In porphyric diseases, the main similarity is the abnormal secretion of substances that are precursors of the porphyrin compound heme (of hemoglobin). The known pathways of porphyrin synthesis begin with glycine and succinate, which are combined to eventually form a compound known as d-aminolevulinic acid (ALA). This goes on to produce a substance known as “porphobilinogen,” composed of a single pyrrole ring. Four of these rings are joined to form the tetrapyrrole compound proporphyrinogen; this is the precursor of protoporphyrin, which, in turn, is the precursor of heme. The tetrapyrrole compounds exist in eight isomers, depending on where certain side groups are located. The only isomeric forms that are clinically important are I and III. Normally, very small amounts of porphyrin degradation products appear in the feces or in the urine; these are called “coproporphyrins” or “uroporphyrins” (their names refer to where they were first discovered, but both may appear in either urine or feces).
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The porphyrias have been classified in several ways, none of which is entirely satisfactory. The most common system includes erythropoietic porphyria (EP), hepatic porphyria, mixed porphyria, porphyria cutanea tarda (PCT), and acquired (toxic) porphyria. EP is a small group of rare congenital diseases characterized clinically by skin photosensitivity without vesicle formation, pink discoloration of the teeth that fluoresces under ultraviolet light, and sometimes mild hemolytic anemia. If erythropoietic porphyria is suspected, the best diagnostic test is measurement of erythrocyte porphyrin.

Hereditary hepatic porphyria may be subdivided into three types: acute intermittent porphyria (AIP; Swedish genetic porphyria), variegate porphyria (VP; South African genetic porphyria), and hereditary coproporphyria (HC). All three are inherited as autosomal dominants, and all three may be associated with episodes of acute porphyric attacks, although such attacks are more widely publicized in association with AIP. All three subdivisions manifest increases in the enzyme ALA-synthetase, which catalyzes formation of ALA from its precursors. AIP is characterized by a decrease of 50% or more in the enzyme uroporphyrinogen-I-synthetase (abbreviated URO-I-S and also known as “porphobilinogen deaminase”), which catalyzes the formation of uroporphyrinogen I from porphobilinogen. Levels of URO-I-S are said to be normal in VP and HC. Acute intermittent porphyria is not associated with photosensitivity, whereas skin lesions due to photosensitivity are common in VP and also occur in HC. Parenthetically, these skin lesions resemble those of PCT, and some of these patients were probably included in the PCT group in some early classifications. In VP and HC, increased amounts of protoporphyrin are excreted in the feces, whereas this does not happen in AIP. Although AIP, VP, and HC have increased amounts of coproporphyrin in the feces, HC patients excrete much larger amounts of fecal coproporphyrin III than does AIP or VP.

The porphyrias can also be classified usefully according to clinical symptoms:

1. Neurologic only: AIP
2. Cutaneous only: PCT, EP, EPP
3. Both neurologic and cutaneous: VP, HC

Acute intermittent porphyria. URO-I-S is said to be decreased in all patients with AIP. However, about 5%-10% of AIP patients have values within the reference range, so that some overlap occurs. URO-I-S is also said to be decreased in relatives of patients with AIP, again with some overlap at the borderline areas of the reference range. At least one kindred with a condition closely resembling AIP has been reported with normal URO-I-S levels, but the significance of this is not clear. There may be some laboratory variation in results, and equivocal results may have to be repeated. Blood samples should be stored frozen and kept frozen during transit to the laboratory to avoid artifactual decrease in enzyme activity. Therefore, falsely low URO-I-S values may be obtained through improper specimen handling. Hemolytic anemia or reticulocytosis greater than 5% may produce an increase in URO-I-S activity. Assay for URO-I-S is available mostly in university medical centers and large reference laboratories.

The acute porphyric attacks consist of colicky abdominal pain, vomiting, and constipation (= 80% of patients); and mental symptoms (10%-30% of patients) such as confusion, psychotic behavior, and occasionally even convulsions. About one half of the patients display hypertension and some type of muscle motor weakness. The attacks are frequently accompanied by leukocytosis. These attacks may be precipitated by certain medications (especially by barbiturates;), by estrogens, and by carbohydrate deprivation (dieting or starvation). The attacks usually do not occur until adolescence or adulthood. Porphobilinogen is nearly always present in the urine during the clinical attacks and is an almost pathognomonic finding, but the duration of excretion is highly variable. It may occasionally disappear if not searched for initially. Between attacks, some patients excrete detectable porphobilinogen and others do not. Urine ALA levels are usually increased during acute attacks but not as markedly as porphobilinogen. During remission, ALA levels also may become normal. Patients with AIP may also have hyponatremia and sometimes have falsely elevated thyroxine (T4) results due to elevated thyroxine-binding protein levels.

Porphobilinogen is usually detected by color reaction with Ehrlich’s reagent and confirmed by demonstrating that the color is not removed by chloroform (Watson-Schwartz test). Since false positive results may occur, it is essential to confirm a positive test by butanol (butyl alcohol) extraction. Porphobilinogen will not be extracted by butanol, whereas butanol will remove most of the other Ehrlich-positive, chloroform-negative substances. Therefore, porphobilinogen is not removed by either chloroform or butanol. A positive result on the porphobilinogen test is the key to diagnosis of symptomatic acute porphyria; some investigators believe that analysis and quantitation of urinary porphyrins or ALA are useful only if the Watson-Schwartz test results are equivocal. However, the majority believe that a positive qualitative test result for porphobilinogen should be confirmed by quantitative chemical techniques (available in reference laboratories) due to experience with false positive Watson-Schwartz test results in various laboratories. They also advise quantitative analysis of porphyrins in urine and feces to differentiate the various types of porphyria. Glucose administration may considerably decrease porphobilinogen excretion.

Some investigators prefer the Hoesch test to the modified Watson-Schwartz procedure. The Hoesch test also uses Ehrlich’s reagent but is less complicated and does not react with urobilinogen. The possibility of drug-induced false reactions has not been adequately investigated. Neither test has optimal sensitivity. In one study the Watson-Schwartz test could detect porphobilinogen only about 50% of the time when the concentration was 5 times normal. Quantitative biochemical methods available in reference laboratories are more sensitive than these screening tests.

Porphyria cutanea tarda is a chronic type of porphyria. There usually is some degree of photosensitivity, but it does not develop until after puberty. There often is some degree of liver disease. No porphobilinogen is excreted and acute porphyric attacks do not occur.

Toxic porphyria may be produced by a variety of chemicals, but the most common is lead. Lead poisoning produces abnormal excretion of coproporphyrin III but not of uroporphyrin III. ALA excretion is also increased.

Familial dysautonomia (Riley-Day syndrome). Riley-Day syndrome is a familial disorder characterized by a variety of signs and symptoms, including defective lacrimation, relative indifference to pain, postural hypotension, excessive sweating, emotional lability, and absence of the fungiform papilli on the anterior portion of the tongue. Most of those affected are Jewish. Helpful laboratory tests include increased urine homovanillic acid value and decreased serum dopamine-beta-hydroxylase (DBH) value, an enzyme that helps convert dopamine to norepinephrine. Besides the Riley-Day syndrome, the DBH value may also be decreased in mongolism (Down’s syndrome) and Parkinson’s disease. It has been reported to be elevated in about 50% of patients with neuroblastoma, in stress, and in certain congenital disorders (results in the congenital disorders have not been adequately confirmed). There is disagreement as to values in patients with hypertension.