PMID- 35929959
OWN - NLM
STAT- MEDLINE
DCOM- 20221027
LR  - 20221027
IS  - 1747-4132 (Electronic)
IS  - 1747-4124 (Linking)
VI  - 16
IP  - 9
DP  - 2022 Sep
TI  - Hyperhomocysteinemia in acute hepatic porphyria (AHP) and implications for 
      treatment with givosiran.
PG  - 879-894
LID - 10.1080/17474124.2022.2110469 [doi]
AB  - 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 beta-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 mumol/L; and involving patients with homocysteine levels >30 mumol/L in 
      decisions to supplement.
FAU - Ventura, Paolo
AU  - Ventura P
AUID- ORCID: 0000-0003-1893-1914
AD  - Department of Surgical and Medical Sciences for Children and Adults, Internal 
      Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy.
FAU - Sardh, Eliane
AU  - Sardh E
AD  - Porphyria Centre Sweden, Centre for Inherited Metabolic Diseases, Department of 
      Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University 
      Hospital, Stockholm, Sweden.
FAU - Longo, Nicola
AU  - Longo N
AD  - Division of Medical Genetics, Departments of Pediatrics and Pathology, University 
      of Utah, Salt Lake City, UT, USA.
FAU - Balwani, Manisha
AU  - Balwani M
AD  - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount 
      Sinai, New York, NY, USA.
FAU - Plutzky, Jorge
AU  - Plutzky J
AD  - Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Gouya, Laurent
AU  - Gouya L
AD  - Centre Francais des Porphyries, Paris, France.
FAU - Phillips, John
AU  - Phillips J
AD  - Division of Hematology and Hematologic Malignancies, Department of Internal 
      Medicine, University of Utah, Salt Lake City, UT, USA.
FAU - Rhyee, Sean
AU  - Rhyee S
AD  - Alnylam Pharmaceuticals, Cambridge, MA, USA.
FAU - Fanelli, Mary-Jean
AU  - Fanelli MJ
AD  - Alnylam Pharmaceuticals, Cambridge, MA, USA.
FAU - Sweetser, Marianne T
AU  - Sweetser MT
AD  - Alnylam Pharmaceuticals, Cambridge, MA, USA.
FAU - Petrides, Petro E
AU  - Petrides PE
AUID- ORCID: 0000-0003-1554-8266
AD  - EPNET Center Munich, Hematology Oncology Center, Ludwig Maximilians University 
      (LMU) of Munich Medical School, Munich, Germany.
LA  - eng
PT  - Journal Article
DEP - 20220825
PL  - England
TA  - Expert Rev Gastroenterol Hepatol
JT  - Expert review of gastroenterology & hepatology
JID - 101278199
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
RN  - 935E97BOY8 (Folic Acid)
RN  - ROV204583W (givosiran)
RN  - 42VZT0U6YR (Heme)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - AE28F7PNPL (Methionine)
RN  - KV2JZ1BI6Z (Pyridoxine)
RN  - 0 (RNA, Small Interfering)
RN  - 70FD1KFU70 (Sulfur)
RN  - 8059-24-3 (Vitamin B 6)
RN  - Porphyria, Acute Hepatic
SB  - IM
MH  - Humans
MH  - Cystathionine beta-Synthase/genetics
MH  - Folic Acid
MH  - Heme
MH  - Homocysteine
MH  - *Hyperhomocysteinemia/diagnosis/drug therapy
MH  - Methionine/metabolism
MH  - *Porphyrias, Hepatic/diagnosis/drug therapy/complications
MH  - Pyridoxine
MH  - RNA, Small Interfering
MH  - Sulfur
MH  - Vitamin B 6
MH  - Clinical Trials as Topic
OTO - NOTNLM
OT  - Acute hepatic porphyria (AHP)
OT  - acute intermittent porphyria (AIP)
OT  - givosiran
OT  - homocysteine
OT  - hyperhomocysteinemia
OT  - small interfering RNA
EDAT- 2022/08/06 06:00
MHDA- 2022/10/27 06:00
CRDT- 2022/08/05 10:53
PHST- 2022/08/06 06:00 [pubmed]
PHST- 2022/10/27 06:00 [medline]
PHST- 2022/08/05 10:53 [entrez]
AID - 10.1080/17474124.2022.2110469 [doi]
PST - ppublish
SO  - Expert Rev Gastroenterol Hepatol. 2022 Sep;16(9):879-894. doi: 
      10.1080/17474124.2022.2110469. Epub 2022 Aug 25.