The legend of the lardaceous liver
Authors: Adrian Reuben
Journal: Hepatology (2004)

If, like the current chronicler of hepatology history and lore, you have time during your busy day in the clinic or at the bench to pause and reflect on your craft, it will not take too long to realize how much the face of medicine has changed over the past 100 years or so. Not only has there been a metamorphosis in the investigation and treatment of disease, but time has transmogrified the ailments too. In the five score years and 10 since Nobel laureate Wilhelm Konrad Röentgen first captured on film the bones and ring of the hand of his wife, Bertha, on Friday, November 8, 1895, those modern voyeurs of the body's interior, the diagnostic imagers—who were once called radiologists—have perfected their tools and skills to peer into our innermost reaches with extraordinary resolution, using electromagnetic, sound, and positron emission vibrations. Not content with spectator status alone, these same imaging specialists now intervene too and with precision penetrate our recesses with their needles, wires, catheters, and balloons to inject, sample, and repair. In the 50 years since James Watson and Francis Crick unraveled the spiral mystery of DNA, molecular technology has been harnessed to diagnose the mutations, deletions, and substitutions of nucleic acids that cause disease, and it is even used to make corrections by inserting or removing genes. Where gene rectification is not possible, whole-organ and tissue transplantation bridges the gap. For those who are interested, these and many, many other advances have been catalogued most ably elsewhere.1, 2 As for the maladies themselves, some, like polio and pediatric Haemophilusinfluenzae in developed countries and smallpox worldwide, appear to have been vanquished, whereas new plagues have appeared, some acronymically like AIDS and SARS, and some geographically—for example Lyme disease and West Nile virus infection. Yet, despite considerable headway made in basic, translational, and clinical research, science and medicine are still beset with fad and fallacy, myth and legend, and deception and delusion, not only in the minds of the lay public but also in the thoughts of some professionals too. And against this distortion, as we will see, hepatology is not entirely immune. One ailment that exemplifies well the transformation of medicine over recent centuries is amyloidosis. This once common affliction lapsed in the wake of 20th century gains in the treatment of chronic infection only to enjoy a renaissance latterly because of our ability to sustain patients with other chronic diseases, like end-stage renal failure and diabetes, and our success in promoting old age. Robert Kyle, the highly distinguished Mayo Clinic hematologist and historian and graduate of the North Dakota School of Forestry, observed in his scholarly and exhaustive review3 that amyloidosis has had a convoluted history ever since the first description of "sago spleen" was reported almost 400 years ago in a patient with a liver abscess, jaundice, epistaxis and ascites, by Nicolaus Fontanus,4 a 17th-century obstetrician who presumably had a culinary interest. For the epicurean physician of the 17th century, the metaphor "sago" may well have suited the appearance of the spleen, with its follicles replaced by white amyloid, but not its wood-hard consistency. According to Thomas Bartholin, the Dane who discovered the lymphatic system and was first to describe the thoracic duct in humans, incising an amyloid spleen at autopsy produced a sound like cutting through spongy timbers,5 wherein perhaps lies the clue to Dr. Kyle's fascination with this disease. Successive physicians through the centuries had equal difficulty in characterizing the curious goo that inexplicably impregnated the liver and other organs of patients mostly suffering from tuberculosis, syphilis, chronic osteomyelitis, and mercury poisoning. In the grossly enlarged liver of a patient with tuberculous cervical adenopathy, or scrofula (also known as the "King's Evil"), Jeremiah Wainewright in 1722 described "a clay-coloured pituitous (i.e. mucus-like) substance."6 To Antoine Portal (1742-1832), the postrevolutionary physician of kings who helped establish the French Royal Academy of Medicine, the substance was reminiscent of bacon and therefore became designated lardaceous. To John Abercrombie, "First physician to His Majesty in Scotland," and his colleagues at the famous Edinburgh School raised on a diet of porridge, whisky, and haggis, the "Pale Degeneration of the Liver" appeared as impure beeswax.7 But irrespective of whether one took the Gallic or the Gaelic view of nomenclature, realization soon dawned that the gelatinous material that infiltrated the liver of chronic tuberculous-infected patients was, as Konrad Freihess Rokitansky predicted,8 albuminous and not fatty. In the 3rd edition of his textbook of liver disease,9 the illustrious and industrious George Budd10 described 5 patients with "scrofulous enlargement of the liver," from one of whom he had hepatic tissue assayed by Mr. Beale. As analyses of other cases by James Drummond also showed, Die speckige Leber–the greasy liver—of Rokitansky9 was "unusually poor in oil"11 but was rich in nitrogen, and as Budd observed, 81% of the solid component was proteinaceous.9 Yet, strangely enough, a committee of the Royal Society of London sided with the French over the lardaceous name, even though their own investigations suggested the presence of protein and not fat. In fact, William Howship Dickinson, who had a special interest in the kidney (which could also be lardaceous13), pleaded for a resolution of the nomenclature chaos,14 and for this reason the aforementioned committee was called.12 Dickinson proposed that the offending deposit for which they sought an appropriate name was formed on precipitation by acid of an albumin-bound protein component of the blood.14 Ironically, this prescient view was vigorously opposed by none other than Budd's notorious sociopathic nephew George Turnavine Budd,15 who, as the reader will no doubt recall, was Arthur Conan Doyle's nemesis.10 The terminal twist in this tortuous tail of taxonomy was as titillating as all that has tantalized us before. In short, Rudolf Ludwig Karl Virchow, the revered German pathologist, statesman, and undisputed high priest of morbid anatomy, decreed that the name that they were seeking all along was amyloid,16 and so it is to this day. But even that choice was circuitous, to say the least. From the Greco-Latin α´μυλo (amylon) or amylum for starch flour, the term amyloid was coined by the German botanist Matthias Schleiden, for an amylaceous material found in plants, probably cellulose (or some would say starch) that reacts blue and then violet with iodine-sulfuric acid.17 Virchow saw similarities between both plants and lardaceous disease, and the iodine-staining degenerative corpora amylacea of the brain that he took to be cellulose (or some would say starch), as the deteriorating human body approached the function of a vegetable.14 Virchow also dismissed the term lardaceous on gastronomic grounds, as he felt that those who used it were not connoisseurs of good bacon.16 Somewhat sarcastically, Virchow has been compared to Christopher Columbus, for the former set out to search for starch in the human body and found amyloid, just as the latter headed to India only to discover America.18 Once the contentious question of what to call the disease was answered, the vista was clear for clinicians, clinical scientists, and basic investigators of amyloidosis to describe its clinical features, define its nosology, discover its pathogenesis, and begin to devise therapy. Johann Heinrich Meckel von Hemsbach, Virchow's successor at Berlin's Charite Hospital, who incidentally preferred the term cholesterin to his predecessor's amyloid, extended the scope of the disease by applying the iodine-sulfuric acid test to many organs, including the intestine and the major blood vessels. In the 140 years or so since Virchow ordained its appellation, we have learned much about the classification, epidemiology, and natural history of systemic amyloidosis,19-21 its pathogenesis and clinical presentations, and diagnosis and treatment19-21 that nowadays can be based on what is known about mechanisms at the molecular level.22, 23 The diverse presentations of hepatic amyloidosis have been appreciated24 to include not only cholestasis,25-27 that seemingly was not seen by the physicians of old,9, 28 but also the complications of portal hypertension29 and liver failure,30 alone or in combination.26, 27, 30 Even the great William Osler remarked, "There are no characteristic symptoms of this condition. Jaundice does not occur; the stools may be light-colored, but the secretion of bile persists."28 Osler and the others would surely have been astounded at the use of liver transplantation for amyloidosis, when the latter is due to a genetic defect.31 This brings us, at last, to that part of the amyloid legend, or rather the myth, that still stalks us, namely the vexing problem of obtaining a tissue diagnosis in patients with presumed hepatic amyloidosis. Ask any seasoned clinician about that prospect, and he or she will become noticeably uncomfortable, as there is a strong tradition in hepatology that to biopsy an amyloid liver is to risk hepatic rupture or fracture. Yet few if any hepatologists have had that experience, and even fewer can cite the evidence that supports the concern. The caveat against biopsying an amyloid liver, which has been handed down from generation to generation of fellows over decades, actually derives from the overinterpretation of a case experience that was cited in a landmark review of the liver biopsy procedure32 published in 1947, which was first-authored by the soon-to-be-eminent Wade Volwiler (Fig. 1A) when he was an assistant in medicine and a fellow to Dr. Chester Jones at the Massachusetts General Hospital in Boston, MA. In their review of 234 attempted biopsies in 191 patients, using a 10-second technique with the Franseen modification of the Iversen-Roholm needle, which predated the far speedier Menghini method,33 there were 2 deaths. One of the deaths occurred in a patient with amyloidosis. In the case in question, the records show that the prothrombin time was prolonged 6 seconds, which was the arbitrary limiting value chosen for the procedure in those days, and, moreover, a main hepatic vein had been pierced that led to enough bleeding to split the friable amyloid and cause shock that was discovered 10 hours later. Although there is an increased bleeding risk due to Factor X deficiency in some patients with amyloidosis,34 and the vessels may be stiff with infiltrate (Fig. 1B), and though spontaneous rupture of the liver has been described in amyloidosis in humans35 and cats,36 most would agree that the demise in this case was due to vascular mishap that was not directly related to amyloidosis. Volwiler himself, who went on to found the renowned Division of Gastroenterology in Seattle and served as president of several prestigious medical organizations,37 a conservative, elegant, thoughtful and gracious man, did not consider amyloidosis to be a contraindication to liver biopsy, which has been done numerous times since without misadventure.24, 38, 39 (A) Dr. Wade Volwiler, founding Chief of the Division of Gastroenterology at the University of Washington in Seattle and one-time president of the American Association for the Study of Liver Diseases, the Western Association of Physicians, and the American Gastroenterological Association. His landmark review32 inadvertently gave birth to the myth of fracture surrounding the risk of biopsying an amyloid liver, as shown below in (B). Given the amyloid infiltrate that encases and props open the vessels, it is not surprising that bleeding could theoretically occur. Photograph of Dr. Volwiler reproduced with permission of the University of Washington. Who knows how such myths get perpetrated. As Robert J. Flaherty has said, medical myths are often persuasive pearls of punditry, which have the ring of truth, the aura of wisdom, and the flavor of logic.40 Medical myths are memes, those self-replicating units of culture that have a life of their own.41 Like viruses, they exhibit mutation from other medical concepts, evolve from pathophysiological principles, spread horizontally through the medical education culture, and exhibit vertical spread down through generations of health professionals. But now that the biopsy fallacy has been exposed, with careful preparation and by using impeccable technique, this mythical part of the legend of the lardaceous liver can be laid to rest. The author thanks Dr. James McGuigan for his reminiscences of Wade Volwiler and the myth of the lardaceous liver biopsy. The author recognizes Margie Myers, whose manuscript and administrative skills continue to delight.