Harper's Illustrated Biochemistry, Volume 1 - Murray R. 1993

Protein and Amino Acid Metabolism
Porphyrins and Bile Pigments
Porphyrias

Porphyrias are a heterogeneous group of disorders characterized by the excessive excretion of Porphyrins or their precursors. Some forms of porphyria are inherited, while others are acquired. Several different classifications of porphyrias have been proposed. It is convenient to divide the inherited forms into three major groups: erythropoietic, hepatic, and those in which metabolic defects occur simultaneously in both erythropoietic and hepatic Tissues (Table 33.2). For most inherited forms, metabolic defects are present in all tissues, yet for reasons unknown, they manifest in only a single tissue type. Described below are the biochemical abnormalities characteristic of the porphyrias.

Class="center">Table 33.2. Classification of Human Porphyrias ¹⁾

¹⁾ Reproduced, with permission, from the review by Meyes U. A., Schmid R. The porphyrias. In: The Metabolic Basis of Inherited Disease, 4th ed. Stanbury J. B., Wyngaarden J. B., Fredrickson D. S. (eds). McGraw-Hill, 1978.

Each type of porphyria is characterized by a specific profile of urinary porphyrins and their precursors. These data and their relationship to various stages of heme synthesis are shown in Fig. 33.11.

Acute intermittent porphyria (AIP) is an autosomal dominant inherited human disease that typically manifests only after Puberty. It is caused by a heritable partial deficiency of uroporphyrinogen I synthase. Because patients are heterozygous for the defective structural Gene, The activity of uroporphyrinogen I synthase in their cells is 50% of normal. Patients with AIP excrete large amounts of porphobilinogen and ALA in their urine. Both of these compounds are colorless, but upon exposure to light and air, porphobilinogen spontaneously forms two colored products: porphobilin and porphyrins. This accounts for the darkening of urine when it is left standing in the light and air.

Porphobilinogen and ALA are present in the plasma and CEREBROSPINAL FLUID of patients, particularly during acute exacerbations. Drugs and Steroid Hormones whose METABOLISM requires heme-containing Proteins, such as cytochrome P-450, can precipitate an acute attack. Compounds that induce porphyria during their metabolism increase the turnover of heme proteins and thereby lower the intracellular heme concentration; this leads to the depression of ALA synthase synthesis. The elevated activity of ALA synthase and partial blockade of uroporphyrinogen I synthase result in a marked accumulation of ALA and porphobilinogen, which is accompanied by acute abdominal pain, vomiting, constipation, cardiovascular abnormalities, and neuropsychiatric disorders. Notably, experimental evidence indicates that reduced heme levels inhibit Tryptophan pyrrolase activity, leading to the accumulation of neuroactive compounds such as tryptophan and 5-hydroxytryptamine.

Patients with AIP do not exhibit the photosensitivity characteristic of other hepatic porphyrias. This is to be expected, since neither porphyrins nor porphyrinogens accumulate in these patients, as the metabolic impairment in heme synthesis occurs at a stage prior to The formation of the first porphyrinogen (uroporphyrinogen).

As noted above, metabolic defects are also detectable in other cells, particularly erythrocytes, as well as in cultured fibroblasts or Amniotic Fluid cells; however, elevated ALA synthase activity, leading to the overproduction of ALA and porphobilinogen, is observed predominantly in the liver. This is presumably because the liver is the primary organ where the metabolism of inducing agents takes place. Acute porphyria is one of the rare Examples of a disease phenotypically expressed in heterozygotes, despite an enzyme deficiency of only 50%.

As predicted by the proposed repression-derepression regulatory mechanism of ALA synthase synthesis, the administration of hematin to patients with AIP can reduce the induction of ALA synthase and thereby alleviate the clinical course of the disease.

Fig. 33.11. Sequential Stages of heme Biosynthesis, indicating precursors excreted in the urine in Various Forms of porphyria. Braces group compounds that are excreted in excess in the urine during exacerbations of the indicated forms of porphyria. ALA — 5-aminolevulinic acid. (Reproduced with modifications from Kaufman L., Merver H.S. Biochemical defects in Two Types of human hepatic porphyria. N. Engl. J. Med 1970;283:954.)

Congenital erythropoietic porphyria is an even rarer inherited disorder transmitted in an autosomal recessive manner. The molecular nature of this disease is not precisely known; however, it is known to be characterized by a distinct imbalance in the relative activities of uroporphyrinogen III cosynthase and uroporphyrinogen I synthase. The formation of uroporphyrinogen I quantitatively far exceeds the synthesis of uroporphyrinogen III, the normal isomer in the heme biosynthetic pathway. Although the genetic defect extends to all cells, for reasons unknown it is expressed predominantly in erythropoietic tissue. Patients with congenital erythropoietic porphyria excrete large amounts of type I isomers of uroporphyrinogen and coproporphyrinogen; in urine, both of these compounds spontaneously oxidize to uroporphyrin I and coproporphyrin I, which are red fluorescent pigments. A case has been reported in which a slight increase in uroporphyrin III concentration was observed, but The ratio of type I to type III isomers was approximately 100:1. Circulating erythrocytes contain large amounts of uroporphyrin I, yet the highest concentration of this porphyrin is found in Bone Marrow cells (rather than hepatocytes).

Presumably, As a result of the reduced Formation of the true heme precursor, uroporphyrinogen III, and the resulting relative heme deficiency in the erythropoietic tissues of patients, ALA synthase is induced. This induction leads to the overproduction of type I porphyrinogens. Along with enhanced ALA synthase synthesis and the overproduction of type I porphyrinogens, the formation and excretion of porphobilinogen and ALA are also increased. Thus, based on biochemical abnormalities, one can predict the appearance of clinical symptoms similar to those observed in AIP, with the additional presence of Skin photosensitivity due to the absorption spectrum of the porphyrin compounds produced in large quantities. Patients develop skin blistering and frequently exhibit hemolytic phenomena.

Hereditary coproporphyria is an autosomal dominant disorder caused by a deficiency of coproporphyrinogen oxidase, a mitochondrial enzyme responsible for converting coproporphyrinogen III into protoporphyrinogen IX. Coproporphyrinogen III is cleared from the body in large quantities via feces and, owing to its Water solubility, is also excreted in large amounts in the urine. Like uroporphyrinogen, coproporphyrinogen rapidly oxidizes upon exposure to light and air to form the red pigment coproporphyrin.

The limited capacity for heme synthesis in this condition (especially under stress) leads to the derepression of ALA synthase. Consequently, there is an Excessive production of ALA, porphobilinogen, and other heme pathway intermediates located upstream of the genetically blocked step. Accordingly, patients with hereditary coproporphyria exhibit all the signs and symptoms associated with excess ALA and porphobilinogen that are characteristic of acute intermittent porphyria, but in addition, they display photosensitivity caused by the presence of excess coproporphyrinogens and uroporphyrinogens. In this condition, the administration of hematin can also induce at least partial repression of ALA synthase and alleviate symptoms caused by the overproduction of heme biosynthesis intermediates.

Variegate porphyria, or hereditary coproporphyria, is an autosomal dominant disorder characterized by a partial block in the enzymatic conversion of protoporphyrinogen to heme. Normally, this conversion is carried out by two Enzymes, protoporphyrinogen oxidase and ferrochelatase, located in the Cell/35.html">Mitochondria. Evidence from cultured skin fibroblasts indicates that the level of protoporphyrinogen oxidase in patients with variegate porphyria is only half of normal. Patients with variegate porphyria experience a relative heme deficiency under stress, as well as derepression of hepatic ALA synthase. As noted above, elevated ALA synthase activity leads to the overproduction of all heme synthesis intermediates situated upstream of the blocked step. Thus, patients with variegate porphyria excrete excess amounts of ALA, porphobilinogen, uroporphyrin, and coproporphyrin in their urine, and eliminate uroporphyrin, coproporphyrin, and protoporphyrin in their feces. The patients' urine is pigmented and fluorescent, and their skin is sensitive to light, much like in porphyria cutanea tarda (see below).

Porphyria cutanea tarda is likely the most common form of porphyria. It is usually associated with underlying liver damage, particularly from excessive alcohol consumption or iron overload. The exact Nature of the metabolic defect is not firmly established, but a partial deficiency of uroporphyrinogen decarboxylase is the probable cause. The disorder appears to be inherited as an autosomal dominant trait, but genetic penetrance is variable and in most cases depends on the presence of hepatic dysfunction. As predicted, the urine contains elevated amounts of type I and type III uroporphyrins; meanwhile, the urinary excretion of ALA and porphobilinogen is relatively rare. Occasionally, the urine contains substantial amounts of porphyrins, imparting a pinkish hue; upon acidification, it most frequently exhibits pink fluorescence in the ultraviolet region.

The liver contains large amounts of porphyrins and therefore fluoresces strongly, whereas erythrocytes and bone marrow cells show no fluorescence. The principal clinical manifestation of porphyria cutanea tarda is increased skin photosensitivity. Patients do not show elevated ALA synthase activity, nor do they have excess urinary porphobilinogen and ALA; this correlates with the absence of acute attacks characteristic of acute intermittent porphyria.

Protoporphyria, or erythropoietic protoporphyria, appears to be caused by dominantly inherited deficient activity of ferrochelatase in the mitochondria of all tissues; clinically, this disease manifests as acute solar urticaria triggered by sunlight exposure. Erythrocytes, plasma, and feces contain elevated amounts of protoporphyrin IX, and reticulocytes (immature red Blood Cells) and skin (on biopsy examination) frequently fluoresce red.

The liver probably also contributes to the increased production of protoporphyrin IX, although urinary excretion of porphyrins and their precursors is not observed.

Acquired (toxic) porphyria can be caused by the action of toxic compounds such as hexachlorobenzene, lead salts, and other heavy metals, as well as drugs such as griseofulvin. Heavy metals are inhibitors of several enzymes in the heme biosynthetic pathway, including ALA dehydratase, uroporphyrinogen synthase, and ferrochelatase.