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Gallstone disease: Pathogenesis and clinical presentations

Gallstone disease: Pathogenesis and clinical presentations. Allan Kwok SET 4 Liverpool Hospital. Approximately 12% of men and 24% of women of all ages have gallstones 80% are asymptomatic 2-3% of patients progress per year to symptomatic disease

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Gallstone disease: Pathogenesis and clinical presentations

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  1. Gallstone disease:Pathogenesis and clinical presentations Allan Kwok SET 4 Liverpool Hospital

  2. Approximately 12% of men and 24% of women of all ages have gallstones • 80% are asymptomatic • 2-3% of patients progress per year to symptomatic disease • 1% of patients with gallstones develop acute complications • Approximately 12% of patients undergoing cholecystectomy found to have CBD stones

  3. Constituents of bile • Lipid component • Bile acids (70%) • Phospholipids (25%) • Cholesterol (5%) • Mucoproteins • Act as a barrier between epithelium and concentrated bile acids • However, also serve as a nidus for cholesterol nucleation

  4. Types of gallstones • Cholesterol • Black pigment • Brown pigment • Mixed (usually contain >50% cholesterol) • Approximately 10-20% have adequate calcification to render stones radio-opaque

  5. Bile acids • Primary bile acids include chenodeoxycholic acid and cholic acid • Conjugated to glycine (75%) or taurine (25%) in the liver before being transported into the bile cannaliculus • Bile acids, phospholipids and cholesterol form vesicles which increase solubility of cholesterol in bile

  6. Cholesterol stone formation • Cholesterol is most soluble when bile acid concentration >50% • When biliary cholesterol concentration increases, the vesicles form multilamellar vesicles or micelles. These have a lower solubility coefficient for cholesterol and crystals form on their surfaces • Mucoproteins promote a pro-nucleation state and encourage further crystals to precipitate • Gallbladder stasis leads to concentration of bile and also contributes to poorer cholesterol solubility

  7. Cholesterol stone formation • There is a small zone where cholesterol will exist in a ‘metastable supersaturated zone’ • Outside of this, crystals of cholesterol will eventually precipitate

  8. Black pigment stones (calcium bilirubinate) • Contain less than 20% cholesterol by weight • Generally smaller and dark in colour • More common in haemolytic conditions and patients with cirrhosis • Haemolytic anaemia • Thalassaemia • Hypersplenism • Are caused by an increase in haem breakdown +/- inability of the liver to conjugate bilirubin • Haem -> biliverdin -> bilirubin • Bilirubin is normally conjugated to glucuronic acid

  9. Black pigment stones (calcium bilirubinate) • In haemolytic conditions, bilirubin concentrations are higher • In cirrhotic patients, the liver is unable to synthesise / conjugate adequately • Conjugated bilirubin is quite water-soluble • However, unconjugatedbilirubin forms insoluble precipitates, especially with calcium, and is secreted into bile in higher-than-normal concentrations in these disease states • Usually form in the gallbladder

  10. Brown pigment stones • Uncommon (5%) in Western society • Associated with biliary stasis and bacterial infection • E.coli, Bacteroides, Ascaris • Bacteria release glucuronidase, which unconjugatesbilirubin • They also hydrolyse lecithin to release fatty acids • Bind calcium to form soft ‘brown’ pigment stones • Often form in bile ducts de novo

  11. Risk factors for gallstone formation • Age • Risk is x4 between the ages of 40-69 compared with younger subjects • Due to increased cholesterol content in bile • Sex • Higher prevalance in women, up to x3 between ages of 30-39 • Pregnancies / hormones • Related to frequency and number of pregnancies • New biliary sludge may form in up to 30% of women • Oestrogens promote cholesterol hypersecretion in bile and reduce bile acid synthesis • Progesterones promote stasis and impair contractility • These changes reverse 1-2 months after giving birth with resolution of sludge in up to 60% of cases

  12. Risk factors for gallstone formation • Oral contraceptives and HRT • As above • Also found to apply to men receiving oestrogen therapy for prostate cancer, compared to those who elected for orchiectomy (small study) • Obesity • Enhanced cholesterol synthesis and secretion

  13. Risk factors for gallstone formation • Gallbladder stasis • Fasting states • Rapid weight loss • TPN use / ICU admission • Major trauma • Somatostatin • Due to excessive reabsorption of water with resultant cholesterol supersaturation • Rapid weight loss • Increases bile calcium concentration • Increases bile mucin concentration

  14. Risk factors for gallstone formation • Cirrhosis • Overall prevalance approaches 30% • Higher incidence with Childs B and C disease • High unconjugatedbilirubin levels • High circulating oestrogen levels (aromatase) • Impaired enterohepatic circulation • Small bowel resection • Crohn’s disease • Reduced levels of bile acid content in bile, leading to poor cholesterol solubility

  15. Risk factors for gallstone formation • Drugs • Ceftriaxone (biliary excretion, forms a complex with calcium and precipitates) • Clofibrate (impairs bile acid formation, leading to supersaturation) • Physical inactivity / sedentary lifestyle

  16. Risk factors for gallstone formation • Increased circulating unconjugatedbilirubin • Haemolytic states • Cirrhosis • Hypersplenism • High-turnover haematological disease • Genetic factors / ethnicity • Pima Native Americans have incidence of up to 75% • Chilean • Mexican

  17. Gallstone formation – in summary • Imbalance of bile content • Cholesterol supersaturation • Too much unconjugated bilirubin • Inadequate bile salt content • Gall bladder stasis

  18. Protective factors • Statins • Aspirin • Vitamin C (but only for women!) • Coffee (>3 cups per day), but decaffeinated coffee not protective • Diet rich in unsaturated fats (mono- and poly-)

  19. CLINICAL FEATURES

  20. Presentation • Depends on the site of gallstone impaction / obstruction • biliary colic • cholecystitis • choledocholithiasis • cholangitis • pancreatitis • Biliary colic • RUQ pain • nausea • vomiting • post-prandial • usually unaffected by movement and lasts only for several hours

  21. Presentation • Cholecystitis may present with all the above, plus • Fever • Positive Murphy’s sign • Elevated WCC, CRP • May be mild derangements in ALT/AST, but unusual to have elevated bilirubin or ALP in uncomplicated cholecystitis

  22. Presentation • Cholangitis • Charcot’s triad (pain, fever, jaundice) • obstructive LFTs • French neurologist (1825-1893) • ‘founder of modern neurology’ • taught Sigmund Freud, Joseph Babinski, George Gilles de la Tourette among others

  23. Presentation • Choledocholithiasis • RUQ pain, nausea, vomiting • traditionally believed that CBD does not produce colicky pain, as it has no smooth muscle • however, may be associated with spasm of Sphincter of Oddi • steatorrhoea • pruritis

  24. Acute cholecystitis • A syndrome encompassing acute inflammation of the gallbladder usually in association with RUQ pain, fever and leucocystosis • Usually due to gall stones • May be acalculous (up to10%, usually in critically unwell patients)

  25. Acute cholecystitis • Experimental animal models have shown either mechanical or chemical irritation of gall bladder mucosa is the inciting event in development of cholecystitis, in conjunction with cystic duct obstruction (which alone does not seem to be adequate) • Inflammatory process mediated by prostaglandins E2 and F1α • Bacterial infection of bile is not a pre-requisite • Healthy control subjects generally have sterile bile on fluid culture • In one study, up to 40% of patients with gallstones (but not necessarily cholecystitis) have positive bile cultures • Similar rates of positive culture in those with acute cholecystitis • E.coli, Klebsiella, Enterococcus, Enterobacter

  26. Chronic cholecystitis • A term used to describe histopathological findings of chronic inflammatory cell infiltrate in the wall of the gallbladder, invariably in association with long-standing mechanical irritation from stones leading to thickening and fibrosis

  27. Differential diagnoses • Biliary colic • Hepatitis • Choledocholithiasis • Cholangitis • Pancreatitis • Pyelonephritis • Right lower lobe pneumonia • Peptic ulcer disease • Colitis • Appendicitis • …

  28. Imaging investigations • FBC • LFT • Bilirubin (conjugated, unconjugated) • 60% of patients with CBD stones will have derangement of at least one LFT • However, elevation of LFTs does not necessarily imply CBD stones • Lipase / amylase

  29. Investigations • US • 85-95% sensitivity, 99% specificity for detection of gallstones • 88% sensitivity, 80% specificity for cholecystitis • Wall oedema, pericholecystic fluid • CT • Poor sensitivity as stones may be isodense to bile • HIDA / DISIDA • Tc-labelled hepatic iminodiacetic acid (or di-isopropyl) • IV injection, biliary excretion • Positive if gallbladder, CBD, duodenum not visualised after 60 minutes • 97% sensitivity, 90% specificity • False positives: sphincterotomy, TPN, severe liver disease • Modification with morphine administration to encourage SofO contraction

  30. Imaging investigations • MRCP • Less sensitive than US for detection of GB wall oedema • More sensitive than US for detection of cystic duct and CBD stones (95%) • Oral cholecystography • Largely abandoned in clinical practice • Takes days to perform • Relies on functional gallbladder to concentrate contrast medium

  31. Complications • Emphysematous cholecystitis • Clostridium welchii • E. coli • Klebsiella • Pseudomonas • Gangrene (up to 20% if left untreated) • Perforation • Cholangitis (Charcot’s triad) • Pancreatitis • Mirizzi syndrome • Cholecystoenteric fistula / gallstone ileus

  32. Mirizzi’s Syndrome • Extrahepatic obstruction in association with cholelithiasis • Occurs in around 1 in 200 • Type I • Stone impacted in cystic duct causes direct pressure or oedema to CHD • Will usually require conversion to open cholecystectomy • Type II • Erosion of stone into CHD • Will usually require hepatojejunostomy

  33. Mirizzi • Pablo Luis Mirizzi (1893-1964) • Cardoba, Argentina • Also introduced use of the intra-operative cholangiogram

  34. TREATMENT

  35. Treatment of asymptomatic gallstones • No evidence to support interventional treatment • 2% of incidentally-discovered gallstones become symptomatic per year

  36. Treatment of symptomatic gallstones – non interventional • Acute • Antibiotics (lower rates of wound infection but no difference re: development of GB empyema) • Anti-inflammatories • Dissolution therapy • Chenodeoxycholic acid • Ursodeoxycholic acid (UDCA) • Takes 6-12 months to have benefit • Requires smaller stones (larger surface area), radiolucency (lack of calcium matrix) • High recurrence rate upon cessation of therapy (30% at 3 years)

  37. Treatment of symptomatic gallstones – non interventional • Lithotripsy • Similar technique to ESWL for renal stones • Poorer results, however, • Seldom used nowadays

  38. Treatment - interventional • Cholecystectomy • Open / mini-laparotomy • Laparoscopic • Needlescopic • Single-incision • NOTES • (Subtotal) • Timing • Higher rates of hospital re-presentation (38% -v- 4%) for those managed conservatively and discharged without cholecystectomy

  39. Treatment - interventional • Cholecystostomy • Percutaneous • Laparoscopic • For high-risk patients with late presentation • Too unwell to tolerate general anaesthetic or prolonged procedures • May not necessarily obviate the need for surgery, e.g. mural gangrene

  40. Laparoscopic cholecystectomy • Contraindications (relative) • Haemodynamic compromise / unstable • Significant upper abdominal surgery • Anaesthetic concerns (pneumoperitoneum) • Positioning • American (supine) • French (lithotomy)

  41. Critical view of safety • Described by Strasburg in 1995 • Mandates three conditions • Calot’s triangle be cleared of fat and fibrous tissue • Lower part of GB should be freed from cystic plate • Two (and only two) structures should be seen to enter the GB • Beware anatomical variations • Right hepatic artery mistaken for cystic a. • Anomalous origins of cystic a. • Anomalous ductal anatomy

  42. Operative risks • Bleeding • Duodenal injury • Vascular injury / compromise • Bile leak / bile duct injury • 0.1% in open cholecystectomy • 0.3% in laparoscopic cholecystectomy • Routine use of IOC conferred a protective effect against CBD injury

  43. Intra-operative cholangiogram • A study of 1,500,000 cholecystectomies in WA found lower rates of CBD injury when IOC was performed (Fletcher et al.) • Confirms anatomy of biliary tree prior to division of ducts (recoverable injury) • Also identifies residual CBD stones

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