Impairments in Blood Vessels Linked to More Severe Porphyria Symptoms
Impairments in endothelial cells — those that line blood vessels — are more likely to be found in people with severe acute hepatic porphyria who have active symptoms than among those without signs of the disease, a study revealed.
Abnormal levels of biomarkers that reflect endothelial cell impairment also were tied to elevated blood pressure and higher levels of porphyrin precursors.
“We demonstrated that endothelial dysfunction is significantly more common and severe in symptomatic patients with AHPs [acute hepatic porphyrias] … than in asymptomatic” individuals, the researchers wrote.
The team suggested that some still undefined disease-related factors might contribute to the clinical picture of the condition through endothelial function.
The study, “Endothelial Dysfunction in Acute Hepatic Porphyrias,” was published in the journal Diagnostics.
Porphyrias are a group of disorders caused by mutations in the genes that encode enzymes needed to produce heme — a molecule that helps transport oxygen throughout the body. Defects in these enzymes lead to the toxic buildup of heme precursor molecules called porphyrins. Hepatic porphyria occurs when defective enzymes are in the liver; such acute porphyrias can lead to both neurological and non-neurological symptoms.
Acute porphyrias mainly affect the nervous system, with symptoms emerging suddenly and lasting from a few days to weeks before subsiding. Hypertension, or high blood pressure, is relatively frequent and often severe during acute porphyria attacks.
Studies suggest that heme metabolism is involved in the function of endothelial cells, and that the buildup of heme precursor molecules can damage these cells.
Nitric oxide (NO) and endothelin-1 (ET-1) are two established bloodstream biomarkers that reflect endothelial function. NO is a molecule that stimulates blood vessel widening, acting as a vasodilator, whereas ET-1 restricts blood vessel width, as a vasoconstrictor.
An imbalance between NO levels — when these are lower than normal — and higher-than-normal ET-1 is associated with compromised endothelial cell function. Moreover, studies in animal models suggest impaired responses to blood vessel widening and constriction may underlie hypertension in acute porphyria attacks.
Given the potential role of endothelial damage causing vascular problems in acute porphyrias, researchers at the University of Modena and Reggio Emilia, in Italy, investigated the presence of endothelial dysfunction in acute porphyria patients.
The team recruited 46 people, ages 8–72, with a genetically confirmed diagnosis of acute porphyria. Among them, 31 had acute intermittent porphyria (AIP), while 15 had been diagnosed with variegate porphyria (VP). Eighteen patients were symptomatic, 10 were asymptomatic with abnormal biochemistry tests, and 18 were asymptomatic without abnormal biochemistry.
Those with active symptoms had significantly higher levels of total porphyrin in their urine samples, as well as elevated aminolevulinic acid (ALA) and porphobilinogen (PBG), two heme precursors. These individuals experienced more frequent arterial hypertension, kidney impairment, and blood clotting events.
Eight participants had arterial hypertension and were being treated with antihypertensive therapy. These individuals had significantly higher levels of ET-1 in the blood compared with those without hypertension (6.05 vs. 4.13 picograms per milliliter, pg/mL). They also had lower levels of NO (20.97 vs. 27.6 micromoles per liter, mcm/L).
NO levels were significantly lower in symptomatic patients compared with asymptomatic carriers and asymptomatic patients with biochemical abnormalities. In contrast, symptomatic participants had the highest ET-1 levels across all three groups and abnormal levels of ET-1 and NO more frequently. The team found no differences in ET-1 or NO levels between AIP and VP patients.
As expected, low NO and high ET-1 levels were significantly related. Although there was no correlation between ALA and PBG with NO or ET-1 in urine samples, those with the most elevated levels of heme precursors had higher ET-1 and lower NO levels.
The 14 individuals on maintenance therapy, either with hemin infusion, sold as Panhematin, or glucose, had significantly higher ET-1 and lower NO levels, with those on hemin having the most abnormal values. Even when hemin-treatment patients were excluded from the analysis, ET-1 and NO levels were significantly altered in those with symptoms compared with those with no signs.
Researchers wrote that “endothelial dysfunction is significantly more common and severe in symptomatic patients with [acute hepatic porphyrias] than in asymptomatic carriers of mutations associated with [acute hepatic porphyrias] or even in asymptomatic patients with biochemical alterations in heme precursors alone.”
“The values of NO and ET-1 were significantly different between asymptomatic and symptomatic patients,” they wrote. “[These] findings help to shed light on the [development] of the protean manifestations of [acute hepatic porphyrias].”