Biochemical abnormalities in the porphyrias are linked to clinical manifestations. Porphyrins deposited in the skin and circulating in dermal blood vessels cause photoactive damage to the skin in the presence of sunlight,[2,3] resulting in photocutaneous manifestations that are seen in some porphyrias. The overproduction of the porphyrin precursors ALA and PBG is characteristic of the porphyrias in which neurologic abnormalities occur. The clinical manifestations have been used to classify the porphyrias into 2 groups: those with photocutaneous manifestations and those with neurologic abnormalities. The latter are called the acute porphyrias (Table 1).[4] The liver is the primary site of expression of biochemical abnormalities that occur in the acute porphyrias.[5] This may fluctuate, giving rise to acute episodes known as acute porphyric attacks. Some patients with acute porphyria have only a few attacks in their lifetime.[6] However, in other patients the attacks are frequent,[6] with some of the clinical features becoming chronic in nature.
There are 4 types of acute porphyria (Table 1). Acute intermittent porphyria (AIP) is the most common type worldwide, particularly among people of Scandinavian, British, and Irish descent. Variegate porphyria (VP) is most frequently observed in South Africa, with many cases tracing back to an individual who emigrated there from The Netherlands in the 17th century.[7] Aminolevulinic acid dehydratase deficiency porphyria (ADP) is a very rare inherited recessive disorder, with only a few cases reported. Hereditary coproporphyria (HCP) is also rare.
The prevalence of the gene defect for AIP, estimated by measurement of erythrocyte PBG deaminase activity in blood donors, is 0.06% in France and 0.22% in Finland.[8] Family studies have shown that only 10% to 20% of individuals who carry the gene defect for AIP have clinical manifestations of the disease.[4] There have been 301 different mutations identified in the PBG deaminase gene in AIP patients through May 2006.[9] Genetic heterogeneity has been found in VP and HCP as well.[10] Thus, specific mutations do not correlate well with specific phenotypes or identify patients who are more prone to severe disease expression. An exception has been the class of mutations that affect the hepatic form of the PBG deaminase protein, not the erythrocyte form, and occur in approximately 5% of AIP patients.[11] In these patients, the level of erythrocyte PBG deaminase activity remains normal even when the level of activity in the liver is deficient. Therefore, measurement of erythrocyte PBG deaminase activity cannot be used to confirm the diagnosis of AIP or to identify other family members who carry the gene defect.
The liver is the major site, and perhaps the sole site, of overproduction of ALA and PBG in AIP, VP, and HCP. This is underscored by the finding that liver transplantation returned the urinary excretion of ALA and PBG to normal, and eliminated recurrent neurologic attacks, in patients with AIP and VP.[12-14] In a single patient transplanted for ADP, excessive urinary excretion of ALA persisted, indicating that in this disorder other tissues contribute to the biochemical
abnormality.[15]
Acute porphyric attacks are associated with a marked increase in urinary excretion of ALA and PBG, which declines and may even normalize during asymptomatic periods, particularly in VP and HCP. This increase in production of ALA and PBG occurs because of a significant induction of the first and rate-limiting enzyme in hepatic heme biosynthesis, ALA synthase-1, during an acute porphyric attack (Figure 2). This has been shown in patients as well as in experimental models of acute porphyria.[16] In the presence of the downstream deficiency of PBG deaminase activity, ALA and PBG accumulate and are excreted in increased amounts. In AIP the defect in PBG deaminase occurs because of a gene mutation, whereas PBG deaminase activity is inhibited in VP and HCP by the compounds protoporphyrinogen and coproporphyrinogen, respectively.[17] These compounds accumulate because of deficient protoporphyrinogen oxidase activity in VP and deficient coproporphyrinogen oxidase activity in HCP.
Multiple precipitating factors may cause induction of hepatic ALA synthase-1, bringing about an acute porphyric attack (Table 2).[4] Some of these factors deplete the regulatory hepatic heme pool that exerts negative feedback control on hepatic ALA synthase-1 by depressing synthesis of the enzyme protein; the regulatory pool also acts by inhibiting translocation of the enzyme protein from the cytosol to the mitochondria, where the enzyme is active.[18,19] Heme may also stimulate degradation of ALA synthase-1 in the mitochondria.[20] Depletion of the regulatory hepatic heme pool is caused by drugs, such as phenobarbital, which increase the synthesis of the heme-containing cytochrome P450 compounds, and by infection, which induces heme oxygenase and thereby increases heme degradation. Some precipitating factors induce hepatic ALA synthase-1 more directly. Experiments have shown that fasting increases the level of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha which then induces ALA synthase-1.[21]
Table 2. Features of Acute Porphyric Attacks
| Precipitating factors |
Many OTC and prescription drugs
Endogenous hormones
Fasting or ↓ carbohydrate intake
Illicit drugs (marijuana, cocaine)
Cigarette smoking
Alcoholism
Infection |
OTC = over the counter
However, the precise mechanism(s) by which the biochemical abnormalities in the acute porphyrias lead to clinical manifestations remains uncertain. A number of observations have indicated that ALA may be a neurotoxin.[22] During an acute attack, ALA is increased in the blood and urine of patients with all 4 types of acute porphyria. Urinary ALA excretion is also increased in patients with hereditary tyrosinemia type 1 and lead poisoning, both of which are associated with neurologic manifestations similar to those in the acute porphyrias. ALA structurally resembles the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and is a GABA receptor agonist; this could account for some of the symptoms in an acute attack. The intraventricular administration of ALA into the brain of experimental animals causes neurotoxicity. The argument against ALA being a major causative factor of acute porphyric attacks is that some asymptomatic patients excrete ALA in high amounts.[22] The recent finding that peptide transporter 2 expression in the brain protects against ALA neurotoxicity in mice suggests that this could be a secondary genetic modifier of disease expression in the acute porphyrias, thus helping to explain the variability in neurotoxicity seen among patients with increased ALA production and excretion.[23]
Another possibility to explain the neurologic dysfunction in acute porphyric attacks may be heme deficiency in the liver and/or nerve tissue.[22] There is little evidence in support of heme deficiency in the nervous system, but there is evidence for impaired hepatic hemoprotein function. It has been shown experimentally that a chemically induced deficiency of heme in the liver cells of rodents causes a decrease in the activity of the hemoprotein tryptophan dioxygenase, causing an increased flux of tryptophan to the brain where it acts as a substrate for the production of serotonin.[24] Serotonin is a neurotransmitter that can cause central nervous system changes as well as features of autonomic neuropathy. Increased blood levels of tryptophan and serotonin, and increased urinary excretion of tryptophan metabolites, have been reported in several patients with acute porphyria.[22]
Autopsy findings in patients with acute porphyria differ according to the duration of attack. There is no structural nerve damage observed if the attack is of short duration; however, with prolonged duration axonal damage and demyelination of nerves may occur.[22] In the brain, mild diffuse neuronal loss and gliosis have been observed.[22] MRI in patients with seizures and hallucinations has shown multiple reversible cerebral lesions, suggesting that vascular mechanisms may also be important in the pathogenesis of cerebral dysfunction in acute porphyria.[25]
Clinical Features of the Acute Porphyrias
Porphyric attacks are of variable severity, sometimes resulting in death. A study of the cumulative survival for 136 patients with AIP in the United States, who were hospitalized for porphyric attacks between 1940 and 1988, showed the standardized mortality ratio to be 3.2 compared with an age-matched hypothetical population.[26] Most deaths occurred during the initial porphyric attack (20% of deaths) or a subsequent attack (38% of deaths). Porphyric complications were also the leading cause of death (32%) in 96 deceased patients with acute porphyria in Finland.[27]
The signs and symptoms that occur during an acute porphyric attack are myriad (Table 2), but all reflect neuropathic changes. Abdominal pain is the most common clinical manifestation, occurring in 85% to 95% of individuals during an attack.[4] There is nothing characteristic about the nature of abdominal pain that leads to the diagnosis of acute porphyria. It is caused by autonomic neuropathy, which also causes vomiting, constipation, tachycardia, and systemic arterial hypertension. Peripheral neuropathy is manifested by pain in the extremities, back, neck, and head, and also by paresis, with proximal arm muscles usually affected first. As the attack progresses, respiratory paralysis may occur necessitating intubation and mechanical ventilation. Central nerve system involvement is also common, with a change in mental status reflected by irritability, anxiety, and behavioral changes. Depression, psychosis, and hallucinations may also occur. Seizures occur in 10% to 20% of porphyric attacks, presenting a difficult clinical problem because many antiseizure medications will significantly exacerbate the attack. Inappropriate secretion of antidiuretic hormone causing hyponatremia has also been observed.[28]
Some women have frequent porphyric attacks during the luteal phase of the menstrual cycle, suggesting that endogenous hormones, particularly progesterone, are a factor in precipitating attacks. Because hormone levels increase during pregnancy, it is possible that pregnancy would also be a precipitating factor for acute porphyric attacks. A series reported in 1977 found 48% of 50 women with acute porphyria (39 AIP, 3 VP, and 8 HCP) to have an acute attack during pregnancy, with 1 maternal death.[29] Infants born to mothers who experienced an acute attack were smaller than those born to mothers in whom no attack occurred.[29] However, a more recent series from Finland of 176 pregnancies in women with acute porphyria (106 in AIP, 70 in VP) found symptoms indicative of porphyria in only 14 pregnancies (8%).[27] In 7 pregnancies (4%), delivery was followed by an acute attack that required hospitalization. No maternal deaths were reported. Thus, there may be an increase in porphyric attacks related to pregnancy, but these attacks do not appear to be more severe, and pregnancy is not contraindicated in patients with acute porphyria.
Chronic medical conditions may develop in patients with acute porphyria. Some patients develop a chronic pain syndrome and become dependent on narcotics. In others, depression may occur; the suicide rate in patients with acute porphyria is significantly increased compared with the general population.[4,26,27] Some patients may develop chronic hypertension, which may lead to renal impairment.[30] There is also an increased incidence of hepatocellular carcinoma in patients with acute porphyria compared with the general population.[31,32] A study in France followed 650 patients with acute porphyria over a 7-year period and found the incidence of liver cancer to be 35 times that expected in the general population.[32] Of the 7 patients who developed primary liver cancer, 5 had AIP, 1 VP, and 1 HCP. Two patients had chronic viral hepatitis with cirrhosis; no etiologic factor was identified in the 5 remaining patients. Histologic study of the nontumor liver tissue was normal in 4 of these patients and showed only fatty infiltration in the fifth. Therefore, the reason for the development of hepatocellular carcinoma is uncertain.
Diagnosis of Acute Porphyria
Acute porphyria is not usually considered in the differential diagnosis of abdominal pain until multiple laboratory, endoscopic, and radiologic studies have failed to reveal an etiology. However, in patients with episodic abdominal pain, who also have signs of peripheral neuropathy and/or manifestations of central nervous system involvement, the index of suspicion should be increased. If the episodes are associated with factors known to precipitate acute porphyric attacks, such as fasting or use of drugs, this should prompt earlier consideration of the diagnosis. A history of unexplained abdominal pain in other family members, as well as the presence of red or purple urine or unexplained hyponatremia, should also increase the index of suspicion.
Because all of the acute porphyrias, except for the very rare condition ADP, are attended by increased urinary excretion of PBG (usually 20-200 mg/L) during a porphyric attack, the initial diagnostic test recommended is a stat determination of the PBG level in a spot urine sample.[4] There is no other disorder in which urinary PBG is elevated; this is in contrast to urine porphyrin, which is elevated in many nonporphyric disorders that may have symptoms of porphyria (termed secondary porphyrinuria). The level of PBG can be rapidly measured on a spot urine sample, using the PBG Test Kit (Thermo Fisher Scientific, Waltham, Massachusetts). This is a sensitive test in which PBG is extracted from urine with an anion exchange resin, followed by reaction with dimethylaminobenzaldehyde to form a magenta-colored product.[33] A color chart is provided for semiquantitative estimation of the PBG level. If positive (> 6 mg/L), therapy for acute porphyria should proceed; however, diagnosis should be subsequently confirmed by quantitative determination of ALA and PBG in a 24-hour urine collection obtained during the attack.
The specific type of acute porphyria is identified through further testing. The erythrocyte level of PBG deaminase activity can be measured to identify patients with AIP, whereas measurement of plasma porphyrin can be used to identify patients with VP (increased porphyrin level with fluorescence peak at 626 nm at neutral pH is characteristic).[34,35] Determination of the fecal coproporphyrin III level or fecal coproporphyrin III/coproporphyrin I ratio is used to identify patients with HCP.[36,37]
Urinary excretion of ALA and PBG usually remains elevated during asymptomatic periods in patients with AIP, allowing the diagnosis to be made between attacks.[4] The erythrocyte level of PBG deaminase activity remains decreased when patients with AIP are asymptomatic.[4] In patients with VP, the plasma porphyrin level may remain elevated between attacks.[35] If these studies are negative but the index of suspicion remains high as a result of clinical features, repeat testing should be done when the patient is symptomatic.
DNA Analysis in the Acute Porphyrias
Molecular techniques have been developed to identify gene mutations in all types of acute porphyria, and DNA analysis is available through the Department of Human Genetics at the Mount Sinai School of Medicine in New York, NY. It is not presently recommended that this be used in the initial evaluation of patients suspected of having acute porphyria.[38] The diagnosis should be established on the basis of clinical features and measurement of porphyrins and porphyrin precursors in plasma, urine, and feces. Once the diagnosis of acute porphyria has been established, and the specific type of porphyria has been determined, DNA analysis should be considered to identify the gene mutation. When this has been determined, molecular analysis is most valuable in kindred evaluation and genetic counseling; it is the most effective strategy to screen asymptomatic family members who are at risk of carrying the gene defect.
Prevention of Porphyric Attacks
Patients should be educated on environmental or physiologic triggers that may precipitate acute attacks. Many drugs, endogenous hormones, fasting, alcohol use, smoking, and other factors can trigger an attack.[4] Susceptibility to environmental or physiologic triggers varies among patients. Acute attacks can be brought on by the additive effects of several factors. Conversely, not all attacks have an identifiable precipitating factor.
Of the known factors that can contribute to an acute attack, drugs are the most common, and the list of unsafe drugs continues to increase as new drugs become available. Medications are considered unsafe for use in patients with porphyria if they have precipitated an attack in individuals or if they are porphyrinogenic in experimental test systems. Drugs that are most frequently associated with porphyric attack include anticonvulsants (carbamazepine and phenytoin), barbiturates, rifampin, dapsone, erythromycin, progestins, sulfonamides, calcium channel blockers, tricyclic antidepressants, and antifungal agents (terbinafine, fluconazole, itraconazole, ketoconazole, voriconazole, and posaconazole). As a general rule, patients with acute porphyria should avoid unnecessary medications and should limit over-the-counter and prescription drugs to those that will not trigger an acute attack. However, there are differences among patients in their tolerance to drugs. If there is concern about using a drug for which information is not available, or the information is discrepant, measurement of urinary ALA and PBG levels can be done before and during treatment to determine whether there is an increase that indicates an adverse reaction. A comprehensive list of safe medications to use in patients with porphyria can be found at The Drug Database for Acute Porphyria, the American Porphyria Foundation, and the European Porphyria Initiative.
There are several factors besides drugs that may cause or contribute to an acute porphyric attack. For example, ethanol can induce ALA synthase and trigger an attack. Attacks have also been reported in patients with infection; these patients may have accelerated heme degradation due to increased heme oxygenase activity. Dieting, fasting, and stress-related attacks have been reported. Polycyclic aromatic hydrocarbons present in tobacco smoke can induce hepatic cytochrome P450 enzymes and heme synthesis, thereby triggering an attack.[39] Illegal drugs, such as marijuana, ecstasy, cocaine, and amphetamines, can also cause an acute attack. Fertile women need to be educated that endogenous hormones can trigger attacks during the luteal phase of their menstrual cycle. Although pregnancy is not contraindicated in these patients, fertile women with acute porphyria should be aware that attacks may occur. Patients should inform friends and family members of their diagnosis and should wear medical bracelets to alert medical personnel in emergencies.
As mentioned earlier, family members must be educated about the autosomal dominant inheritance of AIP, VP, and HCP, and should be evaluated for the gene defect in order to identify those who may be at risk of developing symptoms.[38,40] For family members of patients with AIP, the presence of the gene defect can be identified by measuring the level of PBG deaminase activity in erythrocytes. The Department of Human Genetics at Mount Sinai School of Medicine will also perform DNA testing for acute porphyrias.[4] Further information on genetic testing can be found at the American Porphyria Foundation.
Therapeutic Management of Porphyric Attacks
Therapy should be instituted early in acute porphyric attacks to prevent devastating neurologic damage and even death.[26,27] Patients who have not been previously diagnosed with acute porphyria should be tested for an increased level of PBG via a spot urine sample. Testing is not required in patients who have been previously diagnosed with acute porphyria and are experiencing signs and symptoms consistent with an acute attack, particularly when these patients have had previous attacks. Hospitalization is required for any patient with new neurologic deficits, severe hypertension or cardiac arrhythmia, severe pain, paresis, or dehydration. All patients should be given intravenous fluids, glucose, and hemin. Electrolyte abnormalities need to be corrected and symptoms need to be treated. Medications must be reviewed and discontinued if there is concern that they triggered the attack. Nutritional support and intravenous hemin are needed early because these improve outcomes.
Patients who develop an acute porphyric attack have clinical manifestations that usually require treatment (Table 3). A variety of analgesics, including acetaminophen, meperidine, and morphine, can be used for control of abdominal pain. Phenothiazines, ondansetron, and promethazine can be given for nausea and vomiting. Beta-blockers are used to treat tachycardia and systemic hypertension, but should be given cautiously in the presence of hypovolemia. Seizures can be treated with gabapentin, levetiracetam, and benzodiazepines (phenobarbital and phenytoin must be avoided). Close monitoring is needed to assess progression of motor neuropathy and respiratory collapse. Hyponatremia is another complication that can occur in patients with porphyria. The treatment of hyponatremia needs to be weighed against the risk of developing central pontine myelinolysis; however, hyponatremia can be successfully treated with hypertonic saline.[28]
Table 3. Adjunctive Therapy for Acute Porphyric Attacks
| Patient Management Issues |
Therapy Choices |
NPO = nothing by mouth
Glucose loading with oral or intravenous carbohydrates has demonstrated clinical benefit in patients experiencing an acute porphyric attack; available data indicate that glucose acts by repressing hepatic ALA synthase-1.[21,41,42] A major risk associated with this therapeutic strategy is worsening hyponatremia; however, this risk is small and carbohydrate loading has been routinely used for decades.[43] The standard dose of intravenous glucose is 300-500 g daily.[44] Carbohydrate loading alone may be used in treating mild attacks in which there is mild pain and no paresis.[4] However, more severe attacks require the addition of hemin infusion.
Intravenous Hemin
Hemin therapy restores hepatic heme homeostasis, thus repleting hemoproteins and the regulatory heme pool that exerts control of hepatic ALA synthase-1.[45,46] Data supporting hemin infusion in porphyric attacks are based on many uncontrolled clinical studies published before 1994, which showed benefit in biochemical and clinical outcomes.[46-50] In one published controlled trial, 12 patients were treated a total of 21 times with hemin or placebo starting 2 days after hospitalization.[51] The study showed a significant reduction in porphyrin precursors with hemin infusion compared with placebo; it was difficult to adequately assess other clinical outcomes due to the small number of patients. When administered early, hemin therapy is very effective in an acute attack.[49,50] Hemin is given intravenously in a dose of 3-4 mg/kg of body weight daily for at least 4 days. It is administered into a large vein, and can be reconstituted with human albumin to retard degradation and minimize phlebitis at the site of administration.[52]
Other Therapies
Other therapies used to treat patients during an acute attack include hemodialysis and cimetidine. Dialysis has been used to reduce serum ALA and PBG levels, and increased levels of ALA and PBG have been documented in the spent dialysate.[53] Cimetidine inhibits heme degradation and has been used at intravenous dosages of 900-1200 mg/day with some benefit.[54] However, neither of these therapies replaces hemin infusion.
Patients With Frequent Attacks
Despite correcting and avoiding precipitating risk factors, a subset of patients experience frequent recurring attacks that warrant prophylactic therapy.[55] Although most of these patients are women, sex by itself does not satisfactorily explain the reason for their severe disease.
Diet Measures and Hormone Treatment
As mentioned above, reduced carbohydrate intake increases the level of PGC-1alpha, which may induce hepatic ALA synthase-1.[21] Therefore, patients should avoid reduced carbohydrate intake during weight loss, postoperative periods, and illnesses. In addition, they should be counseled by a nutritionist on a high-carbohydrate diet that does not cause excessive weight gain.
Some women have recurrent attacks related to hormonal changes that occur during the luteal phase of their menstrual cycle. For such cases, suppression of ovulation with a gonadotropin-releasing hormone agonist is often effective.[56] Therapy should begin during the first few days of the menstrual cycle. Patients need to be monitored closely with gynecologic exams and bone density tests twice a year. There is a weak correlation between the use of exogenous estrogens and porphyric attacks; low-dose transdermal estrogens have been used safely in patients with acute porphyria.
Hemin Prophylaxis
Hemin therapy has been used prophylactically to prevent recurrent attacks. The US Food and Drug Administration has not approved the prophylactic use of hemin; however, its use is common in the United States. A recent open-label study examined the use of hemin therapy as prophylaxis in 40 patients, administered as a weekly or biweekly infusion.[57] Of the 31 patients who received prophylaxis for at least 1 month, 68% did not develop another attack during the 8-month study period.[57] The general recommendation is to consider hemin prophylaxis in patients with attacks that occur at least once a month, starting with 1 hemin infusion per week and adjusting the frequency on the basis of treatment results. Frequent infusion of hemin has the potential risk for iron overload, because each 100 mg of hemin contains 8 mg of iron.[4] Therefore, ferritin levels should be monitored to assess the development of iron overload. The goal of hemin prophylaxis is to eliminate or reduce the frequency of attacks, with the minimal effective dose administered at the widest possible interval.
Liver Transplantation
Liver transplantation has been used in a small number of patients with unremitting attacks despite aggressive medical therapy. It has been successful in patients with AIP and VP,[12-14] but not ADP.[15] With only a small number of reported cases undergoing liver transplantation, its role is still limited in this patient population.
Managing Chronic Conditions
Patients with acute porphyria are at risk of developing hepatocellular carcinoma, narcotic dependency, and depression. As noted earlier, the reason for the development of hepatocellular carcinoma remains unclear, but the risk is 30-60 times greater than in the general population.[31,32] Treatment is available if hepatocellular carcinoma is detected early. Therefore, screening adult patients yearly with an imaging study of the abdomen and serum alpha-fetoprotein measurement should be considered.[4]
Patient education, counseling, and a multidisciplinary approach are needed to treat patients who develop narcotic dependency because this can be a significant problem in patients with frequent attacks. Depression and suicide are also increased among patients with acute porphyria when compared with the general population.[4,26,27] Counseling and antidepressants should be used to assist in the management of these patients.
Future Therapies
Because a deficiency in PBG deaminase activity is the result of a gene defect in AIP, enzyme replacement therapy may become a potential means of treating patients with this disorder. Intravenous administration of recombinant human PBG deaminase has been safely administered in healthy subjects, and has been effective at reducing the concentration of PBG in the plasma and urine of asymptomatic PBG deaminase-deficient subjects.[58] The reduction in PBG concentration occurs very soon after administration of the enzyme and persists for approximately 2 hours; it increases to approximately 70% of the initial value 12 hours after administration.[58] Clinical trials are being conducted to assess the efficacy of enzyme replacement therapy in patients with acute porphyric attacks.[59]
Studies in HepG2 cells have also indicated that gene therapy directed toward the liver may be feasible in patients with AIP because transfection with mammalian expression vectors containing PBG deaminase cDNA caused an 8-fold increase in activity over endogenous cellular activity.[60]
