Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + INTRODUCTION Download Section PDF Listen +++ ++ The porphyrias are inherited or acquired disorders in which the activity of an enzyme in the heme biosynthetic pathway is altered. Metabolic intermediates are produced in excess, initially either in the marrow or the liver, and result in neurologic and/or photocutaneous symptoms and signs. + CLASSIFICATION Download Section PDF Listen +++ ++ See Table 28–1. The two organs most active in heme biosynthesis are the marrow and the liver. Photosensitivity (indicated below with the following symbols as either blistering* or nonblistering†) and/or (indicated below with the following symbol as) neurovisceral symptoms‡ may be part of the porphyria phenotype. Therefore, porphyrias are classified as erythropoietic or hepatic and as cutaneous or acute. ++Table Graphic Jump LocationTABLE 28–1HUMAN PORPHYRIAS: SPECIFIC ENZYMES AFFECTED BY MUTATIONS, MODES OF INHERITANCE, CLASSIFICATION, AND MAJOR CLINICAL FEATURES OF EACH OF THE HUMAN PORPHYRIASView Table||Download (.pdf) TABLE 28–1 HUMAN PORPHYRIAS: SPECIFIC ENZYMES AFFECTED BY MUTATIONS, MODES OF INHERITANCE, CLASSIFICATION, AND MAJOR CLINICAL FEATURES OF EACH OF THE HUMAN PORPHYRIAS Porphyriaa Affected Enzyme Known Mutations Inheritance Classification Principal Clinical Features X-linked protoporhyria (XLP) δ-Aminolevulinic acid (ALA) synthase erythroid-specific form (ALAS2) 4 (gain of function) Sex-linked recessive Erythropoietic Nonblistering photosensitivity δ-Aminolevulinic acid dehydratase porphyria (ADP) ALA dehydratase (ALAD) 10 Autosomal recessive Hepaticb Neurovisceral Acute intermittent porphyria (AIP) PBG deaminase (PBGD) 273 Autosomal dominant Hepatic Neurovisceral Congenital erythropoietic porphyria (CEP) Uroporphyrinogen III synthase (UROS) 36 Autosomal recessive Erythropoietic Neurovisceral Porphyria cutanea tarda (PCT) Uroporphyrinogen decarboxylase (UROD) 70 (includes HEP) Autosomal dominantc Hepatic Blistering photosensitivity Hepatoerythropoietic porphyria (HEP) UROD — Autosomal recessive Hepaticb Blistering photosensitivity Hereditary coproporphyria (HCP) Coproporphyrinogen oxidase (CPO) 42 Autosomal dominant Hepatic Neurovisceral; blistering photosensitivity (uncommon) Variegate porphyria (VP) Protoporphyrinogen oxidase (PPO) 130 Autosomal dominant Hepatic Neurovisceral; blistering photosensitivity (common) EPP – classic form Ferrochelatase (FECH) 90 Autosomal recessived Erythropoietic Nonblistering photosensitivity aPorphyrias are listed in the order of the affected enzyme in the heme biosynthetic pathway.bThese porphyrias also have erythropoietic features, including increases in erythrocyte zinc protoporphyrin.cHeterozygous UROD mutations are present in familial (type 2) but not in the more common sporadic (type 1) PCT. In all cases, an acquired inhibition of hepatic UROD reduces the enzyme activity to less than ~20% of normal.dBecause both alleles are abnormal in affected individuals (in most cases with a severe FECH mutation trans to a hypomorphic FECH allele), EPP is now regarded as recessive at the molecular level.Source: Williams Hematology, 9th ed, Chap. 58, Table 58–1. +++ Erythropoietic Porphyrias ++ Principal site of initial accumulation of pathway intermediates: the erythroblast Congenital erythropoietic porphyria (CEP)* Erythropoietic protoporphyria (EPP)† X-linked protoporphyria (XLP)† +++ Hepatic Porphyrias ++ Principal site of initial accumulation of pathway intermediates: the liver δ-Aminolevulinic acid dehydratase porphyria (ADP)‡ Acute intermittent porphyria (AIP)‡ Hereditary coproporphyria (HCP)*‡ Variegate porphyria (VP)*‡ Porphyria cutanea tarda (PCT)* Hepatoerythropoietic porphyria (HEP)* + SPECIFIC DISORDERS Download Section PDF Listen +++ +++ General Considerations ++ Synthesis of heme is catalyzed by a series of eight enzymes. Altered activity of each of these enzymes is associated with a specific form of porphyria (see Figure 28–1). Diagnostic biochemical findings in the individual porphyrias are summarized in Table 28–2. ++ FIGURE 28–1 Enzymes and intermediates in the heme biosynthetic pathway and the type of porphyria associated with a deficiency of each enzyme (indicated by Ø). Gain of function mutation of the erythroid form of ALA synthase is not shown. Abbreviations: ADP, ALA dehydratase porphyria; AIP, acute intermittent porphyria; ALAD, δ-aminolevulinic acid dehydratase; ALAS, δ-aminolevulinic acid synthase; CEP, congenital erythropoietic porphyria; CPO, coproporphyrinogen oxidase; EPP, erythropoietic protoporphyria; FECH, ferrochelatase; HCP, hereditary coproporphyria; PBGD, porphobilinogen deaminase; PCT, porphyria cutanea tarda; PPO, protoporphyrinogen oxidase; SA, sideroblastic anemia; UROD, uroporphyrinogen decarboxylase; UROS, uroporphyrinogen III synthase; VP, variegate porphyria. (Source: Williams Hematology, 9th ed, Chap. 58, Fig. 58–1.) Graphic Jump LocationView Full Size||Download Slide (.ppt) ++Table Graphic Jump LocationTABLE 28–2BIOCHEMICAL FINDINGS INCLUDING MAJOR INCREASES IN PORPHYRINS AND PORPHYRIN PRECURSORS IN THE HUMAN PORPHYRIASAView Table||Download (.pdf) TABLE 28–2 BIOCHEMICAL FINDINGS INCLUDING MAJOR INCREASES IN PORPHYRINS AND PORPHYRIN PRECURSORS IN THE HUMAN PORPHYRIASA Porphyria Erythrocytes Plasma Urine Stool XLP Metal-free and zinc protoporphyrine Protoporphyrin (-634 nm)d f Protoporphyrinb ADP Zinc protoporphyrin ALAb ALA, coproporphyrin III b AIP Decreased PBGD activity (most cases)b ALA, PBGb (~620 nm), some casesc ALA, PBG, uroporphyrin b CEP Uroporphyrin I; coproporphyrin I Uroporphyrin I, coproporphyrin I (~620 nm)c Uroporphyrin I; coproporphyrin I Coproporphyrin I PCT and HEP Zinc protoporphyrin (in HEP) Uroporphyrin, heptacarboxyl porphyrin (~620 nm)c Uroporphyrin, heptacarboxyl porphyrin Heptacarboxyl porphyrin, isocoproporphyrins HCP b d (~620 nm, some cases)c ALA, PBG, coproporphyrin III Coproporphyrin III VP b Protoporphyrin (~628 nm)c ALA, PBG, coproporphyrin III Coproporphyrin III, protoporphyrin EPP Metal free protoporphyrine Protoporphyrine (~634 nm)c f Protoporphyrinb Abbreviations: ADP, ALA dehydratase porphyria; AIP, acute intermittent porphyria; ALA, δ-aminolevulinic acid; HEP, Hepatoerythropoietic porphyria; CEP, congenital erythropoietic porphyria; EPP, erythropoietic protoporphyria; HCP, hereditary coproporphyria; PBG, porphobilinogen; PBGD, porphobilinogen deaminase; PCT, porphyria cutanea tarda; VP, variegate porphyria.aPorphyrias are listed in the order of the affected enzyme in the heme biosynthetic pathway.bPorphyrin levels normal or slightly increased.cFluorescence emission peak of diluted plasma at neutral pH.dPlasma porphyrins usually normal, but increased when blistering skin lesions develop.eZinc protoporphyrin ≤ 15% of total in XLP, but 15%–50% in variant form.fUrine porphyrins (especially coproporphyrin) increase only with hepatopathy.Source: Williams Hematology, 9th ed, Chap. 58, Table 58–2. + ERYTHROPOIETIC PORPHYRIAS Download Section PDF Listen +++ +++ Congenital Erythropoietic Porphyria +++ Pathogenesis ++ This rare (~200 cases reported) autosomal recessive disorder is caused by an almost complete (< 5% of normal) deficiency of uroporphyrinogen III synthase activity. +++ Clinical Findings ++ Cutaneous photosensitivity appears early in life. Subepidermal bullous lesions develop and progress to crusted erosions that heal with scarring, pigmentary changes, hypertrichosis, and alopecia. Bacterial infections contribute to mutilation of facial features and fingers. This condition may present before birth as fetal hydrops. Red teeth with red fluorescence under ultraviolet (UV) light is characteristic. Hemolytic anemia is common, with splenomegaly and compensatory marrow expansion. Late-onset cases may be associated with clonal myeloproliferative or myelodysplastic disorders. +++ Diagnosis and Laboratory Findings ++ In utero, dark brown porphyrin-rich amniotic fluid is characteristic. In newborns, pink or dark brown staining of diapers may suggest the diagnosis. Erythrocyte and urinary porphyrins (predominantly uroporphyrin and coproporphyrin, isomer I), and fecal porphyrins (predominantly coproporphyrin I) are markedly increased. Mutations should be confirmed by DNA studies in all cases. +++ Treatment ++ Avoid sunlight and skin trauma and treat infections promptly. Topical sunscreens that block UVA and visible light are of little value. Hematopoietic stem cell transplantation in early childhood is most effective. Suppression of marrow with hypertransfusion or hydroxyurea, splenectomy, and oral charcoal have been of limited value. +++ Erythropoietic Protoporphyria and X-linked Protoporphyria +++ Pathogenesis ++ Erythropoietic protoporphyria (EPP), the third most common porphyria and the most common in children, is caused either by loss of function mutations of ferrochelatase (FECH) or gain of function mutations of the erythroid form of δ-aminolevulinic acid synthase (ALAS) ([ALAS2]). At the molecular level, EPP is an autosomal recessive disorder (with both FECH alleles affected by loss-of-function mutations) or X-linked (gain of function mutation of one ALAS2 allele). In EPP, functional deficiency in the enzyme to less than ~20% of normal results from a severe FECH mutation trans to a common hypomorphic FECH allele. Occasionally, severe mutations affect both FECH alleles. In the X-linked protoporphyria, a truncated ALAS2 allele leads to gain of function, resulting in significantly increased production of δ-ALA, which is metabolized to protoporphyrin IX in erythroblasts. +++ Clinical Findings ++ Childhood onset of nonblistering cutaneous photosensitivity is characteristic. Symptoms and signs include burning pain, itching, redness, and swelling of the skin soon after light exposure (Table 28–3). Gallstones containing protoporphyrin and presenting at an early age are common. There are no neurovisceral symptoms. Possible features may include impaired iron absorption and mild microcytic anemia. Cholestatic liver disease (protoporphyric hepatopathy), which may present with abdominal pain and jaundice and may progress rapidly but develops in less than 5% of cases. Late-onset cases of EPP may be associated with myeloproliferative or myelodysplastic disorders. ++Table Graphic Jump LocationTABLE 28–3COMMON CLINICAL FEATURES OF ERYTHROPOIETIC PROTOPORPHYRIAView Table||Download (.pdf) TABLE 28–3 COMMON CLINICAL FEATURES OF ERYTHROPOIETIC PROTOPORPHYRIA Symptoms and Signs Incidence (% of Total) Burning 97 Edema 94 Itching 88 Erythema 69 Scarring 19 Vesicles 3 Anemia 27 Cholelithiasis 12 Abnormal liver function results 4 Data from Bloomer J, Wang Y, Singhal A, et al: Molecular studies of liver disease in erythropoietic protoporphyria. J Clin Gastroenterol 2005 Apr;39 (4 suppl 2:S167-S175. +++ Diagnosis and Laboratory Findings ++ Diagnosis is more delayed than in any other type of porphyria in part because symptoms out of proportion to physical findings, and urine porphyrins are normal. Excess concentrations of protoporphyrin occur in red cells, plasma, bile, and feces. Diagnosis is established by finding marked increase in total erythrocyte protoporphyrin with a predominance for metal-free protoporphyrin rather than zinc protoporphyrin. +++ Treatment ++ Therapy includes avoidance of sun exposure, use of topical sunscreens that block UVA and visible light, oral β-carotene (120–180 mg/d), and afamelanotide (approved in Europe). Protoporphyric hepatopathy is treated with erythrocyte transfusions, plasmapheresis, hemin, cholestyramine, ursodeoxycholic acid and vitamin E, and liver and marrow transplantation may be necessary. + HEPATIC PORPHYRIAS Download Section PDF Listen +++ +++ Aminolevulinic Acid Dehydratase Porphyria +++ Pathogenesis ++ This autosomal recessive disorder is due to a severe deficiency of ALA dehydratase. +++ Clinical Findings ++ This is the rarest form of porphyria (six documented cases). Patients have neurovisceral symptoms similar to those of AIP (see below). +++ Laboratory Findings ++ Urine ALA and coproporphyrin III excretion is markedly increased; porphobilinogen (PBG) excretion is normal or only slightly increased. Erythrocyte zinc protoporphyrin is markedly increased. Red cell ALA dehydratase activity of less than 5% of normal. It is necessary to distinguish from other causes of ALA dehydratase deficiency, such as lead poisoning (measure blood lead) and hereditary tyrosinemia I (measure succinylacetone in urine), and identify the causative ALA dehydratase mutations. +++ Treatment ++ The same approach as for AIP is used; hemin appears to be most effective. +++ Acute Intermittent Porphyria +++ Pathogenesis ++ This autosomal dominant disorder is caused by partial deficiency of porphobilinogen deaminase. +++ Clinical Findings ++ Symptoms usually occur as neuropathic acute attacks lasting for days or if not treated, for weeks. Abdominal pain is the most common and often the initial symptom. Extremity pain, nausea, vomiting, constipation or diarrhea, abdominal distention, ileus, urinary retention are frequently present. Abdominal tenderness, fever, and leukocytosis are usually not prominent. Neuropathy, predominantly motor may lead to quadraparesis, respiratory impairment, and bulbar paralysis. Seizures (sometimes associated with hyponatremia and inappropriate antidiuretic hormone secretion) and mental symptoms indicate central nervous system involvement. Tachycardia, hypertension, sweating and tremors indicate sympathetic overactivity. Pain and depression may become chronic. Up to 90% of individuals with decreased PBG deaminase activity remain asymptomatic. Attacks may be precipitated by: — Drugs and hormones (especially progesterone) that induce hepatic ALAS1 and cytochrome P450 enzymes — Reduced caloric or carbohydrate intake — Intercurrent illnesses, infection, or surgery Increased risk of hepatocellular carcinoma Some drugs (Table 28–4) ++Table Graphic Jump LocationTABLE 28–4SOME DRUGS CONSIDERED UNSAFE IN ACUTE PORPHYRIASAView Table||Download (.pdf) TABLE 28–4 SOME DRUGS CONSIDERED UNSAFE IN ACUTE PORPHYRIASA Alcohol Barbituratesa Carbamazepinea Carisoprodola Clonazepam (high doses) Danazola Diclofenaca and possibly other NSAIDs Ergots Estrogensa,b Ethchlorvynola Glutethimidea Griseofulvina Mephenytoin Meprobamatea (also mebutamatea, tybamatea) Methyprylon Metoclopramidea Phenytoina Primidonea Progesterone and synthetic progestinsa Pyrazinamidea Pyrazolones (aminopyrine, antipyrine) Rifampina Succinimides (ethosuximide, methsuximide) Sulfonamide antibioticsa Valproic acida NSAIDs, nonsteroidal anti-inflammatory drugs.aPorphyria is listed as a contraindication, warning, precaution, or adverse effect in U.S. labeling for these drugs.bEstrogens are unsafe for porphyria cutanea tarda, but can be used with caution in the acute porphyrias.Note: More complete sources, such as the websites of the American Porphyria Foundation (www.porphyriafoundation.com) and the European Porphyria Initiative (www.porphyria-europe.com), should be consulted before using drugs not listed here.Adapted with permission from Anderson KE, Bloomer JR, Bonkovsky HL, et al: Recommendations for the diagnosis and treatment of the acute porphyrias, Ann Intern Med. 2005 Mar 15;142(6):439-50. +++ Diagnosis and Laboratory Findings ++ Urine may be dark (porphobilin) or red (porphyrins). Rapid screening for a substantial increase in urinary PBG is recommended. ALA and PBG concentrations in urine are typically ALA 25 to 100 mg/d and PBG 50 to 200 mg/d during attacks (see Figure 28–2). Decreased PBG deaminase activity (~50% of normal) occurs in ~90% of cases. Diagnosis should be confirmed by finding the disease-causing mutation, which is often family-specific. ++ FIGURE 28–2 Recommended laboratory evaluation of patients with concurrent symptoms suggesting an acute porphyria, indicating how the diagnosis is established or excluded by biochemical testing and when specific therapy should be initiated. This schema is not applicable to patients who have been recently treated with hemin or who have recovered from past symptoms suggestive of porphyria. Levels of δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) may be less increased in hereditary coproporphyria (HCP) and variegate porphyria (VP) and decrease more quickly with recovery than in acute intermittent porphyria (AIP). Mutation detection provides confirmation and greatly facilitates detection of relatives with latent porphyria. (Source: Williams Hematology, 9th ed, Chap. 58, Fig. 58–6.) Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ Treatment ++ Ensure adequate caloric intake. Avoid precipitating drugs (an up-to-date list is available at http://www.porphyriafoundation.com/testing-and-treatment/drug-safety-in-acute-porphyria). Initiate prompt treatment of fasting, intercurrent disease, or infection. Acute attacks usually require admission to hospital: — Mild attacks may be treated by glucose loading (at least 300 g/d intravenously). — Intravenous hemin (3–4 mg/kg once daily for 4 days) is the treatment of choice for all but mild attacks. Reconstitution with human albumin rather than sterile water is recommended to prevent infusion-site phlebitis. Long-acting agonists of gonadotrophic-releasing hormone can be effective in preventing frequent premenstrual attacks in women. Liver transplantation can be curative in patients who become refractory to other therapies. Liver imaging at 6- to 12-month intervals is recommended to screen for early hepatocellular carcinoma in all acute porphyrias. +++ Hereditary Coproporphyria ++ This autosomal dominant disorder is caused by partial deficiency of coproporphyrinogen oxidase. +++ Clinical Findings ++ Neurovisceral manifestations are the same as in AIP. Attacks are precipitated by the same factors as in AIP. Blistering skin lesions resembling PCT may occur but much less commonly than in VP. Increased risk of hepatocellular carcinoma. +++ Diagnosis and Laboratory Findings ++ Excessive urinary ALA, PBG, and uroporphyrin occur during attacks, as in AIP. Urine coproporphyrin III is also increased. This disorder is distinguished from AIP by marked increase in fecal porphyrins with a predominance of coproporphyrin III. DNA studies can identify the causative coproporphyrinogen oxidase (CPO) mutation in almost all cases. +++ Treatment ++ Therapy is the same as in AIP. +++ Variegate Porphyria +++ Pathogenesis ++ This autosomal dominant disorder is caused by partial deficiency of protoporphyrinogen oxidase. +++ Clinical Findings ++ Neurovisceral manifestations are the same as in AIP and HCP. Attacks are precipitated by the same factors as in AIP and HCP. Blistering skin lesions resembling PCT are common and may occur apart from the neurovisceral symptoms. There is an increased risk of hepatocellular carcinoma. +++ Laboratory Findings ++ Excessive urinary ALA, PBG, and uroporphyrin occur during attacks, as in AIP. Urine coproporphyrin III is also increased. This type of porphyria is distinguished from AIP and HCP by marked increase in fecal porphyrins with a predominance of both coproporphyrin III and protoporphyrin IX. Presence of increased plasma porphyrins with a fluorescence emission peak at ~628 nm is diagnostic. DNA studies can identify the causative PPO mutation in almost all cases. +++ Treatment ++ Neurovisceral attacks are treated as in AIP. Protective clothing and avoidance of sunlight are important in patients with blistering photosensitivity. Treatments for PCT are not effective in VP. +++ Porphyria Cutanea Tarda +++ Pathogenesis ++ PCT is the most common human porphyria. It results from a substantial deficiency of hepatic uroporphyrinogen (URO) decarboxylase (UROD) activity, which is due to generation of an inhibitor (uroporphomethene). PCT is an iron-related disorder, with hepatic siderosis in almost all cases. The majority of patients have at least several of the following susceptibility factors are found: ethanol use, smoking, estrogen use (in females), hepatitis C, HFE mutations, HIV infection, and UROD mutations. Most patients do not have UROD mutations and are referred to as type 1 (or type 3 if additional family members have PCT). Type 2 patients are heterozygous for UROD mutations, sometimes have affected relatives or earlier onset of disease, but are otherwise indistinguishable from type 1. +++ Clinical Findings ++ Patients have increased skin fragility and blistering of sun exposed areas, especially the backs of the hands. Other findings may include hyperpigmentation, hypertrichosis, alopecia, and scarring. Cirrhosis and increased risk of hepatocellular carcinoma may result from one or more susceptibility factors or PCT itself. Outbreaks due to environmental or occupational exposure to halogenated cyclic aromatic hydrocarbons, such as hexachlorobenzene, have been reported. +++ Diagnosis and Laboratory Findings ++ Levels of highly carboxylated porphyrins, especially uroporphyrin and heptacarboxyl porphyrin are markedly increased in urine and plasma. +++ Treatment ++ Susceptibility factors should be identified, and exposures to alcohol and estrogens discontinued. Hepatitis C should be treated later. Repeated phlebotomy to reduce the serum ferritin to ~20 ng/mL is the preferred treatment and is highly effective. A low-dose regimen of hydroxychloroquine (100 mg twice weekly) is also effective when phlebotomies are contraindicated or poorly tolerated. +++ Hepatoerythropoietic Porphyria +++ Pathogenesis ++ HEP is a rare disorder caused by homozygous or compound heterozygosity for mutations in the URO decarboxylase gene. This is the homozygous form of familial (type 2) PCT, but at least one allele must express some enzyme activity. +++ Clinical Findings ++ HEP is characterized by childhood onset and is clinically similar to CEP. Anemia and hepatosplenomegaly may be present. +++ Diagnosis and Laboratory Findings ++ Porphyrin elevations in urine, serum, and feces resemble PCT, but in addition there is marked elevation of erythrocyte zinc protoporphyrin. Erythrocyte URO decarboxylase activity is reduced to 2% to 10% of normal. +++ Treatment ++ Avoidance of sun exposure is most important; topical sunscreens that block UVA and visible light may be of some benefit. Treatments used in PCT are generally not effective. ++ For a more detailed discussion, see John D. Phillips and Karl Anderson: The Porphyrias, Chap. 58 in Williams Hematology, 9th ed.