Management of hyponatremia associated with acute porphyria-proposal for the use of tolvaptan

Abstract

Hyponatremia is a common feature during the neurovisceral acute attacks which characterize hepatic porphyrias, as well as a sign of its severity. Therapeutic options for first-line acute attacks are intravenous administration of glucose and/or exogenous heme. The former treatment can aggravate hyponatremia by dilution and cause seizures; thus, the correction of hyponatremia must be carried out with extreme caution. This review summarizes recommendations for the management of hyponatremia during acute episodes of porphyria. Hyponatremia should be corrected slowly and seizures treated with medications in order to not exacerbate motor and sensory axonal neuropathy. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is considered a frequent cause of hyponatremia in acute porphyrias and must be identified as a symptom of an acute porphyria attack. Tolvaptan produces aquaresis and is considered a safe drug in porphyria. However, its use has only been reported in isolated cases during a porphyria attack. The convenience and usefulness of this drug in acute porphyria are discussed.

Keywords: Acute hepatic porphyrias; hyponatremia; management; syndrome of inappropriate antidiuretic hormone secretion (SIADH); tolvaptan.

Figure 1

Enzymes and intermediate products of the heme synthesis pathway. Heme synthesis is an important metabolic pathway present in all nucleated cells of the body where its final product is the cofactor of essential hemoproteins involved in biological functions: oxygen binding and transport (myoglobin and hemoglobin), electron transport (cytochromes of the mitochondrial respiratory chain), catalytic decomposition of hydrogen peroxide (peroxidases and catalases), synthesis of steroid hormones and oxidative metabolism of exogenous and endogenous compounds (mitochondrial and microsomal cytochromes of the P450 complex), tryptophan degradation (tryptophan pyrrolase) and nitric oxide synthesis (nitric oxide synthetase). Heme is also essential as substrate for heme oxygenase (HO) to yield carbon monoxide (CO) and biliverdin, which is subsequently reduced to bilirubin by cytosolic biliverdin reductase. CO is a strong vasodilatory, anti-inflammatory and immunomodulatory agent and both biliverdin and bilirubin are efficient scavengers of reactive oxygen species thus reducing the formation of peroxidation products. About 80% of daily heme synthesis occurs in the erythropoietic lineage and hepatocytes synthesize about 15% of total daily body heme. A delicate regulation of the route is essential because both heme and its intermediate metabolites are toxic at high concentrations. The ALA-synthetase (ALAS) is the first enzyme and rate-limiting reaction in heme synthesis. It has two isoenzymes, one ubiquitous (ALAS1) and the other erythroid (ALAS2). Heme regulates ALAS1 by a negative feedback mechanism, its translocation to the mitochondria and degradation. ALAS2 is characterized by high steady state level and is tied to availability of iron. In addition, the first four enzymes have specific erythroid and housekeeping promoters. Finally, the pathway is highly compartmentalized, the first and the final three steps are catalyzed by proteins that reside in the mitochondria while the remaining four steps are catalyzed in the cytosol. Each porphyria is caused by a loss or gain function of one of the enzymes involved in the pathway leading to overproduction and accumulation of porphyrins and/or their precursors. Accumulation of early pathway intermediates (ALA and PBG) leads to neurologic symptoms. These simple molecules are exclusively eliminated by urine. Four monopyrrol PBG are cyclized to form a porphyrinogen molecule. Oxidation of these tetrapyrrole rings lacking metal, leads to the fluorescence responsible for the phototoxic effects primarily affecting the skin. Porphyrinogen excretion (and its corresponding oxidized molecule, the porphyrin) is conditioned by their water solubility. While octacarbonyl URO is water-soluble, dicarboxylic PROTO is hydrophobic and is removed by biliary excretion and through the feces. The tetracarboxylic COPRO is preferably eliminated by bile but also by urine. White boxes represent the intermediate products: ALA, δ-aminolaevulinic acid; PBG, porphobilinogen (also known as Hydroxymethylbilane, HMB); UROgen, uroporphyrinogen; COPROgen, coproporphyrinogen; PROTOgen, protoporphyrinogen. Red boxes are porphyrins, resulting from the oxidation of the corresponding porphyrinogens: URO, uroporphyrin; COPRO, coproporphyrin; PROTO, protoporphyrin. Yellow boxes are enzymes: ALA-S, Amino-aminolaevulinic synthase; ALA-D, Aminolaevulinic acid dehydratase; PBGD, Porphobilinogen deaminase (also known as Hydroxymethylbilane Synthase, HMBS); UROS, Uroporphyrinogen III synthase; UROD, Uroporphyrinogen Decarboxylase; COPROX, Coproporphyrinogen Oxidase, PROTOX, Protoporphyrinogen Oxidase; FECH, ferrochelatase.

Figure 2

Schematic representation of the secretion of ADH by the supraoptic and paraventricular nucleus. The supraoptic nucleus and the magnocellular portion of the paraventricular nucleus, whose axons constitutes the stem of the pituitary gland, discharge ADH into the neurohypophysis in response to elevations in the plasma osmolarity (Osmoregulation). Paraventricular nucleus responds with simultaneous secretion of ADH to the third ventricle in response to pain, stress, cough, nausea and in response to mechanical stimuli in the diaphragm. The floor of the third ventricle has angiotensin II receptors that justify the secretion of ADH in situations of hypovolemia greater than 10% (“Baroregulation”). ADH, antidiuretic hormone; AT II, angiotensin II.