Gallstones

Slide 1and Liver Diseases Research Institute Shahid Beheshti University of Medical Sciences
Gallstones are composed of a mixture of cholesterol, calcium bilirubinate, proteins, and mucin
They are broadly classified as cholesterol, black pigment, or brown pigment stones, depending upon the predominant constituents, although most "cholesterol" stones have a mixed composition with small amounts of calcium and bilirubin salts.
Black pigment stones result from hemolysis and consist primarily of calcium bilirubinate.
Brown pigment stones are associated with bacterial and helminthic infection of the biliary system and are often found in the bile ducts in association with prior biliary manipulation or in association with biliary infestation. They may also occur as de novo common bile duct stones following cholecystectomy.
In industrialized countries, cholesterol gallstones account for about 75 percent of stones, black pigment stones for 20 percent, and brown pigment stones for 5 percent.
Age is a major risk factor for the gallstones. Gallstones are exceedingly rare in children except in the presence of hemolytic states
Age 40 appears to represent the cut-off between relatively low and high rates of cholecystectomies.
Sex — 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 1.2 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.
Supersaturation occurs as a result of an estrogen induced increase in cholesterol secretion and a progesterone induced reduction in bile acid secretion.
In the postpartum period, gallbladder sludge resolves in 61 percent of cases and approximately 30 percent of stones smaller than 10 mm disappear
Oral contraceptives and estrogen replacement therapy —estrogen therapy is associated with higher rates of gallstones.
The risk of gallbladder disease was lower with
transdermal therapy than with oral therapy.
For current users, the risk of cholecystectomy increased with increasing duration of hormone use and higher doses of estrogen.
Family history and genetics —Gallstones occurred more than twice as often in the family group.
The risk was greater in female relatives.
Obesity — Obesity is a well established risk factor presumably due to enhanced cholesterol synthesis and secretion.
The risk is particularly high in women, in those with morbid obesity.
Rapid weight loss —Rapid weight loss is also a risk factor for gallstone formation.
High rates of gallstone formation have also been associated with very low calorie diets.
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.
Obese patients should be started on UDCA, 600 mg at night, during very low calorie diets or after weight reduction surgery.
Diabetes mellitus —Hepatic insulin resistance appears to be important. Other contributing factors may be hypertriglyceridemia and autonomic neuropathy leading to biliary stasis due to gallbladder hypomotility.
Serum lipids —Gallstones appear to be positively associated with 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 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.
Gallbladder stasis —Common examples of this mechanism include spinal cord injuries, prolonged fasting and the use of total parenteral nutrition
Other drugs — In addition to estrogen, oral contraceptives, and octreotide, two other drugs can promote the formation of gallstones: clofibrate and ceftriaxone.
Ceftriaxone is a major cause of biliary sludge formation in hospitalized patients.
Decreased physical activity —Physical activity is associated with a decreased risk of symptomatic cholelithiasis.
Crohn's disease — The prevalence of gallstones is increased in patients with Crohn's disease.
Hemolysis — Disorders associated with hemolysis increase the risk of pigmented gallstones.
Statins — The use of statins has been associated with a decreased risk of gallstone disease.
Ascorbic acid — deficiency of ascorbic acid (vitamin C) is associated with the development of gallstones. 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.
Vegetable protein — increased consumption of vegetable protein in the context of an energy-balanced diet as a protective factor for cholecystectomy.
Poly- and monounsaturated fats — Mono- and polyunsaturated fats inhibit cholesterol gallstone formation.
Patients with uncomplicated gallstone disease may have ultrasound findings of gallstones, gravel, or sludge.
Distinguishing among these three entities is generally not clinically important because they are managed identically.
Gallstones appear as echogenic foci that cast an acoustic shadow and seek gravitational dependency.
Gravel is the appearance of multiple small stones that are echogenic and cast shadows.
The sludge seen on ultrasound represents microlithiasis. Sludge is echogenic in appearance but does not cast an acoustic shadow .
It is also more viscous and does not move to the dependent portion of the gallbladder as rapidly as gravel.
False negative results may be obtained if the gallbladder is completely filled with stones or if it is contracted around many stones.
In such cases, the findings may be confused with gas in a partially collapsed duodenal bulb.
Category 1: Gallstones on imaging studies but without symptoms (incidental gallstones)
Category 2: Typical biliary symptoms and gallstones on imaging studies
Category 3: Atypical symptoms and gallstones on imaging studies
Category 4: Typical biliary symptoms but without gallstones on ultrasound
The overall prevalence of gallstones was 7 percent, was higher in women than men (9 versus 5 percent), and increased with advancing age.
The majority of these patients have no symptoms attributable to the gallstones;
The majority of patients found to have incidental gallstones will remain asymptomatic.
However, approximately 20 percent will become symptomatic during up to 15 years of follow-up.
Patients with asymptomatic gallstones appear to have a slightly lower risk of complications than those with symptomatic gallstones.
When symptoms occur, they are usually biliary colic rather than complications of gallstone disease.
Ransohoff et al reported prophylactic cholecystectomy slightly decreased survival and was not associated with an appreciable gain in discounted life years gained.
Ransohoff DF, Gracie WA, Wolfenson LB, Neuhauser D. Prophylactic
cholecystectomy or expectant management for silent gallstones. A decision analysis to assess survival. Ann Intern Med 1983; 99:199.
Thus, prophylactic cholecystectomy is not indicated in most patients with asymptomatic gallstones.
Possible exceptions include patients who are at increased risk for gallbladder carcinoma or gallstone complications, in whom prophylactic cholecystectomy or incidental cholecystectomy at the time of another abdominal operation can be considered.
Diabetes mellitus —Predominantly anecdotal evidence suggests that diabetic patients are at increased risk for the development of severe gangrenous cholecystitis.
However, the magnitude of the risk and the risks and costs of cholecystectomy do not warrant prophylactic cholecystectomy in diabetics with asymptomatic gallstones.
Patients at increased risk for biliary cancer — These include:
Choledochal cysts Caroli's disease Anomalous pancreatic ductal drainage (in which
the pancreatic duct drains into the common bile duct)
Gallbladder adenomas Porcelain gallbladder
Prophylactic cholecystectomy may be indicated in many of these patients.
Sickle cell disease — Prophylactic cholecystectomy is not recommended, but an incidental cholecystectomy should be considered if abdominal surgery is being performed for other reasons.
Hereditary spherocytosis — Some authorities recommend combined prophylactic splenectomy and cholecystectomy in young asymptomatic patients with hereditary spherocytosis if gallstones are present.
Gastric bypass surgery — Morbidly obese patients who have undergone gastric bypass surgery, have a high incidence of developing gallstones (greater than 30 percent).
An incidental cholecystectomy is recommended by some at the time of surgery, though the issue is controversial.
Dissolution therapy in silent gallstone :
While dietary maneuvers and bile acid therapy may result in gallstone dissolution and prevent further progression of gallstone disease, there are few data suggesting that drug therapy is cost-effective or should be used in this setting.
The classic biliary colic is of an intense, dull discomfort located in the right upper quadrant, epigastrium, or (less often) substernal area that may radiate to the back (particularly the right shoulder blade).
The pain is often associated with diaphoresis, nausea, and vomiting.
Biliary colic is caused by the gallbladder contracting in response to hormonal or neural stimulation, usually due to a fatty meal, forcing a stone (or possibly sludge or microlithiasis) against the gallbladder outlet or cystic duct opening, and leading to increased intra- gallbladder pressure and pain.
The stones often fall back from the cystic duct as the gallbladder relaxes.
The pain typically lasts at least 30 minutes, plateauing within an hour. The pain then starts to subside, with an entire attack usually lasting less than six hours.
The frequency of recurrent attacks is variable, ranging from hours to years, though most patients do not have symptoms on a daily basis.
We prefer ketorolac (30 to 60 mg adjusted for age and renal function given in a single intravenous or intramuscular dose) for patients who present to the emergency department with biliary colic.
We reserve opioids for patients who have contraindications to NSAIDs or who do not achieve adequate pain relief with an NSAID.
While anticholinergic agents are useful in the management of renal colic due to their smooth muscle relaxation effects, they do not appear to help biliary colic.
During an acute attack of biliary colic, patients should be instructed to avoiding eating to prevent the release of cholecystokinin.
Intravenous hydration may be necessary if the attack is prolonged or associated with vomiting.
When the pain has resolved, patients are encouraged to eat three meals daily, with each meal containing sufficient fat or protein to ensure good gallbladder contraction.
In addition, their diet should be high in fiber and calcium, and low in saturated fats
Definitive prophylactic therapy to prevent future attacks of biliary colic and to prevent the complications of gallstone disease is appropriate for patients with recurrent attacks of moderate or severe biliary colic, or with an isolated severe (complicated) attack.
Cholecystectomy is recommended for the majority of patients, but medical dissolution therapy may be appropriate for patients who are poor surgical candidates.
The approach to treatment is not as clear for patients with isolated or recurrent attacks of mild biliary colic.
Options for treating patients with mild symptoms include expectant management, prophylactic cholecystectomy, and oral dissolution therapy with bile acids.
Increased risks of right sided colon cancer, esophageal cancer, and small intestinal cancer in patients who have undergone cholecystectomy have been suggested.
This may be related to the effects of increased concentrations of the bile acid deoxycholic acid in the gut lumen as a result of loss of the gallbladder, which normally acts as a reservoir for concentrated bile acids.
Biliary colic due to gallstone in pregnancy :
For pregnant women with biliary colic, the initial management is supportive care, which is usually successful.
However, if recurrent bouts of biliary colic occur, which is common with conservative therapy , primary surgical management during pregnancy is appropriate.
For these women, cholecystectomy is ideally performed in the second or early third trimester
Although ursodeoxycholic acid has been administered in the management of intrahepatic cholestasis of pregnancy, its safety and efficacy for the treatment of gallstones during pregnancy has not been evaluated.
Pregnant women with complications of gallstones including acute cholecystitis, choledocholithiasis, cholangitis, or biliary pancreatitis require supportive care with hospitalization, intravenous fluids, antibiotics, analgesia, and bowel rest, followed by prompt intervention with surgery and/or ERCP.
Uncomplicated gallstone :
First episode (especially in the first triamester or late third triamester) : conservative and follow up. Postpregnancy management depends on findings on imaging studies and future reproductive plans.
Second episode : Surgery (ideally in the second or early third trimester )
Complicated gallstone :
Pancreatitis : In the prescence of CBD stone: ERCP and then
cholecystectomy during pregnancy
Choledocholithiasis : ERCP and then cholecystectomy during pregnancy
Pain control in pregnant women with biliary colic can usually be achieved with intravenous administration of meperidine
Although NSAIDs can produce effective analgesia for biliary colic, these drugs are generally avoided in pregnancy, especially after 32 weeks of gestation, because of adverse fetal effects (eg, premature closure of the ductus arteriosus, oligohydramnios) when used for more than 48 hours.
After delivery, cholecystectomy is indicated if the patient complicated gallstone during pregnancy and the gallbladder was not removed.
In women with less severe disease during pregnancy, postpregnancy management depends on findings on imaging studies and future reproductive plans.
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 .
If the sludge and stones disappear and future pregnancies are not planned, surgery can be avoided. However, if sludge and stones persist and future pregnancies are planned, surgery should be performed within three months after delivery to prevent recurrent attacks of biliary colic and the occurrence of more severe complications.
While patients may present with atypical symptoms, such as chest pain or nonspecific abdominal discomfort, in the absence of biliary colic should prompt an investigation for alternative diagnoses.
Atypical symptoms seen in patients with gallstones include:
Chest pain
Patients with atypical symptoms without associated biliary colic should be evaluated for alternative diagnoses, even if gallstones are demonstrated on imaging.
Some patients with atypical symptoms and gallstones respond to cholecystectomy, but the response rates are lower than those seen for patients with typical biliary colic.
Thus, a careful search for other causes of a patient's atypical symptoms is indicated.
The probability of patients with atypical symptoms and gallstones responding to cholecystectomy was evaluated in a systematic review.
Among patients with upper abdominal pain (but not necessarily biliary colic), the relief rates for elective and acute cholecystectomy were 72 and 86 percent, respectively.
In patients with dyspeptic symptoms, the relief rates were 56 and 82 percent, respectively. In addition, 65 percent of patients with food intolerance reported relief after 12 months.
An empiric trial of oral dissolution therapy with ursodeoxycholic acid (UDCA) may help identify patients who will benefit from cholecystectomy, provided there has been a thorough evaluation for other causes of the symptoms.
UDCA therapy relieves the symptoms in many patients within three months if the symptoms are due to gallstones.
While UDCA therapy may provide symptomatic relief, the rates of complete stone dissolution are poor (37 percent in a meta- analysis), leaving patients at risk for complications from their gallstones.
As a result, we refer patients who respond to UDCA for cholecystectomy if they are surgical candidates, especially if they are not interested in staying on UDCA for two to three years to see if their stones will dissolve.
We do not suggest cholecystectomy in patients who fail to respond to UDCA, and instead treat for disorders more consistent with the patient's symptoms (eg, functional dyspepsia in a patient with bloating).
In patients with typical biliary colic but no gallstones on ultrasonography, we usually repeat the transabdominal ultrasound in a few weeks.
If the repeat transabdominal ultrasound is negative, the patient may have microlithiasis or may be a category 4 patient
The more definitive approach is to proceed with endoscopic ultrasonography (EUS) to look for missed stones or sludge and, if the EUS is negative, obtain samples of bile for bile microscopy to evaluate for microlithiasis.
However, some centers recommend cholecystokinin-stimulated cholescintigraphy before an EUS with bile sampling. Cholescintigraphy is more widely available and less invasive.
A positive result (low gallbladder ejection fraction) suggests functional gallbladder disorder, though it may also be seen in the setting of microlithiasis or sludge and microcrystals that are interfering with bile ejection through the cystic duct.
Differentiating between the two entities is typically not required since both conditions are treated with cholecystectomy.
If the cholescintigraphy is normal, EUS can then be pursued.
If medical dissolution therapy with oral bile acids is being considered, EUS with bile collection for microscopy should be done first to confirm the presence of microlithiasis or sludge .
Many patients with microlithiasis will respond to a one- to two-year course of oral bile acid therapy.
It is important to thoroughly evaluate category 4 patients who have biliary colic but negative transabdominal ultrasounds because patients with missed stones or microlithiasis will typically respond to cholecystectomy.
However, patients with other diagnoses, such as sphincter of Oddi dysfunction, peptic ulcer disease, dyspepsia, or irritable bowel syndrome, may not improve or may even worsen following cholecystectomy.
Patients with calcified and pigment stones are generally poor candidates for medical therapy.
Bile acids work by reducing biliary cholesterol secretion, increasing biliary bile acid concentrations, and as a result, reducing the cholesterol saturation index.
UDCA has been shown to reduce intestinal absorption of cholesterol and improve gallbladder emptying.
All pure cholesterol stones would be expected to dissolve in bile that is unsaturated with cholesterol. However, most gallstones have a mixed composition, containing significant amounts of calcium salts, which limits the efficacy of this form of therapy.
Occasionally, rim calcification develops, inhibiting further stone dissolution.
Patients selected for oral bile acid therapy should have the following favorable characteristics:
Small stone size (<0.5 to 1 cm)
Mild to moderate symptoms
Minimal calcification and low density on computed tomographic (CT) imaging
Patients with severe medical problems who are at high risk for or refuse surgery and who have mildly to moderately symptomatic gallstone disease should be considered for medical therapy.
The definition of mild to moderate symptoms includes episodic biliary pain that occurs fewer than two to three times a month and can be controlled with the use of oral analgesics, and the absence of complications such as cholecystitis, cholangitis, pancreatitis, or obstructive jaundice.
Patients with complicated gallstone disease who cannot undergo surgery are better treated by percutaneous stone removal, gallbladder drainage, or endoscopic retrograde cholangiopancreatography (ERCP).
UDCA is typically given as a dose of 10 to 14 mg/kg daily. It is suggested that bile acids be given at bedtime to maintain hepatic bile acid secretion overnight.
The rate of gallstone dissolution in patients taking UDCA at a standard dose is about 1 mm per month.
If only ideal patients are selected (those with small, noncalcified, buoyant stones), dissolution rates may exceed 90 percent. Unfortunately, less than 10 percent of patients fall into this category.
The response to treatment is slow, with gallstone size falling by only 1 mm/month on average. Thus, treatment may be required for two years or more.
However, several studies have suggested that treatment with bile acids prevents gallstone- related symptoms, even in patients in whom gallstone dissolution is incomplete.
Some authours suggest a potential benefit of long-term bile acid therapy in symptomatic patients in whom cholecystectomy is undesirable, even if complete gallstone dissolution cannot be accomplished.
There is a significant incidence of stone recurrence following bile acid treatment.
Approximately 15 percent of patients will recur by one year, and 45 percent will recur by five years. The risk appears to be highest in those with multiple stones
We use long-term bile salt therapy in
patients whose medical condition precludes cholecystectomy,
or in whom the risk of gallstone recurrence remains high because of lack of reversible predisposing features.
Statins -
There has been interest in the use of HMG CoA reductase inhibitors (statins) in the treatment of cholesterol gallstone disease.
Based upon the available data, there is insufficient evidence to recommend the use of statins for the treatment or prevention of…