Hereditary Coproporphyria
HCP is a disease caused by a heterozygous deficiency of co-proporphyrinogen oxidase (CPO) activity that is inherited as an autosomal dominant trait.2 Clinically, the disease is similar to AIP, although it is often milder; additionally, HCP may be associated with cutaneous photosensitivity. Very rarely, homozy-gous deficiency of CPO occurs and is associated with a more severe form of HCP.
Table 1 Safe and Unsafe Drugs for Patients with Acute Intermittent Porphyria, Variegate Porphyria, Hereditary Coproporphyria, or ALA Dehydratase Deficiency Porphyria
|
Safe Drugs |
Heme arginate |
Unsafe Drugs |
Nifedipine |
|
Acetaminophen |
Heparin |
Barbiturates1 |
Oral contraceptives1 |
|
Acetazolamide |
Insulin |
Captopril |
Orphenadrine1 |
|
Acyclovir |
Iron |
Chloramphenicol1 |
Oxycodone |
|
Allopurinol |
Lithium salts |
Chlordiazepoxide1 |
Pentazocine1 |
|
Amiloride |
|||
|
Meperidine |
Chlorpropamide1 |
Phenobarbital1 |
|
|
Ampicillin |
Phenytoin1 |
||
|
Aspirin |
Mequitazine |
Diazepam1 |
|
|
Atropine |
Metformin |
Diltiazem |
Piroxicam |
|
Bumetanide |
Metoprolol |
Diphenhydramine |
Pivampicillin1 |
|
Doxycycline |
Progesterone1 |
||
|
Bupivacaine |
Morphine |
Pyrazinamide1 |
|
|
Buprenorphine |
Nadolol |
Ergot compounds1 |
Sodium valproate1 |
|
Erythromycin |
|||
|
Chlorothiazide* |
Oxytocin |
Estrogen |
Terfenadine |
|
Codeine phosphate |
Penicillin |
Ethanol1 |
|
|
Tetracyclines1 |
|||
|
Corticosteroids* |
Procaine |
Furosemide1 |
Theophylline1 |
|
Deferoxamine |
Propofol |
Griseofulvin1 |
Trimethoprim |
|
Demerol |
Propylthiouracil |
||
|
Digoxin |
Quinine |
Hydralazine |
Verapamil |
|
Fentanyl |
Ranitidine* |
Hydrochlorothiazide1 |
|
|
Follicle-stimulating hormone |
Imipramine1 |
||
|
(FSH) |
Salbutamol |
||
|
Senna |
Lidocaine |
||
|
Gabapentin |
Methyldopa1 |
||
|
Gentamicin |
Temazepam |
||
|
Glipizide |
Thyroxine |
Metoclopramide1 |
|
|
Metronidazole |
|||
|
Haloperidol |
Warfarin |
*Has produced conflicting results (occasionally positive but mainly negative) in experiments on porphyrinogenicity. None of the safe drugs listed has been associated with human porphyric attacks.
+Has been associated with acute attacks of porphyria.
^Has produced conflicting results (some positive, some negative) in experiments on porphyrinogenicity.
Molecular defects and pathophysiology CPO is a mito-chondrial enzyme that catalyzes the removal of the carboxyl group and two hydrogens from the propionic groups of pyrrole rings A and B of coproporphyrinogen to form vinyl groups at these positions [see Figure 2]. Molecular analysis of several families with HCP revealed a variety of mutations in the CPO gene. These include missense, nonsense, and splicing mutations, as well as insertions and deletions. CPO activity in HCP is typically reduced by about 50% in heterozygotes and by 90% to 98% in homozygotes, who are rare.18
Diagnosis Neurovisceral symptoms predominate in HCP and are essentially indistinguishable from those seen in other acute hepatic porphyrias. Abdominal pain, vomiting, constipation, neuropathies, and psychiatric manifestations are common. Cutaneous photosensitivity is a feature in about 30% of cases. Attacks can be precipitated by the same factors as those that are known to aggravate AIP.
The biochemical hallmark of HCP is hyperexcretion of copro- porphyrin (predominantly type III) in urine and feces. Hyperex-cretion of ALA, PBG, and coproporphyrin into the urine may accompany exacerbation of the disease; however, in contrast to such findings in AIP, these findings in HCP generally return to normal between attacks.
HCP should be suspected in patients with the signs, symptoms, and clinical course characteristic of the acute hepatic por-phyrias but in whom PBGD activity is normal. Urinary excretion of heme precursors in HCP is similar to that in VP, but the predominant or exclusive presence of fecal coproporphyrin is highly suggestive of HCP. Fecal or urinary predominance of harderoporphyrin, with greatly reduced CPO activity, was reported in a case of harderoporphyria,19 a variant form of HCP.
Treatment Treatment of and prophylaxis for HCP are the same as those for VP and AIP. The use of drugs in patients with HCP should be the same as that in patients with AIP [see Table 1].
ALAD-Deficiency Porphyria
ADP is the rarest of the porphyrias; only four cases have been reported as confirmed by molecular diagnosis. The symptomatology is similar to that seen in AIP, but ADP can be differentiated from AIP by the lack of PBG overproduction. Urinary ALA excretion is greatly increased, whereas urinary PBG excretion is within the normal range. Patients with ADP display markedly decreased activity of ALAD in erythrocytes, as well as in non-erythroid cells (less than 2% of normal), and their parents typically show 50% decreases in enzyme activity.
ADP results from a marked reduction in ALAD activity caused by a homozygous enzyme deficiency [see Figure 2].2 ALAD catalyzes the reaction that converts two molecules of ALA to form a monopyrrole, PBG, by the removal of two molecules of water. The enzyme is a homo-octamer, with a subunit size of 36,274 daltons,20 and requires an intact sulfhydryl group and one zinc atom per subunit for full activity.21 The human ALAD genomic structure is 16 kb in length, with two promoter regions and two alternative noncoding exons, 1A and 1B, that generate housekeeping and erythroid-keeping transcripts, re-spectively.22 The two transcripts encode the same amino acid sequence, because translation begins in exon 2. Lead displaces zinc from the enzyme, resulting in an inactive enzyme and neurologic disturbances, some of which resemble those of ADP.23 The most potent inhibitor of the enzyme is succinylacetone, a structural analogue of ALA, which is found in urine and blood of patients with hereditary tyrosinemia, who frequently develop symptoms similar to those of ADP.
All ALAD point mutations have been studied by bacterial expression. The studies have revealed that eight of nine different mutations are unique and have markedly decreased enzyme activity, indicating the highly heterogeneous nature of the enzyme phenotypes.26
The clinical management of ADP is essentially identical to that of AIP.
Porphyrias associated with cutaneous photosensitivity
The porphyrias associated with cutaneous photosensitivity are porphyria cutanea tarda (PCT), hepatoerythropoietic por-phyria (HEP), erythropoietic protoporphyria (EPP), and congenital erythropoietic porphyria (CEP) [see Figure 1]. CEP, HEP, and EPP are also called erythropoietic porphyrias.
Porphyria Cutanea Tarda
PCT refers to a heterogeneous group of cutaneous porphyric diseases caused by uroporphyrinogen decarboxylase (UROD) deficiency, which may be either inherited or, more commonly, acquired.2,27
Epidemiology PCT is probably the most common of all forms of the porphyrias, but its exact incidence is not clear. The disease is recognized worldwide, and there is no racial predilection except for the high incidence of hemochromatosis found in the Bantus in South Africa. PCT was once considered more common in men, possibly because of greater alcohol intake; however, the incidence in women has recently matched that of men, which may be explained by women’s use of contraceptive steroids and postmenopausal estrogens and increased alcohol intake .
Molecular defects and pathophysiology UROD is a cy-tosolic enzyme that catalyzes the removal of the four carboxyl groups of the carboxymethyl side chains from uroporphyrino-gen to yield coproporphyrinogen [see Figure 2]. In contrast to the unique erythroid-expression mechanism for the first four enzymes of the heme biosynthetic pathway, the UROD gene has only a single promoter, and the gene is transcribed as a single mRNA.28 Both PCT and the much rarer HEP [see Hepatoeryth- ropoietic Porphyria, below] are characterized by a partial and a nearly complete UROD deficiency, respectively. Inherited PCT is caused by heterozygous UROD deficiency, whereas HEP is caused by homozygous UROD deficiency. Both inherited and noninherited forms of PCT display reductions in hepatic UROD activity, but erythrocyte UROD activity may or may not be decreased, depending on the clinical subtype. There are three types of PCT. Type I PCT, which accounts for 80% to 90% of all cases, is an acquired disease that typically presents in adults as decreased hepatic UROD activity but not decreased erythroid UROD activity. The disease may occur spontaneously, but it more commonly occurs in conjunction with precipitating environmental factors, such as use of alcohol, estrogen, or drugs. Type II PCT is inherited as an autosomal dominant trait and is associated with decreased UROD activity in all tissues. Type III PCT is also inherited, but the defect is confined to the UROD activity in the liver and in erythrocytes, and its protein concentrations are normal.
A variety of UROD mutations causing type II familial PCT have been identified, including missense, nonsense, and splice-site mutations; several small and large deletions; and a small insertion. In contrast to genetic defects in type II PCT, UROD mutations are not found in type I PCT.
The pathogenetic processes of PCT are not fully understood. Porphyrin-mediated activation of the complement system after irradiation is implicated as one of the possible mechanisms and has been demonstrated in patients with PCT; activation of the complement system is presumed to result from the generation of reactive oxygen species, most likely singlet oxygen.
Diagnosis The pathognomonic clinical feature of PCT is the formation of vesicles on sun-exposed areas of the skin, particularly the dorsal aspects of the hands, as well as on the face, forearms, and legs. The vesicles are superseded by crusting, superficial scarring, or milia formation and by residual pigmentation. Facial hypertrichosis may be present and is conspicuous in women. Iron, estrogens, alcohol, viral hepatitis, and chlorinated hydrocarbons can aggravate PCT.31 Mild iron overload is nearly always present in patients with PCT. Iron plays a particularly important role in the symptomatology of PCT, in that phlebotomy to decrease hepatic iron overload is effective in treating PCT [see Treatment, below], whereas iron supplementation results in relapse of PCT. A significant number of PCT patients have associated hemochromatosis gene (HFE) mutations.32 Isocopropor-phyrin, unique to PCT and HEP, may be detected in serum or in stool and is diagnostic of PCT. Plasma porphyrin levels are increased in PCT, HEP, and other photosensitizing porphyrias. In PCT, serum ferritin levels are also typically elevated, which is not the case in other cutaneous porphyrias.
Although many PCT patients have moderately excessive alcohol intake or hepatitis C infection, few have advanced liver disease at the time of initial presentation. However, liver abnormalities are seen even in patients without heavy alcohol intake or hepatitis C, indicating PCT itself is associated with liver damage. PCT appears to increase the risk for hepatocellular carcinoma in patients with chronic liver disease.33
Treatment In type I PCT, the identification and avoidance of precipitating factors represent the first line of treatment. Abstinence from alcohol ingestion should be recommended to the patient.
The cornerstone of therapy for all types of PCT is depletion of iron, even in patients lacking biochemical evidence of iron overload. Repeated phlebotomy of one unit of blood twice monthly for a total of 5 to 10 L, with treatment guided by the patient’s hematocrit and ferritin levels, decreases both uroporphyrin excretion and photosensitivity. Improvement occurs within several months to a year. Patients who are on hemodialysis, who are anemic, or who cannot tolerate phlebotomy should receive ery-thropoietin. Subcutaneous infusion of desferrioxamine by portable syringe pump (1.0 to 1.5 g in 8 to 10 ml of sterile water for 8 to 10 hours 5 nights a week for 2 to 5 months) is also effective.34
If phlebotomy is ineffective or contraindicated, low-dose chloroquine therapy may also be considered. Chloroquine, which forms complexes with uroporphyrin, has produced improvement over 3 to 6 months; however, hepatotoxicity may occur. Resolution of type 1 PCT has followed successful interferon therapy for HCV infection.
Hepatoerythropoietic Porphyria
HEP is a rare form of porphyria resulting from a homozy-gous deficiency of UROD.36 Individuals in HEP families who have heterozygous UROD deficiency usually do not have clinical symptoms. HEP is characterized clinically by the childhood onset of severe photosensitivity and skin fragility and is indistinguishable from CEP. Some 20 cases have been reported worldwide.
Molecular defects and pathophysiology As in PCT, HEP is caused by a UROD deficiency [see Figure 2]. A variety of UROD mutations have been identified in HEP patients, indicating the molecular heterogeneity of the disease. Most UROD mutations in HEP have not been found in familial PCT and are associated with residual UROD activity.29
Diagnosis Clinical findings of HEP are very similar to those of CEP. Pink urine, severe photosensitivity leading to scarring and mutilation of sun-exposed areas of skin, sclerodermoid changes, hypertrichosis, erythrodontia, anemia (often hemolyt-ic), and hepatosplenomegaly are characteristic features of HEP. In contrast to PCT, serum iron concentrations are usually normal, and phlebotomy has no beneficial effects in patients with HEP. Isocoproporphyrin concentrations are equal to or greater than concentrations of coproporphyrin found in urine and feces, and although the reasons are unclear, an elevated erythrocyte zinc protoporphyrin concentration is commonly observed.
Urinary fluorescence under ultraviolet light and quantitation and identification of isocoproporphyrin by thin-layer or high-performance liquid chromatography establish the diagnosis of HEP.
As in other photosensitizing porphyrias, plasma porphyrin levels are elevated in HEP. Fecal porphyrin levels are often elevated. The detection of isocoproporphyrin in feces is diagnostic of HEP and PCT. The diagnosis of HEP should be suspected in patients with severe photosensitivity and should especially be included in the differential diagnosis of CEP.
Treatment The identification and avoidance of precipitating factors represent the first line of treatment for PCT. In contrast to treatment for PCT, avoidance of the sun and the use of topical sunscreens are essentially all that can be recommended to patients with HEP; phlebotomy, which is most useful for treatment of PCT, provides no beneficial response in patients with this disorder.
Erythropoietic Protoporphyria
EPP is due to a partial deficiency of ferrochelatase and is inherited as an autosomal dominant trait.2 Biochemically, 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 in CEP. EPP is the most common form of the erythropoietic porphyrias. There is no racial or sexual predilection, and onset is typically in childhood.
Molecular defects and pathophysiology Ferrochelatase catalyzes the final reaction in heme biosynthesis—that is, the insertion of iron into protoporphyrin IX. Unlike other steps in the heme biosynthetic pathway, this mitochondrial enzyme utilizes protoporphyrin IX, rather than its reduced form (i.e., protopor-phyrinogen IX), as substrate. However, the enzyme specifically requires the reduced form of iron (i.e., ferrous, not ferric, iron) [see Figure 2]. The gene for human ferrochelatase has been assigned to chromosome 18q21.3.
Molecular analysis of ferrochelatase mutations causing EPP has revealed a variety of alterations, including missense, nonsense, and splice-site mutations, as well as insertions and deletions. Of these alterations, splice-site mutations are the most frequent. EPP patients have only 10% to 25% of normal fer-rochelatase activity, whereas their asymptomatic family members typically have 50% ferrochelatase activity. A normal coding ferrochelatase sequence allele, expressed at a lower than normal level,37 is present in about 10% of the white population. Inheritance of a ferrochelatase mutation in cis and the low expression allele in trans appears to account for the markedly low ferrochelatase activity and clinical expression of the disease.
Light-excited porphyrins generate free radicals and singlet oxygen.38 Such radicals, notably singlet oxygen, can lead to per-oxidation of lipids and cross-linking of membrane proteins, which, in erythrocytes, can result in reduced deformability and thus hemolysis. Protoporphyrin IX, but not zinc protoporphyrin IX, can be released from erythrocytes after irradiation.39 This finding explains why patients with EPP exhibit elevated levels of free protoporphyrin in plasma and manifest photosensitivity, whereas patients with lead intoxication and iron deficiency, who have elevated zinc protoporphyrin levels in erythrocytes, do not exhibit photosensitivity.
Diagnosis Cutaneous photosensitivity of EPP is quite different from that of CEP or PCT. Stinging or painful burning sensations of the skin occur within 1 hour after exposure to the sun and are followed several hours later by erythema and edema. Petechiae or, more rarely, purpura, vesicles, and crusting may develop and may persist for several days after sun exposure. Symptoms are usually worse during spring and summer and occur in light-exposed skin. Excoriations secondary to scratching may be present. Recurrence of the lesions as a result of chronic sun exposure may result in onycholysis, scarring, altered pigmentation, lichenification, and premature aging of the skin. Gallstones, sometimes presenting at an early age, are fairly common in patients with EPP, and hepatic disease, although unusual, may be severe and associated with significant morbidity.
The biochemical hallmark of EPP is excessive concentrations of protoporphyrin in erythrocytes, plasma, bile, and feces—but not in urine, because of the poor solubility of protoporphyrin in water.
Photosensitivity should suggest the diagnosis of EPP, which can be confirmed by the demonstration of increased concentrations of free protoporphyrin in erythrocytes, plasma, and stool and normal levels of urinary porphyrins. The presence of proto-porphyrin in both plasma and erythrocytes is a finding specific for EPP. Fluorescent reticulocytes on examination of peripheral blood smear also suggest the diagnosis.
Treatment Avoidance of the sun and use of topical sunscreen agents are helpful in the management of EPP. Oral administration of |-carotene can afford systemic photoprotection, resulting in improved, although highly variable, tolerance to the sun. The recommended serum | -carotene level of 600 to 800 Mg/dl is usually achieved with oral dosages of 120 to 180 mg daily, and beneficial effects are typically seen 1 to 3 months after the therapy is begun. The mechanism of this beneficial effect of | -carotene probably involves quenching of activated oxygen radicals.41
Congenital Erythropoietic Porphyria
CEP, which is also referred to as Gunther disease, is an auto-somal recessive disorder caused by a homozygous deficiency of the cytosolic enzyme, uroporphyrinogen cosynthase (UCS). The enzymatic defect results in accumulation and hyperexcretion of predominantly type I porphyrins.2 Fewer than 200 cases have been reported, and some of these cases may have been PCT or HEP. No clear racial or sexual predilection is apparent.2
Molecular defects and pathophysiology UCS catalyzes the formation of uroporphyrinogen III (UROIII) from hydroxy-methylbilane (HMB). In the absence of UCS, HMB is converted nonenzymatically to uroporphyrin I, which is then enzymatical-ly converted to coproporphyrin I [see Figure 2]. Excess por-phyrin causes the staining of bones and teeth (erythrodontia), hemolysis, dark urine, and photosensitivity, all of which are usually identified early in infancy.
Similar to the ALAD and PBGD genes, the UCS gene has alternative promoters that generate housekeeping and erythroid transcripts.39 A heterogeneity of mutations in the UCS gene is found in patients with CEP. A Cys73 ^ Arg point mutation appears to occur more frequently than others, because it has been found in eight of 21 unrelated patients with CEP (about 21% of CEP alleles).42
Diagnosis The first clue suggesting the diagnosis of CEP at birth is pink to dark-brown staining of diapers, which is caused by large amounts of porphyrins in the urine. Early onset of cutaneous photosensitivity is characteristic and is exacerbated by exposure to sunlight. Subepidermal bullous lesions progress to crusted erosions that heal with scarring and either hyperpig-mentation or, less commonly, hypopigmentation. Hypertri-chosis and alopecia are frequent and erythrodontia (appearing as red fluorescence under ultraviolet light) is pathognomonic of CEP. Patients may display symptoms and signs of hemolytic anemia with splenomegaly and porphyrin-rich gallstones. Bone marrow shows erythroid hyperplasia, which may result in pathologic fractures or vertebral compression-collapse and shortness of stature. Urinary levels of uroporphyrins and copro-porphyrins are always elevated (20- to 60-fold), with predominant elevations of type I isomers.
Pink urine or the onset of severe cutaneous photosensitivity in infancy (and rarely in adults) suggests the diagnosis of CEP.
Demonstration of increased levels of urinary, fecal, and erythro-cyte porphyrins, together with elevated type I isomers of uro-porphyrin and coproporphyrin, establish the diagnosis of CEP.
Treatment The avoidance of sunlight, trauma to the skin, and infections is the most important preventive measure. Topical sunscreens may be of some help, as may oral administration of | -carotene. Transfusions with packed erythrocytes transiently decrease hemolysis and its attendant drive to increased eryth-ropoiesis and also decrease porphyrin excretion by suppressing erythropoiesis in the bone marrow. Bone marrow transplantation is curative.43
