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Acute porphyrias
produce intermittent attacks of abdominal pain and neurologic symptoms. Attacks
are precipitated by certain drugs and other factors. Patients with
variegate porphyria and hereditary coproporphyria may develop bullous
eruptions from sunlight exposure. Diagnosis is based on elevated
levels of δ-aminolevulinic acid and porphyrin precursor porphobilinogen
in the urine during attacks. Attacks are treated with glucose or,
if more severe, IV heme. Symptomatic treatment, including analgesia,
is given as necessary.
Acute porphyrias include, in order of prevalence, acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and the exceedingly rare δ-aminolevulinic acid dehydratase (ALAD)-deficiency porphyria.
Among heterozygotes, acute porphyrias are rarely expressed clinically before puberty and, after puberty, in only about 20 to 30%. Among homozygotes and double heterozygotes, onset generally is in childhood, and symptoms are often severe.
Precipitating
Factors
Many precipitating factors exist, typically accelerating heme biosynthesis above the catalytic capacity of the defective enzyme. Accumulation of porphyrin precursor porphobilinogen (PBG) and δ-aminolevulinic acid (ALA), or in the case of ALAD-deficiency porphyria, ALA alone, results.
Hormonal factors are important. Women are more prone to attacks than men, particularly during periods of hormonal change (eg, just before menstruation, during use of oral contraceptives, during the early weeks of gestation, just after delivery). Nevertheless, pregnancy is not contraindicated.
Other factors include drugs (including barbiturates, other antiepileptic drugs, and sulfonamide antibiotics—see Table 4: Porphyrias: Drugs and Porphyria* ) and reproductive hormones (progesterone and related steroids), particularly those that induce hepatic ALA synthase and cytochrome P-450 enzymes. Attacks usually occur within 24 h after exposure to a precipitating drug. Low-calorie and low-carbohydrate diets, alcohol ingestion, and exposure to organic solvents can also precipitate symptoms. Infection or other illness, surgery, and mental problems are sometimes implicated. Attacks usually result from several, sometimes unidentifiable, factors.
Sunlight precipitates cutaneous symptoms in VP and HCP.
Symptoms and Signs
Symptoms and signs involve the nervous system, abdomen, or both (neurovisceral). Attacks develop over hours or days and can last up to several weeks. Most gene carriers experience no, or only a few, attacks in their lifetime. Others experience recurrent symptoms. In women, attacks often coincide with phases of the menstrual cycle.
The
acute porphyric attack:
Constipation, fatigue, irritability, and insomnia typically precede an acute attack. The most common symptoms with an attack are abdominal pain and vomiting. The pain may be excruciating and is disproportionate to abdominal tenderness. Abdominal manifestations may result from effects on visceral nerves or from local vasoconstrictive ischemia. Because there is no inflammation, the abdomen is not tender and there are no peritoneal signs. Temperature and WBC count are normal or slightly increased. Bowel distention may develop as a result of paralytic ileus. The urine is red or reddish brown and positive for PBG during an attack.
All components of the peripheral and central nervous systems may be involved. Motor neuropathy is common with severe and prolonged attacks. Muscle weakness usually begins in the extremities but can involve any motor neuron or cranial nerve and proceed to tetraplegia. Bulbar involvement can produce ventilatory failure.
CNS involvement may produce seizures or mental disturbances (eg, apathy, depression, agitation, frank psychosis, hallucinations). Seizures, psychotic behavior, and hallucinations may be due to hyponatremia or hypomagnesemia, which can also contribute to cardiac arrhythmias.
Excess catecholamines generally produce restlessness and tachycardia. Rarely, catecholamine-induced arrhythmias cause sudden death. Labile hypertension with transiently high BP may cause vascular changes progressing to irreversible hypertension if untreated. Renal failure in acute porphyria is multifactorial; acute hypertension (possibly leading to chronic hypertension) is likely a main precipitating factor.
Subacute or subchronic
symptoms:
Some patients experience prolonged symptoms of lesser intensity (eg, obstipation, fatigue, headache, back or thigh pain, paresthesia, tachycardia, dyspnea, insomnia, mental disturbance, seizures).
Skin
symptoms in VP and HCP:
Fragile skin and bullous eruptions may develop on sun-exposed areas, even in the absence of neurovisceral symptoms. Often patients are not aware of the connection to sun exposure. Cutaneous manifestations are identical to those of porphyria cutanea tarda.
Late manifestations:
Motor involvement during acute attacks may produce persistent weakness between attacks. Hepatocellular cancer, hypertension, and renal impairment become more common after middle age in AIP and possibly also in VP and HCP, especially in patients with previous porphyric attacks.
Diagnosis
Acute attack:
Misdiagnosis is common because the acute attack is confused with other causes of acute abdomen (sometimes leading to unnecessary surgery) or with a primary neurologic or mental disorder. However, in patients previously diagnosed as gene carriers or who have a positive family history, porphyria should be suspected. Still, even in known gene carriers, other causes must be considered.
Red or reddish brown urine, not present before onset of symptoms, is a cardinal sign and is present during full-blown attacks. A urine specimen should be examined in patients with abdominal pain of unknown cause, especially if severe constipation, vomiting, tachycardia, muscle weakness, bulbar involvement, or mental symptoms occur.
If porphyria is suspected, the urine is analyzed for PBG using a rapid qualitative or semiquantitative determination. A positive result or high clinical suspicion necessitates quantitative ALA and PBG measurements preferentially obtained from the same specimen. PBG and ALA levels > 5 times normal indicate an acute porphyric attack unless patients are gene carriers in whom porphyrin precursor excretion occurs at similar levels even during the latent phase of the disorder.
If urinary PBG and ALA levels are normal, an alternative diagnosis must be considered. Elevated ALA with normal or slightly increased PBG suggests lead poisoning or ALAD-deficiency porphyria. Analysis of a 24-h urine specimen is not useful. Instead, a random urine specimen is used, PBG and ALA levels being corrected for dilution by relating to the creatinine level of the sample. Electrolytes and Mg should be measured. Hyponatremia may be present from excessive vomiting or diarrhea with hypotonic fluid replacement or from the syndrome of inappropriate ADH secretion (SIADH).
Determination
of type:
Because treatment does not depend on the type of acute porphyria, identification of the specific type is valuable mainly for finding gene carriers among relatives. When the type and mutation are already known from previous testing of relatives, the diagnosis is clear but may be confirmed by gene analysis. Enzymatic diagnosis is not necessary. If there is no family history to guide the diagnosis, the different forms of acute porphyria are distinguished by characteristic patterns of porphyrin (and precursor) accumulation and excretion in plasma, urine, and stool. When urine analysis reveals increased levels of ALA and PBG, fecal porphyrins may be measured. Fecal porphyrins are usually normal or minimally increased in AIP but elevated in HCP and VP. Often, these markers are not present in the quiescent phase of the disorder. In HCP and VP, plasma porphyrins with characteristic fluorescence are looked for. RBC PBG deaminase levels that are about 50% of normal suggest AIP. Diminished WBC protoporphyrinogen oxidase and coproporphyrinogen oxidase levels suggest VP and HCP, respectively.
Family studies:
Children of a gene carrier have a 50% risk of inheriting the disorder. Because diagnosis followed by counseling reduces the risk of morbidity, children in affected families should be tested before the onset of puberty. Genetic testing is used if the mutation has been identified in the index case. If not, pertinent RBC or WBC enzyme levels are measured. Gene analysis can be used for in utero diagnosis (using amniocentesis or chorionic villus sampling) but is seldom indicated because of the favorable outlook for most gene carriers.
Prognosis
Advances in medical care and self-care have improved the prognosis for symptomatic patients. Still, some patients develop recurrent crises or progressive disease with permanent paralysis or renal failure. Also, frequent need for potent analgesics may give rise to drug addiction.
Treatment
Treatment of the acute attack is identical for all the acute porphyrias. Possible triggers (eg, drugs) are identified and eliminated. Unless the attack is mild, patients are hospitalized in a darkened, quiet, private room. Heart rate, BP, and fluid and electrolyte balance are monitored. Neurologic status, bladder function, muscle and tendon function, respiratory function, and pulse oximetry are continuously monitored. Symptoms (eg, pain, vomiting) are treated with nonporphyrinogenic drugs as needed (see Table 4: Porphyrias: Drugs and Porphyria*).
Dextrose 300 to 500 g daily inhibits ALA synthase and decreases symptoms. It can be given by mouth if patients are not vomiting; otherwise, it is given IV. To avoid overhydration with consequent hyponatremia, 1 L of a 50% dextrose solution can be given by central venous catheter over 24 h.
IV heme is more effective than dextrose and should be given immediately in severe attacks, electrolyte imbalance, or muscle weakness. Heme usually resolves symptoms in 3 to 4 days. If heme therapy is delayed, nerve damage is more severe and recovery is slower and possibly incomplete. Heme is available in the US as lyophilized hematin to be reconstituted in a glass vial with sterile water. The dose is 3 mg/kg IV once/day for 4 days. In this form, heme degradation products form rapidly and may cause phlebitis at the infusion site; they also have a transient anticoagulant effect. Adverse effects can be reduced by reconstitution with, eg, 20% human albumin. Heme arginate is a more stable, generally toxicity-free alternative.
In patients with severe recurrent attacks, who are at risk of renal damage or permanent neurologic damage, liver transplantation is an option. Renal transplantation, with or without simultaneous liver exchange, should be considered in patients with active disease and terminal renal failure, because there is considerable risk that nerve damage will progress at the start of dialysis.
Prevention
Carriers of acute porphyria should avoid the following:
Diets for obesity should provide gradual weight loss and be adopted only during periods of remission. Carriers of VP or HCP should minimize sun exposure; sunscreens that block only UVB are ineffective, but opaque titanium dioxide preparations are beneficial. Support associations for porphyria patients can provide written information and direct counseling.
Patients should be identified prominently in the medical record as carriers and should carry a card verifying the carrier state and precautions to be observed.
A high-carbohydrate diet may decrease the risk of acute attacks. A high-carbohydrate diet or a lump of sugar every hour may help relieve symptoms of an acute attack. Prolonged use should be avoided in order to decrease risk of obesity and dental caries.
Patients who experience recurrent and predictable attacks (typically women with attacks related to the menstrual cycle) may benefit from prophylactic heme therapy given shortly before the expected onset. There is no standardized regimen; a specialist should be consulted. Frequent premenstrual attacks in some women are aborted by administration of a gonadotropin-releasing hormone analog plus low-dose estrogen. Oral contraceptives are sometimes used successfully, but the progestin component is likely to exacerbate the porphyria.
To prevent renal damage, chronic hypertension is treated (using safe drugs). Patients with evidence of impaired renal function are referred to a nephrologist.
The incidence of hepatocellular cancer is high among carriers of acute porphyria, especially in patients with active disease. Patients who are > 50 should undergo yearly or twice yearly surveillance, including liver screening with contrast-enhanced ultrasonography. Early intervention can be curative and increases life expectancy.
Last full review/revision August 2008 by Stig Thunell, MD, PhD
Content last modified August 2008
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