Liver transplantation in propionic and methylmalonic acidemia: A single center study with literature review

Abstract

Background: Organic acidemias, especially propionic acidemia (PA) and methylmalonic acidemia (MMA), may manifest clinically within the first few hours to days of life. The classic presentation in the newborn period includes metabolic acidosis, hyperlactatemia, and hyperammonemia that is precipitated by unrestricted protein intake. Implementation of newborn screening to diagnose and initiate early treatment has facilitated a reduction in neonatal mortality and improved survival. Despite early diagnosis and appropriate management, these individuals are prone to have recurrent episodes of metabolic acidosis and hyperammonemia resulting in frequent hospitalizations. Liver transplantation (LT) has been proposed as a treatment modality to reduce metabolic decompensations which are not controlled by medical management. Published reports on the outcome of LT show heterogeneous results regarding clinical and biochemical features in the post transplantation period. As a result, we evaluated the outcomes of LT in our institution and compared it to the previously published data.

Study design/methods: We performed a retrospective chart review of nine individuals with PA or MMA who underwent LT and two individuals with MMA who underwent LT and kidney transplantation (KT). Data including number of hospitalizations, laboratory measures, cardiac and neurological outcomes, dietary protein intake, and growth parameters were collected.

Results: The median age of transplantation for subjects with MMA was 7.2 years with a median follow up of 4.3 years. The median age of transplantation for subjects with PA was 1.9 years with a median follow up of 5.4 years. The survival rate at 1 year and 5 years post-LT was 100%. Most of our subjects did not have any episodes of hyperammonemia or pancreatitis post-LT. There was significant reduction in plasma glycine post-LT. One subject developed mild elevation in ammonia post-LT on an unrestricted protein diet, suggesting that protein restriction may be indicated even after LT.

Conclusion: In a large single center study of LT in MMA and PA, we show that LT may reduce the incidence of metabolic decompensation. Moreover, our data suggest that LT may be associated with reduced number of hospitalizations and improved linear growth in individuals with PA and MMA.

Keywords: Liver transplantation; Methylmalonic acidemia; Organic acidemia; Propionic acidemia.

Figure 1:

Study subjects. A: Details about the study cohort are provided. B: Clinical characteristics of the subjects in the study are provided. MMA: methylmalonic acidemia; LT: liver transplantation, KT: kidney transplantation; PA, propionic acidemia.

Figure 2:

Reductions in the number of hospitalizations in subjects with MMA and PA post-LT. Samples sizes included 3 subjects with MMA and 7 subjects with PA. Values are means ± SD. Statistical analysis included repeated measures ANOVA with main effects for disease (MMA or PA), time (pre-LT, 0-6 months post-LT, 6-12 months post-LT) and disease × time interaction. A: Subjects with MMA and PA had significantly fewer hospital admissions to the ICU pre-LT or 0-6 months post-LT versus 6-12 months post-LT (disease, p=0.29; time, p=0.02; disease × time, p=0.60). B. Subjects with MMA and PA had significantly fewer hospital admissions to the general floor pre-LT or 0-6 months post-LT versus 6-12 months post-LT (disease, p=0.67; time, p=0.04; disease × time, p=0.75). C. Subjects with MMA and PA had significantly fewer total hospital admissions pre-LT or 0-6 months post-LT versus 6-12 months post-LT (disease, p=0.52; time, p=0.003; disease × time, p=0.81). ICU: intensive care unit; LT: liver transplantation; MMA: methylmalonic acidemia; mo.: months; PA, propionic acidemia.

Figure 3:

Dietary protein intake patterns in subjects with MMA and PA pre- and post-LT. A: Ten of 11 subjects consumed 100% or more of the DRI for dietary protein pre-LT, whereas 5 of 7 subjects consumed 100% or more of the DRI for dietary protein post-LT. Protein intake data as a percentage of the DRI were missing for 4 of 11 subjects during the post-LT period because these subjects were following an unrestricted diet (n=1) or did not document their dietary protein intake (n=3). B: Subjects with MMA and PA ingested a combination of dietary protein from intact sources and amino acid medical foods pre-LT. Ten of 11 subjects transitioned to consume all dietary protein from intact sources post-LT. P3 underwent hemodialysis during the pre-LT period, which may have impacted dietary protein intake patterns. DRI: Dietary Reference Intake; LT: liver transplantation; MMA: methylmalonic acidemia; PA, propionic acidemia.

Figure 4:

Height and weight Z scores pre- and post-LT. Samples sizes included 3 subjects with MMA and 5 subjects with PA. Values are means ± SD. Statistical analysis included repeated measures ANOVA with main effects for disease (MMA or PA), time (pre-LT, 1 year post-LT, 2 years post-LT) and disease × time interaction. A. Subjects with PA had significant higher height Z scores compared to subjects with PA (disease, p=0.002). Subjects with MMA and PA had significantly greater height Z scores pre-LT or 1 year post-LT versus 2 years post-LT (time, p=0.006). There was not a significant interaction (disease × time, p=0.31). B. Height Z scores pre-LT, 1 year post-LT and 2 year post-LT are shown by subject. C. Subjects with PA had significant higher weight Z scores compared to subjects with PA (disease, p=0.0099). Weight Z scores were similar pre-LT, 1 year post-LT and 2 years post-LT in subjects with MMA and PA (time, p=0.91). There was not a significant interaction (disease × time, p=0.48). B. Height Z scores pre-LT, 1 year post-LT and 2 years post-LT are shown by subject. LT: liver transplantation; MMA: methylmalonic acidemia; PA, propionic acidemia.

Figure 5:

Plasma laboratory measures obtained pre- and post-LT in subjects with MMA and PA. Statistical analysis for Fig. 4A-B included a two-way ANOVA utilizing a completely randomized design with crossed data to assess main effects for disease (MMA or PA), treatment (pre-LT vs post-LT) and the disease × treatment interaction. Statistical analysis for Fig. 4C included a one-way ANOVA utilizing completely randomized design with crossed data to assess main effects for treatment (pre-LT vs post-LT). Both models included random effects for the subject. Results show the pre-LT laboratory measure and corresponding post-LT laboratory measure for each subject with PA (black circle) or MMA (white circle). A. Plasma C3 concentrations were similar in subjects with MMA and PA pre- and post-LT (disease, p=0.34; treatment, p=0.16; disease × treatment, p=0.19, n=2 MMA/6 PA). B. Plasma glycine concentrations significantly reduced post-LT in subjects with MMA and PA (disease, p=0.44; treatment, p=0.02; disease × treatment, p=0.053; n=3 MMA/7 PA). C. Plasma MMA concentrations were similar in subjects with MMA pre- and post-LT (treatment, p=0.36; n=3). Dotted lines indicate the reference ranges for the plasma laboratory measures, which included the following: C3, 0-870 nmol/L; glycine, 90-346 μmol/L; MMA, 0-500 nmol/L. C3: propionyl carnitine; LT: liver transplantation; MMA: methylmalonic acidemia or methylmalonic acid; NS, non-significant; PA: propionic acidemia.