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