1110 - Metabolic Disorders and Human Disease Flashcards
Describe the metabolic consequences of insulin deficiency
Increased production, but decreased utilisation of glucose.
Muscle has reduced glucose uptake (and glycolysis), but increased protein catabolism
Adipose tissue has reduced glucose uptake, increased lipolysis (TAG->FFA)
Increased FFA and degraded proteins go into blood to liver..
Liver has increased gluconeogenesis (proteins), FFAs lead to increased TAG synthesis (and VLDL production), reduced glycolysis and increased ketoneogenesis.
Detail the medical complications born of diabetes
Decreased glucose uptake leads to increased lipolysis (TAG->FFA). Oxidation of FA’s leads to ketone body formation and keto-acidosis. This leads to nausea and vomiting, fluid and electrolyte loss.
Filtration of ketones and glucose leads to osmotic diuresis, hypotension/shock, and increased cortisol and catecholamines that further increase insulin deficiency/resistance.
Provide a definition, characteristics and aetiology of familial hypercholesterolaemia (FH)
Genetic disease characterised by high plasma [cholesterol], particularly LDL. Characterised by a defect or deficiency of the LDL receptor in hepatic or peripheral tissues, preventing it from endocytosing LDL.
Describe the metabolic consequences of reduced LDL uptake by cells
Normally, cells synthesise cholesterol form HMG-CoA. Requirements above this base rate are met using LDL cholesterol, internalised via the LDL receptor.
Detail the role of elevated LDL in atherosclerotic plaque formation
High [LDL] is oxidised in the bloodstream, leading to foam cells, fatty streaks, and atherosclerotic plaque.
What is the endogenous Cholesterol Pathway? (KEY EXAM CONCEPT)
Synthesis pathway - lipids are synthesised in liver, and moved to storage, either in liver or peripheral tissues.
In hepatocytes, dietary chylomicrons, together with HDL/LDL from periphery, are synthesised into VLDL. On release, apoproteins are exchanged with HDL, while TAGs and FAs are spun off into peripheral tissues. Eventually, this process leads to LDL, which is packed with cholesteryl esters and returns to the liver via the bloodstream (or gets stuck and forms a plaque).
What strategies are used to manage familial hypercholesterolaemia?
Heterozygous (vast majority) FH managed by lowering blood [cholesterol]. Resins used to reduce absorption and statins to reduce endogenous synthesis.
Homozygous (rare) FH uses LDL apheresis (like dialysis) or liver transplant.
Provide a definition, characteristics and aetiology of PKU
Autosomal recessive disorder that prevents appropriate metabolism of phenylalanine by phenylalanine hydroxylase.
Initially asymptomatic, but patient develops epileptic seizures, microcephaly, eczema/reduced skin pigmentation, intellectual disability, tremors and jerky movements.
How is phenylalanine used in the body?
Phenylalanine is converted into tyrosine, which is then used to synthesize melanin, adrenaline, and acetoacetate (ketone body).
Describe the metabolic alterations in PKU
Instead of hydroxylasing phenylalanine into tyrosine (PheOH), transamination occurs, forming phenyl-pyruvate. In turn, this is metabolised into phenyl-lactate and phenyl-acetate, toxic metabolites that are excreted in urine and impart a characteristic odour (P-A).
How is PKU managed?
Protein-deficient diet to minimise intake of Phe. Hydrolise milk casein to remove it, and avoid protein-rich foods and artificial sweeteners.
What proteins does the LDL receptor bind to on LDL?
B100 and apoE
