Subject: Medicine Topic: Gallbladder & Biliary Tree Date: July 12, 2012 Lecturer: Dr. Gamutan Transcriber: Stalingrad Editor: JC Luna Pages: 7

BILE – an isotonic fluid with an electrolyte composition resembling blood plasma – a digestive secretion -- bile acids - lipid absorption – an excretory fluid -- cholesterol, bilirubin, heavy metals, many organic anions and cations are eliminated in bile – formed in the liver – lipid-rich, protein poor fluid Major solute components of bile by moles % Bile Acids 80% Lecithin & Other Phospholipids 16% Unesterified Cholesterol 4% BILE ACIDS: Functions 1. Biliary excretion of cholesterol 2. Normal intestinal absorption of dietary fats via micellar transport mechanism > Bile acids are detergent-like molecules that form micelles in aqueous solutions above 2 mM > Cholesterol is sparingly soluble in aqueous environments, and its solubility in bile depends on the total lipid concentration and the relative molar percentages of bile acids and lecithin. > Normal ratios of these constituents favor the formation of solubilizing mixed micelles. > Abnormal ratios promote the precipitation of cholesterol crystals in bile via an intermediate liquid crystal phase. 3. Major driving force for hepatic bile flow > Serve as a major physiologic driving force for hepatic bile flow and aid in water-electrolyte transport in the small bowel & colon 4. Aid in H2O & electrolyte transport 5. Bile acid pool – 2-4 g > During digestion of a meal, the bile acid pool undergoes at least one or more enterohepatic cycles, depending on the size and composition of the meal. 6. Conserved – enterohepatic circulation > Bile acids are efficiently conserved under normal conditions. Unconjugated, and to a lesser extent also conjugated, bile acids are absorbed by passive diffusion along the gut.

> Quantitatively much more important for bile salt recirculation, is the active transport mechanism for conjugated bile acids in the distal ileum. > The reabsorbed bile acids enter the portal bloodstream and are taken up rapidly by liver cells, reconjugated & resecreted in bile. BILE ACIDS: Types Primary Bile Acids

• Cholic & Chenodeoxycholic acids – from cholesterol in the liver

–conjugated with glycine or taurine Secondary Bile Acids

• Deoxycholate & Lithocholate – formed in the colon

– bacterial metabolites of 10 bile acids (Lithocholate is much less efficiently absorbed from the colon than deoxycholate)

GALLBLADDER & SPHINCTERIC FUNCTIONS Sphincter of Oddi

• In fasting, provides a hi-pressure zone of resistance to bile flow from the CBD into the duodenum

• Tonic contraction > prevents reflux of duodenal contents into pancreatic & bile ducts > promote bile filling of the gallbladder Cholecystokinin

• Peptide hormone • Controls the evacuation of the

gallbladder • Released from the duodenal mucosa

in response to the ingestion of fats and amino acids

• It produces the following: o powerful contraction of the

gallbladder o decreased resistance of sphincter

of Oddi o increased hepatic secretion of

hepatic bile o enhanced flow of biliary contents

into the duodenum Gallbladder – storage of bile (30 – 50 ml) GALLSTONES – most prevalent in western countries (diet) – 2-3X more common in women

– at least 10% of the population has gallstones – ages 20-55 prevalence for women is 5-20 % – after age 50 prevalence for women is 25-30 % – prevalence in men is half of women Pathogenesis & Risk Factors – Genetic factors – Multifactorial – Formed by concretion or accretion of normal or abnormal bile constituents (Harrison’s : Gallstones are formed because of abnormal bile composition) Major types of based on composition Cholesterol stones (80% of total) > Contain > 50% cholesterol monohydrate plus admixture of calcium salts, bile pigments, proteins Pigment stones (remaining 20%) > Contain < 20% of cholesterol > Primarily calcium bilirubinate 1. black – composed of either pure calcium bilirubinate or polymer-like complexes with calcium and mucin glycoproteins. They are more common in patients who have chronic hemolytic states (with increased conjugated bilirubin in bile), liver cirrhosis, Gilbert’s syndrome, or cystic fibrosis 2. brown – due to chronic biliary infection. These stones are composed of calcium slats of unconjugated bilirubin with varying amounts of cholesterol and protein. They are caused by the presence of increased amounts of unconjugated, insoluble bilirubin in bile that precipitates to form stones. Deconjugation of an excess of soluble bilirubin mono- and diglucoronides may be mediated by endogenous ß-glucoronidase but may also occur by spontaneous hydrolysis. Sometimes the enzyme is also produced when bile is chronically infect by bacteria, and such stones are brown. CHOLESTEROL GALLSTONES 1. Bile supersaturation with cholesterol

• An important prerequisite for gallstone formation but it is generally not sufficient by itself to produce cholesterol precipitation in vivo

• Increased biliary secretion of cholesterol > obesity, metabolic syndrome, high caloric and cholesterol-rich diets, or drugs

(Clofibrate) > increased activity of HMG-CoA reductase (rate-limiting enzyme of hepatic cholesterol synthesis)

• Hyposecretion of bile acids > reduction of the bile acid pool

> enhanced conversion of cholic acid to deoxycholic acid (may result from enhanced dehydroxylation of acid and increased absorption of newly formed deoxycholic bile. Increased deoxycholate secretion is associated with hypersecretion of cholesterol into bile)

2. Nucleation of cholesterol monohydrate with crystal retention & stone growth

• Excess of pronucleating factors (mucin & certain non mucin glycoproteins, Immunoglobulins

• Deficiency of antinucleating factors (Apolipoproteins A1 & AII and glycoproteins)

3. Abnormal gallbladder motor function with delayed emptying and stasis.

• Hypomotility = Stasis • Gallbladder emptying is a major

determinant of gallstone recurrence in patients who underwent biliary lithotripsy

Bile Sludges – Thick mucus materials – Microscopically – lecithin-cholesterol liquid crystals, cholesterol monohydrate crystals, calcium bilirubinate and mucin gels – Forms crescent layers in most dependent portion of GB – Precursor of gallstone disease – Implies:

1. Normal balance between GB mucin secretion & elimination has become deranged. 2. Nucleation of biliary solutes has occurred

Risk Factors: Cholesterol Stones 1. Demographic/genetic factors

– N. American Indians, Chilean Indians & Chilean Hispanics, greater in N. Europe & N. America than in Asia, lowest in Japan – Familial disposition, hereditary aspects

2. Obesity

– Increased biliary secretion of cholesterol

3. Weight loss

– Mobilization of tissue cholesterol leads to increased biliary secretion while enterohepatic circulation of bile acids is decreased

4. Female sex hormones – Estrogens stimulate lipoprotein receptors, uptake of dietary cholesterol, and increase biliary cholesterol secretion – Natural estrogens, OCPs, decreased bile salt secretion, decreased conversion of cholesterol to cholesteryl esters

5. Increasing age

– Increased biliary secretion of cholesterol decreased size of bile acid pool, decreased biliary secretion of bile salts

6. Gallbladder hypomotility leading to stasis and formation of sludge

– Prolonged parenteral nutrition – Fasting – Pregnancy – Drugs such as octreotide

7. Clofibrate therapy

– Increased biliary secretion of cholesterol

8. Decreased bile acid secretion

– Primary biliary cirrhosis – Chronic intrahepatic cholestasis – Harrison’s: genetic defect of the CYP7A1 gene (results in deficiency of the enzyme 7-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis)

9. Decreased phospholipid secretion

– Genetic defect of the MDR3 gene (encodes the phospholipid export pump in the canalicular membrane of the hepatocyte 10. Miscellaneous

– High calorie, high-fat diet – Spinal cord injury

Pigment Stones 1. Black pigment – composed of pure Ca bilirubinate or polymer-like complexes with calcium and mucin glycoprotein – Chronic hemolysis, liver cirrhosis, Gilbert syndrome, cystic fibrosis, ileal diseases, 2. Brown pigment – composed of Ca salts of unconjugated

bilirubin with varying amounts of cholesterol and protein

– Caused by increased amounts of unconjugated, insoluble, bilirubin, in bile that precipitates to form stones

Risk Factors: Pigment Stones

1. Demographic/genetic factors: Asia, rural setting 2. Chronic hemolysis 3. Alcohol Cirrhosis 4. Pernicious anemia 5. Cystic fibrosis 6. Chronic biliary tract infection, parasite infestation 7. Increasing age 8. Ileal disease, ileal resection or bypass CLINICAL MANIFESTATIONS 1. Gallstones – Usually produce symptoms by causing inflammation or obstruction following their migration into the cystic duct or CBD 2. Biliary colic – Severe, steady ache or pressure in the epigastrium or RUQ of the abdomen, radiating to the interscapular area, right scapula, or shoulder. – The most specific and characteristic symptom of gallstone disease – May be precipitated by eating a fatty meal, by consumption of a large meal following a period of prolonged fasting, or by eating a regular meal – Frequently nocturnal (few hours after retiring) 3. Nausea, vomiting – obstruction (Editor’s note: I dunno why nausea and vomiting would lead one to suspect obstruction <of what? The biliary tree?>. Maybe because in obstruction results in visceral pain that “…is characteristically severe, steady ache or fullness in the epigastrium or RUQ of the abdomen with frequent radiation to the interscapular area, right scapula, or shoulder” and that “Nausea and vomiting frequently accompany episodes of biliary pain”.) 4. Fever & chills – complications (i.e. cholecystitis, pancreatitis, or cholangitis) – If the gallstones remain inside the gallbladder, usually there will be no symptoms – If the stones are impacted in the cystic duct, the patients develop symptoms – Gallstones usually produce symptoms by causing inflammation or obstruction following their migration into the cystic duct or CBD. – Obstruction of the cystic duct or CBD by a stone creates increased intraluminal pressure and distention of the viscus that cannot be relieved by repetitive biliary contractions.

DIAGNOSIS – History and PE – Ultrasonography of GB - very accurate

Criteria: 1. acoustic shadowing of opacities w/in GB 2. they change with patients position by gravity

– Plain abdominal X-ray – GS containing sufficient Calcium to be radio opaque (10-15% of cholesterol & 50% of pigment stones); may also be of use in diagnosis of emphysematous cholecystitis, porcelain GB, limey bile and gallstone ileus – Oral Cholecystography – replaced by US, obsolete, used to assess the patency of cystic duct & GB emptying function – US Radioisotope scan – 99mTc-labeled N-substituted iminodiacetic acid NATURAL HISTORY 1. Silent or asymptomatic gallstones – development of symptoms or complications is low, 10% at 5 yrs, 5% at 10 yrs and 18% at 15 yrs – asymptomatic patients for 15 yrs are unlikely to develop symptoms – cumulative risk of death on expectant management is small – prophylactic cholecystectomy is not warranted 2. Symptomatic gallstones – biliary complication is 1 – 2% per year – surgery should be offered to patients only after significant biliary symptoms develop Management A. Cholecystectomy – definitive management Indications 1. Symptoms that are frequent enough or

severe enough to interfere with patients general routine

2. (+) Prior complications like acute cholecystitis, pancreatitis, gallstone fistula

3. (+) Condition predisposing the px to increase the risk of gallstone complications (calcified or porcelain GB & previous attacks of acute cholecystitis, large gallstone >3cm in diameter and in congenitally anomalous GB) B. Medical – Oral bile acid dissolution UDCA

– decreases cholesterol saturation of bile – produce a lamellar liquid crystalline phase – retard cholesterol crystal nucleation – dose of 10-15 mg/kg per day Selected patients a. functioning gallbladder b. radiolucent stones < 10 mm in diameter Disadvantages a. high recurrence 30%-50% over 3-5 yrs of ff up b. expensive drug for indefinite period of time ACUTE CHOLECYSTITIS I. Acute Calculous Cholecystitis – Most frequent complication of gallstones – Acute inflammation of the GB wall secondary to the obstruction of the cystic duct A. Factors which can evoke inflammation 1. Mechanical inflammation – Increased intraluminal pressure &

distension resulting ischemia of the GB mucosa & wall

2. Chemical inflammation – Caused by release of lysolecithin (due to the action of phospholipase on lecithin in bile) and other local tissue factors 3. Bacterial inflammation – May play a role in 50-85% of – Escherichia coli, Klebsiella spp, streptococcus & Clostridium spp. II. Clinical Manifestations

1. 75%- preceded by attack of biliary colic

2. pain lasts > 6 hours 3. generalized in RUQ 4. peritoneal signs 5. anorexia 6. vomiting 7. fever 8. RUQ tenderness 9. Murphy’s sign

2. Acalculous cholecystitis – in 5-10% of patients, no stones obstructing cystic duct are found at surgery – serious trauma, burns (Additionally: postpartum period following prolonged labor, and with orthopedic and other nonbiliary major surgical operations in the postoperative period. It may possibly

complicate periods of prolonged parenteral hyperalimnetation. For some of these cases, biliary sludge in the cystic duct may be responsible. Other precipitating factors include vasculitis, obstructing adenocarcinoma of the gallbladder, diabetes mellitus, torsion of the gallbladder, “unusual” bacterial infections of the gallbladder, and parasitic infestation of the gallbladder. It may also be seen with a variety of other systemic disease processes <carcoidosis, cardiovascular disease, tuberculosis, syphilis, actinomycosis, etc.>) CHRONIC CHOLECYSTITIS – almost always associated with the presence of gallstones – repeated bouts of subacute or acute cholecystitis or from persistent mechanical irritation of the GB wall – presence of bacteria in the bile > 25% – pain lasting more than 6 hours COMPLICATIONS OF CHOLECYSTITIS 1. Empyema & Hydrops a. Empyema > Usually results from progression of acute cholecystitis with persistent cystic duct obstruction to superinfection of the stagnant bile with a pus-forming bacterial organism b. Hydrops or Mucocele > Cystic duct obst ---> GB distended by mucus (mucocele) or clear transudate (hydrops) > Results from prolonged obstruction of the cystic duct, usually by a large solitary calculus 2. Gangrene and Perforation – Ischemia or necrosis ---> perforation 3. Fistula Formation & Gallstone Ileus > Fistula formation into an adjacent organ adherent to the gallbladder wall may result from inflammation and adhesion formation > Gallstone ileus refers to mechanical intestinal obstruction resulting from the passage of a large gallstone into the bowel lumen 4. Limey Bile and Porcelain GB > Limey bile – calcium ppt & diffuse hazy opacification of bile > Porcelain GB – calcium deposition w/ in the chronic inflamed GB wall, associated w/ GB CA

CHOLECYSTITIS – MANAGEMENT Medical Therapy

– Oral intake is eliminated – Nasogastric suction – IV fluids – Meperidine or NSAIDS – IV antibiotics

Surgery

–the optimal timing of surgical intervention in patients with acute cholecystitis depends on stabilization of the patient. The clear rend is toward earlier surgery, and this is due in part to requirements for shorter hospital stays.

–Urgent(emergency) cholecystectomy or cholecystotomy is probably appropriate in most patients in whom a complication of acute cholecystitis such as empyema, emphysematous cholecystitis, or perforation is suspected or confirmed. CHOLEDOCHOLITHIASIS – stones in CBD – occurs in 10-15% of cholelithiasis patients –increases with increasing age of the patients, 25% elderly – secondary calculi are cholesterol or mixed stones formed in the GB – primary calculi are usually pigment stones, formed in the CBD, and usually arise in patients with chronic hemolytic diseases; hepatobiliary parasitism or chronic, recurrent cholangitis; congenital anomalies of bile ducts; dilated, sclerosed, or strictured ducts; or an MDR3 gene defect leading to impaired biliary phospholipid secretion Complications

1. Cholangitis - Charcot’s pain, jaundice, fever

2. Obstructive jaundice 3. Pancreatitis 4. Secondary billiary cirrhosis –

progressive & increasingly severe hepatic cirrhosis

Treatment: Endoscopic Retrograde Cholangiopancreatography (ERCP) CHOLANGITIS • Acute or chronic • Symptoms result from inflammation • Requires at least partial obstruction to

the flow of bile • Presence of bacteria on bile culture –

75% with acute sx

Presentation (Charcot’s Triad) • Biliary colic • Jaundice • Spiking fevers with chills

Types of Cholangitis 1. Nonsuppurative acute cholangitis – most common – respond to supportive measures & to Tx with antibiotics 2. Suppurative acute cholangitis – presence of pus under pressure in a completely obstructed ductal system – symptoms of severe toxicity > mental confusion > bacteremia > septic shock – response to antibiotics is poor – multiple hepatic abscesses are present – mortality rate is 100% unless prompt relief of obstruction & drainage of bile Treatment: ERCP with sphincterotomy Surgery CHOLEDOCHAL CYST – Cystic dilatation, may involve the free portion of the CBD or as diverticulum formation in the intraduodenal segment – Increase risk for development of cholangiocarcinoma – Tx- Sx (Additionally: Surgical treatment involves excision of the “cyst” and biliary-enteric anastomosis) HYPERPLASTIC CHOLECYSTOSES – Group of disorders of the gallbladder – Characterized by excessive proliferation of normal tissue components 1. Adenomyomatosis – Benign proliferation of GB surface epithelium with glandlike formations, extramural sinuses, transverse strictures and or fundal nodule (adenoma, or adenomyoma) formation – Rokitansky-Aschoff sinuses – outpouching of the mucosa 2. Cholesterolosis – Abnormal deposition of lipid especially cholesteryl esters within macrophages in the lamina propria of the gallbladder wall – Strawberry GB – Mucosa is bright red and speckled with bright yellow flecks of lipid studding in the GB wall 50% of cases have gallstone; diffuse form of cholesterolosis 3. Gallbadder Polyps

– prevalence is about 5% – marked male predominance – Tx – Sx (Cholecystectomy) recommended for patients who are: symptomatic, asymptomatic >50 y/o, polyps > 10mm in diameter, or in those with polyp growth on serial ultrasonography BILIARY ASCARIASIS – Intraductal migration of adult ascaris from duodenum Diagnosis: – cholangiography – characteristic ova on stool examination Treatment: – ERCP with extraction of the worm – surgery under antibiotic coverage MALIGNANT TUMORS OF GALLBLADDER > 1%-2% resected GB > Pathology: adenocarcinoma – 80% > Risk factors:

1. chronic cholecystitis 2. age>50yr 3. female sex 4. Environmental, rubber/automotive

workers > Signs and symptoms:

1. abdominal pain 2. jaundice 3. mass (RUQ) 4. weight loss 5. hepatomegaly 6. pruritus

> Treatment: ERCP, Stent surgery > Prognosis: 5% 5-year survival MALIGNANT TUMORS OF EXTRAHEPATIC BDs > Pathology: Adenocarcinoma 90% - scirrhous, nodular, papillary squamous – 10% > Risk factors:

1. sclerosing cholangitis, 2. parasites: ascaris, clonorchis 3. congenital diseases 4. choledochal cysts 5. caroli’s disease 6. chemical exposure, benzidine, etc

> Signs & symptoms: jaundice, pruritus, abd. pain, wt. loss, cholangitis, hepatomegaly, mass

>Laboratory data: markedly increased alkaline phosphatase > Treatment: surgery curative (10%), ERCP, transhepatic stenting > Prognosis: 5% 5 yr survival MALIGNANT TUMORS OF THE AMPULLA > Pathology: Adenocarcinoma virtually all > Risk factors: Adenoma of the papilla/ampulla Congenital diseases: Familial polyposis, Gardner’s syndrome > Signs & Symptoms: jaundice-variable, acholic or silver stools, melena, cholangitis, pancreatitis. > Laboratory data: increased alkaline phosphatase, bilirubin > Treatment:

• Curative (Whipple’s 25% - 40%) • resectable: over all 75% • ERCP, stenting

Prognosis: 25%-40% 5-yr survival;

excellent survival for small (<2 cm) adenocarcinoma

For more info you may read Harrison’s Principles of Internal Medicine, 18th Ed. Chap 311

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