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.

Keywords: acute hepatic porphyrias; chronic kidney disease; endothelial dysfunction; endothelin; heme; hypertension; nitric oxide; porphyria; rare diseases; δ-aminolevulinic acid.

Figure 1

Serum levels of nitric oxide (a) and endothelin-1 (b) according to AHP phenotype.

Figure 2

Number of patients with altered markers of endothelial function according to AHP phenotype. Having an alteration of NO or ET-1 was significantly more frequent in the AP-SP group (symptomatic patients).

Figure 3

Serum levels of ET-1 and NO according to AHP type.

Figure 4

Correlation between serum NO and ET-1 levels. Data points are means of at least six seriate measurements.

Figure 5

Serum levels of ET-1 and NO according to the increase of non-porphyrin heme precursors in urines. ULN, upper level of normal.

Figure 6

Serum levels of ET-1 and NO in patients with and without maintenance therapy.

Figure 7

Serum levels of NO and ET-1 according to AHP phenotype and maintenance therapy. Within symptomatic patients, those on maintenance therapy with hemin had significantly lower NO and higher ET-1 levels. Notably, ET-1 and NO levels were significantly altered in symptomatic patients, compared to the asymptomatic, even when AP-SP under hemin maintenance therapy were excluded. For each comparison, p values are reported over the comparison line; ns, not significant.

Figure 8

Change in NO and ET-1 levels in two couples of patients after two consecutive days of either 10% glucose or hemin infusions. Data points are each mean of two patients.

Figure 9

Other than its role as an oxygen carrier in hemoglobin, heme is an essential cofactor in several processes of the intermediate metabolism. As a consequence of an enzyme impairment in the pathway of heme biosynthesis, $\delta$-aminolevulinic acid and porphobilinogen accumulate: $\delta$-aminolevulinic acid, in particular, self-reacts in the presence of iron, to yield ROS and dioxovaleric acid, a highly reactive oxidant. This is deemed one of the main mechanisms which cause tissue damage in acute porphyrias. Nitric oxide synthases, tryptophan 2,3-dioxygenase, cystathionine $\beta$-synthase, and soluble guanylate cyclases are all hemeproteins. Nitric oxide inhibits endothelin-1 expression at a translational level; additionally, cyclic guanosine monophoshate has inhibitory effects on the signaling pathway which starts from endothelin receptors. Nitric oxide synthases require tetrahydrobiopterin (BH₄) as a cofactor. In conditions of BH₄ deficiency, “uncoupled” reactions may yield peroxynitrite, a highly reactive oxidant and nitrating species (to which cystathionine $\beta$-synthase, the first enzyme in the trans-sulfuration pathway of homocysteine, may be particularly sensitive [70]). ALAD, $\delta$-aminolevulinic acid dehydratase; ALAS, $\delta$-aminolevulinic acid synthase; CBS, cystathionine $\beta$-synthase; cGMP, cyclic guanosine monophoshate; CPOX, coproporphyrinogen oxidase; Fe, iron atom; FECH, ferrochelatase; GTP, guanosine triphosphate; HMBS, hydroxymethylbilane synthase; NOS, nitric oxide synthase; PLP, pyridoxal phosphate; ppET-1, preproendothelin-1; PPOX, protoporphyrinogen oxidase; ROS, reactive oxygen species; TDO, tryptophan 2,3-dioxygenase, UROD, uroporphyrinogen decarboxylase; UROS, uroporphyrinogen synthase; Created with BioRender.com (accessed on 12 May 2022).