Safety and efficacy of liver transplantation for methylmalonic acidemia: A systematic review and meta-analysis

Jiang, Yizhou; Zhou, Guang‐Peng; Wu, Shanshan; Kong, Yuanyuan; Zhu, Zhi‐Jun; Sun, Li‐Ying

doi:10.1016/j.trre.2020.100592

Cited by 10 publications

(8 citation statements)

References 51 publications

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“…A growing number of patients with monogenic metabolic liver diseases (such as urea cycle disorders, maple syrup urine disease, MMA, and PA) undergo LT worldwide [17][18][19][20][21]. The explanted livers from those liver transplant recipients with noncirrhotic liver-based metabolic disorders are morphologically, structurally, and functionally normal except for definite metabolic deficiency.…”

Section: Discussionmentioning

confidence: 99%

Domino hepatocyte transplantation using explanted human livers with metabolic defects attenuates D-GalN/LPS-induced acute liver failure

Zhou

Jiang

et al. 2022

J Transl Med

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Background Explanted livers from patients with inherited metabolic liver diseases possess the potential to be a cell source of good-quality hepatocytes for hepatocyte transplantation (HT). This study evaluated the therapeutic effects of domino HT using hepatocytes isolated from explanted human livers for acute liver failure (ALF). Methods Isolated hepatocytes were evaluated for viability and function and then transplanted into d-galactosamine/lipopolysaccharide-induced ALF mice via splenic injection. The survival rate was analyzed by the Kaplan–Meier method and log-rank test. Liver function was evaluated by serum biochemical parameters, and inflammatory cytokine levels were measured by ELISA. The pathological changes in the liver tissues were assessed by hematoxylin–eosin staining. Hepatocyte apoptosis was investigated by TUNEL, and hepatocyte apoptosis-related proteins were detected by western blot. The localization of human hepatocytes in the injured mouse livers was detected by immunohistochemical analyses. Results Hepatocytes were successfully isolated from explanted livers of 10 pediatric patients with various liver-based metabolic disorders, with an average viability of 85.3% ± 13.0% and average yield of 9.2 × 106 ± 3.4 × 106 cells/g. Isolated hepatocytes had an excellent ability to secret albumin, produce urea, uptake indocyanine green, storage glycogen, and express alpha 1 antitrypsin, albumin, cytokeratin 18, and CYP3A4. Domino HT significantly reduced mortality, decreased serum levels of alanine aminotransferase and aspartate aminotransferase, and improved the pathological damage. Moreover, transplanted hepatocytes inhibited interleukin-6 and tumor necrosis factor-α levels. Domino HT also ameliorates hepatocyte apoptosis, as evidenced by decreased TUNEL positive cells. Positive staining for human albumin suggested the localization of human hepatocytes in ALF mice livers. Conclusion Explanted livers from patients with inheritable metabolic disorders can serve as a viable cell source for cell-based therapies. Domino HT using hepatocytes with certain metabolic defects has the potential to be a novel therapeutic strategy for ALF.

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Section: Discussionmentioning

confidence: 99%

Domino hepatocyte transplantation using explanted human livers with metabolic defects attenuates D-GalN/LPS-induced acute liver failure

Zhou

Jiang

et al. 2022

J Transl Med

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“…251000), have allowed an improved understanding of the molecular pathways involved in disease pathophysiology 2–9 and the development of several small molecule 8,10,11 and genomic therapies, including mRNA, nuclease‐free AAV‐mediated editing, and AAV gene addition 12–16 that are being tested in Phase I/II clinical trials as alternative approaches to organ transplantation. Liver transplantation is currently offered as an elective surgical therapeutic approach to increasingly younger age groups, aiming at normalizing liver methylmalonyl‐CoA mutase (MMUT) enzyme activity, providing metabolic stability, improving neurological outcome and/or delaying the onset of multisystemic complications of the disease 17–23 . On the other hand, kidney or liver–kidney transplantation is offered to patients with advanced kidney disease in need of renal replacement therapy depending on the degree of associated metabolic instability and disease severity.…”

Section: Introductionmentioning

confidence: 99%

“…Liver transplantation is currently offered as an elective surgical therapeutic approach to increasingly younger age groups, aiming at normalizing liver methylmalonyl-CoA mutase (MMUT) enzyme activity, providing metabolic stability, improving neurological outcome and/or delaying the onset of multisystemic complications of the disease. [17][18][19][20][21][22][23] On the other hand, kidney or liver-kidney transplantation is offered to patients with advanced kidney disease in need of renal replacement therapy depending on the degree of associated metabolic instability and disease severity. Isolated kidney transplant as an elective surgery does not provide sufficient enzymatic activity to alleviate disease burden and avoid progression for patients at the severe end of the disease spectrum.…”

Section: Introductionmentioning

confidence: 99%

Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia

Manoli

Gebremariam

McCoy

et al. 2023

J of Inher Metab Disea

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Methylmalonic Acidemia (MMA) is a heterogenous group of inborn errors of metabolism caused by a defect in the methylmalonyl‐CoA mutase (MMUT) enzyme or the synthesis and transport of its cofactor, 5′‐deoxy‐adenosylcobalamin. It is characterized by life‐threatening episodes of ketoacidosis, chronic kidney disease, and other multiorgan complications. Liver transplantation can improve patient stability and survival and thus provides clinical and biochemical benchmarks for the development of hepatocyte‐targeted genomic therapies. Data are presented from a US natural history protocol that evaluated subjects with different types of MMA including mut‐type (N = 91), cblB‐type (15), and cblA‐type MMA (17), as well as from an Italian cohort of mut‐type (N = 19) and cblB‐type MMA (N = 2) subjects, including data before and after organ transplantation in both cohorts. Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function. We have therefore explored the use of the 1‐13C‐propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 [FGF21] and growth differentiation factor 15 [GDF15]) and kidney injury (lipocalin‐2 [LCN2]). Biomarker concentrations are higher in patients with the severe mut0‐type and cblB‐type MMA, correlate with a decreased POBT, and show a significant response postliver transplant. Additional circulating and imaging markers to assess disease burden are necessary to monitor disease progression. A combination of biomarkers reflecting disease severity and multisystem involvement will be needed to help stratify patients for clinical trials and assess the efficacy of new therapies for MMA.

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“…Liver transplantation [11][12][13][14][15], frequently performed during early infancy [16,17], or combined liver-kidney transplantation [14,15,18,19] have been considered as alternative options to medical treatment, but also isolated kidney transplantation has been proposed [15,[20][21][22][23]. Several reports suggest this procedure as an alternative and safer strategy, because the enzyme activity provided by the transplanted kidney could be sufficient to partially restore the metabolic defect [20].…”

Section: Introductionmentioning

confidence: 99%

Renal outcome and plasma methylmalonic acid levels after isolated or combined liver or kidney transplantation in patients with methylmalonic acidemia: A multicenter analysis

Strologo

Vici

Atti

et al. 2022

Molecular Genetics and Metabolism

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Safety and efficacy of liver transplantation for methylmalonic acidemia: A systematic review and meta-analysis

Cited by 10 publications

References 51 publications

Domino hepatocyte transplantation using explanted human livers with metabolic defects attenuates D-GalN/LPS-induced acute liver failure

Domino hepatocyte transplantation using explanted human livers with metabolic defects attenuates D-GalN/LPS-induced acute liver failure

Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia

Renal outcome and plasma methylmalonic acid levels after isolated or combined liver or kidney transplantation in patients with methylmalonic acidemia: A multicenter analysis

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