The Challenges Of Testing For And Diagnosing Porphyrias

AIP rarely presents prior to puberty, with onset most
commonly between ages 20 and 40. It is characterized
by episodes of acute neuropathic symptoms. Most
patients, approximately 95%, 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.
Inheritance of AIP occurs in an autosomal dominant
manner with reduced penetrance. Approximately
10-20% of individuals with a PBGD enzyme deficiency
will become symptomatic during their lifetime,
although some recent 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 (#8562 Porphyrins, Quantitative, Urine),
ALA (#8406 Aminolevulinic Acid [ALA], Urine), and
PBG (#82068 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). 5 This will ensure
that another acute porphyria, with features similar to
AIP, is not missed. PBGD (#9625 Aminolevulinic Acid
Dehydratase [ALA-D] and Porphobilinogen Deaminase
[Pbg-D] (Uroporphyrinogen Synthase [UpgS]),
Erythrocytes) 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. However,
molecular testing is not readily available on a clinical
basis at this time. Urinary ALA and 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 (MML), 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 9-12 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/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
Variegate porphyria (VP) is an autosomal dominant
acute porphyria that results from a reduction in the
activity of protoporphyrinogen oxidase activity. VP is
pan-ethnic, although high prevalence is reported in
South Africa (3/1000 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
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