Porphyrias: Overview of classification and evaluation

INTRODUCTION — The porphyrias are metabolic disorders caused by altered activities of the eight enzymes in the heme biosynthetic pathway. A distinct type of porphyria is associated with each enzyme.

Although uncommon, porphyrias can be encountered by clinicians in any specialty. Diagnosis is challenging because these diseases are rare and their symptoms nonspecific.

Porphyrias are readily diagnosed or excluded by appropriate biochemical testing, but this is often problematic due to lack of standardization of tests offered by major referral laboratories.

This topic provides an overview of the porphyrias, with an emphasis on classification and other information that clinicians in any specialty should know in order to consider porphyria and order appropriate biochemical testing.

Other topic reviews within UpToDate should be consulted for details about individual types of porphyria, including their clinical manifestations, complications, treatments, follow-up, and testing and counseling of relatives. Links to these topics are listed below. (See 'Classification and clinical categories' below.)

DISEASE MECHANISMS

Normal heme biosynthesis — Heme is made in all tissues to serve as the prosthetic group for many essential hemoproteins.

Heme synthesis is most active in the bone marrow and liver.

●Bone marrow – The bone marrow accounts for >80 percent of daily heme synthesis, primarily to provide heme for hemoglobin, the body's most abundant hemoprotein.

Heme and globin synthesis are closely coordinated. The rate of heme synthesis is controlled by expression of the erythroid-specific gene (ALAS2), which encodes the first enzyme in the heme synthetic pathway, as well as genes for several other enzymes in the pathway. (See 'Genes, enzymes, and intermediates' below.)

ALAS2 expression is upregulated by heme and by iron [1,2]. An iron-responsive element (IRE) in the ALAS2 messenger RNA (mRNA) is not present in the mRNA for ALAS1, which encodes the housekeeping form of the enzyme that 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 heme synthesis. Heme is used in the liver primarily in cytochrome P450 (CYP) enzymes, which metabolize toxins and drugs and turn over rapidly. (See "Overview of pharmacogenomics", section on 'CYP isoenzymes and drug metabolism'.)

In the liver, ALAS1 is rate limiting for 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 leads to upregulated ALAS1 expression. ALAS1 is downregulated when the regulatory heme pool is augmented with heme and there is no requirement to increase hepatic heme synthesis.

•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 depletion of the regulatory heme pool and induction of ALAS1 [7]. Upstream enhancer elements shared by ALAS1 and some CYP genes are 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 feedback mechanisms are important in the acute hepatic porphyrias (AHP), which are exacerbated when hepatic ALAS1 is induced [6,9]. Treatment of AHP with intravenous heme, which is taken up primarily in hepatocytes, repletes the regulatory heme pool and results in downregulation of ALAS1 and amelioration of the acute attack [10,11]. (See 'Initial treatment of acute attacks' below and "Acute intermittent porphyria: Management", section on 'Indications and mechanism of action'.)

●Other tissues – Other important heme-containing proteins are present in all tissues [6]. Examples include respiratory cytochromes, catalase, nitric oxide synthase, tryptophan pyrrolase, and myoglobin.

Genes, enzymes, and intermediates — The figure shows the heme synthetic pathway (figure 1).

●Genetics – A pathogenic variant (point mutation, deletion, insertion) in a gene for one of the pathway enzymes underlies seven of the eight types of porphyria. Porphyria cutanea tarda (PCT) is the only type of porphyria that usually develops in the absence of a genetic variant encoding the affected enzyme.

Many different pathogenic variants have been described as causes of each type of porphyria. A pathogenic variant in a particular kindred is often private or shared with only a few other kindreds. Some are more common geographically due to founder effects.

Demonstration of the pathogenic variant is not required for diagnosis but is recommended for confirmation and especially for testing relatives and genetic counseling. (See 'Which test to do first' below.)

Inheritance patterns are discussed below. (See 'Inheritance patterns' below.)

●Intracellular enzyme localization – The first enzyme (ALAS) and the last three enzymes (CPOX, PPOX, FECH) are mitochondrial. The intervening four (ALAD, PBGD, UROS, UROD) are located in the cytoplasm (figure 1).

●Enzymes and porphyria types – The table summarizes important features of these enzymes (table 1). Their abbreviations and roles in porphyria are as follows:

•ALAS (delta-aminolevulinic acid [ALA] synthase, 5-aminolevulinic acid synthase) – Synthesis of heme begins in mitochondria. ALAS is the first enzyme in the pathway; it 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. (See "Overview of water-soluble vitamins", section on 'Vitamin B6 (pyridoxine)'.)

ALAS occurs in two forms that are encoded by different genes. The erythroid-specific form, ALAS2, is produced only in bone marrow erythroblasts.

-ALAS1 – The ALAS1 gene is on chromosome 3. This encodes the housekeeping (or ubiquitous) form of ALAS found in all tissues. No disease-causing ALAS1 variants are described. However, increased ALAS1 expression is pathophysiologically important during exacerbations of the acute hepatic porphyrias. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Enzyme deficiency'.)

-ALAS2 – The ALAS2 gene is on the X chromosome (Xp11.21) [5,12].

Loss of function variants in ALAS2 cause sex-linked sideroblastic anemia. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'X-linked sideroblastic anemia (ALAS2 mutation)'.)

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

•ALAD (ALA dehydratase) – ALAD (also known as PBG [porphobilinogen] synthase) is the second enzyme in the heme synthetic pathway. In the cytoplasm, it catalyzes the synthesis of PBG, a pyrrole, from two molecules of ALA. ALA and PBG are commonly referred to as porphyrin precursors. They can accumulate in large amounts in the acute porphyrias and are associated with neurovisceral symptoms. (See 'Initial testing for suspected AHP (urinary PBG and total porphyrins)' below.)

-Pathogenic variants in the ALAD gene cause autosomal recessive ALAD porphyria (ADP). This ultrarare porphyria (only eight documented cases worldwide) is an acute hepatic porphyria that is also likely to have an erythropoietic component. ALAD is octameric, and some mutations favor hexameric forms of the enzyme that are less active. In ADP, ALA is substantially elevated but PBG is not. (See "ALA dehydratase porphyria".)

-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 potently inhibits ALAD activity [14,15]. Like ADP, lead poisoning and tyrosinemia have elevated urinary ALA (as well as urinary coproporphyrin III and erythrocyte zinc protoporphyrin), 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. It catalyzes the synthesis of hydroxymethylbilane (HMB; a linear tetrapyrrole) from four molecules of PBG. Pathogenic variants in the PBGD/HMBS gene cause acute intermittent porphyria (AIP), which is symptomatic after puberty in some heterozygous individuals. Rare homozygous cases have earlier onset and more profound symptoms. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis".)

•Uroporphyrinogen synthase (UROS) – UROS is the fourth enzyme in the pathway. It catalyzes the synthesis of uroporphyrinogen III (an octacarboxyl porphyrinogen) from HMB. The reaction results in 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 not a heme precursor.

Pathogenic variants in the UROS gene cause congenital erythropoietic prophyria (CEP), an autosomal recessive disorder characterized by accumulation of isomer I porphyrinogens, which undergo autooxidation to the corresponding isomer I porphyrins. (See "Congenital erythropoietic porphyria".)

•Uroporphyrinogen decarboxylase (UROD) – UROD is the fifth enzyme in the pathway. It catalyzes the 4-step decarboxylation of uroporphyrinogen III and I to form coproporphyrinogen III and I (tetracarboxyl porphyrinogens).

UROD is inhibited in the liver in all patients with PCT, of whom only approximately 20 percent also have an inherited UROD pathogenic variant. The inhibitor is a uroporphomethene (a partially oxidized uroporphyrinogen molecule). Iron and cytochrome P450 enzymes are required for generation of this inhibitor.

Inheritance of a monoallelic UROD gene variant can predispose to PCT (referred to as familial PCT, although the family history is usually negative). Other familial cases may be due to hemochromatosis (HFE) C282Y, or possible other inherited predisposing factors.

Biallelic UROD variants cause hepatoerythropoietic porphyria (HEP), which is ultrarare. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

•Coproporphyrinogen oxidase (CPOX) – CPOX the sixth enzyme in the pathway. It is located in the mitochondria, where it catalyzes the synthesis of protoporphyrinogen IX (a dicarboxyl porphyrinogen) from coproporphyrinogen III. A tricarboxyl porphyrinogen, termed harderoporphyrin, is an intermediate in this reaction. Coproporphyrinogen I is not a substrate for this stereospecific enzyme, and as a result, only the isomer III porphyrinogen is metabolized to heme.

Pathogenic variants in the CPOX gene cause hereditary coproporphyria (HCP) in some heterozygous individuals. Neurovisceral symptoms, and rarely blistering photosensitivity, can develop after puberty.

Biallelic pathogenic variants cause more severe, early onset symptoms. Some biallelic CPOX variants cause harderoporphyria, with distinct hematologic features. (See "Hereditary coproporphyria".)

•Protoporphyrinogen oxidase (PPOX) – PPOX is the seventh enzyme in the pathway. It oxidizes protoporphyrinogen IX by removing six protons to form protoporphyrin IX, which is the only oxidized porphyrin intermediate in the pathway.

Pathogenic variants in the PPOX gene cause variegate porphyria (VP) in some heterozygous individuals. Neurovisceral symptoms and blistering photosensitivity may develop after puberty. Homozygous or compound heterozygous PPOX variants cause earlier and more severe symptoms. (See "Variegate porphyria".)

•Ferrochelatase (FECH) – FECH is the eighth and final enzyme in the pathway. It inserts ferrous iron into protoporphyrin IX to form heme (iron protoporphyrin IX). This enzyme accepts other metals and chelates any remaining protoporphyrin with zinc to form zinc protoporphyrin, which is normally found in small amounts in circulating red blood cells.

Biallelic pathogenic variants in the FECH gene cause autosomal recessive erythropoietic protoporphyria (EPP), in which protoporphyrin accumulates, mostly as metal-free rather than zinc protoporphyrin. (See "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Pathogenesis'.)

FECH is genetically deficient in EPP, which impairs formation of heme and zinc protoporphyrin. In contrast to EPP, in many red blood cell disorders, erythrocyte zinc protoporphyrin is markedly increased. This includes iron deficiency, lead poisoning, anemia of chronic disease/anemia of inflammation, and hemolysis. Notably, one of the biallelic FECH variants found in most EPP patients is common in non-African populations and is pathogenic only when it occurs in trans to a severe FECH variant, which are rare.

●Heme pathway intermediates – The table lists primary routes of excretion of the heme synthesis intermediates and their chemically altered metabolites (table 2). Considerations important for diagnostic testing include:

•ALA and PBG – Elevations of ALA (delta-aminolevulinic acid) and PBG (porphobilinogen) are associated with neurovisceral manifestations in acute porphyrias. They are elevated in serum and urine but most concentrated in urine. ALA is often considered causative of these manifestations, but this has not been convincingly proven.

Both ALA and PBG accumulate in AIP, HCP, and VP, especially during symptomatic episodes. A substantial PBG elevation is diagnostically specific for these acute porphyrias. (See 'Which test to do first' below.)

-PBG is normal in all other porphyrias and other medical conditions.

-Greater elevations and longer duration of elevated ALA and PBG are seen in AIP than HCP and VP.

-Slight elevations of ALA occur in some patients with PCT or cirrhosis.

-In the rare porphyria ADP, urinary ALA is elevated but not PBG. ADP also has elevations of coproporphyrin III and erythrocyte zinc protoporphyrin. This pattern is also seen in lead poisoning and hereditary tyrosinemia type 1.

•Porphyrins

-Urine/plasma – Urinary porphyrin elevations are seen during symptomatic acute porphyria episodes. Plasma and urine porphyrins are elevated in all chronic blistering cutaneous porphyrias. However, in protoporphyrias (EPP and XLP), which cause acute nonblistering photosensitivity, porphyrins are markedly elevated only in erythrocytes, with variable elevations in plasma and normal levels in urine.

In acute porphyrias, porphyrins may be sufficiently elevated in plasma to cause chronic, blistering photosensitivity, which is common in VP, less common in HCP, and in AIP occurs only in rare patients with concurrent end-stage kidney disease.

-RBCs – Erythrocyte (red blood cell [RBC]) porphyrins are normal or modestly elevated in hepatic porphyrias, including sporadic (type 1) PCT, which has no pathogenic variants for heme biosynthetic enzymes, AIP, HCP, VP, and familial (type 2) PCT, each of which is due to heterozygosity for a pathogenic variant of the affected enzyme.

In contrast, erythrocyte porphyrins are substantially elevated in the erythropoietic porphyrias (CEP, EPP, and XLP) and in ultrarare homozygous forms of hereditary hepatic porphyrias (ADP, HEP, and homozygous AIP, HCP, and VP), which have more severe enzyme deficiencies due to biallelic or X chromosome pathogenic variants.

Substantial elevations may also be seen in very rare patients with "dual porphyria" due to deficiencies of more than one enzyme in the heme biosynthetic pathway [16].

-Metal-free and zinc protoporphyrin – Metal-free protoporphyrin accumulates in EPP and XLP, and demonstration of predominant elevation of metal-free protoporphyrin is important for their diagnosis. In contrast, erythrocyte zinc protoporphyrin is elevated in many other conditions (iron deficiency, lead poisoning, anemia of chronic disease/anemia of inflammation, hemolysis) and it is not specific for porphyria. (See 'Diagnostic testing (protoporphyria suspected)' below.)

-Plasma fluorescence – In VP, porphyrin-peptides produce a diagnostic fluorescence emission peak at approximately 626 nm when diluted plasma is scanned at neutral pH. This allows rapid biochemical documentation of VP and differentiation from PCT and other blistering cutaneous porphyrias [17-20]. This testing is available in selected specialty laboratories.

-Mechanisms – Mechanisms of porphyrin elevations in the different porphyrias are discussed in separate topic reviews. (See 'Classification and clinical categories' below.)

●Colors and excretion routes of heme pathway intermediates – All of the heme pathway intermediates within cells are colorless and nonfluorescent, except for the final intermediate, protoporphyrin, which, like other oxidized porphyrins, is reddish-colored and displays reddish fluorescence when illuminated by light near 400 nm (the Soret absorption band for porphyrins).

If porphyrinogen intermediates accumulate and leave the intracellular environment, they mostly spontaneously oxidize to the corresponding porphyrins, which are reddish and fluorescent.

Porphyrin precursors (ALA and PBG) and the highly carboxylated porphyrins (uroporphyrin, hepta-, hexa-, and pentacarboxyl porphyrins) are water soluble and thus are mostly excreted in urine. Coproporphyrin (tetracarboxyl porphyrin) is excreted in both urine and bile. Harderoporphyrin (a tricarboxyl porphyrin) and protoporphyin (a dicarboxyl porphyrin) are excreted only in bile and can be measured in feces.

•ALA and PBG are colorless.

•PBG can degrade in urine to porphobilin, which is brownish.

•PBG at high concentrations can also spontaneously form uroporphyrin, which is reddish.

These visible urine colors (red, brown or purple) are the source of the name "porphyria"; the Greek word for the color purple is "porphyrus" [21].

Variants in regulatory genes — In very rare cases, a pathogenic variant affecting a regulatory gene rather than the enzyme itself has been identified. These include:

●Congenital erythropoietic porphyria (CEP) due to a variant in the gene GATA1 (encodes a transcription factor that controls expression of the UROS gene). (See "Congenital erythropoietic porphyria", section on 'UROS gene variants'.)

●Protoporphyria with increased ALAS2 function due to variant in the mitochondrial gene CLPX, which encodes a protease that degrades ALAS2. (See "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'EPP due to CLPX mutation'.)

Variants in other genes — Other genetic traits may influence some forms of porphyria.

As examples:

●Various genetic factors other than pathogenic variants in the UROD gene may contribute to development of PCT, which is an iron-related disease in which oxidative stress in the liver plays a key role.

Examples include the hemochromatosis (HFE) C282Y mutation and variants in genes encoding hepatic cytochromes (CYPs) [22]. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

●For acute hepatic porphyrias, unknown modifying genes undoubtedly contribute to variable penetrance or to disease complications.

●A common variant in the PEPT2 gene, which encodes peptide transporter 2, a transporter for ALA in the kidney, was found to predispose to kidney disease in AIP [23].

●Somatic "second-hit" variants in the liver can lead to loss of heterozygosity and development of liver cancer in patients with AIP (HMBS second hit) or VP (PPOX second hit) [24,25].

Inheritance patterns — All porphyria genes are in the cellular genome, and inheritance of the porphyrias follows Mendelian (rather than mitochondrial) genetic transmission patterns (table 3).

●Autosomal dominant with low penetrance (mostly hereditary hepatic porphyrias-HHP) – In the HHPs, penetrance is low because the individual is heterozygous for a pathogenic variant, activity of the affected enzyme is approximately half-normal, and additional genetic, environmental, and metabolic factors are necessary for the disease to become manifest. Most heterozygous individuals never develop symptoms. This applies to:

•Acute intermittent porphyria (AIP)

•Hereditary coproporphyria (HCP)

•Variegate porphyria (VP)

•Familial porphyria cutanea tarda (PCT), approximately 20 percent of individuals with PCT who have a heterozygous UROD variant

Autosomal dominant inheritance is also seen in a rare type of erythropoietic protoporphyria due to a CLPX variant that increases ALAS2 activity by impairing its degradation [26]. (See 'Variants in regulatory genes' above.)

●Autosomal recessive (mostly erythropoietic porphyrias) – In the erythropoietic porphyrias, and homozygous forms of hepatic porphyrias (which may often have an erythropoietic component), biallelic pathogenic variants lead to more severe enzyme deficiencies. Genotype-phenotype correlations may be more evident in these porphyrias. This applies to:

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

•Congenital erythropoietic porphyria (CEP).

•Hepatoerythropoietic porphyria (HEP; homozygous familial PCT).

•Erythropoietic protoporphyria (EPP).

•Homozygous forms of AIP, HCP, VP and familial PCT. These are very rare, with a different more severe, and earlier onset phenotype.

•Harderoporphyria, which results from certain CPOX variants 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. Symptoms may be absent in female carriers depending on the degree of inactivation of the X chromosome that harbors the variant. This applies to:

•X-linked protoporphyria (XLP)

•CEP due to a GATA1 variant (See 'Variants in regulatory genes' above.)

Environmental and metabolic factors contributing to disease expression — Environmental and metabolic factors are important in the development of disease manifestations, especially in the hepatic porphyrias, which cause acute neurovisceral symptoms (AIP, VP, HCP and ADP) or blistering photosensitivity (PCT, VP, and less commonly HCP).

●Acute porphyrias – Exposure to certain drugs, steroid hormones, and nutritional alterations impact disease penetrance. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Exacerbating factors'.)

For example:

•Increases in progesterone may cause attacks during the luteal phase of the menstrual cycle.

•Attacks can develop with fasting or after bariatric surgery.

•The table lists drugs that commonly exacerbate AHPs (table 4).

How such factors contribute to chronic neurological symptoms in many patients with AHP is not well understood.

●PCT – Iron, oxidative stress, and other susceptibility factors act in combination, leading to generation of a hepatic UROD inhibitor in PCT. These are largely different from the factors that exacerbate AHP; they include genetic variants (UROD and HFE), 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'.)

OVERVIEW OF DIAGNOSIS AND TREATMENT

Importance of timely diagnosis — Porphyrias are rare disorders with nonspecific clinical manifestations that are difficult to differentiate from many other more common diseases. A prompt diagnosis is favored by considering porphyria to be part of the diagnostic workup for common symptoms such as abdominal pain or cutaneous photosensitivity, and by the availability of appropriate first-line testing. Moreover, effective treatments are available but are provided only after a diagnosis of porphyria is suspected or established.

However, diagnosis and appropriate treatment are often delayed, which is unfortunate because sensitive biochemical first-line screening tests are available for diagnosis of these disorders.

Further second line testing that readily confirms and differentiates the various types of porphyria is only obtained if the screening test is positive. Diagnostic confirmation by DNA analysis has also become readily available.

The presenting symptoms and choice of first-line diagnostic testing are very different for the three most common porphyrias (table 5). The flowchart outlines these differences (algorithm 1).

Classification and clinical categories

●Mechanistic classification – Porphyrias are classified as hepatic or erythropoietic, reflecting the major site of initial accumulation of pathway intermediates in either the liver or bone marrow [27]. (See 'Genes, enzymes, and intermediates' above.)

Hepatic porphyrias are recognized mostly during adult life, whereas childhood onset of symptoms is typical for erythropoietic types.

●Clinical categories – The flowchart illustrates a framework for categorizing porphyrias based on clinical features (algorithm 1). There are three distinct types:

•Acute porphyrias, with neurovisceral manifestations (abdominal pain, motor and sensory peripheral neuropathy, neuropsychiatric changes).

•Blistering cutaneous porphyrias, with chronic blistering and scarring of sun-exposed skin.

•Nonblistering cutaneous porphyrias, with acute, recurrent, painful, but mostly nonblistering photosensitivity.

●Most common porphyrias – The three most common porphyrias, in the order shown below, each fall into one of the three distinct clinical categories and are therefore very different from each other:

•Porphyria cutanea tarda (PCT) – Chronic blistering photosensitivity

•Acute intermittent porphyria (AIP) – Neurovisceral manifestations

•Erythropoietic protoporphyria (EPP) – Acute nonblistering photosensitivity

PCT and AIP are symptomatic mainly in adults. EPP is the most common porphyria to present in children and should be familiar to physicians who see children.

Diagnostic testing for each of these porphyrias is different; thus, there is no common screening test for all porphyrias. (See 'Which test to do first' below.)

●List of porphyrias (alphabetical) and links to topic reviews

•ADP – (See "ALA dehydratase porphyria".)

•AIP – (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis".)

•CEP - (See "Congenital erythropoietic porphyria".)

•EPP – (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

•HCP – (See "Hereditary coproporphyria".)

•HEP – (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

•PCT – (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

•VP – (See "Variegate porphyria".)

•XLP – (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

Which test to do first — The initial approach to making the diagnosis in a patient not previously known to have porphyria involves determining which of the three major types of porphyria is being considered, which determines the first-line test to perform.

First line testing involves measuring amounts of heme biosynthetic pathway intermediates that are likely to be increased. Elevated levels of these intermediates may be seen in the absence of symptoms, and further increases are often associated with onset or worsening of symptoms.

Three porphyrias are prototypical examples of the three major types of porphyria presentations. With knowledge of diagnostic approaches for these three most common types, the less common porphyrias will also be diagnosed and therefore not be neglected (algorithm 1).

●Neuropathic symptoms (abdominal pain, weakness, seizures) – Consider acute intermittent porphyria (AIP) or the less common acute hepatic porphyrias. Order spot urine for PBG and porphyrins, with spot urine creatinine so that results can be normalized to creatinine. (See 'Initial testing for suspected AHP (urinary PBG and total porphyrins)' below.)

●Chronic blistering skin lesions – Think of porphyria cutanea tarda (PCT) and less common blistering cutaneous porphyrias, which are managed differently. Measure plasma or urine porphyrins. (See 'Diagnostic testing (blistering cutaneous porphyria suspected)' below.)

●Nonblistering photosensitivity – Think of erythropoietic protoporphyria (EPP) or XLP. Measure erythrocyte total protoporphyrin. (See 'Diagnostic testing (protoporphyria suspected)' below.)

Genetic testing is widely available, however:

●Genetic testing does not distinguish active from latent disease.

●Genetic testing is usually negative in the most common porphyria (porphyria cutanea tarda), which is due primarily to enzyme inhibition specifically in the liver.

Acute hepatic porphyrias (AHP; exemplified by AIP)

When to suspect AHP — AIP and other AHPs 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. (See 'Importance of timely diagnosis' above.)

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.

Delayed diagnosis continues to be a major problem because specific testing for porphyria is seldom considered part of the diagnostic workup for this and other cardinal symptoms of AHP.

Spectrum of neurovisceral manifestations — Abdominal pain, typically severe and with a relatively unremarkable examination, is the most common neurovisceral manifestation of AHP (table 6).

Other common gastrointestinal symptoms of AHP besides abdominal pain include:

●Nausea

●Vomiting

●Constipation

●Diarrhea (less common)

Other symptoms and signs may be present, but their significance not recognized, including:

●Insomnia

●Agitation

●Hallucinations

●Seizures

●Hyponatremia, which is often attributed to the syndrome of inappropriate antidiuretic hormone secretion (SIADH)

●Extremity pain

●Head or neck pain

●Chest pain

●Paresis

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 they are all highly nonspecific, often seen as unrelated, and may not suggest of a unifying diagnosis [28]. Therefore, testing for AHP should be considered even when suspicion has not risen to a high level. (See 'Initial testing for suspected AHP (urinary PBG and total porphyrins)' below.)

Magnetic resonance imaging (MRI) findings can resemble those in posterior reversible encephalopathy syndrome (PRES), suggesting reversible cerebral vasoconstriction [29]. This illustrates the potentially substantial effects of AHP on the central nervous system. AHP can also mimic Guillain-Barre syndrome and should be considered in its differential diagnosis [30,31].

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 [32,33]. Likewise, multiple abdominal surgeries without definite diagnoses or benefits should also trigger testing for AHP. (See 'Clinical vignette' below.)

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 emergency department (ED) with abdominal pain (requiring morphine), nausea, vomiting, and diarrhea. 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 traveled to another part of the country.

She had continuing and progressive symptoms and was hospitalized after developing muscle weakness that 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. 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 for suspected AHP (urinary PBG and total porphyrins)

●Spot urine PBG – AHP is readily ruled in or out at the time of symptoms by a simple spot urine test for porphobilinogen (PBG), which is both sensitive and highly specific, especially for AIP (algorithm 2). The results of spot urine PBG should be normalized to spot urine creatinine from the same sample. A timed urine collection is not needed; collecting urine for 24 hours can cause unnecessary delays in diagnosis.

●Spot urine porphyrins – Urine porphyrins should also be measured (and normalized to creatinine), because PBG is often less elevated and returns to normal more rapidly in HCP and VP than in AIP. In ADP, an ultrarare disease, urine coproporphyrin III, but not PBG, is markedly elevated.

A rapid test kit for urinary PBG is available [34,35]. However, this is seldom found at most medical centers, so samples are usually sent to a referral laboratory. When a result is needed urgently, the laboratory should be contacted and asked to expedite the testing.

Normal urinary excretion of PBG is <2 to 4 mg (<9 to 18 micromol) per day [33]. Amounts expressed per gram of 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 7).

PBG can also be measured in serum or plasma, which is essential if AHP is suspected in a patient with advanced kidney disease [36,37]. However, in patients with AHP and normal kidney function, PBG concentrations are higher in urine, so urinary measurements are more sensitive and therefore preferred.

Positive results from initial testing can prompt initiation of treatment. (See 'Initial treatment of acute attacks' below.)

If first-line testing is positive, second-line testing follows to determine the type of porphyria or to ascertain whether a urine porphyrin elevation alone is due to porphyria or is a nonspecific finding. The samples should be obtained before starting hemin, but treatment should not be delayed while awaiting the results, since the initial treatment does not differ according to the type of AHP. Slight elevations in individual urine porphyrins are seldom of diagnostic significance if the total amount of urinary porphyrins is normal. (See 'Second-line testing to determine the type of AHP (obtain samples but do not wait for results)' below.)

Highly dilute urine can give falsely negative results [38]; 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.

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'.)

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 — Acute attacks of AHP can be life-threatening and should be treated urgently with hemin for quick remission and to avoid prolonged hospitalization and complications such as hyponatremia, seizures, and progressive motor paralysis.

Treatment in a newly diagnosed patient with severe clinical manifestations can be started as soon as elevated urinary PBG (eg, PBG >10 mg per g creatinine [or >10 mg/L]), is documented, and typically should be started without delay. (See 'Initial testing for suspected AHP (urinary PBG and total porphyrins)' above.)

●Additional samples for second line testing are obtained if possible, but treatment should not be delayed. (See 'Second-line testing to determine the type of AHP (obtain samples but do not wait for results)' below.)

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

●If results are negative (PBG <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'.)

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

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

With all acute porphyria attacks, it is also important to evaluate for factors that may have precipitated the attack, such as an infection or other intercurrent illness, nutritional alterations, or exposure to harmful drugs. Individuals with porphyria are equally susceptible as the general population to other medical or surgical conditions that may be mistaken for an acute attack of porphyria, such as appendicitis, pancreatobiliary disease, or a urinary tract infection (UTI).

Acute attacks decrease in frequency in patients treated with givosiran (a preventive therapy for acute porphyria), but attacks may occur even without PBG elevation and are still treated with hemin. (See "Acute intermittent porphyria: Management", section on 'Givosiran'.)

Second-line testing to determine the type of AHP (obtain samples but do not wait for results) — Spot urine, plasma, and stool samples should be obtained for additional testing and sent prior to starting therapy if possible, since treatment with hemin can lead to substantial and rapid decreases in urine PBG and porphyrins [33]. The results of this testing may take weeks to return, and therapy should not be delayed while awaiting the results.

The table outlines biochemical differentiation of the four AHPs (table 8), which is summarized as follows:

●AIP – AIP is the prototypical and most common AHP. Cutaneous manifestations do not occur, except rarely in association with advanced kidney 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 (when plasma is diluted at neutral pH) as well as increased fecal coproporphyrin III and protoporphyrin. (See "Variegate porphyria".)

●ADP – ADP is ultrarare (eight documented case reports). 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 [33]. (See "ALA dehydratase porphyria".)

Testing in currently asymptomatic individuals — AHP diagnosis is more challenging in patients who describe a history consistent with attacks but are currently well; this is because levels of porphyrin precursors and porphyrins may be normal in asymptomatic individuals.

●For previously diagnosed patients, it is important to obtain the original laboratory reports and determine if the diagnosis was well founded. If the initial diagnosis does not appear accurate (eg, if minor abnormalities were likely overinterpreted), comprehensive testing needs to be pursued.

●If comprehensive testing is needed, it should include urinary ALA, PBG, and porphyrins normalized to creatinine; fecal and plasma porphyrins; and erythrocyte PBGD, which may establish a diagnosis of AHP even in asymptomatic patients. Such comprehensive testing is not for initial screening of patients with current or recent symptoms, which only requires measuring urine PBG and porphyrins (normalized to creatinine). (See 'Initial testing for suspected AHP (urinary PBG and total porphyrins)' above.)

●Sequencing of the relevant genes 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 [33]. (See 'Genes, enzymes, and intermediates' above.)

Screening and counseling of asymptomatic relatives 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 and the most common cutaneous porphyria with blistering, but clinical findings, increased urine or plasma porphyrins, or skin biopsy findings are not specific for PCT.

Marked elevation of urine or plasma total porphyrins with a predominance of uroporphyrin and heptacarboxyl porphyrin strongly suggests but is not specific for PCT. Therefore, it remains important to exclude the following less common blistering cutaneous porphyrias, which are commonly misdiagnosed as PCT, by measuring fecal and erythrocyte porphyrins, before initiating specific therapy for PCT.

The approach to excluding these other blistering cutaneous porphyrias is as follows:

●Variegate porphyria (VP) – VP is excluded by the absence of marked fecal porphyrin elevation and/or the absence of the plasma fluorescence peak that is diagnostic for VP.

●Hepatoerythropoietic porphyria (HEP) – HEP is excluded by the absence of marked erythrocyte total porphyrin elevation.

●Congenital erythropoietic porphyria (CEP, especially mild or rare adult-onset cases) – CEP is excluded by the absence of marked elevation of erythrocyte total porphyrin.

●Hereditary coproporphyria (HCP) – HCP is excluded by the absence of marked fecal porphyrin elevation.

●Pseudoporphyria – Pseudoporphyria is not a type of porphyria, but it presents with PCT-like skin lesions in the absence of porphyrin elevations that would be consistent with any type of porphyria.

Exclusion of these other porphyrias is important because repeated phlebotomy or low-dose hydroxychloroquine are effective exclusively in PCT and not in these other conditions. (See 'Treatment of blistering cutaneous porphyria' below.)

Diagnostic testing (blistering cutaneous porphyria suspected) — For suspected blistering cutaneous porphyria, measurement of plasma or urine porphyrins is the recommended 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) [39]. 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. In subclinical or mild cases of PCT, the degree of elevation may be small.

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).

If biochemical testing establishes a diagnosis of a blistering cutaneous porphyria, 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 variant. However, genetic testing for the presence or absence of a heterozygous UROD variant is part of a complete evaluation for multiple susceptibility factors that vary among individual PCT patients.

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. Direct acting antiviral agents are the preferred initial treatment of PCT associated with chronic hepatitis C virus (HCV) infection [40]. 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, hydroxychloroquine, or treatment of hepatitis C. 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 separately. (See "Variegate porphyria", section on 'Management' and "Hereditary coproporphyria", section on 'Management' and "Congenital erythropoietic porphyria", section on 'Management' and "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis", section on 'HEP (biallelic UROD variants)'.)

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), which is manifested by acute pain that compels them to seek shelter from light. With more prolonged exposure, more severe pain, swelling and systemic symptoms may occur and 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 pathogenic variants in the FECH gene, which encodes ferrochelatase, 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 and comprises up to approximately 5 percent of all protoporphyria cases.

●Protoporphyria caused by a variant in mitochondrial CLPX and 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 pathogenic variants in FECH.

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 erythrocyte protoporphyrin is elevated, it must be fractionated to determine the relative amounts of metal-free protoporphyrin and zinc protoporphyrin. Metal-free protoporphyrin is not complexed with iron (as in heme) or zinc. This important fractionation is not offered by all major clinical laboratories.

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 increased to between 300 and 5000 mcg/dL or higher, consisting mostly of metal-free protoporphyrin. Plasma porphyrin levels are usually but not always increased (table 7).

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

●In XLP, both metal-free and zinc protoporphyrin are increased; metal-free protoporphyrin is usually predominant.

●In protoporphyria resulting from a CLPX variant, both metal-free and zinc protoporphyrin are increased.

Elevation of metal-free protoporphyrin is a distinctive feature of protoporphyrias (table 8), whereas elevated erythrocyte total and zinc protoporphyrin is a nonspecific finding seen in many other red blood cell disorders (iron deficiency, lead poisoning, anemia of chronic disease/anemia of inflammation, and hemolysis). (See 'Genes, enzymes, and intermediates' above.)

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

It is important to select an appropriate laboratory for testing [41]. Some referral laboratories in the United States (Quest and LabCorp) measure only zinc protoporphyrin but misleadingly report that they have measured both total and "free protoporphyrin" ("free protoporphyrin" is in fact an obsolete term that originally meant iron-free rather than metal-free). Another laboratory (ARUP) measures total protoporphyrin but does not fractionate into metal-free and zinc protoporphyrin [41]. (See "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Selecting a testing laboratory'.)

Treatment of protoporphyria — Treatment of EPP, XLP, and protoporphyria due to CLPX deficiency emphasizes sun avoidance to prevent acute photosensitivity reactions. This necessitates changes in daily activities and impairs quality of life for patients of all ages. (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 increases skin pigmentation by increasing melanin production and in turn can increase sunlight tolerance substantially in patients with protoporphyria. Other medications are under development. (See "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Afamelanotide'.)

Some patients 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 5^th to 6^th 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 10^th to 12^th 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 and X-linked protoporphyria (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Background – The porphyrias are metabolic disorders caused by altered activities of the eight enzymes (table 1) involved in heme biosynthesis (figure 1). A different type of porphyria is associated with altered activity of each of these enzymes. Porphyrias are associated with accumulation of one or more heme synthesis pathway intermediates (table 3 and table 8). All porphyrias are caused by inherited variants/mutations in heme synthesis genes, except for porphyria cutanea tarda (PCT), in which an acquired inhibitor of UROD is found only in the liver; heterozygosity for a UROD variant contributes in only one-fifth of cases. (See 'Disease mechanisms' above.)

●Classification and typical findings – Porphyrias are classified mechanistically as hepatic or erythropoietic depending on where heme pathway intermediates first accumulate (liver or bone marrow). Clinically, they are categorized based on distinctive features. (algorithm 1). (See 'Classification and clinical categories' above.)

•Acute hepatic porphyrias (AHP) – Abdominal pain or other neurologic symptoms (central, peripheral, sensory, motor, or autonomic) or psychiatric findings. (See 'When to suspect AHP' above.)

-Acute intermittent porphyria (AIP) is most common.

-Others are hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA dehydratase porphyria (ADP; very rare).

•Chronic blistering – Blistering skin lesions on light-exposed areas (dorsal hands, face, neck, feet), often with scarring, hypo- and hyperpigmentation, and underlying skin fragility. Blistering skin lesions resembling PCT are common in VP and less common in HCP. Photomutilation can occur in CEP. (See 'Presenting findings (blistering cutaneous porphyria)' above.)

-PCT is most common

-Others are VP, HCP, CEP, and HEP

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

-EPP is most common.

-Others are XLP and CLPX (extremely rare).

●Evaluation and treatment – Diagnosis is often delayed because porphyria is not considered. Testing differs for each of the three categories. (See 'Importance of timely diagnosis' above.)

•AHP – Prompt diagnosis and treatment of acute attacks are especially important, as these may be prolonged and life threatening. (See 'Initial testing for suspected AHP (urinary PBG and total porphyrins)' above.)

Initial testing is with spot urine PBG and total porphyrins (normalized to creatinine), obtained as quickly as possible during an acute attack. Additional second-line testing is pursued if PBG or porphyrins are increased (algorithm 2). For individuals with known AHP, attacks are diagnosed clinically.

Treatment with hemin should be initiated promptly without waiting for second-line test results to establish the type of AHP. (See 'Initial treatment of acute attacks' above and "Acute intermittent porphyria: Management", section on 'Acute attack: Primary treatment (hemin)'.)  

Givosiran is effective for prevention of frequently recurring attacks. (See "Acute intermittent porphyria: Management", section on 'Givosiran'.)

•Chronic blistering – Initial testing is with total plasma or urine porphyrins. If elevated, more extensive second-line testing is needed to confirm the diagnosis (algorithm 3). (See 'Diagnostic testing (blistering cutaneous porphyria suspected)' above.)

The type of blistering cutaneous porphyria must be identified before treatment. Treatment of PCT is highly effective but specific and is ineffective in all other porphyrias. (See 'Treatment of blistering cutaneous porphyria' above.)

•Acute nonblistering – The first-line test is measurement of erythrocyte total protoporphyrin. If elevated, this is fractionated to determine the relative amounts of metal-free and zinc protoporphyrin (algorithm 5).

A predominance of metal-free protoporphyrin is distinctive for the protoporphyrias, whereas zinc protoporphyrin is increased in many other erythrocyte disorders. Attention to the choice of testing laboratory is essential. (See 'Diagnostic testing (protoporphyria suspected)' above.)

Treatment is focuses on avoiding sunlight, which prevents blistering but impairs quality of life. Afamelanotide, which increases skin melanin, can significantly increase sunlight tolerance. (See 'Treatment of protoporphyria' above.)

●Details on individual porphyrias – These are discussed in topic reviews listed above. (See 'Classification and clinical categories' above.)

ACKNOWLEDGMENTS — UpToDate gratefully acknowledges Stanley L Schrier, MD, who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

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