Acute Porphyria Workup

During acute episodes of porphyria, monitor electrolytes and serum osmolarity because hyponatremia and/or syndrome of inappropriate secretion of antidiuretic hormone can develop and cause seizures.

With the exception of aminolevulinic acid dehydratase (ALAD) deficiency, acute porphyrias can be diagnosed during acute episodes with 2 quick bedside tests to identify PBG. Both tests require porphobilinogen (PBG) levels 4 times the upper limit of normal. In either test, PBG reacts with para-dimethylaminobenzaldehyde (DMAB) to form a red compound. (Phenazopyridinium chloride, methyl red, and urosein may also turn the urine red under acidic conditions; these confounding factors can be excluded by testing a mixture of urine with hydrochloric acid. No simple tests are available to exclude compounds such as cascara sagrada, levomepromazine, methyldopa, antipyrine, phylloerythrinogen, indoles, and pyrrolic acids.)

Hoesch test is the simpler of the 2 tests and less prone to misinterpretation. For this test, mix 1-2 drops of urine with 1 mL of 6-mol/L hydrochloric acid (HCl) and 20 mg of DMAB. Immediate development of a cherry-red color at the top of the mixture indicates a positive result.

For the Watson-Schwartz test, mix 7.5 mL of a DMAB solution (10 mg/mL HCl) with 5 mL water. Mix 1 mL of the solution with 1 mL urine. Immediate formation of a red color suggests PBG excess. A positive result is confirmed by adding 2 mL saturated sodium acetate and then 3 mL chloroform to the positive mixture. After vigorous shaking, a red upper aqueous phase and a pink lower organic solution phase confirms a positive result.

Quantitative urine porphyrin levels vary. PBG levels vary approximately 20% when measured on a week-to-week basis and vary 25% when measured at a 10-week interval. This means that the the probability that the 2-fold increase in PBG concentration is actually related to the patient's disease is 80%. Porphyrin levels are elevated during an episode; hereditary coproporphyria (HCP) and variegate porphyria (VP) have identical urine porphyrin profiles and can be differentiated by examining stool porphyrins.

Table 3. Quantitative Urine Porphyrin Levels (Open Table in a new window)

Comparing the relative increase in PBG levels during acute attacks with the asymptomatic period may be a more sensitive marker for acute neuroporphyria when compared with absolute PBG values. Patients with AIP, VP, or HCP have 2.3-50.5–fold increases in PBG levels during acute attacks.

ALAD deficiency can be diagnosed by detecting numerous fluorescent erythrocytes by microscopically examining the blood with a 100-W iodine-tungsten lamp.

Quantitative stool studies help differentiate between HCP and VP because these disorders have identical urine porphyrin profiles.

Table 4. Quantitative Stool Porphyrin levels (Open Table in a new window)

Despite their limitations, functional assays can help in diagnosing porphyria. ALAD and PBG enzymes are measured in erythrocytes. In ALAD deficiency, a functional deficiency of 25% or greater is diagnostic. This deficit is also detected in lead poisoning and in hereditary tyrosinemia. PBG deaminase is deficient in many patients with AIP; however, in 10% of patients with AIP, the enzyme defect is limited to the liver or housekeeping enzyme. Other assays (eg, test for coproporphyrinogen oxidase in lymphocytes) are available but unreliable.

Many genetic defects responsible for porphyria have been identified. In general, a large number of defects account for each porphyria. This finding limits the use of genetic testing to only 2 situations:

• If a genetic defect is known in an individual, his or her family members can be screened.
• Certain ethnic groups have a high prevalence of a particular mutation. For example, Dutch and Swedish Laplanders have a specific mutation in AIP, and many South African families have a specific mutation in VP.

MRI may reveal selective disturbance on white matter tracts that become myelinated and develop postnatally.

Gray matter and white matter in the brainstem and cerebellum appear to be preserved.

Electromyography and nerve conduction studies are nonspecific.

In patients with porphyrias, motor nerve conduction velocities are usually normal.

Partial antidromic block with significantly slowed conductance may be seen during asymptomatic periods in patients with VP or AIP.

Changes consistent with reinnervation may occur during the recovery of muscle weakness.

Peripheral nervous system

Histology shows axonal degeneration and patchy demyelination of motor axons, particularly short motor axons, which innervate the proximal and bulbar muscles. Axons are thin and irregular, with vacuolization, degeneration, and cellular infiltration. Neuronal loss and chromatolysis of the anterior horn cells may be secondary to retrograde degeneration. Chromatolysis of cranial nerve nuclei, commonly the dorsal vagus nucleus and autonomic nervous system ganglia (eg, celiac ganglion), may be observed.

CNS

Histologic evaluation may show chromatolysis and vacuolization of neurons and selective involvement of oligodendrocytes. Other findings include focal perivascular demyelination, reactive gliosis, and localized changes in the supraoptic and paraventricular nuclei of the hypothalamus.