Freesemann A G, Bhutani L K, Jacob K, Doss M O
Division of Clinical Biochemistry, Faculty of Medicine, Philipps University, Marburg, Germany.
Arch Dermatol Res. 1997 Apr;289(5):272-6. doi: 10.1007/s004030050192.
Various clinical and biochemical observations point to a relationship between degree of disease expression and metabolic disturbance in autosomal recessive congenital erythropoietic porphyria (Günther's disease). Although the clinical manifestations have been well described since Günther's fundamental observations, an interdependence between disease severity and porphyrin excess has yet to be elucidated. We investigated porphyrin metabolism in nine Indian patients suffering from the characteristic clinical symptoms: skin photosensitivity, red-colored urine as a sign of extremely elevated porphyrinuria and mild to severe hemolytic anemia. Porphyrins in urine, feces and blood were analysed by HPTLC and HPLC in conjunction with spectrophotometry and spectrofluorometry. Uroporphyrinogen III synthase activities in red blood cells were determined using a coupled-enzyme assay. Biochemical studies revealed varying degrees of porphyrinuria with total urinary porphyrins between 23 and 102 mumol/24 h (normal < 0.2 mumol/24 h) and uroporphyrin predominance. Urinary and fecal coproporphyrin isomer I were markedly elevated to 87-97% and 81-93% (normal < 31%, < 75%), respectively. Overproduction of porphyrins led to a considerable porphyrinemia with mainly copro- and protoporphyrin. A hitherto undescribed fecal porphyrin pattern with increased protoporphyrin levels was found in three patients. This atypical finding was probably related to severe hemolysis since protoporphyrin can be excreted only via the liver with bile in the feces. High porphyrin levels in urine, feces and blood were associated with worse cutaneous symptoms. Activities of uroporphyrinogen III synthase in red blood cell lysates were decreased to between 9% and 30% of controls. Patients showed increased porphobilinogen deaminase activities, up to 190% of control. Deficiency of uroporphyrinogen III synthase activity was reflected by inversion of the relationship between and isomer III leading to dominance of isomer I. Elevation of porphobilinogen deaminase activities is related to hemolysis and, additionally, to regulatory compensation for the enzyme deficiency. Variations in both the severity of photosensitivity and the enhancement of porphyrin production and excretion indicate the molecular heterogeneity of this disease. These findings suggest a close relationship between the metabolic disturbance reflected by porphyrin excess and the severity of disease expression.
多项临床和生化观察结果表明，常染色体隐性先天性红细胞生成性卟啉病（冈瑟氏病）的疾病表达程度与代谢紊乱之间存在关联。尽管自冈瑟氏的基础性观察以来，临床表现已得到充分描述，但疾病严重程度与卟啉过量之间的相互依存关系仍有待阐明。我们对9名患有典型临床症状的印度患者的卟啉代谢进行了研究，这些症状包括皮肤光敏性、红色尿液（卟啉尿极度升高的迹象）以及轻度至重度溶血性贫血。通过高效薄层层析法（HPTLC）和高效液相色谱法（HPLC）结合分光光度法和荧光分光光度法对尿液、粪便和血液中的卟啉进行分析。使用偶联酶测定法测定红细胞中尿卟啉原III合酶的活性。生化研究显示卟啉尿程度各异，总尿卟啉为23至102 μmol/24小时（正常<0.2 μmol/24小时），且以尿卟啉为主。尿液和粪便中的粪卟啉异构体I显著升高，分别达87 - 97%和81 - 93%（正常<31%，<75%）。卟啉过度生成导致相当程度的卟啉血症，主要为粪卟啉和原卟啉。在3名患者中发现了一种此前未描述过的粪便卟啉模式，原卟啉水平升高。这一非典型发现可能与严重溶血有关，因为原卟啉只能通过肝脏随胆汁排泄到粪便中。尿液、粪便和血液中高水平的卟啉与更严重的皮肤症状相关。红细胞裂解物中尿卟啉原III合酶的活性降至对照组的9%至30%。患者的胆色素原脱氨酶活性增加，高达对照组的190%。尿卟啉原III合酶活性的缺乏表现为异构体III与异构体I之间关系的倒置，导致异构体I占主导。胆色素原脱氨酶活性的升高与溶血有关，此外还与对酶缺乏的调节性补偿有关。光敏性严重程度以及卟啉生成和排泄增强的变化表明该疾病存在分子异质性。这些发现提示卟啉过量所反映的代谢紊乱与疾病表达的严重程度之间存在密切关系。
