Systemic inflammation in acute intermittent porphyria: a case–control study

Abstract

This study aimed to examine whether acute intermittent porphyria (AIP) is associated with systemic inflammation and whether the inflammation correlates with disease activity. A case-control study with 50 AIP cases and age-, sex- and place of residence-matched controls was performed. Plasma cytokines, insulin and C-peptide were analysed after an overnight fast using multiplex assay. Long pentraxin-3 (PTX3) and complement activation products (C3bc and TCC) were analysed using enzyme-linked immunosorbent assay (ELISA). Urine porphobilinogen ratio (U-PBG, µmol/mmol creatinine), haematological and biochemical tests were performed using routine methods. Questionnaires were used to register AIP symptoms, medication and other diseases. All 27 cytokines, chemokines and growth factors investigated were increased significantly in symptomatic AIP cases compared with controls (P < 0·0004). Hierarchical cluster analyses revealed a cluster with high visfatin levels and several highly expressed cytokines including interleukin (IL)-17, suggesting a T helper type 17 (Th17) inflammatory response in a group of AIP cases. C3bc (P = 0·002) and serum immunoglobulin (Ig)G levels (P = 0·03) were increased significantly in cases with AIP. The U-PBG ratio correlated positively with PTX3 (r = 0·38, P = 0·006), and with terminal complement complex (TCC) levels (r = 0·33, P = 0·02). PTX3 was a significant predictor of the biochemical disease activity marker U-PBG in AIP cases after adjustment for potential confounders in multiple linear regression analyses (P = 0·032). Prealbumin, C-peptide, insulin and kidney function were all decreased in the symptomatic AIP cases, but not in the asymptomatic cases. These results indicate that AIP is associated with systemic inflammation. Decreased C-peptide levels in symptomatic AIP cases indicate that reduced insulin release is associated with enhanced disease activity and reduced kidney function.

Feasibility of cellular bioenergetics as a biomarker in porphyria patients

“…Systemic inflammation in any disease state can affect the mitochondrial function and its bioenergetics, as exemplified in certain disease states including diabetes mellitus, sepsis, and alcoholic liver disease [21,22,25]. In a case control study on 50 AIP patients and matched healthy controls, levels of cytokines, chemokines, and growth factors were elevated in AIP compared to healthy controls, suggesting existence of systemic inflammation in AIP [17]. Circulating elevated ALA, PBG, and porphyrins in porphyria patients may cause tissue damage with release of damage associated molecular patterns or DAMPs, with consequent inflammatory signaling and immune cell activation with release of cytokines resulting in systemic inflammatory state [33,34].…”

“…Systemic inflammation impairs mitochondrial function as recognized in sepsis, diabetes mellitus, and liver failure [[14], [15], [16]]. Systemic inflammation due to accumulated porphyrins and precursors in plasma of AIP patients has been described which is directly associated with increased circulating cytokines and increased disease activity [17]. The levels of plasma porphyrins in the cutaneous porphyria such as EPP are also directly associated with dermal photosensitivity and severity of the disease [18].…”

Acute Intermittent Porphyria: A Rare Cause of Acute Disseminated Encephalomyelitis

“…Previous case reports on ADEM have not implicated AIP as an instigator of ADEM which underscores the rarity of our case. Storjord et al concluded that AIP is associated with systemic inflammation with a considerable increase in inflammatory cytokines in patients with AIP when compared to controlled subjects [ 6 ]. We postulate that systemic inflammation in the absence of an instigating infectious etiology led to the development of ADEM in our patient by considering the negative history and subsequent workup for all previously known bacterial and viral etiologies.…”

Multiple roles of haem in cystathionine β-synthase activity: implications for hemin and other therapies of acute hepatic porphyria

“…KA is the KP metabolite with the highest affinity for the aryl hydrocarbon receptor (AhR), a ligandactivated transcription factor that can elicit protective and destructive effects on immune function. Elevation of [KA] resulting from that of [Kyn] in AIP [107] may activate the AhR to induce poly (ADP-ribose) polymerase 1 (PARP 1) to precipitate an NAD + depletion [117] resulting in cell dysfunction.…”

“…By contrast, there is also evidence, as stated above, that CBS exerts feedback control on CγL, as a decrease in the former causes increased expression of the latter enzyme [ 102 ]. Symptomatic AIP patients exhibit increased plasma levels of a wide range of cytokines, chemokines and growth factors [ 107 ]. These latter authors suggested that inflammation in AIP derives from porphyrin precursors inducing liver damage and decreased insulin release causing 5-ALAS 1 induction.…”