Hereditary Coproporphyria

What are the other Names for this Condition? (Also known as/Synonyms)

• HCP (Hereditary Coproporphyria)

What is Hereditary Coproporphyria? (Definition/Background Information)

• Porphyrias are disorders resulting from excess porphyrin buildup in the liver and bone marrow. Manufacturing hemoglobin and related proteins (heme synthesis) involves a class of molecules, called porphyrins. Porphyrias are either inherited or acquired, and are described as acute, chronic, and cutaneous
• Hereditary Coproporphyria (HCP) is a rare congenital condition affecting heme metabolism having an onset in infants and young children. It is similar to acute intermittent porphyria and is triggered by external/internal factors; but additionally, in HCP, skin involvement is noted
• Hereditary Coproporphyria is an acute and cutaneous form of porphyria that is typically inherited in an autosomal dominant manner, due to mutations in the CPOX gene, which causes a defect in heme production in the bone marrow and liver. HCP is termed as a hepatic porphyria, meaning that the porphyrin compounds accumulate in the liver
• During acute attacks (presentation of severe symptoms), the disorder is characterized by severe abdominal pain, constipation or diarrhea, and neurological symptoms that include muscle pain and weakness. Additionally, light-sensitivity of the skin (on exposure to sunlight), results in skin abnormalities including blistering and ulceration. However, many individuals with Hereditary Coproporphyria may be asymptomatic
• A healthcare provider typically diagnoses this genetic disorder by testing porphyrin levels in urine and blood samples, along-with symptom assessment. Establishing the presence of increased levels of protoporphyrin in blood or feces can help confirm the diagnosis
• The treatments for Hereditary Coproporphyria involves removing or treating the triggers causing HCP and symptomatic treatment. It also involves administering intravenous heme and the use of suitable sun protection creams. In many, the symptoms of an acute attack subside on their own
• The prognosis of Hereditary Coproporphyria is determined by the severity of symptoms and whether complications have developed. In many individuals, the prognosis is good with adequate treatment

Who gets Hereditary Coproporphyria? (Age and Sex Distribution)

• Hereditary Coproporphyria is a genetic condition affecting approximately 1 in 500,000 individuals globally
• Since, it is a congenital disorder, the condition is manifested at birth and symptoms are seen right from infancy
• HCP affects females slightly more than males, though both genders are affected
• The disorder occurs without any racial or ethnic bias

What are the Risk Factors for Hereditary Coproporphyria? (Predisposing Factors)

• A family history of Hereditary Coproporphyria increases the risk of a newborn being diagnosed with the condition, since HCP is an inherited disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Hereditary Coproporphyria? (Etiology)

Hereditary Coproporphyria is caused by mutations in the CPOX gene on chromosome 9, which is involved in the production of “heme”.

• Heme is a critical component of iron-containing proteins called hemoproteins. Hemoglobin is one such protein, which is the oxygen carrier in blood. Blood, bone marrow, and liver have the most heme protein in them
• Mutations in the CPOX gene are inherited in an autosomal dominant manner. Mutations in this gene affects porphyrin metabolism. A compromised porphyrin metabolism causes a buildup of porphyrins in the body
• Hereditary Coproporphyria is described as a type of porphyria affecting the liver (hepatic porphyria), because coproporphyrin (a type of porphyrin compound) collects in the liver in excessive amounts
• This mutation affects the function of the specific enzyme coproporphyrinogen oxidase, in the red blood cells and liver. The functional ability of the enzyme, which is important for the multistep-wise process of generating heme, reduces below 50% due to the function of the enzyme being affected
• In the presence of other internal or external triggers, it results in an acute attack, due to the abnormal accumulation of the porphyrin compounds in the body

The external factors or triggers may include:

• Environmental stimuli
• Eating an unusual diet or starvation
• Illegal drug abuse
• Alcoholism
• Use of certain medications

The internal factors may include:

• Emotional or psychological stress
• Menstruation in women
• Any illness or infection
• Other hormonal factors

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Hereditary Coproporphyria?

The various signs and symptoms of Hereditary Coproporphyria (HCP) stem from coproporphyrin buildup in the body. The affected children begin to show symptoms in infancy, which can be severe. Rarely, HCP patients may first show symptoms in puberty.

The various signs and symptoms of HCP may include:

• Stomach pain and cramping abdominal pain
• Diarrhea or constipation
• Retention of urine
• Since, liver involvement is present in HCP, yellowing of skin and eyes may be observed
• The skin is light-sensitive, and thus, exhibits the following symptoms (on exposure to direct sunlight):
  • Skin gets inflamed with burning sensation
  • Blister formation can take place
  • Over time, the skin becomes weak
  • Skin hyperpigmentation and scarring is also noted
• Neuromuscular signs and symptoms may include:
  • Peripheral neuropathy
  • Muscular pain and weak muscles; lethargy
  • If the respiratory muscles are affected, it may cause breathing difficulties
  • Seizures in some cases
• Psychiatric signs and symptoms may include:
  • Change in sensation
  • Feeling confused
  • Hallucinating
• Abnormal color of urine (reddish) on exposure to sunlight; which tends to resolve following treatment, or when the symptoms go away

Despite the above, many children typically do not show any signs and symptoms of the condition.

How is Hereditary Coproporphyria Diagnosed?

The diagnosis of Hereditary Coproporphyria is made by the following tools:

• A complete physical examination and an assessment of symptoms
• An evaluation of the affected individual’s full medical history
• Measurement of the porphyrin levels in blood, urine, or feces
  • Urine screening test (24 hours): Urine may turn red-brown on exposure to sunlight (due to the presence of complex porphyrin compounds), if urine is taken during the acute attack phase
  • Assessment of blood levels of protoporphyrin
  • Assessment of stool levels of protoporphyrin
• Measurement of coproporphyrinogen oxidase enzyme activity
• Molecular genetic testing before or after birth, to confirm CPOX gene mutations

Note: Accumulated porphyrins are excreted through urine and feces in large quantities, and urinary secretion of PBG and ALA is high.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Hereditary Coproporphyria?

The potential complications of Hereditary Coproporphyria may include:

• Severe pain and emotional stress during periods of acute attacks
• Recurrent skin infections (via bacteria or virus)
• Cosmetic issues due to skin of the face, neck, arms being chronically affected
• Anemia and related conditions, due to low levels of oxygen transport
• Increased heart rate and increased blood pressure may be the outcome of autonomic nervous system being affected
• If the neuroendocrine region of brain is affected, it can lead to hyponatremia and hypomagnesemia (low sodium and magnesium levels in blood respectively), resulting in additional complications

How is Hereditary Coproporphyria Treated?

A treatment of Hereditary Coproporphyria symptoms may be undertaken and the treatment measures include:

• When the first signs of disease are recognized, the individual is given oral/intravenous glucose (called glucose loading) and carbohydrate-rich diet
• Medications to control severity of the acute attacks
• Large dose and strong painkillers (narcotic analgesics or opiates) may be given for severe pain
• Antipsychotic medication (chlorpromazine) to treat some of the neurological symptoms, antidepressants for depression
• Beta-blockers, such as propranolol, for cardiovascular conditions (such as hypertension and tachycardia)
• Anticonvulsant medications (such as gabapentin) for seizures
• Blood disorder medications (intravenous heme or hematin) may be used to treat accumulation of the compounds. This measure is generally reported to be an effective treatment method for HCP
• If the symptoms are because of normal menstrual cycles, birth control hormonal pills or synthetic peptide drugs (luteinizing hormone releasing hormone agonist, or LHRH agonist) may be helpful
• Skin-related recommendations for affected individuals include the following:
  • Avoiding direct exposure to sunlight
  • Application of topical sunscreens
• Blood transfusions, based on the severity of anemia
• A splenectomy (removal of the spleen) to alleviate bleeding and worsening anemia (due to spleen enlargement)
• Bone marrow transplant: This procedure is often reserved only for those who have extremely severe cases of HCP due to the risk of rejection and associated complications

In many individuals, the symptoms of an acute attack subside on their own. Sometimes, it may be severe as to requiring treatment in a hospital setting. The treatment also involves removing or treating any internal or external triggers.

How can Hereditary Coproporphyria be Prevented?

Currently, there are no specific methods or guidelines to prevent Hereditary Coproporphyria, since it is a genetic condition.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Hereditary Coproporphyria

Regular medical screening at periodic intervals with tests and physical examinations are highly recommended.

Once the triggers or precipitating factors for Hereditary Coproporphyria are identified, certain steps may be taken to avoid them to the extent possible, such as:

• Having a healthy lifestyle and a regular diet
• Stress avoidance, when possible
• Avoid the use of illegal drugs; avoiding alcohol
• Discontinuing medicines that trigger HCP, instead using alternatives
• Undertaking prompt treatment for any illness or infection

Individuals with HCP are encouraged to wear an emergency (medical) identification tag or suitable bracelet to inform providers/others about their condition, which is particularly helpful in case of an acute attack.

What is the Prognosis of Hereditary Coproporphyria? (Outcomes/Resolutions)

• The prognosis of Hereditary Coproporphyria varies with the severity of the condition. But, it is generally good for mild cases and the symptoms go away with adequate treatment
• If neurological symptoms are severe involving the muscle and sensory faculties, then recovery may be prolonged and it may take many months
• Individuals with an early-onset of signs and symptoms (such as during infancy) may have poorer outcomes than those with late onset, due to increased severity of HCP

Additional and Relevant Useful Information for Hereditary Coproporphyria:

The other acute porphyria forms include acute intermittent porphyria (AIP), amino levulinic acid dehydratase deficiency porphyria (ALAD porphyria), and variegate porphyria (VP).