Acute Porphyria Research Articles

Patient and caregiver experiences of living with acute hepatic porphyria in the UK: a mixed-methods study

BackgroundThis study used quantitative and qualitative research methods to analyze how acute hepatic porphyria (AHP) affects patients with varying annualized porphyria attack rates. The overall impact of AHP on patients and caregivers, including their quality of life, was explored. The nature and treatment of acute attacks, experiences of long-term heme arginate treatment and access to other appropriate treatment, and the extent of and treatment for chronic symptoms were also investigated within this study.MethodsPatient and caregiver data were collected via an online survey of members of the British Porphyria Association, followed by an optional 1-h telephone interview.ResultsThirty-eight patients and 10 caregivers responded to the survey. Of those, 10 patients and three caregivers completed follow-up interviews. Overall, 19 patients (50%) had experienced an acute attack within the previous 2 years, and the severity and types of symptoms experienced during or between acute attacks varied considerably. There were no clear definitions among patients for ‘mild’ or ‘severe’ attacks. Treatments and treatment settings used to manage attacks also varied. Following unsatisfactory care experiences at hospitals, some patients reported avoiding further hospital services for later attacks. Therefore, using settings of care as a measure of attack severity should be avoided. Ninety-four percent of patients also experienced chronic symptoms, which were as varied as acute attacks. Pain was the predominant chronic symptom and was managed with opioids in severe cases. Regardless of AAR, porphyria heavily impacted the daily lives of patients and caregivers. Although patients experiencing frequent attacks generally endured a greater impact on their daily life, patients with less frequent attacks also experienced impacts on all domains (social, leisure activities, relationship with family, relationships, psychological wellbeing, finances, employment, and study). Caregivers were most affected in the finance, relationships with family, and employment domains, and just over half of the caregivers reported a moderate impact on their psychological wellbeing.Conclusions/implicationsThe burden of illness with AHP is high across all patients, regardless of frequency of attacks, and AHP negatively affects patients and caregivers alike.

Givosiran: A Review in Acute Hepatic Porphyria.

Givosiran (Givlaari®) is an δ-aminolevulinic acid synthase 1 (ALAS1)-directed small interfering RNA (siRNA) approved for the treatment of acute hepatic porphyria (AHP). In the phase 3 ENVISION trial, givosiran significantly reduced the annualized rate of composite porphyria attacks (i.e. attacks requiring hospitalization, urgent healthcare visit or intravenous hemin administration at home) compared with placebo in patients with recurrent acute intermittent porphyria (the most common type of AHP) attacks. Givosiran also improved several other outcomes, including hemin use and pain (the cardinal symptom of AHP). While generally well tolerated with an acceptable safety profile, the drug may increase the risk of hepatic and kidney adverse events. Givosiran offers the convenience of once-monthly subcutaneous administration. Available evidence indicates that givosiran is an important newer therapeutic option for patients with AHP and severe recurrent attacks.

Reduction in Pain During and Between Attacks in Patients with Acute Hepatic Porphyria Treated with Givosiran: A Post-Hoc Analysis of the Phase 3 ENVISION Study (1463)

Reduction in Pain During and Between Attacks in Patients with Acute Hepatic Porphyria Treated with Givosiran: A Post-Hoc Analysis of the Phase 3 ENVISION Study (1463)

Острая порфирия: случаи из реальной практики

Острая порфирия: случаи из реальной практики

The acute hepatic porphyrias

The acute hepatic porphyrias (AHP) are a group of four inherited diseases of heme biosynthesis. They present with similar severe, episodic, acute neurovisceral symptoms due to abnormally elevated levels of porphyrin precursors delta-aminolevulinic acid (ALA). Recently genetic screening indicates that the prevalence of mutation carrier state is more common than previously thought, occurring in 1 in 1,500, though the clinical penetrance of symptomatic AHP is low at ~1%. Symptomatic attacks occur primarily in females during their reproductive years. In an acute porphyria attack, the primary symptom is abdominal pain, due to intestinal dysmotility from autonomic nerve injury. Other manifestations include seizures, weakness and mood changes, point to injury involving peripheral and central nervous system. Due to the non-specific nature of the symptoms and signs in AHP, the diagnosis is often delayed by many years. The diagnosis of AHP depends on biochemical evidence of elevated ALA and PBG levels in urine during symptomatic attacks. Genetic testing is used for confirmation of the gene involved and the exact mutation. Treatment involves administration of heme, which downregulates production of ALA. Long-term management centers on educating genetic carriers on avoiding triggers that increase the risk of acute attacks and screening family members.

The acute hepatic porphyrias.

The acute hepatic porphyrias (AHP) are a group of four inherited diseases of heme biosynthesis. They present with similar severe, episodic, acute neurovisceral symptoms due to abnormally elevated levels of porphyrin precursors delta-aminolevulinic acid (ALA). Recently genetic screening indicates that the prevalence of mutation carrier state is more common than previously thought, occurring in 1 in 1,500, though the clinical penetrance of symptomatic AHP is low at ~1%. Symptomatic attacks occur primarily in females during their reproductive years. In an acute porphyria attack, the primary symptom is abdominal pain, due to intestinal dysmotility from autonomic nerve injury. Other manifestations include seizures, weakness and mood changes, point to injury involving peripheral and central nervous system. Due to the non-specific nature of the symptoms and signs in AHP, the diagnosis is often delayed by many years. The diagnosis of AHP depends on biochemical evidence of elevated ALA and PBG levels in urine during symptomatic attacks. Genetic testing is used for confirmation of the gene involved and the exact mutation. Treatment involves administration of heme, which downregulates production of ALA. Long-term management centers on educating genetic carriers on avoiding triggers that increase the risk of acute attacks and screening family members.

Porphyric neuropathy.

Acute hepatic porphyrias are inherited metabolic disorders that may present with polyneuropathy, which if not diagnosed early can lead to quadriparesis, respiratory weakness, and death. Porphyric neuropathy is an acute to subacute motor predominant axonal neuropathy with a predilection for the upper extremities and usually preceded by a predominantly parasympathetic autonomic neuropathy. The rapid progression and associated dysautonomia mimic Guillain-Barré syndrome but are distinguished by the absence of cerebrospinal fluid albuminocytologic dissociation, progression beyond 4 wk, and associated abdominal pain. Spot urine test to assess the porphyrin precursors delta-aminolevulinic acid and porphobilinogen can provide a timely diagnosis during an acute attack. Timely treatment with intravenous heme, carbohydrate loading, and avoidance of porphyrinogenic medications can prevent further neurological morbidity and mortality.

Clinical, biochemical, and genetic characterization of acute hepatic porphyrias in a cohort of Argentine patients.

BackgroundAcute Hepatic Porphyrias (AHPs) are characterized by an acute neuroabdominal syndrome including both neuropsychiatric symptoms and neurodegenerative changes. Two main hypotheses explain the pathogenesis of nervous system dysfunction: (a) the ROS generation by autooxidation of 5‐aminolevulinic acid accumulated in liver and brain; (b) liver heme deficiency and in neural tissues that generate an oxidative status, a component of the neurodegenerative process.MethodsWe review results obtained from Acute Intermittent Porphyria (AIP) and Variegate Porphyria (VP) families studied at clinical, biochemical, and molecular level at the CIPYP in Argentina. The relationship between the porphyric attack and oxidative stress was also evaluated in AHP patients and controls, to identify a marker of neurological dysfunction.ResultsWe studied 116 AIP families and 30 VP families, 609 and 132 individuals, respectively. Genotype/phenotype relation was studied. Oxidative stress parameters and plasma homocysteine levels were measured in 20 healthy volunteers, 22 AIP and 12 VP individuals.ConclusionNo significant difference in oxidative stress parameters and homocysteine levels between the analyzed groups were found.

High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach.

Acute porphyria attacks are associated with the strong up-regulation of hepatic heme synthesis and over-production of neurotoxic heme precursors. First-line therapy is based on carbohydrate loading. However, altered glucose homeostasis could affect its efficacy. Our first aim was to investigate the prevalence of insulin resistance (IR) in an observational case-control study including 44 Spanish patients with acute intermittent porphyria (AIP) and 55 age-, gender- and BMI-matched control volunteers. Eight patients (18.2%) and one control (2.3%, p = 0.01) showed a high HOMA-IR index (cut-off ≥ 3.4). Patients with IR and hyperinsulinemia showed clinically stable disease. Thus, the second aim was to evaluate the effect of the co-administration of glucose and a fast-acting or new liver-targeted insulin (the fusion protein of insulin and apolipoprotein A-I, Ins-ApoAI) in AIP mice. The combination of glucose and the Ins-ApoAI promoted partial but sustained protection against hepatic heme synthesis up-regulation compared with glucose alone or co-injected with fast-acting insulin. In a prevention study, Ins-ApoAI improved symptoms associated with a phenobarbital-induced attack but maintained high porphyrin precursor excretion, probably due to the induction of hepatic mitochondrial biogenesis mediated by apolipoprotein A-I. In conclusion, a high prevalence of IR and hyperinsulinemia was observed in patients with AIP. The experimental data provide proof-of-concept for liver-targeted insulin as a way of enhancing glucose therapy for AIP.

Acute hepatic porphyrias for the neurologist: current concepts and perspectives.

Acute hepatic porphyrias represent an expanding group of complex inherited metabolic disorders due to inborn errors of metabolism involving heme biosynthesis. We aimed to review the main clinical and therapeutic aspects associated with acute hepatic porphyrias. The authors provided a wide non-systematic review of current concepts and recently acquired knowledge about acute hepatic porphyrias. 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. This review article highlights the main biochemical, pathophysiological, clinical, and therapeutic aspects of acute hepatic porphyrias in clinical practice.

Acute Intermittent Porphyria - A Case Presentation

Acute intermittent porphyria (AIP) is a rare autosomal dominant metabolic disorder affecting the production of haem, resulting from deficiency of porphobilinogen (PBG) deaminase. It is the most common form of acute porphyrias. The major symptom of an acute attack is abdominal pain, often accompanied by vomiting, hypertension and tachycardia. Attacks are most common in young women but rare before puberty or after menopause. Severe acute attacks may require hospitalisation. The most common triggers for acute attack are medications, weight loss, diet and surgery. Elevated urine PBG confirms the diagnosis of AIP. The treatment for acute porphyria includes administering intravenous haemin or glucose. This article outlines the disease process and its management. A case report is presented focusing on the nursing management of a patient with AIP using nursing process approach.

Development of siRNA Therapeutics for the Treatment of Liver Diseases.

Small interfering RNA (siRNA)-based therapeutics holds the promise to treat a wide range of human diseases that are currently incurable using conventional therapies. Most siRNA therapeutic efforts to date have focused on the treatment of liver diseases due to major breakthroughs in the development of efficient strategies for delivering siRNA drugs to the liver. Indeed, the development of lipid nanoparticle-formulated and GalNAc-conjugated siRNA therapeutics has resulted in recent FDA approvals of the first siRNA-based drugs, patisiran for the treatment of hereditary transthyretin amyloidosis and givosiran for the treatment of acute hepatic porphyria, respectively. Here, we describe the current strategies for delivering siRNA drugs to the liver and summarize recent advances in clinical development of siRNA therapeutics for the treatment of liver diseases.

Givosiran to treat acute porphyria

Porphyrias are a family of rare diseases chiefly due to inborn errors of heme biosynthesis. The porphyrias are generally characterized either by the main site of overproduction of heme precursors (hepatic or erythropoietic) or the main clinical manifestations (acute or cutaneous). The regulation of 5- (or δ)-aminolevulinic acid synthase 1 (ALAS1) plays a key role in the pathway of normal hepatic heme synthesis, providing insight into the pathophysiologic mechanisms and potential therapeutic targets for the treatment of the porphyrias. Givosiran (Givlaari; Alnylam Pharmaceuticals) is an ALAS1-directed small interfering RNA (siRNA) which has been developed for the treatment of acute hepatic porphyria (AHP). It was first approved in 2019 by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with AHP, and it received also approval in the E.U. in 2020 for the treatment of AHP in adults and adolescents aged 12 years and older.

Acute Variegate Porphyria in a Professional Bodybuilder after Starting a High-protein Diet and Treatment with Testosterone.

Acute Variegate Porphyria in a Professional Bodybuilder after Starting a High-protein Diet and Treatment with Testosterone.

Givosiran, a novel treatment for acute hepatic porphyrias

ABSTRACT Introduction Acute hepatic porphyrias (AHPs) are a group of rare genetic disorders that affect the enzymes of the heme biosynthetic pathway. Patients have a varied presentation, but attacks of severe abdominal pain are the cardinal feature. Until recently, IV hemin was the only definitive treatment option available. Areas covered We summarize salient features of AHP and the work leading to clinical studies of givosiran and to its approval by the US FDA and the EMA. Givosiran is a novel siRNA therapeutic agent that targets hepatic 5-aminolevulinic acid (ALA) synthase-1, the first and rate limiting enzyme in the heme biosynthetic pathway. It has been effective in decreasing the levels of hepatic ALA synthase-1 mRNA, levels of ALA, which likely is the chief neurotoxin, and the composite attack rates in patients with AHP. The drug can cause elevated liver enzymes, elevations in serum creatinine, and injection site reactions. Single doses, given to asymptomatic persons with AIP who are chronic high excretors of ALA and porphobilinogen, caused decreases in CYP1A2 and CYP2D6 activity, raising concern for drug interactions. Expert opinion Givosiran is expensive; insurance plans are likely to limit its availability to patients with well-documented AHP and frequent and severe acute attacks.

Hepatocellular Carcinoma in Acute Hepatic Porphyrias: Results from the Longitudinal Study of the U.S. Porphyrias Consortium

The risk for hepatocellular carcinoma (HCC) is increased in acute hepatic porphyrias (AHP). The aim of this study was to explore the clinicopathologic characteristics, outcomes, and frequency of HCC in patients with AHP in the United States. This cross-sectional analysis evaluated patients with HCC in a multicenter, longitudinal study of AHP. Among 327 patients with AHP, 5 (1.5%) were diagnosed with HCC. Of the 5 HCC cases, 4 had acute intermittent porphyria and 1 had variegate porphyria, confirmed by biochemical and/or genetic testing. All patients were white females, with a median age of 27years (range 21-75) at diagnosis. The median age at HCC diagnosis was 69years (range 61-74). AHP was asymptomatic in 2 patients; 2 reported sporadic attacks; and 1 reported recurrent attacks (>4 attacks/year). All patients had a single HCC lesion on liver imaging that was 1.8-6.5 centimeters in diameter. Serum alpha fetoprotein levels were below 10ng/mL in all 4 patients with available results. Four patients underwent liver resection, and 1 was treated with radioembolization. No significant inflammation or fibrosis was found in adjacent liver tissues of 3 patients who underwent liver resection. Two patients developed recurrence of HCC at 22 and 26months following liver resection. All patients are alive with survival times from HCC diagnosis ranging from 26-153months. In this U.S. study, 1.5% of patients with AHP had HCC. HCC in AHP occurred in the absence of cirrhosis, which contrasts with other chronic liver diseases. Patients with AHP, regardless of clinical attacks, should be screened for HCC, beginning at age 50. The pathogenesis of hepatocarcinogenesis in AHP is unknown and needs further investigation.

Eighteen-Month Interim Analysis of Efficacy and Safety of Givosiran, an RNAi Therapeutic for Acute Hepatic Porphyria, in the Envision Open Label Extension

Eighteen-Month Interim Analysis of Efficacy and Safety of Givosiran, an RNAi Therapeutic for Acute Hepatic Porphyria, in the Envision Open Label Extension

Cost savings with hemin versus givosiran for the treatment of patients with acute intermittent porphyria (AIP)

Objective Since 1983, hemin has been FDA-approved for acute intermittent porphyria (AIP) attacks. In 2019, FDA approved givosiran for the treatment of adults with acute hepatic porphyria. The objective of this research was to estimate and compare the total cost of AIP-related healthcare for patients treated with hemin or givosiran. Methods A microsimulation cost model was developed to estimate the annual economic impact of hemin versus givosiran treatment for patients with AIP from the U.S. healthcare payer perspective. Hemin treatment costs were calculated from the Hemin Shipment Data in which patients were defined as receiving acute attack treatment or prophylaxis treatment based on shipment patterns. Three separate hemin subpopulations were considered: one attack per year, multiple attacks per year, and hemin prophylaxis. Treatment costs for givosiran (with hemin for acute attacks) were simulated based on Phase III trial efficacy results applied to individual treatment histories in the Hemin Shipment Data. Other healthcare utilization was also considered. Outcomes were annualized and expenditures inflated to 2019. Results For all patients with AIP, the average annual total cost of care with hemin was 78% lower (difference = $482,113; 95% CI=$373,638–$594,778) than the average annual total cost of care with givosiran. Average annual total cost of care with hemin was between 46% and 92% lower than givosiran for the three hemin subpopulations: one attack per year (difference = $545,219; 95% CI=$436,584–$657,239), multiple attacks per year (difference = $459,366; 95% CI=$350,291–$574,403), and hemin prophylaxis (difference = $311,950; 95% CI=$191,898–$435,893). Cost savings with hemin were robust to one-way and probabilistic sensitivity as well as scenario analyses. Conclusions Hemin is expected to provide cost savings compared to givosiran for all AIP patients and subpopulations. Lower annual total costs of care with hemin range from $311,950 to $545,219 less depending on whether the patient uses hemin prophylactically or for acute treatment attacks.

5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin

Background5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP) is an ultrarare autosomal recessive disease, with only eight documented cases, all of whom were males. Although classified as an acute hepatic porphyria (AHP), induction of the rate limiting hepatic enzyme 5-aminolevulinic acid synthase-1 (ALAS1) has not been demonstrated, and the marrow may also contribute excess 5-aminolevulinic acid (ALA). Two patients have died and reported follow up for the others is limited, so the natural history of this disease is poorly understood and treatment experience limited. MethodsWe report new molecular findings and update the clinical course and treatment of the sixth reported ADP patient, now 31 years old and the only known case in the Americas, and review published data regarding genotype-phenotype correlation and treatment. ResultsCirculating hepatic 5-aminolevulinic acid synthase-1 (ALAS1) mRNA was elevated in this case, as in other AHPs. Gain of function mutation of erythroid specific ALAS2 – an X-linked modifying gene in some other porphyrias – was not found. Seven reported ADP cases had compound heterozygous ALAD mutations resulting in very low residual ALAD activity and symptoms early in life or adolescence. One adult with a germline ALAD mutant allele developed ADP in association with a clonal myeloproliferative disorder, polycythemia vera. ConclusionsElevation in circulating hepatic ALAS1 and response to treatment with hemin indicate that the liver is an important source of excess ALA in ADP, although the marrow may also contribute. Intravenous hemin was effective in most reported cases for treatment and prevention of acute attacks of neurological symptoms.

Neuropsychiatric Manifestations of Acute Intermittent Porphyria – A Diagnostic Dilemma

Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway (also called porphyrin pathway). They are broadly classified as acute (hepatic) porphyrias and cutaneous (erythropoietic) porphyrias, based on the site of the overproduction and accumulation of the porphyrins or their chemical precursors. They manifest with either neuropsychiatric complications or skin problems or occasionally both. A clinically induced and histologically identical condition is called pseudo porphyria which is characterized by normal serum and urine porphyrin levels.