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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Acute Intermittent Porphyria

Synonyms: PBGD Deficiency, Porphobilinogen Deaminase Deficiency

, PhD and , PhD, FRCPath.

Author Information
, PhD
Department of Medical Biochemistry and Immunology
University Hospital of Wales
Cardiff, United Kingdom
, PhD, FRCPath
Department of Medical Biochemistry
Institute of Molecular and Experimental Medicine, School of Medicine
Cardiff University
Cardiff, United Kingdom

Summary

Disease characteristics. Acute intermittent porphyria (referred to as AIP in this GeneReview) results from half-normal activity of the enzyme hydroxymethylbilane synthase (HMBS). It is characterized clinically by life-threatening acute neurovisceral attacks of severe abdominal pain without peritoneal signs, often accompanied by nausea, vomiting, tachycardia, and hypertension. Attacks may be complicated by neurologic findings (mental changes, convulsions, and peripheral neuropathy that may progress to respiratory paralysis), and hyponatremia. Acute attacks, which may be provoked by certain drugs, alcoholic beverages, endocrine factors, calorie restriction, stress, and infections, usually resolve within two weeks. Most individuals with AIP have one or a few attacks; about 5% (mainly women) have recurrent attacks (defined as >4 attacks/year) that may persist for years. Other long-term complications are chronic renal failure, hepatocellular carcinoma (HCC), and hypertension. Attacks, which are very rare before puberty, are more common in women than men. All individuals with a genetic change in the gene HMBS that predisposes to AIP are at risk of developing acute attacks; however, most never have symptoms and are said to have latent (or presymptomatic) AIP.

Diagnosis/testing. With one exception (5-aminolevulinate dehydratase deficiency [ALAD]), acute attacks of porphyria are associated with an increased urinary concentration of porphobilinogen (PBG). Demonstration that an increased PBG concentration is caused by AIP requires exclusion of other acute porphyrias by analysis of porphyrins in stool and plasma. Molecular genetic testing is used in a symptomatic individual to identify a mutation that can then be used to identify AIP in relatives of the proband. Assay of erythrocyte HMBS enzyme activity may be useful in families in which an HMBS mutation cannot be identified or when molecular testing is not available.

Management. Treatment of manifestations:

Acute neurovisceral attacks:

  • Stop medications that can exacerbate AIP; provide adequate caloric intake by intravenous infusion if required (hypotonic dextrose water solutions should be avoided).
  • Treat any intercurrent infections or disease using drugs known to be safe in acute porphyria.
  • Treat pain with opiate analgesia (often in large amounts); support from a pain team may be required.
  • Treat agitation, vomiting, hypertension, tachycardia using safe drugs.
  • Monitor fluid balance and correct electrolyte disturbances, especially hyponatremia; treat severe hyponatremia with saline infusions, not fluid restriction.
  • Monitor neurologic status carefully and provide respiratory support as needed.
  • Prompt administration of human hemin (panhematin or heme arginate) is the specific treatment of choice to curtail acute neurovisceral attacks and avoid paresis.

Mild attacks: Manage by symptomatic treatment, increased calorie intake, and fluid replacement.

Recurrent acute attacks: Manage together with a porphyria specialist; treatment options include ovulation suppression with gonadorelin analogues, regular hematin infusions, or (as a last resort) liver transplantation.

Evaluation of relatives at risk: If the HMBS mutation is known in a family, at-risk relatives can benefit from molecular genetic testing to clarify their genetic status, so that those at increased risk of developing acute attacks of AIP can be identified early and counseled about preventive measures.

Prevention of primary manifestations: All individuals with latent porphyria, the parents of affected individuals, and patients in remission should be advised about measures that diminish the risk of acute attacks:

  • Avoid precipitating factors (unsafe prescribed and illicit drugs, excessive alcohol consumption, smoking, and severe calorie restriction).
  • Adopt safe practices (maintenance of a regular, balanced diet; prompt treatment of infections; and reduction of stress).

Prevention of secondary complications: Patients treated regularly with heme arginate require monitoring of iron status to detect iron overload.

Surveillance: Individuals who have experienced acute attacks require monitoring of renal function; in some countries annual hepatic imaging to detect HCC is also offered to all individuals with an HMBS mutation after age 50 years (whether or not they have experienced acute attacks).

Genetic counseling. AIP is inherited in an autosomal dominant manner. About 1% of probands may have a de novo mutation. Sibs and offspring of individuals with an HMBS mutation are at 50% risk of inheriting the HMBS mutation; however, because penetrance is low the likelihood of an individual with an inherited HMBS mutation having an acute attack is small. Prenatal testing is possible but is rarely requested because of the low clinical penetrance and favorable clinical outcome for the great majority of symptomatic adults.

Diagnosis

Clinical Diagnosis

Individuals with acute intermittent porphyria (AIP) can be divided into two categories:

  • Clinically manifest (or overt) AIP. Individuals who are currently symptomatic or who are in remission following an acute attack. Persons in remission often continue to excrete excess PBG in their urine long after symptoms have resolved.
  • Latent (or presymptomatic) AIP. Individuals often detected by cascade screening (i.e., screening of at-risk family members) who have never had symptoms of AIP. Up to 50% of adults with latent AIP have increased urinary PBG excretion. The risk that an individual with latent AIP will later develop symptoms depends on age, sex, exposure to provoking agents, and other factors; however, the majority will remain asymptomatic throughout their lives.

An acute attack of AIP should be suspected in individuals with:

  • Otherwise unexplained severe, acute abdominal pain without physical signs (see Note). The pain, which occasionally may be more severe in the back or thighs, usually requires opiate analgesia. Nausea, vomiting, constipation, tachycardia, and hypertension are common. Muscle weakness, convulsions, mental changes, and hyponatremia are all features that may be present alone or in combination and that heighten the probability of acute porphyria [Hift & Meissner 2005, Puy et al 2010]. The urine may be reddish-brown or red; however, this is not a constant finding especially if the sample is fresh. The color is enhanced by exposure to air and light and reflects increased urinary concentrations of porphyrins and porphobilins formed from the porphyrin precursor porphobilinogen (PBG).

    Note: Abdominal pain is present in almost all acute attacks; atypical presentations are rare [Hift & Meissner 2005, Puy et al 2010]. Clinically indistinguishable acute attacks occur in other acute porphyrias. See Differential Diagnosis.
  • A family history consistent with autosomal dominant inheritance of an acute porphyria; however, is often absent given the low penetrance of clinical manifestations of AIP (see Penetrance).

Testing

Clinically manifest AIP. Evidence of an increased concentration of PBG in urine, using a specific quantitative assay, is essential to establish an unequivocal diagnosis of acute porphyria in a symptomatic individual.

Confirmation that the increased urinary PBG is caused by AIP (Table 1) requires evidence that:

  • Total fecal porphyrin concentration or coproporphyrin isomer ratio is normal;
  • Plasma porphyrin fluorescence emission scan either shows a peak around 619 nm or is normal.

Table 1. Biochemical Characteristics of Clinically Manifest AIP

Enzyme DefectEnzyme ActivityErythrocytesUrineStoolPlasma
Hydroxymethylbilane synthase (HMBS) (EC 2.5.1.61)HMBS ~50% of normal 1, 2Erythrocyte porphyrins: normal PBG 3 and ALA 4: increased
Porphyrins: increased 5
Total porphyrin: normal or small increase 6 Coproporphyrin isomer III/I ratio: normal 7Plasma porphyrins: increased fluorescence emission peak ~619 nm 8

1. Activity is decreased in all tissues, except in the 3% of individuals with the non-erythroid variant of AIP in which erythrocyte HMBS activity is normal.

2. Measurement of erythrocyte HMBS activity is not required for the diagnosis of an acute attack of AIP. Mean erythrocyte HMBS activity is 50% of normal but overlap between AIP and reference ranges diminishes its sensitivity and specificity as a diagnostic test for AIP, even when persons with the non-erythroid variant are excluded [Kauppinen & Fraunberg 2002].

3. PBG (porphobilinogen) is increased more than ALA (5-aminolevulinic acid). A normal PBG concentration in a symptomatic individual excludes the diagnosis of AIP. PBG concentrations decrease during remission but may remain increased for months or years.

4. ALA is often measured with PBG by specialist laboratories but does not appear to provide any significant additional diagnostic information in uncomplicated AIP (see Differential Diagnosis).

5. Increase mainly indicates in vitro condensation of PBG to uroporphyrins. Total urinary porphyrin, but not PBG, concentration may be increased in various disorders, including alcohol abuse and liver disease [Badminton et al 2012].

6. The increase may be large if an analytic method that includes ether-insoluble porphyrins, e.g., uroporphyrin, is used [Rossi 1999].

7. Excludes hereditary coproporphyria (see Differential Diagnosis).

8. Plasma porphyrin concentration is usually increased during an acute attack. Plasma porphyrin fluorescence emission scanning excludes variegate porphyria if the peak is at less than 622 nm (see Differential Diagnosis).

Determination of PBG in urine. Testing is best performed on a random urine sample, protected from light prior to analysis. Note: (1) 24-hour urine collection needlessly delays analysis and can lead to degradation of PBG; (2) very dilute urine may produce false negative results.

  • Specific quantitative tests. In the most widely used methods, PBG (and ALA) are separated from other chromogens in urine by ion-exchange column chromatography and PBG is measured by spectrophotometry after reaction with modified Ehrlich’s reagent [Badminton et al 2012].

    Note: Urinary (and plasma) concentrations of PBG and ALA can also be quantified by high-performance liquid chromatography - mass spectrometry [Floderus et al 2006, Zhang et al 2011]. Results should be corrected for urine concentration by expression as the ratio of PBG to creatinine.
  • Qualitative/semi-quantitative screening tests for PBG. The Watson-Schwartz test or the Hoescht test is easy to perform; however, both have problems with sensitivity and specificity. They are positive about 50% of the time when urinary concentrations of PBG are five times the upper limit of normal and are consistently positive when urinary concentrations of PBG are more than ten to 20 times normal, as would be typically found in an acute attack of AIP.

    A rapid, semi-quantitative assay for PBG is available in some countries (Trace PBG kit, Thermo Trace/DMA, Arlington, Texas). The sensitivity compared to the Watson-Schwartz test was 95% vs 38% and specificity was 99% vs 82% [Deacon & Peters 1998].

    Note: (1) All positive qualitative and semi-quantitative tests must be confirmed by a specific quantitative measurement to avoid false-positives. (2) If clinical suspicion of acute porphyria persists, negative tests should also be confirmed in the same way in order to detect false negatives and PBG concentrations below the sensitivity of screening tests.

Interpretation. A normal urinary PBG concentration in an individual with symptoms consistent with AIP excludes the diagnosis.

The concentration of PBG in urine is invariably increased in individuals with symptoms of AIP. During an acute attack, PBG concentration is often more than 10-20 times the upper reference limit [Kauppinen & Fraunberg 2002, Anderson et al 2005, Elder et al 2012].

Adults with latent AIP and persons in remission following an acute attack may excrete increased amounts of PBG. Thus, increased urinary PBG excretion does not necessarily confirm that symptoms are the result of porphyria. Note that a minimum two-fold increase in urinary PBG concentration above the baseline for that individual is consistent with symptoms due to AIP [Aarsand et al 2006]; however, in practice, baseline information is rarely available.

Latent (presymptomatic) AIP. See Related Genetic Counseling Issues, Testing of at-risk asymptomatic family members.

Molecular Genetic Testing

Gene. HMBS is the only gene in which mutation is known to cause AIP.

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in Acute Intermittent Porphyria

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
HMBSSequence analysis Sequence variants 498% 5
Deletion/duplication analysis 6Exonic or whole-gene deletions/duplications

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions, missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Detection frequency for sequence analysis supplemented by deletion/duplication analysis is 98.1% (95% confidence interval: 95.6%-99.2%) [Whatley et al 2009].

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm the diagnosis in a proband. The diagnosis of AIP in a symptomatic individual is based on increased PBG in a random urine sample (protected from light prior to analysis), together with evidence of a normal total fecal porphyrin or normal coproporphyrin isomer ratio, and plasma porphyrin fluorescence emission scan that is either normal or shows a peak emission around 619 nm.

Molecular genetic testing is not required to confirm the diagnosis in a symptomatic individual but may help to confirm or refute a previous diagnosis of overt AIP in an individual who is in full clinical and biochemical remission [Whatley et al 2009]. In addition, molecular genetic testing of an index patient may be indicated if clinical features and/or biochemical findings suggest the presence of homozygous HMBS mutations or dual porphyria (heterozygous mutations in two separate porphyria-related genes) or are otherwise atypical.

The main use of molecular genetic testing of an individual with biochemically proven AIP is to identify a mutation for the molecular investigation of the individual’s family (i.e., cascade screening).

When used, molecular genetic testing usually begins with sequence analysis of HMBS followed by deletion/duplication analysis if a mutation is not identified.

Molecular genetic testing is not useful for assessing prognosis.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Symptoms are present in only a minority of those with a genetic change that predisposes to acute intermittent porphyria (AIP). Symptoms are more common in women than men and very rare before puberty. Onset typically occurs in the third or fourth decade [Anderson et al 2001, Elder et al 2012].

Acute Intermittent Porphyria (AIP)

In AIP, the visceral, peripheral, autonomic, and/or central nervous systems may be affected, leading to a range of findings that are usually intermittent and sometimes life threatening. The course of acute attacks is highly variable within and between individuals.

Affected individuals may recover from acute AIP attacks within days, but recovery from severe attacks that are not promptly recognized and treated may take weeks or months. Clinical expression of AIP is typically caused by exposure to certain endogenous or exogenous factors in most individuals, but it is not uncommon for individuals to have acute attacks in which no precipitating factor can be identified.

Acute attack. Severe abdominal pain, which may be generalized or localized and not accompanied by muscle guarding, is the most common symptom and is often the initial sign of an acute attack. Back, buttock, or limb pain may be a feature. Gastrointestinal features including nausea, vomiting, constipation or diarrhea, abdominal distention, and ileus are also common. Tachycardia and hypertension are frequent, while fever, sweating, restlessness, and tremor are seen less frequently. Urinary retention, incontinence, and dysuria may be present.

Peripheral neuropathy is predominantly motor and is less common now than in the past. Muscle weakness often begins proximally in the legs but may involve the arms or legs distally and can progress to include respiratory muscles resulting in complete paralysis with respiratory failure. Bilateral axonal motor neuropathy may also involve the distal radial nerves [King et al 2002]. Motor neuropathy may also affect the cranial nerves or lead to bulbar paralysis.

Patchy sensory neuropathy may also occur [Wikberg et al 2000].

Mental changes are present in up to 30% of symptomatic individuals but are only very rarely the dominant feature of the disease [Hift & Meissner 2005, Puy et al 2010]. Changes include insomnia, anxiety, depression, hallucinations, confusion, paranoia, amnesia, and/or altered consciousness ranging from somnolence to coma. These symptoms resolve after the attack, though anxiety may persist.

Seizures may occur in acute attacks, especially in individuals with hyponatremia which may be worsened by vomiting and/or inappropriate fluid therapy. The cause of hyponatremia is not clear; both SIADH (syndrome of inappropriate antidiuretic hormone release) and renal salt wasting have been proposed as mechanisms.

Seizures may also occur as a manifestation of central nervous system involvement of the acute attack.

MRI findings. MRI changes were observed in two out of seven individuals with signs of CNS involvement. The main finding is posterior reversible encephalopathy syndrome [Celik et al 2002, Bylesjö et al 2004, Pischik & Kauppinen 2009]. Some MRI findings may result from rapid correction of hyponatremia rather than AIP [Susa et al 1999].

Cutaneous manifestations of porphyria do not occur in AIP.

Precipitating factors. Attacks of acute porphyria may be precipitated by endogenous or exogenous factors [Anderson et al 2001]. These include:

  • Prescribed and illicit drugs which are detoxified in the liver by cytochrome P450 and/or result in induction of ALA synthase and heme biosynthesis. Prescription drugs that can precipitate an attack include, for example, barbiturates, sulfa-containing antibiotics, some antiepileptic drugs, progestagens, and synthetic estrogens (see Agents/Circumstances to Avoid).
  • Endocrine factors. Reproductive hormones play an important role in the clinical expression of AIP. In women, acute neurovisceral attacks related to the menstrual cycle, usually the luteal phase, are common [Andersson et al 2003, Hift & Meissner 2005]. However, the majority of women with AIP fare well during pregnancy, despite massive increases in the serum concentration of various steroid hormones [Andersson et al 2003, Marsden & Rees 2010].
  • Fasting. A recognized precipitating factor is inadequate caloric intake [Anderson et al 2005] in connection with, for example, dieting or heavy exercise schedules.
  • Stress. Psychosocial and other stresses, including intercurrent illnesses, infections, alcoholic excess, and surgery, can precipitate an attack.

Chronic complications

  • Hepatocellular carcinoma (HCC). Individuals with AIP, whether clinically manifest or latent, appear to be at increased risk of developing primary HCC [Linet et al 1999, Innala & Andersson 2011], usually after age 54 years. The highest risk has been reported from Sweden; at present, it is unclear why the risk appears to be lower in other populations [Deybach & Puy 2011].
  • Renal involvement. Some individuals, especially those with long-standing repeated attacks, have renal insufficiency without another apparent cause. Although many have hypertension, others are normotensive despite renal insufficiency [Andersson et al 2000b]. Renal histopathology typically shows diffuse glomerulosclerosis, interstitial changes, and ischemic lesions. Protracted vasospasm in attacks of AIP is a possible cause [Andersson et al 2000b].
  • Recurrent acute attacks. Approximately 3%-5% of individuals with AIP, mainly women, experience repeat attacks (usually defined as >4/year) for a prolonged period, often many years [Elder et al 2012].

Mortality. Mortality directly related to acute attacks is now very rare in most countries as a result of improved treatment (use of human hemin) and identification and counseling of presymptomatic relatives. Deaths may occur as a complication of HCC or liver transplantation.

Homozygous HMBS Deficiency

To date, five children with homozygous HMBS disease-causing mutations have been described. All had less than 3% of the HMBS enzyme activity found in controls.

  • Four had mutations in exon 10. Symptoms started early in childhood and included severe ataxia, dysarthria, severe psychomotor delay, and central and peripheral neurologic manifestations. MRI studies in one showed white matter abnormalities that suggested selective postnatal involvement of cerebral oligodendrocytes [Solis et al 2004].
  • One was homozygous for a mutation in exon 6 and was less severely affected than the four described above [Hessels et al 2004].

Pathogenesis

Two major hypotheses for the pathogenesis of the neurologic lesions that give rise to the clinical features of acute porphyria have been proposed: ALA toxicity and/or neuronal heme deficiency. However, the success of liver transplantation as a cure for recurrent acute attacks [Soonawalla et al 2004] and the transplant of a liver from persons with AIP into unaffected persons who then experienced acute attacks [Dowman et al 2011] clearly implicate release of a hepatic neurotoxin, probably ALA, as their cause. Increased ALA production results from induction of hepatic ALA synthase activity, an effect of many of the factors that provoke acute attacks of AIP [Thunell 2006].

Genotype-Phenotype Correlations

Genotype-phenotype correlations are not evident in AIP, apart from some evidence that mutations that retain about 10% of normal activity may be less penetrant than those that retain less than 10% of normal activity [Andersson et al 2000a, Fraunberg et al 2005].

Penetrance

The penetrance for clinical manifestations of an HMBS disease-causing mutation is not accurately known.

In one study, 52% of relatives ascertained through cascade screening were found to have “typical” clinical symptoms with increased ALA and PBG and decreased HMBS activity in Swiss patients [Schuurmans et al 2001]. However, most reviews written by experienced porphyria specialists quote a penetrance, by which they imply an acute attack (acute abdominal pain ± associated autonomic, motor, or CNS symptoms) leading to a hospital admission for medical management, of 10%-20% [Anderson et al 2005, Puy et al 2010, Badminton et al 2012].

Population surveys suggest a lower figure.

The minimum prevalence of disease-specific HMBS mutations in France is 597 per million inhabitants [Nordmann et al 1997]. The penetrance of overt AIP in France was recently reported as 5.5:1,000,000 [Elder et al 2012], indicating a penetrance of about 1%.

Prevalence

In most countries AIP is the most common of the acute hepatic porphyrias [Anderson et al 2001, Puy et al 2010].

  • In Europe (excluding Sweden) the incidence of newly diagnosed symptomatic individuals with AIP has been reported as 0.13:1,000,000 per year, with a calculated prevalence of 5.9:1,000,000 [Elder et al 2012].
  • In Sweden the incidence and prevalence of AIP are about four times higher than in Europe due to a founder effect originating in Lappland [Floderus et al 2002].

Differential Diagnosis

Clinically indistinguishable acute neurovisceral attacks occur in acute intermittent porphyria (AIP) and the three other acute porphyrias: hereditary coproporphyria (HCP), variegate porphyria (VP), and ALAD deficiency porphyria (ADP), and may complicate hereditary tyrosinemia type 1 (Table 3) [Puy et al 2010].

Lead poisoning may also mimic the symptoms and disturb heme biosynthesis; however, anemia, a feature of lead poisoning, is not a feature of AIP.

Table 3. Disorders to Consider in the Differential Diagnosis of Clinically Manifest AIP

DisorderClinical featuresUrineStoolPlasmaErythrocytes
Hereditary coproporphyria (HCP)Acute attack ± skin lesions 1Increased PBG, ALA 2, porphyrins 3Increased coproporphyrin IIIIncreased plasma porphyrins; fluorescence emission peak ~620 nm 4
Variegate porphyria (VP)Acute attack ± skin lesions 1Increased PBG, ALA 2, porphyrins 3Increased protoporphyrin 5Increased plasma porphyrins; fluorescence emission peak ~626 nm 6
ALAD deficiency porphyriaAcute attackIncreased ALA, coproporphyrin III, normal PBGIncreased zinc-protoporphyrin; decreased ALAD activity
Hereditary tyrosinemia type 1Acute attackIncreased ALADecreased ALAD activity
Lead poisoningAbdominal pain, anemiaIncreased ALA; normal coproporphyrin III, PBG Increased zinc-protoporphyrin; decreased ALAD activity

Diagnostic abnormalities are shown. See Table 1 for biochemical characteristics of clinically manifest AIP.

ALA = 5-aminolevulinic acid

ALAD = 5-aminolevulinate dehydratase

1. Acute neurovisceral attacks are accompanied by porphyric skin lesions (bullae, fragile skin) in about 15% of persons with HCP and about 60% of persons with VP.

2. PBG increased more than ALA; both may decrease rapidly as symptoms resolve.

3. Uroporphyrin from in vitro polymerization of PBG and coproporphyrin; measurement is not required for diagnosis and may mislead.

4. Plasma porphyrin concentration may occasionally be normal; fluorescence emission spectroscopy does not distinguish between HCP and AIP.

5. Protoporphyrin is the main stool porphyrin, but a small increase in coproporphyrin III is also observed

6. Plasma porphyrin concentration is always increased and fluorescence emission spectroscopy distinguishes VP from all other porphyrias.

Hematuria, ingestion of beetroot, some drugs and food additives, and porphyrin excretion in other porphyrias (e.g., porphyria cutanea tarda, congenital erythropoietic porphyria) may produce similar red discoloration of the urine.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with acute intermittent porphyria (AIP) the following evaluations are recommended:

  • Full clinical history and examination, including neurologic evaluation if symptomatic
  • Review of medications to assess risk versus benefit (see Agents/Circumstances to Avoid)
  • Quantitation of urine porphobilinogen excretion to establish a baseline for comparison with future measurements taken during symptoms suggestive of active porphyria
  • Referral to a porphyria specialist for more detailed clinical advice on AIP
  • Referral to medical genetics for counseling

Treatment of Manifestations

Acute Neurovisceral Attack

Immediate treatment of an acute neurovisceral attack does not require confirmation of the specific type of acute porphyria.

Clinical assessment should include a full neurologic evaluation.

In persons known to have AIP consider other causes of abdominal pain in addition to porphyria.

Investigations should include:

  • Full blood count (FBC);
  • Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes;
  • Serum and urine osmolality;
  • Urine sodium concentration if hyponatremic;
  • Other blood tests as indicated by the patient’s condition and possible cause of the attack, e.g., CRP, blood cultures, CK, magnesium.

MRI should be considered if CNS symptoms are present.

General measures

  • Review all medications and discontinue any that can exacerbate acute porphyria [Elder & Hift 2001]. See Agents/Circumstances to Avoid.
  • Restore energy balance using an enteral route if possible. When required, intravenous fluid should contain a minimum of 5% dextrose; however, hypotonic dextrose-water solutions should be avoided because of the risk of hyponatremia.
  • Treat intercurrent infections and other diseases promptly.

Supportive treatment

  • Pain relief. Effective analgesia should be provided as soon as possible, usually in the form of parenteral opiates (morphine, diamorphine, and fentanyl are safe). Very large quantities may be required in a severe acute attack. Consider patient-controlled analgesia and support from a pain team.
  • Nausea and vomiting. Prochloperazine, promazine or ondansetron are considered safe.
  • Hypertension. Beta blockers are considered safe.
  • Convulsions can be terminated with intravenous diazepam, clonazepam, or magnesium sulphate.
  • Fluid balance and electrolytes. Dextrose saline is preferred. Severe hyponatremia should be treated with intravenous saline rather than fluid restriction [Hift & Meissner 2005].

Specific treatment

  • For mild acute neurovisceral attacks, a high carbohydrate intake, preferably oral and together with other supportive measures (see Acute Neurovisceral Attack), may be used for up to 48 hours. If improvement is unsatisfactory or if additional and progressive neurologic features present, intravenous administration of hemin preparations is recommended.
  • Intravenous human hemin is the most effective treatment for acute neurovisceral attacks. Intravenous administration of hemin preparations may be life-saving when employed early when neuronal damage is still reversible, and may help to avoid paresis or prevent its progression.
    • The recommended dose for hemin is 3-4 mg/kg IV, given once daily for four days. Treatment may be extended, depending on the clinical course.
    • Panhematin™ (Ovation Pharmaceuticals, Deerfield, IL) is approved for treatment of acute attacks in the US. This product is supplied as a dried powder, which must be reconstituted with sterile water immediately before intravenous injection and administered over 10-15 minutes. Because the administration of Panhematin™ reconstituted with sterile water is associated with transient, mild coagulopathy, concurrent anticoagulant therapy should be avoided.
    • Heme arginate (Normosang Orphan Europe, Paris) is an arginine-stabilized form of human hemin available in most other countries, including Europe, Africa, the Middle East, and South America. It is infused over at least 30 minutes. It has the same advantage as hemin in treating an acute neurovisceral attack, but has fewer reported side-effects [Hift & Meissner 2005, Puy et al 2010].

Note: (1) Phlebitis after intravenous injection can be minimized by reconstituting hematin in 20% human serum albumin solution and/or by using a large vein or a central catheter for infusion. Peripheral cannulas used to administer hematin should be replaced after each use. (2) An infusion set with an in-line filter is recommended to remove any undissolved particulate matter. (3) Rigorous flushing of venous catheters with boluses of saline totaling 100 mL is recommended.

Recurrent Acute Attacks

Recurrent acute attacks are best managed with support and advice from a porphyria specialist. See information and contact details of specialist porphyria centers at www.porphyria-europe.org.

Medical therapy aims to reduce the frequency and or severity of acute attacks by the following measures:

  • Ovulation suppression with gonadorelin analogues for patients with recurrent menstrual cycle-related acute neurovisceral attacks [Innala et al 2010]. Long acting analogues can be used to prevent ovulation and should be administered during the first few days of the menstrual cycle to minimize the early stimulation effect on hormone release which can trigger an attack. Side effects can be minimized by administering estrogen, preferably by patch. Gynecological review and bone density monitoring are recommended.
  • Prophylactic hemin infusion. The minimum effective infusion frequency should be employed, usually a weekly dose of hemin infused via an in-dwelling venous catheter. Problems include those associated with a venous access device (infection, blockage) and iron overload (see Prevention of Primary Manifestations, Prevention of Secondary Complications).

Other Treatments

Liver transplantation is curative and reported from several centers [Soonawalla et al 2004, Wahlin et al 2010, Dowman et al 2012]. Indications include repeated life-threatening acute attacks, failure of medical therapy, and poor quality of life [Seth et al 2007].

Combined liver and kidney transplantation, which has been successful, can be considered in those with AIP with repeated severe attacks and renal failure [Wahlin et al 2010]. Kidney transplantation has been performed for renal failure in persons with overt and latent AIP [Nunez et al 1987, Warholm & Wilczek 2003].

Cimetidine has been suggested as an alternative treatment [Rogers 1997]; however, evidence for clinical efficacy remains elusive. No recent formal study has been performed, but informal feedback from experienced clinicians at international porphyria meetings indicates that few patients have benefited from this treatment.

Other

Patients should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert® or similar).

Patients should be advised about support available from national patient associations where available.

Good-quality information is now widely available from patient or professional organizations either in paper form or from the Internet; see Resources.

Advice on safe treatment of persons with porphyria in some specific clinical situations (e.g., epilepsy, HIV, malaria, tuberculosis, hyperlipidemia, and hypertension) is available on the European Porphyria Network Web site and/or Porphyria South Africa Web site.

Prevention of Primary Manifestations

To prevent acute attacks patients are advised on the potential triggers as follows:

  • Assure that adequate nutrition is provided by a normal balanced diet. Avoid unsupervised calorie restriction diets, particularly those that exclude carbohydrate completely.
  • Avoid drugs and chemicals known to exacerbate porphyria, particularly prescribed medication and over the counter medication. See Agents/Circumstances to Avoid.
  • Seek timely treatment of systemic illness or infection.
  • Avoid excessive alcohol consumption and smoking.

Prevention of Secondary Complications

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

Because 100 mg of hemin contains 8 mg of iron, frequent administration of hemin may increase the risk for iron overload. Periodic monitoring of serum ferritin concentration and/or transferrin saturation is therefore appropriate in individuals treated repeatedly with hemin.

Surveillance

In view of the high risk for HCC in individuals with AIP in Sweden, annual hepatic imaging is offered after age 50 years. It has been shown to improve survival [Innala & Andersson 2011]. A few other countries have also initiated screening. It is not yet clear whether similar testing should be offered more widely, since the risk appears to be low in some countries [Deybach & Puy 2011, Stewart 2012]. Note: Serum α-fetoprotein measurement is not helpful.

Agents/Circumstances to Avoid

Excessive alcohol consumption and smoking should be avoided.

Knowledge about the safety of many drugs and other over-the-counter preparations in acute porphyrias is incomplete; however, evidence-based guidelines for assessment of drug porphyrogenicity have been published [Thunell et al 2007, Hift et al 2011].

Evaluation of Relatives at Risk

If the HMBS mutation is known in a family, at-risk relatives can benefit from molecular genetic testing to clarify their genetic status, so that those at increased risk of developing acute attacks of AIP can be identified early and counseled about preventive measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The majority of women with AIP have completely normal pregnancies with no clinical problems relating to the porphyria [Marsden & Rees 2010]. However, there is a small chance that pregnancy could initiate or worsen porphyria symptoms.

When a woman with AIP experiences abdominal pain, hypertension, and tachycardia during pregnancy, complications of pregnancy should be excluded before the findings are attributed to an acute attack.

Symptomatic treatment of an acute attack that occurs during pregnancy should take into account drug safety with respect to teratogenicity and precipitating/exacerbating an acute attack of porphyria.

Intravenous human hemin (both available preparations) has been used for the treatment of acute attacks in pregnancy and appears to be safe [Anderson et al 2005, Marsden & Rees 2010]. Several women in the UK and France have received regular heme arginate infusions during pregnancy without any obvious adverse effects on mother or child [Badminton & Deybach 2006].

Prolonged fasting should be avoided during labor and delivery as should the use of unsafe drugs, for example, ergometrine.

Note: In an obstetric emergency, no drug should be restricted if it is likely to be of major clinical benefit or is required in a life-threatening situation.

Stress should be minimized by providing good analgesia. Regional anesthesia, in the form of spinal or epidural anesthesia using bupivacaine, has been safely used.

Therapies Under Investigation

A clinical trial of adeno-associated virus (AAV)-based gene therapy for AIP is underway in Europe (see www.aipgene.org for details).

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

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Acute intermittent porphyria (AIP) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • The majority of individuals diagnosed with AIP have inherited an HMBS mutation from one of their parents, who may or may not be symptomatic.
  • A proband with AIP may also have the disorder as the result of a de novo mutation. About 1% of probands may have a de novo mutation [Whatley et al 1995].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include urinary PBG determination or, if the proband's HMBS mutation has been identified, molecular genetic testing of HMBS.

    Note: In persons with AIP the family history is sometimes negative because of failure to recognize the disorder in family members who have latent AIP (i.e., those with an HMBS mutation without clinical or biochemical manifestations).

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents (i.e., whether one or both parents have an HMBS mutation).
  • If only one of the parents of the proband has an HMBS mutation, which is the rule, the risk to each sib of inheriting the mutation is 50%. Because clinical 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.

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

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

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk asymptomatic family members

  • When the HMBS mutation has been identified in the family, molecular genetic testing is the method of choice for identification of individuals with an HMBS mutation and therefore at risk of an acute attack.
  • Measurement of erythrocyte HMBS activity is less sensitive but may be useful for the few families in which an HMBS mutation cannot be identified or when molecular testing is unavailable.
  • Urinary PBG excretion should not be used as it is normal in all pre-pubertal children with latent AIP and in at least 50% of adults [Kauppinen & Fraunberg 2002].

Testing of at-risk individuals younger than 18 years. Although acute attacks are rare before puberty, children in families with AIP should be offered testing with appropriate consent from parent or guardian in order to preempt this possibility. This affords the opportunity to provide advice/education on avoidance of precipitating factors and ensures rapid diagnosis with prompt treatment should an attack occur.

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 maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability and indications for prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

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.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 (a) most individuals with HMBS deficiency remain asymptomatic throughout life, (b) neither molecular genetic testing nor biochemical testing results can predict a clinical attack of AIP, and (c) 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 regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Porphyria Foundation (APF)
    4900 Woodway
    Suite 780
    Houston TX 77056-1837
    Phone: 866-273-3635 (toll-free); 713-266-9617
    Fax: 713-840-9552
    Email: porphyrus@aol.com
  • National Library of Medicine Genetics Home Reference
  • European Porphyria Network
    Email: info1@porphyria-europe.com
  • NCBI Genes and Disease
  • Swedish Porphyria Patients' Association
    CMMS C2-71 Karolinska University Huddinge
    Stockholm Stockholms Lan 141 86
    Sweden
    Phone: +46 8 711 56 09
    Fax: +46 8 585 827 60
    Email: porfyri@swipnet.se
  • RDCRN Patient Contact Registry: Porphyrias Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Acute Intermittent Porphyria: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
HMBS11q23​.3Porphobilinogen deaminaseHMBS homepage - Mendelian genesHMBS

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Acute Intermittent Porphyria (View All in OMIM)

176000PORPHYRIA, ACUTE INTERMITTENT
609806HYDROXYMETHYLBILANE SYNTHASE; HMBS

Acute intermittent porphyria (AIP) is caused by a defect in HMBS [Grandchamp 1998].

Normal allelic variants. The gene consists of 15 exons distributed over 10 kb that encode a ubiquitous HMBS isoform (exons 1 and 3-15) that is expressed in all tissues [Puy et al 1998] and an erythroid isoform (exons 2-15) that is restricted to erythroid cells [Grandchamp et al 1989].

However, exon 2 encodes only RNA for the 5’ untranslated region of the erythroid specific isoform.

The erythroid-specific and housekeeping mRNAs are produced by alternative splicing under the control of two promoters (reference sequence of longest transcript variant NM_000190.3). The upstream promoter is active in all tissues, while the other promoter, located 3 kb downstream, is active only in erythroid cells. The erythroid promoter displays some structural characteristics of other erythroid-specific promoters, including a CACCC motif, two GATA-1 sites, and one NF-E2 binding site. This finding suggests that common trans-acting factors may co-regulate the transcription of the HMBS enzyme activity of these genes.

Pathologic allelic variants. More than 386 mutations have been identified in HMBS (see Table A, HGMD). Most HMBS mutations are missense/nonsense or small deletions/insertions in the protein-coding regions. Variants in splice consensus regions flanking each exon are common. Larger deletions/duplications/insertions and even whole-gene deletions have been reported.

Normal gene product. HMBS (porphobilinogen deaminase) is the third enzyme in the heme biosynthetic pathway. It functions as a monomer localized within the cytoplasm where it catalyzes the synthesis of the linear tetrapyrrole hydroxymethlbilane from four molecules of porphobilinogen [Anderson et al 2001].

Abnormal gene product. A large proportion of mutations (~85%) are associated with a 50% reduction in enzyme protein in all tissues (previously referred to as CRIM-negative mutations) as a consequence of mutations that render the protein unstable or absent. The remainder, mainly due to missense mutations (previously known as CRIM positive), result in effects on protein stability and folding, cofactor assembly and the catalytic process. Modeling studies based on the crystallographic structure have provided important insight into these mechanisms [Gill et al 2009].

References

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Chapter Notes

Author History

Michael Badminton, PhD, FRCPath (2013-present)
Shigeru Sassa, MD, PhD; The Rockefeller University (2005-2010)
Stig Thunell, MD, PhD; Karolinska University Hospitall Huddinge (2010-2013)
Sharon Whatley, PhD (2013-present)

Revision History

  • 7 February 2013 (me) Comprehensive update posted live
  • 1 September 2011 (cd) Revision: addition of links to Rare Diseases Clinical Research Network Porphyrias Consortium and Registry (Management)
  • 23 March 2010 (me) Comprehensive update posted live
  • 27 September 2005 (me) Review posted to live Web site
  • 3 January 2005 (ss) Original submission
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