Regular monitoring of clinical and nutritional status, to determine adequacy of nutrient intake and to guide modifications in the dietary prescription, is central to management of individuals with PROP. Diet history, activity level, anthropometric, and biochemical data are assessed by the metabolic dietitian at each clinic visit. In a comprehensive diet history, intake from enteral and parenteral sources and supplements is analyzed for nutrient adequacy and evaluated for any variance from the diet prescription. The patient’s eating schedule, home-monitored urinary ketones, and reports of vomiting or poor eating are utilized to detect any early signs of metabolic instability. Anthropometric assessment compares weight, length/height, and growth velocity for infants and children, and body mass index for older patients to standards. Physical assessment, including feeding skills, is recommended to detect the potential for nutrient insufficiencies. Monitoring developmental milestones and psychomotor skills are included in patient assessment.
Assessment of protein status, including albumin and prealbumin (transthyretin), and blood urea nitrogen, provide information about visceral protein status. Plasma amino acid analysis is used to determine the concentration and balance of essential amino acids, and the adequacy of those limited in the nutrition management of PROP (VAL, ILE, MET, THR). Other biochemical indicators of PROP management assessed are plasma acylcarnitine profile and plasma carnitine. Plasma organic acid analysis and blood ammonia concentrations may be tested if signs of metabolic instability or metabolic stressors are present. Monitoring signs of hematologic changes, suggestive of nutritional anemias and hematologic diseases (i.e. thrombocytopenia and pancytopenia) may be is necessary. Routine monitoring includes complete blood count/differential and ferritin. Additional biochemical monitoring that is clinically indicated may include essential fatty acids, vitamins and trace elements and is warranted when physical signs and symptoms are noted. Assessing bone status indices may be performed in patients who are at risk, including failure-to-thrive and protein malnutrition or long term parenteral nutrition. Secondary complications: pregnancy, transplantation, acute metabolic crises and other circumstances trigger additional monitoring.
Conduct nutrition assessment (e.g., dietary history, nutrient analysis, feeding skills and schedule, activity level and nutrition-related physical findings) to determine adherence and nutritional adequacy of dietary prescription. See TABLE #7, Monitoring the Nutritional Management of Well/Stable Individuals with PROP.
Nutrition management in PROP is guided by dietary, anthropometric, and biochemical assessments. A comprehensive dietary history, which should be done by a metabolic dietitian (F.3403, F.3109, F.3477, F.56, F.534, G.12, G.18, G.51, G.78), provides the dietitian and team with data about the individual’s current status, response to treatment, and need for adjustment of the nutrition prescription. A comprehensive dietary history, including nutrient analysis based on oral intake, tube feedings and supplements; feeding schedule and home-monitored urinary ketones; nutrition-related physical assessment, and psycho-social factors, is necessary to assess nutritional adequacy of and adherence to current nutrition prescription (F.56, F.58, F.3403, F.3109, F.3399, F.2807, F.62, F.3194, G.12, G.17, G.18, G.51, G.78). Protein and energy intake compared to growth assessment are used to titrate protein tolerance (F.3399). Assessment for catabolic stressors associated with or potential triggers of metabolic instability, such as prolong fasting, intensive or long-duration physical activity, fever, intercurrent illness, injury or surgery, has been shown to be informative (F.3109, F.3399).
There was consensus (100% of all respondents agreed) that dietary intake should be analyzed whenever a patient is seen in clinic.
There was not consensus (50% of MD and 56% of RD respondents agreed) that the dietary intake should be analyzed each time a blood specimen is taken.
Monitor age appropriate anthropometrics.
Growth and weight status are general indicators of nutritional adequacy and health. Growth parameters, including length/height, weight, head circumference for infants/toddlers, growth velocity and BMI, are compared to population standards for monitoring growth and assessing nutrition status (F.58, F.2807, F.3109, F.3403, F.3399, G.12, G.17, G.18, G.51, G.78, G.80). Delayed growth has been recognized as an issue for infants and children with PROP (F.3109, F.3399, F.3403). Records from 55 individuals, mean age 5.2 yr., found heights and weight below standard for infants; near normal weights for age 1 to 10 years; short stature compared to population standards and genetic target height; and BMI was low for those <1 year but tended to be higher compared to population standards for individuals with PROP >1 year of age. (F.2807). Case studies report catch up growth with appropriate LEU intake ( F.1387) and initiation of gastrostomy feeding (F.3194, G.67)
There was consensus among all respondents for monitoring weight, length/height and head circumference for infants and children with PROP and weight, height and BMI for adolescents and adults with PROP
Assess developmental, psychomotor, and neurocognitive status.
Neurologic manifestations in PROP such as hyptonia and cognitive deficits, impact nutrition through altered energy needs based on level of physical activity, feeding ability, and intellectual capacity to understand and manage dietary restrictions (F.3403, F.2807, F.62). Individuals with PROP have high incidence of feeding difficulties and the assessment of feeding abilities and skill development is done to determine needs for supportive feeding (nasogastric, gastrostomy), and caretaker education (F.3109, F.2807, F.1387). Assessments of neurocognitive development and quality of life provide objective measures on clinical course (F.2807, F.248, F.1387, F.3318). Assessment of early-life psychomotor skills may be helpful in predicting neurologic involvement later in life (F.3196). Monitoring for psychomotor function, muscular hypotonia, and speech delays can influence management by providing the proper interventions to promote positive clinical outcomes (F.1387).
There was consensus among all respondents for conducting formal developmental assessments on all children with PROP.
Use biochemical indicators (e.g., plasma amino acid profile; albumin, transthyretin; complete blood count/differential; plasma acylcarnitine profile and plasma carnitine; and urinary ketones) to assess nutritional adequacy and response to dietary intervention. Consider additional indicators during acute illness or when secondary complications are present. See TABLE #7, Monitoring the Nutritional Management of Well/Stable Individuals with PROP.
Decreased plasma concentrations of branched-chain amino acids have been reported in individuals with PROP which may be caused by either a reduced supply due to a restricted dietary intake of VAL and ILE, precursors of propionyl-CoA, as part of standard treatment of PROP or by enhanced degradation of branched chain amino acids (F.536). Monitoring of plasma amino acid concentrations is necessary to ensure adequate intake of essential amino acids and balance among amino acids (F.3109, F.56, F.55, F.2807, F.1387, F.534, F.62, F.3403, F.58, F.3399, G.17, G.18, G.19, G.51, G.67, G.78, G.80). Low concentrations of LEU (F.56, F.1387), VAL (F.55, F.56) and ILE (F.56, F.3386, F.3189) have been reported. Deficiencies have also been reported in other amino acids, including methionine, threonine and glycine (F.607). Acrodermatitis, with erythematosquamous patches, due to ILE and other amino acid deficiencies have been reported (F.3189, F.487, F.607, F.3315). Insufficient essential amino acids, (e.g. ILE and VAL) have a negative effect on protein synthesis and can result in protein malnutrition (F.490, G.51). Decreased concentrations of branched-chain amino acids have been reported to negatively correlate with elevated ammonia and suggest a catabolic state (F.493). Individual's full plasma amino acid profile is commonly assessed as part of nutrition assessment to assure nutritional adequacy and the support of tissue synthesis and growth (F.3109, F.2807, F.1387, F.534, F.62, F.3403, F.58, F.3399, G.51, G.67 ). Plasma amino acid concentrations are used to assess the diet prescription and make modifications in intact protein and medical foods (F.2807). European consensus recommendations indicated that the target for essential amino acids is within the normal range for the local laboratory (F.3399). A study of plasma amino acid concentrations in 11 individuals over a six year period found low concentrations for glutamine, histidine, threonine, valine, isoleucine, leucine, phenylalanine and arginine; and elevated concentrations of glycine, alanine and aspartate; and significant positive and negative changes by age ranges, suggesting that the use of normal ranges may not be appropriate (F.62).
There was not consensus among all respondents about the timing of blood sampling for plasma amino acids. Almost 90% of RD, but no MD respondents agreed that blood should be taken 2 hours after a meal. About 50% of MD respondents agreed that blood should be taken in the fasting state.
There was not consensus to support weekly plasma amino acid analyses for a rapidly growing well-state infant with PROP.
There was consensus (88% of RD and MD respondents agreed) that at least monthly plasma amino acids be analyzed in the first six months of life to monitor growth and development during in infants during a well state.
There was consensus (88% of RD and MD respondents agreed) that, for infants greater than 6 mo of age, amino acid analysis should be done at every clinic visit. Some respondents listed specific intervals for amino acid analysis, with greater frequency in early childhood and decreasing frequency with age.
There was consensus (100% of MD and 70% RD respondents agreed) that concentrations of plasma propiogenic amino acids (VAL, ILE, MET, THR) affect decisions regarding changes to the nutrition prescription during illness.
There was not consensus among all respondents that assessment of the ratio of VAL:ILE:LEU affects decisions about the nutrition prescription (86% of MD and 30% of RD respondents agreed) that assessment of the ratio of VAL:ILE:LEU affects decisions about the nutrition prescription.
There was consensus among all respondents that quantifying plasma amino acids affects decisions about nutrition prescription modifications during illness. There was 20-30% disagreement between RD and MD respondents regarding the need to monitor plasma amino acids during illness as a requisite for making changes in nutrition prescription.
Measures of protein status indices, including total protein, albumin, and prealbumin (transthyretin,) have been recommended for routinely monitoring to assess adequacy of calorie and protein intake for metabolically stable patients with PROP (F.55, F.2807, F.3109, F.3273, F.3403, F.3273, F.58, F.3399, G.12, G.18, G.51, G.78, G.80). Prealbumin is not an indicator of dietary protein in the acute state because it is impacted by many other factors (F.3273). In some centers, monitoring urinary urea (G.12, G.17, G.19), and BUN (G.80) has been suggested.
There was consensus among all respondents that plasma transthyretin is the best indicator of protein status in individuals with PROP.
There was not consensus regarding routine monitoring albumin and monitoring prealbumin every six months
Comments: individual comments by MD and RD respondents were made supporting assessment of transthyretin at every clinic visits, or every 3 months; and albumin annually.
Free carnitine is required to help conjugate free propionate to produce propionylcarnitine (acylcarnitine) for excretion. Lack of free carnitine may potentially reduce the ability to detoxify toxic propionate and consequently negatively affect outcome. Elevated acylcarnitine (C3 or propionylcarnitine) is a valid biomarker in the confirmatory testing for PROP (F.3109); and elevated acylcarnitines are often found in patients with acute symptoms of decompensation (F.3314, G.19). Lower concentrations of free carnitine have been found in patients with impending decompensation (F.3314, F.498), indicating formation of increasing amounts of acylcarnitines. Carnitine deficiency has been reported to reduce synthesis of essential long-chained polyunsaturated fatty acids, suggesting that monitoring plasma carnitine concentrations may also be important in context of maintaining normal essential fatty acid status (F.435). Monitoring plasma free, acyl, and total carnitine has been recommended to assess the ratio of free: acyl and identify deficiency of the free carnitine pool (F.3109, F.2807, F.3403, F.3314, F.493, F.502, G.18, G.19, G.51, G.78, G.80).
There was not a consensus among all respondents (71% of MD and 60% RD respondents agreed) that that plasma free, total and acylated carnitine be collected routinely at scheduled clinic visits.
Comments: 2 MD respondent suggested assessing plasma carnitine at least annually; one RD stated, every 1-3 months.
Hyperammonemia is a more common feature in early-onset, compared to late-onset PROP (F.3476). Some early-onset individuals may have chronic hyperammonemia with absence of clinical findings (F.3403). Routine monitoring of serum ammonia is indicated for individuals with PROP (F.3476, F.3403, G.18, G.51, G.64)
There was no consensus among RD and MD respondents as to when blood ammonia should be quantified. Seventy percent of RD and 57% MD respondents agreed that blood ammonia should be routinely assessed at most clinic visits. Twenty percent of RDs and 7% MDs do not quantify plasma ammonia during well state.
Comments: one MD stated the difficulty of getting a sample in an outpatient patient, as well as possible mishandling of sample, both making analysis difficult.
In addition to its presence in acute illness, hyperketonuria was found to accompany less serious signs and symptoms of illness including vomiting and food refusal (F.3314). Routine testing of urinary ketones has been recommended as a way to monitor metabolic stability at home (F.3109, F.507, F.3273, G.12, G.17, G.18, G.51, G.64, G.78, G.80). Urine ketones provide an indicator of beta oxidation and are a surrogate marker for propionate metabolites (F.507). When utilized, along with other signs and symptoms like vomiting and food refusal, urine ketones may indicate impending illness and the need to initiate home emergency management until further action taken (F.3109, F.3399)
There was not consensus (only 64% of all respondents agreed) that urine ketones should be monitored at home when clinically appropriate.
There was consensus (88% of RD and MD respondents agreed) that home monitoring should be recommended when ill, but the majority (70%) disagreed with routine daily home monitoring of urine ketones when well. When asked about their practice, 60% of RD and 50% of MD respondents indicated that they routinely assess urine ketones at most clinic visits.
Thrombocytopenia and neutropenia have been typically diagnosed in patients during acute crises (F.2807, F.595, F.498), but have also been found in stable patients (F.2807). Blood tests, including complete blood count (CBC) with differential, should be done as routine measure during clinic visits and especially in any individual with suspected anemias (F.3109, F.3199, G.12, G.78, G.80). Monitoring for signs and symptoms of hematologic changes, including nutritional anemias, may prevent hematologic diseases and improve prognoses for patients with PROP (F.490, F.502). Neutropenia and cytopenias have improved with metabolic control (F.3109, F.2807). In addition to CBC, assessment for underlying causes of nutritional anemias including iron status indices (G.12, G.18, G.78, F.490, F.504), and vitamins ( including folate and vitamin B12) may need to be assessed (G.12, G.80).
There was not consensus about the frequency of monitoring CBC with differential.
There was nearly consensus agreement (79% of RD and MD respondents) with monitoring CBC with differential every 6 months.
Consider additional biochemical parameters and more frequent monitoring when clinically indicated (e.g. long term poor adherence, signs and symptoms of nutritional inadequacy, intercurrent illness, acute metabolic decompensation, pregnancy (see Q #5), secondary complications of PROP (see Q #6), and transplantation (see Q #7).
There is no current evidence to indicate that individuals with PROP have a predisposition to EFA deficiency (G.12), or whether a clinically observed deficiency is simply due to insufficient intake. Plasma and erythrocyte DHA and AA deficiencies were found in a study of 33 individuals with IEM, including 3 with PROP (F.435). Dietary intakes of DHA and AA, and other long chain polyunsaturated fats were lower than controls, and intake did not correlate with plasma or erythrocyte concentrations in this study (F.435). Monitoring of EFAs, including DHA, may be indicated in individuals with insufficient intakes based on dietary intake records, or those at risk, including young children, pregnant females, and those with visual impairment (F.58). Further studies are warranted (G.12).
There was no consensus among all respondents about monitoring the essential fatty acids.
Selenium deficiency has been reported in one individual with PROP who had low dietary intake (F.504). Monitoring serum selenium (with glutathione peroxidase) and zinc may be warranted in patients with insufficient intake, especially those on a low-protein diet alone without use of medical foods (F.58) and those with signs or symptoms suggesting deficiency (F.607). Two separate studies in patients with noted skin rash showed normal zinc concentrations (F.607, F.487).
Statements were not included in the Delphi surveys about recommendations for quantifying selenium and zinc, including frequency.
Bone anomalies in PROP are multifactorial and may be iatrogenic (F.58). Osteopenia and osteoporosis have been documented in patients with PROP (F.2807, F.56, F.58, F.248, F.555, F.534, G.67); however the actual prevalence of bone anomalies is uncertain. In a retrospective study of 55 individuals with PROP only one had diagnosed osteoporosis (F.2807). In a study of MMA and PROP, low bone mineralization was found in most patients while bone metabolism markers, including plasma calcium, phosphorus, osteocalcin, 25-OH vitamin D were reported in normal reference ranges (F.56). Monitoring bone markers, including DEXA, 25-OH vitamin D is conditional and indicated in at-risk patients.
Statements were not included in the surveys about recommendations for quantifying bone markers, including frequency.
Monitoring/screening for cardiomyopathies has been recommended (F.3109, F.447, F.2816, F.557, F.3386), since cardiac disease may be present without symptoms (F.557). Patients with neonatal onset forms of PROP may develop cardiac failure secondary to cardiomyopathy (F.56, F.2807). Routine monitoring with electroencephlographic and echocardiographic techniques has been recommended for patients at risk for severe cardiomyopathy, including sudden cardiac death (F.447, F.557). Cardiac function should be assessed immediately prior to transplantation (F.3460).
There was consensus (96% of RD and MD respondents agreed) with the need to refer, for immediate cardiac evaluation, if shortness of breath or cardiac arrhythmia is present.
Comments: one MD suggested annual screening for cardiac arrhythmias and cardiomyopathy.
Pancreatitis has been reported in patients with PROP (F.2807, F.3109, G.17, G.19, G.80), with presentation during acute metabolic decompensation (F.3109). Monitoring for pancreatitis through serum lipase and amylase activity has been recommended for patients with complaints of anorexia, abdominal pain and nausea (F.3109).
There was consensus (96% of RD and MD respondents agreed) that there is a need to monitor lipase and amylase if acute abdominal pain, suggestive of pancreatitis, is present.
Comments: one MD noted that pancreatitis can occur in the absence of pain, another indicated monitoring lipase with every decompensation rather than relying on symptoms.
Measurement of oxidative stress markers, including plasma and cultured fibroblast glutathione, and urine F2 isoprostanes have indicated that individuals with PROP are at risk of oxidative stress (F.3073, F.541). There is some indication that biomarkers of oxidative stress are lower in PROP with treatment (F.534).
Statements about assessment of oxidative stress markers were not included in the Delphi surveys.
Chronic elevated plasma glycine has been commonly found in patients (F.62, F.502, G.18, G.51)). Plasma glycine concentrations may not be a reliable marker for assessing clinical status and metabolic control (G.51). Plasma glycine has been negatively correlated with dietary energy intakes, (F.55, F.3403); and was higher in individuals after having received large quantities of dietary protein for a prolonged time (F.502). Maintaining slightly elevated plasma glycine may reflect nutritional status, and correlates with good acid-base balance (F.3403). In a study of 5 individuals with 346 events, plasma glycine had been positively correlated with serum bicarbonate (F.240) but remained unchanged with increasing plasma ammonia levels (F.536). In periods of metabolic acidosis, excretion of propionylglycine is favored (F.536).
Studies among individuals with PROP have found that glutamine was either negatively correlated (F.493, F.536) or not correlated (F.240) with ammonia. A 2010 review concluded that protein intake and plasma glutamine did not correlate with ammonia levels (F.3403). Additionally, no correlation was found between CSF glutamine concentration and plasma ammonia (F.497). Glutamine may be quantified as part of standard plasma amino acid panel.
There was no consensus (only 58% of all respondents agreed) that assessment of glycine and/or glutamine should be used guide decisions about the nutrition prescription.
Urinary organic acids have been used for both diagnosis and confirmatory testing for PROP, and for chronic monitoring of status (F.56, F.497, F.3314, F.493, F.516, F.517, F.561, F.3320, F.3386, F.574, F.502, G.12, G.17, G.18, G.19, G.51, G.64, G.78, G.80). Confirmatory urine organic analyses can detect 3-hydroxypropionate, methylcitrate, tiglyglycine, and propionylglycine; and most are identified during acute decompensation. Urinary tiglyglycine is found only during acute illness (F.516, F.248). Monitoring of urinary organic acids during acute crisis has been reported of little to no benefit in regards to management (F.3399). Plasma methylcitrate and 3-hydroxypropionate are preferred for the differential diagnosis of PROP (F.3109). Blood methylcitrate is a useful biomarker in identifying patient status (F.572) and measuring degree of metabolic control (F.3320). Plasma methycitrate has been associated with a rise in blood ammonia (F.3320, F.3403, F.493). Urinary methylcitrate has been shown to correlate with plasma ammonia during acute crisis (F.493, F.3320).
90% of RD and 71% of MD respondents stated that they do not monitor plasma methylcitrate; and 86% of MD and 60% of RD do not monitor plasma propionate.
70% of RD and 36% of MD respondents do not monitor urinary methylcitrate. Urinary 3-OH propionate was monitored: "not at all" by 42%; "routinely at clinic visits" by 29% and "in selected circumstances" by 29%
Participants noted that urine organic acids were “not helpful” in making decisions about nutrient recommendations.
Biochemical parameters found to discriminate best between balanced metabolic state and (impending) metabolic decompensation in PROP are ammonia, anion gap, and acid-base balance (F.3314). A combination of ammonia and anion gap alone accounted for 63.3% accuracy in classification of "metabolic decompensation" (F.3314). During acute crises, urine ketones, blood gases, electrolytes, ammonia and lactate should be closely monitored (F.3314, F.3273, F.3399, F.502, G.19, G.80). It has been reported that blood pH may not be a reliable indicator of acid-base status (F.595). Careful and vigilant monitoring is essential during acute metabolic decompensation (F.3314, F.502, F.3386, F.240, F.3273, F.3476, F.3399, G.17, G.19). A wide range of biomarkers are utilized to manage the metabolic alterations and system consequences in metabolic decompensation, including hydration, glucose, acid-base balance, electrolytes, plasma amino acids, bicarbonate, with the overriding goal of adjusting therapy according to patient responsiveness.
Statements were not included in the survey about quantifying these analytes.
Assessment of blood lactate is considered beneficial during acute metabolic crises, when done along with blood gases and glucose (F.502, F.3386, F.574, F.3314). In individuals with lactic acidosis use of insulin is cautionary (F.3399). CSF lactate has been measured in patients with stroke-like episodes and suggested brain energy metabolic disturbance (F.544, F.3386, G.19). Increases in cerebral lactate have also been observed in stable clinical conditions (F.463).
Statements were not included in the surveys about recommendation for quantifying blood lactate..
Hyperglycemia is a major concern during acute crisis (F.3399, G.19). Blood glucose concentration should be closely monitored during acute crisis and intervention immediately taken (F.3387, F.595, F.574, F.3399, F.3477, G.80). Refer to Nutrition Intervention (Question 2.1.2).
Statements were not included in the surveys regarding recommendations for quantifying blood glucose concentrations.
Sensitivity of OLCFAs to episodes of acute decompensation was found in a longitudinal study of 4 children with PROP. Differential responses were observed for the phosphotidyl choline (PC) and phosphatidylethanolamine (PE) fractions, with elevation of the PC fraction persisting 3 weeks post metabolic crisis (F.561). In another study with 5 patients authors concluded that current evidence did not support use of OLCFA as an indicator of severity or management of PROP (F.575). Further research is necessary to determine the utility of monitoring OLCFA in PROP (F.561, F.2807, F.575, G.19, G.80). See Q#2 , topic 2.6.3.
There was no consensus regarding recommendations for monitoring OLCFA.
One participant noted that you would not restrict dietary OLCFA in a fasted "fed" state. Another stated that dietary OLCFA may be a problem when dietary caloric intake is decreased.