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What is inosinic acid (IMP)?

An intermediate metabolite of AMP (adenylic acid) and GMP (guanylic acid)

Also a product of de novo purine synthesis


Describe the inhibitory and stimulatory controls on this enzyme.

AMP and GMP negatively regulate the activity of PAT PPRP positively regulates the activity of PAT


What inborn error of purine metabolism is characterised by HPRT deficiency?

Lesch-Nyhan syndrome


Describe the inheritance pattern of Lesch-Nyhan syndrome.

X-linked recessive


Outline the clinical features of Lesch-Nyhan syndrome.

Normal at birth Developmental delay at 6 months Hyperuricaemia

Choreiform movements at 1 year

Spasticity and mental retardation

Self-mutilation present in 85% (e.g. biting lips very hard)


Describe the biochemical basis of Lesch-Nyhan syndrome.

It is caused by absolute deficiency of HPRT (Hypoxanthine Phosphoribosyltransferase)

This reduces the production of IMP and GMP by the salvage pathway

This reduces the inhibitory effect of IMP and GMP on PAT, thereby increasing the activity of the de novo pathway This leads to the production of vast amounts of IMP, which will be shunted down the catabolic pathway to produce urate (which accumulates)

Less conversion of guanine --> GMP leads to a build-up of PPRP (which stimulates PAT)


What are the two mechanisms of hyperuricaemia? List some examples.

Increased urate production (e.g. rapid cells turnover in myeloproliferative diseases and psoriasis)

Decreased urate excretion (e.g. saturnine gout (caused by lead poisoning) and diuretic use)


What is birefringence?

The ability of a crystal to rotate the axis of the polarised light

NEGATIVE – appear blue at 90 degrees to the axis of the red compensator

POSITIVE – appear blue in the axis of the red compensator


Describe the management of gout after the acute phase is over.

Encourage fluid intake

Reverse factors that may increase the concentration of uric acid (e.g. stopping diuretics)

Allopurinol – reduces synthesis of urate by inhibiting xanthine oxidase

Probenecid – increases renal excretion of urate (increases FEUA)


Describe the uptake of cholesterol by the intestinal epithelium.

Cholesterol entering the intestines will come from the diet and bile

Cholesterol will be solubilised in mixed micelles It is then transported across the intestinal epithelium by NPC1L1 (this is the main determinant of cholesterol transport)


Name two transporters that transport cholesterol back into the intestinal lumen.




ABC = ATP-binding casette transporter


What are the two fates of cholesterol that is either produced by or transported to the liver?

Hydroxylation by 7-hydroxylase to produce bile acids

Esterification by ACAT to produce cholesterol ester which is incorporated into VLDLs along with triglycerides and ApoB


ACAT: Acyl-CoA cholesterol acyltransferase


Which transfer protein is important in the packaging of VLDLs?

MTP (microsomal triglyceride transfer protein) 


Which transfer protein is important in the packaging of HDLs?



Which receptor is responsible for the uptake of some HDLs by the liver?



Describe the transport and metabolism of triglycerides.

Triglycerides from fatty foods are hydrolysed to fatty acids, absorbed, and resynthesized into triglycerides which are transported by chylomicrons into the plasma

Chylomicrons are hydrolysed by lipoprotein lipase into free fatty acids

Some free fatty acids are taken up by the liver, and some by adipose tissue

The liver resynthesizes fatty acids into triglycerides and packages them into VLDLs

VLDLs are acted upon by lipoprotein lipase to liberate free fatty acids


List the three causes of familial hypercholesterolaemia (type II).

Caused by autosomal dominant gene mutations in:

LDL receptor


PCSK9 (Proprotein convertase subtilisin/kexin type 9)


List the key features of the following forms of familial hypertriglyceridaemia: a. Familial Type I b. Familial Type IV c. Familial Type V

a. Familial Type I Caused by deficiency of lipoprotein lipase and ApoC II NOTE: lipoprotein lipase degrades chylomicrons and ApoC II is an activator of lipoprotein lipase

b. Familial Type IV Characterised by increased synthesis of triglycerides

c. Familial Type V Characterised by deficiency of ApoA V NOTE: these hypertriglyceridaemias show different patterns when the plasma is left overnight to separate


What is familial dysbetalipoproteinaemia (type III)?

Due to aberrant form of ApoE (E2/2)

NOTE: normal form is ApoE (3/3) A diagnostic clinical feature of yellowing of the palmar crease (palmar striae)


List four causes of hypolipidaemia and their underlying genetic defect. Abeta-lipoproteinaemia Hypobeta-lipoproteinaemia Tangier disease Hypoalpha-lipoproteinaemia


• Autosomal recessive

• Extremely low levels of cholesterol

• Due to deficiency of MTP


• Autosomal dominant

• Low LDL

• Caused by mutations in ApoB

Tangier disease

• Low HDL

• Caused by mutation of ABC A1


• Sometimes caused by mutation of ApoA1


List some lipid-lowering drugs and their effect on lipid levels.

Statins – reduce LDLs, increase HDLs, slight increase in triglycerides

Fibrates – lower triglycerides, little effects on LDL/HDL

Ezetimibe – reduces cholesterol absorption (blocks NPC1L1)

Colestyramine – resin that binds to bile acids and reduces their absorption


What is the rate of production of H+ ions per day?

50-100 mmol/day


Which condition classically causes a mixed respiratory alkalosis and metabolic acidosis?

Aspirin overdose Aspirin stimulates ventilation and reduces renal excretion of H+


What reaction is used to measure fractions of bilirubin? Describe how this works.

Van den Bergh reaction The direct reaction measures conjugated bilirubin Methanol is added which completes the reaction and gives you a value for total bilirubin The difference between these two values is used to measure the unconjugated bilirubin (indirect reaction)


What is the inheritance pattern of Gilbert’s syndrome?

Autosomal recessive


Describe the histology of hepatitis.

Hepatocytes will become fatty and swell (balloon cells), containing a lot of Mallory hyaline

There will also be a lot of neutrophil polymorphs

Collagen around individual liver cells is classic of alcoholic hepatitis 


What are the defining and associated histological features of alcoholic hepatitis?

Defining: liver cell damage, inflammation, fibrosis Associated: fatty change, megamitochondria


List a differential diagnosis for fatty liver disease.

NASH (most common cause of liver disease in the Western world) Alcoholic hepatitis Malnourishment (Kwashiorkor)


What is phenylketonuria caused by?

Phenylalanine hydroxylase deficiency This enzyme is responsible for converting phenylalanine to tyrosine Deficiency results in an accumulation of phenylalanine which is toxic (causes blue eyes, fair skin, metnalretardation) NOTE: maple syrup urine disease is also an aminoacidopathy


Which abnormal metabolites are produced in PKU?

Phenylpyruvate Phenylacetic acid (detected in the urine)