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Overview of Porphyrias

By

Herbert L. Bonkovsky

, MD, Wake Forest University School of Medicine;


Sean R. Rudnick

, MD, Wake Forest University School of Medicine

Last full review/revision Dec 2020| Content last modified Dec 2020
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Porphyrias are rare disorders in which hemoglobin is abnormally metabolized due to genetic or acquired deficiencies of enzymes of the heme biosynthetic pathway. These deficiencies allow heme precursors to accumulate, causing toxicity. Porphyrias are defined by the specific enzyme deficiency. Two major clinical manifestations occur: neurovisceral abnormalities (the acute porphyrias) and cutaneous photosensitivity (the cutaneous porphyrias).

Heme, an iron-containing pigment, is an essential cofactor of numerous hemoproteins. Virtually all cells of the human body require and synthesize heme. However, most heme is synthesized in the bone marrow (by erythroblasts and reticulocytes) and is incorporated into hemoglobin. The liver is the second most active site of heme synthesis, most of which is incorporated into cytochrome P-450 enzymes. Heme synthesis requires 8 enzymes (see table Substrates and Enzymes of the Heme Biosynthetic Pathway). These enzymes produce and transform molecular species called porphyrinogens or porphyrins (and their precursors); accumulation of these substances causes the clinical manifestations of the porphyrias.

Etiology

With the exception of the sporadic type of porphyria cutanea tarda (PCT), 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.

Table
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Substrates and Enzymes of the Heme Biosynthetic Pathway and the Diseases Associated With Their Deficiency

Substrate/Enzyme*

Porphyria

Neurovisceral Symptoms

Cutaneous Symptoms

Inheritance

Glycine + succinyl coenzyme A

Erythroid specific delta-aminolevulinic acid synthase-2 (ALAS 2)

X-linked protoporphyria (due to increased enzyme activity) †

No

Phenotypically similar to erythropoietic protoporphyria

X-linked

Delta-aminolevulinic acid

Delta-aminolevulinic acid dehydratase (ALAD)

ALAD-deficient porphyria

Yes

No

Autosomal recessive

Porphobilinogen

Porphobilinogen deaminase

Acute intermittent porphyria

Yes

No

Autosomal dominant

Hydroxymethylbilane

Uroporphyrinogen III cosynthase

Congenital erythropoietic porphyria

No

Severe, mutilating skin disease

Autosomal recessive

Uroporphyrinogen III

Uroporphyrinogen decarboxylase

Porphyria cutanea tarda

No

Fragile skin, blisters

Two variants:

  • Autosomal dominant (20–25% of cases)

  • Without known genetic correlate (sporadic, 75–80%)

Hepatoerythropoietic porphyria

No

Severe blistering

Autosomal recessive

Coproporphyrinogen III

Coproporphyrinogen oxidase

Hereditary coproporphyria

Yes

Fragile skin, blisters

Autosomal dominant

Protoporphyrinogen IX

Protoporphyrinogen oxidase

Variegate porphyria

Yes

Fragile skin, blisters

Autosomal dominant

Protoporphyrin IX

Ferrochelatase

Erythropoietic protoporphyria

No, except in patients with severe hepatobiliary pathology

Skin pain, lichenification and other minor skin changes, but no blistering

Autosomal recessive

Heme (final product incorporated in various heme proteins)

* Listed are successive intermediates in the heme biosynthetic pathway, beginning with glycine and succinyl CoA and ending with heme. Deficiency of an enzyme causes buildup of precursor compounds.

† X-linked protoporphyria results from gain-of-function mutations that increase the activity of ALAS 2, causing accumulation of protoporphyrin. Decreased activity of ALAS 2 causes a sideroblastic anemia.

Pathophysiology

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 abdominal, mental, and neurologic symptoms. They are typically triggered by drugs, cyclic hormonal activity in young women, and other exogenous factors. 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, 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.

Table
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Major Features of the Two Most Common Porphyrias

Porphyria

Presenting Symptoms

Exacerbating Factors

Most Important Screening Tests*

Treatment

Acute intermittent porphyria

Neurovisceral (intermittent, acute)

Alcohol ingestion

Drugs (mostly cytochrome P-450 inducers)

Fasting

Infections

Organic solvents

Progesterone/progestogens

Stress

Urinary PBG

Givosiran

Glucose

Heme

Porphyria cutanea tarda

Blistering skin lesions (chronic)

Alcohol ingestion

Estrogens

Halogenated hydrocarbons

Hepatitis C virus

Iron

Smoking

Urinary or plasma porphyrins

Direct-acting antivirals to cure hepatitis C virus infection

Low-dose chloroquine or hydroxychloroquine

Phlebotomy

* In symptomatic phase.

PBG = porphobilinogen.

Diagnosis

  • 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.

Table
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Screening for Porphyrias

Testing

In Patients With Acute Neurovisceral Symptoms

In Patients With Photosensitivity

Screening

Urinary ALA, PBG (random urine sample)

Plasma porphyrins*

Confirmation (when screening test results are significantly abnormal)

Urinary ALA and PBG (quantitative‡)

Fecal and urinary porphyrins

Red blood cell PBG deaminase

Plasma porphyrins*

Red blood cell porphyrins

Urinary ALA, PBG, and porphyrins (quantitative)

Fecal porphyrins

Plasma porphyrins*

* The preferred method is by direct fluorescent spectrophotometry.

Urinary and fecal porphyrins are fractionated only if the total is increased.

Results are corrected according to urine creatinine level.

ALA = delta-aminolevulinic acid; PBG = porphobilinogen.

Secondary Porphyrinuria

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 the routes of porphyrin excretion. A large number of drugs 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, stiripentol, telmisartan, and valsartan, among others (1, 2). Such drugs 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 dis, 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.

Secondary porphyrinuria references

  • 1. An G, Wang X, Morris ME: Flavonoids are inhibitors of human organic anion transporter 1 (OAT1)-mediated transport. Drug Metab Dispos 42(9):1357–1366, 2014. doi: 10.1124/dmd.114.059337

  • 2. Duan P, Li S, Ni A, et al: Potent inhibitors of human organic anion transporters 1 and 3 from clinical drug libraries: Discovery and molecular characterization. Mol Pharm 9(11):3340–3346, 2012. doi: 10.1021/mp300365t

Drugs Mentioned In This Article

Drug Name Select Trade
PLAQUENIL
No US brand name
DIABINESE
PONSTEL
ALINIA
ARALEN
MICARDIS
DENAVIR
COLAZAL
LOTENSIN
AVAPRO
DIOVAN
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