Porphyria cutanea tarda

PCT results from inhibition of uroporphyrinogen decarboxylase (UROD) in the liver. The inhibitor, a uroporphomethene, is a partially oxidized form of the heme pathway intermediate uroporphyrinogen.[3]Phillips JD, Bergonia HA, Reilly CA, et al. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proc Natl Acad Sci USA. 2007 Jan;104:5079-84. http://www.pnas.org/content/104/12/5079.full http://www.ncbi.nlm.nih.gov/pubmed/17360334?tool=bestpractice.com One or more forms of cytochrome P450 may generate this inhibitor in the presence of iron and oxidative stress.[4]Nichols RC, Cooper S, Trask HW, et al. Uroporphyrin accumulation in hepatoma cells expressing human or mouse CYP1A2: relation to the role of CYP1A2 in human porphyria cutanea tarda. Biochem Pharmacol. 2003 Feb 15;65(4):545-50. http://www.ncbi.nlm.nih.gov/pubmed/12566081?tool=bestpractice.com

Specific environmental factors and infectious agents may enhance susceptibility by increasing oxidative stress in hepatocytes. Moderate iron overload is characteristic, and factors that lead to iron retention, such as hemochromatosis gene mutations, myelofibrosis, and end-stage renal disease, also increase susceptibility.

About 20% of patients are heterozygous for UROD mutations and have half-normal UROD activity in all tissues from birth.[1]Phillips JD, Anderson KE. The porphyrias (Chapter 59). In: Kaushansky K, Lichtman MA, Prchal JT, et al, eds. Williams Hematology, 10th ed. New York, NY: McGraw-Hill;2020:961-86. These individuals are classified as having type 2 (familial) PCT. Those without UROD mutations are classified as type 1 (sporadic) or type 3 (rare instances when more than one family member is affected but there is no UROD mutation).

In all three types, porphyrins do not accumulate until hepatic UROD activity is reduced to <20% of normal. Thus, the same additional susceptibility factors are common in types 1, 2, and 3 PCT. Clinical features are also identical, except that a family history of PCT is occasionally present in type 2 PCT and, by definition, always in type 3. All three types respond to treatment by repeated phlebotomy or low-dose 4-aminoquinolines.[1]Phillips JD, Anderson KE. The porphyrias (Chapter 59). In: Kaushansky K, Lichtman MA, Prchal JT, et al, eds. Williams Hematology, 10th ed. New York, NY: McGraw-Hill;2020:961-86.

The pattern of excess porphyrins in PCT is complex, as a consequence of impairment of the sequential 4-step decarboxylation catalyzed by uroporphyrinogen decarboxylase. The substrate (uroporphyrinogen - an octacarboxyl porphyrinogen), intermediates (hepta-, hexa-, and pentacarboxyl porphyrinogen), and product (coproporphyrinogen, a tetracarboxyl porphyrinogen) of the enzyme reactions are reduced porphyrins and are colorless and nonfluorescent.

In PCT, these intermediates accumulate mostly as the corresponding oxidized porphyrins, which are reddish, fluorescent, and photosensitizing. Further complexity is added by metabolism of some of the accumulated pentacarboxyl porphyrinogen to isocoproporphyrinogen by the next enzyme in the pathway, coproporphyrinogen oxidase, followed by oxidation and modification by gut bacteria to a series of isocoproporphyrins. Porphyrins that accumulate in the liver are transported to the skin, where they are excited by light, produce reactive oxygen species, and cause photosensitivity. Porphyrins are maximally activated by wavelengths of light near 400 nm. Urinary excretion of excess porphyrins accounts for reddish or dark urine.

PCT classification[1]Phillips JD, Anderson KE. The porphyrias (Chapter 59). In: Kaushansky K, Lichtman MA, Prchal JT, et al, eds. Williams Hematology, 10th ed. New York, NY: McGraw-Hill;2020:961-86.

A commonly accepted classification, based on presence or absence of uroporphyrinogen decarboxylase (UROD) mutations and family history of the disease, is described as follows:

Type 1 (sporadic) PCT

• No UROD mutation; no family history of PCT. Enzyme deficiency restricted to hepatocytes. Multiple susceptibility factors contribute to reducing hepatic UROD to <20% of normal. Type 1 PCT accounts for about 80% of PCT diagnoses.

Type 2 (familial) PCT

• Heterozygous for a UROD mutation that reduces enzyme activity in all tissues by about 50% from birth. Penetrance is low, so disease often presents sporadically, and only when additional susceptibility factors reduce hepatic enzyme activity to <20% of normal. Type 2 PCT may present earlier in life than type 1 and occasionally involves other family members, but is not otherwise clinically distinguishable from type 1. The familial form accounts for about 20% of all PCT diagnoses.

Type 3 (familial) PCT

• No UROD mutation; rare. More than one family member affected, but otherwise not distinguished from type 1. Other inherited factors may be found (e.g., hemochromatosis gene mutations).

Chemically induced PCT

• Rare; associated with substantial exposure to halogenated polycyclic aromatic hydrocarbons.

Hepatoerythropoietic porphyria

• Homozygous form of type 2 PCT, which usually presents in infancy or childhood. Usually associated with UROD activity under 10% of normal in all tissues.