The Challenges of Testing For and Diagnosing Porphyrias [Communiqué]
The porphyrias are a group of inborn errors of metabolism caused by enzymatic defects in the heme biosynthetic pathway. Resulting accumulations of intermediary metabolites cause characteristic clinical manifestations including neurological and psychological symptoms and/or cutaneous photosensitivity. Although most of these disorders have genetic causes, environmental factors may exacerbate symptoms and significantly impact the severity and course of disease. Early diagnosis coupled with education and counseling of the patient regarding the nature of the disease and avoidance of precipitating factors are important for successful management.
Heme Biosynthetic Pathway
The heme biosynthetic pathway (Insert 1) consists of 8 enzymes. The first and last 3 enzymes in the pathway are localized in the mitochondria, and the intermediate enzymes function in the cytosol. The formation of heme begins with the condensation of glycine and succinyl-coenzyme A to aminolevulinic acid (ALA). This is followed by a series of enzymatic reactions that convert ALA to porphobilinogen (PBG) and then to the various porphyrinogens. Finally, iron is inserted into protoporphyrin by the enzyme ferrochelatase, forming heme.
The production of heme, a metalloporphyrin containing iron, occurs in all metabolically active cells. The majority is formed in erythropoietic cells where it is incorporated in hemoglobin. Hepatic tissue also produces a significant amount for use in myoglobin and various heme-containing enzymes including cytochromes, catalases, and peroxidases. Heme that is not immediately utilized in a protein complex is metabolized to bile pigments.
Most porphyrias are caused by a specific enzyme defect involved in the heme biosynthetic pathway. Consequently, clinical symptoms result from the accumulation of porphyrinogens, porphyrins, and their precursors, which are formed prior to the enzyme defect. Depending on the primary site of accumulation, porphyrias have been classified as either erythropoietic or hepatic.
Cutaneous, Nonacute Porphyrias
The cutaneous nonacute porphyrias include porphyria cutanea tarda, hepatoerythropoietic porphyria, erythropoietic protoporphyria, X-linked dominant protoporphyria, and congenital erythropoietic porphyria. These disorders are characterized by chronic dermatologic symptoms. While cutaneous photosensitivity is a common feature among these porphyrias, other associated clinical and biochemical features, inheritance patterns, and medical management remain unique for each. (Photo 1 and 2)
Porphyria Cutanea Tarda
Porphyria cutanea tarda (PCT) is the most common porphyria and is most amenable to treatment. It is unique in that it may be an acquired (type I) or an inherited (familial, types II and III) condition. About 75% of patients have type I PCT. In these cases, symptoms are precipitated by complications from liver diseases, such as hepatitis C and hereditary hemochromatosis, or by environmental exposures including certain medications, estrogens, alcohol abuse, iron overload, smoking, and occupational exposures to polychlorinated cyclic hydrocarbons. Historically, outbreaks have been caused by toxic exposure to certain organic chemicals.
Familial PCT is observed less commonly. It is estimated that 25% of patients are affected with this autosomal dominant condition. In type II PCT, uroporphyrinogen decarboxylase activity is approximately 50% of normal in all tissues, while in type III the enzyme is deficient only in hepatic cells. In the absence of a positive family history, type III PCT is virtually indistinguishable from the acquired form.
PCT is characterized by photosensitivity and skin fragility. Patients experience blistering lesions in sun-exposed areas resulting in cutaneous thickening and scarring. The face, neck, forearms, and backs of hands are areas most often affected. Minor trauma may also trigger lesions. Two-thirds of patients experience hypertrichosis (excessive hair growth) on the face, and, less frequently, on the ears and arms. Approximately half of individuals with PCT have hyperpigmentation in sun-exposed areas, while one-third of patients develop patches of alopecia as a result of scarring from large blisters on the scalp. In most cases, patients exhibit abnormal liver function tests. Long-term complications include an increased risk for hepatic cirrhosis and hepatocellular carcinoma. Iron overload may occur in association with PCT. Hemosiderosis (a focal or general increase in tissue iron [hemosiderin] stores without associated tissue damage) is usually mild or moderate, although it can be severe. Interestingly, patients with hereditary hemochromatosis are more likely to experience symptoms of PCT than individuals in the general population.
PCT is more common in males than in females. It is hypothesized that this may be related to varying levels of alcohol consumption and other environmental exposures between men and women. A second theory postulates that menses may provide a level of protection for women as it acts as a form of phlebotomy, which is an effective treatment for PCT.
The diagnosis of PCT is easily established through elevations of uroporphyrin and heptacarboxylporphyrin in urine porphyrins (PQNRU / Porphyrins, Quantitative, Random, Urine or PQNU / Porphyrins, Quantitative, 24-Hour, Urine) and uroporphyrin in plasma (PTP / Porphyrins Total, Plasma). In PCT, urine uroporphyrin levels are typically elevated to at least 4 times the upper limit of normal, but concentrations may reach as high as 250 times the upper limit of normal. In general, heptacarboxylporphyrin is at least 25% of the uroporphyrin value. Elevated uroporphyrin without a concomitant elevation of heptacarboxylporphyrin is often observed in the acute porphyrias, rather than PCT.
A urine uroporphyrin level twice the upper limit of normal is suspicious for PCT and justifies further investigation. Thus, subsequent plasma and fecal (FQPPS / Porphyrins, Feces) porphyrin analyses and a repeat urine porphyrin analysis are recommended, particularly if symptoms continue to persist. Plasma testing in cases of PCT demonstrates plasma porphyrin levels that are typically elevated at least 5 times the upper limit of normal. Conversely, mild elevations in plasma levels are associated with renal disease.
Acquired versus familial PCT can be distinguished by enzyme analysis (UPGD / Uroporphyrinogen Decarboxylase [UPG D], Whole Blood) and eliciting a thorough family history. Enzymatic-based assays are not an appropriate first-level assay as the majority of cases are acquired and the enzyme exhibits normal activity in these cases.
The cutaneous symptoms of PCT are more amenable to treatments than similar complications seen in other forms of porphyria. Phlebotomy therapy and low-dose chloroquine, an antimalarial drug, result in complete remission of skin lesions in most cases. Phlebotomy produces remission by gradually reducing the hepatic iron overload. Serial serum ferritin (FERR / Ferritin, Serum) and plasma porphyrin (PTP / Porphyrins Total, Plasma) levels are useful in evaluating the efficacy of treatment. Low-dose chloroquine treatments have proven valuable as the drug complexes with excess porphyrins, promoting excretion. However, these therapies should only be initiated following biochemical confirmation of the clinical diagnosis, as they are not useful in other porphyrias presenting with cutaneous symptoms.
Occurrences of dermatologic complications can be minimized through elimination or reduction of precipitating factors via sun avoidance and use of sunscreen, abstaining from alcohol, discontinuing estrogen therapy, or treatment of an underlying liver disorder. Even with these treatments, long-term follow-up is important for all patients as a means of monitoring for relapse through urine (PQNRU / Porphyrins, Quantitative, Random, Urine) and plasma (PTP / Porphyrins Total, Plasma) porphyrin analysis, and for the management of any concomitant liver disease.
Generally, PCT is not attributable to a single causal factor. Even in familial PCT, most patients have identifiable risk factors in addition to the hereditary enzyme deficiency. Therefore, all patients presenting with PCT should be evaluated for multiple risk factors, including testing for hepatitis C virus and screening for hemochromatosis, and treated accordingly.
Hepatoerythropoietic porphyria (HEP) is a severe porphyria due to markedly deficient uroporphyrinogen decarboxylase activity inherited in a autosomal recessive manner. Onset of this rare porphyria usually occurs in infancy or childhood, although cases presenting in adulthood have been described. Patients experience severe photosensitivity leading to blistering lesions and scarring. Other complications include pink or red urine, hypertrichosis, hepatosplenomegaly, and hemolytic anemia. Treatment is limited to sun avoidance and the use of sunscreens.
A deficiency of the enzyme ferrochelatase is observed in patients with erythropoietic protoporphyria (EPP). EPP is an autosomal recessive disorder in which there is inheritance of 1 mutation along with a polymorphism in trans to the mutation. Due to this inheritance pattern, only about 10% of individuals with an enzyme deficiency develop clinical symptoms. While onset usually occurs before 10 years of age, clinical presentation may occur later.
Individuals with EPP are sensitive to most of the visible light spectrum. Such exposure causes burning, itching, and painful erythema and edema that can develop within minutes. Blistering and scarring are less common than in other dermatologic porphyrias. Repeated exposures may result in chronic changes giving the skin a waxy, thickened appearance with faint linear scars. Cutaneous photosensitivity is exacerbated in the spring and summer when exposure to sunlight is more likely. Patients are at an increased risk to develop hemolytic anemia. Gallstone formation is common, and some individuals with EPP experience mild hypertriglyceridemia. Liver dysfunction and hepatic failure are observed in up to 20% and less than 5% of patients, respectively.
Patients with EPP accumulate protoporphyrin in erythrocytes, plasma, and feces. Other heme pathway intermediates do not accumulate, and protoporphyrin is not soluble in urine. For these reasons, urinary porphyrin, ALA, and PBG are not useful diagnostic tools for this disorder. When a diagnosis of EPP is suspected, testing for protoporphyrin fractionation (PPFE / Protoporphyrins, Fractionation, Whole Blood) in erythrocytes is appropriate. Unaffected individuals have approximately 80 mcg/dL of total protoporphyrin with approximately 85% being zinc complexed and 15% or less of noncomplexed (free) protoporphyrin. In EPP patients, the erythrocyte free protoporphyrin is significantly increased with values usually >300 mcg/dL. Some patients have been observed with free protoporphyrin exceeding 1000 mcg/dL. Although EPP patients exhibit more free than zinc-complexed protoporphyrin, iron deficiency, lead intoxication, or in very rare cases variegate porphyria should be suspected in patients who exhibit total protoporphyrin in excess of 100 mcg/dL but have more zinc-complexed than free protoporphyrin. FECH gene analysis (FECHS / FECH Gene, Full Gene Analysis) is available to confirm the biochemical findings and for additional family studies.
EPP is the third most common porphyria, yet treatment options are limited. Sun avoidance is essential, and protective clothing and sunscreen are recommended. Oral administration of beta-carotene allows for increased tolerance to sunlight in most patients. Although there are no other known precipitating factors, patients should avoid drugs and other elements that may induce crises in the acute porphyrias. Liver transplantation is an option for the minority of patients who experience hepatic failure. However, this is not a cure as the excessive porphyrins are produced in the erythropoietic cells. Consecutive liver and bone marrow transplants have successfully reversed this disorder.
X-linked Dominant Protoporphyria
X-linked dominant protoporphyria (XLDPP) results from a gain-of-function mutation in the C-terminal end of the ALAS2 gene. This leads to increased activity of aminolevulinic acid synthase 2 in the bone marrow resulting in increased protoporphyrin in the erythrocytes. Elevation of protoporphyrin causes symptoms that are indistinguishable from those seen in patients with EPP (see EPP section.) The biochemical phenotype, however, is slightly different. Erythrocyte protoporphyrin levels are typically higher than those seen in EPP with the majority being zinc-complexed protoporphyrin (40%-60% of total).
Congenital Erythropoietic Porphyria
Congenital erythropoietic porphyria (CEP), also known as Gunther disease, is an extremely rare and severe porphyria. It is an autosomal recessive condition resulting from markedly deficient uroporphyrinogen III cosynthase activity. Although the disorder typically manifests in early infancy, variability in the age of onset and severity are thought to be related to the level of residual enzyme activity. Prenatal manifestation of CEP presents as nonimmune hydrops fetalis (abnormal accumulation of serous fluid in fetal tissues) due to severe hemolytic anemia, whereas only cutaneous lesions are observed in the mildest cases manifesting in adulthood.
Clinically, the majority of patients with CEP present in infancy with dermatological complications including photosensitivity, blistering, erythrodontia (reddish discoloration of the teeth), and hypertrichosis. The skin may become thickened, and areas of hypopigmentation and hyperpigmentation are observed. Recurrent blistering and secondary infection may lead to significant scarring and mutilation. Exposure to sunlight and other sources of ultraviolet light exacerbate the severity of the cutaneous symptoms. In fact, some patients present at birth when undergoing phototherapy for hyperbilirubinemia. Ophthalmological findings include keratoconjunctivitis (inflammation of the conjunctiva and of the cornea), ulcerations, cataracts, and corneal scarring that can lead to blindness.
Hemolytic anemia and other hematologic abnormalities accompanied by splenomegaly are common. To compensate for this, increased metabolic activity and expansion of the bone marrow may lead to pathologic fractures and vertebral compression or collapse. Many patients develop porphyrin-rich gallstones. Pink or reddish-brown urine is often observed as a result of the increased excretion of urinary porphyrins. Moreover, severely affected individuals exhibit growth and cognitive developmental delays and a decreased lifespan.
A combination of urine (PQNRU / Porphyrins, Quantitative, Random, Urine) and fecal (FQPPS / Porphyrins, Feces) porphyrin analyses can diagnose CEP. Porphyrins in urine are predominantly series I isomers of uroporphyrin and coproporphyrin. Coproporphyrin I is detected in feces. The diagnosis of CEP should be confirmed by erythrocyte uroporphyrinogen III cosynthase enzyme analysis (UPGC / Uroporphyrinogen III Synthase (Co-Synthase) (UPG III S), Erythrocytes). Enzyme analysis must be performed prior to blood transfusion to achieve the most accurate results. Furthermore, uroporphyrinogen III cosynthase testing is not useful for carrier testing, as CEP heterozygotes cannot be distinguished from unaffected individuals. Molecular studies are available.
Treatment for CEP requires protection from ultraviolet light to reduce dermatological and ophthalmological complications. To minimize the risk of mutilation, secondary infections must be treated immediately. Blood transfusions and splenectomy are beneficial in some cases by decreasing porphyrin production and limiting hemolytic anemia. Allogeneic bone marrow transplantation has proven curative for a handful of patients. However, this therapy carries a considerable risk for mortality.
The acute porphyrias include acute intermittent porphyria, variegate porphyria (VP), hereditary coproporphyria (HCP), and aminolevulinic acid dehydratase deficiency porphyria. Episodic neurovisceral symptoms that can be life threatening characterize the acute porphyrias. Cutaneous features also may manifest in some patients with VP or HCP. Acute episodes can be precipitated by both endogenous and exogenous factors. These factors and clinical management are similar for all types of the acute porphyrias and are discussed following the clinical descriptions of each.
Acute porphyria is caused by autosomal dominant mutations in 1 of 3 genes: HMBS, associated with acute intermittent porphyria (AIP); CPOX, associated with hereditary coproporphyria (HCP); and PPOX, associated with variegate porphyria (VP). Mutations in these genes show incomplete penetrance, and patients with a confirmed deleterious mutation may be asymptomatic. Molecular studies to differentiate the 3 acute porphyrias are available (PPAN / Acute Porphyria, Multi-Gene Panel, HMBSS / HMBS Gene, Full Gene Analysis, PPOXS / PPOX Gene, Full Gene Analysis, and CPOXS / CPOX Gene, Full Gene Analysis). It is recommended that biochemical testing be performed prior to molecular analysis.
Acute Intermittent Porphyria
Acute intermittent porphyria (AIP) is the second most common porphyria. It is associated with mutations in the HMBS gene, resulting in a deficiency in the enzyme hydroxymethylbilane synthase, also known as porphobilinogen deaminase (PBGD). AIP is aptly named for the intermittent episodes in which patients experience acute neuropathic symptoms. These acute episodes are potentially life threatening, highly variable, and although usually short in duration, may last from a few days to several months. AIP rarely presents prior to puberty, with onset most commonly between ages 20 and 40. It is characterized by episodes of acute neuropathic symptoms. Approximately 85% of patients experience severe abdominal pain, often in conjunction with nausea, vomiting, and constipation. Peripheral neuropathy is common. However, given the extensive list of differential diagnoses for patients experiencing peripheral neuropathy, testing for AIP in the absence of abdominal pain rarely identifies AIP patients and is not recommended. Patients frequently display psychiatric symptoms presenting in the form of psychotic episodes, depression, and anxiety. Other features of an acute attack include circulatory disturbances such as hypertension and tachycardia. Dysuria and urinary retention, sometimes requiring catheterization, may be seen. Less frequently, patients may experience seizures, respiratory paralysis, fever, and diarrhea.
Given the highly variable and nonspecific nature of the neurovisceral symptoms observed in AIP attacks, the condition is often overlooked in the clinical setting. Unfortunately, appropriate laboratory investigations are often not conducted, and many patients are misdiagnosed or become incorrectly labeled as narcotic seeking. This leads to a potentially life-threatening situation as patients continue to be at risk for an acute attack.
Approximately 10% to 20% of individuals with a PBGD enzyme deficiency will become symptomatic during their lifetime, although some studies have questioned this low penetrance rate.1,2 While the vast majority of patients will never exhibit symptoms, the identification of asymptomatic, affected individuals in families with known AIP is crucial. The diagnosis of asymptomatic patients allows for the avoidance of precipitating factors, thereby minimizing the risk of a life-threatening porphyric attack.
With respect to the initial diagnosis of symptomatic patients believed to be in an acute AIP crisis, urine porphyrins (PQNRU / Porphyrins, Quantitative, Random, Urine), aminolevulinic acid (ALAUR / Aminolevulinic Acid [ALA], Urine), and porphobilinogen (PBGU / Porphobilinogen, Quantitative, Random, Urine) should be analyzed. Substantial financial savings and improvement in the appropriateness of testing can be attained by following our suggested testing strategies for the acute porphyrias (see Table 1). This will ensure that another acute porphyria, with features similar to AIP, is not missed. PBGD (PBGD_ / Porphobilinogen Deaminase [PBGD], Whole Blood) enzyme activity should be evaluated either in conjunction with these urine analyses or preferably in a stepwise fashion when indicated, based upon the urine studies.
Identification of asymptomatic, affected family members, including children, is possible and requires either biochemical or molecular analysis. Urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) values are method dependent and can vary by institution. Some experts believe that these analytes will never fall within the normal range in asymptomatic, affected individuals, whereas others argue that these values can normalize in such patients. With the assays available through Mayo Medical Laboratories, elevated urinary ALA and PBG values have been observed in asymptomatic individuals in whom AIP status was previously unknown. Provision of clinical information and reason for referral is important for accurate result interpretation. Regarding the diagnosis of asymptomatic infants and children, there is evidence that PBGD activity fluctuates considerably during the first 9 to 12 months of life; therefore, enzyme analysis should be performed after 1 year of age. In some cases, it is helpful to perform PBGD analysis of known affected family members when attempting to rule in or out AIP in asymptomatic relatives. Given that up to 10% of asymptomatic individuals with AIP will have a normal PBGD result, the urine assays are important diagnostic tools.
Variegate porphyria (VP) is an autosomal dominant cutaneous porphyria caused by mutations in the PPOX gene that result in a reduction in the activity of protoporphyrinogen oxidase activity. VP is panethnic, although high prevalence is reported in South Africa (3 in 1000 individuals) and Finland. Reduced penetrance is observed and symptoms very rarely present before puberty. Clinical presentation of VP is similar to other acute porphyrias, with symptoms including abdominal pain, vomiting, neuropathies, and psychiatric sequelae. However, cutaneous involvement is usually more pronounced. In fact, dermatologic manifestations in VP are very similar to those seen in PCT and include blistering, hyperpigmentation, and hypertrichosis of sun-exposed areas. Moreover, while neuropathic symptoms appear only during acute crisis, photosensitivity remains a chronic symptom.
In rare instances, homozygous VP, with marked deficiency of protoporphyrinogen oxidase enzyme activity, has been described. Patients typically present in early childhood with photosensitivity resulting in severe cutaneous manifestations, neurologic symptoms including seizures, and developmental delay.
The diagnosis of VP relies upon porphyrin analysis in urine (PQNRU / Porphyrins, Quantitative, Random, Urine) and feces (FQPPS / Porphyrins, Feces), as enzyme analysis of protoporphyrinogen oxidase is not readily available on a clinical basis. Depending upon whether the patient is experiencing an acute crisis or is asymptomatic, urine coproporphyrin, ALA, and PBG values are elevated to varying degrees. Values may be as high as 10 to 20 times normal during acute crises but may be normal or only mildly elevated between attacks. ALA and PBG may be normal when the patient is experiencing cutaneous symptoms only. During crises, fecal porphyrin analysis shows coproporphyrin levels are, at a minimum, double with a coproporphyrin III to coproporphyrin I ratio in the 3 to 10 range (normal ratio <1.2). Fecal protoporphyrin IX is elevated to a greater extent than coproporphyrin. In asymptomatic patients, fecal porphyrins may remain elevated for months after an acute episode.
A reduction of coproporphyrinogen oxidase activity results in hereditary coproporphyria (HCP), an autosomal dominant condition caused by mutations in the CPOX gene. HCP is one of the least common of the acute porphyrias. Clinical penetrance is low, and symptoms very rarely present before puberty. Clinical manifestations of HCP are predominantly neurovisceral and closely resemble those of other acute porphyrias. However, about one-fifth of cases exhibit photosensitivity similar to PCT and VP. Those HCP patients not presenting with dermatologic findings are clinically indistinguishable from patients with AIP and VP. Consequently, biochemical analysis is essential for correct diagnosis.
Harderoporphyria is a very rare variant of HCP with very low residual enzyme activity. Homozygous mutations in CPOX have been reported in association with harderoporphyria that is characterized by neonatal hemolytic anemia with mild residual anemia during childhood and adulthood. Affected patients may also present with skin lesions and fecal harderoporphyin (tricarboxylporphyrin) accumulation may be observed. This condition is inherited in an autosomal recessive pattern and all patients identified to date have been compound heterozygous or homozygous for the K404E mutation.
The biochemical hallmark of HCP is hyperexcretion of coproporphyrin in the urine (PQNU / Porphyrins, Quantitative, 24 Hour, Urine) and feces (FQPPS / Porphyrins, Feces) at levels similar to that observed in VP. However, in HCP, the fecal coproporphyrin III to coproporphyrin I ratio is in the 10 to 20 range (normal ratio <1.2) and protoporphyrin is usually not elevated. Thus, fecal porphyrin analysis allows for the distinction between HCP from VP and AIP.
Aminolevulinic Acid Dehydratase Deficiency Porphyria
Aminolevulinic acid dehydratase deficiency porphyria (ADP) is a rare, autosomal recessive disorder that results from homozygous or compound heterozygous deficiency of aminolevulinic acid dehydratase (ALAD). Clinical manifestations of ADP are predominantly neuropathic and include abdominal pain, vomiting, and pain in the extremities. The age of onset and degree of severity are highly variable among the few reported patients. Heterozygote carriers of ADP may be at increased risk for developing an acute porphyric episode following toxic exposure to lead or a variety of other chemicals.
ADP can be differentiated from other acute porphyrias by normal or slightly elevated urinary PBG (PBGU / Porphobilinogen, Quantitative, Random, Urine) in the presence of significantly elevated aminolevulinic acid (ALA) (ALAUR / Aminolevulinic Acid [ALA], Urine) and markedly decreased ALA dehydratase activity. The enzyme assay for ALAD (ALAD / Aminolevulinic Acid Dehydratase [ALAD], Whole Blood) is clinically available and all patients reported to date show <5% of normal ALAD in erythrocytes.3 There is little documented experience in the treatment of ALAD. The current management approach is similar to that for other acute porphyrias, as emphasis is placed on the prevention of acute attacks.
Lead intoxication and hereditary tyrosinemia type I can also produce elevated ALA with normal PBG. Therefore, whole blood lead analysis (PBBD / Lead with Demographics, Blood) and urine succinylacetone analysis (OAU / Organic Acids Screen, Urine) should be pursued in such crises to rule out that possibility.
Precipitating Factors for Acute Porphyrias
There is considerable evidence that acute crises are precipitated by endogenous and exogenous factors. These include hormonal changes, drugs and alcohol, nutritional factors, stress, and infections, which potentially allow for the upregulation of the heme biosynthetic pathway. Consequently, the partial deficiency in PBGD becomes rate limiting, allowing for the buildup of PBG and ALA, culminating in an acute crisis.
Endocrine factors are believed to play a major role in the induction of AIP in some patients. Women are more likely to exhibit clinical disease. Furthermore, acute attacks rarely occur before puberty, and attack frequency and severity decline after menopause. Interestingly, a subset of female patients experience regular, cyclical exacerbations of disease in conjunction with menses.
A variety of drugs, including alcohol, have been implicated in the induction of acute porphyric attacks. There is consensus regarding the use and safety of many common medications in patients with AIP. Other drugs are not as well understood. Drugs which have been classified as safe or unsafe for use by patients with an acute porphyria and those drugs where safety is still in question are available from the American Porphyria Foundation website.3 Medications previously established as safe should be used whenever possible in patients with asymptomatic or symptomatic AIP.
Nutritional status, in particular decreased caloric intake, has been shown to induce the onset of an acute attack. Intercurrent illnesses and surgery exhibit a causal relationship, possibly due to increased energy requirements during these times. Additionally, psychological stress has been reported to contribute to AIP symptomology, though the underlying mechanisms are not understood. Precipitating factors likely act in an additive fashion, and the triggers of a particular crisis cannot always be ascertained.
Treatment for Acute Porphyrias
Hospitalization is often necessary for the treatment of acute attacks. Crises are treated with increased carbohydrate intake that may occur via intravenous administration. Heme (hematin or heme arginate) therapy allows for the excretion of ALA and PBG. Efficacy is compromised if heme therapy is delayed, so treatment should commence as soon as possible after the onset of a crisis. Symptomatic treatment includes frequent doses of analgesics to control pain, and phenothiazines may be administered to control nausea, vomiting, and anxiety. Given that pain tends to be severe, narcotics are typically the analgesia of choice, as nonnarcotic agents are usually inadequate.
Treatment for asymptomatic patients or between acute porphyria crises largely relies upon the prevention of potentially life-threatening episodes. At-risk individuals should be counseled to avoid medications known to precipitate attacks,3 to avoid excessive alcohol intake, to seek prompt treatment for other intercurrent illnesses, and to maintain proper nutritional status, including the avoidance of crash dieting. Patients should be encouraged to wear a medical alert bracelet allowing for proper management in the event that the patient becomes temporarily incapacitated as a result of an accident or acute crisis. Photosensitivity can be minimized in VP and HCP patients by avoidance of sun exposure, and use of protective clothing.
Testing for Porphyria
By following our suggested testing strategy, the quality of patient care and cost-effectiveness of testing can be maximized. Depending upon the specific type of porphyria suspected, certain tests are more informative than other assays. In general, a random urine porphyrins (PQNRU / Porphyrins, Quantitative, Random, Urine) analysis that includes porphobilinogen is the most effective screening tool. However, when EPP is the potential diagnosis, an erythrocyte protoporphyrin fractionation (PPFE / Protoporphyrins, Fractionation, Whole Blood) is the most appropriate test to perform. For a listing of informative biochemical findings for each type of porphyria, refer to Table 1.
Test recommendations for each suspected porphyria are outlined in Table 2. Ordering a battery of tests does not enhance the quality of patient care. Rather, a stepwise diagnostic approach is the most effective means of ruling in or ruling out a specific porphyria. In most cases, when the result of the urine porphyrins test is normal, subsequent testing in the form of fecal, plasma, and erythrocyte porphyrin analyses and enzyme assay are not recommended. As shown, the random urine porphyrins (PQNRU / Porphyrins, Quantitative, Random, Urine) analysis is the most appropriate starting point. If a particular diagnosis is suspected, additional first-line testing may be appropriate (tests listed in black in Table 2); other analyses (listed in red) may be delayed until initial results are available. While providing minimal clinical value, additional testing creates unnecessary expense to the referring laboratory or physician and patient. The patient should abstain from alcohol consumption for at least 24 hours prior to specimen collection since alcohol suppresses some enzymatic activity while it enhances other enzyme activity in the heme biosynthetic pathway.
Abnormal results are reported with a detailed interpretation including an overview of the results and their significance, a correlation to available clinical information provided with the specimen, differential diagnosis, and recommendations for additional testing when indicated and available. For consultation regarding porphyrias, please contact a laboratory director or genetic counselor in the Biochemical Genetics Laboratory by calling Mayo Lab Inquiry (1-800-533-1710).