental toxins, and pollution) cause oxidative stress within the pancreas and may lead to cellular injury and organ damage, especially in the setting of malnutrition. Oxidative and nonoxidative pathways metabolize ethanol. Alcohol dehydrogenase oxidatively metabolizes ethanol first to acetaldehyde and then to acetate. When the alcohol concentration increases, cytochrome P-450 2E1 is induced to meet the metabolic demands.

Although these reactions occur principally in the liver, further increases in ethanol concentration induce pancreatic cytochrome P-450 2E1, and the level of acetate within the pancreas begins to approach that observed in the liver. Reactive oxygen species produced by this reaction may overwhelm cellular defenses and damage important cellular processes.

Although nonoxidative metabolism of ethanol is a minor pathway, the fatty acid ethyl esters produced by this reaction may cause cellular injury and are synthesized in the pancreas to a greater extent than in other organ systems.

Because fewer than 5-10% of people with alcoholism develop chronic pancreatitis, another factor or factors must place these individuals at risk. Researchers have studied genetic polymorphisms of ethanol-oxidizing enzymes, but to date, none have correlated with a susceptibility to alcohol-induced pancreatitis.

A mutation in the gene encoding the serine protease inhibitor, Kazal type 1, has been identified in patients with chronic pancreatitis. The N34S mutation was detected in 5.8% of 274 patients with alcoholic chronic pancreatitis, compared with 1.0% of people with alcoholism without pancreatitis. Although all patients were heterozygous for the mutation, it provides evidence for abnormalities in the pancreatic protease/protease inhibitor system playing a role in the pathogenesis of alcoholic chronic pancreatitis.

Hereditary pancreatitis

Several inherited disorders also are considered metabolic in origin. Hereditary pancreatitis is an autosomal dominant disorder with an 80% penetrance, accounting for about 1% of cases. Research of families with hereditary pancreatitis has led to the identification of several mutations in the cationic trypsinogen gene on chromosome 7. These mutations apparently render the activated enzyme resistant to second-line proteolytic control mechanisms. Mutations were found in the pancreatic secretory serine protease inhibitor Kazal type 1 (SPINK1) gene in 18 of 96 patients with idiopathic or hereditary chronic pancreatitis.

Cystic fibrosis, one of the most common genetic abnormalities, is an autosomal recessive disorder accounting for a small percent of patients with chronic pancreatitis. The cystic fibrosis transmembrane regulator (CFTR) gene transcribes a protein important in regulating chloride transport across cellular membranes.

Several hundred mutations of the CFTR gene have been identified, and the clinical manifestation of any given mutation depends on how severely it affects the protein's ability to regulate chloride transport. Different mutations in CFTR are associated with different functional statuses of the exocrine pancreas.

Specific CFTR genotypes are significantly associated with pancreatitis. Patients with genotypes associated with mild phenotypic effects have a greater risk of developing pancreatitis than do patients with genotypes associated with moderate-severe phenotypes.

This form of chronic pancreatitis accounts for approximately 30% of cases. It has been arbitrarily divided into early onset and late-onset forms. While the cause of idiopathic chronic pancreatitis is not yet known, some evidence points to atypical genetic mutations in CFTR, cationic trypsinogen, and other proteins.

Congenital abnormalities, such as pancreas divisum and annular pancreas divisum, are uncommon (even rare) causes of chronic pancreatitis and usually require an additional factor to induce chronic pancreatitis. For example, while pancreas divisum usually does not cause chronic pancreatitis, patients with divisum and minor papilla stenosis are at risk. In these patients, clear evidence of disease exists in the dorsal pancreas, whereas the ventral pancreas is normal histologically.

Acquired obstructive forms typically result from blunt abdominal trauma or accidents involving motor vehicles, bicycles, horses, or, on occasion, severe falls. In these cases, the pancreas is whiplashed against the spine, causing trauma to the ductal system and resulting in a stricture close to the surgical genu. In rare instances, chronic inflammatory conditions affecting the duodenum, or primarily the duodenal papilla, can induce fibrosis and papillary stenosis in a subset of patients, leading to chronic pancreatitis.

Other causes of chronic pancreatitis include the following:

Hyperlipidemia (usually type I and type V) - However, hyperlipidemia usually presents with repeated attacks of acute pancreatitis
Hypercalcemia due to hyperparathyroidism - Now is a rare cause of chronic pancreatitis, probably because automation of serum chemistries reveals hypercalcemia before it results in pancreatitis
Nutritional, or tropical, chronic pancreatitis - Rare in the United States, but an important cause of disease in other parts of the world
Medications - An infrequent, or possibly underrecognized, cause of chronic pancreatitis
Obstruction of the flow of pancreatic juice can cause chronic pancreatitis. Obstructive forms account for less than 10% of cases and may be congenital or acquired.

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.

Table 1a. 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.

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.

Patients with chronic pancreatitis in whom there is extensive destruction of the pancreas (less than 10% of exocrine function remaining) have steatorrhea and azotorrhea. Among American adults, alcoholism is the most common cause of clinically apparent pancreatic exocrine insufficiency, while cystic fibrosis is the most frequent cause in children. In up to 25% of American adults with chronic pancreatitis, the cause is not known; that is, they have idiopathic chronic pancreatitis. Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been documented in patients with idiopathic chronic pancreatitis. It has been estimated that in patients with idiopathic pancreatitis the frequency of a single CFTR mutation is 11 times the expected frequency and the frequency of two mutant alleles is 80 times the expected frequency. The results of sweat chloride testing are not diagnostic of cystic fibrosis in these patients. However, these patients have functional evidence of a defect in CFTR-mediated ion transport in nasal epithelium. It is suggested that up to 25% of patients with idiopathic chronic pancreatitis may have abnormalities of the CFTR gene. The therapeutic and prognostic implication of these findings remain to be determined. In other parts of the world, severe protein-calorie malnutrition is a common cause. Table 2 lists other causes of pancreatic exocrine insufficiency, but they are relatively uncommon.

Laboratory tests and diagnostic studies

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 in normal 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.

Histologic Findings

· In the early stages of chronic pancreatitis, the parenchyma exhibits an increase in connective tissue around the ducts and between the lobules. The degree of inflammation is minimal to moderate, consisting mostly of T lymphocytes, and a patchy, focal process unevenly affects the pancreas. With increasing severity, the connective issue progresses between the acini, which gradually become distorted and tend to disappear. In advanced disease, fibrous tissue replaces the acinar tissue, and the pancreas becomes contracted, small, and hard. The islets of Langerhans are relatively spared until very late in the disease process.

· Patients can have severe histopathologic changes of chronic pancreatitis despite normal findings on imaging studies. In patients undergoing resection of the pancreas for chronic pancreatitis, focal necrosis is found in 11.9% and segmental fibrosis is observed in approximately 40% of cases.

· In chronic calcific pancreatitis, plugs of precipitated protein develop within the ductal system. While they may be observed in all types of chronic pancreatitis, in alcoholic and tropical forms, these plugs tend to evolve into calculi by deposition of calcium within them. The calcified pancreatic calculi are distributed irregularly, affecting ducts of various sizes, and may be associated with ulcerations of the ductal epithelium. Periductal connective tissue may encroach on the lumen and cause ductal stenoses, creating the "chain of lakes" pancreatogram appearance observed in advanced chronic calcific pancreatitis.

Pathophysiology and Etiology.)

Chronic pancreatitis usually is envisioned as an atrophic fibrotic gland with dilated ducts and calcifications. However, findings on conventional diagnostic studies may be normal in the early stages of chronic pancreatitis, as the inflammatory changes can be seen only by histologic examination (see the images below). (See Workup.)

This endoscopic retrograde cholangiopancreatography (ERCP) shows advanced chronic pancreatitis. The pancreatogram has blunting of the lateral branches, dilation of the main pancreatic duct, and filling defects consistent with pancreatolithiasis. The cholangiogram also shows a stenosis of the distal bile duct and a dilated biliary tree

This patient has recurrent abdominal pain. She used alcohol heavily in the past and was involved in a motor vehicle accident. The pancreatogram shows subtle blunting of side branches consistent with chronic pancreatitis. A stricture also is present in the body of the pancreas where it drapes over the spine, probably resulting from the trauma she sustained in the motor vehicle accident. Air in the stomach makes it difficult to observe that contrast is filling a pseudocyst on the other side of the stricture. These findings are not amenable to endoscopic intervention, and the patient was sent for a distal pancreatectomy.

By definition, chronic pancreatitis is a completely different process from acute pancreatitis. In acute pancreatitis, the patient presents with acute and severe abdominal pain, nausea, and vomiting. The pancreas is acutely inflamed (neutrophils and edema), and the serum levels of pancreatic enzymes (amylase and lipase) are elevated. Full recovery is observed in most patients with acute pancreatitis, whereas in chronic pancreatitis, the primary process is a chronic, irreversible inflammation (monocyte and lymphocyte) that leads to fibrosis with calcification. (See Pathophysiology, Etiology, Presentation, and Workup.)

The patient with chronic pancreatitis clinically presents with chronic abdominal pain and normal or mildly elevated pancreatic enzyme levels. When the pancreas loses its endocrine and exocrine function, the patient presents with diabetes mellitus and steatorrhea. (See Presentation and Workup.)

Pathophysiology

Whatever the etiology of chronic pancreatitis,^[2]pancreatic fibrogenesis appears to be a typical response to injury. This involves a complex interplay of growth factors, cytokines, and chemokines, leading to deposition of extracellular matrix and fibroblast proliferation. In pancreatic injury, local expression and release of transforming growth factor beta (TGF-beta) stimulates the growth of cells of mesenchymal origin and enhances synthesis of extracellular matrix proteins, such as collagens, fibronectin, and proteoglycans.

Evidence indicates involvement of distinct chemokines in the initiation and perpetuation of chronic pancreatitis.

Etiology

The cause of chronic pancreatitis usually is metabolic in nature. The proposed pathologic mechanisms of chronic pancreatitis are as follows:

· Intraductal plugging and obstruction - Eg, ethanol (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; 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.

· Secondary forms of autoimmune chronic pancreatitis are associated with primary biliary cirrhosis, primary sclerosing cholangitis, and Sjögren syndrome.

· While alcohol greatly influences the understanding of its pathophysiology because it is the most common etiology (60-70%), approximately 20-30% of cases are idiopathic and 10% of cases are due to rare diseases.

Autoimmune pancreatitis

Autoimmune pancreatitis is a more recently described entity. Clinical characteristics include symptomatic or asymptomatic, diffuse enlargement of the pancreas, diffuse and irregular narrowing of the main pancreatic duct, increased circulating levels of gamma globulin, the presence of autoantibodies, and a possible association with other autoimmune diseases. Fibrosis with lymphocytic infiltration is seen on pathology. The disorder is associated with elevated immunoglobulin G4 (IgG4) concentrations.

Alcoholic chronic pancreatitis

Excessive alcohol consumption is the most common cause of pancreatitis, accounting for about 60% of all cases.

Hereditary pancreatitis

Several inherited disorders also are considered metabolic in origin.^[4]Hereditary pancreatitis is an autosomal dominant disorder with an 80% penetrance, accounting for about 1% of cases. Research of families with hereditary pancreatitis has led to the identification of several mutations in the cationic trypsinogen gene on chromosome 7. These mutations apparently render the activated enzyme resistant to second-line proteolytic control mechanisms. Mutations were found in the pancreatic secretory serine protease inhibitor Kazal type 1 (SPINK1) gene in 18 of 96 patients with idiopathic or hereditary chronic pancreatitis.

Cystic fibrosis in pancreatitis

Idiopathic chronic pancreatitis

Congenital abnormalities in chronic pancreatitis

Congenital abnormalities, such as pancreas divisum and annular pancreas divisum, are uncommon (even rare) causes of chronic pancreatitis and usually require an additional factor to induce chronic pancreatitis. For example, while pancreas divisum usually does not cause chronic pancreatitis, patients with divisum and minor papilla stenosis are at risk. In these patients, clear evidence of disease exists in the dorsal pancreas, whereas the ventral pancreas is normal histologically.

Acquired obstructive chronic pancreatitis

Acquired obstructive forms typically result from blunt abdominal trauma or accidents involving motor vehicles, bicycles, horses, or, on occasion, severe falls. In these cases, the pancreas is whiplashed against the spine, causing trauma to the ductal system and resulting in a stricture close to the surgical genu. In rare instances, chronic inflammatory conditions affecting the duodenum, or primarily the duodenal papilla, can induce fibrosis and papillary stenosis in a subset of patients, leading to chronic pancreatitis.

Additional causes

Other causes of chronic pancreatitis include the following:

· Hyperlipidemia (usually type I and type V) - However, hyperlipidemia usually presents with repeated attacks of acute pancreatitis

· Hypercalcemia due to hyperparathyroidism - Now is a rare cause of chronic pancreatitis, probably because automation of serum chemistries reveals hypercalcemia before it results in pancreatitis

· Nutritional, or tropical, chronic pancreatitis - Rare in the United States, but an important cause of disease in other parts of the world

· Medications - An infrequent, or possibly underrecognized, cause of chronic pancreatitis

· Obstruction of the flow of pancreatic juice can cause chronic pancreatitis. Obstructive forms account for less than 10% of cases and may be congenital or acquired.

Epidemiology

Based on estimates from hospital discharge data in the United States, approximately 87,000 cases of pancreatitis occur annually.

Comparing the hospital admissions data from several cities around the globe, the overall frequency is similar. Expressed as number of cases per 1000 hospital admissions, the value for Marseille is 3.1; for Cape Town, 4.4; for Sao Paulo, 4.9; and for Mexico City, 4.4. When the data from several centers were compared over time, the incidence of chronic pancreatitis from 1945-1985 appeared to be increasing.

Race-, sex-, and age-related demographics

Hospitalization rates for blacks are 3 times higher than for whites in the United States. In 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 between ages 45 and 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.

In aggregate, the mean age at diagnosis is at age 46 years, plus or minus 13 years. In idiopathic chronic pancreatitis, a bimodal age distribution has been reported, designated as the early onset form (median age 19.2 y) and the late-onset form (median age 56.2 y).

Prognosis

The prognostic factors associated with chronic pancreatitis are age at diagnosis, smoking, continued use of alcohol, and the presence of liver cirrhosis.

The overall survival rate is 70% at 10 years and 45% at 20 years. In an international study, 559 deaths occurred among patients with chronic pancreatitis, compared with an expected number of 157, which creates a standard mortality ratio of 3.6. Taking the opposite view, the 10-year mortality rate is 30%, and the 20-year mortality rate is 55%. The risk of developing pancreatic cancer is approximately 4% at 20 years.

The most common complications of chronic pancreatitis are pseudocyst formation and mechanical obstruction of the duodenum and common bile duct. Less frequent complications include pancreatic ascites or pleural effusion, splenic vein thrombosis with portal hypertension, and pseudoaneurysm formation of the splenic artery.

Pseudocyst

A pseudocyst is a collection of pancreatic juice enclosed by a wall of fibrous or granulation tissue. It arises as a consequence of acute pancreatitis, pancreatic trauma, or chronic pancreatitis. The clinical challenge is to diagnose a cystic pancreatic structure correctly as a pseudocyst. As many as 5% of cysts are retention cysts, another 5% of these cysts are either congenital in origin or acquired (as in von Hippel-Lindau syndrome), and 10% are neoplastic in origin (mucinous vs serous cyst).

Pseudocysts develop in approximately 10% of patients with chronic pancreatitis. They develop as a result of ductal disruptions rather than from peripancreatic fluid accumulations that lead to pseudocyst formation in the setting of acute pancreatitis. Pseudocysts may be single or multiple and can be small or large, and they can be located either within or outside of the pancreas. Most pseudocysts communicate with the pancreatic ductal system and contain high concentrations of digestive enzymes.

The walls of pseudocysts are formed by adjacent structures, such as the stomach, transverse mesocolon, gastrocolic omentum, and pancreas. The lining of pancreatic pseudocysts consists of fibrous and granulation tissue; the lack of an epithelial lining distinguishes pseudocysts from true cystic lesions of the pancreas. Most pseudocysts are asymptomatic. They can, however, produce a wide range of clinical problems, depending upon the location and extent of the fluid collection.

Expansion of the pseudocyst can produce abdominal pain, duodenal or biliary obstruction, vascular occlusion, or fistula formation into adjacent viscera, the pleural space, or pericardium. Spontaneous infection with abscess formation can occur. (See the images below.)

Chronic pancreatitis. Abdominal CT scan showing that a pancreatic pseudocyst is responsible for the distortion of the ductal system

Chronic pancreatitis. Pancreatogram in a patient with a pancreatic pseudocyst. Note how the pancreatic ducts are extrinsically distorted by a mass lesion.

Digestion of an adjacent vessel can result in a pseudoaneurysm, which can produce a sudden expansion of the cyst or gastrointestinal bleeding due to bleeding into the pancreatic duct (hemosuccus pancreaticus).

Pancreatic ascites and pleural effusion can result from disruption of the pancreatic duct, leading to fistula formation to the abdomen or chest, or rupture of a pseudocyst with tracking of pancreatic juice into the peritoneal cavity or pleural space.

The indications for drainage of pseudocysts include rapid enlargement, compression of surrounding structures, pain, or signs of infection. Endoscopic retrograde pancreatograms may be helpful prior to drainage to rule out a stricture of the pancreatic duct, which can lead to persistent drainage from the pseudocyst.

Bile obstruction and duodenal obstruction

Symptomatic obstruction of the bile duct and/or duodenum develops in 5-10% of patients with chronic pancreatitis. Postprandial pain and early satiety are characteristic of duodenal obstruction, while pain and abnormal liver function test results (including hyperbilirubinemia) are suggestive of a bile duct stricture. These complications are most commonly seen in patients with dilated pancreatic ducts; they are either due to inflammation and fibrosis in the head of the pancreas or are the result of a pseudocyst.

Drainage of an obstructing pseudocyst can be accomplished surgically by gastrojejunostomy or choledochoenterostomy. Endoscopic stenting may be helpful for benign bile duct strictures.

Additional complications of chronic pancreatitis

Diabetes mellitus is a late manifestation in about one third of patients. The tendency to develop ketoacidosis is low.

The presence of the splenic vein at the posterior surface of the pancreas predisposes it to thrombosis from adjacent pancreatic inflammation. Patients who are affected can develop gastric varices as a result of associated portal hypertension. Splenectomy is usually curative for patients who develop bleeding from gastric varices.

Pseudoaneurysm is rare, but it can be deadly complication. Affected vessels, including the splenic, hepatic, gastroduodenal, and pancreaticoduodenal arteries, are in close proximity to the pancreas. Surgery for bleeding pseudoaneurysms is challenging and associated with high morbidity and mortality.

Physical Examination

In most instances, the standard physical examination does not help to establish a diagnosis of chronic pancreatitis; however, a few points are noteworthy.

During an attack, patients may assume a characteristic position in an attempt to relieve their abdominal pain (eg, lying on the left side, flexing the spine and drawing the knees up toward the chest).

Occasionally, a tender fullness or mass may be palpated in the epigastrium, suggesting the presence of a pseudocyst or an inflammatory mass in the abdomen. Patients with advanced disease (ie, patients with steatorrhea) exhibit decreased subcutaneous fat, temporal wasting, sunken supraclavicular fossa, and other physical signs of malnutrition.

Diagnostic Considerations

Some patients with cystic neoplasms have undergone cyst-enteric anastomoses, only to develop malignancy later. Consider a cystic neoplasm in any patient without a clinical history of pancreatitis, even if no septa, solid component, or rim calcification is present on the imaging study.

While aspiration of the cyst fluid and measurement of its viscosity, carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9, and other factors are helpful in differentiating the various types of cysts, surgical resection of the cyst is the standard of care in a good surgical candidate.

Groove pancreatitis is a unique form of segmental pancreatitis in which the inflammatory process is confined to the groove between the duodenum, common bile duct, and head of the pancreas, without necessarily involving the entire head of the pancreas.

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

Pancreatic function tests (Table 2) can be divided into the following:

1. Direct stimulation of the pancreas by intravenous infusion of secretin or secretin plus cholecystokinin (CCK) followed by collection and measurement of duodenal contents

2. Indirect stimulation of the pancreas using nutrients or amino acids, fatty acids, and synthetic peptides followed by assays of proteolytic, lipolytic, and amylolytic enzymes

3. Study of intraluminal digestion products, such as undigested meat fibers, stool fat, and fecal nitrogen

4. Measurement of fecal pancreatic enzymes such as elastase

The secretin test, used to detect diffuse pancreatic disease, is based on the physiologic principle that the pancreatic secretory response is directly related to the functional mass of pancreatic tissue. In the standard assay, secretin is given intravenously in a dose of 1 clinical unit (CU) per kilogram, as either a bolus or a continuous infusion. The results will vary with the secretin preparation used, the dose, the mode of administration, and the completeness with which the duodenal contents are collected. Normal values for the standard secretin test are (1) volume output >2.0 mL/kg per hour, (2) bicarbonate (HCO3-) concentration >80 meql/L, and (3) HCO3- output >10 meq/L in 1 h. The most reproducible measurement, giving the highest level of discrimination between normal subjects and patients with chronic pancreatitis, appears to be the maximal bicarbonate concentration.

The combined secretin-CCK test permits measurement of pancreatic amylase, lipase, trypsin, and chymotrypsin. Although there is overlap in the distributions of enzyme output in normal subjects and patients with pancreatitis in response to this test, markedly low enzyme outputs suggest advanced damage and destruction of acinar cells. With frank exocrine pancreatic insufficiency, there is usually an overall reduction in both HCO3- concentration and output of several enzymes. However, with lesser degrees of pancreatic damage there may be a dissociation between HCO3- concentration and enzyme output. There also may be a dissociation between the results of the secretin test and those of tests of absorptive function. For example, patients with chronic pancreatitis often have abnormally low outputs of HCO3- after secretin but have normal fecal fat excretion. Thus the secretin test measures the secretory capacity of ductular epithelium, while fecal fat excretion indirectly reflects intraluminal lipolytic activity. Steatorrhea does not occur until intraluminal levels of lipase are markedly reduced, underscoring the fact that only small amounts of enzymes are necessary for intraluminal digestive activities. An abnormal secretin test result suggests only that chronic pancreatic damage is present; it will not consistently distinguish between chronic pancreatitis and pancreatic carcinoma.

Another test of exocrine pancreatic function is the bentiromide test. This test is an indirect measure of pancreatic function and reflects intraluminal chymotrypsin activity. The test has excellent specificity but is not very sensitive. It no longer is available for clinical use in the United States.

The serum trypsinogen level, which is determined by radioimmunoassay, also has excellent specificity but is not very sensitive. It is a simple blood test that can detect severe damage to the exocrine pancreas. The normal values are 28 to 58 ng/mL, and any value below 20 ng/mL reflects pancreatic steatorrhea.

The amount of elastase in stool reflects the pancreatic output of this proteolytic enzyme. Decreased elastase activity in stool has been reported in patients with chronic pancreatitis and cystic fibrosis.

Table 2 Tests of exocrine pancreatic function

VIDEO 4 (Normal pancreatic secretion, digestion and absorption of food)

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.

Imaging

Various imaging modalities are used, often in combination. Plain abdominal X-ray reveals pancreatic calcification or stones in up to two-thirds of patients. It may be necessary to perform a lateral Xray as vertebrae may obscure the view (Fig. 1).

Fig. 1 Plain X-ray of abdomen showing calcific pancreatitis.

Transabdominal ultrasound has the drawback that overlying bowel may obscure the view obtained, but it is moderately sensitive at detecting abnormalities of texture of the pancreas, variations in ductal calibre and pseudocysts.

УЗИ - поджелудочная железа, норма .

Fig.2a

Fig. 2 B.

Fig. 2 Ultrasound investigation. A. Normal pancreas. B. Chronic pancreatitis: а) calcificates in the head of pancreas; б) Virsungov’s duct; в) pseudocyst of pancreas; г) increase of the head of pancreas; д) spleen vein;

VIDEO 5 (Ultrasonography. Chronic pancreatitis)

Fig. 3 Ultrasound investigation. chronic calcified pancreatitis а) virsungolithiasis б) dilated Virsungov’s duct.

Endoscopic ultrasound overcomes some of the visualisation problems and is probably more sensitive and specific. CT has a sensitivity of up to 90% and specificity of the same order. It will detect variation in ductal diameter, and ectatic side branches, changes in the parenchyma, calcification and complications of chronic pancreatitis such as pseudocyst formation (Fig. 4).

Fig. 4 CT scan with central pseudocyst.

Endoscopic retrograde cholangiopancreatography (ERCP) is probably the most sensitive imaging technique (Fig. 5-7) but still fails to correlate with functional tests in around 25% of cases.

Fig. 5 ERCP of chronic pancreatitis with distortion of the pancreatic duct.

Fig. 6 An endoscopic retrograde cholangiopancreatography image demonstrating massive pancreatic duct dilatation in a patient with bigduct chronic pancreatitis.

Fig. 7 An endoscopic retrograde cholangiopancreatography image demonstrating minimal pancreatic duct abnormalities in a patient with painful small-duct chronic pancreatitis.

An endoscopic ultrasound, which allows a highly detailed examination of the pancreatic parenchyma and pancreatic duct, routinely detects abnormalities in patients with chronic pancreatitis (high sensitivity), but the specificity and reproducibility of the test requires further study [see Figure 8].

Fig. 8 An endoscopic ultrasound image demonstrating a dilated pancreatic duct (markers) in a patient with advanced chronic pancreatitis.

Chronic pancreatitis usually is envisioned as an atrophic fibrotic gland with dilated ducts and calcifications. However, findings on conventional diagnostic studies may be normal in the early stages of chronic pancreatitis , as the inflammatory changes can be seen only by histologic examination

This endoscopic retrograde cholangiopancreatography (ERCP) shows advanced chronic pancreatitis. The pancreatogram has blunting of the lateral branches, dilation of the main pancreatic duct, and filling defects consistent with pancreatolithiasis. The cholangiogram also shows a stenosis of the distal bile duct and a dilated biliary tree.

By definition, chronic pancreatitis is a completely different process from acute pancreatitis .In acute pancreatitis, the patient presents with acute and severe abdominal pain, nausea, and vomiting. The pancreas is acutely inflamed (neutrophils and edema), and the serum levels of pancreatic enzymes (amylase and lipase) are elevated. Full recovery is observed in most patients with acute pancreatitis, whereas in chronic pancreatitis, the primary process is a chronic, irreversible inflammation (monocyte and lymphocyte) that leads to fibrosis with calcification.

Criteria for diagnosis of the complications of chronic pancreatitis.

The complications of chronic pancreatitis are protean. Cobalamin (vitamin B12) malabsorption occurs in 40% of patients with alcohol-induced chronic pancreatitis and in virtually all with cystic fibrosis. It is consistently corrected by the administration of pancreatic enzymes (containing proteases). It may be due to excessive binding of cobalamin by cobalamin-binding proteins other than intrinsic factor, which ordinarily are destroyed by pancreatic proteases and therefore do not compete with intrinsic factor for cobalamin binding. Although most patients show impaired glucose tolerance, diabetic ketoacidosis and coma are uncommon. Similarly, end-organ damage (retinopathy, neuropathy, nephropathy) is also uncommon, and the appearance of these complications should raise the question of concomitant genetic diabetes mellitus. A nondiabetic retinopathy, peripheral in location and secondary to vitamin A and/or zinc deficiency, is common in these patients. Effusions containing high concentrations of amylase may occur into the pleural, pericardial, or peritoneal space. Gastrointestinal bleeding may occur from peptic ulceration, gastritis, a pseudocyst eroding into the duodenum, or ruptured varices secondary to splenic vein thrombosis due to inflammation of the tail of the pancreas. Icterus may occur, caused either by edema of the head of the pancreas, which compresses the common bile duct, or by chronic cholestasis secondary to a chronic inflammatory reaction around the intrapancreatic portion of the common bile duct. The chronic obstruction may lead to cholangitis and ultimately to biliary cirrhosis. Subcutaneous fat necrosis may appear as tender red nodules on the lower extremities. Bone pain may be secondary to intramedullary fat necrosis. Inflammation of the large and small joints of the upper and lower extremities may occur. The incidence of pancreatic carcinoma is increased in patients with chronic pancreatitis who have been followed for 2 or more years. Twenty years after the diagnosis of chronic pancreatitis, the cumulative risk of pancreatic carcinoma is 4%. Perhaps the most common and troublesome complication is addiction to narcotics.

Chronic pancreatitis is characterized by patchy fibrous replacement of whole lobules or parts of lobules, focal fat necrosis in different stages, and chronic inflammation. Grossly, depending on the degree of injury, the gland may have a normal outline, lobular pattern, and color but be slightly firm, or it may be smaller than normal, bosselated, rock-hard, and display foci of fat necrosis, calcification, or fully developed calculi.

Differential Diagnoses

· Ampullary Carcinoma

· Cholangitis

· Cholecystitis

· Crohn Disease

· Gastritis, Chronic

· Intestinal Perforation

· Mesenteric Artery Ischemia

· Myocardial Infarction

· Pancreatic Cancer

· Peptic Ulcer Disease

· Pneumonia, Community-Acquired

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.

The goals of medical treatment are as follows:

Modify behaviors that may exacerbate the natural history of the disease
Enable the pancreas to heal itself
Determine the cause of abdominal pain and alleviate it
Detect pancreatic exocrine insufficiency and restore digestion and absorption to normal
Diagnose and treat endocrine insufficienc

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.

A number of factors may contribute to the pain in chronic pancreatitis, and the principal mechanisms of pain may change with the duration of disease. Sources of pain can include the following:

Acute disease with inflammation and pseudocyst formation may be superimposed on chronic disease
Obstruction of the pancreatic duct by strictures or stones may cause increased duct pressure and pain
Pancreatic ischemia, with decreased pancreatic oxygenation and a decreased tissue pH, caused by a compartment syndrome may cause pain that is relieved by duct decompression
Pancreatic and pancreatic nerves become enlarged, lose some of their cellular sheath, and are inflamed
Obstruction of the duodenum or biliary tract may worsen with acute episodes and improve with time

Diagnostic tests may be necessary to identify an anatomic explanation for the pain and to plan appropriate treatment. If no anatomic explanation for abdominal pain can be found, medical therapy can be attempted. This therapy includes pain control with analgesic agents and a trial of noncoated pancreatic enzymes.

The impetus for using exogenous pancreatic enzymes to reduce pain begins with the hypothesis that stimulation of the pancreas by food causes pain. Cholecystokinin (CCK) is one of the possible mediators of this response.

CCK releasing factor (CRF) typically is secreted into the duodenum. During the interdigestive period, proteolytic enzymes within pancreatic juice rapidly degrade CRF. After a meal, the proteolytic enzymes are occupied with digesting dietary proteins, and enough CRF escapes to bind to duodenocytes, which stimulates CCK release, in turn stimulating pancreatic secretion.

In severe chronic pancreatitis with exocrine insufficiency, CCK levels may be high because proteolytic enzymes are low. When pancreatic enzyme supplements are administered in high doses, degradation of CRF is restored and the stimulus for CCK release is reduced.

This hypothesis is supported by one report that a CCK-receptor antagonist reduces pain in patients with chronic pancreatitis. The digestive products of a meal and the CCK-releasing factor stimulate CCK release from the duodenal mucosa. CCK acts directly on pancreatic cells and indirectly through neural pathways to stimulate the pancreas. Through unknown mechanisms, such stimulation has been hypothesized to cause pain.

When exogenous pancreatic enzymes are taken with a meal, CCK-releasing factors are degraded and CCK release in response to a meal is reduced, as indicated by the smaller CCK. This decreases pancreatic stimulation and pain. Any benefit from this treatment is likely limited to nonalcoholic patients with early chronic pancreatitis and requires the use of uncoated preparations.

Clinical trials investigating the benefits of this approach have provided mixed results. While 4 trials using enteric-coated enzyme preparations demonstrated no effect, these studies may have been flawed if the coating failed to release the enzymes into the feedback-sensitive portion of the duodenum. Two studies using non–enteric-coated tablets have demonstrated a reduction in pain compared with placebo. Female patients and those with idiopathic chronic pancreatitis appear to respond best.

If conventional medical therapy is unsuccessful and the patient has severe, intractable pain, celiac ganglion blockade can be considered. This approach tries to alleviate pain by modifying afferent sensory nerves in the celiac plexus, using agents that anesthetize, reduce inflammation, or destroy nerve fibers.

In a study in which alcohol injections were administered, 12 of 23 patients obtained complete pain relief, and 6 of 23 patients obtained partial pain relief. However, the mean pain-free interval was only 2 months; the longest pain-free interval was only 4 months. Repeated blocks generally were not effective.

Because of the risks of paralysis resulting from a transverse myelopathy and catastrophic hemorrhage resulting from injury to major abdominal vasculature, the use of alcohol blocks should be restricted to patients with intractable, severe pain due to terminal pancreatic cancer.

Percutaneous or endoscopic celiac nerve blocks with either alcohol or steroids have had only limited success in chronic pancreatitis and should be considered an unproven therapy.

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.

Although reduced fat intake is often recommended in patients with chronic pancreatitis, the clinical benefit is unknown. Indeed, the efficiency of fat absorption in dogs increases with increased fat intake. Whether humans have a similar response is unknown.

Medium chain triglycerides are directly absorbed by the small intestine without a requirement for digestion by lipase or micellar solubilization. To supply lipids and calories, medium-chain triglycerides can be used in patients with severe fat malabsorption. There is occasionally sufficient loss of fat-soluble vitamins to cause disease.

Enteric-coated preparations protect lipase from inactivation by gastric acid. Uncoated preparations are often less costly and adequate to relieve steatorrhea. Reducing gastric acid secretion may enhance the effectiveness of uncoated preparations. Enzyme preparations with high lipase content are available and recombinant lipase preparations will probably soon be marketed. Some of the recombinant enzymes are resistant to acidic denaturation. To provide adequate mixing with food, enzymes should be ingested during and just after a meal.

The most serious adverse effects (ie, colonic strictures) were observed with coated preparations that contained high concentrations of enzymes. In recent years, this adverse effect has not been seen; this is probably due to a reformulation of enzyme preparations.

Cobalamin or vitamin B-12 is absorbed complexed to intrinsic factor in the terminal ileum. Some vitamin B-12 absorption that is independent of intrinsic factor occurs throughout the small bowel. When vitamin B-12 enters the stomach, it binds to a protein known as haptocorrin or R-protein. The haptocorrin is proteolytically degraded in the small intestine by pancreatic enzymes and released vitamin B-12 then binds to intrinsic factor. In patients with pancreatic insufficiency, vitamin B-12 can remain bound to haptocorrin and is not available for absorption by the terminal ileum. Although vitamin B-12 malabsorption can be demonstrated in patients with chronic pancreatitis, it rarely causes clinical vitamin B-12 deficiency.

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.

Depending on the individual case, the appropriate intervention may involve endoscopic, radiologic, or surgical techniques.

Prior to percutaneous drainage, performing pancreatography is important in order to understand the anatomy of the pancreatic ductal system and plan appropriate treatment. If a communication exists between the pancreatic ductal system and the pseudocyst, percutaneous drainage may create a persistent pancreaticocutaneous fistula, especially if the duct has a stricture downstream from the site of the disruption.

If the anatomy of the pseudocyst does not lend itself to transpapillary, transgastric, or transduodenal endoscopic drainage, then percutaneous drainage under ultrasonographic or CT scan guidance is an option. Transgastric pseudocyst drainage has been used to treat pancreatic pseudocysts successfully, but a high failure rate has been reported.

Successful treatment of alcoholism and tobacco addiction requires a team approach, including the involvement and expertise of a chemical dependency counselor and a psychologist trained in cognitive therapy.

In patients with uncontrolled abdominal pain, early referral to a pain management specialist may allow better pain control.

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 in normal 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 of chronic pancreatitis 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. 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 is available only 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 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.

Radiography and CT Scanning

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.

CT scanning

The advantage of CT scanning is that interpretation of pancreatic CT images is relatively intuitive. However, although CT scanning 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.

CT scan studies are indicated to look for complications of the disease and are useful in planning surgical or endoscopic intervention. The sensitivity and specificity of CT scanning are 80% and 85%, respectively. (See the images below.)

Chronic pancreatitis. CT scans of the abdomen following an endoscopic transgastric pseudocystogastrostomy. Note that 2 stents are placed through the stomach and into the pseudocyst. Before undertaking this type of endoscopic intervention, the endoscopist must be confident that a cystadenoma has not been mistaken for a pseudocyst

Chronic pancreatitis. This patient developed abdominal pain several weeks after being accidentally hit with a baseball bat. A CT scan showed a large splenic hematoma, and the patient underwent a splenectomy. His postoperative course was notable for recurrent pain, abdominal distension, and elevation of amylase levels over the course of 2-3 months. This repeat CT scan shows postsurgical changes in the left upper quadrant and a large fluid collection.

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. One limitation of ERCP, however, 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 and expensive, requires complete opacification of the pancreatic duct to visualize side branches, and carries a risk (operator-dependent) of pancreatitis.

Magnetic Resonance Cholangiopancreatography

MRCP, demonstrated in the image below, provides information on the pancreatic parenchyma and adjacent abdominal viscera, and MRCP uses heavily T2-weighted images to visualize the biliary and pancreatic ductal system. The use of secretin during the study enhances the quality of the pancreatogram. Accuracy is improving, and MRCP is relatively safe, reasonably accurate, noninvasive, fast, and very useful in planning surgical or endoscopic intervention.

Chronic pancreatitis. This magnetic resonance cholangiopancreatography (MRCP) shows a healthy biliary system. The pancreatic ductal system is not well visualized. A subsequent endoscopic retrograde cholangiopancreatography (ERCP [not pictured]) showed pancreas divisum, with no evidence of a communication with the pseudocyst. The endoscopic features were ideal for an endoscopic transgastric pseudocystogastrostomy.

Endoscopic Ultrasonography

Although studies suggest that endoscopic ultrasonography (EUS) may be the best test for imaging the pancreas, it requires a highly skilled gastroenterologist.^[7]

Eleven sonographic criteria have been developed that identify characteristic findings of chronic pancreatitis. The most predictive endosonographic feature is the presence of stones. Other suggestive features include the following:

· Visible side branches

· Cysts

· Lobularity

· An irregular main pancreatic duct

· Hyperechoic foci and strands

· Dilation of the main pancreatic duct

· Hyperechoic margins of the main pancreatic duct

Before 2001, 3 or more of these criteria on EUS were used to diagnose chronic pancreatitis. However, subsequent data has suggested the use of 5 or more criteria to have higher specificity, rather than sensitivity, to diagnose chronic pancreatitis. In general, the presence of 5 or more of these features is considered highly suggestive of chronic pancreatitis.

EUS may be as sensitive and specific as tube tests for mild and advanced disease, especially when combined with fine needle aspiration or Tru-Cut biopsy.

Histologic Findings

In the early stages of chronic pancreatitis, the parenchyma exhibits an increase in connective tissue around the ducts and between the lobules. The degree of inflammation is minimal to moderate, consisting mostly of T lymphocytes, and a patchy, focal process unevenly affects the pancreas. With increasing severity, the connective tissue progresses between the acini, which gradually become distorted and tend to disappear. In advanced disease, fibrous tissue replaces the acinar tissue, and the pancreas becomes contracted, small, and hard. The islets of Langerhans are relatively spared until very late in the disease process.

Patients can have severe histopathologic changes of chronic pancreatitis despite normal findings on imaging studies. In patients undergoing resection of the pancreas for chronic pancreatitis, focal necrosis is found in 11.9% of cases and segmental fibrosis is observed in approximately 40% of cases.

In chronic calcific pancreatitis, plugs of precipitated protein develop within the ductal system. While they may be observed in all types of chronic pancreatitis, in alcoholic and tropical forms these plugs tend to evolve into calculi by deposition of calcium within them. The calcified pancreatic calculi are distributed irregularly, affecting ducts of various sizes, and may be associated with ulcerations of the ductal epithelium. Periductal connective tissue may encroach on the lumen and cause ductal stenoses, creating the "chain of lakes" pancreatogram appearance observed in advanced chronic calcific pancreatitis.

Approach Considerations

The goals of medical treatment are as follows:

· Modify behaviors that may exacerbate the natural history of the disease

· Enable the pancreas to heal itself

· Determine the cause of abdominal pain and alleviate it

· Detect pancreatic exocrine insufficiency and restore digestion and absorption to normal

· Diagnose and treat endocrine insufficiency

The benefit of antioxidants in the early stages of chronic pancreatitis is still controversial. Most patients can be managed medically. Even in patients with asymptomatic pseudocysts, relatively few develop serious complications (eg, bleeding, infection) requiring urgent surgery, and half never will require surgical intervention.

Surgical care

Intervention is indicated when an anatomical complication that is correctable by a mechanical intervention exists. Generally, this is an acquired abnormality, such as one of the following:

· Pancreatic pseudocyst

· Abscess

· Fistula

· Ascites

· Fixed obstruction of the intrapancreatic portion of the distal common bile duct

· Stenosis of the duodenum with gastric outlet obstruction

· Variceal hemorrhage due to splenic vein thrombosis

Depending on the individual case, the appropriate intervention may involve endoscopic, radiologic, or surgical techniques.

Radiologic evaluation and drainage

Consultations

In patients with uncontrolled abdominal pain, early referral to a pain management specialist may allow better pain control.

Behavior Modification

Cessation of alcohol consumption and tobacco smoking are important. In early stage alcohol-induced chronic pancreatitis, lasting pain relief can occur after abstinence from alcohol, but in advanced stages, abstinence does not always lead to symptomatic improvement. Patients continuing to abuse alcohol develop either marked physical impairment or have a death rate 3 times higher than do patients who abstain.

Recommending abstinence from alcohol usually is not sufficient; the physician must use available resources for evaluation and treatment of alcohol and chemical dependency. Successful treatment requires a team approach, including the involvement and expertise of a chemical dependency counselor and a psychologist trained in cognitive therapy.

Tobacco smoking is a strong and independent risk factor for chronic alcoholic pancreatitis. Because much of the reported excess morbidity and mortality in these patients is related to smoking tobacco, patients also need to overcome their tobacco addiction.

Pharmacologic Alleviation of Abdominal Pain

A number of factors may contribute to the pain in chronic pancreatitis, and the principal mechanisms of pain may change with the duration of disease. Sources of pain can include the following:

· Acute disease with inflammation and pseudocyst formation may be superimposed on chronic disease

· Obstruction of the pancreatic duct by strictures or stones may cause increased duct pressure and pain

· Pancreatic ischemia, with decreased pancreatic oxygenation and a decreased tissue pH, caused by a compartment syndrome may cause pain that is relieved by duct decompression

· Pancreatic and pancreatic nerves become enlarged, lose some of their cellular sheath, and are inflamed

· Obstruction of the duodenum or biliary tract may worsen with acute episodes and improve with time

Exogenous pancreatic enzymes and CCK

The impetus for using exogenous pancreatic enzymes to reduce pain begins with the hypothesis that stimulation of the pancreas by food causes pain. Cholecystokinin (CCK) is one of the possible mediators of this response.

Celiac ganglion blockade

If conventional medical therapy is unsuccessful and the patient has severe, intractable pain, celiac ganglion blockade can be considered.^[8]This approach tries to alleviate pain by modifying afferent sensory nerves in the celiac plexus, using agents that anesthetize, reduce inflammation, or destroy nerve fibers.

Percutaneous or endoscopic celiac nerve blocks with either alcohol or steroids have had only limited success in chronic pancreatitis and should be considered an unproven therapy.

Pharmacologic Restoration of Digestion and Absorption

Endoscopic Treatment

Endoscopic therapy aimed at decompressing an obstructed pancreatic duct can be associated with pain relief in some patients (see the images below). The rationale for this approach is based on the hypothesis that ductal hypertension due to strictures of the main pancreatic duct leads to pain.^{[9, 10]}

Chronic pancreatitis. A nasopancreatic tube courses through the esophagus, stomach, and duodenum and into the pancreatic duct. Externally, the end of the tube is attached to a suction bulb to decompress the ductal system and monitor its function on a daily basis. In contrast to patients treated with transpapillary stents, none of these patients ever has failed to return for a follow-up appointment. In addition, while stent obstruction and subsequent infection can occur with transpapillary stents, the author has not observed this complication while using nasopancreatic tubes.

Chronic pancreatitis. Nine days after placement of a nasopancreatic tube, a pancreatogram obtained via the tube showed that the disruption had healed (see the above image). The tube then was removed.

Chronic pancreatitis. This follow-up CT scan (see the above 2 images) shows a percutaneous tube in the left upper quadrant that was used to drain a fluid collection. It was removed after 4 weeks. The patient returned to work, regained his weight, and had no recurrence of abdominal pain or signs of a recurrent pancreatic leak.

At best, endoscopic treatment can offer pain relief in up to 60% of well-selected patients after 5 years of follow-up care. The one report with long-term follow-up included 1018 patients treated at 8 different centers who were followed for an average of 5 years. Obstruction of the pancreatic duct was due to strictures (47%), stones (18%), or strictures plus stones (32%). Patients were treated using various endoscopic techniques.

At the end of follow-up, 60% had completed endoscopic therapy, while 16% were still undergoing some form of endoscopic therapy and 24% had undergone surgery. Pain relief (based upon a structured questionnaire) was achieved in 65% of patients on intention-to-treat analysis. Pancreatic function did not improve. The techniques involved can be technically challenging, and complications have been described. Currently, it should be performed only in centers with expertise in this area on carefully selected patients.

Endoscopic therapy may be beneficial in chronic pancreatitis with any of the following:

· Papillary stenosis

· Pancreatic duct strictures

· Pancreatic duct stones

· Pancreatic pseudocysts

Papillary stenosis

In a subset of patients with chronic pancreatitis, the papillary sphincter pressure and pancreatic ductal pressure are increased. In appropriately selected patients, a pancreatic duct sphincterotomy will facilitate drainage and reduce ductal pressures and may help to alleviate pain.

Pancreatic duct strictures

Suitable candidates for endoscopic therapy are patients with a dominant distal pancreatic stricture and upstream ductal dilatation. The procedure involves placing a guidewire through the stricture into the proximal duct, performing a pancreatic sphincterotomy, dilating the stricture, and placing a stent. While technical success is achieved in more than 90% of patients, nearly 20% will have a complication and less than two thirds of patients will benefit clinically. Pain relief correlates with a reduction in the diameter of the duct by more than 2mm. Patients with recurrent pancreatitis are more likely to benefit than are those with chronic daily pain.

The stricture rarely disappears, and the stent invariably clogs; therefore, repeated procedures are required to exchange it. Prolonged or inappropriate stenting can injure the pancreatic duct.

Pancreatic duct stones

While pancreatic duct stones are sequelae of chronic pancreatitis, they also may be responsible for recurrent acute pancreatitis or exacerbations of chronic pain related to ductal obstruction and increased ductal pressure. Stones usually form proximal to ductal strictures and usually require a pancreatic duct sphincterotomy and stricture dilation to enable their extraction. In addition to various endoscopic techniques, extracorporeal shockwave lithotripsy often is necessary to break up impacted or large stones into smaller pieces suitable for removal.

Technical success is achieved in approximately 60% of patients and complications occur in 20%. Approximately 70% of patients report improvement in their symptoms.

Pancreatic pseudocysts

Advances in interventional endoscopy now enable endoscopic treatment of many pseudocysts. In the appropriate clinical setting, obtain a pancreatogram to determine whether the pancreatic duct communicates with the pseudocyst. Ideally, communicating pseudocysts found in the head or body can be treated with transpapillary stents (see the images below), with a success rate of 83% and a complication rate of 12%.

This pancreatogram shows a pseudocyst communicating with the main pancreatic duct in a patient with chronic pancreatitis and recurrent abdominal pain. He was treated endoscopically with a transpapillary stent placed into the pancreatic duct.

Four weeks after placement of a transpapillary stent, a patient with a pseudocyst communicating with the main pancreatic duct (chronic pancreatitis with recurrent abdominal pain) had not had a recurrence of pain. The CT scan showed resolution of the cyst, and the follow-up pancreatogram showed marked improvement. Transpapillary stenting of the pancreatic duct should be reserved for patients with established chronic pancreatitis.

Noncommunicating pseudocysts that bulge into the foregut and have a mature wall less than 1 cm thick are treatable by endoscopic transduodenal or transgastric pseudocystostomy. The success rate is 85%, with a 17% complication rate. The transduodenal approach has fewer complications and recurrences than the transgastric approach. The long-term success rate of the initial procedure is reported at 62%.

Diet

A diet low in fat and high in protein and carbohydrates is recommended, especially in patients with steatorrhea. The degree of restriction depends on the severity of fat malabsorption; generally, an intake of 20 g/day or less is sufficient. Patients who continue to suffer from steatorrhea following fat restriction require medical therapy.

Clinically significant protein and fat deficiencies do not occur until over 90% of pancreatic function is lost. Steatorrhea usually occurs prior to protein deficiencies, since lipolytic activity decreases faster than proteolysis.

Specific recommendations include a daily diet of 2000-3000 calories, consisting of 1.5-2 g/kg of protein, 5-6 g/kg of carbohydrates, and 20-25% of total calories consumed as fat (about 50-75g) per day.

Malabsorption of the fat soluble vitamins (A, D, E, and K) and vitamin B-12 may also occur. Oral supplementation of these enzymes is recommended.

Inpatient Care

The need for hospitalization and further inpatient management of patients with an attack of chronic pancreatitis depends on the severity of the attack.

Patients with mild pancreatitis are kept on nothing by mouth and administered intravenous (IV) fluid hydration. Narcotic analgesics generally are required for pain control. Nutritional supplementation is recommended in patients with malnutrition or in patients who are not able to take oral medication after a long hospitalization.

A small percentage of patients with severe pancreatitis may become critically ill, especially early in the natural history of recurrent acute or chronic pancreatitis. Intensive care management is required, and the clinician must look for developing complications, such as shock, pulmonary failure, renal failure, gastrointestinal bleeding, and multiorgan system failure.

Medication Summary

No curative treatment for chronic pancreatitis exists. Medical therapy is determined primarily by symptoms. If no anatomic explanation for abdominal pain can be found, medical therapy can be attempted. This therapy includes pain control with analgesic agents and a trial of noncoated pancreatic enzymes.

The use of exogenous pancreatic enzymes to reduce pain is linked to the hypothesis that pancreatic stimulation by food causes pain. Cholecystokinin (CCK) is one of the possible mediators of this response.

Analgesics, Other

Class Summary

Initial therapy consists of acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). For severe, refractory pain, narcotic analgesics often are required, starting with the least potent agents and progressing to more potent formulations as necessary.

Acetaminophen (Acephen, Cefotan, Mapap, Tylenol, FeverAll, Aspirin Free Anacin)

Acetaminophen is the drug of choice for pain in patients with documented hypersensitivity to aspirin or NSAIDs, those with upper GI disease, and those who are taking oral anticoagulants.

Opioid Analgesics

Class Summary

These medications provide control of moderate to severe pain.

Hydrocodone and acetaminophen (Vicodin, Lorcet, Lortab, Norco, Zolvit)

This drug combination is indicated for moderate to severe pain.

Acetaminophen with codeine (Tylenol-3)

This drug combination is indicated for treatment of mild to moderate pain.

Tramadol (Ultram, Ryzolt)

Tramadol inhibits ascending pain pathways, altering the perception of and response to pain. It also inhibits the reuptake of norepinephrine and serotonin.

Nonsteroidal Anti-Inflammatory Drugs

Class Summary

NSAIDs have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

Naproxen (Naprosyn, Aleve, Naprelan, Anaprox)

Naproxen is indicated for relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Diclofenac (Voltaren, Cataflam, Cambia, Zipsor)

These NSAIDs inhibit prostaglandin synthesis by decreasing cyclooxygenase activity, decreasing formation of prostaglandin precursors.

Ketorolac

Ketorolac is an intravenously administered NSAID and a very powerful analgesic. It inhibits prostaglandin synthesis by decreasing activity of the enzyme cyclooxygenase, which results in decreased formation of prostaglandin precursors. In turn, this results in reduced inflammation.

Ibuprofen (Advil, Motrin, Caldolor)

Ibuprofen is usually the drug of choice for treatment of mild to moderate pain, if no contraindications exist. It inhibits inflammatory reactions and pain by decreasing the activity of the enzyme cyclo-oxygenase, resulting in inhibition of prostaglandin synthesis.

Celecoxib (Celebrex)

Celecoxib inhibits primarily cyclooxygenase-2 (COX-2). COX-2 is considered an inducible isoenzyme; it is induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, celecoxib does not inhibit the COX-1 isoenzyme; thus, GI toxicity may be decreased. The increased cost of celecoxib must be weighed against the benefit of avoidance of GI bleeds. Seek the lowest dose of celecoxib for each patient.

Hormones

Class Summary

Hormones can be used for the reduction of pancreatic exocrine secretion.

Octreotide (Sandostatin)

Octreotide has an 8 ̶ amino acid sequence containing the active portion of somatostatin. In a study, subcutaneous injection of octreotide 3 times daily at 200mcg provided pain relief in 66% of patients. Note that 35% of the control group also experienced pain relief.

Antidepressants, TCAs

Class Summary

In addition to alleviating coexistent depression, tricyclic antidepressants may ameliorate pain and potentiate the effects of opiates.

Amitriptyline hydrochloride

This agent is an analgesic for certain chronic and neuropathic pain.

Clomipramine (Anafranil)

Clomipramine is a dibenzazepine compound belonging to the family of TCAs. The drug inhibits the membrane pump mechanism responsible for the uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons.

Clomipramine affects serotonin uptake while it affects norepinephrine uptake when converted into its metabolite desmethylclomipramine. It is believed that these actions are responsible for its antidepressant activity.

Doxepin (Silenor)

Doxepin increases the concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. It inhibits histamine and acetylcholine activity and has proven useful in the treatment of various forms of depression associated with chronic pain.

Nortriptyline (Pamelor)

Nortriptyline has demonstrated effectiveness in the treatment of chronic pain.

Desipramine (Norpramin)

This is the original TCA used for depression. These agents have been suggested to act by inhibiting reuptake of noradrenaline at synapses in central descending pain-modulating pathways located in the brainstem and spinal cord.

Pancreatic Enzyme Supplements

Class Summary

These are used as dietary supplementation to aid digestion in patients with pancreatic enzyme deficiency. Several preparations are available. The aim is to provide at least 30,000 units of lipase. Because the cost of different preparations is variable, consider the unit price of the enzyme supplement based on the lipase content.

Uncoated pancrelipase is used to treat painful chronic pancreatitis based on the following rationale. Serum CCK levels are higher in patients with severe chronic pancreatitis, ductal or parenchymal hypertension is believed to cause pain, increased CCK levels stimulate pancreatic secretion (which increases ductal hypertension and exacerbates pain), and exogenous pancreatic enzyme supplements trigger a negative feedback inhibition.

Pancrelipase (Creon, Pancreaze, Ultresa, Viokace, Zenpep)

Pancrelipase assists in the digestion of protein, starch, and fat. Nonenteric-coated products are used for pain caused by pancreatitis (ie, Viokace) in combination with a proton pump inhibitor. The enteric-coated products may be used for restoration of digestion and absorption.

Video: pancreas ultrasound

MALABSORPTION is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract.

video

Malabsorption Syndrome: Small Intestinal Causes

Advanced Malabsorption Syndrome

Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety of anaemias.

Classification

Some prefer to classify malabsorption clinically into three basic categories:^[2]

(1) selective, as seen in lactose malabsorption.

(2) partial, as observed in a-Beta-lipoproteinaemia.

(3) total as in coeliac disease.

Pathophysiology

The main purpose of the gastrointestinal tract is to digest and absorb nutrients (fat, carbohydrate, protein, and fiber), micronutrients (vitamins and trace minerals), water, and electrolytes. Digestion involves both mechanical and enzymatic breakdown of food.Mechanical processes include chewing, gastric churning, and the to-and-fro mixing in the small intestine. Enzymatic hydrolysis is initiated by intraluminal processes requiring gastric, pancreatic, and biliary secretions. The final products of digestion are absorbed through the intestinal epithelial cells.

Malabsorption constitutes the pathological interference with the normal physiological sequence of digestion (intraluminal process), absorption (mucosal process) and transport (postmucosal events) of nutrients.

Intestinal malabsorption can be due to:

Mucosal damage (enteropathy)
Congenital or acquired reduction in absorptive surface
Defects of specific hydrolysis
Defects of ion transport
Pancreatic insufficiency
Impaired enterohepatic circulation

Causes

Due to infective agents

HIV related malabsorption
Traveller's diarrhoea
Parasites e.g. Giardia lamblia, fish tape worm (B₁₂ malabsorption); roundworm, hookworm (Ancylostoma duodenale and Necator americanus)
Tropical sprue
Whipple's disease
Intestinal tuberculosis

Due to structural defects

Blind loops
Inflammatory bowel diseases, as in Crohn's Disease
Fistulae, diverticulae and strictures
Infiltrative conditions such as amyloidosis, lymphoma, eosinophilic gastroenteritis
Radiation enteritis
Systemic sclerosis and collagen vascular diseases
Short bowel syndrome

Due to surgical structural changes

Due to mucosal abnormality

Coeliac disease
Cows' milk intolerance
Soya milk intolerance
Fructose malabsorption

Due to enzyme deficiencies

Lactase deficiency inducing lactose intolerance (constitutional, secondary or rarely congenital)
Sucrose intolerance
Intestinal disaccharidase deficiency
Intestinal enteropeptidase deficiency

Due to digestive failure

Pancreatic insufficiencies:

Zollinger-Ellison syndrome
Bile acid/Bile salt malabsorption

Terminal ileal disease such as Crohn's disease
Obstructive jaundice
Bacterial overgrowth
Primary bile acid diarrhea

Due to other systemic diseases affecting GI tract

Coeliac disease
Hypothyroidism and hyperthyroidism
Addison's disease
Diabetes mellitus
Hyperparathyroidism and Hypoparathyroidism
Carcinoid syndrome
Malnutrition
Fiber Deficiency
Abeta-lipoproteinaemia

Clinical features

Small intestine : major site of absorption

They can occur in a variety of ways and features might give a clue to the underlying condition. Symptoms can be intestinal or extra-intestinal - the former predominates in severe malabsorption.

Diarrhoea, often steatorrhoea, is the most common feature. Watery, diurnal and nocturnal, bulky, frequent stools are the clinical hallmark of overt malabsorption. It is due to impaired water, carbohydrate and electrolyteabsorption or irritation from unabsorbed fatty acid. Latter also results in bloating, flatulence and abdominal discomfort. Cramping pain usually suggests obstructive intestinal segment e.g. in Crohn's disease, especially if it persists after defecation.^[3]
Weight loss can be significant despite increased oral intake of nutrients.^[6]
Growth retardation, failure to thrive, delayed puberty in children
Swelling or oedema from loss of protein
Anaemias, commonly from vitamin B₁₂, folic acid and iron deficiency presenting as fatigue and weakness.
Muscle cramp from decreased vitamin D, calcium absorption. Also lead to osteomalacia and osteoporosis
Bleeding tendencies from vitamin K and other coagulation factor deficiencies.

Diagnosis

There is no single, specific test for malabsorption. As for most medical conditions, investigation is guided by symptoms and signs. A range of different conditions can produce malabsorption and it is necessary to look for each of these specifically. Many tests have been advocated, and some, such as tests for pancreatic function are complex, vary between centers and have not been widely adopted. However, better tests have become available with greater ease of use, better sensitivity and specificity for the causative conditions. Tests are also needed to detect the systemic effects of deficiency of the malabsorbed nutrients (such as anaemia with vitamin B12 malabsorption).

Blood tests

Routine blood tests may reveal anaemia, high CRP or low albumin; which shows a high correlation for the presence of an organic disease.^[7]^[8] In this setting, microcytic anaemia usually implies iron deficiency andmacrocytosis can be caused by impaired folic acid or B12 absorption or both. Low cholesterol or triglyceride may give a clue toward fat malabsorption.^[9] Low calcium and phosphate may give a clue toward osteomalacia from low vitamin D.
Specific vitamins like vitamin D or micro nutrient like zinc levels can be checked. Fat soluble vitamins (A, D, E & K) are affected in fat malabsorption. Prolonged prothrombin time can be caused by vitamin K deficiency.
Serological studies. Specific tests are carried out to determine the underlying cause.

IgA Anti-transglutaminase antibodies or IgA Anti-endomysial antibodies for Coeliac disease (gluten sensitive enteropathy).

Stool studies

Microscopy is particularly useful in diarrhoea, may show protozoa like Giardia, ova, cyst and other infective agents.
Fecal fat study to diagnose steatorrhoea is rarely performed nowadays.
Low fecal pancreatic elastase is indicative of pancreatic insufficiency. Chymotrypsin and pancreolauryl can be assessed as well^[9]

Radiological studies

Barium follow through is useful in delineating small intestinal anatomy. Barium enema may be undertaken to see colonic or ileal lesions.
CT abdomen is useful in ruling out structural abnormality, done in pancreatic protocol when visualising pancreas.
Magnetic resonance cholangiopancreatography (MRCP) to complement or as an alternative to ERCP.

Interventional studies

Biopsy of small bowel showing coeliac disease manifested by blunting of villi, crypthyperplasia, and lymphocyte infiltration of crypts.

OGD to detect duodenal pathology and obtain D2 biopsy (for coeliac disease, tropical sprue, Whipple's disease, abetalipoproteinaemia etc.)
Enteroscopy for enteropathy and jejunal aspirate and culture for bacterial overgrowth
Capsule Endoscopy is able to visualise the whole small intestine and is occasionally useful.
Colonoscopy is necessary in colonic and ileal disease.
ERCP will show pancreatic and biliary structural abnormalities.

Other investigations

⁷⁵SeHCAT test to diagnose bile acid malabsorption in ileal disease or primary bile acid diarrhea.
Glucose hydrogen breath test for bacterial overgrowth
Lactose hydrogen breath test for lactose intolerance
Sugar probes or ⁵¹Cr-EDTA to determine intestinal permeability.^[3]

Obsolete tests no longer used clinically

D-xylose absorption test for mucosal disease or bacterial overgrowth. Normal in pancreatic insufficiency.
Bile salt breath test (¹⁴C-glycocholate) to determine bile salt malabsorption.
Schilling test to establish cause of B₁₂ deficiency.

Management

Treatment is directed largely towards management of underlying cause:

Replacement of nutrients, electrolytes and fluid may be necessary. In severe deficiency, hospital admission may be required for nutritional support and detailed advice from dietitians. Use of enteral nutrition by naso-gastric or other feeding tubes may be able to provide sufficient nutritional supplementation. Tube placement may also be done by percutaneous endoscopic gastrostomy, or surgical jejunostomy. In patients whose intestinal absorptive surface is severely limited from disease or surgery, long term total parenteral nutrition may be needed.
Pancreatic enzymes are supplemented orally in pancreatic insufficiency.
Dietary modification is important in some conditions:

Gluten-free diet in coeliac disease.
Lactose avoidance in lactose intolerance.

Antibiotic therapy to treat Small Bowel Bacterial overgrowth.
Cholestyramine or other bile acid sequestrants will help reducing diarrhoea in bile acid malabsorption.

CELIAC DISEASE

A n estimated one of every 100 to 200 people in the United States has celiac disease (also known as gluten-sensitive enteropathy, nontropical sprue, or celiac sprue), an autoimmune inflammatory enteropathy that is triggered by the ingestion of gluten-containing grains in susceptible individuals. Gluten is the main storage protein of wheat. The alcohol-soluble fraction (prolamin) of gluten is damaging in celiac disease, as are similar proteins in barley (hordein) and rye (secalin).

The major site of damage in celiac disease is the proximal small intestine (FIGURE 1). This damage can cause a wide variety of consequences, including maldigestion and malabsorption of nutrients, vitamins, and minerals in the digestive tract. Over time, numerous organ systems--including the skin, liver, nervous system, bones, reproductive system, and endocrine system--can be negatively affected by celiac disease. Treatment of celiac disease consists of the removal of gluten proteins from the diet, which improves and often eliminates the small-intestine pathology.

Celiac disease was first described by Samuel Gee in 1888, although a similar description of a chronic malabsorptive disorder by Aretaeus of Cappadocia (now Turkey) dates back to the second century ad. Gee described the classic features of celiac disease as diarrhea, lassitude, and failure to thrive; he believed that the regulation of food was the main part of the treatment and noted that the disease was not age-specific. Since this time, much has been learned about the diagnosis and treatment of celiac disease. This article examines the pathogenesis, epidemiology, clinical presentation, diagnosis, and treatment of celiac disease and discusses how pharmacists can provide pharmaceutical care to patients with this disorder.

Pathogenesis
Two primary factors are thought to contribute to the development of celiac disease: consumption of gluten proteins and genetic predisposition. It is not completely understood how gluten sensitivity begins or whether early exposure to gluten proteins increases the risk of sensitivity. Most experts agree that celiac disease results from an "unchecked" immune reaction to gluten and that this reaction results in inflammation of the proximal small intestine, where the partially digested gluten proteins make contact with the gut's immune system. This immune response extends beyond just a direct reaction to the exogenous substance, also involving a potent, multifaceted immune response to the exogenous substance that results in substantial damage to the structure and function of the gut and other organs.⁷

Genetics also appears to play a role in the development of celiac disease. Almost all patients with celiac disease exhibit human leukocyte antigen (HLA)-DQ2 or HLA-DQ8, which facilitate the immune response against gluten proteins; some 40% of the general population also carries these HLA haplotypes, however. The presence of these haplotypes is necessary for the development of celiac disease, and their absence virtually excludes the diagnosis. HLA-DQ2 is expressed in more than 90% of patients with celiac disease, and HLA-DQ8 is found in most of the remainder.

Environmental factors may also affect the risk or the timing of developing celiac disease. The risk of celiac disease appears to increase when large amounts of gluten are incorporated into the diet during the first year of life. In contrast, breast-feeding imparts a consistent protective effect; the risk of celiac disease decreases when a child is still being breast-fed at the time dietary gluten is introduced.¹⁰ Interestingly, a recent study found that, in children prone to developing celiac disease as result of HLA-DR3 or -DR4 alleles, initial exposure to wheat, barley, and rye in the first three months or from the seventh month onward significantly increased the risk of developing celiac disease–associated autoantibodies compared with exposure at four to six months.
Epidemiology

Celiac disease previously was thought to be extremely rare in the U.S. Two epidemiologic studies published prior to 2000 estimated that between one and 4,800 and one in 10,000 people in the U.S. were affected by celiac disease. Population studies published in recent years, however, suggest a much higher prevalence, particularly in individuals of European ancestry. One of the largest studies in the U.S. involved 13,145 participants (4,508 first-degree relatives of patients with celiac disease, 1,275 second-degree relatives, 3,236 symptomatic patients, and 4,126 not-at-risk subjects) who underwent screening. The prevalence of celiac disease was 1:22 in first-degree relatives, 1:39 in second-degree relatives, 1:56 in symptomatic patients, and 1:133 in not-at-risk subjects.
The likelihood of having celiac disease increases to 10% to 20% in persons who have a first-degree relative with the disease, and up to 75% in monozygotic twins. In addition, patients who have type 1 diabetes mellitus, Down's syndrome, Turner's syndrome, or other disorders are at increased risk for developing celiac disease (TABLE 1).

Celiac disease also occurs in people not of European descent, although the prevalence is not as great. People from the Punjab and Gujarat regions of India who lived in England developed celiac disease 2.7 times as often as Europeans on a gluten-rich diet; in addition, a disorder termed summer diarrhea has long plagued people of the tropics, especially during the summer months, when wheat commonly replaces maize in the diet. Furthermore, a very high prevalence rate of 5% has been documented in the Saharawi population of northern Africa.⁴

Clinical Presentation

The clinical manifestations of celiac disease vary markedly by the age of the patient, the duration and extent of disease, and the presence of extraintestinal pathology (TABLE 2). Depending on the features at the time of presentation and taking into account the histologic and immunologic abnormalities at the time of diagnosis, celiac disease can be divided into the following three clinical forms: classic (typical), atypical, and silent (asymptomatic).

Classic Celiac Disease: This form typically presents in infancy (age 6 to 18 months) and manifests as failure to thrive, diarrhea, abdominal distention, muscle-wasting, developmental delay, and (occasionally) severe malnutrition. Symptoms typically begin weeks to months after the introduction of weaning foods containing prolamines, and soon there is a progressive decrease in weight gain, with a decline in the child's percentile for weight and weight for height. In many instances, failure to diagnose the disorder can lead to a true medical emergency. Beyond infancy, the symptoms of classic celiac disease tend to be less dramatic. Older children may present with constitutional short stature or dental enamel defects.²

Women constitute approximately 75% of newly diagnosed adult cases of classic celiac disease, and they typically have more clinically conspicuous disease. In adults of both sexes, gastrointestinal (GI)-tract involvement may manifest as diarrhea, constipation, or other symptoms of malabsorption, such as bloating, flatus, or belching. These symptoms may be accompanied by consequences of malabsorption, such as weight loss, severe anemia, neurologic disorders from deficiencies of B vitamins, and osteopenia (low bone mass) from vitamin D and calcium deficiency.

Atypical Celiac Disease: This type is characterized by few or no GI symptoms, and extraintestinal manifestations predominate. Recognition of the atypical features of celiac disease is responsible for much of the increased prevalence, and atypical disease now may be the most common presentation. The clinical features of atypical celiac disease (e.g., iron deficiency, osteoporosis, short stature, infertility) typically are milder than those associated with the classic form of the disease.

Silent Celiac Disease: This form is found during testing of asymptomatic patients (e.g., because of a family history of celiac disease or during an upper endoscopy performed for another reason). It is important to note that asymptomatic patients are still at risk for complications of celiac disease.

Diagnosis
No single test has been universally accepted as the standard for diagnosing celiac disease. However, serologic testing and small-bowel biopsy are highly sensitive and specific for making the diagnosis, especially in patients with symptoms suggestive of celiac disease and in those at increased risk (e.g., having a family history or an associated autoimmune disorder). Diagnostic testing must be performed while the patient is on a diet that includes gluten-containing foods.

As a general rule, testing for celiac disease should begin with serologic evaluation. Immunoglobulin A (IgA) antitissue transglutaminase and IgA endomysial antibody, which have equivalent diagnostic accuracy, are generally considered to be 85% to 100% sensitive and 96% to 100% specific for celiac disease. Antigliadin antibody tests are no longer used routinely because of their lower sensitivity and specificity. Importantly, serologic testing may not be as accurate in children under 5 years of age.

Patients who have a positive IgA endomysial or transglutaminase antibody test should undergo small-bowel biopsy; patients with biopsy-proven dermatitis herpetiformis in whom the diagnosis can be established without small-bowel biopsy are exceptions, however. Biopsy also should be considered in patients with negative serologic test results who are at high risk or in whom the clinician strongly suspects celiac disease.

A diagnosis of celiac disease is presumptively established when there is concordance between the serologic results and the biopsy findings. The diagnosis is confirmed when symptoms resolve subsequently on a gluten-free diet. A demonstration of histologic normalization is not required, however.

Early diagnosis of celiac disease is extremely important because it can minimize, if not prevent, serious complications. A patient's risk of developing other autoimmune diseases and intestinal lymphomas is proportional to the time of exposure to gluten.¹ For this reason, the National Institutes of Health's 2004 consensus statement on celiac disease recommends testing for the disorder in patients at high risk for developing it; patients experiencing GI symptoms (if not otherwise explained) such as chronic diarrhea, malabsorption, weight loss, and abdominal distention; and patients lacking another explanation for signs and symptoms (e.g., persistent elevation of serum aminotransferases, short stature, delayed puberty, iron-deficiency anemia, recurrent fetal loss, and infertility). Treatment
The cornerstone of treatment for celiac disease is strict lifelong adherence to a gluten-free diet. All foods and medications containing gluten (found in wheat, barley, rye, and their derivatives; TABLE 3) should be eliminated from the diet. One of the major controversies in the treatment of celiac disease relates to the amount of gluten allowed. The National Food Authority has redefined the term "gluten-free"; previously, less than 0.02% gluten in a product was considered gluten-free, but gluten-free now means no gluten at all, and less than 0.02% gluten is labeled "low-gluten."

Complete exclusion of dietary gluten generally results in symptomatic, serologic, and histologic remission in the majority of patients. Growth and development in children typically return to normal with adherence to the gluten-free diet, and many disease complications can be avoided in adults. Patients' overall nutritional status should be evaluated so that nutritional and caloric deficiencies can be adequately supplemented.

Understanding the Gluten-Free Diet: Gluten is the primary protein in wheat; therefore, wheat and products containing wheat must be avoided--as must barley and rye, which contain similar proteins. Oats are a subject of controversy; although oats themselves may not be harmful in limited quantities, commercial oat products are measurably contaminated with wheat. Generally speaking, soybean and tapioca flours, rice, corn, maize, buckwheat, potatoes, and other grain substitutes (such as nuts and beans) are gluten-free. Many commercial gluten-free products, including breads, cookies, chips, and cereals, can be found on store shelves. In addition, meats, vegetables, fruits, and most dairy products are free of gluten as long as they were not contaminated during production. Various resources are available for patients with celiac disease, including cookbooks, gluten-free prepared foods, Internet sites, and organizations. See TABLE 4 for some resources.

Correcting Nutritional Deficiencies: In patients presenting with the classic malabsorption of celiac disease, deficiency in fat-soluble vitamins (vitamins A, D, E, and K) is commonly encountered, and supplementation is required. Iron-deficiency anemia is a common manifestation of celiac disease and should be treated with supplemental iron. Osteoporosis should be treated with calcium and vitamin D replacement. Other nutritional deficiencies in celiac disease that frequently require correction involve magnesium, zinc, selenium, copper, and folate.

Since a gluten-free diet can be low in fiber, it may induce constipation. Constipation usually responds to the addition of dietary rice bran or ispaghula husks; psyllium fiber and methylcellulose supplements also are generally gluten-free.

The Pharmacist's Role

It is not surprising that many pharmacists are unsure about how to support patients with celiac disease, since the cornerstone of treatment does not involve pharmaceutical agents. Despite this, pharmacists can play a pivotal role in helping patients with this disorder improve their quality of life.

Pharmacists should encourage patients with celiac disease to seek the advice and guidance of licensed dieticians and explain that many dieticians specifically handle the needs of celiac patients and can instruct them about which foods to avoid, especially foods not inherently known to contain gluten (e.g., sauces, salad dressings, licorice). Trained dieticians also can teach patients key words to look for on food labels (e.g., barley malt extract).

Women make up a majority of newly diagnosed adult cases, so bone loss is of particular concern. Pharmacists should ensure that female patients, especially postmenopausal women, consume at least 1,500 mg of elemental calcium per day while being treated with a bisphosphonate agent. Bisphosphonates may not be needed if the underlying celiac disease is corrected.

Pharmacists should remind patients with celiac disease of the importance of certain vaccinations. Because celiac disease is associated with hyposplenism, prophylactic administration of the pneumococcal vaccine is reasonable. Pharmacists should also encourage patients with celiac disease to receive the influenza vaccine annually.

Pharmacists should be aware than many medications and vitamin and mineral supplements may contain gluten as inactive ingredients. Information about inactive ingredients is found in the package insert. Nebulous inactive ingredients that require further investigation include gums and starches. Vegetable gums commonly contain gluten. If the product lists the starch as "cornstarch" or "starch (corn)," it can be assumed to be gluten-free. Pregelatinized starch and sodium starch glycolate, which are derived from corn, wheat, potatoes, or rice, have been chemically treated and may or may not contain gluten. A call to the manufacturer is the only way to confirm the source of the starch. Likewise, if simply "starch" is listed, the only way to verify the source of the starch and the gluten status is to contact the manufacturer. Importantly, inactive ingredients may differ between brand and generic products; for this reason, it cannot be assumed that a generic product is gluten-free just because a brand product is gluten-free, or vice versa. Additionally, when a product is reformulated, its gluten status may change. If a product is "new and improved," is a new formulation, has a new appearance, or is being made by a new manufacturer, this is a signal that the gluten status of the product may have been altered.

Clearly, pharmacists are advocates who can take an active role in improving the lives of patients with celiac disease. The education that pharmacists can provide for these patients has the potential to have wide-reaching effects in raising awareness about this common disorder.

Conclusion
Adherence to a gluten-free diet remains the mainstay of therapy for celiac disease. Although a gluten-free diet seems simple theoretically, the diet can be difficult for some patients to adhere to. The most common reasons for lack of response are poor compliance and inadvertent gluten ingestion. All patients with celiac disease should be reevaluated periodically. The evaluation should include assessment of growth, assessment of GI and other symptoms associated with celiac disease, and the individual patient's understanding of and compliance with the gluten free-diet.

Celiac Disease Symphoms

Classic Celiac Symptoms

Currently there are four types of recognized forms of Celiac. Each of these forms is only basic and symptoms may vary. You may have symptoms from one or more of these types.

First a reminder, Celiac can manifest in a few ways for a sufferer, these are some of the symptoms of classical or typical celiac. This list was taken from patientsmedical.com

· Autoimmune diseases - This is a disorder which is caused when the body's immune system attacks the tissues causing inflammatory reactions.

· Digestive Diseases - The digestive diseases in a Celiac disease are esophageal achalasia, duodenal ulcer, fecal incontinence, dysentery and whipple disease.

· Chronic digestive diseases - This is a disorder which gives rise to continual digestive disorders. Like other disease like Chorn's disease, ulcers and diverticulitis, Celiac Disease is also cause due to continual digestive disorders.

· Inflammatory bowel disease - This is caused when the immune system of the body attacks the intestine. The digestive disorders are also caused by bowel inflammation.

· Under diagnosed condition - Some of the types under diagnosed conditions are diabetes, whooping cough, hypertension and many other diseases.

· Intestinal conditions - Some of the symptoms of intestinal conditions includes watery stools, frequent stools, diarrhea, anorexia and even blood in the stools.

The four basic type of Celiac (currently recognized) are:

Typical: This shows the above symptoms, this type of Celiac can be found in the blood work and is clear cut, it is easy to diagnose and is what one expect to see in a celiac sufferer.

Atypical or extraintestinal: This form does not always attack the intestinal tract. It also may not show up in blood work. This may show its self by joint pain, neurological disorders, Fertility issues, pregnancy loss, or blood issues. I will go into this type more in my next post.

Silent: The blood work may show celiac but no symptoms are present. These people have the damage and the blood results of a typical celiac without any of the outside symptoms.

Latent: In this form the genetic markers are present, but the disease is un-triggered. This will show up on genetic tests but not in any other form. Sufferers of this type of celiac are asymptomatic. However, they are able to be triggered by an outside force or a traumatic event. If you have celiac you should have your children tested for the genetic markers. If these makers are present it would be wise to keep them off of gluten. This way if or when the disease is triggered there will be little to no damage to the body.

GF Grocery Infographic

Principles of Rational nutrition.

Introduction to nutrition

Nutrition is defined as the processes by which an animal or plant takes in and utilises food substances.Essential nutrients include protein, carbohydrate, fat, vitamins, minerals and electrolytes. Normally, 85% ofdaily energy use is from fat and carbohydrates and 15% from protein. In humans, nutrition is mainly achieved through the process of putting foods into our mouths, chewing and swallowing it. The required amounts of the essential nutrients differ by age and the state of the body, for example: physical activity, diseases present (e.g.prostate cancer, breast cancer or weakened bones – known as osteoporosis), medications, pregnancy andlactation.

Why is nutrition important?

Nutrition is essential for growth and development, health and wellbeing. Eating a healthy diet contributes to preventing future illness and improving quality and length of life. Your nutritional status is the state of your health as determined by what you eat. There are several ways of assessing nutritional status, including anthropometric (i.e. physical body measurement), food intake and biochemical measurement.

Your body mass index (BMI) is a good indicator of your nutritional status. It takes into account your weight and height, and correlates well with total body fat expressed as a percentage of body weight. The correlation depends on age, with the highest correlation seen in ages 26–55 years and the lowest in the young and the elderly. If you take your weight in kilograms and divide it by your height in metres squared, the figure you obtain is your BMI.

BMI	=	___weight (kg)___
		height x height (m²)

High values indicate excessive fat stores and low values indicate insufficient fat stores. Your BMI can therefore be used as a diagnostic tool for both over-nutrition and under-nutrition. If your BMI is between 25.0 and 29.9 you are classisfied as overweight. If it is above 30.0, you are classified as obese. The healthy BMI range is 18.5–24.9. However, the BMI is best used together with waist circumference.

This information will be collected for educational purposes, however it will remain anonymous.

BMI calculations will overestimate the amount of body fat for:

Body builders;
Some high performance athletes;
Pregnant women.

BMI calculations will underestimate the amount of body fat for:

The elderly;
People with a physical disability who are unable to walk and may have muscle wasting.

BMI is not the best measure of weight and health risk. A person's waist circumference is a better predictor of health risk than BMI.

Body mass index

For more information, see Body Mass Index (BMI)

BMI and children

The healthy weight range for adults of a BMI of 20 to 25 is not a suitable measure for children.

For adults who have stopped growing, an increase in BMI is usually caused by an increase in body fat. But as children grow, their amount of body fat changes and so will their BMI. For example, BMI usually decreases during the preschool years and then increases into adulthood.

For this reason, a BMI calculation for a child or an adolescent must be compared against age and gender percentile charts. These charts should be used only by health professionals such as your general practitioner, child health nurse, or dietitian.

Body fat distribution and health risk

A person's waist circumference is a better predictor of health risk than BMI. Having fat around the abdomen or a 'pot belly', regardless of your body size, means you are more likely to develop certain obesity-related health conditions. Fat predominantly deposited around the hips and buttocks doesn't appear to have the same risk. Men, in particular, often deposit weight in the waist region.

Studies have shown that the distribution of body fat is associated with an increased prevalence of diabetes, hypertension, high cholesterol and cardiovascular disease.

Generally, the association between health risks and body fat distribution is as follows:

Least risk – slim (no pot belly);
Moderate risk – overweight with no pot belly;
Moderate to high risk – slim with pot belly;
High risk – overweight with pot belly.

Waist circumference and health risks

Waist circumference can be used to indicate health risk.

For men:

94 cm or more – increased risk;
102 cm or more – substantially increased risk.

For women:

80 cm or more – increased risk;
88 cm or more – substantially increased risk.

Being physically active, avoiding smoking and eating unsaturated fat instead of saturated fat have been shown to decrease the risk of developing abdominal obesity.

Waist circumference

For more information, see Waist Circumference (WC)

Associated health conditions

Dietary factors are associated with some leading causes of death, such as:

Coronary heart disease;
Some types of cancer;
Stroke;
Type 2 diabetes mellitus.

Essential nutrient requirements

Nutrients can be described as the chemical components of food and can be classified into six broad groups: carbohydrates, proteins, fats, vitamins, minerals and water. Water is not technically a nutrient, but it is essential for the utilisation of nutrients. Nutrients perform various functions in our bodies, including energy provision and maintaining vital processes such as digestion, breathing, growth and development.

Energy balance

Your energy requirement depends on your age, size and activity level. If your energy intake equals the amount of energy you expend, then you are in energy balance. If your intake exceeds your expenditure, the excess energy is converted to body fat and you gain weight. On the other hand, if your intake is less than your expenditure, your body uses up fat stores and you lose weight. Therefore, for weight to remain stable, the total amount ofcalories that are consumed must not exceed the total that is used up through metabolic processes (e.g. exercising, sweating, breathing). Energy intake must match energy output. The average energy intake is about 2800 kcal/day for men and 1800 kcal/day for women, although this varies with body size and activity level.

Carbohydrates

Carbohydrates can be classified as monosaccharide (e.g. glucose, fructose, galactose), disaccharide (e.g. sucrose, lactose, maltose) and polysaccharide (e.g. starch, fibre). Carbohydrates must be reduced to the simplest form of glucose (through digestion) before your body can make use of them. Carbohydrates should make up at least 55% of your total energy intake. The brain is a special part of the body that depends primarily on glucose for its energy and requires about 100 g/day of glucose for fuel. In some situations, the body can compensate for decreased levels of carbohydrates by using alternative energy pathways such as burning fatty acids.

Protein

Protein is important for the production, maintenance and repair of tissues in the body. When energy intake is insufficient, protein intake must be raised. This is because ingested proteins are preferentially directed towards glucose (sugar) synthesis and oxidation. The tissues and organs in the body are made up of protein and protein compounds. Enzymes (biological catalysts), antibodies and hormones also consist of protein. The building blocks of protein are called amino acids. The body can make all of the 20 amino acids except eight, which are termed essential amino acids. These are isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Histidine is essential only for infants. The number and nature of amino acids present in a particular protein determines that protein's characteristics.

For adults, the recommended dietary allowance of protein is about 0.75 g/kg body weight per day. Animal products tend to have the highest amount of proteins, followed by legumes (beans), cereals (rice, wheat, corn) and roots. Animal protein (from meat, eggs, fish, milk) contains all the essential amino acids and is normally referred to as 'complete' or 'high biological value' protein. Protein derived from plants lack one or two essential amino acids. However, a good combination of plant-based protein can be of equal value to animal protein. For example, legumes lack methionine but have adequate amounts of lysine. Cereals, on the other hand, lack lysine but have a lot of methionine. Therefore, a mixture of rice and beans will supply all the essential amino acids.

Excess protein cannot be stored in the body, so we need to consume protein daily. Consuming too much protein is not recommended because it promotes increased calcium excretion through urine, which increases the risk of developing osteoporosis. Additionally, too much protein intake may lead to a greater concentration of the amino acid homocysteine in the blood, and the subsequent conversion to thiolactone. Thiolactone is associated with increased levels of atherosclerosis and endothelial damage.

Fats and oils

Most of the fats we consume occur in foods as triglycerides. A triglyceride is comprised of three fatty acid molecules attached to a glycerol molecule. Fatty acids are made up of carbon and hydrogen atoms and can be either saturated or unsaturated. Saturated fatty acids (SFA) have the maximum number of hydrogen atoms attached to the carbon chain, while unsaturated fatty acids have less than the required hydrogen atoms. For example, monounsaturated fatty acids (e.g. oleic acid) have two hydrogen atoms missing. Monounsaturated fats are found mainly in nuts, avocados, olive oil, canola oil, grapeseed oil, peanut oil, flaxseed oil, sesame oil, corn oil, safflower oil, sunflower oil, etc.

Polyunsaturated fatty acids (PUFA) have more than two hydrogen atoms missing (e.g. linoleic acid and linolenic acid). Linoleic and linolenic acids are regarded as essential fatty acids (EFAs) because the body cannot make them. There are two categories of EFAs: omega-3 and omega-6. The number that comes after "omega-" represents the position of the first double bond, counting from the terminal methyl group on the molecule. Omega-3 fatty acids are derived from linolenic acid and omega-6 from linoleic acid. Alpha linolenic acid (ALA) is converted into eicosapentaenoic acid (EPA), and later into docosahexaenoic acid (DHA) in the body. Sources of omega-3 fats include salmon, mackerel, sardines, anchovies, tuna, flaxseed oil, walnuts, etc. Sources of omega-6 fats include palm oil, soybean oil, canola oil, sunflower oil, nuts, etc. Evidence from research indicates that omega-3 fatty acids reduce inflammation and help prevent certain chronic diseases such as heart disease and arthritis. Omega-3 fatty acids are highly concentrated in the brain and appear to be crucial to brain function as well as normal growth and development. Infants who do not get enough omega-3 fatty acids from their mothers during pregnancy are at risk of mental impairment.

Generally, saturated fatty acids raise blood cholesterol levels, whereas unsaturated fatty acids lower them. Saturated fats are found in foods such as butter, meat and dairy fats. Trans fats are artificially created during food processing. In the body, trans fats act in a similar way to saturated fats and may raise cholesterol levels. These fats are considered to be harmful to your health. Trans fats are found mainly in deep-fried fast foods and processed foods made with margarine.

Fats are a concentrated and rich source of energy. It is recommended that your total fat intake is no more than 30% of your energy (calorie/kilojoule) intake. Polyunsaturated fat should be less than 10% of energy, and saturated fat and trans fat together should be less than 10%. The rest of your fat intake should consist of monounsaturated fat.

Vitamins

Vitamins constitute a group of nutrients that are needed in small quantities. Like amino and fatty acids, most vitamins cannot be made in the body and must be obtained from dietary sources. Only vitamin D can be manufactured by the body. Essential vitamins are grouped into two families: water soluble and fat soluble. Water soluble vitamins can dissolve in water (thiamine, riboflavin, niacin, vitamin C, folic acid). These cannot be stored by the body and need to be consumed every day. Fat soluble vitamins can dissolve in a fat medium (vitamins A, D, E, K). These are taken into our bodies when we consume fat-containing foods. Vitamins are needed for various reasons, including the formation of hormones and blood cells. They generally act as coenzymes. An inadequate supply of vitamins in our diet leads to the development of diseases.

Vitamin A: Derived from carotene, vitamin A affects vision, reproduction, and the formation and maintenance of skin, mucous membranes, bones and teeth. Deficiency results in night blindness (difficulty in adapting to darkness). The body obtains vitamin A from either carotene (vitamin A precursor) or by absorbing ready-made vitamin A from plant-eating organisms. Carotene is found in dark green leafy vegetables and yellow-orange fruit/vegetables. Pre formed vitamin A is found in milk, butter, cheese, egg yolk, liver, and fish-liver oil.
Vitamin B complex: The vitamin B complex is a mixture of eight essential vitamins necessary to enhanceimmune and nervous system function, and promote cell growth and division. Pregnant or lactating women,alcoholics and the elderly are more likely to suffer from vitamin B deficiency.
Vitamin B1 (thiamine): Thiamine, or vitamin B1, acts as a catalyst in carbohydrate metabolism. Thiamine deficiency causes beriberi, a vitamin deficiency disorder characterised by muscular weakness, swelling of the heart and leg cramps. In severe cases, beriberi may lead to heart failure and death. The richest dietary sources of thiamine are pork, organ meats (liver, heart, and kidney), brewer's yeast, lean meats, eggs, leafy green vegetables, whole or enriched cereals, wheat germ, berries, nuts, and legumes.
Vitamin B2 (riboflavin): Riboflavin, or vitamin B2, acts as a coenzyme in the metabolism of carbohydrates, fats, and respiratory proteins. The best sources of riboflavin are liver, milk, meat, dark green vegetables, whole grain and enriched cereals, pasta, bread and mushrooms.
Vitamin B6 (pyroxidine): Pyridoxine, or vitamin B6, is necessary for the absorption and metabolism of amino acids. It also plays a role in the body's use of fats and in the formation of red blood cells. The best sources of pyridoxine are whole grains, cereals, bread, liver, avocados, spinach, green beans and bananas.
Folic acid (vitamin B9 or folacin): Folic acid is a coenzyme needed for forming body protein andhaemoglobin. Folic acid deficiency is associated with neural tube defects. Dietary sources are organ meats, leafy green vegetables, legumes, nuts, whole grains and brewer's yeast. Folic acid is lost in foods stored at room temperature and during cooking.

Minerals

Minerals are essential, acting as cofactors of enzymes (i.e. enzymes would not exist or function without minerals). Some of the minerals necessary for health are:

Calcium: Calcium is a very important mineral in the diet, especially for women at menopause. The major function of calcium is to build and help maintain strong bones. It can stop the onset of osteoporosis and reduce bone loss and fragility. It is involved in blood clotting. Calcium deficiency can develop when there is a lack of vitamin D.
Iron: Iron in food exists as haem and non-haem iron. Haem iron, found in red meat, is relatively well (20–30%) absorbed. Non-haem iron, found mostly in cereals, pulses, certain vegetables (e.g. spinach) and eggs, is generally less well absorbed. Non-haem iron absorption depends on other factors in the diet. For example, vitamin C and animal protein enhance non-haem iron absorption, while tea, coffee and phytates inhibit it.
Zinc: Zinc represents only 0.003% of the human body, but is essential for synthesising protein, DNA andRNA. It is required for growth in all stages of life. Sources include meats, oysters and other seafood, milk, and egg yolk.

Calcium Intake Calculator

How much calcium do you consume?

Calcium calculator

Calcium is found in many foods, in particular dairy products and to a lesser degree bony fish, nuts and legumes, fruit and vegetables. It plays an important role in building and maintaining healthy bones and teeth.

Individuals need to consume sufficient amounts of calcium throughout their lifespan. Calcium requirements increase throughout childhood, peak during puberty, then stabilise until an individual is approximately 50 years old, when bone mass deteriorates and more calcium is required.

Click here to calculate your required calcium intake

Water

For adults, 1–1.5 mL water per kcal of energy expenditure is usually sufficient to allow for normal changes in physical activity, sweating, and dietary solute load. Water losses consist of 50–100 mL/day through faeces (stools), 500–1000 mL/day by evaporation, and approximately 1000 mL/day through urine. If external losses increase, we must increase the amount of water we ingest. In special circumstances such as diarrhoea andvomiting, water requirements further increase.

Balanced diet

It is critical that nutrients in our body are available in sufficient amounts and in the right proportions. This can be achieved by eating a balanced diet. We must eat a variety of foods, since different foods contain different nutrients in varying amounts. In stressing the importance of variety in our diet, Nutrition Australia encourages all Australians to ensure that their daily diet includes 30 individual foods. This may appear impossible at first thought, but in reality can easily be attained by eating typical diets based on carefully selected foods. Food selection based on the 'Healthy Eating Pyramid' can assist you in planning your meals for a balanced and healthy diet.

A healthy diet consists mainly of plant foods (e.g. fruits and vegetables, potatoes, cereals, etc.) and moderate amounts of animal products (e.g. milk, fish, lean red meat and poultry). Fats and oils should normally provide less than 30% of our energy, and less than 10% of this should be saturated fat. Lean red meat, poultry and fish, eggs and dairy foods are rich sources of animal protein. Dairy foods, apart from supplying quality protein, are good sources of calcium. Good vegetable sources of protein include legumes (e.g. peanuts, lentils, kidney beans), soya products (e.g. tofu), grains, nuts and seeds.

Healthy eating pyramid

The food pyramid is a simple practical guide to selecting varied foods for meals. The Australian Nutrition Foundation Inc. (Nutrition Australia) has developed its own food pyramid. The rationale behind the food pyramid emphasises the need to include generous amounts of plant-based foods (cereals, legumes, fruits and vegetables) and moderate amounts of animal products (meat, fish, milk, eggs) in our diets. Furthermore, our diet should contain only small amounts of energy-dense foods (e.g. sugar, fats and oils). The base of the pyramid (plant-based foods) is broad, and the top (animal products) is narrow. Eating according to the structure of the food pyramid ensures we consume a healthy diet. With care the food pyramid can also assist vegetarians and vegans to consume a nutritionally balanced diet, although some people will require dietary supplements (e.g. vegans will require vitamin B12).

Food pyramid

Glycaemic index and glycaemic load

Carbohydrates should make up at least 55% of our total daily energy intake. The quality and quantity of these carbohydrates are important in blood sugar and appetite control. After you consume carbohydrate-containing foods, your pancreas secretes insulin to break the carbohydrates down into their building blocks. Insulin acts to lower blood glucose levels. When your blood glucose levels decrease to a particular level, your brain is sent a signal and you become hungry again.

Even though different foods may contain the same amounts of carbohydrate, their effects on blood glucose control may be very different. This has lead to the development of measures such as the glycaemic index (GI) and glycaemic load (GL) of a food product. The concept of GI was formulated by Jenkins and colleagues in 1984. They found that blood glucose response to carbohydrate foods is independent of the amount of carbohydrates they contain. The limitation of the GI lies in the difficulty of translating the concept into practice, since the glycaemic effect of foods is not constant and can vary depending on the way the food is cooked.

Low GI and GL foods have been shown to be associated with health advantages such as decreased blood sugar levels. Foods with a low GI (less than 55) cause a slower and lower rise in blood glucose levels. These include breads such as mixed-grain and oat breads, barley, pasta, noodles, beans, sweet potatoes, green peas and milk. Foods with a high GI (greater than 70) cause a faster and higher rise in blood glucose levels. High GI foods include white bread, steamed white rice and chips.

By incorporating low GI foods into your diet, you will bring down the average GI of your meal, have a lower, slower blood sugar response to the meal and feel 'full' for longer. By consuming low GI foods, you are more likely to be satisfied and feel full for longer periods of time. This helps you to maintain a healthy weight and avoid diseases such as heart disease, diabetes and some cancers.