The Porphyrias Are Genetic Disorders Of Heme Metabolism

The porphyrias are a group of disorders due to abnormalities in the pathway of biosynthesis of heme; they can be genetic or acquired. They are not prevalent, but it is important to consider them in certain circumstances (eg, in the differential diagnosis of abdominal pain and of a variety of neuropsychiatric findings); otherwise, patients will be subjected to inappropriate treatments. It has been speculated that King George III had a type of porphyria, which may account for his periodic confinements in Windsor Castle and perhaps for some of his views regarding American colonists. Also, the photosensitivity (favoring nocturnal activities) and severe disfigurement exhibited by some victims of congenital erythropoietic porphyria have led to the suggestion that these individuals may have been the prototypes of so-called werewolves. No evidence to support this notion has been adduced.

Biochemistry Underlies the Causes, Diagnoses, & Treatments of the Porphyrias

Six major types of porphyria have been described, resulting from depressions in the activities of enzymes 3 through 8 shown in Figure 32-9 (see also Table 32-2). Assay of the activity of one or more of these enzymes using an appropriate source (eg, red blood cells) is thus important in making a definitive diagnosis in a suspected case of porphyria. Individuals with low activities of enzyme 1 (ALAS2) develop anemia, not porphyria (see Table 32-2). Patients with low activities of enzyme 2 (ALA dehydratase) have been reported, but very rarely; the resulting condition is called ALA dehy-dratase-deficient porphyria.

In general, the porphyrias described are inherited in an autosomal dominant manner, with the exception of congenital erythropoietic porphyria, which is inherited in a recessive mode. The precise abnormalities in the genes directing synthesis of the enzymes involved in heme biosynthesis have been determined in some instances. Thus, the use of appropriate gene probes has made possible the prenatal diagnosis of some of the porphyrias.

As is true of most inborn errors, the signs and symptoms of porphyria result from either a deficiency of metabolic products beyond the enzymatic block or from an accumulation of metabolites behind the block.

If the enzyme lesion occurs early in the pathway prior to the formation of porphyrinogens (eg, enzyme 3 of Figure 32-9, which is affected in acute intermittent porphyria), ALA and PBG will accumulate in body tissues and fluids (Figure 32-11). Clinically, patients complain of abdominal pain and neuropsychiatric symptoms. The precise biochemical cause of these symptoms has not been determined but may relate to elevated levels of ALA or PBG or to a deficiency of heme.

On the other hand, enzyme blocks later in the pathway result in the accumulation of the porphyrinogens

Figure 32-7. Decarboxylation of uroporphyrinogens to coproporphyrinogens in cy-tosol. (A, acetyl; M, methyl; P, propionyl.)

IV II

P A Uroporphyrinogen I

IV II

P A Uroporphyrinogen III

4CO,

UROPORPHYRINOGEN DECARBOXYLASE

4CO2

IV II

P M Coproporphyrinogen I

IV II

P M Coproporphyrinogen III

Porphobilinogen

UROPORPHYRINOGEN I SYNTHASE

Hydroxymethylbilane

UROPORPHYRINOGEN I SYNTHASE

Hydroxymethylbilane

COPROPORPHYRINOGEN OXIDASE

Protoporphyrinogen III

PROTOPORPHYRINOGEN OXIDASE

Or light in vitro

Protoporphyrin III

FERROCHELATASE

Heme

Figure 32-8. Steps in the biosynthesis of the porphyrin derivatives from porphobilinogen. Uroporphyrinogen I synthase is also called porphobilinogen deaminase or hydroxymethylbilane synthase.

Hemoproteins

Proteins

8. FERROCHELATASE

Protoporphyrin III

Aporepressor

Protoporphyrinogen III

6. COPROPORPHYRINOGEN OXIDASE

Coproporphyrinogen III

5. UROPORPHYRINOGEN DECARBOXYLASE

Uroporphyrinogen III

4. UROPORPHYRINOGEN III SYNTHASE

Hydroxymethylbilane

3. UROPORPHYRINOGEN I SYNTHASE

Porphobilinogen

2. ALA DEHYDRATASE

1. ALA SYNTHASE

Succinyl-CoA + Glycine

Figure 32-9. Intermediates, enzymes, and regulation of heme synthesis. The enzyme numbers are those referred to in column 1 of Table 32-2. Enzymes 1, 6, 7, and 8 are located in mitochondria, the others in the cytosol. Mutations in the gene encoding enzyme 1 causes X-linked sideroblastic anemia. Mutations in the genes encoding enzymes 2-8 cause the porphyrias, though only a few cases due to deficiency of enzyme 2 have been reported. Regulation of hepatic heme synthesis occurs at ALA synthase (ALAS1) by a repression-derepression mechanism mediated by heme and its hypothetical aporepressor. The dotted lines indicate the negative (Q) regulation by repression. Enzyme 3 is also called porphobilinogen deaminase or hydroxymethylbilane synthase.

J

400 500 600 Wavelength (nm)

Mutations in DNA

Abnormalities of the enzymes of heme synthesis

Accumulation of ALA and PBG and/or decrease in heme in cells and body fluids

400 500 600 Wavelength (nm)

Figure 32-10. Absorption spectrum of hematopor-phyrin (0.01% solution in 5% HCl).

Accumulation of ALA and PBG and/or decrease in heme in cells and body fluids

Accumulation of porphyrinogens in skin and tissues

Spontaneous oxidation of porphyrinogens to porphyrins

Photosensitivity

Figure 32-11. Biochemical causes of the major signs and symptoms of the porphyrias.

Table 32-2. Summary of major findings in the porphyrias.1

Enzyme Involved2 Type, Class, and MIM Number Major Signs and Symptoms Results of Laboratory Tests

1. ALA synthase (erythroid form)

2. ALA dehydratase

3. Uroporphyrinogen I synthase4

4. Uroporphyrinogen III synthase

5. Uroporphyrinogen decarboxylase

6. Coproporphyrinogen oxidase

7. Protoporphyrinogen oxidase

S. Ferrochelatase

X-linked sideroblastic anemia3 (erythropoietic) (MIM 201300) ALA dehydratase deficiency

(hepatic) (MIM 125270) Acute intermittent porphyria

(hepatic) (MIM 176000) Congenital erythropoietic (erythropoietic) (MIM 263700) Porphyria cutanea tarda (hepatic) (MIM 176100) Hereditary coproporphyria (hepatic) (MIM 121300)

Variegate porphyria (hepatic) (MIM 176200)

Protoporphyria (erythropoietic) (MIM 177000)

Anemia

Abdominal pain, neuropsychiatric symptoms Abdominal pain, neuropsychiatric symptoms No photosensitivity

Photosensitivity

Photosensitivity, abdominal pain, neuropsychiatric symptoms

Photosensitivity, abdominal pain, neuropsychiatric symptoms

Photosensitivity

Red cell counts and hemoglobin decreased

Urinary 8-aminolevulinic acid

Urinary porphobilinogen positive, uroporphyrin positive Uroporphyrin positive, porpho-bilinogen negative

Uroporphyrin positive, porpho-

bilinogen negative Urinary porphobilinogen positive, urinary uroporphyrin positive, fecal protopor-phyrin positive Urinary porphobilinogen positive, fecal protoporphyrin positive Fecal protoporphyrin positive, red cell protoporphyrin positive

1Only the biochemical findings in the active stages of these diseases are listed. Certain biochemical abnormalities are detectable in the latent stages of some of the above conditions. Conditions 3, 5, and 8 are generally the most prevalent porphyrias.

2The numbering of the enzymes in this table corresponds to that used in Figure 32-9.

3X-linked sideroblastic anemia is not a porphyria but is included here because 8-aminolevulinic acid synthase is involved.

4This enzyme is also called porphobilinogen deaminase or hydroxymethylbilane synthase.

indicated in Figures 32-9 and 32-11. Their oxidation products, the corresponding porphyrin derivatives, cause photosensitivity, a reaction to visible light of about 400 nm. The porphyrins, when exposed to light of this wavelength, are thought to become "excited" and then react with molecular oxygen to form oxygen radicals. These latter species injure lysosomes and other organelles. Damaged lysosomes release their degradative enzymes, causing variable degrees of skin damage, including scarring.

The porphyrias can be classified on the basis of the organs or cells that are most affected. These are generally organs or cells in which synthesis of heme is particularly active. The bone marrow synthesizes considerable hemoglobin, and the liver is active in the synthesis of another hemoprotein, cytochrome P450. Thus, one classification of the porphyrias is to designate them as predominantly either erythropoietic or hepatic; the types of porphyrias that fall into these two classes are so characterized in Table 32-2. Porphyrias can also be classified as acute or cutaneous on the basis of their clinical features. Why do specific types of porphyria affect certain organs more markedly than others? A partial answer is that the levels of metabolites that cause damage (eg, ALA, PBG, specific porphyrins, or lack of heme) can vary markedly in different organs or cells depending upon the differing activities of their heme-forming enzymes.

As described above, ALAS1 is the key regulatory enzyme of the heme biosynthetic pathway in liver. A large number of drugs (eg, barbiturates, griseofulvin) induce the enzyme. Most of these drugs do so by inducing cytochrome P450 (see Chapter 53), which uses up heme and thus derepresses (induces) ALAS1. In patients with porphyria, increased activities of ALAS1 result in increased levels of potentially harmful heme precursors prior to the metabolic block. Thus, taking drugs that cause induction of cytochrome P450 (so-called microsomal inducers) can precipitate attacks of porphyria.

The diagnosis of a specific type of porphyria can generally be established by consideration of the clinical and family history, the physical examination, and appropriate laboratory tests. The major findings in the six principal types of porphyria are listed in Table 32-2.

High levels of lead can affect heme metabolism by combining with SH groups in enzymes such as fer-rochelatase and ALA dehydratase. This affects porphyrin metabolism. Elevated levels of protoporphyrin are found in red blood cells, and elevated levels of ALA and of coproporphyrin are found in urine.

It is hoped that treatment of the porphyrias at the gene level will become possible. In the meantime, treatment is essentially symptomatic. It is important for patients to avoid drugs that cause induction of cyto-

chrome P450. Ingestion of large amounts of carbohydrates (glucose loading) or administration of hematin (a hydroxide of heme) may repress ALAS1, resulting in diminished production of harmful heme precursors. Patients exhibiting photosensitivity may benefit from administration of P-carotene; this compound appears to lessen production of free radicals, thus diminishing photosensitivity. Sunscreens that filter out visible light can also be helpful to such patients.

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