Acute hepatic porphyrias for the neurologist: current concepts and perspectives

Abstract

Background: Acute hepatic porphyrias represent an expanding group of complex inherited metabolic disorders due to inborn errors of metabolism involving heme biosynthesis. Objective: We aimed to review the main clinical and therapeutic aspects associated with acute hepatic porphyrias. Methods: The authors provided a wide non-systematic review of current concepts and recently acquired knowledge about acute hepatic porphyrias. Results: Acute neurovisceral attacks are the most common and life-threatening presentation of this group and are often considered the main clinical manifestation by clinicians during differential diagnosis and the start of proper diagnostic work-up for acute porphyrias. However, atypical presentations with central nervous system involvement, neuropsychiatric disturbances, and some subtypes with photosensitivity usually make the definite diagnosis difficult and late. Early therapeutic interventions are essential during emergency treatment and intercritical periods to avoid recurrent severe presentations. The availability of new disease-modifying therapeutic proposals based on small interfering RNA (siRNA)-based therapies, complementary to the classic intravenous glucose infusion and hemin-based treatments, emphasizes the importance of early diagnosis and genetic counseling of patients. Conclusions: This review article highlights the main biochemical, pathophysiological, clinical, and therapeutic aspects of acute hepatic porphyrias in clinical practice.

Acute Hepatic Porphyria: Pathophysiological Basis of Neuromuscular Manifestations

“…Porphyrias (from the Greek porphyrus , purple) are a rare group of inherited or acquired metabolic disorders of the heme biosynthesis pathway, which has eight biochemical steps ( Figure 1 ) with abnormal production and accumulation of toxic intermediate metabolites, which enter in the blood circulation and are excreted into the urine or bile ( Bissell et al, 2017 ; Souza et al, 2021 ).…”

“…Heme group production occurs predominantly in erythroblasts from the bone marrow (almost 80% of total heme production) and liver (around 20% of total heme group) and plays a major role as cofactor of different iron-based hemeproteins, such as hemoglobin, hepatic cytochromes P450, myoglobin, mitochondrial respiratory chain cytochromes, some catalases and peroxidases, and microsomal cytochrome b5 ( Bissell et al, 2017 ; Wang et al, 2018 ; Phillips, 2019 ; Souza et al, 2021 ).…”

“…The biochemical synthesis pathway involves eight enzymatic reactions dependent on several cofactors, located in the cytoplasm or mitochondrial compartments and modulated by genetic modifiers and individual high-susceptibility risk factors (i.e., cytochrome P450-coding genes and their polymorphisms), endocrine (i.e., menstrual cycle, pregnancy, and puerperium), environmental (i.e., lead poisoning), dietetic factors (i.e., alcohol consumption, prolonged fasting or low carbohydrate diet, and cigarette smoking), and unsafe porphyrinogenic drugs (i.e., hormonal contraceptives, phenytoin, barbiturates, and sulfonamides) ( Phillips, 2019 ; Souza et al, 2021 ). The rate-limiting step in this pathway is performed by the ubiquitous housekeeping isozyme delta-aminolevulinic acid synthase 1 (ALAS1) in the liver and by the erythroid tissue-specific isozyme ALAS2 in bone marrow, induced directly or indirectly by precipitating factors or triggers ( Besur et al, 2014 ; Stojanovski et al, 2019 ; Souza et al, 2021 ; Figure 1 ).…”

“…Traditionally, the porphyrias have been classified according to the main tissue in which heme precursors accumulate as hepatic or erythropoietic porphyrias, and based on clinical manifestations as acute porphyrias characterized by neurovisceral attacks with abdominal pain and neurologic features or chronic porphyrias with prominent cutaneous involvement in photoexposed skin areas due to overproduction of photosensitizing porphyrins ( Figure 2 ; Bissell et al, 2017 ; Wang et al, 2018 ; Phillips, 2019 ; Souza et al, 2021 ).…”

Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations

“…An alternative hypothesis for chronic neurological impairment in HMBS ‐related disease is a chronic deficiency in neuronal heme that interrupts axonal transport and causes axonal degeneration (Lindberg et al, 1999). This may be relevant also to the polyneuropathy and progressive neurological disease associated with recessive ALAD mutations (Doss porphyria) (Doss et al, 2004; Souza et al, 2021). Mice with HMBS deficiency and normal ALA levels were shown to develop progressive neurological dysfunction, indicating the disease process was not mediated by elevated ALA (Lindberg et al, 1999).…”