Approximately 10-15% of the adult population or more than 20 million people in the US have gallstones. It is estimated that there are about one million newly diagnosed patients annually. Approximately 500,000-600,000 cholecystectomies are performed annually in the US. As a cause of hospitalization, gallstones are the most common and most costly digestive disease, with an annual estimated overall cost of more than five billion dollars in the U.S. Since only about 30% of patients with asymptomatic cholelithiasis will warrant surgery during their lifetime, it is therefore impossible to operate on every patient diagnosed with gallstones and accurate knowledge of the natural history and risk factors in patients with asymptomatic gallstones is essential. There is sparse literature on asymptomatic gallstones, in addition, there is a diversity of methods applied in these studies to diagnose the patient as being asymptomatic, which makes it difficult to compare studies and draw conclusions.
Gallstones are common, their incidence is approximately 15% of the general population in Europe and North America. This incidence varies greatly depending on sex, age, and race. It affects 25% of women and 10-15% of men over the age of 50. They are more prevalent in American-Indians and Mexican-Americans and less common in African-Americans. Principal risk factors are age, sex, and obesity. Lesser risk factors include childbearing, abstinence from alcohol and some medications. More than 20 million people in the US have gallstones and some 500,000-600,000 cholecystectomies are done annually. About 70-80% of people with gallstones are asymptomatic and the proportion of the asymptomatic patients is similar in all age groups, being around 70%. Women were found to have gallstones or cholecystectomy twice as often as men.
Gallstone composition and lithogenic factors
Gallstones are mainly of mixed composure, the main components being cholesterol and bile pigment. The stones are predominantly cholesterol derived in 80% and pigment derived in 20% of cases.
Recent epidemiological studies using ultrasound examination have determined the factors favoring litho genesis. In addition to those that are already well known, such as age, obesity, female gender, high blood triglyceride levels, and multiparity, the risk is also correlated with large, frequent variations in weight, intake of certain drugs and alimentary habits. On the other hand, physical exercise plays a protective role against the development of symptomatic gallstone disease. Risk factors for pigment stones include age, chronic hemolytic states, biliary tract infection, cirrhosis, and alcoholism. The same factors responsible for stone formation are expected to be those responsible for increasing the number and size of existing stones and therefore possibly increasing the chance of developing symptoms.
Age is a factor since gallstones are rare below the age of 20 except in Mexican-Americans where it is commonly seen in teenage girls. Forty is a typical age at diagnosis. The age in Saudis is younger, 59.36% were below 40 and 35.8% were below 30 years of age. Increasing age is an important risk factor for both sexes. While few men have asymptomatic gallstones before the age of 40, 5% of women aged 20-29 and 9% aged 30-39 do. The Female: Male ratio is 2:1 above 50 years of age and higher in younger ages.
Racial factors play an important role; gallstone incidence is high in Scandinavian and Northern European countries and lowest in sub-Saharan Africa. In the US, African-Americans have a risk of hospitalization for gallbladder disease only 40% of that of whites. Prevalence is also extremely high in Chile and low rates have been found in Okinawa and Japan. The Pima Indians of Southern Arizona have the highest recorded prevalence of gallstones in the world, with a prevalence of <70% in Pima women over the age of 25. Other American-Indians groups with a high incidence of gallbladder disease include the Chippewas of Minnesota, the Micmacs of Nova Scotia and several Alaskan tribes.
Family history is also a significant factor. Many have reported that a history of gallstones in first-degree relatives confers a double risk of Cholelithiasis.
Obesity and fat distribution have been found to be a potent risk factor in gallbladder disease, body mass index in particular being one of the principal risk factors for gallstones with a stronger relationship in females compared to males. Hartz et al. found that, in women, the ratio of waist to hip girth was significantly associated with gallbladder disease risk even after controlling for relative weight. Moderate obesity imposes at least a three-fold risk of gallstone disease in Caucasian women. In an ultrasound study on over 2000 patients with asymptomatic gallstones, Hopper et al. found obesity to be the most important risk factor for the development of asymptomatic gallstones in women (P<0.01), although it is not a significant factor in men.
Rapid weight loss whether a result of surgical management for obesity or dieting are associated with a high incidence of gallstones in the immediate following period.
Jorgensen found a strong trend toward increasing stone prevalence with increasing childbirths, especially among women aged 30 years. Maringhini et al. reported a high prevalence of gallbladder sludge in women who were immediately post-partum, although it resolved within a year in most. The number of previous pregnancies is a significant risk factor (χ2 =5.4, P=0.02). For instance, there is a 3, 8, and 17% overall frequency of gallstones in women with zero, three and six or more previous pregnancies, respectively.
There are conflicting reports on the relation between diabetes mellitus and gallstones. Gallbladder emptying in diabetics may be impaired and this in turn may predispose to gallstone formation. In another study using a stepwise logistic regression analysis, after adjusting for age, body mass index and for women, number of pregnancies, no significant increased risk was found related to race (P=0.40), high blood pressure (P=0.43), heart disease (P=0.47) or diabetes (P=0.46).
Petitti et al. in a study of twin women, found that smokers had a relative risk of 1.8 for gallbladder disease history.
There are multiple reports showing an increased risk in males and females on estrogen replacement therapy. Strom et al. demonstrated a dose-response relationship between contraceptive estrogen dose and risk of gallbladder disease. This risk was found to be age related, with a greater risk in younger women compared to women <40.
A study by Zhang et al. confirms the high prevalence of cholelithiasis in liver cirrhosis.
In general, what is required in order to prevent gallstone formation is avoiding those avoidable factors, which are known to be lithogenic. A well-balanced meal is important; however, it should contain some fat to stimulate adequate gallbladder emptying. In order to avoid an imbalance in bile constituents and precipitation of cholesterol, it is recommended to reduce saturated fat. Increasing fiber is important, since it acts as a fat magnet by reducing fat absorption, allowing the fat taken in to stimulate gallbladder emptying but not allowing it to increase weight. Reducing weight although important should be mainly through regular exercise, rapid weight loss especially through fat free diets should be avoided due to their negative effect on gallbladder emptying. Cholesterol lowering agents, although thought to be useful, may actually be harmful, since they actually work by increasing secretion of cholesterol in bile, the exact place we don't want it to be in high concentration.
NATURAL HISTORY OF GALLSTONES
Gallstone disease is considered a benign disease since approximately 80% of patients with stones remain asymptomatic. The proportion of the asymptomatic patients is similar in all age groups. Older patients over 70 years of age have a higher rate of change to the symptomatic group, as compared with younger patients under 70, 29.5% vs. 19.3%, respectively. It appears that serious symptoms and complications develop in about 1-2% of patients with asymptomatic gallstones annually (with fewer complications developing in later years than in years soon after gallstones are discovered), compared to 1-3% if the patient started with mild symptoms.
So, how are gallstones formed and what is their natural history? Gallstones are formed when the constituents of gallbladder bile come out of solution and precipitate. The formation of cholesterol stones is believed to result from cholesterol super saturation, accelerated cholesterol crystal nucleation and impaired gallbladder motility. These cholesterol precipitates are either passed out of the gallbladder, dissolve, remain the same or form the nidus on which more precipitates collect forming larger and larger stones. Stones tend to grow for the first two to three years, at which point growth tends to stabilize; 85% of all gallstones are less than two centimeters in diameter. These formed stones are asymptomatic in about 80% of cases, however in the remaining 20% the patient develops symptoms, which are usually caused by complications of the stones. The common complications of stones include acute cholecystitis, chronic cholecystitis, obstructive jaundice, cholangitis, empyema, and pancreatitis. Lesser common complications are gallstone ileus and cancer of the gallbladder.
About 70% of asymptomatic gallstone patients remain symptom-free and there are no clinical or morphological findings, which can predict the occurrence of symptoms on an individual basis. Other than symptoms, no factors related to prognosis have been established. The rate at which asymptomatic gallstones become symptomatic is low but significant, while patients with mildly symptomatic stones are at even greater risk for future pain and complications. Only 20% of 680 asymptomatic patients, followed for 10-17 years (median 13.3 years), developed biliary symptoms. Acute cholecystitis is the most common severe complication of gallstones. Based on follow-up studies, obstructive jaundice, cholangitis, pancreatitis and cancer of the gallbladder are infrequent complications. Risk of subsequent colon cancer should not ordinarily be a concern when cholecystectomy is considered.
Analyses of cost-effectiveness have not demonstrated substantial differences in life expectancy between patients with asymptomatic gallstones who undergo immediate open cholecystectomy compared with watchful waiting. In a study where 298 patients with gallstones accompanied by mild or non-specific symptoms, 123 with asymptomatic gallstones and 46 with non-function on cholecystogram and mild or non-specific symptoms were followed in the setting of a health maintenance organization for up to 25 years after diagnosis, it was found that during each of the first 5 years after diagnosis, all events, both severe and non-severe (including surgery for continuing mild symptoms) occurred in about 6% of the patients with mild symptoms accompanying either gallstones or non-function and in about 4% of patients with asymptomatic gallstones. The annual probabilities for all events tended to decrease as length of follow-up increased.
In another study, only 10% of the asymptomatic patients followed for 58 months (median 46.3 months) developed symptoms of biliary calculi and 7% required operations. There were 50 deaths in this series of 691 patients (19.5% of which were asymptomatic), 25 in the symptomatic and 25 in the asymptomatic group. Only two of these deaths were biliary tract related and both were in the symptomatic group. This study suggests that patients with silent stones do not need to be operated on prior to the development of symptoms. In addition, many patients with symptoms of biliary calculi can tolerate their symptoms for long periods and prefer this course of action to cholecystectomy.
DEFINITION: WHAT ARE GALLSTONE SYMPTOMS?
A distinction should be made between a symptom and a symptom complex. Patients complaining of symptom complexes such as those associated with acute cholecystitis, cholangitis, obstructive jaundice or gallstone pancreatitis are likely to be complaining of a genuine complication of gallstones. Those complaining of a single symptom, especially a vague symptom such as bloating, intolerance to fatty foods, belching, abdominal fullness or abdominal discomfort require careful questioning before incriminating gallstones for their symptoms. In between these two extremes lie those complaining of a single symptom, which we take for granted to be caused by gallstones. Perhaps what makes it easy to blame gallstones for many of our symptoms is the fact that gallstones are very common and a problem to which we have a good solution, namely cholecystectomy. However, are we justified in doing that? After all having a mischievous son does not justify blaming him for everything that goes wrong at home. There are certain problems in determining the symptomatic status of patients; first, there is no clear agreement on what symptoms gallstones cause. Abdominal symptoms are common in both the presence and absence of gallstones. In a study, the frequency of 'minor' dyspeptic symptoms was not different between women with and those without gallstones. Indigestion and abdominal discomfort are vague symptoms and occur just as frequent in patients without stones. Patients may be easily misdiagnosed as suffering from biliary tract pain, when in fact the pain is due to other organs, especially if the patient is not examined at the time of pain. It is difficult to define the symptoms specific to gallstones and therefore to determine which patients have symptomatic and which have asymptomatic gallstones.
Biliary pain is a result of an acute increase in pressure inside the biliary tract (by a stone transiently obstructing the cystic duct or the sphincter of Oddi) or obstruction of the gallbladder outlet causing inflammation of the gallbladder. A review of recent controlled trials suggests that the pain of biliary colic is constant and infrequent, comes in episodes lasting 1-5 hours, is located in the epigastrium or right upper quadrant of the abdomen and characteristically occurs at night. In other words, the term 'colic' is a misnomer. Brand et al. suggest that a sluggish gallbladder may protect from biliary pain. The pain may be referred to the tip of the right shoulder or between the shoulder blades. Apart from the two commonest sites mentioned above, biliary colic has been reported to occur in the left upper quadrant and substernal areas and to a lesser degree even in the lower quadrants. There are few additional symptoms other than nausea and vomiting. Abdominal pain having other characteristics, dyspepsia, and headache are all not related to biliary lithiasis. Flatulent dyspepsia, a symptom complex of vague pain in the right upper quadrant, fatty-food intolerance and bloating are probably not related to the presence of gallstones in the majority of patients. Some recommend that panendoscopy should be a routine examination performed on each patient qualified to undergo laparoscopic cholecystectomy as they discovered that for some patients with asymptomatic cholelithiasis, pain in fact was caused by peptic ulcer.
It is essential to clearly identify which symptoms the patient is complaining of and to determine whether these symptoms are caused by gallstones or not, before labeling the patient as a symptomatic gallstone patient. Failing to do so will result in unnecessarily removing the patient's gallbladder and leaving your patient with what he/she started with (pain not related to the gallbladder). Both of these situations are major contributors to what is known as the post cholecystectomy syndrome. Nearly 90% of patients with typical biliary pain are rendered symptom free after successful treatment of their gallstones, however, removing the gallbladder relieves only those symptoms caused by the gallbladder.
What are asymptomatic gallstones?
Asymptomatic biliary lithiasis (gallstones) can be defined as gallstones having caused no symptoms. In those patients with vague symptoms, it is essential not to relate the symptoms to gallstones without proof. Failure to do so will alter the ratio between symptomatic and asymptomatic patients in any study. There is sparse literature on asymptomatic gallstones. In addition, there is a diversity of methods applied in these studies to label the patient as being asymptomatic. This diversity is caused by:
1. The different definitions used for gallstone symptoms (what are true gallstone symptoms)
2. The different groups of patients on whom the diagnosis was made:
Although most diagnoses of gallstones whether symptomatic or asymptomatic currently are made based on ultrasound, the difference is in which group of patients the diagnosis was made. If the diagnosis was made as a screening procedure on the general population the results are expected to be different than if they were made on follow-up of ante-natal patients, whether symptomatic or asymptomatic, who as we know are considered a high risk group for developing gallstones. Another point related to the type of patient, is whether the patient fears surgery and therefore may hide or deny his symptoms. The opposite is true for the patient who is convinced that surgery will relieve him of his symptoms, in which case he will push for surgery and in doing so may make up symptoms in order to talk his surgeon into operating on him.
3. The different groups (or specialty) of observers:
Medical physicians, especially those involved in non-surgical methods of treating gallstones will have a tendency to delay referral to the surgeon. Physicians tend to reassure patients and under call symptoms. Surgeons (unfortunately many of them) may be slightly trigger-happy and have a tendency to rush to surgery at an early stage and in order to do so, will need to justify the symptoms. Family practitioners are somewhere in between, depending on their relation or trust in the surgeons or physicians they refer their patients to suggest that a sluggish gallbladder may protect from biliary pain.
RISK FACTORS FOR EARLY SYMPTOMS AND COMPLICATIONS
The natural history of asymptomatic gallstones, according to the best published studies, indicates that 70% of the patients remain symptom-free. While some feel that there are no clinical or morphological findings that can predict the occurrence of symptoms on an individual basis, literature review can identify subgroups of patients in whom cholecystectomy is justified.
While Cucchiaro et al. found age to be an important determinant of outcome, while Tritapepe et al. found that the risk of developing complications is 3.2 times greater in patients aged more than 60 years than in those who are younger and their statistical analysis also revealed that the risk of complications is about ten times greater in patients with both risk factors (age <60 and symptomatic) than in those with neither. Patino et al. considered women below age 60 to be at a higher risk. This difference in opinion can be explained by the fact that Patino et al. also consider life expectancy <20 years to be a high-risk criteria which can make up for the difference.
Stone size, nature, and number
While Capron et al. found that neither the size, number nor the nature of gallstones were predictive of symptoms or complications, Patino et al. considered calculi <2 cm in diameter, calculi <3 mm with a patent cystic duct and radiopaque calculi as high risk criteria. Biagini also identifies patients with micro or macro-lithiasis and patients in whom oral cholecystography reveals multiple floating stones as subgroups of patients in whom cholecystectomy is justified.
Polyps in the gallbladder are considered an indication for cholecystectomy. The nature of the polyp whether benign or malignant cannot be fully determined without histo-pathological analysis, which requires removal of the gallbladder. Pejic et al. suggest that the gallbladder should be removed in cases when: 1. symptomatic polyps are present regardless of size; 2. polyps larger than 10 mm are present because they represent a risk for gallbladder cancer; 3. polyps are showing rapid increase in size; 4. any polyp regardless of size if the patient is older than 50 years or if he has concomitant gallbladder calculosis. They recommend ultrasonography at least every six months for polyps less than 10 mm that are incidentally identified and not removed. This is especially critical for sessile polyps, in which the possibility of a small cancerous polyp is greater than in pedunculated polyps.
Symptomatic vs. asymptomatic
The risk of developing complications is 3.3 times greater in symptomatic than in asymptomatic patients, statistical analysis also revealed that the risk of complications is about ten times greater in patients with both risk factors (age <60 and symptomatic) than in those with neither.
Defective gallbladder emptying is evident in a subgroup of patients, but gallbladder contraction may be normal in patients with cholelithiasis and there is no correlation between gallbladder contraction and the number and size of the stones. However, in a life-table analysis, complications (severe events) developed in about 1% per year in patients with visualized gallstones and in about 2% per year in patients with non-function. Patino et al. and Biagini also consider dysfunction as a subgroup, which justifies cholecystectomy. Brand et al. suggest that sluggish gallbladder may protect from biliary pain.
The management of asymptomatic cholelithiasis in patients with diabetes is controversial. Studies of the natural history of silent gallstones suggest that a large majority of patients with such stones will remain asymptomatic. However, diabetics are at increased risk. Babineau et al. and Aucott et al. believe that available data, although limited, indicate that asymptomatic patients with diabetes do not benefit from screening for gallstones and that cholecystectomy should only be performed in cases of symptomatic cholelithiasis, as is the case in the general population. More recently, Guraya agrees with that line of management. Diabetes in itself does not appear to be a primary risk factor, it may however be a marker for the existence of co-morbid conditions which may increase the rate of conversion from laparoscopic to open cholecystectomy. It may also increase the rate and severity of wound infections as well as other complications that may occur more frequently in diabetic, which makes it necessary to carefully assess these patients. Landau et al. found that diabetics are more likely to be operated on in the acute stage of their gallbladder disease (22% vs. 12%), had a higher rate of septic bile, gangrenous changes and perforations of the gallbladder wall. They also noted that the morbidity rate was higher in the diabetic group (21% vs. 9%) and mortality was slightly higher in the diabetic group. This degree of additional operative risk in their view does not justify recommending cholecystectomy in diabetic patients with asymptomatic gallstones. They however highly recommend early surgery in diabetics with symptomatic gallstones and acute cholecystitis. Friedman et al. used decision analysis to compare expectant management to prophylactic cholecystectomy in asymptomatic diabetic patients. Expectant management was usually the superior course. For example, a 30-year-old diabetic man gains an average of 6.1 months of life by choosing expectant management over prophylactic surgery. The superiority of expectant management was invariant to changes in age, sex, and the extent to which major surgical complications affect the future quality of life. Prophylactic cholecystectomy was superior only with extremely high estimates of the likelihood of developing symptomatic disease, the probability of requiring emergency surgery after symptoms develop and emergency surgical mortality rates. Prophylactic surgery for silent gallstones in diabetic patients does not increase life expectancy or quality of life and may in fact reduce it. This result holds over a wide range of basic assumptions.
The evolution of cholelithiasis in certain groups and areas is more aggressive than in others, Chile is an example as well as the Pima Indians and early surgical treatment in these cases is warranted.
Gallbladder carcinoma and other cancers
In all populations, there is a strong correlation between gallstones and gallbladder cancer: the risk of gallbladder cancer is approximately four to five times higher in patients with gallstones, than in patients without gallstones. In those populations where the onset of gallstone disease occurs in the first few decades, the risk is much higher. Obesity, which is also a risk factor for gallstones, increases the risk of gallbladder cancer, as does the consumption of diets high in fats and calories. Other risk factors, such as increased parity, also increase the frequency of gallbladder cancer, most probably explained by the association between gallstones and parity. However, in spite of this correlation prophylactic cholecystectomy for asymptomatic gallstones cannot be justified to prevent gallbladder cancer (except in cases of porcelain gallbladder)[5863 and in individuals in geographic regions with a high prevalence of GB cancer. An example are the Pima Indians with gallstone disease where an increased cancer mortality and total mortality were found. In reviewing the histo-pathological reports of 549 patients who underwent cholecystectomy at a university hospital in Riyadh, Saudi Arabia, none showed evidence of carcinoma, in spite of the fact that this patient population had many of the risk factors mentioned above (early onset of gallstone disease, obesity, and increased parity). The incidence of gallbladder carcinoma has been shown by others to occur in 1% of patients undergoing cholecystectomy and the risk of carcinoma developing in patients with asymptomatic cholelithiasis has been estimated at less than 1%. These figures should not diminish the role of gallbladder-preserving treatments in elderly and selected high-risk patients for whom cholecystectomy may be hazardous. However, such patients must undergo a thorough imaging assessment both before and after treatment to ensure that a gallbladder carcinoma is not overlooked. Lowenfels notes that cholelithiasis and several common cancers share similar epidemiological and perhaps metabolic factors, however, Linos et al. conclude that no real association exists between cholelithiasis and carcinoma of the colon.
Calcified (Porcelain) gallbladder
The only medical condition in which prophylactic cholecystectomy is indicated to prevent gallbladder carcinoma is in cases of porcelain gallbladder.
Obesity, which is also a risk factor for gallstones, increases the risk of gallbladder cancer, as does the consumption of diets high in fats and calories.
A study by Zhang et al. confirms the high prevalence of cholelithiasis in liver cirrhosis. In spite of that there appears to be a much lower incidence of acute cholecystitis and choledocholithiasis in cirrhotic patients with cholelithiasis than in the normal population and patients with cirrhosis and asymptomatic cholelithiasis can safely be managed without operation. The risk of gallstones becoming symptomatic is significantly lower in men and in alcoholic cirrhosis. Castaing et al. also note a high incidence of cholelithiasis in cirrhotic patients. They also found that complications of gallstones are not frequent but require an emergency operation that carries a high risk in these patients. On the other hand, elective surgical treatment of asymptomatic cholelithiasis at the time of portal diversion does not bear any peculiar risk. In such a situation, cholecystolithotomy is easier and probably safer than cholecystectomy.
DEATH FROM GALLSTONES AND LIFE EXPECTANCY
Cucchiaro et al. demonstrate that death from gallstones is uncommon, as is death from their initial clinical manifestation (1.2%). Age, cirrhosis and diabetes are important determinants of outcome. Fendrick et al. found that the prophylactic laparoscopic cholecystectomy strategy led to fewer gallstone-related deaths than the expectant management strategy, but all of the deaths in the prophylactic laparoscopic cholecystectomy group occurred earlier in life. They therefore concluded that prophylactic laparoscopic cholecystectomy should not be routinely recommended for individuals with asymptomatic gallstones.
HOW ARE GALLSTONES DIAGNOSED?
Although a plain X-ray may diagnose gallstones, this is successful in only 10-15% of cases. These stones contain little if any calcium (the radio-opaque component) as apposed to urinary tract stones, which are 85-90% radio-opaque. The main component in gallstones is cholesterol, which is radiolucent. Gallstones diagnosed through plain X-rays are usually an incidental finding and plain X-rays are not intended as a diagnostic tool for gallstones or gallstone disease. The same applies to CT-scans and magnetic resonance imaging (MRI) scans, although the latter may be part of the magnetic resonance cholangio-pancreaticogram (MRCP), which may be used as may the endoscopic retrograde cholangio-pancreaticogram (ERCP) as a diagnostic as well as a therapeutic tool for common bile duct stones but not gallbladder stones. Cholecystograms whether oral or intravenous which were once the main diagnostic tool for diagnosing gallbladder stones are now reserved for assessing function or gallbladder contraction and are so rarely used nowadays that the dyes or tablets used for the investigation may not be available in most modern health institutions. The hydroxy iminodiacetic acid (HIDA) scan is a radionuclide scan useful in diagnosing bile leak or acute cholecystitis by showing radioactive material outside the biliary system in the first condition and failure to show a gallbladder (in a non-cholecystectomized patient) in the latter. The main method of diagnosing gallstones is Ultrasound, which apart from being the best method, is in addition cheap, non-invasive, not associated with radiation and very informative since it also gives accurate information on the state of the gallbladder, the liver, the biliary ducts and the surrounding organs.
Gallbladder stones present in one of three clinical stages: (1) asymptomatic, (2) symptomatic, and (3) with complications. Considering the fact that gallstones are common, are usually silent and usually remain silent, the argument for prophylactic cholecystectomy is not an easy one. More people are being diagnosed with asymptomatic gallstones nowadays due to easy access to ultrasound, a non-invasive, commonly available and cheap diagnostic tool. However, once diagnosed, how should they be managed? The treating physician is faced with either a wait and see policy, following his patient until he develops symptoms and then operating on him. Or alternatively, the option of doing something. This does not necessarily mean surgical intervention. Only 1-4% per year of asymptomatic patients will develop symptoms or a complication of gallstone disease. Existing data indicate that 10% of patients will develop symptoms in the first five years after diagnosis and approximately 20% by 20 years. For persons with asymptomatic gallstones, the natural history is so benign that treatment is generally not recommended. Conservative follow-up of these patients by clinic visits and an ultrasound twice a year is usually enough. In addition, about 30% of persons who have had pain, do not have further episodes of pain. The expectant (wait and see) management policy, of course puts the patient at risk of developing a complication of gallstones. These can be as minor as just developing mild symptoms or as severe as dying of a complication of gallstones. In between these two extremes is biliary colic, acute cholecystitis, chronic cholecystitis, common bile duct obstruction (leading to obstructive jaundice or more severely acute cholangitis), acute pancreatitis, or even gallbladder cancer. Early elective cholecystectomy will have little positive or negative effect on average life expectancy of patients with gallstones. It seems safe to conclude that in patients with asymptomatic gallstones, serious symptoms, and complications will develop in about 1-2% per year. Using the more pessimistic 2%, after 20 years, 2/3 of patients will remain free of these problems ([1-0.02]20 =0.67). It also seems true that the longer the stones remain quiescent, the less likely it is that complications will occur.
Although the mortality of the operation remains relatively low (about 0.05%, except in older or high-risk individuals), non-surgical approaches have been developed and utilized in selected patient populations. All such alternative approaches leave the gallbladder intact and thus eventual stone recurrence in a significant number of cases is a potential drawback.
In the past 20 years, a variety of treatment options for gallstone disease have been developed. These methods of treating gallstones must be compared to the standard surgical modalities.
Oral bile acid pill
Bile acid therapy with chenodeoxycholic acid (chenodiol) was introduced in the early 1970s. However, because of concerns regarding side effects, chenodiol has been largely supplanted by ursodeoxycholic acid (ursodiol). The most effective use of bile acids in gallstone dissolution is in the symptomatic patient with small (less than 5 mm) floating cholesterol stones within a functioning gallbladder. This represents approximately 15% of patients. About 6-12 months of therapy are required in many patients and monitoring is necessary until dissolution is achieved. It is estimated that gallstones in such patients have a 60% (stones smaller than 10 mm) to 90% (stones smaller than 5 mm) dissolution rate, but in about 1/2 of these patients, gallstones recur within 5 years. Others found oral dissolution therapy to be successful in only 4.2% of attempted cases and associated with a recurrence rate of as high as 20%. Dissolution rates are higher and recurrence rates are lower in patients with single stones, non-obese individuals and in young patients. Presently, the indications for bile acid therapy are limited to patients with a co-morbid condition that precludes a safe operation and to patients who choose to avoid operation.
Extra-corporeal shock wave lithotripsy (ESWL)
ESWL was introduced in the mid-1980s. Various methods of producing shock waves (spark gap and piezo-electric) have been developed and efficacy depends upon the amount of energy delivered to the stone. The group in Munich and others have demonstrated stone clearance in up to 95% of symptomatic patients with solitary non-calcified gallstones less than 20 mm in diameter in a functioning gallbladder. Patients with 20-30 mm gallstones and those with up to three stones in a functioning gallbladder have stone clearance rates of about 60%. Effective ESWL requires adjuvant ursodeoxycholic acid therapy. Recurrence is infrequent following therapy with ESWL for a single small stone but is more common in patients with multiple stones. Complications of ESWL are minor and include transient elevations of liver enzymes, pancreatitis, and hematuria. Effective ESWL depends on fragmentation of stones into much smaller pieces that can be dissolved or readily passed into the gut. The incidence of transient biliary pain has been reported to be as high as 45% after successful stone fragmentation.
Topical (contact) gallstone dissolution
The most commonly used agents are methyl tert-butyl ether (MTBE), which is experimental and to a much lesser degree, monooctanoin, which is approved for the dissolution of bile duct stones. MTBE is usually introduced via a percutaneous transhepatic catheter into the gallbladder. Stones composed predominately of cholesterol can be cleared in hours to days. This technique is most often used in patients who are high surgical risks. Little information is available regarding recurrence rates. Monooctanoin has been used primarily for dissolution of bile duct stones retained following surgery. Catheters are placed within the bile duct, either transhepatically or through an endoscope and monooctanoin is perfused for a period of days via the indwelling catheter or an existing T-tube. The use of contact dissolution agents has limited application in patients with gallstone disease.
Some believe that the risk of a patient developing complications of asymptomatic cholelithiasis is high enough to justify the mortality associated with prophylactic cholecystectomy. Moreover, the operation effectively stops the progression of calcular biliary tract disease. If performed when the patient is young or healthy enough to tolerate the operation and before the occurrence of complications, which increase the mortality risk, the overall mortality and morbidity of calcular biliary tract disease could be significantly reduced. Advocates of this policy also claim that the operative mortality following simple cholecystectomy in patients under 40 is zero and that 50% of all patients with silent gallstones will be operated upon or develop symptoms within 10-20 years after the initial diagnosis. Another concern they have is that carcinoma of the gallbladder is very rarely diagnosed in time and in most cases is incurable at the time of operation. The number of deaths in the Federal Republic of Germany due to carcinoma of the gallbladder has been consistently high in the last decade. Risk factors for complications of cholecystectomy increase with the patient's age. They therefore recommend early cholecystectomy, however, nothing they note that the indication for cholecystectomy is an individual decision. This implies the presence of risk factors for those most likely to develop symptoms and complications.
There are different methods of surgically dealing with a gallbladder:
This operation has been employed for over 100 years and is a safe and effective method for treating symptomatic gallstones. At laparotomy, direct visualization and palpation of the gallbladder, bile duct, cystic duct, and blood vessels allow safe and accurate dissection and removal of the gallbladder.
Laparoscopic cholecystectomy owes much of its rapid growth to market forces generated, not inappropriately, by patient demand. Laparoscopic cholecystectomy is an operation that was first performed in France in 1987. Most patients with symptomatic gallstones are candidates for laparoscopic cholecystectomy, if they are able to tolerate general anesthesia and have no serious cardiopulmonary diseases or other co-morbid conditions that preclude operation. In fact, the indications for laparoscopic cholecystectomy, in general, are similar to those for open cholecystectomy. The availability and advantages of laparoscopic cholecystectomy should not, however, expand the indications for gallbladder removal. Patients have little pain after the operation and hospital stays (1-2 days) and convalescence (1-2 weeks) are usually shorter than after open cholecystectomy. Laparoscopic cholecystectomy decreases pain and disability without increasing mortality and morbidity and can be performed at an equal or lower cost than open cholecystectomy.
This modification of the open operation removes the gallbladder through a substantially smaller incision with the objective of reduced post-operative pain. Published data are limited to fewer than 200 patients highly selected for ease of surgical access.
Drainage of the gallbladder, combined with stone removal, may be achieved percutaneously or operatively under local anesthesia. Indications are limited to poor risk or debilitated patients with an obstructed gallbladder, in whom open operation or laparoscopic interventions are considered high risk. It may also be resorted to in difficult situations when the anatomy is unclear and the patient cannot tolerate a long procedure.
Risks and complications of surgery
Undoubtedly there is some risk in performing surgery on a patient with gallstones. This risk becomes a greater issue when the patient operated on did not require the surgery in the first place.
There is conflicting evidence regarding the relation between duodeno-gastric reflux (DGR), gallstones, and cholecystectomy. Chen et al. found that patients with cholelithiasis were accompanied with DGR or alkaline shift more often than the patients in the control group and cholecystectomy decreased the percentage of time that gastric pH was <2 and increased the time at four and six. They also found that although cholecystectomy itself does cause DGR, most patients with DGR may be asymptomatic. This result is also echoed by Nano et al. 
Cholecystectomy in general and laparoscopic cholecystectomy in particular are safe procedures in the treatment of patients with gallstones. When studying laparoscopic cholecystectomy for asymptomatic patients Fendrick et al. found that the prophylactic laparoscopic cholecystectomy strategy led to fewer gallstone-related deaths than the expectant management strategy, but all of the deaths in the prophylactic laparoscopic cholecystectomy group occurred earlier in life.
Cholecystectomy is a very safe procedure and is being performed with near zero mortality. The results of laparoscopic cholecystectomy compare favorably with those of open cholecystectomy with respect to mortality, complications, length of hospital stay, as well as cosmetically and financially. Laparoscopic cholecystectomy owes much of its rapid growth to market forces generated, not inappropriately, by patient demand.
Analyses of cost-effectiveness have not demonstrated substantial differences in life expectancy between patients with asymptomatic gallstones who undergo immediate open cholecystectomy compared with watchful waiting. Three conclusions were found by Teboul et al. when studying gallstones and their treatment based on cost/effectiveness ratios:
- Watchful waiting in asymptomatic gallstones is better than surgical treatment.
- In high-risk patients requiring treatment, surgery is preferable at the age of 50 years and medical treatment from 70 years onward.
- A comparison between surgery and lithotripsy including the cost/effectiveness ratio concluded in favor of surgery.
More than 20 million people in the US have gallstones and some 500,000 cholecystectomies are done annually. The cost to the American public is approximately 1.5 billion dollars per year. Others estimate the direct costs for the diagnosis and treatment of gallstones to be five billion U.S. dollar annually. Of significance is that 80% of people with gallstones are asymptomatic and 10-30% of symptomatic patients will present with atypical complaints. It is crucial that a detailed history of clients' symptoms be obtained to ensure an accurate diagnosis.
Studies of natural history suggest that the cumulative probability of developing biliary colic after 10 years ranges from 15 to 25%. Patients with asymptomatic stones in the gallbladder require neither surgical nor medical treatment. Consideration of monetary costs disfavors prophylactic cholecystectomy.
Aslar et al.  and Nenner et al.  both studied the impact of laparoscopy on the frequency of surgery for treatment of gallstones. They both found an increase in the frequency at which surgery was performed. In the latter, a study was undertaken in New York State of Medicare claims coded for cholecystectomy and those coded for laparoscopic cholecystectomy for the four-year period 1990-1993. During this period, there was a 28.12% increase in total cholecystectomies performed and an increase in the proportion of laparoscopic cholecystectomies from 15.86 to 50.0%. The increase in total cholecystectomies appears to be driven by a dramatic increase in laparoscopic procedures. They suggest that possible reasons for this increase include the performance of laparoscopy on patients previously assessed as too risky to undergo the conventional procedure, laparoscopy on mildly symptomatic patients who had previously put off a perceived higher risk open procedure and a possible broadening of indications for gallbladder surgery. They also suggest that the dramatic increase in the numbers of cholecystectomies performed in the early 1990s may be due in part to procedures performed on a large pool of procrastinating mildly symptomatic patients. They predicted that if this is the case, then these increased rates should decline to baseline levels as soon as this pool of patients is exhausted. However, if surgeons are performing laparoscopy on asymptomatic patients with gallstones, then these rates may well be sustained. They concluded that such an expansion of indications for gallbladder surgery is of concern to many and has prompted the issuance of guidelines concerning the treatment of gallstones. They also predict that any broadening of indications for gallbladder surgery also has significant implications for health care costs and the use of health care resources.
There are certain factors, which must be considered before generalizing the rule of expectant management in patients with asymptomatic gallstones:
Patients' access to health care facility
The health care facility may not be available to every patient at all times. This may be due to distance from the facility, if the patient lives in the suburbs or if the experienced surgeon is not available due to a long waiting list for the clinic or operating room. In this case the surgeon may be justified in operating on an asymptomatic patient.
Open or laparoscopic cholecystectomy
Although most surgical centers are equipped to perform an open cholecystectomy, not all, especially in developing countries, will have the required instruments or the trained staff to perform a laparoscopic procedure. This may be an important issue for the type of patient in question (young female). If the patient is concerned about cosmesis, is worried about pain and relatively long hospitalization and lives in an area remote of laparoscopic services (especially if the patient is a candidate for complications in case of acute inflammation) then probably prophylactic surgery at the asymptomatic or early symptomatic stage is justified.
Age of patient
Whereas mortality following cholecystolithiasis has been lowered, due to progress in medicine, the surgical risk rises with age and is low below age 60. The elderly tolerate biliary tract operations quite well, especially before acute complications of cholelithiasis occur, however, the older a patient is at the time of cholecystectomy, the more likely it is for that patient to present with an acute biliary complication. Tritapepe et al. found that the risk of developing complications is 3.2 times greater in patients aged more than 60 years than in those who are younger.
There is differing opinion on whether gallstones discovered during surgery for another condition should be removed or not. Studies on the natural history of silent gallstones suggest that a large majority of patients with such stones will remain asymptomatic. Incidental cholecystectomy should not be done in certain patients at high risk for complications of surgery, such as those with cirrhosis and portal hypertension. However, Gibney states that diabetics are at increased risk of complications of stones, as are patients whose stones are detected initially at laparotomy and claims that incidental cholecystectomy is usually safe, however, pre-operative detection by ultrasonic screening is an advantage in planning the operation. Because of the low morbidity and the relatively high number of cholecystectomies that were subsequently necessary, Saade et al. also recommend cholecystectomy en passant unless there is a specific contraindication. They also recommend ultrasonography before major gastrointestinal or vascular surgery in order to plan for cholecystectomy.
The results of Castaing et al. confirm the high incidence of cholelithiasis in cirrhotic patients. They claim that complications of gallstones are not frequent but require an emergency operation that carries a high risk in these patients. They also state that elective surgical treatment of asymptomatic cholelithiasis at the time of portal diversion does not bear any peculiar risk. In such a situation, however, cholecystolithotomy is easier and probably safer.
Prophylactic cholecystectomy is not indicated and asymptomatic gallstones in the bariatric patient may be safely managed identically to those in the non-obese population.
Insufficient data are present to determine whether prophylactic treatment is indicated in certain other groups with asymptomatic gallstones, such as patients with sickle cell disease and children (both of whom may present diagnostic dilemmas), pre-transplantation and/or immuno-suppressed patients who may have markedly increased morbidity and mortality from gallstone complications and those who are isolated from medical care for long intervals. Kao et al. concluded that prophylactic post-transplantation cholecystectomy is the preferred management strategy for cardiac transplant patients with incidental gallstones, resulting in decreased mortality and significant cost savings per quality-adjusted life-year. Expectant management is the preferred strategy for pancreas and/or kidney transplant recipients with asymptomatic cholelithiasis. Jackson et al. agrees with these findings for renal transplant patients, however Park et al. 's results suggest that the incidence of gallbladder stones is higher in renal transplant recipients than in the non-transplant population in Korea and that further studies will be needed to identify the factors contributing to gallbladder stone formation after renal transplantation, especially in regard to immunosuppressive drugs.
Pezzolla et al. studied the case in patients undergoing surgery for colorectal cancer and found that the risk entailed in carrying out an additional cholecystectomy for asymptomatic gallstones is greater than the risk of future morbidity caused by gallstones left in place.
There are special conditions where prophylactic cholecystectomy is justified. These either fall into a condition where complications may make the situation worse or where the chances of developing malignancy is high. Into the former group fall those patients with medical conditions who live in remote areas. In addition, stones in patients with hemolytic anemia should probably be removed because they occur early in these patients, they will continue to form as long as the hemolytic state is present and they may be confused with sickle cell crisis in patients with sickle cell disease. Al-Salem as well as Curro et al. conclude that with good perioperative management, splenectomy in children with sickle cell anemia is not only safe, but also beneficial in treating splenic abscess, reducing the patients' transfusion requirements, eliminating the risks of acute splenic sequestration crisis and eliminating the discomfort and mechanical pressure of the enlarged spleen. Abdominal ultrasound should be done routinely preoperatively for all children with sickle cell anemia undergoing splenectomy and if gallstones are discovered, they should undergo concomitant cholecystectomy. This is even so for asymptomatic gallstones. The addition of cholecystectomy to splenectomy does not increase the morbidity, but eliminates the subsequent complications of gallstones and simplifies their future management in case of abdominal crisis as the possibility of cholecystitis is eliminated.
Into the latter group falls the actual presence of gallbladder cancer, the inability to exclude it without removing the gallbladder as in gallbladder polyps (especially solitary gallbladder polyps greater than 1 cm in diameter), the high chance of developing it (about 25%) as in calcified (porcelain) gallbladder or areas where there is a strong association between stones and cancer due to genetic predisposition, individuals with anomalous pancreatic-biliary ductal junctions and individuals with gallstones greater than 3 cm in diameter. The risk of gallbladder cancer in all of these groups has been reported to be substantially higher than the 1 per 1,000 patients per year risk in other patients with gallstones.
A more difficult question is whether a surgeon should remove the gallbladder in an asymptomatic patient with gallstones simply because the patient wishes it to be removed. This will depend on many factors including surgeon's attitude, patient's attitude, and other conditions mentioned above which may justify the operation. Otherwise the patient should not dictate the management, even upon himself, since the surgeon alone will bear the consequences of the complications and a complication of a procedure, which was not indicated in the first place is more difficult to defend in court.
Gallstones do not disappear on their own and the only effective cure for gallstones today is cholecystectomy. The majority of patients with gallstones are asymptomatic and these asymptomatic patients usually develop symptoms before they develop complications and therefore, in most cases, require no intervention until they develop symptoms. Once gallstone symptoms appear, they tend to recur and laparoscopic cholecystectomy provides a safe and effective treatment for most patients with symptomatic gallstones. It also provides distinct advantages over open cholecystectomy. Oral bile acid therapy, with or without extracorporeal shock-wave lithotripsy, provides a useful and safe, but ultimately less effective, alternative therapy for selected patients. This modality may be indicated for patients whose medical condition and/or personal preference precludes operative cholecystectomy. On the other hand contact dissolution of gallstones by solvents currently has limited clinical applicability. Guidelines of the German Society of Gastroenterology for the treatment of gallstones also conclude that only patients with symptomatic gallstones require treatment, mostly in the form of laparoscopic cholecystectomy. Unlike gallstones, bile duct stones are treated during their symptomatic and asymptomatic stages.
With few exceptions, patients with asymptomatic gallstones require only watchful waiting. On the other hand, patients with typical biliary symptoms and gallstones should be treated. The best treatment to date is laparoscopic cholecystectomy. Our aim should be to develop a single, noninvasive treatment, with minimal side effects, which will both eliminate existing stones and prevent stone formation, and at the same time be superior to cholecystectomy. We can then assess the extent to which this treatment should be applied.
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