Porphyria Coproporphyrins

CEP congenital erythropoietic porphyria, coproporphyrin, EPP erythropoietic protoporphyria, HC hereditary coproporphyria,... 

In most porphyrias, excess metabolites can be detected in urine. Less polar porphyrins (i.e., coproporphyrins and protoporphyrin) are detectable in feces as they are excreted by the bile. The apolar protoporphyrin is eventually only detectable in blood. Porphyrins can easily be detected and measured by their intense fluorescence in mineral acids. The excitation wavelength is around 404 nm, and emission at about 615 nm. ALA is derivatized to a pyrrole and both, ALA and PBG, are detected by dimethylaminobenzaldehyde (DMAB), as described by Mauzerall and Granick [7]. 

Increased porphyrins in clear fluid such as urine may be detected directly by their pink fluorescence if exposed to long ultraviolet (Fig. 7.3.2). The specificity of this screening assay may be improved if porphyrins are extracted by talcum [8]. These isolated porphyrins may be quantified using a spectrofluorimeter. As different porphyrias show specific excretion patterns, separation of the main porphyrins is desirable. The formerly used fractionated extraction enabled to separate the uroporphyrin fraction from the coproporphyrin fraction. In addition to uroporphyrin, the first fraction includes heptacarboxy- and part of hexacarboxyporphyrins, and in addition to coproporphyrin, the second fraction includes part of hexacarboxy- and pentacar-boxyporphyrins. Later on, thin-layer chromatography of methylester derivatives is used. 

Symptomatic porphyria patients usually show urinary porphyrin concentrations that exceed the upper limit of normal by twofold or more. Table 7.3.1 lists most of the diagnostic abnormalities of the different porphyrias. Only slightly abnormal or even fully normal values may be seen in asymptomatic patients. But alcohol overconsumption, enzyme-inducing drugs, stress, and other factors may also induce slightly abnormal values that should not be mistaken for porphyria. A characteristic sign for such a secondary effect is the isolated elevation of coproporphyrin, especially of its... 

All acute porphyrias show similar urinary porphyrin patterns with predominant elevation of uroporphyrin and coproporphyrin III isomer in addition, hepta-, hexa-, and especially pentacarboxyporphyrins are increased (see Fig. 7.3.3). 

Fecal porphyrins are determined to differentiate between the three acute porphyrias, AIP, PV, and HC (Table 7.3.1). Symptomatic PV shows abundant fecal coproporphyrins, whereby the III isomer is always dominant and protoporphyrin is elevated. In symptomatic HC, only fecal coproporphyrins with dominance of the III isomers are increased. Fecal porphyrins are usually normal in AIP. They may be moderately elevated in acute porphyric attacks in AIP, but coproporphyrin I is then higher than coproporphyrin III isomer [11]. 

Minder El (1993) Coproporphyrin isomers in acute-intermittent porphyria. Scand J Clin Lab Invest 53 87-90... 

It may be noted that although the human organism is capable of degrading metal-containing porphyrins such as heme, it has no means of degrading porphyrins containing no metal, for example coproporphyrins and uroporphyrins. These must be excreted as such. The latter two are water-soluble and are thus found in urine and to some extent in the feces. Protoporphyrins, however, are largely water-insoluble and are excreted in the feces. Finally, it may be mentioned that porphyrias make their appearance after puberty. This has been associated with the appearance of 5/3-steroid reductases, as discussed above. 

Lead exposure mcreases urinary ALA and coproporphyrin-III excretion and causes accumulation of 2n-protoporphyrin in erythrocytes. The definitive test for lead toxicity is measurement of blood lead, but occasionally lead exposure is responsible for porphyria-like symptoms and may be an unexpected finding when investigating patients for suspected porphyria. ... 

Increased total fecal porphyrin concentration requires further investigation by fractionation, identification, and quantification of individual porphyrins using a technique, such as HPLC, that resolves coproporphyrin I and III isomers. Porphyria should never be diagnosed on the basis of raised total fecal porphyrin alone. 

Figure 32-4 Representative HPLC chromatograms for (a) working standard b, norma) feces c, normal urine d, feces—hereditary coproporphyria e, urine—congenita erythropoietic porphyria f, feces—variegata porphyria g, urine—porphyria cutanea tarda and h, feces—porphyria cutanea tarda chromatographic conditions as described in the appendix on the Evolve site that accompanies this book. Peaks are I, uroporphyrin- 2, uroporphyrin-l 3, heptacarboxyiate porphyrin-l 4, heptacarboxylate porphyrin-tl 5, hexacarboxylate porphyrin 6, pentacarboxylate porphyrin 7, coproporphyrin-1 8, coproporphyrin- ll 9, deuteroporphyrin-IX ...

Porphyrias are inherited or acquired disorders caused by a deficiency of enzymes in the heme biosynthetic pathway. Porphyrin is synthesized in both the erythroblasts and the liver, and either one may be the site of a disorder. Congenital erythropoietic pOTjdtyria, for example, prematurely destroys eythrocytes. This disease results from insufficient cosynthase. In this porphyria, the synthesis of the required amount of uroporphyrinogen III is accompanied by the formation of very large quantities of uroporphyrinogen I, the useless symmetric isomer. Uroporphyrin I, coproporphyrin I, and other symmetric derivatives also accumulate. The urine of... 

Laboratory tests revealed elevated urinary PBG and coproporphyrin, and plasma fluorescence emission at 626 nm. Which type of porphyria does the patient have and what is the most likely biochemical explanation ... 

Hepatic porphyria is an indicator of liver dysfunction that has been induced in animals following intermediate-duration oral or dermal exposure to Aroclors and other PCB mixtures. Increased urinary excretion of porphyrins has been reported in two studies of PCB workers, and Type B hepatic porphyria (a uroporphyrin/coproporphyrin ratio >1) was a consistent finding in Yu-Cheng patients, including children born to exposed mothers. However, chnically evident porphyrias have not been reported in people with occupational or Yusho/Yu-Cheng PCB exposures. 

Commercial PCB Mixtures. Urinary coproporphyrin levels were increased in rats that ingested 0.3 or 1.5 mg/kg/day Aroclor 1242 in the diet for 2-6 months (Bruckner et al. 1974). Rats treated with 5 mg/kg/day Aroclor 1254 in the diet had maximum increases in liver microsomal P-450 concentration and liver weight after 1 week, but onset of porphyria and induction of 5-aminolevulinic acid (ALA) synthetase was delayed until 2-7 months of treatment (Goldstein et al. 1974). A marked accumulation of uroporphyrins occurred in the liver, and urinary excretion of coproporphyrin and other porphyrins was increased the largest increase was in uroporphyrins. The uroporphyrins in the liver and urine of the treated rats consisted primarily of 8- and 7-carboxyporphyrins. 

Protoporphyrinogen III oxidase (EC 1.3.3.4). Ferro-chelatase activity may also be decreased. Impaired feedback inhibition of 5-aminolevulinate synthase results in excessive porphyrin production. Increased urinary porphobilinogen, 5-aminolevulinate, protoporphyrin and coproporphyrin during acute attacks. Fecal protoporphyrin and coproporphyrin constantly elevated. Fecal porphyrin-peptide conjugates increased. Mild photodermatoses clinical picture otherwise similar to that of acute intermittent porphyria. Treatment as for latter. Rare, except in white South Africans, where frequency is 0.4%. Autosomal dominant. 

The metabolic block in erythropoietic porphyria is not known, but the clinical situation can be summarized as follows uro- and coproporphyrin type I accumulate in bone marrow, spleen, blood, and urine. Yet, there is no marked depression of the ability to synthesize protoporphyrin IX. The metabolic distortion is... 

Under normal conditions, the main pathway for porphobilinogen is its conversion to protoporphyrin IX and heme. Heme is used for heme protein synthesis in the liver (cytochromes, and such enzymes as catalase). An alternative pathway for porphobilinogen is its transformation to uro- and coproporphyrin I, which are not further used by cellular metabolism. A block in porphobilinogen use for heme synthesis is likely to divert the porphobilinogen into the alternative pathway, and then uroporphyrin I accumulates. This does not occur in acute intermittent porphyria. 

The pattern of porphyrin excretion in the urine can also be helpful in identifying lead intoxication. With lead poisoning, the urine concentrations of coproporphyrins I and II, porphobilinogen and uroporphyrin I rise. The most important increase, however, is that of coproporphyrin iii levels may exceed 5,000 pg/l in the urine in lead poisoned individuals, but its correlation with blood lead levels and ZPP are not as good as those of ALA. Increases in urinary porphyrins are not diagnostic of lead toxicity and may be seen in porphyria, some liver diseases, and in patients with high reticulocyte counts. 

There are many porphyrins, which differ from one another in the nature and disposition of the attached groups (vinyl, propionic acid, and methyl in protoporphyrin). Coproporphyrin 1, the principal porphyrin in human feces, has four methyl groups and four propionic acid groups in alternation around the molecule, and uroporphyrin I, sometimes present in human urine, has four acetic acid groups and four propionic acid groups in alternation. In the disease congenital porphyria there is a defect in the enzyme that normally catalyzes the conversion of uroporphyrin to-coproporphyrin. 

HC n-T Uroporphyrin heptacar- Coproporphyrin 1II>I, boxy- (about 30% of uro-h both hexacarboxy- pentacarboxyporphyrin coprapor-phyrin 111 > I s. acute porphyrias... 

A type of porphyrin molecule having methyl and propionate side groups (unlike uroporphyrin, which has acetate and propionate side groups, and protoporphyrin, which has methyl, vinyl and propionate side groups). Excess coproporphyrins are found in the urine and faeces in many types of porphyria and in acquired porphyrinurias (e.g. lead poisoning). 

A type of porphyria which resembles acute intermittent porphyria in that certain drugs can precipitate acute attacks. It is characterized by large amounts of coproporphyrin in the faeces. 

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