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Flashcards in Chemical Pathology Deck (141):
1

Primary hyperparathyroidism caused by hyperplasia is associated with which gene

MEN1 (multiple endocrine neoplasia type 1)

2

Is primary hyperparathyroidism more common in men or women?

Women

3

The commonest cause of hypercalcaemia is

Primary hyperparathyroidism

4

Blood results in primary hyperparathyroidism
PTH
Calcium
Phosphate

PTH inappropriately normal or high
Calcium high
Phosphate low

5

Congenital absence of parathyroids is known as

DiGeorge syndrome

6

Causes of low calcium due to low PTH

Surgical including post thyroidectomy
Auto-immune hypoparathyroidism
DiGeorge syndrome (congenital absence of parathyroids)
Mg Deficiency

7

Formula for osmolality

Osmolality= cations+anions+urea+glucose
So

Osmolality= Na+K+Cl+HCO3+urea+glucose
since anions=cations this can be reduced to

Osmolality 2(Na+K) + Urea+ Glucose

8

Formula for anion gap

Na + K - Cl - Bicarb

9

Normal anion gap=

Approximately 18mM

10

...+... injected is known as speedball

Cocaine
Heroin

11

Acute dangers of cocaine:

Cardiac dysrhythmias, MI, Acute heart failure

12

Fatal dose of methadone in a healthy adult:

60ml

13

Fatal dose of methadone in a child

5ml

14

Benzodiazepine antidote

flumazenil

15

Problems with interpreting post-mortem blood toxicology

PM redistribution of drugs
Degradation of drugs post mortem e.g. cocaine
Individual variation in response (tolerance)
Site dependence


16

Why use hair for post mortem toxicology?

Blood/serum, drugs typically can be detected for no more than 12 hours

Urine, drugs typically detected for 2-3 days

Hair is the only specimen can give information about long term drug use

Drugs are incorporated into hair from the blood stream during the growth phase

Hair growth approx 1cm/month – “tape-recording of drug use”

17

Problems with hair analysis for post mortem toxicology

Environmental Contamination
Absorbed from sweat or sebum coating hair
Passive inhalation
Cosmetic treatment
Shampoo washing
Perming, dyeing, bleaching
Hair colour

18

Most common causes of death after heroin use

Respiratory depression
Aspiration pneumonitis

19

Applications of hair analysis (toxicology)

Applications of hair analysis
• Child custody cases
• Investigating spiked drinks defences
• Drug naïve deaths
• Monitoring drug use prior to return of driving license – Germany, Italy
• Investigation of drug use in exhumed/putrefied bodies
• Employment, pre-employment screening - USA

20

Causes of metabolic acidosis

1. Increased H+ production e.g. diabetic ketoacidosis
2. Decreased H+ excretion e.g. Renal tubular acidosis
3. Bicarbonate loss e.g. intestinal fistula

21

Types of renal tubular acidosis. Brief pathogenesis

Type 1 is distal: due to failure of alpha cells in collecting ducts to secrete H+ into urine. Due to autoimmune e.g. RA, drugs e.g. lithium, genetics and hypercacliuric conditions e.g. hyperPTH

Type 2 is proximal: caused by decrease in bicarbonate reabsorption. Caused by genetics, amyloidosis, multiple myeloma, HAART (HIV meds), basically anything that causes deposits in kidneys.

Type 3: combo of 1 and 2. Not used.

Type 4: Caused by hypoaldosteronism or resistance to aldosterone e.g. CAH, primary hypoaldosteronism, NSAIDs, ACEi, Aldosterone blockers, sarcoidosis.

22

Causes of metabolic alkalosis

Ingestion of bicarb
Reduced H+ excretion e.g. pyloric stenosis
Hypokalaemia

23

Management of hypovolaemia hyponatraemia due to diuretics

Stop diuretic
0.9% NaCl

24

Causes of euvolaemic hyponatraemia

SIADH
Hypothyroidism
Adrenal insufficiency

25

Causes of hypovolaemic hyponatraemia

Diuretics
Diarrhoea
Vomiting
Salt losing nephropathy

26

Causes of hypervolaemic hyponatraemia

Cirrhosis
Cardiac failure
Nephrotic syndrome

27

Features of SIADH

No hypovolaemia
High urine osmolality (over 100)
Low plasma osmolality

28

Causes of SIADH

CNS pathology
Lung pathology
Drugs (SSRI, TCA, opiates, PPIs, carbamazepine)
Tumours (most likely small cell lung cancers)

29

Investigations in suspected diabetes insipidus

Serum glucose (exclude diabetes mellitus)
Serum potassium (exclude hypokalaemia)
Serum calcium (exclude hypercalcaemia)
Plasma & urine osmolality (high plasma osmolality, and low urine osmolality)
Water deprivation test

30

Key features of ECG in hyperkalaemia

Peaked/tented T waves
Absent p waves
Broad complexes

31

Management of hyperkalaemia

10 ml 10% calcium gluconate
50 ml 50% dextrose + 10 units of insulin
Nebulised salbutamol
Treat the underlying cause

32

Features of primary hyperaldosteronism

Hypertension (resistant to treatment)
Low potassium
High sodium
High aldosterone, low renin (negative feedback)

33

Causes of hyperkalaemia

Renal impairment
Drugs (e.g. spironolactone, ACEi, A2RBs)
Adrenal insufficiency (Addison's disease)
Rhabdomyloysis
Acidosis (hydrogen moves into cells, potassium leaves cells)
Type 4 renal tubular acidosis (rare)

34

Drive for potassium secretion in distal nephron

Na reabsorption through ENaC (epithelial sodium channels) leads to tubular lumen negative electrical potential, driving potassium secretion.

Happens in the principal cells of the collecting tubule.

35

How does aldosterone increase potassium secretion?

Aldosterone increases transcription of genes for:
Epithelial sodium channels in collecting tubule (lumen side)
Basolateral sodium/potassium pumps in collecting tubule

So Na absorption is increased

Na reabsorption through ENaC (epithelial sodium channels) leads to tubular lumen negative electrical potential, driving potassium secretion.

36

Stimuli for aldosterone secretion

Angiotensin II
Potassium

37

Causes of hypokalaemia

GI loss: D+V
Renal loss: Loop and thiazide diuretics, Barrter syndrome, Gitelman syndrome, excess aldosterone, excess cortisol
Redistribution into cells

38

What is Barrter syndrome

A rare inherited defect in the thick ascending limb of the loop of Henle.Causes low potassium levels. Caused by mutations in genes for multiple proteins leading to a similar outcome

39

What is Gitelman syndrome

Defect in Na/Cl co-transporters in distal tubule. Leads to hypokalaemia

40

Clinical features of hypokalaemia

Muscle weakness
Cardiac arrhythmia
Polyuria and polydipsia (nephrogenic DI, hypokalaemia makes you resistant to ADH)

41

Management of hypokalaemia

Serum potassium 3.0-3.5 mmol/L:
Oral potassium chloride (two SandoK tablets tds for 48 hrs)
Recheck serum potassium

Serum potassium 20 mmol per hour are highly irritating to peripheral veins

Treat the underlying cause e.g. give spironolactone for Conn's

42

Glucagon is not effective in patients with...

Liver failure
They have no glycogen stores

43

Treatment for hypoglycaemia (acute) if:
Alert and orientated
Drowsy/confused but swallow intact
Unconconcious/ concerns about swallow
Deteriorating / refractory /insulin induced /difficult IV access

Rapid acting oral carbohydrates e.g. Lucozade

Buccal glucose e.g. hypostop

IV access: 50ml 50% glucose (Do not do this in real life!)

Consider IM/SC 1mg glucagon

44

Which patients (with diabetes) most commonly experience no symptoms with hypoglycaemia

Patients on B-blockers
Patients who have recurrent hypoglycaemia

45

First response to hypoglycaemia (substance released/suppressed). Followed by...

Suppression of insulin
THEN

Release of glucagon
Release of adrenaline
Release of cortisol

46

End product of glycogen breakdown in muscle

Glucose-6 phosphate

47

C-peptide is

The cleavage product of pro-insulin (along with insulin).
Secreted in equimolar amounts to insulin

48

Half life of c-peptide
Half-life of insulin

4-6 minutes
30 minutes

49

The 3 ketone bodies

Acetone (pear drop smell in pts with DKA and is volatile), beta hydro and acetoacetate

50

Inherited metabolic disorders leading to hypoketotic hyooglycaemia in neonates

FAOD : no ketones produced
GSD type 1 ( gluconeogentic disorder)
Medium chain acyl coA dehydrogenase def.
Carnitine disorders

51

Beckwith Weidemann syndrome is...

An overgrowth disorder usually present at birth. Characterised by certain features including:
neonatal hypoglycaemia (islet cell hyperplasia)
macgroglossia
Macrosomia
Midline abdominal wall defects
Hepatoblastoma
Ear creases or ear pits

52

Mechanism of action of sulphonylureas

Bind to Sur 1 subunit of potassium channel (on insulin secreting cell) and cause it to close. Membrane depolarisation leads to insulin release

53

MEN1 is associated with tumours of the...

Pituitary
Parathyroid
Pancreas

54

How does Non-islet cell tumour cause hypoglycaemia

Tumour secretes "big IGF-2" which binds to IGF-1 receptors and insulin receptors. Produces downstream effects of insulin

55

Quinine causes hypoglycaemia by...

Stimulating insulin secretion

56

`Rate limiting step in haem biosynthesis

Creation of 5-Aminolaevulinic Acid (ALA) from succinyl-CoA and glycine.
Enzyme: ALA synthase

57

5-Aminolaevulinic Acid (ALA) created from glycine and CoA by ALA synthase. Next step in the haem biosynthesis pathway is...

ALA enters the cytoplasm and porphobilinogen formed from ALA by PBG synthase.

58

Principal sites of haem biosynthesis

Erythroid cells
Hepatocytes

59

Differences between porphyrins and porphyrinogens

Porphyrinogens are raised in porphyria
Colourless compounds
Unstable and readily oxidised to the corresponding porphyrin by the time urine /faeces reaches lab

Porphyrins are highly coloured (detected in urine or faeces)
Porphyrins near start of the pathway are water soluble – urine (uro-)
Porphyrins near end less soluble – faeces (copro-)

60

Deficiency in ALA synthase causes...

Sideroblastic aneamia (inability to incorporate iron into haemoglobin, form sideroblasts)

Presents acutely with neurovisceral attacks:
skin paleness, fatigue, dizziness, and enlarged spleen and liver. Heart disease, liver damage, and kidney failure can result from iron buildup in these organs

NOT A PORPHYRIA

61

PBG synthase deficiency causes...

Acute porphyria. Specifically ALA dehydratase/plumboporphyria

Extremely rare form of porphyria
Build-up of ALA, but not PBG

Diagnostic implications – with a porphyria the Uroporphyrinogen in the urine is measured. However with this deficiency, there is no Uroporphyrinogen produced and therefore cannot be detected.

62

HMB synthase deficiency causes

Acute intermittent porphyria.

Neurovisceral attacks:
Abdo pain and vomiting
Tachycardia and hypertension
Constipation, urinary incontinence
Hyponatraemia +/- seizures (thought to be due to SIADH)
Psychological symptoms
Sensory loss / muscle weakness
Arrythmias / cardiac arrest

No skin symptoms: No production of porphyrinogens

63

Mode of inheritence of acute intermittent porphyria

Autosomal dominant

64

Neurotoxic haem precursor

5-Aminolaevulinic Acid (ALA)

65

Precipitating factors for acute intermittent porphyria

ALA synthase inducers
Barbiturates, steroids, ethanol, anticonvulsants
Stress
Infection, surgery
Reduced caloric intake
Endocrine factors
More common in women and premenstrual
Just started OCP (classic examination)

66

Treatment of acute intermittent porphyria

Avoid attacks
Adequate nutritional intake (high carb diet)
Precipitant drugs
Prompt treatment infection/illness

iv carbohydrate
iv haem arginate
Suppresses pathway from the top

67

Signs/symptoms of acute intermittent porphyria

Neurovisceral attacks
Abdo pain and vomiting
Tachycardia and hypertension
Constipation, urinary incontinence
Hyponatraemia +/- seizures (thought to be due to SIADH)
Psychological symptoms
Sensory loss / muscle weakness
Arrythmias / cardiac arrest

68

Acute porphyrias that cause skin lesions

Hereditary coproporphyria
Variegate porphyria

69

Signs and symptoms of hereditary coproporphyria

Neurovisceral attacks:
Constipation and urinary incontinence
Abdo pain and vomiting
Tachycardia and hypertension
Arrhythmia/ cardiac arrest
Seizures
Psychological symptoms
Sensory loss/ muscle weakness

Skin:
Blistering
Skin fragility

70

Mode of inheritence of coproporphyria

Autosomal dominant

71

Consequence of coproporphyrinogen deficiency

Acute porphyria: specifically hereditary coproporphyria
Neurovisceral attacks and skin symptoms

72

Consequence of protoporphyrinogen deficiency

Acute porphyria: Specifically variegate porphyria

73

Main type of acute porphyria

Acute intermittent porphyria

74

Mode of inheritance of variegate porphyria

Autosomal dominant

75

Signs symptoms of variegate porphyria

Neurovisceral attacks
Abdo pain and vomiting
Constipation and urinary incontinence
Seizures
Sensory loss and muscle weakness
Psychological symptoms
Tachycardia and Hypertension
Arrhythmias/cardiac arrest

Skin symptoms
Photosensitivity
Skin fragility
Blistering

76

How do we use urine and stool testing to differentiate the acute porphyrias

In plumboporphyria tere will be no porphobilinogen produced and no uroporphyrinogen produced (so no porphyrins in stool or urine)

In AIP, VP, and HCP PBG is raised but:
Porphyrins raised in HCP or VP, but not AIP

77

Consequence of uroporphyrinogen III synthase deficiency
.

Congenital erythropoietic porphyria. A non-acute porphyria

78

Consequence of uroporphyrinogen decarboxylase deficiency

Porphyria cutanea tarda. A non-acute porphyria

79

Consequence of ferrochetolase deficiency

Erthropoietic porphyria. A non-acute porphyria.

80

Signs and symptoms of porphyria cutanea tarda

Formation of vesicles on sun-exposed areas of skin crusting, superficial scarring, pigmentation

81

Biochemical features of porphyria cutanea tarda

Urinary and plasma uroporphyrins increased.
Ferritin increased

82

Precipitants of porphyria cutanea tarda

Alcohol
Oestrogen
Hepatic compromise (e.g. hepatitis infection)

83

Features of erythropoetic porphyria

Photosensitivity only, no blisters
Only erythroid cells affected, therefore need to measure RBC protoporphyrin
Caused by ferrochetolase deficiency. Raised RBC protoporphyrin is the result.

84

Features of congenital erythropoietic porphyria

Deficiency of uroporphyrinogen III synthase
Raised HMB

Skin features:
Formation of vesicles that can rupture
Photosensitivity

Haemolytic anaemia
Porphyrins additionally accumulate in the bone and teeth, resulting in erythrodontia (red discolouration of teeth)

Very acute attacks:
Vomiting and constipation can follow attacks

85

Reactions catalysed by ALT and AST

The transfer of the alpha-amino groups of alanine and aspartate, respectively, to the alpha-keto group of ketoglutarate, which results in the formation of pyruvate and oxaloacetate.

86

Reaction catalysed by gamma GT

Gamma-glutamyl transpeptidase (GGT) catalyzes the transfer of the gamma-glutamyl group from gamma-glutamyl peptides such as glutathione to other peptides and to L-amino acids

87

Gamma GT is elevated in...

Chronic alcohol use
Bile duct disease
Hepatic metastases

88

ALP markedly rises in...

Obstructive jaundice or bile duct damage
Bone disease (especially metastatic and pregnancy)

89

Causes of low albumin

low production (chronic liver disease, malnutrition)
loss (eg gut, kidney)
sepsis (“3rd spacing”)

90

Alpha-feto protein raised in...

HCC
Hepatic damage/regeneration
Pregnancy
Testicular cancer

91

Bilirubin is conjugated with

Glucuronic acid

92

In pre-hepatic jaundice bilirubin is (conjugated/unconjugated)

Unconjugated

93

In hepatic jaundice bilirubin is (conjugated/unconjugated)

Both

94

In post hepatic jaundice bilirubin is...

Conjugated

95

Post-hepatic causes of jaundice

Bile duct obstruction
Drugs

96

Hepatic causes of jaundice

Genetic (e.g. Gilbert's)
Hepatitis
Drug reaction

97

Pre-hepatic causes of jaundice

Haemolysis

98

Bilirubin in urine is (conjugated/unconjugated)

Conjugated (but should not be present)

99

Urobilinogen in urine is raised in...

haemolysis, hepatitis, sepsis

100

What is Courvoisier’s Sign

In the presence of a painless palpable gallbladder, jaundice is unlikely to be caused by gall stones

101

Mode of inheritance of Gilbert's syndrome

Autosomal recessive

102

Effect of vitamin A
a) excess
b) deficiency

a) Colour blindness
b) Exfoliation and hepatitis

103

Effect of vitamin A
a) deficiency
b) excess

Rickets/osteomalacia
Hypercalcaemia

104

Effect of vitamin E (tocopherol)
a) Deficiency
b) Excess

a) Anaemia and neuropathy. Possibly malignancy/IHD
b) None

105

Effect of vitamin K (phytomenadione)
a) deficiency
b) Excess

Defective clotting
None

106

Effect of vitamin B1 (thiamine)
a) Deficiency
b) Excess

Beri-beri, Neuropathy and Wernicke syndrome
None

107

Effect of vitamin B2 (riboflavin)
a) Deficiency
b) Excess

Glossitis
None

108

Effect of vitamin B6 (pyridoxine)
a) Deficiency
b) Excess

Dermatitis and anaemia
Neuropathy

109

Effect of vitamin B12
a) Deficiency
b) Excess

Perninicious anaemia (macrocytic anaemia)
None

110

List tests for vitamin B enzymes

B1 (thiamine): RBC transketolase
B2 (riboflavin): RBC glutathione reductase
B6 (pyridoxine): RBC AST activation
B12 (cobalamin): serum B12

111

Effect of vitamin C (ascorbate)
a) Deficiency
b) Excess

Scurvy
Renal stones

112

Effect of folate
a) Deficiency
b) Excess

a)Megaloblastic anaemia
Neural tube defects in foetus

b) None

113

Effect of niacin
a) Deficiency
b) Excess

a) Pellagra
b) None

114

Excess fluoride causes...

Fluorosis: characterised by mottling of the teeth and if severe calcification of the ligaments

115

Effect of copper
a) Deficiency
b) Excess

Anaemia
Wilson's

116

Effect of zinc
a) Deficiency
b) Excess

Dermatitis
None

117

Ideal diet contains 50%....

carbohydrate

118

Definition of overweight and obese according to BMI

25-30 kg/m2 overweight
>30 kg/m2 obese
>40 kg/m2 morbidly obese

119

Metabolic syndrome is...

Metabolic syndrome is a clustering of at least three of five of the following medical conditions:
abdominal (central) obesity,
elevated blood pressure,
elevated fasting plasma glucose,
high serum triglycerides,
low high-density lipoprotein (HDL) levels.

120

Marasmus is...

Marasmus is a form of severe malnutrition characterized by energy deficiency.
It occurs before the age of 1
Marasmus is commonly represented by a shrunken (growth retardation), wasted appearance, loss of muscle mass and subcutaneous fat mass.

121

Kwashiorkor is

A form of severe protein–energy malnutrition characterized by oedema, irritability, ulcerating dermatoses, and an enlarged liver with fatty infiltrates.

Sufficient calorie intake, but with insufficient protein consumption, distinguishes it from marasmus.

Kwashiorkor cases occur in areas of famine or poor food supply

122

Key features of kwashiorkor

Oedematous
Scaling/ulcerated
Lethargic
Large liver, s/c fat
Protein deficient

123

Emergency treatment of hypercalcaemia

Ca2+ >3.0 mmol/L &/or unwell
(Dehydrated, confused, drowsy, coma, seizures, renal failure)
IV access (venflon/central line)
Catheter
Rehydrate: 0.9% saline (can be litres++)
Initiate calciuresis:
0.9% saline
Frusemide
IV pamidronate 30 - 60 mg if cause is cancer (hold off)

124

Non emergency treatment of hypercalcaemia

Keep well hydrated
Avoid thiazides
Surgery

125

What are brown tumours?

The brown tumor is a bone lesion that arises in settings of excess osteoclast activity, such as hyperparathyroidism. It is not a true neoplasm

Brown tumours consist of fibrous tissue, woven bone and supporting vasculature, but no matrix.

The osteoclasts consume the trabecular bone that osteoblasts lay down and this front of reparative bone deposition followed by additional resorption can expand beyond the usual shape of the bone, involving the periosteum thus causing bone pain.

The characteristic brown coloration results from hemosiderin deposition into the osteolytic cysts.

Hemosiderin deposition is not a distinctive feature of brown tumors; it may also be seen in giant cell tumors of the bone

126

Brown tumours are seen in which condition

Hyperparathyroidism

127

In sarcoidosis PTH is...

suppressed to undetectable levels

128

Treatment of sarcoidosis

Steroids

129

Cause of hypercalcaemia in sarcoidosis...

Systemic disease where macrophages express 1 alpha hydroxylase (which activates vitamin D)

So calcium is higher in summer

130

Cause of seasonal hypercalcaemia...

Sarcoidosis

131

Gold-standard measure of GFR

Inulin clearance

132

Urine microscopy:
Urine is examined to look for:

Crystals
Red blood cells
White blood cells
Casts
Bacteria

133

About 80% of kidney stones are partially or entirely formed of...

Calcium oxalate

134

Causes of pre-renal AKI

True volume depletion
Hypotension
Oedematous states
Selective renal ischaemia
Drugs affecting glomerular blood flow

135

Causes of post renal AKI

Ureteric obstruction (bilateral)
Prostatic / Urethral obstruction
Blocked urinary catheter

136

Commonest causes of CKD

Diabetes
Atherosclerotic renal disease
Hypertension
Chronic Glomerulonephritis
Infective or obstructive uropathy
Polycystic kidney disease

137

Consequences of CKD

1]Progressive failure of homeostatic function
-Acidosis
-Hyperkalaemia
2]Progressive failure of hormonal function
-Anaemia
-Renal Bone Disease
3]Cardiovascular disease
-Vascular calcification
-Uraemic cardiomyopathy
4]Uraemia and Death

138

Consequences of renal acidosis

-Muscle and protein degradation
-Osteopenia due to mobilization of bone calcium
-Cardiac dysfunction

139

Features of hyperkalaemia ECG

Tall peaked t wave
Prolonged pr interval
Widened flattened p waves (eventually disappear)
Widened QRS (with tall T wave)

140

Treatment of CKD bone disease

Phosphate control
-Dietary
-Phosphate binders
Vit D receptor activators
-1alpha calcidol
-Paricalcitol
Direct PTH suppression
-Cinacalcet

141

3 phases of uraemic cardiomyopathy

LV hypertrophy
LV dilatation
LV dysfunction