Hereditary Coproporphyria
Summary
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.
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 long-standing photosensitivity.
Diagnostic criteria for HCP have been published [Anderson et al 2005, Whatley et al 2009].
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)
| 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).
Molecular Genetic Testing
The molecular testing approach typically includes single-gene testing targeting the type of acute porphyria suggested by biochemical testing.
- Sequence analysis of CPOX is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
- If detailed CPOX testing is normal, PPOX (the gene for variegate porphyria [VP]) is analyzed. The biochemical findings in HCP and VP can overlap, leading to misassignment of diagnosis in some instances.
Table 2.
Molecular Genetic Testing Used in Hereditary Coproporphyria
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| CPOX | Sequence analysis 3 | 32/33 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | See footnote 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Sequence analysis identified a pathogenic variant in 31 of 32 (97%) individuals with the clinical and biochemical diagnosis of HCP [Whatley et al 2009].
- 5.
Grimes et al [2016], Lambie et al [2018]
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
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 4 Swedish families) [Barbaro et al 2012] have been published.
Clinical Characteristics
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.
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 affected individual 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 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 of the altered affect in acute porphyria, it has been speculated that mental illness is a long-term consequence of an attack and that mental institutions may house 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 performed, with mixed results [Jara-Prado et al 2000]. The experience of those who have monitored affected individuals 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 individuals in the general population; however, a prospective study is needed.
Kidney and liver disease. In people with any type of acute porphyria, the kidneys and liver may develop chronic changes that often are subclinical. One manifestation of the liver problem is excess primary liver cancer (hepatocellular carcinoma). The risk is greatest in women older than age 60 with acute intermittent porphyria (160-fold increased risk above the general population risk); for men there is a 37-fold increase in risk [Sardh et al 2013]. This and the kidney disease may be restricted largely to heterozygotes with chronically elevated plasma or urine delta aminolevulinic acid (ALA). Hypertension may be chronic in those with frequent symptoms and may contribute to renal disease.
Inasmuch as ALA and porphobilinogen (PBG) tend to be minimally elevated or normal in HCP heterozygotes, the risk of hepatic and renal complications may be less in HCP than in acute intermittent porphyria.
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 (ovarian 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 is occasionally 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 Management, 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 Management, 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
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.
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 metabolite (Figure 1).
In Table 3 the porphyrias are grouped by their principal clinical manifestations (neurovisceral 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 individuals with 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 Porphyria | Findings | MOI | ||
|---|---|---|---|---|
| Neurovisceral 1 | Photocutaneous | |||
| Hepatic | ADP | + | 0 | AR |
| AIP | + | 0 | AD | |
| HCP | + | + | AD | |
| PCT type II | 0 | + | AD | |
| VP | + | + | AD | |
| Erythropoietic | CEP | 0 | + | AR |
| EPP, AR | 0 | + 2 | AR | |
| XLP | 0 | + 2 | XL | |
0 = no symptoms; + = mild to severe symptoms; AD = autosomal dominant; ADP = ALA dehydratase-deficiency porphyria; AIP = acute intermittent porphyria; AR = autosomal recessive; CEP = congenital erythropoietic porphyria; EPP = erythropoietic protoporphyria; HCP = hereditary coproporphyria; MOI = mode of inheritance; PCT = porphyria cutanea tarda; VP = variegate porphyria; XL = X-linked; XLP = X-Linked protoporphyria
- 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, some affected individuals develop chronic manifestations, and a few 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 also be seen 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;
- 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.
Management
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).
Table 4.
Recommended Evaluations Following Initial Diagnosis of Hereditary Coproporphyria
| Evaluation | Comment |
|---|---|
| Review of medications for those thought to induce attacks | See Agents/Circumstances to Avoid. |
| Detailed neurologic examination |
|
| Measurement of serum sodium concentration | Hyponatremia is characteristic & may be profound (serum sodium concentration <110 mEq/L), requiring urgent correction w/due regard for risk of central pontine myelinolysis. |
| Quantitation of urinary excretion of PBG on several occasions over a few mos to establish baseline | For future use in determining if a new symptom or drug reaction is due to an acute attack 2 |
| Consultation w/medical geneticist &/or genetic counselor |
PBG = porphobilinogen
- 1.
Tran et al [2013]
- 2.
In an acute attack urinary excretion of PBG is substantially elevated over the baseline.
Treatment of Manifestations
Treatment guidelines for hereditary coproporphyria have been published [Balwani et al 2017] (full text).
Acute Attacks
Table 5.
Treatment of Acute Attacks in Individuals with Hereditary Coproporphyria
| Manifestation | Treatment | Consideration/Other |
|---|---|---|
| Acute abdominal pain | Identify & discontinue any medications thought to induce attacks. | See Agents/Circumstances to Avoid. |
| Discontinue all nonessential medications. | Treat symptoms & complications w/medications known to be safe in acute porphyria (see www | |
| Nausea/vomiting | Administer glucose-containing IV solution to reverse fasting state. | Some individuals recover w/rehydration & glucose infusion only; those who do not respond in 24-48 hours should receive intravenous hematin. |
| Obtain a serum sodium level. 1 | In those w/hyponatremia, rehydration w/10% dextrose in 0.5N sodium chloride is recommended. 2 | |
| Moderate to severe acute attacks | Administer intravenous hematin. |
|
| Motor neuropathy | Administer hematin as soon as possible if signs of motor neuropathy are present. | 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. 7 |
| Seizures | Administer short-acting benzodiazepine (e.g., midazolam) or magnesium. 8 | A number of commonly used anti-seizure medications, incl phenytoin & sodium valproate, are contraindicated because of the risk of exacerbating an attack. |
| Status epilepticus or refractory seizures | Consider propofol. | For more prolonged control of seizures, the combination of gabapentin & propofol is effective & safe. |
| Repeat acute attacks &/or severe disease | Suppress ovulation in females. | Use a GnRH agonist (leuprolide, nafarelin, others). 9 |
| Use hematin prophylactically. | Chronic use of hematin can lead to iron overload. 10, 11, 12, 13 | |
| Consider liver transplantation in selected cases. |
|
- 1.
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.
- 2.
Aggressive administration of dextrose in water may cause the serum sodium concentration to drop to a critically low level.
- 3.
Hematin (350-mg vial) is reconstituted at the bedside as described in the package insert. Human albumin may be used in place of water (147 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].
- 4.
The infusion is started without delay, as hematin in solution decays rapidly [Goetsch & Bissell 1986].
- 5.
The preparation is given into a large peripheral vein or via central line over 10-15 minutes 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.
- 6.
An alternative in Europe and elsewhere is heme arginate (Normosang®; not available in the US).
- 7.
Return of function requires axonal regeneration and takes many months. Although it can be complete, some individuals have residual wrist drop or foot drop.
- 8.
This treatment has been used to control eclamptic seizures [Sadeh et al 1991].
- 9.
Oral contraceptives and progestins should be avoided.
- 10.
Treatment of iron overload is indicated when the serum ferritin exceeds 1,500 ng/mL.
- 11.
An oral chelator, such as deferasirox or deferiprone, is convenient but causes side effects of gastric distress and nausea in some users.
- 12.
A small phlebotomy can be done with each hematin infusion, provided the hemoglobin is >10 g/dL. Withdrawal of 100 mL of blood is sufficient for maintaining iron balance, relative to the amount of iron in a 250-mg dose of injectable hematin.
- 13.
For those with a significant iron burden, withdrawal of 200 cc of blood with each hematin infusion will produce net negative iron balance.
Chronic (Cutaneous) Manifestations
Table 6.
Treatment of Low-Grade Chronic or Seasonal Cutaneous Symptoms in Individuals with Hereditary Coproporphyria
| Treatment | Consideration/Other |
|---|---|
| Avoid sun/light. | This includes both direct sun/light & through window glass. 1 |
| Wear protective clothing: long sleeves, gloves, & wide-brimmed hats. | Topical sunscreens are not helpful because they block UVB light, not the blue light that causes porphyrin-related skin injury. |
| Use protective tinted glass for cars & windows to prevent exposure to blue light. | Gray or smoke-colored filters provide only partial protection. |
- 1.
Damage is caused by blue light and long-wave ultraviolet light (UVA), both of which pass through window glass.
Note: 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 case report of an individual with severe HCP who was given "maintenance" hematin [Ma et al 2011].
Prevention of Primary Manifestations
Table 7.
Prevention of Acute Attacks in COPX Heterozygotes
| Principle | Prevention | Consideration/Other |
|---|---|---|
| Identifying those at risk of attacks | See Evaluation of Relatives at Risk. | |
| Education of at-risk individuals | Educate regarding circumstances that may trigger an acute attack (see Clinical Description). | |
| Selection of appropriate contraception for females | The recommended method of birth control for HCP heterozygotes is an IUD plus a barrier (diaphragm &/or condom). 1 |
|
| Suppress menses using a GnRH agonist. |
| |
| Prevention of acute attacks in those undergoing surgery | Minimize preoperative fast as much as possible. | |
| Provide intravenous glucose (10% dextrose in half-normal saline) in perioperative period. | ||
| Induce anesthesia using non-barbiturate agents that have little or no P450-inducing activity (e.g., propofol, ketamine, short-acting benzodiazepines). | Inhalation agents (isoflurane) & muscle relaxants also appear to be low-risk for triggering an attack. |
- 1.
Oral contraceptives (birth control pills) are risky and not recommended.
- 2.
Andersson et al [2003]
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, and they risk becoming obese. 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.
Surveillance
For those who have chronically elevated ALA (which is infrequent in those who are asymptomatic) and/or are older than age 60 years, an annual assessment of liver and kidney function is recommended.
Current noninvasive techniques for evaluation of fibrosis in the liver include transient elastography (FibroScan®) and a blood-based test (FibroTest® or FibroSure®) [see Balwani et al 2017]. Note: These assessments have been vetted mainly for people with chronic viral hepatitis or steatohepatitis but may also be useful in porphyria.
For affected individuals older than age 60 and anyone with evidence of chronic liver injury, annual screening for hepatocellular carcinoma with abdominal imaging (e.g., ultrasound) and serum alpha-fetoprotein is indicated [Balwani et al 2017].
Agents/Circumstances to Avoid
Avoid the following:
- Extreme caloric deprivation (i.e., total fasting, gastric bypass surgery). A case report of an acute attack occurring in a 23-year-old male who had been taking Hydroxycut®, an over-the-counter weight-loss supplement, has been published [Haimowitz et al 2015].
- Female reproductive hormones. For recommendations regarding contraception, see Prevention of Primary Manifestations.
- Medications. Some drugs are clearly unsafe for CPOX heterozygotes. It is important to note, however, that many other drugs are safe. Providers should not regard individuals with acute porphyria as "untreatable." Compilations of safe and unsafe drugs are available online and are updated as new information becomes available. See porphyriafoundation.org, drugs-porphyria.org/, or the smartphone app found at porphyriadrugs.com.In theory, the most dangerous medications are inducers of CYPs, such as barbiturates and the related compound, phenytoin.
Evaluation of Relatives at Risk
It is appropriate to evaluate relatives at risk for HCP in order to identify as early as possible those who would benefit from education regarding the risk factors associated with acute attacks.
- If the CPOX pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
- If the CPOX pathogenic variant in the family is not known, a first-degree relative with symptoms can be evaluated with biochemical tests (see Diagnosis). Note: Although some CPOX heterozygotes have a diagnostic biochemical profile of heme precursors in urine and feces (see Table 1, Active columns), many have normal findings (see Table 1, Asx [asymptomatic] columns) and can only be diagnosed by molecular genetic testing.
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 antiemetics, ondansetron is not expected to precipitate or exacerbate acute attacks, although several studies have suggested that ondansetron exposure in the first trimester of pregnancy could lead to an increased risk of cleft palate and/or congenital heart defects in the fetus. These suggested risks have not been confirmed. However, metoclopramide 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].
See MotherToBaby for further information on medication use during pregnancy.
Therapies Under Investigation
Hematin for infusion (Panhematin®, Recordati Group) is currently the only approved therapy for symptomatic acute porphyria and is a critical part of management. However, it has shortcomings: poor stability in solution; the need for intravenous administration with the attendant risk of phlebitis; interference with coagulation; and iron overload.
Alternatives are under investigation. One is gene therapy in which the normal gene (CPOX in the case of hereditary coproporphyria) is targeted to hepatocytes (ClinicalTrials.gov NCT02082860). Another uses small interfering RNA (siRNA) directed against ALA synthase to downregulate hepatic production of ALA and PBG (Givosiran, Alnylam Pharmaceuticals, Cambridge, MA) (ClinicalTrials.gov NCT02452372). In principle, the latter should be relevant to any of the acute porphyrias. In Phase I-II trials, a single subcutaneous dose of the siRNA reduced ALA synthase and plasma ALA to target levels for a one-month period. Side effects were minor. In affected individuals with recurrent symptoms, the need for hematin infusion was reduced. A Phase III clinical trial is currently under way (August 2018).
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.