BILIARY FISTULA ( Part two)

Bronchobiliary and Pleurobiliary Fistula
Bronchobiliary and pleurobiliary fistulas are fistulas between the biliary tree, often through the substance of the liver, and the pleural space or the bronchial tree.

• Most frequently they are associated with a subphrenic abscess with or without intrahepatic abscess.
• Echinococcal and amebic hepatic abscesses account for the majority of bronchobiliary or pleurobiliary fistulas.
• Other causes include biliary tract disease (usually obstructive), thoracoabdominal trauma, tuberculosis, syphilis, Hodgkin's disease, ascariasis, and, rarely, congenital communications.

The fistula forms by an abscess extending from within the liver substance coalescing with a right subphrenic abscess, which erodes through the posterior dome portion of the diaphragm.

• If the lung is adhering to the diaphragm because of inflammatory changes (80% of cases), a bronchobiliary fistula forms;
• if the lung does not adhere, a pleurobiliary fistula forms.

The chest radiograph is uniformly abnormal.

The studies most likely to reveal the course of the fistula, and possibly the cause,

• are direct cholangiograms:
• retrograde through an endoscope;
• percutaneous transhepatic;
• or fistulographic through an external biliary fistula, if present.
• Bronchoscopy infrequently establishes the bronchial site of the fistula and does little to demonstrate the responsible disorder.
• Bronchograms are not helpful in demonstrating a fistula or in establishing a cause.
  

Almost all patients with bronchobiliary fistula present with biloptysis, and about half of the patients present with acute dyspnea and bronchopneumonia.

• Three fourths of patients have chronic symptoms, with productive cough, recurrent pneumonia, and bronchiectasis of the lower lobe.
• Patients with pleurobiliary fistula usually present with sepsis.
• Fever, chills, jaundice, and abdominal pain are common presenting symptoms.
• An accompanying external biliary fistula is not infrequent.
  

Treatment follows three principles.

• The first is adequate treatment of intrahepatic and subphrenic abscesses.
• Pyogenic, amoebic, and echinococcal abscesses must be excised or drained as appropriate.
• The subphrenic abscess and any empyema must be well drained.
• The second principle is that any biliary obstruction must be alleviated.
• Operative biliary repair is not recommended until infection and the underlying cause are fully treated.
• Biliary decompression should be established with endoscopically or percutaneously placed stents until the conditions causing the biliary obstruction have resolved or until definitive repair can be approached in the absence of infection.
• The third principle is that the underlying cause must be treated.
  

Operative treatment of bronchobiliary and pleurobiliary fistulas may be complex, and, in the experience of some, it has required several operations in more than 60% of patients.

Biliary-Vascular Fistula
Biliary-vascular fistulas are rare communications between the bile ducts and blood vessels.

• The most commonly involved vessels are the hepatic arterial and portal venous branches within the liver; however, the hepatic veins, the main trunk of the hepatic artery, and the portal vein and other vessels may be involved.
• The most common cause of such connections is trauma,
• including iatrogenic trauma such as that incurred during needle liver biopsy,
• transhepatic drainage of the biliary tree, or
• transjugular intrahepatic portosystemic shunt placement.
• With penetrating trauma, direct communications may be established.
• With blunt trauma, direct communications are established less often; rather, injury to both vascular and biliary structures may occur; simultaneously, a large intrahepatic hematoma develops, and as the hematoma resolves the abnormal communication becomes manifest.
  
• A spontaneously occurring biliary-vascular fistula develops usually as a result of an abscess (pyogenic or parasitic) that erodes to form the biliary-vascular connection.
• Other causes are aneurysms of the hepatic arterial tree and intrahepatic tumor necrosis.
• Patients with these fistulas usually present with right upper quadrant pain, fluctuating jaundice, and mild to occasionally severe GI bleeding from hemobilia.
• Percutaneous or retrograde cholangiography may reveal filling defects in the biliary tree and gallbladder resulting from clot but only infrequently will demonstrate the fistula.

Treatment of fistulas associated with abscess may require operative drainage of the abscess and a difficult direct approach to the fistula.

• However, with the more common intrahepatic arteriobiliary communication, the blood vessel supplying the fistula is frequently amenable to angiographic embolization techniques.
• If the fistula is uncontrolled by angiographic embolization techniques, segmentectomy or lobectomy is generally safer than any attempt at direct approach to an intrahepatic fistula.
  

EXTERNAL BILIARY FISTULA
External biliary fistulas, or biliocutaneous fistulas, and internal bile leaks into the peritoneal cavity are aspects of the same process.

• Rarely, such fistulas occur spontaneously as a result of intrahepatic abscess (pyogenic or parasitic), necrosis and perforation of the gallbladder, or some other inflammatory process involving the biliary tree.
• Most external biliary fistulas and peritoneal bile leaks are postoperative complications of operations on the liver or biliary tree, with a few such fistulas resulting from trauma.
• With the advent of laparoscopic cholecystectomy, the associated increased incidence of bile duct injuries has made such fistulas or leaks more frequent.
• Specific causes of external biliary fistulas include
• leak from the cystic duct stump because of necrosis or inadequate ligation,
• undiscovered operative injury to the biliary ducts,
• prolonged cholecystostomy tube drainage,
• dislodgment of a T-tube from choledochotomy,
• persistent leakage of bile from a damaged liver or one in which a segment has been cut off from communication to the main bile ducts,
• continuing obstruction of the bile ducts by stone or stricture, cancer, or postoperative abscess around the liver.
  

These fistulas also occur after drainage of a hepatic abscess

• (particularly echinococcal),
• drainage of a biliary cyst,
• extensive loss of bile duct wall,
• or leakage from a biliary anastomosis,
• not uncommon after choledochocholedochostomy accompanying liver transplant.
  

Factors keeping such fistulas and leaks open include

• distal obstruction,
• ongoing inflammation,
• foreign body,
• cancer,
• the presence of ascites,
• and poor formation of fibrous connective tissue,
• such as in malnutrition or
• the use of steroids in transplant recipients.
  

Diagnostic studies should be aimed at delineation of the site of origin of the fistula in the biliary tree, the course of the fistula, and any factors operating to keep the fistula from healing.

• Fistulography with water-soluble contrast is often helpful, but when the fistula is indirect, such as through the cavity of an abscess, the internal anatomy is infrequently well demonstrated.
• ERC or percutaneous transhepatic cholangiography is usually necessary to delineate the site of the fistula and the presence of bile duct or intrahepatic stones or strictures that may be causing distal obstruction.
• When there is no communication between the biliary tree from which the fistula arises and the main bile ducts, a combination of fistula tract radiography and percutaneous and endoscopic cholangiography may be needed to delineate completely the anatomy and biliary site of injury and leak.
• Computed tomography or ultrasound should also be used to assess for associated subhepatic, subphrenic, or intrahepatic abscess.
  

Treatment principles for these fistulas consist of

• (1) removal of the inflammatory focus;
• (2) removal of any foreign body, such as bile duct stones or Ascaris lumbricoides; and
• (3) provision of unobstructed drainage of bile, into the intestine if feasible.

Drainage of any associated abscess or biloma is always the essential first step in cases of biliocutaneous fistula and internal bile leak.

• Usually, such drainage can be performed percutaneously under ultrasonographic or computed tomographic guidance.
• Frequently, for communicating fistulas with adequate abscess drainage when abscess is present, spontaneous fistula closure will occur as the abscess cavity closes.

In the past, removal of residual stones or other foreign bodies and provision of adequate bile drainage required an often arduous operative approach to the biliary tree near the site of the fistula, an operation made hazardous by scar and inflammatory tissue in the operative field.

The current approach to stones and other obstructing debris and to strictures is primarily endoscopic, by ERCP for diagnosis and endoscopic sphincterotomy for initial drainage and clearance of stones and debris.

• Many reports of endoscopic transsphincteric approaches to the biliary tree have documented remarkable success in the removal of stones and the provision of adequate drainage.
• Although some endoscopists have reported satisfactory closure of internal or external bile fistulas after endoscopic sphincterotomy alone, an endoscopically placed stent has allowed more consistent rapid closure of the biliocutaneous fistula by presumably more sufficient decompression of the biliary tree.
• An effective alternative for drainage is a nasobiliary tube placed within the leaking portion of the biliary tree and maintained on continuous suction.

When the endoscopic approach for drainage and clearance of stones is not possible, the percutaneous transhepatic approach can be used to provide drainage, although, by itself, the technique is not effective in clearing obstructing foreign material.

• However, at some centers, clearance of biliary debris can be accomplished through the percutaneously established tract, by using a small-diameter flexible scope and flushing and lithotripsy techniques.
• With such approaches, only a small percentage of patients with a communicating fistula will require operation, usually to alleviate obstruction and recurrent stones resulting from development of a stricture associated with the site of bile duct injury.

However, for patients with noncommunicating fistulas, although percutaneous drainage may often result in closure of the fistula by providing an alternate and low pressure route of egress of bile, the underlying lack of internal drainage of bile into the intestine is not solved and must be addressed.

• The anatomic situation leading to noncommunicating fistulas cannot usually be alleviated successfully by endoscopic or transhepatic interventional radiologic techniques alone.
• Percutaneous transhepatic radiologic techniques have been successful in re-establishing internal drainage by creating a tract between an isolated portion of the biliary tree and the intestine, and this re-established internal drainage has allowed the noncommunicating fistula to heal by its conversion to a communicating fistula.
• However, the established communication is not durable.
• Maintaining patency for what is essentially an internal biliary fistula requires a plastic or metal stent.
• Plastic stents require intermittent replacement because of progressive obstruction from buildup of bile salts, and metal expandable stents have not demonstrated prolonged patency when they are used in such an application.
• Central bile ducts with no established connection to the intestine, such as ligated or transected main or major hepatic bile duct branches, are best treated by Roux-en-Y biliary-enteric anastomosis to the appropriate bile duct, with a spatulated mucosa-to-mucosa anastomosis that is as large as possible.
• Concurrent excision of the fistula is feasible.

Noncommunicating biliary fistulas associated with small segmental or subsegmental bile ducts are usually initially best managed by adequate external drainage, usually percutaneously, with the drain placed as near as possible to the opening of the bile duct from the surface of the liver.

• Such placement is often directed at drainage of the biloma that has resulted from the transected or injured noncommunicating bile duct.
• These fistulas are seen most often after a non-anatomic liver resection, but they may occur from a duct of Luschka after cholecystectomy.
• The drain should be maintained on suction for at least 3 to 6 weeks and until any biloma resolves, documented by ultrasound or computed tomography, and until a fibrous tract has been established around the drain, documented by drain injection with water-soluble contrast showing only the drain and the isolated bile duct with no intraperitoneal extravasation.
• The drain can then be withdrawn 2 to 3 cm and maintained on suction.
• Unless the fistula is high volume, usually the fibrous tract will close down to close the fistula, and presumably the affected portion of liver atrophies.
• If the fistula persists, injection of the drain tract with a sclerosant such as hypertonic saline will often result in fistula closure.
• Such sclerosant treatment should be accompanied by appropriate antibiotic coverage.

Small-diameter noncommunicating segmental and subsegmental bile ducts have also been successfully managed with embolization to interrupt their drainage and presumably to initiate sclerosis and obliteration with atrophy of the drained portion of liver.

BILIARY FISTULA (Part one)

Biliary Fistulas
Biliary fistulas are uncommon and are grouped as spontaneously occurring or as iatrogenic, postoperative, or post-traumatic. They are specified also as internal or external by the site of exit of the fistula.
Most spontaneous biliary fistulas result from complications of gallstone disease, frequently when there have been delays in or insufficient treatment of symptomatic disease.

• The most frequent site of fistulization in spontaneous cases is to the gastrointestinal (GI) tract, particularly the duodenum, and passage of a large stone through such a fistula may result in gallstone ileus.
• Rarely, fistulas occur externally to the skin or internally to another part of the biliary tree, to the pleural cavity or bronchial tree, or to the hepatic artery or portal vein or other vascular structures.
  

INTERNAL BILIARY FISTULA
In general, internal biliary fistulas are spontaneously occurring results of biliary tract disease. The major types include biliary-enteric, biliobiliary, bronchobiliary and pleurobiliary, and biliary-vascular fistulas.

Biliary-Enteric Fistula

• The incidence of such fistulas is unknown, but it is low.
• Two thirds of patients with biliary-enteric fistulas have symptoms for 2 years or more.
• Ninety percent of patients with biliary-enteric fistulas have had a history of biliary tract disease for an average of 12 years (range, 1 to 18 years).
• Cholecystoduodenal fistulas constitute 72 to 80% of biliary-enteric fistulas;
• cholecystocolic fistulas make up 8 to 12%;
• cholecystogastric and choledochoduodenal fistulas are almost equal in frequency at 3 to 5%;
• and other bilioenteric fistulas are mostly combination fistulas such as cholecystogastroduodenal or cholecystoduodenocolic and total 2 to 3%.

Gallstones are the primary etiologic agent in most internal biliary-enteric fistulas. Glenn and colleagues proposed the following course:

(1) stone formation in the gallbladder;

(2) acute inflammation with obstruction of the cystic duct that results in adhesions of the gallbladder to the adjacent viscus (usually the duodenum); and

(3) repeated attacks of inflammation inducing gangrene of the gallbladder wall and wall of the adherent viscus, with eventual erosion and fistula formation.

• An alternative mechanism postulates that the fistula is due to direct mechanical pressure of the gallstone on the wall of the containing organ—gallbladder or common bile duct—with erosion and necrosis until a fistula is formed.
• Carcinoma of the gallbladder, bile duct, duodenum, pancreas, or stomach is an infrequent cause of these fistulas.
• Crohn's disease of the duodenum, peptic ulceration into the gallbladder, and paraduodenal abscess have been found as etiologic agents in rare cases.
  

Clinical symptoms and signs are frequently not helpful in diagnosing biliary-enteric fistula.

• Right upper quadrant pain and tenderness are frequently similar to those noted in uncomplicated symptomatic gallbladder disease.
• Jaundice is present at some time in the disease course in over half of patients, and vague right upper quadrant fullness may be present.
• Other symptoms may include fever, chills, nausea, vomiting, bloating, fatty food intolerance, weakness, and backache.
• Cholangitis occurs in approximately 17% of all patients with biliary-enteric fistula but in 60% of those with cholecystocolic fistula and in 40% or more of those with cholecystogastric fistula.
• Gallstone ileus occurs in 13 to 30% of patients with biliary-enteric fistula.
• With cholecystocolic fistula, diarrhea is frequently prominent because of bacterial action on bile salts, and malabsorption may occur.
• An increased incidence of biliary tract carcinoma is associated with biliary-enteric fistulas.
  

Diagnosis has been made preoperatively in 43 to 53% of cases.

• Classic radiologic findings include air in the biliary tree without previous biliary-enteric anastomosis and reflux of barium into the biliary tree on upper or lower contrast studies.
• In the experience of Safaie-Shirazi and associates, only one third of biliary-enteric fistulas will present with air in the biliary tree.
• ERC
• Ultrasonography
• Intraoperatively, at either open or laparoscopic approach to the gallbladder and liver hilum, it is important that the surgeon recognize the characteristic findings associated with biliary-enteric fistula to avoid injury to the biliary tree.
• In general, adhesions in the right subhepatic area are dense and suggest carcinoma.
• The gallbladder is usually small and fibrotic and adherent to a viscus.
• In such cases, cholangiography through the gallbladder may be invaluable for delineating the anatomy and establishing the diagnosis.
• Transcholecystic cholangiography should be done by direct puncture within a pursestring suture to prevent spill in the case of possible malignancy, and then, if necessary, with a
• Foley catheter, after opening the fundus of the gallbladder and removing stones.
  

Treatment of biliary-enteric fistulas must take into account several factors.

• If the fistula is diagnosed non-operatively, determination must be made as to the
• existence of residual stones,
• whether obstruction is present,
• and the anatomy of the fistula.

Cholecystocolic and cholecystogastric fistulas should be corrected operatively because of the high incidence of cholangitis associated with them.

• Obstruction of the biliary tree must be rectified.
• If there are stones in the common duct, in most cases endoscopic sphincterotomy and stone extraction may be a desirable alternative to operative choledochotomy for stone removal.
• If residual stones are present in the gallbladder or if symptoms are associated with the fistula, it should be approached surgically.
• Although some authors have recommended surgery to avoid complications in the presence of any biliary-enteric fistula, a reasoned approach is that, in the absence of obstruction, residual stones, or symptoms, except for cholecystogastric and cholecystocolic fistulas, no operation should be performed because most fistulas close spontaneously.

In patients with concomitant intestinal obstruction from a passed gallstone, most authors recommend examination of the remaining intestine for additional gallstones before enterotomy or resection and removal of the obstructing stone and any others in the GI tract, but no approach to the biliary-enteric fistula during that operation.

• The advanced age and compromised general health status of most patients with gallstone ileus confer a high surgical risk; decrease of surgery time and complexity at the time of alleviation of the bowel obstruction is desirable.

In the operative approach to the fistula,

• the first considerations are determination of anatomy,
• existence of residual stones in gallbladder and common duct,
• and presence of obstruction.
• These are best determined by intraoperative cholangiogram and may require separate visualization of gallbladder and common duct.
• Meticulous examination of the GI tract should be made for stones.

If a cholecystocolic fistula is diagnosed preoperatively,

• mechanical and antibiotic preparation of the colon should be performed.
• For cholecystocolic fistula,
• choledochotomy is recommended as a first step,
• followed by cholecystectomy, and
• finally takedown and repair of the fistula to reduce bacterial contamination.
• In other cases, the usual approach is repair of the fistula, then cholecystectomy and closure of the bowel.
• Biliary ductal stones must be removed, and any biliary obstruction must be relieved.
• Reports have suggested that, for laparoscopic surgeons skilled in advanced laparoscopic techniques, including duodenal mobilization and intracorporeal suturing and tying, that the laparoscopic approach can be successful in the repair of cholecystoduodenal and cholecystocolic fistulas.
• The principles for the laparoscopic approach to these fistulas are identical to those delineated for the open approach.
  

Choledochoduodenal Fistula

• The choledochoduodenal fistula represents a special category of biliary-enteric fistula because a frequent etiologic mechanism is a posterior or superior duodenal bulb ulcer penetrating into the common bile duct.
• Studies based on ERC suggest that parapapillary choledochoduodenal fistulas are probably more common than peptic ulcer-associated choledochoduodenal fistulas.
• Parapapillary fistulas are caused by common bile duct stones in 96% of the cases and by carcinoma in 4%.
• Gallbladder, bile duct, duodenum, pancreas, and stomach cancer have been found infrequently, and Crohn's disease of the duodenum, paraduodenal abscess, duodenal diverticulum, and ascariasis have been found rarely as etiologic agents.
• The choledochoduodenal fistula caused by peptic ulcer disease occurs between the duodenal bulb and common duct, and the symptoms are those of peptic ulcer disease.
• Symptoms resulting from the fistula are unusual, and cholangitis occurs in less than 10%.
• Air is found in the biliary tree in 14 to 58%, but in up to 100% of cases barium enters the biliary tree through the fistula.
• Exact localization and direct visualization and biopsy should be obtained by endoscopy and ERC.

Recommended treatment of the choledochoduodenal fistula caused by peptic ulcer is treatment of the ulcer.

• There is good evidence that such fistulas heal without sequelae on medical therapy; the risk of biliary stricture exists in the long term after the healing of the fistula.
• Surgery should generally be based on operative indications for the ulcer disease rather than the presence of the fistula, with the tenet that absence of distal bile obstruction and of bile duct stones should be established before any operation.
• If common duct stones, cholangitis, or obstruction coexist with the fistula, the common duct should be approached from above and away from the fistula, and biliary-enteric diversion, when indicated, should be through a Roux-en-Y limb of jejunum.
  

Parapapillary choledochoduodenal fistula was found in 1.2% of a reported series of 1,929 patients treated for biliary tract disease in Japan and was found to be the most common of the internal biliary fistulas in that series, three times as common as cholecystoduodenal fistula. Seventy per cent of patients had abdominal pain, 39% had fever, and 36% had jaundice. Diagnosis at ERCP was by (1) passage of a cannula through the papilla and out through the fistula, (2) visualization of contrast injected into the papilla exiting the fistula, or (3) demonstration that cholangiography was possible through both papilla and fistula.

• Two thirds of patients had no history of previous instrumentation of the biliary tree, although a similar fistula can be caused by mispassage of a bougie at bile duct exploration.
• Two general types of parapapillary fistula have been described.
• One type is small, positioned in the longitudinal fold just orad to the papilla, and corresponding to the intramural portion of the common duct.
• The common duct is only dilated slightly in these cases and invariably contains stones.
• The second type is much larger in size (generally at least 1.5 cm in diameter), is located adjacent to the longitudinal fold, corresponds to the extramural portion of the common duct, and is associated with a markedly dilated common duct.
• Stones were found in the common duct in only 50% of cases of the larger type of fistula.

Treatment for the smaller type of fistula could be as little as endoscopic sphincterotomy to, and possibly to above, the fistula and evacuation of stones, with operative cholecystectomy as indicated. The larger type of fistulas are treated best by operative or lithotripsy evacuation of stones and biliary-enteric anastomosis because of the marked dilatation of the common duct.

Biliobiliary Fistula

• Biliobiliary fistulas make up about 3% of all internal biliary fistulas and result from gallstones.
• They occur between the gallbladder and the common hepatic duct or the pericystic duct region of the common duct.
• These fistulas have acquired the designation of the Mirizzi II syndrome, based on a classification proposed by McSherry and co-workers.
• The most commonly accepted pathologic cause for development of Mirizzi's syndrome is that a gallstone becomes impacted in the ampulla of the gallbladder, and subsequent compression of the common duct by the stone and associated inflammation leads to partial obstruction of the common duct, the Mirizzi I syndrome.
• Continued pressure and inflammation may result in necrosis of the compressed tissue, with development of a fistula between gallbladder and common duct, the Mirizzi II syndrome.
• Corlette and Bismuth have classified these fistulas into type 1,
• with the fistula between the gallbladder ampulla and the common hepatic duct, and
• type 2,
• with a large fistula between the gallbladder and the common duct in the "trajectory of the cystic duct," such that no cystic duct is found.
• Although Corlette and Bismuth indicated that 75% of cholecystobiliary fistulas were type 1, Csendes et al. reported that most such fistulas among 196 patients in their series had type 2 fistulas.
  

In approximately 80% of cases the patients are women, with the average age in the sixth decade.

Symptoms include

• jaundice in 79 to 87% of patients,
• pain in 54 to 96% of patients, and
• fever in 62% of patients.

Diagnosis preoperatively is unusual because there is no specific clinical syndrome, although, when biliobiliary fistula is suspected, ERC should make the diagnosis.

• Most biliobiliary fistulas are discovered intraoperatively and should be suspected when
• markedly dense adhesions are found fusing tissues in the right subhepatic area and
• no plane exists between the main bile duct and the gallbladder.
• Other biliary fistulas may coexist.
• The gallbladder is usually shrunken or may be necrotic, it contains a stone more than 1.5 cm in diameter in 88% of cases, and the common duct contains stones in 68 to 75% of patients with a cholecystobiliary fistula.

In treating such fistulas, Corlette and Bismuth recommended

• initial removal of stones,
• followed by a partial cholecystectomy,
• with a remnant of gallbladder left around the fistula margins to aid in closure of the fistula and associated loss of a part of the circumference of the bile duct wall.
• After exploration of the bile ducts through a choledochotomy distal to and away from the biliobiliary fistula, a T-tube is placed into the bile duct through the fistula, and the gallbladder remnant is closed around the tube.
• Use of gallbladder wall to patch biliary duct defects was also described by Sandblom and colleagues, along with a detailed depiction of the method.
• With large fistulas in which tissue loss is great, Corlette and Bismuth recommended hepatojejunostomy.
• Safaie-Shirazi and associates suggested choledochoduodenostomy for large fistulas, or, alternatively, a patch of the bile duct wall with a vascularized pedicle of gallbladder wall to restore lost tissue.
  

Acute cholecystitis

Acute cholecystitis
The inflammation of the gall bladder is most often caused by gall stones. Gall stones are one of the most common disorders of the gastrointestinal tract, affecting about 10% of people in Western society.

• Occurs in 10 – 20% of symptomatic gallstones cases.
• 7 to 15% have concomitant CBD stones.
• Less than 1% have malignant tumor.
• 60% are infected.
• Diabetics are more labile for septic complications.
• Anaerobic (clostridial) infection is more common in diabetics.
• Repeated attacks results in chronic cholescystitis.

presentation

• Fat, fertile,forty years female is the commonest in presentation.
• Pain in URQ is like biliary colic but last longer(> than 6 hours) even for days which is associated with URQ tenderness.
• Nausea, vomiting, anorexia,
• Mild fever, seldom higher than 38°C.
• Chills are unusual, and their presence suggests a complicated cholecystitis (abscess or associated cholangitis).
• Mild jaundice is present in approximately 20% patients with AC, which may be related to common hepatic and/or bile duct edema and higher concentrations of bilirubin >60 µmol/l suggest a diagnosis of choledocholithiasis (a gall stone in the common bile duct) or Mirrizzi's syndrome (obstruction by a stone impacted in Hartmann's pouch that compresses the common hepatic duct).
• Positive Murphy’s sign - inspiratory arrest on deep palpation in RUQ. The Murphy sign can be elicited with an ultrasound probe.
• A palpable right upper quadrant mass – 1/3 of cases-
• Usually represents omentum adhered in response to the inflammation.
• Leucocytosis is pronounced with empyema and is usually in the range of 10,000-15,000/μL.
• Mild rise (up to 5 fold)of AST , ALT & serum amylase.

Inflammation of gallbladder
Over 90% of cases of acute cholecystitis result from obstruction of the cystic duct by gall stones or by biliary sludge that has become impacted at the neck of the gall bladder.

• Mechanical inflammation-
• The sequence is - Obstruction-distension-increase in pressure- ischemia-injury-inflammation
• Biochemical inflammation –
• Lysolecithin, Prostaglandin I2 and E2,
• The trauma caused by the gall stones stimulates the synthesis of prostaglandins I2 and E2, which mediate the inflammatory response.
• Infection –
  • Escherichia coli (41 percent), Enterococcus (12 percent), Klebsiella (11 percent), and Enterobacter (9 percent).
  • Positive bile culture is present in 50 to 80% of the patients with acute cholecystitis.

Acute Acalculous Cholecystitis

• Acute acalculous cholecystitis accounts for 5% to 10% of all patients with acute cholecystitis.
• The disease often has a more fulminant course than acute calculous cholecystitis and frequently progresses to gangrene, empyema, or perforation.
• Acute acalculous cholecystitis usually occurs in the critically ill patient following trauma, burns, long-term parenteral nutrition, and major nonbiliary operations such as abdominal aneurysm repair and cardiopulmonary bypass.
• The etiology of acute acalculous cholecystitis remains unclear although gallbladder stasis and ischemia have been most often implicated as causative factors.
• Stasis is common in critically ill patients not being fed enterally and may lead to colonization of the gallbladder with bacteria.
• Visceral ischemia is also a common denominator in patients with acute acalculous cholecystitis and may explain the high incidence of gallbladder gangrene.
• Decreased arteriolar and capillary filling is present in acute acalculous cholecystitis in contrast to the dilation of these vessels observed in acute calculous cholecystitis.

Differential diagnosis

• Pyogenic or amebic liver abscesses
• Perforation or penetration of peptic ulcer
• Pancreatitis
• Appendicitis
• Hepatitis
• Myocardial ischemia or infarction
• Pneumonia
• Pleurisy
• Herpes zoster involving an intercostal nerve
• Gonococcal perihepatitis (Fitz-Hugh-Curtis syndrome) in women
• Sickle cell crises, and
• Leptospirosis

Diagnosis

Abdominal Ultrasound

• Gall stones along with wall (edema)thickness > 4mm
• Pericholecystic fluid

Radionuclide scanning – HIDA – less frequently used

CT abdomen – if acutely ill and associated with complications – e.g. CBD stones and pancreatic pathology.


Medical management

• Most patients with acute cholecystitis respond to conservative, first line management: the gall stone disimpacts and falls back into the gall bladder, which allows the cystic duct to empty.
• If the gall stone does not disimpact, complications such as advanced cholecystitis (gangrenous cholecysytitis or empyema of the gall bladder) or perforation may result.
• Immediate measures should be taken to rest the gall bladder; this will subdue the inflammatory process in most patients.
• Patients should be fasted, rehydrated with intravenous fluids, and given oxygen therapy and adequate analgesia.
• A single intramuscular dose of diclofenac (75 mg) may substantially decrease the rate of progression to acute cholecystitis in patients with symptomatic gall stones.
• Because of the risk of superimposed infection, intravenous antibiotics should be started empirically if the patient has systemic signs or if no improvement is seen after 12-24 hours.
• A second generation or newer cephalosporin should be used (for example, cefuroxime 1.5 g every 6-8 hours) with metronidazole (500 mg every 8 hours).
• Acute inflammation subsides in 5 – 7 days with conservative treatment
  
  Non-operative management solvent dissolution therapy or extracorporeal shockwave lithotripsy has been used with variable results to treat chronic cholecystitis in patients unfit for surgery, but it has no place in the management of acute cholecystitis.

Surgical treatment

• The treatment of choice for acute cholecystitis is cholecystectomy.
• Open cholecystectomy had been the standard treatment for acute cholecystitis for many years.
• Initially, acute cholecystitis was felt to be a contraindication to laparoscopic cholecystectomy.
• As experience has increased, however, it has become clear that laparoscopic cholecystectomy can be performed safely in the setting of acute cholecystitis.
• In prospective, randomized trials, the morbidity rate, length of hospital stay, and time to return to work have all been lower in patients undergoing laparoscopic cholecystectomy than open cholecystectomy.
• However, the conversion rate in the setting of acute cholecystitis (10% to 35%) is higher than with chronic cholecystitis.
  

The timing of cholecystectomy for acute cholecystitis has been studied for several decades.

• In the distant past, delayed cholecystectomy was preferred in the setting of acute cholecystitis.
• Patients were initially managed nonoperatively and discharged home after their symptoms resolved.
• Elective cholecystectomy was then performed 6 weeks later after the acute inflammation had resolved.
• Recent prospective randomized trials have shown that early laparoscopic cholecystectomy (within 3 days of symptom onset) can be accomplished with a similar morbidity and mortality rate as delayed cholecystectomy.
• No significant differences were observed in the conversion rate to open cholecystectomy among patients undergoing early cholecystectomy versus those managed with delayed surgery.
• Hospital stay, and therefore cost, however, were significantly reduced in both trials in the early laparoscopic cholecystectomy group.
• In addition, approximately 20% of patients in the delayed surgery arm failed initial medical therapy and required operation during the initial admission or before the end of the planned cooling-off period.
• Laparoscopic cholecystectomy should be performed within 24 to 72 hours of diagnosis.
• Early conversion to an open procedure should be considered if dissection is difficult or clear progress cannot be made by the laparoscopic technique.
• In certain high-risk patients whose medical conditions precludes cholecystectomy, a cholecystostomy can be performed for acute cholecystitis.
• Although previously performed operatively and under local anesthesia, percutaneous drainage techniques can usually be accomplished (Fig. 62.12).
• In most cases, prompt improvement is seen after gallbladder drainage and appropriate antibiotics.
• These patients must be observed closely, however, and if improvement does not occur within 24 hours, laparotomy is indicated.
• Failure to improve after percutaneous cholecystostomy is usually caused by gangrene of the gallbladder or perforation.
• After the acute episode resolves, the patient can undergo either cholecystectomy or percutaneous stone extraction and removal of the cholecystostomy tube.
• The latter is an option in elderly or debilitated patients for whom a general anesthetic is contraindicated.
  

INCIDENCE, ASYMPTOMATIC GALLSTONE, DIAGNOSIS AND COMMON SYMPTOMS OF GALLSTONES

Incidence -

Age

Incidence increases with age

• Cholesterol and cholesterol saturation index is high in elderly women
• Sensitivity to CCK decrease with age
  • Pancreatic polypeptide increases with age

Gall stones in children

• Haemolytic diseases
• Congenital disorders
• Short bowel syndrome
• Pt. On TPN

GALLBLADDER DISEASE PREVALENCE BY AGE GROUP
Percentage With Stones
Age (y) Female Male
10-39 5.0 1.5
40-49 12.0 4.4
50-59 15.8 6.2
60-69 25.4 9.9
70-79 28.9 15.2
80-89 30.9 17.9
90+ 35.4 24.4

Diet

• Diet plays an important role in cholesterol supersaturation.
• Cholesterol gallstones are common in populations consuming a Western diet, which is relatively high in animal fat.
• The incidence of cholesterol gallstones rises in a population as it shifts to a higher consumption of dietary fat.

Gender and harmone

Females have much high incidence of gall stones

• Estrogen decreases activity of the hepatic enzyme (7-a-hydroxylase)responsible for converting cholesterol to bile acids,
• Pregnancy
  • progesterone decreases gall bladder contractility
  • relative overproduction of hydrophobic bile acids such as chenodeoxycholate
• Oral contraceptives and estrogen replacement therapy

Family history and genetics

• Gallstones occurred more than twice as often in the family group
• A dramatic example occurs in Pima Indians
• 73 percent in women over the age of 25 years

Obesity,diabetes, vagotomy

• Obesity causes secretion of bile with high concentration of cholesterol
• Rapid weight loss in morbid obese,- low calorie diet- increased fat metabolism
• Bile mucin content increased 18-fold and bile calcium concentration rose 40 percent.

Diabetes mellitus- two fold increase in incidence
• High cholesterol, low bile acid
• Biliary stasis-autonomic neuropathy

Cirrhosis

• Cirrhosis – pigment stones
  • Hypersplenism,
  • reduced hepatic synthesis and transport of bile salts
  • Increase in nonconjugated bilirubin,
  • High estrogen levels, and
  • Impaired gallbladder contraction in response to a meal.

Gallblader stasis
• Somatostatin, otreotide.
• TPN – no stimulation to gallbladder.
Drugs

• Clofibrate – cholesterol lowering agent -reduce bile acid secretion by inhibiting enzyme cholesterol 7-alpha-hydroxylase;
• Estrogen, oral contraceptives
• Ceftriaxone-
• Biliary excretion accounts for up to 40 percent of ceftriaxone elimination.
• Concentrations in bile can reach 200 times that of the serum.
• When supersaturated, ceftriaxone complexes with calcium and precipitates out of bile.

Asymptomatic gallstones

• 50% of all gall stones are asymptomatic.
• 20% to 30% of patients become symptomatic within 20 years.
• 1% to 2% of asymptomatic individuals with gallstones per year develop serious symptoms or complications related to their gallstones.
• Many of them have some kind symptoms including dyspepsia.
• All patients will develop symptomatic disease before developing one of the complications of gallstones.
• Prophylactic cholecystectomy is debatable.

Indications of Prophylactic cholecystectomy

• Choledochal cysts.
• Caroli's disease.
• Long common channel of bile and pancreatic ducts.
• Pediatric gallstones.
• Congenital hemolytic anemia.
• Gallstones >2.5 cm in diameter.
• Calcified (porcelain) gallbladder.
• Incidental gallstones found during intraabdominal surgery.
• No access to medical care.
• Gallbladder adenomas .
• Porcelain gallbladder.
• Gastric bypass surgery in morbid obesity.

Diagnosis of gall stones


X-ray abdomen AP

• Up to 20% gall stones are radio-opaque.
• Air may be trapped in cholesterol stone.
• Air in the wall or in the lumen of gall bladder – emphysematous cholecystitis.
• Air in the biliary tree – entero-biliary fistula.
• Outlining of gallbladder – porcelain gallbladder or milk of calcium bile.

Oral cholecystography (OCG)

• Based on excretion of halogenated compound by liver and concentration by gallbladder.
• Traditionally it has been a gold standard diagnostic test with 95% specificty.
• Inability to absorb the tablet gives no result.
• Can’t be used in hepatic dysfunction and obstruction.

Abdominal ultrasonography

Most preferred investigation
• Non-invasive, no radiation.
• Gives idea of intrahepatic and extrahepatic biliary channels too.
• Gives idea of pancreas and other abdominal organs.
• Tells about inflammation of the organ.
• Patients should receive nothing by mouth for several hours prior to performing an ultrasound examination so that the gallbladder is fully distended.
• Gallstones create echoes that are reflected back to the ultrasound probe.
• The ultrasound waves cannot penetrate the stones; and therefore, acoustic shadowing is seen posterior to the stones .
• In addition, gallstones that are free-floating in the gallbladder will move to a dependent position when the patient is repositioned during scanning.
• When these two features are present, the accuracy is 100%.
• Echoes without shadows may be caused by gallbladder polyps.

Drawback of USG

• Small gallstones may not demonstrate an acoustic shadow.
• Furthermore, a lack of fluid (bile) around the gallstones (stone impacted in cystic duct, gallbladder filled with gallstones) also impairs their detection.
• In addition, an ileus with increased abdominal gas as occurs with acute cholecystitis may hamper gallbladder visualization.
• Overall, the false negative rate for ultrasound in detecting gallstones is approximately 5% but may increase to 15% with acute cholecystitis.

Hepatobiliary scintigraphy

• 99mTechnetium labeled iminodiacetic acid derivatives (hepatic 2,6-dimethyl-iminodiacetic acid [HIDA], diisopropyl-acetanilido-iminodiacetic acid, P-isopropylacetanilido imidodiacetic acid) are injected intravenously, rapidly extracted from the blood, and excreted into the bile.
• Uptake by the liver, gallbladder, CBD, and duodenum should all be present after 1 hour.
• Slow uptake of the tracer by the liver suggests hepatic parenchymal disease.
• Filling of the gallbladder and CBD with delayed or absent filling of the intestine suggests an obstruction at the ampulla.
• Nonvisualization of the gallbladder 1 hour after the injection of the radioisotope with filling of the CBD and duodenum is consistent with total or partial cystic duct obstruction and acute cholecystitis.

Computerized Tomography/Magnetic Resonance Imaging

• Abdominal computed tomography (CT) is less sensitive in diagnosing gallstones than ultrasound.
• Calcified gallstones are visualized in approximately 50% of patients.
• The role of CT scanning is primarily limited to the diagnosis of complications of gallstone disease such as acute cholecystitis (gallbladder wall thickening, pericholecystic fluid), choledocholithiasis (intrahepatic and extrahepatic bile duct dilation), pancreatitis (pancreatic edema and inflammation), and gallbladder cancer.
• More recently, magnetic resonance imaging (MRI)has been shown to be highly sensitive in the diagnosis of both gallstones and common duct stones when heavily weighted T2-weighted images are obtained .

Common clinical features
Non specific symptoms-

• upper right abdominal discomfort.
• Vague, poorly localised pain mainly in right hypochondrium and or in epigastrium usually follows meals.
• Flatulence, eructation and heartburn.

Biliary colic

• Usually associated with impacted stone in Hartmann pouch or in cystic duct or passage of stone through these structures.
• It is not exactly a colic as it is not for short bouts of pain with total remission in between
• Biliary colic is characterized by a rapid increase in pain intensity, with a plateau of discomfort that lasts for several hours, followed by a gradual decrease in intensity.
• Situated in right upper quadrant or middle epigastrium.
• Radiates to inferior angle of right scapula and referred to right shoulder.
  
  

FORMATION OF GALLSTONS

FORMATION OF GALLSTONS


PHYSIOLOGY OF GALLBLADDER

• Approximately 600 to 750 mL of bile is produced daily
• During its passage through the bile ductules, canalicular bile is modified by the absorption and secretion of electrolytes and water
• The bile duct epithelium is also capable of water and electrolyte absorption, which may be of primary importance in the storage of bile during fasting in patients who have previously undergone cholecystectomy.
• The gallbladder mucosa has the greatest absorptive capacity per unit of any structure in the body.
• COMPOSITION OF BILE
  Hepatic Bile Gallbladder Bile
  Na (mEq/L) 140–159 220–340
  K (mEq/L) 4–5 6–14
  Ca (mEq/L) 2–5 5–32
  Cl (mEq/L) 62–112 1–10
  Bile salts (mEq/L) 3–55 290–340
  Cholesterol (mg/dL) 60–70 350–930
  pH 7.2–7.7 5.6–7.4
  
  Major solute components of bile by moles percent
  
• Bile acids (80%),
• Lecithin and traces of other phospholipids (16%),
• Unesterified cholesterol (4.0%).
• In the lithogenic state the cholesterol value can be as high as 8 to 10%.
• Conjugated bilirubin, proteins (IgA, metabolites of hormones, and others), electrolytes, mucus, and, often, drugs and their metabolites.
  
  BILE ACIDS

The primary bile acids,

• Cholic acid & chenodeoxycholic acid (CDCA),
• The enzyme cholesterol 7a-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthes.
• Bile acids are conjugated with glycine or taurine and become soluble.

Secondary bile acids,

• Deoxycholate and lithocholate,
• They are formed in the colon as bacterial metabolites of the primary bile acids.
• However, lithocholic acid is much less efficiently absorbed from the colon than deoxycholic acid.
• Another secondary bile acid, found in low concentration, is ursodeoxycholic acid (UDCA), a stereoisomer of CDCA.

Enterohepatic Circulation

• Unconjugated, and to a lesser degree also conjugated, bile acids are absorbed by passive diffusion along the entire gut.
• The active transport of conjugated bile acids occur in the distal ileum
• The reabsorbed bile acids enter the portal bloodstream and are taken up rapidly by hepatocytes, reconjugated, and resecreted into bile (enterohepatic circulation).
  

Types of gall stones

Gallstones are formed by concretion or accretion of normal or abnormal bile constituents.

They are divided into two major types:

• Cholesterol stones account for 80% of the total, with pigment stones comprising the remaining 20%.
• Cholesterol gallstones usually contain >50% cholesterol monohydrate plus an admixture of calcium salts, bile pigments- bilirubin (yellow/red/brown) or Biliverdin (green/blue/black), proteins, and fatty acids.
• Pigment stones are composed primarily of calcium bilirubinate; they contain <20%>
• Pigment stones
  • Black
  • brown
• They differ in colour, shape, size and configuration
• In an individual they are uniform in composition
• In extra gallbladder position they can be
  • primary or
  • secondary

CHOLESTEROL STONES AND BILIARY SLUDGE
The pathogenesis of cholesterol gallstones is clearly multifactorial but essentially involves four factors:

(a) Cholesterol supersaturation in bile,
(b) Crystal nucleation,

(c) Gallbladder dysmotility, and
(d) Gallbladder absorption.


Insolubility of cholesterol

• Cholesterol has many important functions in the body.
• Unfortunately,it can also cause problem.
• Cholesterol is a pearly-white, waxy substance.

Factors of increased biliary cholesterol

• Dietary cholesterol increases biliary cholesterol secretion
• Obesity,
• High-caloric and cholesterol-rich diets, or
• Drugs (e.g., clofibrate) and
• Increased activity of HMG-CoA reductase, the rate-limiting enzyme of hepatic cholesterol synthesis, and
• Increased hepatic uptake of cholesterol from blood may result in increase secretion of cholesterol
• As such cholesterol is insoluble in aqueous medium
• Oversensitive feedback mechanism to turn off Cholesterol-7-a-hydroxylase,
• Excessive cholesterol synthesis in the face of a normal bile acid pool.
• Endogenous and exogenous estrogen's appear to increase cholesterol secretion and decrease bile acid secretion
• When bile salt molecules in water reach concentrations of 2 to 4 mM, they form spherical complexes called micelles;
• Bile acids are amphipathic compounds means have hydrophilic and hydrophobic ends
• In micelles, the negatively charged hydrophilic ends of the molecules face outward, toward the water, and the uncharged hydrophobic regions face the center of the sphere, toward one another.
• Cholesterol molecules are enclosed in the hydrophobic interiors.
• Cholesterol and phospholipids are secreted into bile as unilamellar bilayered vesicles, which are converted into mixed micelles consisting of bile acids, phospholipids, and cholesterol by the action of bile acids.
• If there is an excess of cholesterol in relation to phospholipids and bile acids,
• Unstable cholesterol-rich vesicles remain,
• which aggregate into large multilamellar vesicles
• from which cholesterol monohydrate crystals precipitate
• Several pronucleating factors including mucin glycoproteins, immunoglobulins, and transferrin accelerate the precipitation of cholesterol in bile.

Gallbladder dysmotility

• Defects in gallbladder motility increase the residence time of bile in the gallbladder thereby playing a role in stone formation.
• Progressive enlargement of individual crystals or stones by deposition of additional insoluble precipitate at the bile-stone interface,
• Fusion of individual crystals or stones to form a larger conglomerate.
  
  
  Gallbladder sludge
• A thickened gallbladder mucoprotein with tiny entrapped cholesterol crystals, is thought to be the usual precursor of gallstones.
• Sludge may also occur in asymptomatic patients with prolonged fasting and can be seen on standard ultrasonography of the gallbladder.
• Sludge can sometimes cause biliary pain, cholecystitis, or acute pancreatitis,
• But may also resolve without treatment.
• The antibiotic ceftriaxone can precipitate in the gallbladder and bile ducts as sludge.
  
  GROWTH OF GALLSTONE
• The crystal acquires additional cholesterol to form a visible stone.
• Cholesterol stones often contain alternating layers of cholesterol crystals and mucoprotein.
• Pure cholesterol crystals are quite soft. Protein adds strength to the stone.
• This stage of stone formation is largely influenced by gallbladder stasis.
• Gallstones forming in patients with high spinal cord injury or treated with the somatostatin analog Octreotide have been largely associated with impaired gallbladder motility.
  
  
  Impaired bile salt return
• Seen with ileal disease (Crohn's),
• Ileal resection or bypass.
• Drugs that bind bile acids in the gut,
• such as cholestyramine could also theoretically cause this problem, but new synthesis of bile acids by the liver usually suffices to compensate for the losses.
  
  Some important observation in stone pathogenesis
  
• Increase in cholesterol or decrease in bile acid
• Saturated insoluble cholesterol formation
• Nucleation
  • Increased cholesterol stimulates mucin secretion
  • That results in the formation of cholesterol crystals
• Growth – gall bladder stasis
• Bacteria, fungi or parasite may be detected in the centre of stone
• Increase in billary calcium – promotes crystal aggregation
  • But calcium in diet has protective role
• Biliary prostaglandins
• Reflux of pancreatic fluid
  
  
  Pigment stones

Black pigment stones
• Bilirubin -color: yellow/red/brown.
• Biliverdin -color: green/blue/blackSource: oxidation of bilirubin

• Consist of polymers of bilirubin, with large amounts of mucoprotein.
• Usually contain less amount of cholesterol.
• Contain 30-60% unconjugated bilirubin by weight.
• 50% are radiopaque, 50% are radiolucent (stones that are more than 4% calcium by weight are radiopaque).
• They are the result of precipitation of calcium with the anions, bilirubin, carbonate, phosphate, or palmitate.
  
• Pigment gallstones are classified as either black or brown pigment stones.
• Black pigment stones are typically tarry and frequently are associated with hemolytic conditions or cirrhosis.
• In hemolytic states, the bilirubin load and concentration of unconjugated bilirubin increases.
• These stones are usually not associated with infected bile.
• They are located almost exclusively in the gallbladder.
  
  Brown Pigment Stones
  
• Earthy in texture
• Typically found in the bile ducts, especially in Asian populations.
• Brown stones often contain more cholesterol and calcium palmitate than black stones
• Occur as primary common duct stones
• In patients, associated with disorders of biliary motility and bacterial infection.
• In these settings, bacteria-producing slime and bacteria containing the enzyme glucuronidase cause enzymatic hydrolysis of soluble conjugated bilirubin glucuronide to form free bilirubin, which then precipitates with calcium.
  
  
  Summary of Pathogenesis of Pigment stones
• Pure pigment stone
  • High unconjugated bilirubin
• Haemolytic
• Cirrhosis – hyperslpenism, decreased conjugation
• Mixed pigment stones
  • Biliary drainage disorder with infection
  • Bacteria deconjugates conjugated bilirubin to unconjugated bilirubin
  • Resulting in insoluble unconjugated bilirubin which combines with calcium-Ca bilirubinate
  • TPN-Stasis of bile – infection
  • Biliary sludge – formed of calcium bilirubinate crystals
  
  
  

Risk factors for gallstones

Risk factors for gallstones

In addition to the variability of gallstones in different ethnic populations, a number of other risk factors for this condition have been identified.

Age — Age is a major risk factor for the gallstones. Gallstones are exceedingly rare in children except in the presence of hemolytic states; in addition, less than 5 percent of all cholecystectomies are performed in children. Age 40 appears to represent the cut-off between relatively low and high rates of cholecystectomies.
Gender — As noted above, a higher prevalence of gallstones has been observed in women in all age groups. The difference between women and men is particularly striking in young adults. The GREPCO study found
a female-to-male ratio of
2.9 between the ages of 30 to 39 years; the ratio narrowed to
1.6 between the ages of 40 to 49 years and
1.2 between the ages of 50 to 59 years.
The higher rates in young women is almost certainly a result of pregnancy and sex steroids.

Pregnancy — Pregnancy is a major risk factor for the development of cholesterol gallstones. The risk is related to both the frequency and number of pregnancies. In one report, for example, the prevalence of gallstones increased from
1.3 percent in nulliparous females to
12.2 percent in multiparous females.
Another study recruited 272 women in the first trimester of pregnancy. The incidence of new biliary sludge and gallstones was 31 and 2 percent, respectively.
Sex hormones induce a variety of physiologic changes in the biliary system, which ultimately cause bile to become supersaturated with cholesterol, thereby promoting gallstone formation: • Supersaturation occurs as a result of an
· estrogen induced increase in cholesterol secretion and a
· progesterone induced reduction in bile acid secretion.
Pregnancy induces a qualitative change in bile acid synthesis characterized by
relative overproduction of hydrophobic bile acids such as chenodeoxycholate,
thereby reducing the ability of bile to solubilize cholesterol
Progesterone induced slowing of gallbladder emptying further promotes the formation of stones by causing bile stasis.
These changes normalize one to two months following delivery.
In the postpartum period, gallbladder sludge resolves in 61 percent of cases and approximately 30 percent of stones smaller than 10 mm disappear due at least in part to unsaturation of bile.

Oral contraceptives and estrogen replacement therapy — Studies evaluating the risk associated with estrogen use have been conflicting, although the majority of studies have shown that estrogen therapy is associated with higher rates of gallstones.
The following associations have been noted in different reports:

• Postmenopausal women given estrogen replacement had 3.7 times the relative risk of developing symptomatic gallstones compared to nonusers. Similar findings were noted in the HERS trial which randomized 2763 postmenopausal women with coronary heart disease to ERT or placebo. After an average follow-up of four years, gallbladder disease was more frequent in those receiving estrogen therapy (6.1 versus 4.5 percent, relative hazard 1.38).

• In the Nurses' Health Study of almost 55,000 postmenopausal women, those currently using postmenopausal hormones were at an increased risk of cholecystectomy (relative risk 2.1) compared to never-users.

• For current users, the risk of cholecystectomy increased with increasing duration of hormone use and higher doses of estrogen.


• The risk for past hormone users decreased substantially in women who had discontinued use within the preceding one to three years (relative risk 1.6), a small but significant risk persisted for women who had stopped taking ERT five or more years previously (relative risk 1.3).

• Men receiving estrogen therapy had an increased rate of gallstones compared to controls.

• In one study of men who had had a myocardial infarction, treatment with estrogen or clofibrate was associated with more than a twofold increase in risk of gallbladder disease compared to those receiving placebo. In another report of men with prostate cancer, new gallstones detected by ultrasonography developed at one year in 5 of 28 men treated with estrogen compared to none of 26 who underwent orchiectomy.


• Estrogen treated men had a 40 percent increase in biliary cholesterol excretion compared to age matched controls.Oral contraceptive use also appears to cause a slight increase in the risk of gallstone formation.


• Women under the age of 40 and those taking high-dose estrogen (>50 µg) preparations have the greatest added risk. It has been suggested that oral contraceptive has only a transient effect on gallstone formation

Family history and genetics — Family history studies suggest that genetics has a significant role in the development of gallstones. Investigators performed oral cholecystography in 171 first-degree relatives of patients with gallstones and 200 age matched controls.
Gallstones occurred more than twice as often in the family group: 20.5 versus 9 percent.
The risk was greater in female relatives in both of these studies.
The great variation in gallstone rates amongst different ethnic groups described above could be due to genetic as well as dietary and cultural habits.
A dramatic example occurs in Pima Indians who have exceptionally high rates of cholesterol gallstones: 73 percent in women over the age of 25 years.

Obesity — Obesity (defined as weight greater than 120 percent of ideal body weight) is a well established risk factor for the development of cholesterol gallstones, presumably due to enhanced cholesterol synthesis and secretion. The risk is particularly high in women, in those with morbid obesity, and in younger age groups in which a threefold increase in risk has been reported.It has also been suggested that the incidence of gallbladder disease in morbidly obese subjects may be higher than expected from ultrasonography or oral cholecystography. In one report, 62 morbidly obese patients underwent prophylactic cholecystectomy at the time of a gastric exclusion procedure. Among the 47 who had normal imaging studies, 40 had abnormal histologic findings in the gallbladder.Rapid weight loss — Rapid weight loss is also a risk factor for gallstone formation, occurring in approximately 35 percent of patients after proximal gastric bypass, a form of bariatric surgery. High rates of gallstone formation have also been associated with very low calorie diets. Gallstones which form in association with rapid weight loss appear to be more common in Caucasians and women.The mechanism by which this occurs is incompletely understood. One report evaluated changes in gallbladder bile during periods of weight loss. Bile mucin content increased 18-fold and bile calcium concentration rose 40 percent. These factors may promote cholesterol nucleation and stone formation.In contrast to the general population in which the great majority of gallstones are asymptomatic, persons with weight loss related cholelithiasis are more likely to be symptomatic. In one series, for example, 28 percent of patients required urgent cholecystectomy within three months after a gastric exclusion procedure.Prophylaxis with ursodeoxycholic acid (UDCA) has been shown to be effective at reducing the risk of stone formation during rapid weight loss. In one trial of 1004 patients treated with a very low calorie diet, ultrasonography was performed at baseline and 8 and 16 weeks. The incidence of gallstones was 28 percent in the placebo group compared to 8, 3, and 2 percent of those treated with 300, 600, and 1200 mg/day of UDCA, respectively.In another controlled trial, 68 obese subjects were randomized to UDCA (1200 mg/day), aspirin, or placebo at the time of entry into a 520 kcal/day diet program. The patients were treated for up to 16 weeks and were reevaluated at four and three weeks after treatment. None of the patients treated with UDCA developed gallstones or cholesterol crystals in the bile compared to five and six patients, respectively, in the placebo group (p<0.001). name="11">Diabetes mellitus — Diabetes mellitus appears to be associated with an increased risk of gallstones. As an example, a case control study compared 336 patients who had gallstones or had undergone cholecystectomy to 336 controls. Diabetes was more prevalent in the patients with gallbladder disease (11.6 versus 4.8 percent). In another case control study, an increased prevalence of gallstones in diabetes could only be demonstrated in women (42 versus 26 percent in nondiabetic women).How diabetes predisposes to gallstones is not well understood. Two possible contributing factors are hypertriglyceridemia and autonomic neuropathy leading to biliary stasis due to gallbladder hypomotility. One study suggested that in women, hyperinsulinemia itself may be a predisposing condition even in those without diabetes.Serum lipids — The precise role of serum lipids on gallstone formation is not known. Gallstones appear to be positively associated with apolipoprotein E4 phenotype and elevated serum triglycerides. In contrast, a negative association exists between gallstones and high density lipoprotein. There is no conclusive evidence linking elevated serum cholesterol and gallstones. Cirrhosis — Cirrhosis is a major risk factor for gallstones. The increased risk was illustrated in a combined cross-sectional and longitudinal study that included 1010 patients with cirrhosis. The overall prevalence of gallstones was 29.5 percent. During an average follow-up of 50 months, 141 of 618 patients (23 percent) developed gallstones (which is approximately 10 times higher than would be expected in a general population). Multivariate analysis demonstrated that the risk was increased in patients with Child classes B and C cirrhosis (regardless of the cause), and in patients with a high body mass index. The increased risk of gallstone formation in these patients may be due to several factors, including reduced hepatic synthesis and transport of bile salts and nonconjugated bilirubin, high estrogen levels, and impaired gallbladder contraction in response to a meal.

Gallbladder stasis — Conditions that result in bile stasis are associated with a higher prevalence of gallstones. In the normal state, the gallbladder avidly absorbs water from bile.
Thus, if bile remains within the gallbladder for a prolonged period, it can become overly concentrated with cholesterol, thereby promoting stone formation.
Common examples of this mechanism include

• spinal cord injuries,


• prolonged fasting


• and the use of total parenteral nutrition (both of which prevent the normal enteral stimulation of gallbladder activity),


• and excess somatostatin.

• Gallstones are a frequent complication of prolonged total parenteral nutrition. As an example, one study of 84 patients with severe short bowel syndrome treated with total parenteral nutrition found asymptomatic gallstones in 44 percent.

Two factors are thought to contribute:

• biliary stasis due to lack of enteral stimulation;
  and,


• in patients with ileal resection, interruption of the enterohepatic circulation of bile acids results in a reduction in hepatic bile acid secretion and an altered composition of hepatic bile which becomes supersaturated with respect to cholesterol.

• Somatostatin, probably via reduced cholecystokinin release, is a potent inhibitor of gallbladder emptying. Thus, stasis-induced gallstones may be seen in patients with a somatostatinoma or the long-term administration of the somatostatin analogue octreotide in the treatment of acromegaly and other disorders.

.Other drugs — In addition to estrogen, oral contraceptives, and octreotide, two other drugs can promote the formation of gallstones: clofibrate and ceftriaxone.

• Clofibrate, a now rarely used cholesterol lowering agent, is strongly associated with gallstones. Clofibrate and other fibrates (eg, bezafibrate) reduce bile acid secretion by inhibiting the rate limiting enzyme in bile acid synthesis, cholesterol 7-alpha-hydroxylase; this results in cholesterol supersaturated bile and stone precipitation.

• Ceftriaxone is a major cause of biliary sludge formation in hospitalized patients. Biliary excretion accounts for up to 40 percent of ceftriaxone elimination and drug concentrations in bile can reach 200 times that of the serum. When supersaturated, ceftriaxone complexes with calcium and precipitates out of bile. This process is probably potentiated in intensive care unit patients who are not fed enterally and have bile stasis.

Decreased physical activity — Physical activity is associated with a decreased risk of symptomatic cholelithiasis. This was illustrated in the Physicians' Health Study, a prospective cohort study of over 45,000 men, in which 828 subjects developed symptomatic gallstones during eight years of follow-up. The study included 60,290 women between the ages of 40 to 65 who were followed for 10 years during which 3257 underwent cholecystectomy. On multivariate analysis, the relative risk for women in the highest compared to the lowest quintile of physical activity was 0.69. In contrast, women who had a sedentary lifestyle were at increased risk of cholecystectomy (relative risk 1.42).

Crohn's disease — The prevalence of gallstones is increased in patients with Crohn's disease. In a population based study in Sweden, for example, gallstones were detected in 26 percent of patients with Crohn's disease, which was approximately twice as frequent as the general population. Gallstones in patients with ileal Crohn's disease (or those who have undergone ileal resection) are frequently pigment based, reflecting an increased concentration of bilirubin conjugates, unconjugated bilirubin, and total calcium in the gallbladder bile due perhaps to altered enterohepatic cycling of bilirubin.

PROTECTIVE FACTORS — A number of drugs have been used to treat patients with symptomatic gallstones disease and to prevent the development of symptoms in high risk patients. In addition, a number of dietary factors have also been suggested as possibly being protective.

Ascorbic acid — The observation that deficiency of ascorbic acid (vitamin C) is associated with the development of gallstones in guinea pigs prompted investigation of the relationship between ascorbic acid levels and gallstones in humans. The benefit of ascorbic acid may be related to its effects on cholesterol catabolism.

Coffee — Moderate coffee consumption was associated with a reduced risk of symptomatic gallstone disease in a cohort study involving 46,008 male health professionals who were followed for up to 10 years. Subjects who consistently drank two to three cups of regular coffee per day were approximately 40 percent less likely to develop symptomatic gallstones during follow-up. The benefit was even greater in those who drank four or more cups per day (relative risk 0.55). In contrast, decaffeinated coffee was not protective.