Category Archives: Liver biliary tract and pancreatic diseases

Endocrine tumours

These turnours arise in the pancreas from APUD (amine precursor uptake and decarboxylation) cells and are sometimes called apudomas. Pancreatic endocrine tumours can occur in association with other endocrine turnours, particularly parathyroid adenoma and pituitary adenoma, as part of multiple endocrine neoplasias. Endocrine turnours predominantly secrete one hormone that produces its clinical effect, but other hormones are often synthesized and can be detected either in the blood or in the resected tumour.

Gastrinoma (Zollinger-Ellison syndrome)

These turnours mainly arise from G cells in the pancreas and secrete large amounts of gastrin. This stimulates maximal gastric acid secretion, so that the main clinical problem is peptic ulceration. Peptic ulcers occur in the usual areas of the stomach and duodenum and also in the jejunum. The ulcers are often large and deep and sometimes multiple. Haemorrhage and perforation can occur.
Diarrhoea due to the low pH in the upper intestine is also a common feature. Jejunal mucosal abnormalities are also seen. A high serum gastrin confirms the diagnosis. Acid studies show high acid output. Treatment is with omeprazole (which inhibits the H+-K+ proton pump necessary for acid secretion). Octreotide is also used. Surgery is reserved for removal of the primary tumour only. The tumour may be demonstrated by scans or local venous sampling for gastrin. These tumours are malignant and although they grow slowly the patients now die of malignancy rather than gastrointestinal problems if the  primary cannot be removed.

Other endocrine tumours

ISLET CELL TUMOURS. These are described.

VIPOMAS. These rare pancreatic tumours produce severe intestinal secretion and watery diarrhoea leading to dehydration. VIP is a neurotransmitter that stimulates adenyl cyclase to produce intestinal secretion. Plasma concentrations of VIP are very high and are diagnostic. Levels of PP hormone are also raised. The role of peptide histidine isoleucine (PHI), levels of which are also raised in this condition, is uncertain but this hormone may be involved in secretion.
Corticosteroids help reduce the stool volume but octreotide is the most effective agent. An attempt should be made to localize the tumour and, if possible, it should be resected.
GLUCAGONOMAS. These are a-cell turn ours of the pancreas that produce pancreatic glucagon. The patients have diabetes mellitus and a unique characteristic necrolytic migratory erythematous rash. The diagnosis is made by measuring pancreatic glucagon in the serum. A tumour originating in the right kidney has been described that produces marked hypertrophy of the villi in the jejunum and produces enteroglucagon (enteroglucagonoma).
SOMATOSTATINOMAS. These have also been described; they produce diabetes, steatorrhoea and weight loss.

Further reading

Go VL, Dimagno EP, Gardner J, Lebenthal E, Reber HA & Scheele GA (1993) The Pancreas, Biology, Pathology and Disease, 2nd edn. New York: Raven Press. Millward-Sadler GH, Wright R & Arthur MJP (1993) Wright’s Liver and Biliary Disease, 3rd edn, Volumes I and II. London: WB Saunders.
Sherlock S & Dooley J (1993) Diseases of the Liver and Biliary System, 9th edn. Oxford: Blackwell Scientific Publications.
Sieisenger MH & Fordtran JS (1993) Gastrointestinal Disease, 5th edn. Philadelphia: WB Saunders.
New England Journal of Medicine progress reports and current concepts, e.g. Runyon BA (1993) Current concepts. Care of patients with ascites. New England Journal of Medicine 330 (5), 337-342. Baillieres Clinical Gastroenterology series, e.g. Sackmann M (ed) (1992) Diagnosis and Management of Biliary Stones. London: Bailliere Tindall. Current Opinions in Gastroenterology- useful updates with extensive references.
Major journals such as Gastroenterology, Gut and Hepatology- monthly reviews and progress reports of current topics.

Carcinoma of the pancreas

The incidence of pancreatic carcinoma is steadily increasing in Western countries. This tumour is now the fourth commonest cause of cancer death in the UK and USA. The incidence increases with age and most patients are over 60 years of age. Males are affected more than females.
There are no known aetiological factors, but the increasing incidence has been attributed to an increase in both smoking and the consumption of alcohol. Excessive coffee and dietary fats have also been implicated. Most carcinomas of the pancreas are adenocarcinomas arising from duct epithelium. In 60% of cases the tumour is in the head of the pancreas. The tumour spreads locally to involve lymph nodes and the liver.

CLINICAL FEATURES

CARCINOMA OF THE HEAD OF THE PANCREAS OR THE AMPULLA OF VATER presents with painless jaundice due to obstruction of the common duct. However, most patients will have pain at some time in the course of their disease. Weight loss also occurs.

CARCINOMA OF THE BODY OR TAIL OF THE PANCREAS

presents with abdominal pain, anorexia and weight loss. The pain is often a dull, boring pain that radiates through to the back. It may be relieved by sitting forward. Jaundice is rare. Diabetes may occur due to insulin resistance. This is now thought to be caused by islet amyloid polypeptide, a hormonal factor secreted from pancreatic 13 cells. There is an increased incidence of thrombophlebitis.
In carcinoma of the head of the pancreas, examination will reveal jaundice with the dilated gallbladder sometimes being palpable (Courvoisier’s sign). A dilated gallbladder is not found with gallstone disease because of the accompanying chronic inflammation of the gallbladder. A palpable mass can be felt in 20% of patients, with hepatomegaly being present in most cases eventually.

INVESTIGATION

Haematological or biochemical tests (including blood glucose) are not helpful. Diagnosis is usually made using ultrasound  or CT scan and confirmed by fine-needle or Trucut biopsy. However, in almost all cases, by the time the tumour is detected resection is impossible. Duodenoscopy with ERCP may detect tumours of the head of the pancreas or of the ampulla. MRI or endoscopic ultrasound may become useful aids to imaging.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis includes all causes of painless jaundice and persistent upper abdominal pain in the elderly.

MANAGEMENT

The 5-year survival rate is miserably low at 2%. Resection of the tumour with total pancreatectomy is not usually possible, and, as this operation carries a very high mortality (20%) and morbidity, it is seldom attempted. Jaundice from carcinoma of the head of the pancreas is usually relieved by a bypass procedure. This is now performed endoscopically with the placement of a stent through the narrowed area of the common bile duct to allow drainage. An expandable metal stent is now being used which remains patent longer. Surgical bypass where the common bile duct is anastomosed to the jejunum is now reserved for cases where the turnour has obstructed the duodenum. Chemotherapy and radiotherapy have had little success in decreasing mortality. Ampullary tumours have a better prognosis than pancreatic carcinomas and every attempt should be made to diagnose these rare lesions, as a resection in these cases can be performed. Pain and symptoms of anxiety and depression are an important part of management and analgesia with longacting oral morphines should be used liberally. Addiction is not a problem in these terminally ill patients. Palliative care teams play an important role in this distressing condition.

Ultrasound showing carcinoma of head of pancreas

Ultrasound showing carcinoma of head of pancreas

Cystic fibrosis

This is the commonest cause of pancreatic disease in childhood. It is inherited as an autosomal recessive condition and a specific gene deletion has been identified in 70% of cases. It has been suggested that the resultant protein defect produces an abnormality in the regulation of a J3-adrenergic-gated chloride channel in the cell membrane. This cystic fibrosis gene product has been named cystic fibrosis transmembrane conductance regulator (CFTR). This basic defect in all exocrine glands produces thick viscoid secretions causing cystic dilatation of the ducts. Increased numbers of patients are now surviving into adult life because of improved therapy.

CLINICAL FEATURES

DIAGNOSIS

SWEAT TESTING  of symptomatic people and siblings of patients with cystic fibrosis identifies 77% by 2 years of age and 95% by the age of 12 years. IN INFANTS, immunoreactive trypsin assay in dried
blood.

PANCREATIC FUNCTION TESTS

TREATMENT

Treatment is required for pancreatic insufficiency and respiratory problems. Steatorrhoea is treated with pancreatic supplements. High-dose pancreatin-containing trypsin and lipase can be given in microspherecontaining capsules which deliver high doses of enzyme to the duodenum for fat digestion. Recently, colonic strictures have been reported in a few patients and patients should be carefully monitored. H2 antagonists are not usually required with these new preparations and the fat content of the diet can be kept normal. Optimal nutrition has been recognized as improving prognosis and a high calorie intake (150% of recommended daily allowance) with vitamin supplements should be given.

Pancreatitis

Classification

The classification of pancreatitis is difficult due to the inability to clearly separate acute and chronic pancreatitis. The original 1983 Marseilles classification was reviewed in 1984 and 1988 and simplified into acute and chronic forms. It was agreed that alcohol, which previously was classified as only causing chronic pancreatitis, can now cause the first episode acutely.
By definition, acute pancreatitis may occur as isolated or as recurrent attacks. It is distinguished from chronic pancreatitis by the absence of continuing inflammation, irreversible structural changes and permanent loss of exocrine and endocrine pancreatic function. The causes of pancreatitis are shown.

Acute pancreatitis

This is an acute condition presenting with abdominal pain and raised pancreatic enzymes in the blood or urine, due to inflammatory disease of the pancreas.

PATHOGENESIS

The exact mechanism by which pancreatic necrosis occurs is unclear. Associated gallstones are mainly found in the gallbladder and only occasionally in the common bile duct. Reflux of bile up the pancreatic duct associated with occlusion of the ampulla may playa role in the pathogenesis. Autodigestion of the pancreas by proteolytic enzymes (particularly trypsin and phospholipase A) released in the pancreas rather than in the intestinal lumen may also be involved in the pathogenesis. Active enzymes could digest cell membranes, leading to proteolysis, oedema, vascular damage and necrosis. The mildest form of pancreatitis is characterized by intestinal oedema with an inflammatory exudate (oedematous pancreatitis), while in the severe form there is pancreatic necrosis and haemorrhage (haemorrhagic pancreatitis).

Causes of pancreatitis.

Causes of pancreatitis.

CLINICAL FEATURES

These vary depending on the severity of the attack. In all patients the principal symptom is abdominal pain that is usually localized to the epigastrium or upper abdomen. It may radiate to the back between the scapulae. The pain will vary from mild discomfort to excruciating pain in severe cases. Rarely, acute pancreatitis can occur in the absence of pain.
Nausea and vomiting accompany the pain in most cases.
In severe cases there may be multisystem failure and/or development of a complication, e.g. pseudocyst. Physical examination may reveal tenderness, guarding and rigidity of the abdomen, with varying degrees of shock depending on the severity of the attack. Rarely, body wall ecchymoses occur, e.g. umbilical (Cullen’s sign) or in the flanks (Grey Turner’s sign). The remaining clinical features depend on the local and systemic complications that occur.
Local pancreatic complications can occur with mild attacks of pancreatitis but systemic complications only occur with severe attacks.

INVESTIGATION AND DIAGNOSIS

The clinical manifestations are so varied that pancreatitis must be considered in the differential diagnosis of all causes of upper abdominal pain. Most present as an acute abdomen and differentiation from an acute perforated ulcer is the most difficult, as both may give rise to abdominal rigidity.

Complications of acute pancreatitis.

Complications of acute pancreatitis.

The diagnosis of acute pancreatitis depends on the serum amylase. A raised serum amylase level can be seen in other acute abdominal emergencies such as acute cholecystitis and perforated peptic ulcer, but if the serum amylase level is five times greater than normal, acute pancreatitis is very likely. However, the serum amylase cannot be entirely relied upon and must be evaluated in conjunction with the history and physical signs. A plain abdominal X-ray may show ileus initially limited to the loop of bowel (sentinel loop) or calcification in acute or chronic pancreatitis. If there is doubt about the diagnosis, exploratory laparotomy must be performed to exclude a potentially fatal but treatable non-pancreatic lesion. Peritoneal aspiration and lavage, with estimation of amylase in the peritoneal fluid obtained, is particularly useful in difficult cases. Ultrasound or contrast enhanced CT scan may reveal a swollen pancreas, sometimes with peri pancreatic fluid collections and gallstones, all of which help with the diagnosis. The differential diagnosis includes all acute abdominal conditions. Factors indicating the severity, which is assessed chiefly on blood investigations, are given . APACHE II score  is also used to grade severity.

TREATMENT

Nasogastric suction is necessary to reduce vomiting and abdominal distension even in mild cases. All feeding isstopped and in severe cases nothing is given by mouth for weeks and intravenous nutrition is required.
Water and electrolyte replacement and analgesia with an opiate (other than morphine) are necessary. No form of drug therapy has been shown to help; results of trials of somatostatin infusion have been disappointing. The efficacy of peritoneal lavage, which is sometimes used for severe cases, is in doubt. In some countries, surgery is used mainly to remove devitalized pancreatic tissue. Management of shock plus respiratory failure

CT showing severe acute pancreatitis (arrow) with a small effusion around the pancreas

CT showing severe acute pancreatitis (arrow) with a small effusion around the pancreas

Factors during the first 48 hours that indicate severe pancreatitis and a poor prognosis.

Factors during the first 48 hours that indicate severe pancreatitis and a poor prognosis.

LOCAL COMPLICATIONS

PHLEGMON. This is a solid inflammatory mass of pancreatic tissue that usually resolves spontaneously. PSEUDOCYSTS. Small pseudocysts are seen on ultrasound or CT in up to 50% of cases of severe pancreatitis, but do not usually require treatment per se. Large collections persisting for weeks can be aspirated under ultrasonic control or removed surgically.

PANCREATIC ABSCESSES. Secondary infection of a peri pancreatic collection of fluid may occur, usually after about 2 weeks. The clinical features are persistent fever, leucocytosis and abdominal distension, with a possible palpable mass. Patients are usually very ill with the accompanying respiratory, cardiac and renal problems. Drainage (either surgically or percutaneously under ultrasound or CT guidance) is performed with vigorous antibiotic therapy. General support of the patient is required, as the disease has a long clinical course of several months.
PANCREATIC ASCITES. This is usually associated with chronic pancreatitis and has a high amylase content.

PROGNOSIS

The mortality rate varies from 1% in mild cases to 50% in severe cases. With multiple complications and the presence of all the bad prognostic signs, the mortality is nearer 100%. The patients who recover may have recurrent attacks, depending on the aetiology and whether accompanying gallstones are dealt with.

Chronic pancreatitis

This is defined as a continuing inflammatory disease of the pancreas characterized by irreversible morphological change and typically causing pain and/or permanent impairment of function.

PATHOGENESIS

The majority of cases occur as a result of high alcohol consumption and it is in these cases that the pathology has been most studied. The earliest change appears to be deposition of protein plugs within pancreatic ducts. These then lead to ductular dilatation followed by acinar atrophy. There is some accompanying infiltration but this is variable. Extensive fibrous tissue is deposited near the pancreatic ducts. Eventually only a few acinar and islet cells remain, with widely dilated pancreatic ducts. Intraluminal calcification of the protein plugs occurs, leading to stone formation. There is controversy as to whether this results from repeated bouts of acute inflammation and necrosis or whether it is due to an insidious chronic process. Chronic pancreatitis is not reversible, but it is possible that the disease will arrest if the patient stops drinking. However, because patients often continue to take small amounts of alcohol, the disease is most often progressive.
The causes of chronic pancreatitis are shown . Other suggested risk factors include excess smoking in males and an added risk factor of a low-protein and high-fat diet in alcohol abusers.

CLINICAL FEATURES

The major symptom is abdominal pain situated mainly in the epigastrium and upper abdomen and radiating to the back. The pain can be severe; in some cases it is comparable to that occurring in acute pancreatitis.
Continuing episodes of pain may occur; sometimes these are mild and of brief duration. In other cases there may be chronic pain interspersed with acute episodes (relapsing pancreatitis). The relationship to alcohol is variable; nevertheless, some acute episodes seem to be precipitated by heavy alcohol consumption. The abdominal pain is accompanied by severe weight loss due to anorexia.
Steatorrhoea occurs when the secretion of pancreatic lipase is reduced by 90%. It occurs in about half the patients. The development of diabetes is more common. The steatorrhoea is often severe and the patient may notice drops of oil in the lavatory pan. Both diabetes and steatorrhoea occur more commonly with calcified pancreatitis. Less common presentations include biliary obstruction with jaundice and occasionally cholangitis. Obstruction of the splenic vein can lead to portal hypertension.

INVESTIGATION

This includes assessment of some of the endocrine and exocrine functions as outlined earlier, as well as visualization of the pancreas. The serum amylase is of little value in chronic pancreatitis but may be raised during an acute episode of pain.
PAT IENTS WITH PAIN are investigated using ultrasound or CT scan, which show abnormalities in size and duct dilatation or the presence of calcification  not seen on a plain X-ray. An ERCP is also useful in these patients to confirm the diagnosis. A dilated pancreatic duct, sometimes associated with stones or stenotic areas, can be identified. Early cases are difficult to diagnose and a combination of all tests with a strong clinical suspicion is necessary. Endoscopic ultrasound can visualize the pancreas and is being assessed.

PATIENTS PRESENTING WITH STEATORRHOEA

require a Lundh test to estimate exocrine function.

(T showing chronic calcific pancreatitis (arrow).

(T showing chronic calcific pancreatitis (arrow).

DIFFERENTIAL DIAGNOSIS

Carcinoma of the pancreas must be suspected, particularly when the history is short; occasionally laparotomy may be necessary to distinguish between these two conditions.

TREATMENT

In alcoholic pancreatitis the patient should stop drinking alcohol. The pain needs to be controlled, often with narcotics, with the problem of addiction. Surgery is used for the treatment of intractable pain, pancreatic resection combined with drainage of an obstructed pancreatic duct into the small bowel being required. The use of surgery is controversial; good results are only obtained in a small number of cases, usually those who stop drinking. Steatorrhoea is treated with a low-fat diet, pancreatic supplements, e.g. pancreatin 2-4 g with each meal, with occasionally cimetidine 400 mg twice daily. Diabetes mellitus is treated with diet, oral hypoglycaemic agents and/or insulin as appropriate. The insulin requirement is greater than in idiopathic diabetes, and patients may experience frequent or severe hypoglycaemia. This may be because pancreatic glucagon is lacking.
COMPLICATIONS The commonest complication is a pancreatic pseudocyst. These are found very frequently if careful ultrasound examinations are performed. Small cysts require no treatment. Large cysts can give rise to increased pain, nausea and vomiting 3-4 weeks after the onset of the most recent attack of pain. A smooth, tender mass may be palpable and the cyst can be easily identified using ultrasound. Surgical treatment has been used for most large pseudocysts but a more conservative approach, with aspiration and close follow-up using ultrasound examination, is preferable. Pancreatic ascites occurs, usually in alcoholic pancreatitis, when there is a communication between the pancreatic
duct and the peritoneal cavity. The amylase content of the ascitic fluid is high. A good prognosis depends on complete abstention from alcohol.

Investigation

Exocrine function

The choice of individual tests is made on the clinical situation. SERUM AMYLASEMEASUREMENT is useful in acute disease but is of no value in chronic disease.
SERUM LIPASE is raised in acute pancreatitis.
MEASUREMENT OF DUODENAL ENZYMES, either after hormone stimulation or after food, is only sometimes helpful in the diagnosis of chronic pancreatitis because of the large reserve in enzyme capacity. A tube is passed into the duodenum and pancreatic secretions are collected after stimulation. Stimulation with secretin or CCK causes a rise in bicarbonate and enzyme, e.g. trypsin levels, which are low with chronic disease. The differential diagnosis between pancreatic tumour and pancreatitis is difficult.
These tests have been largely superseded by imaging techniques. The Lundh test is performed in a similar fashion, the stimulation being produced by a meal. Measurement of trypsin and lipase is undertaken. These are low in chronic pancreatitis. The Lundh meal test is particularly useful in the investigation of steatorrhoea.

Investigations available for the assessment of pancreatic disease.

Investigations available for the assessment of pancreatic disease.

PABA TEST. N-benzoyl-L-tyrosyl p-aminobenzoic acid is a synthetic peptide hydrolysed by pancreatic chymotrypsin to release free PABA, which is absorbed, metabolized and excreted in the urine. Reduction in absorption of free PABA occurs (after an oral load of the peptide) in pancreatic insufficiency and the test is highly specific in expert hands, although not widely utilized.
FAECAL FAT ESTIMATION is performed to demonstrate steatorrhoea. A breath test can also be used; here the amount of 14C02 in expired air is measured following oral ingestion of a labelled fatty acid compared with that after a labelled triglyceride (e.g. [14Cloleic acid compared with [14Cltriolein). Impaired triglyceride absorption with normal fatty acid absorption indicates that pancreatic disease is the cause of the steatorrhoea.

Endocrine function

Assessment of endocrine function is only useful if a hormonesecreting tumour is suspected and the serum measurements are often diagnostic. Plasma PP is raised with all endocrine tumours. The glucose tolerance test is seldom performed as it is affected by so many parameters.

Visualization of the pancreas

This now largely depends on ultrasound examination and CT scan to detect pancreatic size and shape, and the presence of cysts or tumours. An ERCP can be used to outline the pancreatic ducts. MRI with or without dynamic enhancement with contrast is slightly more sensitive than CT. Endoscopic ultrasound is particularly useful in the diagnosis of small endocrine tumours. Arteriography with selective catheterization of the splenic artery shows irregularity and encasement in carcinoma. A combination of two or three tests is often necessary and none of the investigations is diagnostic. Fine-needle aspiration of any abnormality discovered can be performed under ultrasound or CT scan control. The presence of malignant cells in the aspirate indicates tumour but, of course, a negative sample does not exclude malignancy.

THE PANCREAS

Structure and function

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 main pancreatic duct usually joins the common bile duct to enter the duodenum as a single duct at the ampulla of Vater. The main pancreatic duct has many tributary ductules and gradually tapers towards the tail of the pancreas. Pancreas divisum is an anatomical variant in which a small proportion of the pancreas drains through an accessory duct into the duodenum.
Exocrine cells form 98% of the human pancreas. The pancreatic acinar cells form a ductal system that eventually joins into the main pancreatic duct.
Pancreatic acini synthesize digestive enzymes which are stored in secretory glands and released by exocytosis in response to stimulation by several hormones.
These receptors have been divided into two categories:
vasoactive intestinal polypeptide (VIP) and secretin that act via cyclic AMP, and another group that stimulate cellular metabolism of membrane phosphoinositides and calcium.
The main regulators of pancreatic exocrine secretion are the hormones secretin and cholecystokinin (CCK). Secretin is released when acid enters the duodenum; it stimulates pancreatic juice containing water and electrolytes, chiefly bicarbonate. CCK is released, via cholinergic pathways, when fatty acids and amino acids enter the duodenum, stimulating pancreatic enzyme secretion.
Enzymes produced are amylase, lipase, colipase, phospholipase and pro teases (trypsinogen and chymotrypsinogen).
The pro teases are secreted in the inactive form but are then activated in the duodenum by enterokinase.
The endocrine pancreas consists of hormone-producing cells arranged in nests or islets- the islets of Langerhans. They do not connect directly to the duct system. There are four main types of islet cell and these have different secretory granules in their cytoplasm:
1 t3-Cells, which are the commonest cells, produce insulin.
2 a-Cells produce glucagon.
3 D cells produce somatostatin.
4 PP cells produce pancreatic polypeptide (pp).
5 A number of other hormones, e.g. bombesin, neuropeptide Y and galanin, are present in pancreatic neurones and probably act as neurotransmitters.

Diagram showing stimulus-secretion coupling of pancreatic acinar cell protein secretion. VIP, vasoactive intestinal polypeptide; CCK, cholecystokinin; ACh, acetylcholine.

Diagram showing stimulus-secretion coupling of
pancreatic acinar cell protein secretion. VIP, vasoactive
intestinal polypeptide; CCK, cholecystokinin; ACh,
acetylcholine.

Turnours Of the biliary tract

Primary carcinoma of the gallbladder

This adenocarcinoma represents <1% of all cancers. It occurs chiefly in those over 70 years of age and is commoner in females. Gallstones are usually present but a definite relationship is uncertain. The presenting features are of jaundice and occasionally right hypochondrial pain. A mass may be palpable in the right hypochondrium. The diagnosis is often made at operation and cholecystectomy is performed if possible. Few patients survive 1 year.

Cholangiocarcinoma

This sometimes affects the extrahepatic biliary tree, giving rise  to jaundice. Surgery, if possible, is the only effective treatment. Alternatively, a stent or tube can be passed through the obstruction during PTC or ERCP. The progosis is poor.

Malignant tumours of the ampulla

These present with a cholestatic jaundice which may occasionally be intermittent. They may ulcerate and produce gastrointestinal haemorrhage. The diagnosis is usually made at ERCP. Carcinoma of the ampulla can sometimes be resected with a 40% 5-year survival rate (compare with pancreatic carcinoma.

Miscellaneous conditions of the biliary tract

Primary sclerosing cholangitis

Primary sclerosing cholangitis results from inflammation and fibrosis of the bile ducts leading to multiple areas of narrowing throughout the biliary system. The cause is unknown but immunological mechanisms have been implicated. HLA associations have been reported with HLA-B8, DR3; HLA-DR52a and HLA-DW2. DR4 marks for rapid disease progression.
Fifty per cent or more of patients have inflammatory bowel disease, but this may be asymptomatic. Patients with AIDS have been found to have sclerosing cholangitis. The cause here is unclear but infection particularly with Cryptosporidium parvum is a probable aetiological factor.
There may be no symptoms and the diagnosis is suggested by a raised serum AP but a negative mitochondrial antibody. Symptoms that may fluctuate are pruritus, jaundice and occasionally abdominal pain. Portal hypertension can develop. Liver biopsy shows a fibrous obliterating cholangitis with eventual loss of interlobular and adjacent septal bile ducts. An ERCP will show the multiple strictures. Treatment is unsatisfactory. In half of the patients the disease runs a benign course over many years. Steroids and azathioprine are of unproven value but seem to help some patients. The results with methotrexate are encouraging. In associated ulcerative colitis, colectomy does not affect the progress of the condition. Obvious extrahepatic biliary strictures can sometimes be dilated or stented at endoscopy. Liver transplantation is now being performed for this condition.

Non-ca leulous cholecystitis

Occasionally cholecystitis occurs in patients with diabetes mellitus, polyarteritis nodosa and systemic infections. Cholesterolosis of the gallbladder In this condition, deposits of cholesterol are seen in the mucosal wall, producing a fine yellow pattern on a red background (strawberry gallbladder). Cholesterol stones mayor may not be present. The relationship to symptoms is unclear.

Adenomyomatosis of the gallbladder

This may be found as an incidental finding on a cholecystogram and consists of thickening of the mucosal and muscle layers with the presence of Rokitansky-Aschoff sinuses, often associated with small gallstones. It does not usually produce symptoms.

Choledochal cyst

This is a congenital cystic dilatation of the extrahepatic ducts producing jaundice and abdominal pain. Fifty per cent of the patients do not present until early adult life. Treatment is surgical.

Haemobilia

Haemobilia can occur due to hepatic trauma, sometimes from a tumour, and rarely after liver biopsy. Blood enters the biliary tree and produces either obstructive jaundice or gastrointestinal bleeding.

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 with abdominal discomfort or distension. There is no doubt that gallbladders studied histologically can show signs of chronic inflammation and occasionally a small, shrunken gallbladder 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. Common bile duct stones These may be asymptomatic or they may present with anyone or all of the triad of abdominal pain, jaundice and fever. The pain is usually severe and situated in the epigastrium and right hypochondrium. The pain may be accompanied by vomiting. The pain usually lasts for a few hours and then clears up, only to return days, weeks or even months later. Between attacks the patient is well.
The jaundice is variable in degree, depending on the amount of obstruction. The urine is dark and the stools are pale. High fevers and rigors indicate cholangitis. The liver is moderately enlarged if the obstruction lasts for more than a few hours. Prolonged biliary obstruction or repeated attacks lead to secondary biliary cirrhosis, but this is now rare.

INVESTIGATION

BLOOD COUNT. A leucocytosis is present.
BLOOD CULTURES. These may grow an intestinal organism (E. coli, Strep. faecalis).
BIOCHEMISTRY. A cholestatic picture  with a raised conjugated bilirubin and alkaline phosphatase in the serum and relatively normal serum aminotransferases.
PROTHROMBIN TIME. This may become elevated over a few weeks owing to poor vitamin K absorption.
ULTRASOUND EXAMINATION. This reveals a dilated common bile duct sometimes with a visible stone. Stones in the common bile duct can be missed and endoscopic ultrasound is a more accurate method of detecting a stone. Stones in the gallbladder suggest, but do not prove, that gallstones are the cause of the dilatation.
X-RAY. A plain abdominal X-ray may reveal gallstones. ERCP. This is performed to confirm the diagnosis and to remove the stones.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis includes all causes of jaundice.

MANAGEMENT

The acute episode is usually allowed to settle and the serum bilirubin usually falls to normal levels. During this stage the patient normally only requires pain relief but occasionally antibiotics are necessary. The serum AP falls more slowly than the serum bilirubin, and if the patient is seen some time after an acute attack elevation of this enzyme may be the only evidence of biliary tract disease. Further management of common duct stones is discussed below.

Acute cholangitis

Acute cholangitis is due to bacterial infection of the bile ducts and is always secondary to bile duct abnormalities. Th.e common causes are common duct stones, biliary strictures, neoplasms, or following ERCP in the presence of large duct obstruction.
The symptoms are fever, often with a rigor, upper abdominal pain and jaundice. All three symptoms are present in 70% of cases. Older patients can present with collapse and Gram-negative septicaemia.
Specific signs may be minimal but tenderness over the liver occurs.
When all three symptoms are present the diagnosis is not difficult, but the patient can present with only a fever and an accompanying leucocytosis. Blood cultures are often positive (usually for E. coli) and a severe Gramnegative septicaemia can occur.
Treatment is with intravenous amoxycillin 1 g 6-hourly WIth intravenous gentamicin 2-5 mg kg-l daily in divided doses for severe cases. Ceftazidime is also used. Suppurative cholangitis can occur as a complication. The fever continues and shock develops despite adequate antibiotics. Urgent decompression of the duct should be performed, usually endoscopically with placement of a nasobiliary drain. The subsequent treatment of the obstruction is either endoscopic or surgical.

MANAGEMENT OF GALLSTONES

Stones in the gallbladder Cholecystectomy

This is the treatment of choice for virtually all patients with gallbladder stones and symptoms.
L~PAROSC~PIC CHOLECYSTECTOMY is now the operation of chOIce. The abdominal cavity is insufflated with carbon dioxide under a general anaesthetic and the laparoscope and operating channels are inserted through the umbilicus and three other small incisions. The gallbladder is dissected from its bed on the liver and removed whole after the cystic duct and vessels have been clipped and haemostasis achieved with electrocautery or laser. The mortality is less than 0.1% and the patients can leave hospital in 24-48 hours. Complications are low and include wound sepsis, bile duct injury and retained gallstones in the commen bile duct , patient can return to full activity in approximatelyb 7 days , compared to 3 weeks for the open operation.

OPEN CHOLECYSTECTOMY. This is also a safe procedure with a mortality occur in obese and elderly patients.

Only patient who refuse surgery should be considered for alternative terapy .

POST CHOLECYSTECTOMY SYNDROME. Some patient continue to complain of right hypochondrial pain, flatulence, indigestion and intolerance to fatty foods after cholecystectomy, despite a normal radiological appearance of the biliary tree. In the vast majority of these patients the original diagnosis was incorrect and the patient was suffering from functional bowel disease, the gallstones being an incidental finding. The occurrence of severe pain with jaundice suggests a retained stone in the common duct. Gallstone dissolution or disruption Cholesterol gallstones can be dissolved by the bile acids chenodeoxycholic acid and ursodeoxycholic acid, which increase cholesterol solubility in bile. They only dissolve radiolucent stones in a functioning gallbladder and not calcified stones. Only about 10% of patients are suitable for this therapy.
Gallstone dissolution takes anything from 6 months to 2 years and when the treatment is stopped 50% of the gallstones recur. Chenodeoxycholate also produces diarrhoea. Shock-wave treatment of gallstones can be carried out using ultrasound-guided lithotripters that do not require a general anaesthetic or water bath.
Laparoscopic cholecystectomy has made the above techniques redundant except in a very few cases where an anaesthetic is contraindicated. Stones in the common bile duct Endoscopic sphincterotomy with removal of the common bile duct stone, if possible, is performed initially. The sphincter of Oddi is cut with a diathermy wire. Stones can then pass from the common bile duct following this sphincterotomy either naturally through the enlarged opening or they can be removed endoscopically using a Dormia basket. The duct is ‘swept’ with a balloon to ensure that all stones have been removed; a cholangiogram is performed.
Large stones (>15 ern in diameter) that cannot be removed whole, can be crushed with a mechanical lithotripter or fragmented later by extracorporeal shock-wave lithotripsy. Alternatively a double pig-tail endoprosthesis can be inserted to allow biliary drainage.
In a patient with an intact gallbladder containing stones, the endoscopic removal of a stone is usually followed by a laparoscopic cholecystectomy. Whether this is necessary in all cases is debatable as further problems are only encountered in 20% of patients.
Some surgeons can remove common bile duct stones at the time of laparoscopic cholecystectomy, but mostprefer the stones to be removed endoscopically. If an open operation is performed, the duct should  always be explored.
Retained stones after surgery can be treated by:
Removal via the T-tube: this is possible if the T-tube is large (14 French gauge) using a steerable catheter under fluoroscopic control
2 Chemical dissolution by infusion of monooctanoin down the T-tube
3 Endoscopic removal
4 Further surgery if the above fail.

COMPLICATIONS OF GALLSTONES

PANCREATITIS

GALLSTONE ILEUS AND BILIARY ENTERIC FISTULA. Gallstones can occasionally erode through the wall of the gallbladder into the intestine. They can cause obstruction, mainly in the terminal ileum but occasionally in the duodenum.
CARCINOMA OF THE GALLBLADDER may be causally related.

THE GALLBLADDER AND BILIARY SYSTEM

The main cause of disease of the gallbladder and biliary tract is gallstones. The structure, formation and function of bile.

Gallstones

Prevalence of gallstones

Gallstones are present in 10-20% of the population in the Western Hemisphere, but the exact prevalence is unknown. There is a geographical variation. Gallstones are rare in the Far East and Africa and very common in native North Americans and in Chile and Sweden. They occur twice as frequently in young women than in men but this difference decreases with increasing age.

Types of gallstones

Gallstones can be divided into those composed of cholesterol and those composed of bile pigment. Cholesterol stones, which account for 80% of all gallstones in the Western Hemisphere, contain more than 70% cholesterol, often with some bile pigment and calcium (mixed stones). Pure cholesterol stones are often solitary.

Cholesterol gallstones

Cholesterol is partly derived from dietary sources. In addition, it is synthesized, chiefly in the liver, but also in the small intestine, skin and adrenals. The rate-limiting step in cholesterol synthesis is J3-hydroxy-J3- methyl-glutaryl- CoA (HMG-CoA) reductase, which catalyses the first step, i.e. the conversion of acetate to mevalonate. The cholesterol forme  is cosecreted with phospholipids into the biliary caniliculus as unilamellar vesicles. Cholesterol stones only develop in bile that has an excess of cholesterol relative to bile salts and phospholipids (supersaturated bile). This could occur because of excess of cholesterol or because of a decrease in bile salts. There is a reduced bile salt pool in some patients with cholesterol gallstones and the pool circulates more frequently. This may account for the reduction in the ratelimiting cholesterol-7a-hydroxylase found in some patients (feedback inhibition).
Diminished bile salt synthesis is not the only cause of supersaturated bile; there appears to be an increase in HMG-CoA reductase with an increase in cholesterol secretion into bile in some patients. In supersaturated bile the bile acids solubilize phospholipids from the unilamellar vesicles more than cholesterol.
This results in unstable vesicles which are more prone to aggregate, fuse and form multilamellar vesicles. It is from these vesicles that cholesterol crystals nucleate. Factors other than cholesterol saturation are required to form gallstones, as supersaturated bile is found in normal subjects during an overnight fast. The rate of cholesterol crystallization and gallbladder function also play a role.
Glycoproteins in bile promote nucleation of cholesterol crystals, leading to stone formation, but why this occurs only in bile from patients with gallstones is unclear. It may depend on the presence or absence of solubilizing factors. The role of infection is unknown. Definite risk factors for gallstones.

Bile pigment stones

Black pigment stones contain calcium salts of bilirubin, phosphate and carbonate in addition to bilirubin polymers and mucin glycoproteins. The biliary lipids are normal. These stones form in the gallbladder and are seen in patients with chronic haemolysis, e.g. hereditary spherocytosis and sickle cell disease, where there is an increase in bilirubin, and also in cirrhosis. In other situations the pathogenesis is unclear.
Brown pigment stones have layers of cholesterol, calcium salts of fatty acids (mainly palmitate) and calcium bilirubinate. They tend to form in the common bile duct after cholecystectomy and are due to precipitation of bilirubin with calcium. They are also found with strictures, sclerosing cholangitis and Caroli’s syndrome. In the Far East these stones are associated with parasitic infestation of the biliary tract.

Clinical presentation of gallstones

The majority of gallstones (approximately 80%) remain in the gall bladder and are asymptomatic. A gallstone may impact in the neck of the gallbladder or in the cystic duct, giving biliary pain or acute cholecystitis.

Clinical presentation of gallstones.

Clinical presentation of gallstones.

Finally, gallstones may pass into the common bile duct, giving rise to biliary obstruction that produces severe biliary pain and sometimes cholestatic jaundice. Bacterial infection can occur and produce cholangitis. Clinically the type of pain is similar in the above situation. It occurs in the epigastrium and right hypochondrium and is not colicky. Biliary ‘colic’ therefore is a misnomer.
Rarely a gallstone may perforate through the wall of an inflamed gallbladder into the intestine, producing a fistula. Gallstones do not give rise to any other symptom complex, and the idea that they produce indigestion, chronic right hypochondrial pain or intolerance to fatty food is based on a false correlation. Gallstones and upper abdominal symptoms are both common, so great care must be taken to establish that the two are truly related. Fair, fat, fertile females of 40 years of age have the same chance of having gallstones as the rest of the general population (10-20%). Thus, if they are investigated regardless of symptoms, gallstones will obviously be seen frequently by chance alone.

Asymptomatic (silent) gallstones

Gallstones may be discovered accidentally when a patient is being investigated for some other reason. They requireno treatment since the natural history is for them to  remain asymptomatic, with only approximately 18% of patients having symptoms over a IS-year period.Acute cholecystitis

PATHOPHYSIOLOGY

In over 90% of cases the gallbladder contains gallstones. Initially there is obstruction to the neck of the gallbladder or the cystic duct by an impacted stone, leading to distension and inflammation. The inflammation is usually sterile, but within 24 hours gut organisms can be cultured from the gallbladder. Occasionally the inflammation may be mild and quickly subsides, sometimes leaving a gallbladder distended by mucus (mucocele). In this situation the patient may only have slight abdominal pain with a palpable gallbladder.
More commonly, however, the inflammation is more severe, involving the whole wall and giving rise to localized peritonitis and acute pain. Occasionally the gallbladder can become distended by pus (an empyema) and rarely an acute gangrenous cholecystitis occurs with perforation and a more generalized peritonitis.

CLINICAL FEATURES

The disease can occur at any age. The main symptoms are severe pain in the epigastrium and right hypochondrium. The pain is continuous, increasing in intensity over 24 hours. It can radiate to the back and shoulder. It may be accompanied by nausea and vomiting. Mild jaundice occurs in 20% of cases owing to accompanying common duct stones or to surrounding oedema occluding the common hepatic duct .

EXAMINATION

The patient is usually ill with a fever and shallow respirations. Right hypochondrial tenderness is present, being worse on inspiration (Murphy’s sign). There is guarding and rebound tenderness.

INVESTIGATION

1 Blood count. A moderate leucocytosis is found.
2 Biochemistry. The serum bilirubin, alkaline phosphatase and AST may be slightly raised.
3 Ultrasound examination. The detection of gallstones alone is insufficient for a diagnosis of acute cholecystitis. Additional criteria are:
(a) Sonographic Murphy’s sign (focal tenderness directly over the visualized gallbladder)
(b) Gallbladder wall thickening-not specific for acute disease
(c) Distension of gallbladder
(d) The presence of biliary sludge
4 HIDA scintiscan. This is valuable and shows blockageof the cystic duct with the bile duct, but not the gallbladder, being visualized.
Ultrasound and HIDA scintiscans have a similar accuracy and the technique performed will depend on local facilities. S X-ray. A plain abdominal X-ray shows gallstones III 10% of cases; this is not useful diagnostically.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis includes other abdominal emergencies, such as a perforated peptic ulcer, retrocaecal appendicitis and acute pancreatitis. Right basal pneumonia and myocardial infarction must also be considered.

MANAGEMENT

The majority of patients improve with conservative management consisting of bed rest, nil by mouth and intravenous fluids, with the addition of an antibiotic, usually amoxycillin or a cephalosporin. In all but the mild cases, pain relief with an opiate is required.

Ultrasound showing acute cholecystitis with impacted stone. Note distension of gallbladder with thickened wall and sludge. 1, thick wall; 2, stone; 3, acoustic shadow; 4, echogenic debris.

Ultrasound showing acute cholecystitis with impacted stone. Note distension of gallbladder with thickened wall and sludge.

In the absence of vomiting, the patient can soon tolerate oral fluids and nasogastric aspiration is not often required. Signs of complications such as generalized peritonitis or gangrene of the gallbladder (which causes increasing pain and fever) are an indication for urgent surgery, particularly in the elderly.
Cholecystectomy (see below) within days of the acute attack has been advocated for all patients who are not an anaesthetic risk. A firm diagnosis can usually be made using an HIDA scan or ultrasound. Alternatively, cholecystectomy can be performed 2-3 months later. However early surgery means only one hospital visit and no possibility of a recurrent attack while waiting for surgery to be performed. It does not increase operative morbidity or mortality and is, therefore, the recommended treatment.