Williams Hematology



Definition and History
Etiology and Pathogenesis


Control of Heme Synthesis in the Liver and Erythroid Cells
Erythropoietic Porphyrias

Congenital Erythropoietic Porphyria (CEP)

Erythropoietic Protoporphyria
Hepatic Porphyrias

Acute Hepatic Porphyrias

Chronic Hepatic Porphyrias
Chapter References

The porphyrias are both inherited and acquired disorders in which the activities of the enzymes of the heme biosynthetic pathway are partially or almost totally deficient. There are eight enzymes involved in the synthesis of heme and, with the exception of the first enzyme, an enzymatic defect at every step leads to tissue accumulation and excessive excretion of porphyrins and/or their precursors such as d-aminolevulinic acid (ALA) and porphobilinogen (PBG). While heme, the final product of the biosynthetic pathway, is biologically important, porphyrins and their precursors are not only useless but also toxic.
Porphyrias can be classified as either photosensitive or neurological, depending on the type of their symptoms, but some have both symptoms. Alternatively, they can be classified either hepatic or erythropoietic, depending on the principal site of expression of the specific enzymatic defect, but some also show overlapping expression. The tissue-specific expression of porphyrias is largely due to the tissue-specific control of heme pathway gene expression.
Congenital erythropoietic porphyria (CEP), though rare, is a major erythropoietic porphyria in its expression and severity. It is inherited in an autosomal recessive fashion and is characterized by marked skin photosensitivity and hemolytic anemia. The genetic defect is a marked deficiency of uroporphyrinogen III cosynthase activity. The hemolytic anemia is photosensitive in nature, usually manifests at birth, and is due to massive accumulation of isomer I uro- and coproporphyrin in erythrocytes. Increased erythropoietic activity serves as a further stimulus for increased porphyrin production in the bone marrow. Hemolysis may improve after splenectomy. The clinical symptoms of CEP are indistinguishable from those of hepatoerythropoietic porphyria (HEP), hence it is possible that some hepatoerythropoietic porphyria may be confused with CEP.
Erythropoietic protoporphyria (EPP), another erythropoietic porphyria, is inherited in an autosomal dominant fashion. In contrast to CEP, EPP is relatively common. EPP is due to a 30 to 50 percent deficiency of ferrochelatase activity, which results in an excessive accumulation of protoporphyrin in erythrocytes and massive excretion of protoporphyrin into the stool. The disease is characterized by mild to moderate photosensitivity; there are no hematologic manifestations. Clinical expression is highly variable, such that some carriers have only mildly elevated red cell protoporphyrin levels but no skin photosensitivity. EPP is generally a mild disease, but some patients may develop porphyrin-rich gall stones and hepatic failure, resulting in death.
In contrast to CEP and EPP, d-aminolevulinate dehydratase deficiency porphyria (ADP) is an acute hepatic porphyria characterized by severe neurological disturbances; it may involve the gastrointestinal and respiratory systems but does not produce skin photosensitivity. ADP is due to a marked deficiency of d-aminolevulinate dehydratase activity, and patients with ADP excrete a large amount of ALA, but not PBG, into urine. It is the least frequent form of porphyria, and only four well-documented cases have been reported to date.
Acute intermittent porphyria (AIP) is the most common and important acute hepatic porphyria. It is inherited in an autosomal dominant fashion, but disease expression is very variable. Both clinically affected and asymptomatic carriers of AIP have about a 50 percent deficiency of porphobilinogen deaminase activity, but only clinically affected individuals excrete a large amount of ALA and PBG into urine. Many heterozygotes (about 90 percent) are asymptomatic throughout their lives. Patients present with severe neurological symptoms but never develop cutaneous photosensitivity. AIP is almost always latent before puberty, and symptoms are more frequent in females than in males. Hormonal, drug, and nutritional factors may aggravate the disease, probably by inducing hepatic ALA synthase, the rate-limiting enzyme in the heme biosynthetic pathway.
Hereditary coproporphyria (HCP) is also an acute hepatic porphyria, and its symptoms are similar to but generally milder than ADP and AIP. In contrast, HCP patients may additionally display skin photosensitivity. The underlying genetic defect in HCP is an approximately 50 percent deficiency of coproporphyrinogen oxidase activity, which is inherited in an autosomal dominant fashion. Patients excrete an excessive amount of ALA, PBG, and coproporphyrin into their urine and coproporphyrin into their stool. Harderoporphyria is a variant form of HCP, which produces harderoporphyrin III rather than coproporphyrin III. Neonatal hemolytic anemia has been reported with harderoporphyria. Clinical expression of HCP is dependent upon the same metabolic and chemical factors that influence expression of the gene defect in AIP.
Variegate porphyria (VP) has been recognized in many populations but is most common in South African whites, and thus it is also called the South African porphyria. The underlying defect is an approximately 50 percent deficiency of protoporphyrinogen oxidase, which is inherited in an autosomal dominant fashion. Clinical expression and symptoms are similar to HCP but often more severe. Patients with VP excrete a large amount of ALA and PBG into their urine and protoporphyrin into their stool. The same spectrum of factors that activate other acute hepatic porphyrias also induce VP. In South Africa, many patients with VP have the same R59W mutation of the protoporphyrinogen oxidase gene. Clinical management of VP is the same as that for other acute hepatic porphyrias.
Porphyria cutanea tarda (PCT) is the most common form of porphyria and usually begins in middle or late adult life. It is neither an erythropoietic nor an acute hepatic porphyria; instead, it is a chronic hepatic porphyria. Most PCT occurs as an acquired disease, while some occurs as an inherited disease. A deficiency of hepatic uroporphyrinogen decarboxylase activity is present in all patients with PCT. PCT patients have mild to severe photosensitivity and often have overt liver disease but no neurological symptoms. PCT patients excrete a large amount of 8- and 7-carboxylated porphyrins into their urine and isocoproporphyrin into their stool, but not ALA or PBG. Alcohol, estrogens, and hepatic siderosis are common aggravating factors in PCT. Some PCT patients also coinherit the hemochromatosis gene. PCT can be successfully treated by phlebotomy, which reduces hepatic iron stores. Polyhalogenated aromatic hydrocarbons have been associated with development of acquired PCT both in man and in animals.
Homozygous deficiency of uroporphyrinogen decarboxylase is known as hepatoerythropoietic porphyria (HEP), and patients with this condition are characterized by severe photosensitivity, which is indistinguishable from that of CEP. While both PCT and HEP are due to the same uroporphyrinogen decarboxylase deficiency, the heterozygous defect in PCT leads to a chronic hepatic porphyria, whereas the homozygous defect in HEP results in a hepatic and erythropoietic porphyria.
Molecular analysis of the gene defects in the porphyrias has demonstrated that there are numerous types of mutations for each porphyria. Many clinically “homozygous” porphyrias are in reality due to heteroallelic mutations, i.e., compound heterozygosity for two distinct mutations. The existence of rare homozygous (or compound heterozygous) deficiencies has also been recognized in all dominantly inherited forms of porphyrias. Porphyrias occur not only as inherited diseases but also as acquired diseases due to exposure to environmental chemicals or in association with other defects. Clinically unaffected gene carriers of porphyrias may also be at a greater risk than normal subjects for infertility and for intoxication by environmental chemicals, such as lead or dioxin.

Acronyms and abbreviations that appear in this chapter include: ADP, d-aminolevulinate dehydratase deficiency porphyria; AIP, acute intermittent porphyria; ALA, aminolevulinic acid; ALAS-E, erythroid-specific ALA synthase; ALAS-N, nonspecific ALA synthase; CEP, congenital erythropoietic porphyria; CRIM, cross-reactive immunological material; EPP, erythropoietic protoporphyria; HCP, hereditary coproporphyria; HEP, hepatoerythropoietic porphyria; PBG, porphobilinogen; PCT, porphyria cutanea tarda; VP, variegate porphyria.

The porphyrias are metabolic diseases due to deficiencies, usually of a genetic nature, in the activity of specific enzymes in the heme biosynthetic pathway. The intermediates of this pathway, i.e., porphyrinogens, porphyrins, and their precursors such as d-aminolevulinic acid or porphobilinogen, are produced in excess and accumulate in tissues resulting in neurological, photocutaneous, or both types of symptoms. These disorders are classified as either erythropoietic or hepatic, depending on the principal site of expression of the specific enzymatic defect. Erythropoietic porphyrias include congenital erythropoietic porphyria and erythropoietic protoporphyria. Hepatic porphyrias are further classified into acute and chronic forms. Acute hepatic porphyrias refer to a condition which exhibits acute attacks, mostly neurological, related to deranged porphyrin biosynthesis in the liver; they are represented by ALA dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria. In contrast, chronic hepatic porphyrias are characterized by chronic skin photosensitivity due to overproduction of porphyrins, but without acute attacks, as represented by porphyria cutanea tarda. Hepatoerythropoietic porphyria is an intermediate form expressing the defect both in the liver and erythroid cells. There are eight enzymes involved in the synthesis of heme and, with the exception of the first enzyme, i.e., ALA synthase, each enzymatic defect is associated with a specific form of porphyria (Table 62-1 and Fig. 62-1). In this chapter, the genetic defect or disturbances of heme biosynthesis is described for erythropoietic porphyrias, acute hepatic porphyrias, and chronic hepatic porphyrias. The major clinical and laboratory features of the porphyrias are summarized in Table 62-2, and hematological features of the porphyrias are summarized in Table 62-3.


FIGURE 62-1 The enzymatic defects in the porphyrias. The enzymatic defect in each porphyria is shown by a broken line. In patients, the substrate for the defective enzymatic step accumulates in the tissue, e.g., erythrocytes, and plasma, and is excreted in large excess into urine and/or stool. In addition, the excretion of porphyrin precursors, i.e., ALA and PBG, may be increased in patients with acute hepatic porphyrias as a result of derepression of ALA synthase activity in the liver.



Perhaps, the first published case of the acute hepatic porphyria was an elderly woman described by Stokvis in 1889. She excreted dark red urine and later died after taking sulphonal.1 Subsequently, two brothers, 23 and 26 years old respectively, who most likely had CEP, were described by T. McCall Anderson in 1898.2 These patients suffered from early childhood from attacks of hydroa aestivale, a cutaneous vesicular eruption associated with pruritus and burning that occurs on skin surfaces exposed to the sun, which recurred during each summer. The urine of the younger brother was persistently red, while that of the elder was said to be normal in color during the intervals between the attacks of hydroa. Their skin was extensively scarred in regions exposed to light, and there was loss of substance of their ears and noses. F. Harris3 demonstrated that the urine of both patients contained substance related to the hematoporphyrin group. Although the characterization of the nature of porphyrins was understandably primitive, other descriptions match perfectly with those of CEP or HEP. In a monograph published in 1911, Hans Günther classified porphyrias into four different groups, i.e., (1) those which have an acute onset without association with drug ingestion, (2) those which are due to sulphonal or trional, (3) hematoporphyria congenita, and (4) chronic hematoporphyria.4 These groups probably correspond to (1) drug-unrelated relapse of acute hepatic porphyrias (ALA dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria), (2) drug-induced relapse (ALA dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria), (3) congenital erythropoietic porphyria (or hepatoerythropoietic porphyria), and (4) porphyria cutanea tarda (or hepatoerythropoietic porphyria), respectively. In 1923, Archibald Garrod proposed the term inborn errors of metabolism for a group of inherited metabolic disorders that included porphyrias.5
Heme is essential for the function of all aerobic cells. In addition to hemoglobin, heme serves as the prosthetic group of hemeproteins such as myoglobin, mitochondrial and microsomal cytochromes, catalase, peroxidase, tryptophan pyrrolase, and nitric oxide synthase. Heme proteins are involved in the transport of oxygen and electrons, in the oxidative metabolism of various endogenous and exogenous chemicals, in the decomposition of hydrogen peroxide and organic peroxides, and in the oxidation of tryptophan. Most organisms have the ability to synthesize heme and apohemeproteins. Exogenously administered heme can also be incorporated into certain heme proteins such as hemoglobin6 and cytochrome P450.7 There is approximately 500 to 700 g of hemoglobin (of which 3.8 percent is heme) in a normal man with 70 kg body weight.8 Approximately 85 percent of heme is synthesized in the erythropoietic marrow, while the remainder is synthesized largely by the liver.9 In the liver, the majority of heme synthesized is incorporated into microsomal cytochrome P450s that perform important biotransformations of a variety of chemicals, including carcinogens, steroids, vitamins, fatty acids, and prostaglandins.10
Heme, i.e., ferrous protoporphyrin IX, is composed of an iron atom coordinated to the four pyrrole rings of protoporphyrin through the nitrogen atom in each pyrrole ring (Fig. 62-2). The outer periphery of the porphyrin macrocycle is fully substituted with alkyl groups. Heme is readily oxidized in vitro to hemin, i.e., ferric protoporphyrin IX. Hemin has one residual positive charge and is usually isolated as a halide, most commonly as the chloride. It becomes hematin when dissolved in alkaline solution. In hematin, the halide is replaced by a hydroxyl ion (Fig. 62-3). Heme can form further hexacoordinated complexes with nitrogenous bases that are called hemochrome or hemochromogen. Hemochromogen, e.g., pyridine hemochromogen, has a sharp spectrum and is useful for the identification and quantification of heme proteins.

FIGURE 62-2 Structure of heme. Each ring is labeled with the Roman alphabet.

FIGURE 62-3 Forms of iron protoporphyrin IX. The nitrogen atom indicates the pyrrolic nitrogen.

Ferrous ions have six electron pairs per atom. The ferrous iron atom in heme, bound to the pyrrolic nitrogen via four electron pairs, has thus two unoccupied electron pairs, one above and one below the plane of the porphyrin ring. In hemoglobin, one of these pairs is coordinated with a histidyl residue of the globin chain. This histidine is an invariable feature of all normal vertebrate globin chains. The other coordination site of iron is open in deoxyhemoglobin and protected from oxidation by the nonpolar environment provided by the amino acid residues surrounding the heme moiety. It is this sixth coordination position of the iron atom in hemoglobin which binds the oxygen molecule for transport. The iron in hemoglobin must be in the ferrous state in order to be able to reversibly bind oxygen. Although oxidized hemoglobin, i.e., methemoglobin, is generated in erythrocytes, it is continuously reduced to ferrous hemoglobin in the cell by the NADH-cytochrome b5 reductase-cytochrome b5-system (see Chap. 26).
The steps involved in heme biosynthesis are illustrated in Fig. 62-4. In eukaryote cells, the first step and the last three steps take place in mitochondria; the four intermediate steps occur in the cytosol. The two major organs involved in heme synthesis are the bone marrow and the liver. In the bone marrow, heme is made in erythroblasts and reticulocytes, which contain mitochondria, while circulating erythrocytes lack the ability to form heme. The first intermediate of the heme biosynthetic pathway is d-aminolevulinic acid, a 5-carbon aminoketone, which is formed by the condensation of glycine and succinyl CoA. Two molecules of ALA are combined to form the monopyrrole PBG; four molecules of PBG are then combined to form uroporphyrinogen, a cyclic tetrapyrrole. Uroporphyrinogen is converted to coproporphyrinogen and subsequently to protoporphyrin IX. Finally, ferrous ion is inserted into protoporphyrin IX to form heme. Protoporphyrin IX is the immediate precursor of the various hemes and also of the chlorophylls.

FIGURE 62-4 The heme biosynthesis pathway. Subcellular distribution of enzymes and intermediates are shown. ALA, d-aminolevulinic acid; PBG, porphobilinogen; HOCH2-BLN, hydroxymethylbilane; Uro’gen, uroporphyrinogen; Copro’gen, coproporphyrinogen; Proto’gen, protoporphyrinogen; Proto, protoporphyrin. A, -CH2COOH; P, -CH2-CH2-COOH; M, -CH3; V, -CH=CH2; •, the carbon atom derived from the a-carbon of glycine; *, the location of the a-carbon atom from glycine in the pyrrole ring which undergoes reversion; [ ], a presumed intermediate. Step 1, ALA synthase; step 2, ALA dehydratase; step 3, PBG deaminase; step 4, Uro’gen III cosynthase; step 5, Uro’gen decarboxylase; step 6, Copro’gen oxidase; step 7, Proto’gen oxidase; step 8, Ferrochelatase. [This figure was modified after Hayashi N, Protein, Nucleic Acid and Enzyme (Tokyo) 32:797, 1987, and used with permission.]

Step 1. Formation of d-Aminolevulinic Acid [d-Aminolevulinate Synthase (Succinyl CoA: Glycine C-Succinyl Transferase) (Decarboxylating) (EC] The first enzyme in the heme biosynthetic pathway is ALA synthase. ALA synthase catalyzes the condensation of glycine and succinyl CoA to form ALA (Fig. 62-4, step 1). In mammalian cells, the enzyme is localized in the inner membrane of the mitochondria.11 The enzyme reaction requires pyridoxal 5′-phosphate as a cofactor. The enzyme is synthesized as a precursor protein in the cytosol and transported into mitochondria. There are two separate ALA synthase genes, i.e., ALAS1 and ALAS2, encoding nonspecific (ALAS-N) and erythroid-specific (ALAS-E) isoforms, respectively.12,13 The human ALAS-E gene encodes a precursor of 587 amino acids, with a Mr of 64,600. Nucleotide sequences for the ALAS-E and the ALAS-N isoforms are about 60 percent similar; there is no homology in the amino-terminal region, while there is a high homology (about 73 percent) after the hepatic residue 197.14 The two human ALA synthase genes appear to have evolved by duplication of a common ancestral gene which encoded a primitive catalytic site, with subsequent addition of DNA sequences encoding variable functions, mostly at the amino termini.15 The gene locus for the human ALAS-N is at 3p.21, while that for the erythroid ALA synthase is at Xp11.2.13
The promoter in the human ALAS-E gene contains several putative erythroid-specific cis-acting elements including both a GATA-1 and an NF-E2 binding site15; both GATA-1 and NF-E2 are erythroid transcription factors that also bind to multiple DNA sites such as the promoter of the human b-globin gene and the erythroid porphobilinogen deaminase gene.16 These findings suggest that ALAS-E gene expression is likely to be under the regulatory influence of erythroid transcription factors such as GATA-1. Additionally, ALAS-E mRNA contains an iron-responsive element (IRE) in its 5′-untranslated region,15 similar to mRNAs encoding ferritin17 and transferrin receptor18 (see Chap. 24). Gel retardation analysis showed that the IRE in ALAS-E mRNA is functional and suggests that translation of the erythroid-specific mRNA can be upregulated by the availability of iron, or heme, in erythroid cells.19
The ALAS-N level in the liver is under positive and negative controls by porphyrogenic chemicals and hemin, respectively.20 Its level increases dramatically when the liver needs to make more heme in response to various chemical treatments. The enzyme synthesis is also derepressed in heme deficiency during the relapse of acute hepatic porphyrias. Stimuli that increase hepatic heme demands, such as (1) induction of cytochrome P450 by various drugs and/or hormones, or (2) induction of heme oxygenase by stress or fever, are usually associated with clinical aggravation of these disorders. In contrast, administration of hemin,21 or inhibitors of heme oxygenase activity,22 induces clinical remission. At heme concentrations much higher than those that repress the synthesis of the enzyme, heme induces microsomal heme oxygenase, resulting in its enhanced catabolism.23 Thus it can be visualized that the hepatic heme concentration is maintained by a balance between the synthesis of ALAS-N and heme oxygenase, both of which are under the regulatory control of heme.
In contrast to ALAS-N, ALAS-E expression in erythroid cells is not repressed by heme. Instead, it is often upregulated by hemin treatment or increased during erythroid differentiation when heme synthesis is increased.24,25 Thus the regulation of heme synthesis in erythroid cells is distinct from that in the liver.26
The sideroblastic anemias are a heterogeneous group of disorders characterized by hypochromic anemia of varying severity and the presence of ringed sideroblasts in the bone marrow (see Chap. 63). X-linked sideroblastic anemia is the most common form of the inherited forms of sideroblastic anemia, and some 20 different point mutations of the ALAS2 gene have been reported in this disorder. Mutations frequently, but not necessarily, are in exon 9 of the ALAS2 gene, which contains the binding site for pyridoxal 5’phosphate (K391), the essential cofactor for ALA synthase.
Step 2. Formation of Porphobilinogen [d-Aminolevulinate Dehydratase; d-Aminolevulinate Hydrolase (EC] ALA dehydratase is a cytosolic enzyme that catalyzes the condensation of two molecules of ALA to form a monopyrrole, PBG, with the removal of two molecules of water (Fig. 62-4, step 2). The human ALA dehydratase gene is located at chromosome 9q.27 ALA dehydratase activity requires an intact sulfhydryl group and a zinc atom in the enzyme. The enzyme activity is inhibited by sulfhydryl reagents28 or by lead, which displaces zinc.29 Patients with lead poisoning show marked inhibition of ALA dehydratase activity in erythrocytes, excrete excessive amounts of ALA into urine, and exhibit various neurological symptoms which often mimic those of acute hepatic porphyria30 (see Chap. 53). The most potent inhibitor of the enzyme activity is 4,6-dioxoheptanoic acid (succinylacetone). This compound, which is found in urine and blood of patients with hereditary tyrosinemia,31 is a substrate analogue and a potent inhibitor of the enzyme.32,33 Patients with tyrosinemia show little ALA dehydratase activity in blood and in the liver and present symptoms similar to acute hepatic porphyria.31,33
The human ALA dehydratase is encoded by mRNA with an open-reading frame of 990 bp, corresponding to a protein with an Mr of 36,274, and has a high degree of homology to the rat enzyme.34,35 There are sequences essential for enzymatic activity, i.e., those for the active lysine residue, and for the cysteine- and histidine-rich zinc binding sites.36 The gene for human ALA dehydratase is localized at chromosome 9p34.27
Unlike ALA synthase, there is no known tissue-specific isozyme for ALA dehydratase. However, it is known that ALA dehydratase mRNA occurs in housekeeping (1A) and erythroid-specific (1B) forms, and there is a significant tissue-specific control of these transcripts. Namely, both GATA-1 and ALA dehydratase 1B mRNA are significantly upregulated during erythroid differentiation in mice.37 This finding may be accounted for by the fact that, in both man and mouse, the promoter region upstream of exon 1B contains GATA-1 sites.37
Human ALA dehydratase is a polymorphic enzyme,38 with two common alleles (allele 1 and allele 2), which result in three distinct charge isozyme phenotypes, i.e., 1-1, 1-2, and 2-2. The allele 2 sequence is different from the allele 1 sequence only by a G to C transversion of nucleotide 177 in the coding region.39 This base substitution results in the replacement of lysine by asparagine, an amino acid change consistent with the more electronegative charge of the allele 2 subunit.
Step 3. Formation of Uroporphyrinogen I [Porphobilinogen Deaminase; Porphobilinogen Ammonia-Lyase (Polymerizing) (EC] Porphobilinogen deaminase catalyzes the condensation of four molecules of PBG to yield a linear tetrapyrrole, hydroxymethylbilane40 (Fig. 62-4, step 3). In the absence of the subsequent enzyme in the pathway, uroporphyrinogen III cosynthase, the bilane spontaneously forms a ring structure, uroporphyrinogen I. The type I porphyrinogen isomers do not produce any useful metabolites, while the type III isomers are the precursor for heme synthesis. Although PBG deaminase used to be referred to as uroporphyrinogen I synthase, this is incorrect as it does not form uroporphyrinogen I. It should be called either PBG deaminase or hydroxymethylbilane synthase, since the enzyme furnishes hydroxymethylbilane by deamination of four PBG molecules.
The gene locus encoding human PBG deaminase is at chromosome 11q23®11qter.41 The human PBG deaminase gene is split into 15 exons spread over 10 kb of DNA.42 There are two distinct molecular forms of PBG deaminase, i.e., the erythroid- and the nonspecific isoforms.43 The two distinct mRNAs are produced through alternative splicing of two primary transcripts arising from two promoters. The upstream promoter is active in all tissues, and thus the enzyme encoded by the larger transcript is termed the nonspecific, or the housekeeping, PBG deaminase. The size of the human housekeeping isoform predicted from its cDNA is 344 amino acids, with an Mr of 37,627.44 The other promoter, located about 3 kb downstream, is active only in erythroid cells. Erythroid-specific trans-acting factors, e.g., GATA-1 and NF-E2, recognize sequences in the PBG deaminase erythroid promoter.16 There is a 1320-bp stretch of perfect identity between the erythroid and the nonerythroid PBG deaminase, but with a mismatch in the first exon at their 5′ extremities. The additional 17 amino acid residues at the N-terminus of the nonerythropoietic isoform are accounted for by an additional in-frame AUG codon present at 51 bp upstream from the initiating codon of the erythropoietic cDNA.
Step 4. Formation of Uroporphyrinogen III (Uroporphyrinogen III Cosynthase) Uroporphyrinogen III cosynthase, a cytosolic enzyme, catalyzes the formation of uroporphyrinogen III from hydroxymethylbilane. This involves an intramolecular rearrangement which affects only ring D of the porphyrin macrocycle40 (Fig. 62-4, step 4). The protein predicted from a human uroporphyrinogen III cosynthase cDNA, which has an open-reading frame of 798 bp, consists of 263 amino acid residues, with a Mr of 28,607.45 The amino acid compositions of the hepatic uroporphyrinogen III cosynthase and the purified erythrocyte enzyme are essentially identical, suggesting that the enzyme in the liver and in erythroid cells is identical.
Step 5. Formation of Coproporphyrinogen [Uroporphyrinogen Decarboxylase (EC] A cytosolic enzyme, uroporphyrinogen decarboxylase, catalyzes the sequential removal of the four carboxylic groups of the carboxymethyl side chains in uroporphyrinogen to yield coproporphyrinogen (Fig. 62-4, step 5). The single enzyme catalyzes four successive decarboxylation reactions yielding 7-, 6-, 5-, and 4-carboxylated porphyrinogens, and the occurrence of all these intermediates has been identified in urine and stool. The enzyme activity in the liver can be inhibited by environmental chemicals such as polyhalogenated aromatic hydrocarbons. Human uroporphyrinogen decarboxylase is a 42-kDa polypeptide encoded by a single gene, containing 10 exons that are spread over 3 kb.46 The gene has been mapped to chromosome 1p34. Although it contains two initiation sites, both sites are used with the same frequencies in all tissues, and the gene is transcribed into a unique mRNA.47
Step 6. Formation of Protoporphyrinogen IX (Coproporphyrinogen Oxidase) Coproporphyrinogen oxidase in mammalian cells is a mitochondrial enzyme that catalyzes the removal of the carboxyl group and two hydrogens from the propionic groups of pyrrole rings A and B of coproporphyrinogen III to form vinyl groups at these positions, yielding protoporphyrinogen IX (Fig. 62-4, step 6). The gene for human coproporphyrinogen oxidase has been assigned to chromosome 3q12, spans approximately 14 kb, and consists of seven exons and six introns48; cDNA cloning for this enzyme has been reported in mouse erythroleukemia cells.49 The predicted protein comprises 354 amino acid residues (Mr 40,647), with a putative leader sequence of 31 amino acid residues, the result of being a mature protein of 323 amino acid residues (Mr 37,225).49 There are potential regulatory elements in the GC-rich promoter region on the gene, such as six Sp1, four GATA, and one CACCC sites. Coproporphyrinogen oxidase mRNA is known to increase during erythroid cell differentiation.50
Step 7. Formation of Protoporphyrin IX [Protoporphyrinogen Oxidase (EC] The penultimate step in heme biosynthesis, i.e., the oxidation of protoporphyrinogen IX to protoporphyrin IX, is mediated by a mitochondrial enzyme, protoporphyrinogen oxidase, that catalyzes the removal of six hydrogen atoms from the porphyrinogen nucleus (Fig. 62-4, step 7). Human protoporphyrinogen oxidase cDNA has been cloned.51 The gene is present as a single copy per haploid genome, at chromosome 1q22.52 Protoporphyrinogen oxidase consists of 477 amino acids with a Mr 50,800. The deduced protein exhibits a high degree of homology over its entire length to the amino acid sequence of protoporphyrinogen oxidase encoded by the HEMY gene of Bacillus subtilis. Protoporphyrinogen oxidase is a monomer with no apparent transport-specific leader sequence but is ultimately localized in mitochondria.51
Step 8. Formation of Heme [Ferrochelatase; Protoheme-Ferrolyase (EC] The final step of heme biosynthesis is the insertion of iron into protoporphyrin IX. This reaction is catalyzed by a mitochondrial enzyme, ferrochelatase (Fig. 62-4, step 8). Unlike other enzymatic steps in the heme biosynthetic pathway, ferrochelatase utilizes protoporphyrin IX as substrate, rather than its reduced form. However, ferrous, not ferric ion, is utilized for insertion into protoporphyrin IX.53 The gene encoding human ferrochelatase has been assigned to chromosome 18q.54,55 There are two ferrochelatase mRNA species, about 2.5 kb and about 1.6 kb in size, which are derived from the utilization of two alternative polyadenylation sites in the mRNA. The human ferrochelatase gene contains a total of 11 exons and has a minimum size of about 45 kb.54 A major site of transcription initiation is at an adenine, 89 bp upstream from the translation-initiating ATG. The promoter region contains a potential binding site for several transcription factors, Sp1, NF-E2, and GATA-1, but not a typical TATA or CAAT sequence. The transcripts are identical in all tissues examined.
Recently, crystal structure of Bacillus subtilis ferrochelatase has been determined at 1.9A resolution.56 Ferrochelatase seems to have a structurally conserved core region that is common to the enzyme from bacteria, plants, and mammals, and the porphyrin and the metal appear to bind in the identical cleft.
The rate of heme synthesis in the liver is largely regulated by the level of ALAS-N activity. The synthesis of ALAS-N is in turn under feedback control by heme. Compounds that increase hepatic cytochrome P450 synthesis, accelerate the destruction of heme, or inhibit heme formation induce ALAS-N. Regulation of ALAS-N by heme is known to occur at least at four different levels; (1) transcription, (2) translation, (3) transfer into mitochondria, and (4) enzyme inhibition. The last mechanism appears least important, while all the other mechanisms may play an important role in regulating ALAS-N levels.
ALAS-E is not inducible by drugs that induce ALAS-N.57 Unlike ALAS-N, the synthesis of ALAS-E is uninfluenced, or often upregulated, by hemin treatment, both at the transcriptional and the translational level.19,58 While hemin treatment of rats strongly inhibits the synthesis of hepatic cytochrome P450,59 the same treatment of marrow cultures increases erythroid-colony forming units.60 Thus the mode of regulation of ALA synthases in these two major heme-synthesizing organs is distinct. Other aspects of tissue-specific regulation of heme biosynthesis are summarized in Table 62-4.


CEP is an erythropoietic porphyria, inherited in an autosomal recessive fashion. The primary abnormality is an almost total deficiency of uroporphyrinogen III cosynthase activity which results in accumulation and massive excretion of type I porphyrins (Table 62-1 and Fig. 62-1). After the first two cases of CEP described by Anderson in 1898,2 about 130 cases have been reported,61 but some of these individuals may really have had HEP. Patients with CEP suffer from symptoms due to phototoxic reactions including cutaneous lesions and hemolytic anemia.
There is remarkable molecular heterogeneity of the uroporphyrinogen III cosynthase defects in CEP. To date, 18 different mutations of the uroporphyrinogen cosynthase gene have been reported in CEP. They include deletions, insertions, rearrangements, splicing abnormalities, and both missense and nonsense mutations. Six of these are found in exon 4, four in exon 10, and three in both exons 2 and 9.62 Of the twelve single base substitutions, four (T228M, G225S, A66V, and A104V) were hot spot mutations, occurring at CpG dinucleotides. With the exception of V82F, all CEP missense mutations occurred in amino acid residues that are conserved in both the mouse and the human uroporphyrinogen cosynthase.
Genotype-phenotype comparison of the uroporphyrinogen cosynthase was studied using the prokaryotic expression of mutant cDNAs. Mean activities of the mutant enzymes ranged from zero to 36 percent of the activity expressed in E. coli by the normal cDNA. The majority of the mutant cDNAs expressed polypeptides with null enzyme activity, while only V82F, A66V, A104V, and V99A showed 36, 15, 8, and 6 percent enzyme activity, respectively, as compared with the normal control. A66V and V82F were thermodynamically unstable mutants.62 Homoallelism for C73R, the most common mutation, was found in five patients and is associated clinically with the most severe phenotype, hydrops fetalis, and/or transfusion dependency from birth.
Most marrow normoblasts display fluorescence, principally in the nuclei.63 Marrow-derived porphyrins become distributed throughout the body and account for the multiple pathologies of the integument. Splenomegaly is frequently observed in CEP and is presumed to be secondary to the hemolytic process. Hemolysis of erythrocytes may also result from photolysis as porphyrin-laden cells are exposed to light in the dermal capillaries.
Early onset of cutaneous photosensitivity exacerbated by exposure to sunlight is characteristic. Subepidermal bullous lesions progress to crusted erosions which heal with scarring and either hyperpigmentation or hypopigmentation. Hypertrichosis and alopecia are common, and erythrodontia (with red porphyrin fluorescence under ultraviolet light) is virtually pathognomonic of CEP. Hemolytic anemia may be accompanied by splenomegaly and porphyrin-rich gallstones. Compensatory expansion of the marrow may result in pathological fractures, vertebral compression or collapse, shortness of stature, and, rarely, osteolytic and sclerotic lesions in the skeleton.
CEP can be recognized in utero by dark brownish amniotic fluid enriched in porphyrins. The diagnosis of CEP in infants can be made by pink to dark brown staining of the diapers, due to large amounts of urinary porphyrins. Severe cutaneous photosensitivity in infancy (or rarely in adults) should suggest the diagnosis of CEP. Urinary porphyrin levels are always elevated 20-to 60-fold above normal. Uroporphyrin levels are increased more than those of coproporphyrin; type I isomers of uro- and coproporphyrin series predominate, but the levels of type III isomers are also elevated. Fecal porphyrin excretion is usually increased and is predominantly coproporphyrin I. Anemia may be present, and erythrocytes may exhibit polychromasia, poikilocytosis, anisocytosis, and basophilic stippling. Demonstration of elevated urinary and fecal porphyrins of type I isomers, and free erythrocyte uro- and coproporphyrins are diagnostic of CEP. HEP may also present as photosensitivity in childhood, and porphyrin excretion is also elevated, but elevated fecal levels of isocoproporphyrin and 5-carboxylic porphyrins in this condition distinguish it from CEP.
Patients should be advised to avoid sunlight, trauma to the skin, and infections. Topical sunscreens may be of some help as may oral treatment with b-carotene.64 Transfusions with packed erythrocytes transiently decrease hemolysis and its attendant drive to increased erythropoiesis.65 Splenectomy has been performed on many patients but with only short-term reductions in hemolysis, porphyrin excretion, and skin manifestations. Treatment with charcoal for 9 months in a man with CEP was reported to have lowered porphyrin levels in plasma and skin and resulted in complete clinical remission during therapy.66 Oral administration of the free radical scavenger ascorbic acid and a-tocopherol has been reported to be effective in improving anemia.61
EPP is characterized by a partial deficiency of ferrochelatase activity, and the disease is generally inherited in an autosomal dominant fashion with a variable degree of clinical expression (Table 62-1 and Fig. 62-1). This defect results in massive accumulations of protoporphyrin in erythrocytes, plasma, and feces. Clinically, the disease is characterized by the childhood onset of cutaneous photosensitivity in light-exposed areas, but skin lesions are milder and less disfiguring than those seen in CEP, PCT, HEP, and VP. EPP is the most common form of erythropoietic porphyria. By 1976, some 300 case reports had been published.67 There is no racial or sexual predilection, and onset is typically in childhood.
Molecular analysis of the ferrochelatase gene in patients with EPP has revealed missense mutations, splicing mutations, intragenic deletions, and possible nonsense mutations associated with functional deficiency of ferrochelatase.68 Splicing mutations are most common. In a proband’s family, typically one parent is classified as a carrier of the disease because of elevated erythrocyte and stool protoporphyrin levels. In many cases, the mode of inheritance is autosomal dominant, but it is often vague or with a variable degree of penetrance. Parent-to-offspring transmission of the clinical disease is less than 10 percent.69 In addition to the typical dominant inheritance, a few cases of EPP with recessive inheritance have been confirmed.70 Disease expression is also influenced by other factors, including pregnancy.71 These findings suggest that EPP is a heterogeneous disorder.
Histological examinations of skin biopsies from EPP patients show thickened capillary walls in the papillary dermis surrounded by amorphous hyalinelike deposits, immunoglobulin, complement, and PAS-positive mucopolysaccharides.72 Basement membrane abnormalities are observed in EPP but are quantitatively less marked than in other forms of porphyria.73 Thus EPP may be suggested, but not positively identified, from skin biopsies. Light-excited porphyrins are known to generate free radicals and singlet oxygen,74 which then leads to peroxidation of lipids75 and cross-linking of membrane proteins.76 Marrow reticulocytes may display fluorescence, but protoporphyrin content and fluorescence of circulating reticulocytes is nonuniform and decreases with age.77 Erythrocyte protoporphyrin in EPP is free and not complexed with zinc, unlike other conditions associated with increased erythrocyte protoporphyrin content. The content of free protoporphyrin in these cells declines much more rapidly with red cell age than it does in conditions in which erythrocyte zinc protoporphyrin is increased.77a In lead poisoning and iron deficiency the excess erythrocyte zinc protoporphyrin is bound to hemoglobin and persists in the red cell as long as it circulates, whereas free protoporphyrin in EPP binds less readily to hemoglobin and diffuses more rapidly into the plasma. Interestingly, free protoporphyrin, but not zinc protoporphyrin, is released from erythrocytes following irradiation, which may explain why lead intoxication and iron deficiency, which are associated with elevated erythrocyte zinc protoporphyrin levels, are not associated with photosensitivity.78 Skin irradiation in EPP patients leads to complement activation and polymorphonuclear chemotaxis, and this event may also contribute to the pathogenesis of skin lesions in EPP.79
Light and electron microscopic examination of liver biopsies from EPP patients have revealed a wide variability in findings ranging from complete normality to periportal fibrosis and severe cirrhosis. Abnormally elevated, sometimes massive, accumulations of protoporphyrin have been detected as brown pigment in hepatocytes, Kupffer cells, and biliary cannaliculae and are doubly refractive under polarizing lenses.80 Some 20 patients with EPP have developed hepatic failure resulting in death, presumably secondary to protoporphyrin damage. A high ratio of protoporphyrin to bile acids in bile may be indicative of those patients with EPP who have advanced liver disease.81
The most common symptoms in a series of 32 patients with EPP are shown in Table 62-5. Symptoms are usually worse during spring and summer and occur in light-exposed areas, especially of the face and hands. Within 1 h of exposure to the sun, stinging or painful burning sensations occur in the skin and are followed several hours later by erythema and edema. Petechiae, or more rarely, purpura, vesicles, and crusting may develop and persist for several days after sun exposure. Some patients experience burning sensations in the absence of objective signs of cutaneous phototoxicity. Artificial lights may also cause photosensitivity.82 Severe exposure to the sun may result in onycholysis, leathery hyperkeratotic skin over the dorsae of the hands, and mild scarring. Bullae, skin fragility, hypertrichosis, hyperpigmentation, severe scarring, and mutilation are unusual in EPP. Gallstones, sometimes presenting at an unusually early age, are fairly common, and hepatic disease, although unusual, may be severe and associated with significant morbidity. Anemia is uncommon. There are no known precipitating factors and no neurovisceral manifestations. Conversely, pregnancy is known to lower erythrocyte protoporphyrin levels and increase tolerance to sunlight.71


Photosensitivity should suggest the diagnosis which can be confirmed by the demonstration of elevated concentrations of free protoporphyrin in erythrocytes, plasma, and stool, in association with normal urinary porphyrins. The presence of protoporphyrin in both plasma and erythrocytes is specific for EPP. Fluorescent reticulocytes on examination of peripheral blood smear also suggest the diagnosis. Evidence tends to favor the marrow and the newly released reticulocytes or erythrocytes as the major source of elevated protoporphyrin concentrations.77 Mild anemia with hyperchromia and microcytosis may also occur. Mild hypertriglyceridemia occurs with increased frequency in patients with EPP.
Avoidance of the sun and use of topical sunscreen agents may be helpful. Oral administration of b-carotene may afford photoprotection, resulting in improved, but highly variable, tolerance to the sun. The recommended serum b-carotene level of 600 to 800 µg/dl83 is usually achieved with oral doses of 120 mg to 180 mg daily, and beneficial effects are typically seen 1 to 3 months after the onset of therapy; b-carotene probably quenches activated oxygen radicals.84 Hypertransfusion therapy has also been advocated to suppress erythropoiesis,85 but the potential hazards of transfusion are a drawback. Cholestyramine has been reported to improve photosensitivity and reduce hepatic protoporphyrin content.86 Several patients who developed hepatic failure have been treated by liver transplantation, with only temporary relief of deranged liver function and accumulation of protoporphyrin in the liver.87
Definition and History ADP is an autosomal recessive disorder resulting from an almost complete deficiency of ALA dehydratase activity (Table 62-1 and Fig. 62-1). This is the rarest form of the porphyrias; only four well-documented cases have been reported.88 Two cases were German males with onset in their teens,89 the third case was a Swedish infant with severe acute hepatic porphyria,90 and the fourth was a Belgian male with a late onset.91
Pathophysiology The molecular defect of ALA dehydratase in the first German patient has been demonstrated to be compound heterozygosity for two distinct point mutations of the ALA dehydratase gene, one at each allele.92 One, termed G2, was a base substitution of A for G at nucleotide 820, which resulted in an amino acid change, Ala274®Thr, and the other, termed G1, was a C to T transition at nucleotide 718, resulting in an amino acid change, Arg240®Trp.93 The G1 mutation was located within the substrate binding site, while the G2 mutation was present downstream of this site. Expression of the G1 cDNA in Chinese hamster ovary cells produced ALA dehydratase protein with little activity; the G2 cDNA produced the enzyme with about 50 percent normal enzyme activity. Pulse-labeling studies demonstrated that the G1 enzyme had a normal half-life, while the G2 enzyme had a markedly decreased half-life. These findings demonstrated that the proband was a compound heterozygote for two separate point mutations in each ALA dehydratase allele and accounted for the almost complete lack of enzymatic activity in the proband’s cells and the half-normal activity in cells from the family members.
The molecular defect in the Swedish infant with ADP was also reported.94 A maternal G to A transition at nucleotide 397 predicted a Gly133®Arg change, which occurred at the carboxyl end of the zinc binding site in the enzyme. The paternal mutation was a G to A transition at nucleotide 823, resulting in an amino acid change, Val275®Met. The four distinct point mutations in two pedigrees suggest a marked heterogeneity in the mutations in this disorder.88
Clinical Features The symptomatology is similar to that seen in AIP. The two German male patients with onset in their teens were characterized by vomiting, pain in the legs, and neuropathy. In one patient this was also accompanied by abdominal pain.89 Later, the second patient developed paralysis of the arms, legs, and respiratory muscles. Both patients displayed clinical exacerbation following stress, decreased food intake, or alcohol ingestion. Despite these problems, the two patients fared well even 20 years after the onset of the disease.95 The Swedish infant was diagnosed at the age of 2 and had a stormy course characterized by general muscle hypotonia, respiratory insufficiency, and bilateral paralysis of the legs.90 The Belgian patient developed porphyria-related symptoms for the first time at the age of 63. This patient had additionally a myeloproliferative disorder.91
Diagnosis Definitive diagnosis of ADP is dependent on the demonstration of markedly deficient erythrocyte ALA dehydratase activity and the enzyme protein in the proband and intermediate decreases in the proband’s relatives. Supportive evidence for the diagnosis includes massive elevations in urinary ALA and substantial elevation of porphyrins in urine and erythrocytes; in contrast, urinary PBG excretion is within the normal range. Urinary and erythrocyte porphyrins, predominantly coproporphyrin III and protoporphyrin IX, respectively, are markedly elevated (about 100-fold); no satisfactory explanation has been forwarded to account for this observation. Erythrocyte ALA dehydratase activity is markedly decreased (less than 2 percent of normal) in the proband, and intermediately decreased (about 50 percent of normal) in the parents’ erythrocytes.
Lead poisoning can be differentiated by increased blood lead and zinc protoporphyrin, excessive urinary excretion of ALA and coproporphyrin, and markedly inhibited ALA dehydratase activity in erythrocytes, which, however, can be restored to normal by the addition of reduced glutathione, or dithiothreitol in vitro. There is no reduction in the ALA dehydratase protein in lead poisoning,96 which differentiates it from ADP.88
Hereditary tyrosinemia I is due to an inherited deficiency of fumaryl acetoacetate hydrolase.31 Patients with this condition excrete large amounts of ALA into urine, but not PBG. Diagnosis of tyrosinemia can be made by demonstrating succinylacetone in urine, as for example, by showing inhibition of ALA dehydratase activity of normal blood by the addition of a patient’s urine. There is no reduction in the amount of ALA dehydratase protein in this disease.97
Therapy The clinical similarities of ADP to AIP suggest that clinical guideline for treatment of ADP probably should follow that of AIP. However, the reported responses to treatment of the four cases varied greatly. One German patient responded to intravenous glucose, while the Swedish child failed to respond to glucose or to intrave-nous hematin. This child finally required liver transplantation at the age of 7, which did not suppress urinary ALA excretion but improved the patient’s condition to withstand several porphyrogenic challenges.98
Definition and History An autosomal dominant disorder resulting from a partial deficiency of PBG deaminase activity (Table 62-1 and Fig. 62-1), AIP is the major porphyria both in its incidence and severity. In the majority of patients (more than 85 percent) the deficient enzyme activity (about 50 percent of normal) is found in all tissues, including erythrocytes. This is consistent with a heterozygous enzyme deficiency in affected individuals. The first case of porphyria described in 1889 by Stokvis1 was probably a sulfonal-induced AIP. Since then, many cases of AIP, with or without drug ingestion, have been described. The prevalence of AIP was estimated to be 1 to 2 per 100,000 in Europe,99 or 2.4 per 100,000 in Finland.100 A cluster of AIP is known to exist in northern Sweden (1 per 1500101). The frequency of low PBG deaminase activity, which additionally includes latent gene carriers of AIP, is, however, as high as 1 per 500 in the general population of Finland.102 In France, based on molecular defect analysis, the minimal prevalence of the AIP gene has been calculated to be 1:1675.103
Pathophysiology More than 90 different abnormalities of the PBG deaminase gene have been reported in AIP since 1989.104 The prevalence of specific defective alleles among AIP families appears to vary depending on the population studied. Founder effects are likely to account for a high frequency of a single mutation in Finland and, to a lesser extent, in Holland, while many other mutations have only been found once, each of them in a single family. Both negative and positive types of cross-reactive immunological material (CRIM) were reported among AIP patients. Based on these findings, AIP can be classified into three subtypes, which are summarized in Table 62-6.


Type I. Patients with this subtype are characterized by a CRIM-negative mutation of PBG deaminase. Namely, patients exhibit both intermediately reduced enzyme activity and protein content (about 50 percent of normal). The mutations include single base substitutions, deletions that result in either changes in a single amino acid change or truncated proteins produced by splicing defects or frameshift mutations.
Type II. Patients with type II AIP (less than 5 percent of all AIP) are characterized by a partially decreased PBG deaminase activity in nonerythroid cells, but by normal erythrocyte PBG deaminase activity. A G®A transition was reported in a Dutch family at the first position of the first intron of the PBG deaminase gene. This modified the normal splice consensus sequence CGGTGAGT to CGATGAGT. A single base substitution (CG®CT) which resulted in a splicing defect at the last position of exon 1 was found in a Finnish family. Both mutations had no consequence on the expression of PBG deaminase in erythroid cells, since transcription of the gene in this cell type starts downstream of the site of mutation.
Type III. Patients with type III AIP are characterized by a CRIM-positive mutation, i.e., decreased activity with the presence of a structurally abnormal enzyme protein.105 Within this type, there are patients with moderately increased CRIM (type IIIa)106 and those with markedly increased CRIM (type IIIb)107 (Table 62-6).
Pathogenesis of the Clinical Findings The symptomatology of AIP is principally due to neurological dysfunction. Postmortem findings are, however, nonremarkable, suggesting their metabolic nature. Various theories have been put forth for the pathogenesis of neuropathy in AIP: (1) PBG deaminase deficiency in the nervous system tissues could limit the synthesis of heme for brain heme proteins; (2) deficiency in heme synthesis in the liver may adversely influence heme protein formation in the brain; (3) heme pathway intermediates, such as ALA, PBG, or their metabolites, may be toxic to nerve cells; and (4) in acute attacks, hepatic heme deficiency may lead to decreased activity of hepatic tryptophan pyrrolase, resulting in enhanced plasma levels and brain uptake of tryptophan, and ultimately to increased synthesis of 5-hydroxytryptamine, a neurotransmitter.
Precipitating Factors It should be recognized that up to 90 percent of individuals with documented deficiencies of PBG deaminase activity remain asymptomatic throughout their lifetimes. Some individuals with PBG deaminase deficiency may, however, have acute attacks precipitated by various endogenous or exogenous factors. There are at least five different classes of precipitating factors.
Inducers of Hepatic ALA Synthase. Most precipitating factors are inducers of nonspecific hepatic ALA synthase, ALAS-N. An increase in the metabolic demand for hepatic heme synthesis leads to an induction of ALAS-N and an overproduction of ALA. The partial deficiency of PBG deaminase activity (about 50 percent of normal) then becomes rate-limiting.
Endocrine Factors. Hormonal factors play a major role in the induction of ALAS-N activity. Clinical expression of AIP is virtually absent before puberty. The clinical disease is more common in women, especially at the time of menses; a subset of female patients experiences regular perimenstrual exacerbation of their disease. Synthetic estrogens and progesterone are known to induce porphyria.
Caloric Intake. Reducing caloric intake leads to exacerbation of AIP; conversely, carbohydrate-rich diets decrease PBG excretion and suppress clinical attacks.108
Drugs and Foreign Chemicals. Many chemicals, particularly barbiturates, exacerbate AIP. They are inducers of hepatic cytochrome P450 and result in enhanced demand for de novo heme synthesis, also leading to derepression of hepatic ALA synthase activity.
Stress. Various forms of stress, including intermittent illnesses, infections, alcoholic excess, and surgery may contribute to the genesis of an acute attack, via induction of hepatic heme oxygenase, which then results in heme depletion.
Clinical Features The clinical findings from three large series of AIP patients (4l7 was the total number109,110 and 111) are summarized in Table 62-7. The course of an acute attack of AIP is highly variable, with attacks lasting from a few days to several months. Abdominal pain is almost always present and is often the initial symptom of an acute attack. It may be generalized or localized. In severe cases the pain mimics an acute surgical abdomen and may lead to inappropriate laparotomy. Chest, back, and limb pain may also occur. Pains are usually intermittent, but they may also be chronic, and the severity may fluctuate. Gastrointestinal features are common which may include nausea, vomiting, constipation or diarrhea, abdominal distention, and ileus. The incidence of hepatocellular carcinoma is increased.112 Urinary incontinence, dysuria, frequency, and urinary retention may occur. The urine may appear “port-wine red” due to the high content of porphobilin, an auto-oxidation product of PBG and some porphyrins which are formed by nonenzymatic cyclization of PBG.


Neuropathy, particularly of the motor type, is a common feature of AIP, but any type of neuropathy may also occur. Motor neuropathy may involve the cranial nerves (most commonly the seventh and tenth) or lead to bulbar paralysis, respiratory impairment, and death; rarely, AIP may present as respiratory failure.113 Acute attacks of AIP are often accompanied by seizures, especially in patients with hyponatremia due to vomiting, inappropriate fluid therapy, or the syndrome of inappropriate antidiuretic hormone release.
Diagnosis Diagnosis can be established by the demonstration of reduced PBG deaminase activity (about 50 percent of normal) in erythrocytes, except in the case of type II AIP patients who show normal erythrocyte PBG deaminase activity. PBG deaminase activity in type II patients is, however, reduced in nonerythroid cells such as fibroblasts or lymphocytes.114,115 The distinction among (1) silent gene carriers, (2) clinically latent but biochemically manifest carriers, and (3) clinically and biochemically fully expressed patients is dependent on demonstration of elevated urinary excretion of PBG and ALA and on the history of the individual subject. Patients with the clinically expressed disease, as well as some latent gene carriers, excrete increased amounts of ALA and PBG in the urine, often even during clinical remission. The onset of an acute attack is accompanied by further massive increases in excretion of these precursors (ALA 25 to 100 mg/day; PBG 50 to 200 mg/day).116 The Watson-Schwartz test117 is widely used as a screening test for urinary PBG. The column method of Mauzerall and Granick118 should be used to quantify the amount of ALA and PBG in urine. Elevated levels of ALA and PBG may also be seen in HCP and VP. Urinary and stool porphyrin assays differentiate these conditions from AIP. Patients with ADP show elevated ALA in urine, but not PBG.88
Therapy The treatment of AIP as well as ADP, HCP, and VP is essentially identical. Treatment between attacks comprises adequate nutritional intake, avoidance of drugs known to exacerbate porphyria, and prompt treatment of other conditions, e.g., starvation, intermittent diseases, or infections. Unresponsive cases should be admitted to the hospital and intravenous administration of carbohydrate initiated with dextrose to provide a minimum of 300 g of carbohydrate per day. The use of intravenous hematin is now considered the treatment of choice. It curtails urinary excretion of ALA and PBG, acute attacks, and perhaps the severity of neuropathy. Nasal or subcutaneous administration of long-acting agonists of LHRH inhibits ovulation and greatly reduces the incidence of perimenstrual attacks of AIP in such women.119 Pain, which is invariably present and severe, can be treated with frequent regular doses of narcotic analgesics.
Definition HCP is a disease caused by a partial deficiency of coproporphyrinogen oxidase activity (about 50 percent of normal) which is inherited in an autosomal dominant manner (Table 62-1 and Fig. 62-1). Clinically expressed HCP is much less common than is clinically expressed AIP. In Denmark, the incidence of HCP has been estimated to be 2 per 1,000,000.120 However, with the recent improvement of laboratory techniques such as quantitative HPLC of porphyrins and a radioactive assay of coproporphyrinogen oxidase activity, more gene carriers for this condition have been recognized.
Pathophysiology Clinically, the disease is similar to ADP, or AIP, although it is often milder; additionally, HCP may be associated with photosensitivity due to accumulation of coproporphyrin in the tissue. Expression of the disease is variable and influenced by the same precipitating factors responsible for the exacerbation of AIP. Very rarely, homozygous deficiency of this enzyme may occur and is associated with a more severe form of the disease.121
Clinical Features The principal symptoms of HCP are neurological dysfunctions which are indistinguishable from those of ADP, AIP, and VP. Abdominal pain, vomiting, constipation, neuropathy, and psychiatric manifestations are common. Approximately 30 percent of patients with HCP accompany photocutaneous symptoms. Clinical attacks can be precipitated by pregnancy, the menstrual cycle, and contraceptive steroids, but the most common precipitating factor is administration of drugs, such as phenobarbital.
Diagnosis The diagnosis of HCP should be suspected in patients with the signs, symptoms, and clinical course characteristic of the acute hepatic porphyria but in whom erythrocyte PBG deaminase activity is normal. Urinary excretion of porphyrin precursors is similar in HCP and VP, but the predominance of coproporphyrin III is highly suggestive of HCP. Fecal coproporphyrin concentrations are also markedly elevated. Excessive excretion of ALA, PBG, and uroporphyrin into the urine is common during acute attacks, but, in contrast to AIP, these findings generally normalize between attacks. Rarely, two variant forms of HCP have been described. One is harderoporphyria, which is due to a homozygous defect of a structurally altered coproporphyrinogen oxidase, and the other is homozygous HCP, which is due to a homozygous deficiency of the normal enzyme. Fecal or urinary predominance of harderoporphyrin, with greatly reduced coproporphyrinogen oxidase activity, indicates harderoporphyria. Interestingly, harderoporphyria with K404E substitution in the coproporphyrinogen oxidase gene, either in the homozygous or compound heterozygous state, associated with a mutation leading to the absence of functional mRNA or protein, has been found to be responsible for neonatal hemolytic anemia.122
Therapy The identification and avoidance of precipitating factors is essential. Treatment of acute attacks is similar to the treatment of AIP.
Definition and History
VP is caused by a partial deficiency in protoporphyrinogen oxidase activity and is inherited in an autosomal dominant manner (Table 62-1 and Fig. 62-1). The incidence of VP is particularly high in South Africa, i.e., 3 per 1000. In l980, it was estimated that there were 10,000 affected individuals in South Africa,123 and evidence suggests that they are all descendants of a single Dutch settler in 1680.124 However, the disease is also recognized worldwide, and with the exception of South Africa, there is probably no racial or geographical predilection. Incidence in Finland is reported at 1.3 per 100,000.125
Pathophysiology Patients with this disorder may show neurovisceral symptoms, photosensitivity, or both, due to a partial deficiency in protoporphyrinogen oxidase activity.126 Disease expression is highly influenced by factors similar to those which precipitate the acute attack of AIP.
Clinical Features The neurovisceral symptomatology is indistinguishable from that of ADP, AIP, and HCP. Photosensitivity is more common, and cutaneous symptoms tend to be more chronic in VP than in HCP. Lesions are clinically and histologically indistinguishable from PCT, and in the absence of neurovisceral symptoms, the diagnosis of VP is easily overlooked. Skin manifestations are less frequently observed in cold climates (e.g., 45 percent in a series from Finland127) than in hot climates (e.g., 85 percent in a series from South Africa123). The same spectrum of factors which activate ADP, AIP, and HCP also induce VP.
Diagnosis VP should be considered in the differential diagnosis of acute hepatic porphyria, i.e., ADP, AIP, and HCP. If PBG deaminase activity is normal in a patient with an acute hepatic porphyria syndrome, it is particularly important to evaluate VP and type II AIP. Characteristic plasma porphyrin fluorescence is usually seen in VP.128 The differentiation of VP from HCP is usually possible by fecal porphyrin analysis. In patients with only cutaneous manifestations, the demonstration of urinary 8- and 7-carboxylic porphyrins and isocoproporphyrin is usually sufficient for differentiation of PCT from VP. If protoporphyrinogen oxidase assay is not available, screening of family members is best achieved by measuring fecal porphyrin concentrations and profiles.
Four homozygous cases of VP have been described. Parents of these patients had about 50 percent protoporphyrinogen oxidase activity but without clinical symptoms. Clinical features of these patients were severe photosensitivity, growth and mental retardation, and marked neurological abnormalities in two cases; onset was in childhood in all cases. None of the patients were anemic, suggesting that the principal site of protoporphyrinogen oxidase deficiency occurs in the liver, not erythroid cells.
Therapy Identification and avoidance of precipitating factors is essential. Photosensitivity can be minimized by protective clothing, and canthaxanthin (a b-carotene analogue) may be of some help.129 Treatment of neurovisceral symptoms is identical to that described for AIP.
Definition PCT is due to a partial deficiency of uroporphyrinogen decarboxylase activity (Table 62-1 and Fig. 62-1). PCT is the most common of all the porphyrias—genetic and acquired combined—but its exact incidence is not clear. The disease is recognized worldwide, and there is no racial predilection except among the Bantus in South Africa, secondary to their high incidence of hemosiderosis. Previously, PCT was more common in men than in women, in part due to higher alcohol intake in men, but the incidence in women has recently approached that of men, perhaps due to increased use of contraceptive steroids, postmenopausal estrogens, and alcohol. PCT can be classified into three subtypes (Table 62-8). The hallmark of all types of PCT is cutaneous photosensitivity due to increased accumulation of uroporphyrin and 7-carboxylic porphyrin.


Pathophysiology Type I. Patients with type I PCT are characterized by the lack of family history and by normal erythrocyte uroporphyrinogen decarboxylase activity and concentrations, but with decreased enzyme activity in the liver. Type I PCT typically presents in adults, either spontaneously, or more commonly, in conjunction with precipitating environmental factors such as alcohol, estrogen, drug use, iron overload, or in association with other disorders.
Type II. In type II PCT patients, the catalytic activity and the concentration of uroporphyrinogen decarboxylase are both about 50 percent of normal in all tissues, and the enzyme deficiency segregates as an autosomal dominant trait in the patient’s pedigree.
Type III. Patients with type III PCT are characterized by normal erythrocyte uroporphyrinogen decarboxylase activity and concentrations, but with decreased hepatic uroporphyrinogen decarboxylase activity, and this abnormality is found in more than one member in the same family.
Pathogenesis of the Clinical Findings. The initial event in bullous formation is the appearance of membrane-limited vacuoles in the superficial dermis. Porphyrin biosynthesis in the skin of PCT patients is increased compared to normal controls. Thus phototoxic porphyrins in the skin may be derived from both the liver and locally from the skin. Activation of the complement system after irradiation has been demonstrated in PCT patients both in vivo and in vitro in sera130 and is thought to result from generation of reactive oxygen species. Bullous fluid contains prostaglandin E2, and photoactivation of uroporphyrin damages lysosomes; inflammation and autolysis may be attributable to these factors. Liver biopsy specimens from patients with PCT, particularly those with type I, almost invariably display siderosis. Red autofluorescence and needlelike cytoplasmic inclusion bodies, representing crystallized porphyrins, have also frequently been recognized. Most cases of type I PCT have evidence of cirrhosis at autopsy. The incidence of hepatocellular carcinoma in PCT is greater than normal.131 Rarely, primary hepatomas may secrete porphyrins and simulate PCT.132
Precipitating Factors. Sporadic PCT is often triggered by exposure to environmental factors, such as alcohol, estrogens, iron, and polychlorinated aromatic hydrocarbons. Ethanol has long been known to exacerbate PCT, and the incidence of heavy alcohol intake has been reported to range from 25 to 100 percent. The mechanisms by which alcohol exacerbates PCT are unclear, but alcohol has been reported to increase iron uptake,133 which subsequently may contribute to the aggravation of the disease.
Estrogen administration has been associated with clinical relapse of PCT.134 Pregnancy may also aggravate PCT.135 PCT has been associated with the hyperestrogenic condition, Klinefelter’s syndrome.136
Iron plays an important role in the pathogenesis of PCT. Serum iron and ferritin concentrations are frequently elevated in PCT patients,137 and iron absorption and its turnover have been reported either normal or elevated. Hemosiderosis is seen in about 80 percent of liver biopsy specimens from patients with PCT.137 Phlebotomy induces clinical remission, while iron supplementation may lead to relapse of PCT.138 Addition of iron to in vitro systems has been reported either to inhibit139 or to stimulate uroporphyrinogen decarboxylase activity.140
The cause of the hepatic siderosis and mild iron overload in PCT, however, remains elusive. An association between HLA-linked hereditary hemochromatosis and PCT has been suggested, but also contested. Recently, a new histocompatibility-complex (MHC) class I-like gene, HFE, has been identified,141 and two missense variants, 845 G6A (C282Y) and 187 C6G (H63D), were found in the majority of unselected patients with hereditary hemochromatosis (see Chap. 42). It has also been shown that there is a high prevalence of the C282Y mutation in patients with PCT, 142,143 suggesting the involvement of the HFE gene in the pathogenesis of PCT.
Polyhalogenated aromatic hydrocarbons have been associated with development of PCT in man and in laboratory animals; 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was reported to cause PCT in 11 chemical factory workers in Czechoslovakia.144 Three cases of PCT were reported from a factory manufacturing the herbicides 2,4-dichloro- and trichlorophenoxyacetic acid,145 and one janitor developed PCT after accidental exposure to polychlorinated biphenyls (PCB) in a disinfectant.146 A massive outbreak of about 4000 cases of PCT occurred following the ingestion of hexachlorobenzene-contaminated wheat in Turkey from 1956 to 1961.147,148 A number of studies on the porphyrinogenic effects of TCDD, hexachlorobenzene, and PCB suggest that metabolic activation of the compounds (probably by cytochrome P450) is required to decrease uroporphyrinogen decarboxylase activity.
PCT has been observed in association with hemodialysis,149 systemic lupus erythematosus, Sjögren syndrome,150 rheumatoid arthritis,151 diabetes mellitus,152 viral hepatitis,153 Wilson disease,154 striopallidodentate calcinosis (Fahr disease),155 tumors and reticulosis,156 thalassemia minor and hemophilia.157,158 PCT has also been reported to develop after treatment with cyclophosphamide159 and bone marrow transplantation for chronic myelogenous leukemia.160 Recently an increasing number of patients with PCT in association with HIV infection has been reported, and positive links between PCT and AIDS have been suggested.161
Clinical Features Sporadic PCT (type I) almost exclusively presents in adults, while types II and III PCT may occur also in childhood. Patients have increased skin fragility; minor trauma results in erosions from shearing of the skin. Sun exposure may lead to the formation of vesicles and bullae, which crust over, take weeks to heal, and leave a scar. Milia may develop in the skin where bullae have healed. Hyperpigmentation, melanosis, and violaceous-brownish discolorations may develop on light-exposed areas. Facial hypertrichosis slowly develops and is most noticeable in women. Alopecia may develop in sites of repeated trauma or bullous formation. Hypopigmented indurated plaques of skin may develop and may appear as scleroderma-like changes.
Diagnosis The clinical picture of PCT is fairly specific, and its diagnosis is usually not difficult. However, it is necessary to differentiate it from other cutaneous photosensitivity syndromes. Clinical suspicion of PCT should lead to examination of the urine for fluorescence under an ultraviolet light and to quantitation of porphyrins. Uroporphyrin greater than coproporphyrin favors PCT; the reverse favors VP or HCP and may be associated with elevations in urinary ALA and PBG concentrations. Plasma porphyrins are invariably elevated in PCT and in other photosensitizing porphyrias. Isocoproporphyrin in feces represents the most important diagnostic criterion for PCT (Table 62-2).162 In the presence of uroporphyrinogen decarboxylase deficiency, 5-carboxylate porphyrinogen III accumulates and undergoes metabolism by coproporphyrinogen oxidase to yield dehydroisocoproporphyrinogen. This product also accumulates because its conversion to harderoporphyrinogen is impaired by the decarboxylase deficiency. Isocoproporphyrins are then generated by the auto-oxidation of the dehydro compound. Measurement of erythrocytic and hepatic uroporphyrinogen decarboxylase activity is usually a research procedure and decreased erythrocyte enzyme activity identifies only those patients with type II PCT.
Therapy The first line of treatment is the identification and avoidance of precipitating factors. Phlebotomy reduces urinary porphyrin concentrations and induces clinical remissions. There is strong evidence that the beneficial effects of phlebotomy result from a diminution in the stores of body iron. Typically, 450 ml of blood is withdrawn at each phlebotomy, and this is initially repeated 1 to 2 times per week. Remission is usually achieved after withdrawal of a total of about 4 to 10 liters of blood. The best objective indices of progress are the serum iron, or preferably the ferritin levels, which should be reduced to the lower limit of normal.
If phlebotomy is contraindicated by the presence of other diseases such as anemia or cardiopulmonary disorders, chloroquine therapy may be considered. Low-dose chloroquine (125 mg twice weekly) and high-dose therapy (500 mg daily) in refractory cases have been beneficial. Both treatment regimens transiently induce increases in plasma and urinary porphyrin concentrations and in liver transaminases. Continued therapy eventually leads to a reduction in porphyrin excretion, and clinical improvement, or remission, may occur typically in 6 to 9 months.
Definition and History HEP is a rare form of porphyria resulting from a homozygous defect in uroporphyrinogen decarboxylase activity (see Table 62-1 and Fig. 62-1). Clinically, HEP is indistinguishable from CEP and is characterized by childhood onset of severe photosensitivity and skin fragility. HEP is extremely rare; after the first report of HEP by Günther in 1967,163 only some 20 cases have been reported worldwide to date.164
Pathophysiology The uroporphyrinogen decarboxylase mutation in the first patient studied consisted of an 860 G®A change in the cDNA sequence which led to a Gly281®Glu change in the amino acid sequence. In vitro experiments showed that the cDNA with this mutation encoded a polypeptide that was very rapidly degraded in the presence of cell lysates. Two other point mutations were recognized. One was the replacement of Glu167®Lys which produced a protein with an unstable phenotype.165 The other mutation was a Arg292®Gly change.166 It should be noted that the majority of the mutations found in familial PCT and HEP are distinct.
The molecular defect in familial PCT is heterogeneous. A Gly281®Val substitution with unstable phenotype,167 a splice-site mutation,168 and exon 6 deletion (unstable phenotype) have been described.168 The exon 6 deletion has been found in 5 of 22 pedigrees examined and is the only mutation that has been found in more than one pedigree with PCT. HEP patients represent individuals with homozygous or compound heterozygous deficiency of uroporphyrinogen decarboxylase, which is, however, stable enough to meet the requirements for heme synthesis.167 In contrast, patients with familial PCT who are heterozygous for uroporphyrinogen decarboxylase deficiency may carry mutations with little enzyme activity or with a very unstable protein. One patient with HEP was heteroallelic for Val134®Gln substitution which was due to three sequential point mutations (T417G418T419®CCA) and His220®Pro substitution due to A677®C.169 Interestingly, the same Val134®Gln substitution was also found in another pedigree, however, as familial PCT.170
Clinical Features The clinical findings are similar to those seen in CEP; pink urine, severe photosensitivity leading to scarring and mutilation of sun-exposed areas of skin, sclerodermoid changes, hypertrichosis, erythrodontia, anemia (often hemolytic), and hepatosplenomegaly. Unlike PCT, onset of HEP is usually in early infancy or childhood,164 but occasional adult onset has also been described.171 Curiously, some of the cases with onset in childhood have shown spontaneous resolution of their photosensitivity,172 and others have experienced relatively mild symptoms from onset despite markedly elevated urinary porphyrin concentrations.164 In contrast to PCT, serum iron concentrations have usually been normal in HEP patients, and phlebotomy has little effect in improving symptoms. Elevated erythrocyte protoporphyrin level and occasional fluorescent normoblasts suggest the bone marrow as a source of porphyrins.173
Diagnosis The diagnosis must be considered in patients with severe photosensitivity, such as CEP. Diagnostic criteria include elevated levels of fecal or urinary isocoproporphyrin and erythrocyte zinc-protoporphyrin. Patients with EPP, who also show elevated erythrocyte protoporphyrin, can be distinguished from HEP, since they excrete normal amounts of urinary porphyrins. EPP is also clinically milder than HEP. Measurement of erythrocyte or fibroblast uroporphyrinogen decarboxylase activities typically shows reductions to 2 to 10 percent of normal control values with intermediate reductions of uroporphyrinogen decarboxylase activities in family members. As in the case of PCT, isocoproporphyrin concentrations equal to or greater than coproporphyrin is the characteristic of HEP. Elevated erythrocyte protoporphyrin (usually zinc protoporphyrin) has also been a feature of several cases of HEP. In contrast to PCT, serum iron is usually normal.
Therapy Avoidance of the sun and the use of topical sunscreens is all that can be offered to these patients at present. Patients with HEP do not respond to phlebotomy.164

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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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