Introduction

• Between 1-4% with gallstones will have an acute presentation of biliary disease each year
  • About 60% of these are biliary colic and 40% of these are acute cholecystitis

Categorisation

• Bile contains: bile pigments (from Hb breakdown products), cholesterol, and other lipids.
• Stones are generally classified as cholesterol stones or pigment stones; however, in reality they are usually mixed. In the developed world, cholesterol stones are more common, but in the developing world, pigment stones are more common.
  • In Europe and the USA, 75% of gallstones are cholesterol stones.
• Pure cholesterol stones  –
  • Usually solitary and large
  • RF’s – female sex, age, obesity
  • Stones of about 70% or more of cholesterol are usually smaller and more numerous. The rest of the stone is made up of calcium compounds and protein.
• Mixed stones:
  • Usually multiple and irregular shaped
• Pigment stones can also be divided into two categories – Brown and black. Brown stones are softer, and contain a mixture of pigment, cholesterol and calcium salts. Black stones are much harder and made of pure pigment.

Epidemiology

• More common in women
• Cholesterol secretion is a massive factor in gallstone formation – particularly the amount of cholesterol secreted in relation to the concentration of bile salts. Women naturally secrete a higher proportion of cholesterol than men and thus they have a higher incidence of gallstones.
• Incidence increases with age
• At age 30 – 5% of women and 2% of men have / have had gallstones. Aged 55 – 20% / 10%, age 70, 30% / 20%.
• Racial differences: More common in Scandinavia, and Native North and South American Populations.

Aetiology

• Weight
  • Obesity
  • Sudden weight loss
• Family History
• Oestrogen
  • Female gender
  • Oral contraceptive pill
• Diet (high fat, low fibre)
• Increasing age
  • Stones take time to form
• Diabetes

Pathology

Cholesterol stones

• You need three factors for the formation of cholesterol stones:
  • High concentration of cholesterol in the gallbladder
  • Gallbladder stasis
  • Products that promote the crystallisation of cholesterol – some lipoproteins found in bile do this.
• Cholesterol stones form when the concentration of micelles is not great enough to hold all the cholesterol in the micelles. Formation of stones is increased during fasting – particularly extended fasting e.g. in IV nutrition  – as this increases the concentration of cholesterol in the gallbladder relative to other solutes.
• Patients with cholesterol stones generally have a smaller bile pool, which circulates more often.
• Formation – Initially, cholesterol crystals will form in bile that is supersaturated with cholesterol. This results in the production of ‘sludge’. This process is:
  • Inhibited by – caffeine, NSAID’s and bile salts
  • Exacerbated by – Mucin, rapid weight loss, pregnancy, increased serum cholesterol – e.g. by a large amount of body fat, old age, being female, diabetes, high dietary fat – reduced bile production / circulation – e.g. in malabsorption (like Crohn’s) where so much bile is lost, it cannot be replaced quickly enough.
  • Drugs
    • Clofibrate – A fibrate drug, this lowers plasma cholesterol by increasing cholesterol secretion in bile.
    • Contraceptive pill
• Sludge can then go on to form stones, or it can be reabsorbed. Only in about 15% of cases will sludge go on to form stones. It takes about 8 years for a stone to form from the beginning of the initial process. In symptomatic patients, a cholecystectomy is usually performed 12 years after the process of stone formation began.

 

Pigment stones

1. An increase in bilirubin load, as a result of haemolytic anaemia.
   1. 40-60% of patients with haemolytic disease have pigment stones, but the vast majority of pigment stones patients do not have haemolytic disease.
2. Pigments become less water soluble once in the bile as a result of the action of glucuronidases. It is thought that most cases of pigment stones result from the subclinical bacterial colonisation of the gallbladder.  This is particularly common in East Asia, and associated with E. coli.  These stones tend to be softer and brown, and combined with calcium carbonate. The other two types of stone tend to be smaller, blacker and harder, and more commonly encountered in the west.
3. Cirrhosis – with this there will be depletion of glucuronidase inhibitors in the bile.  

Presentation

• 90% of cases are asymptomatic and discovered incidentally
• Gallstones usually do NOT cause flatulence, dyspepsia, fat intolerance or other vague upper abdominal symptoms, unless they are causing an acute flare-up of biliary colic (see below) or other acute manifestations
• Symptomatic gallstones can present as either biliary colic, cholecystitis (infection in the biliary tree – an emergency), pancreatitis, or other acute manifestations

Biliary Colic

• Describes an intermittent RUQ/epigastric pain associated with a blockage in the bile duct. Often it is caused by a stone migrating down the duct.
• The term ‘Colic’ means a wave of pain. It is associated with a tubular structure surrounded by smooth muscle. The wave nature of the pain is related to the fact that smooth muscle has its own ‘pace maker’ that causes contractions a certain intervals. However, in this instance, the term ‘colic’ is misleading. A true colic increases and decreases in intensity gradually in a rhythmic fashion. But in biliary colic, the pain is often constant and crescendoes. The pain is typically associated with an over indulgence in food.
• Pain is typically sporadic and is associated with eating – particularly fatty foods. Pain will subside with analgesia, and is usually reduced with modification of diet.

Clinical Features

• Pain after eating a large and /or fatty meal. Typically, the pain will appear in the mid-evening and last until the early hours of the morning. Pain may radiate to right shoulder tip. Typically begins in the evening and lasts until the middle of the night.
• Nausea and vomiting (in severe attacks)
• More severe prolonged pain suggests association with an underlying condition such as cholecystitis, cholangitis or gallstone induced pancreatitis.
• LFT’s often normal.
• Typically, a recurring condition: over a 5-year period 100% of patients will experience it again. 20% of patients go on to develop something more serious; cholecystitis, obstructive jaundice or pancreatitis.

Differential Diagnosis

• GORD
• Peptic ulcer
• IBS
• Pancreatitis
• Tumour
  • Stomach
  • Pancreas
  • Large bowel

Investigations

• LFT’s – ↑bilirubin, ↑ALP and ↑ALT may be very slightly raised in the presence of cholecystitis, even without current duct obstruction.
  • ALP and bilirubin raised higher than ALT is an obstructive pattern of LFT’s, and tends to signify biliary duct problems.
  • ALT raised higher than ALP and bilirubin usually indicates an intra-hepatic pathology.
• Plain AXR – may show gallstones (only show up in 10-15% of cases, as they need to be calcified to been seen on radiograph). It may also show up gas in the gallbladder, as a result of gas producing organisms, or fistulation to the large bowel. As a result, stones may be seen on XR incidentally, but this is not typically used diagnostically.
• Ultrasound – the gold standard diagnostic test. USS is 95% effective at detecting gallstones- but is operator dependent.
  • On a USS, you can sometimes mistake gallstones for polyps and vice versa. You can tell the difference because gallstones will cast a ‘shadow’ underneath them on the USS screen, but polyps will not.
• Gallstones are very common in the elderly population, and so you should be careful in the absence of conclusive symptoms that gallstones are actually the cause of the symptoms.
• Cholecystitis may be detectable by a thickening of the gallbladder wall to more than 4mm.  There may also be a ‘halo effect’ around the gallbladder which shows oedema surrounding the bladder.  This may also indicate hypoalbuminaemia, portal hypertension or acute viral hepatitis.
• Ductal dilation caused by a blockage of the bile duct may also be visible.
• USS is operator dependent – things may be missed if the operator is not very experienced. In 5% of cases a false negative result is given.
• Oral cholecystography – the patient takes a dose of an oral dye that is absorbed and concentrated by the liver and then secreted in the bile. This should enable you to see the gallbladder on radiograph. If you can’t see the gallbladder, then there could be a blockage in the cystic duct, or there may have been recent cholecystitis. Even when this test works correctly, some stones are too small to see, and so we get a false negative 5% of the time. Used in conjunction with an USS, the false negative rate is reduced to 2%.
• ERCP – this is not normally used in uncomplicated gallstone disease. It is often used where the history is very suggestive of gallstones, but no stones can be seen on ultrasound or with cholecystography. Often a sample of bile is taken, which is then examined histologically for cholesterol crystals and debris.
• Amylase – a stone passing through the very last part of the common bile duct, but then getting lodged can cause pancreatitis. If this is the case it is worth measuring serum and urine amylase. Serum amylase will very quickly return to normal levels if conditions return to normal, however urine amylase can remain elevated for up to 5 days.

Examination

• Courvoisier’s sign – palpable gallbladder – this law states that a palpable gallbladder in the presence of painless jaundice is unlikely to be gallstones. Typically, gallstones result in a fibrotic shrunken gallbladder, which will not usually distend, and thus will not usually be palpable.
• Gallbladder distension is usually a sign of an acute pathology – such as pancreatic malignancy/obstruction of the pancreas.

Complications

• Acute and chronic cholecystitis
• Acute cholangitis
• Pancreatitis
• Increased risk of adenocarcinoma of the wall of the gallbladder (only very small)
• Fistulation – Gallstones may perforate the gallbladder and form a fistula, often to the colon or small intestine. A gallstone passing into the small intestine may cause a blockage in the ileum – gallstone ileus.
• Stones can pass out of the cystic duct and into the bile duct, causing obstructive jaundice. This is called choledocholithiasis and it is commonly accompanied by cholangitis (bacterial infection of the gallbladder)

Treatment

• Management of Biliary Colic
  • Morphine IV – 5-10mg/4hr
  • Antiemetic – e.g. domperidone, metoclopramide, cyclizine
• Elective Cholecystectomy – for some patients with severe colic, elective cholecystectomy may be suitable.This is nearly always accompanied by cholangiography (imaging of the bile ducts using x-ray). This procedure is performed under general anaesthetic after 4 hours of fasting. DVT prophylaxis will generally be used if the patient is over 40. Prophylactic antibiotics will also usually be given in the patient is over 40. Usually this is a single dose of second generation cephalosporin (e.g. cefuroxime) – and this may be continued for 24-48 hours after the operation in the presence of severe sepsis.

The procedure can be ‘open’ or ‘laparoscopic’.

• Open – there is a 10% chance that the patient will have a gallstone in the bile duct at the time of cholecystectomy and as a result, often during the operation, a catheter is put in the bile duct, and dye squirted up to outline the biliary tree. If there is a stone present here, then it should be removed. After this is done, the gallbladder is removed. Some surgeons also like to leave a drain in place of the gallbladder for a few days, as some people have small ducts that take bile directly to the gallbladder, and these may leak. However, the drain is a cause of post-operative pain, and the evidence to suggest it improves the outcome from bile leak is limited.
• Laparoscopic – the camera is inserted in the umbilicus and there are three other incisions made for instruments. This is now a more common procedure than the open version, and the techniques used are virtually the same. Once the gallbladder has been removed from its bed, it is particularly important to examine it for leaks (to check for the little ducts described above). Usually the gallbladder is removed via the umbilicus. The peritoneal cavity will then be washed out, and cleaned up.
• Post operative care. This is quite different depending on which of the above two procedures occurred.
  • Open – patients will require pain relief and nil-by-mouth for up to 48 hours due to the ileus from handling of the gut. IV fluids are required for 2 days as a result of the nil-by-mouth. Patients will also usually require low dose heparin to recue the risk of thrombosis, and many may need physiotherapy and / or early mobilisation to avoid atelectasis (collapse of the lung, a common complication of surgery, particularly in the elderly). The average post-operative stay is 5-days. Normal activity is often resumed within 4 weeks.
  • Laparoscopic –these patients have considerably less pain and ileus. Most are mobile much sooner, and so the need for physio is much less. Average post-operative stay is 2 days. Normal activity is usually resumed within 2 weeks.
  • Generally, open surgery is done on the more high risk patients – e.g. those that are obese or have complications. This means that the outcomes for open surgery are not as good for laparoscopic surgery.
  • Complications (open > laparoscopic)
    • Minor complications – (6% : 3%)
    • Wound infection – (0.5% – 1%)
    • Respiratory complications (1.9% – 2.5%)
    • Bile duct injury (0.15% : negligible)
    • Sphincter of Oddi dysfunction. This can be a cause of post-operative pain, and is often due to trauma sustained in the operation.
    • Post-cholecystectomy syndrome – this is biliary type pain that occurs months or years after cholecystectomy. Patients will say that this pain feels identical to the pain for which the operation was carried out. It basically means that cholecystectomy was not needed, because the gallbladder / gallstones were not originally the cause of the pain. The pain is actually caused by functional colonic disease, where there is spasm at the hepatic flexure (hepatic flexure syndrome).
    • Stones in the common bile duct are later found in between 3-15% of patients after cholecystectomy
    • In an ever smaller number of patients there may be hypertension of the sphincter of Oddi – i.e. it doesn’t relax. Diagnosis of this can be confirmed by imaging of the bile duct which shows a dilated bile ducts when the pain is present, and the lack of a retained stone. You can also measure the pressure of the sphincter of Oddi. It is treated by a spincterotomy.
• Experimental / rarely used –
  • Oral – the bile acid UDCA can be given orally, and this may break down any cholesterol gallstones present. The process by which gallstones are broken down is called dissolution.This treatment is rarely used, and will probably only be used for patient who are not fit to undergo a laparoscopic cholecystectomy. For this treatment to work, the gallbladder must be functioning properly, the gallstones must be almost 100% cholesterol, and less than 10mm in diameter.
    • Only about 20% of gallstone patients meet the above criteria.
    • Dissolution often takes months of treatment.
    • This treatment has a high relapse rate when the treatment is discontinued.
    • Effectiveness of this treatment may be improved by administration of a statin (usually simvastatin) during treatment as this reduces the amount of cholesterol being secreted into the bile.
  • Extracorporeal shockwave lithotripsy – this treatment is very successful, but only in a small proportion of patients. In this treatment, a shockwave is given by ultrasound or radiography onto the stones. Gallbladder function has to be intact when this treatment is used, and stones should be larger than 10mm. The higher the calcium content of the stones, the less likely the chance of success.
• The above two non-surgical therapies are most effective when combined.

Cholestasis – biliary obstruction

Causes of bile duct obstruction

• Basic Liver Physiology
• Bilirubin Metabolism and Jaundice

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy

Read more about our sources

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