Hereditary coproporphyria (HCP) is a rare metabolic disorder characterized by deficiency of the enzyme coproporphyrinogen oxidase. This enzyme deficiency results in the accumulation of porphyrin precursors in the body. This enzyme deficiency is caused by a mutation in the CPOX gene. However, the deficiency by itself is not sufficient to produce symptoms of the disease and most individuals with a CPOX gene mutation do not develop symptoms of HCP. Additional factors such as endocrine factors (e.g. hormonal changes), the use of certain drugs, excess alcohol consumption, infections, and fasting or dietary changes are required to trigger the appearance of symptoms. Some affected individuals experience acute attacks or episodes that develop over a period of days. The course and severity of attacks is highly variable from one person to another. In some cases, particularly those without proper diagnosis and treatment, the disorder can cause life-threatening complications. The CPOX mutation is inherited as an autosomal dominant trait.
HCP belongs to a group of disorders known as the porphyrias. This group is characterized by abnormally high levels of porphyrin precursors and, in many cases, porphyrins, due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins. There are eight enzymes in the pathway for making heme and at least eight major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the hepatic and erythropoietic types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are sometimes referred to as cutaneous porphyrias. The term acute porphyria is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. Most forms of porphyria are genetic inborn errors of metabolism. HCP is an acute, hepatic form of porphyria.
The episodes or “attacks” that characterize HCP usually develop over the course of several hours or a few days. Affected individuals usually recover from an attack within days. However, if an acute attack is not diagnosed and treated promptly recovery can take much longer, even weeks or months. Most affected individuals do not exhibit any symptoms in between episodes. Onset of attacks usually occurs in the 20s or 30s, but may occur at or just after puberty. Onset before puberty is extremely rare. Attacks are more common in women than men.
Intermittent, recurrent body pain, usually affecting the abdomen and the lower back may occur chronically. Pain in these areas is often the initial sign of an attack. Pain usually begins as low-grade, vague pain in the abdomen and slowly over a few days worsens eventually causing severe abdominal pain. Pain may radiate to affect the lower back, neck, buttocks, or arms and legs. Pain is usually not well localized, but in some cases can be mistaken for inflammation of the gallbladder, appendix or another intra-abdominal organ. In a minority of cases, pain primarily affects the back and the arms and legs and is usually described as deep and aching. Abdominal pain is often described as colicky and is usually associated with nausea and vomiting. Vomiting may be severe enough that affected individuals vomit after eating or drinking any food or liquid. The absence of bowel sounds (ileus), which indicates a lack of intestinal activity may be noted. Constipation may also occur and can be severe (obstipation). Affected individuals may also experience a faster than normal heart rate (tachycardia), high blood pressure (hypertension), irregular heartbeats (cardiac arrhythmias), and a sudden fall in blood pressure upon standing (orthostatic hypotension). Hypertension may persist in between acute attacks.
Neurologic symptoms, including seizures, may be associated with HCP. In some cases, new-onset seizures may be the initial sign of the disorder. Abnormally low sodium levels in the blood (hyponatremia) may occur during an attack and contribute to the onset of seizures. Affected individuals may also develop damage to the nerves in the extremities (peripheral neuropathy). Peripheral neuropathy may be preceded by the loss of deep tendon reflexes. Peripheral neuropathy is characterized by numbness or tingling and burning sensations that, in HCP, usually begin in the upper legs and arms. Affected individuals may develop muscle weakness initially in the feet and legs that progresses to affect and paralyze all extremities and the body trunk (motor paralysis) and the respiratory muscles (respiratory paralysis and failure).
This ascending paralysis in HCP can mimic the ascending paralysis seen in Guillain-Barré syndrome (GBS), a disorder in which the body’s immune system attacks the nerves. Differentiating HCP from GBS is extremely important to ensure prompt treatment of HCP and the avoidance of medications that can precipitate or worsen an acute attack. (For more information on GBS, see the Related Disorders section of this report.)
Some individuals develop psychological symptoms, although such symptoms are highly variable. Such symptoms can include irritability, depression, anxiety, and insomnia. Less often, more acute psychiatric symptoms can develop including hallucinations, paranoia, disorientation, mental confusion, delirium, and psychosis.
In some cases, affected individuals may develop skin (cutaneous) lesions affecting the sun-exposed areas of skin such as the hands and face. Affected individuals may develop severe pain, burning, and itching of such areas (photosensitivity). Eventually, the skin may become fragile and develop fluid-filled blisters (bullae). Affected areas may also exhibit darkly discolored (hyperpigmented) scars and excessive hair growth.
The CPOX gene mutation that predisposes individuals to developing HCP is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The CPOX gene creates (encodes) the enzyme coproporphyrinogen-III oxidase (CPO). This enzyme is the sixth enzyme is process of heme biosynthesis. Mutations in the CPOX gene lead to deficient activity of CPO in the body (approximately 50% reduced), which in turn leads to insufficient heme production and occasionally to the accumulation of CPO precursors in the liver.
Many of the triggers of an acute attack act by increasing the demand for heme, which makes the CPO deficiency more significant. For example, heme synthesis is required to metabolize specific medications. However, the underlying genetic mutation in HCP limits the production of heme and increases the accumulation of porphyrin precursors in the body. Additionally, the offending medication is not metabolized and eliminated from the body, thereby precipitating an acute attack. The exact, underlying reasons why symptoms develop in some affected individuals and not others are not fully understood. More research is necessary to determine the specific underlying mechanisms that are involved in the development of symptomatic episodes.
HCP is a rare disorder that can potentially affect males and females in equal numbers, although symptoms are more prevalent in females. The exact incidence and prevalence of HCP is unknown.
A diagnosis of HCP is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. The observation of reddish brown urine that is free of blood is indicative, but not conclusive, of an acute porphyria. The intolerance of medications such as oral contraceptives is also suggestive of an acute porphyria.
Clinical Testing and Workup
Screening tests can help diagnose HCP by measuring the levels of certain porphyrin precursors (e.g. porphobilinogen [PBG] and delta-aminolevulinic acid [ALA] in the urine. Acute attacks are always accompanied by markedly increased excretion of PBG. During a potential acute attack in an individual suspected of an acute porphyria, a random (spot) urine sample can be tested. If urinary PBG is sufficiently increased, then a qualitative 24-hour urine analysis for both PBG and ALA should be performed and compared to urine sample results from when the individual did not exhibit symptoms. Although PBG and ALA may be increased during an acute attack, they return to normal on recovery.
Individuals with HCP may have elevated porphyrin levels such as coproporphyrin in the urine, but this finding is nonspecific (e.g. it can also be associated with other conditions) and therefore does not conclusively confirm a diagnosis of HCP.
Further testing is necessary to exclude HCP from variegate porphyria or acute intermittent porphyria. Fecal CP analysis can be extremely helpful in obtaining the diagnosis. This test can reveal markedly increased levels of coproporphyrin in stool samples, which is characteristic of HCP.
Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the CPOX gene. Family members of an individual positive for a CPOX mutation can be offered testing for this mutation. Molecular genetic testing is available in certain laboratories specializing in porphyria diagnosis.
Individuals and family members who have inherited HCP should be counseled on how to limit their risk of any future acute attacks. This should include information about HCP and what causes attacks, how to check if a prescribed medication is safe or unsafe, and details of relevant patient support groups. Membership in the American Porphyria Foundation is very helpful to affected individuals.
The treatment of HCP is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, hematologists, dermatologists, hepatologists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affected person’s treatment. Genetic counseling may benefit affected individuals and their families.
Initial treatment steps include stopping any medications that can potentially worsen HCP or cause an attack. All triggering factors should be identified, if possible, and discontinued. In addition, ensuring proper intake of carbohydrate, either orally or intravenously, is essential.
An acute neurovisceral attack requires hospitalization and treatment with hematin. In the United States, affected individuals may be treated with panhematin® (hemin for injection), an enzyme inhibitor derived from red blood cells that is potent in suppressing acute attacks of porphyria. Panhematin almost always returns porphyrin and porphyrin precursor levels to normal values. The U.S. Food and Drug Administration (FDA) originally approved panhematin for the treatment of recurrent attacks of AIP related to the menstrual cycle in susceptible women. Numerous symptoms including pain, hypertension, tachycardia and altered mental status, and neurologic signs have improved in individuals with acute porphyria after treatment with panhematin. Because of its potency, it is usually given after a trial of high-dose carbohydrate of any sort, including glucose therapy and should be administered only by physicians experienced in the management of porphyrias in a hospital setting. Panhematin is available from Recordati Rare Diseases, Inc.
Heme arginate (Normosang®) is another heme preparation that can be used to treat individuals with HCP. Heme arginate is not available in the United States, but is often used in other countries.
Some individuals who experience recurrent attacks may benefit from chronic hematin infusion. This is sometimes recommended for women with severe symptoms during the time of their menses.
Treatment for HCP may also include drugs to treat specific symptoms such as certain pain medications (analgesics), anti-anxiety drugs, anti-hypertensive drugs, and drugs to treat nausea and vomiting, tachycardia, or restlessness. Medications to treat any infections that may occur at the same time as an attack (intercurrent infection) may also be necessary. Seizures may require treatment with anti-seizure (anti-convulsant) medications, but many of the common options can worsen an attack and are contraindicated. A short-acting benzodiazepine or magnesium may be recommended. Gabapentin and propofol are considered effective and safe for prolonged control of seizures.
Although many types of drugs are believed to be safe in individuals with HCP, recommendations about drugs for treating HCP are based upon experience and clinical study. Since many commonly used drugs have not been tested for their effects on porphyria, they should be avoided if at all possible. If a question of drug safety arises, a physician or medical center specializing in porphyria should be contacted. A list of these institutions may be obtained from the American Porphyria Foundation (see the Resources section of this report). The Foundation also maintains an Acute Porphyria Drug Database (http://www.porphyriafoundation.com/drug-database).
Additional treatment for individuals undergoing an attack includes monitoring for muscle weakness and respiratory issues and monitoring fluid and electrolyte balances. For example, if affected individuals develop hyponatremia, which can induce seizures, they should be treated by restricting the intake of water (water deprivation). If serum sodium is decreased severely, e.g. from normal (>134 meq/dl) to very low (100-115 meq/dl), then saline infusion is indicated.
Premenstrual attacks often resolve quickly with the onset of menstruation. Hormone manipulation may be effective in preventing such attacks. Some affected women have been treated with gonadotropin-releasing hormone analogues to suppress ovulation and prevent frequent cyclic attacks.
In some cases, an attack is precipitated by a low intake of carbohydrates in an attempt to lose weight. Consequently, dietary counseling is very important. Affected individuals who are prone to attacks should eat a normal carbohydrate diet and should not greatly restrict their intake of carbohydrates or calories, even for short periods of time. If weight loss is desired, it is advisable to contact a physician and dietitian.
In individuals who develop skin complications, avoidance of sunlight will be of benefit and can include the use of double layers of clothing, long sleeves, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective. Affected individuals will also benefit from window tinting and the use of vinyl or films to cover the windows of their homes and cars. Avoidance of sunlight can potentially cause vitamin D deficiency and some individuals may require supplemental vitamin D.
A liver transplant has been used to treat some individuals with acute forms of porphyria, specifically individuals with severe disease who have failed to respond to other treatment options. A liver transplant in individuals with HCP is an option of last resort.
Wearing a Medic Alert bracelet or the use of a wallet card is advisable in individuals who have HCP.
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