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 1% of patients with gallstones develop acute complications Approximately 12% of patients undergoing cholecystectomy found to have CBD stones

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

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

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

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

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

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

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, unconjugated bilirubin 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

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

Risk factors for gallstone formation Age ◦ Risk is x4 between the ages of compared with younger subjects ◦ Due to increased cholesterol content in bile Sex ◦ Higher prevalance in women, up to x3 between ages of 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

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

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

Risk factors for gallstone formation Cirrhosis ◦ Overall prevalance approaches 30% ◦ Higher incidence with Childs B and C disease ◦ High unconjugated bilirubin 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

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

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

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

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-)

CLINICAL FEATURES

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

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

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

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

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)

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 E 2 and F 1 α 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

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

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

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

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

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

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

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

Mirizzi Pablo Luis Mirizzi ( ) Cardoba, Argentina Also introduced use of the intra-operative cholangiogram

TREATMENT

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

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)

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

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

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

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

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

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

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

‘Typical’ bile duct injury CBD is misidentified as the cystic duct and ligated / divided Gall bladder is pulled to the right and the CHD is misidentified as an’ accessory’ cystic duct. Ligated and divided Results in excision of most of the extrahepatic biliary tree

Other types of bile duct injury Strasberg classification, from A to E ◦ A: cystic duct stump leak ◦ B: aberrant right hepatic duct occlusion ◦ C: aberrant right hepatic duct division without ligation ◦ D: lateral CBD injury ◦ E: related to the CHD confluence (further subdivided into 1-5)

CBD stones found at operation Approximately 12% ERCP ◦ Post-operative ◦ Intra-operative Transcystic CBD exploration (successful ~65% of the time) Choledochotomy ◦ Laparoscopic or open ◦ Requires CBD to be >8mm ◦ Often required if multiple large stones remain ◦ After failed transcystic exploration ◦ After failed ERCP (or not available)

CBD stones found at operation Choledochotomy can be followed by either antegrade stent placement and primary closure, or T-tube insertion Trans-duodenal stent allows post-operative biliary drainage and may facilitate subsequent ERCP T-tube placement has the added advantage of providing access for further choledochoscopy without the need for re-operation ◦ Lower complication rate than ERCP ◦ However, ERCP becoming increasingly accessible and avoids morbidity of T-tube care

Post-operative complications May be early (peri-operative period) or late ◦ Retained / recurrent CBD stones (10%) ◦ Bile duct strictures ◦ Bile duct injury ◦ Vascular injury Non-resolution of symptoms (post- cholecystectomy syndrome) ◦ Extra-biliary causes of abdominal pain ◦ Biliary dyskinesia ◦ Sphincter of Oddi dysfunction