The burden of disease and quality of life in patients with acute hepatic porphyria: COPHASE study / Carga de la enfermedad y calidad de vida en pacientes con porfiria hepática aguda: estudio COPHASE

Background: Acute hepatic porphyria (AHP) comprises a group of rare genetic diseases characterized by neurovisceral crises that are manifested by abdominal pain and neurological and/or psychological symptoms that interfere with the ability to lead a normal life. Our objective was to determine the burden of the disease in one year and the health-related quality of life (HRQoL) in patients with AHP. Results: 28 patients were analyzed. The mean age was 36.6±10.2 years, 89.3% were women, and the average number of crises was 1.9±1.5. The average annual cost per patient was €38,255.40. 80.2% of the costs was direct medical costs, 17.5% was associated with loss of productivity and 2.3% was direct non-medical costs. 85.9% of the total cost corresponded to the crises. The intercrisis period accounted for the remaining 14.1%. The global index of the EQ-5D-5L (HRQoL) was 0.75±0.24. The dimensions of pain/discomfort, anxiety/depression and daily activities were the most affected. Leisure, travel/vacations and household activities were the most affected daily activities. 53.6% of patients required a caregiver due to AHP. 92.9% did not present overload and 7.1% presented extreme overload. Conclusions: Patients with AHP are associated with a high economic impact and an affected HRQoL in the pain/discomfort dimension, with a negative impact on the performance of daily activities and a risk of psychiatric diseases.(AU)

Antecedentes: La porfiria hepática aguda (PHA) comprende un grupo de enfermedades genéticas raras caracterizadas por crisis neuroviscerales que se manifiestan por dolor abdominal y síntomas neurológicos y/o psicológicos que interfieren en la capacidad de llevar una vida normal. Nuestro objetivo fue determinar la carga de la enfermedad en un año y la calidad de vida relacionada con la salud (CVRS) en pacientes con PHA. Resultados: Se analizaron 28 pacientes. La edad media fue de 36,6±10,2 años, el 89,3% eran mujeres y la media de crisis fue de 1,9±1,5. El coste medio anual por paciente fue de 38.255,40€. El 80,2% de los costes fueron costes médicos directos, el 17,5% estuvieron asociados a pérdida de productividad y el 2,3% fueron costes directos no médicos. El 85,9% del coste total correspondió a las crisis. El período entre crisis representó el 14,1% restante. El índice global del EQ-5D-5L (HRQoL) fue de 0,751±0,24. Las dimensiones de dolor/malestar, ansiedad/depresión y actividades cotidianas fueron las más afectadas. Ocio, viajes/vacaciones y actividades del hogar fueron las actividades diarias más afectadas. El 53,6% de los pacientes requirieron un cuidador debido a la PHA. El 92,9% no presentaron sobrecarga y el 7,1% presentaron sobrecarga extrema. Conclusiones: Los pacientes con PHA se asocian con un alto impacto económico y una CVRS afectada en la dimensión dolor/malestar, con impacto negativo en el desempeño de las actividades diarias y riesgo de enfermedades psiquiátricas.(AU)

The burden of disease and quality of life in patients with acute hepatic porphyria: COPHASE study.

BACKGROUND: Acute hepatic porphyria (AHP) comprises a group of rare genetic diseases characterized by neurovisceral crises that are manifested by abdominal pain and neurological and/or psychological symptoms that interfere with the ability to lead a normal life. Our objective was to determine the burden of the disease in one year and the health-related quality of life (HRQoL) in patients with AHP. RESULTS: 28 patients were analyzed. The mean age was 36.6±10.2 years, 89.3% were women, and the average number of crises was 1.9±1.5. The average annual cost per patient was €38,255.40. 80.2% of the costs was direct medical costs, 17.5% was associated with loss of productivity and 2.3% was direct non-medical costs. 85.9% of the total cost corresponded to the crises. The intercrisis period accounted for the remaining 14.1%. The global index of the EQ-5D-5L (HRQoL) was 0.75±0.24. The dimensions of pain/discomfort, anxiety/depression and daily activities were the most affected. Leisure, travel/vacations and household activities were the most affected daily activities. 53.6% of patients required a caregiver due to AHP. 92.9% did not present overload and 7.1% presented extreme overload. CONCLUSIONS: Patients with AHP are associated with a high economic impact and an affected HRQoL in the pain/discomfort dimension, with a negative impact on the performance of daily activities and a risk of psychiatric diseases.

[Acute hepatic porphyrias: pathophysiology and pathogenesis of acute attacks].

Heme is an iron-containing molecule essential for virtually all living organisms. However, excessive heme is cytotoxic, necessitating tight regulation of intracellular heme concentration. The acute hepatic porphyrias (AHPs) are a group of rare inborn errors of heme biosynthesis that are characterized by episodic acute neurovisceral attacks that are precipitated by various factors. The AHPs are often misdiagnosed, as the acute attack symptom are non-specific and can be attributed to other more common causes. Understanding how heme biosynthesis is dysregulated in AHP patients and the mechanism by which acute attacks are precipitated will aid in accurate and rapid diagnoses, and subsequently, appropriate treatment of these disorders. Therefore, this review article will focus on the biochemical and molecular changes that occur during an acute attack and present what is currently known regarding the underlying pathogenesis of acute attacks.

A high urinary urobilinogen/serum total bilirubin ratio indicates acute hepatic porphyria in patients with abdominal pain.

Acute hepatic porphyria (AHP) has always been a diagnostic dilemma for physicians due to its variable symptoms. Correct diagnosis mainly depends on the detection of an elevated urinary porphobilinogen (PBG), which is not a routine test and highly relies on the physician's awareness of AHP. In the present study, we identified a more convenient indicator during routine examinations to improve the diagnosis of AHP. We found that AHP patients showed a significant higher "FALSE" urinary urobilinogen level caused by urinary PBG during the urinalysis when detected by strips impregnated with Ehrlich reagent (P < 0.05). And a remarkable increase in the urinary urobilinogen/serum total bilirubin ratio was observed in AHP patients. The area under the ROC curve of this ratio for AHP was 1.000 (95% confidence interval 1.000-1.000, P < 0.01). A cutoff value of 3.22 for this ratio yielded a sensitivity of 100% and a specificity of 100% to distinguish AHP patients from the controls. Thus, we proved that a "falsely" high urinary urobilinogen level that was adjusted by the serum total bilirubin level (urinary urobilinogen/serum total bilirubin ratio) could be used as a sensitive and specific screening marker for AHP in patients with abdominal pain.

Clinical features of acute attacks, chronic symptoms, and long-term complications among patients with acute hepatic porphyria in Japan: a real-world claims database study.

BACKGROUND: Acute hepatic porphyria (AHP) is a family of rare genetic diseases, including acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and delta-aminolevulinic acid dehydratase-deficient porphyria. The objective of this retrospective cohort study was to provide information on the clinical features of AHP in Japan-including acute attacks, chronic symptoms, and long-term complications. METHODS: Patients with AHP between April 2008 and June 2020 were selected from Japan's Medical Data Vision claims database. Patients with AHP were matched 1:10, by sex and age, to patients without AHP. The outcomes were evaluated overall, for patients age ≥ 55 years, and for the matched population. RESULTS: A total of 391 patients with AHP were included from the Japanese Medical Data Vision database. During the observation period (April 2008-June 2020), 18.2% (71/391) of patients experienced 1 acute attack and 10.5% (41/391) experienced ≥ 2 attacks. Chronic symptoms with rates ~ 10% or higher in the AHP population compared with the matched population included neurotic, stress-related, and somatoform disorders (21.7% vs. 6.7% [15.0% difference]); sleep disorders (23.0% vs. 9.9% [13.1% difference]); other and unspecified abdominal pain (13.6% vs. 3.7% [9.9% difference]); and nausea and vomiting, excluding chemotherapy-induced emesis (17.9% vs. 8.1% [9.8% difference]). Long-term complications with higher incidence rates in the AHP population compared with the matched population included fibrosis and cirrhosis of liver (15.9% vs. 3.0% [12.9% difference]), polyneuropathies and other disorders of the peripheral nervous system (20.5% vs. 7.9% [12.6% difference]), liver cancer (16.9% vs. 4.7% [12.2% difference]), renal failure (16.4% vs. 4.3% [12.1% difference]), and hypertension (26.1% vs. 18.8% [7.3% difference]). Among AHP patients age ≥ 55 years, the most common long-term complications were hypertension, kidney failure, and liver cancer. CONCLUSIONS: In Japan, patients with AHP experience a high clinical burden in terms of acute attacks, chronic symptoms, and long-term complications. The clinical burden related to chronic symptoms and long-term complications was substantially higher in Japanese patients with AHP compared with a matched population without AHP. Recognizing these signs and symptoms of AHP may aid physicians in making an earlier diagnosis, which may help patients avoid attack triggers, implement disease management, and reduce lifetime disease burden.

The Hepatic Porphyrias: Revealing the Complexities of a Rare Disease.

The porphyrias are a group of metabolic disorders that are caused by defects in heme biosynthesis pathway enzymes. The result is accumulation of heme precursors, which can cause neurovisceral and/or cutaneous photosensitivity. Liver is commonly either a source or target of excess porphyrins, and porphyria-associated hepatic dysfunction ranges from minor abnormalities to liver failure. In this review, the first of a three-part series, we describe the defects commonly found in each of the eight enzymes involved in heme biosynthesis. We also discuss the pathophysiology of the hepatic porphyrias in detail, covering epidemiology, histopathology, diagnosis, and complications. Cellular consequences of porphyrin accumulation are discussed, with an emphasis on oxidative stress, protein aggregation, hepatocellular cancer, and endothelial dysfunction. Finally, we review current therapies to treat and manage symptoms of hepatic porphyria.

Quantification of Urine and Plasma Porphyrin Precursors Using LC-MS in Acute Hepatic Porphyrias: Improvement in Routine Diagnosis and in the Monitoring of Kidney Failure Patients.

BACKGROUND: The quantification of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) in urine are the first-line tests for diagnosis and monitoring of acute hepatic porphyrias (AHP). Ion-exchange chromatography (IEC), which is time- and staff-consuming and limited to urine, is still the preferred method in many specialized laboratories, despite the development of mass spectrometry-based methods. METHODS: We describe a new LC-MS method that allows for rapid and simple quantification of ALA and PBG in urine and plasma with an affordable instrument that was used to analyze 2260 urine samples and 309 blood samples collected in 2 years of routine activity. The results were compared to those obtained with IEC, and urine reference ranges and concentrations in asymptomatic carriers were determined. Plasma concentrations were measured in healthy subjects and subgroups of symptomatic and asymptomatic AHP carriers. RESULTS: In urine, the clinical decision limits were not impacted by the change of method despite discrepancies in low absolute concentrations, leading to lower normal values. Two-thirds of asymptomatic AHP carriers (with the exception of coproporphyria carriers) showed an increased urine PBG concentration. Urine and plasma levels showed a good correlation except in patients with kidney disease in whom the urine/plasma ratio was relatively low. CONCLUSION: We described an LC-MS based method for the routine diagnosis and monitoring of AHP that allows for the detection of more asymptomatic carriers than the historical method. Blood analysis appears to be particularly relevant for patients with kidney disease, where urine measurement underestimates the increase in ALA and PBG levels.

Acute hepatic porphyrias: Recommendations for diagnosis and management with real-world examples.

Acute hepatic porphyria (AHP) is a group of four rare inherited diseases, each resulting from a deficiency in a distinct enzyme in the heme biosynthetic pathway. Characterized by acute neurovisceral symptoms that may mimic other medical and psychiatric conditions, lack of recognition of the disease often leads to a delay in diagnosis and initiation of effective treatment. Biochemical testing for pathway intermediates that accumulate when the disease is active forms the basis for screening and establishing a diagnosis. Subsequent genetic analysis identifies the pathogenic variant, supporting screening of family members and genetic counseling. Management of AHP involves avoidance of known exogenous and hormonal triggers, symptomatic treatment, and prevention of recurrent attacks. Here we describe six case studies from our own real-world experience to highlight current recommendations and challenges associated with the diagnosis and long-term management of the disease.

Maternal and fetal outcomes in acute hepatic porphyria: A Swedish National Cohort Study.

Current knowledge of pregnancy and perinatal outcomes in women with acute hepatic porphyria (AHP) is largely based on biochemical disease models, case reports, and case series. We performed a nationwide, registered-based cohort study to investigate the association between maternal AHP and the risk of adverse pregnancy and perinatal outcomes. All women in the Swedish Porphyria Register with confirmed AHP aged 18 years or older between 1987 and 2015 and matched general population comparators, with at least one registered delivery in the Swedish Medical Birth Register were included. Risk ratios (RRs) of pregnancy complications, delivery mode and perinatal outcomes were estimated and adjusted for maternal age at delivery, area of residency, birth year and parity. Women with acute intermittent porphyria (AIP), the most common form of AHP, were further categorized according to maximal lifetime urinary porphobilinogen (U-PBG) levels. The study included 214 women with AHP and 2174 matched comparators. Women with AHP presented with a higher risk for pregnancy-induced hypertensive disorder (aRR 1.73, 95% CI 1.12-2.68), gestational diabetes (aRR 3.41, 95% CI 1.69-6.89), and small-for-gestational-age birth (aRR 2.08, 95% CI 1.26-3.45). In general, RRs were higher among women with AIP who had high lifetime U-PBG levels. Our study shows an increased risk for pregnancy induced hypertensive disease, gestational diabetes, and small for gestational age births for AHP women, with higher relative risks for women with biochemically active AIP. No increased risk for perinatal death or malformations was observed.

RNA interference therapy in acute hepatic porphyrias.

The acute hepatic porphyrias (AHPs) are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks precipitated by factors that upregulate hepatic 5-aminolevulinic acid synthase 1 (ALAS1) activity. Induction of hepatic ALAS1 leads to the accumulation of porphyrin precursors, in particular 5-aminolevulinic acid (ALA), which is thought to be the neurotoxic mediator leading to acute attack symptoms such as severe abdominal pain and autonomic dysfunction. Patients may also develop debilitating chronic symptoms and long-term medical complications, including kidney disease and an increased risk of hepatocellular carcinoma. Exogenous heme is the historical treatment for attacks and exerts its therapeutic effect by inhibiting hepatic ALAS1 activity. The pathophysiology of acute attacks provided the rationale to develop an RNA interference therapeutic that suppresses hepatic ALAS1 expression. Givosiran is a subcutaneously administered N-acetylgalactosamine-conjugated small interfering RNA against ALAS1 that is taken up nearly exclusively by hepatocytes via the asialoglycoprotein receptor. Clinical trials established that the continuous suppression of hepatic ALAS1 mRNA via monthly givosiran administration effectively reduced urinary ALA and porphobilinogen levels and acute attack rates and improved quality of life. Common side effects include injection site reactions and increases in liver enzymes and creatinine. Givosiran was approved by the US Food and Drug Administration and European Medicines Agency in 2019 and 2020, respectively, for the treatment of patients with AHP. Although givosiran has the potential to decrease the risk of chronic complications, long-term data on the safety and effects of sustained ALAS1 suppression in patients with AHP are lacking.

Pharmacokinetic-pharmacodynamic model of urinary δ-aminolevulinic acid reduction after givosiran treatment in patients with acute hepatic porphyria.

Givosiran, an RNA interference-based therapeutic, is a recent addition to the limited treatment armamentarium for acute hepatic porphyria (AHP). As a small interfering RNA that is selectively taken up in the liver, both the mechanism and targeted delivery create a complex relationship between givosiran pharmacokinetics (PK) and the pharmacodynamic (PD) response. Using pooled data from phase I-III clinical trials of givosiran, we developed a semimechanistic PK/PD model to describe the relationship between predicted liver and RNA-induced silencing complex concentrations of givosiran and the associated reduction in synthesis of δ-aminolevulinic acid (ALA), a toxic heme intermediate that accumulates in patients with AHP, contributing to disease pathogenesis. Model development included quantification of variability and evaluation of covariate effects. The final model was used to assess the adequacy of the recommended givosiran dosing regimen across demographic and clinical subgroups. The population PK/PD model adequately described the time course of urinary ALA reduction with various dosing regimens of givosiran, the interindividual variability across a wide range of givosiran doses (0.035-5 mg/kg), and the influence of patient characteristics. None of the covariates tested had a clinically relevant effect on PD response that would necessitate dose adjustment. For patients with AHP, including adults, adolescents, and patients with mild to moderate renal impairment or mild hepatic impairment, the 2.5-mg/kg once monthly dosing regimen of givosiran results in clinically meaningful ALA lowering, reducing the risk for AHP attacks.

Pathogenesis of acute encephalopathy in acute hepatic porphyria.

Acute encephalopathy (AE) can be a manifestation of an acute porphyric attack. Clinical data were studied in 32 patients during AE with or without polyneuropathy (PNP) together with 12 subjects with PNP but no AE, and 17 with dysautonomia solely. Brain neuroimaging was done in 20 attacks during AE, and PEPT2 polymorphisms were studied in 56 subjects, 24 with AE. AE manifested as a triad of seizures, confusion and/or blurred vision. Symptoms lasting 1-5 days manifested 3-19 days from the onset of an attack. 55% of these patients had acute PNP independent of AE. Posterior reversible encephalopathy syndrome (PRES) was detected in 42% of the attacks. These patients were severely affected and hyponatremic (88%). Reversible segmental vasoconstriction was rare. There was no statistical difference in hypertension or urinary excretion of porphyrin precursors among the patients with or without AE. In 94% of the attacks with AE, liver transaminases were elevated significantly (1.5 to fivefold, P = 0.034) compared to a normal level in 87% of the attacks with dysautonomia, or in 25% of patients with PNP solely. PEPT2*2/2 haplotype was less common among patients with AE than without (8.3% vs. 25.8%, P = 0.159) and in patients with PNP than without (9.5% vs. 22.9%, P = 0.207), suggesting a minor role, if any, in acute neurotoxicity. In contrast, PEPT2*2/2 haplotype was commoner among patients with chronic kidney disease (P = 0.192). Acute endothelial dysfunction in porphyric encephalopathy could be explained by a combination of abrupt hypertension, SIADH, and acute metabolic and inflammatory factors of hepatic origin.

[Acute hepatic porphyrias]. / Akute hepatische Porphyrien.

Acute porphyrias are caused by rare hereditary disorders of hepatic heme biosynthesis. Episodes of accumulating neurotoxic metabolites lead to multisystemic symptoms such as visceral pain, autonomic dysregulation, neurocognitive impairment, hyponatremia, and occasionally motor paralysis. In addition to protracted non-emergency courses, acute life-threatening crises can occur, often triggered by infection, medication, fasting, or hormonal stimuli. Since the clinical presentation is nonspecific and multifaceted, many patients have gone through a long odyssey until they receive a diagnosis. Acute attacks often lead to presenting initially to the emergency department, where acute hepatic porphyria (AHP) is easily overlooked in the differential diagnosis. Establishing the diagnosis requires a high level of genuine suspicion (e.g., cluster of signs and symptoms along with certain patterns of health care resource utilization). The initial diagnostic work-up requires the measurement of metabolites in the urine. Emergency management consists of infusions of glucose and heme arginate along with symptomatic therapy. However, porphyrinogenic agents must be strictly avoided ( www.drugs-porphyria.org ). After initial diagnosis, a thorough work-up should be done at a porphyria center (confirming the diagnosis, education, genetic counselling) and issuance of an emergency identification card is mandatory. If the frequency of relapses is high, new targeted prophylactic therapies have proven effective. Patients with known porphyria require special attention in any acute medical condition in order to avoid porphyrinogenic triggers and to exclude threatening differential diagnosis (e.g., sepsis) by consistent basic diagnostics.

Population Pharmacokinetic Analysis of the RNAi Therapeutic Givosiran in Patients with Acute Hepatic Porphyria.

BACKGROUND AND OBJECTIVE: Givosiran, approved for the treatment of acute hepatic porphyria (AHP), is the first subcutaneously administered RNAi therapeutic. This analysis was undertaken to describe the plasma pharmacokinetics (PK) of givosiran and its active metabolite, AS(N-1)3' givosiran, and to identify factors that contribute to intersubject PK variability. METHODS: A population PK model was developed using data from givosiran clinical trials that enrolled patients with AHP or who were asymptomatic chronic high excreters (CHEs) of toxic heme intermediates. Givosiran and AS(N-1)3' givosiran PK were modeled simultaneously using non-linear mixed-effects modeling. RESULTS: Plasma PK of givosiran was best described by a two-compartment model. Givosiran absorption after subcutaneous administration and conversion of givosiran to AS(N-1)3' givosiran were incorporated as first-order processes. Hepatic clearance was the major route of elimination from the central compartment, with renal clearance accounting for < 20% of the total clearance. Body weight, East Asian ethnicity, and renal impairment were significant covariates in the model; however, none of the covariates evaluated resulted in clinically meaningful differences in plasma exposures of givosiran and AS(N-1)3' givosiran. The model adequately described observed concentrations and variability across a wide range of dose levels. Model-derived simulations showed similar exposures for givosiran and its active metabolite in adults and adolescents. CONCLUSIONS: The PK of givosiran and its active metabolite were not significantly affected by demographic or clinical parameters that would require adjustment from the approved body weight-based dose of givosiran 2.5 mg/kg once monthly.