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With the exception of the sporadic type of porphyria cutanea tarda (PCT, which also has an inherited type), the porphyrias are inherited diseases. Autosomal dominant inheritance is most common.

In the autosomal dominant porphyrias, homozygous or compound heterozygous states (ie, 2 separate heterozygous mutations, one in each allele of the same gene in the same patient) may be incompatible with life, typically causing fetal death. Disease penetrance in heterozygotes varies; thus, clinically expressed disease is less common than genetic prevalence. Of the 2 most common porphyrias, acute intermittent porphyria (AIP) is autosomal dominant and about 20% of PCT cases are autosomal dominant. The prevalence of PCT is about 1/10,000. The prevalence of the causative genetic mutation for AIP is about 1/1500, but because penetrance is low, the prevalence of clinical disease is also about 1/10,000. Prevalence of both PCT and AIP varies widely among regions and ethnic groups.

In the autosomal recessive porphyrias, only homozygous or compound heterozygous states cause disease. Erythropoietic protoporphyria, the 3rd most common porphyria, is autosomal recessive.

X-linked inheritance occurs in one of the porphyrias, X-linked protoporphyria.

Porphyrias result from a deficiency of any of the last 7 enzymes of the heme biosynthetic pathway or from increased activity of the erythroid form of the first enzyme in the pathway, ALA synthase-2 (ALAS 2). (Deficiency of ALAS 2 causes sideroblastic anemia rather than porphyria.) Single genes encode each enzyme; any of numerous possible mutations can alter the levels and/or the activity of the enzyme encoded by that gene. When an enzyme of heme synthesis is deficient or defective, its substrate and any other heme precursors normally modified by that enzyme may accumulate in bone marrow, liver, skin, or other tissues and have toxic effects. These precursors may appear in excess in the blood and be excreted in urine, bile, or stool.

Although porphyrias are most precisely defined according to the deficient enzyme, classification by main site of overproduction of heme precursors (hepatocytes or erythrocytes) or major clinical features (acute or cutaneous) is often useful.

Acute porphyrias manifest as intermittent attacks of severe pain. Usually patients have abdominal, psychiatric, and neurologic symptoms. Acute attacks are typically triggered by medications, intercurrent illness, life stresses, and other exogenous factors. In young women, cyclic hormonal activity is also a typical trigger of acute attacks.

Cutaneous porphyrias tend to cause continuous or intermittent symptoms involving cutaneous photosensitivity. Some acute porphyrias (hereditary coproporphyria, variegate porphyria) may also have cutaneous manifestations. Because of variable penetrance in heterozygous porphyrias, clinically expressed disease is less common than genetic prevalence (see table Major Features of the Two Most Common Porphyrias).

Urine discoloration (red or reddish brown) may occur in the symptomatic phase of all porphyrias except erythropoietic protoporphyria (EPP) and ALAD-deficiency porphyria. Discoloration results from oxidation of the porphyrinogens to their corresponding porphyrins, the porphyrin precursor porphobilinogen (PBG), or both. Sometimes the color develops after the urine has stood in air or light for minutes to hours, allowing time for non-enzymatic oxidation. In the acute porphyrias, except in ALAD-deficiency porphyria, about 1 in 3 heterozygotes (more frequently in females than males) also have increased urinary excretion of PBG (and urine discoloration) during the latent phase.

• Blood or urine testing

Patients with symptoms suggesting porphyria are screened by blood or urine tests for porphyrins or the porphyrin precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA—see table Screening for Porphyrias). Abnormal results on screening are confirmed by further testing.

Asymptomatic patients, including suspected carriers and people who are between attacks, are evaluated similarly. However, the tests are less sensitive in these circumstances; measurement of red blood cell or white blood cell enzyme activity is considerably more sensitive. However, assays for many of the enzymes of the pathway (eg, uroporphyrinogen III cosynthase [urogen 3 synthase], coproporphyrinogen oxidase [CPOX], protoporphyrinogen oxidase [PPOX], ferrochelatase [FECH]) are not generally or commercially available.

Genetic analysis is highly accurate and preferentially used within families when the mutation is known. Genetic testing will reveal known disease-associated mutations in most patients with the hereditary forms of porphyria; however, in a small percentage (~1%) of clinically and biochemically affected patients, genetic testing will fail to uncover a causative mutation. Therefore, the correct diagnosis continues to require thoughtful integration of clinical, biochemical, and genetic results. Prenatal testing (involving amniocentesis or chorionic villus sampling) is possible but rarely indicated.

Several diseases unrelated to porphyrias may involve increased urinary excretion of porphyrins; this phenomenon is described as secondary porphyrinuria.

Hematologic disorders, hepatobiliary diseases, and toxins (eg, alcohol, benzene, lead) can cause elevated urinary coproporphyrin excretion. Elevated coproporphyrin excretion in the urine can occur in any hepatobiliary disorder because bile is one of the routes of porphyrin excretion. A large number of medications and chemicals inhibit organic anion transporters, which normally transport porphyrins, especially coproporphyrins, into the bile; common examples include artesunate, balsalazide, benazepril, chlorpropamide, cortisol, demeclocycline, diflunisal, flavonoids, irbesartan, mefenamic acid, nitazoxanide, penciclovir, probenecid, rifampicin, rosuvastatin, stiripentol, telmisartan, and valsartan, among others (1, 2). Such medications may also lead to an increase in urinary porphyrin excretion. Uroporphyrin may also be elevated in patients with hepatobiliary disorders. Protoporphyrin is not excreted in urine because it is water insoluble.

Disorders that cause secondary porphyrinuria (as well as disorders that cause clinical syndromes mimicking acute porphyrias) typically do not elevate urinary levels of ALA and PBG, so normal levels of ALA and PBG help distinguish secondary porphyrinuria from acute porphyrias. However, some patients with lead poisoning can have elevated urinary ALA levels. Blood lead levels should be measured in such patients. If urinary ALA and PBG are normal or only slightly increased, measurement of urinary total porphyrins and high-performance liquid chromatography profiles of these porphyrins are helpful for differential diagnosis of acute porphyric syndromes.

Coproporphyrin (CP) I and III and other biomarkers may be useful as selective and sensitive biomarkers for certain drug–drug interactions (3–6). In addition, CP I and III are potential biomarkers that can track nonalcoholic steatohepatitis (NASH) progression (7).