Gallstone Diseases and Related Disorders

Gallstone Composition

In most developed countries, most gallstones are of mixed composition and contain a predominance of cholesterol; this is mixed with some bile pigment (calcium bilirubinate) and other calcium salts . A small proportion is virtually ‘pure’ cholesterol stones (‘ cholesterol solitaire ’). In Asia, most gallstones are composed of bile pigment alone. The composition and pathogenesis of the various types of gallstone are summarised in Table 20.1 and Fig. 20.2 , and some examples are illustrated in Fig. 20.3 .

The physical structure of mixed gallstones gives an insight into their sequence of formation. There is usually a small core of organic material, often containing bacteria. The main body of the stone is made up of concentric layers, demonstrating that stones form in a series of discrete precipitation events. Furthermore, in the same gall bladder, there are often several ‘families’ of gallstones, each of a different size. This suggests each generation began at a different time, presumably because of some transient change in local conditions. All families then build up at the same rate by lamination, leading to the range of different sizes. Radioisotope dating studies have shown that the average gallstone is 11 years old when removed!

The main factors in stone formation are: (1) changes in concentration of the different constituents of bile, (2) biliary stasis and (3) infection. It is likely that several subtle abnormalities combine synergistically to bring about precipitation of bile constituents.

Bile salts and lecithin are responsible for maintaining cholesterol in a stable micelle formation. The normal micellar structure of bile supports a greater concentration of cholesterol than could otherwise be held in solution, and is therefore inherently unstable. An excess of cholesterol in proportion to bile salts and lecithin is probably one of the main factors in cholesterol stone formation. This is supported by the fact that patients in whom the terminal ileum has been resected or who have chronic distal ileal disease have a threefold risk of developing cholesterol-rich stones. The mechanism is likely to be as follows: the terminal ileum is the main site for reabsorption of bile salts and when it is diseased or has been removed, reabsorption declines, leading to bile salt loss via the bowel and, eventually, a decline in the bile salt pool. The remaining bile salts are then insufficient to maintain the micellar structure of cholesterol in suspension.

Precipitation from bile is enhanced by biliary stasis . This occurs if the gall bladder becomes obstructed or contractility becomes defective. It is not known whether obstruction of the gall bladder outlet is a primary event in formation of stones, but it probably plays a part in their continued accretion. Obstruction can be caused by dysfunction of the spiral valve in the cystic duct, by reflux of duodenal contents (which may be infected) or by small stones already formed. The muscular gall bladder wall is damaged by longstanding inflammation or infection which interferes with its ability to empty. Pregnancy is also a predisposing factor.

The Role of Inflammation and Infection

Inflammation and infection probably both play a part in gallstone formation. Abnormalities of bile composition may cause chemical inflammation of the gall bladder, resulting in inflammatory exudation and accumulation of inflammatory debris. Bacteria usually form the organic nidus upon which gallstones are built; they enter the gall bladder intermittently by reflux from the duodenum or via the bloodstream. This process is probably normal but becomes pathological if the bacteria are not flushed out, as occurs when the gall bladder does not adequately empty. In support of this, is the fact that faecal organisms can be cultured from at least 25% of cholecystectomy specimens.

The Role of Chronic Obstruction

Most gall bladders removed for chronic pain show histological features more in keeping with a chronic obstructive aetiology , than an infective one. These include atrophic mucosa, submucosal and subserosal fibrosis, hypertrophy of the muscular wall, and mucosal diverticula extending into the muscular layer (known as Rokitansky–Aschoff sinuses ). Evidence of active or previous infection is uncommon. In some cases, the gall bladder is so grossly scarred, distorted or contracted that its absorptive and contractile functions have been completely destroyed.

Other Pathological Mechanisms

In about 10% of patients with typical symptoms of gall bladder disease, no stone can be found during investigation or at operation. In some of these, a stone may have passed out of the duct system into the bowel. In others, acute or chronic inflammation occurs independently of stones, called acalculous cholecystitis ; once again, chronic obstruction may be the cause. Finally, the terms biliary dyskinesia and cystic duct syndrome may sometimes explain the condition where patients have typical symptoms of gall bladder disease but standard investigations are essentially normal. When biliary manometry is used, some patients have an abnormally high pressure in the sphincter of Oddi. Confirming this diagnosis is difficult but a fair proportion of patients suspected of this are cured by endoscopic sphincterotomy.

Epidemiology of Gallstones

In developed countries, at least 10% of adults probably develop gallstones during their lifetime, although most remain asymptomatic. Gallstones are rare before adulthood and increase in prevalence with age. Women are affected four times more often and pregnancy appears to be an important predisposing factor; obesity and diabetes may also play a part. The typical patient is said to be a ‘fair fat fertile female of forty’, but many gallstone patients do not fit this description. Gallstone disease is rare in rural communities of developing countries but is increasing with urbanisation. Western-style processed foods, high in fats and refined carbohydrates but poor in fibre, may be responsible. Dietary contributions to gall bladder disease support the theory that changes in composition of bile are important in stone pathogenesis.

Blood Tests for Haematological and Liver Abnormalities

Haemolytic disorders , such as hereditary spherocytosis, thalassaemia and sickle-cell trait should be considered, as they may predispose to pigment stones. Liver function tests (LFTs) are indicated to look for indications of common duct stone obstruction, if there is any suggestion of jaundice, and to exclude other liver abnormalities.

Imaging in Investigating Gall Bladder Pathology

Ultrasonography ( Fig. 20.4 ) can reliably identify stones in the gall bladder and any increase in thickness of the wall (caused by inflammation or fibrosis). Ultrasound also provides a simple and accurate means of demonstrating dilatation of the common duct system , often indicating distal duct obstruction. Unfortunately, it is unreliable for directly identifying bile duct stones, particularly at the lower end, because the image tends to be obscured by overlying duodenal gas. Ultrasound has the great advantage of being suitable for use in the seriously ill or jaundiced patient, as it is noninvasive and can be performed at the bedside.

Investigating the Biliary Duct System ( Fig. 20.5 )

The Nonjaundiced Patient

Patients with gallstones but no history of obstructive jaundice do not require preoperative investigation for duct stones, apart from an ultrasound scan and LFTs. If cholecystectomy is needed, intraoperative (or perioperative) cholangiography may be carried out. A cannula is passed through the cystic duct into the common bile duct and radiopaque contrast material injected to fill the biliary tree. X-rays or fluoroscopic imaging are then used to demonstrate the duct morphology and abnormalities, such as duct dilatation, filling defects caused by stone, or distortion of the tapering lower end of the common duct, as well as obstruction of flow into the duodenum. If cholangiography shows stones, the duct may be explored at the time or else dealt with later by endoscopic retrograde cholangiopancreatography (ERCP).

Patients with a history of transient jaundice , possibly attributable to stones, will have either operative cholangiography at cholecystectomy or preoperative ERCP.

Chronic Symptoms Suggestive of Gall Bladder Disease

Many patients are referred with a history of intermittent pain in the RUQ or epigastrium often accompanied by nausea or even vomiting. The pain may be brought on by large or fatty meals and may radiate around towards the back. Symptoms are often vague and ill-defined so patients often delay consulting a doctor. Examination rarely reveals more than vague upper abdominal tenderness. Many turn out not to have gallstones on ultrasonography and the pain may be caused by irritable bowel syndrome but the differential diagnosis includes peptic ulcer disease, urinary tract infection and chronic constipation. Note that even if a patient has upper abdominal symptoms and demonstrable gallstones, this does not prove the pain is caused by stones. When symptoms are less specific, a more extensive diagnostic search is needed, perhaps including upper gastrointestinal endoscopy, plasma amylase and electrocardiography as well as bowel investigations.