What Is Hereditary Coproporphyria?

Overview

Enzymes play an essential role in each process made in our body, speeding up chemical reactions. When a person has an enzyme deficiency, or if it is missing, their body is affected, which leads to permanent health conditions. This is the case with Hereditary Coproporphyria (HCP). HCP is a rare metabolic disorder that implies the lack of the enzyme coproporphyrinogen-III oxidase (CPO). This enzyme is essential in the production of haem, a compound present in red blood cells. Haem attaches to an iron atom, forming haemoglobin and participating in oxygen exchange between the lungs and tissues. In HCP, the CPO enzyme is not present, so the body does not produce enough haem. The disorder can also lead to the accumulation of CPO precursors in the liver, from which the CPO enzyme is normally created.¹ Hereditary coproporphyria belongs to a group of porphyrias. These are diseases in which haem production is changed as there are low levels of particular enzymes. As the production of haem is slower, the compounds which are normally used in the process (precursors) accumulate. This causes increased secretion of porphyrins and their precursors, such as CPO enzyme precursor in HCP.

According to its characteristics and impact on the body, HCP is considered to be an acute porphyria. Acute means there is a sudden attack of pain and other neurological symptoms. HCP is also termed to be a hepatic type of porphyria, with precursors mainly accumulating in the liver. Other types of porphyrias can be chronic, with symptoms occurring in episodes, and erythropoietic, with precursors accumulating in the bone marrow. If an individual has a type of porphyria, he or she will not develop any of the other types of porphyria.  

Causes and genetics

HCP is caused by a mutation (change in the DNA) in the CPOX gene.¹ That gene holds information about how to build the CPO enzyme, so any changes in the gene can affect its function. The CPO enzyme defect in HCP leads to low levels of production of haem from its precursors. 

As the HCP name shows, it is a hereditary disease, so it can be passed down from parent to child. HCP is also known as an autosomal dominant disease, which means that a single mutated gene from one of the parents can be enough to pass the disease to the child.²  There is a 50% probability of passing an abnormal gene from an affected parent to a child for each pregnancy.1 It is important to mention that the mutation by itself does not produce the symptoms of the disease, and many individuals with the mutation do not develop symptoms in their lifetime.² Fortunately, people affected by HCP can access genetic counselling to be fully informed about family planning. It is worth considering genetic testing to see whether other family members can be affected without knowing, especially when the disease symptoms develop after one has been exposed to certain external factors.¹

Signs and symptoms 

The development of symptoms of HCP is caused by external factors known as triggers, such as infections, medication, excess alcohol consumption, dietary changes and hormonal changes.¹ These triggers can stimulate acute attacks by increasing the demand for haem, such as in the case where haem production is needed to metabolise (process) certain medications.² 

When symptoms of HCP appear, they are considered episodes, and those can develop over several hours or days.² The recovery process from each episode will depend on the severity of the symptoms.¹ In most cases, individuals will recover within days but acute episodes can take weeks or months, and in some cases result in hospitalisation.¹ Usually episodes start during the 20s or 30s of an individual or just after puberty, it is very rare to see episodes previous to puberty.² 

Some of the symptoms that an individual with HCP can experience are:^2,3 

• Body pain, especially in the abdomen area, the lower back, buttocks, arms, neck and legs
• Vomiting and nausea, particularly after eating or drinking any type of food or liquid
• Lack of bowel sounds, which might indicate difficulties and lack of intestinal activity 
• Constipation
• Abnormal heart rate, which is faster than normal (tachycardia) and abnormal heart rhythm (cardiac arrhythmias)
• High blood pressure 
• Neurological symptoms that include peripheral neuropathy (damage in the nerves) and seizures
• Hyponatremia due to low levels of sodium in the blood. 
• Numbness, tingling and burning sensations
• Muscle weakness that, in severe cases, might lead to paralysing all extremities and respiratory muscles
• Cutaneous (skin) lesions (damage), especially in areas exposed to the sun, such as the face and hands
• Photosensitivity 
• Psychosis

It is important to mention that HCPs can be misdiagnosed with other diseases or even with other types of porphyrias due to the similarity of their symptoms.⁴ Among the diseases with similar symptoms, we have Guillain-Barré syndrome, and among similar types of porphyrias, we have acute intermittent porphyria, variegate porphyria, and ALAD porphyria.4 That is why it is crucial to test and identify the disease to provide appropriate patient care. 

Diagnosis

The diagnosis process of HCP is complex because it has to take into consideration multiple elements, including a detailed patient and family history, characteristics of the symptoms, clinical evaluation and specialised tests, such as:¹ 

• Urine samples to measure the levels of porphyrin precursors, such as porphobilinogen (PBG) and delta-aminolevulinic acid (ALA)
• Faecal porphyrin analysis to discard other types of porphyria, as HCP can lead to increased levels of coproporphyrin in stool samples 
• Molecular genetic testing is used to confirm the mutation in the CPOX gene. If an individual gets a positive result for porphyria, the medical personnel will recommend that the family undertake a genetics test.¹ It is important to test other family members in case they have inherited a changed CPOX gene from the parents and have not yet developed symptoms. This could help them to prevent developing acute episodes or recognise the symptoms if they experience an episode. 

Treatment and management

There is no cure for HCP. Instead, the treatment is directly targeted towards the symptoms. Depending on the severity and frequency of the symptoms, HCP management will require a joint effort between different health professionals such as neurologists, hepatologists, paediatricians and psychiatrists.1 Among the available treatments and management strategies, we have:

• Avoiding any kind of medication that could potentially cause an acute attack of HCP
• Having an efficient intake of carbohydrates¹ 
• Hospitalisation if there is evidence of an acute neurovisceral attack (excessive, sudden haem production)^3,4 
• Specific medication for body pain, hypertension (high blood pressure), anxiety, tachycardia (increased heart rate), vomiting or anticonvulsant medication for seizures ⁴
• Monitoring and controlling levels of fluid intake and electrolyte balances² 
• In the case of people assigned female at birth (AFAB), manipulating hormone balance to prevent premenstrual attacks
• Avoiding direct sunlight exposure, using topical sunscreen and protective garments such as hats, sunglasses and gloves
• In extreme cases, medics may recommend a liver transplant as an option of last resort.

Complications 

Among the complications of HCP, we have:

• Permanent organ and neurological damage: if the episodes are very severe and not treated properly they can lead to permanent damage to the patient's body.^1,4 The potential organs affected included the skin, liver and kidneys. 
• Respiratory distress: severe episodes can lead to muscle weakness and chronic pain, provoking respiratory distress, which can become life-threatening if not treated on time.¹
• Digestive complications: originated from abdominal pain, which can lead to nutritional deficiency and weight loss.¹ 
• Late diagnosis or misdiagnosis: Due to the similarity to other types of porphyrias and other diseases, diagnosis can take longer than expected, in some cases complicating the treatment.
• Reduction of quality of life: due to the chronic pain caused by the frequency and severity of the episodes experienced by each patient.¹

FAQs

What triggers acute attacks in HCP?

Acute attacks can be triggered by diverse factors, including stress, medication, hormonal changes, alcohol, physical trauma, surgery, exposure to sunlight and diet.¹  

How common is HCP?

HCP is a very rare genetic disorder, it can potentially affect people assigned male and female at birth in equal ranges, however, symptoms appear more frequently among people AFAB of reproductive age.¹ This is due to the hormonal exchanges taken during the menstrual cycle. 

When should I see a doctor?

You should seek medical advice if you experience any of the symptoms mentioned before if you experience new symptoms if you are having an acute attack, and if you are trying to get pregnant.

Summary

Hereditary Coproporphyria is a rare metabolic disorder that implies the lack of the enzyme coproporphyrinogen-III oxidase caused by a mutation in the CPOX gene and is part of the group diseases of the porphyrias. According to its characteristics and impact on the body, HCP is considered acute porphyria. This is an autosomal dominant disease, which means that a single mutated gene from one of the parents can be enough to pass the disease to the child. HCP provokes insufficient heart production and sometimes the accumulation of CPO precursors in the liver. The development of symptoms of the disease is caused by external factors known as triggers; these can be stress, medication, hormonal changes, alcohol, physical trauma, surgery, exposure to sunlight and diet. HCP can be misdiagnosed with other diseases or even with other types of porphyrias due to the similarity of their symptoms. The diagnosis process comprehends a detailed patient and family history, characteristics of the symptoms, clinical evaluation and specialised test.