Hereditary Coproporphyria Causes and Treatment

HCP is due to a mutation in coproporphyinogen oxidase (CPOX), which is part of the pathway that produces porphyrins and heme. It is an autosomal dominant disorder, meaning that a mutation is present in only one of the pair of CPOX genes.

The incidence of active HCP appears to be at most 2 per 1,000,000. The prevalence of the genetic carrier state is unknown.

Hereditary coproporphyria is one of the porphyrias, a group of diseases that involves defects in heme metabolism and that results in excessive secretion of porphyrins and porphyrin precursors. Inheritance is autosomal (usually autosomal dominant, but sometimes autosomal recessive).

Many persons with the disorder remain asymptomatic. Attacks may be triggered by chemicals (including many medications) or situations (eg, fasting) that boost heme synthesis.

Coproporphyria manifests with signs and symptoms that include abdominal pain, neuropathies, constipation, and skin changes.

Pathophysiology

Coproporphyria is an autosomal dominant disease that results from defects in the enzyme coproporphyrinogen oxidase. This enzyme speeds the conversion of coproporphyrinogen to protoporphyrinogen.

In coproporphyria, the porphyrin precursors porphobilinogen and amino-levulinic acid (ALA) accumulate, as well as the formed porphyrin coproporphyrin.

The predominant problem is neurologic damage that leads to peripheral and autonomic neuropathies and the psychiatric manifestations. In coproporphyria, skin disease also is present but not as commonly as the neurovisceral symptoms.

The etiology of the skin disease may be the deposition of formed porphyrins in the skin that react with sunlight and lead to skin damage.

Although patients with acute neurovisceral attacks always have elevations of porphobilinogen and ALA, researchers still are unclear about how this leads to the symptomatic disease because most patients with the genetic defect have excessive porphyrin secretion but no symptoms.

Who gets Hereditary Coproporphyria?

HCP is termed a disease with low penetrance, meaning that many genetic carriers (defined by having a CPOX mutation) never have signs or symptoms of active porphyria. Active disease in general requires the presence of environmental factors such as certain drugs, hormones, and dietary changes, as in AIP.

Lists are available of drugs that are risky for HCP genetic carriers as well as drugs that are safe (http://www.porphyriafoundation.com/testing-and-treatment/drug-safety-in-acute-porphyria).

The worst offenders are barbiturates, sulfonamide antibiotics, anti-seizure drugs, rifampin, and oral contraceptives (progesterone, in particular). Attacks in women may occur after ovulation and during the last part of the menstrual cycle when progesterone levels are high.

Reduced food intake, often in an effort to lose weight, as well as infections, surgery, and stressful situations may also precipitate attacks.

Alcohol has been implicated in some attacks. People with repeated attacks are at risk for developing chronic renal disease and liver cancer (hepatocellular carcinoma)

How is Hereditary Coproporphyria diagnosed?

The initial test for people with symptoms is quantitative urinary aminolevulinic acid (ALA), porphobilinogen (PBG) and porphyrins.

Elevation of ALA, PBG and coproporphyrin (predominantly isomer III) is highly suggestive of HCP. For asymptomatic individuals,the urine studies may be normal, but a fecal porphyrin analysis will show elevation of coproporphyrin III. Screening tests of this kind should be confirmed by DNA analysis to confirm a CPOX mutation.

What are treatments for Hereditary Coproporphyria?

Treatment, complications, and preventive measures are the same as in AIP. Hospitalization is often necessary for acute attacks.

Medications for pain, nausea, and vomiting and close observation are generally required. During treatment of an attack, attention should be given to sodium (salt) and water balance. Harmful drugs should be stopped.

Attacks are treated with either glucose loading or hemin (Panhematin®, Recordati). These are specific treatments that lower the production of heme pathway intermediates by the liver. Glucose or other carbohydrates are given by mouth if possible, otherwise by vein.

However, unless an attack is mild, it is now common practice to give hemin as soon as it is available, because it works more quickly than glucose loading, preventing the neurological complications of prolonged attacks.

Patients with severe renal disease tolerate hemodialysis or kidney transplantation. Liver transplantation has been very effective for patients who have repeated attacks and who are resistant to other treatments. However, experience with transplantation as a treatment is still limited.

Causes

Like AIP, coproporphyria is due to a combination of a genetic enzyme defect and acquired causes that become symptomatic in rare cases. In patients with coproporphyria, the function of coproporphyrinogen oxidase is only 40-60% of normal.

Also, like AIP, most patients with defects in coproporphyrinogen oxidase never have any symptoms. The classic inducers of porphyria are chemicals or situations that boost heme synthesis. This includes fasting and many medications.

Although extensive lists of safe and unsafe drugs exist, many of these are based on anecdotes or laboratory evidence rather than meeting strict criteria.

In general, drugs that lead to increased activity of the hepatic P450 system (eg, phenobarbital, sulfonamides, estrogens, alcohol) are associated with porphyria. A large and detailed list, shown below, is available through the European Porphyria Network.

Fasting for several days also can trigger an attack. Many attacks will occur, however, without any obvious provocation.

What is the long-term outlook after an attack of Hereditary Coproporphyria?

The prognosis is usually good if the disease is recognized and treated promptly, before nerve damage develops. Although symptoms usually resolve after an attack, recovery of neuromuscular function (in a severe case) may require several months or longer.

Mental symptoms may occur during attacks but are not chronic. Premenstrual attacks often resolve quickly with the onset of menses.

Physical Examination

Vital signs are as follows:

  • Tachycardia develops in 30-80% of patients
  • Fever can be present in some patients
  • Hypertension develops in 50% of cases and may persist between attacks
  • Neurologic manifestations are as follows:

Typically, the neuropathy is a motor neuropathy that is more predominant in the lower limbs

Areflexia is observed during the examination; however, any nerve can be involved. Cranial neuropathies also are observed, and the patient may have cortical blindness

Abdominal examination: Despite the intense pain that may accompany a severe attack, the findings on abdominal examination often are nonspecific.

Skin manifestations are as follows:

  • Patients can have blisters, chronic erosion, and areas of excessive hair growth
  • Skin damage develops in sun-exposed areas of the skin

Can attacks be prevented?

Yes, particularly with regard to drugs and diet. Genetic HCP carriers should become informed on drugs and other factors that can lead to symptoms (see above).

They should be prepared to point their healthcare providers to drugs and medications to avoid. The American Porphyria Foundation offers a mobile phone app that pulls up this information on line (http://porphyriadrugs.com/).

A Medic Alert bracelet is useful for a situation in which the patient is incapacitated. Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance.

In selected cases, frequent noncyclic attacks can be prevented by once- or twice-weekly infusions of hemin.

Individuals who are prone to attacks should consume a normal balanced diet. Despite on-line discussion, there is no evidence that pushing carbohydrate prevents attacks, and it has the side effect of weight gain, which is undesirable for most people.

Fasting, fad diets (for example, high protein) and gastric reduction surgery should be avoided.

If weight loss is desired, it is advisable to consult a physician and a dietitian about an individualized diet with modest caloric restriction (ca. 10%), which will produce gradual weight loss without increasing the risk of an attack of porphyria. Exercise is safe in porphyria, and recommended.

Source & More Info: EMedicine and Rare Diseases Network

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