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Flashcards in Chem Path Deck (147):

If pt has a normal fasting glucose, but a OGTT (2hr reading) of 9mmol/L, what does this pt has?

This pt has impaired OGTT


Polyuria, polydipsia pt with fasting glucose of 9mmol/L but OGTT of 14mmol/L, what does hit pt has?

Fasting glucose is normal but OGTT meets requirements for diabetes. Hence this pt has T2DM.

This is probably a pregnant women or a patient with significant insulin resistance, where although the fasting glucose shows IFG, the 2h value in fact diagnoses diabetes.

Thus you can only diagnose IFG where the 2h value on a GTT is <7.8 (normal) or where a GTT is not done.


Cut off values for fasting glucose and OGTT for diagnosis of T2DM

Diabetes is diagnosed on the basis of history (ie polyuria, polydipsia and unexplained weight loss) PLUS

1) a random venous plasma glucose concentration >= 11.1 mmol/l

2) OR a fasting plasma glucose concentration >= 7.0 mmol/l (whole blood >= 6.1 mmol/l)

3) OR 2 hour plasma glucose concentration >= 11.1 mmol/l 2 hours after 75g anhydrous glucose in an oral glucose tolerance test (OGTT)

If pt is asymptomatic, repeat blood test


Ham's test

The Ham test is a test used in the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). The test involves placing red blood cells in mild acid; a positive result (increased RBC fragility) indicates PNH or Congenital dyserythropoietic anemia.[1][2] This is now an obsolete test for diagnosing PNH due to its low sensitivity and specificity.[3]


Anti-mitochondrial antibody


Characterised by chronic granulomatous inflammation leading to damaged inter lobular bile ducts. Chronic inflammatory process leads to cholestasis, cirrhosis and portal hypertension.

Patients are usually asymptomatic. Diagnosis made based on deranged LFTs and abnormal rise in serum ALP.

98% of pts are anti-mitochondrial antibodies (AMA) positive. ANA, SMA and ANCA may be positive but in low levels compared to AMA.
IgM may be raised.
TSH and cholesterol may be raised.



Systemic sclerosis

Multisystemic disease of unknown cause. May be limited to the skin and soft tissue in limited cutaneous systemic sclerosis (e.g hands, face and feet) or also involve the organs in diffuse cutaneous systemic sclerosis.

Raised levels of ANA, anti-centromere (limited cutaneous systemic sclerosis), anti-Ro, anti-topoisomerase antibodies are associated with systemic sclerosis. (SCL70)


What is Whipple's triad

Defines hypoglycaemia

Initially used to describe insulinomas but also apply to all insulin resistance states

1. Low glucose
2. Symptoms of hypoglycaemia (adrenergic e.g. tremors, palpitations, sweating, hunger and neuroglycopaenic e.g. somnolence/sleepiness, confusion, incoordination, seizures, coma)
3. Immediate relief of symptoms with glucose administration


Treatment for hypoglycaemia.
- Scenario 1: Pt is alert and orientated
- Scenario 2: Pt is drowsy/confused but intact swallow
- Scenario 3: Pt is unconscious/poor swallow

1. Oral glucose and carbs
- rapid acting: juice and sweets
- long acting: sandwich/bread

2. Buccal glucose and IV access
- hypostop/glucogel

3. IV access
- 50ml of 50% glucose or 100m of 20% glucose

If deteriorating, refractory, insulin induced, difficult IV access consider IM glucagon (but only if the pt has glycogen stores i.e. not in anorexia nervosa)


Caution about high % glucose given via IV line - what can happen if the glucose do not go into the vein properly

This is called extravasation of IV glucose: irritant and cause phlebitis


How is glucagon administered? Route + dose. What precautions? What indications?

Indication: hypoglycaemia that is refractory to initial treatments e.g. oral, buccal glucose, IV glucose

Route: IM
Dose: 1mg

Caution: Danger of rebound hypo because release of glycogen stores as glucose may trigger insulin release


List some causes of non-diabetic reasons for hypoglycaemia?

• Fasting or reactive?
• Paediatric vs. adult
• Critically unwell
• Organ failure
• Hyperinsulinism
• Post gastric-bypass
• Drugs
• Extreme weight loss
• Factitious


Common reasons for hypoglycaemia in diabetics

• Commonest cause of hypoglycaemia
• May be related to:
o Medications
o Inadequate CHO intake/ missed meal
o Impaired awareness
o Excessive alcohol
o Strenuous exercise
o Co-existing autoimmune conditions
(sometimes, Addison’s diseases)


Schmidt's disease

Diabetes + Addison's disease
Also known as polyglandular autoimmune syndrome


What is carnitine deficiency? (from hypoglycaemia lecture)

Carnitine is a naturally occurring hydrophilic amino acid derivative, produced endogenously in the kidneys and liver and derived from meat and dairy products in the diet. It plays an essential role in the transfer of long-chain fatty acids into the mitochondria for beta-oxidation.

Form of fatty acid oxidation defect

Causes neonatal hypoglycaemia with suppressed insulin and C-peptide


Beckwith–Wiedemann syndrome

Beckwith–Wiedemann syndrome is an overgrowth disorder usually present at birth, characterized by an increased risk of childhood cancer and certain congenital features.

Common features used to define BWS are:[1]
- macroglossia (large tongue),
- macrosomia (above average birth weight and length),
- midline abdominal wall defects (omphalocele/exomphalos, umbilical hernia, diastasis recti),
- ear creases or ear pits,
- neonatal hypoglycemia (low blood sugar after birth).
- Hepatoblastoma


50 year old A&E regular, presents to A&E, appearing very unwell and intoxicated. Serum creatinine was 3x higher than that the average measured from his previous visits. Urine microscopy reveals calcium oxalate crystals.


Ethylene glycol poisoning

Ethylene glycol is the major ingredient of almost all radiator fluid products in the United States. It is added to prevent the radiator from overheating or freezing, depending on the season.

The diagnosis may be suspected when calcium oxalate crystals are seen in the urine or anion ion gap acidosis is present in the blood.

The antidotes for ethylene glycol poisoning are ethanol and fomepizole.


Equation for creatinine clearance

Calculate the creatinine clearance for the following renal patient, following a 24 hour urine collection: urine volume 2litres; urine creatinine concentration 3mmol/l and plasma creatinine concentration 208 micro mol/l.

Creatine clearance = (creatinine's urine concentration)* (Vol) / (plasma creatinine concentration) (note: the units have to match).

Ans: 20ms/min


The 3 forms of calcium in the body and which the most common form

* Free ‘ionised’ ~50% biologically active
* Protein-bound ~40% albumin
* Complexed ~10% - citrate/phosphate


Formula for corrected Ca2+

* Corrected Ca2+ levels adjusted for any deficient in albumin
* Serum Ca2+ + 0.02*(40-serum albumin in g/L)
* ^ the real level of Ca if albumin was normal at 40 g/L


Why does Ca2+ needs to be corrected in blood tests?

* Because calcium binds to albumin, if you have low albumin, the amount of protein-bound Ca decreases but the amount of free calcium stays the same, hence you get a ‘low’ Ca2+ on sampling
* Serum Ca2+ + 0.02*(40-serum albumin in g/L)
* If the corrected Ca is normal, means that the deficient in Ca was caused by albumin and free Ca (which is the biologically active/important component) is normal and is not of concern


What is the normal range for ionised Ca2+ and what kind of sample provide you with ionised Ca2+ readings

* Normal blood samples you cannot measure ionised Ca alone because the sample clots - hence ‘corrected Ca2+’ method
* But on blood gas machine, they measure ionised Ca2+ directly hence normal would be about ~1.1-1.3 mM


What is the corrected Ca2+ if a patient is septic and has a low albumin of 30? Plasma reading of Ca from a blood test is 2.2mM

Example of Ca calculation
* Pt septic, low albumin = 30, Measured calcium = 2.2
* Corrected calcium = 2.2 + 0.02 (40-30)
= 2.2 + 0.02(10)
= 2.4mM (normal)
* Serum Ca2+ + 0.02*(40-serum albumin in g/L)


When calcium is low you look at PTH. what are some causes of low calcium and high PTH

Vit D def - dietary, malabsorption, lack of sunlight
CKD (1a hydroxylation of the kidney is impaired)
PTH resistance (psuedohypoPTH)


When calcium is low you look at PTH. What are some causes of low calcium and low PTH

Surgical (post thyroidectomy)
Autoimmune hypoPTH
Congenital absence of parathyroids (e.g. DiGeroge syndrome - do not have thymus)
Mg deficiency (PTH regulation - Mg is required to make PTH)


Biochemistry of primary hyperPTH

High PTH, High Ca, Low Phosphate


Biochemistry of secondary hyperPTH

Low Ca → high PTH → Low phosphate


Actions of PTH (Organs and what processes) (2+1)

1. Bone - osteoclast - breakdown of bone (calcium phosphate store)
2. Kidneys - reabsorption and activation of 1x hydroxylase which makes activated Vit D. Vit D then also increases intestinal absorption of Ca)
3. Kidneys - stimulates renla Pi wasting


How many aa are there in PTH? where is PTH made?

* 84aa protein, only released by parathyroids


Name the animal and plant source of Vit D

* D3 (cholecalciferol) is synthesised in the skins of mammals
* D2 (ergocalciferol) is a plant vitamin


Describe the synthesis of D3 in humans

* Diet → Liver
* 100% of absorbed Vit D (ergo or chole) is hydroxylated in the liver by 25 hydroxylase
* Inactive levels are inconsequential to Ca
* Major store
* Liver → Kidney
* 1a-hydroxylase converts 25OH to 1,25(OH2) which is active
* Rarely this enzyme can be wrongly expressed in the lung cells of sarcoid tissue, which is not controlled by PTH (one reason for uncontrolled hypercalcaemia)
* Role of calcitriol (1,25 OH2 D3)
* Intestinal Ca2+ absorption
* Intestinal Pi absorption
* Critical for bone formation
* It is associated but not causative for cancer, autoimmune disease, diabetics etc etc. Vit D levels is associated with poorer social class and so are those conditions mentioned


Causes of Vit D deficiency

* Renal failure - lack of 1a hydroxylase to make activated VitD
* Anticonvulsant induce breakdown of VitD - children with seizures given anticonvulsants. Overcome by giving Vit D concurrently with anti-seizure medicine
* Lack of sunlight
* Phytic acid in chapatis (unleaven flour)


Risk factors of Vit D Deficiency

* Lack of sunlight
* Dark skin
* Dietary
* Malabsorption


Biochemistry of osteomalacia

Low vit D → low Ca → High PTH → low phosphate
(because body unable to absorb Ca without Vit D)
Raised ALP (osteoblasts trying to make new bone)


Buzzword: Looser’s zones (pseudofractures)



Presentation of osteomalacia

* Bone pain
* Tenderness
* Fractures
* Proximal myopathy (waddling gait) due to low PO4 and vit D deficiency


Define osteomalacia

Normal amount of bone but low mineralisation. This is the reverse of osteoporosis where there is loss of bone but normal mineralization.

This is most commonly due to ↓ Vit D before low Ca but also can be caused by phosphate loss when Ca and Vit D are normal.


How can low PO4 cause osteomalacia?

1. Equilibrium shift. Ca + PO4 = calcium hydroxyapatitie (ie the mineral)
2. Less PO4 = less mineral
In osteomalacia, there is LOW mineralisation although AMOUNT of bone is normal (v osteoporosis where there is loss in AMOUNT of bone but normal mineralisation)


Causes of osteomalacia

* Vit D deficiency due to malabsorption, poor diet, lack of sunlight
* Renal osteodystrophy: RF → no 1a hydroxylase → no 1,25(OH)2D calcitriol
* Liver disease: reduced 25 hydroxylase → no 25(OH)D
* Drug-induced: anticonvulsants may induce liver enzymes, leading to increased breakdown of 25(OH)D
* Tumour (oncogenic hypophosphataemia): Tumour production of FGF-23 ↑ PO4 in urine, = hypoPO4 → weakness and myalgia
* Vit D resistance: inherited conditions that require high dose Vit D supplementation


Treatment of osteomalacia according to aetiology (3)

* Vit D if deficiency
* If renal and no 1a hydroxylase, give 1a hydroxylase (alfacalcidol) or just give calcitriol straight
* If Vit D resistance, high does vit D or just give calcitriol 


Presentation of rickets in children (4)

* Bowed legs
* Costochondral swelling
* Widened epiphysis at the wrists
* Myopathy
* Featuers of hypoCa - mild


Define osteoporosis. Describe the biochemical changes

* Reduction in bone density (normal mineralisation)
* No biochemical changes - Ca, PTH, VitD normal


Presentation of osteoporosis

* Cause of pathological fracture - first symptom of osteoporosis is a fracture
Typically neck of femur fracture, vertebral, wrist (Colle’s)


osteoporosis is a age-related process that happens in everyone. But what are some risk factors that exacerbates the decline or starts it earlier?? Think of both dietary/lifestyle and hormonal

* Poor diet of Ca
* Oestrogen and testosterone deficiency e.g. post menopausal women, Klinefelters
* Cushing’s and hyperthyroidism
* Meds e.g. steroids
* Prolonged intercurrent illness/childhood illness which means that they might fail to attain peak bone mass


How to interpret a DEXA scan? what is a the T-score or Z-score. How are they different and what is the cut off for diagnosing osteoporosis

* T-score - sd from mean of young healthy population (useful to determine fracture risk)
* Z-score - sd of mean of aged-matched control (useful to identify accelerated bone loss in younger patients)
* T


At which age do bone start undergoing decline in bone mass



Treatment for osteoporosis (both lifestyle and meds)

* Lifestyle
* Weight-bearing exercise
* Stop smoking
* Reduce EtOH
* Drugs
* VitD/Ca
* Bisphosphonates (e.g. alendronate) to decrease bone resorption
* MOA: phosphonate don’t exist in nature. When given bisphosphonates, calcium sometimes instead of combining with phosphate (normal) in bone, it combines with phosphonate. Calcium phosphonate is added to the bone and cannot be broken down
* SE: nausea, gastric
* Teriparatride (PTH derivative) - anabolic
* Strontium - anabolic + anti-resorptive
* (Oestrogen - HRT if early menopause) but can cause breast cancer
* SERMs e.g. raloxifene (agonist in bone but antagonist in breast), but worsen hot flushes/vasomotor symptoms


Symptoms of high Ca (distinguish these from symptoms of hyperPTH)

* Polyuria/polydipsia (due to peripheral DI)
* Constipation - slows down gut transition - thrones
* Neuro - confusions/seizures/coma - psychiatric undertones
* Unlikely unless Ca>3.0mM

You don't get bone issues because those are related to PTH and low phosphate


DDx of high Ca and high PTH/inappropriately normal PTH

1. Primary hyperPTH
2. Familial hypocalcuric hypercalcaemia


Ddx of high Ca and low PTH

1. Malignancy
2. Sarcoid
3. Vit D Excess
4. Hyperthyroidism
5. Milk alkali syndrome


Causes of primary hyperPTH (list from most common to list common)

* Parathyroid adenoma
* PTH hyperplasia → also associated with MEN1 with pit adenoma and pancreatic tumours
* PTH carcinoma
(most common to least common)

1. 80% due to solitary adenoma
2. 20% hyperplasia of all glands
3. <0.5% parathyroid cancer



Pituitary adenoma
PTH hyperplasia
Pancreatic tumours


Sx of hyperPTH (distinguish from hyperCa)

* Bones - PTH bone disease
* Renal stones
* Constipation, pancreatitis - abdominal moans
* Confusion - psychiatric groans
*High BP (triggered by high ca)

Commoner signs of bone resorption of PTH
* Pain
* Fractures
* Osteopenia and osteoporosis
RARE: osteitis fibrosa cystica (due to severe resorption, rare) - subperiosteal erosions, cysts or brown tumours +/- pepperpot skull


Biochemistry of hyperPTH + any other investigations

* Blood:
* High Ca
* High PTH
* Low PO4
* Raised ALP from bone activity

* Urine: High Ca

* Imaging: osteitits fibrosa cystica (due to severe resorption, rare) - subperiosteal erosions, cysts or brown tumours +/- pepperpot skull
* DEXA for osteoporosis
* US/MRI to localize an adenoma


Treatment for hyperPTH

* Increase fluid intake to prevent stones (for high Ca)
* Avoid thiazides, high Ca or high Vit D intake
* Thiazides prevent Ca excretion
* Excise adenoma or all 4 hyperplastic glands to prevent fractures and peptic ulcers. If recur after excision give Cinacalcet (to increase sensitivity of parathyroid to Ca so that will suppress PTH


What is FHH (familial hypocalcuric hyperCa)? And how do you differentiate these pts from primary hyperPTH

* Gene defect in calcium sensing receptor (CaSR)
* Results in higher ‘set point’ for PTH release → mild hypercalcaemia
* Reduced urine Ca2+ - Differentiating point
* You do not want to remove parathyroid in these patients


Cancer and hypercalcaemia - 3 types

* Small lung cancer - PTHrP
* PTHrP is always 0 un adults unless there is cancer
* Useless in adult life but in foetus, PTHrP overrides mum’s PTH to allow baby to make skeleton/monopolise mother’s Ca.
* Also important for breasts to produce milk
* But this also means if that you have PTHrP in adulthood, it is very aggressive in causing hypercalaemia and most likely do not survive for more than 6 months
* Bone mets (e.g. breast cancer)
* Haematological malignancy (e.g. myeloma)
* Cytokines


Other causes of non-PTH driven hypercalcaemia besides cancer

* Sarcoidosis (non-renal 1a hydroxylase)
* Thyrotoxicosis (thyroxine drives bone resorption)
* Hypoadrenalism (renal Ca2+ transport)
* Thiazide diuretics (renal Ca2+ transport, excrete Ca-free urine)
* Excess Vit D


Treatment of hyperCa

* Acute: Fluids++++
* If cause is known to be cancer - given bisphosphonate (to stop invasion of osteoclast into bone). Otherwise avoid
* Treat underlying cause


What is Paget's disease (bone)

* Focal disorder of bone remodelling, increased bone turnover, ↑ osteoblast also ↑ osteoclast (quick build and quick destroy) → bone remodelling
* osteolytic stage
* Osteolytic-osteosclerotic
* Quiescent osteosclerotic


Epidemiology of Paget's disease

Rare <40, incidence rise with age
Commoner in Anglo-Saxons, rare in Asians and Africans


Presentation of Page'ts disease

* Focal pain, warmth, deformity, fracture, SC compression, risk of malignancy in the area of high turnover, cardiac failure
* Asymptomatic in 70%
* Deep, boring pain
* Bone deformity and enlargement - typically more proximal bones e.g. pelvis, femur, skull tibia


Biochemistry of Paget's

* Elevated ALP due to high turnover, normal Ca, normal P
Normal serum Ca and phosphate but raised ALP >1000U/L.


Treatment for Pagets

* Treatment = bisphosphonates for pain relief, stop rapid bone turnover


X-ray features of Paget's

X-ray: localised enlargement of bone with patchy cortical thickening with sclerosis, osteolysis and deformity


What causes renal oestodystrohy

due to secondary hyperPTH + retention of aluminium from dialysis fluid


One way of testing neuromuscular excitability as seen ins hypoCa

Take blood pressure cuff and pump up around pt' arms to above systolic bp for 3 minutes → induces carbo-pedal spasms → Trousseau's sign
Chvostek's sign - twitching of the facial muscles in response to tapping over the area of the facial nerve.


Blood results show:
Na: 145
K: 5
U: 10
pH: 6.85
Glucose: 25
Pt is unconscious. Why?

Brain cannot function at such high acidity


Formula for calculating osmolality and state what is normal plasma osmolality

Ans: 2(Na+K) + U + G

Why is it 2 (Na+K) because osmolality = cations (Na+K) + anions (Cl and HCO3) + urea + glucose. But because Na + K = Cl + HCO3 (they are balanced), hence easier to just take Na+K and multiple by 2 to account for Cl and HCO3 instead of individually measuring them.

Normal plasma osmolality 275-295 mosm/kg


Formula for calculating anion gap and state what is normal

Anion gap = Na + K - Cl - bicarb
* Normal AG = 18mM


What is HHS (hyperosmolar non-ketotic coma HONK/hyperosmolar hyper osmotic state)? Mx

DKA/HHS - very high glucose, very high osmolality, glucose of 70, drowsy confused, very dry
* brain is dehydrated hence coma/confused

Fluid, insulin, potassium


Pt has anion gap acidosis DDx?

Ketones (from DKA)
Lactate (from metformin)
Also seen in ethylene glycol poisoning


Why might a pt who has been on metformin for a long period sudden develop anion gap acidosis?

SE of metformin as metformin can cause lactate acidosis.
Esp. if the diabetic pt develops CKD (metformin is renally excreted) or if the pt OD-ed


Na: 145
K: 2.5
U: 40
pH: 7.65
* PCO2: 6.1kPa (N 4.7-6.0)
* PO2 = 15kPa
Glucose: 46
Bicarb: 55mM
Cl = 80

What does this blood gas show? What is the anion-gap? What is the diagnosis

Blood gas shows metabolic acidosis with some respiratory compensation. It also flags up high glucose.
Which makes me think DKA
BUT anion gap is normal:
Anion gap = Na + K - Cl - bicarb
Therefore AG = 145 + 2.5 - 80 - 55 = 12 (no anion gap)

This proves that this is NOT DKA because there is no extra anions (aka ketones) which is present in DKA because of ketoacidosis.

Hence this is a hypokalaemia alkalosis.


Hypokalaemia is associated with acidosis or alkalosis? What is the pathophysiology in the body (all cells) and in the kidneys?

Hypokalaemia and alkalosis goes together. (H+ out, K+ in)

* low extracellular K = cannot Na/K pump
* Na stuck inside the cell and H+ enter
* leads to extracellular alkalosis

* continue from above, cells now have high intracellular H+
* kidney tries to get rid of excess ICF H+ by excreting H+ into urine in exchange for Na


Causes of hypokalaemia

* Intestinal loss - diarrhoea, vomiting, fistula
* Renal loss - Mineralocorticoid excess, diuretics, Renal tubular disease
* Distribution - insulin, alkalosis
* Decrease intake - rare


Order of physiological responses to low glucose (list from fastest to slowest)

Order of responses
1. Suppression of insulin
2. Release of glucagon (relatively quick)
3. Release of adrenaline
4. Release of cortisol (late response)


methods of investigating glucose levels in a person? (2) What are some cautions/ limitations of each?

Venous blood sampling → take with a grey top which contains fluoride oxalate. The fluoride oxalate stops glycolysis immediately once sample is taken and shaken.
Else will result in erroneously low glucose reading as glycolysis continues outside the body
* Gold standard
* Limitations: takes time to get back from lab

Capillary blood glucose → Instant reading from capillary blood (which may differ slightly from venous blood)
* Poor precision at low glucose levels
* Machine may be poorly maintained v lab machine


WHO criteria of diabetes mellitus (3)

1. Symptoms of hyperglycaemia (e.g. polyuria, polydipsia, unexplained weight loss, visual blurring, genitla thrust, lethargy) and raised venous glucose detected once - fasting or random
2. OR raised venous glucose on 2 occasions but asymptomatic
3. HbA1C > 48mmol


A chronically stable DM pts suddenly presents with hypo (did not OD on meds)? What should you think of?

* CO-existing renal/liver failure alters drug clearance and reduced doses needed
* Rarely concurrent Addison’s can result in hypos (polyglandular autoimmue syndrome type 2 - Schmit’s disease)


Glucokinase activating mutation (congenital hyperinsulinism) (4)

* GLUD-11


Physiological neonatal hypoglycaemia in preterm mechanism

* Premature (glycogen stores double at 36 weeks), co-morbidites, IUGR, SGA
* Inadequate glycogen and fat stores
* Should improve with feeding


before diagnosing an insulinoma, you must prove this is negative

must prove that sulphonylurea is negative (so a SUR screen)


60M cachectic man - unconscious by daughter, smoker
* Glucose 1.9mmol/L
* Hypoglycaemia persists despite glucose infusion
* Insulin and C-peptde undetectable
* FFA undetectable
* Ketones negative

Ans: Non-islet cell tumour hypoglycaemia
* Tumours that cause a paraneopastic syndrome
* Secretion of ‘big IGF-2’
* Big IGF2 binds to IG1 receptor and insulin receptor and activates it (hence you have low glucose)
* (mimic the action of insulin)
* Body think insulin is binding
* Hence do not produce ketones, turn off body insulin production and C-peptide
* Mesenchymal tumour (mesothelioma/fifbroblastoma)
* Epithelial tumours (carcinoma)


How does a baby with glycogen storage disorder type 1 present

Hypoglycaemia → GSD type 1 often presents when illness prevents feeding/decrease feeding frequency
Hepatomegaly → Hepatomegaly easily missed as it is soft
Lactate acidosis → lactate raised as alt source of energy
Neutropenia → Type 1b differentiated from type 1a with neutropenia


What are glycogen storages disorders? what is the enzyme that is deficient in GSD type 1 (von Gierke)?

* Prevents mobilisation of glucose from glycogen
* Results in abnormal storage of glycogen in liver &/or muscle
* Presentation of GSD type 1 (von Gierke): severe hypoglycaemia due to inability to mobilise glycogen stores for glucose, deficiency of glucose-6-phosphate


Describe GSD type V (mcArdle) and the enzyme that is deficient

Presentation of GSD type V (mcArdle): exercise intolerance relieved by rest, ‘second wind’ phenomenon, deficiency of myophosphorylase


Normal values of Na with units

135-145 mmol/L


Key irrefutable evidence that a pt is dehydrated (not on examination)

key irrefutable evidence is low urine Na+ (<20mmol/L) - kidneys trying to hang on to Na for water retention
* but this is not valid if pt is taking diuretics! Stop it and check 24 hours later


mechanism of hypoNa in hypovolaemia

Low blood vol/pressure → Increased ADH → increased water retention → Hyponatraemia


Causes of hyponatraeamic in euvolaemic pt

* HypoT
* Adrenal insufficiency
* SIADH (inappropriate secretion)


Investigations of euvol, hypoNa

* HypoT: TFT
* Adrenal: Short synACTHen test
* SIADH: low plasma (because Na is low) and high urine osmolality


Treatment of hyponatraemia (hypvol and eu/hypervol)

Hypovol = give fluids 0.9% saline
Euvol/Hypervol = fluid restrict + treat underlying cause


If severe hypoNa (sx and what treatment by specialists)

If severe hypoNa,
* Reduced GCS
* Seizures
* Seek expert help (treat with hypertonic 3% saline). Give only in severe cases + fitting/seizing


When correcting hypoNa at what rate should you not exceed and why

When correcting severe hyponatramia, MUST NOT CORRECT >8-10mmol/L in the first 24 hours
* Risk of osmotic demyelination (central pontine myelionlysis)
* Quadriplegia, dysarthria, dysphagia, seizure, coma, death


2 Drugs to treat SIADH

* Water restriction - total 750ml of every fluid
* Demeclocycline - increase ADH resistance, but risk of nephrotox
* Tolvaptan - V2 receptor antagonist


Define Diabetes insipidus

Defined as passing >3L of dilute urine a day


You suspect this hyperNa pt has DI. What investigations do yo want to do?

2 test to exclude other possible conditions that are more common and also cause same symptoms

* Serum glucose - exclude DM which is more common

* Serum K and Ca - nephrogenic causes of DI, ADH resistance
* Correct these and the DI/hyperNa will go away
* Exclude hypoK
* Exclude hyperC
* Both hypoK and hyperC can cause polyuria and polydipsia

* Plasma and urine osmolality
* Should be high plasma, low urine osmolality

* Water deprivation test
* normal person will conc urine, urine osmolality will go up
* Make sure to weigh the pt before starting and stop if losing >3% of body weight
* Give DDAVP (desmopressin suppression test) If respond to DDAVP = cranial DI as there was deficient ADH which is now been replaced exogenously. If do not respond to DDAVP = peripheral as resistance still persist


Treatment of hyperNa

* Fluid replacement - 5% dextrose (correct water deficit) + 0.9% saline (correct extracellular fluid volume depletion)
* Serial Na measurements every 4-6 hours


Treatment for DI (Cranial and peripheral)

Cranial DI → Give DDAVP via nasal spray, oral etc Risk of dilution hypoNa
Peripheral DI → Give bendrofluthiaxide (paradoxical effect)


Normal range of plasma osmolality with units

275-295 mOsm/kg


Normal range of urinary osmolality and cut off for SIADH

Normal range in healthy person is 50-1200 mOsm/kg

In SIADH, diagnostic criteria is low plasma osmolality and high urinary osmolality >100mOsm/kg


Normal Hb in males and females with units

Men: 135-180 g/l Women: 115-160 g/l


Normal Mean cell volume with units

82-100 fl


normal platelets with units

150-400 * 109/l


normal K with units

3.5 - 5.0 mmol/l


Normal urea with units

2.0-7 mmol/l


Normal creatinine with units

55-120 umol/l


Normal bicarb with units

22-28 mmol/l


Normal chloride with units

95-105 mmol/l


Normal bilirubin with units

3-17 umol/l


Normal ALT and AST with units

AST: 3-40 iu/l
ALT: 3-30 iu/l


Normal ALP with units

30-100 umol/l


Normal Ca with units



Classical phenylketonuria (PKU) - what enzyme is problematic? how do babies present? how do we test for this?

* Phenylalanine hydrolase deficiency
* Disadvantage – IQ<50
* Common – 1:5000 to 1:15000
* Test – blood Phe
* Gene – >400 mutations
* Treatment – effective (if started early and not cheap)
* Phe is an essential amino acid that is metabolised to tyrosine by phenylalanine hydroxylase through the addition of an OH group
* Deficiency increases the concentration of Phe in the blood, which is toxic at high levels
* There is also the production of abnormal metabolites of Phe – phenylpyruvate and phenylacetic acid (seen in the urine)
* Features: fair hair, blue eyes, eczema, seizures and impaired intelligence (IQ<50)
* Treatment is effect is involving the restriction of dietary Phe
* Important to monitor phenylalanine in these patients as it is an essential amino acid and cannot be taken out of the diet completely
* Treatment needs to be started within the first 6 weeks of life
* Screening for PKU started in 1969
* The PPV for classical PKU is ~80%


How is CF testing in the neonate? and what is cystic fibrosis?

* CF results from a defect of the CFTR gene
* Normally, there is chloride leaving the epithelial cells lining the lung and other organs, and sodium entering via the endothelial sodium channels (eNaC)
* In CF, not only is there less chloride leaving the cell, there is also dysregulation of the eNaC, so more sodium also enters the epithelial cell, and water follows the sodium paracellularly due to the osmotic gradient created
* This results in the formation of the sticky, thick mucus that is characteristic of CF
* This is called the ‘low volume hypothesis’

* The symptoms of cystic fibrosis are as follows in different organ system:
* Lungs – recurrent infection and fibrosis
* Pancreas (pancreatic insufficiency) – malabsorption, steatorrhoea, diabetes
* Liver – cirrhosis
* Neonates suffer from high blood immune reactive trypsin (IRT) – tested in the heel prick test


what is MCADD

* Medium chain acyl-CoA dehydrogenase deficiency (OMIM 201450)
* Incidence 1:10000
* Screening based on tandem MS determination of acylcarnitine levels
* Blood spot octanoyl carnitine

They have carnitine deficiency


Hyperammonia - what is likely the problem? what investigations to run?

think urea cycle defects or organic acidurias

* Investigations in patient suspected to have hyperammonaemia
* Free flowing, venous sample (delivered to laboratory stat on ice)
* Plasma amino acids (glutamine, citrulline, argininsuccinate, arginine, ornithine)
* Urine amino and organic acids (orotic acid)


Urea cycle defects - red flag symptoms and what's the problem?

* Redflags
* Vomiting without diarrhoea
* Neurological encephalopathy
* Respiratory alkalosis
* Hyperammonaemia
* Avoidance or change in diet

* There are 7 enzymes in this pathway and documented deficiencies in all of them
* All 7 defects are autosomal recessive, apart from ornithine transcarbamylase deficiency,which is X-linked
* >300μmol/L results in hyperammonaemic coma
* May also be due to severe liver dysfunction
* Ammonia is highly toxic, usual plasma level <50 mmol/L and values >300 mmol/l may be lethal – 1 day in a hyperammonaemic coma and your IQ is irreversibly and dramatically worsened
* Associated with encephalopathy, respiratory alkalosis and irreversible neurological damage
* Typically diagnosed in childhood as we are looking out for them otherwise they can present in teens or early adulthood
* These are typically those who have a less severe state of disease
* They typically present after family celebrations where there is lots of meat, like Christmas

* Treatment for uric cycle defects
* Remove ammonia with sodium benzoate
* Reduce ammonia production


Organic acidurias - acute presentation and what is it?

Involves the complex metabolism of branched chain amino acids (leucine, isoleucine, valine)
Presents with HYPERAMMONIA (also seen in urea cycle defects) with metabolic acidosis and anion gap

* unusual odour e.g cheesy
* Lethargy, pancytopenia, feeding difficulties
* hypocalcaemia
* truncal HYPOtonia with limb HYPERtonia, myoclonic jerks


Organic acidurias chronic presentation

Recurrent episodes of ketoacidotic coma with cerebral abnormalities

Reye syndrome - trigged by salicylate, anti-emetics, valproate
* * Collect during acute episode:
* Plasma ammonia
* Plasma amino acids
* Urine organic acids (ideally whilst symptomatic)
* Plasma glucose and lactate
* Non-acute collection
* Blood spot for carnitine (remains abnormal even in remission)

CARNITINE cross ref with mitochondria fatty acid oxidation defect and MCADD


Mitochondrial fatty acid β-oxidation specifically peroxisomal deficiency

* 13 recognised disorders including those involved with the carnitine transport system.
* Failure of b-oxidation leads to hypoketotic hypoglycaemia often with hepatomegaly and cardiomyopathy

* Investigations
* Blood ketones
* Urine organic acids – whilst symptomatic
* Blood spot for acylcarnitine profile

Peroxisomal def → inability to metabolise very long chain fatty acid and synthesise complex phospholipids
Presents as neonate with
* Severe muscular hypotonia
* Seizures
* Hepatic dysfunction (mixed hyperbilirubin)
* Dysmorphism

Infant presentation
* Retinopathy - blindes
* Sensorineural deafness
* Hepatic dysfunction
* Dysmorphic signs
* failure to thrive
* Mental deficiency
* Bone changes e.g. large fontanelle (closes >1 year), long bone osteopenia, and calcified stippling esp patella

Ix: VLCFA profile


Carbohydrate disorders - galactosaemia

* Cause of neonatal metabolic liver disease
* Very rare
* Autosomal recessive
* Pt has reduced or absent enzyme galactose-1-phosphate-uridyltransferase (gal-1-PUT) which metabolises galactose-1-phosphate (substrate)
* Galatose-1-phosphate then builds up in the liver and kidneys
* Raised galactose-1-phosphate results in liver& kidney dx
Infant develops poor feeding, vomiting, prolonged jaundice and hepatomegaly when fed milk → liver failure → DIC/sepsis, shock and haemorrhage
* Common neonatal presentation is conjugated hyperbilirubinaemia, hepatomegaly, E. coli sepsis and hypoglycaemia
* Accumulation of galatose-1-phosphate activates alternative pathway (pathological) where by it is reduced by aldolase into galactitiol (which cannot be broken down by the body) leading to bilateral cataracts

* Investigations
* Bilirubin – conjugated hyperbilirubinaemia
* Urine reducing substances – shows huge preponderance of galactose
* Red cell Gal-1-PUT (galactose-1-phoshate-uridyl-transferase)

* Tx with galactose-free diet (prevents liver dx) but ovarian failure and learning difficulties may still occur later
* Not part of routine newborn screening
* Typically, present before screening results available so it is not in the heel prick test


Glycogen storage disease type 1a or b

* Deficiency of glucose-6-phosphatase activity leads not only to excessive glycogen storage but also prevents glucose export from gluconeogenic organs
* Every time glycogen is broken down it forms glucose-1-phosphate or glucose-6-phosphate –without required enzyme (phosphatase) cannot export the phosphate metabolite
* Most common presentation is 3-6 months
* Hepatomegaly and nephromegaly
* Hypoglycaemia with lactic acidosis
* Neutropenia
* Raised triglyceride, urate and transaminases
* Investigations → Muscle biopsy for enzyme studies

- Maintain blood glucose levels:
1. Younger children:f req. feeds or CHO infusion (gastrostomy/NG tube)
2. Older children: slow-release oligosaccharides


Mitochondrial disorders - what are they and how do they present?

* Can occur at any age, in any organ, with any pattern of inheritance
* Mitochondrial DNA is very small compared to nuclear DNA
* During development, the mitochondria are constantly turning over – heteroplasty means that clinical manifestations become evident at a certain threshold of mutant DNA
* Mitochondrial DNA is maternally inherited,however nuclear genomes also play a role in mitochondrial function
* Defective oxidative phosphorylation/ATP production leads to multi system disease especially affecting organs with a high energy requirement such as brain, muscle, kidney, retina and endocrine organs
* Classic presentation is chronic muscle weakness with hyperlactataemia

Birth - Barth syndrome (cardiomyopathy, neutropenia, myopathy)
5-15 y.o - MELAS (mito encephalopathy, lactate acidosis, stroke like episodes)
12-30y.o - Kearns-Sayre syndrome (chronic progressive, opthalmoplegia, retinopathy, deafness, ataxia)


Mitochondrial disease - investigations and tx principles

* Investigations
* Elevated lactate (alanine) – especially after periods of fasting (e.g. overnight)
* Elevated creatine kinase
* CSF lactate/pyruvate – deproteinised at bedside
* CSF protein (raised in Kearns-Sayre syndrome)
* Mitochondrial DNA analysis
* Muscle biopsy/ragged red fibres and oxidative phosphorylation complex activities

* As a rule of thumb, defects affecting small molecules are treatable and further metabolic decompensation can be avoided
* Treatment advice is available from specialist metabolic centres, see the National Metabolic Biochemistry Network at


Congenital disorders of glycosylation (CDG)

* Defect of post-translational protein glycosylation
* Multisystem disorders associated with cardiomyopathy, osteopenia, hepatomegaly and in some cases facial dysmorphia and abnormal fat distribution (e.g. CDG type 1a characterised by abnormal subcutaneous adipose tissue distribution with fat pads and nipple retraction)
* Investigations
* Transferrin glycoforms (serum)


Lysosomal storage diseases

Lysosomal storage diseases
* Defects of lysosomal hydrolases lead to intra-organelle substrate accumulation
* Consequently, leads to organomegaly (connective tissue, solid organs, cartilage, boneand, above all, nervous tissue), with dysmorphia and regression

* Investigations
* Urine mucopolysaccharides/oligosaccharides
* Leucocyte enzyme activities

* Treatment:
* Bone marrow transplant
* Exogenous enzyme


3 clases and examples within each for inborn errors of metabolism

Toxicity from accumulation
* Urea cycle disorder
* Organic acidaemia - hyper ammonia and cheese neonate/Reye syndrome, is is isovaleric acidaemia (screened for in Guthrie)
* Carbohydrate disorder - galactosaemia, accumulation of galatose-1-phosphate
* Neurotransmitter disorders

Energy metabolism disorder
* Mitochondria dx - Barth, MELAS, Kearns-Sayre
* fatty acid chain oxidation defects - MCADD e.g. carnitine transporter deficiency
* Glycogen storage disorder - GSD1 (liver) and GSD5 (muscle)

Complex organelle disorder
* Lysosomal storage disorder - Defects of lysosomal hydrolases lead to intra-organelle substrate accumulation
* Peroxisomal disorder - inability to metabolise very long chain fatty acid and synthesise complex phospholipids



Ca 1.8
PTH 9.6 (0.8-8.5 pmol/L)
ALP 50 (30-150 u/L)
PO4 1.9 (0.8-1.2mmol/L)
Vit D 82 (60-105 mol/L)

What is the likely diagnosis?
1. primary hyperPTH
2. secondary hyperPTH
3. tertiary hyperPTH
4. Osteoporosis
5. Osteomalacia
6. Familial benign hypercalcamia
7. PsuedohypoPTH
8. Primary hypoPTH

7. PsuedohypoPTH

This is due to PTH resistance (genetic condition). As a result, pts have HIGH PTH and phosphate but are HYPOCALCAEMIC

It is NOT secondary hyperPTH because ALP is normal. in secondary hyperPTH, there is also bone breakdown to increase Ca therefore should have high ALP. most common cause if renal failure

FHH occurs where there is genetic mutation in the calcium receptor in the PTH and kidneys, meaning they underestimate the level of Ca causing high PTH despite high Ca. Receptor failure also leads to hypocalcuric which differentiates this from primary hyperPTH where there is HIGH Ca and HIGH CA excretion so body is trying to get rid of all the excess Ca driven by PTH excess


13 y.o boy with parotitis and pain in testes + incomplete vaccination Hx

Which plasma protein should be tested?


This is mumps (which can also cause male factor infertility)
Amylase is also predicted in the parotid gland besides the pancreas


Name the cancer marker for GI cancers e.g colorectal (full name)


Carcino-embyronic antigen


which vit is deficient?
1. A
2. B1
3. B2
4. B6
5. B12
6. C
7. D
8. E
9. I

26 y.o M present to GP with 5 month Hx of bleeding gums + petechiae on feet. Man admits he had to visit dentist regularly due to poor dentition

Vit C

Scurvy! Vit C deficiency = collagen cannot cross link = weak vessels and easy damage/bleeding esp in gums, skin joint and bone weakness. Gum disease is a characteristic feature

Also Vit K deficiency leads to pro-bleeding. Ecchymoses, petechiae and slow healing.


which vit is deficient?
1. A
2. B1
3. B2
4. B6
5. B12
6. C
7. D
8. E
9. I

5 y.o F, known cystic fibrosis noted by mother to develop poor coordination with hands and reflexes are absent. Blood test also reveal anaemia

Vit E

Vit E def → haemolytic anaemia due to oxidative damage (vit E is anti-oxidant)

Spino-cerebellar neuropath is a manifestation (ataxia + areflexia)

Also increase risk of IHD in later life


Vit B6 deficiency

Vit b6 = pyridoxine

Common cause
- isoniazid use for TB

- sideroblastic anaemia
- seborrhoea dermatitis

Diagnosis made by determine erythrocyte levels of aspartate AMINOtransferase


Cherry red spot

Which IBM?

Fabry's disease

Lysosomal storage disorder
Deficiency in alpha-galactosidase

Development delay with dysmorphia


SE of common drugs that require monitoring

1. Procainamide
2. Lithium
3. Methotrexate
4. Theophylline
5. Gentamicin
6. Carbamazepine
7. Cyclosporin
8. Phenytoin
9. Digoxin

35M attends A&E with lightheadness, slurred speech, walks around like a drunk, low BP


Hypotension, heart block, ventricular arrhythmias and ataxia


SE of common drugs that require monitoring

1. Procainamide
2. Lithium
3. Methotrexate
4. Theophylline
5. Gentamicin
6. Carbamazepine
7. Cyclosporin
8. Phenytoin
9. Digoxin

45F displays signs of toxicity 12 hours after initial dose - coarse tremor and nauseous


12 hours, coarse tremor, diarrhoea and vomiting, dysarthria
Severe - convulsions, renal failure and death


SE of common drugs that require monitoring

1. Procainamide
2. Lithium
3. Methotrexate
4. Theophylline
5. Gentamicin
6. Carbamazepine
7. Cyclosporin
8. Phenytoin
9. Digoxin

65M inpatient develops sudden onset tinitus and difficulty hearing


also nephrotoxic


SE of common drugs that require monitoring

1. Procainamide
2. Lithium
3. Methotrexate
4. Theophylline
5. Gentamicin
6. Carbamazepine
7. Cyclosporin
8. Phenytoin
9. Digoxin

Prolonged PR interval + abdo pain and tiredness


prolonged PR interval and bradycardia


SE of common drugs that require monitoring

1. Procainamide
2. Lithium
3. Methotrexate
4. Theophylline
5. Gentamicin
6. Carbamazepine
7. Cyclosporin
8. Phenytoin
9. Digoxin

45M complains of diarrhoea and headache. GP notes that patient have been treated with erythromycin for Cap 1 week prior


toxic effects potentiated by erythromycin and ciprofloxacin

D&V, tacky, arrhythmias and headaches


SE of common drugs that require monitoring

1. Procainamide
2. Lithium
3. Methotrexate
4. Theophylline
5. Gentamicin
6. Carbamazepine
7. Cyclosporin
8. Phenytoin
9. Digoxin

Drug induced SLE with rash and fever
Also agranulocytosis

Procainamide - anti-arrhythmic


SE of common drugs that require monitoring

1. Procainamide
2. Lithium
3. Methotrexate
4. Theophylline
5. Gentamicin
6. Carbamazepine
7. Cyclosporin
8. Phenytoin
9. Digoxin

Ulcerative stomatitis, leukcytopenia and rarely pulmonary fibrosis



SE of common drugs that require monitoring

1. Procainamide
2. Lithium
3. Methotrexate
4. Theophylline
5. Gentamicin
6. Carbamazepine
7. Cyclosporin
8. Phenytoin
9. Digoxin

Toxic effects include headaches, ataxia and abdo pain
If severe also SIADH and aplastic anaemia


other common side effect is HYPONATRAEMIA

because carbamazepine activates vasopressin production. VP binds to kidneys to activate aqua porin 2 which cause water re-absorption


SE of common drugs that require monitoring

1. Procainamide
2. Lithium
3. Methotrexate
4. Theophylline
5. Gentamicin
6. Carbamazepine
7. Cyclosporin
8. Phenytoin
9. Digoxin

SE of gum hypertrophy and hirsutism


immune suppressant


19F with bulimia, taking citalopram, shows clinical dehydration + anaemia

Blood test show
- hypoK
- alkalosis
- low Hb
- normal Usea and creatinine

Urinalysis shows acidura

Explain the mechanism for the acidic urine
1. AKI
2. Renal tubular acidosis
3. Citalopram
4. Anaemia
5. Physiological

5. Physiological

HypoK because of laxative abuse or purging - which also leads to he loss of H+, hence metabolic alkalosis on ABG

As normal homeostatic mechanism in the kidneys, K is exchanged for H in DCT. Hence to salvage the K, the kidneys in this patient takes in the K from the urine and releases H, hence you get acidic urine DESPITE being in metabolic alkalosis

Purging/laxative anorexia


Multiple myeloma is associated with raised ALP



Although there is BONE involvement in MM (CRAB), the bone pain/lesions in MM is due to direct osteoclast activation through cytokines and ALP is NORMAL.


erythematous and pigmented areas around the neck in a necklace like distribution
Forgetful and unable to perform normal daily tasks
Frequent bowel movements

Pellagra / Vit B3/ Niacin deficiency

Cascal necklace

Poor diet