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Alcohol‐Related Liver Disease

2021; Lippincott Williams & Wilkins; Volume: 18; Issue: S1 Linguagem: Inglês

10.1002/cld.1162

2046-2484

Kyle E. Robinson, Vijay H. Shah,

Alcoholism and Thiamine Deficiency

Content available: Author Interview and Audio Recording Kyle Robinson Vijay H. Shah On a cold Florentine winter night, a 100-year-old man lay dying in the hospital of Santa Maria Nuova. At the end of his hospital bed, sat a middle-aged Tuscan polymath: a well-known engineer, scientist, and artist. The two men spoke, and the old man said he felt no pain, only fatigue. Slowly, on that night in 1507, the old man passed away without any movement or sign of distress. Leonardo da Vinci (1452-1519), curious to discover how a man "could die so sweet a death, which I found to be a fainting away through lack of blood to the artery which nourishes the heart and the other parts below …", made away with the body.1, 2 Breaking medieval taboo* and possibly the law too (although on the face of it, his reputation as an anatomist would have assured him permission), da Vinci dissected the body, "… very diligently and with great ease because of the absence of fat and humors which greatly hinder the recognition of the parts".1, 2 Da Vinci discovered the links between atherosclerosis and heart failure and drew cirrhosis for the first time. He claimed to have dissected 30 bodies toward the end of his life, probably mostly in the winter of 1507/1508, compiling his newfound knowledge into a manuscript that he intended to publish since the 1480s (Fig. 1). However, the notorious procrastinator5 (Fig. 2) frequently started new projects which distracted him from his anatomical studies. At his passing in 1519, the manuscript lay unpublished among the many papers crowding his desk.1, 2 After the poignant beginning of this essay on the History of Alcoholic Liver Disease (ALD) – presumably the Tuscan centenarian had alcoholic cirrhosis – it has to be conceded that the ALD story began many thousands of years before Leonardo arrived on the scene. Accordingly, we must now invoke the phrase: "New readers start here …`", a directive that often preceded individual instalments of stories serialized in magazines, which practice incidentally began with the Chapman and Hall publication in 19 issues over 20 months (March 1836 through October 1837) of The Posthumous Papers of the Pickwick Club (Fig. 3) by Boz – the nom de plume of Charles Dickens – illustrated by his friend Phiz.† In short, for a comprehensive History of ALD, the narrative should include a discussion, however brief, of the natural origins and the commercial synthesis of alcohol (i.e., ethanol) as a beverage, the proclivity of non-humans and humans alike for indulging and overindulging in alcohol, a chronological, ethnological, and geographic exposition of human industry and encounters with intoxicating liquors, and the association between excessive imbibition and liver injury. And here it must be emphasized that the recognition and acceptance of a cause-and-effect relationship between intemperance and liver disease are relatively recent events in a history that spans millennia. In 1530, the Swiss physician Paracelsus (1493-1541), Philippus Aureolus Threophrastus Bombastus von Hohenheim originated the term alcohol from kohl (Arabic: الكحل, romanized: al-kuḥl). Kohl referred to the fine dark powder produced by sublimating the mineral stibnite to antimony trisulfide, which was used for eye shadow and other purposes in Ancient Arabia, Persia, and elsewhere in the ancient world. The meaning of alcohol was then extended to distilled substances in general, including alcohol of wine, later narrowed to spirit of wine (known as ethanol since 1892), when "spirits" was a synonym for hard liquor. Ethyl alcohol (ethanol), the specific simple 2-carbon primary alcohol of beverages and inebriation‡, is usually produced as a byproduct of fermentation, the biological process in which yeast converts sugars such as 6-carbon glucose and fructose and 12-carbon sucrose (via glucose and fructose) into cellular energy. Each mole of 6-carbon species yields 2 moles of ethanol, 2 moles of CO2, and 2 moles of adenosine triphosphate (ATP). Nowadays cultivated varieties of Brewer's (or Baker's) yeast, Saccharomyces cerevisiae, are used – from Greek σάκχαρον μύκης for sugar fungus and Latin cervisia for beer. Ingestion of sugar-rich fruits, mostly but not exclusively those having fallen on the ground, that have been fermented by contaminating yeast (on the skin or within) or some species of bacteria, has been implicated to explain drunkenness in the animal world, as described in Swedish moose, spider monkeys (Ateles Atelinae of the family Atelidae), other primates, and an even wider menagerie.6 Yet it seems that pen-tailed treeshrews of Malaysia that feed on fermented nectar in the flower buds of the bertam palm plant and even fruit bats, hold their drink better than most. The unripe fruit of the Astrocaryum palm, which mantled Panamanian Howler monkeys (Alouatta, Alouattinae) eat, contains no ethanol compared to the 0.6% proof of ripe hanging fruit and the 0.9% and 4.5% (by weight), respectively, of ripe and over-ripe fallen fruit.7 In Los Angeles between 2005 and 2007, some 90-odd Cedar Waxwings (Bombycilla cedrorum, Fig. 4) died a traumatic death by flying under the influence (FUI) and ramming into windows, walls, and fences, after feasting on the naturally fermenting red berries of Brazilian Peppertrees. Alcoholic fermentation can also take place in goldfish, carp, and other species of fish, in nectars (3.8%) and honey, and it has even been suggested that various Drosophila melanogaster (fruit flies and vinegar flies) can become inebriated. Conversely, the oft repeated tale that African elephants (Loxodonta africana) get voluntarily uncontrollably drunk by eating the fruit of the Marula tree has been debunked as a myth for tourists.8 Perhaps the recent finding that there is genetic evidence of widespread variation in ethanol metabolism among mammals (Fig. 5),6 including elephants, may suggest that the conclusions about the quantity of fruit ingestion needed and the amount of ethanol required to produce inebriation in African elephants, were likely erroneous and the myth of inebriation may well be substantiated. It is in this genetic context that the mysteries of human alcohol use disorders9 are being disentangled. A good starting point is the now legendary but sometimes contested "Drunken monkey hypothesis," originally proposed by Robert Dudley,10 which posits that the proclivity of modern humans to consume alcohol may stem from a deep-rooted affinity present in all frugivorous nonhuman primates for naturally occurring ethanol within ripe fruit.7, 10, 11 Although molecular determinants of excessive alcohol consumption are difficult to study in humans, an interim approach has been to perform microarray analyses of brain gene expression in selected lines and isogenic strains of mice known to differ markedly in voluntary alcohol consumption,12 and by evaluating the role of Neuropeptide F in male Drosophila vinegar flies that find solace in alcohol after being spurned by the females.13 Human exploitation of fermentation has been global, enterprising, and resourceful. Reliance on the local availability of suitable substrates has resulted in a dazzling selection of choices that were once geographically restricted but are now truly globally distributed, and even mimicked. Wine comes from grapes; brandy by distillation of fruit-fermented beverages; cider and perry from apples and pears, respectively; mead from honey; beer, whisky, and occasionally vodka are prepared from grain starches that have been converted to sugar with amylase that is present in malted (sprouted) grain kernels, and perhaps potato or unmalted grain starch are added too. Of course, whisky and vodka are subsequently distilled. Whisky for a century or more was proudly synonymous with Scotland, but now has long been manufactured in Ireland, Japan, and the United States too, and even recently in England and Wales and as far afield as India, Canada, South Africa, Australia, Taiwan, Spain, and Sweden.‖ Rice wines including sake are derived by fermenting grain starches (after conversion to sugar by Aspergillus onyzae mold), which on distillation yields the respective spirits: Chinese Baijiu, – the most widely consumed liquor worldwide – Korean Soju, and Japanese Shōchū. Other beverages, still – no pun intended – are produced by fermentation and distillation of sugarcane while tequila and Mezcal are squeezed from the succulent Maguey (agave) plant; rum comes from the sugarcane product molasses, whereas cahaça, a favorite in Brazil, is from sugarcane juice. Here it is relevant to allude to the other concoctions of Meso- and South America, the lands of the Aztecs, Mayans, and Incas (who were conquered by the Spanish), in which the indigenous peoples had their own brews: Pulque from fermented Maguey sap, Balché wine of fermented honey and the bark of the Balché tree, Mexican Tepache from fermented pineapple and maize-based Tejuino, Tiswin from maize or Saguro sap, Caium and Andean Chiche from maize, yuca root, plantains, or fruit, which uniquely require cooking and chewing to break down the starch prior to fermentation. Who knew that the modern delight of combining chocolate with alcohol was celebrated by Mayan and Aztec kings, who drank a ferment of the pulp of the chocolate fruit, as far back as the second millennium BCE, long before the cacao bean was popular (Fig. 6).14 And so the list goes on, there seemingly being no end to human ingenuity when it comes to the search for a tipple. Not too long was to elapse after the serendipity of the discovery of natural fermentation, before Neolithic entrepreneurs began devising commercial means of manufacturing alcohol for human consumption. Undoubtedly, appreciation of the pleasurable effects of the key product of fermentation – not ATP or CO2 – on the higher centers, drove this enterprise. Alcohol has been used for pleasure, nutrition, medicine, antisepsis, ritual and secular payment, ceremony and funerary¶ purposes, and it even underpins modern scholarly exchanges. These days, a symposium refers to a conference or meeting to discuss a particular academic or specialist subject, or to a collection of related papers by a number of contributors, usually arising from such a conference. In ancient Greece, in contrast, symposium (συμπόσιον) literally stemmed from sympinein (συμπίνειν), "to drink together," as it described a drinking party or (mostly) convivial discussion held after a banquet (Fig. 7). In the light of the wide geographic distribution and myriad inventory of local and ethnic intoxicating beverages that reflect peculiar sociological, cultural, and religious attributes and not just botanical, and mycological ones, it is no wonder that there are archaeological reports of sites of mercantile beer brewing, vinification, and spirit distillation in places as diverse as the Middle East, India, Meso- and South America, Europe, and China. The quest for readily available, i.e., commercial, sources of alcoholic beverages began to be satisfied more or less simultaneously, independently, and often repeatedly, approximately 10,000 years ago (13,000-9,000 BCE), likely on every continent of the then known world. Sadly, space does not permit a full disquisition of the tantalizing legends from near the dawn of civilization and beyond, of brewers, vintners, and distillers, and of their nomadic Stone Age hunter-gatherer predecessors, who were persuaded to settle and cultivate grains, like the ancient wheat einkorn, which would have made very poor bread, and other crops, as an opportunity to produce beer and not bread. As Jonathan D. Sauer and Robert J. Braidwood opined in the 1950s, in what came to be known as the legendary but counter-intuitive "Beer-before-Bread Hypothesis",16 "…thirst rather than hunger may have been the stimulus behind the origin of small grain agriculture". There are several engaging accounts available17-21 of the successful adventures worldwide in alcoholic beverage production by Homo imbibens, as the University of Pennsylvania biomolecular archaeologist, Patrick Edward McGovern, has nicknamed our species, A few examples will be mentioned here: the evidence for an ancient alcohol industry was provided by the chemical identification of residues (e.g., calcium oxalate) in pottery or stone jars, basins, troughs, mortars, and other vessels, from beer and wine and/or from its soaking, mashing, and fermentation, as described in detail.21 More recently, the novel isolation and characterization of live yeast cells from ancient vessels has been developed as a tool in bio-archaeology.22 In this field, it is worth mentioning what is reputedly the oldest verifiable brewery found in a prehistoric Natufian burial site in Raqieet Cave near Haifa in northern Israel.23 Not far away, near a necropolis at the ancient Egyptian city of Abydos, a beer mega-factory was discovered from the reign of King Narmer24 (approximately 3,100 BCE), the Pharaoh who was credited with unifying Egypt at the beginning of the First Dynastic Period. Not to be outdone, the prehistoric residents of Jiahu in Henan Province, Northern China, in the seventh millennium BCE, had a penchant for a mixed fermented beverage produced locally from rice, honey, hawthorn berries, and/or grapes,25 but the Chinese later turned away to their unique fermented but not distilled cereal beverages, such as a kind of huangjiu from millet. In the UNESCO World Heritage Site of Göbekli Tepi in southeastern Turkey, which predates Stonehenge by 6,000 years, giant stone troughs were found in which there were traces of calcium oxalate that indicated that basic beer had been brewed there more than 10,000 years ago.26 The additional presence of hundreds of thousands of gazelle and auroch (prehistoric cow) bones at the excavation site, implied that a massive barbecue feast had taken place, to bribe the hunter-gatherer guests to help with the construction of the site's massive pillars.26 It has been reasoned that a subsequent benefit of feasts, such as proposed to have taken place at Göbekli Tepi, would have been a cementing of relationships, and alcohol was vital in helping to strengthen social bonding and to break down inhibitions.27 Throughout history, alcohol has made its mark from lubricating parties to facilitating complex rituals and affirming loyalty. Half a world away in India, from the Vedic age to the Mughals and the British Raj, and as far back as the civilization in the Indus Valley that now comprises modern India and Pakistan, alcohol was consumed – since there, both fermentation and distillation of beverages made from cereals and juices of flowers and special grasses, were perfected.28 In India as in all civilizations in which alcoholic drinks were consumed, the dangers of excesses leading to inebriation were recognized; we know that they had been in Ancient Egypt, as seen in 3,500-year-old hieroglyphs from the time of the Pharaoh Akhenaten, father of Tutankhamun (Tutankhamen), and from the intoxication of the first recorded viticulturist, Noah of the Old Testament.29 Various degrees of self-restraint have been recommended throughout history or even mandated, sometimes to the point of complete prohibition, in many religions or individual sects, notably among Buddhists, Jains, Hindus, Baha'is, Sikhs, Muslims, and others. In a sense, ancient and to a degree modern India serve as a microcosm for all civilizations in which alcohol has been produced and consumed, with regard to social and religious attitudes, both within and between castes and cults, and gods and mortals.28 It is doubtful, however, if the ancients recognized the injurious effects of excessive alcohol use on the liver, although the liver was always an organ to be reckoned with in the hepatocentric world and even after its spiritual dominance was usurped by the heart and then the brain. Piero Amodio, of the University of Padua, recently reminded us30 that his predecessor at his Alma Mater, Giovanni Battista Morgagni (1682-1771) – who had been Professor of Theoretical Medicine (1710) and later Chair of Anatomy (1715) – in 1761 published the case (in the 38th letter of the third book of his treatise 'De sedibus et causis morborum per anatomen indagatis', Fig. 8) of an alcoholic Venetian nobleman who died of advanced decompensated chronic liver disease and was subsequently shown at post-mortem to have cirrhosis – although this now familiar term was not published by Laennec for approximately another 60 years31 – the presumption is one of cause and effect. Returning to Da Vinci's observations, an interval of 175 years passed before the disease of cirrhosis resurfaced to the scientific world, first in John Browne's 1685 – paper to the Royal Society on the autopsy of a "Hydropical person"; "A Remarkable Account of a Liver Appearing Glandulous to the Eye"32 (Fig. 9). But, aside from the circumstantial evidence of the demise of Mogagni's alcoholic nobleman, 108 years would pass again before people took serious note of the link between alcohol and cirrhosis. In 1793, Matthew Baillie published33 "The morbid anatomy of some of the most important parts of the human body."§ In it, he noted "one of the most common diseases of the liver, and perhaps the most common…is the formation of tubercles in its substance. This disease is hardly ever met with in a very young person, but frequently takes place in persons of middle or advanced age: it is likewise more common in men than women. This would seem to depend upon the habit of drinking being more common in one sex than the other; for this disease is most frequently found in hard drinkers, although we cannot see any necessary connection# between that mode of life and this disease" (Fig. 10).33 At that time, this disease was labeled "scirrhous liver," which was confusingly too similar to the French squirrhe that was reserved for malignancies. It seems incredible that the link between man's** favorite toxin and liver disease would be made so late in history. As long as there has been humanity, there has been alcohol. Ten million years ago, as climates changed and trees receded from the African savanna, our forebears gained the ability to break down alcohol, thanks to the enzyme alcohol dehydrogenase.35 As we began to walk upright between diminishing forests, fruit from high in the trees was replaced with low-hanging riper fruit and, as we have observed earlier, some fermenting on the ground. We have found evidence of mead – reputedly the world's oldest booze – in China,25 and beer and wine in the Middle East as far back as fifteen millennia.23 However, for most of history, obtaining sufficient calories was a struggle. Drinking in excess was a luxury restricted to the wealthy and to special holidays. The commoners of Rome were reported to dilute their wine, one part to 20 parts water. Short life spans prevented the development of ALD, and for the cases that did develop, the link to alcohol went unnoticed among the prevailing diseases of infectious hepatitis, malaria, syphilis, tuberculosis, and parasitic infections. The industrial revolution brought industrial alcohol production. As lifespans increased and the relative cost of alcohol decreased, the links between drinking, jaundice, and a "scirrhous liver" became more apparent. During the 19th century, a more formal understanding of alcoholic liver disease arose, but not yet of its pathogenesis. René-Théophile Hyacinthe-Laennec (1781-1826), the French physician who invented the stethoscope, coined for us the name cirrhosis in the footnote to his 1819 treatise31 "De l'auscultation mediate." While performing an autopsy on a 66-year-old man, Jean Edmé, who died of "a great quantity of spit mixed with blood" followed by progressive confusion, Laennec noted the tawny-brown color of the nodules in a patient's "liver reduced a third in size entirely composed of a multitude of small grains." Laennec, an accomplished classicist, decided to name this condition "la cirrhose" after the Greek word for tawny kirrhos (Κίρρος), which he had actually pre-empted 15 years earlier in a little-known 16-page essay on "les cirrhose" that was part of an incomplete manuscript for a proposed Treatise of Pathological Anatomy.36 Incidentally, Laennec did not mention Edmé's drinking history nor that of Françoise Cuvi, a 39-year-old domestic, whose 1805 case history and autopsy he also described to reinforce his observations. From the mid-19th century onward, the notion was established that heavy alcohol intake – "hard" drinking as described by George Budd in his textbook of liver disease,37 the first in the English language – caused cirrhosis, which was also true of the other contemporary leading liver disease tomes38, 39 (Fig. 11), although standalone individual chapters were not yet devoted to ALD per se. William Osler would later spread the use of the word "cirrhosis" throughout the United States and Canada in his 1892 book "The Principles and Practice of Medicine"40 which was regarded as the world's most significant medical textbook for over 40 years. By this time, the links between alcohol and liver disease were no longer in doubt. Even so, it was not until the late 1970s, that a dose-risk relationship between the alcohol intake and cirrhosis was established.41, 42 Osler noted that "the abuse of spirits is the common cause" of cirrhosis, and that "it is more frequent in countries in which strong spirits are taken than in those in which malt liquors and wines are used." At the time, it was generally thought that the clinical symptoms of ALD only developed after many years of liver inflammation. Osler noted that, although "French writers [laid] great stress" on the chronic course of alcoholic cirrhosis, there seemed to exist a form of alcoholic liver disease which may "come on acutely…intense like an obstructive jaundice," where "ascites do not develop" and "enlargement of the liver may be the sole diagnostic criterion".40 For the first time, Osler had described acute alcoholic hepatitis and helped to differentiate the condition from alcoholic cirrhosis. It would take another seven decades before Beckett, Livingstone, and Hill published "Acute Alcoholic Hepatitis" in the British Medical Journal in 1961.43 Their paper gave a formal name and diagnosis to "acute hepatic insufficiency in chronic alcoholics." At the time, the condition was often misdiagnosed as infectious hepatitis. The trio noted that "severe jaundice may occur in alcoholics before cirrhosis is established when "…the liver is enlarged and tender and shows histologically acute inflammatory changes." They stressed treating the condition with vitamin B, a high-carb, low-fat, low-protein diet, and broad-spectrum antibiotics "to suppress the formation of as yet unidentified products of bacterial action." For this, the trio may have been ahead of their time given the now recognized link between gut bacteria, liver disease progression from alcohol, and increased risk of infection. However, they did not mention the use of corticosteroids. Toward the end of their paper, they noted that "despite the long-accepted association between alcoholism, a fatty liver, and cirrhosis, no conclusive evidence exists to show that alcohol is directly responsible, and other mechanisms, such as malnutrition and vitamin-B deficiency, have been blamed.43 The Belgian-American Charles Lieber would later emerge as the man to "catch alcohol in the act." Lieber had seen alcoholics develop cirrhosis even with adequate diets in his country of origin, and he was troubled by the prevailing theory in America that nutritional deficiencies were the true cause of alcohol-related liver disease. His suspicion was reinforced by a series of experiments that he conducted in baboons in which he demonstrated that a sufficient diet supplemented with alcohol still led to the development of cirrhosis. Finally, in 1966, Lieber published "Hepatic and Metabolic Effects of Alcohol" in Gastroenterology.44 In this paper, Lieber carefully traced the pathway by which alcohol dehydrogenase leads to an increase in the NADH to NAD ratio and the manner in which this increases lipogenesis and decreases lipolysis in the liver. Furthermore, Lieber noted that in experiments with rats fed an isocaloric diet with differing levels of macronutrients, alcohol had the greatest propensity to produce fatty liver. He concluded,44 "Alcohol itself has to be considered as a direct etiological agent in the pathogenesis of fatty liver." Yet, despite all of this evidence, Lieber was still left doubting "whether alcoholic fatty liver per se leads to cirrhosis, or whether independent of fatty liver or in conjunction with it, other lesions are necessary." This is largely where we remain today, as new questions circulate whether alcohol directly damages the liver, or whether its effects on the gut and the microbiome lead to the majority of inflammation seen in alcoholic liver disease. Numerous questions remain as to the genetic, environmental, and microbiotic reasons that only 10-20% of heavy drinkers will develop severe liver disease and that women may be more susceptible to develop ALD than men.45 Topics that relate to the causes, mechanisms, and consequences of ALD and models of investigation, have been ably, consummately and comprehensively reviewed recently.46 Just the same, many of the secrets of alcohol, which have been in our glasses for thousands of years, still remain as elusive as always. Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved. Kyle Robinson, who is in his third year at Mayo's Alix Medical School, enjoys research, medical history, and is passionate about global health. He helps to run the nonprofit Mada Clinics in Maventibao, on the Indian Ocean island of Madagascar, providing free medical care and education to the rural north of the island. He hopes to pursue an academic career in obstetrics and gynecology, specializing in either gynecologic oncology or maternal-fetal medicine. Vijay Shah MD – whom the editor has known since the latter's fellowship days with the late Roberto Groszmann at Yale – is the Carol M. Gatton Professor of Medicine and Physiology at Mayo Clinic College of Medicine and Science, and currently Chair of the both the Division of Gastroenterology and Hepatology, and the Department of Internal Medicine there, where he has maintained an NIH-funded basic, translational, and clinical research program for upward of two decades, focusing broadly on portal hypertension and alcohol-related liver disease. The current essay traces the multifaceted time-honored relationship between humanity and alcohol, and highlights the inventive, entrepreneurial, commercial, social, and societal aspects of this interconnection. Despite the millennia-long story of human indulgence in vast array of alcoholic beverages, the deleterious consequences to the liver of intemperance by some humans have only been recognized for a few hundred years, and even then the genetics and pathophysiology of cause and effect have yet to yield up fully their cellular mysteries.