- Email: [email protected]
Current status of investigations into the etiology of gallstones
JULY 1971
The
American
Journal
of murgery VOLUME 122 NUMBER 1
EDITORIAL
Current Status of Investigations into the Etiology of Gallstones RONALD K. TOMPKINS,
Remarkable advances in biochemical discoveries and technics over the last decade make it rational to predict that the solution of the hroblem of gallstones in man, literally as well as figuratively, can be accomplished in the next few years. Surgeons have both a unique scientific opportunity and a moral obligation to work toward the realization of this goal. As an example, Maki has recently advanced a biochemical explanation of the formation of calcium bilirubinate stones, the most common type found in the rural Japanese population. He has shown that B-glucuronidase from bacteria frees bilirubin from its glucuronide and allows it to combine with calcium to form a precipitate in bile. Clinically, he has observed that virtually all patients with this type of gallstone have bile infected with the B-glucuronidase producing bacteria. There is now no doubt that the events which lead to formation of biliary tract stones are biochemical alterations in bile which lead to the insolubility of one or more of the normal biliary constituents such as cholesterol, calcium, or bile pigments. In this country and others of western culture, over 90 per cent of all gallstones are composed of cholesterol, either “pure” or combined with bile pigments. The most fruitful studies of cholesterol stone formation have been those directed toward discovering the factors which normally maintain this lipid in an aqueous bile solution. Isaksson, in 1954, demonstrated that bile
From the Department of Surgery. University of California School of Medicine, Los Angeles. California. This work was supported by a grant from the John H. Hartford Foundation, Inc. New York, New York.
Volume
122, July 1971
MD, Los Angeles, California
salts alone could not solubilize all the cholesterol in a given bile sample. He concluded that biliary phospholipids (chiefly phospatidyl choline or “lecithin”) were necessary to aid the bile salts in cholesterol solubility. Subsequent studies of model bile solutions have shown that the solubility of cholesterol is approximately eight times greater, mole per mole, in lecithin solutions than in solutions of bile salts. The clinical importance of high biliary lecithin concentrations has been emphasized by our finding that patients with cholelithiasis have only one third the level of gallbladder bile lecithin that is found in human subjects with normal biliary systems. Since the cholesterol concentrations in these two groups are similar, normal human subjects have a biliary phospholipid : cholesterol (P/C) ratio which is three times greater than that found in patients with cholesterol gallstones. The reason for this discrepancy is not yet known. Further in viva evidence of lecithin’s role in solubilizing cholesterol is the observation that cholesterol gallstones in man dissolve at an average rate of 17 mg per day in the dog’s gallbladder, where the bile has a P/C ratio twelve times greater than that in the normal human subject. Theoretically, it may seem an oversimplification to attempt to explain the formation of gallstones on changes in only one of the many biliary constituents. However, this hypothesis has led to practically productive research. Lecithin addition to diets low in fat and cholesterol has resulted in the elevation of P/C ratio of hepatic bile obtained from our patients with T tubes in place. This phospholipid-rich bile has shown the ability to hold more cholesterol in solution than bile from
1
Editorial the same patient, before lecithin feeding. Feeding studies in animals, using labeled lecithin, have demonstrated that a substantial portion of the phospholipid is transported intact via thoracic duct lymph chylomicra to the systemic circulation. Other laboratory studies indicate that labeled lecithin appears a few hours later in the common duct bile. The oral administration of lecithin to human subjects has been without complications and generally well tolerated. Future efforts should be directed to making the diet as rich in lecithin as possible while not palling to the appetite. Further metabolic studies may show that feeding precursors of biliary lecithin synthesis, rather than crude lecithin, will be more effective in elevating the P/C ratio. The importance of discovering a nontoxic, easily tolerated method of increasing the cholesterol-dissolving capacity of human bile, such as that of feeding lecithin, is evident. It may be some time before elective surgical removal of gallstones, with its low morbidity and mortality, is replaced by chemical or dietary therapy. However, there is an immediate need for a meaningful alternative to surgical treatment for a large number of patients with gallstones. These are the unfortunate per-
sons who are considered not to be suitable candidates for operation because of coexistent heart disease, obesity, personal preference, or other medical reasons. Although it is difficult to estimate the number of persons in this group, it must be sizable. It is also possible that such dietary modifications would have preventive value in those persons in whom the development of cholelithiasis is more likely. Patients undergoing vagotomy and gastric drainage procedures, diabetic males, and women with multiple pregnancies as well as those taking oral contraceptives have been indicated to be at risk in this regard. Nobel-laureate Dr Frances Peyton Rous once characterized gallstone research as “top-heavy with hypotheses and dismal with uncorrelated observations.” Surgeons trained in the basic sciences of physiology and physiologic chemistry, by virtue of their direct access to the human biliary tract and its secretions, are now in a unique position to correlate these observations with well planned and executed clinical experiments. To these investigators, th’e challenge of reducing the necessity for surgical removal of gallstones should be irresistible.
The American
Journal
of Surgery
The
American
Journal
of murgery VOLUME 122 NUMBER 1
EDITORIAL
Current Status of Investigations into the Etiology of Gallstones RONALD K. TOMPKINS,
Remarkable advances in biochemical discoveries and technics over the last decade make it rational to predict that the solution of the hroblem of gallstones in man, literally as well as figuratively, can be accomplished in the next few years. Surgeons have both a unique scientific opportunity and a moral obligation to work toward the realization of this goal. As an example, Maki has recently advanced a biochemical explanation of the formation of calcium bilirubinate stones, the most common type found in the rural Japanese population. He has shown that B-glucuronidase from bacteria frees bilirubin from its glucuronide and allows it to combine with calcium to form a precipitate in bile. Clinically, he has observed that virtually all patients with this type of gallstone have bile infected with the B-glucuronidase producing bacteria. There is now no doubt that the events which lead to formation of biliary tract stones are biochemical alterations in bile which lead to the insolubility of one or more of the normal biliary constituents such as cholesterol, calcium, or bile pigments. In this country and others of western culture, over 90 per cent of all gallstones are composed of cholesterol, either “pure” or combined with bile pigments. The most fruitful studies of cholesterol stone formation have been those directed toward discovering the factors which normally maintain this lipid in an aqueous bile solution. Isaksson, in 1954, demonstrated that bile
From the Department of Surgery. University of California School of Medicine, Los Angeles. California. This work was supported by a grant from the John H. Hartford Foundation, Inc. New York, New York.
Volume
122, July 1971
MD, Los Angeles, California
salts alone could not solubilize all the cholesterol in a given bile sample. He concluded that biliary phospholipids (chiefly phospatidyl choline or “lecithin”) were necessary to aid the bile salts in cholesterol solubility. Subsequent studies of model bile solutions have shown that the solubility of cholesterol is approximately eight times greater, mole per mole, in lecithin solutions than in solutions of bile salts. The clinical importance of high biliary lecithin concentrations has been emphasized by our finding that patients with cholelithiasis have only one third the level of gallbladder bile lecithin that is found in human subjects with normal biliary systems. Since the cholesterol concentrations in these two groups are similar, normal human subjects have a biliary phospholipid : cholesterol (P/C) ratio which is three times greater than that found in patients with cholesterol gallstones. The reason for this discrepancy is not yet known. Further in viva evidence of lecithin’s role in solubilizing cholesterol is the observation that cholesterol gallstones in man dissolve at an average rate of 17 mg per day in the dog’s gallbladder, where the bile has a P/C ratio twelve times greater than that in the normal human subject. Theoretically, it may seem an oversimplification to attempt to explain the formation of gallstones on changes in only one of the many biliary constituents. However, this hypothesis has led to practically productive research. Lecithin addition to diets low in fat and cholesterol has resulted in the elevation of P/C ratio of hepatic bile obtained from our patients with T tubes in place. This phospholipid-rich bile has shown the ability to hold more cholesterol in solution than bile from
1
Editorial the same patient, before lecithin feeding. Feeding studies in animals, using labeled lecithin, have demonstrated that a substantial portion of the phospholipid is transported intact via thoracic duct lymph chylomicra to the systemic circulation. Other laboratory studies indicate that labeled lecithin appears a few hours later in the common duct bile. The oral administration of lecithin to human subjects has been without complications and generally well tolerated. Future efforts should be directed to making the diet as rich in lecithin as possible while not palling to the appetite. Further metabolic studies may show that feeding precursors of biliary lecithin synthesis, rather than crude lecithin, will be more effective in elevating the P/C ratio. The importance of discovering a nontoxic, easily tolerated method of increasing the cholesterol-dissolving capacity of human bile, such as that of feeding lecithin, is evident. It may be some time before elective surgical removal of gallstones, with its low morbidity and mortality, is replaced by chemical or dietary therapy. However, there is an immediate need for a meaningful alternative to surgical treatment for a large number of patients with gallstones. These are the unfortunate per-
sons who are considered not to be suitable candidates for operation because of coexistent heart disease, obesity, personal preference, or other medical reasons. Although it is difficult to estimate the number of persons in this group, it must be sizable. It is also possible that such dietary modifications would have preventive value in those persons in whom the development of cholelithiasis is more likely. Patients undergoing vagotomy and gastric drainage procedures, diabetic males, and women with multiple pregnancies as well as those taking oral contraceptives have been indicated to be at risk in this regard. Nobel-laureate Dr Frances Peyton Rous once characterized gallstone research as “top-heavy with hypotheses and dismal with uncorrelated observations.” Surgeons trained in the basic sciences of physiology and physiologic chemistry, by virtue of their direct access to the human biliary tract and its secretions, are now in a unique position to correlate these observations with well planned and executed clinical experiments. To these investigators, th’e challenge of reducing the necessity for surgical removal of gallstones should be irresistible.
The American
Journal
of Surgery