Acute intermittent porphyria: focus on possible mechanisms of acute and chronic manifestations

Abstract

acute intermittent porphyria, mechanisms, aminolevulinic acid (ALA), attack Porphyrias are a group of inherited metabolic diseases that include eight types, each of which is caused by a mutation that affects an enzyme of the heme biosynthetic pathway. When an enzyme defect has physiological significance, it leads to overproduction of pathway precursors prior to the defective step. The partial absence of the third enzyme in the heme biosynthetic pathway, porphobilinogen deaminase (PBGD) also known as hydroxymethylbilane synthase (HMBS), results in acute intermittent porphyria (AIP), which affects mainly women. Subjects who had AIP symptoms were deemed to have manifest AIP (MAIP). Clinical manifestations are usually diverse and non-specific. Acute AIP episodes may present with abdominal pain, nausea, and vomiting, and repeated episodes may result in a series of chronic injuries. Therefore, studying the mechanisms of acute and chronic manifestations of AIP is of great significance. This review aims to summarize the possible mechanisms of acute and chronic manifestations in patients with AIP.

Clinical-Pathological Conference Series from the Medical University of Graz

“…As in the discussed patient, abdominal complaints in acute intermittent porphyria further frequently include constipation and abdominal distention [6]. Clinical features associated with adverse effects of porphyrins on the central nervous system include seizures, SIADH and porphyria-induced posterior reversible encephalopathy syndrome (PRES) [6]. Mechanistically, neurotoxic [41,42] but also vasoconstrictive [6,43] effects of delta-aminolevulinic acid are discussed.…”

“…Patients with acute intermittent porphyria present with various clinical symptoms affecting the autonomic, central and peripheral nervous system. Manifest or overt acute intermittent porphyria is considered when patients develop typical acute neurovisceral attacks, neurologic symptoms such as peripheral neuropathy but also SIADH (hyponatremia) and psychiatric disturbances including hallucinations [6,7,29]. More than 80% of patients present with pseudoacute abdomen which usually lasts hours or days, does not respond well to analgesics and is often disproportional to the findings on physical examination [30].…”

“…Besides acute intermittent porphyria, they include some infectious diseases such as typhoid fever, leptospirosis, malaria or hantavirus infection, and a variety of specific clinical states such as diabetic ketoacidosis due to possible irritation of the peritoneal pain receptors by osmotic mechanisms or by acid-base disturbance [32], sickle cell crisis with impaired capillary and subsequent organ perfusion caused by vascular occlusion [33], mucosal swelling in angioedema [34,35], acute glaucoma which triggers a direct oculoabdominal reflex involving the trigeminal nerve and the vagal visceral motor and visceral sensory branches [36], chronic lead poisoning causing negative effects on intestinal motility [37], the intestinal neural web or smooth muscles mediated by lead or increased levels of deltaaminolevulinic acid [38,39], and spontaneous bacterial peritonitis [40]. As in the discussed patient, abdominal complaints in acute intermittent porphyria further frequently include constipation and abdominal distention [6]. Clinical features associated with adverse effects of porphyrins on the central nervous system include seizures, SIADH and porphyria-induced posterior reversible encephalopathy syndrome (PRES) [6].…”

“…Clinical features associated with adverse effects of porphyrins on the central nervous system include seizures, SIADH and porphyria-induced posterior reversible encephalopathy syndrome (PRES) [6]. Mechanistically, neurotoxic [41,42] but also vasoconstrictive [6,43] effects of delta-aminolevulinic acid are discussed. Due to its structural similarity to gamma-aminobutyric acid (GABA), accumulation of delta-aminolevulinic acid is further assumed to impair normal GABA function in the central nervous system (CNS) [44,45].…”

“…Moreover, the patient presented with a "highly elevated bilirubin" in urine, but a normal serum bilirubin level, which may be a false positive result of the urinary test stick due to excretion of porphyrins. In addition, the history of suspected macrohematuria hints to an earlier episode of acute intermittent porphyria as urine of these patients can appear red or brown after exposure to oxygen, light or heat due to conversion of porphobilinogen into porphobilin [5,6]. Porphyrias are clinical syndromes that arise due to deficiency or defect in a particular enzyme involved in a specific step of the heme synthesis pathway.…”