7 : 5b

Increasing prevalence of Gallstones; Diagnostic and therapeutic Options

Cholesterol stones have been noted in Egyptian mummies and the disease thus might have existed for more than 35 centuries. The advent of laparoscopic cholecystectomy in 1989 caused a rapid increase in gallbladder surgeries world over. In the US 700,000 cholecystectomies are performed per year. A real increase in the incidence of cholelithiasis, increased frequency of symptomatic gallstones, very sensitive diagnostic studies and a lowered threshold for surgery are factors that influence the dramatic increase in the number of cholecystectomies world over. I. Epidemiology of gallstone disease in the world Worldwide gallstone disease is increasing (1, 2). In the last 50 years the prevalence of gallstone disease in Japan has doubled and there has been a change from pigment to cholesterol gallstones. Similar increases are noted elsewhere also. The highest prevalence of gallstone disease is noted in Native American Indians (Pima) in Arizona. An alarming frequency of 73% of Pima women having gallstones around the age of 30 was noted. Similarly a high incidence is noted in other Native American tribes of USA, Mexico and South America. Thus in Chile nearly 50% of women and 12.6% of men have gallstones. Abdominal ultrasound revealed a high prevalence in Norway (21.9%) and former East Germany (19.7%). Gallstone disease in the US is similar to that in Europe ranging from 5.9% to 21.9%. An excellent article by Shaeffer in 2006 (2) nicely summarizes the prevalence of gallbladder disease in Europe and in the US. Most of these data are pertaining to cholesterol stones, the predominant type of gallstone disease in the West. Brown pigment stones consist of calcium bilirubinate, calcium soaps, mucin (predominantly from the biofilm of bacteria) and cholesterol. They develop in bile ducts usually in association with infection and parasitic infestation (Clonorchis sinensis, Opistochus vivarii or Ascaris). Brown pigment stones are reported from East Asia. The frequency of hepatolithiasis varies from a high of 20% in China and Taiwan to 2-3% in Japan, Singapore and Hong Kong (3-5).The discussion here is mostly on cholesterol gallstones, the most prevalent one.

CS Pitchumoni, USA
in the West. In many standard textbooks of Medicine and Gastroenterology published from the West, India is included along with countries with a low incidence of gallstones. The prevalence of gallstone disease varies in different parts of India. Malhotra as early as in 1966 conducted an epidemiological study in Indian Railway employees and showed that North Indians had seven times higher prevalence of gallstones compared to South Indian employees. In northern states including Kashmir where good epidemiological studies have been performed, a very high and increasing prevalence were reported (7-11). Khuroo from Kashmir reported a prevalence of 6.12% (men 3.07% and women 9.6%) the prevalence increasing progressively to reach a peak in the sixth decade (10). The prevalence rate is significantly higher in multiparous women (10). There was no correlation with diet, obesity or socioeconomic status (8). The identification of large number of cases of cancer of the gallbladder is in agreement with the high prevalence of gallstones observed (11). The pathogenesis of gallbladder cancer albeit only in a small number of patients with gallstone disease is not well understood. A high concentration of glucourso deoxycholate and the duration of cholelithiasis are postulated. A recent prospective study has shown however that the development of gallbladder cancer in patients with gallstones followed over decades remains a rare event (12). Migrants from India to the UK, Australia, Fuji, Kuwait and Singapore have a higher incidence of mortality from gallbladder cancer as compared to native populations of the areas (13). It is interesting to note the association of gallstones, chronic typhoid carrier state and gallbladder carcinoma (14). Sharma and associates from Banaras Hindu University studied the association in 390 patients. There was an about 84 times higher risk of developing gallbladder carcinoma in patients who were bile culture positive for typhoid bacilli (15). The role of prophylactic cholecystectomy in patients (with gallstones) from high risk areas for gallbladder cancer is not clear, but should be individualized (13). Factors like age, geography, race, size of stone help to identify suitable cases for prophylactic cholecystectomy. Many other studies from

II. The epidemiology of gallstone disease (and gallbladder carcinoma) in India: Although well documented by authors in India, the data has not received much attention

Increasing Prevalence of Gallstones; Diagnostic and Therapeutic Options

Table 1 : Pigment Stones: Risk factors
Hemolytic disease: E.g.: Sickle cell disease Demographic Factors-Far East Alcoholic Cirrhosis Pernicious Anemia Cystic Fibrosis Elderly Population Ileal Disease: E.g.: Cohns Disease

insulin (ml/ml) fasting glucose (mmol/l) 22.5. IV. Pathogenesis of gallstone formation: There are three major types: cholesterol, black pigment and brown pigment stones based on their composition and pathogenesis. Cholesterol gallstones form as a result of changes in the composition of bile. Gallstones are formed by an increase in the composition of a normal biliary component bilirubin or cholesterol that overwhelms the solubility, a decrease in the solubilizing component or both. An associated dysmotility of the gallbladder is an added pathogenetic factor.The net result is an insoluble substance called a nidus that becomes supersaturated and insoluble particles become sequestrated and aggregate to form a calculus. The causes of pigment stones are tabulated but not discussed further (Table 1). Cholesterol stones are the most prevalent and contribute to more than 80% of the stones in most of the countries. These stones are rich in cholesterol containing cholesterol monohydrate crystals agglutinated by a mucin glycoprotein matrix, unconjugated bilirubin and small amounts of calcium phosphate are other components. The pathogenesis of cholesterol gallstones is well studied; major components of bile are bile acids (salts), phospholipids and cholesterol. Bile salts synthesized from cholesterol are the two primary bile acids cholic and chenodeoxy cholic acid. Cholesterol is only slightly soluble in aqueous media but that is made soluble through formation of mixed micelles with bile salts and phospholipids, mainly lecithin. Bile salts are secreted into the duodenum with bile and reabsorbed through the ileum. Enterohepatic circulation of bile acids along with adequate daily production of bile acids in the liver from cholesterol is sufficient to keep the cholesterol in solution. There are at least four separate mechanisms in the genesis of cholesterol gallstones. The risk factors for cholesterol gallstones are tabulated (Table 2). 1. Supersaturation of bile with cholesterol. 2. Nucleation of cholesterol monohydrate with subsequest crystallization and stone growth. 3. Gallbladder stasis delayed emptying. 4. Decreased enterohepatic circulation increased loss of bile acids (eg: ileal resection / Crohns disease).

Chandigarh and New Delhi confirm the high number of gallstone disease in North India (6-17). A different picture arises from data available from south India. Jayanthi et al (18) reported that mixed and pigment stones were more common than cholesterol stones in Tamilnadu. They found no correlation with demographic features or social customs. An interesting observation that needs confirmation is an association with high consumption of tamarind. There is no scientific explanation for this observation. The overall prevalence of gallstones in Tamilnadu appears to be lower than in the North. However cholecystectomy once an extremely uncommon surgery in south India has become very frequent reflecting either a real increase in the prevalence of the disease, better diagnosis because of ease of detecting stones by abdominal ultrasound or the availability of LAP cholecystectomy. Since the prevalence of diabetes, obesity and metabolic syndrome independently and collectively are increasing; their relationship with gallstone disease needs a review. Cholelithiasis especially in women with Type 2 Diabetes is frequent. A number of autopsy studies showed an increased prevalence of gallstones in diabetics, while others have shown no association. One noteworthy clinical study where gallstone disease was diagnosed by abdominal ultrasound or history of cholecystectomy in 308 diabetics and 318 controls showed a higher incidence in diabetics (32.7%) compared to controls (20.8%) (19). This correlation is often mentioned in the literature. In Diabetics the total body cholesterol is increased independently of obesity, which leads to more lithogenic bile. Secondly, they may have diminished gall bladder motility. However diabetes alone does not significantly increase the risk for gallstones. With growing incidence of diabetes in India, gallstone disease in type 2 diabetics offers a fertile area for critical studies. Metabolic syndrome wherein diabetes is only a component is increasing in prevalence all over the world including India. In one elegant study participants with waist to hip ratio of >0.85, (abdominal obesity), hypertriglyceridemia, hypertension and diabetes were studied for gallstone disease (20). Among 245 subjects metabolic syndrome was present in 46% of gallstone patients vs 17.2% in the controls. Homeostasis model assessment (HOMA index) was significantly associated with gallstone disease. (HOMA index=fasting

III. Diabetes / metabolic syndrome and gallstones

Gallbladder sludge is the reversible but probably the early stage of gallstone formation. Sludge formation comprises of suspension of cholesterol monohydrate crystals, calcium bilirubinate, calcium phosphate and calcium carbonate. Sludge may disappear or go on to develop into gallstones. The body pool of cholesterol is derived from both dietary sources and denovo synthesis in the liver. Supersaturated bile alone does not lead to gallstones. Although crystals develop in supersaturated bile the need for a pronucleating agent, in this case mucin secreted by the gallbladder epithelium is an important factor. Calcium and other pronu-

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Table 2 : Risk Factors for Cholesterol Stones

Factor Comment Age Uncommon <20(exception: Mexican American girls) Gender Female/male ratio highest in the youngest; narrows to2:1 after age50 Nationality Highest: Scandinavia, Northern Europe, Chile, Northern parts of India Race/Ethnicity Highest: Pima Indians of southern Africa (70%, Pima women older than 25) Other Native American tribes, Alaskans Lowest: American blacks Family History Higher risk in first-degree relatives of gallstone patients Obesity Relative risk rises sharply as the degree of obesity increases; more in women Waist-to hip girth is an important association (Metabolic Syndrome) High body mass index is a risk factor Rapid Weight Loss Bile is lithogenic because of reduced bile acid secretion Parity Moderately elevated risk with increased parity Diabetes Mellitus Good association in Mexican Americans Unclear association in others Ileal/Colon Disease Bile is lithogenic when ileal reabsorption is decreased TPN Usually sludge/pigment stones caused by bile stasis, gallbladder distension Medications Estrogen therapy, oral contraceptive use, octreotide therapy. Diet Association with high consumption of simple sugars Low prevalence in vegetarians Spinal Cord Injury Abnormal gallbladder motility may be a factor Miscellaneous Celiac disease, vagotomy,duodenal diverticula are rare associations No significant relationship with hyperlipoproteinemia

Table 3 : Prophylactic Cholecystectomy Considered for Patients with Silent Gallstones

High risk for gallbladder cancer Native American women with gallstones Gallstones larger than 3 cm in diameter Porcelain gallbladder (calcification in the wall) Gallbladder polyps larger than 12 mm Carriers of Salmonella typhosa Lifestyle Working for prolonged periods in remote parts of the world with poor medical facilities Note: Diabetes mellitus is not an indication for prophylactic cholecystectomy

1. Asymptomatic Gallstones: Most do not develop symptoms even after follow up periods as long as 20 years. Approximately 20% of patients develop symptoms by 15 years. Asymptomatic gallstone disease (in many Western countries) does not need surgery although there are exceptions. Exceptions to the rule are tabulated (Table 3). The role of prophylactic cholecystectomy in young patients from various parts of India is emphasized in many recent papers, but criticized in one (13). 2. Symptomatic Gallstone Disease: a. Biliary colic: Frequently characterized as post prandial pain in the right upper abdomen. Contrary to popular belief may not necessarily occur only after fatty foods. b. Acute Cholecystitis. Often patients will have history of biliary pain in acute cholecystitis; pain lasts for > 3 hours, associated with fever and right upper quadrant tenderness (Murphys sign). c. Chronic Chlolecystitis: Patients will have episodic epigastric, right upper quadrant pain lasting for more than 30 minutes. Patients, may present with complications of gallstones-pancreatitis, choledocholithiasis and cholangitis.

leating factors are noted to play important roles in crystal formation. In addition gallbladder stasis promotes gallstone formation. Gallbladder not only stores bile, it also acidifies, concentrates the bile by absorbing water increasing the concentration of cholesterol, calcium and bilirubin.The two major factors that contribute to crystal formation are the retention of bile in the gallbladder as a result of dysmotility and the alteration of nucleation kinetics. V. Clinical Manifestations of Gallstones: We recognize four types of gallbladder disease: 1. Asymptomatic gallstone disease 2. Symptomatic gallstone disease 3. Pain abdomen from another etiology such as peptic ulcer, with asymptomatic gallstones 4. Cholecystitis with no gallstones The decision to do surgery is based on a careful understanding of the above.

d. Choledocholithiasis: Maybe asymptomatic or present with biliary colic, acute cholangitis or pancreatitis. e. Acute Cholangitis: is a medical emergency. Patients may present with Charcots triad- right upper quadrant pain, fever and jaundice. With advances in clinical chemistry, imaging studies the diagnosis can be made before the classic triad develops.

The diagnostic tests in the evaluation of Gallstone disease, treatment options for symptomatic gallstones, rare complications of gallstone disease are tabulated. (Table 4) We have chosen two special groups of patients for discussion on treatment- the elderly and the pregnant woman.

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Table 4 : Diagnostic Tests in the Evaluation
1. 2. 3. 4. 5. 6. Abdominal Ultrasonography: Single most useful test to evaluate gallstones, CBD size and stones Endoscopic Ultrasound (EUS): Excellent to evaluate CBD stone, size. Expensive. Not easily available. ERCP: As solely a diagnostic test it has lost its value. Can be used to do sphincterotomy, therapeutically HIDA, DIDA, Radioisotope Scans: Accurate identification of cystic duct obstruction. Diagnosis of acute cholecystitis. CT Scan Abdomen: Not ideal. Radiation. Not useful in pregnancy MRI/MRCP: MRCP does not require contrast. It can be safely used in 2nd/3rd trimester of pregnancy. Reduces the number of invasive ERCPs. 1. 2. 3. 4. 5. 6. 7. 8. 9.

Table 6 : Complications of Gallstone Disease:

Pancreatitis Cholecystoenteric fistula, gallbladder perforation Gallstone ileus Mirizzi Syndrome Emphysematous cholecystitis Gangrene Bouverets syndrome (gastro-duodenal obstruction) Choledocholithiasis, cholangitis (Porcelain gallbladder-intra mucosal calcification of gallbladder wall can occur with or without gallstones)

Table 5 :Treatment Options for Symptomatic Gallstones:

Option 1. Laparoscopic Cholecystectomy 2. ERCP/ Sphincterotomy 3. ESWL Oral bile acid dissolution Stone Clearance Comment 100% Standard of care. Invasive .General Anesthesia 70-80% In selected cases. Advanced age and pregnancy 70% Rarely helpful in very selected cases. Is used in sludge prevention in high risk patients, not ideal in dissolving stones in symptomatic patients

4.

VI. Treatment options for gallstones and complications (see Table 5). Gallstone Disease in Special Situations: 1. Elderly Population: The growing number of elderly (> 65 years) warrants a careful estimation of gallstone disease in the older adult. Laparoscopic cholecystectomy and Endoscopic sphincterotomy with stone extraction from common bile duct have reduced surgical morbidity and have offered therapeutic options even in the very elderly. As age advances there is increased lithogenicity of bile, deconjugation of bile pigments, increased bacteria and altered gallbladder motility. These changes probably contribute to a higher prevalence of gallstones in the older adult. In patients over 75 years the upper limit of common bile duct size may be upto 10 mm with the gallbladder in situ and 14 mm post cholecystectomy. Older adult patients have increased incidence of complications as a result of cholelithiasis. Clinicians should have an increased awareness of atypical biliary symptoms in the older adult to avoid a delay in treatment. Altered mental status may be the only manifestation of biliary sepsis. Laparoscopic cholecystectomy remains the standard therapy regardless of age. Acute acalculous cholecystitis or necrotizing cholecystitis is an acute inflammation of the gallbladder in the absence of stones.

2. In Pregnant Women: An important clinical problem as a consequence of gallstone disease is acute pancreatitis. In this discussion we have chosen to elaborate on this problem in pregnancy. Acute pancreatitis in pregnancy is almost always secondary to gallstone disease. The prevalence of gallstone disease in pregnancy varies with ethnicity. Although pregnancy itself is a high risk factor, the risk increases with parity. Weight gain and hormonal changes predispose pregnant women to biliary sludge and gallstones. Cholesterol in bile increases in the second and third trimester compared to bile acids and phospholipids leading to supersaturated bile. Up to 10% of pregnant women develop stones or sludge over the course of each pregnancy. Gallstone disease and acute pancreatitis in pregnancy pose multiple problems. Any medical / surgical disease poses a threat to the fetus as well as the mother. Abdominal ultrasound with no radiation is the initial imaging technique of choice to identify gallstones as well as to estimate CBD size and a CBD stone. EUS a semi invasive procedure is expensive, not available easily, but is an excellent mode of evaluation. MRCP is not associated with radiation, but is expensive and is not suitable for claustrophobic patients.The safety of MRCP in the first trimester is debated. However, MRCP helps to avoid unnecessary ERCP procedures. ERCP and Endoscopic Sphincterotomy can be reserved for patients found to have a strong evidence for CBD stones/cholangitis. CT scan is not recommended in patients because of radiation exposure. The best time to do Laparoscopic cholecystectomy is in the second trimester when the fetal mortality is low and the enlarged uterus will not be posing a hindrance to abdominal surgery. Natural orifice transgastric endoscopic surgery pioneered by Dr.Nageswara Reddy might change the therapeutic options available in the management of gallstone disease. (21-22) The dietary changes, lack of exercise, increasing obesity, increase in the prevalence of diabetes, attempts to lose weight rapidly after gaining weight are the future trends in many parts of the world- all of these factors enhance the prevalence of gallstone disease. Preventive measures should take note of the above trends in the

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epidemiology.

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