Praise ye the god of iron1

Authors

  • Adrian “Rusty” Reuben MBBS, FRCP

    Member, The International BioIron Society, Professor of Medicine
    1. Division of GI/Hepatology, Department of Medicine, Medical University of South Carolina
    Search for more papers by this author

Eagle-eyed readers of Landmarks in Hepatology will surely have noticed the frequent references to birds in the history, lore and science of hepatology. Orioles and pigeons were considered by the Ancient Greeks and the writers of The Talmud to dissipate jaundice,2 force-fed geese provided the first animal model of hepatic steatosis for the Ancient Egyptians and Romans in turn,3 and an eagle (or was it a vulture?) first demonstrated to the Ancient Greeks the remarkable regenerative powers of the liver.4 In modern times, wild mute swans give inight into hepatic copper overload,5 and ducks,6 herons7 and storks8 highlight the biology of the hepadnaviruses. Why there is even a Liver Bird, two of which, with spreading wings, adorn the twin clock towers of W. Aubrey Thomas's magnificent Royal Liver Building that stands proud and majestic against the skyline of the City of Liverpool, at Pier Head on the banks of the Mersey River (Fig. 1). These mythical creatures sculpted just before the first World War, by German émigré Carl Bernard Bartels, for the building that still houses the offices of the Royal Liver Assurance Friendly Society, are unfortunately as fictitious as the Roc and as dead as the Dodo and have nothing to do with the liver. Instead, the Liver Bird (pronounced with a long “i” as “lyver” bird) was modeled loosely on the cormorant, which in earlier times was known as the “laver” bird from the laver or seaweed on which it fed along the Mersey. In 1655 the Liver Bird became the emblem and seal of Liverpool after the original corporate Seal — the eagle of St. John, the emblem of the House of King John (adopted by the city in 1207) — was lost when the city was sacked by cavalier forces in 1644. Whereas the Liver Bird cannot justifiably be an avian symbol for hepatology, fortuitously another fowl fits the bill perfectly, so to speak, namely the mynah bird (Gracula religiosa) of the family Sturnidae. Mynahs are uncommonly susceptible to hepatic iron overload and have a defect in iron metabolism that resembles human hemochromatosis.9 Although other animal species, such as New World Monkeys10 and the black rhinoceros,11 and some other bird families such as toucans and birds of paradise,12 show a high prevalence of iron overload and progressive hepatic iron deposition, this is the most common metabolic disorder in the mynah, which is also the most frequently reported bird species to suffer from hemochromatosis.13 What better crest for a common human liver disease could there be?

Figure 1.

Carl Bernard Bartels's 18 foot tall copper Liver Birds, perched with wings outstretched atop the clock towers of the famed Royal Liver Building. Local legend is that if these mythical creatures fly away, Liverpool will cease to exist. Photograph reproduced with permission © FreeFoto.com.

It is unnecessary to stress the importance of iron for the solar system, planet earth, terrestrial life and human civilization but, nonetheless, it is worth reminding the readership of a few salient ferreous facts. Although the sun contains only trace amounts iron, the recent finding in meteorites of daughter isotopes of the short-lived extinct radioisotope 60Fe — which has a half-life of only 1.5 million years — provides what is being called a “smoking gun” in favor of a supernova explosion preceding and probably triggering the formation of the solar system.14 In contrast, a third of the mass of the earth, the densest major body in the solar system, consists of iron, which is found with nickel in solid state in the inner core and as an electrically conducting liquid in the outer core that is responsible for the earth's magnetic field. In a sense, iron is the most precious of metals whose existence and use dates from prehistoric times, more than 7,000 years ago. Earlier civilizations referred to iron in their writings, including the use of steel in China 2,500 years BCE15 and the Vedic poets' assertion that their ancestors created utensils from it. The Iron Age, the last stage of the archeological sequence known as the Three-Age System (stone, bronze and iron) marked the period of development of technology, and in Ancient Babylon the god of iron was praised along with the gods of gold, silver, wood, stone and brass.1 Iron can be thought of as a basis for terrestrial life, being the core of enzyme systems in organisms ranging from bacteria to elephants, and serving as an integral part or cofactor in many reactions, such as hydroxylations, DNA synthesis, oxygen carriage and electron transport. But, whereas the Greeks felt that iron was a gift of the Gods, this benevolence has turned out to be a double-edged sword, of benefit and risk.

The early history of hemochromatosis reads like a Who's Who of 19th and early 20th century medical eponyms. The French physician Armand Trousseau, who in later life suffered from his own eponymous syndrome of venous thrombosis associated with visceral cancer, is credited with the first clinical allusion to hemochromatosis. In a lecture on glycosuria, he mentioned a diabetic patient with “an almost bronzed” appearance.16 The first detailed description of a case of hemochromatosis by French pathologist Emile Troisier, included not only the fact that the patient whose autopsy he had performed had both diabetes and cirrhosis, but that the reddish-brown liver contained clumps of pigment.17 From these and subsequent reports by fellow countrymen, arose the French view that hemochromatosis was a syndrome of bronze diabetes and pigment cirrhosis.18–20 The hapless Victor Charles Hanot, who committed suicide (because of domestic strife) just before achieving his lifelong goal of a chair in medicine, championed the idea that diabetes was the primary disorder causing both cirrhosis and pigmentation.18, 19 Friederich Daniel von Recklinghausen, a colorful German pathologist who also had a syndrome or two named after him, espoused the opinion that the iron pigment was derived from the blood. Von Recklinghausen coined the term “hemochromatosis” that we use to this day, and his view could be reasonably thought to represent the German hypothesis of pathogenesis.21, 22 Variations on these two themes abounded at the turn of the 20th Century, along with other suggestions, such as Frank Burr Mallory's preoccupation with chronic copper poisoning as the culprit in this23 and other liver disorders. An answer to the contentious and sometimes even provincial dispute over the nature of hemochromatosis came in 1935 with the publication from Wolverhampton in the Black Country of England's Midlands, of Joseph Harold Sheldon's landmark 340 page, 569 reference monograph that was simply entitled “Hæmochromatosis”,24 which was based on his Bradshaw Lecture to the Royal College of Physicians.25 Sheldon had migrated from Kings College Hospital to the Royal Hospital Wolverhampton in 1921, just after the First World War, as a pioneer of the “brain drain” from the teaching hospitals of London to the provinces (Fig. 2). Although Sheldon is remembered for his seminal contribution on hemochromatosis, his greatest achievements were in geriatrics and these earned him the presidency of the International Association of Gerontology (1954–1957) among many other honors (Fig. 2). In a comprehensive review from the literature of 311 cases that he considered to be genuine (he discarded 34), Sheldon delineated the clinical features throughout the body of hemochromatosis, including suggested mechanisms for symptoms, a description of the metabolism of iron and other compounds, the pathological appearance of every organ system, chemical analyses of the tissues and, most important, a discussion of theories about the disease. As one eminent ferrophile recently explained to the author, without a pun intended, “Sheldon hit the nail on the head” when he stated, in conclusion, that a single disease was responsible for the involvement of many organs, and that this disease was caused by in inborn error of iron metabolism that had familial occurrence.

Figure 2.

Portrait of Joseph Harold Sheldon, which hangs near his commemorative plaque in the main corridor of the Sheldon Building, at New Cross Hospital in Wolverhampton UK. Photograph reproduced with permission of the Wolvenhampton History and Heritage Society, UK.

After the publication of Sheldon's authoritative study, one would have thought that the nature of hemochromatosis that he proposed would have been widely accepted and, in particular, that the disease was caused by excess body iron due to a genetically-mediated flaw in iron metabolism. Yet fully 28 years later the view was still being purveyed that nurture and not nature was the cause, in the form of excessive dietary iron that was often ingested unwittingly in alcoholic beverages.26 Richard MacDonald in Boston reasoned that idiopathic hemochromatosis was acquired and not genetic, and for this he proposed the name “Dietary Hemochromatosis”26 basing his hypothesis on evidence from several lines of inquiry. Having questioned Boston alcoholics, observed them in their natural habitat, collected their discarded bottles to identify the contents, and tried with limited success to speak to their retail liquor dealers, MacDonald was able to estimate the nature and quantity of their alcohol intake (mostly in the form of cheap wine27) and to estimate the cumulative input of iron from alcohol over the course of their drinking careers. MacDonald's study included a trip to Rennes, France, to estimate iron ingestion there too, as it seems that the population of Rennes, young and old (including children), quaffed iron-rich cider by the liter in place of water to quench their thirsts. MacDonald concluded from this and similar avenues of investigation that all cases of idiopathic hemochromatosis are actually acquired and not genetic, in the form of partial or nutritional cirrhosis (e.g., alcoholic cirrhosis) in which iron overload comes from ingestion too. Irrespective of the amount of iron in alcoholic beverages and any overingestion by this route, via other comestibles and even by hypochondriac ferrophages, overabsorption of dietary iron plays a major role in causing the iron overload of classical hereditary hemochromatosis,28 and iron acts synergistically with alcohol in causing liver damage.29 It also follows that the best means of removing iron from the body is by the medieval-like practice of blood letting, which was introduced even before the mechanism of disease was understood.30

Continuing support for Sheldon's genetic hypothesis was to come approximately 40 years later, when the results of the next landmark study in the field established a close association between hemochromatosis and HLA-A3 haplotype, which is located in the region of the short arm of chromosome 6.31 Another 20 years were to pass, however, before the most recent landmark event occurred, explicitly the identification of a gene that is mutated in the commonest form of hereditary hemochromatosis. Led by a small biotechnology company in California called Mercator Genetics, a regiment of investigators — even MEDLINE truncates the list of authors to 25 — commanding a fleet of DNA sequencers, successfully used a blunderbuss positional cloning strategy to find the responsible gene.32 Originally termed the HLA-H gene, because of the similarities between its proposed gene product and proteins of the major histocompatibility complex, its name was soon mutated to HFE, although this new designation invites continuing semantic speculation over its mysterious meaning and cryptic origin.33 Notwithstanding, the explosion of knowledge about all forms of hereditary hemochromatosis that has taken place in less than a decade since the publication of the HFE gene mutation would surely have delighted Joseph Sheldon, whose genetic prediction for this disease has been so completely vindicated. It does seem to be a pity, however, that the plaque that honors him and which hangs in the Sheldon Building of the hospital in which he worked, is made of aluminium and not iron.

Detailed descriptions of the phenotypic and genotypic features of the various forms of hereditary hemochromatosis, their pathogenesis and general iron pathophysiology, the role of HFE protein and players such as hepcidin, transferrin receptors, ferroportin, hephaestin, hemojuvelin and others, have all been consummately reviewed recently.34, 35 As with other genetic disorders that are widely distributed in the world, especially autosomal recessive ones, intriguing questions of an almost philosophical nature are posed concerning the origin of the gene mutation, its mode and pattern of spread and the presumed survival advantage that it confers.36 And so it is for HFE. The most popular suggested origin for the common cysteine to tyrosine substitution of HFE, at amino acid 282 (C282Y), is often referred to as the “Celtic mutation” because of its proposed beginning among the Celts of Northern Europe. This mutation probably occurred as a single unique event on the chromosome carrying an extensive histocompatibility haplotype, an “ancient haplotype”, possibly at or before the time of the Neolithic revolution approximately 4,000BCE, when the change from an iron-rich meat diet to a lower iron-availability cereal diet took place and when an increase in intestinal iron absorption would clearly have given a survival advantage. Other benefits of increased iron absorption may include resistance to certain infections.37 As for the spread of the gene, there are many hypotheses including blaming the Vikings, who are also held responsible for the origin and spread of the Z allele α1-antitrypsin deficiency trait38 and for Dupuytren's contracture39 — both of which are also associated with liver disease, as it turns out. One might say that the Vikings are identified in more than one way with a double-edged sword. The debate whether iron is a boon or burden to humans and mynah birds remains a philosophical polemic. In the meantime, we can leave the last word on the supremacy of iron to the poetry of Rudyard Kipling.40

‘Gold is for the mistress — silver for the maid!

Copper for the craftsman cunning at his trade.’

‘Good!’ said the Baron, sitting in his hall,

‘But Iron — Cold Iron — is master of them all.’

Acknowledgements

The author thanks Dr. Bruce Bacon for the loan of his personal copy of J. H. Sheldon's landmark monograph on hemochromatosis, and acknowledges him and Dr. Paul Adams for their iron-clad advice on this subject. Margie Myers is appreciated, as usual, for manuscript and literature retrieval skills.

Ancillary