COPROPORFIRIA HEREDITARIA PDF

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly.

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NCBI Bookshelf. 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.

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. Treatment of symptoms and complications, such as seizures, should be with medications known to be safe in acute porphyria see www.

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 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. 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. 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.

Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in an affected family member is known. 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.

Acute hepatic porphyria should be suspected in individuals with the following symptoms or findings:. 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.

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.

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. 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.

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.

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 View in own window. The enzyme assay is not widely available and is not used for diagnostic purposes. Values normalized to urine creatinine are satisfactory for clinical use, making a hour collection unnecessary.

The molecular testing approach typically includes single- gene testing targeting the type of acute porphyria suggested by biochemical testing. See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene. Sequence analysis detects variants that are benign, likely benign, of uncertain significance , likely pathogenic, or pathogenic.

For issues to consider in interpretation of sequence analysis results, click here. Grimes et al [] , Lambie et al []. 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. A kb deletion extending from exon 4 to the 3'UTR [ Whatley et al ] and a 1.

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. An earlier British study of individuals with HCP reported similar findings [ Brodie et al ]. Symptoms prior to puberty in individuals who are heterozygous for a CPOX pathogenic variant have never been observed.

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.

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.

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.

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 fold increased risk above the general population risk ; for men there is a fold increase in risk [ Sardh et al ]. 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. Circumstances commonly associated with acute attacks are caloric deprivation, changes in female reproductive hormones, and use of porphyria-inducing medications or drugs:. 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.

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. 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.

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 P family of heme-proteins, which are present in high concentration in the liver and have a relatively high turnover rate.

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. 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 ].

Experimental studies indicate that ALA is a pro-oxidant species that is capable of damaging the inner membrane of mitochondria [ Vercesi et al ]. Liver transplantation has established that this organ is responsible for acute attacks. Liver transplantation has cured individuals with refractory acute symptoms [ Soonawalla et al ].

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Hereditary coproporphyria

Only comments seeking to improve the quality and accuracy of information on the Orphanet website are accepted. For all other comments, please send your remarks via contact us. Only comments written in English can be processed. Hereditary coproporphyria is a form of acute hepatic porphyria see this term characterized by the occurrence of neuro-visceral attacks and, more rarely, by the presence of cutaneous lesions.

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NCBI Bookshelf. 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.

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Hereditary coproporphyria HCP is a disorder of heme biosynthesis, classified as an acute hepatic porphyria. Unlike acute intermittent porphyria , individuals with HCP can present with cutaneous findings similar to those found in porphyria cutanea tarda in addition to the acute attacks of abdominal pain, vomiting and neurological dysfunction characteristic of acute porphyrias. Like other porphyrias, attacks of HCP can be induced by certain drugs, environmental stressors or diet changes. Biochemical and molecular testing can be used to narrow down the diagnosis of a porphyria and identify the specific genetic defect. Overall, porphyrias are rare diseases. The combined incidence for all forms of the disease has been estimated at , The exact incidence of HCP is difficult to determine, due to its reduced penetrance.

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