Acute Intermittent Porphyria

Clinical Diagnosis

The diagnosis of acute intermittent porphyria is suspected in individuals with neuropsychiatric symptoms and certain biochemical findings. It is confirmed in individuals with a disease-causing mutation in hydroxymethylbilane synthase (HMBS), also called porphobilinogen deaminase (PBGD).

Testing

Urinary excretion of δ-aminolevulinic acid (ALA) and porphobilinogen (PBG).  Measurement of urinary porphobilinogen (PBG) is the best biochemical test for AIP, although further tests are necessary to distinguish AIP from other acute porphyrias [Kauppinen & von und zu Fraunberg 2002].

• δ-aminolevulinic acid.   Normal excretion of ALA is typically less than seven mg per 24 hours; in an attack of AIP, urinary ALA excretion is markedly elevated, with typical values being several or sometimes more than 10 times the upper limit of normal.

• Porphobilinogen.   Normal excretion of PBG is typically less than two mg per 24 hours; in an attack of AIP, urinary PBG excretion is markedly elevated, with typical values being several or sometimes more than 10 times the upper limit of normal.

  
  Note: (1) The excretion of PBG in AIP is usually greater than that of ALA (expressed as mg/24 hours). (2) In acute attacks, urinary PBG excretion can often reach 20 mg/24 hours and on occasion 200 mg/24 hours [Anderson et al 2005].

Note: (1) Although the above values are those that are generally reported, they may vary by laboratory. (2) Individuals with clinically expressed AIP, as well as a few individuals with latent AIP*, excrete variably increased amounts of ALA and PBG in the urine between attacks. In 196 individuals with mutation-positive AIP in Finland, urinary PBG determination by ion-exchange column chromatography measured by spectrophotometry identified 100% of the 35 individuals with AIP during an acute attack,and 85% of the 81 individuals with AIP evaluated during a remission. The mean excretion of PBG was 50-fold above the reference interval. (3) In children with an HMBS mutation, urinary excretion of ALA and PBG is normal or only slightly elevated [Hultdin et al 2003], a finding consistent with the observation that clinical expression of AIP is minimal in children [Llewellyn et al 1992].

* Latent AIP is defined as absence of the clinical features of AIP in an individual with an HMBS disease-causing mutation. Latent AIP includes many relatives of an index case who have never had an attack, the great majority of whom have normal urinary excretion of PBG. On occasion, latent AIP is associated with increased urinary excretion of ALA and PBG.

Tests for urinary PBG:

• Watson-Schwartz test [Watson & Schwartz 1941]. This test is positive about 50% of the time when urinary concentrations of PBG are five times the upper limit of normal; it is consistently positive when urinary concentrations of PBG are more than 10 to 20 times normal [Buttery et al 1989].

  
  Note: This test can be used for rapid detection of PBG in a single-void urine sample when results are needed immediately; however, such results must be confirmed by specific PBG quantitation by an ion-exchange column method.

• Ion-exchange column chromatography.   PBG (and ALA) is first separated from other chromogens in urine by ion-exchange column chromatography, and then its concentration is determined by spectrophotometry. These tests are more sensitive and specific than the Watson-Schwartz test [Mauzerall & Granick 1956, Buttery et al 1989]. For example, the sensitivity of a semiquantitative kit using an ion-exchange resin (Trace PBG kit, Thermo Trace/DMA, Arlington, Texas) compared to the Watson-Schwartz test was 95% vs 38%, and specificity was 99% vs 82% [Deacon & Peters 1998].

For laboratories offering biochemical testing, see .

• Type I: HMBS enzyme activity and protein are decreased by approximately 50% in all tissues.

• Type II: HMBS enzyme activity and protein are decreased in non-erythroid cells only (e.g., fibroblasts, lymphocytes, hepatocytes); erythrocyte HMBS enzyme activity and protein are normal.

• Type III: HMBS enzyme activity is decreased in all tissues. HMBS protein in erythrocytes is greater than 50% of normal, and may reach 270% in extreme cases.

Note: In all three types, the decrease in erythrocyte HMBS enzyme activity is similar for symptomatic individuals (i.e., those with "clinically expressed" AIP) and asymptomatic at-risk individuals (i.e., those with "latent" disease).

Urine porphobilin.  In severe cases, the urine may develop a port-wine color resulting from a high concentration of porphobilin, an auto-oxidation product of PBG. Porphobilin and uroporphyrin I, which is formed from PBG, have a reddish color.

Plasma concentration of ALA, PBG, and porphyrins may be elevated in acute attacks; they are undetectable in remission.

Stool porphyrin concentrations are usually normal or only slightly elevated.

Note: Although these tests are discussed in the older medical literature, they are rarely performed.

Hemoglobin and bilirubin production rates are normal. Individuals with AIP are neither anemic nor jaundiced [Sassa & Shibahara 2002].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene.   HMBS(PBGD) is the only gene known to be associated with AIP.

Molecular genetic testing: Clinical uses

• Confirmatory diagnostic testing

• Presymptomatic testing in at-risk family members when the HMBS mutation has been identified in an affected relative

Molecular genetic testing: Clinical methods

• Sequence analysis/mutation scanning.  Sequence analysis/mutation scanning identifies mutations in 98% or more of individuals with AIP [Kauppinen & von und zu Fraunberg 2002].

Table 2 summarizes molecular genetic testing for this disorder.

Table 2. Molecular Genetic Testing Used in Acute Intermittent Porphyria

Test Methods	Mutations Detected	Mutation Detection Rate	Test Availability
Sequence analysis/mutation scanning	HMBS sequence alterations	>98%  1	Clinical

1. Refers to the detection of an HMBS mutation and not the presence of clinically expressed AIP

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy for a Proband

Diagnosis

• 1

  During an acute attack of AIP that includes neurovisceral symptoms, measurement of urinary concentration of PBG is highly sensitive and specific and is the first step in the diagnosis of AIP [Kauppinen 2004]. Urinary concentration of ALA is also increased, and assists in the diagnosis. Initially the Trace PBG Kit [Thermo Trace/DMA, Arlington, Texas] can be used on a single-void urine. Then quantification of PBG should be made in the same sample or a 24-hour urine sample using ion-exchange chromatography followed by spectrophotometry.

• 2

  Assay of erythrocyte HMBS enzyme activity is useful in confirming the diagnosis in more than 95% of persons with AIP. However, in the fewer than 5% of persons with type II, AIP erythrocyte HMBS enzyme activity is normal and testing of HMBS enzyme activity in non-erythroid cells, such as fibroblasts or lymphocytes, is necessary.

• 3

  Molecular genetic testing of HMBS assures 98% sensitivity if the mutation in the family has not yet been identified and around 100% sensitivity if the mutation present in the family is already known [Kauppinen 2004].

Genetic counseling

• 1

  Measurement of erythrocyte HMBS enzyme activity is useful in clarifying the genetic status of at-risk relatives if the proband has type I or type III AIP, but is not useful if the proband has type II AIP.

• 2

  If the HMBS mutation in the proband is known, molecular genetic testing is superior to measurement of urinary PBG or ALA excretion for clarifying the genetic status of at-risk relatives, because biochemical methods cannot identify all individuals with latent AIP [Elder 1998].

Genetically Related Disorders

No other phenotypes are known to be associated with mutations in the HMBS gene.

Some investigators [Sanders et al 1993], but not others [Nimgaonkar et al 1992, Owen et al 1992, Wang et al 1993], have suggested that schizophrenia is associated with genetic variation at or near the HMBS gene; this suggestion continues to be controversial.

Natural History

Acute intermittent porphyria (AIP) is a potentially severe and debilitating form of acute hepatic porphyria.

When "manifest," i.e., "clinically expressed as an acute attack," AIP affects visceral, peripheral, autonomic, and central nervous systems, leading to a wide variety of manifestations, which are usually intermittent and sometimes life-threatening. The course of an acute attack is highly variable within an individual as well as among individuals. AIP is almost invariably expressed clinically after puberty and more commonly in women than in men [Anderson et al 2001, Schuurmans et al 2001]. Affected individuals may recover from acute attacks within days, but recovery from severe attacks that are not promptly recognized and treated may take weeks or months. Although clinical expression of AIP is caused by exposure to certain endogenous or exogenous factors in most individuals, it is also common for individuals to present with an acute attack in which no precipitating factor can be identified.

When a potentially disease-causing HMBS mutation is not associated with symptoms, AIP is said to be "latent."

Acute attack.  Abdominal pain, which may be generalized or localized, is the most common symptom and is often the initial sign of an acute attack. Other gastrointestinal features may include nausea, vomiting, constipation or diarrhea, abdominal distention, and ileus. Urinary retention, incontinence, and dysuria are also common. Tachycardia and hypertension are quite frequent, while less frequently, fever, sweating, restlessness, and tremor may also be seen.

Peripheral neuropathy is common. Muscle weakness often begins proximally in the legs but may involve the arms or the legs distally. Motor neuropathy may also involve the cranial nerves, or lead to bulbar paralysis, respiratory impairment, and death. Patchy sensory neuropathy may also occur [Wikberg et al 2000]. Permanent quadriplegia after severe attacks may occur. Individuals with manifest disease have significantly more signs of distal chronic, symmetrical axonal neuropathy than do individuals with latent disease. Bilateral axonal motor neuropathy may also involve the distal radial nerves [King et al 2002]. More grave neurological problems appear to develop after severe attacks.

Psychiatric findings may be prominent in AIP and may represent the sole feature of the disease [Tishler et al 1985, Burgovne et al 1995]. These psychiatric findings include hysteria, anxiety, apathy or depression, phobias, psychosis, organic disorders, agitation, delirium, and altered consciousness, ranging from somnolence to coma. Some individuals develop a psychosis similar to schizophrenia. Suicide is common [Jeans et al 1996].

Seizures may occur in acute attacks, especially in individuals with hyponatremia caused by vomiting, inappropriate fluid therapy, or the syndrome of inappropriate antidiuretic hormone release (SIADH). In a survey of 268 individuals with AIP in Sweden, 3.7% reported epileptic seizures, either tonic-clonic seizures, or partial seizures becoming secondarily generalized [Bylesjo et al 1996].

MRI findings.  Multiple high-signal white-matter lesions are found by MRI in about 25% of individuals with HMBS mutations [Bylesjo et al 2003]. Those with previous acute attacks tend to have more lesions than those who have not experienced an acute attack. These lesions seem to improve following appropriate treatment of the attack [Utz et al 2001, Celik et al 2002]. Some MRI findings may result from rapid correction of hyponatremia rather than AIP [Susa et al 1999]. As most of these MRI findings involve case reports, it remains unknown whether they are generally true.

Hepatocellular carcinoma.  Individuals with HMBS mutations have an increased risk of developing hepatocellular carcinoma (HCC) [Lithner & Wetterberg 1984, Kauppinen & Mustajoki 1988, Andersson et al 1996, Bjersing et al 1996, Linet et al 1999, Schaffer et al 2001]. A retrospective population-based study in two municipalities in northern Sweden with a high prevalence of AIP found HCC in 27% of deceased individuals with AIP versus 0.2 % of those without AIP (p<0.0001) [Andersson et al 1996]. This association may be related to the fact that 4,5-dioxovaleric acid, an oxidation product of ALA, is capable of alkylating guanine moieties within both nucleosides and isolated DNA [Douki et al 1998], possibly leading to carcinogenic mutations in liver cells [Bjersing et al 1996].

Renal involvement.  Some individuals with AIP have renal insufficiency without another apparent cause. Although many have hypertension, others are normotensive despite renal insufficiency [Andersson, Wikberg et al 2000]. Histopathology typically shows diffuse glomerulosclerosis, interstitial changes, and ischemic lesions. Protracted vasospasm in attacks of AIP is a possible cause [Andersson, Wikberg et al 2000]. Increased urinary excretion of lipid peroxides in an individual with AIP with tubulointerstitial nephritis suggests that lipid peroxides cause oxidative injury to the mitochondria in the renal tubular cells [Onozato et al 2001].

Cutaneous manifestations.  are not observed in AIP [Sassa & Shibahara 2002].

Precipitating factors.  In individuals with either latent or previously clinically expressed AIP, attacks may be precipitated by endogenous or exogenous factors [Moore et al 1987, Nordmann & Deybach 1990, Kappas et al 1995, Sassa & Shibahara 2002]. Precipitating factors include [Anderson et al 2001]:

• Induction of hepatic ALA synthase (non-erythroid ALAS, or ALAS-N).  Most precipitating factors increase the level of ALAS-N activity in the liver, which is normally the rate-limiting enzyme in hepatic heme biosynthesis [Kappas et al 1995]. With the increased ALAS-N enzyme activity, the partially deficient HMBS enzyme activity becomes the rate-limiting step in heme biosynthesis, causing accumulation of the porphyrin precursors, ALA and PBG, which precipitate the acute attack.

  
  Note: ALAS-N inducers do not influence gene expression of the erythroid-specific ALAS (ALAS-E), which probably accounts for the absence of hematological abnormalities in individuals with AIP.

  • Alcohol ingestion affects heme synthesis by inducing ALAS-N and possibly by inhibiting uroporphyrinogen decarboxylase.

  • Barbiturates, certain steroids, sulfa-containing antibiotics, and other foreign chemicals can induce cytochrome P450 [Kappas et al 1995], resulting in enhanced heme synthesis and induction of hepatic ALAS-N. Cytochrome P450-dependent drug metabolism in individuals with AIP is often prolonged [Song et al 1974, Anderson et al 1976, Ostrowski et al 1983] (See Management).

  • Smoking.  Chemicals in tobacco smoke such as polycyclic aromatic hydrocarbons induce hepatic cytochrome P450 enzymes and heme synthesis [Baron & Tephly 1970]. More frequent attacks have been described in individuals with AIP who smoke.

• Reduced caloric intake.  A common precipitating factor is inadequate caloric intake [Anderson et al 2005]. Fasting induces hepatic microsomal heme oxygenase-1, resulting in decreased hepatic heme concentrations, loss of heme repression of ALAS-N, and the onset of clinical symptoms [Rodgers & Stevenson 1990].

• Stress.  Stress, including intercurrent illnesses, infections, alcoholic excess, and surgery, upregulate the gene encoding heme oxygenase-1, leading to exacerbations of AIP [Rodgers & Stevenson 1990].

• International air travel.  The combination of dehydration, missed meals, alcohol use, infection, hypoxia, and stress that may occur during international air travel are risk factors for an acute attack [Peters & Deacon 2003].

• Endocrine factors.  Clinical expression of AIP is more common in women than in men, especially during the premenstrual period [Schuurmans et al 2001]. A subset of women experience debilitating cyclical premenstrual exacerbations of AIP [McColl et al 1982]. Synthetic estrogens and progesterones are risk factors for an acute attack [Levit et al 1957, Welland et al 1964]. Hormone replacement therapy (HRT) in menopausal women with a history of AIP rarely precipitates acute attacks, whereas 25% of women with manifest AIP on HRT report acute attacks [Andersson et al 2003]. On the other hand, women with AIP often fare well during pregnancy, despite massive increases in the concentration of various steroid hormones [Anderson et al 2001, Aggarwal et al 2002].

Protective factors.  Development of type 2 diabetes mellitus (DM) may reduce disease severity. After the onset of DM, individuals with AIP no longer experienced acute attacks or other AIP-related symptoms [Lithner 2002]. Urinary ALA and PBG excretion also decreased [Andersson et al 1999].

Note: The beneficial effect of carbohydrate loading, a standard treatment for acute attacks, may be mediated by repression of ALAS-N [Tschudy et al 1964].

Mortality.  In the US, mortality caused by symptomatic AIP was threefold higher than the general population [Jeans et al 1996]. Most deaths from AIP occurred during acute attacks, which were often confounded by delayed diagnosis and treatment. Although survival was improved after 1971, the year in which hemin therapy became available, it did not reach statistical significance.

Pathogenesis.  The mechanisms underlying the neurologic findings are not well understood; hypotheses include:

• Direct neurotoxicity caused by PBG [Pierach & Edwards 1978] or ALA [Shanley et al 1975, Pierach & Edwards 1978, Bechara 1996, Puy et al 1996]

• Generation of reactive oxygen species (ROS) by ALA, which may result in oxidative damage to membranes within the central nervous system [Princ, Juknat et al 1998]

• Inhibition of γ-aminobutyric acid (GABA) release at central synapses by ALA [Brennan & Cantrill 1981]

• Loss of heme in the central nervous system, which may be deleterious for the synthesis of important heme proteins such as cytochrome P450 or nitric oxide synthase [Kappas et al 1995]

• Decreased activity of hepatic tryptophan pyrrolase, a heme-dependent enzyme, leading to increased levels of brain tryptophan and increased turnover of 5-hydroxytryptamine, a neurotransmitter [Litman & Correia 1985]

• Decreased plasma melatonin concentration [Puy et al 1996], which enhances ALA-mediated lipid peroxidation [Carneiro & Reiter 1998; Princ, Maxit et al 1998]. ALA-induced lipid peroxidation in the cerebellum and hippocampus was reduced by melatonin in a rat model [Carneiro & Reiter 1998].

Homozygous AIP.  To date, five individuals homozygous or compound heterozygous for two HMBS disease-causing mutations have been described. Homozygous mutations were R167Q/R167Q, R167W/R167W, L81P/L81P, and compound heterozygous mutations were R167W/R173Q [Edixhoven-Bosdijk et al 2002, Hessels et al 2004, Solis et al 2004]. All these individuals had less than 2% of HMBS enzyme activity compared to controls. Clinical symptoms of those with homozygous AIP occurred early in childhood and were debilitating; symptoms included severe ataxia, dysarthria, severe psychomotor delay, and central and peripheral neurologic manifestations. MRI studies in one such individual showed white matter abnormalities that suggested selective cerebral oligodendrocyte postnatal involvement [Solis et al 2004].

Genotype-Phenotype Correlations

Genotype-phenotype correlations are not evident in AIP [Elder 1998] as a result in part of HMBS enzyme activity in heterozygotes that is adequate for normal heme synthesis and the effect of environmental factors on clinical expression of the disease. Unidentified modifying genes may also be important.

In a Swedish study of 468 individuals with DNA-verified AIP, a higher prevalence of clinically manifest AIP was found in individuals with W198X or R173W mutations when compared with those with R167W mutations [Andersson, Floderus et al 2000].

These findings suggest that the lower HMBS enzymatic activity observed with the W198X or R173W mutations than in the R167W mutation may contribute to genotype-phenotype correlations, but other factors may also play a role.

Penetrance

Penetrance defined as neurovisceral symptoms of AIP and increased urinary excretion of ALA and PBG in individuals heterozygous for an HMBS mutation has varied, ranging from less than 10% [Kappas et al 1995] to 20% [Anderson et al 2005] to 52% [Schuurmans et al 2001]. The reduced penetrance is thought to be the result in a large part to the requirement of an additional factor, usually drugs, hormones, decreased caloric intake, stress, etc., for clinical expression of the disease.

Anticipation

Anticipation has not been observed.

Nomenclature

AIP has also been called intermittent acute hepatic porphyria (IAP) or Swedish porphyria.

As individuals with AIP produce and excrete excess porphyrin precursors, i.e., ALA and PBG, it is also called "acute pyrroluria."

AIP and other hepatic porphyrias have been classified as pharmacogenetic or ecogenetic conditions to emphasize the importance of additional factors, including certain drugs, on clinical expression of the underlying genetic defect [Sassa & Shibahara 2002].

Prevalence

AIP is the most common of the acute porphyrias in most countries [Kappas et al 1995, Sassa & Shibahara 2002]. Although it has been reported in many populations, the highest prevalence of symptomatic AIP occurs in northern Sweden and the United Kingdom. Prevalence is 1:10,000 in Sweden [Floderus et al 2002]. The prevalence of AIP has been estimated to be one to two per 100,000 in Europe, 2.4 per 100,000 in Finland, and as high as one per 500 individuals with psychiatric disease [Tishler et al 1985]. The prevalence of low HMBS enzyme activity, which includes both individuals with clinically manifest AIP and those with latent AIP, is as high as one per 500 in the Finnish population [Mustajoki et al 1992], which is much higher than that of the prevalence of clinical AIP.

Evaluations at Initial Diagnosis

Neurologic evaluation including MRI should be considered.

Treatment of Manifestations

Treatment of acute attacks entails [Sassa 1996, Sassa & Shibahara 2002]:

• Stopping immediately all medications that can exacerbate the hepatic porphyrias, including alcohol [Doss et al 2000] and tobacco [Lip et al 1991]. See Agents/Circumstances to Avoid.

• Prompt treatment of any intercurrent infections and other diseases

• Prompt treatment of hypertension, pain, and electrolyte disturbances, especially hyponatremia caused by the syndrome of inappropriate anti-diuretic hormone (SIADH)

• Use of bedside spirometry to measure vital capacity to determine if mechanical support of respiration is required because of bulbar paralysis

• For mild attacks, intravenous administration of dextrose to provide a minimum of 400 g of carbohydrate/day [Anderson et al 2005]. If improvement is unsatisfactory after two days of administration of carbohydrate, intravenous administration of hemin preparations is recommended.

• Total parenteral nutrition (TPN) for individuals unable to tolerate oral feeding [Robert et al 1994]

• Intravenous hemin preparations (hematin, heme albumin or heme arginate), which should be started without an initial trial of carbohydrate [Anderson et al 2005], except for mild attacks. Hemin preparations repress ALAS-N enzyme activity, and thus reduce ALA and PBG excretion [Mustajoki et al 1989, Sassa 1996]. They are most effective in curtailing acute neurovisceral attacks. Intravenous administration of hemin preparations may be life-saving when employed early [Mustajoki & Nordmann 1993]. Their early use, when neuronal damage is still reversible, may also help to avoid paresis or prevent its progression.

  
  The recommended initial dose for hemin is three to four mg of heme/kg IV, given over a period of 10 to 15 minutes, once daily for four days. Treatment may be extended, depending upon the clinical course. No more than six mg/kg should be given in any 24-hour period, since reversible renal shutdown has been reported at higher doses.

  
  The only available hemin preparation in the US is Panhematin^TM, which has been approved by the FDA for treatment of acute porphyric attacks [Ovation Pharmaceuticals, Deerfield, Illinois]. This product contains hematin (heme hydroxide) prepared using hemin chloride, sodium carbonate, HCl, and sorbitol. It is supplied as a dried powder, which must be reconstituted with sterile water immediately before intravenous injection.

  
  Note: (1) Panhematin may cause phlebitis after its intravenous injection. This problem can be minimized by reconstituting Panhematin with an equimolar amount of human serum albumin and/or by using a large vein or a central catheter for infusion [Bonkovsky et al 1991]. (2) Terminal filtration through a sterile 0.45-micron or smaller filter before injection is recommended to remove any undissolved particulate matter. (3) Because the administration of Panhematin reconstituted with sterile water is associated with transient, mild coagulopathy, concurrent anticoagulant therapy should be avoided. (4) Heme arginate, another hemin preparation, is more stable in solution and causes fewer side effects, but is not available in the US. Coagulopathy and phlebitis, which are caused by degradation products of heme, are less common with heme arginate or Panhematin reconstituted with albumin than with Panhematin reconstituted with sterile water.

• Liver transplantation. A 19-year-old woman with severe AIP had an excellent biochemical and clinical remission lasting for more than 1.5 years following orthotopic cadaveric liver transplantation [Soonawalla et al 2004]. Consideration of liver transplantation, however, should be reserved for those individuals with the most severe symptoms who fail to respond to other treatments.

Prevention of Primary Manifestations

Preventive measures:

• Adequate nutrition. Caloric supplementation may reduce urinary excretion of ALA and PBG and suppress clinical symptoms [Welland et al 1964]. Adequate nutrition is especially helpful in individuals with previous poor intake or with excessive rapid weight loss.

• Avoidance of drugs and chemicals known to exacerbate porphyria. See Agents/Circumstances to Avoid.

• Prompt treatment of intercurrent diseases or infections

• Use of low-dose oral contraceptives to prevent cyclic attacks; however, there is some risk that these may exacerbate porphyria.

• Nasal or subcutaneous administration of long-acting agonistic GnRH analogues to inhibit ovulation and prevent premenstrual attacks in women with cyclic exacerbations of AIP [Anderson et al 1984]. Because of the low risk of GnRH agonists, these should be used before oral contraceptives.

• Although a regimen of intravenous hemin therapy for prevention of attacks has not been established, three to four mg/kg given intravenously once or twice a week has been effective in some individuals [Lamon et al 1978; Anderson KE, personal communication].

Prevention of Secondary Complications

As suicide is more common than expected in AIP [Jeans et al 1996], early psychiatric care and effective pain management are important.

End-stage renal disease, which is thought to result from chronic systemic arterial hypertension, may be delayed through effective blood pressure control [Andersson, Wikberg et al 2000].

Surveillance

Periodic monitoring of serum ferritin concentration is appropriate in individuals treated repeatedly with hemin. Because 100 mg of hemin contains eight mg of iron, frequent hemin injections increase the risk for iron overload.

Periodic hepatic imaging is appropriate because of the increased incidence of hepatocellular carcinoma in individuals with AIP [Lithner & Wetterberg 1984, Kauppinen & Mustajoki 1988, Andersson et al 1996, Bjersing et al 1996, Linet et al 1999, Schaffer et al 2001].

Note: Monitoring serum α-fetoprotein concentration is much less useful, because it is seldom increased in persons with AIP who have HCC.

Agents/Circumstances to Avoid

• Alcohol

• Smoking

• Drugs that can induce acute attacks.  Although updated lists of unsafe and potentially unsafe agents are available at the following Web sites, knowledge about the safety of many drugs and other over-the-counter preparations in acute porphyrias is incomplete.

  • Porphyria, A Patient's Guide

  • The American Porphyria Foundation

  • European Porphyria Initiative

Almost all antiepileptic drugs (AEDs) can exacerbate acute porphyria, including AIP. Gabapentin and vigabatrin might be safer than other AEDs [Hahn et al 1997].

Testing of Relatives at Risk

It is appropriate to:

• Clarify the genetic status of at-risk relatives by either assay of erythrocyte HMBS enzyme activity, if a member of the family with AIP is known to have decreased enzyme activity in erythrocytes, or preferably by molecular genetic testing of the HMBS gene if the mutation has been identified in an affected family member.

  
  Note: Molecular genetic testing is accurate for detecting HMBS mutations, but cannot predict a clinical attack of AIP; however, elevated urinary PBG concentration may indicate increased risk of an acute attack in individuals known to be heterozygous for an HMBS mutation.

• Advise relatives with latent AIP to practice preventive measures and avoid known risk factors.

Therapies Under Investigation

Heme arginate has the same advantage as hemin in treating an acute attack, but has fewer side-effects than hemin [Balla et al 2000]. It is a stable reaction product between hemin and L-arginine and is available as solution [Mustajoki et al 1989].

Synthetic heme analogues, e.g., tin-protoporphyrin or tin-mesoporphyrin, which inhibit heme oxygenase activity, result in decreased heme catabolism and increased hepatic heme concentration. These agents diminish the output of ALA, PBG, and/or porphyrins in individuals with AIP and VP [Galbraith & Kappas 1989, Dover et al 1991, Dover et al 1993]. Their use to prolong the effects of hemin remains investigational.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Medical alert bracelets and wallet cards should be provided to HMBS heterozygotes to help them avoid unnecessary exposure to unsafe drugs or substances.

Cimetidine has been suggested as an alternative treatment [Horie et al 1995, Rogers 1997], although evidence for clinical efficacy remains elusive. Cimetidine, an inhibitor of hepatic cytochrome P450 enzymes, ameliorates experimental porphyrias caused by chemicals that are activated by these enzymes, but this mechanism does not necessarily relate to human genetic porphyrias.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

AIP is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with AIP have inherited the mutation from a parent, who may or may not be symptomatic.

• A proband with AIP may also have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is unknown.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include include urinary ALA and PBG determinations, assay of erythrocyte HMBS enzyme activity, and, if the proband's HMBS mutation has been identified, molecular genetic testing of the HMBS gene.

Note: In persons with AIP the family history is often negative because of failure to recognize the disorder in family members who have latent AIP.

Sibs of a proband

• The risk to the sibs of the proband depends upon the genetic status of the proband's parents.

• If a parent of the proband is affected or is asymptomatic and has an HMBS mutation, the risk to the sibs of inheriting the mutation is 50%. Because penetrance is low (10-50%), it is not possible to predict whether individuals who inherit an HMBS mutation will be symptomatic, or if they are, the age of onset, severity, or type of symptoms.

• If the disease-causing mutation identified in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband.  Each child of an individual with AIP has a 50% chance of inheriting the HMBS mutation.

Other family members of a proband.   The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected or to have a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adults.   Testing of at-risk asymptomatic adults for AIP is available using either assay of erythrocyte HMBS enzyme activity or, if the mutation is known in an affected family member, molecular genetic testing of the HMBS gene. Such testing is not useful in predicting if or when individuals who inherit the HMBS mutation will become symptomatic. Identification of individuals at risk for AIP, however, alters management because avoidance of known risk factors and other measures may be helpful in preventing acute attacks and other symptoms. Before testing at-risk individuals for AIP, it is necessary to first test an affected family member to confirm that the disorder in the family is actually AIP.

Considerations in families with an apparent de novo mutation.  When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder or the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.

Family planning.  The optimal time for determination of genetic risk is before pregnancy.

DNA banking.  DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Molecular genetic testing can determine if the HMBS mutation present in one parent is present in the fetus, and HMBS enzyme assay of amniotic fluid cells obtained by amniocentesis usually prformed at about 15-18 weeks' gestation [Sassa et al 1975] can diagnose AIP prenatally; however, no laboratories offering molecular genetic testing or biochemical testing for prenatal diagnosis of AIP are listed in the GeneTests Laboratory Directory. Prenatal testing using molecular genetic methods may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing, see .

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Because most individuals with AIP remain asymptomatic throughout life, because neither molecular genetic testing nor biochemical testing can predict a clinical attack of AIP, and because treatment and prognosis of adults with AIP has improved considerably, requests for prenatal testing are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Readings

Revision History

• 27 September 2005 (me) Review posted to live Web site

• 3 January 2005 (ss) Original submission