Endothelial Dysfunction in Acute Hepatic Porphyrias

Abstract

Background Acute hepatic porphyrias (AHPs) are a group of rare diseases caused by dysfunctions in the pathway of heme biosynthesis. Although acute neurovisceral attacks are the most dramatic manifestations, patients are at risk of developing long-term complications, several of which are of a vascular nature. The accumulation of non-porphyrin heme precursors is deemed to cause most clinical symptoms. Aim We measured the serum levels of endothelin-1 (ET-1) and nitric oxide (NO) to assess the presence of endothelial dysfunction (ED) in patients with AHPs. Forty-six patients were classified, according to their clinical phenotype, as symptomatic (AP-SP), asymptomatic with biochemical alterations (AP-BA), and asymptomatic without biochemical alterations (AP-AC). Results Even excluding those under hemin treatment, AP-SP patients had the lowest NO and highest ET-1 levels, whereas no significant differences were found between AP-BA and AP-AC patients. AP-SP patients had significantly more often abnormal levels of ED markers. Patients with the highest heme precursor urinary levels had the greatest alterations in ED markers, although no significant correlation was detected. Conclusions ED is more closely related to the clinical phenotype of AHPs than to their classical biochemical alterations. Some still undefined disease modifiers may possibly determine the clinical picture of AHPs through an effect on endothelial functions.

Maternal and fetal outcomes in acute hepatic porphyria: A Swedish National Cohort Study

“…In the present study, we observed an increased risk of pregnancy‐induced hypertensive disorder in women with AHP, which is consistent with some previous reports 38,39 . Underlying mechanisms in terms of endothelial dysfunction have been suggested 40 . One previous Norwegian register‐based cohort study, 30 did not observe a clear correlation between AHP and pregnancy‐induced hypertensive disorder.…”

“…38,39 Underlying mechanisms in terms of endothelial dysfunction have been suggested. 40 One previous Norwegian register-based cohort study, 30 did not observe a clear correlation between AHP and pregnancyinduced hypertensive disorder. Our observations are based on a larger group of women with AHP (214 vs. 90) during a more recent period (1987-2015 vs. 1967-2006) with a more updated diagnostic classification system.…”

“…The higher prevalence of SGA infants in the women with AHP may partly be explained by placental insufficiency which commonly accompanies pregnancyinduced hypertensive disorder. Another pathogenetic mechanism could be a potential vasoconstrictive effect of heme precursors, particularly ALA, on placental vessels, 17,40 which are small molecules that can pass the placenta barrier, a hypothesis which remains to be investigated.…”

Pathogenesis of acute encephalopathy in acute hepatic porphyria

“…Mild haem protein deficiency during an attack has been demonstrated in the liver [ 15 , 19 ]. Significant alteration of NO level in addition to endothelin-1, has been demonstrated in symptomatic AHP patients, but the origin of this alteration is unclear [ 53 ]. The deficiency of haem-containing endothelial nitric oxide synthase (NOS) 1 in the brain has been assumed to be responsible for NO deficiency and cerebral vasoconstriction [ 54 ].…”

Pain in acute hepatic porphyrias: Updates on pathophysiology and management

“…Chronic peripheral sensitization reflects functional up-regulation of some sodium channels including Na v1.7, Na v1.8, and Na v1.9 on the free nerve endings. This could be elicited by proinflammatory mediators from the liver that are significantly elevated in AIP patients with recurrent attacks ( 58 , 59 ). Some mediators potentially induce glutamate-mediated activation of N-methyl D-aspartate receptors.…”