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Hereditary Coproporphyria Case Study

The first case of coproporphyria, reported by Berger and Goldberg (1955), was the offspring of first-cousin parents, both of whom showed excessive excretion of coproporphyrin III. The authors suggested that the disorder is autosomal dominant and that their proband was homozygous.

Barnes and Whittaker (1965) described 4 of 5 sibs who were affected. The parents were not tested. Marked elevation of coproporphyria in the feces differentiated the condition from acute intermittent porphyria (AIP; 176000) in which stool porphyrins are usually normal and from variegate porphyria (VP; 176200) in which both coproporphyrin and protoporphyrin fractions are increased in the stool. The proband experienced typical acute porphyria. Constipation and abdominal colic were striking features in these patients.

Goldberg et al. (1967) added 20 new cases. A massive excretion of coproporphyrin III in the urine and predominantly in the feces was demonstrated. Attacks resembling those of AIP were precipitated by drugs, and during attacks porphobilinogen and delta-aminolevulinic acid were excreted in the urine in excess. Photosensitivity is occasionally present and the only manifestations may be psychiatric. About half of cases are asymptomatic. This is an hepatic form of porphyria.

In the family of Haeger-Aronsen et al. (1968), 13 persons in 5 sibships of 2 generations showed latent coproporphyria, in addition to the symptomatic proband.

Cripps and Peters (1970) found that tranquilizers, including meprobamate and chlorpromazine, precipitated attacks.

McIntyre et al. (1971) noted that increased hepatic delta-aminolevulinic acid synthetase has been demonstrated in 3 forms of hereditary porphyria: AIP, VP, and coproporphyria.

In cultured skin fibroblasts, Elder et al. (1976) found that the activity of coproporphyrinogen oxidase was about half normal. Similar findings were reported for leukocytes (Brodie et al., 1977). In the homozygous patient reported by Grandchamp et al. (1977), activity of coproporphyrinogen oxidase was only 2% of control values.

Andrews et al. (1984) found 27 cases of coproporphyria in a kindred in which 135 members were screened for fecal porphyrins. Of the 135, 6 females and 1 male had probably suffered clinical attacks; the M:F ratio of cases revealed by screening was 13:14. The proband had her first attack at age 84 years; diazepam and nitrazepam were incriminated in her attack, and other drugs in the other patients. The late manifestation is indicated by the fact that this report was from a department of geriatric medicine. The earliest attack in an affected person was at age 14 years.

Barohn et al. (1994) described acute peripheral neuropathy with hereditary coproporphyria. This is a common feature of AIP but is rare with this form of porphyria.

Gross et al. (2002) reported the molecular, enzymatic, and clinical study of a family with hereditary coproporphyria in which the proband was a 30-year-old woman suffering from acute crises with abdominal, neurologic, and psychiatric complaints. The proband's father, 1 brother, and a sister were found to be new carriers. The patient was treated with intravenous interval therapy with heme arginate for 10 months, with good clinical and metabolic response.

Harderoporphyria

In 3 sibs (2 boys, 1 girl) with intense jaundice and hemolytic anemia at birth, Nordmann et al. (1983) found a high level of coproporphyrin in the urine and feces. The pattern of fetal porphyrin excretion was atypical because the major porphyrin was harderoporphyrin (more than 60%; normal, less than 20%). Homozygosity was suggested by the fact that the level of lymphocyte coproporphyrinogen III oxidase was 10% of controls in the sibs and 50% of normal in both parents (who showed only mild abnormalities of porphyrin excretion). The mutant enzyme showed abnormal kinetics.

Treatment

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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