Worldwide, patients with porphyrias face critical delays in diagnosis. In Mexico this situation is no exception and, due to the characteristics of the local health system, population distribution and lack of access to health services and specialized porphyria centers, diagnosis and treatment are complex. Much work remains to be done, in collaboration with government authorities, physicians, advocacy groups and the pharmaceutical industry, to provide knowledge, diagnostic tools and targeted therapies to all porphyria patients in need.

cT1 is an MRI-derived biomarker of liver disease activity 800 ms = upper limit of normal Cardiovascular events: Hospitalization: 1.27 (1.18-1.37)Atrial fibrillation: 1.3 (1.12-1.51)Heart failure: 1.3 (1.08-1.58)Any cardiac event: 1.14 (1.03-1.26)Hazard Ratios (with 95% confidence intervals) All-cause mortality: 1.19 (1.02-1.38)Increasing cT1 is associated with an increased risk of developing: HighlightsLiver disease on cT1 MRI is associated with a high risk of CVD events, CVD-related hospitalization, and allcause mortality.The association between liver disease on cT1 and CVD is independent of liver function tests, fibrosis and metabolic risk.Risk of CVD events is increased even in the early stages of chronic liver disease. Impact and implicationsChronic liver disease (CLD) is associated with a twofold greater incidence of cardiovascular disease.Our work shows that early liver disease on iron-corrected T1 mapping was associated with a higher risk of major cardiovascular disease (14%), cardiovascular disease hospitalisation (27%) and all-cause mortality (19%).These findings highlight the prognostic relevance of a comprehensive evaluation of liver health in populations at risk of CVD and/or CLD, even in the absence of clinical manifestations or metabolic syndrome, when there is an opportunity to modify/address risk factors and prevent disease progression.As such, they are relevant to patients, carers, clinicians, and policymakers.

BACKGROUND & AIMS:Acute hepatic porphyria (AHP) is caused by defects in hepatic heme biosynthesis, leading to disabling acute neurovisceral attacks and chronic symptoms. In ENVISION (NCT03338816), givosiran treatment for 6 months reduced attacks and other disease manifestations compared with placebo. Herein, we report data from the 36-month final analysis of ENVISION. METHODS:Ninety-four patients with AHP (age ≥12 years) and recurrent attacks were randomized 1:1 to monthly double-blind subcutaneous givosiran 2.5 mg/kg (n = 48) or placebo (n = 46) for 6 months. In the open-label extension (OLE) period, 93 patients received givosiran 2.5 or 1.25 mg/kg for 6 months or more before transitioning to 2.5 mg/kg. Endpoints were exploratory unless otherwise noted. RESULTS:During givosiran treatment, the median annualized attack rate (AAR) was 0.4. Through Month 36, annualized days of hemin use remained low in the continuous givosiran group (median, 0.0 to 0.4) and decreased in the placebo crossover group (16.2 to 0.4). At end of OLE, in the continuous givosiran and placebo crossover groups, 86% and 92%, respectively, had 0 attacks. AAR was lower than historical AAR in 98% and 100%, respectively (post hoc analysis), and there were 0 days of hemin use in 88% and 90%, respectively. The 12-item short-form health survey physical and mental component summary scores increased by 8.6 and 8.1, respectively (continuous givosiran) and 9.4 and 3.2, respectively (placebo crossover). EQ-5D health-related questionnaire scores increased by 18.9 (continuous givosiran) and 9.9 (placebo crossover). Lower urinary delta-aminolevulinic acid and porphobilinogen levels were sustained. Safety findings demonstrated a continued positive risk/benefit profile for givosiran. CONCLUSIONS:Long-term monthly givosiran treatment provides sustained and continued improvement in clinical manifestations of AHP. CLINICALTRIALS: GOV IDENTIFIER:NCT03338816. EUDRACT NUMBER:2017-002432-17. IMPACT AND IMPLICATIONS:Acute hepatic porphyria (AHP) is a group of rare, chronic, multisystem disorders associated with overproduction and accumulation of neurotoxic heme intermediates (delta-aminolevulinic acid and porphobilinogen), sometimes resulting in recurrent acute attacks and long-term complications. Givosiran, a small-interfering RNA that prevents accumulation of delta-aminolevulinic acid and porphobilinogen, is approved for the treatment of AHP. These final 36-month results of ENVISION, a phase III study of givosiran in patients with AHP and recurrent attacks, show that long-term monthly treatment with givosiran leads to continuous and sustained reductions in annualized attack rate and use of hemin over time, as well as improved quality of life, with an acceptable safety profile. These results are important for physicians, patients, families, and caregivers who are grappling with this debilitating and potentially life-threatening disease with few effective and tolerable treatment options.

A subgroup of congenital disorders of glycosylation (CDGs) includes inherited GPI-anchor deficiencies (IGDs) that affect the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, including the first reaction catalyzed by the X-linked PIGA. Here, we show the first PIGA-CDG case reported in Mexico in a male child with a moderate-to-severe phenotype characterized by neurological and gastrointestinal symptoms, including megacolon. Exome sequencing identified the hemizygous variant PIGA c.145G>A (p.Val49Met), confirmed by Sanger sequencing and characterized as de novo. The pathogenicity of this variant was characterized by flow cytometry and complementation assays in PIGA knockout (KO) cells.

One‐year data from EXPLORE Part A showed high disease burden and impaired quality of life (QOL) in patients with acute hepatic porphyria (AHP) with recurrent attacks. We report baseline data of patients who enrolled in EXPLORE Part B for up to an additional 3 years of follow‐up. EXPLORE B is a long‐term, prospective study evaluating disease activity, pain intensity, and QOL in patients with AHP with ≥1 attack in the 12 months before enrollment or receiving hemin or gonadotropin‐releasing hormone prophylaxis. Data were evaluated in patients with more (≥3 attacks or on prophylaxis treatment) or fewer (<3 attacks and no prophylaxis treatment) attacks. Patients in the total population (N = 136), and more (n = 110) and fewer (n = 26) attack subgroups, reported a median (range) of 3 (0–52), 4 (0–52), and 1 (0–2) acute attacks, respectively, in the 12 months prior to the baseline visit. Pain, mood/sleep, digestive/bladder, and nervous system symptoms were each experienced by ≥80% of patients; most received hemin during attacks. Almost three‐quarters of patients reported chronic symptoms between attacks, including 85% of patients with fewer attacks. Pain intensity was comparable among both attack subgroups; most patients required pain medication. All groups had diminished QOL on the EuroQol visual analog scale and the European Organisation for Research and Treatment of Cancer Quality‐of‐life Questionnaire Core 30 versus population norms. Patients with AHP with recurrent attacks, even those having fewer attacks, experience a high disease burden, as evidenced by chronic symptoms between attacks and impaired QOL.

The cover image is based on the Original Article Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study by Paolo Ventura et al., https://doi.org/10.1111/liv.15090.

transaminases levels.Culture of HuH-7 liver cells with THCA increased ROS production and the ER stress biomarkers GRP78, CHOP and XBP1-S/XBP1-U ratio, whereas decreased cell viability.THCA-induced toxicity was higher than that of major BAs.Among 14 in silico selected genetic variants, in vitro functional tests identified 6 ACOX2 variants as a potential cause of ADILF.Conclusion: Dysfunctional ACOX2 is found in a substantial proportion of patients with unexplained hypertransaminasemia, suggesting that this disorder of BA metabolism causes enhanced liver fragility, which can be attenuated by UDCA treatment.

Introduction: Acute hepatic porphyria (AHP) is caused by genetic defects in heme biosynthesis. Intravenous hemin is recommended for acute attacks and can be used prophylactically but has side effects. Gonadotropin-releasing hormone (GnRH) has been used prophylactically for women with recurrent premenstrual attacks, with variable efficacy. EXPLORE (NCT02240784) is a prospective, natural history study of patients with AHP with recurrent attacks. Part A followed patients for up to 12 months. Part B included optional long-term evaluation of pain intensity and changes in disease activity in eligible patients from Part A, and newly enrolled patients, for up to 3 additional years. Methods: Patients with AHP with ≥1 attack in the prior 12 months or receiving hemin/GnRH prophylaxis were eligible for Part B. Pain intensity and impact were measured by Brief Pain Inventory (BPI) form (scale 0–10). Changes in disease activity were captured via questionnaires. Quality of life (QOL) was assessed by the European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and the EuroQOL visual analog scale (EQ-VAS) (scale 0–100 for total scores of both questionnaires). Assessments were conducted by mail and confirmed by telephone every 3–6 months over 3 years. Results: Overall, 136 patients (43 from Part A) were enrolled from 18 countries (mean age, 41 years; 90% female) and 90% had acute intermittent porphyria. In the 12 months prior to enrollment, all patients reported a median (range) of 3 (0–52) acute attacks, with 46% on hemin and/or GnRH prophylaxis. A subgroup with < 3 attacks a year (N = 27) without prophylaxis had a median (range) of 1 (0–2) acute attack in the past 12 months. Most patients required hemin (70%) and pain medication (96%), including opioids (59%), during attacks, and most (85%) also had chronic symptoms. At baseline, mean worst pain and average pain scores (BPI form) were 3.6 and 3.3, respectively. Patients taking pain medications regularly (N = 19) reported that, on average, only 42% of their pain had been relieved in the last 24 hours. Mean EQ-VAS score was 71 in the subgroup with < 3 attacks versus 63 in the subgroup with ≥3 attacks; mean EORTC Overall Health and QOL scores were 67 and 54, respectively. Conclusion: These data demonstrate that AHP patients with recurrent attacks, even those having fewer attacks, suffer from a high burden of disease, shown by chronic symptoms between attacks and impaired QOL.

Introduction: Acute hepatic porphyria (AHP) is caused by defects in hepatic heme biosynthesis leading to accumulation of the neurotoxic heme intermediates 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Intravenous (IV) hemin, the recommended treatment for an acute attack, can have side effects. Givosiran reduced ALA and PBG levels, annualized attack rate (AAR; by 73%), hemin usage, and daily pain versus placebo in the 6-month, double-blind (DB) period of the ENVISION study (NCT03338816). Continued givosiran in the open-label extension (OLE) led to sustained clinical benefit, with 85% of patients attack free at months >15–18. Here we report data from the 24-month interim analysis of ENVISION. Methods: Patients with AHP (≥12 years old) with ≥2 attacks requiring hospitalization, urgent care, or IV hemin at home in the previous 6 months were randomized (1:1) to monthly subcutaneous givosiran 2.5 mg/kg (N = 48) or placebo (N = 46) for 6 months; 93 patients subsequently received givosiran 2.5 or 1.25 mg/kg in the OLE. Analysis included urinary ALA and PBG levels and annualized days of hemin use. QOL was assessed by 12-item Short Form Health Survey (SF-12), EuroQOL visual analog scale (EQ-VAS), and Porphyria Patient Experience Questionnaire (PPEQ). Results: During the OLE, givosiran led to a sustained lowering of median urinary ALA and PBG to near-normal levels in the continuous givosiran group and a >75% sustained reduction in the placebo crossover group. Continued givosiran treatment also led to a sustained reduction in attacks and hemin use in both groups (Table 1). Proportion of patients with zero attacks per 3-month interval improved over the OLE, with 83% of the continuous givosiran group attack free at months >21–24. Overall, 68% of patients did not require hemin during the OLE. Patients experienced further improvements in QOL and activities of daily living during the OLE versus the DB period, as assessed by SF-12 Physical Component Summary (Table 1), EQ-VAS, and PPEQ. Adverse events (AEs) included injection-site reactions and elevations of serum aminotransferases. Three patients (3.2%) discontinued treatment due to AEs. Conclusion: The ENVISION 24-month interim analysis further confirms that long-term givosiran provides sustained and continuous benefit to patients with AHP, maintaining reduced frequency of attacks and hemin use, and further improving QOL. The safety profile of givosiran remained acceptable and consistent with that previously observed.Table 1.: Efficacy of Long-term Givosiran in the Continuous Givosiran Group and Placebo Crossover Group in the DB and OLE Periods of the ENVISION. trial. AAR, annualized attack rate; DB, double-blind; OLE, open-label extension, SF-12, 12-item Short Form Health Survey.

BACKGROUND & AIMS:Upregulation of hepatic delta-aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta-aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria.AIMS:evaluate long-term efficacy and safety of givosiran in acute hepatic porphyria.METHODS:Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double-blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open-label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta-aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events.RESULTS:Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double-blind period, 0.0 in open-label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double-blind period) and 0.0 (open-label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long-term givosiran led to sustained lowering of delta-aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double-blind period.CONCLUSIONS:Long-term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.