Biallelic inactivation of protoporphyrinogen oxidase and hydroxymethylbilane synthase is associated with liver cancer in acute porphyrias.

Variegate porphyria (VP) and acute intermittent porphyria (AIP), the two most common types of acute porphyrias (AHPs), result from a partial deficiency of protoporphyrinogen oxidase (PPOX) and hydroxymethylbilane synthase (HMBS), respectively. A rare but serious complication in the AHPs is hepatocellular carcinoma (HCC). However, the underlying pathomechanisms are yet unknown. We performed DNA sequence analysis in cancerous and non-cancerous liver tissue of a VP and an AIP patient, both with HCC. In samples of both cancerous and non-cancerous liver tissues from the patients, we identified the underlying PPOX and HMBS germline mutations, c.1082dupC and p.G111R, respectively. Additionally, we detected a second somatic mutation, only in the cancer tissue i.e., p.L416X in the PPOX gene of the VP patient and p.L220X in the HMBS gene of the AIP patient, both located in trans to the respective germline mutations. Both somatic mutations were not detected in 10 non-porphyria-associated HCCs. Our data demonstrate that in the hepatic cancer tissue of AHP patients, somatic second-hit mutations result in nearly complete inactivation of the enzymes catalyzing major steps in the heme biosynthetic pathway. Both PPOX and HMBS, which might act as tumor suppressors, play a crucial role in the development of HCC in these individuals.

Protective effects of ß-carotene and melanin against protoporphyrine IX-induced phototoxicity in the photo hen's egg test.

PURPOSE: The aim of our study was to evaluate the photoprotective potential of melanin and ß-carotene against protoporphyrine IX-induced phototoxicity via photo hen's egg test. METHODS: In three independent test groups, the yolk sac blood vessel system of hen's eggs was exposed to protoporphyrine IX and irradiated with ultraviolet A (UVA). One of the test groups also received melanin to investigate its photoprotective capacity; another test group received ß-carotene for the same purpose. Morphological changes and embryo lethality were recorded in these three test groups for a period of 24 h. The same parameters were obtained in five different control groups. RESULTS: The control groups exhibited only minimal morphological changes and no fatalities. In contrast, severe phototoxic damage and a high lethality rate (75%) were observed in the test group exposed to protoporphyrine IX and UVA. Lethality was somewhat lower in the ß-carotene test group (58%) and was considerably lower in the melanin test group (17%). CONCLUSIONS: The photoprotective potential against protoporphyrine IX-induced phototoxic damage was moderate for ß-carotene and was remarkable for melanin. Given that synthetic melanocyte stimulating hormone (MSH) analogues induce a de novo synthesis of melanin without any previous ultraviolet irradiation in human skin, the application of MSH analogues might be conceived of as 'light hardening' without light. Synthetic MSH analogues thus may represent a new promising therapeutic option for photodermatoses especially for erythropoietic protoporphyria.

The acute hepatic porphyrias: current status and future challenges.

The porphyrias are predominantly inherited metabolic disorders, which result from a specific deficiency of one of the eight enzymes along the pathway of haem biosynthesis. Historically, they have been classified into hepatic and erythropoietic forms, based on the primary site of expression of the prevailing dysfunctional enzyme. From a clinical point of view, however, it is more convenient to subdivide them into acute and non-acute porphyrias, thereby primarily considering the potential occurrence of life-threatening acute neurovisceral attacks. Unrecognised or untreated, such an acute porphyric attack is associated with a significant mortality of up to 10%. The acute hepatic porphyrias comprise acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and δ-aminolevulinic acid dehydratase deficiency porphyria. Making a precise diagnosis may be difficult because the different types of porphyrias may show overlapping clinical and biochemical characteristics. To date, the therapeutic possibilities are limited and mainly symptomatic. In this overview we report on what is currently known about pathogenesis, clinic, diagnostics, and therapy of the acute hepatic porphyrias. We further point out actual and future challenges in the management of these diseases.

The prognostic value of cord blood analysis in erythropoietic protoporphyria: the 'Duesseldorf Cord Blood Study'.

BACKGROUND: Erythropoietic protoporphyria (EPP) is the most common porphyria in childhood, presenting with painful and burning skin sensations as well as erythema and edema after sun exposure. It represents an inherited disorder of heme metabolism that is due to a reduced ferrochelatase enzyme activity. The diagnosis is usually established when symptoms start by measuring elevated levels of protoporphyrin in erythrocytes. The aim of our study was to question the predictive value of cord blood analysis in newborn relatives of EPP patients as this may offer the earliest possible diagnosis of EPP in newborn relatives of affected patients. METHODS: Erythrocyte porphyrin (EP) was measured immediately after birth in 18 newborn relatives of EPP patients. EP was correlated to the subsequent clinical follow-up of mean 9 years after birth. RESULTS: We found EP to be within reference values in all 18 newborn relatives of EPP patients at birth. Out of 14 patients who were included in the follow-up period of median 9 years, 13 remained asymptomatic whereas one boy developed the typical symptoms of EPP at the age of three in combination with elevated EP. CONCLUSION: Based on the findings of our study, we assume that cord blood analysis is not a reliable prognostic tool in EPP from the actual point of view.