Lecture 8 (Part 2) Porphyria

autosomal dominant inheritance Due to the deficiency of the porphobilinogen deaminase

Diagnosis: Affected patients will excrete large amounts of ALA and porphobilinogen in the urine during acute attacks.

Results from a deficiency of protoporphyrinogen oxidase caused by a gene mutation of the protoporphyrinogen oxidase enzyme protein (PPOX).

inherited disorder characterised by skin photosensitivity (reaction to light), systemic symptoms arising from neurological problems, or both.

Due to decreased activity in UROD ( hepatic uroprophyrinogen decarboxylase) in the liver causing overproduction of uroporphyrin Uroporphyrin auto-oxidizes to porphyrins, which accumulate in the liver and skin, where they act as photosensitizers and are excreted in urine and bile.

Either inherited (auto dominant) or acquired

Alcohol is known participant Hepatitis C HIV HFE Gene mutations Liver cancer

Most patients with hereditary hemochromatosis have a mutation in one of the mentioned HFE genes located on chromosome 6. When a mutant or non-functional variant of the HFE gene is present, ferritin levels are not under influence of a normal and functional HFE gene, which leads to enhanced accumulation of iron in peripheral tissues (This interaction also may modulate cellular iron uptake and decrease ferritin levels). This causes the formation of an inhibitor of UROD in liver cells results from an oxidation reaction thats is promoted by iron causing PCT to occur. HHC, as an iron storage disease, precipitates the clinical manifestation of porphyrias through various mechanisms. The excessive amount of iron inhibits URO-D indirectly with oxidized metabolites that block the enzyme. n HH patients, hepcidin levels are reduced, causing excess ferroportin-mediated iron export and, as a consequence, increased dietary iron uptake and release from macrophages HIGH hepacidin: Inhbits Ferroprotein: inhibits iron entry into cells REGULATES IRON LEVEL. Increased iron stores = inhibit ferroprotein Hepcidin is induced in response to increased body iron stores to inhibit further iron absorption and prevent iron overload IN HAEMOCHROMATOSIS: There is HFE gene mutation causing LOW hepacidin : Activates ferroproten : INCREASED IRON INTAKE AND RELEASE. Release of IRON prompts more absorption LOW hepacidin: Activates Ferroprotein: Iron entry into cells

inherited in an autosomal dominant manner. Inherited deficiency of the enzyme ferrochelatase caused by mutations in the uroporphyrinogen synthase (UROS) gene. leads to the accumulation of the non- physiologic and photoreactive porphyrinogens, uroporphyrinogen I and coproporphyrinogen I, which damage erythrocytes and elicit a phototoxic reaction upon light exposure.

The disorder results from low levels of the enzyme responsible for the fourth step in haem production. Mutations in the UROS (The UROS gene makes an enzyme called uroporphyrinogen III synthase, which is critical to the chemical process that leads to haem production) gene cause congenital erythropoietic porphyria.

is characterized by blistering skin lesions on sun-exposed areas of the skin resulting in severe damage to skin beginning in childhood. Easily rupture, thickened skin, excessive hair growth where hair typically doesnt grow.

Erythropoietic Protoporphyria has elevated accumulationofthenon- physiologic and photoreactive porphyrinogens, uroporphyrinogen I and coproporphyrinogen I WHEREAS Congenital Erythropoietic Porphyria DOES NOT ONLY elevated Uroprophyrin

The patient does not have elevated PBG. As PBG absorbs resin and through Ehrlichs reaganet will create red colour. However, lack of PBG means this process doesnt happen. THUS no acute attack of porphyria. PINK = POS

Cutaneous: Red to brown or Pink to red Due to the excessive excretion of porphyrins, the urine of PCT patients turns red to brown with exposure to natural light and pink to red fluorescence when exposed to a UVA light) Photoreactive porphyrins are COPRO and URO. PCT has a build up of URO and therefore this porphyrin will accumulate and therefore due to being photo reactive will react (colour change) when exposed to light

Lecture slide

Acute: Abdominal pain: The accumulation of PBG and ALA in neural tissue Neuropathy due to precursors in the central autonomous system Cutaneous lesions: Photosensitivity occurs due to the light causing excitation to the porphyrins where the absorption of light causes damage to the lysosome membrane in skin tissues which release protease (local damage)