Clinical Guidance

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 .

Source: GeneReviews — "Hereditary Coproporphyria"

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 . HCP, along with AIP and VP, are genetic disorders with reduced penetrance. Heme production in most heterozygotes appears to be adequate for physiologic homeostasis.

Source: GeneReviews — "Hereditary Coproporphyria"

Diagnostic Criteria

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 .

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

Source: GeneReviews — "Hereditary Coproporphyria"

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. In 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

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with hereditary coproporphyria (HCP), the evaluations listed in 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 . Detailed neurologic exam | • For signs of motor neuropathy (indicating a more advanced attack thus, need for early treatment w/hematin; see ) • Inquiry into possibility of seizures1 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 attack2 Consultation w/medical geneticist /or genetic counselor | PBG = porphobilinogen 1. 2. In an acute attack urinary excretion of PBG is substantially elevated over the baseline. Treatment of Manifestations Treatment guidelines for HCP have been published (full text). Acute Attacks No curative therapy for HCP exists. Supportive therapy by multidisciplinary specialists is summarized in . Details regarding treatment with givosiran, which was approved for prophylactic treatment for individuals with HCP with frequent recurrent acute neurovisceral pain episodes (defined as more than four attacks per year) in the US, but not necessarily in all countries, follow . Table 5. Treatment of Acute Attacks in Individuals with Hereditary Coproporphyria

Source: GeneReviews — "Hereditary Coproporphyria"

Clinical Guidance

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 .

• Female reproductive hormones. For recommendations regarding contraception, see .

• 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.

Source: GeneReviews — "Hereditary Coproporphyria"

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 Identifier NCT02082860). 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.

Source: GeneReviews — "Hereditary Coproporphyria"

Surveillance Guidelines

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 ]. 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 .

Source: GeneReviews — "Hereditary Coproporphyria"