Researchers from Cima Universidad de Navarra and Hospital Universitario 12 de Octubre de Madrid, members of group Español para el Estudio de las Porfirias (GEEP), have identified new mechanisms involved in the development of acute porphyria.

Acute porphyria is a rare disease Genetics of hepatic origin that affects approximately 5 out of every 100,000 inhabitants. It manifests as acute crises, with abdominal pain, nausea, constipation, tachycardia, anxiety and depression. 

"The concentration leave of sodium (or hyponatremia) is a marker of poor prognosis in acute porphyria crises. These patients suffer from syndrome of inadequate ADH antidiuretic hormone secretion (siADH), which decreases the concentration of sodium in the blood by dilution, aggravating the neurological symptoms (seizures, disorientation and low level of consciousness)," says Prof. Rafael Enriquez de Salamanca, from high school of research of the Hospital 12 de Octubre i+12 in Madrid. This syndrome, of multifactorial etiology, is partly dependent on the accumulation of heme precursors that characterizes the acute attack of porphyria.

The water restriction required in siADH is not a therapeutic option in these patients, and the salt overload required for correction of hyponatremia may cause pulmonary congestion and hypoxemia. "In addition, intravenous administration of high doses of glucose saline, required in a porphyria crisis, may overcome the dilutional capacity of the kidney. The result would be the exacerbation of hyponatremia," says Dr. Isabel Solares, of the Hospital 12 de Octubre i+12 in Madrid.

In the article published in Annals of Translational Medicinethe authors recommend the use of Tolvaptan, (an ADH antagonist) considered safe for porphyria, which produces a renal elimination of water without modifying sodium salts producing a slow but sustained correction of the concentration of salts in the blood. "Once adrenal and thyroid insufficiency has been ruled out in the patient, Tolvaptan should be administered following strict criteria of urinary osmolarity (>100 mOsm/kg), urinary sodium (> 40 mEq/l) and confirmation of hyponatremia after correcting plasma sodium figures for glucose, protein or lipid levels" comments Dr. Monserrat Morales-Conejo, from the CSUR of Inborn Errors of Metabolism in Madrid. Tolvaptan can be fail when plasma sodium reaches safe levels (between 132 and 140 mmol/L). Acute porphyria attacks usually last 5 to 7 days and persistence of symptomatic hyponatremia beyond the crisis is unusual.

Blood vessel dysfunction

Arterial hypertension is a symptom present in a majority of patients with active acute porphyria. In their joint work , the Spanish researchers describe cerebral blood flow changes in human porphyria that were confirmed in a clinically relevant mouse model for the disease. "Our programs of study suggest that, during an acute attack of porphyria, small vessel dysfunction in association with systemic arterial hypertension can cause a decrease in cerebral blood flow, and small changes in brain structure if this status is maintained over time," states Dr. Antonio Fontanellas, from the Hepatology Program at Cima University of Navarra. This is one of the conclusions published in the scientific journal Human Molecular Genetics.

Furthermore, this experimental work reveals that liver-targeted gene therapy restores cerebral perfusion and provides protection against cerebral ventricular enlargement in mice. "These findings advance the understanding of acute hepatic porphyrias and confirm the role of the liver in central nervous system dysfunctions associated with these inherited metabolic diseases" comments Dr. Matías A. Ávila director of the Hepatology program at Cima University of Navarra.

The current lack of knowledge on the nature and mechanisms of the alterations affecting the central nervous system in this rare disease limits its therapeutic management. The difficulty in the fluid balance of patients with acute porphyria is that it coincides with the need for large amounts of volume in the form of glucose saline or hemin administered intravenously, for the treatment of a patient already hypertensive due to the stimulation of the autonomic nervous system during acute crises. Hyponatremia corrected by the administration of more volume, in this case hypertonic (3% NaCl), will have a hemodynamic impact on the patient. Hypertension and electrolyte imbalances, and especially hyponatremia, should be corrected and controlled during acute episodes of porphyria. The authors address the use of Tolvaptan during these crises associated with moderate-severe hyponatremias, under the strict conditions previously specified.

These two studies highlight the particularity of patients with acute porphyria and emphasize the need for personalized and precision medicine. "Today more than ever, it is necessary to continue working and betting on science to increase the knowledge not only of pandemics that threaten the global population, but also of rare diseases. Important medical journals report the neglect of patients with diseases not related to COVID-19. With optimism, it is important to stress the importance of continuing research and collaboration between related groups to increase the knowledge in all areas of science," the researchers point out.

• reference letter bibliography:
  -Management of hyponatremia associated with acute porphyria-proposal for the use of tolvaptan.
  Annals of Translational Medicine. 2020 Sep;8(17):1098.
  -Brainventricular enlargement in human and murine acute intermittent porphyria.
  Human Molecular Genetics. 2020 Nov 25;29(19):3211-3223.