Therapy Follows Diagnosis: Old and New Approaches for the Treatment of Acute Porphyrias, What We Know and What We Should Know

Abstract

Heme, iron protoporphyrin IX, is one of life’s most central molecules. Hence, availability of the enzymatic machinery necessary for its synthesis is crucial for every cell. Consequently, inborn errors of porphyrin metabolism that compromise normal synthesis, namely the family of porphyrias, undermine normal cellular metabolism given that heme has functions in catalytic centers, signal transduction and functional regulation and its synthesis is fully integrated into the center of intermediary metabolism. Very often, diagnosis of porphyrias is difficult and therefore delayed. Therapy can be as complicated. Over the last 50 years, several strategies have been developed: because of its integration with other parts of intermediary metabolism, the infusion of glucose (glucose effect) was one of the first attempts to counterbalance the dysregulation of porphyrin synthesis in porphyrias. Since heme synthesis is impaired, infusional replacement of heme was the next important therapeutic step. Recently, siRNA technology has been introduced in order to downregulate 5-ALA-synthase 1, which contributes to the patho-physiology of these diseases. Moreover, other novel therapies using enzyme protein replacement, mRNA techniques or proteostasis regulators are being developed.

An Overview of Acute Hepatic Porphyrias: Clinical Implications, Diagnostic Approaches, and Management Strategies

“…The final step of heme biosynthesis pathway is catalyzed by ferrochelatase that is responsible for the insertion of ferrous iron (Fe2+) into protoporphyrin IX resulting in heme production. 5 , 6 …”

“…Plasma sodium levels should be checked closely during high glucose infusions as it can precipitate hyponatremia. 5 …”

“…Hemin (Panhematin®) was approved in the US in 1983, heme arginate (Normosang®) in 2006 in the European Union, and both drugs have been accepted as the standard first-line treatment of an acute neurovisceral attack. 5 Similar to glucose loading, hemin/heme acts also as a hepatic ALAS1 transcription downregulator. However, they are more effective in replenishing heme pool when compared to glucose.…”

Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment

“…Despite all of this, the relationship between porphyrin precursor levels and prodrome symptoms is still unclear. Different authors have also pointed out that in porphyria, elevation of ALA may be necessary but not sufficient for the development of an acute attack [21], since ALA administration in a male volunteer [22] and in mice [23] did not produce acute symptoms. In fact, a large urinary loss of liver succinyl-CoA and glycine (used for the production of ALA and PBG) during the acute porphyria attack supports the hypothesis of a profound, although reversible, impact of acute attack on mitochondrial energy metabolism [24].…”

Hematin- and Hemin-Induced Spherization and Hemolysis of Human Erythrocytes Are Independent of Extracellular Calcium Concentration

“…At the same time, hemin supplements have been established as the standard of care for the treatment of acute attacks of porphyria. Thus, Panhematin (hemin black powder) and Normosang (complex of hemin, arginine, and ethanol) are effectively used in clinical practice [ 20 ]. However, such treatment is associated with hemostasis-affecting side effects, which include phlebitis and coagulopathies characterized by thrombocytopenia [ 21 ].…”