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Metabolica Flashcards

1
Q

OTC?

A

Ornithine transcarbamylase deficiency

Urea cycle defect

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2
Q

Hyper ammonia?

A

In urea cycle state indicates catabolism
Sodium benzoate:
Combines win glycine to form hippuric acid which the kidneys then excrete

Treat by returning to anabolic:
Low protein feeds
Lipids
Sugar

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3
Q

Most common CF mutation?

A

66% is CFTR Delta F 508 (Cystic Fibrosis Transmembrane conductance regulator protein
DELETION of phenylalanine at Amino Acid 508
Chloride Channel
CLASS 2 - MISFOLDED, Can’t make it to cell surface
Correctors like lumacaftor or tezcaftor help it fold and get to surface

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4
Q

Micropenis causes in neonate?

A

Stretched penile length <2.5SD = <1.9cm
Hormonal abnormality after 14/40
Hypogonadotrophic hypogonadism - GNRH deficiency (Prader Willi, Kallmann, Lawrence Moon-Biedel)
Hypergonadortophic hypogonadism - primary testicular failure
Idiopathic

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5
Q

Congential PanHypo Pit Symptoms?

A 
Micropenis (Low FSH/LH)
Optic Atrophy
Midline defects
Poor Growth
Hypoglycaemia (Low ACTH/GH)
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6
Q

Difference between 5 Alpha Reductase and Androgen Insensitivity?

A

5AR is Autosomal recessive, can’t convert testosterone into DHT, effects XY Genotype with variable phenoytype and virilisation at puberty.

Androgen Insensitivity effects XY genotype, X-Linked recessive, cryptorchidism, absent uterus, feminization at puberty

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7
Q

Homocystinuria?
Prevalance
Symptoms
Pathophys

A

1:300,000 - More in Ireland/Germany/Norway/Qatar (1:1800)

//
Ectopia lentis - Free floating anterior lens - MYOPIC
Marfanoid - reduced flexibility
Learning difficutlies, thrombosis, chest wall deformties, osteoperosis
//
Methionine -> Cysteine via homocysteine
High plasma/urine homocysteine
CBS (Cystathionine beta-synthase) enzyme Pyridoxine-dependent 
GIVE Pyriodoxine and FOLATE
Or Low methionine diet
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8
Q

What is inappropriate ketosis?

A

Ketones (beta-hydroxybutyrate of <2.5) when hypoglycaemic is EITHER:

Hyperinsulinism (which suppresses formation)
OR
Fatty Acid Oxidation defect (not mobilising)

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9
Q

MCAD

A 
Medium Chain Acyl0CoA Dehydrogenase deficiency
-
HYPOGLYCAEMIA and HYPOKETONEMIA
(Carnitine deficiency, fatty acid transportation defects, defects of beta oxidation enzymes)
MCAD is most common
Low BSL
Low Carnitine (free + total)
Low Ketones
Elevated FFA
Urine - Dicarboxylic acids, acylglycine)
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10
Q

Treatment for PKU?

A 
Phenylketonuria
Low Phenylalanine (protein) diet
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11
Q

Findings in SEPTIC OPTIC DYSPLASIA?

A

Optic nerve hypoplasia
Optic chiasm hypoplasia
Absent septum pallucidum
Pituitary stalk hypoplasia

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12
Q

Clues to a mitochondrial disorder?

A

Tissues with an energy requirement effects (Brain/Skeletal Muscle/Heart)
Abnormal brains
Raised creatinine Kinase
Raised Lacate

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13
Q

3 MethylGlutaconic Aciduria

-Types?

A

Type 1 - Super Rare
Type 2 BARTH Syndrome - TAZ Gene, Xlinked, taffazzin portine, cardiolipin abnormalities - Cardiomyopathy, Skeletal Myopathy, Neutropaenia, FTT
Type 3 - COSTEFF syndrome 0 Opthal and neuro
Type 4 - Catarcts, Neurtopaeniua, Epilepsy
Type 5 - Cardiomyopathy, cerebellar ataxia, testicular dysgenesis

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14
Q

GLUT 1 Deficiency?

Gene
Product
Symptoms

A 
Gene is SLC2A1 on 1p34.2
Solute Carrier Family 2 , member 1
GLUT 1 Product
Glut 1 across blood brain barrier
Low CSF glucose cf. paired serum glucose

Causes 
Seizures age <4 yr
Developmental delay
Paroxysmal exertional dyskinesia
TREAT with KETO DIET
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15
Q

Propionic Acidemia?

A

Organic acidemia - defect in fatty acid oxidation
Deficinecy of propionyl-CoA carboxylase
If catabolic can have acute metabolic deompensation
Ax with metabolic stroke - bilateral infarcts to basal ganglia due to toxi metabolites causing endothelial injury

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16
Q

Three broad patterns of metabolic illness?

A

Intoxication
Energy Metabolism
Complex molecules

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17
Q

Describe intoxication in regards to metabolic disorders

A

Placental unit can detoxify, therefore unlikely dysmorphic/congenital injury
Subsequent toxin accumulates (Amino acid to NH3, Organic Acidemia, Translation), or CHO Toxin (Galactose/Fructose) or Fat Toxin
Related to trigger
Occur due to cytoplasm or mitochondrial defect
Treatable with sugar 8-10 mg/kg/min

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18
Q

Describe energy metabolism defect in regards to metabolic

A

Failure to utilise CHO or Fat for energy - KREB Cycle related (All roads lead to Rome)
Defect worst for high energy organs (Brain, Liver, Muscle, Heart (Which also prefers ketones))
May be congenital as placenta can’t supply cellular energy
Damage to structures with scarring/cysts

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19
Q

Describe Complex molecule metabolic disorders

A

Problem with complex molecules - peroxismoe, lysosome, golgi apparatus, endoplasmic reticulum, protein glycosylation

Complex, multisystem, dysmorphic
Less likely to have liver derangement than Intox or Energy metabolism
Rarely treatable

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20
Q

If sick enough for an LP - Think Metabolic?

A

And DO AN AMMONIA

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21
Q 
If not responding to standard treatment?
And tachypnoea
Respiratory alkalosis
Feeding difficulty
Hypotonia
What might you think?
A

THINK METABOLIC

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22
Q

Altered mental state, tachypnoea -

THINK?

A

Hyperammonemia

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23
Q

Ketoacidosis and an unexplained anion gap?

A

Organic acidemia or disorder of gluconeogenesis

24
Q

Ketones present in neonate?

A

Abnormal - Think organic acidemia or gluconeogenic defect

25
Ketones NOT present when hypoglycaemic?
Abnormal - Hyperinsulinism OR | Disorder of beta oxidation of fats
26
What presenting clue to a metabolic crisis?
Poor feeding/vomiting - to dehydration Lethargy/altered consciousness - to coma Appear ‘septic’ Tachypnoea - hyperammonemia, or metabolic acidosis Abnormal neurological examination - due in nature to disorder: Ataxia, Diffuse hypotonia/hypertonia, twictching, seizure PHx of BRUE, or severe illness in response to gastro etc.
27
What presenting biochemical clues for metabolic crisis?
``` Metabolic acidosis Lactic acidemia/acidosis Increased anion gap Hyperammonemia Hypoglycemia KETONES - High (organic acidemia) or inappropriately low (fatty acid oxidation defects) ```
28
What late signs of metabolic crisis?
``` Apnoea Bradycardia Seizures Hypothermia Multi organ dysfunction Suddeny Death ```
29
Metabolic conditions that may present with sudden death (and hence masquerade as SIDS?)
Fatty acid oxidation Disorders of carnitine transport/metabolism Urea cycle defect Organic acidemia Disorders of pyruvate metabolism Oxidative phosphorylation Carbohydrate disordes (galactosemia, hereditary fructose intolerance, glycogen storage disease, disorder of gluconeogenesis)
30
In setting of catabolism - which IEM may be triggered?
Defects in catabolic pathways - TREATABLE Glycogen storage disease 1, or gluconeogenesis Fatty acid beta-oxidation defects Carnitine transport disorder Ketogenesis defects Amino acid disorders Organic acidemia
31
What defines a metabolic crisis?
Metabolic disorder associated with acute CLINICAL and BIOCHEMICAL decompensation
32
Catabolic cascade? AKA triggers for catabolism?
Prolonged fasting Infection Surgery Steroid therapy Vaccination (fever and increased metabolic rate) Neonatal physiology (Newborns lose weight, they are all catabolic) Excess protein intake ***
33
How does protein differ from other metabolic disorders?
EXCESS intake alone can trigger AA degradation pathways and crisis without corresponding catabolic state
34
Biochemical profile of organic acidemia in NEONATE?
``` pH LOW Bicarbonate LOW Anion gap HIGH Ammonia elevated Urinary KETONES elevated Bone marrow suppression ```
35
Diet related causes of metabolic trigger
Excess Protein - Urea cycle defect or acidemia Galactose - galactosemia - cataracts + jaundice Fructose - herediatry fructose intolerance
36
Hereditary Fructose Intolerance - Fructose load leads to:
Post prandial hypoglycaemia
37
Glycogen storage disease - Von Gierke | Clinical Vignette?
``` Distended abdomen Weight loss Difficulty sleeping >3 hours Mild transaminase rise With trigger at FEVER 6/12 Hypoglycaemia, mild metabolic acidosis, HCO3 - 15, lactate 3.6, elevated transaminases, Urine pH 6.5 - aka not very good acidification - Renal Tubular Acidosis develops with metabolic liver disease “renal fanconi” syndrome ```
38
Glycogen store length?
10-12 hours, gluconeogenesis kicks off early
39
Fatty Acid oxidation- time to kick in post fasting?
10-12 hours
40
Gluconeogenesis time to effect?
Starts within hours but ramps up to full speed by 10 hours, (muscles and RBCs) eventually spares muscles after ~ 24 hours and just RBC And also fatty acid oxidation as ketone fuels
41
Glycogen Storage Disease Type 1 - Biochemical Abnormalities
GLUCONEOGENESIS FINAL PATHWAY - Glycogen metabolism + Gluconeogenesis - GLUCOSE 6 PHOSPHATASE (G6Pase) Low sugar, body catabolic Glycogen instead of being converted to glucose, accumulates as G6P, which tricks liver, to paradoxically behaves anabolically - Elevated lactate/pyruvate/triglycerides Inhibited ketones (lower than expected) (As Trigs being made) Elevated FFA - Xanthoma Elevated glycogen in liver (hepatomegaly)
42
4 Metabolic Crisis Questions?
1. Is the patient sick (infections/stress/vaccine/fever/surgery)? 2. Is the patient eating too much protein? 3. Is the patient having a food that is toxic for them? (Protein, galactose, fructose) 4. When are symptoms in relation to food (glycogen storage disorder, gluconeogenesis, fatty acid ox)
43
Biochemical pathways - which tests in acute metabolic diseases?
Crisis are either: Intoxication OR Energy Metabolism Proteins - NH3 Urea Cycle Organic acids - organic acidemia Therefore: Order - ammonia, pH, anion gap need bicarb, Cl vs. N + K // CHO disorders: Herediatry fructose intolerance, can’t convert to glucose Fructose sequesters phosphate F1P - liver failure with LOW ATP state F1,6 bisphosphatase inhibits gluconeongenesis without interfering with glycogen ORDER Glucose (LOW), Lactate (HIGH) (accumulates at end) // Fatty Acids - Fatty acids oxidise to acetyl-coa then ketones produced Order Ketones (LOW) (Urine, First Pass post presentation) with Glucose To support fatty acid oxidation defect ``` THEREFORE: Ammonia Electrolytes Blood Gas Glucose Lacate Urinalysis (Ketones) ```
44
Method of tachypnoea in urea cycle disorder?
Ammonia is a RESPIRATORY STIMULANT Low CO2 drives by respiratory alkalosis ALKALOTIC STATE Body compensates by dumping HCO3 - compensatory ‘metabolic acidosis’
45
Body wastes HCO3 (diarrhoea or renal) | How does body compensate?
Compensation is retaining chloride | Gives a NON ANION GAP ACIDOSIS
46
Causes of raised ammonia?
Urea cycle primary OR Urea cycle can be impacted on a secondary
47
Metabolic Crisis in organic acidemia changes in LFT and FBE?
Raised transaminases | Neutropaenia and thrombocytopaenia
48
Metabolic Crisis Shopping list: LEVEL 1 LEVEL 2
``` Gas Electrolytes Ammonia Urinary Ketones LFT FBE Glucose Lactate ``` ``` // Level 2 - to CONFIRM Metabolic Screen Blood AA Amino Acids Urine OA Organic Acids Blood AC Acyclcarnitines ```
49
How do metabolic confirmatory tests work, what effects them?
BLOOD AA Urine or CSF occasionally Acute Specimens more likely diagnostic Nutritional status, age of patient URINE OA GAS MS - detects organic metabolites - intermediates of energy metabolism and fatty acid oxidation Tandem Mass Spec for Acyclcarnitine Sort by mass Smashed , resorted Carnitine bound metabolites - aka acylcarnitine Carnitine binds long chain fat, escorts into mitochondria But fickle - will bind to organic acids and fatty acids too And if you mass spec for carnitine, then mass spec again - u get what carnitine is bound to (and what is therefore hanging about)
50
Regarding metabolic algorithims - What information necessary if metabolic acidosis?
Consider ketosis Consider sugar Consider lactate In order to differentiate: Organic acidemias, glyogen storage disease, defects in gluconeogenesis, fatty acid oxidation, multiple carboxylase deficiency, mitocondrial
51
Regarding metabolic algorithims - what information for hyperammoniaemia
Consider Ketoacidosis Consider presence of significant liver disease Consider response to glucose if liver disease Primary respiratory alkalosis - ? Urea Cycle Defect Primary Liver disease Primary metabolic acidosis - ?Organic acidemia with inhibition of UC, ?Valproic acide inhibiting urea cycle, or sick ++ with perfusion or aponea leading to MAcidosis overtaking RespAlkalosis Or with nil liver disease or resp alkalosis or ketoacidosis - Fatty Acid Oxidation
52
Regarding metabolic algorithms - what information for hypoglycaemia
What is the character of hypoglycaemia? Persistent = Hyperinsulinism/endocrine Post feeding = Hereditary fructose intolerance, or galactosemia with liver injury or hyperinsulinism If with fasting consider hepatomegaly or not If nil hepatomegaly assess ketones (fatty acid ox vs. ketotic hypoglycemia/MCAD) If hepatomegaly assess duration of fast to genearte lacetmia (GSD1 vs. fatty acid ox, gluconeogensis def)
53
Glycogen storage disease | What sorts?
All Glycogen enzyme issues - All autosomal recessive GSD 1 - Von Gerkes “Jerky” factory - Glucose-6-phosphatase, final step to create glucose in gluconeogenesis and glycogenolysis - LACTIC ACIDOSIS, due to downstream pyruvate buildup, hypoglycaemia -> seizures, High triglycerides, hepatomegaly, gout/uric acid GSD 2 - Pompe disease “Pompei volcano” - Lemon Acid Maltase deficiency, LYSOSOMAL, Alpha 1,4,glucosidase, HCM, cardiomegaly, hepatomegaly, respiratory distress, Limb girdle weakness, hypotonia, PAS stain pink from lysosomes, big tongue GSD 3 TREE- Cori “Quarry” - debranching enzyme/delimit GSD 5- HIVE McArdle - Hurdler - Glycogen phsophorylase - muscle breakdown (Muscle cramps with excercise) - Myoglobinuira - skeletal muscle injury, arrythmias due to electrolyte changes - hyperkalemia - “2nd wind phenomenon”- increased blood flow compensates
54
Compare and contrast GSD2’s two forms
Infantile form - little/no enzyme - Cardiac involvement - HCM, large tongue, large liver Juvenile form - reduced enzyme - adolescent or later onset Both AR, lysosomal build up glycogen, PROXIMAL (Girdle) limb weakness, diaphragm weakness GAA gene Alglucosidase alfa - Gene Therapy
55
Farber disease?
``` Farber’s Lipogranulomatosis Hoarse/weak cry Lipogranulomas under skin Swollen painful joints - AR, abnormal lipid metabolism which accumulates ```

RACP METABOLICS (1 decks)

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