ESPEN Congress Madrid 2018

Transcription

1 ESPEN Congress Madrid 2018 Inborn Errors Of Metabolism Inborn errors of carbohydrate metabolism G. Pintos (ES)

2 INBORN ERRORS OF METABOLISM INBORN ERRORS OF CARBOHYDRATE METABOLISM Guillem Pintos-Morell, MD, PhD Centre for Rare Diseases University Hospital Vall d Hebron, Barcelona Universitat Autònoma de Barcelona

3 INBORN ERRORS OF METABOLISM CONFLICTS OF INTEREST Speaker and travel grants Alexion, Amicus, BioMarin, Kyowa, Shire, Vitaflo Advisory boards Lucane, Kyowa

4 INBORN ERRORS OF CARBOHYDRATE METABOLISM LEARNING OBJECTIVES Basic metabolic pathways Common clinical presentations Laboratory diagnosis and biochemical markers Suggested management guidelines Frequent clinical complications Treatment recommendations

5 INBORN ERRORS OF CARBOHYDRATE METABOLISM JM Saudubray. Orphan Academy, Paris 2010

6 CARBOHYDRATE METABOLIC PATHWAY

7 COMMON SIGNS & SYMPTOMS PRESENT IN IEM OF CARBOHYDRATES GSD 0 GSD I GSD III GSD IV GSD VI GSD IX GSD XI Gluconeogenesis disorders Fructose 1,6 bisphosphatase Hereditary Fructose Intolerance Fasting hypoglycaemia Growth failure Hepatomegaly Increased AST & ALT Hyperlipidaemia Proximal renal tubular dysfunction Hyperlactatemia Increased uric acid

8 Metabolic profile in GSD I: GSD I metabolic profile Fasting hypoglycaemia, W/O ketoacidosis Hyperlactatemia (> 5 mmol/l) Hyperlipidaemia: Chol, TG Hyperuricemia CPK normal, no cardiac involvement Oral glucose challenge : glucose, lactate Response to glucagon: glucose -, lactate (fasting )

9 OVERVIEW OF HEPATIC GSDs Disorders of gluconeogenesis: Fructose 1,6 bisphosphatase deficiency Hereditary fructose intolerance Differential diagnosis with other IEM of carbohydrate metabolism: Hypoglycaemia after more prolonged fasting or intercurrent illness Gastrointestinal symptoms, long-term liver and kidney damage Prolonged PT, hypoalbuminaemia, elevation of bilirubin, and proximal tubular dysfunction; hypoglycaemia provoked by fructose intake Improvement of symptoms with fructose restriction

10 Hormonal profile and metabolic products in response to hypoglycemia in different clinical situations Insuline Lactate Fatty acids β Hydroxibutyrate Alanine Cortisol, GH Hyperinsulinism N N N N β-oxidation defects N N Panhypopituitarism N N Ketotic Hypoglycemia N Glycogenolysis GSD type I N Glycogenolysis GSD III, VI, IX N Neoglucogenesis defects

11 OVERVIEW OF HEPATIC GSDs Differential diagnosis of GSD I: GSD 0: No hepatomegaly, fasting ketosis GSD III: Normal lactate and uric GSD IV: No hypoglycaemia until advanced liver dis. Prolonged PT GSD VI: only fasting hypoglycaemia and ketosis. Lactate is normal GSD IX: only fasting hypoglycaemia and ketosis. Lactate is normal GSD XI (Fanconi Bickel synd due to GLUT 2 deficiency): GI symptoms, hypophosphataemic rickets GSD I (Van Gierke) Ia and Ib: Ia: Glc-6-phosphatase a (G6PC) Ib: Glc-6-phosphate transporter (G6PT, SLC37A4) GSD Ia and Ib typical complications: Liver adenomas hepatocellular carcinoma Chronic kidney disease with renal failure Osteopenia Osteoporosis Nephrolithiasis Gout Anaemia, platelet dysfunction GSD Ib: Neutropenia, impaired neutrophil function Inflammatory bowel disease

12 OVERVIEW OF HEPATIC GSDs Distinguishing features from GSD III: GSD 0: No hepatomegaly GSD I: Increased uric acid and lactate, lack of severe ketosis, nephromegaly, and lack of myopathy GSD IV hepatic: No hypoglycaemia until advanced liver disease GSD IV neuromuscular: Hypotonia, amylopectin-like inclusions, muscle atrophy GSD VI: no muscle involvement GSD IX: X-linked form typically less severe clinically GSD XI (Fanconi Bickel synd due to Glut-2 deficiency): GI symptoms, hypophosphataemic rickets, RTA GSD IIIa/b (Cori, Forbes) Debranching enzyme/agl GSD IIIa: Hepatic and myopathic GSD IIIb: Hepatic Associated features: Liver fibrosis Cirrhosis Liver failure Liver adenomas Hepatocellular carcinoma Progressive myopathy Concentric hypertrophic cardiomyopathy Cardiac dysfunction Arrhythmias

13 GSDs and hypoglycaemia Good metabolic control: Glucose > 72 mg/dl TG < 531 mg/dl Uric acid < 6 mg/dl Lactate < 22 mg/dl The glycogenosis presenting more frequently with hypoglycaemia is GSD type I (1: : RN) Clinical presentation: severe hypoglycaemia with normo-ketosis, hepatomegaly and growth failure Hyperlactataemia and metabolic acidosis GSD type III (deficit of debranching enzyme), type VI (hepatic phosphorylase deficiency) and GSD 0/XII (glycogen synthase deficiency), may present also hypoglycaemia, but less frequently

14 G6P metabolic pathways The primary anabolic and catabolic pathways of G6P in the gluconeogenic organs, liver, kidney and intestine. Production of intracellular glucose by the hydrolysis of G6P Produced in the terminal step of gluconeogenesis and glycogenolysis by G6Pase- Control of interprandial blood glucose homeostasis

15 GSD-Ia, Ib, and Irs manifest distinct and overlapping phenotypes

16 GSD I: LONG TERM COMPLICATIONS GSD TYPE I: CLINICAL CHARACTERISTICS Doll-like faces Growth delay Short stature Distended abdomen: hepatomegaly, nephromegaly Hypoglycaemia, seizures Recurrent bacterial infections Oral and/or intestinal mucosa ulcerations Short stature Liver adenomas Hepatocellular carcinoma Bleeding diathesis due to impaired platelet function Anaemia Decreased bone mass. Increased risk for osteoporosis and fractures Proximal renal tubular dysfunction. Glomerular impairment that may progress to ESRF (FSGS) Polycystic ovaries Increased risk for IBD, hypothyroidism Early atherosclerosis, acute pancreatitis, xanthomata

17 GSD I: LONG TERM COMPLICATIONS Wang DQ etal. J Pediatr 2011; 159:

18 NUTRITION MANAGEMENT OF GSDs Education to caregivers and patients Glucose monitoring Risks: Obesity Insulin resistance Micronutrient deficiency Infantile period: Feeds every 3-4 hours Soy milk Alternative: continuous feeds through NG tub or 8-10 to 4-8 mg/kg/min, depending on the age As children grow: uncooked corn starch (1-2.5 g/kg/dose) Low fat content MCT, EFA (essential fatty acids) High protein 65% of total energy intake from CH

19 DIFERENT APPROACHES TO NUTRITION MANAGEMENT IN GSDs To maintain similar energy intake that general or peer population and incorporate dietary starch within the 65% target, thereby limiting fat or protein intake To take a similar diet to peers but with treatment starch as extra leading to a greater energy intake and risk of obesity To take less energy than is required with a particular risk of micronutrient deficiencies Risks: Obesity Insulin resistance Micronutrient deficiency

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22 Hypoglycemia and metabolic control with extended release cornstarch Patients benefit from the extended release cornstarch by avoiding the overnight dose while maintaining metabolic control There is no difference between missed doses of traditional therapy and the extended release therapy, but the longer duration between doses increases the risk The extended release formulation is about 15 times more expensive than regular cornstarch However, an emergency department visit due to a missed overnight cornstarch dose would be more expensive than several years of the extended release formulation Ross KM at al. JIMD Reports. DOI /8904_2015_488

23 GSD TYPE I: CLINICAL CHARACTERISTICS Doll-like faces Growth delay Short stature Distended abdomen: hepatomegaly, nephromegaly Hypoglycaemia, seizures Recurrent bacterial infections Oral and/or intestinal mucosa ulcerations Case report (Moest W et al. Hepatology 2018; 68 (2): 780-2): 25 year-old women at ED for acute abdominal pain in right upper quadrant and fever Laboratory tests: hypoglycemia (2.5 mmol/l) hyperlactatemia (9.1 mmol/l) hyperlipidemia (triglycerides 10.6 mmol/l, total cholesterol (6.1 mmol/l) No urinary ketones Working diagnosis: sepsis with abdominal focus Treatment: symptoms recover quickly with a bolus of 10% glucose and 5% maintenance but blood glucose levels persist relatively low Medical history: 4 months before was referred because fatigue, weight loss, nocturnal sweating, hypermenorrhea, and nose bleeding associated with microcytic anemia Abdominal imaging: hepatomegaly with multiple hepatocellular adenomas Referred to centre of expertise with the working diagnosis of GSD Genetic analysis: homozygous mutation in G6PC gene Further medical history: Child of a first-degree cousins. Since 7-8 years of age she was evaluated because tiredness, failure to thrive (-2.5 SD, delayed bone age), hepatomegaly, increased erythrocyte sedimentation rate, and hyperuricemia. Signs of fasting intolerance during the day and night (hungry, sweating, and had to woke 1-2 times to eat and drink carbohydrate containing substances). Evolution: good response to uncooked cornstarch (40 g/4 h, day and night, initially). After 5 weeks, nocturnal 120 g of extended-release cornstarch for the 8 h of sleep