Chem Path Flashcards
A 29 year old man presents with eruptive xanthomas and a yellow discolouration to the palm. Blood tests reveal high total cholesterol and triglyceride levels. Genetic studies reveal ApoE2. What is the diagnosis?
Type 3 hyperlipoproteinemia
Human apolipoprotein E (ApoE) plays a crucial role in cholesterol and lipid metabolism. There are three major isoforms of ApoE: ApoE2, ApoE3, and ApoE4.
ApoE3 is the most common isoform found in the majority of the population.
ApoE4 is found with increased prevalence amongst those with Alzheimer’s disease and is thought to confer increased risk of the condition, whereas ApoE2 is thought to provide some protection against Alzheimer’s disease.
ApoE2 is also the cause of Type 3 hyperlipoproteinemia (Familial dysbetalipoproteinaemia), a condition characterised by increased total cholesterol and triglycerides.
Which term describes the total number of particles per Kilogram of solution and is measured with an osmometer?
Osmolality
OsmolaLity is a measure of all the particles in a solution and is measured in mmol/kg.
OsmolaRity is an alternative measure of the particles in solution and has the units mmol/L. OsmolaRity is calculated using the formula below:
Osmolarity = 2(Na + K ) + urea + glucose
You may notice we do not need to know the concentration of negative ions in order to calculate osmolarity. The concentration of negative ions should equal the concentration of positive ions. Therefore we simply multiply the positive ions by 2.
OsmolaLity and OsmolaRity should roughly equal. If they do not this is called the Osmolar gap.
You may ask why we have two different but similar terms. OsmolaRity can be easily calculated from the concentration of electrolytes, however, because it is measured per 1 Litre of solvent it can vary with temperature. OsmolaLity requires measuring in a lab using an osmometer, but does not vary with temperature as it is measured per 1 Kilogram of solvent, and is therefore the preferred term for biological systems.
In a patient with pseudopseudohypoparathyroidism, what would you expect the serum calcium level to be?
Normal
Pseudopseudohypoparathyroidism presents with the phenotypic appearances of Albright hereditary osteodystrophy but with normal biochemical findings and without resistance to parathyroid hormone (PTH).
Name a drug used in the treatment of non-acute gout to reduce urate levels by increasing the fractional excretion of uric acid?
Probenecid
The aim of treatment in an acute flare up of gout is to reduce inflammation. First line is NSAIDs (eg. Diclofenac). Colchicine is also useful in reducing inflammation and acts by inhibiting polymerisation of tubulin to reduce migration of neutrophils. Glucocorticoids can be injected or given orally.
During the intervals between acute gout, the aim is to reduce urate levels. Patients should be advised to drink plenty of water and avoid dietary sources high in purines such as port wine and organ meats. Medications should also be reviewed and diuretics stopped. Allopurinol inhibits the enzyme xanthine oxidase to reduce urate synthesis, and Probenecid increases fractional excretion of uric acid.
Which protein, found in blood plasma, exchanges triglycerides and cholesterol esters between lipoproteins?
Cholesteryl ester transfer protein (CETP)
Cholesteryl ester transfer protein (CETP) mediates the movement of cholesteryl ester from HDL into VLDL/LDL, and the movement of triglyceride from VLDL/LDL into HDL.
A defect in this protein is a cause of hyperalphalipoproteinemia 1 (HALP1) where there are raised levels of HDL-cholesterol.
Lomitapide is a low density lipoprotein lowering drug.
What protein does Lomitapide inhibit?
Microsomal triglyceride transfer protein
Lomitapide is a lipid lowering medication used in the treatment of Familial Hypercholesterolemia.
Lomitapide acts by inhibiting Microsomal triglyceride transfer protein (MTP), thereby blocking the release of VLDL from the liver.
This in turn leads to reduced LDL levels.
A 15 year old girl has a panic attack and is brought into A&E.
What acid base disturbance would you expect this patient to have?
Respiratory alkalosis
When interpreting blood gases always look at the pH first. Low pH indicates acidosis whereas high pH indicates alkalosis.
Next look at the CO2 and HCO3- to see if the change in pH has a metabolic or respiratory cause. There may be a mixed picture.
Respiratory compensation for a metabolic disturbance can occur quickly, however, metabolic compensation for respiratory pathology may take several days.
This allows you to distinguish between acute and chronic respiratory pathology.
An asymptomatic 50 year old man attends his GP for a routine check-up. His fasting plasma glucose is measured as 6.7 mmol/L. What is the diagnosis?
Impaired fasting glucose
Impaired fasting glucose and impaired glucose tolerance describe the early metabolic abnormalities that precede diabetes but do not quite reach the cut-off for a diagnosis of diabetes.
Impaired fasting glucose and impaired glucose tolerance are both risk factors for future type 2 diabetes mellitus.
Impaired fasting glucose is defined as fasting plasma glucose between 6.1 - 6.9 mmol/L.
Impaired glucose tolerance is defined as 2 hour oral glucose tolerance test plasma glucose 7.8 - 11.0 mmol/L.
These patients are at high risk of developing future diabetes without lifestyle modification.
An alcoholic is admitted for treatment of alcohol withdrawal. He is started on chlordiazepoxide and vitamin supplementation. The patient is found to have a low serum sodium and so the F1 starts him on IV fluids and his serum sodium rises rapidly. Over the next few days he becomes progressively lethargic, has trouble speaking, swallowing and walking.
What is the most likely diagnosis?
Central pontine myelinolysis
Central pontine myelinolysis is most commonly associated with rapid corrections of hyponatraemia. Quadraparesis and pseudobulbar palsy are characteristic and result from involvement of the corticospinal tracts in the pons and midbrain. Delirium tremens as a result of alcohol withdrawal or Wernicke’s encephalopathy from chronic malnutrition may have contributed to the patient’s symptoms. However, the question states he was started on Chlordiazepoxide and vitamin supplementation. Therefore this is less likely and would not explain all his symptoms. The rapid rise in serum sodium was the clue to this question.
A 14 month old boy presents showing signs of delayed motor development and self-mutilation of the lips and fingers. He is found to have hyperuricaemia.
What enzyme is deficient in this condition?
HGPRT (Hypoxanthine-guanine phosphoribosyltransferase)
A young boy with developmental delay and self-mutilation of the lips and digits is characteristic of Lesch Nyhan syndrome. The X-linked disorder results from an absolute deficiency of HGPRT (or HPRT), the key enzyme in the salvage pathway of purine metabolism. This results in hyperuricaemia causing juvenile gout.
ApoE4 classically gives an increased risk of developing which neurodegenerative condition?
Alzheimer’s disease
Human apolipoprotein E (ApoE) plays a crucial role in cholesterol and lipid metabolism. There are three major isoforms of ApoE: ApoE2, ApoE3, and ApoE4.
ApoE3 is the most common isoform found in the majority of the population.
ApoE4 is found with increased prevalence amongst those with Alzheimer’s disease and is thought to confer increased risk of the condition, whereas ApoE2 is thought to provide some protection against Alzheimer’s disease.
ApoE2 is also the cause of Type 3 hyperlipoproteinemia (Familial dysbetalipoproteinaemia), a condition characterised by increased total cholesterol and triglycerides.
A patient with Bipolar Affective Disorder complains of excessive thirst and says they have been drinking more than usual and passing urine more frequently for some time now. Urine osmolality is low. Blood glucose is 5.1 mmol/L. You decide to do a water deprivation test. At the start of the test urine osmolality is 196 mOsmol/kg and after 4 hours urine osmolality remains low. After a subcutaneous injection of Desmopressin is given urine osmolality is 204 mOsmol/kg.
What is the most likely underlying diagnosis?
Nephrogenic Diabetes Insipidus
A thorough history is key in the diagnosis and management of a patient with Diabetes Insipidus (DI). A history of surgery or traumatic brain injury may indicate Cranial DI whereas Nephrogenic DI is commonly associated with long-term lithium therapy, for example in those with Bipolar Affective Disorder.
Blood glucose or urine dip is important to exclude Diabetes Mellitus and a fluid deprivation test can rule out Primary Polydipsia and help differentiate Nephrogenic and Cranial DI. Nephrogenic DI results from a resistance to ADH (Vasopressin) in the renal collecting duct causing reduced reabsorption of water. This leads to inappropriately dilute urine with low urine osmolality. In this question the water deprivation test confirms the DI is Nephrogenic in origin as the urine osmolality remains low after administration of Desmopressin, a Vasopressin analogue. In Cranial DI the urine osmolality would be expected to rise to >600 mOsmol/kg but smaller rises are sometimes seen in partial defects.
Levels of what enzyme must be checked before starting azathioprine?
Thiopurine methyltransferase
Biochemical theory
Azathioprine is a powerful immunosuppressant drug used in the treatment of inflammatory bowel disease and other conditions.
TPMT deficiency is a congenital deficiency in an enzyme used to convert 6-mercaptopurine, a breakdown product of azathioprine, into less toxic, excretable metabolites. Approximately 1 in 300 people are deficient.
There are only two ways the body can clear 6-mercaptopurine: TPMT and the Xanthine Oxidase pathway.
If a patient is on both azathioprine and allopurinol AND they have TPMT deficiency - this leads to a buildup of toxic metabolites that may lead to profound leukopenia and death.
Clinical relevance:
All patients starting azathioprine need TPMT levels checked
Be cautious about patients on both allopurinol + azathioprine - have their TPMT levels been checked?
Phytosterolemia (Sitosterolemia) is a disorder characterised by raised levels of plant sterol in the blood.
Name a gene which undergoes a mutation causing this disorder?
ABCG5
ABCG5 and ABCG8 are genes encoding transporter proteins sterolin-1 and -2 respectively. These proteins are involved in regulating the absorption and excretion of cholesterol and non-cholesterol sterols.
Non-cholesterol sterols, for examples plant sterols, are mostly excreted and are not retained. However, mutations of ABCG5 and ABCG8 cause more non-cholesterol sterols to be retained causing the autosomal recessive disorder Phytosterolemia (Sitosterolemia). The raised levels of non-cholesterol sterols presents with premature atherosclerosis and tendon xanthomas.
The van den Bergh reaction is used to measure serum bilirubin via fractionation. What kind of bilirubin is measured with the direct reaction?
Conjugated
The van den Bergh reaction is used to measure serum bilirubin via fractionation.
The direct reaction measures conjugated bilirubin whereas a complete reaction measures total bilirubin.
The indirect reaction refers to the difference between these two and measures unconjugated bilirubin.
What is the most common joint to be affected in acute gout?
1st metatarsophalangeal
Gout is a crystal arthropathy caused by the deposition of monosodium urate crystals in the synovium of joints. In chronic gout (tophaceous) there may also be deposition of crystals (tophi) around joints and at other locations such as the ear lobes. Acute gout (podagra) presents as a rapid build-up of severe pain in a red and swollen joint. The most common joint to be affected is the 1st metatarsophalangeal joint and it is more common in men.
Monosodium urate crystals are negatively birefringent which means under polarised light they appear orange when parallel to a red light filter and blue when perpendicular. This allows them to be differentiated from calcium pyrophosphate crystals of pseudogout which show positive birefringence.
What enzyme would you classically expect to be raised in Paget’s disease of bone?
Alkaline Phosphatase
Paget’s disease of bone is a focal disorder of bone remodelling with increased bone turnover. This leads to localised areas of poorly organised bone overgrowth causing fractures and deformities. The only biochemical abnormality detected is a raised Alkaline Phosphatase (ALP) due to the increased action of osteoblasts. Patients may present with localised pain and warmth, loss of hearing and bowing of the legs.
A 35 year old type 2 diabetic complains of skin changes around the back of her neck and in her armpits. On examination the skin appears dark and velvety. What is the most likely diagnosis?
Acanthosis nigricans
Acanthosis nigricans is a skin condition typically associated with insulin resistance, for example in those with diabetes, obesity and other endocrinopathies. Rarely, it can be due to a malignancy.
The affected skin is typically described as dark and velvety and is usually found in areas of skin folds and creases such as the armpits, groin and neck.
A 24 year old gentleman is brought into hospital by ambulance. He was recovered by firefighters from a house fire. He has a reduced GCS (M6 V4 E4) and is confused. He has no visible burns and there is no obvious airway oedema. However, he has a cough productive of black sputum.
He is complaining about a severe headache and a bitter almond taste in his mouth.
Observations reveal he is tachycardic and hypertensive. An ECG shows first degree AV block.
What chemical compound is responsible for his symptoms?
Cyanide
Cholestyramine is a cholesterol lowering drug. What does Cholestyramine bind to in the gut in order to cause the liver to break down more cholesterol?
Bile acids
Most bile acids are reabsorbed from the gut in the ileum and are then recycled back to the liver for secretion into the biliary system again. This enterohepatic circulation of bile acids minimises the conversion of cholesterol into new bile acids.
Cholestyramine binds to bile acids in the gut stopping them from being reabsorbed. The liver then has to convert greater amounts of cholesterol into bile acids in order to maintain adequate secretion of bile acids into the biliary system. Cholestyramine therefore acts as a cholesterol lowering drug.
In familial hypocalciuric hypercalcaemia (FHH), which receptor has suffered a mutation?
Calcium Sensing Receptor
The calcium sensing receptor on the parathyroid glands regulates release of PTH. In FHH a mutation of this receptor causes it to be relatively insensitive to calcium. This results in a greater release of PTH in response to a normal calcium level. The mutation also causes reduced calcium loss in the urine (hypocalciuria). These two mechanisms together result in hypercalcaemia. FHH is also known as Familial Benign Hypercalcaemia as it is often asymptomatic and does not require treatment. FHH must be differentiated from primary hyperparathyroidism causing hypercalcaemia. A calcium/creatinine clearance ratio measured from a 24 hour urine collection tends to be lower in FHH than in primary hyperparathyroidism. Diagnosis of FHH can be confirmed with genetic testing of the CASR gene.
A 24 year old lady is referred to a cardiologist. She has irregular yellow growths on her hands and one on her achilles tendon. The cardiologist informs her she has premature atherosclerosis. Blood tests show grossly raised levels of plant sterol in her blood. Which autosomal recessive disorder does she most likely have?
Phytosterolemia
ABCG5 and ABCG8 are genes encoding transporter proteins sterolin-1 and -2 respectively. These proteins are involved in regulating the absorption and excretion of cholesterol and non-cholesterol sterols.
Non-cholesterol sterols, for examples plant sterols, are mostly excreted and are not retained. However, mutations of ABCG5 and ABCG8 cause more non-cholesterol sterols to be retained causing the autosomal recessive disorder Phytosterolemia (Sitosterolemia). The raised levels of non-cholesterol sterols presents with premature atherosclerosis and tendon xanthomas.
What protein is commonly measured clinically as a marker of liver synthetic function?
Albumin
Prothrombin time, bilirubin and albumin are all measures of liver function.
AST and ALT, classically part of LFTs (liver function tests) are in fact enzymes released when the liver is damaged and so are not technically measures of liver function.
A 27 year old lady presents regularly to A&E with hypoglycaemia of an unknown cause. She lives with her partner who has type 1 diabetes.
Her serum insulin levels are measured as high.
The consultant is unsure whether this is factitious hypoglycaemia from taking her partner’s insulin, or whether there is an endogenous cause of excessive insulin.
Measurement of what molecule would confirm whether the excessive insulin is exogenous or endogenous?
C-peptide
C-peptide is a short chain of amino acids cleaved in the conversion of proinsulin to insulin. It is created in equimolar amounts to insulin making it useful in the investigation of hypoglycaemia.
Hypoglycaemia with high insulin and low C-peptide suggests an exogenous source of insulin. This may be in a type 1 diabetic or from surreptitious use of insulin.
Hypoglycaemia with high insulin and high C-peptide suggests an endogenous source of insulin. Causes include insulinoma and inborn errors of metabolism. Sulfonylureas, used to lower blood sugar in type 2 diabetes, may also cause hypoglycaemia with high C-peptide due to increased release of endogenously produced insulin.
Factitious hypoglycaemia may be caused by surreptitious use of insulin or sulfonylureas. A Sulfonylurea screen is useful in distinguishing an insulin-secreting tumour from surreptitious sulfonylurea ingestion.
A patient with chronic kidney disease (CKD) has low calcium and raised phosphate. PTH levels are found to be high. What kind of hyperparathyroidism does this patient have?
Secondary
Secondary hyperparathyroidism can be caused by any disorder that results in hypocalcaemia, with chronic kidney disease being a common example. CKD results in reduced vitamin D activation (due to reduced renal 1-alpha hydroxylation) and also reduced phosphate excretion. This in turn leads to hypocalcaemia and secondary hyperparathyroidism as a response.
A patient with acute gout undergoes arthrocentesis of the affected joint. What kind of birefringence is shown by a monosodium urate crystal under polarised light?
Negative
Gout is a crystal arthropathy caused by the deposition of monosodium urate crystals in the synovium of joints. In chronic gout (tophaceous) there may also be deposition of crystals (tophi) around joints and at other locations such as the ear lobes. Acute gout (podagra) presents as a rapid build-up of severe pain in a red and swollen joint. The most common joint to be affected is the 1st metatarsophalangeal joint and it is more common in men.
Monosodium urate crystals are negatively birefringent which means under polarised light they appear orange when parallel to a red light filter and blue when perpendicular. This allows them to be differentiated from calcium pyrophosphate crystals of pseudogout which show positive birefringence.
Which enzyme has reduced activity in Gilbert’s syndrome and is responsible for the elevated unconjugated billirubin levels?
UDP glucuronyl transferase
Gilbert’s syndrome is an inherited metabolic disorder and common cause of isolated unconjugated hyperbilirubinaemia. It is caused by defective conjugation of bilirubin in the liver but liver function is otherwise unaffected. Jaundice is often precipitated by fasting or periods of physiological stress.
Haemolysis may also cause raised unconjugated bilirubin, and this must be excluded before a diagnosis of Gilbert’s can be made.
Which enzyme forms the rate limiting step in de novo purine synthesis?
PAT
Phosphoribosyl pyrophosphate amidotransferase (PAT) is the enzyme responsible for the conversion of PRPP into PRA. This is the rate limiting step in the de novo synthesis of purines. Guanylic acid (GMP) and adenylic acid (AMP) exert negative feedback on PAT.
A patient is hypocalcaemic, has an elevated serum phosphate and has an elevated parathyroid hormone (PTH).
Upon examination you notice they have short 4th and 5th metacarpals.
What is the most likely diagnosis?
Pseudohypoparathyroidism
The endocrinologist Fuller Albright was first to suggest pseudohypoparathyroidism results from an inherited resistance to PTH. He also identified the characteristic phenotypic appearance amongst these patients which includes short 4th and 5th metacarpals, obesity and rounded facies. This syndrome is now known as Albright hereditary osteodystrophy.
A patient presents to A&E with a red swollen joint at the base of their big toe. They say it is exquisitely painful. Following arthrocentesis, microscopy shows needle shaped crystals. Under polarised light, what colour would you expect these needle shaped crystals to appear when parallel to a red filter?
Orange
Gout is a crystal arthropathy caused by the deposition of monosodium urate crystals in the synovium of joints. In chronic gout (tophaceous) there may also be deposition of crystals (tophi) around joints and at other locations such as the ear lobes. Acute gout (podagra) presents as a rapid build-up of severe pain in a red and swollen joint. The most common joint to be affected is the 1st metatarsophalangeal joint and it is more common in men.
Monosodium urate crystals are negatively birefringent which means under polarised light they appear orange when parallel to a red light filter and blue when perpendicular. This allows them to be differentiated from calcium pyrophosphate crystals of pseudogout which show positive birefringence.
In the liver which cytochrome P450 enzyme catalyses the first step in the formation of bile acids via the classical pathway?
Cholesterol 7 alpha-hydroxylase
Bile acid synthesis from cholesterol occurs in the liver via two different pathways; the classical pathway and alternative pathway.
The classical pathway begins with the conversion of cholesterol into 7-alpha-hydroxycholesterol. This is the first and rate limiting step in the classical pathway and is catalysed by the cytochrome P450 enzyme cholesterol 7 alpha-hydroxylase (CYP7A1).
A patient presents with hyperkalaemia and changes are detected on his ECG.
What should be given intravenously as a cardioprotective measure?
Calcium Gluconate
Severe hyperkalaemia with ECG changes requires urgent administration of calcium gluconate to reduce myocardial excitability. This is only temporary and does not lower serum potassium levels. To lower the potassium level, an intravenous injection of insulin with dextrose is given. This acts to drive potassium into cells. Salbutamol can act to reduce potassium in a similar way. These are also only temporary. The cause of the hyperkalaemia must also be addressed along with any underlying acidosis.
What is the name of the cholesterol transport channel targeted by the drug Ezetimibe?
NPC 1L1
NPC1L1 (Niemann-Pick C1-like 1) transporter is found on epithelial cells of the GI tract and hepatocytes and is involved in the absorption of cholesterol from the gut.
Ezetimibe is a sterol absorption inhibitor which targets the NPC1L1 transporter. Ezetimibe results in lower blood cholesterol and can be prescribed alongside a statin.
A 16 year old presents to A&E following an overdose of medications from the family medicine cabinet 4 hours ago.
His mother says he took 20 of her antidepressant tablets.
Observations show he is tachycardic and hypotensive with a GCS of 14.
He has dilated pupils, an ataxic gait and has very flushed hands and feet. He says he feels very thirsty and has a dry mouth.
An ECG shows first degree heart block with tachycardia.
What class of medication is he likely to have overdosed on?
Tricyclic Antidepressants
Looser’s zones are a pathognomonic X-ray finding of which condition?
Osteomalacia
Looser’s zones, also known as milkman fractures, are pseudofractures lying perpendicular to the surface of the bone. They are seen in osteomalacia as a result of defective bone mineralisation and are often bilateral and symmetrical.
What class of drug must not be co-administered with azathioprine in individuals with TPMT deficiency, else a potentially fatal buildup of toxic metabolites may occur?
Xanthine Oxidase inhibitors
Biochemical theory
Azathioprine is a powerful immunosuppressant drug used in the treatment of inflammatory bowel disease and other conditions.
TPMT deficiency is a congenital deficiency in an enzyme used to convert 6-mercaptopurine, a breakdown product of azathioprine, into less toxic, excretable metabolites. Approximately 1 in 300 people are deficient.
There are only two ways the body can clear 6-mercaptopurine: TPMT and the Xanthine Oxidase pathway.
If a patient is on both azathioprine and allopurinol AND they have TPMT deficiency - this leads to a buildup of toxic metabolites that may lead to profound leukopenia and death.
Clinical relevance:
All patients starting azathioprine need TPMT levels checked
Be cautious about patients on both allopurinol + azathioprine - have their TPMT levels been checked?
A 9 year old boy presents to the GP with enlarged orange coloured tonsils. Examination elicits a peripheral neuropathy and blood tests show very low plasma HDL levels. What is the most likely diagnosis?
Tangier disease
Tangier disease is an inherited disorder caused by mutations in the ABCA1 gene.
This prevents the release of cholesterol and lipids from cells which results in them accumulating in certain organs.
This may present as hepatomegaly, splenomegaly, or classically as enlarged orange tonsils in children.
The condition is characterised by low HDL levels in the blood conferring an increased risk of cardiovascular disease.
What kind of inheritance is shown by the Multiple Endocrine Neoplasia syndromes?
Autosomal Dominant
he Multiple Endocrine Neoplasias (MEN) describe syndromes of associated neoplasias which are inherited in an autosomal dominant fashion.
MEN 1 Pituitary adenoma Parathyroid hyperplasia Pancreatic tumours
Think MEN 1 = PPP
MEN 2A Parathyroid hyperplasia Medullary thyroid carcinoma Phaeochromocytoma Think all the Cs: Calcitonin (medullary thyroid cancer), Calcium (Parathyroid hyperplasia) and Catecholamines (Phaeo)
MEN 2B Medullary thyroid carcinoma Phaeochromocytoma Marfanoid body habitus Mucosal neuromas Think B is for Big (marfanoid) and Belly problems (mucosal neuromas)
