March 2017, v.1.2
Updated: September 2017
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- Overview
- Methodology
- Background
- Biochemical Pathway and Nutrition Treatment Rationale
- Nutrition Assessment
- Comparative Standards
- Nutrition Problem Identification
- Nutrition Intervention
- Nutrition Recommendations
- Monitoring and Evaluation
- Resources
- Benefits and Harms of Implementing the Recommendations
- Barriers to Implementation
- Areas for Future Research
- List of Tables
- References
- Contributors
- Appendix A: Recommendation Rating Definitions
- Appendix B: Terms
- Disclaimer
Derived from evidence and consensus based clinical practice
Liver transplantation is recognized as a viable treatment modality for PROP, as the liver is the major site of branched-chain amino acid (BCAA) metabolism and propionic acid (PA) production. Indications for liver transplant have included neonatal onset, frequent metabolic decompensation, uncontrolled hyperammonemia, poor growth, and sibling death, with consideration of risks and benefits of medical treatment for the patient who is a potential candidate. The metabolic team input, including contributions from the metabolic RD, is integral in the pre-transplant planning, peri-transplant period, and the post-transplant era for the individual with PROP.
The goal for nutritional management of the individual with PROP undergoing liver transplant is to establish and maintain good metabolic control prior to, during, and after surgery. The nutrient recommendations for the pre-transplant period do not change from the individual’s usual intake. The transplant and metabolic teams should prepare for possible surgical and other complications that may impact metabolic control. During the surgery, continuous IV access for appropriate D10 and sodium bicarbonate infusion is recommended. Protein intake post-transplant is less restrictive when compared to pre-transplant, with the goal of meeting the DRI for protein with intact protein, and possibly advancing protein intake while monitoring individual tolerance. Use of medical food as a protein source post-transplant was infrequent. Continuation of carnitine supplementation was common but not universal.
Liver transplantation in PROP is only partially curative. As there are extrahepatic sources of PA production, some individuals continue to experience periods of acidosis and/or remain at risk of central nervous system metabolic crises. However, liver transplantation appears beneficial for severely affected individuals with PROP by significantly reducing the number of episodes of decompensation. Improved metabolic control following transplant has been shown to slow and stabilize neurological decline, improve cardiac function, growth and quality of life.
Definitions of the protein terminology used throughout this guideline are listed in Appendix B.
Consider liver transplantation as a potential treatment modality for individuals with PROP
| Insufficient Evidence | Consensus | Weak | Fair | Strong |
| Conditional | Imperative |
Indications for liver transplant (LT) have included neonatal onset, frequent metabolic decompensation, uncontrolled hyperammonemia, poor growth, and sibling death (F.3040, F.2779). Many of the individuals with PROP who have undergone LT had suffered severe and frequent metabolic decompensation prior to their receiving a new liver. Therefore, early liver transplant was recommended for the individuals with neonatal onset of PROP because it appears that LT reduces the magnitude of progressive neurologic/cardiac disability as a result of poor metabolic control (F.2740).One review of literature on 17 transplanted patients and one case study stated that individuals with PROP should be in good metabolic control immediately prior to and during transplant (F.3040, F.2779). However, one case study reported that liver transplant was successful in a patient who had been ill and not in good metabolic control (F.565).
There were no statements in the Delphi surveys that addressed eligibility for liver transplant among individuals with PROP.
Pre-transplant period
Before transplant surgery, establish and maintain good metabolic control and continue individual's appropriate and usual medical nutrition therapy.
| Insufficient Evidence | Consensus | Weak | Fair | Strong |
| Conditional | Imperative |
The recommended diet for an individual with PROP who is preparing for liver transplant does not differ from the medical nutrition therapy (MNT) recommendation for an individual who is not preparing for transplant. The MNT in the pre-transplant period included a protein-restricted diet, and medical food without propiogenic amino acids; with some patients having been tube fed (F.246, F.495, F.448, F.565, F.467, F.469, F.2779, F.3070, F.594, F.443, F.460, F.598). Supplement recommendations were also unchanged (F.2779, F.246, F.467, F.469, F.3070, F.594, F.443, F.598). Limited evidence exists about monitoring during the pre-transplant period. Case reports have used a variety of pre-operative criteria in their evaluations including acid balance, nutritional state, muscle tone, mental status, gastrointestinal function, renal function, immunological assessment, and cardiac function (including echocardiogram) (F.2779, F.3221) in addition to the typical monitoring that is recommended for individuals with PROP. Comparison with assessments in the pre-transplant period has allowed determination of the long term outcomes of the transplant (F.495, F.448, F.3109, F.467, F.469, F.3070, F.465, F.594, F.2740, F.3221, F.3460, F.443, F.460, F.533).
There were no statements in the Delphi surveys that addressed pre-transplant dietary intake recommendations for individuals with PROP.
During transplant surgery, provide continuous D10 infusion with electrolytes, with close monitoring for metabolic decompensation or other complications.
| Insufficient Evidence | Consensus | Weak | Fair | Strong |
| Conditional | Imperative |
There are limited reports describing MNT and use of nutritional supplements during transplant. Continuous D10 during a liver transplant for the individual with PROP has been recommended: one team reported a successful transplant after patient was NPO for 6 hours and then was provided D10 during the transplant (F.565). Another case report described a patient who was provided D5 intermittently prior to and during transplant, as well as bicarbonate infusion “as needed”; however, this patient expired after hepatic failure and severe metabolic acidosis (F.2779). Sodium bicarbonate infusion to prevent acidosis during liver transplant has been reported in a limited number of cases: one retrospective study of 3 individuals with PROP stated that all were provided sodium bicarbonate infusion during transplant to combat “significant acidosis”; these patients survived with stable outcomes (F.2740).
There were no statements in the Delphi surveys that addressed MNT in the peri-transplant period for individuals with PROP.
After liver transplantation surgery, provide intact protein at approximately the DRI and advance protein intake beyond the DRI as tolerated. Continue carnitine supplementation post-transplant as a precaution against metabolic decompensation. Continue clinical and biochemical monitoring in individuals post-transplant.
| Insufficient Evidence | Consensus | Weak | Fair | Strong |
| Conditional | Imperative |
There are reports that individuals with PROP, who undergo liver transplant, have been able to tolerate a higher protein intake after a successful transplant. The exact protein recommendation after a liver transplant has not always been stated (F.3221), but evidence has pointed to less restriction of dietary protein after a liver transplant. Several studies supported an “adequate”(F.3070) or mild protein restriction (F.594, F.460, F.495, F.467, G.19), or avoidance of high protein foods (F.448, F.3322, F.3460). However, some studies reported the ability of PROP patients to tolerate a “normal level of protein intake” (F.246, G.77) or unrestricted diet (F.469, F.467, F.466, F.533) after a liver transplant.
Delphi 1:
There was no consensus with the statement that, in the days immediately after transplantation, the individual with PROP tolerates gradual increments of offending amino acids in parenteral nutrition support solution.
There was no consensus that dietary intact protein goals should be adjusted to meet DRIs for age for post-transplant management.
There was no consensus about the use of medical food to provide 50% of the recommended total PRO intake.
Delphi 2:
There was consensus (80% of all respondents agreed) that, after liver transplantation, the PROP diet should NOT be discontinued and replaced with "a regular diet."
There was consensus (80% of all respondents agreed) that, after liver transplantation, intact protein should be advanced toward the DRI for protein, while decreasing medical food and monitoring tolerance.
A case series of 3 post-transplant individuals with PROP reported that one patient experienced severe episodes of acidosis when the carnitine (and protein restriction) recommendations were not followed (F.467). Evidence pointed to a need for appropriate carnitine supplementation post-transplant to prevent metabolic decompensations and late complications (F.467, F.3399). The majority of centers have recommended that carnitine supplementation be continued post-transplant as a precaution against metabolic decompensation and possible late complications (F.467, F.469, F.3070, F.465, F.3399, F.443, F.460, F.466). Reduction in propionyl-CoA metabolites has been reported as minimal post-transplant, which supports the recommendation of continued carnitine supplementation (F.469). Specific carnitine doses were not discussed. Some centers maintain carnitine therapy on specific individuals, post-transplant (F.594, F.3221, G.19); one UK Center continued carnitine on a post-transplant individual who also had epilepsy (F.3384). However, some centers discontinued carnitine supplementation in all post-transplant individuals (F.246, F.3384, F.594).
There were no statements in the Delphi surveys that addressed the need for carnitine supplementation after liver transplant in individuals with PROP.
Liver transplantation does not fully correct the biochemical profile, as only hepatic PCC is restored, and PCC is found in non-hepatic locations, including skin fibroblasts and leukocytes. Most references indicated that the urine organic analysis (UOA) and acylcarnitine profile did not normalize post-transplant, and pathognomonic PROP metabolites in blood and urine persisted (F.3322). However correction of the hepatic PCC deficiency have been shown to change towards clinical normalization and milder biochemical phenotype (F.594, G.17, G.19); one case reported that metabolic parameters were only minimally abnormal post-transplant (F.533). Propionylcarnitine; (F.495, F.448, F.467, F.3070), 3-OH propionate (F.495, F.448), urine methylcitrate (F.495, F.448, F.467), and acetylcarnitine (F.467) did not decrease, and remained elevated post-transplant. However, two studies reported that UOA revealed a "prominent decrease" in propionyl metabolites post-transplant, propionylcarnitine (F.594), methylcitrate (F.3070, F.594) and 3-OH-propionate (F.3070, F.594), and the propionylcarnitine: acetylcarnitine ratio decreased to <1.0 (F.3070)). In one case report, free carnitine levels increased, on supplementation, post-transplant (F.467). In another report of 2 post-transplant individuals, plasma odd chain fatty acids decreased, but there was an increase in the odd chain fatty acids in the transplanted livers (F.495). Plasma ammonia levels were normalized immediately after transplantation was performed (F.469, F.246). The overall acylglycines (F.594), or more specifically propionyl glycine and tigylglycine disappeared post-transplant (F.495, F.448).
Delphi 1:
There was no consensus (only 9% of respondents agreed) with the statement that plasma amino acids and propionic acid concentrations normalize post-transplantation. However, 73% of respondents agreed that the plasma amino acid, acylcarnitine profile, ammonia, and propionic acid concentrations should be monitored every 6 months for post-transplant management.
Delphi 2:
There was consensus (100% of all respondents agreed/strongly agreed) that an individual with PROP should continue to have their biochemical profile and nutritional status monitored post-transplant as the liver transplant does not fully correct the metabolic abnormality of PROP
Liver transplantation may improve outcomes in PROP (F.3109). A case study reported that their patient had improved metabolic control immediately post-transplant, with ammonia levels normalizing (F.246). One review reported surgical complications in 3/17 PROP patients transplanted, including 2 patients with hepatic artery thrombosis and one patient with intestinal perforation (F.3040). Another review of 5 patients reported one patient with ischemic cholangiopathy secondary to acute hepatic artery thrombosis within first week after transplant, and 3/5 patients had episodes of steroid responsive acute cell rejection within first 2 weeks (F.3221). A study of 2 cases reports that metabolic liver function recovered within 12 hr post-operatively (F.594). Anemia improved gradually and became normal after 4 weeks (F.469). Diabetes requiring insulin treatment occurred following the transplant in two case reports, and persisted in one (F.495, F.594).
There were no statements in the Delphi surveys that addressed immediate post-transplant outcomes in individuals with PROP
Continue lifelong routine biochemical, nutritional and clinical monitoring of individuals who have undergone liver transplant, with the understanding that liver transplantation does not fully correct the metabolic abnormality of PROP (see Question 4).
| Insufficient Evidence | Consensus | Weak | Fair | Strong |
| Conditional | Imperative |
One case study indicated that individuals with PROP have improved metabolic control for the long-term post-transplant (F.246), and many case reports and reviews reported that they did not experience metabolic decompensation after transplant (F.3384, F.469, F.3322, F.3221, F.3460, F.460, G.77) despite severe post-transplant complications (F.495). Two PROP review articles indicated that orthotopic liver transplant (OLT) decreased the frequency of metabolic decompensations (F.3109, F.3322). One case had a hyperammonemic event due to ear infection 4 years after transplant; this patient did not have any metabolic decompensation reported (F.246). Another review of 12 patients post-transplant reported elimination of hyperammonemic episodes for one year post-transplant (F.3322). However, metabolic decompensation post-liver transplant has been reported. In one case series report of 3 post-transplant patients, one patient had a metabolic decompensation 3 years post-transplant during an asthma attack: after the single metabolic decompensation, she remained episode-free. (F.467). One review of 17 post-transplant patients reported one patient with metabolic stroke (F.3040).
Delphi 2:
There was consensus (100% of all respondents agreed/strongly agreed) that an individual with PROP should continue to have their biochemical profile and nutritional status monitored post-transplant as the liver transplant does not fully correct the metabolic abnormality of PROP
The effects of liver transplant on neurocognitive status are still unclear (F.3221). Two case reports with follow up data noted that further deterioration of development did not occur post-transplant (F.246, F.460); one review of 12 cases indicated that transplant slowed and stabilized neurological decline (F.3322). One report of 2 cases detailed that transplant improved development and neurocognition in both individuals (F.448). In one case report of a 7 mo old female, who underwent a live donor liver transplant (LDLT), had had an MRI at 5 mos (prior to transplant) that revealed cortical atrophy, caused by neonatal metabolic failure and continuing exposure to propionate. At 10 mos, 3 month after the transplant, dramatic improvement was observed in the brain mass, both in the grey and white matter; and at 27 mos, 20 months post-transplant, the MRI showed myelination to be age-appropriate, and signal abnormalities in the basal ganglia were not observed. (F.3070). Another report of two patients indicated that liver transplantation appeared to provide systemic metabolic stability that may have protected the brain: both patients had normal appearing basal ganglia, cortex and white matter (greater than 10 years post-transplant) on MRI findings, and normal basal ganglia total N-acetylaspartate (tNAA), slightly decreased glutamine, elevated white matter tNAA and decreased total choline in MRS findings (F.3384). However, one patient in a report of 8 patients had a complication of basal ganglia involvement (F.57). In one case study report of 3 individuals post-transplant, developmental quotient (DQ) data was available for one patient that showed that DQ improved from 49 (pre-transplant) to 52 (6 months post-transplant), to 63 (3 years post-transplant) (F.467). Another case report showed improvements in mental development (especially in cognition and adaptation) with the DQ increasing from 49 to 55 (F.469). Another case report quantified pre-transplant DQ to be 77, with an increase to 100 post-transplant (F.3070). However; DQ did not improve post-transplant for all individuals: one case report of 3 subjects noted very little change in DQ before and after transplant. Pre-transplant DQs were: 77, 82, 54 and post transplant DQs were: 80, 83, and 59, respectively.
There were no statements in the Delphi surveys that addressed long term neurocognitive outcomes for individuals with PROP who have undergone liver transplant..
Reported cardiac outcomes post transplant have been variable. One review of 12 post-transplant individuals with PROP indicated that transplant stabilized cardiac function and prevented cardiomyopathy (F.3322). In another case study report of 2 individuals with review of the PROP literature, cardiomyopathy did not regress but did not appear to progress, and no deaths were reported due to cardiomyopathy post-transplant (F.448). Another case report of an individual who underwent liver transplant at 3 months after cardiac decompensation did not experience any further cardiac events (F.460). Mild cardiomyopathy improved in one case report (F.495). A review article of PROP indicated liver transplant reversd dilated cardiomyopathy (F.3109). Two individuals, in a review of 17 post-transplant cases, experienced cardiac failure (F.3040). In one retrospective study with 2 individuals who had cardiomyopathy prior to transplant, one patient had a cardiac arrest during the transplant procedure, but displayed a rapid improvement in heart function and 3 months after transplant, without heart medication had a normal ECHO. Tthe other individual had normal ECHO results within the year after transplant (F.443). In a case study report of a 7 month old female who underwent LDLT, her EEG showed dramatic improvement 2 months post-transplant, and was normal 20 months after transplant (F.3070). In another case study, a 16 year old male presented with congestive heart failure that had deteriorated into cardiogenic shock; 70 days after transplant, systolic function was near normal (F.533).
There were no statements in the Delphi surveys that addressed cardiac function in individuals with PROP who have undergone liver transplant..
Post-transplant, individuals have experienced normal growth (F.246, G.51). In three case study reports (6 total individuals), the two younger post-transplant patients (F.467) and the other subjects (F.469, F.448) had significantly improved growth rates, with one individual's growth velocity increasing from 3.5 cm per year prior to transplant to 9.1 cm per year after transplant (F.469).
There were no statements in the Delphi surveys that addressed long term growth outcomes for individuals with PROP who have undergone liver transplant..
The graft function survival rates are reported to be between 46.9-85%. Good graft function was reported in a 2012 review of 12 patients (F.3322). One 2011 review of 5 post-transplant outcomes reported overall graft survival to be 85% (F.3221). In a 2006 review of the PROP literature and United Network for Organ Sharing (UNOS) findings, after 1 year the graft remained functional in 56.3% of patients, and after 5 years (n=3) 46.9% of patients (F.448). However a 1995 case report of 2 patients showed one patient had chronic rejection, and developed incomplete hepatic arterial thrombosis, with biopsy showing vanishing bile duct syndrome, requiring re-transplantation, and later developed chronic hyperammonemia and neurologic basal ganglia sequelae and died 15 months post-OLT(F.594). A 2011 review of 5 cases showed that 1/5 patients required re-transplant after 3 months (F.3221).
There were no statements in the Delphi surveys that addressed long term graft survival rates for individuals with PROP who have undergone liver transplant..
One review of 17 post-transplant individuals reported one with acute cellular rejection and two with post-transplant lymphoproliferative disorder (F.3040, F.3221). Diabetes occurred and persisted in one of two individuals described in one report (F.495). One report of 6 individuals indicated those with PROP may have a heightened response to immunological stimuli post-transplant, and may experience higher oxidative stress post-transplant and therefore may benefit from targeted immunosuppressive therapy (F.2731). In a review of 5 post-transplant patients, one reported worsening renal function (F.3221). Two of 5 post-transplant patients experienced oral herpetic lesions; one 5 years post LT (F.3221).
There were no statements in the Delphi surveys that addressed long term secondary complications such as renal disease, diabetes, etc, for individuals with PROP who have undergone liver transplant..
A review article and a gray literature source indicated that liver transplant improves QOL for individuals with PROP (F.3109, G.51). Another review from 2006 stated that liver transplantation "does not clearly demonstrate the effectiveness of this therapy to either prevent further deterioration or to improve survival and quality of life" (F.247). One group of researchers created a model to simulate the costs and outcomes associated with liver transplantation vs. nutritional support in two theoretical cohorts of newborns with early onset PROP (or classical MMA); the results of this analysis supported the performance of early liver transplant for patients with neonatal-onset PROP, as transplant is a more effective and less costly strategy compared to nutritional support for newborns with early-onset MMA or PA. The cost savings associated with LT in this patient population is significant to society and likely to the families as well (F.3463).
There have been reported case studies and reviews of 90 patients who underwent liver transplant for PROP (although there may be overlap of patients). Eighteen (20%) were reported to have died post-transplant at time of the publication of case studies/reviews. One review of 17 individuals with PROP, who underwent liver transplan,t reported the death of 4 individuals (F.3040). Another review of 11 individuals who underwent transplant had a 72.2% survival rate after one year (F.3322, F.448). The 5 year survival rate (n=3) based in one review was reported as 56.3% (F.448). One report of 8 individuals reported 4 of 5 individuals receiving cadaveric livers died; the 3 patients who received living donor livers were alive at time of publication, 3-36 months post-transplant (F.57). Another study reported an individual who developed chronic rejection and hyperammonemia, neurological sequelae that involved the basal ganglia and died 15 mos after OLT with severe lymphoproliferative disease (F.495, F.594). One study of 3 individuals with PROP who underwent transplant found that patients whose height is not less than 2 standard deviations below the 50th percentile for age and gender would have a better chance of survival after a liver transplant (F.465).
There were no statements in the Delphi surveys that addressed mortality in individuals with PROP who have undergone liver transplant.