Gallstones: The thing in itself

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Frank Lammert

In his chief published work, Twelve Books of Medicine (Figure 1), ¹ in which one whole book is devoted to ailments of the liver, the Greek itinerant physician Alexander of Tralles ^{2 , * *} was the first to describe calculi in the human gallbladder ³ as “dried up humors concreted like stones.” ⁴ Since then, gallstones and their manifestations have excited the interest of numerous scientific disciplines. Yet, this same Alexander Trallianus (525–605 CE)—whose practice of medicine and medical writings earned him high esteem throughout Byzantium and beyond—was not necessarily inherently interested in concretions in the gallbladder per se. Rather he regarded the unique finding of gallstones in the gallbladder in humans only indirectly, in that it provided the much sought‐after explanation for the then age‐old curiosity of jaundice associated with the disease that he and others had termed constipation (émpraxis, ἔμφραξις) of the liver, or liver obstruction. ³ The latter affliction had been recognized since Diocles of Carystus ^{† †} (c.375–c.295 BCE), whom Pliny the Elder had described in his Natural History as next in age and fame to Hippocrates.

FIGURE 1.

Alexander Trallianus holding his book. Ninth century CE, Bibliothèque Nationale de France, Paris. Reproduced with permission from Journal of Cranio‐Maxillofacial Surgery. ¹ Copyright 2014, Elsevier.

Liver obstruction was attributed by the most renowned physician in Rome, Galen of Pergamon (129–216 CE), to stone‐like coagulation (hóper líthos, ὥσπερ λίθος) of one of the four Hippocratic humors (Figure 2), namely, yellow bile, Hippocrates' “warm and dry like fire” choleric humor (shown in the right upper panel of Figure 2), to which hypothesis Trallianus readily subscribed. ⁵ Irrespective of a definite cause, in today's pathophysiological parlance this was obstructive jaundice, although in that cholestatic setting gallstones were rarely mentioned in the medical texts of antiquity, ⁴ save those by Trallianus ¹ , ² and Aristotle from Stagira. ⁶ Aristotle (384–322 BCE) reported in De Partibus Animalium that stones may be seen in the livers of sacrificed animals. It is unlikely that these calculi were explicitly identified as gallstones by Aristotle or any of his successors in antiquity ⁵ , ⁷ , ⁸ until the late Middle Ages. ⁹ , ¹⁰

FIGURE 2.

Image of woodcut from Physiognomische Fragmente, zur Beförderung der Menschenkenntnis und Menschenliebe (1775–1778) by Johann Caspar Lavater, depictions of the four humors: phlegmatic, upper left (i.e., mucus); choleric, upper right (i.e., yellow bile); sanguine, lower left (i.e., blood); and melancholic, lower right (i.e., black bile).

In the Middle Ages, many mystic and mythical properties, as well as clinical signs, were attributed to gallstones. Pigmented stones from oxen were used by painters, sought by alchemists and apothecaries for draughts and potions, and the gallstones of Persian goats and Peruvian llamas and even hedgehogs were prized as gems to drive out poisons from the body. ¹¹ The two celebrated Medieval Persian physicians and polymaths, Abū Bakr Muhammad Zakariyyā Rāzī (Persian: ابوبكر محمّد زکرياى رازى)—also known by his Latinized name Rhazes (854–925 CE)—and Ibn Sina (Persian: ابن سینا)—also known as Abu Ali Sina and Pur Sina, and in the West as Avicenna (980–1037 CE)—spoke of using ox gallstones to sharpen the vision. Notwithstanding the observations of the Greco‐Roman, Persian, and other physicians of old, gallstones have bedeviled humanity since ~1500 BCE or earlier, according to manual and radiographic examinations of mummies from ancient Egypt (Figure 3, ^{‡ ‡}), ¹² , ¹³ , ¹⁴ of skeletons from graves outside the walls of Mycenae in Greece, and from pre‐Hispanic South America. ¹⁵

FIGURE 3.

Photograph of liver (showing calculi imbedded in the undersurface) and gallbladder from the mummy of a priestess of Amun of the 21st dynasty (c.1500 BCE). Presented to the Royal College of Surgeons Museum in London by Sir Grafton Elliot‐Smith. Reproduced with permission from British Journal of Surgery. ¹⁴ Copyright 1937, Oxford University Press.

The field of gallstone research seems to have held a particular fascination for German medical scientists, although not exclusively so. Among the first detailed analyses of the structure of gallstones is that in Johann Gottlieb's (1734–1818) and Friedrich August Walter's (1764–1826) beautifully illustrated work Museum anatomicum, ¹⁶ published in Berlin in 1796 (Figure 4), based on their large private collection of stones. Hence in those days, the focus was on possessing and perceiving nature, that is the focused, structured, and reflective art of observatio that was practiced proficiently until the late 18th century. Two hundred years before the digital age, the idea of these collections of objects that were created through collaboration and networking was to generate curiosity and knowledge by seeing and touching. In the center were the objects and things of nature—or as the contemporary philosopher Immanuel Kant (1724–1804) claimed cryptically das Ding an sich (“the thing in itself”) ¹⁷ —and we as observers only get to know their appearance and properties by the way in which we are affected by them.

FIGURE 4.

Gallstone images from Friedrich August Walter, ¹⁶ Anatomical Museum (collected by Johann Gottlieb Walter, Belitz und Braun, Berlin, 1796). This colored copperplate was deposited in the Countway Library of Medicine of Harvard University, Boston, Massachusetts, and was unopened until 2001.

Other fundamental work on gallstones dates back to Heinrich Meckel von Hemsbach (1821–1856), the last scientist in the renowned Meckel dynasty and predecessor of Rudolf Virchow as head of pathology (Prosektur) at the Charité hospital in Berlin. In his book Mikrogeologie, published posthumously, ¹⁸ he described the composition of gallstones (that included both cholesterol and calcium salts), as well as their localization and clinical manifestations. Only a few years later, in 1861, the European patriarch of hepatology, Friedrich Theodor von Frerichs (1819–1885)—who was later the first to describe, in a footnote in his text on diabetes, in vivo human liver biopsies ¹⁹ that were actually performed by his assistant, 1908 Nobel laureate Paul Ehrlich, to measure hepatic glycogen—published the second volume of his famous book Klinik der Leberkrankheiten. ²⁰ This formidable tome was translated into English and published in 1879 by Charles Murchison (Figure 5A), who published his own textbook on liver disease (Figure 5B) as a series of lectures with case histories. ²¹ Frerichs's textbook includes a most consummate account of all aspects of gallstone disease, from its history through 19th‐century chemistry to clinical manifestations, which is complemented by masterly illustrations (Figure 6). Frerichs gives credit for discoveries related to gallstones and their complications to upward of a score of famous European investigators over the centuries, including Herman Boerhaave, Gabriele Falloppio, ¹¹ Francis Glisson, Friedrich Hoffmann, Johannes Kentmann, Giovanni Battista Morgagni, and Andreas Vesalius, ¹¹ to name a few of the most familiar illustrious personalities. In addition, he explains the composition of gallstones and indicates age, female gender, sedentary behavior, and dietary indiscretions (Diätfehler) as risk factors for gallstone disease, reminiscent of the “5 Fs” inventory mnemonic, that is female, fertile, fat, fair, and forty (to which we now add family), which we learned at medical school. ^{§ §}

FIGURE 5.

Title pages of historic textbooks on liver disease. (A) Charles Murchison's 1879 English translation of Friedrich Theodor von Frerichs, Klinik der Leberkrankheiten. Vol. II Braunschweig: Verlag von Friedrich Vieweg und Sohn; 1861. (B) Charles Murchison, Clinical Lectures on Diseases of the Liver. 2nd edition. London; 1877.

FIGURE 6.

“Concremente,” that is concretions. Colored copperplate from Friedrich Theodor von Frerichs, Pathologisch‐anatomischer Atlas zur Klinik der Leberkrankheiten. Vol. II, Tafel XIV. Braunschweig: Verlag von Friedrich Vieweg und Sohn; 1861.

In 1909, Ludwig Aschoff (1866–1942) and Adolf Bacmeister (1882–1945), working together at the Institute of Pathology at the University of Freiburg, published their observations on the formation of gallstones, ²² predicting that the prevention of primary gallbladder stones that they attributed to altered lipid metabolism and hereditary factors could avoid the inflammatory complications of cholelithiasis. The prevailing wisdom during the first half of the 20th century concerning the mechanism of gallstone formation put the cart before the horse, to use an idiom that was already mentioned by Marcus Tullius Cicero (100–43 BCE) but did not enter current language until the late 16th century. Bernhard Naunyn (1839–1925), Professor of Medicine in Berne and later Strasburg, already thought that it was the diseased gallbladder that rendered bile lithogenic. ²³ Consequently, Johann Ludwig Wilhelm Thudichum (1829–1901), a German expatriate physician and chemist who made his home in London, had a prescient inkling that gallstones form when cholesterol can no longer be solubilized by the bile salts in bile and would therefore precipitate with prolonged stasis. ⁷ Thudichum was implying that there was a concentration limit at which bile would be saturated with cholesterol, and therefore at higher biliary concentrations, cholesterol precipitation (that we would now identify as crystallization) was inevitable.^{¶ ¶} But what he could not have imagined was that bile in gallstone patients could actually be supersaturated with cholesterol ²⁴ —and it would be from this unstable supersaturated solution that precipitation/crystallization would occur.

Meanwhile, the 1950s saw elucidation of the properties of detergents, ²⁵ including the natural detergents in bile, the bile acids/salts, ²⁶ and their actions in micellar systems on lipid solutes, ²⁷ such as those found in bile. It took quite a while, however, before the key cooperative physicochemical role of biliary lecithin (mostly the phospholipid phosphatidylcholine) was appreciated in the micellar solubilization of cholesterol by bile salts. ²⁸ The medical visionary of this era was Dresden‐born Franz Ingelfinger (1910–1980), one‐time 30‐year Chief of Gastroenterology at the Boston University Medical Centre and then later Editor of the New England Journal of Medicine. ²⁹ Ingelfinger suggested that the US national gallstone problem deserved a similar research approach to that afforded to heart disease, ³⁰ and he intuited that the solution would lie in the realm of physical chemistry. ³¹ Associated with Ingelfinger's more than 50 gastroenterology fellows—self‐nicknamed “The Fingerlings,” was resident Donald M. Small (1931–2019; Figure 7), whom The Finger encouraged to study the principles of physical chemistry under the preeminent Egyptian‐born physical chemist, Dikran Dervichian (1903–1988), ³² at L'Institut Pasteur in Paris. After his return to Boston University, Small founded the Department of Biophysics, serving as Chair of the combined Department of Physiology and Biophysics until 2006. ³³ For more than 40 years, Small and colleagues investigated the physical biochemistry of bile and lipoproteins. ^{** **} In Paris, Small studied the principles of cholesterol solubility in aqueous lipid systems ³⁶ that would later be extended to model aqueous systems of cholesterol, lecithin, and bile salts to model bile. ³⁷ Cholesterol is, of course, almost completely insoluble in water, whereas bile salts are exquisitely the opposite. To mix metaphors, lecithin, which takes its name from the Greek for egg yolk (lekythos, λέκιθος), is the chameleon of the trio because it is almost completely insoluble in water, too, but being amphipathic, that is having both hydrophilic and hydrophobic domains, it swells in water to form paracrystalline structures that—depending on hydration and temperature—form micelles, lamellae, or vesicles, that is spherical bilayer water‐filled chambers. Mixed bile salt‐lecithin micelles may also exist as spheres or worm‐like cylinders, depending on the lecithin‐to‐bile salt ratio. In model bile systems that are supersaturated, cholesterol occurs either as crystals or liquid crystals. ^{†† ††} When a solid compound melts into a liquid, it can undergo two transitions before fully melting, and thereby it takes on the appearance of a liquid while maintaining aspects of a rigid, crystal‐like molecular structure. This fleeting moment between states of matter is known as the liquid crystal phase. It was an apparently morbid view of Small's mentor, Dervichian, when he stated that “Liquid crystals stand between the isotropic liquid phase and the strongly organized solid state. For life stands between complete disorder, which is death, and complete rigidity, which is death again” emphasizes the central and essential role that liquid crystals play in the living versus the nonliving world. And yet, liquid crystals now have an incredibly wide range of applications in our inanimate world, from flat‐screen monitors and telecommunication switches to high‐performance fibers, membranes, transfection agents, and messenger RNA vaccines. Ingelfinger's expectation was ultimately realized, that is that results based on physical chemistry would be forthcoming to explain cholesterol gallstone formation. Conjugated bilirubin, which colors the bile and is the basis of brown and black pigment stones with their own pathophysiology, ³⁹ was not anticipated to influence biliary cholesterol solubility and therefore was initially not accounted for in these studies of cholesterol gallstone pathogenesis. The relationship between biliary lipid proportions and the phases present at equilibrium in such model systems was depicted most clearly using the triangular coordinate plotting system (Figure 8A), ³⁶ , ³⁷ which Small learned from Felix Lucien Lachampt (1902–1988), a chemist at the Parisian cosmetic company L'Oréal.

FIGURE 7.

Donald M. Small (1931–2019). Reproduced with permission from Journal of Lipid Research. ³³ Copyright 2019, American Society for Biochemistry and Molecular Biology.

FIGURE 8.

(A) Phase equilibria present in the model system consisting of bile salt, lecithin, and cholesterol, the three biliary lipids. The tetrahedron shown in the upper right corner has been used to express the physical state of all possible combinations of bile salt, lecithin, and cholesterol. The section in the tetrahedron taken at 90% water results in a triangular phase diagram that has been enlarged and is shown on the left. This diagram shows the physical state of all possible combinations of bile salts, lecithin, and cholesterol in aqueous solutions containing a total of 10% solids and 90% water. The closed circles indicate the upper limits of the micellar zone, and all mixtures having the composition under the line form one liquid phase. The open circles represent mixtures forming two‐ or three‐phase systems (clear liquid plus cholesterol crystals and/or islets of lamellar liquid crystals). The line separating the open and closed circles indicates the maximum amount of cholesterol solubilized by any mixture of lecithin and bile salts. (B) The biliary lipid composition of gallbladder bile from healthy subjects and patients with gallstones compared with the limits of cholesterol solubility, as determined from a model system. The lipid composition of bile from healthy subjects, represented by closed circles, is such that all circles fall within the micellar zone. The bile samples from patients with cholesterol or mixed gallstones in which no microcrystals were present, represented by open triangles, fall very near the line indicating maximum cholesterol solubilization. The bile samples from gallstone patients, which contained microcrystals of cholesterol, represented by closed triangles, fall well above the line of maximum saturation. Both diagrams are reproduced with permission from Journal of Clinical Investigation. ³⁷ Copyright 1968, American Society for Clinical Investigation, with legends modified by Alan Hofmann in Gallstone disease: physical chemical research sheds new light on an old disease and points the way to medical therapy. J Hepatol 2004;41:195–200.

Back in Boston, Small and his fellow, William Admirand (1933–2012), showed that it was also possible to represent the composition of human bile on the by‐then established triangular coordinate phase diagram, which they recruited for their clinical study. In that landmark report, ³⁷ they demonstrated that supersaturated gallbladder bile from patients with versus those without gallstones contained not only an excessive amount of cholesterol, that is beyond the capacity of micellar solubilization by its bile salt and lecithin content (Figure 8B), but also housed cholesterol crystals that aggregate to form stones. As predicted by Fausto Hegardt ⁴⁰ using model systems, when he was a fellow at the Danmarks Tekniske Hojskole in Copenhagen under the supervision of Henrik Dam, ^{‡‡ ‡‡} supersaturated bile is not infrequent in healthy individuals who do not necessarily form cholesterol crystals or gallstones. ⁴¹ , ⁴² From this we can infer that cholesterol supersaturation—which originates in hepatic bile and is not simply the result of bile being concentrated in the gallbladder ⁴² —is a necessary but not sufficient condition for gallstone formation. In sooth, it turned out the nucleation time—the time it takes for cholesterol crystals to form—is far shorter in bile from patients with gallstones compared with bile from stone‐free control patients, ⁴³ even though the cholesterol saturation index calculated from the biliary lipid concentrations was similar in both groups of patients. ⁴² It was inferred, therefore, that promoting (and/or inhibiting) factors, ⁴⁴ promoting in particular biliary mucin and/or impaired gallbladder motility ⁴⁵ , ⁴⁶ play a role in gallstone formation. It emerged that a highly relevant proposal in biliary lipid physiology, to wit that the bilayer vesicles that Neiderhiser and Roth ⁴⁷ controversially claimed to have isolated from human bile, could really exist in supersaturated model bile, human bile, and even unsaturated native bile; a prediction that was in fact supported by nonperturbing techniques for vesicle imaging, ⁴⁸ , ⁴⁹ generation, ⁵⁰ and isolation. ⁵¹

Many key figures who dissected the complexity of the physicochemical composition of bile and shared an interest in gallstone pathogenesis and treatment met at a conference on “The Physical Chemistry of Bile in Health and Disease” (1983) ⁵² that was sponsored by the now‐defunct Kroc Foundation in California's Santa Ynez Valley (Figure 9) and 6 years later at a colloquium held at Airlie House, Virginia, under the auspices of the National Institutes of Health ⁵³ (Figure 10). The delegates scrutinized, debated, and summarized the progressive changes in biliary lipid vesicles as bile moves from the hepatocyte canaliculus into the gallbladder, where vesicle fusion and nucleation occur. ⁵³ Results of studies by Martin Carey, Thomas Holzbach and their respective coworkers, and those who measured biliary secretion directly in humans, ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ had already shown that in gallstone patients, the liver secretes either excessive amounts of cholesterol or insufficient amounts of cholesterol‐solubilizing factors, that is bile salts and/or lecithin. The lecithin secretion shortfall, noted earlier, is now attributed to a deficiency of the ATP‐dependent hepatocanalicular translocase, ABCB4, which was discovered by Raoul Poupon and colleagues. ⁵⁸ From initial studies in mice to subsequent genetic studies in humans, we now know that more than 70 gene variants predispose to gallstone disease, the most common being the p.D19H variant of the hepatocanalicular cholesterol transporter ABCG8, with the α₁‐antitrypsin gene and the Gilbert variant of the enzyme‐conjugating bilirubin as prominent cofactors. ⁵⁹ , ⁶⁰ , ⁶¹ The results of all of these and many other studies elucidated the molecular mechanisms underlying hepatic cholesterol metabolism and biliary lipid secretion into bile ⁵⁹ (Figure 11) and demonstrated that cholesterol cholelithiasis represents a disease of defective hepatic bile secretion, rather than solely the consequence of cholesterol precipitation as a result of prolonged bile stasis ⁷ or because the diseased gallbladder alters the composition of bile. ²³

FIGURE 9.

Participants at the 1983 Kroc Foundation Conference on “The Physical Chemistry of Bile in Health and Disease,” held on December 5–9, 1983. First row, left to right: Stephen Barnes, Margaret Hays, Alan Hofmann, Kyrol Mysels, Sarah Kasler, Aldo Roda, Roberto Pellicciari, and Thomas Holzbach. Second row: Steven Strasberg, Bjorn Lindmann, Josip Kratohvil, George Nancollas, Adrian Reuben, Donald Ostrow, Siegfried Lindenbaum, Peter Schurtenberger, Karl Muller, and Don Whedon. Top row: Donald Small, Martin Carey, Joseph Bogardus, Gordon Lindblom, Pasupati Mukerjee, Thomas La Mont, Padmanabhan Balaram, Tom Parker (transcriber), William Higuchi, and Edward Moore. Reproduced with permission from Hepatology. ⁵² Copyright 1984, American Association for the Study of Liver Diseases.

FIGURE 10.

Participants at the 1989 American Association for the Study of Liver Diseases Workshop on “Frontiers of Gallstone Formation. Biliary Cholesterol Transport and Precipitation.” Reproduced with permission from Hepatology. ⁵³ Copyright 1990, American Association for the Study of Liver Diseases.

FIGURE 11.

Cholesterol metabolism in the hepatocyte and the molecular mechanism of biliary lipid secretion. The hepatic uptake of cholesterol is mediated by LRP1 for chylomicron remnants, LDLR for LDL, and SRB1 for HDL. Biosynthesis of hepatic cholesterol from acetate is regulated by the rate‐limiting enzyme HMDH. A large proportion of cholesterol is used for the synthesis of bile salts via the classical and alternative pathways, which are regulated by the two rate‐limiting enzymes cytochrome P450 (CYP) 7A1 and CYP27A1, respectively. Bile salt synthesis is determined by farnesoid X receptor (FXR; also known as NR1H1) through small heterodimer partner and fibroblast growth factor (FGF) 19 through its receptor (FGFR4). In addition, some of the cholesterol is esterified by ACAT (also known as SOAT1) for storage within the hepatocytes. Part of the cholesterol is used for the synthesis of VLDL, which is secreted into the circulation. A group of ABC transporters located in the canalicular membrane is responsible for hepatic lipid secretion: the heterodimers ABCG5 and ABCG8 for cholesterol, ABCB11 for bile salts, and ABCB4 for phosphatidylcholine. NPC1L1 in the canalicular membrane might contribute to the reuptake of cholesterol from hepatic bile into hepatocytes. Liver X receptor (LXR; also known as NR1H3) has a crucial role not only in cholesterol and bile salt synthesis through CYP51A1 and uridine diphosphate glucuronosyltransferases 1 to 3, respectively, but also in biliary cholesterol secretion by activating ABCG5 and ABCG8 at the transcriptional level. Dysregulation of uptake, biosynthesis, catabolism, and/or biliary secretion of cholesterol at the hepatocyte level results in the formation of cholesterol‐supersaturated bile. Reproduced with permission from Nature Reviews Disease Primers. ⁵⁹ Copyright 2016, Springer Nature Limited.

It was the latter misconception that explicitly persuaded Carl Johann August Langenbuch (1846–1901; Figure 12) that neither “taking of the spa waters at Karlsbad, Vichy, Bad Kissingen, Homburg, Marienbad or Bad Ems,” nor cholecystotomy and gallstone removal were the answer to symptomatic cholelithiasis. Langenbuch championed cholecystectomy because he thought that merely to remove the offending gallstones would be to invite recurrence, or as he stated pithily, “The gallbladder should be removed not because it contains stones but because it forms them.” ⁶² , ⁶³ Langenbuch's critics, especially Lawson Tait (1845–1899), had a diametrically opposite (erroneous) opinion.

FIGURE 12.

Carl Langenbuch. Reproduced with permission from Chirurgie der Gallenwege. ⁶³ Stuttgart: Verlag von Ferdinand Enke; 1913:11–22.

FROM TREATMENT TO PREVENTION

After experimental studies, ⁶³ Langenbuch first accomplished open gallbladder extirpation (Exstirpation der Gallenblase) ⁶² on July 15, 1882, at the Lazarus Hospital in Berlin, where he had been director since the age of 27. Langenbuch's surgical talents were not restricted to the biliary tract, as he excelled in arthrotomy, laryngectomy, nephrectomy, splenectomy, thoracotomy, and more, ⁶⁴ not to mention his impressive opus, Chirurgie der Leber und Gallenblase, that was originally published in two parts (1894 and 1897, respectively). ^{§§ §§} Langenbuch's 43‐year‐old patient, whose 16 years of biliary colic had rendered him a morphine addict, was pain‐free on postoperative day 1 and discharged 7 weeks after the historic operation. Although some attribute familiarity with cholecystitis caused by cystic duct obstruction to the 14th century Italian Professor of Medicine at Perugia and disciple of Avicenna, Gentile da Foligno (c.1285–1348), ⁶⁶ the first account of symptomatic gallbladder disease, that is biliary colic, apparently was reported by Antonio Benivieni (1443–1502) in his De abditis nonnullis ac mirandis morborum & sanationum causis (“Hidden causes of disease”) in 1507. ⁶⁷ Here, the Florentine described the autopsies of two women of noble birth who had been “laid low” and “greatly tormented” during their lives by abdominal pains that had perplexed and divided their physicians. At post mortem, Bienvieni described a collection of small gallstones of various shapes and colors. Jean Fernel (1497–1558), physician to the court of Roi Henri II de France, who coined the term “physiology,” endorsed Galen's hypothesis of biliary concretion formation ¹¹ and also described the symptoms of cholelithiasis, ⁴ including biliary colic and obstructive jaundice. ⁶⁸ Gallstones, it must be noted, were not only the province of the nobility of Ancient Egypt, Renaissance Florence, and 16th century France. Other sufferers from gallstones included such notables as Francis Glisson,^{¶¶ ¶¶} John Hunter the anatomist, Samuel Johnson the lexicographer, Sir Walter Scott the author, ^*** *** Sir Anthony Eden (Prime Minister of Great Britain during the Suez Crisis in 1956), and at least four American presidents of the 20th century (Figure 13).

FIGURE 13.

(A) Lyndon Baines Johnson (1908–1973), 36th President of the United States, photographed on the hospital heliport, demonstrating the scar of his cholecystectomy that had been performed at Bethesda Naval Hospital in 1965 by George Hallenbeck, Chief of Surgery at Mayo Clinic. Photograph: Charles Tasnadi, Associated Press, reproduced with permission. (B) Caricature depicting Johnson demonstrating his cholecystectomy scar that, curiously enough, resembles the map of Vietnam. David Levine, The New York Review of Books, 1968, reproduced with permission.

Not unexpectedly, there was much skepticism and frank opposition to cholecystectomy that included a withering assault led by the Scottish surgeon Robert Lawson Tait (1845–1899) in favor of cholecystostomy, ⁶⁹ which Jean‐Louis Petit (1674–1750) had proposed in 1733. Petit, the acknowledged Parisian founder of gallbladder surgery, came up with cholecystostomy after finding a percutaneous tract to the gallbladder, that is a cholecystocutaneous fistula, which had formed spontaneously when an abscess ruptured through the abdominal wall and allowed access to gallstones ⁶⁹ ; this phenomenon may have already been known to Avicenna. ⁶⁸ In Tait's mind, cholecystectomy was “radically absurd,” “wholly unnecessary,” and a “delusion” ⁶⁹ , ⁷⁰ , ⁷¹ —meaning that, in his experience, gallstones did not recur if the focus morbi, as Langenbuch referred to the diseased gallbladder in his book, was left in situ. Cholecystostomy, in effect a surgically created cholecystocutaneous fistula, was subsequently advocated by Thudichum in London, ⁷ John Stough Bobbs in Indiana, Emil Theodor Kocher in Bern, Franz König in Göttingen, and the controversial, some would say notoriously unethical, South Carolinian James Marion Sims (who was best known as the “Father of Gynecology”). About this time, the surgeon Ludwig Georg Courvoisier (1843–1918) in Basel was among the first to remove a stone from the common bile duct, and he also published his observation that was later formulated into “Courvoisier's law,” whereby gallbladder distension occurs in malignant obstructive jaundice. ⁴ Even so, the standard of care before the turn of the century was still opiate analgesia, belladonna and sedation, poultices and other cutaneous applications, and emersion in and ingestion of spa waters. Medicine has been fraught with feuds from the time of Galen and Harvey until the present, ⁷² and this includes the ridicule and ostracization of Harold Ridley in England, who devised cataract surgery, ⁷³ and of Gerhard Küntscher in Finland, who pioneered internal fixation of broken long bones—each ironically working on opposite sides during World War II, yet each caring for soldiers of both sides. Needless to say, Langenbuch's operation and Kocher's incision were the victors of the debate, except that cholecystostomy, which is performed nowadays by interventional radiology ⁷⁴ or via endosonography, ⁷⁵ is the choice for patients too sick for cholecystectomy.

Results of the pathobiological and physicochemical studies discussed earlier provided the framework for the development of cholesterol gallstone dissolution therapy in the United States, Japan, and Europe, which was based on the oral administration of the 3,7‐dihydroxy bile acids chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), respectively. ⁷⁶ , ⁷⁷ , ⁷⁸ UDCA, the 7β‐epimer of CDCA, soon replaced CDCA for gallstone dissolution. UDCA is of similar dissolution efficacy to CDCA, but in contrast with the latter, a bona fide agonist of the farnesoid X receptor (FXR)—a nuclear bile acid receptor that acts as central bile acid sensor and regulates bile salt transporters—UDCA was virtually without hepatotoxicity and did not provoke troublesome diarrhea. Notably, UDCA remains the treatment of choice for ABCB4 deficiency. ⁷⁹

To overcome the long duration of treatment usually required for successful gallstone dissolution and its high failure rate, the technique of extracorporeal shock wave lithotripsy (ESWL) that had originally been developed for the fragmentation of kidney stones was adapted by Tilman Sauerbruch and Gustav Paumgartner (Figure 14) in Munich to gallstone fragmentation, combined with bile acid treatment. ⁷⁸ , ⁸⁰ , ⁸¹ This noninvasive approach challenged surgical cholecystectomy, which had remained the standard of care for the treatment of symptomatic gallstones since Langenbuch's breakthrough achievement in Berlin in 1882. However, as Langenbuch predicted for cholecystostomy, gallstone recurrence with the gallbladder in situ compromised up to 40% of ESWL cases within 5 years, and this was soon realized as a distinct disadvantage of ESWL and its combination with bile acid therapy. ⁸¹

FIGURE 14.

Gustav Paumgartner in 1973 (left), 1982 (middle), and 1996 (right). Reproduced with permission from Hepatology. ⁸⁰ Copyright 2004, American Association for the Study of Liver Diseases.

The outlook for sufferers from gallbladder cholelithiasis finally changed for the better with the advent of laparoscopic cholecystectomy, which had seemingly first been performed in Erlangen (Germany) in 1985 by Erich Mühe (1938–2005; Figure 15), ⁸² , ⁸³ inspired by Kurt Semm's pioneering use of laparoscopy. Mühe's precedence was later challenged by the discovery of hitherto unknown publications in Russian. ⁸⁴ Other surgical pioneers reported their success with laparoscopic cholecystectomy in short order in the late 1980s: in France, Phillipe Mouret first performed it in Lyon in 1987, Francois Dubois in Paris in 1988, and Jacques Perrisat in Bordeaux, followed by Barry McKernan and William Saye in Georgia, and Eddie Reddick and Douglas Olsen in Tennessee. In the company of other trailblazers in medicine and surgery, Mühe's innovative successes were met initially not merely with resounding silence but with rejection and ridicule. Laparoscopic cholecystectomy was mocked as a “futureless technique,” “circus surgery,” and “a media show of a tightrope dancer who is totally careless of the risks for the patients.” ⁸⁵ As word of the technique spread further afield, to Alfred Cuschieri in Scotland, Namir Katkhouda in France, Christian Klaiber in Switzerland, Edward Phillips in Los Angeles, Hans Troidl in Germany, and others, appreciation grew. The reasons behind the rebuff of the procedure were many, ⁸⁶ but Mühe was ultimately afforded the respect that he was due. In 1992, the Deutsche Gesellschaft für Chirurgie awarded him the Rudolf‐Zenker‐Preis, and the following year, the president of the society's congress apologized to Mühe, describing his work as “without a doubt one of the greatest original achievements of German medicine in recent history.” In 1999, the Society of American Gastrointestinal and Endoscopic Surgeons formally recognized Mühe as the first surgeon to perform laparoscopic cholecystectomy.

FIGURE 15.

Erich Mühe, innovative surgeon and 1985 national and 1987 international cycling champion, here doing what he loved best, apart from laparoscopic surgery. Reproduced with permission from Indian Journal of Surgery. ⁸⁸ Copyright 2021, Springer Nature Limited.

Today, all guidelines advise laparoscopic cholecystectomy to treat symptomatic uncomplicated gallstones, but persistent abdominal pain in up to 40% of patients ⁸⁷ and the large variation of cholecystectomy rates worldwide ⁵⁹ should encourage physicians involved in the care of patients with gallstones to redefine treatment and focus instead on prevention in at‐risk individuals in particular and also in the population in general. The option to prevent gallstone disease has only become a reality in recent years, because the pathobiology of cholelithiasis is being elucidated at the physiological, biophysical, cellular, molecular, and genetic levels, as observed and predicted previously by Thudichum with insight: “Before knowing the cause and origin of gallstones a little better, prevention is out of the question.” ⁷ , ⁶⁸ Here and now, our better understanding of genetic and other risk factors (Figure 16, Table 1) might serve to individualize the treatment of patients. ⁵⁹ These findings should help circumvent the currently recommended invasive treatment of this exceptionally prevalent and economically costly digestive disease.

FIGURE 16.

Risk factors for the development of (A) cholesterol and (B) brown pigment gallstones, respectively. Reproduced with permission from Nature Reviews Disease Primers. ⁵⁹ Copyright 2016, Springer Nature Limited.

TABLE 1.

Exogenous risk factors for the development of gallstones

Factors associated with metabolic syndrome

Obesity, particularly central adiposity a

Physical inactivity a

Insulin resistance and diabetes mellitus a

Nonalcoholic fatty liver disease a

Dietary factors

High calorie intake a

High carbohydrate intake a

High glycemic load a

Low fiber intake a

High heme iron intake a

Factors that cause gallbladder hypomotility

Prolonged fasting a

Rapid weight loss or bariatric surgery a

Weight cycling a

Prolonged total parenteral nutrition a

Spinal cord injury a

Gastrectomy a , b

Factors increasing enterohepatic bilirubin cycling

Liver cirrhosis a , b

Crohn's disease a , b

Ileal resections b

Drugs

Calcineurin inhibitors a

Fibrates a

Glucagon‐like peptide‐1 analogues a

Hormone replacement therapy a

Octreotide a

Note: Modified and updated with permission from Nature Reviews Disease Primers. ⁵⁹ Copyright 2016, Springer Nature Limited.

^a Cholesterol stones.

^b Black pigment stones.

SERIES EDITOR'S POSTSCRIPT

Pedants, or should we call them purists, might argue that there is no place for the gallstone saga in a history of hepatology, no matter how intriguing or colorful the tale. Yet I would counter that this intriguing and epic adventure in cholelithiasis is indeed a hepatological saga in its own right, especially because it turns out that the liver is responsible for secreting lithogenic bile for which, moreover, there is an intrahepatic genetic basis. Moreover, given the substantial participation of German scientists and physicians in the gallstone narrative, it is a happy accident that our current author is a distinguished German card‐carrying hepatologist who has been deeply involved in gallstone studies that were given an impetus when, as a research fellow at Harvard Medical School in Boston before the turn of the 20th century, in the laboratory of the renowned and exuberant maestro of biliary physiology, biochemistry, and biophysics and Gaelic musicologist, Martin C. Carey, he worked on the genetics of cholesterol cholelithiasis in susceptible mouse strains. Over the subsequent decades he has published upward of three score and ten manuscripts on all aspects of gallstone disease from molecular pathogenesis to therapy and management.

Frank Lammert is a Full Professor of Medicine and Health Sciences at Hannover Medical School, where he has been Vice President since 2021, having previously been Professor of Medicine and Director of the Department of Medicine II at Saarland University Medical Center, Homburg. His many hepatology credentials include memberships of the Governing Board of the German Association for the Study of Liver (GASL) and the European Association for the Study of the Liver (EASL). He has served as Associate Editor of the Journal of Hepatology and has been President of the German Gastroenterological Association (DGVS) since 2017.

In this essay, Frank skillfully navigates the convoluted history of gallstones from the observations and myths of physicians of yore to their cellular and molecular pathogenesis; he lucidly explains the arcane phenomena of liquid crystal formation and cholesterol supersaturation of bile and the cryptic triangular representation of the biliary lipid composition; and he takes us stepwise through the evolution of gallstone therapy and the controversies surrounding invasive and noninvasive surgery. I think that you will agree that this tour de force deserves its place in the current series.

CONFLICT OF INTEREST

Nothing to report.

Lammert F. Gallstones: The thing in itself. Clin Liver Dis. 2022;20:57–72. 10.1002/cld.1269