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Hereditary coproporphyria

Hereditary coproporphyria
Authors:
Ashwani K Singal, MD, MS, FACG, FAASLD
Karl E Anderson, MD, FACP
Section Editor:
Robert T Means, Jr, MD, MACP
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Sep 2022. | This topic last updated: Jan 07, 2022.

INTRODUCTION — Hereditary coproporphyria (HCP) is an inherited condition characterized by acute neurovisceral as well as chronic blistering cutaneous manifestations. The neurovisceral manifestations are indistinguishable from those of other acute hepatic porphyrias (acute intermittent porphyria [AIP], variegate porphyria [VP], and delta-aminolevulinic acid [ALA] dehydratase porphyria [ADP]), and the chronic cutaneous manifestations are similar to the other chronic blistering cutaneous porphyrias (porphyria cutanea tarda [PCT], VP, and hepatoerythropoietic porphyria [HEP]).

Because it can have both neurovisceral and cutaneous manifestations, HCP has also been called "mixed porphyria," an obsolete term that was also applied to VP. As with AIP and VP, rare homozygous cases with distinct clinical features occur. "Harderoporphyria" is a form of homozygous HCP with prominent hematologic features caused by certain CPOX mutations.

The spectrum of HCP disease manifestations is broad, and the condition is rare, making diagnosis challenging. Acute neurovisceral attacks are potentially fatal. Thus, it is especially important to make the diagnosis accurately and in a timely fashion so that appropriate treatment can be administered.

This topic review discusses the pathophysiology, epidemiology, clinical features, diagnosis, and treatment of HCP. Separate topic reviews provide an overview of porphyria categories and discuss the individual acute neurovisceral and cutaneous porphyrias:

Schematic of categories (algorithm 1) and general overview – (See "Porphyrias: An overview".)

Acute neurovisceral features alone – (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis" and "ALA dehydratase porphyria".)

Acute neurovisceral and chronic blistering cutaneous features – (See "Variegate porphyria".)

Chronic blistering cutaneous features alone – (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis" and "Congenital erythropoietic porphyria" and "Variegate porphyria".)

Acute nonblistering cutaneous features alone – (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

PATHOPHYSIOLOGY

CPOX gene mutations — HCP (OMIM #121300) is an autosomal dominant condition with incomplete penetrance caused by heterozygosity for a pathogenic variant in the coproporphyrinogen oxidase gene (CPOX, previously called CPO; OMIM 612732).

The CPOX gene is located on chromosome 3 and consists of seven exons and six introns [1]. The first pathogenic CPOX variant was identified in 1994, approximately 40 years after HCP was first described [2,3]. A variety of pathogenic variants have since been reported in heterozygous and homozygous cases [4-18]. Case reports have described individuals who have a CPOX mutation in combination with mutation of a different enzyme in the heme biosynthetic pathway (so-called "dual porphyria") [19,20].

Pathogenic CPOX variants reduce the activity of the CPOX enzyme, as discussed below. (See 'Enzymatic defect and accumulation of heme metabolites' below.)

Genotype-phenotype correlations have not been evident in most individuals who are heterozygous for a CPOX variant. An exception is some CPOX mutations associated with harderoporphyria, an extremely rare form of homozygous HCP with hematologic features [21]. Harderoporphyrinogen III (a tricarboxyl porphyrinogen) is the intermediate in the two-step decarboxylation of coproporphyrinogen III (a tetracarboxyl porphyrinogen) to protoporphyrinogen IX (a porphyrinogen with two carboxyl groups). It was first isolated in its oxidized form (harderoporphyrin) from the rodent Harderian gland, hence its name [21,22]. (See 'More severe phenotypes of HCP' below.)

Enzymatic defect and accumulation of heme metabolites — Coproporphyrinogen oxidase (CPOX) is the sixth enzyme in the heme biosynthetic pathway (table 1). It is localized to the mitochondrial intermembrane space, where it catalyzes the conversion of coproporphyrinogen III to protoporphyrinogen IX by oxidative decarboxylation (figure 1) [23,24]. CPOX is closely associated in the mitochondrial membrane with protoporphyrinogen oxidase (PPOX), the next enzyme in the heme synthetic pathway, mutations of which cause variegate porphyria (VP). (See "Variegate porphyria", section on 'PPOX gene variants'.)

Because CPOX is a mitochondrial enzyme, it can be measured in many cell types (eg, fibroblasts, lymphocytes) but not in mature red blood cells (RBCs; which do not contain mitochondria) [25]. Most individuals with HCP have approximately half-normal CPOX activity [26]. In rare homozygous cases, the enzyme activity is <10 percent of normal [27]. Some degree of CPOX activity appears to be essential for life, as no individuals with absent CPOX activity have been described.

In hepatocytes, half-normal CPOX activity in heterozygotes with CPOX mutations is sufficient except when there is a requirement to increase heme synthesis. A requirement for increased heme synthesis leads to upregulation and increased activity of delta-aminolevulinic acid synthase (ALAS1), the initial and rate-limiting enzyme in the heme synthesis pathway in the liver; in this setting, reduced CPOX activity in individuals who are heterozygous for a CPOX mutation leads to accumulation of coproporphyrinogen III, which becomes auto-oxidized to coproporphyrin III and is excreted in urine and bile. Biliary excretion leads to high levels of coproporphyrin III in the stool. Elevated urinary and fecal coproporphyrin III during and often after an acute attack is the diagnostic feature of HCP, as discussed below. Patients with harderoporphyria have associated increased fecal harderoporphyrin, a tricarboxyl porphyrin [21]. (See 'Diagnostic evaluation' below.)

Heme synthesis is not severely impaired and hemoproteins are not markedly depleted in the liver during exacerbations of HCP and other acute porphyrias. However, half-normal activity of CPOX becomes significant when heme synthesis is stimulated because this can deplete the regulatory heme pool, which serves to downregulate the rate-limiting enzyme ALAS1. Thus, the half-normal activity of CPOX in HCP causes disease manifestations when exacerbating factors that induce ALAS1 are present (eg, certain drugs, hormones, or starvation) and there is depletion of the regulatory heme pool. Such factors may also induce hepatic ALAS1 directly. Coproporphyrinogen III accumulates and is thought to inhibit the upstream enzyme porphobilinogen (PBG) deaminase, which may explain why PBG becomes elevated. Marked induction of ALAS1 accounts for elevation in delta-aminolevulinic acid (ALA) [28].

Cutaneous manifestations in HCP are thought to be due to the accumulated porphyrins, which are photoactivated by light. (See 'Cutaneous manifestations' below.)

Mechanism of acute attacks — As noted above, the exact mechanism of neurovisceral attacks remains speculative (see 'Enzymatic defect and accumulation of heme metabolites' above) and in some cases is likely to be multifactorial.

Neurovisceral symptoms are believed chiefly to be related to accumulation of ALA, as in other acute hepatic porphyrias [29,30]. Excess ALA rather than PBG is considered the most likely cause of neurotoxic effects, although heme deficiency in neuronal or vascular tissue is an additional or alternative potential mechanism [31,32].

Seizures may be a neurologic effect of acute porphyria, or caused by hyponatremia. Although hyponatremia has been ascribed to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), when blood volumes were measured in patients with AIP, they were found to be significantly decreased [33]. If, as is likely, such contraction of blood volume also occurs during acute attacks of HCP and other types of acute porphyria, it may be more accurate to refer to this as an appropriate increase in ADH. Other factors that predispose to seizures include effects of heme intermediates, especially ALA, and/or metabolites on the central nervous system and vasculature [34]. Reversible perfusion defects in the brain, suggestive of vasospasm, have been observed in HCP and acute intermittent porphyria (AIP) by single-photon emission computed tomography (SPECT) [35]. On magnetic resonance imaging (MRI), these changes can resemble posterior reversible encephalopathy syndrome (PRES) and are not specific to porphyria. Central nervous system imaging is helpful in eliminating other possible diagnoses but does not confirm or refute a diagnosis of acute porphyria. (See 'Differential diagnosis' below.)

Pathologic examination has revealed dying-back axonal degeneration in individuals with HCP-associated peripheral neuropathy [36]. Nerve biopsy is not indicated for evaluation or diagnosis of porphyria but may be done in rare cases in which another diagnosis is being considered.

Precipitating factors — There are a number of factors that can precipitate or contribute to an acute neurovisceral attack in an individual with HCP. These are the same factors that can precipitate acute attacks in the other acute porphyrias (acute intermittent porphyria [AIP] and variegate porphyria [VP]). Much of the information about exacerbating factors for acute neurovisceral attacks has come from patients with AIP, which is the most common acute porphyria. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Exacerbating factors'.)

Triggering factors for acute neurovisceral attacks can be broadly classified as follows:

Medications – Common examples of medications that can exacerbate or trigger an acute attack are summarized in the table (table 2). Clinicians considering medications in patients with HCP should consult frequently updated sources for information regarding medication safety, such as the websites of the American Porphyria Foundation (https://porphyriafoundation.org/) and the European Porphyria Network (EPNET; porphyria.eu). 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.

Hormonal changes – Steroid hormones, especially progesterone, induce ALAS1 and can trigger an acute attack in some individuals. Progesterone increases that occur at puberty (see 'Age of onset' below), during the luteal phase of the menstrual cycle, and during pregnancy may contribute to the onset of symptoms, and progestin-containing contraceptives may exacerbate symptoms. Variants in unknown modifying genes are likely contributors, but these remain to be identified. Such modifying genes would explain why, with normal endocrine function, most women who are heterozygous for pathogenic CPOX mutations never develop acute porphyria attacks, while a minority of others develop frequent symptoms. Pregnancy is usually well tolerated despite elevation in progesterone, but attacks become more frequent in some pregnant women. (See 'Pregnancy' below.)

Alcohol and cigarette smoke – Alcohol and cigarette smoking can contribute to the development of acute attacks. Whether alternatives such as vaping are safe or harmful is not known, but would depend on the nature of the inhaled chemicals.

Fasting and metabolic stress – Metabolic stress from fasting (eg, during crash dieting or after bariatric surgery), infection, and acute illness can lead to attacks [29].

The mechanism by which these factors precipitate acute neurovisceral attacks is thought to be an increased demand for hepatic heme synthesis and/or direct induction of the ubiquitous form of ALA synthase (ALAS1) in the liver. Induction of cytochrome P450 enzymes (CYPs, which are heme-containing enzymes) is one of the main means of increasing the demand for heme synthesis in the liver. Expression of the genes for ALAS1 and certain hepatic CYPs is upregulated in response to inducing chemicals. This includes most of the unsafe medications (eg, barbiturates, phenytoin, most other antiepileptics, rifampin); progestins, which are ligands for the pregnane X receptor (PXR) and other nuclear receptors; and polycyclic aromatic hydrocarbons in cigarette smoke [37,38].

Fasting and metabolic stress induce ALAS1 via 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.

ALAS1 is normally rate limiting for heme synthesis in the liver, and under normal conditions or with modest increases in heme synthesis, CPOX does not become rate limiting and its substrate does not accumulate. However, as described above (see 'Enzymatic defect and accumulation of heme metabolites' above), the regulatory heme pool in hepatocytes is more easily depleted than are important cellular hemoproteins (such as cytochrome P450 enzymes [CYPs]). Therefore, precipitating factors that induce ALAS1 and CYPs can increase the production of all heme pathway intermediates, and, because CPOX activity is reduced, these factors can lead to the accumulation of coproporphyrinogen III and to less heme availability for repletion of the regulatory heme pool. Reduction in regulatory heme can greatly accentuate ALAS1 induction and further accentuate accumulation of coproporphyrinogen III and other pathway intermediates.

Exacerbating factors for cutaneous manifestations include exposure to sunlight and, to a lesser extent, to certain forms of artificial light (eg, light with wavelengths in the range of 380 to 420 nm; the ultraviolet A [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.

EPIDEMIOLOGY — The prevalence of HCP has been estimated at approximately two to five per million population [39,40]. However, not all individuals with the causative genetic defect will manifest clinical disease. The prevalence of the genetic defect is unknown.

HCP is found throughout the world. While the frequency of CPOX mutations is the same in males and females in HCP families, disease manifestations are more common in females than males (2-5 to 1 in one series) [41]. This may reflect the role of sex hormones in precipitating acute attacks. (See 'Precipitating factors' above.)

Among the acute porphyrias, HCP is less common than acute intermittent porphyria (AIP) and variegate porphyria (VP) but more common than delta-aminolevulinic acid (ALA) dehydratase porphyria (ADP). In a study from the European Porphyria Network, the relative incidence for symptomatic AIP versus VP versus HCP was 1.00 to 0.62 to 0.15 [40].

CLINICAL FEATURES

Typical presentation

Age of onset — HCP typically manifests after puberty in a heterozygote for a pathogenic CPOX variant and is seen more frequently in women. As noted above, this may be related to the exacerbating effects of hormones such as progesterone during the menstrual cycle. (See 'Precipitating factors' above.)

Earlier presentation (eg, during the neonatal period or in childhood) has been reported, but typically in individuals who are homozygous or compound heterozygous for a CPOX mutation. (See 'More severe phenotypes of HCP' below.)

Neurovisceral manifestations — HCP is characterized by acute neurovisceral attacks with manifestations that may include symptoms or findings of central, peripheral, and autonomic nervous system dysfunction.

The neurovisceral manifestations in HCP are not distinguishable from those in the other acute porphyrias (acute intermittent porphyria [AIP] and variegate porphyria [VP]). Although acute attacks are generally milder than those seen in AIP, they can be severe and even fatal [2,4,41].

Abdominal pain is the most common symptom. This and other neurovisceral findings are summarized in the table (table 3) and include one or more of the following [34,41-44]:

Abdominal pain (usually steady, but may be cramping), nausea, vomiting, constipation, abdominal distention (from ileus), diarrhea (less common)

Pain in the back, chest, and/or extremities

Systemic arterial hypertension, tachycardia, fever

Anxiety, disorientation, agitation, psychosis

Urinary retention (from bladder paresis)

Brownish or reddish urine

Motor weakness, especially proximal, that may progress to flaccid quadriparesis and/or respiratory failure (may be fatal)

Seizures

Sensory deficits

Hyponatremia, which may be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or to diarrhea and decreased oral intake

These findings are highly variable, but often an individual who has recurrent attacks will have similar symptoms from one attack to another [45].

Acute attacks are reversible if treated promptly (see 'Treatment of acute attacks' below), although motor weakness, if present, may take months and even several years to resolve. (See 'Long-term complications' below.)

Brain imaging is not used to diagnose or exclude HCP, but it may be used to evaluate for other conditions in the differential diagnosis (see 'Differential diagnosis' below). Brain imaging during severe attacks of acute porphyrias may show reversible densities in white matter resembling posterior reversible encephalopathy syndrome (PRES). (See "Reversible posterior leukoencephalopathy syndrome".)

Cutaneous manifestations — HCP may be associated with chronic blistering cutaneous manifestations, similar to those seen in porphyria cutanea tarda (PCT) or VP [44]. This may include blistering, scarring, and pigment changes on sun-exposed areas of skin, especially on the dorsal aspects of the hands and less often on the face, neck, ears, and feet. However, these cutaneous findings are far less common than neurovisceral manifestations in individuals with HCP and are much less common than in VP.

More complete discussions of these skin findings are presented separately. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Blistering skin lesions and other cutaneous manifestations' and "Variegate porphyria", section on 'Cutaneous symptoms'.)

Long-term complications — In some cases of HCP, the neurologic manifestations of an acute attack are very slow to resolve, and persistent neurologic changes may be seen (eg, peripheral neuropathy, causing pain and paresis). These may lead to chronic disability, as well as depression in the setting of chronic pain and immobility [29].

Some individuals may have persistent liver function abnormalities. Chronic liver abnormalities in this and other acute porphyrias are poorly understood and deserve further study.

Individuals with HCP are at risk for hepatocellular carcinoma (HCC), even if there is no previously identified pre-existing liver disease or other HCC risk factors [40,46]. HCP is too rare to accurately determine the incidence of HCC. However, a prospective study involving a cohort of 650 patients with acute hepatic porphyrias identified seven cases of HCC (four in symptomatic individuals and three in asymptomatic individuals) and calculated a standardized rate ratio (SRR; number of cases observed divided by cases expected) of 36 (95% CI 14-74). The increased risk for HCC persisted if the two cases associated with cirrhosis and chronic hepatitis were excluded (SRR 26 [95% CI 8-59]) [47]. The ages at diagnosis of HCC ranged from 37 to 65 years.

More severe phenotypes of HCP — Severe cases of HCP due to homozygous or compound heterozygous coproporphyrinogen oxidase (CPOX) mutations have been described, with disease onset in the neonatal period or in childhood [3,6,21,27]. This is extremely rare (case reports). In such individuals, neurologic impairment and chronic photosensitivity are prominent rather than acute attacks. A case report has also described a neonatal presentation in an individual who was heterozygous for a CPOX mutation [12].

Harderoporphyria is an extremely rare variant form of homozygous HCP with notable hematologic manifestations in which certain CPOX mutations result in increased excretion of both harderoporphyrin III and coproporphyrin III [6,21]. Mutations affecting the D400-K404 region of the CPOX enzyme, a region that may be important in preventing diffusion of harderoporphyrinogen away from the catalytic site, are especially likely to be associated with harderoporphyria. Hemolytic anemia, neonatal jaundice, hepatosplenomegaly, and cutaneous photosensitivity are prominent features of harderoporphyria [21,48,49]. Rarely, the diagnosis of harderoporphyria may be delayed until late in life after life-long symptoms [50]. Iron overload may occur, perhaps related to ineffective erythropoiesis [48]. Individuals who are heterozygous for harderoporphyria-associated mutations have similar findings as other individuals with HCP [7,18].

DIAGNOSTIC EVALUATION

Overview of the evaluation — HCP may be suspected in an individual with a known family history of the disease and/or an individual (typically an adult, but rarely a child) who presents with unexplained abdominal pain or other symptoms characteristic of an acute neurovisceral attack. (See 'Neurovisceral manifestations' above.)

Like other acute porphyrias, the evaluation depends on whether the individual is in the midst of an acute attack, has a history of remote attacks, has a positive family history, and/or has chronic skin manifestations:

For a new patient with current symptoms suggesting an acute attack, the diagnosis of acute porphyria (AIP, HCP, or VP) is established by finding an elevated urinary porphobilinogen (PBG), after which treatment can be started if clinically indicated (algorithm 2). If PBG is elevated, further testing is done to determine the type of acute porphyria (table 4). (See 'New patient, acute attack' below.)

Measurement of total urine porphyrins is also recommended as part of first-line testing for acute porphyrias, because porphyrins may be more elevated and remain elevated longer in HCP and VP than in AIP [29]. However, unlike PBG elevation, urine porphyrin elevation is nonspecific. Therefore, further second-line testing is needed to demonstrate whether porphyrinuria is due to acute porphyria or another medical condition.

A patient who is not in the midst of an acute attack but gives a history consistent with acute attacks can be evaluated by biochemical testing as outlined above.(See 'New patient, history of neurovisceral attacks' below.)

For a patient with known HCP, the presence of an acute attack is diagnosed clinically rather than based on PBG testing. (See 'Patient with known HCP, confirming an acute attack' below.)

For any patient with an acute attack (suspected or known porphyria), concomitant infections and other potential triggering conditions should be evaluated. (See 'Importance of evaluating for associated/triggering conditions' below.)

Patients with skin findings are evaluated with plasma and/or urine total porphyrins as a screening test (algorithm 3); if porphyrins are elevated, this is followed by fractionation of porphyrins in urine, feces, plasma, and red blood cells (RBCs) (table 5). (See 'Evaluation of skin findings' below.)

Genetic testing is widely available and is recommended to confirm the diagnosis of HCP or other acute porphyria. Knowledge of the familial disease variant facilitates genetic testing of asymptomatic relatives. (See 'Evaluation of asymptomatic relatives' below and 'Diagnostic confirmation/role of genetic testing' below.)

Evaluation of neurovisceral symptoms

New patient, acute attack — As noted above, a low threshold for screening for acute porphyria should be maintained in individuals with neurovisceral symptoms such as abdominal pain, autonomic dysfunction, and/or neurologic findings after initial workup excludes more common conditions. The diagnosis is often made when HCP and other acute porphyrias are not strongly suspected. (See 'Clinical features' above.)

There are no specific findings on routine laboratory testing, such as complete blood count (CBC), electrolytes, and liver chemistries that can confirm or exclude the diagnosis of HCP or other acute porphyrias.

In HCP, routine testing may show nonspecific abnormalities and/or findings that suggest another (concomitant) condition. For example, HCP may be associated with hyponatremia, and less commonly with hypomagnesemia and/or hypercalcemia [29]. Chronically elevated transaminases and mild elevations of serum amylase or lipase are common, but bilirubin is usually normal. Leukocytosis, anemia, thrombocytopenia, and elevation in amylase or lipase are generally absent; their presence suggests another, possibly concurrent, disorder. (See 'Importance of evaluating for associated/triggering conditions' below.)

The first step in evaluating a patient for HCP (or other acute porphyria) is a spot urine test for PBG and total porphyrins (algorithm 2). In individuals with advanced kidney disease, PBG can be measured in serum. An effective rapid test kit for PBG that was useful for rapid diagnosis of acute porphyria is no longer available, and urine PBG and porphyrins are send-out tests at most medical centers. The send-out laboratory should be made aware if a result is needed urgently; they should also be asked to normalize the final result to creatinine, which is not done routinely in all laboratories. Results expressed per liter of urine can be reported initially, but this may be misleadingly low if the urine sample happens to be dilute. A substantial elevation in PBG (usually >10 mg/g creatinine) is a highly specific finding and confirms that the patient has one of the acute porphyrias and is sufficient to initiate treatment if clinically indicated (table 4). (See 'Treatment of acute attacks' below.).

Interpreting urine PBG and porphyrin results as multiples of the upper limit of normal (ULN) has become less useful because ULNs vary greatly between laboratories. Total urine porphyrins should be measured on the same sample because PBG is often less elevated and may return to normal more rapidly in HCP (and variegate porphyria [VP]) than in acute intermittent porphyria (AIP), whereas porphyrin elevations, although nonspecific, persist longer.

Additional samples should be collected and sent at the same time as the urinary PBG (and porphyrins), before treatment is initiated, but the results of this testing is not required for (and should not delay) treatment of an acute attack if the PBG is reported to be substantially elevated. These samples include the following:

Urine – The initial spot urine specimen should be sent for total porphyrins, with fractionation of porphyrins if the total porphyrins are elevated. Delta-aminolevulinic acid (ALA) is generally also measured but is usually less elevated than PBG (when both are expressed in milligrams rather than millimoles). The urine specimen should also be tested for creatinine so that the results of PBG can be normalized to creatinine.

Plasma – A plasma (or serum) sample should be sent for total porphyrins, with fractionation if the total is elevated. Plasma fluorescence scanning is important for excluding variegate porphyria (VP) [51].

Stool – A stool sample should be sent for total porphyrins, with fractionation if the total is elevated.

RBCs – Red blood cell (RBC) total porphyrins should be sent. This is important especially for patients with blistering skin lesions that might be due to congenital erythropoietic porphyria (CEP) or hepatoerythropoietic porphyria (HEP), which cause markedly elevated erythrocyte porphyrins.

Measurement of erythrocyte PBG deaminase (PBGD) activity is also useful in distinguishing among the acute porphyrias; erythrocyte PBGD is decreased in most patients with AIP [29]. The deficient enzyme in HCP is mitochondrial and is not measured in mature erythrocytes, which lack mitochondria [21].

Results of biochemical testing in HCP (and findings in other porphyrias) are listed in the table (table 5). Key distinguishing points include the following:

The most dramatic and distinctive biochemical feature of HCP is a significantly elevated level of fecal and urinary coproporphyrin, especially coproporphyrin III, during an acute attack, and often between attacks (table 6).

Fecal porphyrin elevation is particularly sensitive for the diagnosis of HCP and VP. In rare individuals with harderoporphyria, coproporphyrin III and harderoporphyrin are both elevated, with a predominance of fecal harderoporphyrin (>60 percent harderoporphyrin in one study) [21]. Fecal porphyrins are markedly elevated in active and some inactive cases of HCP and VP, but the fractionation in VP reveals elevations in both coproporphyrin III and protoporphyrin IX, whereas in HCP the fecal porphyrins are almost entirely coproporphyrin III. Fecal porphyrins are normal or only slightly elevated in AIP.

Urinary ALA, PBG, and uroporphyrin (which forms enzymatically and non-enzymatically from PBG) are elevated in HCP. The typical range for PBG in acute porphyrias and especially AIP is 20 to 200 mg/g creatinine; in HCP and VP the levels are often in the lower part of this range [29]. Urinary porphyrins in HCP and VP are likely to remain elevated after an attack for longer than urinary ALA and PBG.

Plasma porphyrins are generally normal or only modestly elevated in HCP; greater elevations of plasma porphyrins may be seen in individuals with concurrent skin manifestations. (See 'Cutaneous manifestations' above and 'Evaluation of skin findings' below.)

Elevations in urinary porphyrins (especially coproporphyrin) are not specific for HCP or other porphyrias and are seen in many medical conditions other than porphyria, including hepatobiliary and bone marrow disorders. Therefore, an elevation in urinary coproporphyrin is consistent with HCP but insufficient for diagnosis unless there is also a marked elevation in fecal coproporphyrin III. Not uncommonly, HCP is misdiagnosed in patients based solely on nonspecific urinary coproporphyrin elevations.

RBC protoporphyrin levels are normal or only slightly elevated in HCP. Substantial elevation is seen in individuals with homozygous HCP (and in individuals with harderoporphyria, RBC harderoporphyrin levels are also elevated) [50].

Measurement of CPOX activity in mitochondria-containing cells such as lymphocytes helps to confirm a diagnosis of HCP, but such assays are not widely available [52]. This is almost never needed clinically as DNA testing is now widely available.

Genetic testing (DNA analysis) is used to characterize the pathogenic variant in an affected individual and then used to screen asymptomatic first-degree relatives. Sometimes genetic testing is done early in the diagnostic evaluation of a patient with neurovisceral symptoms and demonstrates a pathogenic mutation for one of the acute porphyrias. Biochemical testing then focuses mostly on assessing disease activity as related to symptoms, and less toward exclusion of the other acute porphyrias. However, expertise is needed for interpretation of available molecular and biochemical findings, because some genetic variants are benign or of unknown significance [53]. (See 'Diagnostic confirmation/role of genetic testing' below.)

New patient, history of neurovisceral attacks — Evaluation for acute porphyrias is challenging in an individual who gives a history consistent with acute neurovisceral attacks but is currently well. This is because the levels of PBG, ALA, and porphyrins may return to normal between attacks and/or after elimination of exacerbating factors.

In such individuals, we test urine ALA, PBG, and porphyrins, as well as plasma and fecal porphyrins. The most sensitive biochemical testing for HCP, especially after symptoms have cleared, is fecal porphyrins, and for VP, plasma and fecal porphyrins (algorithm 2). If the results are normal and suspicion for acute porphyrias remains, urine PBG and porphyrins and fecal porphyrin can be measured again in the future if symptoms recur. In testing first-degree relatives with or without a history of symptoms, a high ratio of coproporphyrin III to I in feces is sensitive for detecting those with HCP [54]; however, biochemical testing is not as sensitive as testing for a known CPOX mutation.

Genetic testing for a pathogenic variant in the CPOX gene is widely available and can be used for initial diagnosis in an individual who gives a history consistent with HCP but who does not have active symptoms. However, it would be necessary to screen for AIP, HCP, and VP by sequencing three genes if biochemical findings were normal.

Patient with known HCP, confirming an acute attack — Prior laboratory documentation of HCP, including both biochemical and molecular confirmation, should be available to the treating clinician from the medical records or from records provided by the patient.

In an individual with known HCP who is experiencing neurovisceral symptoms, it is advisable to obtain a spot urine for PBG and creatinine; treatment can typically be started before the result is available. The confirmation of an acute attack, as well as initiation of appropriate treatment, is made on clinical grounds. (See 'Treatment of acute attacks' below.)

Importantly, it is not necessary to wait for the results of PBG testing or porphyrin levels before initiating treatment for an acute attack, and such delay may increase the risk of serious adverse outcomes. However, we do obtain this testing because it is helpful in retrospect to confirm the PBG elevation and determine its degree relative to previous attacks (eg, to determine if attacks are escalating or lessening). If PBG is not increased, a more extensive evaluation may be required to determine the cause of the symptoms that were thought to be due to an acute attack. (See 'Differential diagnosis' below.)

It is also important to thoroughly evaluate the individual for other potential causes of their symptoms, which may have triggered the acute attack or may have occurred as a result of the acute attack. (See 'Importance of evaluating for associated/triggering conditions' below.)

Importance of evaluating for associated/triggering conditions — In any patient with suspected or confirmed HCP who presents with acute neurovisceral symptoms, it is important to evaluate for associated conditions that may have triggered an acute attack, may be masquerading as an acute attack, or may be caused by an acute attack. In some cases, both the HCP and the associated condition may require concurrent interventions.

Examples include [55]:

Infections (eg, urinary tract infection, pulmonary infection, intestinal infection)

Liver disease, pancreatitis, or cholecystitis

Major surgeries, injuries, or medical illnesses

Use of a porphyrinogenic medication, hormone, alcohol, or recreational drug

Fasting, dieting, or other metabolic stress

The mechanisms by which these factors cause porphyric attacks are described above. (See 'Precipitating factors' above.)

Evaluation of skin findings — Cutaneous porphyria is suspected in individuals who present with chronic blistering cutaneous changes on sun-exposed areas of skin (most commonly, blistering on the dorsal hands and hair growth on the face). (See 'Cutaneous manifestations' above.)

The evaluation for suspected cutaneous porphyria begins with testing for plasma or urine porphyrins as a screening test, followed by measurement of porphyrins in plasma and erythrocytes, in addition to urine, and measurement of individual porphyrins if totals are elevated (eg, ≥1 mcg/dL in plasma or serum or 300 mcg/g creatinine in urine; typically much higher).

Normal results for plasma and/or urine total porphyrins exclude all chronic blistering cutaneous porphyrias. If total porphyrins are increased, the next step is to distinguish among the blistering cutaneous porphyrias (HCP; porphyria cutanea tarda [PCT], the most common blistering cutaneous porphyria; VP; CEP; and HEP). These are distinguished by the porphyrin patterns in urine, plasma, and feces (table 5) [21]. Clinical findings should not be relied upon to differentiate these conditions because neurovisceral symptoms are highly nonspecific; neurovisceral findings are sometimes but not always present in individuals with HCP and VP who have skin manifestations. Such findings are not caused by PCT, CEP, or HEP, but they are very nonspecific and may be present due to a concurrent condition.

The finding of markedly elevated coproporphyrin III and a high III/I ratio without elevation of other fecal porphyrins is typical of HCP, and even if not specific is useful for screening first-degree relatives of a known HCP patient. However, genetic testing is more effective and can accurately screen relatives for the familial variant. (See 'New patient, acute attack' above.)

This approach is illustrated in the algorithm (algorithm 3) and discussed in more detail separately. (See "Porphyrias: An overview", section on 'Diagnostic testing (blistering cutaneous porphyria suspected)'.)

A more general approach to other causes of blistering skin lesions (ie, if testing for porphyria is negative) is also presented separately. (See "Approach to the patient with cutaneous blisters".)

Evaluation of asymptomatic relatives — Relatives can be screened in a cascade fashion, with priority given to first-degree relatives and those with symptoms suggesting porphyria. DNA testing is most reliable once the familial mutation is known. If biochemical testing is used, it should emphasize fecal porphyrin analysis and the fecal coproporphyrin III/I ratio.

Diagnostic confirmation/role of genetic testing — We consider the diagnosis of HCP to be confirmed if biochemical testing demonstrates elevated urinary or fecal coproporphyrin III and if other porphyrias that can cause PBG elevation (AIP and VP) are excluded biochemically.

The diagnosis is also confirmed if genetic testing demonstrates a pathogenic variant in the CPOX gene. Some CPOX variants may be benign or may have uncertain pathogenicity [53]. Confirming that symptoms are due to HCP in an individual with a pathogenic variant in CPOX requires demonstration of elevations of PBG and porphyrins.

Genetic testing is widely available. This testing is helpful and recommended for the following reasons and in the following settings:

Making the diagnosis in an individual who is currently asymptomatic and thus may not have substantial elevations of urine and fecal coproporphyrin

Confirming the diagnosis if clinical findings and/or results of biochemical testing are atypical, or if dual enzyme defects are suspected

Sensitive and specific screening of first-degree relatives, once the familial mutation is identified

Preconception counseling

Several caveats are important to consider with genetic testing:

Finding a pathogenic variant in CPOX with normal PBG and porphyrin levels establishes a diagnosis of latent HCP and can suggest but not prove that past symptoms were due to HCP.

As with other genetic disorders, rare patients with HCP have cryptic variants that are not detected by sequencing; these can usually (but not always) be demonstrated by other methods such as dose analysis [56].

Expert interpretation of DNA results is required because some identified variants are benign or of uncertain significance, including some mistakenly reported in the past as causing HCP or other acute porphyrias [57]. This caveat applies to other genetic diseases but is especially relevant to porphyria. As an example, one CPOX variant (N272H), which is not found in HCP, causes an unusual urinary porphyrin pattern after mercury exposure and may alter susceptibility to mercury [58]. Individuals with this CPOX variant have been misdiagnosed as having HCP, as are individuals with other CPOX variants that are benign or of uncertain significance.

Advice on genetic testing for porphyrias can be accessed through expert centers such as those in the Porphyrias Consortium.

DIFFERENTIAL DIAGNOSIS — The major considerations in the differential diagnosis of HCP are other acute porphyrias (and less commonly other cutaneous porphyrias) as well as other causes of abdominal pain, other causes of neuropathic or psychiatric symptoms, and other causes of liver disease. Elevated urinary porphobilinogen (PBG) distinguishes acute hepatic porphyrias from non-porphyria conditions, and excretion patterns of heme pathway intermediates (PBG, delta-aminolevulinic acid [ALA], porphyrins) in urine, plasma, and feces distinguish the acute porphyrias from each other.

Other acute porphyrias – Like HCP, other acute porphyrias can cause acute attacks of abdominal and neuropsychiatric symptoms and increases in urinary porphyrin precursors (PBG, ALA) and porphyrins. Other acute porphyrias have different patterns of porphyrin precursors and porphyrins in blood, urine, erythrocytes, and stool (table 5 and table 4); and some (variegate porphyria [VP] and less commonly HCP) have skin manifestations (table 7). Because attacks of all acute porphyrias are treated in the same manner, it is not important to differentiate them before treatment is started for an acute attack if a substantial elevation in PBG has been documented; however, samples needed for differentiating these disorders should be collected before treatment. Genetic testing is best obtained after biochemical diagnosis of one of these acute porphyrias. (See "Porphyrias: An overview".)

AIP – Acute intermittent porphyria (AIP) is an acute porphyria like HCP. AIP and VP are more common than HCP. Like HCP, AIP is characterized by elevated urinary PBG, especially during an acute attack; PBG elevations may be higher in AIP than in HCP or VP, and may return to normal more quickly in the latter conditions. HCP may cause blistering photosensitivity, which does not occur in AIP except in cases where concomitant chronic renal failure increases plasma porphyrin levels. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis".)

VP – Variegate porphyria (VP) is an acute neurovisceral porphyria like HCP. Like HCP, VP can cause either neurovisceral or cutaneous manifestations, which may occur together or at different times. Like HCP, VP is characterized by elevated urinary PBG and urine and fecal porphyrins, especially during an acute attack. Compared with HCP, VP is much more common and more likely to cause blistering photosensitivity, and in VP, the elevated fecal porphyrins include both coproporphyrin III and protoporphyrin (in HCP, coproporphyrin III predominates substantially. The coproporphyrin III/I ratio is elevated in HCP as well as VP and AIP). Compared with HCP, VP is more likely to have increased plasma porphyrins, with a characteristic peak fluorescence at approximately 626 nm when plasma is diluted at neutral pH; this fluorescence peak distinguishes VP from all other types of porphyria [51]. (See "Variegate porphyria".)

ADP – ALA dehydratase porphyria (ADP) is an acute neurovisceral porphyria like HCP. ADP is extremely rare. Unlike HCP, ADP is characterized by elevated urinary ALA, increased urinary coproporphyrin III, normal levels of urinary PBG, and markedly increased zinc protoporphyrin in erythrocytes. (See "ALA dehydratase porphyria".)

Other cutaneous porphyrias – Rarely, other blistering cutaneous porphyrias that can cause elevations in porphyrin levels, such as congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and hepatoerythropoietic porphyria (HEP), may be misdiagnosed as HCP (or VP), especially if a concurrent condition is causing abdominal pain or other symptoms that suggest an acute porphyria. Erythropoietic protoporphyria (and X-linked protoporphyria) cause nonblistering photosensitivity and can cause abdominal pain due to biliary stones or protoporphyric hepatopathy. Unlike HCP, patients with protoporphyrias lack elevations in urinary PBG and porphyrins. Thus, a biochemical evaluation can determine the type of cutaneous porphyria (algorithm 3 and algorithm 4).

Other causes of abdominal pain – Abdominal pain can occur in numerous clinical settings and is often difficult to diagnose. Unlike HCP (and other acute porphyrias), 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 (eg, lead poisoning). (See "Evaluation of the adult with abdominal pain" and "Causes of abdominal pain in adults".)

Importantly, an individual known to have porphyria may present with another cause of abdominal pain (eg, appendicitis, diverticulitis, pancreatitis, inflammatory or ischemic bowel disease, renal stones), and these conditions can precipitate an acute porphyria attack. Therefore, an elevated PBG is diagnostic for acute porphyria but does not exclude these other conditions.

Other causes of neuropathy – Neuropathies can have a variety of clinical presentations and etiologies. Unlike HCP, other causes of neuropathy do not cause elevations of urinary PBG. However, lead poisoning causes elevations of urinary ALA and porphyrins. (See "Overview of polyneuropathy" and "Overview of hereditary neuropathies".)

Other causes of neuropsychiatric symptoms – There are a variety of causes of nonspecific neuropsychiatric symptoms (eg, anxiety, agitation, insomnia, hallucinations). Examples include neurodegenerative disease, alcohol and drug use, psychiatric illness, and psychotropic medications. Like HCP, some of these other conditions may be associated with hyponatremia and increased antidiuretic hormone secretion. Unlike HCP, these other causes of neuropsychiatric symptoms do not cause elevations of urinary PBG. (See "Approach to the patient with visual hallucinations".)

Other causes of seizures – Seizures may occur in a setting of acute medical illness including hypoglycemia, hypocalcemia, hyponatremia, uremia, and drug or alcohol intake. Unlike acute porphyria, these other causes of seizures do not cause elevations in PBG. (See "Evaluation and management of the first seizure in adults".)

Liver disease – Like HCP, liver disease of any cause may be associated with elevated urinary porphyrin excretion, especially coproporphyrin. This occurs because coproporphyrin is excreted in both bile and urine, and more appears in the urine when hepatobiliary function is impaired. Unlike HCP, patients with liver disease do not have elevated PBG (although they may have slight elevations in ALA) and often have slight or even substantial elevations in porphyrins (especially coproporphyrin). (See "Approach to the patient with abnormal liver biochemical and function tests".)

MANAGEMENT

Treatment of acute attacks — Acute neurovisceral attacks in an individual with porphyria can be potentially life-threatening, and treatment should be initiated as soon as possible:

For new patients, treatment for an acute attack, if clinically indicated, is started as soon as the patient is diagnosed as having acute porphyria (based on a substantial increase in urinary porphobilinogen [PBG]) [29,59,60]. Treatment should not be delayed in an individual confirmed to have acute porphyria while first determining which acute porphyria is present or while administering a carbohydrate load.

Ideally, in the absence of prior laboratory evidence of acute porphyria, an elevation in urinary PBG should be documented before initiating treatment with hemin, unless delay would be potentially detrimental. In rare cases with life-threatening neurovisceral manifestations, a high likelihood of porphyria, and an expected long delay in obtaining results of diagnostic testing, we may initiate treatment before urinary PBG results are available. This is justified because hemin is considered highly effective and has few side effects if administered into a large vein and/or after reconstitution with human albumin. The patient and others should understand that without confirmation by a high PBG, the clinical diagnosis of acute porphyria is provisional and may not be confirmed even in a patient with "classic" (but nonspecific) symptoms. However, starting hemin treatment without sending urine for PBG creates a difficult diagnostic situation because PBG and porphyrin levels are lowered by hemin rapidly and for an unpredictable period of time, so later PBG determinations may be normal even if initial samples would have been elevated.

For established patients who present with symptoms of an acute attack, treatment is started based on the clinical findings and should not be delayed while determining the presence or degree of urinary PBG elevation (unless this information can be obtained within a few hours). However, as noted above, a spot urine should be collected for PBG measurement before starting hemin.

The following summarizes the components of treatment:

Give hemin – For any acute attacks that are severe enough to warrant hospitalization, intravenous hydration (eg, due to nausea, vomiting, or ileus), opioid analgesia, or other intravenous medication; or associated with seizures, paresis, agitation, delirium, or hyponatremia, we recommend hemin, consistent with published guidelines [29,60,61]. Hemin is administered intravenously at a dose of 3 to 4 mg/kg of body weight per day and continued until the attack abates and/or for at least four days, whichever is longer [29]. Some patients may respond more quickly, especially if treatment is started promptly, and others may require treatment for more than four days. Additional details of hemin dosing, adverse events, different products, and supporting evidence in individuals with acute intermittent porphyria (AIP) are presented separately. (See "Acute intermittent porphyria: Management", section on 'Acute attack: Primary treatment (hemin)'.)

The other available treatment for acute porphyric attacks is carbohydrate loading (ie, administration of a 10 percent solution of intravenous glucose or glucose and saline; typical dose, 300 to 400 grams per 24 hours), but observational reports and our experience suggest this is less effective than hemin in aborting the acute attack. Carbohydrate loading should only be used in attacks that are mild (ie, not associated with vomiting, ileus, pain requiring opioid analgesia, need for intravenous medication, seizures, paresis, agitation, delirium, or hyponatremia) and/or as a temporizing measure while awaiting administration of hemin, as long as use of carbohydrate loading does not delay definitive therapy with hemin administration.

There are no adequately powered randomized trials comparing hemin with glucose loading or placebo for acute attacks in individuals with HCP or other acute porphyrias. Available evidence includes case series that show a clear benefit of hemin therapy in reducing the severity and duration of acute attacks of other acute porphyrias; this is confirmed by continued experience at many centers. As an example, in a series of 112 patients with an acute attack of AIP or variegate porphyria (VP), hemin resulted in dramatic improvement in symptoms and reduction in opioid requirements, typically within 24 to 48 hours [62]. These outcomes are similar to our experience and that in published series [63-65]. Details of administration are presented separately. (See "Acute intermittent porphyria: Management", section on 'Carbohydrate loading as a temporizing measure'.)

Avoid harmful medications – Medications that are considered unsafe in acute porphyrias should be avoided. If present, their use should be discontinued if at all possible. This includes barbiturates, sulfonamide antibiotics, metoclopramide, griseofulvin, rifampin, anticonvulsants (eg, phenytoin, carbamazepine), ergot alkaloids, and progestins (table 2). (See 'Precipitating factors' above.)

It is strongly advised that clinicians consult the websites of the American Porphyria Foundation (https://porphyriafoundation.org/) and the European Porphyria Network (EPNET; porphyria.eu), which are frequently updated; list many other drugs, including those that are not classified with certainty; and provide evidence for these classifications. These lists of classified drugs derive from judgments based on the best evidence, which for many drugs is inadequate.

Treat concurrent illnesses – As noted above, treatment for concurrent conditions (eg, infections, dehydration, metabolic abnormalities) should also be provided as soon as possible, both to resolve the condition as well as to optimally treat the acute porphyria attack [29,59]. (See 'Importance of evaluating for associated/triggering conditions' above.)

Provide supportive care – Supportive care may include hydration, analgesia, anticonvulsants (if seizures are present and do not rapidly resolve), and/or correction of metabolic abnormalities such as hyponatremia. Pain during attacks is severe, and opioids are almost always required. Details are identical to patients with AIP and are discussed separately. (See "Acute intermittent porphyria: Management", section on 'Acute attack: Management of symptoms and complications' and "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)

Non-acute management

Prevention of acute attacks — Although recurrent attacks are less common in HCP than in AIP, factors that have contributed to past acute attacks or might precipitate future attacks should be identified and addressed [61]:

Avoid unsafe drugs – Potentially harmful drugs should be avoided whenever possible. Anesthesia for major surgery should avoid barbiturates and include safe agents such as propofol [66]. Information on safe and harmful drugs based on regularly updated evidence is available at the websites of the American Porphyria Foundation and the European Porphyria Network (web-links are listed above). (See 'Treatment of acute attacks' above.)

We advise patients to wear a medical alert bracelet or to carry a wallet card explaining their condition so that clinicians will be aware of avoiding unsafe medications and of treating neurovisceral manifestations in the event that the patient is unable to provide this information [29].

Avoid smoking and alcohol – We counsel individuals with acute porphyria to avoid or discontinue smoking, including use of marijuana, and to avoid alcohol intake. These substances can precipitate acute attacks via their stimulatory effects on hepatic heme synthesis. (See 'Precipitating factors' above.)

Balanced diet – A balanced diet somewhat high in carbohydrates (eg, as 60 to 70 percent of total calories) is recommended. Additional dietary carbohydrates and/or calories are unlikely to be helpful and may lead to excessive weight gain. If used, weight loss diets should provide for gradual weight loss and should be used during periods of clinical stability, in consultation with a dietitian. A dietician may also help identify dietary factors responsible for precipitating acute attacks. Precipitation of acute porphyria symptoms after bariatric surgery has been reported, and we prefer other methods of weight loss if possible [67].

Rapid treatment and prevention of infections – We ensure that all age-appropriate vaccinations are updated and rapidly treat infections that may cause metabolic stress. (See "Standard immunizations for nonpregnant adults".)

Prevention of unexplained, frequent attacks after removal of identified exacerbating factors — Unexplained, frequent attacks are rare, but such attacks are disabling and markedly affect quality of life. They can sometimes be prevented by prophylactic weekly infusions of a single dose of hemin, as discussed separately. (See "Acute intermittent porphyria: Management", section on 'Prophylactic hemin'.)

Frequent attacks occur during the luteal phase of the menstrual cycle in some females, and these can be prevented with a gonadotropin-releasing hormone (GnRH) analogue such as leuprolide acetate, which is started during the first few days of a menstrual cycle [68].

Givosiran (Givlaari) is an interfering RNA therapeutic that was approved by the US Food and Drug administration in late 2019 for the prevention of frequent recurrent attacks of acute porphyrias; approval was based on high quality evidence from clinical trials [69,70]. Experience has almost exclusively been with AIP, but the drug is likely to be effective in preventing attacks of other acute hepatic porphyrias including HCP. Givosiran targets hepatocytes. It reduces ALA and PBG for at least a month after administration by downregulating ALAS1 mRNA. Dosing and administration are discussed in detail separately. (See "Acute intermittent porphyria: Management", section on 'Givosiran'.)

Prevention and treatment of skin lesions — As in VP and porphyria cutanea tarda (PCT), blistering skin lesions are prevented by advising patients to avoid sunlight exposure. For those prone to developing symptomatic skin lesions, protective clothing and opaque mineral sunscreens containing zinc oxide or titanium oxide that block all wavelengths of light should be used. (See "Selection of sunscreen and sun-protective measures" and "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection".)

Avoidance of sunlight increases risk for vitamin D deficiency. Routine supplementation is used for those who must avoid sunlight. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

Treatment of skin lesions includes keeping them clean and dry, treating bacterial superinfection with topical (or rarely, systemic) antibiotics, and avoiding medications that appear to exacerbate the disease (eg, hormonal contraceptives in some individuals). Pain may require analgesic therapy, including aspirin, acetaminophen, or opioid analgesics. Topical steroids should be avoided.

Beta-carotene may offer some protection against acute nonblistering photosensitivity in erythropoietic protoporphyria, but is not of value in chronic blistering porphyrias such as HCP. Charcoal or cholestyramine, which act by binding porphyrins in the intestine and preventing their reabsorption, have sometimes been helpful [71]. (See "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Beta-carotene'.)

Importantly, interventions used to treat acute neurovisceral attacks and/or to treat skin lesions of PCT are not effective in treating the skin lesions of HCP and should not be used for this purpose.

Pregnancy — Pregnancy is often well tolerated in individuals with acute porphyria. If acute attacks occur during pregnancy, they should be treated similarly to other acute attacks. There are limited reports on the use of hemin in pregnancy, but experience suggests that hemin is safe and effective [72,73]. Termination of pregnancy is rarely, if ever, indicated for an acute attack of porphyria [61].

Screening and interventions for long-term complications — Long-term management issues include the following:

Monitoring of urine and plasma PBG and porphyrin levels at least yearly. Changes over time may reflect susceptibility to attacks.

Some patients with HCP may develop chronic pain, depression, or other psychiatric problems, similar to other acute porphyrias. Because there may be risk for suicide, these manifestations must be recognized and managed appropriately [29,61]. (See "Unipolar depression in adults: Assessment and diagnosis" and "Approach to the management of chronic non-cancer pain in adults".)

The risk of hepatocellular carcinoma (HCC) is increased in HCP, similar to other acute porphyrias [46]. It is generally recommended that patients with acute porphyrias, especially those with persistent increases in porphyrin precursors and porphyrins, be screened for HCC by imaging (eg, hepatic ultrasound) at six-month intervals after age 50. Screening may be initiated at a younger age for those with other risk factors such as cirrhosis, hepatitis C virus infection, or excess alcohol use. Experience indicates that monitoring serum alpha-fetoprotein levels is not useful for surveillance.

Genetic testing and counseling — Identifying a pathogenic variant in the CPOX gene in an affected patient helps confirm the diagnosis of HCP and facilitates reliable identification of relatives with latent HCP. These individuals can then be counseled to avoid certain drugs and other factors that may precipitate acute attacks of the disease, and if they develop symptoms, the diagnosis of active HCP will not be delayed. (See 'Evaluation of asymptomatic relatives' above.)

The diagnosis of HCP can be made in utero by amniocentesis, but this is seldom indicated because the prognosis in most heterozygotes is favorable and therefore pregnancy interruption is not often considered.

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".)

SUMMARY AND RECOMMENDATIONS

Pathogenesis – Hereditary coproporphyria (HCP) is an acute hepatic porphyria that causes neurovisceral symptoms (table 3) and chronic blistering cutaneous photosensitivity. HCP is autosomal dominant with incomplete penetrance. The cause is mutation in coproporphyrinogen oxidase (CPOX). The CPOX enzyme (figure 1) converts coproporphyrinogen III to protoporphyrinogen IX (table 1). Neurotoxic effects are attributed to accumulation of heme precursors (especially delta-aminolevulinic acid). Cutaneous effects are thought to be attributed to light activation of porphyrins that circulate to the skin. (See 'Pathophysiology' above.)

Prevalence – HCP affects approximately two to five per million population. (See 'Epidemiology' above.)

Presentation – HCP typically manifests after puberty; diagnostic delays are common. Neurovisceral attacks may cause central, peripheral, and autonomic nervous system dysfunction, with abdominal pain as the most common symptom (table 3). Cutaneous manifestations are uncommon and include blistering, scarring, and pigment changes on sun-exposed skin. Residual neurologic defects, depression, persistent liver enzyme elevations, and hepatocellular carcinoma can occur. (See 'Clinical features' above.)

Evaluation

Acute attack – Acute porphyria is diagnosed by elevated urinary porphobilinogen (PBG), after which treatment is started if clinically indicated (algorithm 2). Further testing determines the type of porphyria (table 4). HCP markedly increases coproporphyrin III in urine and feces (table 6 and table 5). For a patient with known HCP, acute attacks are diagnosed clinically. Infections and other triggering conditions should be evaluated. (See 'Overview of the evaluation' above and 'Evaluation of neurovisceral symptoms' above.)

Skin findings – Plasma, urine, and fecal total porphyrins are measured (algorithm 3), with fractionation of porphyrins if elevated (table 5), to differentiate HCP from other blistering cutaneous porphyrias. (See 'Evaluation of skin findings' above.)

Genetic testing – Genetic testing is recommended to confirm the diagnosis and to enable accurate screening of relatives. (See 'Evaluation of asymptomatic relatives' above and 'Diagnostic confirmation/role of genetic testing' above.)

Differential diagnosis – Considerations include other acute and cutaneous porphyrias (algorithm 1) and other causes of abdominal pain, neuropsychiatric symptoms, seizures, and liver disease. (See 'Differential diagnosis' above.)

Treatment – Neurovisceral attacks can be life-threatening. Treatment should be initiated as soon as possible. (See 'Treatment of acute attacks' above.)

Acute attacks – For attacks severe enough to warrant hospitalization, opioids, or intravenous medications or hydration; or associated with vomiting, seizures, paresis, agitation, delirium, or hyponatremia, we recommend hemin rather than carbohydrate loading (Grade 1B). Dosing is 3 to 4 mg/kg intravenously, daily until the attack abates.

For mild attacks (without the features noted above), we suggest hemin (Grade 2C). However, some mild attacks may respond to carbohydrate loading, and carbohydrate loading may be used to temporize if hemin is delayed.

Harmful medications (table 2) are avoided, concurrent illnesses/infections treated, and analgesics, hydration, anticonvulsants, and mechanical ventilation provided if needed. Listings of safe and harmful drugs are updated by the American Porphyria Foundation and European Porphyria Network.

Prevention – Triggering factors should be identified and addressed. GnRH analogues may be used to prevent frequent cyclic attacks.

For adults with ≥4 attacks per year despite avoiding triggers, we suggest givosiran (Grade 2B). Prophylactic hemin may also be effective. (See 'Prevention of acute attacks' above.)

Skin – Sun avoidance and rapid treatment of skin infections is important for selected patients. (See 'Prevention and treatment of skin lesions' above.)

Other considerations – Pregnancy is generally well tolerated. During asymptomatic periods, liver function tests and porphyrin levels may be monitored, and patients are screened for depression and hepatocellular cancer. Genetic testing and counseling is appropriate for patients and first-degree relatives. (See 'Pregnancy' above and 'Screening and interventions for long-term complications' above and 'Genetic testing and counseling' above.)

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

  1. Cacheux V, Martasek P, Fougerousse F, et al. Localization of the human coproporphyrinogen oxidase gene to chromosome band 3q12. Hum Genet 1994; 94:557.
  2. Berger H, Goldberg A. Hereditary coproporphyria. Br Med J 1955; 2:85.
  3. Martasek P, Nordmann Y, Grandchamp B. Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms. Hum Mol Genet 1994; 3:477.
  4. Martásek P. Hereditary coproporphyria. Semin Liver Dis 1998; 18:25.
  5. Fujita H, Kondo M, Taketani S, et al. Characterization and expression of cDNA encoding coproporphyrinogen oxidase from a patient with hereditary coproporphyria. Hum Mol Genet 1994; 3:1807.
  6. Lamoril J, Martasek P, Deybach JC, et al. A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria. Hum Mol Genet 1995; 4:275.
  7. Lamoril J, Puy H, Whatley SD, et al. Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria. Am J Hum Genet 2001; 68:1130.
  8. Gross U, Puy H, Meissauer U, et al. A molecular, enzymatic and clinical study in a family with hereditary coproporphyria. J Inherit Metab Dis 2002; 25:279.
  9. To-Figueras J, Badenas C, Enríquez MT, et al. Biochemical and genetic characterization of four cases of hereditary coproporphyria in Spain. Mol Genet Metab 2005; 85:160.
  10. Sassa S, Kondo M, Taketani S, et al. Molecular defects of the coproporphyrinogen oxidase gene in hereditary coproporphyria. Cell Mol Biol (Noisy-le-grand) 1997; 43:59.
  11. Lambie D, Florkowski C, Sies C, et al. A case of hereditary coproporphyria with posterior reversible encephalopathy and novel coproporphyrinogen oxidase gene mutation c.863T>G (p.Leu288Trp). Ann Clin Biochem 2018; 55:616.
  12. Hasegawa K, Tanaka H, Yamashita M, et al. Neonatal-Onset Hereditary Coproporphyria: A New Variant of Hereditary Coproporphyria. JIMD Rep 2017; 37:99.
  13. Dragneva S, Szyszka-Niagolov M, Ivanova A, et al. Seven Novel Mutations in Bulgarian Patients with Acute Hepatic Porphyrias (AHP). JIMD Rep 2014; 16:57.
  14. Barbaro M, Kotajärvi M, Harper P, Floderus Y. Identification of an AluY-mediated deletion of exon 5 in the CPOX gene by MLPA analysis in patients with hereditary coproporphyria. Clin Genet 2012; 81:249.
  15. DiPierro E, Brancaleoni V, Cappellini MD. Novel human pathological mutations. Gene symbol: CPOX. Disease: Coproporphyria. Hum Genet 2010; 127:489.
  16. Aurizi C, Lupia Palmieri G, Barbieri L, et al. Four novel mutations of the coproporphyrinogen III oxidase gene. Cell Mol Biol (Noisy-le-grand) 2009; 55:15.
  17. Gorman CS, Gill D, Darby C, et al. Hereditary coproporphyria: Report of an Irish kindred and identification of a novel gene mutation. Ir Med J 2008; 101:125.
  18. Schmitt C, Gouya L, Malonova E, et al. Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria. Hum Mol Genet 2005; 14:3089.
  19. Akagi R, Inoue R, Muranaka S, et al. Dual gene defects involving delta-aminolaevulinate dehydratase and coproporphyrinogen oxidase in a porphyria patient. Br J Haematol 2006; 132:237.
  20. Rudd A, Grant J, Varigos G, et al. Co-existence of hereditary coproporphyria and porphyria cutanea tarda: The importance of genetic testing. Australas J Dermatol 2013; 54:e50.
  21. Nordmann Y, Grandchamp B, de Verneuil H, et al. Harderoporphyria: A variant hereditary coproporphyria. J Clin Invest 1983; 72:1139.
  22. Jackson AH, Jones DM, Philip G, et al. Synthetic and biosynthetic studies of porphyrins, Part IV. Further studies of the conversion of corporporhyrinogen-III to protoporphyrin-IX: mass spectrometric investigations of the incubation of specifically deuteriated coproporhyringen-III with chicken red cell haemolysates. Int J Biochem 1980; 12:681.
  23. Elder GH, Evans JO. Evidence that the coproporphyrinogen oxidase activity of rat liver is situated in the intermembrane space of mitochondria. Biochem J 1978; 172:345.
  24. Grandchamp B, Phung N, Nordmann Y. The mitochondrial localization of coproporphyrinogen III oxidase. Biochem J 1978; 176:97.
  25. Elder GH, Smith SG, Smyth SJ. Laboratory investigation of the porphyrias. Ann Clin Biochem 1990; 27 ( Pt 5):395.
  26. Elder GH, Evans JO, Thomas N. The primary enzyme defect in hereditary coproporphyria. Lancet 1976; 2:1217.
  27. Grandchamp B, Phung N, Nordmann Y. Homozygous case of hereditary coproporphyria. Lancet 1977; 2:1348.
  28. Meissner P, Adams P, Kirsch R. Allosteric inhibition of human lymphoblast and purified porphobilinogen deaminase by protoporphyrinogen and coproporphyrinogen. A possible mechanism for the acute attack of variegate porphyria. J Clin Invest 1993; 91:1436.
  29. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 2005; 142:439.
  30. Bonkovsky HL. Neurovisceral porphyrias: What a hematologist needs to know. Hematology Am Soc Hematol Educ Program 2005; :24.
  31. Meyer UA, Schuurmans MM, Lindberg RL. Acute porphyrias: Pathogenesis of neurological manifestations. Semin Liver Dis 1998; 18:43.
  32. Bissell DM, Lai JC, Meister RK, Blanc PD. Role of delta-aminolevulinic acid in the symptoms of acute porphyria. Am J Med 2015; 128:313.
  33. Bloomer JR, Berk PD, Bonkowsky HL, et al. Blood volume and bilirubin production in acute intermittent porphyria. N Engl J Med 1971; 284:17.
  34. Seshabhattar P, Morrow JS. Syndrome of inappropriate antidiuretic hormone secretion associated with coproporphyria: Case report and review of literature. Endocr Pract 2007; 13:164.
  35. Valle G, Guida CC, Nasuto M, et al. Cerebral hypoperfusion in hereditary coproporphyria (HCP): A single photon emission computed tomography (SPECT) study. Endocr Metab Immune Disord Drug Targets 2016; 16:39.
  36. Di Trapani G, Casali C, Tonali P, Topi GC. Peripheral nerve findings in hereditary coproporphyria. Light and ultrastructural studies in two sural nerve biopsies. Acta Neuropathol 1984; 63:96.
  37. Podvinec M, Handschin C, Looser R, Meyer UA. Identification of the xenosensors regulating human 5-aminolevulinate synthase. Proc Natl Acad Sci U S A 2004; 101:9127.
  38. Peyer AK, Jung D, Beer M, et al. Regulation of human liver delta-aminolevulinic acid synthase by bile acids. Hepatology 2007; 46:1960.
  39. With TK. Hereditary coproporphyria and variegate porphyria in Denmark. Dan Med Bull 1983; 30:106.
  40. Elder G, Harper P, Badminton M, et al. The incidence of inherited porphyrias in Europe. J Inherit Metab Dis 2013; 36:849.
  41. Brodie MJ, Thompson GG, Moore MR, et al. Hereditary coproporphyria. Demonstration of the abnormalities in haem biosynthesis in peripheral blood. Q J Med 1977; 46:229.
  42. Kühnel A, Gross U, Doss MO. Hereditary coproporphyria in Germany: Clinical-biochemical studies in 53 patients. Clin Biochem 2000; 33:465.
  43. Barohn RJ, Sanchez JA, Anderson KE. Acute peripheral neuropathy due to hereditary coproporphyria. Muscle Nerve 1994; 17:793.
  44. Bonkovsky HL, Maddukuri VC, Yazici C, et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med 2014; 127:1233.
  45. Ramanujam VM, Anderson KE. Porphyria diagnostics - Part 1: A brief overview of the porphyrias. Curr Protoc Hum Genet 2015; 86:17.20.1.
  46. Andant C, Puy H, Deybach JC, et al. Occurrence of hepatocellular carcinoma in a case of hereditary coproporphyria. Am J Gastroenterol 1997; 92:1389.
  47. Andant C, Puy H, Bogard C, et al. Hepatocellular carcinoma in patients with acute hepatic porphyria: Frequency of occurrence and related factors. J Hepatol 2000; 32:933.
  48. Lamoril J, Puy H, Gouya L, et al. Neonatal hemolytic anemia due to inherited harderoporphyria: Clinical characteristics and molecular basis. Blood 1998; 91:1453.
  49. Hasanoglu A, Balwani M, Kasapkara CS, et al. Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R. J Inherit Metab Dis 2011; 34:225.
  50. Moghe A, Ramanujam VMS, Phillips JD, et al. Harderoporphyria: Case of lifelong photosensitivity associated with compound heterozygous coproporphyrinogen oxidase (CPOX) mutations. Mol Genet Metab Rep 2019; 19:100457.
  51. Hift RJ, Davidson BP, van der Hooft C, et al. Plasma fluorescence scanning and fecal porphyrin analysis for the diagnosis of variegate porphyria: precise determination of sensitivity and specificity with detection of protoporphyrinogen oxidase mutations as a reference standard. Clin Chem 2004; 50:915.
  52. Sassa S. Modern diagnosis and management of the porphyrias. Br J Haematol 2006; 135:281.
  53. Chen B, Whatley S, Badminton M, et al. International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias. Genet Med 2019; 21:2605.
  54. Blake D, McManus J, Cronin V, Ratnaike S. Fecal coproporphyrin isomers in hereditary coproporphyria. Clin Chem 1992; 38:96.
  55. Savić Z, Vracarić V, Hadnadev L, et al. [Hereditary coproporphyria from clinician's point of view--a case report]. Med Pregl 2013; 66:411.
  56. Whatley SD, Badminton MN. Role of genetic testing in the management of patients with inherited porphyria and their families. Ann Clin Biochem 2013; 50:204.
  57. Chen B, Solis-Villa C, Hakenberg J, et al. Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease. Hum Mutat 2016; 37:1215.
  58. Woods JS, Heyer NJ, Echeverria D, et al. Modification of neurobehavioral effects of mercury by a genetic polymorphism of coproporphyrinogen oxidase in children. Neurotoxicol Teratol 2012; 34:513.
  59. Harper P, Wahlin S. Treatment options in acute porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria. Curr Treat Options Gastroenterol 2007; 10:444.
  60. Stein P, Badminton M, Barth J, et al. Best practice guidelines on clinical management of acute attacks of porphyria and their complications. Ann Clin Biochem 2013; 50:217.
  61. Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: Recommendations for evaluation and long-term management. Hepatology 2017; 66:1314.
  62. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: Evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine (Baltimore) 2005; 84:48.
  63. Anderson KE, Collins S. Open-label study of hemin for acute porphyria: Clinical practice implications. Am J Med 2006; 119:801.e19.
  64. McColl KE, Moore MR, Thompson GG, Goldberg A. Treatment with haematin in acute hepatic porphyria. Q J Med 1981; 50:161.
  65. Pierach CA, Bossenmaier I, Cardinal R, et al. Hematin therapy in porphyric attacks. Klin Wochenschr 1980; 58:829.
  66. Meissner PN, Harrison GG, Hift RJ. Propofol as an I.V. anaesthetic induction agent in variegate porphyria. Br J Anaesth 1991; 66:60.
  67. Bonkovsky HL, Siao P, Roig Z, et al. Case records of the Massachusetts General Hospital. Case 20-2008. A 57-year-old woman with abdominal pain and weakness after gastric bypass surgery. N Engl J Med 2008; 358:2813.
  68. Anderson KE, Spitz IM, Bardin CW, Kappas A. A gonadotropin releasing hormone analogue prevents cyclical attacks of porphyria. Arch Intern Med 1990; 150:1469.
  69. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med 2017; 377:862.
  70. Ventura P, Bonkovsky HL, Gouya L, et al. Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study. Liver Int 2022; 42:161.
  71. Hunter JA, Khan SA, Hope E, et al. Hereditary coproporphyria. Photosensitivity, jaundice and neuropsychiatric manifestations associated with pregnancy. Br J Dermatol 1971; 84:301.
  72. Farfaras A, Zagouri F, Zografos G, et al. Acute intermittent porphyria in pregnancy: a common misdiagnosis. Clin Exp Obstet Gynecol 2010; 37:256.
  73. Wenger S, Meisinger V, Brücke T, Deecke L. Acute porphyric neuropathy during pregnancy--effect of haematin therapy. Eur Neurol 1998; 39:187.
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