Manfred O. Doss1, Ulrich Groß1, Thomas Stauch2

1Clinical Biochemistry - Consultation Porphyria, Marburg an der Lahn, 2Laboratory Prof. Seelig and Colleagues, Karlsruhe, Germany

Starting porphyria research in1965 with in vitro and in vivo systems,  an investigative diagnostic laboratory was established with a scientific and consiliary approach.

Acute versus non-acute hepatic porphyrias: In a forty-year period 840 patients with acute hepatic porphyrias were diagnosed (female:male ~ 2:1): AIP > variegate porphyria > hereditary coproporphyria > doss porphyria (compound heterozygous); relation 81 : 12 : 7 : 0.3. In ~5% of AIP cases RBC PBG deaminase activity was normal reflecting a subtype with normal PBG deaminase gene in erythrocytes. Primary liver tumor was found in 5 patients with acute hepatic porphyrias.

Only the metabolite excess reflects the pathobiochemical disease process and clinical expression of an acute or non-acute porphyria. The severity of clinical symptoms correlates with the dimension of metabolic aberration. Both for acute and non-acute porphyrias a phase concept was established, recognizing the stage of the subclinical and clinical disease process. Regulatory treatment of the acute hepatic porphyria syndrome by glucose and/or heme was highly effective, but fails in patients with persistent pareses. The background of this complicated courses was belated diagnosis in most cases. Latent phases and ovulocyclic forms were stabilized by intervall therapy with heme arginate.

60 cases of severe acute and chronic lead intoxication were detected. Most of them reached us primarily misdiagnosed as AIP or HCP due to a similar acute clinical syndrome.

PCT or chronic hepatic porphyria associated with liver injury was observed two times more than acute hepatic porphyrias. Acute porphyrias are induced by cumulatively acting manifestation factors as drugs, fasting, sex hormones, whereas PCT is triggered by alcohol, estrogens, iron and hepatitis virus infection. Homozygous PCT as hepatoerythropoietic porphyria was observed in three males.

Erythropoietic porphyrias: A quarter of patients with protopophyria develop hepatobiliary liver involvement ranging from mild to severe cholestatic liver disease as studied from 170 cases in the forty year period. About 10% of the patients developed protoporphyrin-induced cholestatic liver cirrhosis with excessive protoporphyrinemia, isomer I-coproporphyrinuria and decrease of fecal protoporhyrin. 11 patients underwent liver transplantation between 1987 and 2002. According to protoporphyria also in congenital erythropoetic porphyria (Günther’s disease: 30 cases) an interdependence between degree of porphyrin excess and disease severity has been elucidated. Two children with Günther`s disease were treated succesfully by bone marrow transplantation.

Dual porphyrias: Four types of dual porphyrias with the coexistence of two different enzyme deficiencies in one patient were investigated. Family studies have shown that they do not segregate together. Three dual forms were described first: AIP and PCT, CEP and HCP as well as PCT and HCP.

Porphyrinurias: Coproporphyrin isomer studies are important for the early diagnosis of the hepatobiliary involvement in protoporphyria, for the recognition of gene carriers of VP and HCP, and for the characteriziation of hereditary hyperbilirubinurias.

Secondary coproporphyrinurias were observed four times more than acute porphyrias. They lack clinical significance, but represent the most frequent diagnostic pitfall suggesting porphyria.

Molecular genetics: Molecular genetic analyses  of the genes from all enzymes of the heme biosynthetic chain were carried out. The aims were ensuring the diagnosis, family studies, detection of compound heterozygosity, investigation of  AIP family members with normal RBC PBG deaminase or normal metabolite excretion and analysing the mutations of the genes from the mitochondrial enzymes in HCP, VP and protoporphyria. Molecular heterogeneity is evident in all types of porphyrias.

Conclusion: A competence center for porphyria investigation and consultation should be responsible for elaborationg and ensuring the diagnosis porphyria as well as  for therapeutic management. (www.porphyria.com).