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Porphyrias: An overview

Porphyrias: An overview
Author:
Karl E Anderson, MD, FACP
Section Editor:
Robert T Means, Jr, MD, MACP
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Nov 2022. | This topic last updated: Mar 11, 2022.

INTRODUCTION — The porphyrias are metabolic disorders caused by altered activities of enzymes within the heme biosynthetic pathway. Porphyrias can cause neurovisceral manifestations (eg, abdominal pain, motor and sensory peripheral neuropathy, neuropsychiatric changes) and/or cutaneous photosensitivity (either chronic and blistering or acute and mostly nonblistering). Although uncommon, they are likely to be encountered by clinicians in any specialty, and they are readily diagnosed by biochemical and genetic testing. This topic provides an overview of the porphyrias, with an emphasis on information that clinicians in any specialty should know about these diseases.

Altered enzyme activity is usually due to an inherited mutation in the gene for that enzyme. The most notable exception is the most common of the porphyrias, porphyria cutanea tarda (PCT), which is caused by acquired inhibition of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the pathway, specifically in the liver. A heterozygous disease variant in the UROD gene predisposes to PCT in approximately 20 percent of cases but is not sufficient by itself to cause the disease (ie, penetrance is very low).

Porphyrias can be challenging to diagnose because they are rare and their symptoms are nonspecific. Biochemical diagnostic testing is essential and need not be complex if only one or a few first-line tests are used for screening, with further testing only when a screening test is positive. The specific screening test used depends on the type of porphyria suspected. Porphyrias are categorized into three clinical types, which guide the choice of screening tests (ie, there is no "porphyrin screen" that tests for all porphyrias).

The three most common porphyrias (porphyria cutanea tarda [PCT], acute intermittent porphyria [AIP], and erythropoietic protoporphyria [EPP], in that order) differ completely from each other in terms of clinical manifestations, diagnostic testing, and treatment, as discussed below. Each represents one of the three clinical categories of the porphyrias – acute neurovisceral, chronic blistering cutaneous, and acute nonblistering cutaneous. Other topic reviews within UpToDate should be consulted when one of the specific porphyrias is suspected or diagnosed. Links to these topics are presented in the section on classification. (See 'Classification and clinical categories' below.)

NORMAL HEME BIOSYNTHESIS

Sites of synthesis and regulation — Heme is made in all tissues, but its synthesis is most active in the bone marrow and liver.

Bone marrow – The bone marrow accounts for >80 percent of daily heme synthesis; this is because the bone marrow must provide the large amounts of heme needed to serve as the prosthetic group for hemoglobin.

The synthesis of heme and globin is closely coordinated in erythroblasts and reticulocytes. The rate of heme synthesis depends on the expression of the erythroid-specific gene (ALAS2) as well as genes for several other enzymes in the pathway (see 'Enzymes and intermediates' below). Expression of these enzymes is also upregulated by heme and by iron [1,2]. Upregulation by iron is controlled by an iron-responsive element (IRE) in the ALAS2 messenger RNA (mRNA) that is not present in the mRNA for ALAS1, which encodes the housekeeping form of the enzyme and is active in all tissues including liver [3]. (See "Structure and function of normal hemoglobins", section on 'Hemoglobin structure'.)

Liver – The liver accounts for most of the rest of overall heme synthesis. In the liver, heme is used primarily as the prosthetic group for various cytochrome P450 (CYP) enzymes, which metabolize toxins and drugs in the endoplasmic reticulum. These are especially abundant and inducible in the liver and have high rates of turnover. (See "Overview of pharmacogenomics", section on 'CYP isoenzymes and drug metabolism'.)

In the liver, ALAS1 has a key regulatory role in heme synthesis, and ALAS1 is rate limiting for hepatic heme synthesis [4-6]. A regulatory heme pool controls the expression of the hepatic ALAS1 gene and the transport of ALAS1 into mitochondria. This provides a sensitive feedback mechanism, whereby an increased need for liver heme results in upregulation of ALAS1 expression. Likewise, ALAS1 is downregulated when the regulatory heme pool is augmented with heme and there is no requirement to increase hepatic heme synthesis. This regulatory heme pool has not been specifically defined and may comprise multiple intracellular pools.

Since most of the heme synthesized in liver is used for the production of CYPs, induction of CYPs by drugs and other factors leads to induction of ALAS1 through this feedback mechanism [7]. In addition, the ALAS1 gene and certain CYP genes share upstream enhancer elements that respond to inducing chemicals and interact with the pregnane X receptor (PXR); this is an additional mechanism for coordinated induction of hepatic ALAS1 and hepatic CYPs [8].

Induction of hepatic heme oxygenase, which enzymatically degrades heme, can cause depletion of the regulatory heme pool and consequently cause ALAS1 induction.

These hepatic feedback mechanisms are important in the acute hepatic porphyrias (AHP), which are exacerbated when hepatic ALAS1 is induced [4,9]. Accordingly, treatment of AHP with heme, which, when infused intravenously, is taken up primarily in hepatocytes, where it repletes the regulatory heme pool, results in downregulation of ALAS1 and amelioration of the acute attack [10,11]. (See "Acute intermittent porphyria: Management", section on 'Indications and mechanism of action'.)

Other tissues – Other important heme-containing proteins are present in all tissues, usually in smaller amounts, and most turn over more slowly than hepatic CYPs [4]. Examples include respiratory cytochromes, catalase, nitric oxide synthase, tryptophan pyrrolase, and myoglobin.

Enzymes and intermediates — The eight enzymes and intermediates that comprise the heme synthetic pathway are shown in the figure (figure 1), and the important features of these enzymes are summarized in the table (table 1).

Synthesis of heme begins in mitochondria, where the first enzyme in the pathway, delta-aminolevulinic acid synthase (ALAS, 5-aminolevulinic acid synthase), catalyzes a reaction between two simple molecules, glycine and succinyl-coenzyme A (succinyl-CoA), to form delta-aminolevulinic acid (ALA), an amino acid committed exclusively to the synthesis of heme. ALAS requires pyridoxal-5'-phosphate (a derivative of vitamin B6 [pyridoxine]) as a cofactor.

Importantly, ALAS occurs in two forms that are encoded by different genes. The housekeeping (or ubiquitous) enzyme, which is found in all tissues, is termed ALAS1; the ALAS1 gene is found on chromosome 3. No disease-causing ALAS1 mutations are described; however, increased ALAS1 expression is important in the acute hepatic porphyrias. The erythroid-specific form, termed ALAS2, is produced only in bone marrow erythroblasts. The ALAS2 gene is found on the X chromosome (Xp11.21) [6,12]. ALAS2 mutations cause sex-linked sideroblastic anemia (loss-of-function mutations) or X-linked protoporphyria (gain-of-function mutations). (See 'Classification and clinical categories' below.)

The eight pathway enzymes are listed below, with their functions and standard abbreviations.

ALA synthase (ALAS) – Catalyzes the synthesis of ALA (an amino acid) from glycine and succinyl-CoA.

ALA dehydratase (ALAD) – Catalyzes the synthesis of porphobilinogen (PBG; a pyrrole) from two molecules of ALA. ALA and PBG are commonly referred to as porphyrin precursors. This enzyme is also known as PBG synthase.

PBG deaminase (PBGD) – Catalyzes the synthesis of hydroxymethylbilane (HMB; a linear tetrapyrrole) from four molecules of PBG. This enzyme is also known as HMB synthase (HMBS).

Uroporphyrinogen synthase (UROS) – Catalyzes the synthesis of uroporphyrinogen III (an octacarboxyl porphyrinogen) from HMB. The reaction includes cyclization of this linear tetrapyrrole and inversion of one pyrrole to form the first of the asymmetric porphyrins required for heme synthesis. Any remaining HMB cyclizes nonenzymatically to form uroporphyrinogen I, which is a symmetrical molecule.

Uroporphyrinogen decarboxylase (UROD) – Catalyzes the synthesis of coproporphyrinogen III and I (tetracarboxyl porphyrinogens) from uroporphyrinogen III and I.

Coproporphyrinogen oxidase (CPOX) – Catalyzes the synthesis of protoporphyrinogen IX (a dicarboxyl porphyrinogen) from coproporphyrinogen III. Coproporphyrinogen I is not a substrate for this stereospecific enzyme, and as a result, isomer III porphyrinogens are exclusively metabolized to heme.

Protoporphyrinogen oxidase (PPOX) – Oxidizes protoporphyrinogen IX by removing six protons to form protoporphyrin IX (the only oxidized porphyrin intermediate in the pathway).

Ferrochelatase (FECH) – Inserts iron into protoporphyrin IX to form heme (iron protoporphyrin IX). This enzyme also chelates any remaining protoporphyrin with zinc to form zinc protoporphyrin, which is normally found in small amounts in circulating erythrocytes.

The first and last three enzymes (ALAS, CPOX, PPOX, FECH) are mitochondrial, and the intervening four (ALAD, PBGD, UROS, UROD) are located in the cytoplasm (figure 1). All genes that encode these enzymes are in the cellular genome, and inheritance of the porphyrias follows Mendelian (rather than mitochondrial) genetic transmission patterns.

PATHOPHYSIOLOGY

Genes and enzymes affected in specific porphyrias — Each porphyria is due to abnormal (deficient or enhanced) activity of an enzyme in the heme synthesis pathway (table 1). In seven of the eight types of porphyria, mutation of a gene that affects one of the pathway enzymes is responsible. The exception is porphyria cutanea tarda (PCT), which is caused by an acquired inhibitor (uroporphomethene, a uroporphyrinogen molecule that has become partially oxidized) rather than a gene mutation. This inhibitor contributes to reducing activity of the uroporphyrinogen decarboxylase (UROD) enzyme in the liver to less than approximately 20 percent of normal. Approximately 20 percent of individuals with PCT are heterozygous for a pathogenic variant in the UROD gene that acts as a predisposing factor. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'UROD inhibitor'.)

In most inherited cases of porphyria, a causative variant affects the gene that encodes the relevant heme synthesis enzyme. In a few cases, the mutation affects a regulatory gene rather than the enzyme itself. Rare examples include cases of congenital erythropoietic porphyria (CEP) due to a mutation of GATA-1 (a transcription factor that controls expression of the UROS gene) rather than a UROS mutation, and protoporphyria with increased ALAS2 function due to mutation of mitochondrial CLPX, which degrades ALAS2. (See "Congenital erythropoietic porphyria", section on 'UROS gene variants' and "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'EPP due to CLPX mutation'.)

Heme synthetic enzymes and the various porphyrias and other diseases resulting from their alterations are as follows:

ALAS (delta-aminolevulinic acid [ALA] synthase) – ALAS is the first enzyme in the heme synthetic pathway. There are two forms.

ALAS1 – Mutations causing porphyria (or other diseases) have not been described for ALAS1. However, upregulation of hepatic ALAS1 is an important feature during exacerbations of the acute hepatic porphyrias. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Enzyme deficiency'.)

ALAS2 – Gain-of-function mutations in ALAS2 have been described in X-linked protoporphyria (XLP) [13]. (See "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'XLP due to ALAS2 gain-of-function mutations'.)

Loss-of-function mutations in ALAS2 are present in many cases of X-linked sideroblastic anemia (an inherited anemia with ring sideroblasts in the bone marrow; these individuals do not have porphyria). (See "Causes and pathophysiology of the sideroblastic anemias".)

ALAD (ALA dehydratase) – ALAD is the second enzyme in the heme synthetic pathway.

Mutations in ALAD cause autosomal recessive ALAD porphyria (ADP). (See "ALA dehydratase porphyria".)

Because other causes of ALAD deficiency are associated with the same nonspecific symptoms, DNA studies to identify the responsible mutations are essential for diagnosis of ADP.

ALAD is inhibited in lead poisoning and hereditary tyrosinemia type 1. Lead displaces zinc from its binding sites on the ALAD enzyme, and succinylacetone (4,6-dioxoheptanoic acid), a metabolite that accumulates in tyrosinemia, is structurally similar to ALA and is a potent inhibitor of ALAD enzymatic activity [14,15]. Accordingly, lead poisoning and tyrosinemia are both associated with accumulation of ALA and other heme pathway intermediates, along with symptoms that resemble acute porphyria. (See "Disorders of tyrosine metabolism", section on 'Hereditary tyrosinemia type 3'.)

PBGD (porphobilinogen [PBG] deaminase, also known as hydroxymethylbilane synthase [HMBS]) – PBGD is the third enzyme in the pathway. Mutations in PBGD/HMBS cause acute intermittent porphyria (AIP) in some heterozygotes. Rare homozygous cases have earlier onset and more profound symptoms. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis".)

UROS (uroporphyrinogen synthase) – UROS is the fourth enzyme in the pathway. Mutations in UROS cause CEP, an autosomal recessive disorder. (See "Congenital erythropoietic porphyria".)

UROD (uroporphyrinogen decarboxylase) – UROD is the fifth enzyme in the pathway. As noted above, UROD is inhibited in the liver in all cases of PCT. Mutations in UROD predispose to the development of familial PCT (if monoallelic) or cause hepatoerythropoietic porphyria (HEP; if biallelic). (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

CPOX (coproporphyrinogen oxidase) – CPOX is the sixth enzyme in the pathway. Mutations in CPOX cause hereditary coproporphyria (HCP) in some heterozygotes. Biallelic mutations cause more severe, early onset symptoms. Some biallelic CPOX mutations cause harderoporphyria, with distinct hematologic features. (See "Hereditary coproporphyria".)

PPOX (protoporphyrinogen oxidase) – PPOX is the seventh enzyme in the pathway. Mutations in PPOX cause variegate porphyria (VP). Homozygous or compound heterozygous PPOX mutation causes earlier and more severe symptoms. (See "Variegate porphyria".)

FECH (ferrochelatase) – FECH is the eighth and final enzyme in the pathway. Mutations in FECH cause erythropoietic protoporphyria (EPP). (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

For each of these enzymes, many different mutations have been described as causes of porphyria, as discussed in the linked topic reviews. The disease-causing mutation in a particular family is often private or shared with only a few other families. Some are more common geographically due to founder effects. Detection of the responsible mutation is not required for diagnosis but is recommended for confirmation and especially for family studies and genetic counseling.

Role of environmental and metabolic factors — In addition to gene mutations, environmental and metabolic factors are especially important in the development of disease manifestations in the hepatic porphyrias. As noted below, the hepatic porphyrias include those that cause acute neurovisceral symptoms (acute hepatic porphyrias) and PCT.

Acute hepatic porphyrias (AHP) – As noted above, gene variants that affect specific heme pathway enzymes are essential in these diseases. However, exposure to certain drugs, steroid hormones, and nutritional alterations are important in precipitating attacks. Variants in unidentified modifying genes are also thought to be important. Increases in progesterone may cause attacks during the luteal phase of the menstrual cycle. A table of drugs that commonly exacerbate AHP is provided separately. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Exacerbating factors'.)

PCT – Iron, oxidative stress, and a set of important susceptibility factors act in combination to lead to generation of a hepatic UROD inhibitor in PCT. These are largely different from the factors that exacerbate AHP, and include genetic factors (UROD and HFE mutations), infections (hepatitis C virus [HCV] and HIV), alcohol and estrogen use, and deficiencies of antioxidants. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Susceptibility factors'.)

Accumulation of heme pathway intermediates — The heme biosynthetic pathway intermediates that accumulate in the various porphyrias correlate with (and in some instances, determine) what clinical manifestations will be seen. The heme synthesis intermediates, their chemically altered metabolites, and the primary routes of excretion are listed in the table (table 2).

Acute hepatic porphyrias (AHP)

ALA and PBG are associated with neurovisceral manifestations in AHP. ALA is likely causative of these manifestations, but this has not been thoroughly proven. PBG is not substantially increased in any medical conditions other than AIP, HCP, and VP. ALA and PBG both accumulate in AIP, HCP, and VP; ALA but not PBG accumulates in ADP (as well as in other conditions where ALAD activity is decreased, particularly lead poisoning and hereditary tyrosinemia type 1). ALA and PBG are normal in porphyrias other than AIP, HCP, VP, and ADP, except for slight ALA elevations sometimes seen in PCT.

Porphyrins are also elevated in all AHPs, sometimes to levels in plasma that cause chronic, blistering photosensitivity, especially in VP, less commonly in HCP, and in AIP only with concurrent end-stage kidney disease. Excess porphyrins in AIP may be explained by two processes:

-Nonenzymatic formation of various uroporphyrin isomers from PBG when concentrated in body fluids

-Enzymatic formation of uroporphyrinogen III after tissue accumulation of ALA.

The latter mechanism also accounts for excess formation of coproporphyrin III and protoporphyrin in ADP. Urine coproporphyrin III and erythrocyte zinc protoporphyrin are increased in ADP, lead poisoning, and hereditary tyrosinemia. In HCP and VP, porphyrin accumulation occurs because the enzyme deficiencies lead to accumulation of their substrate porphyrinogens, which are then auto-oxidized to the corresponding porphyrins.

Cutaneous porphyrias – Porphyrins are substantially elevated in all porphyrias that cause photosensitivity (as measured in plasma, urine, and/or erythrocytes). Where porphyrins accumulate and how they are excreted depends on the site of their production and their solubility.

Substantial elevations of erythrocyte porphyrins are found in erythropoietic porphyrias such as CEP and EPP, which are biallelic, and in XLP. Erythrocyte porphyrin levels are also elevated in very rare biallelic cases of hepatic porphyrias such as HEP and homozygous AIP, HCP, and VP, but they are normal or only slightly elevated in the more common monoallelic cases of these hepatic porphyrias, namely AIP, HCP, and VP and familial PCT.

Highly carboxylated porphyrins (uroporphyrin, hepta-, hexa-, and pentacarboxyl porphyrins) are water soluble and thus are mostly excreted in urine.

Protoporphyrin and tricarboxyl porphyrin are not water soluble and thus are excreted in bile and feces.

Coproporphyrin (tetracarboxyl porphyrin) is excreted in both urine and bile. Coproporphyrin I is more readily excreted in bile compared with coproporphyrin III.

In VP, porphyrin-peptide conjugates produce a diagnostic fluorescence emission peak at approximately 626 nm when diluted plasma is scanned at neutral pH. As discovered by Poh-Fitzpatrick, this allows rapid biochemical distinction of VP from PCT and other blistering cutaneous porphyrias [16-19]. This testing is available in selected specialty laboratories.

Protoporphyrin (mostly metal-free rather than zinc-chelated) accumulates in the protoporphyrias (EPP and XLP) and causes acute nonblistering photosensitivity. Greater solubility of protoporphyrin in nonaqueous cellular components may explain this distinctive type of photosensitivity. As noted above, protoporphyrin is excreted only in bile and feces. Erythrocyte zinc protoporphyrin is elevated in many disorders (iron deficiency, hemolysis, lead poisoning); for diagnosis of EPP and XLP, it is important to demonstrate predominant elevation of metal-free protoporphyrin.

All of the heme pathway intermediates are colorless and nonfluorescent, with the exception of protoporphyrin, which, like other oxidized porphyrins, is reddish-colored and fluoresces, especially when illuminated by light near 400 nm (the Soret absorption band for porphyrins). When porphyrinogen intermediates accumulate and leave the intracellular environment, they mostly spontaneously oxidize to the corresponding porphyrins, which are reddish and fluorescent.

While PBG is colorless, it can degrade in urine to porphobilin, which is brownish. PBG at high concentrations can also spontaneously form porphyrins, which are reddish. These urine colors are the source of the name "porphyria"; the Greek word for the color purple is "porphyrus" [20].

INHERITANCE PATTERNS — Patterns of inheritance of the porphyrias are as follows (table 3):

Autosomal dominant with low penetrance – Porphyrias with autosomal dominant inheritance have low penetrance; other genetic, environmental, and metabolic factors are necessary for the porphyria to become manifest. This pattern is seen in the following porphyrias:

Acute intermittent porphyria (AIP)

Hereditary coproporphyria (HCP)

Variegate porphyria (VP)

Familial porphyria cutanea tarda (PCT; applies to the approximately 20 percent of cases of PCT with a heterozygous UROD mutation)

Exacerbating factors important in AIP, HCP, and VP (the three most common acute hepatic porphyrias [AHP]) are generally distinct from those in PCT. (See 'Role of environmental and metabolic factors' above.)

Autosomal recessive – In porphyrias with autosomal recessive inheritance, the severity of disease appears to be mostly related to the severity of the specific familial disease variant. This pattern is seen in the following porphyrias:

Delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria (ADP)

Congenital erythropoietic porphyria (CEP; typically due to UROS variants)

Hepatoerythropoietic porphyria (HEP; homozygous familial PCT)

Erythropoietic protoporphyria (EPP; due to a FECH variant [common] or a CLPX variant [extremely rare, autosomal dominant])

Homozygous forms of AIP, HCP, and VP are very rare, with a different, more severe, and earlier onset phenotype. Harderoporphyria results from certain CPOX variants, only when biallelic.

X-linked – In X-linked inheritance, mothers can pass the trait to sons or daughters; fathers can only pass the trait to daughters. This pattern is seen in the following porphyrias:

X-linked protoporphyria (XLP)

CEP due to a GATA-1 mutation (rare)

CLASSIFICATION AND CLINICAL CATEGORIES — Porphyrias are classified as hepatic or erythropoietic based on whether pathway intermediates first accumulate in the liver or the bone marrow, respectively. This classification reflects pathophysiology but not necessarily other important features of these diseases.

It is useful to group porphyrias clinically into three categories, based on the presence of acute neurovisceral and/or skin manifestations (chronic blistering or acute); these do not fully correspond with the hepatic versus erythropoietic designation (table 3). These groups are exemplified by the three most common porphyrias, which differ completely from each other in their clinical manifestations, diagnostic testing, and treatment (table 4) [21]. A framework for categorizing porphyrias is illustrated in the figure (algorithm 1) and discussed below. (See 'Overview and diagnostic framework' below.)

Acute hepatic porphyrias (AHP) — Acute hepatic porphyrias include (table 3):

Acute intermittent porphyria (AIP), the most common

Delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria (ADP)

Hereditary coproporphyria (HCP)

Variegate porphyria (VP)

These porphyrias cause acute and chronic symptoms due to effects on the nervous system. The most common presenting symptom is neuropathic abdominal pain. The motor, sensory, and autonomic nervous systems are often affected, resulting in autonomic changes (eg, tachycardia, hypertension), muscle weakness, sensory loss, and pain in the back, chest, and extremities. Even severe symptoms may be discounted because they mimic other diseases, and physical findings are often minimal.

The prototype and most common of these is AIP. Identical symptoms occur in the other AHPs (ADP, HCP, and VP). HCP and VP may also present with blistering skin lesions.

AIP, HCP, and VP are autosomal dominant inherited disorders with low penetrance and female predominance. Erythrocyte porphyrins are normal or only slightly elevated in these AHPs. Approaches to diagnosing and distinguishing among AHPs are discussed below. (See 'Acute hepatic porphyrias (AHP; exemplified by AIP)' below.)

ADP is autosomal recessive and extremely rare, with only eight documented cases worldwide, all of whom have been males (which is unexplained), usually with onset of attacks in their early teens. All cases of ADP have elevated erythrocyte zinc protoporphyrin, suggesting an erythropoietic component.

Very rare cases of homozygous AIP, HCP, and VP have a completely different phenotype and marked elevations of erythrocyte zinc protoporphyrin. Clinical features include impaired neurologic development and chronic, blistering skin lesions starting in early childhood, with an absence of acute attacks.

Blistering cutaneous porphyrias — Blistering cutaneous porphyrias include (table 3):

Porphyria cutanea tarda (PCT), the most common

Congenital erythropoietic porphyria (CEP)

Hepatoerythropoietic porphyria (HEP)

Variegate porphyria (VP), in which skin manifestations are common

Hereditary coproporphyria (HCP), in which skin manifestations are rare

Acute intermittent porphyria (AIP) is not typically considered a cutaneous porphyria, but skin manifestations can be seen in individuals with AIP who develop advanced chronic kidney disease that elevates levels of plasma porphyrins.

These porphyrias cause chronic blistering cutaneous lesions on sun-exposed areas, often with scarring and pigment changes. The prototype and most common of this type is PCT. The others (CEP, HEP, VP, and HCP) are less common. As noted above, chronic blistering photosensitivity with elevations in erythrocyte porphyrins is also seen in very rare cases of homozygous AIP, HCP, and VP. (See 'Blistering cutaneous porphyrias (exemplified by PCT)' below.)

Acute nonblistering cutaneous porphyrias — Acute nonblistering photosensitivity occurs in erythropoietic protoporphyria (EPP) and in two other rare types of protoporphyria, X-linked protoporphyria (XLP) and EPP due to mutation of the CLPX gene, described in a 2017 report [22]. These are erythropoietic porphyrias with elevations of erythrocyte total and metal-free protoporphyrin. (See 'Acute nonblistering photosensitivity (exemplified by EPP)' below.)

APPROACHES TO DIAGNOSIS

Overview and diagnostic framework — Porphyrias are rare disorders with nonspecific clinical manifestations similar to those of many other more common diseases. As a result, their diagnosis and appropriate treatment are often delayed. This is unfortunate because biochemical first-line screening tests are sensitive for diagnosis of these disorders, and additional second-line testing readily differentiates the various types of porphyria. Diagnostic confirmation by DNA analysis is readily available. Moreover, effective treatments are available but will not be provided unless a diagnosis is made.

The three most common porphyrias are porphyria cutanea tarda (PCT), acute intermittent porphyria (AIP), and erythropoietic protoporphyria (EPP), in that order (table 4). Presenting symptoms and diagnostic testing are very different for these three conditions, which are prototypical examples of the three major types of porphyria presentations (algorithm 1). With knowledge of diagnostic approaches for these three most common types, the less common porphyrias will also be diagnosed and therefore not neglected.

Acute hepatic porphyrias (AHP; exemplified by AIP)

Presenting findings — AIP and other AHP should be considered in the evaluation of any patient with unexplained abdominal pain (the most common symptom) or other neurovisceral symptoms after an initial workup for common causes does not provide an answer.

Diagnostic guidelines on the evaluation of abdominal pain may neglect to mention porphyrias, or they may not provide guidance on how and when testing should be done. Therefore, specific testing for porphyria is seldom considered an important part of the diagnostic workup for the cardinal symptoms of these disorders, and delayed diagnosis continues to be a major problem.

Spectrum of neurovisceral manifestations — Abdominal pain with a relatively unremarkable examination is the most common neurovisceral manifestation of AHP (table 5). Other symptoms and signs may be present, but their significance not recognized. Effects on the central nervous system may cause insomnia, agitation, hallucinations, seizures, or hyponatremia, which is often attributed to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Manifestations of peripheral neuropathy (extremity pain, paresis) are often present. Rarely, one or more of these manifestations occur in the absence of abdominal pain. These three groups of symptoms (abdominal pain, central nervous system abnormalities, and peripheral neuropathy) have been described as a "classic triad" that should suggest acute porphyria, but because they are all highly nonspecific, they are often seen as unrelated and not suggestive of a unifying diagnosis. Therefore, screening for AHP (by measuring urine porphobilinogen [PBG] and porphyrins) should be considered even when suspicion has not risen to a high level.

Other common gastrointestinal symptoms of AHP include nausea, vomiting, constipation, and, less commonly, diarrhea. Additional symptoms may include pain in the limbs, head, neck, or chest; and others listed in the table (table 5). Magnetic resonance imaging (MRI) findings can resemble those in posterior reversible encephalopathy syndrome (PRES), which points to the potentially substantial effects of AHP on the central nervous system. AHP can also mimic Guillain-Barre syndrome [23] and cause reversible cerebral vasoconstriction [24].

Multiple previous hospitalizations and/or visits to the emergency department (ED) with abdominal pain and negative evaluations, especially if accompanied by neurologic or psychiatric symptoms, can be important diagnostic clues [21,25]. Multiple abdominal surgeries without definite diagnoses or benefits should also trigger testing for AHP.

In AIP and the other acute porphyrias, attacks are often precipitated by factors such as stress, caloric restriction, medications, or cyclic hormonal changes. Many of these factors act through induction of hepatic ALAS1. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Exacerbating factors'.)

In severe cases of AIP, hereditary coproporphyria (HCP), or variegate porphyria (VP), the urine may develop a red or brown color due to a high concentration of porphobilin, a brownish auto-oxidation product of PBG, and porphyrins, which are reddish.

Clinical vignette — The typical clinical presentation, disease course, and delay in diagnosis of AHP is illustrated by the following case of AIP:

A 30-year-old woman presented to a hospital ED with abdominal pain, nausea, vomiting, and diarrhea. The pain required morphine for relief. She was hospitalized for two weeks for a suspected intestinal infection. The evaluation was negative, including a computed tomography (CT) scan and upper and lower endoscopies. She gradually improved and was discharged.

The same symptoms recurred two years later, resulting in multiple ED visits. She reported some increase in alcohol intake to compensate for stressful circumstances. She was admitted to a psychiatric unit with mental status changes and hallucinations and then transferred to an ED for evaluation of abdominal pain. In the ED, she had a grand mal seizure associated with hyponatremia. She was admitted to a medical unit with tachycardia and hypertension (heart rate 120 beats per minute; blood pressure 174/114), along with disorientation; there were no focal neurologic signs.

Examination of the cerebrospinal fluid showed no abnormalities; MRI of the brain showed multiple areas of subcortical signal abnormalities. Electroencephalogram (EEG) was abnormal with recurring single and multiple spike and sharp discharge activity appearing to arise from the left anterior temporal region. Laboratory testing revealed increased aminotransferases (ALT 114 international units/L, AST 94 international units/L), which were attributed to alcohol.

Phenytoin was started for seizures. Abdominal pain and hyponatremia worsened (serum sodium 116 mEq/L). The syndrome of inappropriate ADH (SIADH) was suspected and attributed to fluoxetine. An abnormal hepatobiliary scan led to laparoscopic removal of a histologically normal gallbladder with no gallstones. She was discharged with diagnoses of alcohol withdrawal and alcoholic liver disease and referred for rehabilitation. Urine porphyrins were ordered and reported as "positive" after discharge, but the ordering physician was unable to contact the patient; she had moved to another part of the country.

She had continuing and progressive symptoms, and she was hospitalized after developing muscle weakness. This progressed to quadriparesis and respiratory failure complicated by aspiration pneumonia. Urinary PBG was 44 mg/24 hours (reference range 0 to approximately 4), and a diagnosis of AIP was made. Harmful drugs (including phenytoin) were stopped. She improved gradually with intravenous glucose but was not treated with hemin. Gradual improvement began, and she was discharged for prolonged physical therapy and rehabilitation. Recovery was almost complete, but some objective muscle weakness, painful hyperesthesia of the legs, and impaired short-term memory persisted. She continued to have attacks one to two times yearly, sometimes in the luteal phase of her menstrual cycle.

This case illustrates many of the challenges related to diagnosing and treating AHP, including the delayed recognition of the classic features, the consequences of delay in diagnosis and failure in some cases to provide preferred treatment (hemin) even after diagnosis. Recovery can be complete or nearly complete, but lasting damage may persist.

Initial testing (suspected AHP) — Importantly, AHP is readily ruled in or out at the time of symptoms by a simple urine test for porphobilinogen (PBG), which is both highly sensitive and highly specific. Thus, urine PBG is the most important first-line screening test when AHP is suspected (algorithm 2). Urine porphyrins should also be measured, as discussed below.

A timed urine collection is not needed; a spot urine sample is sufficient and generally preferred. Collecting urine for 24 hours can cause unnecessary delays in diagnosis. Highly dilute urine can give falsely negative results [26]; thus, if an initial test result is expressed as PBG per liter of urine, the urine creatinine should also be measured on the same sample and the PBG result expressed per gram (or micromol) of urine creatinine. However, a very high result expressed per liter is diagnostically meaningful.

If results are positive (eg, PBG level >10 mg per g creatinine [or >10 mg/L]), treatment with hemin can (and typically should) be initiated without delay if clinical manifestations are severe. (See 'Initial treatment of acute attacks' below.)

If results are negative (eg, PBG level <5 mg per g creatinine [or <5 mg/L]), testing for other conditions in the differential diagnosis is appropriate. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Differential diagnosis'.)

PBG can also be measured in serum or plasma, which is essential if AHP is suspected in a patient with advanced renal disease [27,28]. However, in patients with AHP and normal kidney function, PBG concentrations are higher in urine, so urinary measurements are more sensitive and therefore preferred.

Normal urinary excretion of PBG is <2 to 4 mg (<9 to 18 micromol) per day [25]. Amounts expressed per gram creatinine are roughly the same, since adults excrete 0.7 to 2.0 grams of creatinine daily. PBG excretion during an AHP attack is markedly elevated, with typical values at least 5 to 10 times the upper limit of normal (eg, >10 to 100 mg/day [or per g/creatinine]; >44 to >440 micromol/day) (table 6).

Additional nuances of different methods for PBG testing (mass spectrometry versus ion exchange chromatography) are discussed separately. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Test urinary PBG and initiate treatment if positive'.)

A rapid test kit for urinary PBG is no longer available, and samples at most sites must be sent to a referral laboratory. When a result is needed urgently, the laboratory should be contacted and asked to expedite the testing.

The most common AHP is AIP. Less common possibilities include hereditary coproporphyria (HCP), variegate porphyria (VP), and delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria (ADP; which is very rare). To help diagnose these AHPs, total porphyrins are also measured at the time of presentation.

Total porphyrins are elevated in all four AHPs. In HCP and VP, total porphyrins may remain elevated for a longer period of time than PBG. However, urine porphyrin elevations are very nonspecific and occur in many medical conditions other than porphyrias.

ALA can also be measured but is not essential at screening. Normal urinary excretion of ALA is <7 mg (<53 micromol) per day. In an acute attack of AIP, HCP, or VP, urinary ALA excretion is elevated, but generally less so than PBG (when expressed in mg).

Initial treatment of acute attacks — Attacks of acute neurovisceral porphyria can be life-threatening and should be treated urgently with hemin to achieve remission quickly and avoid prolonged hospitalization and complications such as hyponatremia, seizures, and progressive motor paralysis.

As noted above, treatment with hemin can begin in a newly diagnosed patient as soon as a substantial elevation in PBG is documented. (See 'Initial testing (suspected AHP)' above.)

For an individual who already carries a well-documented diagnosis of porphyria, starting therapy for an acute attack can be based on clinical features, without waiting for biochemical confirmation. However, a urine sample should be sent before treatment to document a PBG elevation. (See "Acute intermittent porphyria: Management", section on 'Diagnosis of an acute attack in a patient with an established diagnosis of acute porphyria'.)

With all acute porphyria attacks, in addition to treatment with hemin, it is important to evaluate appropriately for any other condition that may have precipitated the attack, such as an infection or other intercurrent illness. Importantly, individuals with porphyria are equally susceptible as the general population to the development of other medical or surgical conditions that may be mistaken for an acute attack of porphyria (eg, appendicitis, urinary tract infection [UTI]).

Hemin is given intravenously (as Panhematin [hematin/heme hydroxide] in the United States and Normosang [heme arginate] in Europe and South Africa). Typical dosing and evidence to support the efficacy of hemin in acute porphyria attacks is described separately. (See "Acute intermittent porphyria: Management", section on 'Indications and mechanism of action'.)

In addition to administration of hemin, additional interventions are required for control of symptoms including severe pain, nausea, vomiting, and bladder distension, as well as close monitoring for complications. Any harmful drugs should be discontinued and other triggering factors addressed. These and other aspects of management are discussed in more detail separately. (See "Acute intermittent porphyria: Management", section on 'Overview of approach'.)

As noted below, although additional test results other than substantially elevated urinary PBG are not required to start treatment, it is important that samples (spot urine and plasma; stool when available) for additional testing be obtained and sent prior to starting therapy if possible, since treatment with hemin can lead to substantial and rapid decreases in urine PBG and porphyrins. (See 'Subsequent testing to distinguish among acute porphyrias in symptomatic patients' below.)

Givosiran is an RNA interference therapy that reduces production of ALA and PBG by downregulating hepatic ALAS1, the first enzyme in the heme synthetic pathway (see 'Genes and enzymes affected in specific porphyrias' above). Givosiran may be used as preventive therapy in individuals who have frequent attacks of AHP, as discussed separately. (See "Acute intermittent porphyria: Management", section on 'Givosiran'.)

Subsequent testing to distinguish among acute porphyrias in symptomatic patients — As noted above, if acute attack manifestations are severe, treatment with hemin should be initiated as soon as the diagnosis of AHP is made based on an elevated urinary PBG level.

Additional samples to determine the type of AHP should be obtained before starting treatment. We obtain samples for the following:

Spot urine porphyrins

Plasma porphyrins

Stool porphyrins

Extended (24-hour) collections are not needed.

In HCP and VP, urinary porphyrins may remain increased longer than the porphyrin precursors ALA and PBG. Fecal porphyrin elevations in VP and HCP and plasma porphyrin elevations in VP are especially durable after symptoms improve. Measuring erythrocyte PBG deaminase (PBGD) activity is useful because it is low in most cases of AIP, although mutation analysis is preferred.

Biochemical differentiation is outlined in the table (table 7) and can be summarized as follows:

AIP – AIP is the prototypical and most common acute, neurovisceral porphyria. Cutaneous manifestations do not occur, except, rarely, in association with advanced renal disease. Fecal and plasma porphyrins are normal or modestly elevated. In 9 out of 10 patients with AIP, the level of erythrocyte PBGD activity is approximately half normal. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis".)

HCP – HCP produces neurovisceral attacks and, less commonly, blistering cutaneous manifestations. Biochemically, HCP can be differentiated from other AHPs because it produces a markedly increased concentration of coproporphyrin III in urine and especially in feces, with little increase in fecal protoporphyrin. (See "Hereditary coproporphyria".)

VP – VP produces neurovisceral attacks; blistering cutaneous manifestations are also common, often leading to an incorrect diagnosis of PCT. Biochemically, VP is characterized by elevated plasma porphyrins and a plasma fluorescence peak at approximately 626 nm as well as increased fecal coproporphyrin III and protoporphyrin. (See "Variegate porphyria".)

ADP – ADP is exceedingly rare (case reports only). It produces neurovisceral attacks but not cutaneous findings. Laboratory testing reveals markedly increased urinary ALA and coproporphyrin III, with normal or only slight elevations of PBG. Erythrocyte zinc protoporphyrin is also markedly elevated [25]. (See "ALA dehydratase porphyria".)

Importantly, testing to establish the type of AHP may take weeks, and treatment of an acute attack with hemin should not be delayed while awaiting the results of testing to distinguish among the three types of AHP that elevate PBG. Before hemin is given, samples (spot urine and serum; stool when available) should be obtained and sent for further testing to establish the type of AHP [25]. (See "Acute intermittent porphyria: Management", section on 'Indications and mechanism of action'.)

Testing in currently asymptomatic individuals — The diagnosis of AHP becomes more challenging in patients without symptoms (eg, if the patient describes a history consistent with attacks but is currently well) because levels of porphyrin precursors and porphyrins may be normal in asymptomatic individuals. As a result, it can be difficult to diagnose or to "rule out" acute porphyria when symptoms were present months or years previously. For previously diagnosed patients, it is important to obtain the original laboratory reports and determine if the initial diagnosis was accurate. If the initial diagnosis does not appear accurate (eg, if minor abnormalities were likely over-interpreted), then comprehensive testing needs to be pursued, similar to an asymptomatic individual with a history that suggests AHP.

If comprehensive testing is needed, it should include urinary ALA, PBG, and porphyrins; fecal and plasma porphyrins; and erythrocyte PBGD, which may establish a diagnosis of AIP even in asymptomatic patients. Such comprehensive testing is not cost-effective and not warranted in patients with current or recent symptoms, and, as described above, screening by measuring only urine PBG and porphyrins is recommended for individuals who present with acute porphyria symptoms. (See 'Initial testing (suspected AHP)' above.)

Sequencing of the relevant genes (see 'Genes and enzymes affected in specific porphyrias' above) is an option if AHP is strongly suspected in an asymptomatic individual when biochemical testing is negative. However, consultation with a specialist laboratory and porphyria expert is useful in planning these evaluations [25].

Information regarding the screening and counseling of asymptomatic family members of an individual diagnosed with AHP is discussed in topic reviews on the specific disorders.

Blistering cutaneous porphyrias (exemplified by PCT)

Presenting findings (blistering cutaneous porphyria) — Blistering cutaneous porphyrias are characterized by chronic blistering, scarring, and pigment changes on sun-exposed areas of skin, especially on the dorsal hands and less often the face, neck, ears, and feet.

PCT is the most common porphyria with this presentation, but neither the clinical findings nor increased total porphyrins are specific for PCT. It is necessary to exclude other less common blistering cutaneous porphyrias, which are commonly misdiagnosed as PCT, including variegate porphyria (VP), hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), and hereditary coproporphyria (HCP), as well as pseudoporphyria, before initiating specific therapy for PCT, because phlebotomy and low-dose hydroxychloroquine are effective exclusively in PCT and will not treat these other conditions. (See 'Diagnostic testing (blistering cutaneous porphyria suspected)' below.)

Especially severe disease (exemplified by most cases of CEP) correlates with especially high porphyrin levels and can lead to photomutilation, with loss of facial features and digits.

Diagnostic testing (blistering cutaneous porphyria suspected) — For suspected blistering cutaneous porphyria, measurement of plasma or urine porphyrins is the first-line screening test (algorithm 3). Porphyrins are light-sensitive, so samples should be protected from light during processing and transit. However, substantially elevated porphyrin levels are very unlikely to be reduced to normal even by lengthy light exposure.

Normal levels of plasma porphyrins are typically <1 mcg/dL (higher in individuals with end-stage kidney disease) [29]. Elevations in plasma and urine total porphyrins are found in all active cases with blistering cutaneous porphyrias (PCT, HEP, VP, HCP, and CEP), with the degree of elevation generally reflecting the severity of the lesions. For example, in subclinical or mild cases of PCT, the degree of elevation may be small.

When total plasma or total urine porphyrins are elevated, fractionation of porphyrins in urine, feces, plasma, and erythrocytes by high-performance liquid chromatography (HPLC) enables recognition of specific patterns that differentiate the various types of blistering cutaneous porphyria (PCT, HEP, VP, HCP, CEP). Specific findings are outlined in the table (table 7) and summarized as follows:

PCT – PCT is the most common porphyria; it is due to acquired inhibition of hepatic uroporphyrinogen decarboxylase (UROD). It is an iron-related condition that usually presents in adults with blistering skin lesions; neurovisceral manifestations are absent. Susceptibility factors include alcohol or estrogen use, smoking, hepatitis C, HIV infection, HFE (hemochromatosis) mutations, or heterozygous UROD mutations. Because these factors occur in varying combinations, the disease is clinically heterogeneous. Rare affected children are likely to have UROD mutations and to have received chemotherapy for leukemia or other neoplasms [30]. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

In PCT, porphyrins are chronically elevated in plasma and urine; either can be measured for diagnosis, but porphyrins are also nonspecifically elevated in other porphyrias and other medical conditions. If PCT has been effectively treated (eg, with phlebotomy or low-dose hydroxychloroquine), there may be no biochemical abnormalities, and prior laboratory results must be reviewed to verify the diagnosis retrospectively.

The diagnosis of PCT is confirmed by finding the characteristic pattern of highly carboxylated porphyrins in urine (or plasma) with little or no elevation in erythrocyte porphyrins (table 6) [31]. This pattern of increases in highly carboxylated porphyrins (uroporphyrin, hepta-, hexa-, and pentacarboxyl porphyrins) in plasma or urine is characteristic, although not absolutely specific for PCT. Urinary ALA may be modestly increased, but urinary PBG excretion is normal. Erythrocyte porphyrins are normal or mildly elevated (mostly zinc protoporphyrin) in PCT, in contrast to substantial elevations in HEP and CEP.

VP – Individuals presenting with VP are frequently misdiagnosed as having PCT, which is much more common. VP can cause blistering cutaneous manifestations, neurovisceral manifestations, or both. (See "Variegate porphyria".)

Biochemically, VP is characterized by a plasma fluorescence peak at 626 nm, elevation in fecal coproporphyrin III and protoporphyrin IX, as well as increased urinary ALA and PBG, especially during acute attacks.

HCP – HCP produces both blistering cutaneous and neurovisceral manifestations, but cutaneous manifestations are much less common than in VP. Biochemically, HCP can be differentiated from other blistering cutaneous porphyrias because it produces a markedly increased concentration of coproporphyrin III in urine and feces with little increase in fecal protoporphyrin. (See "Hereditary coproporphyria".)

CEP – CEP produces blistering skin lesions without neurovisceral manifestations. This rare porphyria typically presents in childhood but can begin at any age. Mild and adult-onset cases are rare, and when seen, are commonly misdiagnosed as PCT. When CEP develops in adults, it may be due to a clonal myeloproliferative or myelodysplastic disorder. (See "Congenital erythropoietic porphyria".)

CEP is characterized by markedly increased porphyrins in plasma, urine, stool, and erythrocytes, with a predominance of uroporphyrin I and coproporphyrin I.

HEP – HEP is caused by biallelic UROD pathogenic variants. It is characterized by blistering cutaneous lesions that are often more severe than seen in PCT or that present much earlier (eg, in childhood). Mild cases of HEP are easily misdiagnosed as PCT. The pattern of porphyrin elevations in HEP closely resembles that seen in PCT but is distinguished by a marked elevation in erythrocyte protoporphyrin (mostly zinc protoporphyrin). Additional details of the diagnostic evaluation are presented separately. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

If biochemical testing establishes a diagnosis of a blistering cutaneous porphyrias, genetic testing is recommended to confirm the diagnosis and to enable genetic counseling. However, approximately 80 percent of affected individuals with PCT do not have a UROD mutation, so genetic testing in this disease is part of a complete evaluation for susceptibility factors that vary among individual patients, as noted above. Details of genetic testing and counseling are discussed in the linked topic reviews on the individual disorders listed above.

A normal level of total porphyrins in plasma or urine (expressed per gram or mmol of creatinine) is sufficient to eliminate the possibility of a blistering cutaneous porphyria, even with slight increases in some individual porphyrins (separated and measured by HPLC).

Other causes of blistering skin lesions may also be considered in an individual with normal total porphyrins and/or while awaiting results of porphyrin testing (algorithm 4). A discussion of these disorders, including pseudoporphyria, and an approach to their evaluation are discussed separately. (See "Approach to the patient with cutaneous blisters".)

Treatment of blistering cutaneous porphyria — Blistering cutaneous porphyrias are largely chronic, and treatment is seldom urgent. Avoidance of sunlight is advised but is not usually of immediate benefit for these chronic conditions, in part because skin fragility contributes to blister formation and is slow to resolve. Blistering lesions are prone to bacterial infections, which should be treated promptly.

PCT is the most readily treated porphyria; it responds well to treatments that reduce hepatic iron, such as phlebotomy, or to low-dose hydroxychloroquine, which mobilizes porphyrins from the liver. These treatments must be appropriately chosen and well executed to be effective. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis".)

The other blistering cutaneous porphyrias (VP, HCP, CEP, and HEP) do not respond to iron-directed therapies or hydroxychloroquine. Their treatment is more difficult and less effective. Because treatment differs for each type of blistering cutaneous porphyria, accurate diagnosis is needed before treatment is initiated. Other aspects of treatment for each disorder are discussed in detail in the linked topic reviews listed above. (See 'Diagnostic testing (blistering cutaneous porphyria suspected)' above.)

Acute nonblistering photosensitivity (exemplified by EPP)

Presenting findings (protoporphyria) — Acute nonblistering photosensitivity occurs in the protoporphyrias, of which EPP is the most common. Patients with protoporphyria develop immediate photosensitivity (usually within minutes of sunlight exposure) manifested by acute pain, which compels them to seek shelter from light. With more prolonged exposure, pain may be followed by erythema, swelling, and systemic symptoms that may last for several days, but with few if any blisters or lasting skin changes. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

This type of photosensitivity is distinctive and contrasts with other cutaneous porphyrias, which cause chronic blistering and scarring on sun-exposed skin, but with little or no acute pain. Indeed, patients with blistering porphyrias may not perceive that light exposure is a problem.

EPP, which results from inheritance of ferrochelatase (FECH) mutations, is the prototypic form of protoporphyria; it is the third most common porphyria overall and the most common porphyria in children. Two other less common forms of protoporphyria with the same phenotype have been described:

X-linked protoporphyria (XLP), which is due to ALAS2 gain of function mutations

Protoporphyria caused by mitochondrial CLPX mutation (described in one family in 2017)

All of these protoporphyrias generally present in early childhood. Rarely, EPP develops in adults with clonal myeloproliferative or myelodysplastic disorders. The nomenclature for these disorders is in flux, with a trend towards EPP being used exclusively to describe individuals with FECH mutations.

Individuals with protoporphyria may have hepatobiliary manifestations. Gallstones containing protoporphyrin are common. Severe cholestatic liver disease due to excess protoporphyrin presented to the liver for biliary excretion occurs in less than 5 percent of patients.

Diagnostic testing (protoporphyria suspected) — In individuals with suspected protoporphyria, the initial screening test is erythrocyte total protoporphyrin (algorithm 5). If the total is elevated, erythrocyte protoporphyrin must be fractionated to determine the relative amounts of metal-free and zinc protoporphyrin. Elevation of metal-free protoporphyrin is a distinctive feature of protoporphyrias, whereas zinc protoporphyrin is elevated in many other erythrocytic disorders.

The deficient enzyme in EPP is ferrochelatase (FECH), which catalyzes the insertion of iron into protoporphyrin to make heme (see "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Pathogenesis'). FECH can accept other metals and therefore catalyzes formation of zinc protoporphyrin from any protoporphyrin remaining after completion of heme and hemoglobin synthesis. Deficient FECH activity in EPP impairs synthesis of both heme and zinc protoporphyrin, so the excess protoporphyrin that accumulates in EPP is mostly metal-free.

The normal range for erythrocyte total protoporphyrin is up to approximately 80 mcg/dL, with some variation related to age. In EPP and XLP, erythrocyte total protoporphyrin is usually increased to between 300 and 5000 mcg/dL or higher, and consists mostly of metal-free protoporphyrin (ie, protoporphyrin not complexed with iron [as in heme] or zinc [as in zinc protoporphyrin]). Plasma porphyrin levels are usually but not always increased (table 6).

Increased erythrocyte total porphyrin is not specific for EPP and is also seen in many non-porphyria conditions such as lead poisoning, iron deficiency, anemia of chronic disease, and hemolytic conditions, but in contrast to EPP, the excess protoporphyrin in these conditions is mostly zinc-chelated because FECH activity is not impaired.

In EPP, the increased erythrocyte protoporphyrin is typically >85 percent metal-free and <15 percent zinc protoporphyrin.

In XLP, both metal-free and zinc protoporphyrin are increased, and metal-free protoporphyrin is usually predominant. The ALAS2 gain-of-function mutations in XLP lead to the formation of amounts of protoporphyrin exceeding the capacity of normal FECH activity, resulting in excess metal-free as well as zinc protoporphyrin.

In protoporphyria resulting from CLPX mutation, reduced CLPX activity prolongs ALAS2 activity. Therefore, as in XLP, there are increases in both metal-free and zinc protoporphyrin.

The presence of both markedly elevated erythrocyte total protoporphyrin and a predominance of metal-free protoporphyrin (rather than zinc protoporphyrin) allows for ready diagnosis of protoporphyria (table 7).

However, selection of an appropriate laboratory for testing of erythrocyte protoporphyrin is important [32]. Some referral laboratories in the United States (Quest and LabCorp) measure only zinc protoporphyrin but report misleadingly that they have measured both total and "free protoporphyrin". The term "free protoporphyrin" is in fact an obsolete term that originally meant iron-free rather than metal-free protoporphyrin. When this term originated, the existence of zinc protoporphyrin in erythrocytes had not yet been described. Another laboratory (ARUP) measures total protoporphyrin but does fractionate into metal-free and zinc protoporphyrin [32].

Fractionation of metal-free and zinc protoporphyrin is important because increased erythrocyte total protoporphyrin, but with a predominance of zinc protoporphyrin, is a nonspecific finding seen in a variety of conditions, as noted above. Therefore, even a marked increase in erythrocyte total protoporphyrin is not diagnostic for protoporphyria unless the proportion of metal-free exceeds that of zinc protoporphyrin.

Marked erythrocyte protoporphyrin elevations do not occur in other photosensitivity disorders causing such immediate reactions. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment".)

Laboratory testing for protoporphyria is discussed in more detail separately. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

Treatment of protoporphyria — Treatment of protoporphyrias (EPP, XLP, and protoporphyria due to CLPX deficiency), as discussed in more detail separately, emphasizes sun avoidance to prevent acute photosensitivity reactions. This is especially difficult in children, who may not have been diagnosed. At all ages, sun avoidance necessitates changes in daily activities and impairs quality of life and professional opportunities. (See "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Photoprotection'.)

Beta-carotene was originally developed for treatment of EPP, and is available as a pharmaceutical grade, over-the-counter nutritional product. Most patients find it is marginally effective for increasing sunlight tolerance.

Afamelanotide, a synthetic analogue of the naturally occurring hormone alpha-melanocyte stimulating hormone (alpha-MSH), increases skin pigmentation by increasing melanin production and in turn can increase sunlight tolerance substantially in patients with protoporphyria. It was approved by the FDA for this indication in 2019. (See "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Afamelanotide'.)

Certain individuals may require interventions for gallstones or hepatopathy. (See "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Treatment of gallstones and protoporphyric hepatopathy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Porphyria".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Porphyrias (The Basics)" and "Patient education: Porphyria cutanea tarda (The Basics)" and "Patient education: Acute intermittent porphyria (The Basics)" and "Patient education: Erythropoietic protoporphyria (The Basics)")

SUMMARY AND RECOMMENDATIONS

Background – The porphyrias are metabolic disorders caused by altered activities of one of the eight enzymes (table 1) involved in heme biosynthesis (figure 1). Porphyrias are associated with accumulation of one or more heme synthesis pathway intermediates (table 3 and table 7). All are caused by disease variants in heme synthesis genes except porphyria cutanea tarda (PCT), in which an acquired inhibitor of UROD is found only in the liver. Heterozygosity for a UROD variant contributes in approximately one-fifth of cases. (See 'Normal heme biosynthesis' above and 'Pathophysiology' above.)

Classification – Porphyrias are hepatic or erythropoietic depending on where heme pathway intermediates first accumulate (liver or bone marrow). Clinically, they have distinctive features (acute neurovisceral, with increased ALA or PBG, or cutaneous, due to photosensitizing porphyrins; further divided as chronic blistering or acute nonblistering) (algorithm 1). (See 'Classification and clinical categories' above and 'Overview and diagnostic framework' above.)

Typical findings

Acute hepatic porphyria (AHP) – Causes abdominal pain or other suggestive symptoms (central, peripheral, sensory, motor, or autonomic nervous system findings; psychiatric findings) diagnosed after an initial evaluation has excluded common explanations. (See 'Presenting findings' above.)

Chronic blistering – Causes blistering skin lesions on light-exposed areas (dorsal hands, face, neck, feet), often with scarring, hypo- and hyperpigmentation, and skin fragility. Photomutilation with loss of facial features and digits can occur with marked porphyrin elevations. (See 'Presenting findings (blistering cutaneous porphyria)' above.)

Acute nonblistering – Causes immediate (within minutes) photosensitivity with acute pain, stinging, tingling, and redness, usually starting in early childhood. Gallstones and rarely severe liver damage can occur. (See 'Presenting findings (protoporphyria)' above.)

Diagnosis and initial treatment – Considerations differ for the three categories (algorithm 1):

AHP – Prompt diagnosis and treatment are especially important. Exemplified by acute intermittent porphyria (AIP). Other AHPs are hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA dehydratase porphyria (ADP; very rare). Initial screening is with spot urine PBG and total porphyrins (normalized to creatinine), obtained as quickly as possible during an acute attack if the diagnosis has not already been established. Additional testing is pursued if PBG is increased (algorithm 2). For individuals with known porphyria, attacks are diagnosed clinically. (See 'Initial testing (suspected AHP)' above.)

AHP can cause prolonged illness and death. Hemin should be initiated based on elevated urinary PBG (new porphyria diagnosis) or clinical features (known porphyria). (See 'Initial treatment of acute attacks' above.)

Chronic blistering – Exemplified by PCT. Other chronic blistering porphyrias include VP, HCP, CEP, and HEP. Initial screening is with total plasma or urine porphyrins, followed by fractionation and plasma fluorescence screen if positive (algorithm 3). (See 'Diagnostic testing (blistering cutaneous porphyria suspected)' above.)

Treatment of PCT is highly effective and specific; the type of blistering cutaneous porphyria must be identified before treatment (other than sun avoidance). (See 'Treatment of blistering cutaneous porphyria' above.)

Acute nonblistering – Exemplified by EPP. Less common are X-linked protoporphyria (XLP) and CLPX protoporphyria. Children or adults with acute nonblistering photosensitivity should be screened for protoporphyria by measuring erythrocyte total protoporphyrin. If elevated, this is fractionated to determine the relative amounts of metal-free and zinc protoporphyrin (algorithm 5). Attention to the choice of an appropriate diagnostic laboratory is essential. (See 'Diagnostic testing (protoporphyria suspected)' above.)

Treatment is focused on sun avoidance; additional interventions (afamelanotide, treatment of gallstones or hepatopathy) may be appropriate for some individuals. (See 'Treatment of protoporphyria' above.)

Details on individual porphyrias – These are discussed in topic reviews listed above. (See 'Genes and enzymes affected in specific porphyrias' above.)

ACKNOWLEDGMENT — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.

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Topic 7101 Version 48.0

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