Gallstones

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Contents

Introduction

The gall bladder is second only to the appendix as the intra-abdominal organ most commonly requiring surgical intervention. The surgical management of the gall bladder pathology has changed because of the following developments. The first is the development of ultrasound, which allows accurate diagnosis of the presence of gallstones as well as the presence of complications such as acute cholecystitis, obstructive jaundice/cholangitis and pancreatitis. Such accurate diagnosis has allowed early surgical intervention. The second major advance has been duct imaging by endoscopic retrograde cholangiopancreatography (ERCP), allowing both diagnosis and treatment of one of the major complications of gallstones, obstructive jaundice. The third major change has been the development of laparoscopic cholecystectomy.

Aetiology and pathogenesis

Incidence

Gallstones are common; they are more common in females, with the incidence rising with age. At the age of 30 years, 5% of females and 2% of males either have or have had gallstones, with the proportion rising at 55 years to 20% and 10%, and at 70 years to 30% and 20%, respectively.

Types of stones

Gallstones are composed of two basic components, cholesterol and pigment.

Cholesterol stones

Cholesterol stones account for 80% of gallstones, either as pure cholesterol stones or more commonly as mixed stones. The process of cholesterol stone formation is summarised in Pathogenesis of cholesterol gallstones.. Cholesterol is delivered to the liver from the gut in chylomicrons or from other tissues in low-density lipoproteins. Plasma cholesterol is then regulated by hepatic synthesis or excretion of cholesterol. Synthesis of cholesterol can be from acetate under the influence of the enzyme HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A). Cholesterol elimination occurs as a result of its secretion into bile in three ways: as cholesterol itself, as bile salt (under the influence of 7α-hydroxylase) or as cholesterol esters. Once in bile, the cholesterol is kept in solution in vesicles that are stabilised by secreted phospholipids. During fasting, and particularly if there is prolonged fasting (e.g. during intravenous alimentation), cholesterol crystals form in the supersaturated bile and, combined with gall bladder stasis, results in sludge. This process is exacerbated by mucin and inhibited by bile salts (particularly ursodeoxycholic acid), non-steroidal anti-inflammatory drugs and caffeine. This is perhaps another example of how a daily dose of aspirin (besides its effect in the cardiovascular system), perhaps washed down by a cup of coffee, may be of value. Any factor that increases plasma, and thus bile cholesterol, also exacerbates the production of sludge, for example, increased body fat (further increased by age and female sex), high animal fat in the diet, or metabolic conditions (diabetes, cystic fibrosis, familial hyperlipidaemias, pregnancy). Stones may also occur as a result of bile salt depletion (e.g. from drugs such as clofibrate) or from malabsorption of bile salts in the distal ileum due to disease or resection.

Pathogenesis of cholesterol gallstones.

Biliary sludge, once formed, can re-absorb or can go on to stone formation. In patients who become symptomatic, the time from stone initiation to the development of symptoms is approximately 8 years, and the time to cholecystectomy approximately 12 years.

Pigment stones

Pigment in bile is a result of bilirubin production, the bilirubin first being solubilised by conjugation to form a diglucuronide. Stones may occur as a result of three processes. First, if there is an increase in bilirubin load due to haemolytic anaemias. Second, if the bilirubin once more becomes insoluble due to glucuronidases in bile (e.g. if there is stasis or obstruction, allowing contamination with glucuronidase-containing bacteria). Third, if the patient has cirrhosis, in which there is depletion of glucuronidase inhibitors in the bile.

The deposition of this pigment in the gall bladder bile results in the formation of multiple small black stones. When this process occurs in the bile duct, it produces a primary duct stone.

Clinical diagnosis

Biliary pain is of two types, obstructive or inflammatory. Obstructive symptoms occur when the neck of the gall bladder is obstructed by a stone and gall bladder contraction continues under the influence of cholecystokinin and neural reflexes from the duodenum. The rise in tension in the gall bladder wall is detected by sparsely distributed bare nerve endings of sympathetic afferents. These fibres pass centrally via the coeliac plexus. The resultant visceral foregut pain is therefore dull, poorly localised, usually extends right across the region of the epigastrium and may radiate around to the back, most commonly via the right side, and can be felt between the scapulae. The pain will be noted to be of fairly rapid onset as the pressure in the gall bladder increases (unless the patient is woken from sleep by the pain), and is invariably associated with nausea and often vomiting. The pain usually lasts a number of hours and abates only when the stone either dislodges or, less commonly, passes through the cystic duct into the bile duct. The patient is left feeling unwell for as long as 1–2 days. The pain is not colicky because there is no cyclical peristalsis of note in the gall bladder.

Inflammation

If the stone does not become dislodged, at first a sterile inflammatory response develops and this may be followed by an infective cholecystitis. The most common organism is Escherichia coli, followed by a Klebsiella and, occasionally, Streptococcus faecalis. The inflammatory process extends to involve the parietal peritoneum, and involves somatic afferents of that dermatome segment, and the patient's perception of the pain will change. The pain moves to the right hypochondrium, becomes sharp and well localised, and is exacerbated by movement or deep breathing. The pain (parietal) is sharper and more localised because of the dense innervation of the peritoneum by specialised sensory nerves of the somatic nervous system. On examination of the right hypochondrium, guarding and Murphy's sign may be present. If the gall bladder is under the liver and not in contact with the parietal peritoneum, the diagnosis can be made by having the patient take a deep breath while a hand indents the right upper quadrant. As the inflamed gall bladder descends and contacts the sensitive peritoneum, sharp parietal pain occurs and muscle tone reflexly or immediately rises (involuntary guarding).

Complications

If the gall bladder remains obstructed and the inflammatory process continues, an empyema results and nearby omentum, colon and duodenum become inflamed and adherent to the gall bladder, producing a phlegmon. If the abdomen is gently examined, through the increased muscle tone a mass can usually be identified. The patient has now usually had symptoms for 2–3 days and has a high fever and hyperdynamic circulation of sepsis. If the inflammation still remains unresolved, the next development may be gall bladder gangrene and local perforation, which is indicated by the development of a swinging fever. Exceedingly rarely, the whole process may spontaneously resolve if the gall bladder develops a fistula into the associated bowel, usually the duodenum. Even more rarely, the discharged gallstone, as it passes down the bowel, may produce a small-bowel obstruction, most commonly at the duodenojejunal (DJ) flexure, or the distal ileum - this is commonly called gallstone ileus. A plain abdominal X-ray will show gas in the biliary tree (pneumobilia) in association with the small bowel obstruction. This triad of gallstones, pneumobilia and small bowel obstruction on radiology is known as the Rigler's triad.

Investigations

Ultrasound

Ultrasound has been a major advance in the diagnosis of gallstones. The typical appearance is of a bright echo (white), with acoustic shadowing (dark area) radiating beyond the stone (Ultrasound of gall bladder containing gallstones, showing an echo with acoustic shadowing.). Cholecystitis might be inferred by the demonstration of thickening of the gall bladder wall (>4 mm) with, occasionally, a decrease in density adjacent to the gall bladder wall suggesting a halo effect, which is a manifestation of surrounding oedema. Gall bladder wall thickening may also be due to fibrosis but, in this case, gall bladder volume is usually reduced. The ultrasound may also suggest the presence of duct stones by showing ductal dilation or may occasionally suggest another complication of gallstone disease, pancreatitis, as shown by altered echogenicity in the pancreas. In acute cholecystitis, the lower bile duct and the pancreas may be difficult to visualise because of gas in the duodenum.

Ultrasound is particularly operator dependent and unless the entire gall bladder is visualised, stones may be missed. Biliary sludge may also be missed because it frequently does not produce an acoustic shadow. False negative examinations (i.e. missed stones) occur in approximately 5% of examinations.

Ultrasound of gall bladder containing gallstones, showing an echo with acoustic shadowing.

Oral cholecystography

Failure of the gall bladder to concentrate orally administered contrast (i.e. failure to visualise the gall bladder) is suggestive of either cystic duct obstruction or the presence of a recent attack of acute cholecystitis. Even if the gall bladder does concentrate the contrast, small stones can be easily missed, resulting in a false negative examination rate of 5%.

Oral cholecystography is now used rarely but is of value as a follow-up to ultrasound if there is a strong clinical suspicion that the patient has stones but the ultrasound is normal. Performing the two procedures reduces the false negative rate to less than 2%, particularly if the cholecystogram is performed soon after the acute episode of pain.

Cholescintigraphy

This test is rarely used, again since the advent of ultrasound. Failure of the intravenously delivered dose of technetium-labelled hepato-iminodiacetic acid (99mTc- HIDA) to outline the gall bladder suggests cystic duct obstruction. Some suggest that the test can diagnose occult gall bladder calculus disease by showing delaying emptying in response to a fatty meal. This requires validation because many patients with chronic biliarytype pain (i.e. recurrent upper abdominal pain over a long period of time) have a normal gall bladder and are frequently shown to have irritable (spastic) bowel syndrome.

Endoscopic retrograde cholangiopancreatography

This examination is not necessary in uncomplicated gallstone disease. It is only used for sampling bile in patients with recurrent biliary-type pain or recurrent pancreatitis where gallstones are strongly suspected on history, but have not been identified by either ultrasound or oral cholecystography. The aspirated bile is examined under the microscope for cholesterol crystals and debris (microlithiasis).

Haematology and biochemistry

An elevated white cell count will confirm acute cholecystitis, but adds little to the history and examination findings of the diagnosis.

Liver function tests and serum amylase should be measured routinely because approximately 10% of patients will have concomitant common duct stones (see Tumours of the head and neck). The liver function tests will be abnormal only if the stone is currently obstructing the duct. Similarly, the amylase may be elevated for approximately 24 hours if a stone passing through the final common channel of the bile/pancreatic ducts induces an episode of pancreatitis. Because of renal secretion of amylase, plasma amylase rapidly normalises, although urine amylase frequently remains elevated for up to 5 days.

Operative treatment

The procedure is cholecystectomy with operative cholangiography ().

Pre-operative preparation

The procedure is performed under general anaesthesia after a minimum 4-hour fast. Prophylaxis against deep vein thrombosis is considered if the patient is older than 40 years of age. Prophylactic antibiotics are generally used, especially if the patient is more than 40 years of age, a duct stone is suspected, the patient's immune state is depressed (diabetes, steroid administration) or the patient is morbidly obese. A single dose of a second-generation cephalosporin is adequate but may be extended for 24–48 hours post-operatively in the presence of severe sepsis.

Surgical technique

Open cholecystectomy

The abdomen is opened, usually by a right subcostal incision. The cystic duct and artery are carefully dissected and confirmed to arise and terminate, respectively, in the gall bladder. An intra-operative cholangiogram is then performed by passing a catheter into the cystic duct and injecting contrast to outline the biliary tree. This is done because there is approximately a 10% probability of a stone being present in the bile duct at the time of cholecystectomy; this probability rises with increasing age. Some surgeons would suggest that a cholangiogram only be performed in those in whom a bile duct stone is suspected (i.e. those with a past history of jaundice or pancreatitis, abnormal liver function tests, dilated cystic duct, common bile duct or a palpable stone in the duct). These criteria, however, underestimate the presence of duct stones (approximately 4% of patients have an unsuspected stone). If a bile duct stone is identified on the cholangiogram the duct is explored (see Benign and malignant diseases of the hepatobiliary system).

After the cholangiogram is confirmed to be normal, the cystic duct and artery are ligated and the gall bladder is removed from the bed of the liver. Many surgeons will place a drain to the gall bladder bed for approximately 24 hours because, occasionally, a small leak of bile may occur from small ducts that pass directly to the gall bladder from the bed. The abdomen is then closed.

Laparoscopic cholecystectomy

Laparoscopic cholecystectomy was first performed in 1987 by Mouret in France and by Uhre in Germany. It was made possible by the development of the miniature video-chip camera which, when attached to a laparoscope and handled by an assistant, allowed the surgeon to operate with both hands. A cannula is inserted in the umbilicus, through which the laparoscope is passed. Three other cannulae are inserted for grasping and exposing the gall bladder and for performing the dissection. The principles and techniques are the same as for the open procedure.

For a period after the introduction of the technique, unlike the practice in the era of open cholecystectomy, some surgeons were not using intra-operative cholangiography to diagnose concomitant duct stones. Those patients with suspected duct stones (see above) were given a pre-operative ERCP. This preliminary procedure and the associated endoscopic sphincterotomy to remove any duct stones identified was an unnecessary risk because the stones would have passed spontaneously in half to two-thirds of patients by the time of cholecystectomy. However, intra-operative cholangiography to detect duct stones and to help outline bile duct anatomy and reduce duct injury is becoming common once more.

The cholangiogram is performed either via a catheter passed through one of the cannulae or via a needle puncture in the abdominal wall. Following completion of the cholangiogram, the cystic duct and artery are clipped with small metal clips and divided. The gall bladder is removed from its bed, using electrocautery. The gall bladder bed is carefully examined for any evidence of bile leaks. The gall bladder is then removed via the umbilicus, the peritoneal cavity is washed out and the small incisions closed. Most surgeons do not use a drain to the gall bladder bed, first because evidence to suggest that it improves the outcome from bile leak is limited and, second, the drain is a major cause of post-operative pain.

Post-operative care

The post-operative management of patients who have undergone laparoscopic versus open procedures are vastly different. Following the open procedure, patients require adequate pain relief either via narcotic infusion or patient-controlled analgesia. They have nil by mouth for 24–48 hours because of the ileus resulting from intra-operative handling and thus require intravenous fluids for approximately 2 days. Because the post-operative pain leads to atelectasis, they need early mobilisation and elderly patients with pre-existing respiratory disease require active physiotherapy. Lowdose heparin needs to continue in patients at high risk of thromboembolism until they are fully ambulant. The mean post-operative stay is 5 days.

In contrast, patients undergoing laparoscopic cholecystectomy have markedly less pain and ileus. As most patients are ambulant the day of surgery, physiotherapy is rarely required. Narcotic analgesics are usually required as an occasional injection during the first 24 hours, with simple oral analgesics perhaps then required for up to 10 days after discharge. Most patients are discharged home on the second post-operative day. Return to normal activity is rapid with the laparoscopic approach: 2 weeks compared to 4 weeks for the open approach.

Significant complications

The laparoscopic approach has fewer minor complications (3% cf. 6%), less wound infection (0.5% cf. 1.5%) and fewer respiratory complications (1.9% cf. 2.5%) compared with open cholecystectomy. The early experience, however, suggests that the laparoscopic approach has had more major complications. Significant bile duct injury occurs in 0.15% of open cholecystectomies, but has reduced twofold since the introduction of laparoscopic cholecystectomy. This is partly because surgeons who were new to the technique had difficulty in identifying the cystic duct from the bile duct with a fixed, two-dimensional view of the anatomy via the laparoscope. In this regard intra-operative cholangiography is particularly helpful. Any patient with persistent pain following a laparoscopic procedure, particularly if they develop a fever, must be suspected of having a duct injury. Liver function tests must be performed immediately. If these are abnormal, then the operative cholangiogram should be reviewed in case it demonstrates a missed injury (e.g. contrast leaks or missing duct segments). An ultrasound is then used to identify a fluid collection and an ERCP is used to identify the nature of the ductal injury.

Although not a complication, persistence or recurrence of biliary-type pain may occur. A proportion of these patients will either have a retained common duct stone, sphincter of Oddi dysfunction (usually secondary to trauma from duct exploration or passage of stone) or possibly wound neuralgia due to segmental nerve injury. Many, in whom no cause for further pain can be identified, have been labelled as having postcholecystectomy syndrome. This condition does not exist and represents those patients who did not require a cholecystectomy in the first place (i.e. their pain was not due to the gallstone and therefore the gall bladder removal has not influenced their symptomatology).

Choice of operation

With the introduction of laparoscopic cholecystectomy, the approach has been to reserve the laparoscopy for the easiest cases; that is, those patients who do not have acute cholecystitis, are not excessively overweight and do not have evidence of stone in the bile duct. As a result, operative mortality is low (0.1%). The high-risk patients, therefore, are the ones who are still having open cholecystectomy. This explains why, in the current era, patients having open cholecystectomy are having a higher complication rate and a higher operative mortality (rising sixfold from 0.3 to 1.8% in the past decade). It is this high-risk group of patients who would benefit most from the less morbid laparoscopic approach. Experienced surgeons are now offering laparoscopic cholecystectomy more often, and now more than 80% of cholecystectomies performed in Australia are being performed laparoscopically. If the biliary anatomy is too complex because of severe inflammation, the laparoscopic procedure can be converted to open cholecystectomy. Severe respiratory disease may require a lower intra-abdominal insufflation pressure, and portal hypertension (because of the risk of intra-operative bleeding) remains a relative contraindication.

Management of clinical situations

Incidental gallstone on ultrasound

Unless it is clear from the history that any symptom the patient has can be attributed to the gallstone, then the gall bladder should be left untreated, particularly if there are serious co-morbid factors. Asymptomatic gallstones become symptomatic at a cumulative rate of 1% per year (e.g. a 30-year-old with asymptomatic stones who lived to 80 years would have a 50% chance of requiring their gall bladder to be removed, while for a 60-year-old there would only be a 20% chance that they would need to have their gall bladder removed in their lifetime). The probability that the gall bladder needs to be removed reduces even further if the patient has associated medical conditions likely to shorten their life that concomitantly increase the risk of prophylactic surgery. A major complication in a patient who did not need a cholecystectomy in the first place is the biggest disaster of all. Prophylactic cholecystectomy might be considered in one limited circumstance; that is, in patients with diabetes because they tend to develop more serious cholecystitis.

Incidental gallstone at laparotomy

For some unknown reason, the incidental gallstone palpated at laparotomy performed for another procedure has a higher probability of developing future symptoms, possibly as high as 75% at 12 months. As the abdomen is already open, and provided the incision gives adequate exposure of the gall bladder and bile ducts and, further, that the patient is tolerating the anaesthetic, the addition of cholecystectomy and operative cholangiography is preferable to a subsequent procedure, which will be required in the majority.

Biliary pain

Once gallstones cause biliary pain, recurrence is inevitable; during a 5-year period all patients get further symptoms and 20% develop a complication (cholecystitis, obstructive jaundice, pancreatitis). Unless operative risk is high or survival short, elective laparoscopic cholecystectomy should be performed. The decision as to whether the pain is biliary is a clinical one.

Acute cholecystitis

In the past, patients presenting with presumed acute cholecystitis were treated with analgesics, antibiotics to deal with biliary sepsis, nil by mouth, and intravenous fluids until the episode subsided. At 6 weeks, when the inflammation was presumed to have completely settled, elective cholecystectomy was performed. The problem was that this meant the expense of two hospital admissions. In addition, in 15% of patients the inflammation did not settle and empyema or gangrene developed, forcing cholecystectomy when the anatomy was most inflamed and difficult to identify, and raising the risk of common bile duct injury. By that stage the patient was septic and catabolic, further increasing the risk of complications.

With the development of ultrasound and a confident diagnosis of acute cholecystitis, immediate cholecystectomy became the norm. If done early in the attack, the oedema of early inflammation made dissection easy. All cases have their pathology dealt with in the same admission, reducing costs. The window of opportunity to perform laparoscopic acute cholecystectomy is shorter. The procedure has to be performed before the gall bladder becomes too thick-walled or gangrenous, or the anatomy becomes too difficult to identify. Ideally, acute laparoscopic cholecystectomy should be performed within 48 hours of onset of the attack. While an operating-theatre list is obtained, analgesic is given, the patient is fasted, intravenous fluids used and antibiotics (second- or third-generation cephalosporins) given.

Post-endoscopic sphincterotomy for complicated common bile duct stone

This problem occurs particularly in the older age group. Of patients over 60 years of age presenting for the first time with biliary calculi, in nearly 50% of cases the symptoms will be because of stones in the common bile duct rather than stones in the gall bladder. If the presentation is because of a complication of that duct stone, ideal management is by endoscopic sphincterotomy. After successfully treating the duct stone, the dilemma is then what to do with the gallstones (i.e. what is the probability they will become symptomatic in the patient's remaining life). If the cystic duct is unobstructed at ERCP then, during a 2-year period, 30% of patients will die from other causes associated with age and only 30% overall will require gall bladder removal. If the cystic duct is obstructed at ERCP, all patients will develop complications. Therefore, if the patient has an unobstructed cystic duct and, particularly, if they have associated co-morbidity, they should be advised of the nature of gall bladder symptoms and asked to present promptly should the symptoms occur, so that the cholecystectomy can be performed acutely. Those patients with an obstructed cystic duct should have an early elective (laparoscopic) cholecystectomy.

Gallstone pancreatitis

Gallstone pancreatitis is dealt with in Chapter 17. However, in brief, gallstones are a major cause of pancreatitis occurring as a result of the passage of a stone through the common channel of the pancreatic and bile ducts. The advent of better diagnostic tests, including ERCP/bile sampling, has shown that more than half of the cases of pancreatitis previously thought to be idiopathic are due to gall bladder microlithiasis. All patients admitted with pancreatitis must have gallstones as a cause excluded.
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