Variegate porphyria

INTRODUCTION — Variegate porphyria (VP) is an inherited porphyria characterized by cutaneous blistering and/or acute neurovisceral attacks. VP has also been called porphyria variegata, South African genetic porphyria, mixed porphyria (an obsolete term also applied to hereditary coproporphyria [HCP]), protocoproporphyria, and porphyria cutanea tarda hereditaria (which likely included some cases of familial porphyria cutanea tarda [PCT]). The spectrum of disease manifestations is broad, ranging from life-threatening neurovisceral attacks and/or chronic photosensitivity and blistering skin lesions to patients who remain asymptomatic throughout their lives.

It is especially important to make an accurate diagnosis of VP in symptomatic individuals with neurovisceral or cutaneous manifestations to provide appropriate treatment.

●The acute neurovisceral attacks can be life threatening and are treated in the same manner as other acute hepatic porphyrias (AHP), which are acute intermittent porphyria (AIP), HCP, and the ultra-rare delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria.

●The skin manifestations are identical to PCT, congenital erythropoietic porphyria (CEP; especially mild cases), hepatoerythropoietic porphyria (HEP), and HCP. Although these porphyrias are readily differentiated by well-chosen biochemical studies, most VP patients who present with skin manifestations are initially misdiagnosed as having PCT.

The pathogenesis, clinical features, diagnosis, and treatment of VP will be discussed here.

Other porphyrias, as well as a general overview, are presented separately:

●Overview – (See "Porphyrias: An overview".)

●HCP (cutaneous and neurovisceral manifestations) – (See "Hereditary coproporphyria".)

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

●ADP (neurovisceral) – (See "ALA dehydratase porphyria".)

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

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

●CEP (cutaneous) – (See "Congenital erythropoietic porphyria".)

PATHOGENESIS

PPOX gene variants — VP is an autosomal dominant condition caused by heterozygosity for a pathogenic variant in the gene protoporphyrinogen oxidase (PPOX; OMIM 600923) [1]. PPOX encodes the seventh enzyme in the heme biosynthetic pathway (figure 1). Over 200 different pathogenic variants in PPOX have been identified following what was probably the initial description of the disease in 1937 [2-6]. Genotype-phenotype relationships have been reported in some smaller studies, but these correlations are less evident in larger studies [3,7].

In South Africa, about 95 percent of VP cases are due to the R59W missense mutation in PPOX [8]. This founder mutation was carried from Holland by one of two immigrants to South Africa who were married in the late 1600s. Initial speculations that King George III of England and others in the royal houses of Europe had VP ("the Royal malady") were subsequently discounted [9]. (See 'Epidemiology' below.)

PPOX oxidizes protoporphyrinogen IX to protoporphyrin IX (figure 1). PPOX pathogenic variants found in VP families abolish or nearly abolish enzymatic activity. Therefore, heterozygotes have approximately 50 percent of normal PPOX activity in all cells, largely reflecting the enzymatic activity produced by the wildtype PPOX gene [10,11]. This reduced enzymatic activity, along with induction of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), cause accumulation of protoporphyrinogen IX within hepatocytes. The excess protoporphyrinogen IX is mostly auto-oxidized to protoporphyrin IX and is found in plasma before excretion in the bile and feces.

Cutaneous manifestations of VP occur because excess protoporphyrin IX is transported in plasma to the skin, where it becomes photoactivated by light, especially with wavelengths in the range of 380 to 420 nm (the Soret band), which overlaps the intersection of long-wave ultraviolet (UVA) and visible light. This leads to the release of reactive oxygen species that damage skin cells. (See 'Cutaneous symptoms' below.)

Neurovisceral symptoms in VP are believed chiefly to be related to accumulation of the earlier heme pathway intermediates delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), as in other acute hepatic porphyrias [12,13]. Excess ALA is considered the most likely cause of neurotoxic effects in this and other acute porphyrias, although heme deficiency in neuronal or vascular tissue is an additional or alternative potential mechanism [14,15]. (See 'Neurovisceral symptoms' below.)

Elevated ALA and PBG in plasma and urine may result in part from induction of hepatic ALAS1 and also inhibition of hepatic porphobilinogen deaminase (PBGD) by protoporphyrinogen IX and coproporphyrinogen III, which accumulate in the liver in VP [16]. In a chemically-induced porphyria model in rabbits that resembled VP, restoration of PBGD activity by administering PBGD mRNA corrected a number of biochemical abnormalities and suggested that reduced PBGD activity might be more important than reduced PPOX activity in altering heme synthesis in VP [17].

Elevations in coproporphyrin III as well as protoporphyrin IX may occur because PPOX and coproporphyrinogen oxidase (CPOX) are closely associated in the mitochondrial membrane; in VP, this interaction may reduce CPOX activity leading to accumulation of coproporphyrinogen III, which is auto-oxidized to coproporphyrin III [18].

Very rarely, an individual may be homozygous or compound heterozygous for PPOX pathogenic variants, either through consanguinity or by inheritance of two different PPOX variants, one from each unrelated parent. At least one of the variant alleles must express some enzymatic activity, as complete loss of PPOX function is incompatible with life. Homozygotes and compound heterozygotes present early in childhood with impaired development and severe cutaneous photosensitivity. (See 'Clinical features' below.)

Exacerbating factors — As described below, cutaneous manifestations of VP result from high plasma porphyrin levels and exposure of the skin to light with wavelengths in the range of 380 to 420 nm (UVA-visible light intersection). These wavelengths, which are not removed when light passes through window glass, photoactivate porphyrins in skin capillaries or cells, with release of activated oxygen species that damage cells. Sunlight and to a lesser extent artificial lights that include these wavelengths can cause skin damage in VP and other cutaneous porphyrias. (See 'Cutaneous symptoms' below.)

As with other acute hepatic porphyrias, neurovisceral symptoms in VP can be exacerbated by certain drugs and steroid hormones (especially progesterone), as well as alcohol, cigarette smoke, and fasting or metabolic stress. This occurs through induction of hepatic delta-aminolevulinic acid synthase-1 (ALAS1), the rate-limiting enzyme for heme biosynthesis in the liver, and induction of cytochrome P450 enzymes (CYPs), the latter increasing the demand for heme synthesis in the liver. Both ALAS1 and certain hepatic CYP genes respond to inducing chemicals that are ligands for the pregnane X receptor (PXR) and other nuclear receptors, which then bind to sites in the promoter regions and upregulate expression of genes that encode ALAS1 and CYPs [19].

●Drugs – A partial listing of potentially unsafe drugs in VP and other acute hepatic porphyrias (AHPs) is included in the table (table 1). Most of the unsafe agents (barbiturates, phenytoin, most other antiepileptics, rifampin) induce hepatic ALAS1 and CYPs [19,20]. Clinicians considering medications in patients with VP should consult frequently updated sources for information regarding medication safety, such as the website of the International Porphyria Network (https://porphyrianet.org/en/content/worldwide-network). Of note, the evidence for these listings is often limited and sometimes controversial or even contradictory, and it is useful to consult an expert center for advice, particularly for patients with frequent attacks.

●Hormones – Increases in sex hormones at puberty and cyclic progesterone production in ovulating women contribute to the onset of symptoms in some heterozygotes. Oral contraceptives may exacerbate symptoms in acute porphyrias because progestins are inducers of ALAS1 and CYPs, and in VP in particular estrogens may impair hepatobiliary excretion of porphyrins and increase plasma porphyrin levels and photosensitivity. Pregnancy is usually well tolerated, but attacks become more frequent in some pregnant women with acute porphyria.

●Alcohol and cigarette smoke – Alcohol and polycyclic aromatic hydrocarbons in cigarette smoke can induce ALAS1 and CYPs, resulting in the development of acute attacks.

●Fasting/metabolic stress – Reduced food intake, for example during crash dieting or after bariatric surgery, can lead to attacks; in this setting, ALAS1 is induced in the liver by peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1-alpha, a member of a family of transcription coactivators that plays a central role in the regulation of cellular energy metabolism. PGC-1-alpha is increased by starvation and glucagon and decreased by glucose and insulin. Metabolic stress due to concurrent medical conditions or surgery may also precipitate acute neurovisceral attacks [21-24].

●Unknown genes – As yet-uncharacterized genes are likely to have major influences on disease expression and are under active investigation [25].

EPIDEMIOLOGY — VP occurs worldwide. The prevalence is not accurately known because many individuals with pathogenic variants in PPOX remain asymptomatic.

The prevalence of symptomatic VP has been estimated at 0.3 per 100,000 in Europe (approximately 1 in 300,000). Some countries such as Finland may have a higher prevalence of VP (1.3 in 100,000; equivalent to approximately 1 in 77,000) [26]. By comparison, acute intermittent porphyria (AIP) and porphyria cutanea tarda (PCT) are more common, with estimated prevalences of 1 in 5000 to 1 in 25,000, depending on the population.

The prevalence of VP is high in South Africans of Dutch descent; an incidence as high as 1 in 300 has been reported [8,27,28]. This occurred because a Dutch ancestor carried the PPOX founder mutation R59W and the population expanded greatly while remaining quite isolated for many decades [29-32]. As many as 30,000 individuals in South Africa carry this variant [8]. (See 'PPOX gene variants' above.)

CLINICAL FEATURES

Typical age and severity of presentation — Clinical features of VP are variable and may include chronic blistering cutaneous lesions on light-exposed skin and acute neurovisceral attacks of abdominal pain and neuropathic extremity pain and weakness. Skin manifestations are generally chronic and more common than neurovisceral symptoms, which are typically acute and intermittent but may be chronic [2,18,27,33]. Overall, acute attacks are less severe and frequent than in acute intermittent porphyria (AIP), but nonetheless can be severe and life threatening [34].

The typical age of presentation is after puberty, during adolescence or early adulthood. Females are more commonly symptomatic for both skin and neurovisceral symptoms than males [33].

Many individuals with a pathogenic variant in PPOX (eg, as identified by family screening) are entirely asymptomatic throughout life. These individuals are referred to as having latent disease. (See 'Genetic testing and counseling' below.)

Cutaneous symptoms — Cutaneous manifestations are chronic and are one of the most common manifestations of VP; they are seen in 10 to 50 percent of affected individuals. Many patients with VP have only skin findings without neurovisceral symptoms [2,12,18]. Cutaneous symptoms may be more common in countries such as South Africa where there are longer periods of intense sun exposure than in northern European countries such as Finland [2,18,26,27]. Cutaneous manifestations are much more common in VP than HCP [33].

Skin manifestations result from photodamage causing increased skin fragility and typically include painful vesicles and bullae, erosions or ulcers that often crust over and are slow to heal, scarring, areas of increased or decreased pigmentation and milia [2,26,33]. These changes occur on sun-exposed areas of skin such as the dorsal hands and forearms, legs and feet (if exposed), neck, ears, and face (picture 1). Hypertrichosis of the face and forearms may occur (picture 2). These findings are indistinguishable from other cutaneous blistering porphyrias, the most common being porphyria cutanea tarda (PCT). (See 'Differential diagnosis' below.)

Sunlight is the strongest source of light-causing photoactivation of porphyrins; however, any source of light that contains wavelengths capable of activating porphyrins (eg, fluorescent lights) may contribute to phototoxicity. Maximum absorption and photoactivation of porphyrins occurs at about 400 nm (a light absorption peak called the Soret band) [33]. Wavelengths of light in this range can pass through standard window glass and automobile windshields.

Neurovisceral symptoms — Neurovisceral symptoms are a feature of VP but are less common than cutaneous manifestations [2]. When they occur, acute neurovisceral attacks are indistinguishable from those of other acute hepatic porphyrias (AHPs), although on average they may be somewhat milder than in AIP [2,18,26,27,33]. While neurovisceral findings are highly variable, individuals who have recurrent acute attacks often have similar symptoms from one attack to another [33]. Acute attacks requiring hospitalization have become less frequent, especially among females [35].

Neurovisceral findings during acute attacks are nonspecific and may include abdominal pain, vomiting, and constipation; pain may also occur in the back, chest, and extremities. Abdominal pain can be unremitting for hours or more, poorly localized, and associated with cramping [13]. There is often little or no tenderness or other peritoneal signs. However, there may be abdominal distention from intestinal ileus, and bladder paresis with urinary retention. Bowel intussusception has been reported [36].

Additional common autonomic/neuropsychiatric findings during attacks include systemic arterial hypertension, tachycardia, anxiety, disorientation, and agitation. Psychotic features may be present. Some of these findings may reflect autonomic dysfunction and adrenergic stimulation. Motor neuropathy may lead to neuromuscular weakness, and patients are at risk for quadriparesis and respiratory failure.

Seizures may be a direct neurologic manifestation of porphyria or due to hyponatremia often resulting from the syndrome of inappropriate antidiuretic hormone (SIADH) (see "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)"). Hyponatremia may result in part from vomiting and renal sodium loss.

During acute attacks, patients may have brown or reddish urine (the term porphyria is derived from the Greek word for the color purple, "porphyrus" [33]). This coloration is due to porphyrins, which are reddish, and porphobilin, a brown polymerized degradation product of PBG (which is colorless).

Peripheral neuropathy — Peripheral neuropathy, which is primarily motor, occurs especially in more prolonged attacks and can lead to flaccid paralysis of all extremities and respiratory failure. Weakness usually begins proximally, and may not be detected until it has progressed distally and is more readily appreciated on physical examination. Severe extremity pain reflects sensory involvement; symptoms and signs of sensory loss may be present as well [9,13,33,37].

Long-term complications — Individuals with VP are at increased risk for certain other hepatic and renal complications.

●Liver – The risk of hepatocellular carcinoma (HCC) is increased, even in patients without pre-existing liver disease or other risk factors for HCC. The magnitude of the risk increase is unknown, with most evidence coming from case reports [38-41]. As with other acute neurovisceral porphyrias, chronic mild increases in liver function tests, especially transaminases, may be seen in patients with persistent elevations of ALA, PBG, and porphyrins, suggesting ongoing chronic liver disease. It has also been suggested that patients with VP have an increased risk of gallstones [42].

●Kidney – Individuals with VP and other acute porphyrias are also at risk for chronic kidney disease and may require long-term dialysis or kidney transplantation. The risk of hypertension is also increased. Kidney damage in acute porphyrias is poorly understood; it may be caused by chronic hypertension and/or the effects of excess heme pathway intermediates such as ALA.

These potential complications warrant ongoing surveillance, as discussed below. (See 'Screening for long-term complications' below.)

Homozygous VP — Very rarely, an individual may have homozygous or compound heterozygous pathogenic variants in the PPOX gene. (See 'PPOX gene variants' above.)

These individuals may present in childhood with severe cutaneous photosensitivity and severe neurologic manifestations, but they seldom have acute neurovisceral attacks [43,44]. (See 'Cutaneous symptoms' above and 'Peripheral neuropathy' above.)

DIAGNOSIS

Overview of diagnosis — The diagnosis of VP can be made by biochemical and/or genetic testing (table 2 and table 3). The presence of an acute attack is established from a combination of biochemical and clinical findings. The approach depends on the manner in which the patient comes to medical attention. It most often begins with establishing a diagnosis by biochemical testing.

●Acute attack – In a patient not previously known to have VP, the diagnosis is often made during an acute attack (algorithm 1). In the setting of signs and symptoms consistent with an acute porphyria attack (see 'Neurovisceral symptoms' above), demonstration of elevated urinary porphobilinogen (PBG) is sufficient to make a diagnosis of acute porphyria and initiate treatment. PBG may be less elevated and may decrease more rapidly in VP and hereditary coproporphyria (HCP) than in acute intermittent porphyria (AIP), and screening biochemical testing should include total urinary porphyrins, which remain elevated longer than PBG [45]. Additional biochemical testing, including plasma and fecal porphyrins, can distinguish between VP and other acute porphyrias. Genetic testing is not used to diagnose an acute attack because it detects, but cannot distinguish between, both latent and active disease. (See 'New patient, acute attack' below.)

●Cutaneous symptoms – The diagnosis of a blistering cutaneous porphyria such as VP is established by demonstrating elevated plasma and urinary porphyrins in a patient with consistent skin findings (see 'Cutaneous symptoms' above), followed by distinction from other blistering cutaneous porphyrias based on the specific biochemically determined patterns of porphyrins in plasma and feces (algorithm 2). A skin biopsy is not helpful because the findings are the same in all blistering cutaneous porphyrias, including the most common, porphyria cutanea tarda (PCT) [46]. (See 'New patient, skin-only findings' below.)

●Latent disease – Latent VP can be detected by targeted DNA analysis in asymptomatic family members of an affected individual with a known PPOX disease variant. Such individuals are counseled on how to avoid exacerbations of VP, and to inform their doctors that they have a PPOX variant and thereby hasten a diagnosis if future symptoms occur. (See 'Asymptomatic relatives' below.)

Once a biochemical diagnosis is made, we perform genetic testing to identify the specific PPOX variant in the kindred. This provides additional diagnostic confirmation in the index case and facilitates testing of relatives by targeted genetic analysis, beginning with first degree relatives of the index case. (See 'Genetic testing and counseling' below.)

Assays of PPOX activity in cells that have mitochondria, such as circulating lymphocytes or cultured fibroblasts or lymphocytes, are also useful for confirming a diagnosis of VP, but these are not widely available [16,47].

New patient, acute attack — VP or another type of acute porphyria should be considered, even when the index of suspicion is not high, such as in a patient who presents with acute neurovisceral symptoms (abdominal pain, neuropsychiatric or autonomic symptoms) for whom there is not an alternative explanation after an initial workup for more common conditions. The presenting findings are nonspecific and can be quite variable, and the diagnosis of acute porphyria is often made even when it is not strongly suspected. Screening is important because early diagnosis and treatment can avert long-term and life-threatening complications.

Importantly, a negative family history is not helpful in excluding the diagnosis of VP or other acute hepatic porphyria (AHP), because penetrance is low and symptom onset in those who become affected is variable.

For effective management, the diagnosis of AHP must be established as quickly as possible to facilitate rapid and appropriate treatment. A urine sample for first-line testing should be obtained before treatment with hemin, which can lower levels of PBG and porphyrins and thereby obscure the diagnosis. As with other acute porphyrias, the preferred approach for VP is measuring urine PBG and total porphyrins as first-line/screening tests, and more extensive second-line testing, to include plasma and fecal porphyrins, if screening testing is positive (algorithm 1) [45].

Urinary PBG and total porphyrins — Initial first-line laboratory evaluation for acute porphyria in a patient during an acute attack should be measurement of urine PBG and porphyrins on a spot urine sample.

A kit for demonstration of a substantial PBG elevation in a spot urine sample was valuable for rapid (qualitative) testing but is no longer available. A urine sample should be sent to a laboratory and an urgent result requested. Since a randomly collected urine sample may be dilute, it is strongly advised to express the result per gram or mmol of creatinine [45].

A positive spot urine test for a substantially elevated PBG level (eg, at least 10 to 15 mg/g creatinine) confirms a diagnosis of acute porphyria. If symptoms are consistent with an acute attack and other causes of the acute symptoms are excluded or considered unlikely, the finding of a substantially elevated PBG is sufficient to initiate therapy with hemin in an acutely ill patient (see 'Treatment of acute attacks' below). PBG can be measured in serum if acute porphyria is suspected in a patient with advanced kidney disease.

After finding a substantial PBG elevation, therapy should not be delayed or withheld while waiting for additional testing to determine the specific type of acute porphyria. However, spot samples (urine, blood, and feces) for this subsequent testing should be obtained at the time of the acute attack and before therapy is initiated. Collection of a 24-hour urine or a timed fecal collection is not necessary and can delay treatment.

Urinary total porphyrins are also measured because PBG may be less elevated and decrease more rapidly in urine in both VP and HCP than in AIP, and because urinary porphyrins are markedly elevated (along with delta-aminolevulinic acid [ALA]) in ALA dehydratase porphyria (ADP).

Samples collected at the time of the acute attack have the greatest likelihood of detecting AHP. Samples collected later as the attack regresses may approach normal or may not show diagnostic abnormalities, especially in HCP and VP. Samples should be collected before treatment with hemin, which can greatly lower levels of porphyrin precursors and porphyrins.

Additional biochemical testing — For patients with elevated urinary PBG and/or total porphyrins, additional second-line biochemical testing is needed to distinguish VP from AIP and HCP (table 3 and table 2). Elevation of porphyrins alone is a nonspecific finding, and further testing is needed to determine whether or not this is due to porphyria.

In addition to further testing on the original urine sample, spot samples of plasma and feces are collected for testing. If PBG is substantially elevated, these additional samples are collected before treatment with hemin, which should not be delayed while awaiting results of this testing.

Requests for both first- and second-line testing must be specific. ALA is an amino acid and PBG a pyrrole (they are porphyrin precursors, not porphyrins), and ALA and PBG may not be measured if only porphyrins are requested. Ordering a "porphyrin screen" or "porphyrin profile", which are not specific tests, may lead to rejection of the request or to undesired results [45].

The correct order for initial screening for acute porphyria should be measurement of PBG and porphyrins on a spot urine sample. Second-line testing should be requested as follows:

●Urine – Testing the same urine sample used for initial PBG testing is preferable to testing a new spot sample or a 24-hour collection, because PBG, ALA, and porphyrins may decrease as the acute attack is treated and/or resolves [12]. Measuring creatinine in the spot urine sample is strongly recommended to allow results to be expressed per gram or mmol of creatinine [45].

VP is associated with elevated urinary PBG, ALA, and porphyrins (especially coproporphyrin III). Elevations of PBG and ALA are often less marked and more transient in VP than in AIP (see 'Differential diagnosis' below). Elevations in total urinary porphyrins persist longer in VP than do elevations in ALA and PBG, with the caveat that urinary porphyrin elevations are much less specific than elevations in PBG [12,45,48]. Fractionation of urinary porphyrins usually is not informative. If done, it will usually show a predominance of coproporphyrin III, but some patients may have substantial proportions of uroporphyrin and heptacarboxyl porphyrin, which can suggest porphyria cutanea tarda (PCT) [49].

●Plasma – Plasma is obtained primarily for measurement of porphyrins. If kidney function is normal, ALA and PBG are lower in plasma than in urine, so urine measurements are more sensitive. However, in active cases of VP, plasma porphyrins are increased with a distinctive fluorescence peak at approximately 626 nm with dilution at neutral pH, which distinguishes VP from all other porphyrias (table 3) [50]. This distinctive finding in VP occurs due to protoporphyrin IX that is covalently bound to plasma proteins.

●Stool – Stool is sent for porphyrins. In active VP, fecal porphyrins are increased markedly, with a predominance of both coproporphyrin III and protoporphyrin IX (table 3 and table 2). As in HCP, the coproporphyrin III/I isomer ratio is elevated.

●Red blood cells – Testing enzymatic activity in red blood cells (erythrocytes) is not relevant for the diagnosis of VP, because PPOX, the deficient enzyme in VP, is a mitochondrial enzyme and erythrocytes lack mitochondria. If performed, erythrocyte PBG deaminase activity is normal in VP and typically decreased in AIP (see 'Differential diagnosis' below). Erythrocyte zinc protoporphyrin may be elevated, but not substantially, in VP, HCP, and AIP.

While not required to initiate therapy for the acute attack, it is important to distinguish VP from other porphyrias for the purpose of subsequent treatment and potentially for genetic testing and evaluation of first degree relatives [12,48].

New patient, skin-only findings — Many patients with VP will only have cutaneous findings. Such patients are often misdiagnosed as having PCT, a much more common porphyria, because adequate biochemical testing is not completed. Some patients may have past or even current symptoms that suggest neurovisceral involvement as well.

The diagnosis of VP in patients with current skin findings is made by analyzing porphyrins in plasma (or serum) or in a spot urine sample (algorithm 2).

In VP, this testing will show an increase in plasma porphyrins with the distinctive fluorescence peak at approximately 626 to 628 nm at neutral pH; increases in urinary porphyrins (predominantly coproporphyrin III in most cases); and increases in fecal porphyrins (predominantly coproporphyrin III and protoporphyrin IX) (table 3). However, the urine porphyrin pattern is not specific and can resemble that seen in PCT [49]. Porphyrin elevations in VP are substantial and persistent together with the chronic blistering skin manifestations.

Urinary ALA and PBG may also be elevated but levels of these porphyrin precursors may be normal, especially in the absence of neurovisceral symptoms.

●If plasma or urinary porphyrins are not elevated, VP (and other blistering cutaneous porphyrias) are excluded as the cause of the skin lesions.

●If plasma, urinary, and fecal porphyrins are elevated in a patient with blistering skin lesions, it is important to distinguish VP from other blistering cutaneous porphyrias, because their treatments differ, and neurovisceral manifestations will be seen only in those with VP or HCP. In particular, VP must be differentiated from PCT, which is much more common, based on biochemical findings, because there is a risk of developing neuropathic manifestations in VP but not PCT, and PCT is effectively treated by phlebotomy or low-dose hydroxychloroquine, whereas VP and other porphyrias do not respond to such treatment.

●Biochemical differences are presented in the table (table 3). Fluorescence scanning of diluted plasma at neutral pH is especially useful as a specific marker for VP and for excluding PCT and other blistering cutaneous porphyrias [50].

Skin biopsy is not required for diagnosis of VP, because histological findings are the same as in PCT and other blistering cutaneous porphyrias [46] but may be performed as part of the evaluation for blistering cutaneous disease. If performed, biopsy of a blistering lesion may show PAS (periodic acid-Schiff)-positive thickening of vascular walls in the dermis, and immunostaining may demonstrate IgG deposition and reduplication of the basal lamina [10].

New patient, history of acute attack(s) — If VP and other acute porphyrias are suspected based on a history of past neurovisceral symptoms, testing should include urine ALA, PBG, and porphyrins, and plasma and fecal porphyrins. The most sensitive biochemical tests for VP during asymptomatic phases are plasma porphyrins (including a fluorescence scan) and fecal porphyrins. If results are normal, the testing can be repeated in the future if symptoms recur. Genetic testing is an option but is generally not recommended in this setting and would require sequencing of HMBS/PBGD and CPOX in addition to PPOX.

Asymptomatic relatives — Diagnosis or exclusion of latent VP in asymptomatic relatives of a patient with VP and a known pathogenic variant in PPOX is occurring more frequently as genetic testing becomes more widely used for diagnosis. Individuals with latent VP can benefit from taking precautions to avoid attacks and from prompt diagnosis of overt VP should symptoms occur.

Such testing should begin with first degree relatives of an index case, followed by testing of offspring of those identified to have inherited the familial PPOX pathogenic variant. Individuals to be screened should be informed that positive test results may cause anxiety and worry, and if results are disclosed might affect employment and insurance eligibility, where legislative or other protections against such discrimination are not in force. (See 'Genetic testing and counseling' below and "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)

Some individuals may prefer not to pursue genetic testing; these individuals should be advised that if symptoms develop they should inform their physicians of their family history of VP.

Relatives who have inherited a PPOX pathogenic variant but do not have overt symptoms may be referred to as having latent disease. These individuals may develop clinical manifestations of VP later in life, possibly after exposure to an exacerbating factor, although their risk is lower than that of individuals who have already had symptoms.

Confirming an acute attack in a patient with known VP — In a patient with an established diagnosis of VP, the diagnosis of an acute attack is based on clinical evaluation.

The presentation of an acute attack is often similar to previous attacks. However, the possibility of another cause of abdominal pain or other symptoms should always be considered.

Demonstration of an increase in urinary PBG over baseline is desirable. However, quantitative PBG results are seldom rapidly available, and multiple test results during asymptomatic periods are required to establish a meaningful baseline. (See 'Clinical features' above and 'Differential diagnosis' below.)

Importantly, therapy for a recurrent acute attack should not be delayed while awaiting the results of biochemical testing. (See 'Treatment of acute attacks' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of VP includes other cutaneous and acute neurovisceral porphyrias, other causes of blistering skin lesions, other causes of neurovisceral symptoms such as abdominal pain, and other causes of elevated porphyrin levels.

●Blistering cutaneous porphyrias – Other blistering cutaneous porphyrias include porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP, the homozygous form of familial PCT), hereditary coproporphyria (HCP), and congenital erythropoietic porphyria (CEP). PCT is by far the most common of these. Like VP, these conditions can present with blistering skin lesions on sun-exposed skin. Like VP, HCP can also have neurovisceral symptoms. Each of these cutaneous porphyrias has a different pattern of urine and plasma ALA, PBG, and porphyrins that enables a specific diagnosis to be established (table 3 and table 2). PCT responds readily to treatment with phlebotomy or low-dose hydroxychloroquine, whereas all other blistering cutaneous porphyrias, including VP, do not. Therefore, specific biochemical differentiation of PCT from VP and these other forms of porphyria is important before starting these treatments. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis" and "Hereditary coproporphyria" and "Congenital erythropoietic porphyria".)

●Other blistering skin diseases – A variety of skin disorders can present with blistering skin lesions and scarring. Pseudoporphyria causes the same type of blistering on sun exposed areas as PCT and VP, but in the absence of significant porphyrin elevations. Pseudoporphyria can sometimes be attributed to drugs such as a nonsteroidal anti-inflammatory drug (NSAID) or an antibiotic, especially a tetracycline [46]. Other blistering cutaneous diseases typically are not confined to sun-exposed areas of skin and show histopathological features that are different from blistering cutaneous porphyrias. (See "Diagnosis of epidermolysis bullosa" and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment" and "Epidermolysis bullosa acquisita" and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

●Neurovisceral porphyrias – Other neurovisceral porphyrias include acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and ALA dehydratase porphyria (ADP); AIP is the most common of these and ADP is extremely rare. Like VP, AIP and HCP can present with acute neurovisceral attacks that include pain, vomiting, psychiatric symptoms and autonomic nervous system findings, and elevated urinary PBG, especially during an acute attack. Like VP, HCP can also have blistering cutaneous symptoms. These other neurovisceral porphyrias have different biochemical patterns of urine and plasma ALA, PBG, and porphyrins that distinguish them from VP (table 3 and table 2). ADP is differentiated by finding elevations in urinary ALA and coproporphyrin but not PBG and elevated erythrocyte zinc protoporphyrin. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis" and "Hereditary coproporphyria" and "ALA dehydratase porphyria".)

●Abdominal pain – Other causes of abdominal pain are numerous and include inflammatory conditions, infection, ischemia, obstruction, and others. Like VP and other acute porphyrias, these may present with nonspecific abdominal symptoms. Unlike acute porphyrias, these other causes of abdominal pain do not cause elevations of urinary PBG. However, other causes of abdominal pain may be associated with elevations in urinary porphyrins (eg, hepatobiliary disease) or ALA and porphyrins (eg, lead poisoning).

Importantly, an individual with porphyria may present with another cause of abdominal pain (eg, appendicitis, diverticulitis, inflammatory or ischemic bowel disease, renal stones), and these conditions can also precipitate an acute porphyria attack. Therefore, an elevated PBG is diagnostic for VP, HCP, or AIP, but does not exclude other causes of abdominal pain, and the presence of another cause of abdominal pain does not exclude VP (or other acute porphyrias). (See "Evaluation of the adult with abdominal pain" and "Causes of abdominal pain in adults".)

●Neuropathy – There are numerous other causes of motor and sensory neuropathy. Like VP and other acute porphyrias, these causes of neuropathy may have variable presentations. Unlike VP, HCP, and AIP, these causes of neuropathy do not cause elevation of urinary PBG. However, lead poisoning, tyrosinemia type 1, and ADP cause neuropathy and elevations of urinary ALA and coproporphyrin and increased erythrocyte zinc protoporphyrin. (See "Overview of polyneuropathy" and "Overview of hereditary neuropathies" and "Overview of acquired peripheral neuropathies in children" and "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Lead exposure, toxicity, and poisoning in adults".)

●Elevated porphyrin levels – Other non-porphyria conditions that can cause increased urine porphyrin levels include liver disease and a variety of other medical conditions and drugs. The frequency and degree of porphyrinuria in these various medical conditions have been little studied. However, elevation of urinary coproporphyrin can be substantial in liver disease of any kind. Like VP, patients with non-porphyria conditions may have nonspecific complaints that can suggest porphyria. Unlike VP, patients with these other conditions and elevated urine porphyrin levels do not have elevations in PBG and seldom have elevated porphyrins in plasma and feces. Rarely, hepatocellular tumors have been associated with marked porphyrin elevations, but these cases were not described in enough detail to know if a deficiency in a heme biosynthetic pathway enzyme in the tumor itself was causative. (See "Approach to the patient with abnormal liver biochemical and function tests".)

MANAGEMENT

Treatment of acute attacks — Acute attacks in VP are potentially life-threatening if not recognized promptly and managed appropriately. (See 'New patient, acute attack' above.)

Acute attacks of VP usually require hospitalization and are treated with hemin or glucose loading, similar to acute attacks in acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), or ALA dehydratase porphyria (ADP). Hemin is the preferred treatment for acute attacks but is expensive and sometimes not immediately available [13]. Treatment of pain, other symptoms, dehydration, and hyponatremia is also important.

●Severe attacks – Severe attacks are best managed in hospital and even in an intensive care setting to provide monitoring and treatment for imbalances in fluids and electrolytes and to monitor respiratory function by spirometry [12]. We recommend intravenous administration of hemin for all patients with an acute attack of VP (or other acute porphyria) that is severe enough to require hospitalization, opioid analgesia, or other intravenous medication; or accompanied by nausea and vomiting, motor neuropathy, paresis, seizures, agitation, delirium, psychosis, ileus that prevents oral intake, or hyponatremia [12,51-53].

Hemin should be administered without delay once a diagnosis of an acute attack of porphyria is established (ie, we do not perform an initial trial of glucose loading prior to starting hemin). However, glucose loading should be used until hemin becomes available, if it is not immediately available on site. Although hemin is costly, prompt administration can lead to rapid resolution of an attack, usually within four to five days (four to five doses) [34]. Hemin can be continued for more than four to five days for more prolonged attacks. Hemin dosing, adverse events, and information about different products are discussed separately. (See "Acute intermittent porphyria: Management", section on 'Indications and mechanism of action'.)

Seizures may be due to hyponatremia or porphyria itself, and are difficult to treat because most anticonvulsants can exacerbate acute porphyrias. Seizures may be treated with anticonvulsant medications if rapid spontaneous resolution does not occur. (See "Acute intermittent porphyria: Management", section on 'Seizures'.)

●Milder attacks – Mild attacks can be treated with hemin or glucose loading; but we suggest hemin even for mild attacks. This is based on our observations that even for mild attacks, recovery is likely to be more rapid with hemin than with glucose, although comparative data in this setting are lacking. Glucose loading should only be used for attacks that are mild (ie, not accompanied by nausea and vomiting, paresis, agitation, hallucinations, seizures and other central neurological manifestations, or hyponatremia and do not require administration of opioid analgesics). Mild attacks can be treated with intravenous or even oral glucose loading. However, if the attack worsens, treatment should be changed to hemin. Dosing for glucose loading is discussed separately. (See "Acute intermittent porphyria: Management", section on 'Carbohydrate loading as a temporizing measure'.)

●All patients – For all patients, it is important to remove or reduce precipitating factors and provide appropriate supportive care:

•Eliminate harmful drugs – Potentially harmful drugs, such as barbiturates, sulfonamide antibiotics, metoclopramide, griseofulvin, rifampin, anticonvulsants (phenytoin, carbamazepine), alcohol, ergot alkaloids, and progestins should be discontinued if at all possible [54]. The table lists many of the drugs that are known to be unsafe or safe in the acute porphyrias (table 1). It is strongly recommended that clinicians consult the website of the International Porphyria Network (IPNET; https://porphyrianet.org/en/content/worldwide-network), which is frequently updated, lists many other drugs including those that are not classified with certainty, and provides evidence for these classifications. It is also important to be aware that the evidence for this and other listings often is not strong and may be controversial.

•Correct metabolic stress – Inadequate intake of calories and carbohydrates, metabolic stress due to another illness, or luteal phase increases in endogenous progesterone should be recognized and addressed [12,13]. (See "Acute intermittent porphyria: Management", section on 'Avoidance of exacerbating factors'.)

•Treat pain and nausea – Opioid analgesics such as morphine are almost always required, especially for severe attacks [34]. Meperidine (pethidine) should be avoided, since it may lower the seizure threshold [51]. A phenothiazine such as prochlorperazine or promethazine is useful for treating nausea and vomiting as well as agitation and restlessness. Ondansetron and related drugs are effective for nausea, whereas metoclopramide is reported by some to be contraindicated [55].

•Treat autonomic symptoms – Tachycardia and hypertension can be treated with propranolol or other non-selective beta blockers, if symptomatic or severe. Certain other antihypertensive medications such as lisinopril and diltiazem are also safe. A laxative can be given for constipation, or loperamide for diarrhea [51].

There are no adequately powered randomized trials comparing hemin with glucose loading or placebo for acute attacks in individuals with VP or other acute porphyrias. Available evidence includes case studies and case series in acute porphyrias, which show a clear benefit of hemin therapy in reducing the severity and duration of acute attacks; this is confirmed by continued experience at many centers. As an example, in a series of 112 patients with an acute porphyria attack that included 10 individuals with VP, hemin resulted in dramatic improvement in symptoms and reduction in the opioid requirement, typically within 24 to 48 hours [34]. Evidence for the efficacy of hemin treatment in other porphyrias such as AIP is presented separately. (See "Acute intermittent porphyria: Management", section on 'Overview of approach'.)

Termination of pregnancy is rarely, if ever, indicated for an acute attack of porphyria.

Some patients may develop chronic pain, depression, or other psychiatric problems, and there is risk for suicide, especially after repeated attacks and with chronic pain. These issues must be recognized and managed appropriately [12]. (See 'Screening for long-term complications' below.)

Prevention of acute attacks — Recurrent attacks are less common in individuals with VP than with AIP. However, recurrent attacks may be potentially serious and life threatening [34]. Frequently recurring attacks in any of the acute hepatic porphyrias (AHPs) are often accompanied by chronic pain between attacks, and this combination can greatly impair quality of life. The risk of recurrence can be reduced by identifying and avoiding exacerbating factors such as drugs, dietary habits, and other factors that have contributed to past acute attacks [56]:

●Potentially harmful drugs should be avoided whenever possible (table 1). Information on safe and harmful drugs is available at the website of the International Porphyria Network.

●Anesthesia for major surgery should avoid barbiturates and include safe agents such as propofol [57].

●Frequent attacks in women during the luteal phase of the menstrual cycle can be prevented with a gonadotropin releasing hormone (GNRH) analogue, which is started during the first few days of a cycle [58,59]. This approach should be evaluated after consulting with a porphyria expert center.

●Frequent, unexplained, non-cyclic attacks can sometimes be prevented by prophylactic weekly infusions of a single dose of hemin [60]. An experienced porphyria center should be contacted for advice if this is contemplated.

●Givosiran, a small interfering RNA (siRNA) therapeutic that is conjugated with N-acetylgalactosamine for hepatocyte targeting, was approved by the US Food and Drug Association (FDA) in 2019 and by the European Medicines Agency (EMA) in 2020 for prevention of frequently recurring attacks of AHP, including VP. Its mechanism of action involves downregulation of hepatic ALAS1, which can reduce ALA and PBG levels and decrease the frequency of acute attacks.

For adults with ≥4 acute attacks per year, we suggest monthly subcutaneous administration of givosiran. Details and evidence for efficacy are presented separately. (See "Acute intermittent porphyria: Management", section on 'Givosiran'.)

Experience in patients with VP that has become refractory to treatment with hemin for neurovisceral symptoms is limited. Whether VP will become refractory to givosiran in some patients is not known. Patients with VP may benefit from liver transplantation if their disease becomes refractory to available medical therapies, as in some patients with AIP [51]. One patient in whom the diagnosis of VP was suggested but not firmly established underwent successful liver transplantation for cirrhosis [61]. (See "Acute intermittent porphyria: Management", section on 'Liver transplantation'.)

Prevention and treatment of skin lesions — Patients with symptomatic skin lesions of VP should wear protective clothing, including gloves and broad-brimmed hats, to avoid exposure to sunlight. Long-term protection should be emphasized because skin damage is not evident immediately after sunlight exposure. Opaque mineral sunscreens containing zinc oxide or titanium oxide that block all wavelengths of light, may be somewhat effective [2,62]. Sunscreens that absorb UVB are not effective, and those that absorb UVA up to approximately 400 nm may be marginally so. (See "Selection of sunscreen and sun-protective measures".)

Patients may become vitamin D deficient due to lack of sun exposure, and this should be routinely supplemented for those who must avoid sunlight to prevent skin lesions. (See "Vitamin D insufficiency and deficiency in children and adolescents" and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

For individuals with VP who develop skin lesions in the setting of hormonal contraceptive use, an alternative method of contraception should be used if possible so that the hormonal contraceptive can be discontinued.

Effective treatment of blistering skin lesions is not available. Lesions should be kept clean and preferably dry. Limited areas of bacterial superinfection are usually treated with topical antibiotics, and more extensive infection may require systemic antibiotics. (See "Impetigo".)

The lesions will heal gradually, especially if greater efforts are made to avoid sunlight and new lesions thereby avoided. Pain may require analgesic treatment, including acetaminophen, aspirin, or short-term opioid analgesics. Topical steroids should be avoided.

Unlike acute neurovisceral attacks, the skin lesions in VP are generally chronic, are due to chronic elevation in plasma porphyrin levels, and do not respond to short-term treatments such as hemin or glucose loading. Possibly, measures implemented to avoid acute neurovisceral attacks, such as avoiding harmful drugs, might sufficiently reduce plasma porphyrin levels and occurrence of skin lesions over time, but this has not been documented.

Other therapies that are not effective include:

●Phlebotomy and low-dose hydroxychloroquine, which are only used to treat PCT.

●Oral activated charcoal, which has been used to treat congenital erythropoietic porphyria (CEP) but has been reported to cause paradoxical worsening of the skin manifestations of VP.

●Beta-carotene, which can somewhat reduce the acute photosensitivity of erythropoietic protoporphyria (EPP), but is of little benefit in chronic, blistering cutaneous porphyrias, including VP [63-66].

●Afamelanotide, which increases skin melanin and helps prevent the acute nonblistering photosensitivity that occurs in erythropoietic protoporphyria (EPP).

Pregnancy — Pregnancy is usually well tolerated, but in some patients is associated with more frequent attacks. Attacks during pregnancy should be treated with hemin, unless they are mild. Pregnancies in women with acute porphyrias are considered high risk, which facilitates monitoring of nutritional intake and status and prompt treatment of attacks should they occur. However, as noted above, it is virtually never necessary to terminate a pregnancy due to an acute attack. (See 'Treatment of acute attacks' above.)

Screening for long-term complications — Potential long-term complications of VP include renal disease, liver function test abnormalities, and hepatocellular cancer:

●Abnormal kidney function – Kidney function can become impaired in individuals with VP and other acute porphyrias. The cause is not known, but hypertension may contribute to its development. We monitor blood pressure and screen for hypertension according to standard practices. If present, hypertension should be controlled, nephrotoxic drugs avoided, and kidney function monitored (serum creatinine and BUN, and urinalysis). Renal function should be monitored in all patients with VP who have continuing attacks or persistent elevations in urine ALA, PBG, or porphyrins. Long-term management of advanced kidney failure may include chronic dialysis and renal transplantation.

●Liver function test elevations – Liver function tests should be monitored yearly in patients with repeated attacks of VP or continued elevations in urine porphyrin precursors or porphyrins. Persistent elevations of transaminases suggest that VP and other acute porphyrias can cause chronic liver damage in some individuals, although this remains to be conclusively studied. Investigation for other causes of liver damage is important, and this evaluation may include liver biopsy.

●Hepatocellular cancer – Hepatocellular cancer (HCC) can occur even in the absence of liver function test abnormalities or cirrhosis, as is the case with other acute porphyrias [38,40,41,67-70]. However, careful longitudinal observations of individuals who eventually develop HCC are lacking. The incidence of HCC in patients with VP is unknown but is likely similar to that for AIP. (See "Acute intermittent porphyria: Management", section on 'Monitoring for disease complications'.)

We perform surveillance for HCC in patients with VP, preferably every six months, especially in those who are over 50 years of age or have persistent elevations of ALA, PBG, or porphyrins, based on evidence that this strategy improves survival in individuals with AIP [12,71,72].

Serum alpha-fetoprotein may also be monitored but has been found not to increase in most patients with acute porphyrias who develop HCC. The emphasis is on detection of early presymptomatic HCC for which a number of treatment options may be available.

Treatment of advanced HCC in individuals with acute porphyrias is difficult and may include liver transplantation.

Information about imaging (eg, ultrasound, computed tomography [CT], or magnetic resonance imaging [MRI]) and additional investigation if imaging results are abnormal is presented separately. (See "Surveillance for hepatocellular carcinoma in adults".)

Genetic testing and counseling — We perform gene sequencing for pathogenic variants in PPOX in all patients with a biochemical diagnosis of VP, although this is not required for diagnosis or routine management. In contrast, genetic testing is not appropriate for initial diagnosis of VP in either acutely ill patients or those with chronic skin lesions. Each VP kindred is likely to have a different disease variant, with the exception of South Africans of Dutch descent, almost all of whom have the highly prevalent R59W missense mutation [8]. (See 'Epidemiology' above.)

Results of PPOX gene sequencing provide additional diagnostic confirmation, may identify previously unrecognized variants, and facilitate genetic counseling and/or testing of relatives. Genetic testing is more sensitive for detecting asymptomatic relatives with latent disease compared to biochemical methods [48,73,74]. Testing of relatives by targeted genetic analysis is possible and less expensive than gene sequencing, once the familial variant has been identified. A listing of available resources for genetic testing is provided on the Genetic Testing Registry website.

A genetic counselor or other expert can explain the inheritance of VP to the family (autosomal dominant with incomplete penetrance). The likelihood of an individual with VP passing the disease variant to their children is approximately 50 percent. During counseling, appropriate testing of first-degree relatives can be facilitated; this is done only after identification of a pathogenic variant in the PPOX gene in an index case. Finding the familial PPOX variant identifies a relative who is at risk to develop clinical manifestations of VP. Genetic testing of relatives can occur at any age, although the risk of symptoms is very low until after puberty. Amniocentesis to obtain fetal cells for DNA studies is not advised because the prognosis of offspring who inherit a PPOX variant is generally favorable.

Heterozygotes for a pathogenic variant PPOX gene who are asymptomatic are advised to avoid factors that can exacerbate acute porphyrias (see 'Exacerbating factors' above), although they are at lower risk than those who have previously had symptoms. These individuals should be counseled regarding avoidance of medications and other exposures to reduce the risk of developing symptoms, including avoidance of heavy alcohol use and smoking. We advise repeating urinary ALA, PBG, and porphyrins, and plasma porphyrins, at approximately yearly intervals, since increases may suggest a greater likelihood of future symptoms. However, confirmatory longitudinal observations are lacking. Testing at least yearly is also useful to characterize baseline levels of these metabolites during asymptomatic periods. (See 'Prevention of acute attacks' above.)

PROGNOSIS — The long-term outcome in most patients with VP who have had symptoms is favorable. Patients usually recover from acute attacks, and even advanced neuropathy may improve over months or years [2]. However, some patients have recurrent attacks in the absence of known exacerbating factors, and pain and other symptoms sometimes become chronic and difficult to manage. Depression and other chronic psychiatric manifestations may occur, but are usually not attributable to VP, except in patients with frequent recurring attacks and chronic pain [56,63]. Monitoring of such patients for depression is recommended.

The proportion of patients who develop acute attacks has decreased, and more individuals who are heterozygous for a pathogenic variant in the PPOX gene who remain asymptomatic has increased, likely due to increased use of biochemical and genetic testing, reduced use of harmful drugs such as barbiturates and sulfonamides, and greater knowledge about and avoidance of exacerbating factors. The proportion of patients with acute attacks has decreased in South Africa and Finland from approximately one-third before 1980, to approximately 5 to 9 percent in the 2000s [2,18,26,27,75].

The increased identification of individuals with latent (asymptomatic) VP has occurred the most in regions of the world with a high prevalence of VP, such as South Africa and Finland. In South Africa, the proportion of asymptomatic individuals has progressively increased from 10 percent in 1980 to an estimated 60 percent in the 2000s [2,18,27].

Morbidity and mortality in VP also have decreased, presumably for the same reasons [56]. As an example, in a series of 112 cases in South Africa, none died during an acute attack and only one died after a protracted course [34]. Improved long-term management of hypertension and chronic renal disease may also have contributed to better long-term outcomes.

Hepatocellular carcinoma (HCC) is one of the most common causes of morbidity and mortality over long-term follow-up, and surveillance should be performed, especially among patients >50 years of age and/or those with concomitant risk factors for chronic liver disease, such as harmful alcohol use, fatty liver disease, or chronic hepatitis B or C infection. (See 'Screening for long-term complications' above.)

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" and "Society guideline links: Photosensitivity disorders (photodermatoses)".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Variegate porphyria (VP) is an autosomal dominant condition caused by heterozygosity for a pathogenic variant in the PPOX gene (OMIM 600923). PPOX encodes protoporphyrinogen oxidase, the seventh enzyme in heme biosynthesis (figure 1). (See 'Pathogenesis' above.)

●Prevalence – Most individuals with PPOX variants remain asymptomatic, making prevalence estimates challenging. Symptomatic VP is estimated to affect approximately 1 in 300,000 in Europe (higher in populations from Finland and Dutch South Africans). (See 'Epidemiology' above.)

●Clinical – Clinical features are variable and may include blistering lesions on light-exposed skin; neurovisceral symptoms (acute attacks of abdominal pain, motor weakness, and peripheral neuropathy); or latent (asymptomatic) disease. Skin manifestations are more common than neurovisceral symptoms. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of VP can be made by biochemical or genetic testing (see 'Diagnosis' above):

•For an acute attack in a previously undiagnosed patient, elevated urinary porphobilinogen (PBG) on a spot urine is sufficient to diagnosis acute porphyria (VP, hereditary coproporphyria [HCP], or acute intermittent porphyria [AIP]) and initiate treatment (algorithm 1). Additional testing can distinguish between VP from other porphyrias (table 2 and table 3). (See 'New patient, acute attack' above.)

•For chronic cutaneous findings, diagnosis is made with elevated plasma and urinary porphyrins (algorithm 2), followed by additional biochemical testing to distinguish VP from other cutaneous porphyrias (especially porphyria cutanea tarda [PCT]). (See 'New patient, skin-only findings' above.)

•Asymptomatic first-degree relatives can undergo targeted genetic analysis. (See 'Asymptomatic relatives' above.)

●Differential – The differential diagnosis includes other cutaneous and acute neurovisceral porphyrias and conditions that cause blistering skin lesions, abdominal pain, neuropathy, or elevated porphyrins. (See 'Differential diagnosis' above.)

●Management – Potentially harmful drugs should be discontinued (table 1); metabolic stresses should be corrected; pain, nausea, and autonomic symptoms should be treated.

•Acute attack (severe) – Severe attacks are potentially life threatening. For an attack requiring hospitalization, opioids, or other intravenous medication, or accompanied by nausea and vomiting, motor neuropathy, paresis, seizures, agitation, delirium, psychosis, ileus that prevents oral intake, or hyponatremia, we recommend intravenous hemin (Grade 1B). (See 'Treatment of acute attacks' above.)

•Acute attack (less-severe) – We also suggest hemin for less-severe attacks (Grade 2C). Intravenous or oral glucose are reasonable alternatives; however, the response with hemin is generally faster, and some mild attacks become severe if not treated with hemin. (See 'Treatment of acute attacks' above.)

•Prevention – For adults with ≥4 attacks per year, we suggest givosiran (Grade 2B). Givosiran is a small interfering RNA that reduces ALAS1 mRNA and ALA and PBG levels. For attacks that coincide with the luteal phase of the menstrual cycle, a gonadotropin releasing hormone (GNRH) analog may be used. Prophylactic hemin is another option. (See 'Prevention of acute attacks' above.)

•Skin protection – Patients with blistering skin lesions of VP should wear protective clothing. Affected areas should be kept clean and skin infections treated with topical or systemic antibiotics. Pain may require acetaminophen, aspirin, or short-term opioids. Topical steroids should be avoided. Hemin and glucose are not effective for treating cutaneous lesions. (See 'Prevention and treatment of skin lesions' above.)

•Complications – Potential complications for which screening is appropriate include kidney disease, liver function test abnormalities, and hepatocellular cancer. (See 'Screening for long-term complications' above.)

●Genetic testing – We perform PPOX sequencing in all patients with a biochemical diagnosis of VP, for diagnostic confirmation, identification of new variants, and genetic counseling and testing of first-degree relatives. (See 'Genetic testing and counseling' above.)

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