Pancreatitis has been reported as a fairly common complication in the organic acidemias (F.3117). Although there have been several detailed case reports of pancreatitis in individuals with PROP (F.61, F.593, F.244, G.75), broader studies, through retrospective analysis of medical histories, literature reviews or through patient/family surveys (F.3118, F.3117, F.3109, F.3381) have suggested a prevalence of approximately 20%, with some individuals have recurring episodes (F.61, F.593, F.3117, F.2962).

Delphi 1:

22% of RD respondents to the Delphi I survey had no experience with treating pancreatitis in their patients with PROP

Pancreatitis should be suspected in individuals presenting with vomiting, anorexia, abdominal tenderness/pain and unexplained acidosis. The suggested evaluations have included serum amylase and lipase measurements and abdominal X-ray (F.3109, F.3403, F.532). In a report of a single acute case, the lipase and amylase levels were normal at presentation, but rapidly increased (F.593). Individuals may present with or without metabolic decompensation (F.3117).

It is not known if systemic acidosis is a causative factor or a consequence of pancreatitis (F.3403, F.61). Acute episodes have been treated with bowel rest for up to 2-5 weeks (F.61), jejunal feeds, and pain management (F.3403). Parenteral, or a combination of parenteral and enteral, feedings have been used safely with total protein provided at or near RDA for age (F.3403, F.3399, G.75). IV carnitine at 200-300 mg/kg/day has been used maximize propionylcarnitine excretion (F.3403, G.51). The intake of other nutrients should follow the individual’s “recommended intake during illness” as described in Q#2.

Delphi 1:

There was not consensus regarding all proposed interventions for treating pancreatitis in individuals with PROP, comments suggested that this was partly due to the small number of cases and partly to the the greater role of the medical institiutions' G.I. teams

There was not consensus (only 46% of RD and MD respondents agreed) that individuals with acute pancreatitis, who are admitted, require IV parenteral support customized without offending amino acids.

Comments: one RD reported using both customized amino acids and 10-15% amino acid formulation to balance and meet the required amounts of propiogenic amino acids. If customized TPN is not available, one RD reported starting at low protein (0.3-0.5g PRO/kg) from standard TPN solutions. Two RDs and one MD noted that they use the standard/regular TPN solution but in reduced amounts.

There was not consensus (only 46% of RD and MD respondents agreed) that individuals with acute pancreatitis, who are admitted and require IV parenteral support, should be treated with IV lipids. 33% of RDs disagree and the rest were neutral.

Comments: one MD commented that lipids are used if triglycerides are not excessively elevated as it can be difficult to initiate anabolism unless lipids are included.

Delphi 2:

There was consensus (83% of all respondents agreed) that jejunal and/or parenteral feeding should be used to provide the appropriate recommended nutrient intake during an acute attack and to rest the gut.

Comments: one RD felt that this would not be supported by the institution's GI team, while one MD commented that this practice is absolutely necessary to stabilize the patient as quickly as possible

The Pediatric Cardiomyopathy Registry reported that 15% of all cases of cardiomyopathy are due to inherited metabolic disorders (F.446), so it not surprising that an increased risk for developing cardiomyopathy has been observed in individuals with PROP. A literature review done in 2010 put the estimated risk of developing cardiomyopathy in individuals with PROP at 25-33% (F.3403). A patient/family survey of the 58 individuals with PROP reported that 19% had cardiomyopathy and 30% had arrhythmias (F.3117). Retrospective studies in two different centers reported the prevalence of cardiomyopathy among individuals with PROP at 30% (F.443) and 32% (F.601), respectively.

There were no statements regarding prevalence of cardiac complications in individuals with PROP.

Cardiac evaluation should be part of the periodic monitoring of individuals with PROP, as further described in Q#4.  Although presentation of cardiomyopathy has been reported to  occur at any age from neonate through adult (F.442, F.3457, F.449, F.2816, F.446, F.598, F.2963, F.3386, F.444, F.532, F.3118, F.543) the risk has been shown to increase with age (F.447). Presenting symptoms have included shortness of breath, arrthymias, decreased level of consciousness, and other signs of cardiac involvement (F.3403).

Delphi 2:

There was consensus (96% of all respondents agreed) that, if shortness of breath and/or cardiac arrythmia are present, the individual with PROP should be immediately referred for a cardiac evaluation

Comment:

One MD stated that annual screening should be done for cardiac arrythmia and cardiomyopathy

While the management of cardiomyopathy is mainly through medical and pharmacologic interventions, nutritional support provided by enteral and/or parenteral feedings has been found to be an important adjunct for patient health (F.543). Cardiomyopathy has occurred in individuals with long-term appropriate dietary control, carnitine intake and aggressive treatment during illness, as well as in those who have not had optimal treatment (F.3109, F.3118, F.447). Neither age at diagnosis or amount of residual propionyl CoA carboxylase (PCC) activity have been shown to impact the risk of developing cardiomyopathy (F.3109). Autopsy analysis of cardiac tissue of an individual with PROP who died as a result of cardiomyopathy revealed a decrease in myocyte carnitine even though there was a normal concentration in the plasma (F.59). It has been suggested that the usual carnitine dose should be doubled when treating cardiomyopathy (F.443), although long term outcome studies have not been reported. Oxidative phosphorylation (OXPHOS) deficiency, with reduced levels of complex I and III activity, has been documented in at least one individual who succumbed to cardiomyopathy (F.532). The results are consistent with the hypothesis that there is secondary mitochondrial dysfunction in PROP (F.3118, F.444, F.3399). It has been suggested that giving antioxidant/coenzyme Q10 (CoQ10) supplementation could replete the mitochondrial stores and may prevent the cardiac involvement (F.532, F.3399). The use of these supplements has been documented in individuals with PROP and cardiomyopathy, but no assessment of outcome has been published (F.443, F.449). Symptoms of cardiac involvement have been reversed in several individuals with PROP who have received a liver transplant (F.444, F.3322, G.74).

Delphi 1:

There was no consensus regard fluid restriction. Only 36% of RD and MD respondents agreed that older children and adults with cardiomypathy should have fluid intake restricted to 25cc/kg or less and dietary sodium should also be restricted. Two-thirds of RD were neutral and one MD somewhat disagreed.

Comments: 2 respondents stated that intake depends on evaluation of cardiac output, congestive heart failure and edema.

Delphi 2:

There was no consensus among the respondents regarding the use of the carnitine and antioxidant agents to prevent or lessen the severity of cardiomyopathy. Nine of 14 MD respondents stated that they were familiar with the use of CoQ in relation to cardiomyopathy in the clinical/research literature

There was no consensus among the respondents regarding the use of these agents to prevent or lessen the severity of cardiomyopathy. It was stated that more research is needed

There was no consensus among the respondents regarding the use of a higher dose carnitine to prevent or lessen the severity of cardiomyopathy. However, it was noted that carnitine deficiency will make cardiomyopathy worse. When asked about dosage of carnitine to be used in relation cardiomyopathy prevention, 6 RD and 5 MD respondents stated that they had no experience with this intervention.

Optic neuropathy has been reported as a late complication in several published case studies (F.3179, F.3088, F.3327) and the prevalence has been estimated, through literature reviews, retrospective review of patient histories and surveys, to occur in 7-11% of individuals with PROP ( F.2807, F.3117, F.3399).

There were no statements regarding prevalence of optic neuropathy in individuals with PROP.

The literature presents some evidence that tight metabolic control may lessen or forestall development of the complication of optic neuropathy. In one case, a 24 year old male had a lifetime of good metabolic control but after an elective surgery that involved fasting and was complicated by metabolic decompensation and elevated ammonia, he developed optic neuropathy (F.3088). In another case, two brothers had early good metabolic control and no visual problems, but after decreased dietary compliance and several episodes of hyperammonemia, they each developed optic neuropathy (F.3179). In another report, an individual, without documented metabolic decompensation, developed optic neuropathy along with other secondary complications (F.3327). Mild chronic hyperammonemia was noted in this individual (F.3327).

There were no statements in the Delphi surveys about the possible clinical associations with optic neuropathy.

Also see associations above.

It has been observed that there are similarities between the optic neuropathy in individuals with PROP (and MMA) and those with Leber hereditary optic neuropathy and this suggests a secondary mitochondrial dysfunction (F.3327). Visual acuity was increased after supplementation with the antioxidants vitamin E and CoQ10 in a single report of an individual with MMA and optical neuropathy (F.3399). 

Delphi 2:

There was no consensus among the RD and MD respondents regarding the prevention or reversal of hyperammonemia to prevent/delay the onset or severity of optic neuropathy

There was no consensus among the RD and MD respondents regarding the use of antioxidants to prevent/delay the onset or severity of optic neuropathy. There was awareness among the MD (7) and RD (1) respondents of the use of vit E, CoQ, A, C, K, lecithin, lutein and taurine in treatment of optic neuropathy

One case of abnormal B-cell production (F.599) was treated with IV gamma globulin at 400mg/kg. A reduced dietary intake of protein was prescribed for two days pre- and post-infusion and prophylactic antibiotics were given during hospitalizations (F.599). Another report described the use of IV gamma globulin at 1 gm/kg/day for two days. No modifications of dietary protein were noted in this later case (F.3199).

Delphi 2:

There was no consensus among the RD and MD respondents regarding altering PRO intake in individuals receiving IV gamma globulin .

Comments: they neither agreed nor disagreed because of lack of experience.

Cytopenia and recurrent infections are reported to be prevalent among individuals with PROP (F.599, F.3109). While true immunodeficiency is rare (F.3399), case studies have indicated specific abnormalities. Among 24 patients with PROP in Saudi Arabia, 17% had pancytopenia during metabolic crises (F.3381). In a survey of 58 patients and their families, the following were reported: leucopenia 31%; thrombocytopenia 17%; anemia 32% and immunodeficiency 15%.

There were no statements regarding prevalence of cytopenia or immunodeficiency in individuals with PROP.

With MS/MS NBS allowing earlier diagnoses and initiation of treatment of PROP, there is the potential for decreased mortality (F.3399). However, morbidity in individuals with PROP remains high. This may include development of renal disease as a late-onset complication that has been reported in 3 cases, where ages were given as 29 and 45 years (F.3399, F.2967).  There is evidence that individuals with PROP may have a greater tolerance for dietary (intact) protein with age (F.3399), but there still remains the continued need to carefully monitor and adjust intake during illness.

Delphi 2:

There was consensus (100% agreement among all RD and MD respondents) that lifetime monitoring and nutrient adjustment is important for all individuals with PROP to help delay the development of secondary complications.