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Congenital Erythropoietic Porphyria

(Porphyrinuria, Pink tooth, Osteohemochromatosis)

By George M. Barrington, DVM, PhD, DACVIM, College of Veterinary Medicine, Washington State University

Congenital erythropoietic porphyria (CEP) is a rare hereditary disease of cattle, pigs, cats, and people that results from a significant yet variable decrease in uroporphyrinogen III synthase (URO-synthase) activity. URO-synthetase is the fourth enzyme in the heme biosynthesis pathway, and it normally converts hydroxymethylbilane to uroporphyrinogen III. With decreased URO-synthase activity, hydroxymethylbilane accumulates primarily in erythrons and is nonenzymatically converted to uroporphyrinogen I. Further decarboxylation of uroporphyrinogen I leads to the formation of various porphyrinogen I isomers, with coproporphyrinogen I occurring as the final product. Coproporphyrinogen l cannot be further metabolized to heme and is thus nonphysiologic. Porphyrinogen l isomers are pathogenic when they accumulate in large amounts and are oxidized to their corresponding porphyrins. Accumulation of porphyrinogen isomers in bone marrow erythroid precursors results in cell damage and hemolysis. Porphyrin I isomers are also released into circulation and deposited in skin, bone, and other tissues. Cutaneous photosensitivity occurs, because porphyrins deposited in skin are photocatalytic and cytotoxic. Presumably, exposure of skin to sunlight (and other sources of long-wave ultraviolet light) leads to phototoxic excitation of isomers, formation of oxygen radicals, and subsequent tissue and vessel damage. Urinary porphyrin excretion is greatly increased (100–1,000 times normal) and primarily consists of uroporphyrin l and coproporphyrin I with lesser amounts of other isomers. Although isomer l porphyrins predominate, isomer lll porphyrins are also increased.

CEP was first reported in South African Shorthorn cattle; however, most cases have since been reported in the Holstein breed. It is inherited as a simple autosomal recessive and is usually confined to herds in which inbreeding or close line-breeding is practiced. It has been recognized in the USA, Canada, Denmark, Jamaica, England, South Africa, Australia, and Argentina. This broad geographic distribution suggests that the disease likely is found worldwide and probably affects all meat-producing animals, especially cattle, swine, and sheep.

Heterozygous animals seem to be normal, but homozygous recessive animals are affected at birth with reddish brown discoloration of the teeth, bones, and urine that persists for life. The excess coproporphyrin I and uroporphyrin I in the urine colors it an amber or reddish brown. Bones, urine, and teeth (especially the deciduous teeth) fluoresce pink when irradiated with near-ultraviolet light. Prolonged exposure to sunlight causes typical lesions of photosensitization with hyperemia, vesicle formation, and superficial necrosis of unpigmented portions of the skin. Severity of the skin lesions depends on the intensity of the solar radiation and the extent of cutaneous pigmentation found in specific families of animals. A normochromic, hemolytic anemia with macrocytes and microcytes and marked basophilic stippling develops. Splenomegaly eventually develops. The texture of bones is not altered except in cases in which bones have increased fragility because of a diminished cortex. Affected animals are generally of medium to good condition unless solar injury has occurred. Some animals become progressively unthrifty unless protected from sunlight. A similar disease, bovine protoporphyria (see Cutaneous Manifestations of Multisystemic and Metabolic Defects), causes photosensitivity only in Limousin cattle and people. A recent molecular study of CEP in cattle supports the hypothesis that CEP is caused by a mutation affecting the URO-synthetase gene; however, additional functional studies are needed to identify the exact causative mutation.

In people, a series of porphyrias caused by defective functions of enzymes in porphyrin-heme biosynthesis have been described and grouped according to their presenting signs. These vary broadly and may include severe cutaneous lesions on exposed areas of the body, acute photosensitivity reactions, serious liver damage, and acute attacks of neurologic dysfunction. In animals, the recognized diseases are commonly classified as CEP, congenital erythropoietic protoporphyria, or porphyria. It is likely that all of the syndromes described in people also occur in animals and that a broader classification could be used.

Porphyria in swine is rare and incompletely described. Affected pigs have discoloration of teeth and excessive uroporphyrin in urine. In contrast to CEP in cattle and people, affected swine are not anemic and do not present with signs of photosensitization. The specific genetic defect is unknown; therefore, its relevance to CEP in other animals is also unknown. Nonetheless, the disorder is inherited as an autosomal dominant trait.

Recently, the first feline model of human CEP due to deficient URO-synthase activity was identified by characteristic clinical phenotype and confirmed by biochemical and molecular genetic studies. In this case, sequencing of the cat’s URO-synthetase gene revealed two homozygous, missense mutations in exons 3 and 6. This synergistic interaction of two rare amino acid substitutions in the URO-synthase polypeptide resulted in the feline model of human CEP. Previously, cats presenting with brownish discolored teeth that fluoresced pink under UV light and increased URO and coproporphyrinogen concentrations were believed to have CEP. The disease was also observed to be inherited as an autosomal dominant trait (as in some pig models), whereas in people and cattle, the disease is inherited as an autosomal recessive trait. It is now understood that cats with the CEP-like phenotype and autosomal dominant inheritance actually have feline acute intermittent porphyria and not CEP.

Diagnosis should be based on the excretion of abnormal uroporphyrins, the brown discoloration of the teeth (which fluoresce when irradiated with near-ultraviolet light), the appearance of discolored urine, and hemolytic anemia.

The recessive genetic character is widely distributed in cattle, but the clinical condition is comparatively rare. Clinically normal heterozygotes have lower levels of uroporphyrinogen III cosynthetase than do normal animals, but laboratory identification of the carrier state is impractical because of the low incidence of the disease and is not widely used. Morbidity can be controlled by keeping affected animals indoors and out of direct sunlight.