Acute Hepatic Porphyria: Pathophysiological Basis of Neuromuscular Manifestations

Abstract

Acute hepatic porphyria represents a rare, underdiagnosed group of inherited metabolic disorders due to hereditary defects of heme group biosynthesis pathway. Most patients have their definite diagnosis after several years of complex and disabling clinical manifestations and commonly after life-threatening acute neurovisceral episodes or severe motor handicap. Many key studies in the last two decades have been performed and led to the discovery of novel possible diagnostic and prognostic biomarkers and to the development of new therapeutic purposes, including small interfering RNA-based therapy, specifically driven to inhibit selectively delta-aminolevulinic acid synthase production and decrease the recurrence number of severe acute presentation for most patients. Several distinct mechanisms have been identified to contribute to the several neuromuscular signs and symptoms. This review article aims to present the current knowledge regarding the main pathophysiological mechanisms involved with the acute and chronic presentation of acute hepatic porphyria and to highlight the relevance of such content for clinical practice and in decision making about therapeutic options.

Keywords: acute hepatic porphyria; dysautonomia; inborn errors of metabolism (IEM); inherited metabolic diseases; neuromuscular; neuropathy; pathophysiology; rhabdomyolysis.

FIGURE 1

Metabolic pathways and steps of heme group biosynthesis and correlation of enzyme deficiency and associated porphyria. The classic and alternative pathways associated with heme biosynthesis are presented with the specific transporters, cofactors, and reagents involved in each chemical reaction. The enzymes involved in each step of biosynthesis are represented at the right side of the metabolic route. After the heme group has been produced, it promotes downregulation of ALA synthase and can be incorporated by mitochondrial hemoproteins or leave the mitochondrial compartment by the FLVCR1b transporter and come to the cytoplasm to be incorporated by several compounds. In the plasma membrane, the ABCG2/FLVCR1a transporter is present and can regulate the efflux of the heme group. Acute hepatic porphyria (AHP) types are presented in gray boxes. Cytosolic steps are represented in red boxes, and intramitochondrial enzymes are presented in white boxes. Legend: ALA, delta-aminolevulinic acid; CoA, coenzyme A; NO, nitric oxide; (–), inhibition (downregulation) of the enzymatic step; (+), upregulation (stimulation) of the step.

FIGURE 2

Examination findings in patients with AHP. (A) Amyotrophy of the tenar region (black arrow) and (B) severe amyotrophy of the first dorsal interosseous muscle of the hand (black arrows) in patients with variegate porphyria. (C,D) Distal amyotrophy and photosensitivity lesions in the lower limbs (white arrows) in patients with hereditary coproporphyria.

FIGURE 3

Diagram disclosing the different pathophysiological mechanisms involved with axonal damage in AHP during acute neurovisceral attacks. Different trigger (precipitating) factors lead to cytochrome P450 induction, heme group degradation, and/or the inhibition of heme synthesis, giving rise to ALA synthase induction and the secondary formation of high contents of neurotoxic ALA and PBG metabolites, leading to acute neurovisceral attack. ALA synthase induction is also associated with abnormal production of hemoprotein (related to several of the multisystemic signs and symptoms of AHP) and secondary depletion of pyridoxal-phosphate (leading to potentially reversible axonal damage). Legend, ALA, delta-aminolevulinic acid; GABA, gamma-aminobutyric acid; IL-6, interleukin-6; MPO, myeloperoxidase; NO, nitric oxide; OXPHOS, oxidative phosphorylation; PBG, porphobilinogen; PGC-1a, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha; SOD, superoxide dysmutase.

FIGURE 4

Diagram showing the location of pathogenic and likely pathogenic variants in the four genes (HMBS, PPOX, CPOX, and ALAD) associated with AHP. Variants were included according to data from the Genome Aggregation Database (gnomAD, browser v2.1.1), the Ensembl Project browser, and the ClinVar database public archive (all last accessed on August 10, 2021). Most variants in exon regions (black color) are missense. Intronic variants are represented in red color. Legend: Ex, exon; GRCh, human Genome Reference Consortium.

FIGURE 5

Possible therapeutic approaches in the management of AHP and their associated mechanism of action in the multistep pathway of heme biosynthesis. This figure highlights the different steps of heme biosynthesis pathway in which different therapy options may be used to treat AHP. Glucose overload and hemin-based therapies are directed to downregulate hepatic ALAS1 production and reducing, thus, heme biosynthesis pathway activation, limiting neurotoxic metabolite production. Hemodialysis represents an option to withdraw neurotoxic metabolites from circulation in acute severe presentation without available hemin-based therapy. Pharmacological chaperone aids in the proper function of misfolded enzymes and directing properly to the targeted route. Gene therapy approaches are directed to provide liver production of the specific deficient enzyme of the pathway. Small interfering RNA-based therapies are targeted to hepatocyte delivery, promoting association with the antisense strand of ALAS1 mRNA and the formation of RISC in the cytosol and then inhibiting ALAS1 production. Liver or hepatocyte transplantation enables the restoration of normal functioning enzyme in different types of AHP. Legends: AAV5, adeno-associated virus type 5; ALA, delta-aminolevulinic acid; ALAS, delta-aminolevulinic acid synthase; CoA, coenzyme A; GalNAc, N-acetylgalactosamine; PBG, porphobilinogen; PBGD, porphobilinogen deaminase; RISC, RNA-induced silencing complex; siRNA, small interfering RNA; (+), treatment option for the step—normal enzyme activity; (–), treatment option associated with inhibition of enzyme production.