57 Gallstones (Cholelithiasis)

Classification

Gallstones are quite common in modem populations, occurring in nearly 20 percent of autopsies. Though often asymptomatic, they can produce significant morbidity, leading to cholecystitis, cholangitis, bi­liary cirrhosis, and pancreatitis.

The chief constituents of gallstones are choles­terol, bilirubin, and calcium. Other components may include fatty acids, triglycerides, protein, and poly­saccharides. Descriptively, there are four major types of gallstones: (1) pure cholesterol stones; (2) mixed stones composed of cholesterol, bilirubin, and calcium; (3) combined stones having a cholesterol center and laminated exterior of cholesterol, bili­rubin, and calcium; and (4) black or brown pig­mented stones composed of calcium bilirubinate.

The first three types comprise the vast majority of gallstones and may be grouped together as choles­terol-based stones, Pathogenetically related to abnor­mal cholesterol and bile salt metabolism. Black pig­mented stones are commonly associated with chronic hemolysis, particularly sickle-cell disease. Gall­stones occur in 40 to 60 percent of patients with sickle-cell disease. Brown pigmented stones are asso­ciated with infection. These were historically more common in China and Japan, perhaps related to bile stasis and infection caused by Ascaris Iumbricoides (roundworm) and Clonorchis sinensis.

Etiology and Epidemiology

Though incompletely understood, the three major factors in gallstone formation are abnormality in bile composition, biliary stasis, and gallbladder infec­tion. These factors are interrelated, but current thinking ascribes the primary role to abnormal bile composition, related to cholesterol and bile acid me­tabolism. This in turn is affected by dietary, genetic, and hormonal factors.

A common medical maxim describes a typical pa­tient with gallstones as “fat, fair, female, and forty.” Obesity is associated with increased cholesterol se­cretion, producing a supersaturated or Iithogenic bile.

Gallstones are two to four times more common in females than in males. Estrogen causes increased secretion of cholesterol as well as decreased produc­tion of bile salts required to form soluble micelles with cholesterol. In addition, childbearing results in further elevation of estrogen in the third trimester and also promotes biliary stasis; thus multiparity is a risk factor.

There is a steady increase in gallstone prevalence with advancing age. Clinically, the symptoms of gall­bladder disease related to gallstones most commonly present between the ages of 40 and 60 years.

Distribution and Incidence

Conclusions regarding the geographic distribution of gallstones are based on a variety of autopsy, hospi­tal admission, and population survey data. The large Framingham, Massachusetts, study showed a preva­lence of documented gallbladder disease among adult males (30 to 62 years old) of 1.3 percent and among adult females of 5.9 percent (Friedman, Kannel, and Dawber 1966). Many studies have shown a higher prevalence among American Indian groups, particularly in the Southwest (Brown and Christensen 1967; Comess, Bennett, and Burch 1967; Heaton 1973). For example, a study of the Pima Indians using identical criteria and age groups as the Framingham study showed a prevalence of 5.9 percent among adult males and 36 percent among females (Comess et al. 1967).

Gallstones are usually asymptomatic. This fea­ture, in combination with the increased prevalence with age, explains the much higher incidence of gall­stones at autopsy. A large autopsy series from Phila­delphia spanning the years 1920 to 1949 demon­strated gallstones in 7.8 percent of males and 16.8 percent of females.

A similar prevalence of gallstones has been dem­onstrated in autopsy series from Europe, including England, France, and Germany, as well as Western­style societies such as Israel, South Africa, and Aus­tralia (Brett and Barker 1976). Sweden appears to be second only to certain American Indian groups in the frequency of gallstones. An autopsy survey from Malmo found stones in 32 percent of men and 57 percent of women over 20 years old. The prevalence rose to peaks of 70 percent in women by age 70, and 50 percent in men by age 90.

Gallstones are relatively uncommon in oriental countries; prevalence rates as low as 1.8 percent among adult men and 3.9 percent of adult women are found in Thailand. Prevalence remains low in Japan; however, there has been a shift from the infection-related pigmented stones to the Western diet-related cholesterol stones.

Most African populations demonstrate an ex­tremely low prevalence of gallstones. Only 1.3 per­cent of autopsied adults in Uganda had gallstones. Many of these were black pigmented stones related to chronic hemolysis (Owor 1964). No gallstones were found in a series of 4,395 autopsies in Ghana. The disease is virtually unknown among the Masai of East Africa.

There is a general impression that gallstones are increasing in frequency in industrialized countries as well as in countries undergoing rapid develop­ment. A recent review of pre- and post-1940 autopsy series shows increasing prevalence of gallstones in Europe, North America, Japan, Chile, and Australia (Brett and Barker 1976).

A genetic tendency to develop gallstones under certain dietary conditions may account for the high rates of gallstones noted in various American Indian groups, including Pima, Navajo, and Chippewa as well as in groups with significant Indian admixture from Mexico, Bolivia, Chile, and Peru (Weiss et al.

The geographic epidemiology of gallstones indi­cates a susceptibility in New World populations that is not shared, however, by their Asian ancestral rela­tives. The Americas were settled by crossing via the Bering land bridge formed during glacial epochs. Survival under the harsh climatic conditions de­pended on hunting and gathering strategies with unpredictable periods of near starvation. Individu­als who could rapidly store excess calories as fat would have had a pronounced survival advantage over individuals lacking this trait. This is the “thrifty gene” theory postulated to explain the preva­lence of diabetes among American Indians (Neel 1962, 1982) and possibly accounting for the associa­tion of obesity, parity, and puberty, with the forma­tion of gallstones in American Indian females and to a lesser degree in males now exposed to a perpetual “feast” of calories and sedentary living (Weiss et al. 1984). Indeed, the worldwide distribution of other populations with high risk of gallstones corresponds closely to the area covered by the last glacial epoch (Lowenfels 1988).

History and Paleopathology

Hippocrates and Aristotle were familiar with the clinical findings of jaundice and biliary disease, but their writings do not specifically mention gallstones. Hippocrates differentiated four types of jaundice due to disease of the liver, but he did not describe any cause related to obstruction. Diodes of Carystus re­ferred to possible mechanical obstruction of the flow of bile. Accounts of Alexander the Great’s illness prior to his death in 323 B.C. are quite suggestive of gallstones and cholecystitis (Gordon-Taylor 1937).

Galen described various types of jaundice, includ­ing obstructive jaundice. He stated that small for­eign bodies such as grain or fig and pomegranate seeds could obstruct the common bile duct.

Alexander of Tralles of the sixth century was a Byzantine physician with wide clinical experience but scanty knowledge of anatomy and physiology. He described both gallstones and renal calculi. Haly Abbas, a tenth-century Persian physician often quoted in early Renaissance medicine, recorded the presence of calculi in the gallbladder and liver (Wilkie 1934).

Mundinus was professor of anatomy and surgery at the University of Bologna from 1295 to 1326. His manuscript on anatomy was based on the writings of Hippocrates, Galen, and Arabic authors and was widely used for nearly 250 years. He also mentions stones formed within the gallbladder and kidneys. Gentile da Foligno was a graduate of Bologna and professor at Padua, who died of the plague in 1348. In 1341 he carried out one of the earliest autopsies on record, and an account of that autopsy states that a gallstone was found embedded in the cystic duct of the gallbladder.

Antonio Benivieni wrote the first book devoted to pathological anatomy, which was published posthu­mously by his brother in 1507. This work, De Adbitis, contains 111 observations based on 20 autop­sies, including two descriptions of gallstones found within the gallbladder and liver. Numerous other Renaissance physicians were familiar with gall­stones encountered in clinical practice or more often at autopsy (Steinbock 1990).

Giovanni Battista Morgagni profoundly altered medicine in 1761 with the publication of On the Sites and Causes of Disease. He provided a vast array of pathological findings related to the clinical picture for a large number of diseases, including gallstones.

Gallstones have been recovered in burial excava­tions, and this evidence greatly extends the known antiquity of the disease. Given their frequency, more such examples should be expected. The earliest case comes from Mycenae, Greece, dating 1600 to 1500 B.C. Several gallstones were found between the right lower costal margin and right iliac crest of the skeleton of a 45- to 55-year-old man (Angel 1973). The stones are reddish brown in color with green patches and have several facets.

The mummy of a priestess of Amen, who died 945 B.C., revealed an intact gallbladder filled with stones. A radiograph of an intact mummy from the late Dynastic period (525 to 343 B.C.) shows a clus­ter of gallstones in the gallbladder. Subsequent analysis showed these to be the mixed variety (Gray 1967).

An extremely well preserved body of a 50-year-old female from the Hunan province of central China demonstrated multiple gallstones, including one ob­structing the common bile duct. This example dates to the Han Dynasty (206 B.C. to A.D. 220) (Wei 1973).

In Europe, gallstones were recovered along with skeletal remains in a wooden coffin dating to Merovin­gian times or about A.D. 750. The coffin was found in Mainfranken, Germany. In Herault₁ France, the re­mains of an older adult buried in the ninth century also yielded gallstones. A single gallstone was recov­ered from 234 graves in a London cemetery dating from A.D. 1000 to 1200 (Steinbock in press).

In the New World, 16 individuals from the Libben site in Ohio exhibited gallstones (Lovejoy 1979). This Late Woodland site dates from A.D. 1000 to 1200. In northern Chile, at a site dating from A.D. 100 to 300, 2 of 75 mummies had gallstones (Munizaga, Allison, and Paredes 1978). Both indi­viduals had pure cholesterol stones.

The frequency of cholesterol-based gallstones is affected by age, sex, parity, diet, genetics, and other factors. Infection and hemolysis are important in the formation of pigmented stones. A variable frequency in ancient human populations is to be expected, and because of dietary factors they may have been quite rare in many instances.

R. Ted Steinbock

Bibliography

Angel, L. 1973. Human skeletons from grave circles at Mycenae. Appendix in The grave circle B of Mycenae, G. E. Mylonas, 379-97. Archaeological Society of Athens.

Bennion₁ L. J., and S. M. Grundy. 1978. Risk factors for the development of cholelithiasis in man. New England Journal OfMedicine 299: 1161-7.

Brett, M., and D. J. P. Barker. 1976. The world distribution of gallstones. International Journal OfEpidemiology 5: 335-41.

Brown, J. E., and C. Christensen. 1967. Biliary tract dis­ease among the Navajos. Journal of the American Medical Association 202: 1050-2.

Comess, L. J., P. H. Bennett, and T. A. Burch. 1967. Clini­cal gallbladder disease in Pima Indians. New England Journal of Medicine 277: 894—8.

Friedman, G. D., W. B. Kannel₁ and T. R. Dawber. 1966. The epidemiology of gallbladder disease: Observa­tions in the Framingham study. Journal of Chronic Disease 19: 273-92.

Gordon-Taylor, G. 1937. Gallstones and their sufferers. British Journal of Surgery 25: 241-51.

Gray, P. H. K. 1967. Radiography of ancient Egyptian mummies. Medical Radiography and Photography 43: 34-44.

Grundy, S. M., A. L. Metzger, and R. Adler. 1972. Patho­genesis of Iithogenic bile in American Indian women with cholesterol gallstones. Journal of Clinical Investi­gation 51: 3026-31.

Heaton, K. W. 1973. The epidemiology of gallstones and suggested etiology. Clinical Gastroenterology 2:67-83.

Lieber, M. M. 1952. The incidence of gallstones and their correlation with other diseases. Archives of Surgery 135: 394-405.

Lovejoy, C. O. 1979. Referred to in December Paleopathol­ogy Association Newsletter 28: 7.

Lowenfels, A. B. 1988. Gallstones and glaciers: The stone that came in from the cold. Lancet 1: 1385—6.

Munizaga, A., M. J. Allison, and C. Paredes. 1978. Cholelithiasis and cholecystitis in pre-Columbian Chileans. American Journal of Physical Anthropology 48: 209-12.

Neel, J. V. 1962. Diabetes mellitus: A “thrifty” genotype rendered detrimental by “progress”? American Jour­nal of Human Genetics 14: 353-62.

1982. The thrifty genotype revisited. In The genetics of diabetes mellitus, ed. J. Kobberling and R. Tattersall, 283-93. New York.

Newman, H. F., and J. D. Northup. 1959. Collective re­view: The autopsy incidence of gallstones. Interna­tional Abstracts of Surgery 109:1-12.

Owor, R. 1964. Gallstones in the autopsy population at Mulago Hospital, Kampala. East African Medical Journal 41: 251-3.

Steinbock, R. T 1990. Studies in ancient calcified soft tissues and organic concretions. III. Gallstones (chole­lithiasis). Journal of Paleopathology.

Wei, O. 1973. Internal organs of a 2100 year old female corpse. Lancet 2: 1198.

Weiss, K. M., et al. 1984. Genetics and epidemiology of gallbladder disease in New World native peoples. American Journal of Human Genetics 36: 1259-78.

Wilkie, D. P. D. 1934. Gallstones. In A short history of some common diseases, ed. W. R. Brett, 146-53. London.