910 The initial clinical manifestations are character ized by nonspecific neurological abnormalities such as irritability, poor feeding, or somnolence, followed by rapid deterioration The diagnosis is[.]
L Barcat et al 910 Intoxication Liver Muscle Detoxication Toxic Intestine Fig 47.1 Endogenous intoxication model: the toxic metabolite produced by the intestine and muscle amino acid catabolism (NH3, propionic acid, etc., depending on the inborn error of metabolism) is not metabolized by the liver, resulting in toxic accumulation and brain damage (Courtesy of D. Rabier (Biochemical Laboratory, Necker Hospital, France)) The initial clinical manifestations are characterized by nonspecific neurological abnormalities such as irritability, poor feeding, or somnolence, followed by rapid deterioration The diagnosis is suspected based upon the combination of clinical course and laboratory investigations Metabolic crisis may occur at any age from the neonatal period to adulthood A recent case report of a multifactorial non-cirrhotic hyperammonemic encephalopathy in adulthood recalls the importance of evaluating serum ammonia in front of any atypical clinical picture at any age of life [5] Each attack can follow a rapid course that ends in either spontaneous improvement or unexplained death, despite supportive measures in the PICU. The following events may trigger acute decompensation by increasing neurotoxic metabolite production: prolonged fasting, anesthesia and surgery, infections, prolonged exercise, drugs (valproic acid, steroids, and adrenocorticotropic hormone), and high protein intake Despite multiple etiologies, intercurrent infection is recognized as the leading cause of metabolic decompensation in patients with IEM. Some authors 47 Dialytic Therapy of Inborn Errors of Metabolism in Case of Acute Decompensation have recently revisited the mechanism of impact of infection in the IEM patient and the central role of the liver as a metabolic and immunologic organ [6] An inborn error of metabolism should be suspected when the following history is found (1): recurrent coma (2), unexplained death in the family or any neonatal death, even if it was attributed to another cause (e.g., sepsis, anoxia, etc.), and (3) consanguinity Although most genetic disorders are hereditary and transmitted as recessive disorders, the majority of cases appear sporadically in developed countries because of small family sizes Hepatomegaly, abnormal urine or body odor and myoglobinuria may help to refine the diagnosis [7] General supportive measures and laboratory investigations should be undertaken as soon as metabolic encephalopathy is suspected The initial approach for investigations is outlined in Table 47.1 It is important to perform these investigations as early as possible, and all laboratory tests should be obtained simultaneously, as most disorders may produce only intermittent abnormalities The determination of plasma ammonia concentration is crucial when metabolic encephalopathy is suspected 911 Etiologies Inborn errors of metabolism with endogenous intoxication include urea cycle defects, maple syrup urine disease, and organic aciduria (propionic or methylmalonic aciduria) They are difficult to diagnose, and the biologic signs described in Table 47.2 and Fig. 47.2 should prompt consideration of such diseases Metabolic acidosis with increased anion gap is observed in intermediate acid accumulation, such as organic acid disorders (propionic and methylmalonic acid) Severe hyperammonemia (>300 μmol/L) is observed in primary urea cycle defects, organic acid disorders, and fatty acid oxidation defects [8] Treatment The principles of therapy include (1) suppression of the de novo synthesis of toxic metabolites by adapted nutritional support including high caloric intake and no protein initially (2), pharmacological scavenging of ammonia by supplementation of substrates lacking physiological or alternative pathways, and (3) rapid removal of the small, water-soluble neurotoxic metabolites by dialysis Table 47.1 Laboratory investigations in inborn errors of metabolism Urine Blood Miscellaneous Routine tests Smell (special odor) Look (special color) Ketones (Acetest) Ketoacids (DNPH)b pH Glucose Osmolality Blood gases Transaminases, bilirubin, γGT Ammonia Lactic acid Creatine kinase Storage of samples and metabolic testsa Fresh sample in the refrigerator, frozen sample at −20 °C, for metabolic testing (AAC, OAC, orotic acid) Plasma heparinized at −20 °C (5 mL) for AAC, etc Whole blood (10 mL) collected on EDTA at −20 °C (for molecular biology studies) Plasma or blood on filter paper for acylcarnitine dosage Redox status if lactate >10 mmol/L Skin biopsy for fibroblast culture If death: liver and muscle biopsy DNPH dinitrophenylhydrazine test, AAC amino acid chromatography, OAC organic acid chromatography a Tests should be discussed with specialists in metabolic diseases b This test screens for the presence of alpha-keto acids, as occur in maple syrup urine disease It can be replaced by an amino acid chromatography, if available, in an emergency situation L Barcat et al 912 Table 47.2 Etiologies of inborn errors of metabolism with neurotoxic accumulation, presenting with encephalopathy and which may be treated by dialysis Clinical presentation Metabolic coma without focal neurologic signs Neurologic coma with focal signs, seizures, severe intracranial hypertension, strokes, or stroke-like episodes Predominant metabolic disturbances Metabolic acidosis Hyperammonemia Hypoglycemia Hyperlactatemia Associated metabolic disturbances With ketosis Without ketosis Normal glucose Hypoglycemia With acidosis Without acidosis Normal glucose Hypoglycemia Biologic signs are variable, can be absent or moderate Cerebral edema Hemiplegia or hemianopsia Extrapyramidal signs Stroke-like Most frequent diagnoses Organic aciduria (MMA, PA), MSUD FAOa Urea cycle defects FAOa MSUD FAOa FAOa MCD FAOa MSUD OTC MSUD OTC MMA PA MMA Urea cycle defect MMA PA MMA methylmalonic academia, PA propionic academia, MSUD maple syrup urine disease, OTC ornithine transcarbamylase, FAO fatty acid oxidation, MCD multiple carboxylase deficiency a Usually not an indication for dialysis Inborn errors of the metabolism encephalopthy/vomiting/failure to thrive/myopathy/cardiomyopathy/ shock Defects in metabolism of energy sources Proteins Lipids Amino acidopathies Organic Acidemia Urea cycle disorders MSUD MMA PA Hyperammonemia OTC Citrullinemia Argininosuccinic aciduria MCD FAO Dysfunction in pathways within cellular organelles Mitochondries Carbohydrate Carnitine shuttle Glycogen storage disorders Peroxysomes Lysosomes Galactosemia Blood gas, lactate, ammonium, glucose Urine metabolic screen (urine organic acid, urine amino acid), plasma amino acid, acyl carnitine profile, carnitine analysis Hypo glycémia Metabolic acidosis Hyperammonemia Ketones Respiratory alkalosis Hyperammonemia Lactic acidosis Hypoglycemia +/hyperamonemia Dialysis for endogenous intoxication (NH3 or endogenous acids) Fig 47.2 Etiologies of inborn errors of metabolism with neurotoxic accumulation, presenting with encephalopathy, and which may or may not be treated by dialysis MSUD, maple syrup urine disease; MMA, methylmalonic Lactic acidosis Lactic acidosis No dialysis for endogenous intoxication acidemia; PA, propionic acidemia; OTC, ornithine transcarbamylase; FAO, fatty acid oxidation; MCD, multiple carboxylase deficiency 47 Dialytic Therapy of Inborn Errors of Metabolism in Case of Acute Decompensation Nutritional and Pharmacological Management As soon as an endogenous intoxication is diagnosed, nutritional support should be discussed with the specialist, and it can include the following: • Rehydration first: Many patients with metabolic defects are dehydrated at presentation as a result of poor oral fluid intake Restoration of normal hydration to protect normal renal function and promote protein anabolism is crucial for effective treatment • High caloric intake to promote protein anabolism Glucose is the only nutrient infused initially The rate of glucose infusion should be high, so that enough energy is generated via glycolysis Intravenous administration of 10% glucose with semi-normal saline solution is preferable to physiological saline solution in patients with hyperammonemia, since ammonia scavenging drugs contain large amounts of sodium [9] When a central line is inserted, concentrated solutions of glucose are infused (>1000 kcal/m2/day) which may require the addition of insulin infusion so as to avoid hyperglycemia When the diagnosis is confirmed, nutritional support should be started, consisting of glucose and lipids (in the absence of a fatty acid oxidation defect) without protein, preferably by continuous enteral feeding with a caloric intake of at least 1500 kcal/m2/ day Special amino acid mixtures are used to supply nontoxic amino acids For example, in MSUD, the enzyme defect involves the branched chain amino acids (leucine, valine, and isoleucine) The mixtures used are initially free of these three branched chain amino acids but include the other essential amino acids • Avoidance of any factor that promotes protein catabolism, including steroid therapy (see above) • Specific medications in some inborn errors of metabolism, such as ammonia removal drugs (see Table 47.3) Ammonia scavengers (sodium phenylacetate and sodium benzoate) with an initial loading dose are key 913 treatments in case of hyperammonemia [10] Carbamylglutamate has been used successfully in methylmalonic and propionic acidurias as an allosteric activator Carbamylglutamate resulted in a dramatic decrease in ammonia blood levels with a similar effect to dialysis in some cases [11] Metabolite Removal by Dialysis Since the brain damage induced by neurotoxic metabolites is correlated with the duration of exposure to high levels of these metabolites, metabolic crises are considered emergency indications for dialysis requiring use of the most readily available and effective dialysis modality [7] After 3–4 h of the nutritional and pharmacological treatment described above, medical management is evaluated with respect to neurological recovery, evolution of biochemical markers (serum ammonia, pH, etc.), and nutritional tolerance However, this 4-h window should be used to prepare for having dialysis ready for nonresponders The criteria for dialysis and the optimal modality to use are not yet well established for each disease and are currently based on individual institutional experience The decision is made with a multidisciplinary approach that involves intensivists, specialists in metabolic diseases, and nephrologists For technical aspects of each dialysis methods see corresponding chapters Hyperammonemic Disorders In hyperammonemic disorders, increasing serum ammonia level or values persistently above 300– 500 μmol/L are usual indications for dialysis [10, 12] Since rapid toxic removal is crucial for limiting damage to susceptible tissues, particularly in hyperammonemic crises, the selection of dialysis modality must focus upon its efficacy of metabolite clearance Other factors to consider in critically ill children are hemodynamic stability and intracranial hypertension Dialysis is ended when ammonia blood levels are below 100 μmol/L [13–15] L Barcat et al 914 Table 47.3 Specific treatments of inborn errors of metabolism Drug Sodium benzoate Effect Ammonia removal Sodium phenylacetate Ammonia removal Sodium phenylbutyrate Ammonia removal NH3 >200 μmol/L Urea cycle disease Arginine Ammonia removal NH3 >200 μmol/L Urea cycle disease Carglumic acid Ammonia removal Carnitine Primary or secondary deficiency 50–100 mg/kg/day in divided doses every 3–4 h IVC or PO Vitamin B12: hydroxycobalamin Enzyme cofactor Methionine synthase deficiency Decreased toxin production by intestine bacteria PC cofactor NH3 >200 μmol/L N acetylglutamate deficiency MMA PA FAO Organic aciduria FAO Mitochondrial disorders MMA 1–5 mg/kg/day IM or IV MMA PA 15–20 mg/kg/day divided in 2–3 doses PO PA Biotinidase deficiency Carboxylase deficiencies FAO 5–20 mg once /day PO 20–40 mg/day IV or PO MSUD 50–200 mg/day IV or IM Metronidazole Biotin Riboflavin Thiamine Cofactor of acyl dehydrogenase Enzymatic cofactor Indication (s) NH3 >200 μmol/L Urea cycle disease Ketotic hyperglycinemia NH3 >200 μmol/L Urea cycle disease Dose (s) Loading dose: 500 mg/ kg Maintenance: 500 mg/ kg/24 h Loading dose: 500 mg/ kg Maintenance: 500 mg/ kg/24 h 450–600 mg/kg/days 3–6 times a day max 20 g/day Loading dose: 600 mg/ kg Maintenance: 600 mg/ kg/day then 200 mg/kg/ day 100–250 mg/kg/day 2–4 doses Administration IV 90 min IV 24 h IV 90 min IV 24 h PO IV IV 24 h PO In suspected cases of IEM, the above specific treatments may be indicated in metabolic encephalopathy, after specialist consultation Some therapies are specific for toxic accumulation (i.e., hyperammonemia) and some are specific a disease MSUD maple syrup urine disease, MMA methylmalonic acidemia, PA propionic acidemia, OTC ornithine transcarbamylase, FAO fatty acid oxidation, MCD multiple carboxylase deficiency, NH3 ammoniac, PC pyruvate carboxylase, IV intravenous, IVC continuous intravenous infusion, IM intramuscular, PO per os In hyperammonemic metabolic crises, experimental evidence suggests that ammonium is more efficiently removed by extracorporeal techniques than by peritoneal dialysis (PD) [16, 17] PD is of limited efficacy in hyperammonemic patients, because normalization of blood ammonia levels occurs in no less than 24 h, continued dialysis is required over 1–5 days on average, and a failure to decrease ammonia levels is seen in individual cases [17–25] Better results are obtained using continuous venovenous extrarenal therapies (CERT) including continuous hemofiltration [9] and continuous hemodialysis; blood ammonia is typically reduced 50% within 4–8 h and by >90% within 10 h, and therapy usually can be discontinued within 24 h [22, 26–29] The most 47 Dialytic Therapy of Inborn Errors of Metabolism in Case of Acute Decompensation efficient toxic removal is achieved by the use of intermittent hemodialysis (iHD), which reliably decreases blood ammonia concentrations by 75% within 3–4 h [17, 20, 21, 30–32] However, repeated hemodialysis sessions or a switch to CERT are usually required due to rebound hyperammonemia [17, 20] Hence, continuous venovenous hemodialysis (CVVHD) until attainment of complete normalization of blood ammonium 915 levels is considered the treatment of choice in most centers The routine use of this technique has become feasible with the advent of dialysis machines specifically adjusted for use in small children Whatever the method used (iHD or CERT), the expected clearance should be greater than 40 mL/min/1.73 m2 Metabolite clearance is measured by the formula: Clearance mL / blood flow mL / Cpre Cpost / Cpre , where Cpre and Cpost are the pre- and post-dialyzer metabolite blood concentrations Maple Syrup Urine Disease (MSUD) The incidence rates of inborn metabolic diseases vary by country MSUD is an autosomal recessive disease with an incidence ranging from 1/120,000 to 1/290,000 in the United States [33] For some authors, dialysis is indicated if two of the three following criteria persist 3–4 h after initial treatment: coma, gastrointestinal intolerance, and plasma leucine levels ≥1700 μmol/L [34] Dialysis is concluded when plasma leucine levels are below 1000 μmol/L In patients with MSUD, the low endogenous clearance of leucine and other branched chain- keto and amino acids is insufficient to reverse the accumulation of branched-chain amino acid (BCAA) that occurs during catabolic states Since several fold higher BCAA clearance rates are achieved by PD, this technique has been regarded as the method of choice since its introduction in the 1980s [19, 23, 35] More recently, 100–150% higher BCAA removal rates have been demonstrated experimentally with continuous extracorporeal blood purification techniques compared to PD (Fig. 47.3) [17, 36] In clinical practice, CERT resulted in better leucine clearance than PD [27, 28, 37] In children, iHD provided higher leucine clearance and required shorter sessions than CERT (5.4 ± 0.6 h vs 17.1 ± 6.0 h) A leucine clearance ≥50 mL min−1.1.73 m−2 resulted in a similar kinetic profile both with CERT and iHD [34, 38] Currently, a major technical limit in monitoring the acute treatment of MSUD is the difficulty in obtaining rapidly serial plasma leucine levels during treatment With CERT, leucine plasma levels decreased according to a bicompartmental model similar to that of nonprotein-bound small-molecular-weight solutes such as urea or creatinine This suggests that leucine clearance can be estimated from the creatinine clearance [38] However, when extracorporeal technics are not available, there is one case report of successful treatment of acute MSUD with sodium phenylacetate/sodium benzoate and sodium phenylbutyrate [39] Other Organic Aciduria The incidence of these rare diseases is also variable While individually rare, the cumulative incidence of inborn errors of metabolism has been shown to be upward of 1/800 To date, more than 1000 different IEM have been identified [40] In methylmalonic or propionic aciduria, dialysis is indicated if two of the four following criteria persist 3–4 h after initial treatment: coma, gastrointestinal intolerance, and pH 90% within 10 h, and therapy usually can be discontinued within 24 h [22, 26–29] The most 47 Dialytic Therapy of Inborn... Proteins Lipids Amino acidopathies Organic Acidemia Urea cycle disorders MSUD MMA PA Hyperammonemia OTC Citrullinemia Argininosuccinic aciduria MCD FAO Dysfunction in pathways within cellular organelles... organic acid chromatography a Tests should be discussed with specialists in metabolic diseases b This test screens for the presence of alpha-keto acids, as occur in maple syrup urine disease It