Disturbed iron metabolism in erythropoietic protoporphyria and association of GDF15 and gender with disease severity

Barman-Aksoezen, Jasmin; Girelli, Domenico; Aurizi, Caterina; Schneider‐Yin, Xiaoye; Campostrini, Natascia; Barbieri, Luca; Minder, Elisabeth I.; Biolcati, G.

doi:10.1007/s10545-017-0017-7

Cited by 23 publications

(27 citation statements)

References 47 publications

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“…In two patients, iron substitution increased liver damage as seen by an increase in liver transaminases, which led to discontinuation of the treatment 23,24 . In the same direction points the observation of lower PPIX levels in females than in males, the former being more prone to iron deficiency 13 . Additionally, the majority of EPP-patients under our care, who received iron supplementation at some point in their life from their family doctor or other physicians for suspected iron deficiency, informally reported worsening of photosensitivity after iron substitution.…”

Section: Ambivalent Experiences With Iron Substitutionsupporting

confidence: 60%

“…EPP patients frequently show signs of iron deficiency e.g. a mild microcytic, hypochromic anemia and low serum iron, low transferrin saturation and ferritin and a slightly elevated zinc-protoporphyrin [8][9][10][11][12][13] . Female patients, who are physiologically more likely to develop iron deficiency, tend to have lower PPIX levels than male patients 13,14 .…”

Section: Introductionmentioning

confidence: 99%

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Iron in erythropoietic protoporphyrias: Dr. Jekyll or Mr. Hyde?

Barman-Aksoezen¹,

Schneider‐Yin²,

Minder³

2017

J Rare Dis Res Treat

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Erythropoietic protoporphyria consists of two different genetic diseases, erythropoietic protoporphyria (EPP) and X-linked erythropoietic protoporphyria (XLEPP). Both of them are often accompanied by iron deficiency. Iron supplementation appears to be beneficial in XLEPP, although the clinical experience until to date is limited. In EPP, iron supplementation is discussed ambiguously and may cause harm in the majority of cases. This minireview summarizes the limited knowledge on the connections of iron metabolism to regulation of porphyrin and heme synthesis and the influence these regulations may have on disease severity in the protoporphyrias. Further, we propose clinical guidelines, how to manage iron deficiency in both XLEPP and EPP.

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Section: Ambivalent Experiences With Iron Substitutionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Iron in erythropoietic protoporphyrias: Dr. Jekyll or Mr. Hyde?

Barman-Aksoezen¹,

Schneider‐Yin²,

Minder³

2017

J Rare Dis Res Treat

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“…Iron deficiency and IDA are common in patients with EPP . In patients with XLP with iron deficiency, there is sufficient evidence that iron repletion improves photosensitivity and reduces Erc‐PPIX and even liver damage .…”

Section: Discussionmentioning

confidence: 99%

“…However, in most published reports, iron supplementation has been associated with increasing PPIX levels and worsening photosensitivity and liver function . Iron deficiency may, in fact, be protective in these patients, as ALAS2 expression is positively regulated by iron . The increased ALAS2 function following iron administration explains the increase in PPIX levels.…”

Section: Discussionmentioning

confidence: 99%

Management of Patients With Erythropoietic Protoporphyria–Related Progressive Liver Disease

et al. 2019

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Erythropoietic protoporphyria (EPP) is an inherited metabolic disorder of heme synthesis resulting from overproduction of protoporphyrin IX (PPIX), which can lead to progressive liver disease characterized by recurrent EPP crises and end‐stage liver disease. We used the Australian Transplant Registry to identify 5 patients referred for liver transplantation between 2008 and 2017. A total of 4 patients had EPP secondary to ferrochelatase deficiency, and 1 patient had X‐linked EPP. No patient had follow‐up with a specialist prior to the diagnosis of progressive liver disease. There were 3 patients who underwent orthotopic liver transplantation, whereas 2 died while on the transplant waiting list. Parenteral PPIX‐lowering therapy was used in 4 patients and was effective in 3 patients, although 2 of these had rebound porphyria and worsening liver function following a decrease in the intensity of therapy. Early disease recurrence in the allograft following transplantation occurred in 2 patients requiring red cell exchange (RCE) to successfully attain and maintain low PPIX levels, but RCE was associated with hemosiderosis in 1 patient. Allogeneic stem cell transplantation (AlloSCT) was performed in 2 patients. One failed engraftment twice, whereas the second rejected the first graft but achieved full donor chimerism with a second graft and increased immunosuppression. In conclusion, our observations suggest that progressive liver disease needs parenteral PPIX‐lowering treatment with the intensity adjusted to achieve a target Erc‐PPIX level. Because EPP liver disease is universally recurrent, AlloSCT should be considered in all patients with adequate immunosuppression to facilitate engraftment. RCE appears to be effective for recurrent EPP liver disease but is associated with an increased risk of iron overload.

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“…Interestingly, iron substitution can decrease protoporphyrin concentrations and improve symptoms in patients with XLP-sufficient iron as second substrate promotes conversion of toxic PPIX to heme by FECH. 127,128 In contrast, iron substitution can worsen EPP by stimulating the bone marrow enzyme ALAS2. 129 Moreover, mild iron deficiency might protect patients with EPP.…”

Section: Therapymentioning

confidence: 99%

Clinical Guide and Update on Porphyrias

Stölzel¹,

Doss²,

Schuppan³

2019

Gastroenterology

129

158

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Physicians should be aware of porphyrias, which could be responsible for unexplained gastrointestinal, neurologic, or skin disorders. Despite their relative rarity and complexity, most porphyrias can be easily defined and diagnosed. They are caused by well-characterized enzyme defects in the complex heme biosynthetic pathway and are divided into categories of acute vs non-acute or hepatic vs erythropoietic porphyrias. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and aminolevulinic acid dehydratase deficient porphyria) manifest in attacks and are characterized by overproduction of porphyrin precursors, producing often serious abdominal, psychiatric, neurologic, or cardiovascular symptoms. Patients with variegate porphyria and hereditary coproporphyria can present with skin photosensitivity. Diagnosis relies on measurement of increased urinary 5-aminolevulinic acid (in patients with aminolevulinic acid dehydratase deficient porphyria) or increased 5-aminolevulinic acid and porphobilinogen (in patients with other acute porphyrias). Management of attacks requires intensive care, strict avoidance of porphyrinogenic drugs and other precipitating factors, caloric support, and often heme therapy. The non-acute porphyrias are porphyria cutanea tarda, erythropoietic protoporphyria, X-linked protoporphyria, and the rare congenital erythropoietic porphyria. They lead to the accumulation of porphyrins that cause skin photosensitivity and occasionally severe liver damage. Secondary elevated urinary or blood porphyrins can occur in patients without porphyria, for example, in liver diseases, or iron deficiency. Increases in porphyrin precursors and porphyrins are also found in patients with lead intoxication. Patients with porphyria cutanea tarda benefit from iron depletion, hydroxychloroquine therapy, and, if applicable, elimination of the hepatitis C virus. An a-melanocytestimulating hormone analogue can reduce sunlight sensitivity in patients with erythropoietic protoporphyria or Xlinked protoporphyria. Strategies to address dysregulated or dysfunctional steps within the heme biosynthetic pathway are in development.

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Disturbed iron metabolism in erythropoietic protoporphyria and association of GDF15 and gender with disease severity

Cited by 23 publications

References 47 publications

Iron in erythropoietic protoporphyrias: Dr. Jekyll or Mr. Hyde?

Iron in erythropoietic protoporphyrias: Dr. Jekyll or Mr. Hyde?

Management of Patients With Erythropoietic Protoporphyria–Related Progressive Liver Disease

Clinical Guide and Update on Porphyrias

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