History of Porphyria

 A Little Bit of History

1841 The term 'porphyrin' comes from the Greek word, porphyus, meaning reddish-purple. It was first thought that the reddish color of blood was from iron. One early scientist performed an experiment to prove that this was not the case. He washed dried blood with concentrated sulfuric acid to free the iron. He then treated it with alcohol and the resulting iron free residue took on a reddish purple color though it contained no iron compound

1844 Gerardus Johannes Mulder determined the chemical composition of this purplish, iron free substance, which he named "hematin," He also illustrated that hematin took up oxygen.

1867 J.L.W. Thudichum described the beautiful spectrum and fluorescence of these red porphyrins after he published his first book on the analysis of urine.

1871 Felix Hoppe-Seyler crystallized hematin and described its spectrum. He then demonstrated that the crystalline form differed from one animal species to another. Using his own newly constructed gas pump, he found that oxygen formed a loose, dissociable compound with hemoglobin, which he called "oxyhemoglobin." He renamed the iron free hematin ‘hematoPorphyrin’.

1874 Dr. J.H. Schultz described a case of a 33-year-old male weaver who suffered from skin sensitivity, an enlarged spleen and reddish urine since he was an infant. He called the condition pempigus leprosus. His was most likely the first description of protoporphyria. Dr. Schultz was later credited with giving the disease its name.

1880 MacMunn described a patient’s dark reddish urine of a patient with symptoms of an attack of acute Porphyria.

1888 Shortly after, sulphonal was introduced as a hypnotic drug, Joseph Stokvis had a patient who, after taking the drug, excreated the tell-tale dark reddish urine typical of porphyria. The elderly woman then became paralyzed and died. Stokvis deducted that the pigment in her urine was the hematoporphyrin.

1889 B.J.Stokvis published the first case and clinical description of acute hepatic porphyria.

1890 George Harley (1829-96) studied a 27-year-old who also excreted reddish urine and an "unusual nerve disturbance after taking sulphonal.

1898 T.McCall Anderson described two brothers had eruptions with burning and pruitus on the sun exposed areas of their skin so severe that they lost part of their ears and nose. They exhibited dark urine.

1898 Alfred F. Harris demonstrated that the urine of both brothers contained the hematoporphyrin group.

1906 Dr. Max Dobrschansky described the first case of acute porphyria after a patient had a barbiturate.

1911 H. Gunther classified the diseases of porphyria, including congenital erythropoietic porphyria (CEP), which he called congenital hepatoporphyria, the rarest porphyria.

1913 Dr. Friedrich Meyer Betz injected himself with hematoporphyrins to determine their photodynamic impact. He subjected himself to the sun and became so photosensitized that the extremely painful photosensitive effect lasted several months. The photos of Dr. Betz taken hours after he injected himself illustrated his badly swollen face. He was unrecognizable until the swelling decreased. The-experiment is used today in dermatology text books. View these photos on the APF website.

1915 Hans Fischer studied one of H. Gunther’s patients, Mr. Petry, who had the rare type of Porphyria, CEP. Using data from Mr. Petry’s case, Fischer provided significant insight into the chemistry of porphyrins. He also found that uroporphyrins and coproporphyrins were different from hematoporphyrins and subsequently suggested that the hemato prefix be dropped.

1923 A. E. Garrod credits H. Gunther with first recognizing that hematoporphyria was, in fact, an inherited metabolic problem in his manuscript, Inborn Errors of Metabolism. This is the first time the term "inborn errors" of metabolism had been ever used for a group of inherited metabolic disorders and the year CEP was first identified.

1937 Dr. Jan G. Waldenstrom suggested that the name of the diseases of porphyrin metablolism be porphyrias rather than Hematoporphyrias. Using Paul Ehrlich’s aldehyde reagent, Waldenstorm identified 103 patients with acute porphyria by testing their urine and noting the red color. He discovered that asymptomatic family members of these patients also had the same reaction if they ingested even small amounts of barbiturates and sulphonal.

1949 Dr. Cecil J. Watson identified cases in which there were excessive amounts of coproporphyrins in the stool and urine and suggested that this was caused by an inborn error of metabolism. He continued his research in the United States, where he and Dr. Samuel Schwartz discovered a fundamental test, the "Watson-Schwartz tests".

1954 R. Schmid, Samuel Schwartz and Cecil. J. Watson classified the porphyrias according to the porphyrin content in the bone marrow and liver.

1955 A. Goldberg and H. Berger showed that individuals with an excess of coproporphyrin had another inherited form of porphyria that they called hereditary coproporphyria. HCP is an autosomal dominant form of hepatic porphyria that is very similar to acute intermittent porphyria, except that some patients develop skin photosensitivity, too.

1960's Earnest Porphyria research in Europe and US.

1961 Heinrich Gustav Magnus described erythropoietic protoporphyria (EPP) as a genetic disorder arising from impaired activity of ferrochelatase, which is what adds iron to protoporphyrin to form heme.

1970-2011 Drs. Anderson, Desnick, Bissell, Bloomer, Bonkovsky,, Bottomley, Dailey, Galbraith, Kappas, Kreimer-Birnbaum, Kushner, Lamon, Levere, Levine, Mathews-Roth, McDonaugh, Nichols, Peters, Sinclair, Pimstone, Pierach, Poh-Fitzpatrick, Sassa, Shedlofsky, Schmid, Sassa, Tishler, Tschudy, Watson,, Phillips and many others too numerous to name have furthered porphyria research and have bettered the health care of all of us with Porphyria. We owe all these people a great debt and a great measure of thanks.

2008-2011 The APF Protect the Future program to train the next generation of experts was initiated. We are grateful for the newest experts; Drs. Manisha Balwani, Lawrence Lui, Gagen Sood, Manish Thapar, Bradley Freilich, Charles Lourenco, Brenden McGuire, Bruce Wang, Majid Rizk, Guiherme Perini, Jennifer Guy, JJeffery Wickliffe, Aswani Singal, Sajid Mittal,Charles Parker.

 

King George III and Porphyria

Some historians have speculated that King George III of England suffered from Variegate Porphyria. According to notes made by the physicians attending him at that time, he suffered symptoms similar to those seen in an acute attack of porphyria: abdominal pain, constipation, rashes, confusion and severe weakness in his limbs. They also mentioned that he had dark reddish urine during these sieges and that he was often "mad." The royal physicians were not permitted to conduct extensive physical examinations, so they had to depend on what King George told them about his condition.

On one occasion when he was having a relapse of his mental and physical symptoms, Parliament debated his ability to maintain his position as King. Interestingly, he spontaneously recovered. Since George III ruled during the American Revolution, he was thought to have had a significant impact on Britain’s loss to the revolutionaries. His mental and physical lapses were blamed for much of the mishandling of the war. In 1811, George suffered a severe relapse and subsequently was dethroned by the Prince of Wales.

After researching the physicians' reports, Drs. Ida Macalpine and Richard Hunter proposed that King George might have had one of the acute porphyrias. They published their theory in the British Medical Journal in 1966 and later wrote a book, George III and the Mad Business, which presented more detailed accounts of King George's malady. It is important to note that a number of Porphyria specialists and other physicians disagree with their theory. However, over the years it has been widely publicized.

 

Porphyria in Turkey

In southeastern Turkey, between 1956 and 1961, there were reports of an epidemic of PCT. Apparently, in 1954 the Turkish government distributed a supply of wheat seed that had been treated with fungicides containing 10% hexachlorobenzene (HCB). The wheat was originally intended for planting, but the shipment arrived too late in the season. Because there was a limited food supply in the Turkish provinces of Dijarbakir, Mardin, and Urfa, the seed was diverted for food production. It was difficult to quantify the extent and duration of HCB exposure from existing surveys, because the HCB-treated seed appeared no different from untreated supplies.

As many as 5000 individuals were reported to have been affected by the HCB treated seeds. They exhibited PCT-like syndromes as early as 1956. The government discontinued using the HCB-containing fungicide in 1959, but it was not until around 1961 that the PCT outbreak waned. Researchers from clinics near the area began to trace the dietary histories of the affected individuals and discovered that HCB appeared to be the cause of the acquired form of PCT.

Prior to this time, acquired Porphyria associated with exposure to environmental toxins was observed in experimental animal models but only rarely in humans. Shortly after the reports from Turkey were published, the association between the chronic administrations of HCB to induce excessive porphyrin accumulation was confirmed in animal models as well.

Although quantitative reports of HCB exposure from Turkey are incomplete, some accounts estimate that the amount of HCB ingested by the affected individuals ranged from 0.05 to 0.2 g/d over an unknown, but "relatively long period," before changes in their skin became evident. Long-term follow-up studies by Drs. Cripp and Peters and their colleagues at the University of Wisconsin indicated that the average lag time between HCB ingestion and clinical manifestation of disease was about six months. Furthermore, their study indicated that the levels of excreted porphyrins did not correlate with the individual's age at exposure, sex, serum HCB levels, or severity of initial symptoms.

 

Source: Porphyria Foundation