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Hereditary Coproporphyria

, MD, , MD, , BS, and , MD.

Author Information
, MD
University of California San Francisco
San Francisco, California
, MD
University of California San Francisco
San Francisco, California
, BS
University of California San Francisco
San Francisco, California
, MD
University of California San Francisco
San Francisco, California

Initial Posting: .

Summary

Disease characteristics. Hereditary coproporphyria (HCP) is an acute (hepatic) porphyria in which the acute symptoms are neurovisceral and occur in discrete episodes. Attacks typically start in the abdomen with low-grade pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting. In some individuals, the pain is predominantly in the back or extremities. When an acute attack is untreated, a motor neuropathy may develop over a period of days or a few weeks. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Some individuals experience respiratory insufficiency due to loss of innervation of the diaphragm and muscles of respiration. Acute attacks are associated commonly with use of certain medications, caloric deprivation, and changes in female reproductive hormones. About 20% of those with an acute attack also experience photosensitivity associated with bullae and skin fragility.

Diagnosis/testing. The most sensitive and specific biochemical screening test for any one of the acute porphyrias (including HCP) during an acute attack is a striking increase in urinary porphobilinogen (PBG). Quantitative analysis of porphyrins in both urine and feces is essential to distinguish between the different acute porphyrias and establish the diagnosis of HCP. Identification of a heterozygous mutation in CPOX (encoding the enzyme coproporphyringen-III oxidase) confirms the diagnosis and enables family studies.

Management. Treatment of manifestations: Acute attacks are treated by discontinuation of any medications thought to induce attacks, management of dehydration and/or hyponatremia, administration of carbohydrate, and infusion of hematin. Treatment of symptoms and complications should be with medications known to be safe in acute porphyria (see www.drugs-porphyria.org).

A minority of affected individuals experience repeat acute attacks, in which case management strategies include suppression of ovulation in females, prophylactic use of hematin, and liver transplantation when attacks and neurologic complications persist despite multiple courses of hematin.

Prevention of primary manifestations: Agents or circumstances that may trigger an acute attack (including use of oral contraception in women) are avoided. Suppression of menses using a GnRH agonist (leuprolide, nafarelin, and others) may help CPOX heterozygotes who experience monthly exacerbations.

Prevention of secondary complications: In CPOX heterozygotes undergoing surgery, intravenous glucose is provided in the perioperative period and non-barbiturate agents are used for induction of anesthesia.

Agents/circumstances to avoid: Fasting, use of female reproductive hormones, and certain drugs including barbiturates and phenytoin.

Evaluation of relatives at risk: If the family-specific CPOX mutation is known, clarification of the genetic status of relatives at risk allows early diagnosis of heterozygotes and education regarding risk factors for an acute attack.

Genetic counseling. HCP is inherited in an autosomal dominant manner with reduced penetrance. Most individuals with HCP have an affected parent; the proportion with a de novo mutation is unknown. Each child of an individual with HCP has a 50% chance of inheriting the CPOX mutation. Because of reduced penetrance, many individuals with a CPOX mutation have no signs or symptoms of HCP. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in an affected family member is known. However, because the prenatal detection of a CPOX mutation does not predict the presence or severity of symptoms, the authors’ opinion is that prenatal testing is not warranted unless pregnancy termination is being considered.

Diagnosis

Hereditary coproporphyria (HCP) is classified as both an acute (hepatic) porphyria (with neurologic manifestations that occur as discrete, severe episodes) and a chronic (cutaneous) porphyria with longstanding photosensitivity.

Acute hepatic porphyria. HCP is suspected in individuals with the following symptoms or findings:

  • Nausea for at least 48 hours
  • Abdominal, back, or extremity pain for at least 48 hours
  • New-onset seizures
  • Hyponatremia

    Note: Although disease-causing CPOX mutations occur equally in males and females, acute attacks are much more frequent in women, mainly between ages 16 and 45 years (the years of active ovulation).

Chronic cutaneous porphyria. HCP is suspected in individuals with bullae and fragility of light-exposed skin which result in depigmented scars; however, the cutaneous signs occur in only a minority of heterozygotes, even during an acute attack.

Testing

The most sensitive and specific biochemical diagnostic tests for HCP are detailed in Table 1.

  • Active HCP is suggested by a quantitative urinary PBG that is at least threefold the upper limit of normal.
  • The characteristic finding in stool is COPRO >> PROTO, quantified as units/g dry weight of feces. Note: Some laboratories report units/24 hours, which is inherently inaccurate. US laboratories that do the more precise analysis include ARUP (Salt Lake City, UT) and the Porphyria Laboratory, University of Texas Medical Branch, K Anderson, MD, Director (Galveston, TX).
  • The diagnosis is further substantiated by analysis of the COPRO-III/COPRO-I fecal porphyrin ratio, showing that 60%-95% of the total COPRO is isomer-III. In a normal (or ‘negative’) test, the predominant fecal porphyrin is PROTO, and the COPRO isomer III/I ratio in many cases is <0.5 [Kühnel et al 2000].
  • Identification of a heterozygous mutation in CPOX, encoding the enzyme coproporphyringen-III oxidase, confirms the diagnosis (Table 2).

Table 1. Biochemical Characteristics of Hereditary Coproporphyria (HCP)

Deficient EnzymeUrineStool
ActiveAsxActiveAsx
Coproporphyringen-III oxidase 1, 2↑PBG 3, 4, 5
↑COPRO 6
Normal PBG
COPRO 7
COPRO >> PROTO 8See footnote 9

Active = symptomatic CPOX heterozygotes

Asx = asymptomatic CPOX heterozygotes

PBG = porphobilinogen

NormaI PBG = <2 mg (0.85 μmol) per g urine creatinine

COPRO = coproporphyrin

PROTO = protoporphyrin

1. Also known as coproporphyrinogen oxidase and coproporphyrinogen decarboxylase

2. The enzyme assay is not widely available and is not used for diagnostic purposes

3. Results of the rapid qualitative test for PBG (Thermo Scientific) agree well with standard quantitative measurements [Vogeser & Stauch, 2011].

4. Active HCP is suggested by a quantitative PBG that is at least 3-fold the upper limit of normal

5. Commercial laboratories offer quantitative delta aminolevulinic acid (ALA), PBG, and fractionated urine porphyrins. Values normalized to urine creatinine are satisfactory for clinical use, making a 24-hour collection unnecessary.

6. See Differential Diagnosis for discussion of nonspecific elevation of COPRO in the urine.

7. Fractionated urine porphyrins may reveal a minor rise in COPRO (<3-fold the upper limit of normal); however, this is nonspecific and insufficient for diagnosis (see Differential Diagnosis).

8. 60%-95% of the total COPRO is isomer-III.

9. Fecal porphyrin analysis is the best test for distinguishing HCP from nonspecific coproporphyrinuria: heterozygotes show a predominance of fecal COPRO and an elevated COPRO III/I ratio (see Testing).

Molecular Genetic Testing

Gene. CPOX is the only gene in which mutations are known to cause hereditary coproporphyria (HCP).

Table 2. Summary of Molecular Genetic Testing Used in Hereditary Coproporphyria

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
CPOXSequence analysisSequence variants 429/31 5
Deletion / duplication analysis 6 Exonic or whole-gene deletionsSee footnote 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Sequence analysis found a mutation in 29 of 31 (94%) individuals with the clinical and biochemical diagnosis of HCP [Whatley et al 2009].

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. To date, a 13-kb deletion extending from exon 4 to the 3’UTR [Whatley et al 2009] and a 1.3-kb deletion spanning exon 5 (found in four Swedish families) [Barbaro et al 2012] have been reported.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • For an individual with pain and neurologic signs, the initial goal is to determine if the symptoms can be attributed to an attack related to any one of the acute porphyrias (i.e., ALA dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria) (see Differential Diagnosis), which can be determined by a rapid test for urinary porphobilinogen (PBG) (Table 1). Acute attacks are associated invariably with a striking increase in urinary PBG.

    Note: Since initial management is the same for all four types of acute porphyria, it is not necessary to determine at the outset of treatment which one of the four types of acute porphyria is present.
  • Once the diagnosis of an acute porphyria is established, quantitative analysis of porphyrins in both urine and feces may help define the specific type (Figure 1).
  • The specific type of porphyria is confirmed by molecular genetic testing for mutation of the relevant gene.
Figure 1

Figure

Figure 1. Excretion profile of the hepatic porphyrias

Profile of heme precursor excretion for the types of hepatic porphyria. The pathway of heme synthesis (arrows) is served by a series of enzymes (boxes). Mutations that decrease the (more...)

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family. Note: Although some CPOX heterozygotes have a diagnostic biochemical profile of heme precursors in urine and feces (see ‘Active’ columns in Table 1), many have normal biochemical test results (see ‘Asymptomatic’ columns in Table 1) and can be diagnosed only by molecular genetic testing.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Note: Because of reduced penetrance, many individuals heterozygous for a CPOX mutation do not manifest signs and symptoms of HCP.

Clinical Description

Natural History

Hereditary coproporphyria (HCP) is classified as both an acute and chronic porphyria. Porphyrias with neurologic manifestations are considered acute, because the symptoms occur as discrete, severe episodes. Porphyrias with cutaneous manifestations are considered chronic, because photosensitivity is longstanding (see Table 3).

In a German study of 46 individuals with acute HCP, 90% had abdominal pain; only 13% had cutaneous findings despite substantial overproduction of coproporphyrin [Kühnel et al 2000]. An earlier British study of 111 individuals with HCP reported similar findings [Brodie et al 1977].

Fertility and longevity do not appear to be reduced in CPOX heterozygotes.

Acute Attacks

The initial symptoms of an acute attack are nonspecific, consisting of low-grade abdominal pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting of all oral intake.

Typically the pain is not well-localized but in some instances does mimic acute inflammation of the gallbladder, appendix, or other intra-abdominal organ. In most instances the abdominal examination is unremarkable except for diminished bowel sounds consistent with ileus, which is common and can be seen on abdominal radiography. Typically fever is absent. In a young woman of reproductive age, the symptoms may raise the question of early pregnancy.

Prior to the widespread use of abdominal imaging in the emergency room setting, some individuals with abdominal pain and undiagnosed acute porphyria underwent urgent exploratory surgery. Thus, a history of abdominal surgery with negative findings was considered characteristic of acute porphyria.

A minority of affected individuals has predominantly back or extremity pain, which is usually deep and aching, not localized to joints or muscle groups.

Neurologic manifestations. Seizures may occur early in an attack and be the problem that brings the patient to medical attention. In a young woman with abdominal pain and new-onset seizures, it is critical to consider acute porphyria because of the implications for seizure management (see Management).

When an attack is unrecognized as such or treated with inappropriate medications, it may progress to a motor neuropathy, which typically occurs many days to a few weeks after the onset of symptoms. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Neurosensory function remains largely intact.

In some individuals the motor neuropathy eventually involves nerves serving the diaphragm and muscles of respiration. Ventilator support may be needed.

Tachycardia and bowel dysmotility (manifest as constipation) are common in acute attacks and believed to represent involvement of the autonomic nervous system.

Of note, when the acute attack is recognized early and treated appropriately (see Management), the outlook for survival and eventual complete recovery is good.

Psychosis. The mental status of people presenting with an acute attack of porphyria varies widely and can include psychosis. Commonly, however, the predominant feature is distress (including pain) that may seem hysterical or feigned, given a negative examination, absence of fever, and abdominal imaging showing some ileus only. Incessant demands for relief may be interpreted as drug-seeking behavior.

Because people with an acute porphyria attack may display an altered affect, it has been speculated that mental illness is a long-term consequence of acute porphyria and that mental institutions may house a disproportionately large numbers of individuals with undiagnosed acute porphyria. Screening of residents in mental health facilities by urinary PBG and/or PBG deaminase activity in blood (which diagnoses acute intermittent porphyria) has been done, with mixed results [Jara-Prado et al 2000]. The experience of those who have monitored patients over many years suggests that heterozygotes who are at risk for one of the acute porphyrias are no more prone to chronic mental illness than the general population; however, a prospective study is needed.

Circumstances commonly associated with acute attacks are caloric deprivation, changes in female reproductive hormones, and use of porphyria-inducing medications or drugs:

  • Caloric deprivation. Fasting appears to sensitize the heme-synthetic pathway to an inducer, which could be external (i.e., a medication) or internal (progesterone and related hormones). The sensitizing effect of caloric deprivation was demonstrated in the 1960s in experimental animals and has been confirmed by clinical observation. People who fail to eat because of intercurrent illness or who undertake drastic weight loss are predisposed to an acute attack. First attacks have been reported after reduction gastroplasty for obesity [Bonkovsky et al 2008]. CPOX heterozygotes undergoing surgery are at risk because of the routine preoperative fast. This and other anecdotal experience have led to consensus that the first line of treatment for an acute attack is intravenous glucose, which occasionally is helpful.
  • Changes in female reproductive hormones. A role for female reproductive hormones can be inferred from the fact that acute attacks are infrequent prior to menarche and after menopause. Some women have monthly attacks that appear a few days before the onset of menstruation (when progestins peak). Attacks have been linked to use of oral contraceptives; the risk may be associated more with the progesterone component than the estrogen component.
  • Use of porphyria-inducing medications or drugs. See Agents/Circumstances to Avoid.

Chronic (cutaneous) manifestations. Photocutaneous damage is present in only a small minority of those with acute attacks. Bullae and fragility of light-exposed skin, in particular the backs of the hands, result in depigmented scars. Facial skin damage also occurs, with excess hair growth on the temples, ears, and cheeks; this is more noticeable in women than in men.

The cutaneous findings in HCP resemble those in porphyria cutanea tarda (PCT) and in variegate porphyria (VP).

Threshold for a pathogenic effect of porphyrins and their precursors. Clinically active acute porphyria is associated with substantial elevation of the precursors ALA and PBG in the blood and urine; the cutaneous porphyrias are associated with increased porphyrins in blood, urine, and feces. In the acute porphyrias and cutaneous porphyrias, a threshold for symptoms appears to exist.

  • Acute (hepatic) porphyrias. A threshold for acute attacks is suggested by the fact that in virtually all symptomatic individuals, urinary PBG excretion exceeds 25 mg/g creatinine, or more than tenfold the upper limit of normal. Urinary ALA excretion increases roughly in parallel.
  • In contrast, in asymptomatic individuals the baseline urinary PBG excretion varies widely, usually low or normal but occasionally exceeding 25 mg/g creatinine. For this reason, it is advisable to establish the baseline urinary PBG excretion for CPOX heterozygotes (see Evaluations Following Initial Diagnosis).
  • Chronic (cutaneous) porphyrias. A threshold has been well defined for porphyria cutanea tarda (PCT), in which photosensitivity occurs at values of urine uroporphyrin (the predominant pathway intermediate) that are more than 20-fold the upper limit of normal. However, the same is not apparent with regard to urine coproporphyrin: only a minority of CPOX heterozygotes exhibit any photosensitivity.

    Of note, in individuals with HCP and chronic liver disease the cutaneous component may be more prominent than expected for the observed urine or plasma PBG concentration. Coproporphyrin leaves the plasma largely via the liver going into bile. In chronic liver disease, bile transport processes or bile formation may be impaired, leading to accumulation of coproporphyrin in plasma, which then results in photosensitivity.

Pathophysiology

Although the bone marrow actively produces heme (for hemoglobin synthesis), the liver is the main source of precursors in the acute (hepatic) porphyrias: acute attacks are precipitated when environmental factors stimulate increased hepatic heme synthesis and the genetically altered step in heme production becomes rate-limiting (Figure 1). Heme synthesis in the liver largely serves production of the cytochrome P450 family of heme-proteins, which are present in high concentration in the liver and have a relatively high turnover rate.

It is estimated that 20%-25% of total heme production normally occurs in the liver [Billing 1978]; however, that proportion increases when the liver is exposed to xenobiotics that undergo oxidative metabolism and stimulate cytochrome production (especially CYP3A4).

Acute attacks. The precursors ALA and PBG, unlike porphyrins, are colorless and non-fluorescent and do not contribute to photosensitivity in porphyria. Rather, ALA and PBG are highly associated with the neurologic manifestations of acute porphyria and are probably causal, although the mechanism remains speculative. The currently favored hypothesis implicates ALA (more than PBG), in part because acute neurologic symptoms occur in two other conditions involving overproduction of ALA but not PBG (delta aminolevulinic acid dehydratase deficiency porphyria (ADP) and tyrosinemia). Experimental studies indicate that ALA is a pro-oxidant species that is capable of damaging the inner membrane of mitochondria [Vercesi et al 1994].

Organ transplantation has established that the liver is responsible for acute attacks. Liver transplantation has cured individuals with refractory acute symptoms [Soonawalla et al 2004]. Moreover, in one instance, transplantation of a porphyric liver into an older male with cancer (who had no other donors) resulted in high circulating levels of ALA and PBG and symptoms of porphyria [Dowman et al 2011].

Cutaneous manifestations. Porphyrins are energized by blue light (peak wave length 410 nm). In a test tube, as activated porphyrins relax back to the ground state the released energy is evident as red fluorescence (ca. 625 nm). In vivo, the cycle of light activation and relaxation back to the ground state causes tissue damage, the nature of which varies with the porphyrin. URO and COPRO give rise to bullae and fragility of light-exposed skin, in particular the backs of the hands.

Genotype-Phenotype Correlations

HCP. HCP-causing mutations in CPOX are not clustered around the enzymatic site. Furthermore, no correlation exists between the clinical phenotype and the residual enzymatic activity measured in vitro for a given mutation [Lamoril et al 2001].

Homozygotes for CPOX mutations that cause minimal or no symptoms in heterozygotes have been reported to have very low coproporphyringen-III oxidase activity and a severe phenotype [Schmitt et al 2005, Hasanoglu et al 2011]. (See Genetically Related Disorders.)

Double heterozygosity for mutations in genes causing two different types of acute (hepatic) porphyria. Double heterozygotes for a mutation in CPOX and either a mutation in PPOX (variegate porphyria [VP]) [van Tuyll van Serooskerken et al 2011] or ALAD (ALA dehydratase deficiency porphyria [ADP]) [Akagi et al 2006] have been described. The phenotypes of such double heterozygotes vary but are not necessarily more severe than those associated with heterozygosity for either mutation alone, suggesting that double heterozygotes for two different types of acute porphyria may not be as rare as has been assumed.

Penetrance

Because population studies to determine the prevalence of HCP heterozygosity have not been done, the penetrance of CPOX mutations is unknown. Given the rarity of acute attacks of HCP relative to AIP, it is suspected that only a small minority of CPOX heterozygotes express the clinical disease. In 32 members of an Australian family, 14 (including 10 adults) were determined to have HCP on the basis of a high fecal COPRO III/I ratio and/or low lymphocyte CPOX enzyme activity; however, only one had clinical symptoms of porphyria [Blake et al 1992].

HCP, along with AIP and VP, are genetic disorders with reduced penetrance. Heme production in most heterozygotes appears to be adequate for physiologic homeostasis. Thus, environmental or physiologic factors play a role in the pathogenesis of acute attacks (see Agents/Circumstances to Avoid). Although genetic co-factors may also be involved, none has been identified to date.

Nomenclature

‘Coproporphyria’ describes urine with an elevated level of coproporphyrin of any cause.

Coproporphyria in individuals heterozygous for a CPOX mutation is referred to as hereditary coproporphyria.

Prevalence

Clinical experience suggests that HCP is the least prevalent of the three principal types of acute porphyria: AIP, VP, and HCP. However, symptoms in HCP may be less frequent than in AIP or VP. Population surveys for CPOX mutations have not been reported.

Differential Diagnosis

The genetic porphyrias comprise a group of distinct diseases, each resulting from alteration of a specific step in the heme synthesis pathway that results in accumulation of a specific substrate (Figure 1).

In Table 3 the porphyrias are grouped by their principal clinical manifestations (neurolovisceral or cutaneous) and the tissue origin of the excess production of pathway intermediates (liver [i.e., hepatic] or bone marrow [i.e., erythropoietic]).

  • Porphyrias with neurovisceral manifestations are considered acute because the symptoms occur as discrete, severe episodes, which may be spontaneous but frequently are induced by external factors. The four acute porphyrias are: ALA dehydratase-deficiency porphyria (ADP), acute intermittent porphyria (AIP), HCP, and variegate porphyria (VP). Only a few cases of ADP have been reported in the world literature.
  • Porphyrias with cutaneous manifestations include either chronic blistering skin lesions (i.e., VP as well as PCT, HCP, CEP, and hepatoerythropoietic porphyria [HEP]) or acute non-blistering photosensitivity (i.e., EPP and XLP).

Table 3. Classification of the Hereditary Porphyrias

Type of PorphyriaFindingsMode of Inheritance
Neurovisceral 1 Photocutaneous
Hepatic
ADP+0AR
AIP+0AD
HCP++AD
PCT type II0+AD
VP++AD
Erythropoietic
CEP0+AR
EPP, AR02AR
XLP02XL

ADP = ALA dehydratase-deficiency porphyria

AIP = acute intermittent porphyria

HCP = hereditary coproporphyria

PCT = porphyria cutanea tarda

VP = variegate porphyria

CEP = congenital erythropoietic porphyria

EPP = erythropoietic protoporphyria

XLP= X-Linked protoporphyria

0 = no symptoms

+ = mild to severe symptoms

AR=autosomal recessive

AD=autosomal dominant

XL=X-linked

1. Porphyrias with neurovisceral manifestations have been considered ‘acute’ in part because the most common of these disorders, named “acute intermittent porphyria,” is the prototype for the neurovisceral porphyrias in which symptoms can occur acutely as discrete, severe episodes; however, affected individuals develop chronic manifestations and remain susceptible to exacerbating factors throughout their lives.

2. Photocutaneous manifestations of EPP are acute and non-blistering, in contrast to the chronic blistering in the other cutaneous porphyrias (including VP).

While these clinical distinctions are important for the differential diagnosis, biochemical analysis is always necessary; however, biochemical testing may fail to distinguish HCP from VP, in which case molecular genetic testing of CPOX (HCP) and PPOX (VP) may be the only definitive diagnostic test.

In individuals with progressive weakness due to the motor neuropathy caused by one of the acute porphyrias (AIP, VP, HCP, and ADP), the entity most likely to be considered is acute ascending polyneuropathy, the Guillain-Barré syndrome. However, abdominal pain, constipation, and tachycardia precede the acute neurologic illness in the acute porphyrias but not in Guillain-Barré syndrome. CSF protein is normal in the acute porphyrias, but elevated in Guillain-Barré syndrome. Urinary PBG is markedly elevated in the acute porphyrias when symptoms are present, but normal in Guillain-Barré syndrome.

Coproporphyrinuria

  • Lead intoxication. The predominant elevation of coproporphyrin that is characteristic of HCP can also be seen in lead intoxication, in which the symptoms resemble those of an acute porphyria. The additional diagnostic finding in heavy metal poisoning is elevation of ALA unaccompanied by any increase in PBG.
  • Rotor syndrome, inherited in an autosomal recessive manner and caused by simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3, is also associated with coproporphyrinuria [van de Steeg et al 2012].
  • Nonspecific coproporphyrinuria. The most important differential diagnosis in an individual with elevated urine coproporphyrin is HCP vs. nonspecific coproporphyrinuria. Of all the people referred to a porphyria center, the largest subgroup has nonspecific coproporphyrinuria. Elevation of urine coproporphyrin is associated with a wide range of clinical conditions. It is particularly frequent in acquired liver disease (e.g., chronic viral hepatitis), but can be seen also in neurologic or hematologic diseases. Rarely, it is caused by an inherited hepatic transporter defect.

    Two tests helpful for the differential diagnosis of coproporphyrinuria are:
    • Urine PBG, which is more than tenfold elevated in the inherited acute porphyrias with active symptoms

      AND
    • The ratio of copro-III to copro-I in feces as measured by high-performance liquid chromatography (used for fecal porphyrin fractionation in most commercial labs). In nonspecific coproporphyrinuria the ratio is usually similar to that in normal controls [Gibson et al 2000].

For a case example of misdiagnosis of nonspecific coproporphyrinuria, click here.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with hereditary coproporphyria (HCP), the following evaluations are recommended in an individual with acute abdominal symptoms:

  • Review of medications for those that are thought to induce attacks (See Agents/Circumstances to Avoid.)
  • Detailed neurologic examination for signs of motor neuropathy (which indicates a more advanced attack and, therefore, the need for early treatment with hematin).
  • Inquiry into possibility of seizures
  • Measurement of serum sodium concentration; hyponatremia is characteristic and may be profound (serum sodium concentration <110 mEq/L), requiring urgent correction with due regard for the risk of central pontine myelinolysis.
  • Quantitation of urinary excretion of PBG on several occasions over a few months to establish a baseline for future use in determining if a new symptom or drug reaction is due to an acute attack (In an acute attack urinary excretion of PBG is substantially elevated over the baseline.)
  • Medical genetics consultation

Treatment of Manifestations

Acute Attacks

Further details on the treatment of acute porphyria are available in a published review [Anderson et al 2005].

In an individual presenting with acute abdominal symptoms:

  • Identify and discontinue any medications that are thought to induce attacks (see Agents/Circumstances to Avoid).
  • Discontinue all non-essential medications.
  • Evaluate those with nausea and vomiting for dehydration and hyponatremia, which is characteristic and may be profound (serum sodium concentration <110 mEq/L), requiring urgent correction with due regard for the risk of central pontine myelinolysis.
  • Provide glucose-containing IV solution to reverse the fasting state. Note: Caution is indicated in patients with hyponatremia as aggressive administration of dextrose in water may cause the serum sodium concentration to drop to a critically low level.
  • Treat seizures with a short-acting benzodiazepine (e.g., midazolam) or with magnesium, which has been used for eclamptic seizures [Sadeh et al 1991]. Note: A number of the commonly used anti-seizure medications, including phenytoin and sodium valproate, are contraindicated because of the risk of further exacerbating an attack (see Agents/Circumstances to Avoid).
  • Intravenous hematin is considered the treatment of choice in moderate to severe acute attacks. Order hematin at the time that an acute attack requires hospitalization. Although hematin is not stocked by most hospital pharmacies, it can be obtained by overnight express from the manufacturer (Panhematin®, Lundbeck, 1-800-455-1141). An alternative in Europe and elsewhere is heme arginate (Normosang®; not yet approved in the US).
    • Some individuals recover with a glucose infusion only; those who do not respond in 24 to 48 hours should receive intravenous hematin.
    • When signs of a motor neuropathy are present, hematin is given as soon as possible. Hematin given at the initial signs of motor neuropathy may halt its progression; however, it has no effect on established motor deficits, which are the result of axonal degeneration.
    • Hematin is reconstituted at the bedside as described in the package insert. Human albumin may be used in place of water (132 mL of a 25% albumin solution) to reduce the risk of a chemical phlebitis, which is the main side effect of hematin administration [Anderson et al 2006].
      • The infusion is started without delay, as hematin in solution decays rapidly [Goetsch & Bissell 1986].
      • The preparation is given into a large peripheral vein or via central line over 10-15 minutes so as to minimize the risk of phlebitis. The dose is weight based at 3-4 mg/kg; 200 mg once daily is appropriate for most individuals.

The following responses to hematin infusion can be expected:

  • Decrease in the urine concentration of PBG, the first sign, occurs after two doses.
  • Clinical improvement is seen after a total of three or four doses, and typically is dramatic, with no further need of narcotic analgesia [Bissell 1988].
  • The motor neuropathy of acute attacks, when it occurs, does not respond to hematin administration. Return of function requires axonal regeneration and takes many months. Although it can be complete, some individuals have residual wrist drop or foot drop.

Liver transplantation. The experience with liver transplantation in acute porphyria is growing, with accumulating evidence that transplantation is curative in selected severe cases. The status of the disease in candidates for liver transplantation must be well-documented biochemically: they must not have responded to multiple courses of hematin and must be demonstrating neurologic complications.

Chronic (Cutaneous) Manifestations

For low-grade chronic or seasonal cutaneous symptoms, the only effective current treatment is avoidance of sun/light, whether direct or through window glass. Damage is caused by long-wave ultraviolet light, which passes through window glass:

  • Sun protection using protective clothing such as long sleeves, gloves, and wide brimmed hats
  • Protective tinted glass for cars and windows to prevent exposure to UV light. Grey or smoke colored filters provide only partial protection.

Note: Topical sunscreens are not helpful because they block UV light, not the blue light that causes porphyrin-related skin injury.

The association of cutaneous manifestations with severe attacks (in which porphyrins as well as ALA and PBG are markedly increased) suggests that the cutaneous, as well as the neurovisceral, symptoms could respond to hematin administration. Indeed, this is the finding of a recent case report of an individual with severe HCP who was given ‘maintenance’ hematin [Ma et al 2011].

Other. For more prolonged control of seizures, the combination of gabapentin and propofol is effective and safe.

Prevention of Primary Manifestations

Prevention of acute attacks involves the following:

  • Molecular genetic testing of at-risk relatives to identify those heterozygous for the CPOX mutation identified in the proband
  • Education of CPOX heterozygotes regarding circumstances that may trigger an acute attack (see Clinical Description).
  • Selection of appropriate contraception for females. Oral contraceptives (birth control pills) are risky and not recommended. The recommended method of birth control for HCP heterozygotes is an IUD plus a barrier (diaphragm and/or condom).
    • A copper-eluting IUD is theoretically the safest in porphyria.
    • The hormone-eluting variety also may be safe because the systemic increase in hormone is quite small; however, little information exists.
  • Suppression of menses using a GnRH agonist. Leuprolide, nafarelin, and other GnRH agonists may help CPOX heterozygotes who experience monthly exacerbations.

Prevention of acute attacks does not involve the following:

  • Use of glucose. Because glucose is used to treat acute attacks, its use in preventing attacks has been suggested, and is in fact touted in lay discussions of porphyria; however, there is no evidence that heterozygotes can protect themselves by overeating or adopting a high-carbohydrate diet; furthermore, such a diet increases the risk for obesity. Heterozygotes should adhere to a healthful diet with the usual balance of protein, fat, and carbohydrate. Weight loss is possible but only by incremental restriction of calories combined with exercise. Extreme diets (e.g., all bacon, all brown rice, starvation) are risky and should be avoided.
  • Liver transplantation. Because the vast majority of attacks respond to hematin and other supportive measures, liver transplantation has no role in prevention of acute attacks in a CPOX heterozygote.

Prevention of Secondary Complications

CPOX heterozygotes undergoing surgery are at increased risk for an acute attack because of the routine preoperative fast and the (former) use of barbiturate (thiopental) induction of anesthesia. Adherence to the following recommendations greatly reduces the risk of an acute attack:

  • Minimizing the preoperative fast as much as possible and providing intravenous glucose (10% dextrose in half-normal saline) in the perioperative period.
  • Anesthesia induction using non-barbiturate agents that have little or no P450-inducing activity (e.g., propofol, ketamine, short-acting benzodiazepines). Inhalation agents (isoflurane) and muscle relaxants also appear to be low-risk for triggering an attack.

Agents/Circumstances to Avoid

Avoid the following:

  • Caloric deprivation, i.e., fasting
  • Female reproductive hormones. Birth-control pills are risky and not recommended. For recommendations regarding contraception, see Prevention of Primary Manifestations, Selection of appropriate contraception for females.
  • Medications. Some drugs are clearly unsafe for CPOX heterozygotes. It is important to note, however, that many drugs are safe, lest providers regard people with acute porphyria as “untreatable.” Compilations of safe and unsafe drugs are available online and are updated as new information becomes available. (www.porphyriafoundation.com; www.porphyria-europe.com).

    In theory, the most dangerous medications are inducers of CYPs, such as barbiturates and the related compound, phenytoin.

Evaluation of Relatives at Risk

Testing of at-risk relatives for the family-specific CPOX mutation allows early education of CPOX heterozygotes regarding how to avoid risk factors known to be associated with acute attacks.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The effect of pregnancy on inducing acute attacks is unpredictable. In general, serious problems during pregnancy are unusual. In fact, some women with recurrent symptoms associated with the menstrual cycle report improvement during pregnancy. Attacks, if they occur, are usually in the first trimester. The women most at risk are those with hyperemesis gravidarum and inadequate caloric intake [Aggarwal et al 2002]. Among anti-emetics, ondansetron is not expected to precipitate or exacerbate acute attacks or to increase the risk for congenital anomalies in the fetus; however, metoclopramide (a porphyrinogenic agent) should be avoided, as it may precipitate acute attacks [Shenhav et al 1997].

The experience with administration of hematin (or heme arginate, which is not available in the US) during pregnancy is limited. Badminton & Deybach [2006] published an anecdotal report of successful heme arginate treatment (without adverse fetal effect) in several women experiencing attacks of variegate porphyria or other acute porphyrias during pregnancy. Based on the absence of reported adverse effects, use of hematin to control exacerbations of acute intermittent porphyria during pregnancy has been recommended [Isenschmid et al 1992, Farfaras et al 2010].

Therapies Under Investigation

Due to the rarity of symptomatic acute porphyria, the efficacy of intravenous hematin has never been documented in a controlled trial. Efforts to accomplish this are under way.

Planned studies focus onindividuals who have spontaneous acute attacks in the absence of any known external trigger in order to identify genetic co-factors that may be involved in such attacks and, thus, are potentially targets for new therapies.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hereditary coproporphyria (HCP) is inherited in an autosomal dominant manner.

Risk to Family Members

  • Most individuals with HCP have an affected parent.
  • A proband with HCP may harbor a new mutation. The proportion of de novo mutations is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing for the CPOX mutation identified in the proband. Evaluation of parents may determine that one has a CPOX mutation but has not been previously diagnosed because of reduced penetrance. Therefore, an apparently negative family history cannot be confirmed until molecular genetic testing has been performed.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is heterozygous for the CPOX mutation identified in the proband, the risk to the sibs of inheriting the CPOX mutation is 50%. Because of reduced penetrance, many individuals heterozygous for a CPOX mutation do not manifest signs and symptoms of HCP.
  • If the disease-causing CPOX mutation found in the proband cannot be detected in either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with HCP has a 50% chance of inheriting the CPOX mutation. Because of reduced penetrance, many individuals with a CPOX mutation do not manifest signs and symptoms of HCP.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is heterozygous for a CPOX mutation, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation, it is likely that the proband has a de novo mutation. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be considered.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must be identified in the family before prenatal testing can be performed. Note: The presence of a CPOX mutation detected by prenatal testing does not predict whether individuals will be symptomatic, or if they are, the severity of the clinical manifestations. It is common for the offspring of a severely affected individual to be completely asymptomatic. In addition, because symptoms never appear prior to puberty in individuals who are heterozygous for a CPOX mutation, the authors’ opinion is that prenatal testing is not warranted unless pregnancy termination is being considered.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the purpose is pregnancy termination rather than early diagnosis. Parents are encouraged to seek genetic counseling before reaching a decision on the use of prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Porphyria Foundation (APF)
    4900 Woodway
    Suite 780
    Houston TX 77056-1837
    Phone: 866-273-3635 (toll-free); 713-266-9617
    Fax: 713-840-9552
    Email: porphyrus@aol.com
  • National Library of Medicine Genetics Home Reference
  • European Porphyria Network
    Email: info1@porphyria-europe.com
  • NCBI Genes and Disease
  • Swedish Porphyria Patients' Association
    CMMS C2-71 Karolinska University Huddinge
    Stockholm Stockholms Lan 141 86
    Sweden
    Phone: +46 8 711 56 09
    Fax: +46 8 585 827 60
    Email: porfyri@swipnet.se
  • RDCRN Patient Contact Registry: Porphyrias Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Hereditary Coproporphyria: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Hereditary Coproporphyria (View All in OMIM)

121300COPROPORPHYRIA, HEREDITARY; HCP
612732COPROPORPHYRINOGEN OXIDASE; CPOX

Normal allelic variants. CPOX comprises seven exons; the reference sequence of the transcript is NM_000097.5.

Pathogenic allelic variants. To date, at least 64 mutations involving all seven exons have been identified in persons with HCP (Human Gene Mutation Database, updated from Rosipal et al [1999]). They include missense and nonsense mutations, large deletions, small deletions and insertions, indels, and splice mutations.

Normal gene product. Coproporphyringen-III oxidase (synonyms: coproporphyrinogen oxidase and coproporphyrinogen decarboxylase), the product of CPOX, performs an oxidative decarboxylation without a metal, reducing agents, or obligatory cofactors. The details of this unusual reaction remain to be elucidated. The crystal structure of human coproporphyringen-III oxidase points to a dimer as the catalytically active unit.

Abnormal gene product. Some CPOX mutations that give rise to HCP likely alter enzyme activity by disrupting dimer formation [Lee et al 2005].

The 110-residue N-terminal segment is responsible for targeting the enzyme to mitochondria and is the site of its action on the substrate, coproporphyrinogen. Mutations in this region may affect translocation of the protein and, thus, reduce enzymatic function in tissues without changing activity in cell extracts.

References

Literature Cited

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Chapter Notes

Acknowledgments

The work has been carried out under the auspices of the Porphyria Rare Disease Clinical Research Consortium (KE Anderson, Galveston, TX; DM Bissell, San Francisco, CA; JR Bloomer, Birmingham AL; HL Bonkowsky, Charlotte, NC; RJ Desnick, New York, NY; and JD Phillips, Salt Lake City, UT). The Consortium receives essential support from the NIH/NIDDK (1 U54 DK083909) and the American Porphyria Foundation.

Revision History

  • 13 December 2012 (me) Review posted live
  • 9 April 2012 (mb/bw) Original submission
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