Acute Porphyrias By By Herbert L. Bonkovsky, MD, University of North Carolina at Chapel Hill, and University of Connecticut Health Sciences Center ; Vinaya Maddukuri, MD, Carolinas Medical Center
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Acute porphyrias (see Overview of Porphyrias) include, in order of prevalence:
- Acute intermittent porphyria (AIP)
- Variegate porphyria (VP)
- Hereditary coproporphyria (HCP)
- δ-Aminolevulinic acid dehydratase (ALAD)–deficiency porphyria (exceedingly rare)
Patients with VP and HCP, with or without neurovisceral symptoms, may develop bullous eruptions especially on the hands, forearms, face, neck, or other areas of the skin exposed to sunlight.
Among heterozygotes, acute porphyrias are rarely expressed clinically before puberty; after puberty, they are expressed in only about 2 to 4%. Among homozygotes and compound heterozygotes, onset typically is in childhood, and symptoms are often severe.
Many precipitating factors exist, typically accelerating heme biosynthesis above the catalytic capacity of the defective enzyme. Accumulation of the porphyrin precursors porphobilinogen (PBG) and δ-aminolevulinic acid (ALA), or in the case of ALAD-deficiency porphyria, ALA alone, results.
Attacks probably result from several, sometimes unidentifiable, factors. Identified precipitating factors include
- Hormonal changes in women
- Low-calorie, low-carbohydrate diets
- Exposure to organic solvents
- Infections and other illnesses
- Emotional stress
Hormonal factors are important. Women are more prone to attacks than men, particularly during periods of hormonal change (eg, luteal phase of the menstrual cycle, during oral contraceptive use, during early weeks of gestation, in the immediate postpartum period). Nevertheless, pregnancy is not contraindicated.
Other factors include drugs (including barbiturates, hydantoins, other antiepileptic drugs, and sulfonamide antibiotics—see Table: Drugs and Porphyria*) and reproductive hormones ( 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.
Exposure to sunlight precipitates cutaneous symptoms in VP and HCP.
Symptoms and signs of acute porphyrias 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 during their lifetime. Others experience recurrent symptoms. In women, recurrent attacks often coincide with the luteal phase of the menstrual cycle.
Constipation, fatigue, irritability, and insomnia typically precede an acute attack. The most common symptoms of an attack are abdominal pain and vomiting. The pain may be excruciating and is disproportionate to abdominal tenderness or other physical signs. 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 only 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 nervous system and the CNS 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 cause respiratory failure.
CNS involvement may cause seizures or mental disturbances (eg, apathy, depression, agitation, frank psychosis, hallucinations). Seizures, psychotic behavior, and hallucinations may be due to or exacerbated by hyponatremia or hypomagnesemia, which can also contribute to cardiac arrhythmias. Hyponatremia may occur during an acute attack due to excessive vasopressin (antidiuretic hormone [ADH]) release and/or administration of hypotonic IV solutions (5% or 10% dextrose in water), a standard therapy for acute attacks.
Excess catecholamines generally cause 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.
Some patients have prolonged symptoms of lesser intensity (eg, obstipation, fatigue, headache, back or thigh pain, paresthesia, tachycardia, dyspnea, insomnia, depression, anxiety or other disturbances of mood, seizures).
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; lesions typically occur on the dorsal aspects of the hands and forearms, the face, ears, and neck.
Motor involvement during acute attacks may lead to persistent muscle weakness and muscle atrophy between attacks. Cirrhosis, hepatocellular carcinoma, systemic arterial 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.
- Urine screen for PBG
- If urine results are positive, quantitative ALA and PBG determination
- For confirmation of AIP, measurement of PBG deaminase activity in erythrocytes
- Genetic analysis if type is to be identified
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. Measurement of urinary total porphyrins and high-performance liquid chromatography profiles of these porphyrins are helpful. Elevated urinary ALA and coproporphyrin with normal or slightly increased PBG suggests lead poisoning, ALAD-deficiency porphyria, or hereditary tyrosinemia type 1. Analysis of a 24-h urine specimen is not necessary. Instead, a random urine specimen is used, and PBG and ALA levels are corrected for dilution by relating to the creatinine level of the sample. Electrolytes and Mg should be measured. Hyponatremia may be present because of excessive vomiting or diarrhea after hypotonic fluid replacement or because of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
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. Activity of the enzymes ALAD and PBGD in the red blood cells is readily measurable and can be helpful for establishing the diagnosis in ALAD-deficiency porphyria and acute intermittent porphyria, respectively. RBC PBG deaminase levels that are about 50% of normal suggest AIP. 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 urinalysis 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. Plasma fluorescence emission after excitation with Soret band of light (~410 nm) can be used to differentiate HCP and VP, which have different peak emissions.
Children of a gene carrier for an autosomal dominant form of acute porphyria (AIP, HCP, VP) have a 50% risk of inheriting the disorder. In contrast, children of patients with ALAD-deficiency porphyria (autosomal recessive inheritance) are obligate carriers but are very unlikely to develop clinical disease. Because early 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.
Advances in medical care and self-care have improved the prognosis of acute porphyrias for symptomatic patients. Still, some patients develop recurrent crises or progressive disease with permanent paralysis or renal failure. Also, frequent need for opioids analgesics may give rise to opioid dependence.
- Triggers eliminated if possible
- Dextrose (oral or IV)
- IV heme
Treatment of the acute attack is identical for all the acute porphyrias. Possible triggers (eg, excessive alcohol use, 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 O2 saturation are continuously monitored. Symptoms (eg, pain, vomiting) are treated with nonporphyrinogenic drugs as needed (see Table: Drugs and Porphyria*).
Dextrose 300 to 500 g daily down-regulates hepatic ALA synthase (ALAS 1) and relieves symptoms. Dextrose can be given by mouth if patients are not vomiting; otherwise, it is given IV. The usual regimen is 3 L of 10% dextrose solution, given by a central venous catheter over 24 h (125 mL/h). However, to avoid overhydration with consequent hyponatremia, 1 L of 50% dextrose solution can be used instead.
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 to 4 mg/kg IV once/day for 4 days. An alternative is heme arginate, which is given at the same dose, except that it is diluted in 5% dextrose or half-normal or quarter-normal saline. Hematin and heme arginate may cause venous thrombosis and/or thrombophlebitis. Risk of these adverse events appears to be lower if the heme is administered bound to human serum albumin. Such binding also decreases the rate of development of hematin aggregates. Thus, most authorities recommend administration of hematin or heme arginate with human serum albumin.
In patients with severe recurrent attacks, who are at risk of renal damage or permanent neurologic damage, liver transplantation is an option. Successful liver transplantation leads to permanent cure of all acute porphyrias other than ALAD-deficiency porphyria. Patients with acute porphyrias should not serve as liver donors even though their liver may appear structurally normal (ie, no cirrhosis) because recipients have developed acute porphyric syndromes; such an outcome helped establish that the acute porphyrias are hepatic disorders. 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.
Carriers of acute porphyria should avoid the following:
- Potentially harmful drugs (see Table: Drugs and Porphyria*)
- Heavy alcohol use
- Physical or emotional stress or exhaustion
- Exposure to organic solvents (eg, in painting or dry cleaning)
- Crash diets
- Periods of starvation
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 ultraviolet B light are ineffective, but opaque zinc oxide or titanium dioxide preparations are beneficial. Support associations, such as the American Porphyria Foundation and the European Porphyria Network, 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. Some patients can sometimes treat mild acute attacks by increasing their intake of dextrose or glucose. 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 agonist plus low-dose estrogen. Low-dose oral contraceptives are sometimes used successfully, but the progestin component is likely to exacerbate the porphyria.
To prevent renal damage, chronic hypertension should be treated aggressively (using safe drugs). Patients with evidence of impaired renal function are referred to a nephrologist. Recent anecdotal experience indicates that, an ADH blocker, is helpful in the management of hyponatremia during acute attacks.
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 ultrasonography. Early intervention can be curative and increases life expectancy.
- Acute porphyrias cause intermittent attacks of abdominal pain and neurologic symptoms; some types also have cutaneous manifestations that are triggered by sun exposure.
- Attacks have many triggers, including hormones, drugs, low-calorie and low-carbohydrate diets, and alcohol ingestion.
- Attacks typically involve severe abdominal pain (with a non-tender abdomen) and vomiting; any component of the peripheral and central nervous system may be affected but muscle weakness is common.
- Urine is often reddish-brown during an attack.
- Do a qualitative urine test for PBG and confirm a positive result with quantitative ALA and PBG measurements
- Treat acute attacks with oral or IV dextrose and, for severe attacks, IV heme.
- Drug NameSelect Trade
- LisinoprilPRINIVIL, ZESTRIL
- AtracuriumNo US brand name
- SuccinylcholineANECTINE, QUELICIN
- LevofloxacinIQUIX, LEVAQUIN, QUIXIN
- IbuprofenADVIL, MOTRIN IB
- ScopolamineTRANSDERM SCOP
- FentanylACTIQ, DURAGESIC, SUBLIMAZE
- CiprofloxacinCILOXAN, CIPRO
- NiacinNIACOR, NIASPAN
- FormoterolFORADIL AEROLIZER, PERFOROMIST
- LoratadineALAVERT, CLARITIN
- TobramycinTOBI, TOBREX
- NitrofurantoinFURADANTIN, MACROBID, MACRODANTIN
- RifampinRIFADIN, RIMACTANE
- NaproxenALEVE, NAPROSYN
- MorphineDURAMORPH PF, MS CONTIN
- DiclofenacCATAFLAM, VOLTAREN
- DiltiazemCARDIZEM, CARTIA XT, DILACOR XR
- MethenamineHIPREX, UREX
- FluphenazineNo US brand names
- FluoxetinePROZAC, SARAFEM
- MethyldopaNo brand name
- OfloxacinFLOXIN OTIC
- NifedipineADALAT CC, PROCARDIA
- ErythromycinERY-TAB, ERYTHROCIN
- AlbuterolPROVENTIL-HFA, VENTOLIN-HFA