Never say dye

Authors

  • Adrian Reuben M.B.B.S., F.R.C.P.

    1. Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC
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“Life is short, the art is long, occasion sudden, to make experiments dangerous…”.1 With these opening phrases, the first 2 of which are chiseled in daunting admonition over many a medical school entrance,2 Hippocrates began his maiden aphorism more than 2000 years ago, and reinforced the idea he alluded to repeatedly in his Oath, namely that Medicine is an art and not a science. Perhaps that is why so many private physicians' offices in this country are housed in commonly named Medical Arts Buildings and seldom, if ever, in Clinical Science Buildings (Author's note: see author's address below). However, if the Science of Medicine is inexact, even today, how much more so is the Language of Medicine,3 with its glut of abbreviations, surfeit of acronyms, overabundant superfluity of tautomerism, ostentatious grandiloquism, ambiguity, euphemism, and occasional obfuscation. I have not even mentioned the use of trade names, slang, jargon, and gibberish.3 This is not to imply that physicians as a profession are antisemantic but simply to note that while they are busy saving lives with dedication and skill, they are recklessly murdering the language. This may be the reason that physicians turn to other occupations4 such as politics (Sun Yat-Sen was the first President of the Chinese Republic in 1911/1912, Che Guevara a political activist in Cuba, and Howard Dean is a current Presidential aspirant in the U.S.), music (Alexander Borodin and Hector Berlioz), painting (Sir Roy Calne, a transplantation surgeon in Cambridge, UK), and, most of all, literature. Perhaps these individuals choose such endeavors to escape from or atone for the linguistic transgressions of their coprofessionals. Goldsmith, Chekhov, Keats, Schiller, Somerset Maugham, Conan Doyle, Gertrude Stein, Michael Crichton, and many others thus absconded from the clinic to write.

Few of us now yearn for the days of copious longhand notes written painstakingly in copperplate, but it would take a cryptographer of the stature of Jean François Champillion (the ultimate decipherer of the Rosetta Stone) to fathom the admission jottings of contemporary medical residents. Who could tell that a “69yo WM, PMH COPD, CABG, CVA and DMII c/o DOE and CP” actually refers to a 69-year-old white man with a past history of chronic bronchitis, coronary artery bypass surgery, a stroke, and late-onset diabetes who complained of exertional dyspnea and chest pain. No doubt on PE (physical examination), the patient was NAD (in no apparent distress) and then had a CXR and EKG (both self-explanatory), followed by a CAT scan (by computed axial tomography and not by cognitive analytic therapy nor any form of coital alignment technique) to r/o (rule out) PE (pulmonary embolism).

Acronyms are not usually intuitive either. HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome expresses a degree of urgency but it does not explicitly demand the services of an accoucheur. POEMS syndrome has a lyricism that is not fitting for the association of polyneuropathy, endocrinopathy, monoclonal gammopathy, and skin disease that it summarizes. NAFLD (nonalcoholic fatty liver disease), all too popular today, sounds like an adjective for a bored or disgruntled patient. Some of the more ingenious abbreviations are Bx for biopsy, Sx for symptoms, Tx for transplant, Hx for history, and Dx for diagnosis, which follow the form of Rx for treatment. Rx is derived from the ancient symbol ℞, the so-called superscription on a prescription, which generally is believed to be a contraction of the Latin imperative recipe, “take thou” (from the verb recipio), whereas the flourish at the end of ℞ is possibly the sign of Jupiter (itself probably derived from the Egyptian Eye of Horus5), whose name is invoked in the therapy to aid the healing.6, 7 In similar format, one could suggest the use of Xx for female and Yx for male, to replace the commonly used symbols of Venus and Mars, respectively. When physicians describe the stools of a patient with esophageal variceal or peptic ulcer bleeding as melenic, melanic, or melanotic, is this their classical Greek education breaking through or do they simply not know that melena already means a dark tarry stool? The use of diaphoresis for sweat, ambulate for walk, and syncope for faint are examples of grandiloquence, and what could be more ambiguous, euphemistic, and obfuscated than the words idiopathic, cryptogenic, primary, or essential when used to hide our ignorance of the diagnosis or its cause. However, what is certain to “stiffen the sinews, summon up the blood, disguise fair nature with hard favour'd rage; Then lend the eye a terrible aspect”8 in every self-respecting card-carrying hepatologist is use of the phrase liver function tests or its equally opprobrious abbreviation (LFTs).

It is tempting to dismiss LFTs much as Voltaire did the Holy Roman Empire–the Northern European territory (which had pretensions as a successor state to Charlemagne's empire) over which German princes ruled from the time of the coronation of Otto I (962 CE) to the renunciation of Francis II in 1806. Voltaire joked that it was neither Holy nor Roman nor an Empire (“…ni saint, ni romain, ni empire”9) and, in the same vein, we know that LFTs are neither liver-specific, nor do they assay liver function solely or well, nor are they really tests (in the sense of a glucose tolerance test, a cardiac stress test, pulmonary function tests, etc). The other criticism of LFTs is the absence of an accepted strict definition of what is actually meant by the term. In an informal opinion poll conducted recently at the Medical University of South Carolina (unpublishable personal observations) of fledgling, mature, and latent physicians (from nonspecialists to those specializing in gastroenterology), including the Chair of Medicine, Chief of Staff of the hospital, Dean of the College of Medicine, Academic Compliance Officer (who was formerly Chair of the Institutional Review Board and Director of the Office of Research Integrity), and the President of the University, there was some degree of consensus but not uniformity. All but 1 of the 52 physicians polled admitted that they use the term LFTs but many, on questioning, became noticeably uncomfortable at this confession. With only four exceptions, the residents and fellows identified serum bilirubin (sometimes direct as well as total), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and albumin as core measurements; one each mentioned lactic acid dehydrogenase and γ-glutamyltransferase; and a few noted prothrombin time (INR) whereas approximately two-thirds included total protein. Such unanimity was less likely among the older physicians, some of whom counted only AST and ALT as LFTs, whereas others included only proteins and prothrombin time in their definition of LFTs. Some senior respondents admitted to using the term liver function tests but gave politically correct and not factual answers for their definitions.

Early in the 20th century, publications first appeared that described the performance of true liver function tests in humans, achieved by following the fate of orally or parenterally administered substances that were believed to be handled by the liver.10–14 Of course the detection of bilirubin in the blood had been described in 1858 by Kühne,15 made possible by the discovery of bilirubin itself16 and prompted by the fact that jaundice was a cardinal presenting feature in hepatobiliary disease, before subclinical detection was feasible or even imagined. The major challenge therefore was to distinguish between mechanical biliary obstruction and disease of the liver itself, at which the van den Bergh reaction hinted,17 by separating indirect-reacting bilirubin from the direct-reacting component that was found in patients with large bile duct obstruction (and some other liver disorders) but not with hemolytic jaundice. In this clinically important endeavor, several approaches evolved in the era before accurate cross-sectional imaging of the biliary tree by CAT scan, ultrasound (US), and magnetic resonance cholangiopancreatography (MRCP) or direct biliary visualization by endoscopic retrograde cholangiopancreatography (ERCP), and percutaneous transhepatic cholangiography (PTHC) added yet another acronym and more abbreviations to the medical dictionary. Early on, methods that were devised to detect changes in serum globulins without the use of electrophoresis18 were found to give abnormal results in patients with liver disease. These laboratory procedures relied on either the precipitation of gammaglobulins from serum by solutions of zinc sulfate or other heavy metals19; thymol, phenol, naphthols, carvacrol, and other pungent phenols20; or the flocculation (precipitation) by serum globulins, specifically gammaglobulin, of negatively-charged colloids of gold21 or a mixture of sheep brain cephalin and cholesterol22 in the stabilizing presence of albumin. Although it was readily acknowledged that the results of these precipitation and flocculation tests reflected the influence of parenchymal liver injury on serum protein fractions and did not measure any known liver function,23 the phrase liver function test21 (or tests of liver dysfunction20), which had been in use since the 1930s at least,24, 25 became popular23, 26, 27 and its use spread.28, 29 In addition to the claim that such tests could reliably differentiate obstructive from nonobstructive jaundice22 and generally but nonspecifically indicate the presence of liver injury,23, 27–29 it also was alleged that differences in results between individual tests when performed as a battery could distinguish cirrhosis from hepatitis,23 discern the different causes of acute parenchymal damage,20, 21 and even predict early resolution of acute hepatitis.27

The advent of assays for tissue enzymes in the circulation brought an additional dimension to the diagnosis and even the detection of hepatobiliary disease. These new tests did not assess liver function either but, by now, the die was cast and they too came under the “liver function test” rubric. The measurement of serum alkaline phosphatase30–32 and later γ-glutamyltransferase33 and 5′-nucleotidase34 helped clarify the diagnosis of cholestatic or obstructive jaundice but, in common with other circulating tissue enzymes, alkaline phosphatase in the serum is not organ-specific nor restricted to a hepatobiliary origin. Similarly, the measurement of what were once called transaminases35 (serum glutamic-oxaloacetic transaminase [SGOT]36, 37 and serum glutamic-pyruvic transaminase [SGPT]) played a parallel role in identifying parenchymal injury, having been applied initially to the diagnosis of myocardial infarction38 (in the case of SGOT) using methodology devised by Karmen in the 1950s, while he was still a medical student.39 Although most helpful in typical clinical cases,40 no enzyme measurement or any of the remaining battery of blood tests has never been a panacea for diagnosis.41 Once hepatologists became comfortable with the term transaminase and used it frequently, the predecessor of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) ordained in Moscow in August 1961 that the less easily pronounced name aminotransferase should be used instead.42 On reflection, perhaps this was a good thing because it discourages use of the jargon transaminitis, which is applied to a minor elevation of transaminases that is not necessarily accompanied by obvious or significant liver disease. However, for those wishing to perpetuate this custom, the more accurate but cumbersome terms aminotransferaseosis or aminotransferasemia could be substituted.

Throughout the 20th century, investigators continued to probe the liver's ability to handle exogenous compounds, to characterize the physiology of hepatic transport, and perhaps to come up with the ideal liver function test.43, 44 The turn of the 20th century was a colorful time in medicine and science, as chemists synthesized a profusion of dyes that were used as starting points for medicinal compounds, as well as for stains in histopathology, intravascular contrast agents in radiology, and test substances in physiologic studies, especially of the circulation and hepatic transport. Parenthetically, it should be noted that dye-based agents are no longer current in interventional radiology; the term contrast agent should be used instead and we should “‘never say dye.’ Among the palette of dyes used in liver studies were phenoltetrachlorophthalein, bromsulph(th)alein (BSP), indigo carmine, congo red, methylene blue, Evans blue, Rose Bengal, and indocyanine green (ICG). Based on earlier studies with phenoltetrachlorophthalein,45 the clearance of BSP from the blood46 became a popular test of hepatobiliary physiology and function47, 48 for nearly 50 years until the compound itself was phased out by the manufacturer (Hynson, Wescott, and Dunning, Inc., Baltimore, MD) because ICG, whose biochemical and physiologic properties were more suitable for this purpose anyway, did not cause tissue necrosis if inadvertently injected outside of the vein and was less likely than BSP to cause serious adverse systemic effects.49 An attempt had even been made to introduce radioiodinated BSP as an hepatobiliary nuclear medicine scanning agent50 but, figuratively speaking, the effort lasted only a little longer than the half-life of the 123I that was used for labeling, and 123I-BSP was abandoned in favor of the technetium 99m-labeled iminodiacetate radiopharmaceuticals that still are in use today for the nostalgically misnamed HIDA scan.

ICG, a pigment that was used in infrared photography and in the manufacturing of Kodak Wratten™ filters (Eastman Kodak, Rochester, NY), first was introduced into medicine and physiology in the late 1950s by Irwin J. Fox, a cardiologist at the Mayo Clinic. As a gift from a grateful patient who happened to be an official of the Eastman Kodak Company, Fox received a collection of dyes, including ICG, to test in circulatory indicator-dilution experiments. The physicochemical and physiologic properties of ICG51 suited Fox's studies well, especially because blood did not interfere with the spectrophotometric analysis of the dye. Indicator-dilution methods and results were published52 using what initially was called “Fox green”and later “ICG,” “green dye,” or, simply, “green.” The absorption and emission wavelengths (800–810 nanometers [nm] and 835 nm, respectively) are in the near infrared part of the spectrum and therefore can penetrate tissues, allowing the detection of the dye throughout many parts of the body. The development of a stable lyophilized dosage form by Hynson, Wescott, and Dunning, Inc. solved the pharmaceutical problem of the relatively brief aqueous stability of ICG. Soon after success was reported using ICG in indicator-dilution studies, the hepatic uptake of ICG, its secretion into bile without enterohepatic cycling, and its lack of urinary excretion were discovered.53, 54 Interest in ICG rose because its use promised to provide a reliable estimate of liver blood flow55 and a potential measurement of liver function.56

A key investigator in the hepatobiliary biology of ICG was Gustav Paumgartner (Figure), who retired just 4 years ago as Head of the prestigious Second Department of Medicine at the Klinikum Grosshadern Ludwig-Maximilian University in Munich. Dr. Paumgartner is widely considered to be one of the premier physician-scientists in Europe, with a publication record of greater than 500 articles; he was an Editor of the Journal of Hepatology, a past President of the German Society of Digestive and Metabolic Disorders, and is the recipient of numerous awards, including medals from the University of Helsinki and Chiba University, and the Hepatobiliary Biliary Achievement Award of the Sammy Davis Jr. National Liver Institute. Dr. Paumgartner has been on the Editorial Board of many prestigious journals, including the New England Journal of Medicine; he has been an Associate Editor of HEPATOLOGY and was elected a Fellow of the Royal College of Physicians of London. Dr. Paumgartner was raised in Neumarkt in southern Austria (where the family still maintains a small castle, Pichlschloss, which often is used for social and scientific getaways [see Figure]) and was a Fulbright Scholar at Princeton University. He graduated with a degree in Medicine from the historic medical school in Vienna and became involved in hepatic organic anion transport, and the hepatic handling of ICG in particular,56 during a fellowship with Carroll Leevy in New Jersey in the mid-1960s. Dr. Paumgartner's subsequent studies concerning ICG, bile acids, and other organic anions ranged from experiments at the membrane level to isolated hepatocytes, perfused livers, experimental animals, and humans in health and disease. Dr. Paumgartner's contributions to hepatology have included seminal works on bile acid metabolism and transport, gallstone dissolution with oral bile acid feeding and extracorporeal gallstone lithotripsy, and the pathogenesis and therapy of many liver diseases. The definitive work on the handling of ICG by the liver is his landmark review article published 28 years ago,57 which is a tour de force of scholarly detail, organization, clarity, and comprehensibility that is a model for understanding the physiologic background of organic anion transport by the liver, and provides a backdrop for modern studies on transport proteins, their respective genes, and the processes that regulate them.

Figure 1.

Gustav Paumgartner at Falk- Symposia #12 and #33, respectively, in 1973 (above left) and 1982 (above middle) (reprinted with permission by the Falk Foundation); relaxing at Pichlschloss in 1996 (above right) (photographs courtesy of Dr. Alan Hofmann); with wife Christel and young friends in hepatic transport (and their families) at Pichlschloss in 2002 (below) in a photograph taken by Dr Peter Fickert (courtesy of Dr. Ulrich Beuers).

Despite the fact that gallstone dissolution and lithotripsy have been eclipsed by laparoscopic cholecystectomy and there does not appear to be a place in the modern world of MELD (Model for End-Stage Liver Disease) for a true test of liver function (unless this becomes useful in the future in the evaluation of donor livers,58 liver rejection, or resection), there is no doubt that Dr. Paumgartner represents the best in European clinical science and has enriched the world of medicine, physiology, and pharmacology, especially as applied to the liver. All of this has been accomplished with an enviable mixture of charm, wisdom, integrity, sincerity, precision, and clarity, and an understated sense of humor. Space does not permit comment on his prowess in dance, skiing, and scuba diving. In short, he is the epitome of a scholar and a gentleman.

Although the brilliance of ICG may have faded a little in the world of hepatology, it is enjoying a new lease on life in many other fields in medicine, particularly in ophthalmology59 and coronary artery surgery.60 With regard to the dye indocyanine green, it appears justified to apply Mr. Price's optimistic exclamation, “Never say die”, from Charles Dickens' The Pickwick Papers,61 with the original spelling, meaning, and intent intact. With regard to the dysfunctional label LFTs, it appears as if we are burdened with that clumsy designation unless we can persuade an influential world body such as the NC-IUBMB to mandate that we refer to the consensus panel of biochemical tests that our residents identified together with INR by the acronym BAAAATI (Bilirubin, AST ALT, Alkaline phosphatase, Albumin, Total protein, INR), or BA4TI for short, in which A4I addresses liver synthetic function, A1A2 indicates parenchymal cell injury, BA3 addresses cholestasis, and total protein permits the calculation of globulin. The acronym LIMP, for Liver Ill-health Metabolic Panel, is somewhat more catchy although one wonders whether it sounds vigorous enough to garner widespread support.

Acknowledgements

The author acknowledges with deep gratitude Dr. Alan F. Hofmann of the University of California at San Diego for enriching this article with so much information and for providing photographs and his personal appreciation of Dr. Gustav Paumgartner; similar sentiments also were generously forthcoming from Dr. James L. Boyer of Yale University and Dr. Ulrich Beuers of Ludwig-Maximilian University, Munich. Dr. Theodore R. Carski, formerly Corporate Medical Director of Becton Dickinson and Company, Inc. (of which Hynson, Westcott, and Dunning, Inc., was a small division), generously provided the colorful information concerning the history of indocyanine green (now marketed by Akorn Inc., Buffalo Grove, IL). Dr. Ronald O. Nickel, Associate Professor of Pharmacy Practice at the Medical University of South Carolina, delved into the origins of ℞. Finally, Margie Myers continues to win the monthly Library Award for archived literature retrieval and marathon photocopying, as well as the author's continuing appreciation for her expeditious manuscript preparation.

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