J Clin Pathol: first published as 10.1136/jcp.25.12.1013 on 1 December 1972. Downloaded from J. clin. Path., 1972, 25, 1013-1033 The porphyrias: a review G. H. ELDER, C. H. GRAY, AND D. C. NICHOLSON From the Department of Chemical Pathology, King's College Hospital Medical School, Denmark Hill, London The porphyrias are disorders of the biosynthesis of Chemistry and Biochemistry of the Porphyrins protohaem, the ferrous iron complex of proto- porphyrin IX, in which characteristic clinical The general pathway of biosynthesis of haem for features are accompanied by specific patterns of haem protein formation is well known except for porphyrin and porphyrin precursor overproduction, the details of very early stages and the later stages accumulation, and excretion, each pattern defining in uroporphyrinogen and coproporphyrinogen syn- a particular form of porphyria. thesis. Until the formation of protoporphyrin IX All those forms of porphyria in which there is this pathway involves not the porphyrins but overproduction of porphyrins have one clinical porphyrinogens, the hexahydro derivatives of feature in common-sensitivity of the skin to porphyrins. Succinyl co-enzyme A, derived from sunlight-although the nature of the lesions pro- acetate via the Kreb's cycle and a-oxoglutarate, is duced differs between diseases. The photosensitivity condensed by the enzyme 5-aminolaevulinic acid is due to the photodynamic action ofthe porphyrins synthetase (ALA-S) with glycine, pyridoxal phos- by copyright. that accumulate in the skin when the plasma porphy- phate participating, to form a-amino-fl-ketoadipic rin concentration is increased (Rimington, Magnus, acid which rapidly loses CO2 non-enzymically to Ryan, and Cripps, 1967) and which probably act as form ALA. Under the influence of the sulphydryl sensitizers for singlet-oxygen-mediated destructive enzyme ALA dehydratase, two molecules of ALA processes, for example, the peroxidation of lipids in condense to form one molecule of the monopyrrole the membranes of lysosomes (Allison, Magnus, and PBG with the structure of 2-aminomethyl-3- Young, 1966; Magnus, 1972). carboxymethyl-4-carboxyethyl pyrrole (Fig. la). The other main clinical feature ofthe porphyrias- The enzyme uroporphyrinogen synthetase (Bogorad, neurological lesions typically causing severe abdom- 1958) causes four molecules of porphobilinogen to inal pain, peripheral neuropathy, and often mental condense to give uroporphyrinogen I in which http://jcp.bmj.com/ disturbance, and frequently precipitated by drugs 4-carboxymethyl and 4-carboxyethyl groups are such as the barbiturates-is associated with in- arranged alternately around the hexahydroporphin creased excretion of the porphyrin precursors, ring. When uroporphyrinogen synthetase acts in the porphobilinogen (PBG) and 5-aminolaevulinic acid presence of uroporphyrinogen III co-synthetase, (ALA) and does not occur in those forms of which may be a separate enzyme (Bogorad, 1963), porphyria in which excretion of these precursors is or, as in mammalian liver, part of a complex con- always normal. taining the synthetase (Bogorad, 1958), uropor- on September 23, 2021 by guest. Protected In some patients only the biochemical features phyrinogen III is formed; in this the carboxymethyl are apparent. Such clinically latent porphyria may andcarboxyethylgroups attachedtopyrrole ringDare occur either as a phase in an episodic illness or as the reversed (Fig. Ib). Two otherisomericporphyrinogens only manifestation throughout life. Proper treatment are theoretically possible but are not found in nature. of patients with porphyria depends upon accurate In haem-synthesizing tissues, four carboxymethyl diagnosis, which in turn depends entirely upon the groups are presumed to be successively decarboxy- accurate interpretation of proper laboratory in- lated to methyl groups to give hepta-, hexa-, and vestigations and proper enquiry into the family pentacarboxyl porphyrinogens and finally the history. Discussion of the prevention and manage- tetracarboxyl coproporphyrinogens I and III. Copro- ment of porphyria is beyond the scope of this review porphyrinogen I is not further metabolized but and is summarized by Goldberg (1971). coproporphyrinogen III undergoes a dehydrogena- tion-decarboxylation reaction convertingthecarboxy- Received for publication 19 October 1972. ethyl groups on rings A and B to vinyl groups 1013 J Clin Pathol: first published as 10.1136/jcp.25.12.1013 on 1 December 1972. Downloaded from 1014 G. H. Elder, C. H. Gray, and D. C. Nicholson (c0011 COOH (LY(CINF (H2 Fig. la The biosynthetic CH2 P A haem IN2NCH2 COOH ALA CH, [1 pathway of formation synthetase H. N (H COOH -co, CH2 ALA dehydratase L (formation ofporphobilinogen) 1OOCCCH2 C(i2 COCoA O=(('H ('12COOH C=O N CHH2 sH SUCCINYL COENZYMF A a AMINO KETOADIPI(' AC(' ) CH, NH, PORPHOBILINOGFN Transient) NH, 5 AMINOLAEVULINIC A = -CH2COOH ACID P = -CH2CH2COOH M = -CH3 V = -CH=CH2 lIllIORI'lI RI\( (,I \NII (IlI III kI\( \ RIoXllRt4\ I \1I \I \l SvI I,' \II,\1,> \ tsp I' I' I' I' VJ(~~~~~~~~~~~~~~~~~~~~~~~~I S("Rt(112MI5- It.§ /I71\IIAilI,-\J fithretaw [l\Xj(}- nl rlol ie<1 1 by copyright. / ( 0(lIItti% '111d11 'O OIl1 N\INlt!tl S(li\Il 1,11\ I~~~~~~~~~~,\ A 1 \s 1'5s 1 \4 .,k 1 1 http://jcp.bmj.com/ I R1OPO'0NII <I\N(n1 \ R110'111d11\0(,(1 \ Fig. b The biosynthetic pathway of haemn formation (conversion ofporphobilinogeni to porphy!rins and haem) on September 23, 2021 by guest. Protected yielding protoporphyrinogen which is readily de- unknown and there may well be a separate pool of hydrogenated to provide protoporphyrin (Sano and this compound not directly formed via the Kreb's Granick, 1961). In the presence of iron and the cycle. Secondly, the mechanism of formation of enzyme ferrochelatase (Labbe, Hubbard, and uroporphyrinogens I and III from porphobilinogen Caughey, 1963), this is converted to haem for haem remains obscure although numerous theories have protein synthesis (Figure lb). At all stages in the been proposed (Llambias and Batlle, 1970). There biosynthetic pathway the porphyrinogens are is need for this to be established as there are almost readily converted to the corresponding porphyrins certainly enzymic deficiencies of this pathway other which, with the exception of protoporphyrin, than that of uroporphyrinogen III co-synthetase in cannot be further metabolized. congenital erythropoietic porphyria. Thus there is There are several points of this pathway that are evidence that abnormality or deficiency of uropor- in need of further elucidation. The precise source of phyrinogen synthetase itself may be the primary succinyl coenzyme A used for ALA synthesis is abnormality in acute intermittent porphyria (Strand, J Clin Pathol: first published as 10.1136/jcp.25.12.1013 on 1 December 1972. Downloaded from The porphyrias: a review 1015 Felsher, Redeker, and Marver, 1970; Miyagi, R NI Cardinal, Bossenmaier, and Watson, 1971). The H third area which requires elucidation, particularly in C mammalian liver, is the decarboxylation of uropor- phyrinogen III to coproporphyrinogen III which is usually accepted as occurring sequentially. Recently r7, Dowdle, Goldswain, Spong, and Eales (1970), HC (H studying that form of porphyria known as sympto- matic porphyria, attribute a paradoxical distribution of isomers I and III in conversion of uroporphy- rinogen through hepta- and pentacarboxyl porphy- rinogens to two distinct metabolic pathways in the P p liver. In one, ALA is converted sequentially to haem via PBG, uroporphyrinogens I and III, copropor- Fig. 2 New porphyrins recently isolatedfromfaeces phyrinogen III and protoporphyrinogen, while in (see text). the other, which operates under conditions of ALA Isocoproporphyrin (IR = CH2 * CH3) overload, uroporphyrinogen III gives rise only to Deethylisocoproporphyrin (11 R = -H) hexa- and heptacarboxyl porphyrinogens which Hydroxyisocoproporphyrin (IIIR = -CH(OH)CH3) accumulate and are excreted as the respective Dehydroisocoproporphyrin (IVR = -CH= CH2) porphyrins. Isotope experiments have suggested that In I, II, III, IV, R' = CH2COOH (Elder, 1971, 1972) there may be two distinct metabolic pools of uro- Acrylic analogue ofcoproporphyrin-III isomer (VR = -CH=CH2 R' = CH3) porphyrinogen (Goldswain, Dowdle, Spong, and (French, Nicholson, and Rimington, 1970) Eales, 1970). The situation of the acrylic group shown here in More recently, detailed studies of urinary and position 2 of structure V still requires final proof. faecal and biliary porphyrins have shown that in one form of porphyria-variegate porphyria-there is by copyright. excretion of a peptide conjugate of a porphyrin Changeux, and Jacob, 1963), thus inhibiting its (Rimington, Lockwood, and Belcher, 1968). In activity. End product repression usually involves symptomatic cutaneous hepatic porphyria a vinyl combination oftheendproductwithan 'aporepressor' tricarboxyethyl carboxymethyl trimethyl porphyrin molecule synthesized by the activity of a regulator occurs (Elder, 1972) (Fig. 2, IV) which is excreted in gene (Jacob and Monod, 1961). Normally the the bile with a hydroxy derivative in which the aporepressor molecule combined with the end pro- elements of water have been added to the vinyl duct acting as a co-repressor represses the activity of group and is partially converted to ethyl and hydryl an operator gene directing the synthesis of the (deutero) derivatives by intestinal microorganisms m-RNA controlling the synthesis of the enzyme. If http://jcp.bmj.com/ (Elder, 1972). It is not known whether this reflects