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
  
  
  

SURGICAL CONSIDERATIONS IN IBD

SURGICAL CONSIDERATIONS IN IBD

• The primary indication for surgical intervention in IBD is the lack of response to medical management.
• In UC, patients are being considered for surgery at an earlier stage of disease, mainly because of restorative procedures that can be offered with successful results.
• In addition, it has been recognized that the complications and side effects of maintaining young patients on high doses of steroids or immunosuppressives, or both, for prolonged periods of time far outweigh the complications of surgical intervention.
• The absolute indications for surgery in UC include
• the development of cancer or severe dysplasia in the colon,
• the presence of growth retardation because of the disease process or its medical treatment,
• and the presence of a stricture or a mass lesion in the colon that precludes complete surveillance or accurate diagnosis.
• In addition, patients who have developed extraintestinal manifestations of the disease may improve when they have undergone surgery.
• This applies to some patients who have developed pyoderma gangrenosum and some patients with musculoskeletal manifestations.
• Some complications, such as sclerosing cholangitis, are unaffected by surgical extirpation of the colon and may continue to be slowly progressive over time.
• The evidence suggests that although medical management is often successful on a temporary basis, it is certainly not curative.
• The majority of patients will require surgery for colon or perianal disease.
• Indications for surgery in Crohn's colitis include failure to respond to medical management or complications of the disease.
• These complications include intestinal obstruction, fistula or abscess formation, and rectal stricture.
• The indications for surgery tend to differ somewhat from those for small bowel disease.
• In a review of patients who underwent surgery at the Cleveland Clinic, bowel obstruction and internal fistula or an abscess tended to be the most common reasons for surgery in patients with small bowel disease.
• The indications for surgery in 127 patients with colonic disease were poor response to medical care (25%), internal fistula and abscess (23%), toxic megacolon (20%), perianal disease (19%), and intestinal obstruction (12%).
• Like all of the operations for CD, recurrence is the major consideration.
• Patients with colon disease alone had a lower recurrence rate than patients with either ileocolonic disease or ileitis.
• The type of operation performed varies depending on the location of the disease.
• Because the rectum and the distal colon are often spared in Crohn's colitis, colectomy with preservation of the rectum is often possible.
• Ileorectal or ileosigmoid anastomosis has the obvious advantage that an ileostomy is not necessary.
• However, to perform an ileorectal anastomosis, the rectum should be spared from disease or be only minimally involved.
• There should be good distensibility of the rectum on air insufflation, sphincter tone should be adequate, there should be no extensive ileal or perianal disease, and patients should not have had a prior significant small bowel resection, because the functional result might be poor.
• None of these criteria are absolute.
• Another option for the patient may be colectomy, ileostomy, and preservation of the rectum in a fashion similar to that described for UC.
• This procedure also allows the option for a future anastomosis if local conditions are favorable.
• During this interval, the patient may be better able to become prepared psychologically for a permanent ileostomy in case removal of the rectum in the future becomes necessary or if reanastomosis appears to be unwise.
• If the rectum is left indefinitely, there is the possibility of the future development of carcinoma.
• Segmental resection for CD is controversial, because disease usually is widespread and occurs both proximally and distally in a patchy distribution.
• Although experience is limited, recurrence after segmental resection appears to be high. Nevertheless, segmental resection may be indicated in patients who have had multiple bowel resections in the past.
• Loop ileostomy may be useful in situations in which the patient may be at some risk with an unprotected anastomosis—for example, after an ileocolic or a sigmoid resection for CD associated with an abscess.
• CD, particularly in the small bowel, may present with obstruction due to stricture formation.
• These strictures are alleviated by a procedure called stricturoplasty.
• To perform a stricturoplasty, the intestine is incised longitudinally and closed horizontally in one layer.
• The results from several institutions, including ours, were reported to be good.
• Stricturoplasty is usually used in CD of the small bowel, and its role in the colon appears to be more limited.
• It has been used in some patients with short colonic strictures and a relatively normal intervening bowel, especially if a significant amount of the intestine has already been removed.
• If a stricture in the colon is present, one must be cautious in offering a stricturoplasty as opposed to a resection because of the risk of carcinoma occurring at the site of the stricturoplasty.

Perianal disease often poses difficult management decisions.

• Treatment will vary in view of the wide spectrum of perianal lesions.
• In making management decisions, one must consider the nutritional status of the patient, the extent and severity of the disease in the remainder of the gastrointestinal tract, and the symptomatology.
• Many patients will have relatively few symptoms from perianal disease, even though it may appear to be quite severe.
• One must understand the limitations of attempting to eradicate the disease, and the aim of treatment, as in other forms of CD, should be to provide symptomatic relief.
• Although treatment may vary according to the specific lesion and the individual patient, certain general measures may be of benefit to most patients, including hospitalization to improve the nutritional status, assessment of the extent and severity of any proximal disease, and treatment of this proximal disease.
• Local skin care includes sitz baths, anesthetic ointments, and frequent dressing changes.
• Skin tags are rarely symptomatic, and their excision should be avoided.
• If they produce symptoms, it is usually because of irritation caused by diarrhea, which results in edema of the tags and generally responds to local care and control of the diarrhea.
• Anal dilatation for anal stenosis is only rarely indicated.
• Dilatation should be performed cautiously and should be limited to one or two fingers only.
• Long strictures, which are also rare occurrences, are a complication of severe rectal disease and, if symptomatic, may require proctectomy.

The typical broad-based fissure seen in CD is often asymptomatic, and no treatment is usually indicated.

• If a fissure is painful, one should suspect associated sepsis, and an examination under anesthesia may be necessary.
• Sphincterotomy should be avoided, because the fissure or ulcer is often a sign of severe rectal or anal involvement.
• Wounds from CD heal poorly, and the disease itself has often damaged the ability of the sphincter to act reliably.
• Treatment with antibiotics, such as metronidazole, or with steroid suppositories may be beneficial in treating the commonly associated rectal disease.

Abscesses and fistulas tend to be the most difficult lesions to treat.

• We do not hesitate to examine the patient under anesthesia to more fully assess the extent and severity of the perianal and rectal disease.
• An abscess should be suspected in patients who complain of severe pain in a previously asymptomatic fissure or fistula.
• Treatment should consist of incision, unroofing, and drainage of the abscess .
• Usually, primary fistulotomy should not be undertaken unless the fistula is of the lowlying variety.
• When cellulitis is associated, broad-spectrum antibiotics such as metronidazole and an aminogly-coside should be prescribed.
• There are several approaches in the treatment of perianal fistulas, depending on various local and general factors.
• low fistula may be managed by fistulotomy with good wound healing.
• For complex fistulas with rectal involvement, treatment should first concentrate on medical management of the rectal disease.
• Antidiarrheal agents may be used judiciously, and nutritional improvement is important.
• Drainage of the abscess with unroofing of the fistula, as well as long-term drains or setons, may be used.
• Metronidazole, azathioprine, 6-mercaptopurine, and cyclosporin have all been used with some success.
• Some patients for whom these treatments fail may require diversion of the intestinal tract as a loop or split ileostomy, and eventually a proctectomy may be necessary.
• After the construction of an ileostomy, initial improvement in the local perianal disease usually occurs; however, it does not usually change the natural history of the disease.
• Relapse is common, and it is not usually possible to restore intestinal continuity.
• Despite these poor long-term results, there may be some merit in the construction of a diverting ileostomy.
• First, the general and nutritional status of the patient often improves, and the perianal sepsis resolves to some extent.
• Therefore, at least theoretically, a subsequent proctectomy or other definitive procedure can be performed with fewer complications.
• Second, some patients may be loath to have definitive surgery in the form of a proctectomy as an initial procedure.
• A loop or split ileostomy allows them to adjust psychologically to a stoma without committing themselves to a permanent ileostomy.

If perianal disease continues and is symptomatic, proctectomy may be necessary, although it is not usually required to treat perianal disease alone.

• Almost always, patients have associated severe rectal or perineal involvement.
• Before a proctectomy is performed, it is important that the patient be in optimal condition, because this operation is associated with relatively high morbidity rates.
• Thus, preoperative measures to decrease local sepsis and improve healing should be undertaken.
• To decrease local sepsis, a staged procedure may be planned.
• As previously discussed, by performing a subtotal colectomy and ileostomy or ileostomy alone, temporary improvement in local perianal sepsis can be expected.
• The general status of the patient is improved, and steroids may be tapered before rectal excision.
• At the time of surgery, measures to decrease the potential for sepsis should be used, including an adequate mechanical bowel preparation and the administration of prophylactic antibiotics.
• An intersphincteric dissection of the anorectum along anatomic planes with meticulous hemostasis is important in preventing the perineal wound problems previously discussed.
• There are some reports that suggest surgical treatment of proximal gastrointestinal disease may result in improvement in the perianal disease.

Laparoscopic Management of Inflammatory Bowel Disease

• The evaluation of the results of these reports reveals that laparoscopy in patients with IBD offers significant advantages compared with laparotomy.
• Reduction in postoperative pain, reduced postoperative ileus, decreased hospitalization time, enhanced cosmesis, less disability, earlier return to work, and a reduction in symptoms attributable to adhesion formation are all advantages of the use of laparoscopy.

Disadvantages of laparoscopic surgery are

• prolonged surgical time,
• difficult instrumentation,
• and demanding expertise.
  

Medical Versus Surgical Approaches in Inflammatory Bowel Disease
Medical as well as surgical efforts in IBD are directed at decreasing and controlling symptoms, thereby improving the patient's quality of life.

• A careful selection of the therapeutic agents is necessary, based on the severity of the disease and of drug side effects.
• Because IBD often is a chronic illness with an unpredictable course and with a significant impact on the patient's quality of life, patient education takes on a very important role in management.
• The medical management of these patients includes systemic, oral, and topical drugs (steroids or 5-ASA derivatives); antibiotics where indicated; immunosuppressives; and the latest cytokines and immunomodulators (see earlier for a detailed discussion).
• Complications, whether chronic or acute, often accompany the course of the disease, necessitating recurrent hospitalizations and surgery when indicated.
• In the United States, the total annual costs (both direct and indirect) incurred by the estimated 380,000 to 480,000 patients affected have been estimated at around $2 billion.
• Drugs were estimated to account for only 10% of total costs, whereas hospitalizations and surgery account for approximately half.
• There are other considerations when weighing medical versus surgical therapy in these patients.
• Side effects of long-term medical treatment (especially steroids and immunosuppressives) and patient compliance are other important concerns with which the physician who treats these patients is faced.
• Although the patient who is compliant, takes his or her medicines regularly, and appears for periodic follow-up on a regular basis can continue on medical treatment, the patient who is noncompliant medically will likely undergo surgery earlier.
• The nature and the extent of the disease are also very important when weighing medical versus surgical treatment.
• An initial medical trial of CD is the usual approach.
• When complications of the disease occur or when patients are noncompliant or do not wish to undergo medical management for fear of the complications involved, then surgery should be undertaken.
• In the case of UC, once operated on, the patient is for all intents and purposes "cured" of the disease, although a different lifestyle is required and follow-up is still necessary.
• Finally, as mentioned, the patient must have an active role in the decisions regarding which kind of therapy should be adopted.
• Patients should be informed about their disease and given all the options of treatment as well as information pertaining to quality of life, and the patient together with the caring physician will then be able to reach the decision of whether to continue the medical therapy or to undergo surgery.
  

QUALITY OF LIFE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE
There is increasing recognition that quality of life is an important outcome measure in patients with IBD, whether they are treated medically or surgically.

• Quality of life incorporates not only the physical or functional outcome but also the emotional and social well-being of the patients.
• Sometimes somatic sensation (presence or absence of pain) is also included. Calman proposed a definition for quality of life as "the gap between a person's expectation and achievements," which seems appropriate and incorporates the concept that quality of life is personal and may vary among individuals.
• In the area of surgery, particularly surgery for IBD, morbidity and mortality rates have traditionally been used to assess surgical outcome.

Surgery is rarely performed for a life-saving indication; rather, the most common indication for surgery in patients with IBD is failure of medical therapy or, in effect, poor quality of life.

• In view of the high rate of recurrence of CD after surgical resection, surgical therapy is not curative but palliative.
• Operative therapy is reserved for complications of the disease, and bowel resection in patients with uncomplicated disease is justified only in rare circumstances.
• Surgery is also indicated when medical therapy has failed and the patient is chronically debilitated due to the disease.
• Failure of medical management includes intractability, suggesting that the patient's well-being, life-style, and employment are significantly impaired by unrelenting symptoms, and debilitating side effects of medical therapy.
  
• It is difficult to compare the quality of life of patients treated medically with that of those treated surgically.
• For patients who have undergone surgery, their health status is usually much more stable (except for the early convalescent period).
• Thus, quality of life soon after surgery is probably lower than if it is assessed at a later date.
• Another issue that might result in incorrect conclusions is the reporting of stool frequency. Stool frequency is an important indication of disease activity in UC and, by inference, the quality of life in patients under medical treatment.
• On the other hand, stool frequency seems to have less impact on the quality of life of patients after ileal pouch-anal anastomosis.
• These patients have an excellent quality of life, having five or six bowel movements per day, whereas the same number of bowel movements in a patient treated medically may indicate active disease and an impaired quality of life.
• Reasons for this include urgency and bleeding during the active phase of the disease.
  
• Many studies that compared the quality of life in medical versus surgical therapy have shown that patients who undergo surgery seem to have a better outcome (at least in some domains) than those on medical treatment.
  
• In conclusion, quality of life of most patients after surgery for UC is excellent.
• This is true for most patients, unless there is some associated illness or long-term complication related to the procedure.
• Although the ileal pouch-anal anastomosis procedure has become the procedure of choice for most patients, those who undergo conventional ileostomy also seem to have an excellent quality of life.

THERAPY OF ULCERATIVE COLITIS AND CROHN'S DISEASE

THERAPY OF ULCERATIVE COLITIS AND CROHN'S DISEASE

• Although traditional drugs such as steroids, sulfasalazine, and 5-ASA compounds are the mainstays of the medical management of IBD, many other modalities and drugs are used, including the immunomodulator drugs (azathioprine and 6-mercaptopurine), immunosuppressives (cyclosporine and methotrexate), and the latest cytokine therapy.
  

Sulfasalazine and 5-Aminosalicylic Acid

• Sulfasalazine is composed of sulfapyridine linked to 5-ASA.
• It is poorly absorbed in the upper gastrointestinal tract and is degraded into its two components—sulfapyridine and 5-ASA—by colonic bacteria.
• 5-ASA is the active anti-inflammatory compound of sulfasalazine, whereas sulfapyridine acts only as the carrier for 5-ASA.
• It is the sulfapyridine moiety to which some patients have side effects and allergic reactions.
• Because of this, various 5-ASA compounds have been developed (mesalamine [Asacol, Rowasa]) that have been shown to be as effective as sulfasalazine but with reduced side effects.
• Both sulfasalzine and the various 5-ASA compounds inhibit the various products of the metabolism of arachidonic acid (prostaglandin G2, leukotriene B4, and thromboxane A2)—all known to play a major role in the inflammatory process in the intestinal mucosa.
• They also decrease the synthesis of other inflammatory cytokines (IL-1 and TNF-β) and inhibit the action of interferon.
• Sulfasalazine and 5-ASA enemas may be of benefit in limited colonic distal disease and proctitis.
• Foam preparations and suppositories are more effective than the liquid preparations due to the enhanced retention and absorption, but both can be used for distal disease.
• Mesalamine in the form of suppositories or enemas is the most effective agent in the treatment of distal UC, but its efficacy has not been proved in anorectal CD.
  

Sulfasalazine

• Sulfasalazine is the oldest and the least expensive 5-ASA compound in use.
• In a low dosage (1 to 2 g/day), it is used to maintain remission in patients with UC, whereas in a higher dosage (4 to 6 g/day), it can be used to treat active UC.
• In CD, the efficacy of sulfasalazine is less clear and depends on the site of the disease.
• Because sulfasalazine is cleaved into its active compounds in the colon, its use is limited to CD with ileocolonic or colonic involvement.
• It is of little known benefit in isolated small bowel disease.
• Side effects of sulfasalazine are common and include nausea, headaches, malaise, and vomiting.
• These side effects can be minimized or prevented by initiation of therapy with a relatively low dose and gradual increase in the dosage.
• Hypersensitivity reaction to sulfasalazine can cause rash, fever, hemolytic anemia, hepatic toxicity, and sperm abnormality.
• Should these side effects or hypersensitivity reactions occur, administration of the drug should be discontinued immediately.
  

Olsalazine

• Olsalazine (Dipentum) delivers intact 5-ASA to the terminal ileum, which is then cleaved by the colonic bacteria.
• Olsalazine has been shown to be of benefit in patients with active UC, but no therapeutic benefit has been shown in patients with mild to moderate attacks of CD.
  

Mesalamine

• Pentasa is one brand of mesalamine in which the 5-ASA is coated with ethyl cellulose that is gradually released from the small bowel to the colon.
• Mesalamine at dosages between 3 and 4 g/day has been shown to cause clinical improvement or remission in the mild to moderately active form of CD.
• At a dosage of 2.4 to 4.6 g/day, mesalamine has been beneficial in patients with UC and was found to be as effective as sulfasalazine in maintaining remission in patients with UC.
• In a comparison of medically with postoperatively induced remission in patients with CD, mesalamine has been shown to be more effective in preventing clinical relapse after surgical resection than after medically induced remission.
• In patients with mild to moderate UC, improvement can be achieved with 2 to 4 g/day of a 5-ASA compound.
• Once improvement has been achieved, mesalamine can be continued at the same dose to maintain remission.
• Mesalamine enemas at dosages of 1 to 4 g/day are effective in treating patients with distal UC, whereas patients with limited ulcerative proctitis can benefit from mesalamine suppositories at a dosage of 500 mg twice a day.
  

Steroids

• The benefit of corticosteroid therapy for UC was first reported by Truelove and Witts, and they are the most commonly used agents in the treatment of moderate to severe forms of IBD.
• Their mechanism of action is thought to be via prevention of the liberation of arachidonic acid from the membranes.
• Steroids also decrease neutrophilic phagocytosis and diminish adherence and chemotaxis of neutrophils, eosinophils, and monocytes.
• They inhibit the release of other inflammatory cytokines—mainly IL-1 and IL-2.
• The initial treatment in patients with moderate to severe UC is prednisone at 40 to 60 mg/day.
• In severely ill, hospitalized patients, initial therapy is 100 mg intravenous hydrocortisone three times daily.
• Steroids are also effective in the treatment of moderate to severe CD.
• Prednisone administered at dosages of 0.25 to 0.75 mg/kg/day to 85 patients with active CD resulted in remission in 60% of patients compared with a rate of only 30% in a placebo group.
• The systemic side effects of the traditional steroids in use have led to the development of more potent steroid formulations, which are more rapidly metabolized and offer the promise of being as effective as the traditional steroids with fewer systemic side effects.
• Similar to 5-ASA preparations, different packaging of these agents is available, which offers the possibility of drug delivery to the small bowel and the colon with minimum side effects.
• Budesonide is the most notable of these new steroids used in IBD, and favorable results were demonstrated in distal UC and in active CD.
• Steroids applied topically may be of benefit in patients with either limited distal disease or with rectal involvement along with more proximal disease.
• Steroid enemas or foams can be used for the treatment of active disease, but no role in maintenance therapy has been proved.
  

Antibiotics

• The results of clinical and experimental trials suggest that bacteria may play a role in the pathogenesis of Crohn's disease due to an unusual response of the mucosa to the intestinal flora, a breakdown in the normal mucosal barrier that allows micro-organisms to invade the intestinal mucosa, or even a specific bacteria such as Mycobacterium.
• Metronidazole is the most studied and used of the antibiotics.
• This drug is effective in patients with CD, particularly in those with perianal disease.
• However, when treatment with metronidazole is discontinued, relapse is common.
• Another antibiotic that has also been effective in CD is ciprofloxacin.
• Its maximum benefit is reached within 1 month and continues for at least an additional 5 months.
• Ciprofloxacin can be combined with metronidazole.
• Such combination therapy of metronidazole and ciprofloxacin in fistulous CD produced fistula healing in 3 of 14 patients and improvement in 9 of 14 patients after 3 months of therapy.
• When therapy was discontinued, most patients experienced a relapse, so continuous treatment may be necessary.
• Clarithromycin is another broad-spectrum antibiotic that may be effective in the eradication of micro-organisms at the center of the granulomas in CD.
• A trial with clarithromycin in patients with active CD, of whom many had been resistant to other forms of therapy, demonstrated impressive results.
  

Immunomodulators and Immunosuppressives

• Immunosuppressive agents are of routine use in the treatment of patients with refractory IBD.
• Their use is widely accepted in patients who are not candidates for surgery and in patients in whom steroid treatment has already caused significant adverse reactions.
• These drugs act by blocking the proliferation and activation of the T-helper lymphocytes, which play a major role in the inflammatory cascade through the production of various cytokines, of which the most important in IBD are IL-1, IL-2, IL-6, IL-8, TNF-β, and interferon-γ.
• In the case of Imuran, the therapeutic effects are not seen until after 3 to 4 months of treatment, a period that can sometimes be shortened by initial intravenous loading of the drug.
  

Cyclosporin A

• Cyclosporin A is a potent immunosuppressive drug that is used in organ transplantation as well as in patients with IBD, especially those with more severe or refractory disease.
• It acts via inhibition of the T-helper lymphocytes, thus inhibiting the production and liberation of the above-mentioned cytokines.
• Intravenous cyclosporin A has been shown to be effective in the short term in patients with severe cases of UC as well as CD.
• The major problem with the drug is that although short-term improvement may be achieved, long-term maintenance with the oral form of the drug produces excessive side effects.
• Side effects and toxicity of treatment with cyclosporin A include seizures, nephrotoxicity, hypertension, tremors, and headaches, which can occur in up to 60% of patients treated.[
  

Azathioprine and 6-Mercaptopurine

• Azathioprine (Imuran) and 6-mercaptopurine are purine analogue compounds used in the management of steroid-dependent IBD.
• They act either via inhibition of purine RNA synthesis and cell proliferation or via inhibition of natural killer cells and suppression of cytotoxic T-cell functions.
• These mechanisms of action likely explain the 3- to 4-month delay in the onset of their clinical effectiveness.
• Azathioprine and 6-mercaptopurine are both used in the management of patients with active CD and UC who have not responded to systemic steroids.
• In addition, both drugs have been successfully used as steroid-sparing agents in patients with IBD who are unable to be weaned from steroid therapy.
• Furthermore, as maintenance therapy, both drugs have been shown to be effective in UC as well as in CD.
  
• Among the side effects of azathioprine and 6-mercaptopurine are pancreatitis, which occurs in 3 to 5% of patients, usually presents within the first 6 weeks of therapy, and resolves promptly when the drug is withdrawn.
  

Methotrexate

• Methotrexate acts via impairment of DNA synthesis and reduction in IL-1.
• A multicenter, placebo-controlled trial with 141 patients with active CD confirmed that methotrexate at a dosage of 25 mg administered intramuscularly or subcutaneously once a week, over 16 weeks, allowed steroid tapering and maintenance of remission in 39% of patients treated compared with 19% in those receiving placebo.
• Potential side effects of methotrexate include
• leukopenia and
• hepatic fibrosis, necessitating routine monitoring of blood count and liver function.
  

Cytokine Therapy
In the discussion of the cause and pathogenesis of IBD, the role of cytokines was mentioned. Based on these findings, a rationale for treatment with cytokines was defined, and the number of trials in which the efficacy of cytokine therapy is investigated is rapidly increasing. The effect of cytokine therapy is achieved either through the administration of anti-inflammatory cytokines (IL-4, IL-10, or TGF-β) or through the inhibition of proinflammatory cytokines (IL-1 and TNF).

• Patients with steroid refractory UC who were treated with IL-10 enemas showed clinical improvement.
• When rats with experimental colitis received an expression vector carrying the TGFp cDNA, the colitis was alleviated, suggesting that this therapy for IBD patients merits further investigation.
• IL-1, one of the anti-inflammatory cytokines, may be inhibited in one of three ways:
• with an IL-1 receptor antagonist,
• with soluble IL-1 receptors, or
• with IL-1-specific monoclonal antibodies.
• However, most of the studies were performed on mice, and beneficial effects were not demonstrated.
  

As early as 1995, Van Dullemen et al. showed that the use of anti-TNF antibodies (infliximab [Remicade]) decreased the Crohn's Disease Activity Index score while producing an improvement in the colonoscopic findings in patients with CD.

• A similar randomized, placebo-controlled trial in another population of CD patients showed that a single infusion of infliximab induced a clinical response in 81% of patients and clinical remission in 48%.
• Retreatment of those patients with infliximab every 8 weeks maintained a clinical benefit in nearly all patients throughout the treatment period and 8 weeks after the last infusion.
• In another study of patients with active CD who were treated with infliximab, a response rate was achieved in 82% and closure of fistulas occurred in 68%.
• The consistent benefit of infliximab treatment in patients with moderate to severe active CD and in patients with fistulas was further shown in other studies.
• The treatment with infliximab in another placebo-controlled trial of patients with fistulous CD showed a reduction by more than 50% from baseline in the number of draining fistulas.
• The second stated end point was the closure of all fistulas, and 55% of the patients receiving infliximab had closure of all fistulas.
  

Another cytokine used in the treatment of IBD is interferon.

• Interferon-α has been used in several trials of CD and UC patients.
• Clinical results were impressive in patients with UC but only moderate in patients with CD.

Although the newer agents seem to have great potential, many questions must be answered before cytokines can be considered standard treatment for IBD. Their longer-term efficacy as well as the complications produced must be further assessed.

GRANULOMATOUS COLITIS

GRANULOMATOUS COLITIS

• Granulomatous colitis (Crohn's disease, CD, of the colon) is also an inflammatory disease of the large bowel of unknown cause.
• It is well accepted that CD of the large and small intestine is one disease, but it is separate and distinct from UC.
• CD is more common in Jews, uncommon in blacks, and more frequent in populations of Westernized civilizations than those of Africans and Asians.
• The disease primarily affects young individuals, with 80% of cases occurring in patients younger than 35 years.
• Disease in which the colon is primarily involved affects women slightly more often than men and occurs at a somewhat older age.
• The colon may be involved with granulomatous disease in one of several ways.
• First, the colon alone may be the site of the primary granulomatous disease.
• The large bowel may be involved in its entirety, but more often there is segmental disease with sparing of the rectum and part of the sigmoid.
• In addition to granulomatous disease of the colon, there may be involvement of the small bowel.
• This form of ileocolitis is the most common type of CD.
• The colon may become involved with granulomatous disease only after surgery for regional ileitis, but this is not particularly common, because most recurrences appear at the site of or proximal to the anastomosis.
• Finally, the colon may be involved indirectly via fistula formation from a loop of small bowel that is the site of the primary disease.
• In this case, most commonly there is no primary disease in the colon but only secondary inflammation from the disease in the small intestine.

Pathologic Features

• Granulomatous colitis involves all layers of the bowel wall as a transmural reaction.
• This transmural reaction may be noted grossly but is present in the early phases of the disease when only microscopic changes are noted.

Crohn's disease of the colon.

• Transmural involvement is present with mucosal ulceration (U),
• edema of the entire bowel wall and
• serosal noncaseating granuloma.

Although the gross and microscopic features of CD are well established, there is no pathognomonic feature.

The features of UC and CD are-

• In approximately 10 to 15% of patients, it may be difficult to equivocally differentiate CD from UC.
• The term indeterminate colitis has been used in these cases in which a definitive pathologic diagnosis cannot be made.

Characteristics of Crohn's Colitis and Ulcerative Colitis
Feature
Crohn's Colitis Ulcerative Colitis
Thickened bowel wall + + + +
Narrowing of bowel lumen + + + +
Discontinuous disease + + ○
Rectal involvement ○ + + +
Deep fissures and fistulas + + ○
Confluent linear ulcers + + ○
Perianal disease + + ○
Microscopic
Transmural inflammation + + + +
Submucosal infiltration + + + +
Submucosal thickening, fibrosis + + + ○
Ulceration through mucosa + + + + +
Fissures + + + +
Granulomas + + ○
Features are characterized as being present consistently (+ + +), frequently (+ +), infrequently (+), or rarely (○).

On macroscopic examination

• the bowel wall appears to be thickened, particularly in the submucosal layer.
• Correspondingly, there is narrowing of the lumen.
• Edema, thickening, and overgrowth of the mesenteric fat encroaching on the serosal aspect of the bowel wall are the rule with granulomatous disease of both the small and large intestine.
• The serosa tends to be hyperemic with visible vessel engorgement, and there are chronic subserosal inflammatory changes with exudate production.
• Mesenteric lymph nodes may be enlarged.

The gross appearance of the mucosal surface varies depending on the extent and severity of the disease.

• The mucosa may appear to be normal except for hyperemia and edema, or there may be longitudinal ulcers that cause the mucosal surface to have a cobblestone appearance.
• The ulcers vary in depth but usually extend at least to the submucosa and often to the serosa.
• Because of this, frequently other loops of intestine adhere to the involved segment, and fistulas may occur.

In addition, skip areas may be seen.

Microscopic changes include

• infiltration of inflammatory cells in all layers and
• marked submucosal and subserosal thickening and
• intramural fissures that can extend through to the mesenteric fat.
  

Criteria for the histologic diagnosis of granulomatous colitis have been classified as major and minor.
The major criteria are
(1) giant cells or epithelioid granulomas that occur either intramurally or within regional lymph nodes
(2) intramural fissures or fistulas,
(3) transmural mononuclear inflammation, and
(4) transmural fibrosis.
The minor criteria are
(1) submucosal lymphangiectasia,
(2) chronic serositis when there has been no prior surgery,
(3) muscle wall thickening (more than twice that of normal), and
(4) segmental involvement.

Clinical Features
Symptoms of granulomatous colitis include

• diarrhea,
• mid-abdominal and lower abdominal crampy pain,
• malaise, and
• weight loss.

Other symptoms and clinical findings include

• fever,
• rectal bleeding,
• anemia,
• nausea, and vomiting.

Occasionally, patients may present with symptoms suggestive of an acute abdomen.

It is now recognized that toxic megacolon can complicate Crohn's colitis as well as other forms of colitis.
Extraintestinal manifestations are common, with musculoskeletal manifestations being the most frequent.
Clinically, granulomatous colitis often has an extremely variable onset and course.

• Although diarrhea is a dominant feature of both UC and granulomatous colitis,
• colonic bleeding is less common with granulomatous disease.
• However, massive bleeding from acute granulomatous colitis can occur on occasion.
• Colonic sinuses, fistulas, and strictures are characteristic of granulomatous colitis.
• However, these internal complications do not occur as frequently in colon disease as they do in terminal ileum disease.

Perianal disease is a frequent complication.
· It is an extremely troublesome problem and difficult to treat successfully.
· In the National Cooperative Crohn's Disease Study,

• more than 46% of patients with colon disease had associated perianal lesions,
• whereas the rate was 25% in those with disease localized to the small bowel.
• The perianal lesions can precede the clinical appearance of the colitis by a variable number of years.
• Buchmann and Alexander-Williams classified perianal disease into the following categories: skin lesions, anal canal lesions, fistulas, and hemorrhoids.

Skin lesions include

• maceration,
• erosion,
• ulceration,
• abscess formation,
• and skin tags.

Because of the frequency of diarrhea in this disease, the skin around the anus may become macerated, leading to ulceration and subcutaneous abscess formation.

• Skin tags are frequent manifestations.
• They tend to be edematous and larger, thicker, and harder than those seen in patients without CD.

Anal canal lesions include

• fissures,
• ulcers, and
• stenosis of the anal canal.
  o The fissures tend to be deep and wide, with undermined edges.
  o Particularly important is the fact that they may be eccentrically placed in any position around the anus, in contradistinction to the uncomplicated fissure in patients who do not have CD.
• The fissures in these patients usually lie in the midline; unless there is associated sepsis, they tend to be painless.

Fistulas and abscesses

• are perhaps the most difficult of the perianal lesions.
• They may arise from an infected anal gland, as in patients without CD.
• However, more commonly they result from penetration by anal canal or rectal fissures or ulcers.
• On occasion, these fistulas are low lying and can be treated in a conventional manner.
• The more complex fistulas, however, may have a high internal opening with multiple indirect tracks opening on the buttocks or scrotum.
• Some of these tracks may communicate with each other.
• The fistulas tend to be chronic, indurated, and cyanotic, but despite their appearance, they are often painless.
• If the patient does complain of pain, one should suspect an abscess.

Rectovaginal fistulas can also complicate CD and tend to result from direct penetration of rectal wall fissures into the vagina.

• They are a relatively frequent complication of severe perianal disease, with rates varying from 3.5 to 20%.
• Quite frequently, these fistulas are asymptomatic, and no surgical intervention should be attempted.
• However, if the patient is symptomatic, surgery is indicated.
• Various local procedures have been described, but none are extremely successful.
• Some patients will require proctectomy

Diagnosis of Granulomatous Colitis

• Endoscopic evaluation of the colon and rectum is essential.
• Colonoscopy is particularly important to determine the extent of the disease and,
• in our opinion, is a more sensitive test than radiologic examination.
• For gross features of the disease, endoscopy and radiology might be equivalent.
• However, for the detection of early manifestation of the disease such as superficial ulcers, colonoscopy is superior.
• In addition, the discontinuous nature of the disease can be seen better with the colonoscope than on radiologic examination.
• It is our routine practice for all patients who undergo surgery for CD, including those with CD of the small bowel, to undergo a total colon examination before surgery to fully determine the extent of the disease.

The endoscopic appearance of Crohn's colitis is quite different from that of UC.

• The rectum is spared in approximately 50% of patients with large bowel involvement.
• Depending on the extent and severity of the disease,
• there may be isolated aphthous ulcers with normal intervening mucosa,
• or there may be
• irregular mucosal thickening,
• congestion,
• edema, and
• a cobblestone appearance with
• deep linear ulcerations and fistulas.
• Pathognomonic features of CD (i.e., granulomas) are present in only 20 to 40% of cases.

Radiologic features characteristic of Crohn's colitis are similar to those seen in terminal ileum disease.
The radiologic features that substantiate the diagnosis of Crohn's colitis include

• skip areas,
• longitudinal ulcerations,
• transverse fissures,
• eccentric involvement,
• pseudodiverticula,
• narrowing,
• strictures,
• pseudopolypoid changes,
• a cobblestone pattern,
• internal fistulas,
• sinus tracks,
• and intramural fistulas that extend parallel to the lumen of the thickened bowel.

Any portion of the colon may be involved with Crohn's colitis.

• The segments most frequently involved are the
• transverse colon,
• the cecum, and
• the ascending colon.
• The segment least frequently involved is the rectum.
• The skip areas must be sought carefully,
  o because discontinuous involvement may be limited to one wall,
  o may appear as a nodular filling defect,
  o or may involve straightening and rigidity of a short segment of the colon.

The combination of longitudinal ulcers, edematous mucosa, and transverse linear ulcers produces the cobblestone pattern previously described.

• Transverse linear ulcers may penetrate so deeply into the wall of the colon that they appear in contour as numerous long, thin spicules perpendicular to the long axis of the bowel or as a sinus track.
• They may ultimately lead to small intramural abscesses or fistulas.
• A small bowel enema or enteroclysis should be included as part of the workup in patients with Crohn's colitis to document the total extent of the disease.

Granulomatous Colitis and Carcinoma
Granulomatous ileocolitis has been recognized as a condition predisposing to the development of colorectal carcinoma.
The risk of developing carcinoma in CD is not as well defined as in UC, but some sources quote up to a 20-fold increase in gastrointestinal malignancy in patients with CD.
Carcinoma may also occur in chronic perianal fistulas.
A dilemma arises concerning the association of granulomatous colitis and carcinoma when one considers patient follow-up.
Although the incidence of cancer in Crohn's colitis is increased, it is still unclear how frequently these patients should be followed with either colonoscopy, radiology, or a combination of both.
Our recommendations for patients with Crohn's colitis are similar to those for patients with chronic UC (see earlier).