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Hematology Center
Porphyria

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DIAGNOSING THE PORPHYRIAS




There are at least 8 different types of porphyria.



More Common:

Acute intermitted porphyria (AIP),

hereditary coproporphyria (HC),

variegate porphyria (VP), &

porphyria cutanea tarda (PCT).



Prevalence:

PCT 1:25,00, AIP 1-2:100,000, VP 1:250,000, HC 1-2:500,000



(AIP):

Manifested by neurovisceral symptoms,

PCT by cutaneous symptoms, &

VP & HC by both.



The neurovisceral symptoms consist of autonomic neuropathies (constipation, colicky abdomen pain, vomiting, hypertension), peripheral neuropathy, seizures, delirium, coma and depression. The abdomen pain is severe and lasts for several days. The attacks may be accompanied by a moderate leukocytosis. Severe abdomen pain of short (less than one day) duration or chronic abdomen pain is unusual. Most patients are free of symptoms between attacks. The cutaneous manifestations are characterized by bullae formation in sun exposed areas, fragile skin, and hypertrichosis. Acute photosensitivity consisting of erythema and edema is seen only with protoporphyria and not with PCT, VP, and HC.







DIAGNOSIS



The key to diagnosis is suspicion of the disease, but this must be tempered by the fact that these are rare diseases. The first line of action is to screen the urine for the presence of porphyrin precursors, delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). These substances are always present if the patient is having an acute neurovisceral attack. Most patients with latent AIP and some with latent HC and VP will have elevated levels. If the urine screen is negative, then one can safely eliminate porphyria as a cause of acute neurovisceral symptoms. Abnormal urine screens should be verified by quantitative measures of urine ALA, PBG and porphyrins. Most elevated urine porphyrins on screening tests are false positives, mainly due to rises in coproporphyrin excretion seen with alcohol users, liver disease, acute illness, etc.., and not porphyria. The diagnosis of HC or VP is demonstrated by increased levels of porphyrins in the urine and stool. The vast majority of patients with HC have extreme elevations levels of coproporphyrin in their stool - 5 to 100 times normal. Patients with VP have elevated stool coproporphyrin and protoporphyrin. Patients with PCT have elevated stool isocoproporphyrin and protoporphyrin and increased urine coproporphyrin and uroporphyrin. Minor elevations of urine and stool porphyrins (espcially coproporphyrins) are common and non-specific.



Measuring levels of enzyme activity to diagnose symptomatic porphyria is inappropriate. Over 90% of patients with decreased PBG-deaminase (the defect in AIP) do not excrete porphyrins and never have symptoms of porphyria. Also, 10% of patients with AIP have normal activity of RBC PBG-deaminase. It may be useful to measure PBG-deaminase in patients with biochemically-proven AIP to help in screening family members, but most patients with deficiencies will never have AIP.



Most people with HC never have symptoms (the first four patients in the literature with this diagnosis were all asymptomatic). There is a commercial assay for the genetic defect in HC (coproporphyringen oxidase [CO]). However, the validity of this assay is questionable, given that it measures RBC CO activity but CO is located in the mitochondria and obviously RBC's do not have mitochondria. This may explain why 75% of our send-out CO are reported as abnormal. There is currently is no literature supporting the use of this test and it should not be routinely ordered.



SUMMARY



1. To rule out porphyria as a cause of acute neurovisceral symptoms: urine porphyrin and PBG screen.

2. To follow-up an abnormal screen: quantitative urine for PBG, ALA and total porphyrins plus stool total porphyrins. To diagnose PCT one must perform total porphyrins on urine and stool.

3. Patients with history of "porphyria": obtain records. In most patients with the diagnosis of porphyria, review of the record reveals no diagnostic abnormality. In unclear cases, repeat urine and stool studies.