Metabolism Flashcards
Metabolism definition
sum of all chemical reactions occurring within the cells of the body
Goal of metabolism
Maintain a constant source of energy for the body
Polysaccharides
Complex carbs
Monosaccharides
Simple sugars (mostly glucose)
What is the primary energy source of the body
Glucose
What is excess glucose stored as
glycogen
Where is glycogen stored
Liver and muscle
What is glucose converted into once glycogen stores are full
fatty acids and glycerol
What does glycerol get converted to in storage
Triglycerides
How many essential amino acids are there
9
How many non-essential amino acids are there
11
What are essential amino acids
Amino acids that aren’t created by the body
Extra amino acids are converted to
Glucose and fatty acids (fatty acids eventually stored as triglycerides)
Three types of fats
Triglycerides, monoglycerides, and free fatty acids
Excess circulating fatty acids are incorporated into
triglycerides
Where are triglycerides stored
mostly adipose tissue (fat), some muscle
Stages of energy use in the body
Glycogenolysis, gluconeogenesis, ketogenesis
Glycogenolysis time
1 hour after eating
Gluconeogenesis time
5 hours after eating
Ketogenesis time
10-12 hours after eating
Glycogenolysis definition
breakdown of glycogen into glucose (1-4 hours of fasting)
Gluconeogenesis definition
New creation of glucose from amino acids (3-12 hours of fasting)
Ketogenesis definition
fatty acid oxidation, creation of ketones from fatty acids (10+ hours of fasting)
Anabolism
Feeding/fed state
Buildup (synthesis) of larger organic macromolecules from smaller subunits
Anabolism results
Manufacture of material needed in the cell
Storage of excess ingested nutrients that are not immediately needed for energy production or as cellular building blocks
Catabolism
Fasting state
Breakdown (degradation) of large, energy-rich organic molecules within cells
Catabolism results
Breakdown of stored energy resources into smaller nutrients available for energy use (glycogen to glucose)
Primary energy users of the body
brain and muscle
Preferred source of energy for the brain
Glucose (can’t store glycogen)
Prolonged fasting can lead to brain using ketones
Primary site for amino acid storage
Muscle
Which organ is concerned with maintenance of normal blood glucose levels
Liver
Stores glycogen when excess glucose is available
Releases glucose into blood when needed
Principal site for conversion of glycogen into glucose
Other functions of liver
Production of enzymes for blood clotting
Metabolism of bilirubin
Primary energy storage site
Adipose tissue
Adipose tissue helps regulate what
fatty acid levels in blood
Lysosomes do what
Intracellular digestion
What happens if lysosomal enzyme doesn’t work
massive buildup/storage of material can cause lysosome to swell and burst
Mitochondria do what
Energy organelles that are powerhouse of cell
How do mitochondria work
Extract energy from nutrients via mitochondrial oxidation phosphorylation (respiratory chain)
B-oxidation of fatty acids
Peroxisomes do what
Intracellular waste treatment center
Major product of peroxisome
Hydrogen peroxide (H2O2)
Peroxisomes contain what
enzymes responsible for processing B oxidation of very long chain fatty acids (VLCFA)
Emia suffix
Regarding the blood
Uria suffix
Regarding the urine
Hyper prefix
too much
Hypo prefix
too little
Lys suffix
break down
Genesis suffix
creation
cofactor
Helper molecules for enzymes
Vitamins and minerals
Inborn errors of metabolism (IEMs) disease mechanism
Toxic accumulation of substances
Reduction of normal compounds
IEMs are usually caused by what
single-gene disorders
Code for enzymes that convert substrate into product
How many IEMs are there
1000
Incidence of IEMs
1/1500
Most IEMs have what inheritance pattern
AR
Can be X-linked or AD
Continuum of disease
Acute (PKU)
Late-onset (Gaucher)
Acute IEMs
Onset early in life
Severe if untreated
Progressive
Late onset IEMs
Onset may be in adulthood
Can live long time without treatment
Progressive
Genetic mutations of IEMs cause
reduced activity of enzyme
Reduce or lessen effectiveness of cofactors or activators for the enzyme
Produce defective transportation of compounds in the bodyl
Disruptions of metabolic pathway can cause
shunting of accumulated substrates on other pathways
Accumulation of toxic substrates/products
Deficient products of the missing enzyme
Treatment of IEMs
Limit substrate and substrate precursors
Process toxic products through alternative pathways
Supplement cofactor
Provide missing enzyme (enzyme replacement therarpy/transplant)
Supplement products and downstream products
Clinical features of IEMs in infant/child
Vomiting, seizures, ataxia, lethargy, coma, hepato-encephalopathy
Dysmorphic (coarse) features
Skeletal abnormalities
Poor feeding, FTT
Dilated or hypertrophic cardiomyopathy, hepatomegaly, jaundice, and liver dysfunction
Developmental delays
Hypotonia/hypertonia
Visual/auditory disturbances
Clinical features of IEMs in older children/adults
Varying degrees of LD/DD/ID, autism
Exercise intolerance
Muscle weakness (can be progressive)
Behavioral disturbances (delirium, hallucinations, agitation, aggressiveness)
Ataxia
Anxiety/panic attacks
Seizures
Episodes of symptoms for IEMs can be
Acute
Intermittent
Precipitated by stress (mental and physical-infection, pregnancy)
Progressive
Associated with feeding
Hypoglycemia
Normal: 70-140 mg/dl (80-120)
Hypoglycemia in children: <50 mg/dl
Hypoglycemia in adults: <55 mg/dl
Glucose is recovered from three different sources
Exogenous glucose via food is used immediately, excess stored in liver as glycogen
Liver glycogen maintains fasting blood glucose via continuous glycogenolysis - capacity for storage in this form is relatively small and can provide gluocse for 24-48 hours
Gluconeogenesis: formation of glucose from amino acids and other sugars - occurs coincidentally with glycogenolysis but can supply glucose for much longer period of time
Energy production alternatives for hypoglycemia
Fatty acid oxidation
Ketone production and oxidation (brain)
Metabolism of lactate
IEMs with hypoglycemia as prominent component
Glycogen storage disease type 1 - carb metabolism
MCAD deficiency - fat metabolism
IEMs with hypoglycemia as secondary component
Disorders of protein metabolism
Mitochondrial disease
Hyperammonemia
Normal <80 umol/l
Elevated >80 umol/l
Ammonia
NH4
Constantly produced by liver, intestinal mucosa, and kidneys
How is free ammonia removed from the blood
By the liver and kidneys
Excreted in urine as urea after traveling through the urea cycle
What happens when ammonia accumulates
Disrupts ATP production
Neurologic symptoms frequently result from
hyperammonemia
Many disorders with hyperammonemia present
after initial asymptomatic/normal period following birth
Stress - labor and delivery, inter-current infections
Significant hyperammonemia
> 300 umol/l - 1000 umol/l
Urea cycle defects have what level of hyperammonemia
10-100X above normal
2-3x above normal level of hyperammonemia can be seen in
mitochondrial disorders and other protein metabolism problems
pH
normal 7.4
Acidosis - <7.35
Alkalosis - >7.45
How is pH caluclated
logarithmic of hydrogen-ion concentration
Every unit change in pH is tenfold change in H+
Excretion of H+ makes
CO2
Respiratory alkalosis
caused by excessive loss of CO2 as a result of hyperventilation
Respiratory acidosis
Caused by abnormal CO2 retention arising from hypoventilation
Metabolic alkalosis
Reduction of plasma (H+) arises most commonly from - vomiting, ingestion of alkaline drugs such as calcium carbonate
Metabolic acidosis
Caused by net gain of H+ or loss of HCO3- (bicarbonate)
Encompasses all types of acidosis besides that caused by excessive CO2 in body fluids
Metabolic acidosis arises from
severe diarrhea, diabetes mellitus, strenuous exercise, and severe renal failur
Metabolic acidosis secondary causes
severe infection/sepsis, advanced catabolic state, tissue hypoxia, dehydration, and intoxication
Anion gap
difference between major cations (NA+ and K+) and major measured anions (Cl- and bicarbonate)
Normal anion gap
<16
Possible reasons for anion gap increase
lactate, ketones, organic acids
Can be measured in blood or urine
Primary IEMs associated with metabolic acidosis
Disorders of protein metabolism
Disorders of fat metabolism
Mitochondrial disease
Lactic acidosis
Too much lactic acid in blood
Best diagnostic markers for disturbed mitochondrial energy metabolism
Elevated lactate and pyruvate
Lactate is produced from
Pyruvate
Lactate is easier to measure than pyruvate by
blood and spinal fluid
Plasma lactate levels increase by what two mechanisms
Increased pyruvate production (glycolysis)
Decreased pyruvate consumption/oxidation (by pyruvate dehydrogenase complex or pyruvate carboxylase)
Primary hyperlacticacidemia
Carbohydrate metabolism (disorders of liver glycogen metabolism)
Mitochondrial disease (electron transport/respiratory chain defects)
Secondary hyperlacticacidemia
Protein or fat metabolism (organic acidemias, urea cycle defects, fatty acid oxidation defects)
Ketoacidosis
Acidosis caused by too many ketones
How are ketones formed
excess acetyl-CoA (involved in carbohydrate and lipid metabolism)
Used as alternative energy sources in tissues
Ketones are formed by
liver during times of fasting
Ketoacidosis from
Ketone utilization or increased ketone production
Ketoacidosis is usually what type of result of metabolic disorders
secondary
Creatine Kinase (CK)
Provides information regarding muscle breakdown and injury
Creatine kinase levels
Normal for adult 22-170 U/L
Serum CK levels can be due to
Muscle damage
Elevations due to acute muscle trauma elevated 4-6 hours after event
Peak values 18-30 hours
Return to normal by 72 hours
CK-MB isoenzyme
Measure of cardiac muscle damage
Rhabdomyolysis
Sudden increase in serum concentrations of CK
Rhabdomyolysis can be observed in
Carbs, fat, and mitochondrial IEMs associated with muscle disease
Myoglobinuria
Muscle tissue pigment in urine
Severe rhabdomyolysis
Carnitine
Fatty acids and proteins are broken down and their backbone structures are attached to carnitine
Shuttle across mitochondrial membrane and within mitochondria as they are metabolized into energy/ATP (move carbon chain backbones)
Help with transport of LCFAs
Carbon chain backbones are broken down by mitochondria by
B-oxidation
Used t provide energy in form of ATP
Two forms of carnitine
bound and free - describes carrier state
Bound carnitine-carbon complexes
varying lengths and are acylcarnitines
Divided into lengths - very long, long, medium, and short
Defects in carbohydrate metabolism
Galactosemia
Hereditary Fructose Intolerance
Glycogen storage disease (GSD)
Hepatic forms of glycogen storage
GSD1 - von Gierke’s disease
GSD III - Cori Disease
Enlarged liver - excess glycogen
Treatment with cornstarch
Muscular forms of GSD
GSD II - Pompe disease (also a lysosomal storage disease)
GSD V - McArdle’s disease
Galactosemia
Due to deficient activity of galactose - I - phosphate uridyltransferase (GALT)
GALT catalyzes production of UPD galactose from galactose-I-Phosphate and UDP glucose
Gene at 9p13
AR
Classic galactosemia
complete or near complete enzyme deficiency - 5% or less
Partial transferase deficiency galactosemia
More frequent than classic galactosemia
Enzyme activity 10-50% of normal
Generally asymptomatic
Duarte variant is best known
Newborn screening diagnosis of Galactosemia
high levels of Galactose-I-Phosphate
Confirm diagnosis by enzyme deficiency (GALT) in heparinized whole blood or RBC
In classic form GALT is almost complete (0%)
Mutation panel and sequence analysis of GALT
For classic (G/G) - panel of 6 common mutations
71%: two common mutations
10%: one common mutation and one private mutation
19%: two private mutations
Clinical features of Galactosemia
Feeding problems/vomiting/diarrhea
Lethargy
FTT
Hypoglycemia
Liver failure/jaundice
Bleeding
Sepsis/shock
Females - increased risk for primary or secondary premature ovarian failure (75-96% before age 30)
DD/ID
Cataracts
Delayed growth
Speech apraxia
Treatment for Galactosemia
Immediate dietary intervention for infants with GALT activity less than 10%
Begin formula that is lactose free
Calcium supplementation
Defects in protein metabolism
PKU (maternal PKU, defects in biopterin)
Tyrosinemia
Alcaptonuria
Homocystinuria
Nonketotic hyperglycinemia
PAH Deficiency
Phenylalanine hydroxylase
Severe PAH deficiency
Classic PKU
Classic, moderate, and mild forms tolerate different levels of Phe in diet
Maternal PKU
Poor control of plasma Phe levels during pregnancy adversely affects fetal development
Growth restriction
Microcephaly
Birth defects
Diagnosis of PKU
Newborn screening
Untreated PKU infants will
develop typically for first few months and then start showing symptoms
Seizures
Severe-profound ID
Microcephaly
Behavioral problems
Mousy odor (urine)
Very light skin and hair
PKU geneitcs
PAH
AR
Treatment of PKU
Diet
some Phe needed for normal growth/development
Avoidance of high-Phe foods (meat, fish, eggs-high protein foods)
Use of Phe-free formula as supplement (Tyrosine)
Phe restriction life long
Keep blood Phe 120-360 umol/L
Biopterin Cofactor Deficiency Tetrahydrobiopterin (BH4)
2% of hyperphenylalaninemias
Biopterin recycling defects
Dihydropteridine reductase (DHPR) deficiency
Pterin-4 acarbinolamine dehydratase (PCD) deficiency
Biopterin synthesis defects
Guanosine triphosphate cyclohydrolase (GTPCH) deficiency
6-pyruvoyl tetrahydrobiopterin synthase (PTPS) deficiency
Diagnosis for BH4
CHPR and biopterin in blood spot
Urine biopterins
High neopterin, low biopterin
biopterin recycling defect
low neopterin, low biopterin
pterin synthesis defect
Urea cycle defects
Urea cycle rids body of waste nitrogen
Waste nitrogen mostly from
amino acid metabolism
Product of protein catabolism
Ammonia
What organ conjugates waste nitrogen as ureea
Liver
Excreted by kidneys
Inherited defect of urea cycle manifests as
elevated blood ammonia - toxic to brain
Urea Cycle defects inside
Ornithine transcarbamylase (OTC) deficiency - one of few that is X-linked
Argininosuccinate synthetase deficiency - citrullinemia
Arginosuccinic aciduria - ASA lyase deficiency
Argininemia - Arginase deficiency
Urea cycle defects outside
NAGS - secondary inhibition by organic acids
CPS - Carbamyl phosphate synthetase deficiency
Urea Cycle defects treatment
Precursor and substrate restriction - dietary protein restriction
Provide/supplement deficient enzyme - liver transplant
Increase alternative pathway use - oral medications to help remove nitrogen via alternative mechanisms
Supplement products - citrulline or arginine supplementation
Organic acidurias
Maple syrup urine disease (MSUD)
Isovaleric aciduria (IVA)
3-methyl crotonyl-CoA carboxylase (3MCC) deficiency
Methylmalonic acidemia (MMA)
Propionic aciduria (PA)
Glutaric acidemia, Type I (GA I)
Biotinidase deficiency
Classical Organic acidurias features
Usually well at birth and for first few days
Toxic encephalopathy
Vomiting
Poor feeding
Hypotonia
Lethargy progressing to coma
Macrocephaly
Seizures
Metabolic acidosis - organic acids accumulate
Secondary hyperammonemia
Cerebral organic acidurias features
Cerebral (neurological) symptoms without the typical metabolic/lactic acidosis and hypoglycemia
Treatment of organic acidurias
Diet control - AA supplementation, AA avoidance, Carnitine supplementation
Emergency protocol - Carnitine supplementation increase during times of stress, avoidance of fasting (catabolic state)
Treatment is lifelong
Unusual odors in urine
Maple syrup - MSUD
Cat urine (ammonia) - 3MCC deficiency
Sweaty feet - IVA
Mousy - PKU
Fatty acids are released by
Lipoprotein lipase and hepatic lipase cleaving triglycerides, in endothelial cell and on surface of hepatocytes
Triglycerides released from
fat cells
Triglycerides convert to
glycerol and 3 fatty acids
FAOD
Fatty acid oxidation disorder
Mitochondria store energy in forms of
ATP from ADP and phosphate
Defects of fat metabolism
VLCAD deficiency
LCHAD deficiency
Trifunctional protein (TFP) deficiency
MCAD deficiency
SCAD deficiency
Short chain L-3-Hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency - now 3-hydroxy acyl CoA dehydrogenase deficiency (HADH)
Electron transfer flavoprotein (ETF) dehydrogenase deficiency
3-Hydroxy-3 Methylglutaryl-CoA Lyase Deficiency (HMG)
Carnitine disorders
Carnitine transport defect - main one
Carnitine-acylcarnitine translocase deficiency
Carnitine Palmitoyl Transferase I and II
Clinical features of FAO defects
cause infant or childhood deaths, following minor illness with fasting
Affect multiple siblings in a family
Associated symptoms: hypoglycemia, coma, seizures, heart failure, muscle breakdown
Treatment of FAO defects
dietary management
MCAD deficiency
Gene ACADM
Common mutation - 985A>G, K304E - 90%
80% homozygous
1:40 carriers among Northern Europeans
Low plasma carnitine, high medium-chain acylcarnitines
Symptoms of MCAD deficiency
Vomiting, lethargy, seizures, breathing difficulties, brain damage, coma, sudden death (from hypoketotic hypoglycemia when ill/fasting
MCAD Treatment
Typical infant feeding
30% calories from fat
Supplement carnitine as needed
Avoidance of prolonged fasts
Understand chronic health needs
Peroxisomal disorders
X-linked adrenoleukodystrophy (X-ALD) - Lorenzo’s Oil
Porphyrias disorders
Defects in synthesis of heme
Can be acute (neurologic) or cutaneous (primarily affect skin)
Photosensitivity, mental disturbances, hepatic disease
Purines and Pyrimidines disorders
Lesch-Nyhan Syndrome - X-link recessive, self-injurious behavior
Metal metabolism disorders
Hemochromatosis - iron metabolism
Wilson disease - copper metabolism
Menkes disease - copper metabolism - X-linked characterized by sparse, kinky hair, FTT, and neurological sx
Bone metabolism/mineralization disorders
Familial X-linked hypophosphatemic Rickets (XL dominant)
Hypophosphatasia (AR or AD)
Cholesterol metabolism disorders
Smith-Lemli-Opitz Syndrome (SLOS)
Congenital disorders of glycosylation (CDG) syndromes
Variable, umbrella term for disorders involving glycoproteins/glycolipids
Goals of medical nutrition therapy
Promote healthy brain function - prevention of neurlogical damage d/t metabolic crises/decompensation, preserve cognition/intellect
Promote healthy physical growth and development - prevention of malnutrition or FTT, growth delay, poor bone health, support healthy weight and exercise
Challenges of medical nutrition therapy (MNT)
Introduction of foods as patients age
Adherence to diet
Family member/caregiver compliance
Adolescence
Emergency situations
Macronutrients
Carbs (glucose) - fuel brain/body, fiber
Protein (essential amino acids) - required for growth, cell repair, enzyme formation
Fats (EFS0: protection, temperature regulation, hormone regulation, energy
Micronutrients
Vitamins (fat and water soluble) - hormones, enzymes, co-enzymes
Minerals (major and trace) - bone and tissue health
Simple sugars
table sugar, jelly, candy, honey, syrup, fruit, fruit juice - quick sources of energy
Complex carbs
Cereals, breads, grains, pasta, potatos, beans, corn, veggies - helps with prolonged glucose release
Goals for carb disorders
avoid prolonged periods of fasting
Restrict the offending simple sugar
Provide adequate nutrients to promote normal growth and development
Prevent hypoglycemia which can progress to metabolic crisis, seizures, and death
Laboratory monitoring: lactic acid, uric acid, blood glucose
GSD Type IA
Enzyme defect - Glucose-6-phosphate
Roadblock is final step of gluconeogenesis - glycogenolysis to release glucose - no internal source of glucose
Can store glycogen but can’t break it down
Uncontrolled leads to hypoglycemia, lactic acidosis, high uric acid, elevated TGs, cholesterol
Can progress to seizures and death
Nutrition guidelines for GSD IA
High protein, low carb diet - restrict fructose (sucrose), limit lactose (galactose), sucrose and lactose free formula, consume complex carbs
Nighttime feedings
Limit fat, especially saturated fat
Possible G-tube
Dairy to one serving per day
Limit fats and choose mono-unsaturated fats
Multivitamin+calcium citrate supplementation
Avoid sucrose and fructose
Avoid sorbitol
Tyrosinemia IA
Enzyme defect: hepatic fumarylacetoacetate hydrolase (FAH)
Buildup of succinylacetone which is toxic to the liver
needs dietary management and medication
Essential FAs
Linoleic acid
Alpha-linolenic acid
Medical food
food which is formulated to be consumed or administered entirely under supervision of physician and intended for specific dietary management of disease
Dietary supplement
product taken by mouth that contains a dietary ingredient
PKU
Body cannot metabolize essential AA, phenylalanine
Criteria for NBS conditions
Wilson and Jungner criteria
condition should be important health problem
Natural history of condition should be well understood
Recognizable latent or early symptomatic stage
Suitable tst or examination
Test should be acceptable to population
Should be agreed upon policy on who to treat
Accepted treatment for patients with disease
Must have facilities for diagnosis and treatment
Cost of case-finding should be economically balanced in relation to possible expenditure on medical care as whole
Case finding should be continuing process
Tandem mass spec
multiplex analysis of many different analytes
NBS tests
heel prick
Cardiac screen
Hearing screen
When is blood spot collected for NBS
24-48 hours after birth
Steps after positive NBS
Diagnostic confirmation
Intervention
Medical management
Sudden increase in CK, evidence of muscle breakdown, and urine that looks like cola
Rhabdomyolysis
Cataracts, jaundice, vomiting, lethargy
Classic Galactosemia
