At a Glance
The term porphyria refers to a group of disorders in which porphyrins (or their precursors) accumulate in body fluids and tissues. All but one of the porphyrias is hereditary. Each disease is caused by a partial deficiency in one of the enzymes of heme synthesis. With the exception of two very rare porphyrias, inheritance is autosomal dominant. Cutaneous damage is due to the photosensitizing effects of porphyrins in the skin. The basis of the neurologic attacks remains obscure.
The porphyrias can be separated into two categories based on clinical presentation.
There are three porphyrias in which patients develop signs and symptoms related to the skin:
Porphyria cutanea tarda (PCT)
As the name suggests, PCT presents later than the other cutaneous porphyrias (typically at older than 40 years of age). Patients develop blisters, scarring, and hyperpigmentation in sun-exposed areas. PCT is by far the most common porphyria. In most cases, it is acquired rather than hereditary. Factors that stimulate the development of skin lesions include excess hepatic iron, alcoholic liver disease, use of estrogens, and exposure to certain toxic substances.
This disorder most commonly presents in childhood or adolescence. Patients develop redness, swelling, itching and burning of sun-exposed skin within minutes to hours of the exposure. There is little or no long-term evidence of skin damage, as scarring is usually mild or absent. A small number of these patients may develop liver disease or gallstones that contain protoporphyrin. The clinical expression of protoporphyria is variable; some gene carriers are severely affected, whereas others are asymptomatic.
Congenital erythropoietic porphyria (CEP)
The most damaging of the cutaneous porphyrias is CEP. It typically presents within the first few years of life as extreme photosensitivity. Over time, there may be extensive scarring and erosions of the fingers, hands, and face. Porphyrins accumulate in the teeth and cause them to stain a yellowish-brown color (under ultraviolet light they fluoresce a reddish-pink color). Excretion of porphyrins in urine may cause it to turn dark. These patients also develop anemia due to shortened red cell survival. This is an extremely rare disease; most physicians never see a case of CEP.
There are four porphyrias in which patients develop signs and symptoms related to the nervous system:
Acute intermittent porphyria (AIP)
The most common of the neurologic porphyrias is AIP. Signs and symptoms usually begin in late adolescence or early adulthood and affect females more often than males. Patients experience attacks of abdominal pain, constipation, vomiting, and neurologic dysfunction that typically last for days or weeks. Neurologic findings may involve the peripheral, autonomic, and/or central nervous systems. Acute attacks are often precipitated by fasting, infections, alcohol consumption, hormonal factors (e.g., menstrual cycle), and a number of drugs. Between attacks, patients usually have no signs or symptoms related to the disease. Photosensitivity and skin lesions are not present in AIP, because the enzyme defect causes overproduction of aminolevulinic acid (ALA) and porphobilinogen (PBG), but not porphyrins.
Variegate porphyria (VP)
VP may present with acute attacks (as described for AIP), photosensitivity, and skin lesions that resemble those seen in PCT, or both. It is a rare disorder, except in the white South African population, in whom the prevalence may be as high as 1 in 300.
Hereditary coproporphyria (HCP)
HCP is also a rare disorder. It usually presents with attacks of abdominal pain and neurologic signs and symptoms similar to those in AIP. However, some patients have photosensitivity and skin lesions.
Aminolevulinic acid dehydratase (ALA-D) deficiency
A few patients with an almost complete deficiency of the enzyme ALA dehydratase have been described. Signs and symptoms are similar to those for AIP, with no photosensitivity. Inheritance is autosomal recessive, and heterozygotes are not affected.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
Testing should be based on the clinical presentation.
Cutaneous Signs and Symptoms
If the patient is an adult and has blistering skin lesions, scarring, and hyperpigmentation in sun-exposed areas, order a urine porphyrin screening test (random urine specimen). If the test is positive, order quantitative urine porphyrins (24-hour urine specimen). Patients with porphyria cutanea tarda typically show a 5- to 20-fold increase in urine porphyrins, most of which is uroporphyrin and 7-carboxyl porphyrin.
For children, adolescents, and adults who present with acute onset of redness, swelling, itching, and burning following sun exposure, order free erythrocyte protoporphyrin. A large increase (>5-fold the upper limit of normal) will diagnose patients with protoporphyria.
In children with extreme photosensitivity who are suspected to have CEP, both urine porphyrins and free erythrocyte protoporphyrinshould be ordered. Values for both tests are greatly elevated in this disease.
Neurologic Signs and Symptoms
For three of the neurologic porphyrias (AIP, VP, and HCP), order a porphobilinogen (PBG) screening test. Collect a random urine specimen when the patient is symptomatic, protect it from the light, and submit it to the laboratory. Values are elevated during the acute attack but are lower and may be within the reference range between attacks. A positive test should be confirmed with quantitative urine PBG, which requires a 24-hour urine specimen. A negative test, properly collected and analyzed, effectively rules out a neurologic porphyria.
A large increase in PBG (typically 5- to 50-fold the upper reference limit) means the patient has a neurologic porphyria. To determine which is present, order two tests:
Fecal porphyrins can be performed on a random specimen, protected from the light. Each of the three porphyrias has a characteristic excretion pattern.
Porphobilinogen deaminase is the enzyme deficient in acute intermittent porphyria. It is measured in red blood cell lysates. Collect whole blood in a heparin- or EDTA-containing tube (check with the laboratory ahead of time for their requirements). Patients with AIP have decreased enzyme activity, whereas those with VP and HCP have values within the reference range.
Urine porphyrins are also increased in these three disorders. The patterns of excretion are less helpful than the tests described, but they do provide additional evidence that a porphyria is or is not present. Screening and quantitative tests can be run on the samples collected for PBG analysis.
The concentration of aminolevulinic acid (ALA)in urine rises in all of the neurologic porphyrias. It goes up less than PBG in the three porphyrias mentioned, and it is less specific, because there are several other disorders that can produce an elevation. The only situation in which it is necessary to order ALA is in the work-up of suspected ALA dehydratase deficiency.
The subsequent table provides laboratory test results for each of the porphyrias. Entries for ALA and PBG indicate whether values are increased or normal (—–). Entries for porphyrins in urine, red blood cells, and feces indicate which porphyrins are elevated. *Uroporphyrin may be elevated only during an acute attack.(Table 1)
|Disease||Urine ALA and PBG||Urine porphyrins||Red blood cell porphryins||Fecal porphyrins|
|Acute intermittent porphyria||Increased*||Uroporphyrin*||——-||——-*|
|ALA dehydratase deficiency||Increased (ALA only)||Coproporphyrin||Protoporphyrin||——-|
|Porphryia cutanea tarda||——-||Uroporphyrin, 7-carboxyl*||——-||7-, 6-, 5-carboxyl|
|Congenital erythropoietic porphyria||——-||Uroporphyrin||Uroporphyrin|
*The key diagnostic tests for each porphyria.
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
Analytical factors that Affect Test Results
Because all porphyrins have a unique fluorescence spectrum, measurement of total porphyrins by fluorometry is very specific for these compounds. Some drugs have been reported to interfere with fluorometric assays. These interferences can be overcome by HPLC analysis; each porphyrin elutes at a characteristic retention time.
Measurement of PBG is based on its reaction with p-dimethylaminobenzaldehyde (Ehrlich’s reagent) to produce a pink-purple color. The only known endogenous interferent is urobilinogen; some drugs have also been reported to interfere with the test. These substances can be removed by treating urine with an ion-exchange resin that adsorbs PBG but not the interfering substances. After washing the resin, PBG is eluted and Ehrlich’s reagent is added to the eluate. The amount of PBG is determined by measuring the absorbance of this solution at a specific wavelength.
Positive Test Results Seen in Conditions Other than Porphyria
Urine ALA is increased in lead poisoning and hereditary tyrosinemia.
Urine porphyrins—coproporphyrin is increased (< 2-fold) in liver disease, lead poisoning, alcohol ingestion, and acute illness.
Red blood cell porphyrins – increased in iron deficiency and lead poisoning.
Fecal porphyrins is increased up to 3-fold in healthy individuals, depending on intestinal flora.
What Lab Results Are Absolutely Confirmatory?
Mutations causing all of the porphyrias have been identified. A few specialized laboratories in North America and Europe perform molecular testing for these disorders. Finding a mutation provides unequivocal proof that the patient is a gene carrier. However, the penetrance of the porphyrias (particularly the neurologic porphyrias) is variable. The presence of a mutation does not predict whether the course of the disease will be asymptomatic, mild, or severe.
Molecular testing should not be used in place of standard biochemical tests to diagnose patients who may have a porphyria. It is most useful for identifying family members of a known patient who have inherited the abnormal gene and are, therefore, at risk for developing signs and symptoms.
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- At a Glance
- What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
- Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?
- What Lab Results Are Absolutely Confirmatory?