Therapeutic options for gallstones.

Patients with asymptomatic gallstones should not be considered surgical candidates; patients with defined symptoms of biliary tract disease, however, should be advised not to postpone surgery or endoscopic sphincterotomy with stone retrieval. A smaller group of patients who fulfill specific criteria may benefit from chenodiol (Chenix) therapy and long-term follow-up. Such experimental techniques as dissolution with methyl tert-butyl ether and fragmentation with extracorporeal shock waves hold exciting promise for the future.

The present status of agents for dissolving gallstones.

Chenodiol therapy appears especially appropriate only for the small group of patients who have floating radiolucent gallstones, are over 60 years of age, and have increased surgical risk factors. Such patients may benefit from a trial of Chenodiol therapy at a dose of 15 mg/kg of body weight and experience both fewer symptoms and reduced need for medically indicated cholecystectomy. Other patients should be evaluated on an individual basis, with consideration given to simple observation for silent gallstones, and to direct intervention if bile duct obstruction occurs. When therapy is chosen, periodic laboratory assessment is indicated and treatment should be continued 3 months beyond apparent dissolution or for 16 months if there is no change in gallstone size. Periodic assessment at annual intervals after dissolution is also indicated because of frequent gallstone recurrence. Where both Chenodiol and UDCA are available, physicians have generally preferred UDCA because of its absence of bile acid diarrhea and liver enzyme changes, even though clinical efficacy is the same.

Management of gallstones. The new option of bile acid therapy.

Recent approval of chenodiol by the Food and Drug Administration has given physicians a new choice of therapy for silent gallstones, but it also presents a dilemma. The longest double-blind study of the drug in one patient population covered only two years and two dosages; no equally controlled data are available documenting drug safety beyond that period or at higher dosages. Recurrence of gallstones after discontinuation of dissolution therapy is common, and thus chronic treatment may be needed. Only the future can tell what place bile acid therapy will assume in the management of gallstone disease.

Risk factors for cholecystectomy: analysis of 935 patients.

We evaluated 935 patients for risk factors of cholecystectomy. Factors assessed included reason for cholecystectomy, preoperative laboratory values, sex, age, weight, presence of associated disease, and pathologic findings. Evaluation revealed an overall significant complication rate of 10.50% and a mortality of 1.07%. Risk factors were age over 60 years, hypertension, atherosclerotic cardiovascular disease with prior heart failure, and acute cholecystitis. Incidental cholecystectomy was associated with an increased risk due to concomitant associated disease. Patients with obesity and uncomplicated diabetes had the same risk as the general population.

Drug and treatment efficacy of chenodeoxycholic acid in 97 patients with cholelithiasis and increased surgical risk.

Patients with symptomatic cholelithiasis who represent higher than normal surgical risks may be the most suitable candidates for medical dissolution of gallstones. Chenodeoxycholic acid was given to 97 patients in a dosage of 15 mg/kg of body weight per day for a period of two years. Complete gallstone dissolution occurred in 27 of 97 patients (28%). If dropouts are excluded then the success rate is 27 of 64 patients (42%). Diarrhea was a common but manageable side effect for most. Thirty-two percent of patients developed chemical liver test abnormality; however, in only 13% was the degree of abnormality sufficient to require temporary (3%) or permanent (10%) cessation of therapy. Although better chemotherapeutic agents are needed, chenodeoxycholic acid is a reasonable choice for patients with non-calcified cholelithiasis in a functioning gallbladder if the patient is a heightened surgical risk. Because of the prolonged treatment period and the possibility of hepatotoxicity this treatment program requires a substantial commitment on the part of both the patient and the physician.

Medical therapy for gallstones. 2. Initiation and monitoring.

After review of the history and baseline laboratory studies, gallstone dissolution therapy with chenodeoxycholic acid is begun at a dosage of 500 mg/day and gradually increased to an optimum dosage of 15 mg/kg/day. Periodic assessment is necessary to monitor progress of stone dissolution and to detect hepatocellular injury or bile duct obstruction. The risks of complications of biliary tract disease do not abate until the stones are dissolved. Unless there is unequivocal evidence of progressive dissolution within 16 months, treatment should be discontinued.

Prevalence of gallstones in obese Caucasian American women.

Although the association between gallstones and obesity is well known, no attempt has been made to quantitate the increased risk for gallstone formation associated with moderate obesity commonly seen in clinical practice. To determine the prevalence of both asymptomatic and symptomatic gallstones, screening oral cholecystograms were combined with prior documented history in 249 consecutive obese Caucasian women aged 20-59 yr who were seeking treatment for obesity in an out-patient clinic. To ascertain the relative risk of moderate obesity for gallstone formation, the results were compared with a control group of 60 consecutive women who were undergoing screening health examinations in the same clinic. Both groups were without gastrointestinal symptoms. Gallstone prevalence averaged 31 percent among obese women compared to 10 percent in the control group. Sixty percent of gallstones in the combined 20-29 yr age group were asymptomatic. However, among all patients with gallstone disease 59 percent had symptomatic disease evidence by prior cholecystectomy. Moderate obesity imposes at least a three-fold risk of gallstone disease in Caucasian women.

Dissolution of gallstones--when and how?

Availability of bile acid therapy for gallstone dissolution adds another therapeutic choice for treatment of gallstone disease. Because dissolution is slow and eventual outcome uncertain, surgery remains the treatment of choice for most patients who have experienced symptoms clearly related to their gallstones. Patients with only dyspeptic or no gastrointestinal symptoms, especially if significant associated cardiac or pulmonary disease exists, may be candidates for bile acid therapy with chenodeoxycholic acid or its 7-beta epimer, ursodeoxycholic acid, when available. Fifty to 75 per cent of patients, depending on individual criteria, may anticipate complete dissolution. Radiolucent gallstones and gallbladder opacification are basic requirements for cholelitholytic therapy. Periodic assessment of laboratory parameters is necessary at routine visits and when unexpected symptoms occur. In a few patients, evidence of obstructive gallstone disease will develop during bile acid therapy and surgery will be required. The value of bild acid therapy for the relief of dyspeptic symptoms, the role of bile analysis, and optimal long-term therapy remain to be established.

Manifestations of gallstone disease.

In some patients, gallstones are asymptomatic, lying dormant in the gallbladder or wedged in the cystic duct. In others, stones cause specific symptoms of gallbladder disease, such as biliary colic, acute cholecystitis, or cholangitis. Symptoms of flatulent dyspepsia are not markers of gallstone disease, since they occur equally in those with and without gallstones. Complications of gallstone disease include pancreatitis, biliary-enteric fistulas, hydrops, limy bile, porcelain gallsbladder, and carcinoma of the gallbladder. Cholecystectomy is indicated for symptomatic gallstones; for suspected stones in diabetics, who are at high risk should complications of gallstone disease occur; and in a few other limited situations. Prophylactic cholecystectomy for asymptomatic gallstones remains controversial.

Who gets gallstones and why.

Gallstone formation is a heterogeneous disease for which supersaturation of bile with cholesterol and hemolysis of RBCs are major driving forces associated with initial formation and growth. Specific risk factors are superimposed on the gradually increasing prevalence of gallstones with age in most populations. Major risk factors associated with cholesterol gallstone formation are American Indian ancestry, female sex, obesity, and ingestion of lithogenic drugs, such as estrogen-containing preparations and clofibrate. Hemolysis and cirrhosis are risk factors for pigment stones.

Biliary lipid secretion in hypercholesterolemia.

A report on the effects of primary bile acid ingestion alone or in combination with plant sterols on serum cholesterol levels, biliary lipid secretion, and bile acid metabolism. Biliary bile acid and cholesterol secretion were measured in four patients with type IIa hypercholesterolemia before and after randomized treatment periods. During these periods either a bile acid mixture (cholic-chenodeoxycholic 2:1, a proportion similar to that endogenously synthesized in health), at a level of 20 mg/kg, or the same mixture plus sitosterols, 200 mg/kg, was fed. Serum cholesterol and the cholesterol saturation of fasting-state bile was also measured. Pretreatment biliary lipid secretion was within normal limits. Bile acid kinetic measurements were also recorded before treatment and showed that cholic acid synthesis was disproportionately decreased relative to that of chenodeoxycholic acid, a finding previously reported by others. Administration of the bile acid mixture increased biliary bile acid secretion in 3 of 4 patients, but did not influence biliary cholesterol secretion. The combination of sitosterol-bile acid, however, caused a relative decrease in cholesterol secretion in bile, and fasting-state bile became unsaturated in all patients. No change in fecal neutral sterol excretion occurred during the beta-sitosterol-bile acid regimen, suggesting that simultaneous bile acid feeding blocks the compensatory increase in cholesterol synthesis known to be induced by beta-sitosterol feeding in hypercholesterolemic patients. Serum cholesterol levels also fell modestly during the sitosterol-bile acid regimen, the decrease averaging 15%. We conclude that the abnormally low rate of bile acid synthesis in patients with type IIa hyperlipoproteinemia does not influence biliary lipid secretion; that increasing the input of the two primary bile acids into the enterohepatic circulation does not increase biliary cholesterol secretion or lower serum cholesterol levels in such patients; and that the usual increase in cholesterol synthesis induced by beta-sitosterol feeding does not occur if bile acids are administered simultaneously.

Biliary secretion of copper in healthy man. Quantitation by an intestinal perfusion technique.

A duodenal perfusion technique which permitted a normal daytime eating pattern of three liquid meals and an overnight fast was used to measure the 24-hr output of copper in bile in 19 studies in 14 persons with normal hepatic and gallbladder function. Daily biliary output was also determined by direct measurement on four 24-hr bile collections obtained from 3 patients with complete biliary diversion, and in 4 patients measurements of dietary copper intake and fecal copper output were also made. A mean bile copper output of 25 +/- 13 microng per kg-day (1.7 mg +/- 0.8) (mean +/- SD) was obtained in 19 perfusion studies; the range was 9.0 to 53.0 microng per kg-day. The values in the 24-hr bile collections were similiar to those obtained using the perfusion method. Biliary copper output was similar during the day and night, and there was no correlation between hourly rates of copper output and hourly rates of bile acid output, nor was there any correlation between daily copper output and daily bile acid output. The similar values for dietary intake, biliary output, and fecal output provide additional support for the current view that in healthy man copper balance is maintained by biliary secretion and subsequent fecal excretion of copper which has been absorbed in the stomach and proximal duodenum.

Alcohol and liver disease.

It has recently been shown that alcohol may produce liver damage even in the presence of adequate nutrition. Absolute intake, regardless of the type of alcoholic beverage consumed, appears to be the important determinant of whether liver damage will occur. The spectrum of liver injury produced by alcohol includes fatty liver, hepatitis, and cirrhosis. Liver biopsy is necessary for confirmation and to determine prognosis. Therapy includes abstinence, supportive care and nutritional replacement.