Porphyria

Introduction

The porphyrias are metabolic disorders, each arising from a predominantly hereditary deficiency of one of the eight enzymes of the porphyrin-heme biosynthetic pathway ( Fig. 49.1 ) . Traditionally, these disorders are subdivided into erythropoietic and hepatic forms, according to the major site of expression of the enzyme deficiency. From a dermatologist's perspective, the porphyrias can be classified into cutaneous and non-cutaneous forms ( Table 49.1 ), whereas from a general clinician's point of view, it is more appropriate to classify the porphyrias into acute and non-acute forms, thereby emphasizing the presence or absence of potentially life-threatening acute neurologic attacks ( Table 49.2 ) . Therefore, we will adhere to the latter classification throughout this chapter.

The porphyrias are of particular dermatologic interest because most forms have characteristic cutaneous manifestations that often allow a presumptive diagnosis. Laboratory tests are then used to confirm the suspected diagnosis. The genetic defects underlying the porphyrias have been well characterized ( Table 49.3 ), facilitating molecular diagnosis and genetic counseling for affected families.

History

In 1874, Schultz described a man with a history of cutaneous photosensitivity, accompanied by the excretion of wine-red urine . Subsequently, Baumstark detected urinary pigments, which he named “urorubrohaematin” and “urofuscohaematin” . Günther established the first classification of the porphyrias in 1911, recognizing them as hereditary metabolic disorders characterized by increased porphyrin excretion. He distinguished between two different forms: (1) haematoporphyria acuta, characterized by acute neurovisceral attacks without skin lesions; and (2) haematoporphyria congenita and chronica, both disorders having cutaneous findings in sun-exposed areas of the body . In 1937, the terms “acute intermittent porphyria” and “porphyria cutanea tarda” were introduced. Over the next four decades, variegate porphyria (in 1953), hereditary coproporphyria (in 1955), erythropoietic protoporphyria (in 1961), hepatoerythropoietic porphyria (in 1969), and δ-aminolevulinic acid (ALA) dehydratase deficiency porphyria (in 1979) were described . Most recently, X-linked dominant protoporphyria was recognized .

Epidemiology

The porphyrias are rare disorders, occurring in all races and both sexes. Whereas some forms appear during infancy, other variants usually do not present until puberty or adulthood. Prevalence rates vary from 0.1 to 10 per 100 000 individuals (see Table 49.2 ) . However, the precise prevalence of the various porphyrias is not known, due primarily to geographic differences, the likelihood of underdiagnosis, and the incomplete penetrance of the dominantly inherited porphyrias.

Pathogenesis

Mutations in any of the genes encoding the enzymes in the heme biosynthetic pathway can lead to a pathologic accumulation and excess excretion of porphyrins and/or porphyrin precursors, as a result of enzyme dysfunction . Except for patients with acquired porphyria cutanea tarda, all forms of porphyria are inherited as monogenetic traits (see Table 49.3 ).

Clinical and Laboratory Investigation

In establishing the diagnosis of a specific type of porphyria, the medical evaluation involves up to four steps:

• a thorough clinical assessment that includes a family history and physical examination, with particular reference to sun-exposed sites

• biochemical measurement of porphyrins and porphyrin precursors in urine, feces, blood, and/or plasma ( Table 49.4 )

  Table 49.4

  Characteristic biochemical findings in the porphyrias.

  In patients with variegate porphyria or hereditary coproporphyria who have no symptoms (cutaneous or systemic), urine porphyrins may not be elevated (shaded areas). ALA, aminolevulinic acid; ALA-D, aminolevulinic acid dehydratase; COPRO, coproporphyrin; ISOCOPRO, isocoproporphyrin; PBG, porphobilinogen; PROTO, protoporphyrin; URO, uroporphyrin. N = normal; NA, not available; + = above normal range; ++ = slightly elevated; +++ = highly elevated; ++++ = very highly elevated; ↑ = increase.

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• determination of the activity of specific enzymes (specialized laboratories)

• DNA mutational analysis (specialized laboratories).

Difficulties in obtaining a definitive diagnosis are primarily a result of the different types of porphyria having overlapping clinical and/or biochemical features ( Fig. 49.2 ). This is especially true of variegate porphyria and hereditary coproporphyria, which may present with cutaneous lesions similar to those observed in porphyria cutanea tarda and/or neurologic and visceral findings resembling those encountered in acute intermittent porphyria.

With regard to biochemical analyses, markedly elevated urinary levels of the porphyrin precursors ALA and PBG can be found during an acute attack. However, asymptomatic “carriers” (who harbor mutations) are rarely detected via measurement of urinary porphyrin precursors because the latter can exhibit significant variability and levels may be only slightly elevated or even normal during the intervals between acute attacks. In addition, diagnoses based upon measurements of enzymatic activity in fibroblasts or lymphocytes are not always conclusive. This is because an overlap exists between the values obtained in patients, asymptomatic carriers, and normal control individuals .

Therefore, the ability to detect specific genetic mutations has made a significant impact on the precise diagnosis of porphyrias and the ability to provide accurate genetic counseling .

The Non-Acute Porphyrias

The non-acute porphyrias consist of porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), X-linked dominant protoporphyria (XLDPP), congenital erythropoietic porphyria (CEP), and hepatoerythropoietic porphyria (HEP). All these porphyrias present primarily with cutaneous findings (see Tables 49.1 & 49.2 ) . While histologic examination of involved skin is not required to confirm a presumptive diagnosis of any of the cutaneous porphyrias, a biopsy specimen may have been obtained to exclude other entities in the differential diagnosis. Occasionally, the pathologist may identify histologic features that support the diagnosis of cutaneous porphyria even though the clinician suspected another disorder, e.g. epidermolysis bullosa acquisita.