红细胞生成性原卟啉症(EPP)是一种超罕见的遗传性疾病,在成熟的成红细胞中原卟啉过度产生。这种过量的原卟啉导致在暴露于阳光的皮肤中失能光毒性灼伤。它的胆汁消除导致20%的胆汁淤积性肝损伤和4%的EPP患者的终末期肝衰竭。因此,肝损伤的风险随着红细胞原卟啉浓度的增加而增加。Afamelanotide,α-黑素细胞刺激激素(MSH)类似物诱导皮肤色素沉着,被证明可以提高EPP的耐日光性。除了这种众所周知的对色素沉着的影响,MSHs具有肝脏保护作用,提高成熟成红细胞的存活率,迄今仅在动物或体外模型中描述的效果。我们调查了EPP中的非美拉诺肽治疗是否对红细胞生成有影响,原卟啉浓度,和肝损伤通过回顾性分析我们的长期安全性数据。
自2006年以来在我们中心接受治疗的47名瑞士EPP患者中,我们将这38名患者纳入当前分析,这些患者在2016年至2018年间接受了至少一次阿非美拉诺肽剂量,并在治疗前和治疗期间接受了定期实验室检查。我们将预处理测量的方法与治疗期间的方法进行了比较。
■原卟啉浓度从治疗前的21.39±11.12(平均值±SD)下降到治疗期间的16.83±8.24µmol/L(p<.0001)。天冬氨酸转氨酶从26.67±13.16下降到22.9±7.76IU/L(p=.0146)。对于这两个实体,值较高的患者表现出更多的进行性下降,表明EPP相关肝病的风险降低。在afamelanotide下,预先存在的低血色素和广泛的平均红细胞分布宽度进一步增加。这更可能是由于阿非美拉诺肽对成熟成红细胞的影响,而不是由于铁缺乏加剧,平均锌-原卟啉显著下降,铁蛋白保持不变。在总共240个治疗年中,没有观察到严重的与阿非美拉诺肽相关的不良事件。
■我们的发现指出了阿非美拉诺肽对红细胞成熟和原卟啉诱导的肝损伤的保护作用。
■Afamelanotide,一种皮肤晒黑激素,不仅可以保护红细胞生成性原卟啉症患者免受皮肤灼伤,还有与疾病有关的肝损伤。红细胞生成性原卟啉症(EPP)患者,一种遗传性代谢疾病,光敏剂原卟啉积累引起的光致皮肤烧伤和肝损伤。过量的原卟啉是在骨髓的红细胞前体中产生的,它通过肝脏和胆汁从体内排出。高的原卟啉排泄负荷会损害肝细胞,这种风险随着原卟啉浓度的增加而增加。大约20%的EPP患者表现出一定的肝损伤迹象,4%的患者出现危及生命的肝功能障碍。Afamelanotide,与天然α-黑素细胞刺激素(MSH)密切相关,诱导皮肤晒黑。如先前研究中所示,这种作用保护EPP患者免受光诱导的皮肤灼伤。自2006年以来,我们一直使用阿非美拉诺肽治疗瑞士EPP患者,并定期进行这种治疗的安全性测试。最近的体外和动物研究表明,除皮肤晒黑外,α-MSH效应包括改善骨髓中红细胞前体的合成和保护肝脏免受实验诱导的损伤。直到现在,目前尚不清楚阿非美拉诺肽是否对人体有类似的作用。为了研究这个问题,我们回顾性分析了38例瑞士患者的安全性实验室数据,从2016年到2019年,他至少接受了一剂阿非美拉诺肽。我们发现两者,平均原卟啉浓度和天冬氨酸氨基转移酶,肝功能测试,与以前相比,在非美拉诺肽治疗期间有所改善。我们得出的结论是,将阿非美拉诺肽应用于EPP患者以保护他们免受光致皮肤灼伤也可以降低他们的肝损伤风险。
Erythropoietic protoporphyria (EPP) is an ultra-rare inherited disorder with overproduction of
protoporphyrin in maturating erythroblasts. This excess
protoporphyrin leads to incapacitating phototoxic burns in sunlight exposed skin. Its biliary elimination causes cholestatic liver injury in 20% and terminal liver failure in 4% of EPP patients. Thereby, the risk of liver injury increases with increasing erythrocyte
protoporphyrin concentrations. Afamelanotide, an α-melanocyte-stimulating hormone (MSH) analog inducing skin pigmentation, was shown to improve sunlight tolerance in EPP. Beyond this well-known effect on pigmentation, the MSHs have liver-protective effects and improve survival of maturating erythroblasts, effects described in animal or in vitro models to date only. We investigated whether afamelanotide treatment in EPP has effects on erythropoiesis,
protoporphyrin concentrations, and liver injury by analyzing retrospectively our long-term safety data.
UNASSIGNED: From the 47 Swiss EPP-patients treated at our center since 2006, we included those 38 patients in the current analysis who received at least one afamelanotide dose between 2016 and 2018 and underwent regular laboratory testing before and during the treatment. We compared the means of pretreatment measurements with those during the treatment.
UNASSIGNED: Protoporphyrin concentrations dropped from 21.39 ± 11.12 (mean ± SD) before afamelanotide to 16.83 ± 8.24 µmol/L (p < .0001) during treatment. Aspartate aminotransferase decreased from 26.67 ± 13.16 to 22.9 ± 7.76 IU/L (p = .0146). For both entities, patients with higher values showed a more progressive decrease, indicating a risk reduction of EPP-related liver disease. The pre-existing hypochromia and broad mean red-cell distribution width were further augmented under afamelanotide. This was more likely due to an influence of afamelanotide on maturating erythroblasts than due to an exacerbated iron deficiency, as mean zinc-protoporphyrin decreased significantly and ferritin remained unchanged. No serious afamelanotide-related adverse events were observed for a total of 240 treatment years.
UNASSIGNED: Our findings point to a protective effect of afamelanotide on erythroblast maturation and protoporphyrin-induced liver injury.
UNASSIGNED: Afamelanotide, a skin tanning hormone, may protect patients with erythropoietic protoporphyria not only from skin burns, but also from liver injury associated with the disease. Patients with erythropoietic protoporphyria (EPP), an inherited metabolic disease, suffer from light-induced skin burns and liver injury elicited by the accumulated light sensitizer protoporphyrin. The excess protoporphyrin is produced in red cell precursors in the bone marrow, and it is eliminated from the body via the liver and bile. A high protoporphyrin excretion burden damages the liver cells, the risk for this increases with higher
protoporphyrin concentrations. About 20% of EPP patients show some sign of liver injury and 4% develop life-threatening liver dysfunction.Afamelanotide, closely related to natural α-melanocyte stimulating hormone (MSH), induces skin tanning. This effect protects EPP patients from light-induced skin burns as shown in previous studies. We have treated Swiss EPP patients with afamelanotide since 2006, and we regularly perform safety tests of this treatment.Recent in vitro and animal studies demonstrated α-MSH effects other than skin tanning, including an improved synthesis of red blood cell precursors in the bone-marrow and protection of the liver from experimentally induced damage. Until now, it is unknown whether afamelanotide has similar effects in the human organism.To study this question, we analyzed retrospectively the safety laboratory data of 38 Swiss patients, who received at least one dose of afamelanotide from 2016 to 2019. We found that both, the average protoporphyrin concentrations and aspartate aminotransferase, a test for liver function, improved during afamelanotide treatment as compared to before.We concluded that afamelanotide applied to EPP patients to protect them from light-induced skin burns also may reduce their risk of liver injury.