Gall bladder and biliary system

The structure, formation and function of bile is discussed on page 305.

Gallstones

Prevalence of gallstones

Gallstones may be present at any age but are unusual before the 3rd decade. The prevalence of gallstones is strongly influenced both by age and gender. There is a progressive increase in the presence of gallstones with age but the prevalence is two to three times higher in women than in men, although this difference is less marked in the 6th and 7th decade. At this age, the prevalence ranges between 25% and 30%. The increase in life expectancy is reflected in an increased burden of symptomatic gallstone disease. There are considerable racial differences, gallstones being more common in Scandinavia, South America and Native North Americans but less common in Asian and African groups.

Types of gallstones

The large majority of gallstones are of two types: cholesterol (containing >50% of the sterol) and less frequently ‘pigment stones’, being predominantly composed of calcium bilirubinate or polymer-like complexes with calcium, copper and some cholesterol.

Cholesterol gallstones

This type of stone accounts for 80% of gallstones in the western world. The formation of cholesterol stones is the consequence of cholesterol crystallization from gall bladder bile. This is dependent upon three factors:

Cholesterol supersaturation of bile

Crystallization-promoting factors within bile

Motility of the gall bladder.

The majority of cholesterol is derived from hepatic uptake from dietary sources. However, hepatic biosynthesis may account for up to 20%. The rate-limiting step in cholesterol synthesis is β-hydroxy-β methyl glutaryl CoA (HMG-CoA) reductase, which catalyses the first step, i.e. the conversion of acetate to mevalonate. The cholesterol formed is co-secreted with phospholipids into the biliary canaliculus as unilamellar vesicles. Cholesterol will only crystallize into stones when the bile is supersaturated with cholesterol relative to the bile salt and phospholipid content. This can occur as a consequence of excess cholesterol secretion into bile which, in some instances, has been shown to be due to an increase in HMG-CoA reductase activity. Recently, leptin (see p. 216) has been shown to increase cholesterol secretion into bile. Elevated levels of leptin during rapid weight loss may account for the increased incidence of cholesterol gallstones. An alternative mechanism of supersaturation is a decreased bile salt content which may occur as a consequence of bile salt loss (e.g. terminal ileal resection or ileal involvement with Crohn’s disease).

The composition of the bile salt pool may also influence the ability to maintain cholesterol in solution. There is evidence that an increased proportion of the secondary hydrophobic bile acid (deoxycholic acid) in the bile acid pool may predispose to cholesterol stone formation. This has been linked with slow colonic transit during which the primary bile acid cholic acid may undergo microbial enzyme metabolism yielding deoxycholic acid which is then absorbed back into the bile salt pool (see Fig. 7.4).

While cholesterol supersaturation of bile is essential for cholesterol stone formation, many individuals in whom such supersaturation occurs will never develop stones. It is the balance between cholesterol crystallizing and solubilizing factors that determines whether cholesterol will crystallize out of solution. A number of lipoproteins have been reported as putative crystallizing factors.

There is increasing evidence from epidemiological, family and twin studies of the role of genetic factors in gallstone formation. A number of lithogenic genes have been identified which may interact with environmental factors. The process of bile formation is maintained by a network of ATP-binding cassette (ABC) transporters in the hepatocyte canalicular membrane which enable biliary secretion of cholesterol, bile salts and phospholipids. This process is regulated by the nuclear receptors FXR and LXR. Loss of function mutations in specific ABC transporter genes have been associated with cholesterol gallstones secondary to bile salt and phospholipid deficiencies within the nascent bile (Fig. 7.29). However, monogenic susceptibility appears uncommon. There are rare cases in which a single missense mutation of the MDR3 gene has been associated with extensive intra- and extrahepatic cholelithiasis at an early (<40 years) age.

Figure 7.29 Nascent bile formation at the hepatocytic canalicular membrane, biliary cholesterol solubilization and gallstone formation. ABCG5-G8 transports cholesterol into bile (regulated by nuclear receptor LXR). ABCB11, ABCB4 transport bile salts and phosphatidylcholine into bile (regulated by nuclear receptor FXR). Bile cholesterol is solubilized in mixed micelles or contained in cholesterol–phospholipid vesicles. Most gallstones are due to excess biliary cholesterol secretion and subsequent crystallization from supersaturated vesicles (continuous lines). LPAC (low phospholipid associated cholelithiasis) occurs if there is phospholipid in bile due to function mutations in gene ABCB4. Benign recurrent intrahepatic cholestasis (BRIC) type 2 is characterized by bile salts in bile due to function mutations in gene ABCB11. In both LPAC and BRIC type 2, there is increased risk of gallstone formation.

A high cholesterol diet increases biliary cholesterol secretion and decreases bile salt synthesis and bile salt pool in cholesterol gallstone subjects but not in controls. These findings suggest that increased intestinal uptake of the sterol could play a role in gallstone pathogenesis. In support of this observation, pharmacological inhibition of cholesterol absorbtion prevents gallstone formation in a mouse model. This may offer a potential therapy for the management/prevention of gallstone formation in patients.

Gall bladder motility represents a further factor that may influence the cholesterol crystallization from supersaturated bile. There is evidence from animal models that gall bladder stasis leads to cholesterol crystallization mediated by hypersecretion of mucin.

Abnormalities of gall bladder motility have been suggested as factors in such circumstances as pregnancy, multiparity and diabetes as well as octreotide-related gall bladder stones (p. 954). Recognized risk factors for gallstones are shown in Table 7.17.

Table 7.17 Risk factors for cholesterol gallstones

Increasing age

Sex (F > M)

Family history

Multiparity

Obesity ± metabolic syndrome

Rapid weight loss

Diet (e.g. high in animal fat/low in fibre)

Drugs (e.g. contraceptive pill)

Ileal disease or resection

Diabetes mellitus

Acromegaly treated with octreotide

Liver cirrhosis

FURTHER READING

Wang HH, Portincasa P, Mendez-Sanchez, N et al. Effect of ezetimibe on the prevention and dissolution of cholesterol gallstones. Gastroenterology 2008; 134:2101–2110.

Bile pigment stones

The pathogenesis of pigment stones is entirely independent of cholesterol gallstones. There are two main types of pigment gallstones, black and brown.

Black pigment gallstones are composed of calcium bilirubinate and a network of mucin glycoproteins that interlace with salts such as calcium carbonate and/or calcium phosphate. These stones range in colour from deep black to very dark brown and have a glass-like cross-sectional surface on fracturing. Black pigment stones are seen in 40–60% of patients with haemolytic conditions such as sickle cell disease and hereditary spherocytosis in which there is chronic excess bilirubin production. However, the majority of pigment stones occur without haemolysis. There has been evidence that bile salt loss into the colon (consequent upon ileal resection or ileal disease) promotes solubilization and colonic reabsorption of bilirubin. This enhances the enterohepatic circulation and biliary secretion of bilirubin with the formation of gallstones. Pigment stones have also been linked with bacterial colonization of the biliary tree. Some pigment stones have been shown to contain bacteria, many of which produce glucuronidase and phospholipase, factors that are known to facilitate stone formation. It is speculated that this subclinical bacterial colonization of the bile duct is responsible for the pigment stone formation.

Brown stones are usually of a muddy hue and on cross-section seem to have alternating brown and tan layers. These stones are composed of calcium salts of fatty acids as well as calcium bilirubinate. They are almost always found in the presence of bile stasis and/or biliary infection. Brown stones are a common cause of recurrent bile duct stones following cholecystectomy and may also be found in the intrahepatic ducts in circumstances of duct disease such as Caroli’s syndrome and primary sclerosing cholangitis. In the Far East such brown stones are identified within both the intra- and extrahepatic biliary tree and have been linked with chronic parasitic infection.

Clinical presentation of gallstones

The majority of gallstones are asymptomatic and remain so during a person’s lifetime. Gallstones (Fig. 7.30) are increasingly detected as an incidental finding at the time of either abdominal radiography or ultrasound scanning. Over a 10–15-year period, approximately 20% of these stones will be the cause of symptoms with 10% having severe complications. Once gallstones have become symptomatic there is a strong trend towards recurrent complications, often of increasing severity. Gallstones do not cause dyspepsia, fat intolerance, flatulence or other vague upper abdominal symptoms.

Figure 7.30 Clinical presentation of gallstones.

Biliary or gallstone colic

Biliary colic is the term used for the pain associated with the temporary obstruction of the cystic or common bile duct by a stone usually migrating from the gall bladder. Despite the term ‘colic’, the pain of stone-induced ductular obstruction is severe but constant and has a crescendo characteristic. Many sufferers can relate the symptoms to over-indulgence with food, particularly when this has a high fat content. The most common time of day for such an episode is in the mid-evening and lasting until the early hours of the morning.

The initial site of pain is usually in the epigastrium but there may be a right upper quadrant component. Radiation may occur over the right shoulder and right subscapular region.

Nausea and vomiting frequently accompany the more severe attacks. The cessation of the attack may be spontaneous after a number of hours or terminated by the administration of opiate analgesia. More protracted pain, particularly when associated with fevers and rigors, suggests secondary complications such as cholecystitis, cholangitis or gallstone-related pancreatitis (see below).

Acute cholecystitis

The initial event in acute cholecystitis is obstruction to gall bladder emptying. In 95% of cases, a gall bladder stone can be identified as the cause. Such obstruction results in an increase of gall bladder glandular secretion leading to progressive distension which in turn may compromise the vascular supply to the gall bladder.

There is also an inflammatory response secondary to retained bile within the gall bladder. Infection is a secondary phenomenon following the vascular and inflammatory events described above.

The initial clinical features of an episode of cholecystitis are similar to those of biliary colic described above. However, over a number of hours, there is progression with severe localized right upper quadrant abdominal pain corresponding to parietal peritoneal involvement in the inflammatory process. The pain is associated with tenderness and muscle guarding or rigidity. Occasionally the gall bladder can become distended by pus (an empyema) and rarely an acute gangrenous cholecystitis develops which can perforate, with generalized peritonitis.

Investigations

Biliary colic as a consequence of a stone in the neck of the gall bladder or cystic duct is unlikely to be associated with significant abnormality of laboratory tests. Acute cholecystitis is usually associated with a moderate leucocytosis and raised inflammatory markers (e.g. C-reactive protein).

The serum bilirubin, alkaline phosphatase and aminotransferase levels may be marginally elevated in the presence of cholecystitis alone, even in the absence of bile duct obstruction. More significant elevation of the bilirubin and alkaline phosphatase is in keeping with bile duct obstruction.

An abdominal ultrasound scan is the single most useful investigation for the diagnosis of gallstone-related disease (Fig. 7.31). It has a positive predictive value of 92% and a negative predictive value of 95% in patients with a clinical history of acute cholecystitis and Murphy’s sign. Look for:

– Gallstones within the gall bladder, particularly when these are obstructing the gall bladder neck or cystic duct

– Focal tenderness over the underlying gall bladder

– Thickening of the gall bladder wall. This may also be seen with hypoalbuminaemia, portal hypertension and acute viral hepatitis.

Figure 7.31 Ultrasound scan in a patient with acute cholecystitis. There is a stone (casting an acoustic shadow – thin arrow) impacted in the gall bladder neck, with a distended gall bladder (thick arrow) and thickening and oedema of the gall bladder wall.

Gallstones are a common finding in an ageing population, and in the absence of specific symptoms great care should be taken when determining whether the gallstones are responsible for the symptoms.

Biliary scintigraphy using technetium derivatives of iminodiacetate. These isotopes are taken up by hepatocytes and excreted into bile. They delineate the extrahepatic biliary tree. The absence of cystic duct and gall bladder filling provides evidence towards acute cholecystitis although the findings must be closely correlated with the presenting symptoms.

Differential diagnosis

Typical cases of biliary colic are usually suspected by the clinical history. The differential diagnosis includes the irritable bowel syndrome (spasm of the hepatic flexure), carcinoma of the right side of the colon, atypical peptic ulcer disease, renal colic and pancreatitis.

The differential diagnosis of acute cholecystitis includes a number of other conditions marked by severe right upper quadrant pain and fever, e.g. acute episodes of pancreatitis, perforated peptic ulceration or an intrahepatic abscess. Conditions above the right diaphragm such as basal pneumonia as well as myocardial infarction may on occasions mimic the clinical picture.

Management of gall bladder stones

Cholecystectomy

Cholecystectomy is the treatment of choice for virtually all patients with symptomatic gall bladder stones. In patients admitted with specific gallstone-related complications (see below), cholecystectomy should be carried out during the period of that admission to prevent the risk of recurrence. For those presenting with pain alone an elective procedure can be planned but the waiting time should be minimized to avoid the high risk of recurrent symptoms (approximately 30% over 4 months) and the need for another hospital admission.

Cholecystectomy should not be performed in the absence of typical symptoms just because stones are found on investigation. There is an ongoing debate as to whether prophylactic cholecystectomy is justified in young patients found to have small stones. Such patients have a long period over which they may develop symptomatic disease and small stones are an independent risk factor for the potentially serious complication of gallstone pancreatitis. Each case should be discussed on an individual risk benefit basis.

The laparotomy approach to cholecystectomy has now been replaced by the laparoscopic technique. Postoperative pain is minimized with only a short period of ileus and the early ability to mobilize the patient. Laparoscopic cholecystectomy can be safely carried out on a day-care basis in otherwise fit patients (although in most cases an overnight stay remains the norm). This has considerable cost benefits over open cholecystectomy, which is now reserved for a small proportion of patients with contraindications such as extensive previous upper abdominal surgery, ongoing bile duct obstruction or portal hypertension.

In approximately 5% of cases a laparoscopic cholecystectomy is converted to an open operation because of technical difficulties, in particular adhesions in the right upper quadrant or difficulty in identifying the biliary anatomy.

Acute cholecystitis

The initial management is conservative, consisting of nil by mouth, intravenous fluids, opiate analgesia and intravenous antibiotics (dictated by local policy with options including extended-spectrum cephalosporins, fluoroquinolones or piperacillin/tazobactam).

Cholecystectomy is usually delayed for a few days to allow the symptoms to settle but can then be carried out quite safely in the majority of cases.

When the clinical situation fails to respond to this conservative management, particularly if there is increasing pain and fever, an empyema or gangrene of the gall bladder may have occurred. In this circumstance urgent imaging (transabdominal ultrasound or CT scan) is required to define the pathology. Surgical intervention is usually required although a radiologically placed gall bladder drain can be used as a temporizing measure for the management of an empyema.

Specific complications of cholecystectomy include a biliary leak either from the cystic duct or from the gall bladder bed. Injury to the bile duct itself occurs in up to 0.5% of laparoscopic operations and may have serious long-term sequelae in the form of a bile duct stricture and secondary biliary liver injury. There is an overall mortality of 0.2%.

Stone dissolution and shock wave lithotripsy

These non-surgical techniques for the management of gall bladder stones are infrequently used but still have a role in a few highly selected patients who may not be fit for cholecystectomy or have declined the surgical option.

Pure or near-pure cholesterol stones can be solubilized by increasing the bile salt content of bile. Oral chenodeoxycholic acid and ursodeoxycholic acid have been successfully utilized. The approach requires long-term therapy and the recurrence rate of gallstones is high when therapy is stopped. Additional pharmacological tools for treating cholesterol gallstones include cholesterol-lowering agents that inhibit hepatic cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe), or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis.

Extracorporeal shock wave lithotripsy

A shock wave can be directed either radiologically or by ultrasound on to gall bladder stones. This technique was highly successful but in only a restricted patient population.

The post-cholecystectomy syndrome

This refers to right upper quadrant pain, often biliary in type, which occurs a few months after the cholecystectomy but may be delayed for a number of years. The patients often comment that the pain is identical to that for which the original operation was carried out. In many cases this syndrome is related to functional large bowel disease with colonic spasm at the hepatic flexure (hepatic flexure syndrome). In a small proportion of patients the pain is a result of a retained common bile duct stone. In a further minority of patients, hypertension of the sphincter of Oddi is a potential cause. This is most likely in patients with abnormal liver biochemistry and dilatation of the common bile duct (on ultrasound) during episodes of pain (and in the absence of a documented retained stone). The diagnosis is confirmed by pressure measurements of the sphincter of Oddi, and the condition can be successfully managed by endoscopic sphincterotomy (see below).

Common bile duct stones

The classical features of common bile duct (CBD) stones are biliary colic, fever and jaundice (acute cholangitis). This triad is only present in the minority of patients. Abdominal pain is the most common symptom and has the typical features of biliary colic (see above). Jaundice is a variable accompaniment and is almost always preceded by abdominal pain. A patient with bile duct stones may experience sequential episodes of pain, only some of which are accompanied by jaundice. In contrast to malignant bile duct obstruction, the level of jaundice associated with CBD stones characteristically tends to fluctuate. In the elderly or immunocompromised patient cholangitis may present with very nonspecific symptoms and only associated abnormal liver biochemistry may point to the diagnosis.

Fever is only present in a minority of cases but indicates biliary sepsis and sometimes an associated septicaemia. The presence of such biliary sepsis is a significant adverse prognostic factor.

A minority of patients with bile duct stones are discovered incidentally during imaging for gall bladder disease. A total of 15% of patients undergoing cholecystectomy will have stones within the bile duct only detected at the time of operative cholangiography. The frequency of asymptomatic bile duct stones resulting in complications is not well documented. It is likely that many such stones will pass into the duodenum without causing symptoms. However, the potential for serious complication is well recognized and in most circumstances incidentally identified bile duct stones are removed (see below).

Physical examination

If the patient is examined between episodes, there may be no abnormal physical finding. During a symptomatic episode the patient may be jaundiced with a fever and associated tachycardia. There is tenderness in the right upper quadrant varying from mild to extremely severe.

More widespread abdominal tenderness extending from the epigastrium to the left upper quadrant, associated with distension, may indicate associated stone-related pancreatitis (see below).

Investigations

Laboratory tests

Full blood count is usually normal in the presence of uncomplicated bile duct stones.

An elevated neutrophil count and raised inflammatory markers (ESR and CRP) are frequent accompaniments of cholangitis.

The raised serum bilirubin tends to be mild and often transient. Very high concentrations of bilirubin (>200 µmol/L) almost always reflect complete bile duct obstruction.

Serum alkaline phosphatase and γ-glutamyl transpeptidase are similarly elevated in proportion to the degree of hyperbilirubinaemia.

Aminotransferase levels are usually mildly elevated but with complete bile duct obstruction there may be very marked rises to 10–15 times the normal value. The alanine aminotransferase is characteristically higher than the aspartate aminotransferase. These high levels may lead to an initial misdiagnosis of a hepatitic process.

Serum amylase levels are often mildly elevated in the presence of bile duct obstruction but are markedly so if stone-related pancreatitis has occurred.

Prothrombin time may be prolonged if bile duct obstruction has occurred; this reflects decreased absorption of vitamin K.

Imaging

Transabdominal ultrasound is the initial imaging technique of choice.

Bile duct obstruction is characterized by dilatation of intrahepatic biliary radicles, which are usually easily detected by the ultrasound scan. It may, however, not be possible to identify the cause of obstruction. Stones situated in the distal common bile duct are poorly visualized by transabdominal ultrasound and up to 50% are missed. The detection of stones within the gall bladder is poorly predictive as to the cause of bile duct obstruction. Asymptomatic gallstones are common (up to 15%) in patients who are 65 years and older. Conversely, in 5–10% of patients with bile duct stones, no calculi can be seen within the gall bladder.

Magnetic resonance cholangiography (MRC) delineates the fluid column within the biliary tree and is a sensitive technique for the detection of common bile duct stones in the presence of a dilated duct. The technique may be less accurate in the absence of duct dilatation (see the role of endoscopic ultrasound, below) (Fig. 7.32).

Figure 7.32 (a) A magnetic resonance cholangiogram in a patient presenting with abdominal pain and jaundice. This shows evidence of a distal common bile duct stricture with a stone in the bile duct proximal (arrows). (b) An ERCP in the same patient confirming the details identified in the MRCP scan. The stones (arrowed) were removed at the time of the ERCP after initial dilatation of the stricture.

CT scanning is an alternative way to detect bile duct dilatation. Opaque stones are more readily identifiable within the bile duct than radiolucent cholesterol stones. CT scanning also provides a means of excluding other causes of bile duct obstruction such as carcinoma of the head of the pancreas.

Endoscopic ultrasound scanning (Figs 7.33, 7.34) has enabled high-resolution imaging of the common bile duct, gall bladder and pancreas, although unlike the preceding imaging techniques it is an invasive procedure. The endoscopic ultrasound probe in the duodenum is in close proximity with the distal common bile duct and hence can identify the majority of stones at this level.

Figure 7.33 An endoscopic ultrasound scan with the probe in the first part of the duodenum identifying the gall bladder (GB) and multiple small echo-poor stones within (microlithiasis). The patient had presented with recurrent episodes of unexplained abdominal pain.

Figure 7.34 An endoscopic ultrasound scan with the probe within the first part of the duodenum (D1) and defining the common bile duct (BD) and a stone (S) clearly identified within the lumen of the common bile duct.

This technique is particularly useful for identifying small calculi (microcalculi), in a non-dilated common bile duct.

Endoscopic retrograde cholangiography (ERC)

In experienced hands, visualization of the common bile duct will be successful in 98% of cases, providing good documentation of bile duct stones (Fig. 7.32, Fig. 7.35). However, microcalculi can still be missed. ERC is an invasive procedure with recognized risks. In almost all circumstances this is a therapeutic tool used to remove the stones that have been identified by the investigations described above.

Figure 7.35 An ERCP carried out in a patient with abdominal pain, fluctuating jaundice and fever. The cholangiogram shows a markedly dilated biliary tree (arrowed) with multiple large stones within (ST). These stones were removed at the time of ERCP using a mechanical lithotripsy device to crush the stones before removing from the duct by means of balloon and basket retrieval.

Differential diagnosis

Cholangitis may occur independently of gallstones in any condition associated with impaired biliary drainage. It is commonly associated with conditions such as primary sclerosing cholangitis and Caroli’s syndrome. Cholangitis may also complicate post-traumatic or surgery-associated bile duct strictures. It is unusual in malignant bile duct obstruction unless there has been prior endoscopic or surgical intervention. Jaundice may also be a feature of acute cholecystitis in the absence of bile duct stones. A stone impacted in the cystic duct may compress and obstruct the bile duct (Mirizzi’s syndrome). Common bile duct stones may produce pain, but in the absence of jaundice, the differential diagnosis is that of biliary colic (see above).

Management

Acute cholangitis has a high morbidity and mortality, particularly in the elderly. Successful management depends on intravenous antibiotics (see as for acute cholecystitis), and urgent bile duct drainage. In most circumstances this is achieved by the endoscopic retrograde approach. Access to the bile duct is achieved by sphincterotomy, and thereafter the stones can be removed either by balloon or basket catheters. In the severely ill patient a piece of plastic tubing (termed a stent) can be inserted into the bile duct to maintain bile drainage without the need to remove the stones; hence minimizing the time period to complete the procedure. The residual stones can then be removed endoscopically when the patient has recovered from the episode. If endoscopic drainage is not available or prevented by inability to access the second part of the duodenum then a radiologically placed percutaneous biliary drain represents an alternative management option. Surgical drainage has been associated with a high mortality and is now limited to those very few cases which cannot be managed by the endoscopic or percutaneous approach.

Urgent endoscopic bile duct clearance is also indicated in some patients with acute gallstone pancreatitis (see below). Patients who have retained common bile duct stones after a previous cholecystectomy are also optimally managed by endoscopic clearance. Patients shown to have common bile duct stones as well as gall bladder stones may be treated by two different approaches:

Laparoscopic cholecystectomy which can also include exploration of the CBD via the cystic duct or by direct choledochotomy. By using these techniques the laparoscopist can extract stones from the CBD. This, however, prolongs the procedure, particularly in the presence of large stones or biliary sepsis.

Endoscopic approach either immediately before or after the cholecystectomy. Removal of CBD stones by this method is the preferred way in the UK. Large bile duct stones (>10 mm) may present a significant challenge to endoscopic removal. Mechanical lithotripsy facilitates stone fragmentation and removal into the duodenum. Both extracorporeal and intraductal shock wave stone fragmentation has also been used.

Complications of gallstones

Acute cholecystitis and acute cholangitis have been discussed (p. 353).

Gallstone-related pancreatitis is discussed on page 363.

Gallstones can occasionally erode through the wall of the gall bladder into the intestine giving rise to a biliary enteric fistula. Passage of a gallstone through into the small bowel can give rise to an ileus or true obstruction.

There is little evidence that gallstones are associated with an increased risk of adenocarcinoma of the gall bladder (p. 357).

Miscellaneous conditions of the biliary tract

Gall bladder

There are a number of non-calculous conditions of the gall bladder, some of which have been associated with symptoms.

Non-calculous cholecystitis

Almost 10% of gall bladders removed for biliary symptoms are shown to have chronic inflammation within the wall but an absence of gallstones. Such cases are described as non-calculous cholecystitis. In many instances the gall bladder inflammation is minor and of doubtful significance. In a minority of cases non-calculous cholecystitis is characterized by severe inflammation frequently associated with gall bladder perforation. This condition is characteristically found in an elderly and critically ill group of patients. Chemical inflammation of the gall bladder may also occur from reflux of pancreatic enzymes back into the biliary tree, usually through the common channel at the ampulla of Vater. Bacterial and viral infections of the gall bladder have been recognized as a cause of non-calculous cholecystitis.

The decision to carry out cholecystectomy in the absence of defined gall bladder stones should be guided by the specific features of the history and whether there is evidence of a diseased gall bladder wall on ultrasound scanning.

Cholesterolosis of the gall bladder

In cholesterolosis, cholesterol and other lipids are deposited in macrophages within the lamina propria of the gall bladder. These may be diffusely situated, giving a granular appearance to the gall bladder wall, or on occasions more discrete, giving a polypoid appearance (see below). Cholesterolosis of the gall bladder may co-exist with gallstones but occurs independently. Some degree of cholesterolosis may be found in up to 25% of autopsies in an elderly population. It is doubtful whether this is a cause of symptoms.

Adenomyomatosis of the gall bladder

Adenomyomatosis is a gall bladder abnormality characterized by hyperplasia of the mucosa, thickening of the muscle wall and multiple intramural diverticula (the so-called ‘Rokitansky–Aschoff sinuses’).

The condition is usually detected as an incidental finding during investigation for possible gall bladder disease. It has been suggested that this condition is secondary to increased intraluminal gall bladder pressure but this is not proven. Gallstones may frequently co-exist but there is no evidence to support a direct relationship.

It is unlikely that adenomyomatosis alone is a cause of biliary symptoms.

Chronic cholecystitis

There are no symptoms or signs that can conclusively be shown to be due to chronic cholecystitis. Symptoms attributed to this condition are vague, such as indigestion, upper abdominal discomfort or distension. There is no doubt that gall bladders studied histologically can show signs of chronic inflammation, and occasionally a small, shrunken gall bladder is found either radiologically or on ultrasound examination. However, these findings can be seen in asymptomatic people and therefore this clinical diagnosis should not be made. Most patients with chronic right hypochondrial pain suffer from functional bowel disease (p. 230).

Extrahepatic biliary tract

Primary sclerosing cholangitis (see p. 334)

In up to 40% of patients with PSC the clinical course is influenced by a dominant extrahepatic/hilar stricture. This is relevant in those patients who do not have established advanced liver involvement in whom maintaining bile flow can protect the liver from secondary biliary injury. Drainage with a surgical hepaticojejunostomy has been beneficial in some cases. More recently repeated endoscopic balloon dilatation and temporary stenting of the extrahepatic/hilar stricture has been reported with prolonged benefit.

Autoimmune cholangitis

Immunoglobulin (Ig)G4-associated cholangitis is the biliary manifestation of a multisystem fibroinflammatory disorder in which affected organs have a characteristic lymphoplasmacytic infiltrate rich in IgG4-positive cells. The original description of this condition was in the context of autoimmune pancreatitis (see p. 365). The large majority of cases are recognized in middle-aged or elderly men and presentation is varied depending upon the systems involved but includes abdominal pain and jaundice. Both intra- and extrahepatic biliary strictures maybe seen and the findings may be misinterpreted as representing cholangiocarcinoma. The diagnosis relies upon clinical suspicion and confirmation of an elevated serum IgG4 level and a typical lymphocytoplasmic infiltrate on histological examination of involved tissue. The condition is almost always responsive to steroids but can lead to hepatic failure.

Choledochal malformation (cysts)

Congenital malformation of the bile ducts may occur at all levels of the biliary tree, although most commonly are extrahepatic. The resulting dilatation of the choledochus may be saccular, diverticular or of fusiform configuration. In many cases there is associated pancreatobiliary malunion with the pancreatic duct draining directly into the common bile duct. The majority of symptomatic cases present in childhood with features of cholangitis. The formation of stones and sludge within the cystic segment may predispose to acute relapsing pancreatitis. In adult life, choledochal cysts may be a differential diagnosis in patients presenting with symptoms suggestive of bile duct stones. The cyst must be fully resected to avoid the recurrent biliary complications as well as averting the risk (approximately 15%) of subsequent cholangiocarcinoma.

Benign bile duct strictures

Benign strictures area a recognized complication of biliary surgery. This may include inadvertent stapling of the duct or as a consequence of ischaemic injury (often in association with a bile duct leak). A stricture may also occur at the level of a bile duct anastomosis either enteric or duct to duct. A bile duct stricture can also result from major trauma to the right upper quadrant. The distal common bile duct is commonly compressed in the presence of chronic pancreatitis (see below).

In most cases the initial therapy will be endoscopic including balloon dilatation of the stricture and temporary bile duct stenting (see below). This may provide definitive management but in some cases surgical intervention is required.

Haemobilia

Haemobilia is the term used to describe bleeding into the biliary tree. This may be as a consequence of liver trauma or as a complication of liver surgery. Biopsy of the liver is also a well-recognized cause. The end result is a fistula between a branch of the hepatic artery and an intrahepatic bile duct.

Haemobilia may be a cause of significant gastrointestinal blood loss and should be suspected when melaena is accompanied by right-sided upper abdominal pain and jaundice. However, the bleeding may occur without any overt biliary symptoms. If the diagnosis is suspected, bleeding may be managed by occlusion of the feeding artery by thrombosis performed radiologically.

Some patients will require surgery to control the bleeding point.

Tumours of the biliary tract

Gall bladder polyps

Polyps of the gall bladder are a common finding, being seen in approximately 4% of all patients referred for hepatobiliary ultrasonography. The vast majority of these are small (<5 mm), are non-neoplastic and are inflammatory in origin or composed of cholesterol deposits (see above). Adenomas are the most common benign neoplasm of the gall bladder. Only a proportion of these have a cancerous potential. The only reliable means of defining those at risk is polyp size (>10 mm). Cholecystectomy is recommended for any polyp approximating to 1 cm in diameter or larger.

Primary cancer of the gall bladder

Adenocarcinoma of the gall bladder represents 1% of all cancers. The mean age of occurrence is in the early 60s, with a women to men ratio of 3 : 1. Gallstones have been suggested as an aetiological factor but this relationship remains unproven. Diffuse calcification of the gall bladder (porcelain gall bladder), considered to be the end stage of chronic cholecystitis, has also been associated with cancer of the gall bladder and is an indication for early cholecystectomy. Adenomatous polyps of the gall bladder in excess of 10 mm in diameter are also recognized as premalignant lesions (see above).

Carcinoma of the gall bladder is often detected at the time of planned cholecystectomy for gallstones and in such circumstances resection of an early lesion may be curative. Early lymphatic spread to the liver and adjacent biliary tract precludes curative resection in more advanced lesions. There are no proven chemotherapeutic agents for carcinoma of the gall bladder. A small proportion of cases are sensitive to radiotherapy but the overall 5-year survival is less than 5%.

Cholangiocarcinoma (see also p. 348)

Cancer of the biliary tree may be intra- or extrahepatic. These malignancies represent approximately 1% of all cancers. A number of associations have been identified such as that with choledochal malformation (see above), and with primary sclerosing cholangitis. Chronic infection of the biliary tree with, e.g. Clonorchis sinensis, has also been implicated. The bile duct malignancy usually presents with jaundice and may be suspected by imaging, initially ultrasound and thereafter CT and in particular magnetic resonance cholangiopancreatography (MRCP). Histological/cytological diagnosis may be difficult to attain because the malignant cells are often few in number and contained within a dense stroma. Endoscopically obtained cytology specimens have only 30% sensitivity. The can be enhanced by using techniques such as fluorescent in situ hybridization and digital image analysis. Improved techniques of endoscopic cholangioscopy have enabled direct visualization of the lesions and allowing targeted biopsy.

The disease spread is usually by local lymphatics or local extension. Cholangiocarcinoma of the common bile duct may be resectable at presentation but local extension precludes such management in the majority of more proximal lesions. Localized disease justifies an aggressive surgical approach including partial hepatic resection. Chemo-radiation has been used to treat localized small hilar cholangiocarcinoma and in a few cases has facilitated successful liver transplantation, but the carcinoma recurs.

Secondary malignant involvement of the biliary tree

Carcinoma of the head of the pancreas frequently presents with common bile duct obstruction and jaundice. Metastases to the bile ducts from distant cancers are uncommon. Melanoma is the most frequent neoplasm to do so.

Other carcinomas that have caused bile duct metastases, in order of frequency, are those arising in the lung, breast and colon as well as those from the pancreas (metastatic as compared to direct infiltration). Infiltration of the bile duct is not uncommon in disseminated lymphomatous disease.

Palliation of malignant bile duct obstruction

A small proportion of cholangiocarcinomas are surgically resectable, more commonly those in the distal bile duct as compared to the hilar region. All patients must be fully screened for operability using the imaging techniques described above. However, in the greater proportion of patients the treatment is palliative. Relief of bile duct obstruction has been shown to improve quality of life considerably and with pain control is the major end point of palliation. In recent years, endoscopic techniques have allowed the insertion of stents into the biliary tree to re-establish bile flow. The initial use of plastic stents has largely been replaced by self-expanding metal stents which have considerably longer periods of patency (Fig. 7.36). In the small proportion of patients in whom bile duct drainage is not possible endoscopically, the percutaneous route offers an alternative method of stent placement. There is some evidence of benefit from the use of photodynamic therapy in those patients in whom biliary drainage has been achieved. This technique involves the use of a porphyrin derivative to sensitize the malignant cells prior to activation by an endoscopically placed laser probe. The aim is to provide local tumour destruction and maintain bile duct patency.

Figure 7.36 An ERCP in a patient presenting with painless jaundice. (a) There is a tight stricture in the mid-common bile duct (CBD) and extending proximally over 4 cm (extent defined by arrows). The intrahepatic ducts (IHD) proximally are dilated. A catheter has been place endoscopically across the stricture. (b) A self-expanding metal stent has been placed across the stricture and released. The stent is compressed at the level of the stricture but will open fully over 24 h. The contrast in the intrahepatic ducts (IHD) has largely drained through the stent. The distal margin of the stent is in the duodenum.

The pancreas

Structure and function

Structure

The pancreas extends retroperitoneally across the posterior abdominal wall from the second part of the duodenum to the spleen. The head is encircled by the duodenum; the body, which forms the main bulk of the organ, ends in a tail that lies in contact with the spleen. The pancreas consists of exocrine and endocrine cells, the former making up 98% of the human pancreas.

The pancreatic acinar cells are grouped into lobules, forming the ductal system which eventually joins into the main pancreatic duct.

The main pancreatic duct has many tributary ductules and gradually tapers towards the tail of the pancreas. The main pancreatic duct itself usually joins the common bile duct to enter the duodenum as a short single duct at the ampulla of Vater.

Exocrine function

The pancreatic acinar cells are responsible for production of digestive enzymes. These include amylase, lipase, colipase, phospholipase and the proteases (trypsinogen and chymo-trypsinogen). These enzymes are stored within the acinar cells in secretory granules and are released by exocytosis (Fig. 7.37).

Figure 7.37 Stimulus-secretion coupling of pancreatic cell protein secretion. There is no CCK receptor in humans; stimulation is probably via neural fibres. VIP, vasoactive intestinal polypeptide; CCK, cholecystokinin; ACh, acetylcholine.

After ingestion of a meal, pancreatic exocrine secretion is regulated by cephalic, gastric and intestinal stimuli. The cephalic phase is mediated by the central nervous system and is stimulated by behavioural cues related to the sight and smell of food. With ingestion of food, the gastric phase commences and in response to distension of the stomach a neural pathway involving the central nervous system stimulates pancreatic secretion. Both these phases are under vagal control. Finally, the presence of protein, fat and gastric acid within the small intestine further augments pancreatic secretion by both hormonal and neurotransmitter activity which produces local enteropancreatic control of secretion. Feedback regulatory events eventually terminate pancreatic secretion.

Cholecystokinin (CCK) is produced in specialized gut endocrine cells (I cells) of the mucosa of the small intestine and is secreted in response to intraluminal food. In animals, it exerts its biological activity by binding to specific G-protein-coupled receptors on target cells in the pancreas. Activated G-proteins lead to the activation of phospholipases. This in turn leads to calcium release from intracellular stores, which in turn results in the fusion of the digestive enzyme granules to the apical plasma membrane and enzyme release. There are no CCK receptors in pancreatic cells in humans, and CCK acts via receptors on vagal afferent fibres to stimulate pancreatic secretion. Of the enzymes produced by the pancreatic acinar cells, the proteases and colipase are secreted as inactive precursors and require duodenal enterokinase to initiate activity.

Secretin is also released from specialized enteroendocrine cells of the small intestine during a meal and in particular during duodenal acidification. Secretin has a direct effect on the pancreatic acinar cells as well as the ductal cells. There is also a vagal-mediated secretory response. Secretin action is mediated via G-coupled receptors and calcium-mediated enzyme release. Secretin results in a bicarbonate-rich pancreatic secretion.

Completion of the postprandial secretory phase involves both neural and hormonal control.

Central neuronal inhibition of pancreatic secretion acts through dopamine and somatostatin receptors mediated by noradrenergic nerves.

Pancreatic polypeptide from the islet cells is released from the pancreas in response to a meal and has an inhibitory effect upon acinar enzyme secretion both by a local effect and via central receptors.

Somatostatin, present within the pancreas, stomach and central nervous system, is released in response to food. Its effect is mediated both by direct pancreatic acinar inhibition and by a central nervous system effect.

Two other mechanisms of inhibition have been described. First, proteases within the duodenal lumen have a negative feedback on acinar secretion. Second, nutrients within the ileum inhibit pancreatic secretion by means of local hormone release (peptide YY and glucagon-like peptide) acting on the acinar cells themselves as well as centrally.

The gut-related peptides, leptin and ghrelin, as well as influencing appetite behaviour, are also regulatory factors in the exocrine function of the pancreas. This effect is believed to occur via hypothalamic centres.

The endocrine pancreas

This consists of hormone-producing cells arranged in nests or islets (islets of Langerhans). The hormones produced are secreted directly into the circulation and there is no access to the pancreatic ductular system. There are five main types of islet cell corresponding to different secretory components. The beta cells are the most common and are responsible for insulin production. The alpha cells produce glucagon. The D cells produce somatostatin, PP cells produce pancreatic polypeptide and enterochromaffin cells produce serotonin.

A number of other hormones have been identified within the endocrine pancreas including gastrin-releasing peptide, neuropeptide Y and galanin. These are believed to be neurotransmitters active in the neuro-gastrointestinal axis.

Investigation of the pancreas

Assessment of exocrine function

The assessment of pancreatic exocrine function is used in the investigation of patients with possible chronic pancreatic disease. Clinically evident fat malabsorption does not occur until there has been an 85–90% reduction in pancreatic lipase and is therefore a very late manifestation of pancreatic disease.

Direct tests of pancreatic function

These tests rely upon the analysis of a duodenal aspirate following pancreatic stimulation.

The original test involved the oral administration of a specified meal (Lundh meal). Pancreatic stimulation is now achieved by intravenous secretin and cholecystokinin.

The aspirate is assessed for pancreatic enzymes and bicarbonate production. The procedure is time-consuming and requires a meticulous technique. There is good correlation with moderate to severe pancreatic function loss, but not for mild damage. These tests are not widely available.

The measurement of peak bicarbonate secretion following secretin stimulation is also performed using an endoscopic technique for aspirate collection. This method offers similar levels of predictive accuracy as seen with the secretin–cholecystokinin stimulation test but does require a 30 min endoscopic intubation.

Non-invasive indirect tests of pancreatic function

Faecal test

Faecal fat estimation (see p. 264).

Faecal elastase. This pancreatic specific enzyme is not degraded in the intestine and has high concentrations within the faeces. Diminished levels may be detected in moderate as well as severe pancreatic insufficiency. This has replaced the faecal chymotrypsin test.

Oral pancreatic function tests

N-benzoyl-L-tyrosyl-p-aminobenzoic acid (basis of PABA test) and fluorescein dilaurate are oral compounds utilized in pancreatic function tests. Both are digested by pancreatic enzymes releasing substrates which are excreted and measured in the urine. Both tests are commercially available and have good sensitivity in moderate to severe pancreatic exocrine failure.

Clinical application of pancreatic function tests

While the invasive duodenal aspiration tests represent the most sensitive and specific means of assessing pancreatic function, these are very rarely used outside specialized centres. The non-invasive tests are widely available but are only highly sensitive in the detection of severe pancreatic insufficiency. The faecal elastase test (in a commercially available form) provides similar sensitivity and specificity and is the test of choice as a screening tool for pancreatic insufficiency.

Pancreatic imaging

Imaging (see p. 309) has a pivotal role in the investigation and management of pancreatic disease, which covers the spectrum of acute, chronic and malignant conditions.

A plain abdominal radiograph may show the calcification associated with chronic pancreatitis, particularly when alcohol is the aetiology.

Ultrasound of the pancreas is a useful screening investigation for inflammation and neoplasia. Views may be limited by overlying bowel gas.

CT scan with contrast enhancement and following a specific pancreatic protocol remains the ‘gold standard’ imaging technique for the investigation of pancreatic disease.

MRI scanning represents an alternative to CT. Magnetic resonance cholangiopancreatography (MRCP) gives clear definition of the pancreatic duct as well as the biliary tree. Gallstones (including microcalculi) may also be identified in the biliary tree using MRI/MRCP.

Endoscopic ultrasound is very useful for identifying distal common bile duct stones which may be the aetiology of an episode of acute pancreatitis. Endoscopic ultrasound can identify the early changes of chronic pancreatitis before these are evident on other imaging methods. There is also an increasing role for this technique to stage the operability of pancreatic adenocarcinoma, particularly with respect to vascular invasion. Endoscopic ultrasound is now considered the imaging technique of choice for investigating cystic lesions of the pancreas (see below). The technique allows fine-needle aspiration and histological sampling as well as the therapeutic option of cyst drainage. Endoscopic ultrasound is a sensitive means of detecting small pancreatic tumours, particularly those of neuroendocrine origin.

Endoscopic retrograde cholangiopancreatography (ERCP) was considered the ‘gold standard’ for diagnosing pancreatic disease. However, with the advent of MRCP and endoscopic ultrasound, ERCP is largely restricted to therapeutic intervention.

In summary, an initial transabdominal ultrasound supplemented by CT provides sufficient diagnostic information for most inflammatory and neoplastic conditions of the pancreas. MRI and MRCP are now widely available and provide additional information, particularly with respect to pancreatic ductular and biliary anatomy. Endoscopic ultrasound is a useful tool for the investigation of both benign and malignant disease of the pancreas and facilitates fine-needle aspiration and biopsy of targeted lesions.

Pancreatitis

Classification

Pancreatitis is divided into acute and chronic. By definition acute pancreatitis is a process that occurs on the background of a previously normal pancreas and can return to normal after resolution of the episode. In chronic pancreatitis there is continuing inflammation with irreversible structural changes.

In practice, the differentiation between acute and chronic pancreatitis may be difficult. Any of the causes of acute pancreatitis if untreated may result in recurrent episodes classified as acute relapsing pancreatitis. In other cases the recurrent episodes of recurrent pancreatitis may represent exacerbations of an underlying chronic process.

Acute pancreatitis

Acute pancreatitis is a syndrome of inflammation of the pancreatic gland initiated by an acute injury. The causes of acute pancreatitis are listed in Table 7.18. In the western world, gallstones and alcohol account for the vast majority of episodes. Alcohol also causes chronic pancreatitis (see below). The severity of the pancreatitis may range from mild and self-limiting to extremely severe, with extensive pancreatic and peripancreatic necrosis as well as haemorrhage. In the most severe form (approximately 10% of cases), the mortality is between 40% and 50%.

Table 7.18 Causes of pancreatitis

Acute	Chronic
Gallstones	Alcohol
Alcohol	Tropical
Infections (e.g. mumps, Coxsackie B)	Hereditary
Pancreatic tumours	Trypsinogen and inhibitory protein defects
Drugs (e.g. azathioprine, oestrogens, corticosteroids, didanosine)	Cystic fibrosis
Iatrogenic (e.g. post-surgical, post-ERCP)	Idiopathic
Hyperlipidaemias	Trauma
Miscellaneous	Hypercalcaemia
Trauma
Scorpion bite
Cardiac surgery
Idiopathic

Pathogenesis

The pancreatic inflammatory response is secondary to the premature and exaggerated activation of digestive enzymes within the pancreas itself. An acute rise in intracellular calcium may be the initiating mechanism, leading to early activation of trypsinogen to trypsin and impairment of trypsin degradation by chymotrypsin C. It is these activated enzymes which are responsible for cellular necrosis. In the case of gallstone-related pancreatitis it is believed that stones occlude the pancreatic drainage at the level of the ampulla leading to pancreatic ductular hypertension. Such ductular hypertension has been shown in animal models to increase cytosolic free ionized calcium. There is also evidence that alcohol interferes with calcium homeostasis in pancreatic acinar cells.

Clinical features

Acute pancreatitis is a differential diagnosis in any patient with upper abdominal pain. The pain usually begins in the epigastrium accompanied by nausea and vomiting. As inflammation spreads throughout the peritoneal cavity, the pain becomes more intense. Involvement of the retroperitoneum frequently leads to back pain.

The patient may give a history of previous similar episodes or be known to have gallstones. An attack may follow an alcoholic binge. However, in many cases there are no obvious aetiological factors.

Physical examination at the time of presentation may show little more than a patient in pain with some upper abdominal tenderness but no systemic abnormalities. In severe disease, the patient has a tachycardia, hypotension and is oliguric. Abdominal examination may show widespread tenderness with guarding as well as reduced or absent bowel sounds. Specific clinical signs that support a diagnosis of severe necrotizing pancreatitis include periumbilical (Cullen’s sign) and flank bruising (Grey Turner’s sign). In patients with a gallstone aetiology, the clinical picture may also include the features of jaundice or cholangitis.

FURTHER READING

Frossard JL, Steer ML, Pastor CM. Acute pancreatitis. Lancet 2008; 371:143–152.

Diagnosis

Blood tests

Serum amylase is an extremely sensitive test if it is three times the upper limit of normal when measured within 24 h of the onset of pain. A number of other conditions may occasionally cause a very elevated amylase (Table 7.19). Amylase levels gradually fall back towards normal over the next 3–5 days. With a late presentation the serum amylase level may give a false-negative result.

Urinary amylase levels may be diagnostic as these remain elevated over a longer period of time.

Serum lipase levels are also raised in acute pancreatitis and these remain elevated for a longer period of time than those of amylase. However, overall, the accuracy of serum lipase is not significantly greater than amylase and it is technically more difficult to measure.

C-reactive protein level is useful in assessing disease severity and prognosis.

Other baseline investigations include a full blood count, urea and electrolytes, blood glucose, liver biochemistry, plasma calcium and arterial blood gases. These are documented at presentation and then repeated at 24 and 48 hours and provide a basis for assessing the severity of an attack (see below).

Table 7.19 Elevation of serum amylase unrelated to pancreatitis

Leakage of upper gastrointestinal contents into the peritoneum

Upper gastrointestinal perforation

Biliary peritonitis

Intestinal infarction

Inherited abnormalities of amylase

Macroamylasaemia

Radiology

An erect chest X-ray is mandatory to exclude gastroduodenal perforation, which also raises the serum amylase (Table 7.19). A supine abdominal film may show gallstones or pancreatic calcification.

An abdominal ultrasound scan is used as a screening test to identify a possible biliary (gallstone) cause of pancreatitis. Gallstones are difficult to detect in the distal common bile duct but dilated intrahepatic ducts may be present in the presence of bile duct obstruction. Stones within the gall bladder are not sufficient to justify a diagnosis of gallstone-related pancreatitis. The ultrasound may also demonstrate pancreatic swelling and necrosis as well as peripancreatic fluid collections if present. In severe pancreatitis the pancreas may be difficult to visualize because of gas-filled loops of bowel.

Contrast-enhanced CT scanning is essential in all but the most mild attacks of pancreatitis. It should be performed after 72 h to assess the extent of pancreatic necrosis. CT provides very valuable prognostic information. Later, repeated CT scans can detect other complications including fluid collections, abscess formation and pseudocyst development (Fig. 7.38).

MRI (MRCP) assesses the degree of pancreatic damage and identifies gallstones within the biliary tree. MRI is particularly useful to differentiate between fluid and solid inflammatory masses.

ERCP is used as a treatment measure to remove bile duct stones in selected cases of gallstone-related pancreatitis (see below).

Figure 7.38 (a) An abdominal CT scan with arterial phase contrast in a patient presenting with acute pancreatitis 48 h previously. The pancreas is swollen with very little uptake of contrast suggesting a severe necrotizing process. There are peri-pancreatic inflammatory changes (inf). The liver and spleen are identified for reference. (b) A coronal view of a CT scan in the same patient carried out in second week after presentation. There is now a large fluid collection with debris within. This is a precursor of a large pseudocyst, which extends down the left paracolic gutter into the pelvis. This has occurred as a consequence of a pancreatitis-induced ductal leak. The liver, stomach and duodenum are defined for reference. PV, portal vein; Ps, pseudocyst.

Assessment of disease severity

The majority of cases of acute pancreatitis are mild and run a short, self-limiting course. Approximately 25% run a more complicated course and in 10% this may be life-threatening. In the more severe cases, the clinical course may be marked by haemodynamic instability and multiple organ failure. The early prediction of such a severe attack allows appropriate monitoring and intensive care to be in place.

Early clinical assessment has been shown to have poor sensitivity for predicting a severe attack. Similarly, individual laboratory tests have very limited value. Elevations of CRP of >200 mg/L in the first 4 days have an 80% predictive value of a severe attack. Multiple factors are also used to develop scoring systems (Table 7.20). The Ranson and Glasgow scoring systems are based on such parameters and have been shown to have an 80% sensitivity for predicting a severe attack, although only after 48 h following presentation. The acute physiology and chronic health evaluation (APACHE) score has been extensively adopted as a means of assessing the severity of a wide spectrum of illness. The APACHE scoring system is based on common physiological and laboratory values and adjusted for age as well as the presence or absence of a number of other chronic health problems (Table 7.21). This scoring system appears to have a high sensitivity as early as 24 h after onset of symptoms. There is evidence that obesity predicts the outcome from an episode of pancreatitis as the excessive adipose tissue is a substrate for activated enzyme activity. This will in turn generate an extensive inflammatory reaction. Even modest obesity (BMI between 25 and 30) has an adverse effect. This is incorporated as an adverse factor in the APACHE score (p. 897) for acute pancreatitis, and other variables have also been added.

Table 7.20 Severe pancreatitis – factors during the first 48 h that indicate severe pancreatitis and a poor prognosis (three or more factors present predict a severe episode)

Age	>55 years
WBC	>15 × 10⁹/L
Blood glucose	>10 mmol/L
Serum urea	>16 mmol/L
Serum albumin	<30 g/L
Serum aminotransferase	>200 U/L
Serum calcium	<2 mmol/L
Serum LDH	>600 U/L
P_aO₂	<8.0 kPa (60 mmHg)

LDH, lactate dehydrogenase.

Table 7.21 The APACHE (Acute Physiology and Chronic Health Evaluation) II scoring system parameters

Physiological	Laboratory
Temperature	Oxygenation (P_aO₂)
Heart rate	Arterial pH
Respiratory rate	Serum:
Mean arterial pressure	Sodium
Glasgow Coma Scale	Potassium
	Creatinine
	Haematocrit
	White blood cell count

Score 0–4 (normal–abnormal). Adjust for age and severe organ insufficiency or for immunocompromised. BMI is an additional parameter.

Treatment

The initial management of acute pancreatitis is similar, whatever the cause. A multiple factor scoring system (ideally APACHE II with a modification for obesity) should be used at the end of the first 24 h after presentation to allow identification of the 25% of patients with a predicted severe attack. This should be repeated at 48 h to identify a further subgroup who appear to be moving into the severe category. These patients should then be managed on a high-dependency or intensive care unit. Even patients outside the severe category may require considerable supportive care.

Early fluid losses in acute pancreatitis may be large, requiring well-maintained intravenous access as well as a central line and urinary catheter to monitor circulating volume and renal function.

Nasogastric suction prevents abdominal distension and vomitus and hence the risk of aspiration pneumonia.

Baseline arterial blood gases are a key predictive factor for severity of an episode and determine the need for continuous oxygen administration.

Prophylactic antibiotics. Controlled data for the use of antibiotics are available but the results are not uniform in showing benefit, particularly in showing improved mortality. There is evidence that the beta lactam imipenem reduces the incidence of infected pancreatic necrosis.

Analgesia requirements. Tramadol or other opiates are the drugs of choice for immediate post-presentation pain control. Unless there is prompt resolution of pain, a patient-controlled system of administration is indicated to provide continuous and adequate pain relief. Fentanyl has been used widely for this application. There is a theoretical risk that morphine and diamorphine might exacerbate pancreatic ductular hypertension by causing sphincter of Oddi contraction and they are best avoided in acute pancreatitis.

Feeding. In patients with a severe episode there is little likelihood of oral nutrition for a number of weeks. Total parenteral nutrition has been associated with a high risk of infection and has been replaced by enteral nutrition. In the absence of gastroparesis most patients will tolerate nasogastric administration of feed without exacerbation of pain. In those with gastroparesis or poorly tolerated nasogastric feeding (exacerbation of pain or precipitation of nausea and vomitus), post-pyloric feeding should be instituted by the endoscopic placement of a nasojejunal tube.

Anticoagulation with a low molecular weight heparin for DVT prophylaxis.

In a small proportion of patients, multiorgan failure will develop in the first few days after presentation, reflecting the extent of pancreatic necrosis. Such patients will require positive-pressure ventilation and often renal support. The mortality in this group is extremely high (in excess of 80%).

Gallstone-related pancreatitis

In patients with gallstone-related pancreatitis and associated bile duct obstruction (particularly when complicated by cholangitis), endoscopic intervention with sphincterotomy and stone extraction is the treatment of choice. In the absence of bile duct obstruction, sphincterotomy and stone extraction is only of proven benefit when the episode of pancreatitis is predicted as severe. In less severe cases of gallstone-related pancreatitis the presence of residual bile duct stones can be assessed electively by MRCP or endoscopic ultrasound in the recovery phase of the acute episode and, if present, removed at the time of ERCP. To prevent a recurrent episode of pancreatitis cholecystectomy should be carried out as soon as feasible after the acute episode has resolved.

Complications of acute pancreatitis (Table 7.22)

Within the first 7 days, the morbidity and mortality of acute pancreatitis reflect the systemic inflammatory response, which in turn results in multiple organ failure. After this initial period, the prognosis thereafter is most closely related to the extent of pancreatic necrosis. This can be most accurately assessed by contrast-enhanced CT, which should be carried out in all patients with severe disease after the first week. Extensive necrosis (>50% of the pancreas) is associated with high risk of further complicated disease, frequently requiring surgical intervention.

Table 7.22 Complications of acute pancreatitis

Systemic	Systemic inflammatory response syndrome (SIRS)
	Multiorgan dysfunction (MOD)
Pancreas	Pancreatic fluid collections
	Necrosis ± infection
	Pancreatic abscess
	Pancreatic pseudocyst (after 4–6 weeks)
Lungs	Pleural effusion
	ARDS – hypoxia
	Pneumonia
Kidney	Acute kidney injury
Gastrointestinal tract	Gastrointestinal bleeding from gastric or duodenal erosions
	Paralytic ileus
Hepatobiliary	Jaundice
	Common bile duct obstruction
	Portal vein thrombosis
Metabolic	Hypoglycaemia
	Hyperglycaemia
	Hypercalcaemia
Haematological	Disseminated intravascular coagulation (DIC)

In this minority of patients with extensive necrosis of the pancreatic and peripancreatic tissues, superimposed infection is associated with a greatly increased risk of mortality. The established techniques of open surgical debridement are being challenged by ‘minimally invasive’ endoscopic necrosectomy through transgastric, laparoscopic, and retroperitoneal routes. The aims of intervention are to control infection, evacuate devitalized tissues (that are the culture medium for invasive infection), and promotion of conditions for healing.

There is now a consensus that the best outcomes from intervention are achieved when debridement is delayed until approximately 4 weeks after the onset of pancreatitis. When the damaged area has been walled off and liquefaction has begun a pseudocyst develops. If necessary, acute sepsis can be preliminarily controlled by percutaneous drainage as a bridge to the later evacuation of the more solid elements within the necrotic tissue. Although percutaneous drainage alone has been associated with some success in the treatment of pancreatic ‘abscesses’, the success rate in definitively treating infected necrotic tissue without the need for débridement is limited.

Long-term outcome

The vast majority of patients with a mild to moderate episode of acute pancreatitis will make a full recovery with no long-term sequelae. Recurrent episodes of pancreatitis may occur, particularly if there has been any long-term pancreatic ductular damage. Patients with more severe acute pancreatitis may become pancreatic insufficient both with respect to exocrine (malabsorption) and endocrine function (diabetes).

Chronic pancreatitis

Aetiology

In developed countries, alcohol is reported to be the only aetiological factor in 60–80% of cases. There is a sizeable list of other reported aetiological factors which can be categorized into toxic-metabolic, genetic, autoimmune, recurrent acute or severe acute pancreatitis, obstruction and idiopathic categories (Table 7.18).

FURTHER READING

Braganza JM, Lee SH, McCloy RF et al. Chronic pancreatitis. Lancet 2011; 377:1184–1197.

Pathogenesis

There is increasing evidence that an increase in activated trypsin within the pancreas is a common pathway for the development of chronic pancreatitis. This may occur as a result of increased/premature activation of trypsinogen to trypsin or by impaired inactivation/clearance of the activated enzyme from the pancreas. It is believed that the increased/prolonged intrapancreatic enzyme activity leads to the precipitation of proteins within the duct lumen in the form of plugs. These then form a nidus for calcification but are also the cause of ductal obstruction leading to ductal hypertension and further pancreatic damage (Fig. 7.39).

Figure 7.39 Histology of chronic pancreatitis. There is considerable loss of acini and replacement by fibrosis. Inflammatory cells are relatively inconspicuous at this late stage. Islets of Langerhans (one is arrowed) sometimes escape destruction but their loss can result in diabetes mellitus.

(From Underwood JC (ed.) General and Systematic Pathology, 4th edn. Edinburgh: Churchill Livingstone; 2004, with permission).

In the case of alcohol-related chronic pancreatitis there is evidence that alcohol impairs calcium regulation leading to increased levels. These in turn promote trypsinogen activation as well as diminishing the inactivation pathway. The observation that the vast majority of people drinking excess alcohol do not develop pancreatitis suggests that the disease process is a complex interaction of different mechanisms. It is proposed that the alcohol is only one factor which interacts with other environmental and/or genetic influences (see below).

Genetic aspects of chronic pancreatitis

A number of genetic factors have been identified which influence the process of trypsin activation and inactivation. Cationic trypsinogen is the major form of trypsinogen produced in the pancreas and encoded by the PRSS1 gene (Fig. 7.40). Gain of function mutations of this gene are recognized as the major factor in hereditary pancreatitis, an autosomal dominant condition with variable penetrance.

Figure 7.40 Genetic factors in trypsinogen activation and trypsin inactivation. Early activation of trypsinogen to trypsin within the pancreas is crucial in the development of pancreatitis. Trypsinogen activation is promoted by cationic trypsinogen mutations (PRSS1+), active trypsin, high calcium (Ca²⁺) and low pH. Calcium levels are regulated in part by calcium-sensing receptor (CASR) and dysregulated by ethanol (EtOH). Active trypsin degradation is facilitated by CTRC and by other active trypsin molecules, but blocked by high calcium. Active trypsin within the pancreas leads to pancreatic injury, which leads to an acute inflammatory response (AIR). AIR upregulates expression of serine protease inhibitor Kazal 1 (SPINK1), which blocks active trypsin and therefore prevents further activation of trypsinogens and limits further tissue injury. Cystic fibrosis transmembrane conductance regulator (CFTR) represents an extra-acinar cell mechanism to eliminate trypsin by flushing it out of the pancreatic duct and into the duodenum.

(Adapted from Whitcomb DC 2010 Genetic aspects of pancreatitis Annual Reviews of Medicine 61:413–424.)

Calcium levels within the pancreas have a role in the process of activation and inactivation of trypsinogen/trypsin and are in part modulated by the calcium sensing receptor. Mutations coding for this receptor have been associated with pancreatitis and are believed to facilitate the damaging effects of alcohol on the pancreas.

The serine protease inhibitor Kazal type 1 (SPINK-1) is a specific trypsin inhibitor and is co-secreted with trypsinogen by the acinar cells. Loss of function mutations of the SPINK-1 gene have been associated with the development of chronic pancreatitis and in particular as a factor in the development of tropical pancreatitis (almost certainly interacting with environmental triggers).

Chymotrypsin C is produced in trace amounts by the acinar cells and has also been shown to have a role in trypsin inactivation. Loss of function mutations of the encoding gene have been identified in patients with chronic pancreatitis.

The cystic fibrosis transmembrane conductance regulator (CFTR) is expressed on the apical surface of the acinar cells and is responsible for maintaining a high volume bicarbonate rich pancreatic secretion. This high volume secretion is responsible for flushing the activated trypsin into the duodenum. The homozygote or complex heterozygote CFTR mutations associated with the cystic fibrosis disease state are almost always manifest by perinatal/early pancreatic exocrine failure (see p. 366). Recent work has identified an increased frequency of a single CFTR mutation in patients with idiopathic chronic pancreatitis.

The identification of this genetic component to the development of chronic pancreatitis has led to speculation that in many cases the evolution of the disease is dependent upon complex interaction of gene–gene and gene–environmental factors.

Autoimmune chronic pancreatitis (ACP)

This condition is now recognised as one of the IgG4-related disorders which include autoimmune cholangitis, Reidel’s thyroiditis, aortitis and tubulo-interstitial nephritis. In all these disorders there is a raised serum IgG4 level and pathologically there is a dense lymphoplasmacytic infiltrate with many IgG4-positive plasma cells, a mild to moderate eosinophil infiltrate and an obliterative phlebitis in some organs, e.g. pancreas. ACP is one of the few settings in which the pathogenesis of the disease may be independent of the activated trypsin pathway. The hallmark of autoimmune pancreatitis is the evidence of responsiveness to steroids. Two types have been identified. The most common variant (type 1) is seen predominantly in middle-aged men and associated with raised serum and tissue levels of IgG4. Other autoantibodies including those directed towards nuclear and smooth muscle antigens are also observed. Extrapancreatic tissue involvement is common including the biliary tree (autoimmune cholangitis see above) as well as thyroid, salivary gland, and renal. The second variant (type 2) tends to occur in early midlife with equal sex distribution and does not have the autoimmune markers described for type 1. This type is commonly seen in association with inflammatory bowel disease.

The presentation of autoimmune pancreatitis is varied particularly in type 1 in which extrapancreatic disease may predominate. Abdominal pain and weight loss are common features and jaundice may be an early symptom both secondary to bile duct obstruction by the inflamed head of pancreas as well as a manifestation of cholangitis seen in type 1 cases.

Clinical features

Pain is the most common presentation of chronic pancreatitis. It is usually epigastric and often radiates through into the back. The pattern of pain may be episodic, with short periods of severe pain, or chronic unremitting. Exacerbations of the pain may follow further alcohol excess although this is not a uniform relationship.

During periods of abdominal pain anorexia is common and weight loss may be severe. This is particularly so in those patients with chronic unremitting symptoms. Exocrine and endocrine insufficiency may develop at any time, and occasionally malabsorption or diabetes is the presenting feature in the absence of abdominal pain. Jaundice secondary to obstruction of the common bile duct during its course through the fibrosed head of pancreas may also occur and may be a presenting feature in a small proportion of patients.

Investigations

The extent to which investigations are required is dependent upon the clinical setting.

Serum amylase and lipase levels may be elevated but in advanced disease there may not be sufficient residual acinar tissue to produce this elevation.

Faecal elastase level will be abnormal in the majority of patients with moderate to severe pancreatic disease.

Gene mutation analysis in selected cases in whom the aetiology is uncertain. Common mutations of the PRSS1, SPINK-1 and CFTR encoding genes are available via reference centres.

Transabdominal ultrasound scan is used for initial assessment.

Contrast-enhanced spiral CT scan provides a more detailed assessment. In the presence of pancreatic calcification and a dilated pancreatic duct the diagnosis of chronic pancreatitis can be easily established (Fig. 7.41). This may be much more difficult when these features are not present and in particular with an atypical presentation such as with steatorrhoea alone.

MRI with MRCP is increasingly utilized to define more subtle abnormalities of the pancreatic duct which may be seen in non-dilated chronic pancreatitis.

Endoscopic ultrasound is used increasingly when doubt about the diagnosis remains after the above imaging or specifically for assessing complications of chronic pancreatitis including pseudocyst formation and possible development of malignancy.

Diagnostic ERCP has been replaced by MRCP.

Figure 7.41 Contrast-enhanced CT scan demonstrating multiple calcific densities (arrow) along the line of the main pancreatic duct in a patient with chronic pancreatitis.

FURTHER READING

Stone JH et al. IgG4-related disease. N Engl J Med 2012; 366:539−551.

Differential diagnosis

The differential diagnosis is that of pancreatic malignancy. Carcinoma of the pancreas can reproduce many of the symptoms and imaging abnormalities that are commonly seen with chronic pancreatitis. The diagnosis of malignancy should be considered in patients with a short history and in whom there is a localized ductular abnormality. Considerable difficulties may arise when a malignancy develops on the background of established chronic pancreatitis (the latter being a recognized premalignant lesion).

High-quality imaging is able to define malignant features with a localized mass lesion, local invasion and lymph node enlargement. Endoscopic ultrasound may provide the most accurate assessment of a potential mass lesion.

Treatment

In patients with alcohol-related chronic pancreatitis long-term abstinence is likely to be of benefit although this has been difficult to prove.

Abdominal pain. For short-term flare-ups of pain a combination of a non-steroidal anti-inflammatory drug and an opiate (tramadol) is usually sufficient for symptomatic relief. In patients with chronic unremitting pain this may be inadequate and also risks opiate dependance.

Tricyclic antidepressants (e.g. amitriptyline) and membrane stabilizing agents (e.g. pregabalin) are used for chronic pain and reduce the need for opiates. Coeliac axis nerve block may produce good pain relief but is unreliable in its extent and duration of action. In the majority of patients some spontaneous improvement in pain control occurs with time. After a 6–10-year period, some 60% of patients will become pain-free. For patients with recurrent severe or debilitating chronic pain, both endoscopic and surgical intervention has been used but with limited success. The endoscopic approach has centred upon improving duct drainage by removing intraductal stones and repeated stenting to maintain duct patency. Extracorporeal shock wave lithotripsy has been used to fragment stones within the head of pancreas. Surgical intervention usually involves a duct drainage procedure combined with partial resection of the diseased head of pancreas. Improved symptom control following surgical intervention as compared with the endoscopic approach has been demonstrated. However, it is reasonable to attempt endoscopic therapy as a first measure.

Steatorrhoea. The steatorrhoea associated with pancreatic insufficiency may be high, with up to 30 mmol of fat lost per 24 h. This will usually improve with pancreatic enzymes supplements. Current preparations are presented in the form of microspheres which reduce the problems of acid degradation in the stomach. An acid suppressor (H₂-receptor antagonist or proton pump inhibitor) is also given. Despite this, a proportion of patients continue to malabsorb, usually reflecting the inadequate mixing of the pancreatic supplements with the food as well as the low pH in the duodenum secondary to inadequate pancreatic bicarbonate production. There is no justification to reduce fat intake below the recommended levels of a normal diet as this will contribute to malnutrition seen in patients with chronic pancreatitis.

Diabetes associated with pancreatic endocrine failure may be difficult to control, with a rapid progression from oral hypoglycaemic agents to an insulin requirement. Brittle control is a common problem secondary to inadequate glucagon production from the damaged pancreas.

FURTHER READING

Conwell DL, Banks PA. Chronic pancreatitis. Curr Opin Gastroenterol 2008; 24(5):586–590.

Pannala R, Chari ST. Autoimmune pancreatitis. Curr Opin Gastroenterol 2008; 24(5):591–596.

Complications

The most common structural complication of chronic pancreatitis is a pancreatic pseudocyst, a fluid collection surrounded by granulation tissue (see p. 364). These usually occur in relationship to a period of enhanced inflammatory activity within the pancreas giving abdominal pain but may develop silently during what would appear to be a stable phase. Intra- or retroperitoneal rupture, bleeding or cyst infection may occur. The larger cysts may occlude nearby structures including the duodenum and the bile duct. In pseudocysts less than 6 cm in diameter, spontaneous resolution can be anticipated. In larger cysts that have been present for a period in excess of 6 weeks, resolution is less common and a long-term complication rate of approximately 30% can be anticipated. Many pseudocysts are closely apposed to the posterior wall of the stomach or duodenum and can be successfully drained endoscopically using endoscopic ultrasound to identify the optimum drainage site. A direct fistula is created between the pseudocyst lumen and the gastric or duodenal lumen which is then kept patent by the insertion of plastic stents. This approach will be successful in approximately 75% of cases. Surgical drainage is required for failures of endoscopic therapy or in circumstances in which the pseudocyst anatomy does not allow endoscopic access.

Ascites and occasionally pleural effusions can be a direct consequence of chronic pancreatitis when there has been disruption of the main pancreatic duct. A high ascites or pleural fluid amylase will confirm the aetiology. Such disruptions of the main pancreatic duct require surgical intervention.

There is an increased risk of pancreatic cancer in patients with chronic pancreatitis. This may be as high as 15% in patients with alcohol-associated disease. The highest incidence has been reported in hereditary pancreatitis when the lifetime risk is as high as 40%. This has prompted the introduction of surveillance programmes for this very high risk group, usually starting around the age of 40 years and relying upon yearly imaging and tumour marker measurement.

Cystic fibrosis

Some 85% of people with cystic fibrosis (see p. 44 and Chapter 16) will have pancreatic failure, and in the majority of these, this will develop in utero and be present from the perinatal period.

Treatment of pancreatic disease

The management of pancreatic insufficiency is necessary to optimize the growth and overall nutrition. Pancreatic supplements are closely titrated against the level of steatorrhoea. Fat intake should be maintained to avoid nutritional deficit. Enteric-coated supplements should be taken during the meal. A daily lipase intake of up to 10 000 units/kg bodyweight is required. Higher doses of enteric-coated preparations are available but have been implicated in right-sided colon stricture formation in children. The exact mechanism is unknown but these preparations are no longer recommended in children.

Increasing the jejunal pH with an H₂-receptor antagonist or a proton pump inhibitor can improve absorption. About 11% of patients will develop clinically significant diabetes mellitus, often insulin dependent.

Carcinoma of the pancreas

Incidence of pancreatic cancer in the West has been estimated at approximately 10 cases per 100 000, with no increase over the last 20 years. Pancreatic cancer is now the fifth most common cause of cancer death in the western world. The incidence increases with age and the majority of cases occur in patients over the age of 60. Approximately 60% of patients with this condition are male. Some 96% of pancreatic cancers are adenocarcinoma in type and the large majority are of ductal origin.

Aetiology. Smoking is associated with a two-fold increase. Excess intake of alcohol, intake of coffee and use of aspirin have been implicated. There is an increased incidence of pancreatic cancer among patients with a history of diabetes and chronic pancreatitis. Approximately 5–10% of patients with pancreatic cancer have a family history of the disease.

Pathogenesis. In some patients, pancreatic cancer develops as part of a well-defined cancer-predisposing syndrome for which germline genetic alterations are known (Table 7.23). A genetic factor has been suggested, as the risk of pancreatic cancer is 57 times as high in families with four or more affected members as in families with no affected members. The genetic bases for these associations are not known, although a subgroup of such high-risk kindred carry germline mutations of DNA repair genes such as BRCA2 and the partner and localizer of BRCA2.

Table 7.23 Relative risks of pancreatic cancer in patients who have a family history or carry gene mutations associated with the disease

Risk factor	Relative risk
Familial pancreatic cancer
2 first-degree relatives affected	18
3 first-degree relatives affected	57
Hereditary pancreatic cancer syndromes
BRCA2 mutation	5.9
Familial atypical multiple mole melanoma	16
Peutz–Jeghers syndrome	36
Hereditary pancreatitis	50

Data suggest that pancreatic cancer results from the successive accumulation of gene mutations. The cancer originates in the ductal epithelium and evolves from premalignant lesions to fully invasive cancer. The lesion called pancreatic intraepithelial neoplasia (PanIN) is the best-characterized histologic precursor of pancreatic cancer. The progression from minimally dysplastic epithelium (PanIN grades 1A and 1B) to more severe dysplasia (grades 2 and 3) and finally to invasive carcinoma is paralleled by the successive accumulation of mutations that include activation of the KRAS2 oncogene, inactivation of the tumour-suppressor gene CDKN2A (which encodes the inhibitor of cyclin-dependent kinase 4 [INK4A]), and, last, inactivation of the tumour-suppressor genes TP53 and deleted in pancreatic cancer 4 (DPC4, also known as the SMAD family member 4 gene [SMAD4]) (Fig. 7.42).

Figure 7.42 Genetic model for the development of pancreatic ductal adenocarcinoma. The stages indicate histological progression with specific gene alterations. PanIN, pancreatic intraepithelial neoplasia.

(Modified from Maitra A, Adsay NV, Argani P et al. Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Modern Pathology 2003; 16:902–912, with permission from the Nature Publishing Group.)

A small percentage of pancreatic adenocarcinomas arise from cystic lesions including intraductal papillary mucinous tumours (IPMT) and mucinous cystic neoplasia (see below). There is evidence that these cystic neoplasms demonstrate a similar multistep genetic and histological progression to invasive adenocarcinoma.

FURTHER READING

Koorstra J-B, Hustinx SR, Offerhaus GJ et al. Pancreatic carcinogenesis. Pancreatology 2008; 8:110–125.

Clinical picture

Pancreatic adenocarcinoma may be viewed clinically as two diseases – the lesions of the head and lesions of the body and tail.

Symptoms

Head of pancreas and the ampulla of Vater. This is the most frequent site for cancer to develop. It tends to present earlier with obstruction to the bile duct as this passes through the head of pancreas giving jaundice (Fig. 7.43). These more localized lesions are usually painless, although pain may become a feature with tumour progression. Obstruction of the pancreatic duct may lead to symptomatic episodes of pancreatitis. Pancreatic damage secondary to duct obstruction is frequently associated with abnormalities of glucose homeostasis. Pancreatic cancer should be considered in the differential diagnoses of acute pancreatitis and newly diagnosed diabetes.

Figure 7.43 Carcinoma of the head of the pancreas. A diagrammatic representation of the close relationship of a carcinoma of the head of pancreas to the surrounding structures.

Carcinoma localized to the body or tail of the pancreas is much more likely to present with abdominal pain as well as nonspecific symptoms such as anorexia and weight loss. The pain is often dull in character with radiation through into the back. A characteristic feature is partial relief of pain by sitting forward. Bile duct obstruction and jaundice may infrequently be late phenomena.

Physical signs

Carcinoma of the head of pancreas. The patient is jaundiced with characteristic scratch marks secondary to cholestasis. In a proportion of cases, the gall bladder will be palpable (Courvoisier’s sign). With metastatic disease, a central abdominal mass may be palpable as well as hepatomegaly.

Carcinoma of the body and tail. There are often no physical signs.

Other presenting physical signs include thromboembolic phenomena, polyarthritis and skin nodules. The latter are secondary to localized fat necrosis and associated inflammation. These manifestations, distant to the tumour itself, have not been fully explained but may precede the overt presentation of pancreatic cancer by months to years.

Investigations

Transabdominal ultrasound is the initial investigation in the majority of patients. In the presence of bile duct obstruction this will confirm dilated intrahepatic bile ducts as well as a mass in the head of the pancreas. Ultrasound is less reliable when the cancer is found in the body and tail of the pancreas because of overlying bowel gas, with a sensitivity of detection of 60%.

Contrast-enhanced CT scan should confirm the presence of a mass lesion (Fig. 7.44). It is also necessary prior to possible surgical resection with contrast providing vascular definition to exclude tumour invasion as well as local lymph node involvement and distant metastases.

Laparoscopy is also used for preoperative assessment.

ERCP is usually restricted to palliative treatment but may provide a source of cytology to confirm the diagnosis when this is in question.

Percutaneous needle biopsy is discouraged in potentially operable cases as this may be a source of tumour cell spread within the peritoneum. If palliative chemotherapy is considered, a histological diagnosis is essential prior to treatment.

MRI scanning and endoscopic ultrasound are techniques that are useful in a small proportion of patients in whom the tumour has not been adequately defined. Endoscopic ultrasound is now the technique of choice to obtain histological/cytological confirmation of malignancy (Fig. 7.45).

Several tumour markers have been evaluated for the diagnosis and monitoring of pancreatic cancer. The CA19–9 has a high sensitivity (80%) but a high false-positive rate. In individual patients, single values of these tumour markers may be of little help but a progressive elevation over time is often diagnostic, and in such circumstances tumour marker levels can be used to monitor response to treatment.

Figure 7.44 A contrast-enhanced CT scan showing a cancer of the body of the pancreas. There is retroperitoneal tumour extension enclosing the branches of the coeliac axis (arrow).

Figure 7.45 Pancreatic cancer. An endoscopic ultrasound scan with the probe in the distal stomach. The patient presented with intractable periumbilical pain. A mass lesion of the pancreatic body is defined (tumour). There is invasion by the lesion into the splenic vein (SV) (vasc invasion). The line of a trans-endoscopic needle is seen (needle tip), which has been placed under the guidance of the ultrasound probe to obtain a needle aspirate for cytological diagnosis.

Differential diagnosis

The diagnosis should not be difficult in the presence of painless jaundice or epigastric pain radiating into the back with progressive weight loss. Unfortunately, many patients present with very minor symptoms including pain, change in bowel habit and weight loss. Imaging, particularly abdominal CT, should be performed if pancreatic cancer is suspected. IgG4-related autoimmune pancreatitis is now recognized as a differential diagnosis in patients presenting with abdominal pain, possible jaundice and an abnormal pancreas on imaging (localised or diffuse enlargement) (see above). Pancreatic cancer may rarely present with recurrent episodes of typical acute pancreatitis.

Management

The 5-year survival rate for carcinoma of the pancreas is approximately 2–5%, with surgical intervention representing the only chance of long-term survival. Approximately 20% of all cases have a localized tumour suitable for resection but in an elderly population many of these have co-morbid factors that preclude such major surgery. To optimize the percentage of patients undergoing possible surgical resection it is necessary to review each case in a multidisciplinary meeting. This approach also allows formulation of treatment strategies for those considered unsuitable for surgery.

Obstructive jaundice will occur at some stage in 70% of cases and is a debilitating complication, often associated with severe pruritus but also the cause of nonspecific malaise, lethargy and anorexia.

Endoscopic placement of endoprostheses (stents) offers excellent palliation with a low associated procedural morbidity and mortality (see above).

Palliative surgery has a role in duodenal obstruction (a complication seen in 10% of cases) but in advanced disease self-expanding metal stents can be placed across the duodenal obstruction with excellent short-term results.

Radiotherapy results have been disappointing (see p. 479).

Chemotherapeutic agents (see p. 479) have been shown to have survival benefit in patients treated as adjuvant therapy to pancreatic resection. New targeted agents are in clinical development.

With disease progression, abdominal pain is a frequent complicating factor which may prove extremely difficult to treat. This is best managed by experienced palliative care teams which offer a multidisciplinary approach. Endocrine and exocrine pancreatic failure occur and are managed as described on page 366.

Cystic tumours of the pancreas

Cystic lesions of the pancreas are not uncommon. Seventy-five per cent of these lesions will be pseudocysts (see above) but of the remainder the majority are true cystic neoplasms.

Serous cyst adenomas are composed of multiple small cystic cavities lined by cuboidal glycogen-rich, mucin-poor cells. These lesions tend to occur in an elderly age group and are often an asymptomatic finding. Malignant transformation in a serous cystadenoma is extremely rare. Larger serous cystadenomas may cause local compressive complications (when over approximately 5 cm).

Mucinous cyst adenomas are almost exclusively found in women in the 5th and 6th decades and are sited in the pancreatic body and tail. Multilocular cysts are lined by tall mucin-synthesizing cells. Of these lesions, 20% are malignant at the time of presentation and the majority appear to have a malignant potential. As a consequence, they are much more likely to produce symptoms.

Intraductal papillary mucinous tumour (IPMT) is a pancreatic cystic neoplasm that can arise from either the side branches or the main duct. The majority are found in men between the ages of 60 and 70. The presentation is usually with pancreatic pain but may be an incidental finding. The lesion is slowly progressive with a significant malignant potential; this appears to be more so when the main duct is the site of origin.

There is a high potential for the development of malignancy in cystic lesions and therefore resection is usually appropriate. The decision-making process may be difficult in patients with small (<3 cm) lesions of the head of pancreas (in the absence of confirmed malignancy at presentation) and in whom there are significant risks associated with surgery. An initial conservative approach with follow-up imaging may be justified. The differentiation between pseudocysts and true cystic neoplasms may be difficult, even with multiple imaging techniques. Patients with pseudocysts may have a history of pancreatitis. Endoscopic ultrasound scanning and fine-needle aspiration can be helpful in the differentiation. The measurement of cyst fluid CEA and CA19–9 may help to identify malignant change.

Neuroendocrine tumours of the pancreas

The incidence and prevalence of pancreatic endocrine tumours have increased during the last two decades, reaching an incidence of 4–5/1 000 000 population. They represent a heterogeneous group of tumours with varying tumour biology and prognosis and 40–50% of the patients present with symptoms related to the substances released from the tumours (see below). The remainder are referred to as ‘non-functioning’ and usually present with symptoms related to tumour bulk such as obstruction, jaundice, bleeding and abdominal mass. Of pancreatic endocrine tumours, 10–15% are linked to an inherited syndrome such as the multiple endocrine neoplasia type 1 (MEN-1).

Diagnosis is based upon a combination of biochemical and histopathological markers. The histopathology includes features such as positive staining for chromogranin A and specific hormones such as gastrin, proinsulin, and glucagon. The biochemical diagnosis includes measurement of circulatory chromogranin A or specific hormones such as gastrin, insulin, glucagon and vasoactive intestinal polypeptide (VIP).

Investigation and management

Tumour localization depends upon cross-sectional imaging, including CT and MRI scanning. The majority of neuroendocrine tumours express somatostatin receptors and can be mapped by scintigraphy. Recently, positron emission tomography (PET scanning) with specific isotopes such as ¹¹C-5-hydroxytryptamine (¹¹C-5-HTP), fluorodopa and ⁶⁸Ga (DOTA)-octreotate have been introduced.

Where possible, surgery of the primary lesion is the optimal management of pancreatic endocrine tumours. The propensity of many endocrine tumours to metastasize early precludes cure in many cases. Debulking of the tumour including liver metastases is frequently carried out to facilitate systemic treatment. The chemotherapeutic agents, streptozotocin, 5-fluorouracil and doxorubicin, produce partial remission in approximately 40% of cases.

Somatostatin analogues are used to control hormonal related symptoms and also have a tumour modulating effect. Recent advances include the introduction of tyrosine kinase and the mammalian target of rapamycin (mTOR) inhibitors (see p. 446). Radionuclide therapy using somatostatin analogues has proven benefit in patients with tumours that express high content of somatostatin receptors. In the future, treatment will be based on individualized tumour biology and molecular genetics.

The islets of Langerhans (p. 360) have the capacity to synthesize more than one hormone. They also synthesize ectopic hormones that are not usually found in the pancreas such as gastrin, adrenocorticotrophin, vasoactive intestinal peptide and growth hormone. While many pancreatic endocrine tumours are multihormonal, one peptide tends to predominate and is responsible for the clinical syndrome. Other tumours, while containing peptide hormone, are functionally inactive.

These tumours are rare with an incidence of less than 1 in 100 000 of the population. Insulinomas are the commonest variant (50%), gastrinomas account for 20% and the rarer functioning tumours 5%. The remaining 25% are non-functioning tumours. Approximately 25% of islet cell tumours are associated with a multiple endocrine neoplasia syndrome (type 1) (see p. 997). The majority of the endocrine neoplasia pancreatic tumours are malignant in their behaviour.

Presentation of pancreatic neuroendocrine tumours is most commonly related to the actions of ectopic hormone secretion. Identification of the primary and possibly metastatic lesions may be difficult despite multiple imaging techniques. Endoscopic ultrasound may be the most sensitive means of detecting small tumours. Many of these tumours have somatostatin receptors, and radiolabelled somatostatin analogue (such as octreotide) scanning provides a means of tumour localization.

Treatment options for pancreatic neuroendocrine tumours require a multidisciplinary approach and depend upon the presence or absence of metastatic (usually hepatic) disease. Surgical resection of the pancreatic lesion is the only potential curative approach. Aggressive surgical intervention including a resection of the primary lesion as well as liver resection for metastasis has been used in selected cases. Somatostatin analogues such as octreotide and lanreotide have been used specifically for the control of symptoms secondary to the hormonal secretion.

There is some evidence that the somatostatin analogues combined with interferon-α also control tumour proliferation. The chemotherapeutic agents, streptozotocin, 5-fluorouracil and doxorubicin, produce partial remission in approximately 40% of cases. Pancreatic neuroendocrine tumours show a very high degree of vascularization as well as abundant production and secretion of growth factors. There is preliminary evidence of benefit from antiangiogenesis therapy utilizing vascular endothelial growth factor (VEGF) antagonists. Antagonists to a number of oncogenic growth factors are currently under investigation.

In patients with extensive liver metastasis, occlusion of the arterial blood flow by hepatic arterial embolization may control hormone-related symptoms. In most cases the tumours are slowly progressive and may allow a reasonable quality of life for many years.

Clinical syndromes

Insulinoma is described on page 1031.

A gastrinoma accounts for approximately 1 in 1000 cases of duodenal ulcer disease. This results from hypersecretion of gastric acid secondary to ectopic gastrin secretion within the endocrine pancreas (Zollinger–Ellison syndrome). Recurrent severe duodenal ulceration occurs with only a partial response to acid suppression. The diagnosis is confirmed by an elevated gastrin level. High-dose proton pump inhibitors are used to suppress symptoms.

A VIPoma is an endocrine pancreatic tumour producing vasoactive intestinal polypeptide (VIP). This causes a severe secretory diarrhoea secondary to the stimulation of adenyl cyclase within the enterocyte (Verner–Morrison syndrome). The clinical syndrome is one of profuse watery diarrhoea, hypokalaemia and a metabolic acidosis. To produce the syndrome, the tumours are usually in excess of 3 cm in diameter.

Glucagonomas are rare α-cell tumours which are responsible for the syndrome of migratory necrolytic dermatitis, weight loss, diabetes mellitus, deep vein thrombosis, anaemia and hypoalbuminaemia. The diagnosis is made by measuring pancreatic glucagon in the serum.

Somatostatinomas are rare malignant D cell tumours of the pancreas and 30% occur in the duodenum and small bowel. These tumours cause diabetes mellitus, gallstones and diarrhoea/steatorrhoea. They can be diagnosed by high serum somatostatin levels.