Metabolism Clinical Conditions

Question 1

Galactosaemia

Answer 1

Autosomal recessive
- Galactokinase deficiency - blocks galactose -> galactose-1-P, buildup of galactose in tissues, excreted in urine
Some enters aldose reductase, depletes NADPH reserves
-> disulphide bridges formed within the lens of the eye -> clouding (cataracts)
- G-1-P uridyl transferase deficiency (classic) - leads to build up of galactose-1-P, hepatotoxic, leads to death if untreated
Treatment - diet adjustment (avoid lactose and galactose

Question 2

Galactose-6-phosphate dehydrogenase (G6PD) deficiency

Answer 2

X linked recessive
Rate-limiting enzyme in PPP (main source of NADPH)
Less NADPH -> Heinz body formation (can’t deal with oxidative stress) -> haemolytic anaemia
Primaquine (an anti-malarial) generates reactive oxygen species and makes symptoms worse

Question 3

Marasmus

Answer 3

Total energy malnutrition from all major food groups
Body has broken down fat and muscle (emaciated)
Diarrhoea and anaemia, hair dry and thin
Treatment - nutritional diet to revers malnourishment

Question 4

Kwashiorkor

Answer 4

Adequate energy intake but no protein intake
Fatty liver as no LDLs around (fat can’t leave liver)
Oedema due to low albumin (osmotic pressure not maintained)

K - Kwashiorkor 
O - oedematous 
A - anorexic/Apathetic 
L - lethargic 
A - ascites (oedema within abdomen)

Treatment - just enough protein for anabolic metabolism to restore muscle mass
Urea cycle down regulates when no ammonia heads through it -> excessive catabolic breakdown of AAs -> refeeding syndrome -> hyperammonaemia -> death

Question 5

Lactose intolerance

Answer 5

Impaired lactase function -> lactose not broken down -> used by gut flora within large intestine (colon) -> flatulence, diarrhoea and cramps

Question 6

Lactate dehydrogenase (LDH) deficiency

Answer 6

Lack of enzyme means no reconversion to pyruvate

Buildup -> lactic acidosis

Question 7

Cyanide poisoning

Answer 7

Non-competitively inhibits cytochrome C oxidase (part of electron transport chain)
No regeneration of NAD+, NADP+ or FAD+
Stops oxidative phosphorylation -> death

Question 8

Phenylketonuria

Answer 8

Autosomal recessive
Lack of phenylalanine hydroxylase -> buildup of phenylalanine (no conversion to tyrosine) -> phenylpyruvate instead (interferes with brain metabolism -> retardation)
Tyrosine is also a precursor for dopamine and noradrenaline so lack of this -> retardation too
Phenyl ketones in urine, too much to reabsorb -> peed out
Treatment - removing phenylalanine from diet (tyrosine becomes essential AA)
Screening - heel prick just after birth as easy to treat

Question 9

Homocystinuria

Answer 9

Autosomal recessive
Absence/deficiency of cystathione B synthase -> homocysteine buildup (should be converted to cysteine)
Fibrillin affected (can be confused with Marfan’s)
2nd pathway converts to methionine (found in urine)
Treatment - give vit. B6 to stimulate CB synthase or B12 to stimulate conversion to methionine

Question 10

Hyperlipidaemia

Answer 10

Deficiency of lipoprotein lipase means chylomicrons aren’t broken down -> cholesterol levels remain high in blood
High lipid levels block pancreas -> pancreatitis
Treatment - low fat diet

Question 11

Hypercholesterolaemia

Answer 11

Caused by diet, too much animal fat -> increased LDL production
Treatment - low cholesterol diet (if this fails, give statins -> block HMG CoA reductase to block cholesterol formation from acetyl CoA)

Question 12

Hypoglycaemia

Answer 12

BM

Question 13

Paracetamol OD

Answer 13

Normally conjugated with glucoronic acid
OD saturates primary pathway, secondary pathway generates NAPQI which is extremely toxic to hepatocytes
Glutathione depleted in attempt to break down NAPQI -> no defence against ROS
Death in 2 weeks
Treat with N-acetyl cysteine until NAPQI eliminated

Question 14

Diabetes Mellitus

Answer 14

Chronic hyperglycaemia resulting in death due to CV damage
- Type 1 - autoimmune destruction of B cells in Islets of Langerhans in endocrine pancreas -> complete loss of insulin production
- Type 2 - constant high glucose intake -> resistance to insulin and eventual overload of pancreas -> loss of insulin production
Polydipsia, polyuria and weight loss
Tests..
- HBA1C > 6.5%
- Fasting glucose > 7mmol
- Random plasma glucose > 11mmol
- 2 hours after GTT > 11mmol (1 result with symptoms, 2 without)
Management type 1 - IM insulin, monitoring with BM, regular HBA1C
Management type 2 - diet, metformin (decreases gluconeogenesis in liver), sulphonylureas (stimulate insulin production), GLP1 analogues (increase insulin release, inhibit glucagon release)

Question 15

Diabetic ketoacidosis

Answer 15

Life threatening
Untreated type 1 diabetes
Absolute lack of insulin activates HMG-CoA lyase, acetyl CoA -> ketones -> lowers blood pH -> denatures enzymes -> death
Treatment - IV glucose and insulin to max out activity of HMG-CoA reductase and switch off lyase
Kidneys will correct acidosis by retaining HCO3

Question 16

Hypoadrenalism (Addison’s disease)

Answer 16

Low circulating cortisol levels
Autoimmune destruction of zona fasiculata of adrenal cortex (secondary hypoadrenalism - reduced ACTH - anterior pituitary pathology)
- Presentation - weakness, fatigue, malaise, cachexia, abdominal pain, postural hypotension w/ tachycardia, hyperpigmentation of palmar creases (POMC -> ACTH and a-MSH, which darkens palmar creases), hypoglycaemia
- Diagnosis - serum cortisol measurement, insulin tolerance test, SynACTHen (synthetic ACTH analogue stimulate zona fasiculata even if ACTH production is decreased
Treatment - daily cortisol injections and reg. checkups
- Complications - Addisonian crisis - complete lack of cortisol - usually a result of extreme physiological stress (car crash)

Question 17

Hyperadrenalisim (Cushing’s disease)

Answer 17

High circulating cortisol levels
Cushing’s - pituitary adenoma -> increased ACTH production
Adrenal adenoma - increased cortisol production
Paraneoplastic syndrome - ectopic ATCH producing malignancy -> increased ACTH production
Iatrogenic cortisol overdose/patient mismanaging hypoadrenalism
- Presentation - moon face, fat posterior neck, fat anterior abdomen, purple striae, hyperglycaemia, hypertension (cort. acts weakly at mineralocorticoid receptors in kidney inc. Na+ retention -> inc. blood pressure), atrophic limbs, vision problems (Cushing’s only)
- Diagnosis - Serum cortisol measurement, dexamethasone suppression test (steroid that drops cortisol levels by inhibiting pituitary adenoma - Cushing’s only), serum ACTH (high - pituitary/ectopic tumour / low - adrenal tumour)
- Management - surgery to remove tumour, adjust cortisol use

Question 18

Hypothyroidism (Hashimoto’s disease)

Answer 18

Low circulating thyroxine (T3/4) levels
Autoimmune condition that produces an antibody to block TSH receptors (Hashimoto’s) / Pituitary defect -> reduced [TSH] / Hypothalamic defect -> reduced [TSH] / Iodine deficiency (3rd world)
- Presentation - intolerant of cold, unexpected weight gain, lethargy/apathy, constipation, dry skin/dull hair, thyroid goitre (Hashimoto’s and iodine deficiency)
- Diagnosis - measure TRH, TSH and T3/4

TRH TSH T3/4 Diagnosis
High High Low Hashimoto’s
High Low Low Pituitary defect
Low Low Low Hypothalamic defect
High High High Iodine deficiency

Treatment - Hashimoto’s - oral thyroxine daily
Pituitary/hypothalamic defect - investigate further CT/MRI
Iodine deficiency - iodine supplements

Question 19

Hyperthyroidism (Grave’s disease)

Answer 19

High circulating thyroxine levels
Grave’s - autoimmune condition that produces an antibody that stimulates thyroid follicles - inc. T3/4
Thyroid adenoma - excess T3/4 production
Pituitary adenoma - excess TSH produced
Hypothalamic disorder - excess TRH production
Thyroxine overdose
- Presentation - hyperactivity, intolerant of heat, unexpected weight loss, increased bowel movements, muscle weakness, constant fatigue, thyroid goitre, exophthalmos (bulging eyes)
- Diagnosis - measure TSH, TRH and T3/4

TRH TSH T3/4 Diagnosis
Low Low High Grave’s
Low Low High Thyroid adenoma
Low High High Pituitary adenoma
High High High Hypothalamic disorder
Low Low High Thyroxine OD

Treatment - Investigate for tumours and remove as appropriate, carbimazole (reduce thyroxine production), radioactive iodine (destroys part of thyroid gland -> reduced thyroxine production), partial thyroidectomy

Question 20

Gestational diabetes

Answer 20

Result of too many anti-insulins (oestrogen/progesterone) produced during pregnancy
Body becomes resistant to insulin
Evolutionary mechanism to increase glucose diffusion to placenta
B cells usually show hypertrophy/plasia to compensate
Treatment - diet management or insulin
Usually corrects after birth