Hyperhomocysteinemia in acute hepatic porphyria (AHP) and implications for treatment with givosiran.

INTRODUCTION: Homocysteine is a sulfur-containing amino acid formed in the intermediary metabolism of methionine. Amino acid metabolism and heme biosynthesis pathways are complexly intertwined. Plasma homocysteine elevation, hyperhomocysteinemia (HHcy), has been reported in patients with acute hepatic porphyria (AHP), a family of rare genetic disorders caused by defects in hepatic heme biosynthesis. AREAS COVERED: This article summarizes published case series in which givosiran, a subcutaneously administered small interfering RNA approved for AHP treatment, appeared to exacerbate dysregulated homocysteine metabolism in patients with AHP. A comprehensive exploratory analysis of ENVISION trial data demonstrated that on a population level, givosiran increased homocysteine but with wide interpatient variations, and there is no proof of correlations between HHcy and changes in efficacy or safety of givosiran. EXPERT OPINION: The strong correlation and co-increase of homocysteine and methionine suggest that HHcy associated with givosiran is likely attributable to the impaired trans-sulfuration pathway catalyzed by cystathionine ß-synthase, which uses vitamin B6 as a cofactor. Data-based consensus supports monitoring total plasma homocysteine and vitamin B6, B12, and folate levels before and during givosiran treatment; supplementing with pyridoxine/vitamin B6 in patients with homocysteine levels >100 µmol/L; and involving patients with homocysteine levels >30 µmol/L in decisions to supplement.

Acute intermittent porphyria: prevalence of pathogenic HMBS variants in China, and epidemiological survey in Hebei Province, China.

Background: Acute intermittent porphyria (AIP) is a rare inherited disorder with extremely low prevalence. Early detection of patients with potential pathogenic hydroxymethylbilane synthase (HMBS) variants is crucial for clinical prognosis. This study was designed to investigate the prevalence of pathogenic HMBS variants in Chinese population. Methods: The China Metabolic Analysis Project (ChinaMAP) database was employed to predict the prevalence of pathogenic HMBS variants in the Chinese population according to the variant interpretation guidelines of The American College of Medical Genetics and Genomics (ACMG). And the prevalence of pathogenic HMBS variants in Mixed American (AMR), African/African American (AFR), and Non-Finnish European (NFE) populations were estimated based on the Genome Aggregation Database (gnomAD) genome V3.0 database according to the guidelines of ACMG. An epidemiological investigation of AIP was conducted in Hebei Province, China through collecting the annual newly-diagnosed AIP cases of inpatients in 32 comprehensive grade III A hospitals from January 2011 to December 2020 in Hebei, China. Results: A total of 5 pathogenic/likely pathogenic (P/LP) HMBS variants were identified and the prevalence of pathogenic HMBS variants was predicted to be 1/1,765. Furthermore, based on the gnomAD genome V3.0 database, the estimated prevalence of pathogenic HMBS variants was 1/1,367, 1/1,403, and 1/621 in AMR, AFR, and NFE populations, respectively. The distribution of these variants varied among different racial populations. Moreover, AIP patients were predominantly hospitalized in comprehensive grade III A tertiary hospitals in Hebei province over a 10-year period. A total of 39 patients were newly-diagnosed with AIP, and a majority of them were female (n=36). The annual incidence between 2011 and 2017 {0.03 [95% confidence interval (CI): 0.01 to 0.11] to 0.05 (95% CI: 0.07 to 0.14) per million population} was generally lower than [0.07 (95% CI: 0.03 to 0.17) to 0.08 (95% CI: 0.03 to 0.18) per million] in 2018 and thereafter. Conclusions: China has made great strides in the management of AIP. More nationwide epidemiological surveys and study of the prevalence rate of AIP patients in China are urgently required.

Normal reference ranges for urinary δ-aminolevulinic acid and porphobilinogen levels.

Acute hepatic porphyria (AHP) is a family of rare, serious, and potentially life-threatening metabolic disorders caused by mutations in genes encoding enzymes involved in hepatic heme biosynthesis. AHP is characterized by accumulation of neurotoxic heme intermediates, δ-aminolevulinic acid (ALA), and porphobilinogen (PBG), which are thought to be causal for the disease manifestations. Novel therapeutic treatments such as givosiran, an RNA interference therapeutic that was recently approved for treatment of adults with AHP, are focused on reducing the levels of ALA and PBG in patients toward levels observed in a healthy population. While there are two published reports on the distribution of urinary ALA and PBG levels in healthy subjects, these lacked the required details to enable the calculation of reference limits for ALA and PBG. Therefore, urinary ALA and PBG levels were quantified in 150 healthy subjects using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method that is highly sensitive, specific, accurate, and reproducible. These data were used to establish the upper limit of normal (ULN) values for ALA and PBG as 1.47 and 0.137 mmol/mol Cr, respectively. Relative to these ULN values, baseline urinary ALA and PBG levels in AHP patients were found to be 9.3- to 12-fold, and 238- to 336-fold higher, respectively. Results from this study can serve as a guide to assess the effectiveness of therapeutic interventions in lowering ALA and PBG.

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.

Sex differences in vascular reactivity in mesenteric arteries from a mouse model of acute intermittent porphyria.

BACKGROUND AND AIMS: Acute intermittent porphyria (AIP) results from a partial deficiency of porphobilinogen deaminase (PBGD). Symptomatic AIP patients, most of whom are women, experience acute attacks characterized by severe abdominal pain and abrupt increases in blood pressure. Here, we characterized the reactivity of mesenteric arteries from male and female AIP mice with ~30% of normal PBGD activity and wild type C57BL/6 mice. METHODS: An acute porphyric attack was induced in AIP mice by treatment with phenobarbital. Vascular responses to K+, phenylephrine (PE), acetylcholine (ACh), and hemin were determined (Wire Multi Myograph). RESULTS: Maximal contraction to PE was increased in arteries from male and female AIP mice (p < .05) during an induced attack of acute porphyria. Female AIP arteries had increased sensitivity to PE (p < .05) even after nitric oxide (NO) blockade with Nω-nitro-L-arginine methyl ester (L-NAME) (p < .05). Maximal relaxation to ACh was similar in males and females with lower sensitivity in female AIP arteries (p < .05). Hemin induced greater relaxation in AIP arteries in both males and females (p < .05). SUMMARY/CONCLUSIONS: Sex differences in this AIP mouse model include a pro-contractile response in females. These alterations may contribute to the increased blood pressure during an acute attack and provide a novel mechanism of action whereby heme ameliorates the attacks.

Acute hepatic porphyrias: Identification of 46 hydroxymethylbilane synthase, 11 coproporphyrinogen oxidase, and 20 protoporphyrinogen oxidase novel mutations.

The acute hepatic porphyrias (AHPs) are inborn errors of heme biosynthesis, which include three autosomal dominant porphyrias, Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), and Variegate Porphyria (VP), and the ultra-rare autosomal recessive porphyria, δ-Aminolevulinic Acid Dehydratase Deficiency Porphyria (ADP). AIP, HCP, VP, and ADP each results from loss-of-function (LOF) mutations in their disease-causing genes: hydroxymethylbilane synthase (HMBS); coproporphyrinogen oxidase (CPOX); protoporphyrinogen oxidase (PPOX), and δ-aminolevulinic acid dehydratase (ALAD), respectively. During the 11-year period from January 1, 2007 through December 31, 2017, the Mount Sinai Porphyrias Diagnostic Laboratory diagnosed 315 unrelated AIP individuals with HMBS mutations, including 46 previously unreported mutations, 29 unrelated HCP individuals with CPOX mutations, including 11 previously unreported mutations, and 54 unrelated VP individuals with PPOX mutations, including 20 previously unreported mutations. Overall, of the 1692 unrelated individuals referred for AHP molecular diagnostic testing, 398 (23.5%) had an AHP mutation. Of the 650 family members of mutation-positive individuals tested for an autosomal dominant AHP, 304 (46.8%) had their respective family mutation. These data expand the molecular genetic heterogeneity of the AHPs and document the usefulness of molecular testing to confirm the positive biochemical findings in symptomatic patients and identify at-risk asymptomatic family members.

Hydroxymethylbilane synthase gene mutations and polymorphisms in Brazilian families with acute intermittent porphyria.

Acute intermittent porphyria (AIP), an autosomal dominant disorder, is caused by a deficiency of hydroxymethylbilane synthase (HMBS). In the present study, we sought to establish a correlation between HMBS activity with the presence of mutations and polymorphisms. Enzyme activity was measured in red blood cells of four Brazilian unrelated AIP families (n = 124) and in blood donors (n = 80). The HMBS mutations in AIP family members were studied by PCR-SSCP followed by direct sequencing. Six intragenic SNPs (1345 G>A, 1500 T>C, 2377 C>A, 2478 A>G, 3581 A>G, and 7064 C>A) were determined by PCR-RFLP. Abnormal SSCP patterns in exons 7, 9, 12, and 15 were observed. DNA sequencing analysis revealed one nonsense mutation, R149X, two missense mutations, G111R and L338P, and one deletion, CT 730-731. All mutation carriers had lower enzyme activity. All polymorphisms, except 2377 C>A and 7064 C>A, showed no significant differences compared with previous reports. Mutation screening allowed the detection of the missense mutation, L338P, and the 730_731delCT deletion, two as yet unreported mutations in Brazilian AIP patients. Our findings also showed a high frequency of 2478 A>G and 3581 A>G polymorphism combinations suggesting that these polymorphisms contributed to enzymatic activity reduction in our study population.

Safety of fluoxetine treatment in a case of acute intermittent porphyria.

Acute intermittent porphyria (AIP) is a metabolic disease characterized by recurrent attacks of neurological and psychiatric dysfunction. It is a rare disorder of heme metabolism that usually presents with abdominal pain, gastrointestinal symptoms and autonomic nervous system disturbances. Exposure to certain drugs, dieting, starvation and infection during pregnancy may precipitate AIP attacks. Psychiatric manifestations of AIP include mood changes, organic brain syndrome and psychosis. Here, we present a 21-year-old female patient with AIP and major depression. She had a caesarean section under general anesthesia with pentothal and her recovery time from anesthesia took longer than usual. She had a blood transfusion because of severe anemia following the operation. Three days after her discharge she was readmitted to the hospital with confusion and seizure. It was her first AIP attack and it started 6 days after caesarean section. Two months after her first attack, we saw her for anxiety and depressive symptoms. She was in severe anxiety and depression and she was put on fluoxetine (20 mg/day liquid form). Following the treatment she did not develop any other porphyria attack. Her symptoms vanished and she improved functionally. She stayed on fluoxetine for 6 months without any new AIP attack. Despite limited data regarding fluoxetine therapy in porphyria patients, it seems to be safe for the treatment of depressive and anxiety symptoms in these patients.