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Hereditary coproporphyria
HCP is a genetic condition that impacts the body's ability to produce haem, leading to a build-up of porphyrin precursors. This can cause sudden, severe attacks affecting the nervous system and gut, often triggered by certain medications, hormones, or stress.
Overview
Hereditary coproporphyria (HCP) is a rare genetic disorder that belongs to a group of conditions known as acute hepatic porphyrias. These conditions result from problems in the pathway responsible for making haem, a vital component of haemoglobin and other proteins. In HCP, a partial deficiency of a specific enzyme causes an accumulation of porphyrin precursors in the body, which can become toxic, especially to the nervous system [PMID:33671239]. The condition often remains dormant, with many individuals never experiencing symptoms, but certain triggers can provoke acute, debilitating attacks. Understanding these triggers is key to managing HCP.
Symptoms & clinical features
Symptoms of an acute HCP attack can be wide-ranging and severe, primarily affecting the nervous system and the gastrointestinal tract. Common neurological symptoms include severe abdominal pain, often disproportionate to physical examination findings, along with nausea, vomiting, and constipation [PMID:33671239]. Psychiatric symptoms such as anxiety, depression, hallucinations, and confusion may also occur. Muscle weakness, which can progress to paralysis, is a serious complication, and seizures are possible. Some individuals may experience changes in heart rate or blood pressure. Skin problems, such as blistering and fragility upon sun exposure, are less common in HCP compared to some other porphyrias, but can occur in some cases.
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Affected organs
HCP primarily affects the nervous system, leading to neurovisceral symptoms that involve both the peripheral and central nerves. The gastrointestinal tract is also significantly impacted, causing severe abdominal pain and digestive issues. During acute attacks, the liver, where the problematic metabolic pathway largely occurs, is the source of the accumulating toxic substances. Kidneys may also be affected, with some individuals experiencing electrolyte imbalances or kidney damage in severe attacks. The skin can be affected by photosensitivity in some cases, leading to skin lesions upon exposure to sunlight.
Risks & severity
The severity of HCP varies considerably, even within the same family. Many individuals who inherit the genetic change never develop symptoms and lead normal lives. However, for those who do experience symptoms, acute attacks can be severe and life-threatening if not promptly managed [PMID:33671239]. Triggers for attacks commonly include certain medications (e.g., barbiturates, some antibiotics), alcohol, fasting or strict diets, physical or emotional stress, infections, and hormonal changes, particularly those associated with the menstrual cycle in women. Recurrent attacks can lead to chronic pain and neurological damage. The exact prevalence of HCP is not well established due to its rarity and the high proportion of asymptomatic carriers.
Genetic causes
Hereditary coproporphyria is caused by pathogenic variants in the CPOX gene. This gene provides instructions for making an enzyme called coproporphyrinogen oxidase. This enzyme is crucial in the fifth step of the eight-step biochemical pathway that produces haem [PMID:20301720]. When a pathogenic variant occurs in CPOX, the enzyme's activity is reduced by about 50%. This partial deficiency causes coproporphyrinogen and other porphyrin precursors to accumulate in the body. These accumulated substances are thought to be responsible for the symptoms observed during an acute attack.
- CPOX coproporphyrinogen oxidase
Inheritance pattern
HCP is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered CPOX gene from one parent to have the condition. If a parent has HCP, there is a 50% chance with each pregnancy that their child will inherit the pathogenic variant. It is important to remember that inheriting the genetic variant does not always mean a person will develop symptoms; many carriers remain asymptomatic throughout their lives.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of HCP is often suspected based on the characteristic neurovisceral symptoms, especially when triggered by known factors. Initial diagnostic tests typically involve measuring porphyrin precursors in urine, particularly elevated levels of coproporphyrin and aminolevulinic acid (ALA) during an acute attack. Genetic testing for pathogenic variants in the CPOX gene confirms the diagnosis. Such testing is available through the NHS Genomic Medicine Service, often following referral from a specialist clinic. The relevant NHS National Genomic Test Directory R-code for hereditary porphyrias can guide appropriate testing panels.
Management & lifestyle
Management of HCP focuses on preventing acute attacks and treating symptoms when they occur. Avoiding known triggers, such as certain medications, alcohol, and strict diets, is paramount. People with HCP should consult a specialist regarding any new medication to ensure it is safe. During an acute attack, treatment typically involves intravenous haem arginate to suppress the production of porphyrin precursors. Pain management and treatment for other symptoms, such as nausea and anxiety, are also important. Regular follow-up with a specialist centre experienced in porphyrias is recommended, often through an NHS clinic.
UK care pathway
In the UK, individuals suspected of having HCP are typically referred to specialist centres, often through a clinical genetics service or a metabolic disease clinic. Genetic testing for conditions like HCP is available via the NHS Genomic Medicine Service (GMS) as part of the National Genomic Test Directory. A genetic counsellor can provide essential support, explaining the inheritance patterns, implications for family members, and discussing the nuances of living with a genetic condition. The R-codes relevant to porphyrias in the NHS Test Directory guide which genetic tests are appropriate for diagnosis and family screening.
Frequently asked questions
What triggers an acute attack in HCP?
Acute attacks can be triggered by various factors, including certain medications, alcohol consumption, fasting, physical or emotional stress, infections, and hormonal changes, particularly in women. Avoiding these triggers is a key part of managing the condition.
Can HCP be cured?
Currently, there is no cure for HCP, but it is a manageable condition. Treatment focuses on preventing acute attacks by avoiding triggers and managing symptoms effectively when attacks occur. Research continues into new therapies for porphyrias.
Will my children inherit HCP?
HCP is inherited in an autosomal dominant pattern. If you have HCP, there is a 50% chance that each of your children will inherit the pathogenic CPOX variant. However, many individuals who inherit the variant may never develop symptoms.
How is HCP diagnosed?
Diagnosis typically involves checking for elevated porphyrin precursors in urine, especially during an acute attack. The diagnosis is confirmed by genetic testing to identify pathogenic variants in the CPOX gene.
What kind of specialist manages HCP?
Management of HCP usually involves a team of specialists, often led by a metabolic specialist or a hepatologist, working closely with clinical geneticists and genetic counsellors. They can provide guidance on avoiding triggers and managing attacks.
References
- Stölzel U, Doss MO, Schuppan D. Clinical Guide and Update on Porphyrias. Gastroenterology. 2019. PMID: 31085196
- Adam MP, Bick S, Mirzaa GM. Hereditary Coproporphyria. 1993. PMID: 23236641
- Besur S, Schmeltzer P, Bonkovsky HL. Acute Porphyrias. The Journal of emergency medicine. 2015. PMID: 26159905
- Wang B, Bonkovsky HL, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review. Gastroenterology. 2023. PMID: 36642627
- Marques I, Marcos P. Acute hepatic porphyrias. Porto biomedical journal. 2025. PMID: 41287633
- Schulenburg-Brand D, Katugampola R, Anstey AV. The cutaneous porphyrias. Dermatologic clinics. 2014. PMID: 24891059
- Kothadia JP, LaFreniere K, Shah JM. Acute Hepatic Porphyria. 2023. PMID: 30725863
- Martásek P. Hereditary coproporphyria. Seminars in liver disease. 1998. PMID: 9516675