Liver fibrosis: Our evolving understanding

Liver fibrosis — a consequence of excess alcohol consumption, viral infection, metabolic dysfunction, disorders due to mutations in the genetic code, and autoimmunity (when the body’s immune system cannot distinguish between self and foreign), among many etiologies — has sickened people from paupers to princes for millennia. The aforegoing opinion reflects the timelessness of the causes of liver fibrosis as well as the commonality of its mechanisms. Only recently, however, has the mechanism of liver fibrosis begun to be understood. While this has been a decidedly nonlinear process of discovery, we find ourselves today considering fibrosis at length scales ranging from the nano- (derived from the Greek word νάνος nanos for dwarf) and implying a factor of 10−9, for example, a nanometer or one thousand millionth of a meter, to the meso- (from the Greek μεσαίο mesaio meaning intermediate) and the macro- (from Greek μακρός makrós for large) levels. Time scales range from milliseconds to days to decades. [Other extreme factors are 10−24 or yocto and 1024 for yotta, and as long as we are considering extraordinary dimensions of scale, it is amusing to recall that the proprietary name of the Internet search engine Google — a creative or accidental misspelling of googol for the number 10100 that signifies the large amount of information that can be retrieved — has become a generified verb, and yet the Google trademark has been legally upheld and so far, at least, has avoided genericide.] This review will provide a historical overview of liver fibrosis research, and then will highlight some of the key advances and most memorable and impactful publications in liver fibrosis in the modern era, particularly those most likely to impact the field through the next decades. LIVER FIBROSIS AND CIRRHOSIS IN THE PRE-MODERN AND MODERN ERAS: RECOGNITION AND NAMING Given the many etiologies of liver fibrosis and cirrhosis, including alcohol excess, it is certain that these pathological states have existed since antiquity. Greek physicians are credited with palpating the liver and recognizing hardening as abnormal; however, it wasn’t until the Renaissance that Leonardo da Vinci (1452–1519) and Andreas Vesalius (1514–1564) carried out anatomical dissections of human livers, describing the appearance of cirrhosis and, in the case of Vesalius, linking it to excess alcohol consumption.1,2 In the modern era, the great anatomic pathologist and physician of Padua, Giovanni Battista Morgagni (1682–1771), father of the mechanistic approach to medicine and the use of autopsies to advance understanding of the disease,3,4 is credited with identifying liver fibrosis and cirrhosis in some of the more than 600 autopsies he reported in his 1761 book De sedibus, et causis morborum per anatomen indagatis (The Seats and Causes of Diseases Investigated by Anatomy) (Figure 1).4FIGURE 1: Frontispiece from Giovanni Battista Morgagni’s book, De sedibus et causis morborum per anatomen indagatis libri quinque. Venetiis: ex Thypographia Remondiniana; 1761.3 Available at the Open Library (https://openlibrary.org/)René Laennec gave cirrhosis its name after the Greek word κίρρωση kirrhosi, meaning tawny (orange-brown), in a footnote in an 1819 paper (De l’auscultation mediate) describing the physical signs of pulmonary diseases and the development of the stethoscope. More substantially, Laennec provided extensive descriptions of cirrhosis in an incomplete and only partially published manuscript (1804–1808), Treatise of Pathological Anatomy, that had been cited in an 1824 French medical dictionary5 and an 1839–1847 British Encyclopedia of Anatomy and Physiology6 — all of which is discussed in detail by Jacalyn M. Duffin,7 of the University of Ottawa, Canada. Cirrhosis was, however, first described across the English Channel by pathologists John Browne in 1685, in a treatise entitled “A liver appearing glandulous to the eye”8 and Matthew Baillie in 17939 but, strange to relate, he only published the accompanying illustrations (Figure 2) 6 years later.10 Cirrhosis and fibrosis were described histologically in the 18th and 19th centuries by, among others, Robert Carswell (1793–1857, Professor of Pathological Anatomy at the University College, London), who characterized cirrhosis as a state of atrophy with variable amounts and distribution of contractile fibrous tissue, cirrhotic nodules, and vascular compression (Figure 3).11 In the 20th century, the “Father of Hepatology,” Hans Popper (1903–1988, one of the founders of the American Association for the Study of Liver Diseases [AASLD]), further defined the pathological features of fibrosis and cirrhosis,12 notably in alcoholic and cholestatic liver disease, although his writings encompassed all of the major liver diseases and he was the first to describe capillarization of the sinusoids in chronic liver disease.13FIGURE 2: (A) John Browne’s illustration of a glandulous-appearing (ie, cirrhotic) liver. Key: Browne’s own upper case letters, A–G, are shown within the drawing of the cirrhotic liver itself): A, left lobe; B, concave part of the right lobe; C, cut surface of the right lobe; D, black spots, possibly representing divided vessels; E, gallbladder; F, portal vein together with the bile duct; G, liver tissue lying between the vena cava and the portal vein and bile duct; and H, vena cava.8 (B) Matthew Baillie’s illustration of a cirrhotic liver. From a series of engravings accompanied with explanations that are intended to illustrate the morbid anatomy of some of the most important parts of the human body, Fascicle 5, Plate II. A portion of the external surface (top) and cross-section (bottom) of the liver studded with tubercles. Line drawings by William Clift (John Hunter’s former assistant) and engraving by James Basire.10FIGURE 3: Plates from Carswell’s 1838 book Elementary Forms of Disease.11 (A) Plate shows various stages of cirrhosis in humans and (mid-right) a cow, with a human liver showing venous compression (bottom). The upper right shows the same liver, with lobules surrounded by fibrous tissue. (B) Section of the same human liver (above in A), showing atrophy and fibrous replacement.STERNZELLEN USHER IN THE 20th CENTURY AND A NEW ERA OF FIBROSIS RESEARCH While the great 19th and 20th century anatomists and pathologists provided landmark descriptions of fibrotic liver disease, it was in the late 19th century that Karl Wilhelm von Kupffer paved the way for the modern era of liver fibrosis research and specifically an understanding of the cell biology of the disease. In an 1876 letter to the anatomist Wilhelm von Waldeyer, von Kupffer provided the first description of hepatic stellate cells (HSCs), which he called “Sternzellen” after staining dog liver sections with a gold chloride method in an unsuccessful attempt to identify nerve fibers (Figure 4).15,16 We now appreciate that the gold precipitation Kupffer observed was the result of vitamin A within the cells. Although Kupffer himself later concluded that these new cells were “special endothelial cells of the sinusoids,” he had suggested in his original description of Sternzellen that they were connective tissue cells (part of the perivascular connective tissue network, or “perivasculäre Bindgewebzellen” described by Waldeyer),17 a prescient view given our present understanding of stellate cells as pericytes with a critical role in liver fibrogenesis, and his report stands as the first to appreciate the unique localization and anatomy of the HSC.FIGURE 4: Kupffer’s drawing of Sternzellen in a dog liver, as stained by the gold chloride method.14After Kupffer’s initial description, HSCs (also known in the literature as fat-storing cells, lipocytes, and eponymously as Ito cells15) were found to be widespread in the liver and were reidentified many times as painstakingly detailed by Kenjiro Wake (Tokyo Medical and Dental University), and the German anatomist, pathologist, and histologist Karl Wilhelm Zimmerman (1861–1935), who highlighted their pericyte nature; Toshio Ito (1904–1991)15 who noting their fat storage called them “Fettspeicherungszellen”; and by Shinsuke Suzuki (who appreciated their interstitial nature).18 The most extraordinary descriptions of stellate cells after their original identification by Kupffer were from Wake (Figure 5), who used silver impregnation to visualize their extraordinarily complex cytoplasmic processes and their anatomic relationships to the hepatic sinusoid and other components of the liver microanatomy.18 Wake also contributed significantly to the field with detailed descriptions of the history of HSC research.16,18 The recognition that the varied concepts of HSCs were unified came with the agreement by 98 investigators in 1996 on the use of the term HSC as a unified nomenclature.20 Although there was significant initial disagreement in the field, the name is now widely used.15FIGURE 5: Images from Kenjiro Wake, showing: (A) The complexity of HSC processes and relationship to the sinusoid. (B) Rat HSC showing complex processes around sinusoids, Golgi silver method. Reprinted from Wake.19 (https://creativecommons.org/licenses/by-nc/4.0/).THE GOLDEN AGE OF STELLATE CELLS What could be viewed as the “golden age” of HSCs years with descriptions from et (Figure and et describing to of stellate cells from and then from was appreciated that HSCs — to in the literature as or — on tissue or and that the cells and a of other components and of the fibrotic The that stellate cells were cells in the of of from in on the and of as by his former in the field of and of The role of stellate cells, as to other cells of the liver as Kupffer cells, and endothelial as of was however, a paper from then in the of at the University of that stellate cells, among the liver cell are to a for their role in HSCs from liver by the of that the and the due to the long Reprinted with from et a of in fibrosis research, as by the days of the in (Figure with significant in understanding the the many and factors the and the of by stellate cells. The research from this was by Professor of at the of at in in in a that to stellate cells as and cells of the of the most important of stellate cells, and the after of their is which and and other and the of and key incomplete that contributed to this in the late 20th century, in to those most of the in the liver fibrosis the of who contributed to understanding the and other factors by and stellate cell fibrogenesis, and in fibrosis of liver fibrosis as in a review from by Professor of of the University for Liver and and of at the University now at the University of Medical per in and from of the investigators who this of fibrosis research While — as a — and — as a — were the of initial research and are appreciated to be major of stellate cell there is a complex of between cells of the liver immune and a of and cells, and and among many now in great through cell and other at the in the and of is around the HSC research was stellate cells were by first paper as a was a review of stellate cells the the pathologist James Professor and of and and the and of at which was in to those stellate cells. in to hepatic stellate cells, vitamin cells are found the body, at stellate cells are now appreciated as key for the in and disease, with a particularly important role in LIVER FIBROSIS IN THE CENTURY The which term the of has the and of of the of also the of new — — research and and is a in fibrosis research and between and In of the it is that in many fibrosis and cirrhosis a characterized by cell and and that there are components of a liver fibrosis of tissue fibrosis in there are between fibrosis and and as by and in their on the the are the many for the of fibrotic diseases of the liver, including the and for chronic (Figure and the system for liver now metabolic liver to all of these is a on of the of other the the of cirrhosis, is in the history and of with liver as well as the for however, have to a new for the of and features of In a of investigators an of the 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