Clinical Conditions

Question 0

Describe sickle cell anaemia:

What kind of genetic inheritance
What is replaced
Comsequence

Answer 0

Autosomal recessive
A->T = glutamate (hydrophilic) -> valine (hydrophobic)
In beta subunits of Hb

Can have trait: mainly no SCA symptoms, but protects against malaria

Creates sticky hydrophobic pocket.
Polymerised Hb causes cell to adopt sickle shape
Can block micro vasculature & cause sickle cell crisis

Crisis precipitated by factors that reduce O2 availability/promote T state (smoking, obesity, cold, infection)

Haemolytic anaemia: result of spleen removing sickled RBCs

Jaundice: excess bilirubin from excess breakdown

Question 1

Describe amyloidosis

Answer 1

Mis folding of proteins
= insoluble form of normally soluble protein
Effects vary dependent on location
In brain = Alzheimer’s

Question 2

Describe cystic fibrosis:
Genetic basis
What is affected
Consequences
Treatment

Answer 2

Autosomal recessive: mutated chromosome 7. Normally 1 codon del.

Defective cystic fibrosis transmembrane regulator (CFTR) gene.

Impaired ability to transport Na+/Cl-:
Cl- doesn’t move from inside to outside cell
Na+ doesn’t follow
No solute produced outside cell / NaCl inside cell
Water doesn’t follow to dissolve solute
Mucus mot hydrated

Resp tract: ciliary escalator impaired, bacteria aren’t cleared = infection
Pancreatic duct: mucus blocks = pancreatitis, stops fat digestioon
Sweat: salty
Males: vas deferens doesn’t form = infertility

Prophalaxis for lung infections
Lipase tablets to digest fats
Recover sperm from testes; bypass vas deferens

Question 3

Thalassaemias: 2 types

Answer 3

Alpha: decreased/absent alpha chains in Hb. Symptoms before birth
Beta chains Can form stable tetramers.

Beta: decreased/absent beta chains in Hb. Symptoms after birth:
Fetal Hb is alpha & gamma chains.
Cannot form stable tetramers
Reduced Hb = reduced O2 capacity. Anaemic symptoms

Question 4

Haemophilia A:
Type of genetic condition
Consequences
Treatment

Answer 4

Recessive X linked

No/reduced factor VIII production: blood cant clot as well (factor Xa down by 50%)

Treat with recombinant factor VIII
Avoid thrombolytics/blood thinners

Question 5

Scurvy:
What kind of deficiency
Consequences

Answer 5

Vit C deficiency

= Lack of prolyl hydroxylation in collagen synthesis
interchain H bind formation impaired
Unable to form stable triple helix
Collagen fibrils cant be cross linked
Reduced tensile strength
Bruising

Question 6

Down’s Syndrome

Type of genetic condition/cause

Consequences

Diagnosis

Answer 6

Extra 21st chromosome: trisomy 21
meiotic division error or Robertsonian translocation

Characteristic facial features, impaired intelligence, heart defects, increase prevalence leukaemia, early onset Alzheimer’s

Can be screened during pregnancy

Question 7

Edwards syndrome
Type of genetic condition
Consequences

Answer 7

Trisomy 18
‘Rocker bottom’ feet, overlapping fingers, small jaw
Live 1-2 weeks

Question 8

Patau’s syndrome
Type of genetic condition
Consequences

Answer 8

Trisomy 13
Congenital heart defects, cleft lip etc
Median survival 2.5 days

Question 9

Turner’s syndrome
Type of genetic condition
Consequences

Answer 9

Monosomy X
Only occurs in women
Missing one copy of small autosomal region at start of sex chromosomes
Short stature, heart defects, mild LDs, neck webbing, incertility

Question 10

Kleinfelter’s syndrome
Type of genetic condition
Consequence

Answer 10

XXY
occurs in men
Extra chromosome = smaller testes/reduced testosterone production/lack male sex characteristics/infertility
Treat with testosterone

Question 11

Ectopic pregnancy

Answer 11

Implantation of embryo in fallopian tube
= rupture of tube
Miscarriage, haemorrhage

Question 12

Placenta praevia

Answer 12

Implantation of embryo in lower segment of uterine wall
Placenta blocks cervix
C section required

Question 13

Marfan’s syndrome
Type of genetic condition
Consequences

Answer 13

Autosomal dominant
Misfolding of fibrillin
More elastic connective tissue
Tall, long digits, aortic rupture likely (arteries too elastic)

Question 14

Ethlers-Danlos disease

Answer 14

Type 3 collagen deficiency
Loss of structure (reticulin = scaffold)
Stretchy skin, unstable joints, easy bruising etc

Question 15

Vitiligo

Answer 15

Autoimmune destruction of melanocytes
Depigmentation
Psychosocial probs for dark skinned people

Question 16

Alopecia areata/universalis

Answer 16

Autoimmune destruction of hair follicles

Worsened by stress

Question 17

Psoriasis

Answer 17

Extreme over production of skin cells
Too much corneum
Scaling
Genetic link but cause unknown
Treat with steroids

Question 18

Malignant melanoma

Answer 18

UV damage indices mutations that = malignant cancer
Prognosis good if not penetrated basement membrane
Uncommon with darker skin: melanin provides protection

Question 19

Oesteogenesis imperfecta
Type of genetic condition
Consequences

Answer 19

Autosomal dominant
Type 1 collagen deformity/deficiency
Major component in ground substance of bone
Severe = conversion fetal hyaline cartilage skeleton: lethal
Repeated fractured = bowed long bones
Blue sclera ? Thinning cornea due to collagen probs

Question 20

Rickets/osteomalacia

Answer 20

Deficiency in Vit D
Less absorption of Ca2+ by small bowel
Less rigid bones
More common in darker skin: less synthesis of Vit D

Rickets: children
Bowed bones (still growing)

Oestemalacia: adults
Bone/back ache
Can be secondary to impaired hepatic/renal function (less absorption)

Question 21

Osteoporosis

2 types

Answer 21

Both osteoclast > osteoblast

Type 1: menopausal
Oestrogen no longer mediating osteoclast function.
Fractures more likely

Type 2: old age
Loss of osteoblast function: no remodelling

Question 22

Acromegaly

Answer 22

Too much GH
Adults:
increased bone width from intramembranous growth (periosteal)
Epiphyseal plates fuse at end of puberty so no lengthening

Question 23

Gigantism

Answer 23

Too much GH
children:
Increased height: excessive growth from epiphyseal growth plates

Question 24

Cretinism

Answer 24

Neonatal hypothyroidism Retardation, short stature Give thyroxine before 3 weeks

Question 25

Achondroplasia Type of genetic condition Consequences

Answer 25

Autosomal dominant Deformed fibroblast growth factor receptor Decreased endochondral ossification Short limbs, enlarged forehead, normal trunk

Question 26

Myasthenia Gravis

Answer 26

Autoimmune destruction end plate nicotinic ACh receptors Antibodies target nAChr on post synaptic membrane of skeletal musc Contraction ends suddenly when [ACh] drops End plate potentials reduced in amplitude = musc weakness/fatigue Droopy eyelids (small musc worst affected), fatigue (esp after exercise), sudden collapse Each quantum of Ach released produces smaller response than in more musc; less nAch receptors available (same amt of Ach released) Treat by immunosuppressin & ACh esterase inhibitors (keep more ACh in symapse)

Question 27

Muscular Dystrophy Type of genetic condition Consequences

Answer 27

``` Absence (Duchenne's) or truncation (Becker's) of dystrophin Muscle fibres tear in contraction Ca2+ induced necrosis Fat & CT laid down (pseudohypertrophy) Gower's sign (brace thighs with arms) Degenerative Chest musc destroyed = death ```

Question 28

Botulism

Answer 28

Botulism toxin blocks ACh release | No musc contraction

Question 29

Thyrotoxicosis

Answer 29

Increased BMR protein catabolism Atrophy

Question 30

Hypoparathyroidism

Answer 30

Lack PTH Lack Ca 2+ absorption Tetany

Question 31

Malignant hyperthermia Type of genetic condition Consequences Treatment

Answer 31

Autosomal dominant Life threatening reaction to general anaesthesia (succinylcholine) Leads to release of all Ca 2+ from all sarcoplasmic reticulum Spike in Ox Phor in skeletal musc Temperature spike Overwhelms control mechanism = death ``` Manage symptoms (paracetamol & other antipyrexials) Dentrolene (prevents Ca 2+ release) ```

Question 32

Multiple sclerosis

Answer 32

Autoimmune destruction of myelin sheath & schwann cells Decrease in conduction Loss of function Beta interferon Steroids (Mediate immune function)

Question 33

Von Gierke's Disease Cause What area of the body it affects Consequences

Answer 33

Deficiency of glucose 6 phosphatase (gluconeogeneic: hydrolysis of G6P to release free glucose) Mainly liver & kidneys Increased conc G6P in liver & kidneys = increased amt of normal glycogen stored Liver & kidneys unable to release glucose btw meals to regulate BG in response to glucagon = fasting hypoglycaemia Hepatomegaly Failure to thrive Ketosis: body tries to use other fuels

Question 34

Hyperthyroidism (Grave's): Cause (cause Grave's) Symptoms Treatment

Answer 34

Increased production/release T3/T4 Graves = Autoimmune disease: produces antibodies that stimulate TSH receptors ``` Increased T4/T3 Decreased TSH (negative feedback) Heat intolerance, increased BMR Weight loss Hyperactivity Tachycardia Myopathy Goitres ``` Carbimazole Radioactive iodine Thyroidectomy

Question 35

Hypothyroidism (Hashimoto's) Causes (cause Hashimoto's) Symptoms Treatment

Answer 35

Destruction thyroid follicles, iodine deficiency (rare) Hashimoto's: antibody production blocking TSH receptors ``` Cold intolerance, reduced BMR Weight gain Tiredness, lethargy Bradycardia Goitre Cretinism (in children if untreated) Skin dry/flaky ``` Oral thyroxine (T4)

Question 36

Galactosaemia: Definition Deficient enzymes (which is more common, which is rarer) Consequences Treatment

Answer 36

Inability to use galactose = increased levels in blood Galactokinase (non-classical galactosaemia): Galactose build up Galactosuria (above renal threshold) Galactose -> Galactitol (aldose reductase/NADPH) Reduced NADPH = cysteine residues not maintained = cataracts High Galactose & Galactitol have osmotic effects on eye = glaucoma Galactose 1 P uridyl transferase (classical galactosaemia): Galactose 1P build up Toxic to hepatocytes = jaundice, vomiting Epimerase: Prevents transfer of UDP between glucose & galactose (So cannot convert galactose 1 P to glucose 1 P, which is fed into glycolysis)

Question 37

Anaemia: Definition/process Types

Answer 37

Reduced no rbc's / reduced amt O2 reaching organs/tissues Many diff types: Blood loss: GIT ulcers etc Excess breakdown: sickle cell Deficient release of rbc's: poor heamatopoiesis

Question 38

Gestational diabetes: Process

Answer 38

During pregnancy, rate of insulin secretion & synthesis increases If pancreas fails to respond to demands of pregnancy, less insulin than required released Loss of metabolic control: increased blood glucose = diabetes Normally reverses after birth But increased chance of future diabetes

Question 39

Hypercalcalcaemia: Process Presentation Consequences of chronic increased levels of calcium Treatment

Answer 39

Increased PTH (hyperparathyroidism) PTH related peptide, from cancer Excess calcitrol? Stones (kidney stones/damage) Moans (tiredness, depression) Groans (abdo pain, constipation) Bone loss (when due to excess PTH) Replace fluid Remove tumour from PTH

Question 40

Hypocalcaemia: Consequences chronic reduced calcium levels Causes

Answer 40

Hyper-excitability of the NS: Parasthesia Tetany/convulsions Paralysis (death if paralysis diaphragm) Hypoparathyroidism (rare) Removal of PT gland Vit D & calcium deficiency (When due to diet, not PTH: Ca maintained at expense of bone = rickets in children)

Question 41

Type 1 Diabetes Mellitus: Definition Clinical presentation (incl biochem) Treatment

Answer 41

Complete autoimmune destruction of beta cells of pancreas = no insulin production Normally younger person Often post viral infection Triad: polyuria, polydipsia, unexplained weight loss Hyperglycaemia: rbg >11.1, fbg >7.0 Ketone body production (noticed in urine/on breath): ketoacidosis Immediate subcutaneous insulin Patient education

Question 42

Ketoacidosis: Cause (& process) Leading to...

Answer 42

T1DM: Lack insulin Metabolism of FAs Increased ketone body production (noticed in urine/on breath) ``` Hyperventilation Nausea Vomiting Dehydration Abdo pain ```

Question 43

Leptin deficiency: Normal function of leptin Consequences of deficiency

Answer 43

Hormone that controls appetite: Inhibits stimulatory / stimulates inhibitory neurone Obesity (therefore a key hormonal target in managing obesity)

Question 44

Type 2 Diabetes Mellitus: Definition Clinical presentation Treatment

Answer 44

Gradual destruction beta cells of pancreas With tissue insulin resistance ``` Normally older person, obese/overweight Gradual onset Triad: polyuria, polydipsia, weight loss (less noticeable) Hyperglycaemia Usually no ketone production ``` ``` Diet & exercise initially Non-insulin therapies (sulphonylureas: increase insulin release/reduce insulin resistance, metformin: reduce gluconeogenesis) Insulin treatment ```

Question 45

Diabetes: Macrovascular problems Microvascular problems Management

Answer 45

MI Stroke Poor circulation Neuropathy Nephropathy Retinopathy Diabetic foot Monitory with HBA1C every 3m: Non-enzymatic glycosylation test

Question 46

Lactic acidosis: How/why occurs Consequences Clinical presentation

Answer 46

Increased lactate produced in cells Anaerobic exercise: Reduction of pyruvate (via lactate dehydrogenase) Supplies more NAD+ to maintain ATP production If proton conc in blood > blood buffering capacity = reduced pH (Excess protons dont come from lactic acid) Deep breathing, abdo pain, nausea)

Question 47

Metabolic syndrome: Prevalence Diagnosis/clinical presentation

Answer 47

12-25% (developed countries) ``` W:H ratio >0.9 (men), >0.85 (women) BMI > 30kg/m2 BP > 140/90 mmHg Triglycerides >1.7mM HDL < 0.9mM (men) 7.8mM Glucose uptake lowest quartile ```

Question 48

Cushings: Definition Causes Consequences Test

Answer 48

Increased secretion glucocorticoids (zona fasciculata) = increased cortisol Adrenal cortex increased activity Pituitary: increased ACTH secretion Ectopic tumour (adenoma in pituitary): increased ACTH secretion Increased proteolysis (thin arms/legs) Increased gluconeogenesis Hyperglycaemia (polyuria/polydipsia) Lipogenesis (moon face, buffalo hump, weight gain) Hypertension (increased production mineralocorticoid) Acne (immunosuppressed) Dexamethasone suppression test (synthetic steroid) Normally reduce ACTH & therefore cortisol Suppression >50% indicates cushings (Retains some sensitivity; distinguishes from tumours)

Question 49

Addison's Disease: ``` Definition Causes Clinical presentation Test Treatment (Addisonian crisis - worsened by stress) ```

Answer 49

Reduced activity adrenal cortex Autoimmune destruction adrenal cortex (reduced glucocorticoids & mineralocorticoids) Pituitary/hypothalamic disorder (Reduced ACTH/CRF release) Insidious onset: weight loss, tiredness, anorexia, abdo pain Hypotension Muscle weakness & dehydration Hypoglycaemia Increased pigmentation (ACTH acts as MSH: both POMC derived) Synacthen (synthetic analogue of ACTH) Normally increases cortisol Normal response excludes Addisons Cortisol Fluid replacement

Question 50

Hyperammonaemia: Definition When can occur Consequences

Answer 50

Increased amount of ammonia in blood (NH3+) High protein diet & partial urea cycle deficit Amino acid metabolism deficit Re-feeding syndrome (reduced urea cycle from reduced food, rapid re-intro of food, excess aa degradation, reduced urea cycle activity to dispose of ammonia) Toxic to CNS (tremors, slurred speech, coma, death) Increased blood pH Reacts with alpha ketoglutarate; removes TCA substrate = reduced energy supply

Question 51

Phenylketoniria (PKU): Definition Consequence (process, clinical) Test Treatment

Answer 51

Inherited condition: defective enzyme phenylalanine hydroxylase Prevents conversion phenylalanine -> tyrosine (used to make hormones & neurotransmitters; noradrenaline, adrenaline, dopamine, as well as thyroid hormones) Build up phenylalanine; drives alternative path- converted to phenylpyruvate Lack of neurotransmitter synthesis (phenylpyruvate prevents pyruvate uptake to mitochondria: brain energy metabolism) Can cause mental retardation (phenylalanine inhibits brain dev) Heel prick test @ birth Diet low in phenylalanine Tyrosine supplements

Question 52

Uncouplers: ``` Process 2 causes (unnatural, natural) ```

Answer 52

Increase permeability of inner mitochondrial membrane to protons Uncoupling ETC from Oxidative Phosphorylation Dissipation of p.m.f. As heat Protons bypass ATP synthase ``` Pesticide poisoning (e.g. dinitrocresol, dinitrophenol) Brown adipose tissue via UCP-1: allows non shivering thermogenesis ```

Question 53

Cyanide poisoning: How works Process

Answer 53

Blocks ETC Binds to electron transport proteins Prevents oxidation NADH & FAD2H Prevents ETC initiating No free energy released by REDOX reactions of ETC = proton translocation complexes unable to pump protons into intermembrane space Prevents establishment of p.m.f.

Question 54

Glycogen storage disease: Consequences: too much / too little

Answer 54

``` Too much: Tissue damage (liver, musc) ``` Too little: Poor exercise tolerance Fasting hypoglycaemic tendencies

Question 55

Hyperglycaemia: Clinical presentation (on testing) Tests & thresholds

Answer 55

Glucose in urine; above renal threshold Polyuria, polydipsia (osmosis) Random blood glucose > 11.1 mM Fasting blood glucose > 7.0 mM Non-enzymatic glycosylation of proteins (HbA1C) >10% (normal 4-6) Plasma glucose 2 hrs after OGTT >11.1 mM

Question 56

Hypoglycaemia: Test & threshold Consequences Clinical presentation

Answer 56

Blood glucose conc < 3.0 mM Can be rapidly fatal: glucose essential for CNS function ``` Slurred speech Reduced coordination Dizziness/headache Coma Death ```

Question 57

Excess paracetamol: Normal metabolism Metabolism after toxic dose Treatment

Answer 57

Normally straight to phase 2 metabolism Phase 2 metabolism saturated so induces phase 1: Phase 1 Creates toxic intermediate (NAPQI): toxic to hepatocytes Phase 2 conjugation with glutathione (reduces ROS defences) Activated charcoal to reduce adsorption / N-acetyl cysteine

Question 58

Lactose intolerance: Enzyme deficiency Consequence Clinical presentation (& explanation) Treatment

Answer 58

Lactase Lactose cant be broken down; remains in gut Stomach cramps, diarrhoea (water drawn in to lumen of colon by osmosis) (Bacteria colonise un-hydrolysed lactose; ferments to produce organic acids: irritate GIT) Lactose free diet (avoid most dairy products)

Question 59

Homocystinuria: Definition Cause Clinical presentation Treatment

Answer 59

Inherited condition; defect in CBS enzyme Build up of methionine & homocysteine (from breakdown of aa's that cannot then be converted to cysteine) Affects Fibrillin-1 protein structure (Stretchy skin; affect on CT - similar to Marfans, chest pain, dev delay; methionine) Low methionine diet Vit B6 to increase remaining CBS activity

Question 60

Glucose 6 phosphate dehydrogenase deficiency: What this enzyme does Consequences of deficiency

Answer 60

Oxidise G6P; responsible for pentose phosphate pathway (Produces 5C ribose sugars for nucleotide synthesis in actively dividing tissues, produces NADPH) Reduction in NADPH = Reduced lipid synthesis Reduced maintenance of SH residues in lens of eye = cataracts Reduced maintenance of SH residues in rbc's = disulphide bonds form (Heinz bodies) Prevents glutathione reduction: important in rbc's etc for ROS detox

Question 61

Hyperlipidaemia: Definition Cause Clinical presentation Treatment

Answer 61

Increased triglyceride lvl in blood (often after fatty meal) Increased chylomicrons in blood many hrs after meal (lack of breakdown) Defect in lipoprotein lipase Abdo pain Low fat diet

Question 62

Marasmus: ``` Kind of deficiency Where seen/what population Clinical presentation (& explanation) Why proteins need to be reintroduced slowly ```

Answer 62

Calorific & protein deficiency Young children/developing world Muscle wasting, emaciated, loss body fat, no oedema (Fat metabolised to make ketones in liver, but need lipoproteins to transport ketones, therefore breakdown muscle) SOB, tachycardic (Not enough water to maintain BP) Protein broken down in liver to lipids But no protein to transport out = fatty liver

Question 63

Kwashiorkor: ``` Kind of deficiency Clinical presentation (& explanation) Why need to re-introduce food slowly ```

Answer 63

Low protein, adequate calories Ascites & oedema (Low oncotic pressure because low serum protein production e.g. Albumin; water out to tissues & not returning) Hepatomegaly (Lack aa's for transport proteins, less fat transport, fat builds up in liver, less fat breakdown) Thin limbs Liver damage = urea cycle not working well: toxic ammonia not converted to urea No albumin stores = inadequate colloid pressure = water not drawn out = oedema

Question 64

Jaundice: Process that causes

Answer 64

Damage to liver Broken down rbc's = Hb = heme = bilirubin Less bilirubin conjugated (made water soluble) by liver Unconjugated bilirubin builds up & released into blood Insoluble therefore moves into tissues Brown/yellow unconjugated bilirubin in blood & tissues = jaundice

Question 65

Familial hypercholesterolaemia: Cause Clinical presentation Treatment

Answer 65

Absence/deficiency of LDL receptors = increased LDL & cholesterol kn blood Xanthelasma Corneal arcus Increased atherosclerosis (LDLs -> cholesterol deposit -> plaque) ``` Lifestyle changes (diet, exercise) Statins (inhibit HMG CoA reductase) ```

Question 66

Obesity: BMI: clinical & morbid obesity Causes Treatments A risk factor for...

Answer 66

>30 >35 Excessive energy intake (increased fat, alcohol) Exercise Reduce fat content ``` T2DM CHD: atherosclerosis Oesteoarthritis Cancers Psychological damage ```

Question 67

Oxidative stress: Definition Poss causes Management

Answer 67

Antioxidant levels too low to deal with ROS levels ``` G6P-dh deficiency (Normally Reduces glutathione: key part of defences) Superoxide dismutase deficiency Catalase deficiency (Both deficiencies = reduced superoxide radicals) ``` Important in many disease states e.g. alzheimers) Increase antioxidants e.g. Fruit

Question 68

Excess alcohol (chronic): Consequences Treatment

Answer 68

Acetaldehyde can increase sufficiently to cause liver damage Reduced NAD+/NADH ratio: affects many normal liver processes incl gluconeogenesis Increased FA synthesis & reduced lipoprotein (fatty liver) Loss enzymes in cells due to leakiness GI disturbances Disulfiram: Inhibits aldehyde dehydrogenase causing 'hangover' which can inhibit alcohol dependency (Alcohol -> acetaldehyde -> acetate -> acetyl coA) (Alcohol dh, aldehyde dh) (Also reduced NAD+ to NADH, ATP to AMP)