Take a closer look at UCD management

Transcription

1 Take a closer look at UCD management An evaluation tool to help determine whether patients with urea cycle disorders (UCDs) may be experiencing treatment failure

2 What is treatment failure and how do you respond to it? Treatment failure in UCDs often refers to an overt hyperammonemic crisis or a trip to the hospital after patients have experienced a triggering event. 1-5 However, it also refers to situations in which patients with UCDs are experiencing more subtle signs and symptoms that may indicate their overall management is not controlling the disease. 1,2 INTRODUCTION When addressing UCD management, it is important to keep in mind that ammonia elevations can present with subtle symptoms that may not be recognized; therefore, regular monitoring is required. 1 When treatments are delayed or not optimized, patients with UCDs may experience permanent or serious harm. 1,2 Therefore, it is critical to identify signs and symptoms of UCDs as early as possible so that patient outcomes can be optimized. 1,2 Could you be missing important clues? There are numerous challenges and complexities when managing UCDs. 1 This tool aims to provide a framework for evaluating patients with UCDs and their responses to disease management. Step 1 Look for signs and symptoms that may indicate a need to reassess your management protocol. Step 2 Consider potential shortcomings in current UCD management. Step 3 Take action and modify your UCD management strategy if needed. Pay close attention to subtle signs and symptoms that may indicate a potential failure in UCD management. 1,2 2

3 Are these patients a under control or under-controlled? Characteristics: I take my medicine, but I m struggling with fatigue, which makes it hard for me to concentrate at school. PATIENT PROFILES Age: 17 UCD type: argininosuccinate synthetase (ASS) deficiency Management: low-protein diet, prescription supplements, and sodium benzoate Last recorded fasting ammonia level: 40 μmol/l (lab upper limit of normal [ULN], 35 μmol/l) 6 Characteristics: My life is so hectic. I don t always follow my prescribed low-protein diet. Age: 25 UCD type: ornithine transcarbamylase (OTC) deficiency Management: low-protein diet and prescription supplements Last recorded fasting ammonia level: 44 μmol/l (lab ULN, 35 μmol/l) 6 It s difficult to get my son to take his medication. Caregiver Characteristics: Age: 10 UCD type: argininosuccinate lyase (ASL) deficiency Management: low-protein diet, prescription supplements, and sodium phenylbutyrate tablets Last recorded fasting ammonia level: 80 μmol/l (lab ULN, 35 μmol/l) 6 3 a These profiles represent hypothetical patients with UCDs. See next page for a closer look

4 Are these patients a under control or under-controlled? Recent signs and symptoms of a UCD, and current life events Nausea Occasionally misses treatment doses Stage-of-life change: getting ready for college PATIENT PROFILES Recent signs and symptoms of a UCD, and current life events Chronic gastrointestinal issues Recent difficulty concentrating Increased stress at work Recent signs and symptoms of a UCD, and current life events Elementary school teacher suspects attention deficit disorder Does not want to play with others at recess Poor appetite; unpalatability of food that is mixed with medication 4 a These profiles represent hypothetical patients with UCDs.

5 Step 1 Evaluate signs and symptoms Look for signs and symptoms that may indicate a need to reassess your management protocol. SIGNS AND SYMPTOMS ADHERENCE Poor adherence to treatment 7,8,a Refusal to eat or drink because of taste and smell of medication 7-9,a Child s refusal to take medication 7-9,a PHYSICAL Growth retardation 10 Lethargy 11,12,b Gastrointestinal issues Nausea/vomiting 13,14 Poor appetite 13 Elevated biomarkers c STEP 1: LOOK FOR SIGNS Ammonia 11,12,15,b,d Glutamine 12,15,16,b,d Phenylacetate/phenylacetylglutamine ratio (PAA:PAGN) 17 Decreased biomarkers c Arginine (except for arginase deficiency) 12,16,b MENTAL Cognitive Problems with executive function 18,19 Difficulties with neurocognitive skills 18 Confusion 12,b Attention and learning Attention problems 16,19,20 Learning disabilities 18 Attention deficit hyperactivity disorder 15,16,18,d Autism spectrum 16,20 Psychological Psychosocial and psychological problems 16,18 5 Continued on next page

6 Step 1 Evaluate signs and symptoms (cont d) Look for signs and symptoms that may indicate a need to reassess your management protocol. SIGNS AND SYMPTOMS LIFESTYLE Personal Poor body image 21,e Body odor 13,14 Poor relationships with friends 21,e Less frequent leisure activities 21,e Emotional Emotional instability 20 Social difficulties 18,20 Internalizing problems (introversion) 11,20 Withdrawal 20 Decreased general well-being 21,e Family Interference with family life 22 Poor physical health of parents 21,e Family/parental stress 7,23,a,f Difficulties with maintaining low-protein diet 3 School Interference with school 11 STEP 1: LOOK FOR SIGNS a Case report of a pediatric patient with ASL deficiency. 7 b Based on the studies of 3 related female patients with OTC deficiency. 12 c For more information on biomarker testing, please see step 3 of this guide. d Case report of a pediatric patient with OTC deficiency. 15 e Preliminary assessment of survey data of children and parents affected by inborn errors of metabolism (including UCDs), in which French norms were used for comparison. 21 f Based on survey data from families of patients with UCDs. 23 6

7 Step 2 Evaluate current management Consider potential shortcomings in current UCD management. UCD MANAGEMENT FACTORS DIET AND SUPPLEMENTS STEP 2: ANALYZE MANAGEMENT Diet and supplements may not be sufficient to prevent ammonia elevations. 2,3,24,25 Patient may be nonadherent with prescribed diet and supplements. 26,27 At times of growth and development, it may be difficult for patients to receive sufficient protein. 28 TREATMENT FORMULATION AND ADMINISTRATION The following may contribute to nonadherence: Amount and frequency of medication 26 Taste and odor of medication 7,13,26,a Difficulty with swallowing medication 26 MECHANISM OF ACTION Type of waste nitrogen vehicle can possibly affect clearance of ammonia and/or glutamine Some treatments produce intermediates that may be toxic at higher levels. 17 Some treatments may reduce the plasma level of branched-chain amino acids. 32 a Case report of a pediatric patient with ASL deficiency. 7 7

8 Step 3 Modify management plan Take action and modify your UCD management strategy if needed. Because patients often experience silent ammonia elevations, regular monitoring is required. 1 Recommended guidelines are as follows 2 : Every 3 months for young patients and severely affected patients 2 Every 6 months for asymptomatic OTC deficiency the most common form of UCD 2 STEP 3: MODIFY MANAGEMENT INCREASE MONITORING OF AMMONIA LEVELS AND OTHER MEASURES Check fasting ammonia levels, which strongly correlate with the risk and rate of hyperammonemic crises. 6 Consider longitudinal assessment of glutamine levels, the average of which can be predictive of neurocognitive outcomes. 32 However, note that glutamine levels do not predict hyperammonemic crises as effectively as fasting ammonia. 6 Expand use of biomarkers according to UCD subtype, such as those listed in the chart on reverse. 2 Consider executive function testing (eg, Stroop test or Comprehensive Trail-Making Test) to assess a patient s neurocognitive ability. 18,19 When monitoring your patients with UCDs, remember that trends in measurements may be more useful than single values. 32,33,a As noted in step 1, each time your patient with a UCD comes into the office, look closely for evidence of both silent and overt signs and symptoms of the disease, which may indicate treatment failure. 1 If the evidence points to signs and symptoms of a UCD that may be under-controlled, take steps to modify your management strategy. 1,2 Take steps to ensure that a patient s evaluation includes input from all members of the UCD management team, including nurses, dietitians, psychologists, and social workers. 1 For improved patient outcomes, continually assess new treatment goals and therapies as they emerge. 4,32,34 Continued on next page 8

9 Step 3 Modify management plan (cont d) Take action and modify your UCD management strategy if needed. Consider expanding the use of biomarkers by subtype, as noted by the examples below. UCD SUBTYPE BIOMARKERS SIGNIFICANCE STEP 3: MODIFY MANAGEMENT Ornithine transcarbamylase (OTC) deficiency Argininosuccinate synthetase (ASS) deficiency Urinary orotic acid 11,12,15,16,b,c Citrulline 12,16 Elevation may indicate need to reevaluate diet and/or treatment regimen 2 Low level may signal need for increased use of supplement 1,2 Citrulline 16,27,35 Elevations of either may indicate Pyrimidine need to reevaluate diet and/or metabolism treatment regimen 2 intermediates 36 Continually monitor liver function 1 Argininosuccinate lyase (ASL) deficiency Alanine and aspartate aminotransferases 7,37,a Argininosuccinic acid 1,2,7,a Continued elevation may indicate need to reevaluate diet and/or treatment regimen 2 Arginase 1 (ARG1) deficiency Arginine Guanidinoacetate 38 Elevations of either may indicate need to reevaluate diet and/or treatment regimen 2 Carbamoyl phosphate synthetase I (CPSI) deficiency Citrulline 16 Low level may signal need for increased use of supplement 1,2 N-acetylglutamate synthetase (NAGS) deficiency Citrulline 1,2 Low level may signal need for increased use of supplement 1,2 a Case report of a pediatric patient with ASL deficiency. 7,33 b Case report of a pediatric patient with OTC deficiency. 15 c Based on the studies of 3 related female patients with OTC deficiency. 12 9

10 Have you taken a closer look at UCD management? Three key considerations for evaluating and optimizing UCD management 1 Is my patient experiencing subtle and overt signs and symptoms of a UCD? 2 Are there potential shortcomings in current management approaches for my patient? 3 Is it time to increase monitoring and order biomarker tests for my patient? For more information about UCDs and their management, visit UCDinsights.com. 10

11 References: 1. The Physician s Guide to Urea Cycle Disorders. National Organization for Rare Disorders website nordphysicianguides.org/urea-cycle-disorders/. Accessed August 17, Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. doi: / Smith W, Kishnani PS, Lee B, et al. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin. 2005;21(4)(suppl):S9-S17. doi: /j. ccc Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008;97(10): doi: /j x. 5. McGuire PJ, Lee HS, Summar ML; Urea Cycle Disorders Consortium. Infectious precipitants of acute hyperammonemia are associated with indicators of increased morbidity in patients with urea cycle disorders. 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