i86 Postgrad Med J: first published as 10.1136/pgmj.32.366.186 on 1 April 1956. Downloaded from

PORPHYRIA By PROFESSOR CHARLES GRAY King's College Hospital Medical School, London

Three types of porphyria are recognized The involvement of the central nervous system clinically: (i) A congenital, or photo-sensitive, leads to irregularly distributed flaccid paralyses, form, (2) an acute intermittent form and (3) a sometimes involving only a single muscle group, chronic or mixed form. Although on clinical sometimes involving most of the striated muscle of grounds these differ greatly from one another so the body. The clinical picture is very varied, that they have been regarded as distinct diseases, it however, and the neurological features may be now seems possible that this is not so. They are limited to ptosis, a facial palsy, diplopia, disphonia usually regarded as uncommon diseases but it is or dysphasia. Many cases have been erroneously likely that as they become more widely known they diagnosed as hysteria, acute psychosis, polio- will more frequently be recognized. The por- myelitis or encephalitis. These neurological phyrias are characterized by an abnormal excretion manifestations are essentially those of a poly- of or of derivatives. Normal neuritis and histological studies reveal a patchy urine and faeces contain minute quantities of degeneration of peripheral nerves and anterior porphyrins and only small increases in the horn cells. When the bulbar centres are affected quantities' excreted occur in such conditions as there is early respiratory failure and rapid death.by copyright. pernicious anaemia, liver disease, lead poisoning, On the other hand, if recovery occurs it may be poliomyelitis and various forms of haemolytic remarkably complete even in the most serious anaemia. This. small increase in the normal cases. The immediate prognosis is thus difficult excretion of porphyrins is termed porphyrinuria to assess, although the long-term prognosis is and is not regarded as a primary disturbance of uniformly bad. porphyrin metabolism. In the true porphyrias Hypertension frequently occurs during the acute there is a major abnormality of porphyrin meta- attack but is often labile and then the alternating bolism and there is usually an excretion of periods of hypotension and skin pigmentation abnormal porphyrins or of their derivatives. which is frequently present may lead to anhttp://pmj.bmj.com/ However, in some forms of chronic porphyria erroneous diagnosis of Addison's disease. Oliguria (porphyria cutanea tarda) there is at least a tenfold is a common feature probably because of the and often a thousandfold increase in the excretion restriction of fluid and electrolyte intake which of normal porphyrins. invariably occurs during the acute attack. Waldenstr6m describes a pure abdominal form in which the abdominal symptoms occur without Acute Porphyria involvement of the nervous as well as a

system, on September 27, 2021 by guest. Protected In. acute, or acute intermittent, porphyria, nervous form without the abdominal symptoms. characteristic episodes of colicky pain and con- He also describes a comatose form. Photo- stipation are associated with symptoms referable to sensitivity, an essential feature of the other forms the central nervous system. If they are not rapidly of the disease, is rare but when found is mild in fatal the acute episodes may be followed by periods character. of partial or complete remission lasting a variable The urine may be normal in colour but is often time-sometimes a few days but sometimes several dark red or brown especially on standing in light. years. The attacks usually, but not always, begin When freshly passed the urine during the attacks in early adulthood and often seem to be pre- always contains , a colourless cipitated by the administration of sulphonamides compound readily detected by the chloroform or barbiturates for some incidental condition. The insoluble red pigment formed on adding Ehrlich's abdominal colics may be very severe and simulate a aldehyde reagent. On standing in light, especially surgical emergency such as acute appendicitis, when the reaction is acid, porphobilinogen is con- ileus, cholecystitis, ectopic pregnancy or a twisted verted to a brown pigment, porphobilin, and ovarian cyst but the abdomen is not usually rigid. uroporphyrin III. These two pigments are often Postgrad Med J: first published as 10.1136/pgmj.32.366.186 on 1 April 1956. Downloaded from April 1956 GRAY: Porphyria I87 COOH COOH COOH ICOOH '3I ce 3 - Ha, -- Ha o CO

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ea CH, COO" UROPORPHYRIN present in the urine as passed and are responsible and one case studied over a long period of time had for the reddish-brown hue. The porphyrin is lost an eye, both ears and much of the nasal tissue. usually present in the urine as a metal complex, The teeth are red or pink in colour and because of the absorption spectrum of which appears very their high content of porphyrin fluoresce bright similar to that of haemoglobin. Some cases of red in ultra-violet light. At post-mortem the bones http://pmj.bmj.com/ acute porphyria, therefore, have been diagnosed as are found to be similarly impregnated with por- haemoglobinuria. phyrin. The clinical aspects of the condition are identical with those of hydroa oestivali and Congenital Porphyria epidermolysis bullosa but not all patients with one In congenital porphyria a severe photo- or other of these conditions prove to be cases of sensitivity is present at, or soon after, birth. There congenital porphyria. abdominal or central nervous lesions. Associated with this extreme are no system photo-sensitization on September 27, 2021 by guest. Protected The skin exposed to light becomes covered with there is usually haematological evidence of in- bullae, crusts and residual scars. The bullae, creased haemolysis with reticulocytosis, greatly in- which contain serosanguinous or seropurulent creased faecal urobilinogen excretion and some- fluid are succeeded by yellow crusts which times anaemia. Splenomegaly usually develops in gradually turn black and become dense, dry and the second decade of life or sometimes earlier. very adherent. The residual scars may be depressed The urine is cherry red or deep burgundy in and pale with the tissue-paper type of epidermal colour and contains large amounts of porphyrins, atrophy, but later these scars become hyper- mainly uroporphyrin I with smaller quantities of pigmented with loss of hair. Secondary infection coproporphyrin I and other porphyrins. Although leads to gross deformation of the skin and under- the uroporphyrin I sometimes appears as a colour- lying tissues so that the fingers become claw-like less precursor, porphobilinogen is not present and and restricted in movement. The skin around the the Ehrlich test is negative. digits becomes tightly-drawn leading to a false impression of a fusiform thickening around the Chronic Porphyria (Porphyria cutanea tarda) joints. Soft tissue destruction may be extensive In this condition there is a mild photo-sensitivity 188 POSTGRADUATE MEDICAL JOURNAL April I956Postgrad Med J: first published as 10.1136/pgmj.32.366.186 on 1 April 1956. Downloaded from which, however, does not lead to the severe of type I porphyrin are produced in contrast to scarring and deformities characteristic of the con- about 200-300 mg. of type III porphyrins required genital form of the disease. Sometimes there are for synthesis of protoporphyrin for incorporation mild abdominal symptoms but no central nervous in the haem protein. In congenital porphyria there system lesions are present. Exposure to light, heat is a genetically determined abnormality of this or mild trauma leads to a blistering of the exposed enzymic conversion so that the amounts of type I skin. The complexion is usually of a dusky and type III porphyrins are much more nearly bluish-red hue, often with some degree ofmelanosis equal, and the excretion of uroporphyrin I and and hypertrichosis. The condition is often pre- coproporphyrin I in this disease may amount to cipitated by liver disease, either an acute or sub- Ioo mg. or more per day. These type I porphyrins acute hepatitis or cirrhosis. Many cases show no are of no value to the body for synthesis of haem clinical or biochemical evidence of active liver proteins and they are not degraded to bile pigments. disease but are chronic alcoholics. They are therefore excreted or deposited in the During attacks the urine may contain proto- body, in the bones and the teeth. The presence of porphyrin IX or a considerable excess of copro- the free porphyrins in the tissues is known to be as- porphyrin III. Between attacks, however, the sociated with the release of histamine and accounts urinary excretion of porphyrins may be normal but for the photo-sensitivity characteristic ofcongenital a great excess of either copropotphyrin III or porphyria. It is possible that the presence of protoporphyrin IX may be found in the faeces. uroporphyrin I in the red cells may lead to a Often there is a reciprocal relationship between sensitivity of the red cells resulting in the haemo- the urinary porphyrins and faecal porphyrins. lysis which is a characteristic feature of the Apparently in these patients the normal route of condition. The increased haemolysis is usually excretion of these excess porphyrins is via the liver, accompanied by hyperplasia of the bone marrow bile and the gut, but when there is liver damage so that anaemia is rare. The increased synthesis of there is a diversion to the renal route. haem proteins in the bone marrow is, of course, increased of uro- Abnormalities of in accompanied by quantities Porphyrin Biosynthesis porphyrin I which is a by-product of that activity.by copyright. the Porphyrias Splenectomy has been reported to cause a diminu- During the last decade considerable knowledge tion in the porphyrin excretion by reducing the has accumulated concerning the biosynthetic path- rate of haemolysis and thereby diminishing the way of the porphyrins. It is now known that need for haemoglobin synthesis and thus reducing acetic acid is converted in the Krebs cycle to a the production of the type I porphyrin by- derivative of succinic acid which can condense products; this is by no means a constant or with glycine to form a-amino p-keto adipic acid. permanent result. This acid loses carbon dioxide to form 8 amino- Acute porphyria. In acute porphyria the urine laevulic a acid five carbon acid, carboxy containing often contains a complex mixture of porphyrins,http://pmj.bmj.com/ atoms and bearing a ketone group and an amino the precise nature of which is unimportant because group. Two molecules of 8 aminolaevulic acid the essential feature of the disease is the excretion condense to form porphobilinogen, a monopyrrolic of porphobilinogen. In the experimental por- compound which has long been known as the phyria induced by Sedormid there is evidence that colourless precursor of porphyrins excreted in there is a diminution in the synthesis of catalase, acute porphyria, but the structure of which was a haem protein, and it is assumed that because of not elucidated until I952. Four molecules of por- this block in synthesis the excess porphobilinogen phobilinogen can condense together to form either is excreted in the urine. There is no evidence that on September 27, 2021 by guest. Protected uroporphyrin I or uroporphyrin III which differ a similar mechanism is responsible for the human according to the arrangement of the acetic acid and disease. It is much more probable that porpho- propionic acid side-chains in the four pyrrole ring. bilinogen formation is in excess of that required for Although the uroporphyrins are readily converted normal haem synthesis. Indeed recent work in vitro into the corresponding coproporphyrins, suggests that in acute porphyria the conversion of and protoporphyrin IX is theoretically derived 8 aminolaevulic acid to porphobilinogen is greatly from coproporphyrin III, there is evidence that the increased and that an increased amount of 8 pathway of conversion of uroporphyrin III to aminolaevulic acid is formed from glycine and protoporphyrin IX and the haem of the haem succinic acid. An alternative possibility is a proteins is not direct and does not involve copro- decreased metabolism of 8 aminolaevulic acid via porphyrin IlI. pathways other than porphobilinogen. Congenitalporphyria. Normally the formation of For many years the view has been held that the porphyrins from porphobilinogen is so directed lesions of the nervous system and the abdominal enzymically that only a few hundred micrograms colic were due to direct action of porphyrins on April 1956 GRAY: Porphyria 189 Postgrad Med J: first published as 10.1136/pgmj.32.366.186 on 1 April 1956. Downloaded from the nervous system and gut respectively. There is be accompanied by a positive Schlesinger reaction. no evidence that porphyrins have either of these If the urine is not fresh the porphobilinogen may actions when they are in the pure state and neither partly or wholly have been converted to a mixture porphobilinogen nor 8 aminolaevulic acid has any of porphyrins, usually present as a metal complex. pharmacological effect. It is probable, therefore, This has a two-banded spectrum superficially that the lesions are due to some enzymic resembling that of haemoglobin, but which is abnormality in the glycine-succinate metabolism unaffected by reducing reagents such as sodium of the central nervous system and that the hydrosulphite. abdominal colics perhaps may be related to a Congenital porphyria is readily diagnosed from similar impairment in the autonomic nervous the red or pink colour of the urine which on system. Such a view would account more readily spectroscopic examination reveals the typical four- for the extremely patchy and diverse nature of the banded spectrum of a free porphyrin, usually clinical lesions in the disease. ether insoluble and with absorption maxima at Porphyria cutanea tarda. It is impossible with about 612, 560, 539 and 504 m,u. In ultra-violet the present state of knowledge to speculate on the light the urine fluoresces an intense red. It is nature of porphyria cutanea tarda. For some time reported that occasionally in congenital porphyria this variety of the condition has been regarded as a the porphyrins are also excreted as a colourless separate entity from the other two forms of the precursor, , which is different from disease. The occasional occurrence of mild photo- porphobilinogen. Porphyrinogen is converted by sensitivity in acute porphyria and a few reports light and air or other reducing agents into por- indicating that the clinical condition in a patient phyrins but does not react with Ehrlich's reagent. with porphyria cutanea tarda may change into that The diagnosis of porphyria cutanea tarda is often of acute porphyria, suggests that these two forms more difficult since during remission the urine may may be very closely related. Indeed recent studies be normal and the only abnormality is the excretion have suggested that in all forms of porphyria the of excess porphyrin in the faeces. It is necessary, body pools of 8 aminolaevulic acid and porphobili- therefore, to examine both urine and faeces, the nogen are considerably increased. It is not im- former by spectroscopic examination in a depth of by copyright. possible that the same fundamental lesion of por- at least 4 in. and the latter by a simple technique phyrin synthesis may be present in all forms ofpor- such as is used in the routine spectroscope phyria but that in the congenital form of the disease examination of faeces for occult blood. That of and in the porphyria cutanea tarda form there has Snapper is particularly valuable since it separates been an enzymicadaptation resulting in the disposal the iron-containing derivatives of haem from the of the excess porphobilinogen by its conversion porphyrins. Often such simple tests will suffice to into other porphyrins which are then excreted. confirm the diagnosis, but sometimes in cases of doubt it is better to refer the materials to some The of in Diagnosis Porphyria laboratory specializing this kind of investigation. http://pmj.bmj.com/ Until lately, the view has been held that in In acute phases the plasma itself may fluoresce in congenital porphyria the excreta contained free ultra-violet light. porphyrins of type I, while in acute porphyria the porphyrins, mainly of type III, were excreted Treatment of Porphyria partly as a metal complex and partly as the colour- The treatment of porphyria is highty unsatis- less precursor' porphobilinogen.' It is now known factory. The favourable results reported using that the porphyrins in the excreta are in fact clacium, various vitamin preparations, especially of complex mixtures, the precise compositions of the B. complex, cortisone, ACTH and, more on September 27, 2021 by guest. Protected which are still a subject of research so that complex recently, BAL have not been confirmed and their quantitative and qualitative investigations are effects have probably been confused with spon- usually unnecessary for clinical purposes. taneous remissions in the disease. In the state of In acute porphyria the urine may be red-brown present knowledge, treatment of all forms of or normal in colour. The essential test is for the porphyria can only be symptomatic. Barrier presence of porphobilinogen in the freshly passed creams, avoiding sunlight and antibiotics for urine which on the addition of Ehrlich's aldehyde infected lesions, are all that can be offered to the reagent will give a red pigment insoluble in patient with congenital porphyria or porphyria chloroform. This test is often positive even after cutanea tarda. In congenital porphyria splenec- the urine is diluted one in ten or more. The red tomy may perhaps be considered if there is pigment formed from ' urobilinogen' on the evidence of considerably increased haemolysis. addition of Ehrlich s reagent is extractable by Strict abstinence from sulphonamide and bar- chloroform. Moreover, a positive Ehrlich's test biturate drugs must be a rule for the patient with due to increased urinary urobilinogen will always acute porphyria, the treatment of which must also I90 POSTGRADUATE MEDICAL JOURNAL April 1956Postgrad Med J: first published as 10.1136/pgmj.32.366.186 on 1 April 1956. Downloaded from of necessity be symptomatic. Orthopaedic treat- carry a card to inform any doctor that they are ment may be necessary to minimize the effect of sufferers from the disease so that the condition may the paralyses. Pethidine and other morphine be borne in mind should any question arise of substitutes may be needed to alleviate the diagnosing an acute surgical emergency. abdominal pain. The poor nutrition and vomiting the acute BIBLIOGRAPHY which may sometimes accompany BORST, M., and KOENIGSDORFFER, H. (I929), 'Unterus- attacks may lead to sodium and even potassium chungen uiber Porphyrine,' Leipzig, Hirzch. and such strict DOBRINER, K., and RHOADS, C. P. (1940), Phys. Rev., 20, 416. deficiency patients may require FISCHER, H., and ORTH, H. (I937), 'Die Chemie des Pyrrols control of their fluid, electrolyte and nutritional Band II,' Leipzig, Akademische Verlagsgesellschaft M.B.H. intake. MUIR, H. M. (I954), 'The Chemical Pathology of the Animal Pigments,' Cambridge, University Press, p. 4. The disease is undoubtedly transmitted by POPJAK, G. (I955), 'Royal Institute of Chemistry Monograph and the urine of all relatives of a case of No. 2.' heredity RIMINGTON, C. (1952), Acta med. Scand., 143, I6i, I77. acute porphyria should be tested for porpho- VANNOTTI, A. (I954), ' Porphyrins,' translated by C. Rimington, Latent is found London, Hilger & Watts. bilinogen. porphyria frequently WATSON, C. J. (I954), ' Advances in Internal Medicine,' Vol. VI, and such individuals should be warned to avoid Year Book Publishers Inc., Chicago. barbiturates and sulphonamides. They should WATSON, C. J., and LAWSON, E. A. (I947), Phys. Rev., 27, 478. CARDIAC DISEASE (Postgraduate Medical Journal) Price 3s. 10d. post free INTRODUCTION DRUG TREATMENT OF HYPERTENSION Walter Somerville, M.D., M.R.C.P. E. G. McQueen, M.B., M.R.C.P., and F. H.

ANGIOGRAPHY Smirk, M.D., F.R.C.P. by copyright. J. Norman Pattinson, M.B., B.Chir., D.M.R.D., TREATMENT OF BACTERIAL F.F.R. ENDOCARDITIS BEDSIDE DIAGNOSIS OF CONGENITAL E R IT HEART DISEASE ''' Ian G. W. Hill, C.B.E., T.D., F.R.C.P.E., Walter Somerville, M.D., M.R.C.P. ^M.R.C.P., F.R.S.E. SURGICAL TREATMENT OF CONGENITAL THE MANAGEMENT OF COR PULMONALE HEART DISEASE J. F. Goodwin, M.D., M.R.C.P. W. P. Cleland, M.R.C.P., F.R.C.S. PREGNANCY AND RHEUMATIC HEART THE CARDIAC RISK IN ANAESTHESIA

DISEASE AND SURGERY http://pmj.bmj.com/ Samuel Oram, M.D., F.R.C.P. Graham W. Hayward, M.D., F.R.C.P. Published by THE FELLOWSHIP OF POSTGRADUATE MEDICINE 60, Portland Place, London, W.1 on September 27, 2021 by guest. Protected RUTHIN CASTLE, NORTH WALES A Clinic for the diagnosis and treatment of Internal Diseases (except Mental or Infectious Diseases). The Clinic is provided with a staff of doctors, technicians and nurses. The surroundings are beautiful. The climate is mild. There is central heating throughout. The annual rainfall is 30.5 inches, that is, less than the average for England. The Fees are inclusive and vary according to the room occupied. For particulars apply to THE SECRETARY, Ruthin Castle, North Wales. Telegrams: Calde, Ruthin. Telephone: Ruth 64