Case-based discussion of the acute hepatic porphyrias: Updates on pathogenesis, diagnosis and management.

The acute hepatic porphyrias (AHPs) include three autosomal dominant disorders, acute intermittent porphyria, variegate porphyria  and hereditary coproporphyria, and the ultra-rare autosomal recessive 5-aminolevulinic acid dehydratase-deficient porphyria. All four are characterized by episodic acute neurovisceral attacks that can be life-threatening if left untreated. The attacks are precipitated by factors that induce hepatic 5-aminolevulinic acid synthase 1 (ALAS1), resulting in accumulation of the porphyrin precursors, 5-aminolevulinic acid and porphobilinogen, which are believed to cause neurotoxicity. Diagnosis of these rare disorders is often delayed because the symptoms are non-specific with many common aetiologies. However, once clinical suspicion of an AHP is raised, diagnosis can be made by specialized biochemical testing, particularly during attacks. Moderate or severe attacks are treated with intravenous hemin infusions, together with supportive care to relieve pain and other symptoms. Prophylactic treatments are recommended in patients with confirmed recurrent attacks (≥4 attacks in a maximum period of 12 months), the most effective being givosiran, an RNAi therapeutic targeting hepatocyte ALAS1 mRNA. AHP patients with clinically and/or biochemically active disease are at elevated risk for developing long-term complications, including chronic kidney disease, chronic hypertension and hepatocellular carcinoma, thus, surveillance is recommended. Here, using a case-based format, we provide an update on the pathogenesis, diagnosis and treatment of the AHPs based on literature review and clinical experiences.

Advancing disability-inclusive climate research and action, climate justice, and climate-resilient development.

Globally, more than 1 billion people with disabilities are disproportionately and differentially at risk from the climate crisis. Yet there is a notable absence of climate policy, programming, and research at the intersection of disability and climate change. Advancing climate justice urgently requires accelerated disability-inclusive climate action. We present pivotal research recommendations and guidance to advance disability-inclusive climate research and responses identified by a global interdisciplinary group of experts in disability, climate change, sustainable development, public health, environmental justice, humanitarianism, gender, Indigeneity, mental health, law, and planetary health. Climate-resilient development is a framework for enabling universal sustainable development. Advancing inclusive climate-resilient development requires a disability human rights approach that deepens understanding of how societal choices and actions-characterised by meaningful participation, inclusion, knowledge diversity in decision making, and co-design by and with people with disabilities and their representative organisations-build collective climate resilience benefiting disability communities and society at large while advancing planetary health.

Key terms and definitions in acute porphyrias: Results of an international Delphi consensus led by the European porphyria network.

Acute porphyrias are a group of rare inherited disorders causing acute neurovisceral attacks. Many terms used frequently in the literature and clinical practice are ambiguous, which can lead to confusion in the way patients are managed, studied, and reported in clinical studies. Agreed definitions are a necessary first step in developing management guidelines and will facilitate communication of results of future clinical research. The Delphi method was used to generate consensus on key terms and definitions in acute porphyria. The process started with a brainstorming phase offered to all members of the European Porphyria Network followed by two Delphi rounds among international experts in the field of porphyria (the Acute Porphyria Expert Panel). A consensus of 75% or more was defined as the agreement threshold. A total of 63 respondents from 26 countries participated in the brainstorming phase, leading to the choice of nine terms and definitions. A total of 34 experts were invited to take part in the Delphi rounds. Seven of the initial nine terms and definitions which entered the first Delphi round achieved the threshold for agreement. Following a second Delphi round, all nine definitions achieved agreement. Agreement on the definitions for nine important terms describing acute porphyrias represents a significant step forward for the porphyria community. It will facilitate more accurate comparison of outcomes among porphyria centres and in clinical trials and provide a strong framework for developing evidence-based clinical guidelines.

A Case of Acute Intermittent Porphyria Leading to Severe Disability in a Young 21-Year-Old Female.

Acute intermittent porphyria (AIP) is a rare metabolic disorder that is challenging to diagnose and treat. Symptoms are nonspecific and severe acute attacks may be life-threatening. This is a case of a previously healthy 21-year-old woman diagnosed with an acute attack of AIP following recurrent hospitalizations with undiagnosed abdominal pain over a 12-month period with gradual onset of motor neuropathy which resulted in complete paralysis and respiratory failure. Through our case, we will highlight the challenges in AIP diagnosis and management, its potential severity, and how an early diagnosis could have prevented severe disability.

Update on the diagnosis and management of the autosomal dominant acute hepatic porphyrias.

The autosomal dominant acute hepatic porphyrias (AHPs), acute intermittent porphyria, hereditary coproporphyria (HCP) and variegate porphyria (VP), are low penetrance adult onset disorders caused by partial deficiency of enzymes of haem biosynthesis. All are associated with acute neurovisceral attacks, which are a consequence of the increased hepatic demand for haem triggered by hormones, stress, drugs or systemic infections which leads to upregulation of the pathway and overproduction of haem precursors 5-aminolaevulinic acid (ALA) and porphobilinogen (PBG). Acute episodes are characterised by severe abdominal pain, nausea, vomiting, hyponatraemia, hypertension and tachycardia, behavioural disturbance and can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if undiagnosed and untreated. VP and HCP may also present with photocutaneous skin lesions either alone or during acute symptoms. Diagnosis involves demonstrating increased excretion of PBG in urine. Treatment focuses on removing or managing triggers, supportive treatment and suppressing the hepatic haem pathway by administering human haemin. Chronic complications include hypertension, chronic kidney disease and hepatocellular carcinoma. A small proportion of symptomatic patients with AHP progress to repeated acute attacks which require preventative therapy. A new RNA interference therapy has recently been licensed and is likely to become the treatment of choice in this situation.

Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study.

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.

Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.

BACKGROUND: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria. RESULTS: A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions. CONCLUSIONS: Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.).

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks.

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.

Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria.

BACKGROUND: Induction of delta aminolevulinic acid synthase 1 ( ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations in patients with acute intermittent porphyria, a rare inherited disease of heme biosynthesis. Givosiran is an investigational RNA interference therapeutic agent that inhibits hepatic ALAS1 synthesis. METHODS: We conducted a phase 1 trial of givosiran in patients with acute intermittent porphyria. In part A of the trial, patients without recent porphyria attacks (i.e., no attacks in the 6 months before baseline) were randomly assigned to receive a single subcutaneous injection of one of five ascending doses of givosiran (0.035, 0.10, 0.35, 1.0, or 2.5 mg per kilogram of body weight) or placebo. In part B, patients without recent attacks were randomly assigned to receive once-monthly injections of one of two doses of givosiran (0.35 or 1.0 mg per kilogram) or placebo (total of two injections 28 days apart). In part C, patients who had recurrent attacks were randomly assigned to receive injections of one of two doses of givosiran (2.5 or 5.0 mg per kilogram) or placebo once monthly (total of four injections) or once quarterly (total of two injections) during a 12-week period, starting on day 0. Safety, pharmacokinetic, pharmacodynamic, and exploratory efficacy outcomes were evaluated. RESULTS: A total of 23 patients in parts A and B and 17 patients in part C underwent randomization. Common adverse events included nasopharyngitis, abdominal pain, and diarrhea. Serious adverse events occurred in 6 patients who received givosiran in parts A through C combined. In part C, all 6 patients who were assigned to receive once-monthly injections of givosiran had sustained reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and porphobilinogen levels to near normal. These reductions were associated with a 79% lower mean annualized attack rate than that observed with placebo (exploratory efficacy end point). CONCLUSIONS: Once-monthly injections of givosiran in patients who had recurrent porphyria attacks resulted in mainly low-grade adverse events, reductions in induced ALAS1 mRNA levels, nearly normalized levels of the neurotoxic intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack rate than that observed with placebo. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02452372 .).

Porphyria: often discussed but too often missed.

The diagnosis of acute intermittent porphyria (AIP) is often overlooked. We describe a patient with this condition who had all the 'bells and whistles', in whom the diagnosis was only made after considerable delay. Far from an esoteric condition haunting examination candidates, AIP is an important cause of a broad spectrum of neurological symptoms. Its early recognition allows the astute clinician to prevent potentially devastating sequelae. We provide practical guidance on the investigation and management of this complex disorder. With a 'back to basics' approach to the underlying genetics and biochemistry, we hope to dispel some of the confusion that may obstruct a timely diagnosis.

Insights into Hunter syndrome from the structure of iduronate-2-sulfatase.

Hunter syndrome is a rare but devastating childhood disease caused by mutations in the IDS gene encoding iduronate-2-sulfatase, a crucial enzyme in the lysosomal degradation pathway of dermatan sulfate and heparan sulfate. These complex glycosaminoglycans have important roles in cell adhesion, growth, proliferation and repair, and their degradation and recycling in the lysosome is essential for cellular maintenance. A variety of disease-causing mutations have been identified throughout the IDS gene. However, understanding the molecular basis of the disease has been impaired by the lack of structural data. Here, we present the crystal structure of human IDS with a covalently bound sulfate ion in the active site. This structure provides essential insight into multiple mechanisms by which pathogenic mutations interfere with enzyme function, and a compelling explanation for severe Hunter syndrome phenotypes. Understanding the structural consequences of disease-associated mutations will facilitate the identification of patients that may benefit from specific tailored therapies.

An Audit of the Use of Gonadorelin Analogues to Prevent Recurrent Acute Symptoms in Patients with Acute Porphyria in the United Kingdom.

Severe recurrent acute attacks of porphyria have traditionally been treated with either prophylactic human haemin or gonadorelin analogues (GnA) in females. Evidence on the most effective treatment for this patient subgroup is lacking. This audit surveyed the use of prophylactic GnA in the UK.Twenty female patients (who experienced between 2 and 45 acute attacks of porphyria requiring hospitalisation and treatment with human haemin prior to GnA prophylaxis) were included in the audit. Data was retrospectively collected based on patient history and case review.Twenty three treatment courses were given lasting a median period of 12 months. Monthly subcutaneous Goserelin was most commonly used. In three patients in whom timing with the menstrual cycle was not considered, an acute attack occurred after initiation of the first dose. The majority of patients experienced oestrogen deficiency symptoms during treatment. Fifty percent of the prescribed courses of GnA resulted in a degree of clinical benefit. This successfully treated group experienced between 3 and 20 acute attacks prior to and between 0 and 6 acute attacks during GnA treatment.The audit revealed large variation in practice in the United Kingdom regarding indication, duration of treatment, specific drug used and management of side effects. In view of the limited treatment options available for this cohort and the mixed outcome successes reported, we believe it is reasonable for porphyria specialists to continue offering GnA treatment to women with severe recurrent debilitating acute attacks of porphyria associated with the menstrual cycle, and we propose best practice guidelines to standardise management.

Update review of the acute porphyrias.

Acute porphyrias are rare inherited disorders due to deficiencies of haem synthesis enzymes. To date, all UK cases have been one of the three autosomal dominant forms, although penetrance is low and most gene carriers remain asymptomatic. Clinical presentation is typically with acute neurovisceral attacks characterised by severe abdominal pain, vomiting, tachycardia and hypertension. Severe attacks may be complicated by hyponatraemia, peripheral neuropathy sometimes causing paralysis, seizures and psychiatric features. Attacks are triggered by prescribed drugs, alcohol, hormonal changes, fasting or stress. The diagnosis is made by finding increased porphobilinogen excretion in a light-protected random urine sample. Management includes administration of intravenous human haemin and supportive treatment with non-porphyrinogenic drugs. A few patients develop recurrent attacks, a chronic illness requiring specialist management. Late complications include chronic pain, hepatocellular carcinoma, chronic renal failure and hypertension. In the UK, the National Acute Porphyria Service provides clinical advice and supplies haemin when indicated.

Acute Porphyria Presenting as Major Trauma: Case Report and Literature Review.

BACKGROUND: Acute porphyria is historically known as "the little imitator" in reference to its reputation as a notoriously difficult diagnosis. Variegate porphyria is one of the four acute porphyrias, and can present with both blistering cutaneous lesions and acute neurovisceral attacks involving abdominal pain, neuropsychiatric features, neuropathy, hyponatremia, and a vast array of other nonspecific clinical features. CASE REPORT: A 40-year-old man presented to the Emergency Department (ED) as a major trauma call, having been found in an "acutely confused state" surrounded by broken glass. Primary survey revealed: hypertension, tachycardia, abdominal pain, severe agitation, and confusion with an encephalopathy consistent with acute delirium, a Glasgow Coma Scale score of 13, and head-to-toe "burn-like" abrasions. Computed tomography was unremarkable, and blood tests demonstrated hyponatremia, acute kidney injury, and a neutrophilic leukocytosis. The next of kin eventually revealed a past medical history of variegate porphyria. The patient was experiencing an acute attack and received supportive management prior to transfer to intensive care, subsequently making a full recovery. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the importance of recognizing acute medical conditions in patients thought to be suffering from major trauma. Acute porphyria should be considered in any patient with abdominal pain in combination with neuropsychiatric features, motor neuropathy, or hyponatremia. Patients often present to the ED without any medical history, and accurate diagnosis can be essential in the acute setting to minimize morbidity and mortality. The label of the major trauma call must be taken with great caution, and a broad differential diagnosis must be maintained throughout a diligent and thorough primary survey.

Audit of the Use of Regular Haem Arginate Infusions in Patients with Acute Porphyria to Prevent Recurrent Symptoms.

The National Acute Porphyria Service (NAPS) provides acute care support and clinical advice for patients in England with active acute porphyria requiring haem arginate treatment and patients with recurrent acute attacks.This audit examined the benefits and complications of regular haem arginate treatment started with prophylactic intent to reduce the frequency of recurrent acute attacks in a group of patients managed through NAPS. We included 22 patients (21 female and 1 male) and returned information on diagnosis, indications for prophylactic infusions, frequency and dose, analgesia, activity and employment and complications including thromboembolic disease and iron overload.The median age at presentation with porphyria was 21 years (range 9-44), with acute abdominal pain as the predominant symptom. Patients had a median of 12 (1-400) attacks before starting prophylaxis and had received a median of 52 (0-1,350) doses of haem arginate. The median age at starting prophylaxis was 28 years (13-58) with a median delay of 4 years (0.5-37) between presentation and prophylaxis. The frequency of prophylactic haem arginate varied from 1 to 8 per month, and 67% patients were documented as having a reduction in pain frequency on prophylaxis. Only one patient developed clinically significant iron overload and required iron chelation, but the number of venous access devices required varied from 1 to 15, with each device lasting a median of 1.2 years before requiring replacement. Six patients stopped haem arginate and in three this was because their symptoms had improved. Prophylactic haem arginate appears to be beneficial in patients with recurrent acute porphyria symptoms, but maintaining central venous access may prove challenging.

Best practice guidelines on clinical management of acute attacks of porphyria and their complications.

The British and Irish Porphyria Network guidelines describe best practice in the clinical assessment, investigation and management of acute porphyria attacks and their complications, including severe attacks with neuropathy. Acute attacks of porphyria may occur in acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP). Aminolaevulinic acid dehydratase deficiency porphyria (ADP) is a very rare autosomal recessive porphyria; only six cases substantiated by mutation analysis have yet been described in the literature. Urinary porphobilinogen (PBG) is always raised in an acute attack due to AIP, VP or HCP and this analysis is essential to confirm the diagnosis. A positive result in a qualitative or semi-quantitative screening test must be followed by PBG quantitation at the earliest opportunity. However in a severely ill patient, treatment should not be delayed. Removal of precipitating factors, effective analgesia and control of symptoms with safe medication, attention to nutrition and fluid balance are essential. The indications for use of intravenous haem arginate are set out, together with advice on its administration. A small proportion of acute porphyria patients develop recurrent attacks and management options that may be considered include gonadotrophin-releasing hormone analogues, 'prophylactic' regular haem arginate infusion or ultimately, liver transplantation.

Solving serpin crystal structures.

Essentially the same steps are required to solve the crystal structure of a serpin as for any other protein: produce and purify protein, grow crystals, collect diffraction data, find estimates of the phase angles, and then refine and validate the structure. For the phasing step, experimental phasing methods involving heavy atom soaks were required for the first few structures, but with the large number of serpin structures now available, molecular replacement has become the method of choice. Two things are special about serpins. First, because of the central role of conformational change in serpin mechanism, it is advisable to consider a variety of molecular replacement models in different conformations and then to allow for rigid-body motions in the initial refinement steps. Second, probably owing to the flexibility of serpins, the average serpin crystal is significantly less well ordered than the average crystal of another protein, which increases the difficulty of solving and refining their structures.

Insights into Krabbe disease from structures of galactocerebrosidase.

Krabbe disease is a devastating neurodegenerative disease characterized by widespread demyelination that is caused by defects in the enzyme galactocerebrosidase (GALC). Disease-causing mutations have been identified throughout the GALC gene. However, a molecular understanding of the effect of these mutations has been hampered by the lack of structural data for this enzyme. Here we present the crystal structures of GALC and the GALC-product complex, revealing a novel domain architecture with a previously uncharacterized lectin domain not observed in other hydrolases. All three domains of GALC contribute residues to the substrate-binding pocket, and disease-causing mutations are widely distributed throughout the protein. Our structures provide an essential insight into the diverse effects of pathogenic mutations on GALC function in human Krabbe variants and a compelling explanation for the severity of many mutations associated with fatal infantile disease. The localization of disease-associated mutations in the structure of GALC will facilitate identification of those patients that would be responsive to pharmacological chaperone therapies. Furthermore, our structure provides the atomic framework for the design of such drugs.