Pocket Oncology (Pocket Notebook Series), 1st Ed.

PORPHYRIAS

Melody Smith and Raajit Rampal

Definition

• Metabolic disorders caused by altered activities of enzymes w/in the heme biosynthetic pathway leading to the accumulation of porphyrins or porphyrin precursors

• Often due to an inheritied Mt in the gene for that enzyme

• Heme biosynthetic pathway & porphyrias (Lancet 2010;375:924)

Figure 28-2

Background of Heme Biosynthesis

• BM (>80% of daily) & liver are the 1° sites of heme synthesis, although heme is made in all tissues

Epidemiology

• Rare diseases, affect fewer than 20000 people in the United States

• Most common prohyria is PCT, prevelance of 1 in 10000

Classification of the Porphyrias

• Hepatic or erythropoietic depending on whether the site of initial production & accumulation of pathway intermediates is the liver or BM

• Acute or cutaneous based upon the 1° clinical manifestation

• Acute:

• Visceral complaints or life-threatening neurologic complications (J Clin Neurosci 2011;18:1147)

• Elevations in the porphyrin precursors delta ALA & porphobilinogen

• Seen in AIP, delta-ALA deficiency porphyria (ADP), HCP, & VP

• Cutaneous

• Photosensitivity due to activation of porphyrins in the skin upon exposure to UV-A

• Chronic blistering skin lesions

• May be some overlap in these classifications

Genetics

• Each porphyria has many different Mt that have been identified

• The disease-causing Mt in a particular family is often private or shared w/only a few other families

• The hepatic enzyme deficiency in PCT, UROD, is most often acquired.

• About 20% of pts w/PCT are heterozygous for a Mt in this enzyme

• Heme pathway enzymes can also be affected by environmental & metabolic factors

Porphyria Subtypes

• 8 different porphyrias have been identified:

• Acute Intermittent Porphyria (AIP): AD inheritance, deficient enzyme is PBGD, many people w/genetic Mt never develop sx, often manifests after puberty (J Clin Pathol 2012;65:976)

• Delta-ALA Deficiency Porphyria (ADP): AR inheritance, extremely rare

• Hereditary Coproporphyria (HCP): AD form of hepatic porphyria similar to AIP except that some pts develop photosensitivity

• Variegate Porphyria (VP): AD, common among white South Africans, hepatic porphyria

• Porphyria Cutanea Tarda (PCT): Hepatic porphyria, deficiency of UROD enzyme, essentially an acquired disease, mainly p/w skin manifestations

• Strong association between sporadic form of PCT & hepatitis C (Liver Int 2012;32:880)

• Erythropoietic Protoporphyria (EPP) or Protoporphyria: Mt in ferrochelatase gene (FECH) or delta-aminolevulinic acid synthase- 2 gene (ALAS2), termed X-linked protoporphyria (ALP) when due to ALAS2 Mt as this gene is on chromosome X, presents in early childhood, characterized by photosensitivity

• Congenital Erythropoietic Porphyria (CEP): AR, extremely rare, a/w photosensitivity

• Hepatoerythropoietic Porphyria (HEP): AR, very rare porphyria, deficiency of UROD, skin blistering that usu begins in infancy

Diagnosis

• Consider porphyria in the Ddx of a pt who p/w abdominal complaints w/o other explanation

• Measurement of porphyrin precursors ALA & PBG, as well as porphyrins in urine, plasma, erythrocytes, & feces

• 3 porphyrias cause elevations in PBG: AIP, HCP, & VP

• Can be differentiated by Mt detection, measuring erythrocyte PBGD, urinary porphyrins, fecal porphyrins, & plasma porphyrins

Treatment

• Acute porphyrias should be treated urgently w/hemin or glu in order to avoid a prolonged or fatal attack

• Avoidance of sunlight is recommended

• in those pts who have photosensitivity, such pts w/CEP & EPP

• skin blistering, as in pts w/VP & HCP

• PCT responds readily to tx by iron reduction