Gallstone disease: Pathogenesis and clinical presentations Allan Kwok SET 4 Liverpool Hospital.
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Transcript of Gallstone disease: Pathogenesis and clinical presentations Allan Kwok SET 4 Liverpool Hospital.
Gallstone disease:Gallstone disease:Pathogenesis and clinical Pathogenesis and clinical presentationspresentations
Allan KwokSET 4Liverpool 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 bileConstituents of bileLipid 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 gallstonesTypes of gallstonesCholesterolBlack pigmentBrown pigmentMixed (usually contain >50%
cholesterol)
Approximately 10-20% have adequate calcification to render stones radio-opaque
Bile acidsBile acidsPrimary 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 Cholesterol stone formationformationCholesterol 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 Cholesterol stone formationformationThere 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 Black pigment stones (calcium bilirubinate)(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 Black pigment stones (calcium bilirubinate)(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 stonesBrown pigment stonesUncommon (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 Risk factors for gallstone formationformation 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
Risk factors for gallstone Risk factors for gallstone formationformationOral 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 Risk factors for gallstone formationformationGallbladder 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 Risk factors for gallstone formationformationCirrhosis
◦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 Risk factors for gallstone formationformationDrugs
◦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 Risk factors for gallstone formationformationIncreased 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 Gallstone formation – in summarysummaryImbalance of bile content
◦Cholesterol supersaturation◦Too much unconjugated bilirubin◦Inadequate bile salt content
Gall bladder stasis
Protective factorsProtective factorsStatinsAspirinVitamin C (but only for women!)Coffee (>3 cups per day), but
decaffeinated coffee not protective
Diet rich in unsaturated fats (mono- and poly-)
CLINICAL FEATURESCLINICAL FEATURES
PresentationPresentation 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
PresentationPresentationCholecystitis 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
PresentationPresentationCholangitis
◦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
PresentationPresentationCholedocholithiasis
◦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 cholecystitisAcute cholecystitisA 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 cholecystitisAcute 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
Chronic cholecystitisChronic cholecystitisA 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 diagnosesDifferential diagnosesBiliary colicHepatitisCholedocholithiasisCholangitisPancreatitisPyelonephritisRight lower lobe pneumoniaPeptic ulcer diseaseColitisAppendicitis…
Imaging investigationsImaging investigationsFBC
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
InvestigationsInvestigations 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 investigationsImaging investigationsMRCP
◦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
ComplicationsComplicationsEmphysematous cholecystitis
◦ Clostridium welchii◦ E. coli◦ Klebsiella◦ Pseudomonas
Gangrene (up to 20% if left untreated)PerforationCholangitis (Charcot’s triad)PancreatitisMirizzi syndromeCholecystoenteric fistula / gallstone ileus
Mirizzi’s SyndromeMirizzi’s SyndromeExtrahepatic 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
MirizziMirizziPablo Luis Mirizzi (1893-1964)
Cardoba, Argentina
Also introduced use of the intra-operative cholangiogram
TREATMENTTREATMENT
Treatment of asymptomatic Treatment of asymptomatic gallstonesgallstones
No evidence to support interventional treatment
2% of incidentally-discovered gallstones become symptomatic per year
Treatment of symptomatic Treatment of symptomatic gallstones – non gallstones – non interventionalinterventionalAcute
◦ 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 Treatment of symptomatic gallstones – non gallstones – non interventionalinterventionalLithotripsy
◦Similar technique to ESWL for renal stones
◦Poorer results, however,◦Seldom used nowadays
Treatment - interventionalTreatment - interventionalCholecystectomy
◦ 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 - interventionalTreatment - interventionalCholecystostomy
◦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 Laparoscopic cholecystectomycholecystectomyContraindications (relative)
◦Haemodynamic compromise / unstable
◦Significant upper abdominal surgery◦Anaesthetic concerns
(pneumoperitoneum)
Positioning◦American (supine)◦French (lithotomy)
Critical view of safetyCritical view of safetyDescribed 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 risksOperative risksBleedingDuodenal injuryVascular 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 Intra-operative cholangiogramcholangiogramA 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 injuryTypical’ bile duct injuryCBD 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 Other types of bile duct injuryinjuryStrasberg 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 CBD stones found at operationoperation 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 CBD stones found at operationoperationCholedochotomy 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 Post-operative complicationscomplicationsMay 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