The pioneers
The first description of a patient with haemochromatosis has been attributed to a French physician, dr. Armand Trousseau (1801 – 67), who in 1865 gave a lecture on glycosuria and a new syndrome presenting with diabetes, liver cirrhosis with yellow-grey granules and brown skin pigmentation in a 36-year-old male (fig 3) (4) .
Figure 3 a) Armand Trousseau. Lithography by J.B.A. Lafosse from 1866 (CC BY 4.0). b) First page of article from 1865 in which Trousseau describes the first known case of haemochromatosis. Clinique médicale de l'Hôtel-Dieu de Paris, digitised by the University of Ottawa.
The second case report was published in 1871 by his compatriot, professor Charles Troisier (1844 – 1919) (5) . At the time, it was not known that the pigment was in fact iron, and the disease was referred to as «pigment cirrhosis» until professor Victor Hanot (1844 – 96) introduced the name of «bronze diabetes» in 1886 (6) .
Rudolf Virchow (1821 – 1902), in his autopsies on organs with internal bleeding, had described a yellow-brown pigment referred to as haematin as early as in 1847 (7) . The pigment could be stained Berlin blue and thus contained iron. Berlin blue was a staining method known from Berlin, where alchemists in 1704 had discovered that a combination of blood, iron sulphate and potassium carbonate formed an insoluble dark blue pigment (8) . The pigment was also called Prussian blue because it was used to dye the uniforms of the Prussian army. In 1867 the German pathologist Max Perls (1843 – 81) improved the staining method by using potassium ferrocyanide which reacts specifically with trivalent iron oxide (9) . Perls’ staining reaction became the standard histological technique used to demonstrate iron pigment, which since 1888 has been called «haemosiderin» (10) .
In 1889 the German doctor Friedrich von Recklinghausen (1833 – 1910) was the first to stain liver autopsies from patients with bronze diabetes, thus demonstrating that the yellowish brown pigment was caused by massive iron deposition (11) . He believed that the iron stemmed from internal bleeding with haemolysis and catabolism of haemoglobin, which is why he named the pigment «haemochromatosis».
Over the next few decades, discussions about the cause of haemochromatosis centred around two main theories (12) . The first theory argued that haemochromatosis was secondary to diabetes, but this idea was gradually dropped as it became clear that most patients with diabetes did not suffer from iron overload. However, patients suffering from haemochromatosis did have diabetes and haemosiderin deposits in the pancreas, which is why «bronze diabetes» came to signify late-stage haemochromatosis.
The second theory argued that portal liver cirrhosis was the primary cause, a stance explained by cirrhosis being a consistent post mortem finding in cases of haemochromatosis. However, in the early 1930s it was established that liver cirrhosis is rarely accompanied by haemochromatosis. Nevertheless, a link was not ruled out, and some predicted the true answer by maintaining that iron deposits in the liver could cause sclerosis, and that the iron stemmed from food.
At the same time, the haemolysis theory was discarded – a theory on the origin of iron which had ruled supreme since the time of von Recklinghausen. It was now scrapped because it was impossible to demonstrate that internal bleeding or any other haematological change was the cause of the haemosiderin deposits in the liver (12) . Theories of infection, toxins and chronic lead and copper poisoning could not be verified. The answer to where the iron came from remained illusive, and the disease came to be known as «idiopathic haemochromatosis».