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). Individuals with more than four attacks per year have historically been at highest risk for developing chronic neurologic manifestations. Givosiran, an siRNA that works directly against ALAS1 and is effective in preventing acute attacks in such individuals, was approved in the US in November 2019; however, its effectiveness remains to be determined with long-term study. 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.