Hereditary Coproporphyria

Clinical 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. 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 pathogenic variant in CPOX (encoding the enzyme coproporphyrinogen-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 (Panhematin^®, Recordati Group). Treatment of symptoms and complications, such as seizures, 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. Treatment of chronic (cutaneous) manifestations is through avoidance of sun/light, including wearing protective clothing and using protective tinted glass for cars and windows to prevent exposure to blue light.

Prevention of primary manifestations: Agents or circumstances that may trigger an acute attack (including use of oral contraception and progestins in women) are avoided. Suppression of menses using a GnRH agonist (leuprolide, nafarelin, and others) may help CPOX heterozygotes who experience monthly exacerbations. Menopausal symptoms may occur as a side effect of GnRH agonists and can be treated with a low dose of estrogen. In CPOX heterozygotes undergoing surgery, minimize preoperative fasting and provide intravenous glucose in the perioperative period. Anesthesia induction using non-barbiturate agents is recommended.

Surveillance: Annual liver and kidney function in those with chronically elevated ALA levels and/or those older than age 60 years; assessment for liver fibrosis (transient elastography [FibroScan^®] or a blood-based test [FibroTest^® or FibroSure^®]); annual screening for hepatocellular carcinoma with abdominal imaging and serum alpha-fetoprotein in those older than age 60.

Agents/circumstances to avoid: Fasting, use of oral contraception and progestins in females, and certain drugs including barbiturates and phenytoin.

Evaluation of relatives at risk: If the family-specific CPOX pathogenic variant is known, clarification of the genetic status of relatives at risk allows early diagnosis of heterozygotes and education regarding how to avoid risk factors known to be associated with acute attacks.

Genetic counseling.

HCP is inherited in an autosomal dominant manner with low penetrance. Most individuals with HCP have an affected parent; the proportion with a de novo pathogenic variant is unknown. Each child of an individual with HCP has a 50% chance of inheriting the CPOX pathogenic variant. Because of reduced penetrance, many individuals with a CPOX pathogenic variant have no signs or symptoms of HCP. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in an affected family member is known.

Suggestive Findings

Acute hepatic porphyria should be 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
• Family history of porphyria

Note: (1) Although CPOX pathogenic variants 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). (2) Absence of a known family history of porphyria does not preclude the diagnosis.

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

Establishing the Diagnosis

The diagnosis of HCP is established in a proband by biochemical testing (see Table 1), followed by identification of a heterozygous pathogenic variant in CPOX by molecular genetic testing (see Table 2).

Biochemical Testing

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). 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.

The most sensitive and specific biochemical diagnostic tests for HCP are detailed in Table 1. Once the diagnosis of an acute porphyria is established by identification of a striking increase in urinary porphobilinogen (PBG), quantitative analysis of porphyrins in both urine and feces may help define the specific type (Figure 1).

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). Pathogenic variants that decrease the function of a particular (more...)

• 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 Center, University of Texas Medical Branch (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].

Table 1.

Biochemical Characteristics of Hereditary Coproporphyria (HCP)

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Deficient Enzyme	Urine		Stool
	Active	Asx	Active	Asx
Coproporphyringen-III oxidase 1, 2	↑PBG 3, 4 ↑COPRO 5	Normal PBG COPRO 6	COPRO >> PROTO 7	See footnote 8

Active = symptomatic CPOX heterozygotes; Asx = asymptomatic CPOX heterozygotes; COPRO = coproporphyrin; NormaI PBG = <2 mg (0.85 μmol) per g urine creatinine; PBG = porphobilinogen; 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.

Active HCP is suggested by a quantitative urine PBG that is at least threefold the upper limit of normal.

4.

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.

5.

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

6.

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).

7.

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

8.

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 Biochemical Testing).

Clinical Description

Hereditary coproporphyria (HCP) is classified as both an acute and a 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 long standing (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].

Symptoms prior to puberty in individuals who are heterozygous for a CPOX pathogenic variant have never been observed.

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

Pathophysiology

The regulation of heme synthesis differs in liver and in bone marrow, the principal sites of heme production in the body. 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 inherited conditions involving overproduction of ALA but not PBG (delta ALA dehydratase deficiency porphyria and tyrosinemia). In addition, lead poisoning causes a similar biochemical derangement by binding the sulfhydryls of ALA dehydratase and reducing enzymatic activity; the symptoms in lead poisoning closely mimic those of acute porphyria [Bissell et al 2015]. Experimental studies indicate that ALA is a pro-oxidant species that is capable of damaging the inner membrane of mitochondria [Vercesi et al 1994].

Liver transplantation has established that this organ is responsible for acute attacks. Liver transplantation has cured individuals with refractory acute symptoms [Soonawalla et al 2004]. Moreover, transplantation of a porphyric liver into a normal recipient in two cases 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 wavelength 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. CPOX pathogenic variants 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 pathogenic variant [Lamoril et al 2001].

• Neonatal-onset HCP. In two reported cases, heterozygous (but not biallelic) CPOX variants have been associated with massive elevation of coproporphyrins, cutaneous blistering, and hemolytic anemia with onset in the neonatal period. In one case, the pathogenic variant was in exon 6 causing exon 6 skipping. In the other, it was a four-base-pair deletion in exon 7. The clinical picture resembled harderporphyria (see Genetically Related Disorders), but fecal analysis indicated HCP (markedly increased coproporphyrin and normal harderoporphyrin). Both cases also manifested adrenal insufficiency and hypospadias (with a 46,XY karyotype) [Hasegawa et al 2017]. The syndrome has been termed "neonatal-onset HCP," although the same CPOX variants also give rise to typical adult-onset HCP. The reason for the dramatic difference in presentation is unknown. It has been suggested that adrenal insufficiency is the proximal cause of the neonatal form, perhaps because heme synthesis is regulated by adrenal steroids to a degree that has not been appreciated.
• Homozygotes for CPOX pathogenic variants that cause minimal or no symptoms in heterozygotes 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 pathogenic variants in genes causing two different types of acute (hepatic) porphyria. Double heterozygotes for a pathogenic variant in CPOX and either a pathogenic variant 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 pathogenic variant 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 pathogenic variants is unknown. Given the rarity of acute attacks of HCP relative to acute intermittent porphyria (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 Management, Agents/Circumstances to Avoid). Genetic co-factors may also be involved; none has been identified to date.

Nomenclature

"Coproporphyrinuria" describes urine with an elevated level of coproporphyrin of any cause.

Coproporphyria in individuals heterozygous for a CPOX pathogenic variant 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 pathogenic variants have not been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with hereditary coproporphyria (HCP), the evaluations listed in Table 4 are recommended (if they have not already been completed).