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A History of the Assessment of Liver Performance

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

10.1002/cld.1100

2046-2484

Omar Y. Mousa, Patrick S. Kamath,

Organ Transplantation Techniques and Outcomes

Content available: Author Interview and Audio Recording Omar Y. Mousa Patrick S. Kamath In antiquity, inspection of the liver, hepatoscopy (hēpatoskōpia, from the Greek ηπατοσκόπια), was a common method among Babylonians, Etruscans, Greeks (Fig. 1), and Romans to use the liver to seek knowledge of the future using supernatural means,1 but not for the purpose of assessing the performance of this royal organ. Ezekiel, the sixth century BCE biblical prophet who lived during the Babylonian captivity and had warned earlier about the impending destruction of Jerusalem, documented the popular Babylonian practice of hepatomancy (ηπατομανία) that is divination of the will of the gods via hepatoscopy of the livers of carefully selected sheep. In this context, the venerable prophet reported that "the king of Babylon (i.e., Nebuchadnezzar) has stood at the fork of the road, at the crossroad of the two ways, to perform divination, to shake out arrows, to inquire of the household gods, to inspect the liver. On its right lobe was the omen of Jerusalem…"2 Hepatoscopy convention ordained that signs on the right side (later called the pars familiaris) of the liver that were deemed favorable, such as gallbladder swelling, paradoxically predicted success of the enemy when present on the left (pars hostilis) side.1 Guided by the omens, Nebuchadnezzar went to Jerusalem and not Rabbah (modern Amman in Jordan), with devastating effect. How different might the Middle East have looked today had the configuration of that ovine liver been different? Was the clue a tight embedding of the gallbladder in the substance of the liver on the left or deep enclosure of the hepatic duct in the porta hepatis?1 We can only speculate. Since Paleolithic times, the liver was appreciated to be a highly vascular organ, as evidenced by the remarkable cave art of prehistoric hunters, found at Lascaux in Southern France.3 Moreover, the liver was also long considered to be the source of blood—the basis of life itself—described by the most esteemed of all Roman physicians, Aelius (alternatively Claudius) Galen (c. 130-210 CE; Fig. 2) of Pergamon (modern-day Bergama, in Izmir Provence, Western Turkey), as the sanguifactionis officina,4 "the factory of the blood," that is the site of sanguification. It is not surprising, therefore, that the liver was chosen for inspection as a natural consequence of the deep-grounded belief that the soul, which was the jurisdiction of priests in those civilizations, resided there along with the source of emotions, feelings and desires, and even sexual potency. Later, of course, the heart usurped the liver's claim as the seat of the soul.1 A Babylonian priest, known as a Bārû, was trained to recognize the predictive signs in the liver, and thus was collected a mountain of omens called the Bārûtu. These priests recognized that livers from similar animals never looked alike, which in Mesopotamia led to the use of clay liver models,5 examples of which are held in the Middle East Department of the British Museum (Fig. 3) and date back to the Temple of Marduk in Babylon in 2000 BCE, in the age of Hammurabi (perhaps better written phonetically as Hammurapi6). These historic details were revealed in a trove of some 800 fragments of medical texts out of tens of thousands of potsherds excavated at Mound Kouyunjik, opposite the site of ancient Nineveh (modern Mosul), among the vast library of King Ashurbanapal of Assyria (668-626 BCE).6 A clay model of an ox liver, dating from the 15th century BCE, was also found at the archeological site of Tel Hazor in the Upper Galilee, Israel, at the site of the Middle Bronze Age fortified city of Hazor.7 Subsequently, durable Etruscan bronze models were produced (Fig. 4),8 in which inscriptions on the liver surface showed divisions into regions assigned to specific deities of the Etruscan religion. In the Etruscan tradition that was practiced in Ancient Rome (and which even persisted to the Middle Ages9), divination was performed by a haruspex (Fig. 1), who was trained to look for omens by performing haruspicy, from the Latin haruspicina meaning "inspecting entrails," and especially the livers, of sacrificed animals (after the archaic word haru and the root spec, "to observe"). Perhaps the most famous haruspex in ancient Rome was the soothsayer Spurinna, at whose warnings about the Ides of March** Et immolantem haruspex Spurinna monuit, caveret periculum, quod non ultra Martias Idus proferretur. "Again, when he was offering sacrifices, the soothsayer Spurinna warned him to beware of danger, which would come not later than the Ides of March." (De Vitis Caesarum, Divus Iulius ch. LXXXI). Julius Caesar scoffed to his cost, at least according to Suetonius.10 Haruspicy contrasts with divination performed by an augur, who interprets the will of the gods by "taking the auspices," that is, studying the flight of birds. It was not until the Renaissance dawned, 1000 years after the fall of Rome, that there was any advance in understanding the anatomy and function of the liver. Throughout the Dark Ages and even in the latter part of the Middle Ages, the spiritual soul was more important than the physical body. Leonardo da Vinci (1452-1519) studied the anatomy of the human liver thoroughly11 (Fig. 5), and apparently he even described different liver diseases, including cirrhosis, but his work in hepatology was relatively unknown until the latter half of the 18th century. Andreas Vesalius (1514-1564) mistakenly portrayed the liver as having five lobes in his famed anatomical drawings (Tabulae Anatomicae Sex, Venice 1538) based on his earlier dissection of a baboon (Fig. 6A), but he later derided that representation in his 1543 De Humani Corporis Fabrica Septum and accurately described the anatomy of the human liver and biliary tree in detail12 (Fig. 6B), while yet perpetuating his errors of its portal venous anatomy.13 He may have even found a correlation between excessive alcohol consumption and cirrhosis.14 Galen and his adherents believed that the major function of liver was to convert digested food from the intestines into blood by concoction (pepsis) and to separate the light (yellow) bile for excretion via the biliary tree from the heavy (black) bile that would pass via the spleen to the stomach. Yet, even up to the late Middle Ages, there was still no inkling that the liver had any function other than bile production.15 Several centuries elapsed before the celebration of the liver by Dutch anatomist Thomas Bartholin,† † As expressed in his Latin dirge on the death of the liver, which was published in 1653: Bartholinus T. Vasa lymphatica, nuper Hafniae in animalibus inventa et hepatis exsequiae. Paris. as "the body's master cook and engineer" that "cooks and stews for us…"16 In 1654, Francis Glisson (1597-1677 CE), a young colleague of William Harvey and a founder of both the Royal Society (of Great Britain) and the Royal College of Physicians, London, declared in his authoritative monograph on the liver that the hepatic parenchyma was responsible for the liver's function,17 namely, the separation of bile from the blood by the mechanisms of so-called affinity. A finding published in 1666 by Marcello Malpighi (1628-1694),18 using primitive microscopy, albeit antedated a couple of years earlier by Johan Jacob Wepfer,19 that the parenchyma was arranged into grape-like out-budding structures that he termed lobules, comprising lobuli and glandulosi acini, convinced him that there had to be a functional connection between the hepatic parenchyma and adjacent vascular structures. The architecture of the hepatic lobule in humans was elegantly demonstrated by Kiernan in 1833 using only a hand lens.20 There are intriguing links between the appreciation of liver function and Glisson's pivotal demonstration of intravascular channels in the liver21 (Fig. 7), which he proved by injecting "warm water, coloured with a little milk" into the portal vein of a fresh human cadaver, using an ox bladder attached to a siphon (such as was used for administrating enemas). With the result of this perfusion experiment, Glisson vindicated the renowned physician-anatomist, Erasistratus of Chios (310-250 BCE),22 who postulated the existence of intrahepatic vascular channels and who had actually coined the term parenchyma (παρέγχυμα, meaning "adjoining infusion") that in Glisson's mind was the locus of the liver's function. It is likely that, in common with Glisson, Erasistratus considered that in anatomy, as in architecture, "Form follows function," thereby presciently espousing the 1896 views of the renowned Chicago architect Louis Sullivan (1856-1924) that the latter published over the course of 1901 as his Kindergarten Chats in the Interstate Architect and Builder.‡ ‡ These essays were not published in book form until 1934, a decade after Sullivan's death. Or, as Sullivan's most distinguished apprentice, Frank Lloyd Wright (1867-1959), later paraphrased in his Dear Master's ordinance, "Form and function are one."23 Galen did not ignore the impressive body of anatomical discoveries of his Alexandrian predecessor, but he was bitterly critical of the latter's inference about an organ's function, based on its anatomy. Incidentally, Francis Glisson's experiment also provided crucial evidence for the hypothesis by that Man of Kent from Folkestone, United Kingdom, William Harvey (1578-1657 CE),24 that blood flows through the lungs, because the milky water he injected into the portal vein passed sequentially through the right heart, the lungs, and the left heart into the systemic arterial circulation. It was reasoned that if blood could pass through a dense organ like the liver from the portal vein to the vena cava seemingly without any propulsive force, then blood could surely flow through the delicate spongy lungs driven by the contraction of the heart's right ventricle. Cirrhosis was described in detail from the 17th century onward, although the notion that a "hard" liver was a bad sign, especially in association with jaundice, can be traced back to Greek and Roman medicine from Hippocrates25 and Aulus Cornelius Celsus26 to Aretæeus the Cappadocian27 and Caelius Aurelianus,28 over a span of almost 1000 years (from 400 BCE though 500 CE). However, the terminology was not always unequivocally lucid, making interpretation of early clinicopathological entities difficult. Swelling that probably meant inflammation (i.e., hepatitis) was thought to progress to hardness, which we presume to equate with cirrhosis, and then to a scirrhus state that we interpret as carcinoma. Confusion was compounded by the widespread application of the label tubercle that was introduced by Giovanni Battista Morgagni (1682-1771) in his 1761 seminal mechanistic book, De sedibus et causis morborum per anatomen indagatis (Fig. 8)29, to refer to any discrete liver mass that George Budd later referred to as nodules, often the size of peas, while scarring gave the surface of the liver a "hob-nailed appearance."31 In the years before Laennec and Budd, livers were described as being tubercular and even tuberculated, despite there being no hint of tuberculosis. Further, Morgagni's failure to distinguish between cirrhosis and carcinoma30 only contributes more uncertainty. St Thomas's Hospital London surgeon John Browne (1642-1702) has long been credited with being the first to publish an illustration of a cirrhotic liver32 (Fig. 9) that was drawn by the distinguished crayon artist and engraver William Faithorne the Elder,§ § During the English Civil War, Faithorne was imprisoned as a monarchist and briefly exiled to France. from an autopsy that the artist witnessed and was carried out by Browne himself. Although Browne attended both Charles II and his nephew William III (of Orange), and had an impressive list of innovations and achievements, it is sad to report that his reputation was stigmatized by brazenly copying from others, an apparently common practice in his time that was called piracy but which now would be plagiarism, an act that was not yet illegal in those days.33 Matthew Baillie (1761-1823),34 a Scottish physician, nephew of William and John Hunter (from each of whom he inherited a substantial museum of pathological specimens) and Physician in Ordinary to George III, was credited with having published the first systematic study of pathology and the first publication in English on pathology as a separate subject.35 Oddly enough, he did not publish the accompanying illustrations from his own specimens and those from his uncles' considerable inheritance until much later, in a separate volume.36 His description of cirrhosis is vivid, graphic, and almost lyrical,37 but the name he chose for this pathological entity, namely, Common tubercle of the liver (Fig. 10), is a startling throwback to Morgagni. Tubercles of the liver include ordinary cirrhotic nodules, presumed neoplasms, and lesions related to scrofula or syphilitic gumma, and these Baillie carefully distinguished from tubercles that were "commonly produced by a long habit of drinking spirituous liquors."37 Most notable, Baillie had recognized an association between drinking alcohol and liver disease. Since the opportunity to give this multifaceted clinicopathological entity an enduring name was passed up by liver luminaries from antiquity to Browne and Baillie, the nomenclator's baton was taken up 25 years later by a tuberculous Parisian physician from Normandy,38 who delighted in Latin and Greek. In what must surely be the all-time most celebrated footnote39 in the History of Hepatology, René Theophile Hyacinthe Laennec (1781-1826), who had invented the stethoscope and made major contributions to the pathological understanding and diagnosis of diseases of the chest, coined the neologism "cirrhosis" that as a devoted classicist he derived from the Greek kirrhos (κιρρός), meaning "tawny yellow." The orange-yellow color referred to the appearance of the nodules in the diseased liver of the patient (whose pleurisy was the main focus of the famous 1819 case report), which he had in fact already described in a little known 16-page essay on Les Cirrhoses that was part of his incomplete Treatise on Pathological Anatomy (1804-1808) from 15 years earlier.38 Whether the Laennec eponym that is popular in the United States, less so in Great Britain, and hardly at all in France is deserved for alcoholic cirrhosis, the memory of Laennec will surely prevail for devising the generic nomenclature itself, cirrhosis, for the clinicopathological entity that pervades our chosen field. It should come as no surprise that Laennec's moniker was not universally applauded; none other than Baron Carl (Freiherr) von Rokitansky (1804-1878), the renowned Bohemian Viennese pathologist, humanist philosopher, and liberal politician, preferred terms like granular atropy (atrophie in German) and tuberculization.40 Parenthetically, in a later edition of Traite de l'Auscultation, Laennec cautions that the nodules of cirrhosis may be mistaken for malignant tumors (squirrhe in French). Jaundice, the yellowing of the eyes, skin, mucous membranes and secretions, was perhaps the earliest appreciated expression of liver dysfunction to be recognized in all ancient systems of medicine—in the clay tablets of Mesopotamia, repeatedly in The Old Testament and Talmud,41 in exquisite detail in the Hippocratic Corpus,42 and in Ayurvedic43 and Chinese44 sources, where a plethora of traditional remedies were offered. Thus was created the need for one of the foremost early tests of liver function, which survives to this day. Once it had been determined that the function of the liver parenchyma was bile formation, the liver dysfunction responsible for jaundice (otherwise named morbus regius by Celsus45 because of its gold color, or perhaps because of cure by the touch of a king or because only a king could afford its costly therapy) was deduced by Erasistratus to be due to impaired bile secretion. Yet in Letter 37 in the 1769 edition of The seats and causes of diseases, investigated by anatomy…, Morgagni attributed jaundice to constriction of the liver by hepatic nerves caused by passion or emotional disturbance, for which Celsus some 1800 years previously had already recommended rest in a "good bed in a tasteful room" and emotional support.45 Encephalopathy and ascites also featured prominently in times of yore as manifestations of chronic liver dysfunction and, even now, together with jaundice, are included in a time-honored index that purports to assess liver performance.46 For the first, we must distinguish the sudden delirium of acute liver injury, which had been observed and described by Hippocrates, Celsus, Galen, and their successors, in which there is fairly abrupt impairment or loss of true liver function, that is, the syndrome of acute liver failure (ALF; also known as fulminant hepatic failure)—as reviewed elegantly elsewhere in this series by Will Bernal and the late Roger Willims47—from the neuropsychiatric syndromes of disturbed behavior and reduced consciousness associated with portosystemic shunting in cirrhosis, that is, portosystemic encephalopathy. The History of Encephalopathy is the subject of a lively forthcoming essay in this series by Nathan Bass. The challenge of ascites to the well-being of the individual was appreciated by the ancient Egyptians, the Hebrews, the Greeks, and the Mayans (Fig. 11) alike.48 Hippocrates observed pithily that "when the belly becomes full of water, death follows."49 Methods were devised early on to alleviate ascites, including physical drainage and the early introduction of dietary salt restriction. The obvious expeditious remedy for massive ascites was to drain the offending fluid rapidly by tapping the barrel-shaped distended abdomen—a practice that Celsus favored and for which he even designed a lead or bronze tube with a retaining collar.49 Erasistratus cautioned against rapid paracentesis, which he had abandoned in favor of opening the abdomen and inserting a catheter50 (in his hands an implement shaped like a Roman S), as had been performed since the Hippocratists. Adherence to Erasistratus's counsel against the rapid removal of ascites (which Paul of Ægena thought would prove immediately fatal because it also "evacuates the vital spirit"51) persisted until the group in Barcelona documented that it is safe when performed in conjunction with intravenous (IV) albumin as a plasma expander.52 As far back as Erasistratus, paracentesis was usually effected via the umbilicus (as described by Ambroise Paré53), but this site would scarcely be countenanced nowadays,54 because of the risks for permanent leakage from the hernia sac and of puncture of portal hypertensive collateral veins (varices) even in the absence of a visible caput Medusa. In the 18th and 19th centuries, additional observations were made in hepatobiliary disease regarding gallstones, liver tumors, fatty liver, hepatic congestion, and acute hepatic necrosis; coincidentally, several formidable tomes (now of historic hepatological interest) devoted exclusively to liver disease were published by William Saunders,55 George Budd,31 Friedrich Theodor von Frerichs,56 and Charles Murchison.57 The 20th century was the beginning of the modern era of hepatology, spurred on by the exponential progress in the physical and biological sciences, epidemiology, immunology, microbial discovery, pathology, and light and electron microscopy. Among a plethora of anatomic features studied were the lobules of the human liver and its microcirculatory units,58 along with a host of physiological, pathophysiological, and biochemical functions for which tests had already been devised in the early decades of the century,59 including heme catabolism to bilirubin; bile composition and function; glycogenesis, gluconeogenesis, and other facets of carbohydrate metabolism; urea synthesis as the end stage of protein metabolism; detoxification processes; and aspects of deranged hepatic lipid metabolism that underlie microvesicular and macrovesicular fatty degeneration. Many scientists, in the tradition of Hippocrates and Galen, reported on jaundice caused by biliary obstruction, the infective hepatitides,‖ ‖ All five human viral hepatitides have already been reviewed in this series by Drs. Shouval, Gish, Alter, Rizzetto, and Seth and Sherman, respectively.s and other causes of dysregulated bilirubin metabolism and transport. Autoimmune hepatitis and primary biliary cirrhosis (later updated to primary biliary cholangitis) were recognized, and hemochromatosis and Wilson disease were differentiated from other causes of liver disease.¶ ¶ The history of these entities and many others have already been published in this series (see essays by Albert Czaja on Autoimmune Hepatitis [Clin Liver Dis (Hoboken) 2020;15(suppl 1):S72-S81] and Paul Adams on Hemochromatosis [Clin Liver Dis (Hoboken) 2020;16(suppl 1):83-90]; others are scheduled to be covered in due course. Compared with these sublime scientific pursuits, clinical interest in "tight-lace" or "corset" liver, as a consequence of the capricious fashion of wearing barbarously rigid corsets to achieve an hourglass waist,60 now appears almost comical. Yet an unexpected benefit of the end of the First World War, namely, the welcome demise of this misogynistic torture, is ostensibly not yet complete.61-63 The recognition of different classes and etiologies of liver disease, their influence on patient morbidity and mortality, and the development of medical and surgical therapies demanded the introduction of techniques not only for diagnosis but also for assessment of disease severity, as judged by the impairment of overall liver performance and ultimately its impact on prognosis. The early decades of the 20th century witnessed the development of a serum bilirubin test,64 utilization of Bauer's 1906 galactose test,65 hippuric acid synthesis assays66 based on the research of Armand J. Quick (of Quick Test fame67), and tests based on the disposal by the body of a rainbow of dyes: indigo carmine, Congo red, methylene blue, Evans blue, Rose Bengal, indocyanine green (ICG), and arguably the most popular, the now-obsolete bromsulphalein (BSP) that is gloriously purple in alkaline solution. The clinical importance of the 1913 van den Bergh reaction for bilirubin estimation in the blood64 was endorsed by many clinicians.68 Serum bilirubin measurement subsequently became an important tool for distinguishing the different causes of scleral icterus—the equivalent Greek term for the Latin/French descriptor jaundice that refers to the yellow discoloration of the sclera, mucous membranes, the skin, and even cerebrospinal fluid—that Galen inferred as being either obstructive, concomitant, or hemolytic.15 This included the detection of latent jaundice,68 meaning an elevation of serum bilirubin below a level of ~3 mg/dL that should be evident on careful clinical inspection in a good light. The linguistic origins of both jaundice and icterus are discussed elsewhere in this series, as well as the ancient Greek and Jewish beliefs that placing a golden thrush or pigeon near the umbilicus would cure jaundice/icterus69—a practice that was fatal to the bird and that Celsus might have considered to be "complementary and alternative medicine." It was not until the 1950s that the diagnostic value of the serum transaminases (officially referred to as aminotransferases since 196170) was appreciated in the diagnosis of viral hepatitis.71 There are many clinical applications for liver-associated serum biochemical tests that include aminotransferases, bilirubin, alkaline phosphatase, and albumin,72 which are usually bundled together with the Quick prothrombin time (i.e., the number of seconds that it takes plasma to clot in a test tube)—a major facet of blood coagulation in which the liver has a near monopoly.67 Such blood test bundles are popularly but, as Gerald Klatskin pointed out in 1948,73 erroneously denoted as "liver function tests" (LFTs), yet they are widely used essential noninvasive tools of hepatology. It is not commonly known that the term liver function test had been in use since the 1930s59 at least and included some curious laboratory procedures that are reminiscent of alchemy and witchcraft, in which the flocculation of negatively charged colloids of gold by serum globulin or the precipitation of gammaglobulins from serum by heavy metals, pungent phenols, or mixtures of sheep brain cephalin and cholesterol was relied on to distinguish among different etiologies of jaundice and other liver afflictions.74 Yet it must be conceded that, like Voltaire's quip about the Holy Roman Empire,# # In his 1756 Essay on Customs (Essai sur les mœurs et l'esprit des nations; Fig. 12), Voltaire (the nom de plume of François-Marie Arouet, 1694-1778; Fig. 12) joked sarcastically of the Holy Roman Empire, that "It was…ni saint, ni romain, ni empire" (neither Holy, nor Roman, nor an Empire).75 LFTs are neither liver-restricted, nor measures of its function, nor really tests of tolerance or performance73 (in the sense that a glucose tolerance test assesses glucose handling quantitatively or that creatinine clearance and cardiac output reflect the percent of kidney and heart performance, respectively). Be that as it may, LFTs are widely used to: (1) screen for liver disease, including injury caused by a wide spectrum of medical, surgical, radiological, and radiation interventions, and by medicinal and recreational agents, including herbal and dietary supplements and other complementary and alternative medicines; (2) assess its severity; (3) monitor disease progression; and (4) measure the efficacy of various therapies. Despite the obvious limitations, LFTs are indeed often interpreted as global tests of liver function. Biochemical tests by themselves or combined with complications of portal hypertension like ascites and encephalopathy have been used to assess global hepatic function. Incorporation of both biochemical and clinical information to determine prognosis was the basis of the Child-Turcotte classification that was developed, using actuarial statistics for the first time in surgical research, by Jeremiah G. Turcotte76 (1933-2020), who was an instructor in the Department of Surgery chaired by Prof. G.C. Child 3rd (1908-1991) at the University of Michigan (Fig. 13). The Child-Turcotte classification used preoperative serum albumin, serum bilirubin, the severity of ascites and encephalopathy, respectively, and an assessment of nutritional status. Using these variables, patients with cirrhosis who had undergone portosystemic shunting under Child's care were designated as class A, B, or C75 (according to a liver disease stratification scheme published 3 years previously by Wantz and Payne77); patient survival was compared among these three classes.76 Child-Turcotte class A patients were determined to be the best surgical candidates. With time, unfortunately, the designation often came to be abbreviated as the "Child Class," as Turcotte's name was rather unceremoniously dropped. In a follow-up study published by Pugh, a medical resident, and others from the late Roger Williams's group in the United Kingdom,46 nutritional status was thought to be difficult to define and was replaced by the prothrombin time (and later the international normalized ratio [INR]); the ensuing Child-Turcotte-Pugh**** All too often, the score or class is known as Child-Pugh, once again denying Turcotte his eponymous due. (CTP) classification became the standard to determine operative risk for portosystemic shunt surgery. Scores of 1 to 3 were assigned to the values of the five individual variables, namely, prothrombin time (or INR), bilirubin, albumin, ascites, and hepatic encephalopathy, and the sum of the five individual scores was then used to score the severity of liver disease (Table 1). Patients with scores of 5 to 6 points were classified as CTP class A, 7 to 9 points as CTP class B, and 10 to 15 points as CTP class C. Transjugular intrahepatic portosystemic shunts (TIPSs) were described in 198978 and started becoming widely used in the 1990s, but some patients were at high risk for procedure-related mortality. Similar to the development of the CTP score and using data from four centers in the United States, investigators at the Mayo Clinic developed a prognostic model to predict survival after TIPS.79 The variables in the model were the serum total bilirubin, INR (for prothrombin time), serum creatinine, and etiology of liver disease. Later this model was also found to predict survival among patients with cirrhosis not undergoing TIPS.79 The model, originally termed the Mayo End-Stage Liver Disease Model (MELD), was validated in hospitalized patients with cirrhosis and ambulatory patients with cirrhosis of varying etiologies, including primary biliary cirrhosis, as it was then known; it was independently validated in an inception cohort of patients with cirrhosis in Italy.80 Although developed as a prognostic tool to determine mortality risk after TIPS, the MELD score received widest recognition as a tool to prioritize organ allocation for liver transplantation. Organ allocation for liver transplant in the United States was prioritized in the 1990s largely on waiting time on the transplant waiting list. Patients with ALF received the highest priority (Status 1). Patients with CTP scores ≥10 were assigned to Status 2,