Acquired Metabolic Disorders

Question 1

The liver: functions, and what happens when fails

Answer 1

• can function on 20%
• filters blood 20x per hour
• handles protein turnover and is principle site of urea synthesis which is excreted in urine (handles toxic NH3)- converts glutamine (from muscle) to urea, also converts ammonia produce by gut bacteria into urea
• jaundice is a sign of liver failure as would normally push bilirubin out in bile but due to failure it is stuck in skin
• if liver fails can get hepatic encephalopathy

Question 2

Hepatic encephalopathy: causes, symptoms, severity assessment, types

Answer 2

• cause: liver failure causes nitrogen build up which can cerebral oedema and may cause neuropsychiatric syndrome and increased inter-cranial pressure
• symptoms/ severity (West Haven Criteria): 0 (covert HE), 1 (confusion), 2 (drowsiness), 3 (somnolence), 4 (coma)
• can causes brain to collapse in on self
• type A: caused by acute liver failure. Leads to astrocytic swelling and increased intercranial pressure
• Type C: cirrhosis (chronic disease). Causes alzheimers type II astrocytosis and normal ICP

Question 3

Cytotoxicity in HE: what causes swelling?

Answer 3

• normally have myoinositol and taurine controlling osmolarity of astrocytes
• in acute disease have increased influx of glutamine/ NH3 rapidly and cannot control osmolality and therefore causes swelling

Question 4

Adverse effects of ammonia in the body

Answer 4

• causes neuroinhibiton and down regulation of neuroexcitation
• inhibits Cl- channels
• derangement of the blood brain barrier

Question 5

Precipitants of hepatic enencephalopathy

Answer 5

• excess protein (although a low protein diet has shown no beneficial effect for HE therefore normal guidelines apply)
• alcohol
• hepatic cell carcinoma
• infection
• GI bleed
• sedative/ hypnotics
• diuretics

Question 6

Metabolic syndrome symptoms and diagnostic criteria (WHO and IDF)

Answer 6

• IDF requires central obesity + 2 other abnormalities
• WHO requires microalbuminema in addition (albumin/ creatinine ratio of >30mg/g creatinine)
• obesity: IDF (central obesity, 80cm waist women and 94cm men), WHO (waist/hip ratio >0.9 men and >0.85 women)
• abnormal fasting glucose: IDF (>5.6mmol/L or previous T2DM), WHO (presence of diabetes, insulin resistance)
• hypertension: IDF (BP 130/85 mmHg), WHO (BP >140/90 mmHg)
• dyslipidemia: IDF (TG of 1.7mmol/L, HDL <40mg/dL men and <50mg/dL women), WHO (TG 1.7 mmol/L, HDL <35 mg/dL men and <39 mg/dL women)
• microalbuminema (just WHO)

Question 7

Risk factors and diseases related to MetS

Answer 7

• risk factors: proinflammatory states, prothrombotic states
• diseases at risk of: T2DM, hypertension, PCOS, NAFLD, sleep apnea, CVD (stroke, MI), cancer (breast, prostate, colorectal, liver)

Question 8

Causes of hyperglycaemia in T2DM

Answer 8

• partial defect of insulin secretion: lipid droplets accumulate in pancreas and inhibit b cell ability to secrete insulin, and these cells undergo apoptosis. Due to lack of insulin secretion, still lots of endogeneous glucose production in liver (gluconeogenesis). Glycation of proteins on b cells may also reduce function
• resistance to action of insulin: downregulation in use of glucose oxidation in periphery due to circulating FFA (excess released from AT), causes reduced uptake of glucose from muscle

Question 9

Link between MetS insulin resistance and atherosclerosis

Answer 9

• increased TG decreased HDL cholesterol and forms dense LDL contributing to plaque formation
• increased BP and endothelial dysfunction (response to injury hypothesis for atherosclerosis)

Question 10

Complications of T2DM

Answer 10

• retinopathy
• abnormal ECG
• absent foot pulses/ ischemic feet
• impaired reflexes
• myocardial infarction
• stroke

Question 11

Diagnosis of insulin resistance using oral glucose tolerance test

Answer 11

• in a fasted state a glucose load (75g oral) given and blood sampled every 2-4 hours)
• a normal person will have a small transient rise in BG
• if insulin resistant BG curve may look normal
• impaired glucose tolerance: basal glucose high and continues to rise after load
• diabetes mellitus: very high BG and linear increase in BG after load

Question 12

Consequences of insulin resistance in the muscle, liver and pancreas

Answer 12

• muscle: increase in intramyocellular lipids, decreased glucose uptake
• liver: increased TG synthesis, increased gluconeogenesis (contributing to high BG)
• pancreas: lipid droplets accumulate and make beta cells apoptotic and decrease circulating insulin

Question 13

Treatment options for insulin resistance

Answer 13

• diet and exercise: to reduce fat mass, improve lean body mass and improve insulin sensitivity
• insulin releasing drugs: to stimulate pancreas to release more insulin, and so plasma glucose is taken up by cells
• hepatic insulin sensitisers: works selectively on lover inhibiting glycogenolysis and gluconeogenesis, to reduce hepatic BG output