Chemical Pathology SBAs Flashcards
- Arterial blood gas sample
A 67-year-old woman presents to accident and emergency after having a fall.
She is diagnosed with a fractured neck of femur which is fixed with a hemiarthroplasty.
She also suffers from metastatic breast cancer. Four days postoperatively,
she develops shortness of breath with an increased respiratory rate of
24 breaths per minute. The doctor on call takes an arterial blood gas sample
which shows the following results:
pH 7.48 PaO2 15.4 kPa on 2 L of oxygen pCO2 2.6 kPa Base excess +1 Saturations 99 per cent What does the blood gas show?
A Metabolic alkalosis with respiratory compensation
B Metabolic alkalosis
C Respiratory alkalosis with metabolic compensation
D Respiratory alkalosis
E None of the above
D Respiratory alkalosis
This lady has most likely suffered a pulmonary embolism manifesting
as an acute onset of shortness of breath. Acid–base questions are best
approached in three steps: first, decide if the pH shows an alkalosis or an
acidosis. Next look at the PaCO2 and decide if it is high or low. Carbon
dioxide dissolves in water to form carbonic acid, a weak acid. Therefore,
if the concentration of carbon dioxide is high, it will lower the pH. You
must then decide if the PaCO2 is compounding or helping the patient’s
pH – in other words, is it worsening an acidotic patient or compensating
for an alkalotic patient? Finally, look at the base excess. A greater
positive base excess implies a higher concentration of bicarbonate, which
is a base. Unlike carbon dioxide, therefore, high levels of bicarbonate
will raise the pH. In this scenario, the pH is 7.48 meaning the patient
is alkalotic with a low PaCO2, implying a respiratory cause. There is no
compensation as the base excess of +1 is within normal limits. Unlike
respiratory compensation, metabolic compensation takes several days.
Below is a table of common causes of the different acid–base abnormalities
with the likely carbon dioxide and base excess values.
- Paradoxical aciduria
A 19-year-old female student presents to the GP with low mood, lethargy and
muscle weakness. She is anxious that she is putting on weight and admits to
purging after meals to keep her weight under control for several months. She has
a past history of depression and is taking citalopram. On examination, her body
mass index is 18, she is clinically dehydrated with signs of anaemia including
conjunctival pallor. She has bilateral parotidomegaly and the GP also notices
erosions of the incisors. He orders some blood tests which reveal the following:
Hb 9.5 White cells 7.8 Platelets 345 Na 143 K 3.1 Urea 8.5 Creatinine 64 Arterial pH 7.49
Urinalysis is normal except for acidic urine. The cause of this patient’s acidic
urine is:
A Acute renal failure
B Renal tubular acidosis
C Citalopram
D Anaemia
E Physiological
E Physiological
This is a difficult question but the answer can be deduced with a basic
knowledge of electrolyte physiology. This patient suffers from bulimia
nervosa as characterized by the use of characteristic purging after meals
to keep her weight under control. The main abnormalities in the investigations
reveal a hypokalaemia with arterial alkalosis and paradoxical
aciduria. The alkalosis is likely to be due to excessive purging leading
to a loss of hydrogen ions. The hypokalaemia is secondary to the metabolic
alkalosis as potassium and hydrogen are transported across cell
membranes by the same transporter. The reduction of plasma hydrogen
ions leads to increased potassium uptake leading to hypokalaemia. As
part of a normal homeostatic mechanism, potassium is exchanged for hydrogen
ions in the distal convoluted tubule of the nephron, resulting
in an apparent paradoxical aciduria.
- Hyponatraemia
A 55-year-old man with severe learning difficulties presents with shortness of
breath on exertion, fever and a productive cough of rusty red sputum. On examination,
there is increased bronchial breathing in the lower right zone with inspiratory
crackles. The patient is clinically euvolaemic, and urine dipstick is normal.
A chest X-ray demonstrates right lower zone consolidation with the presence of
air bronchograms. He is on carbemezepine for epilepsy and risperidone. Blood
tests reveal the following:
Hb 13.4 White cell count 12.8 C reactive protein 23 Na 123 K 4.7 Urea 6 Creatinine 62
What is the most likely cause of hyponatraemia?
A Pneumonia
B Carbamezepine
C Risperidone
D Syndrome of inappropriate antidiuretic hormone (SIADH)
E Cerebral salt wasting syndrome
B Carbamezepine
This patient’s hyponatraemia is most likely secondary to
Carbamezepine therapy (B), a well documented side effect of this antiepileptic
medication. Carbamezepine stimulates the production of vasopressin,
the mechanism of action of which will be discussed shortly.
It is also one of the ‘terrible 3 Cs’ which cause aplastic anaemia, the
other two being carbimazole
and chloramphenicol. Any patient with
signs of infection or bleeding must be taken very seriously as fulminant
sepsis may ensue without prompt treatment. This patient, however,
has mounted a white cell response with a normal platelet count
therefore making aplastic anaemia unlikely.
Pneumonia (A) does not normally cause a sodium abnormality on its
own. Less commonly, Legionnaire’s disease caused by the bacterium
Legionella pneumophilia can have extrapulmonary features including
hyponatraemia, deranged liver function tests and lymphopenia. This is
unlikely to be the case as this organism often colonizes water tanks in
places with air conditioning and has a prodromal phase of dry cough
with flu-like symptoms. The alternative indirect pulmonary cause of
hyponatraemia is lung cancer producing a SIADH; the tumour predisposes
the patient to pneumonia by obstructing the normal ciliary clearance of the bronchi. It is unlikely in this patient given the lack of
smoking history or cachexia.
Hypercalcaemia
A patient with end stage renal failure presents with depression. He is on haemodialysis
three times a week but feels it is not working anymore and is getting more
tired lately. He says he has lost his appetite and consequently feels rather constipated
too. He feels his mind is deteriorating and there is little worth in attending
dialysis anymore. His doctor wants to exclude a reversible cause of his depression
and orders some blood tests. The doctor finds the patient has a raised corrected
calcium, normal phosphate levels and high parathyroid hormone levels. What is the
diagnosis?
A Primary hyperparathyroidism
B Secondary hyperparathyroidism
C Tertiary hyperparathyroidism
D Pseudohypoparathyroidism
E Pseudopseudohypoparathyroidism
C Tertiary hyperparathyroidism
This patient has tertiary hyperparathyroidism (C) given the presence of
elevated calcium levels with high parathyroid levels in the presence of
chronic renal failure. Plasma calcium levels are controlled via parathyroid
hormone (PTH) which is produced in the parathyroid glands situated
within the thyroid gland. Reduced ionized calcium concentration
is detected by the parathyroid glands leading to a release of PTH which
circulates in the blood stream. PTH increases calcium resorption from the kidneys whilst increasing phosphate excretion. PTH also stimulates
1-alpha hydroxylation of 25-vitamin D to make 1,25-vitamin D. Finally,
PTH increases bone resorption of calcium via osteoclast activation.
The sum effects of increased PTH levels are to increase plasma calcium
concentration and to reduce phosphate concentration. PTH has an indirect,
but very important, mechanism via 1,25-vitamin D which acts to
increase gut absorption of calcium.
Tertiary hyperparathyroidism (C) is seen in the setting of chronic renal
failure and chronic secondary hyperparathyroidism leads to hyperplastic
or adenomatous change in the parathyroid glands resulting
in autonomous
PTH secretion. The causes of calcium homeostasis dysregulation
are multifactorial including tubular dysfunction leading
to calcium
leak, inability to excrete phosphate leading to increased PTH levels
and parenchymal loss resulting in lower activated vitamin D levels.
Vitamin deficiency tests
A 59-year-old man presents with a fall and haematemesis after a heavy night
drinking at the local pub. This is his third admission in a month with alcoholrelated
problems. He has stopped vomiting, and on examination he is haemodynamically
stable. He has digital clubbing, spider naevi and gynaecomastia. He is
admitted for neurological observations overnight as he hit his head. The doctors
notice the patient suffers from complex ophthalmoplegia, confusion and ataxia.
Given his neurological symptoms which test would confirm the associated vitamin
deficiency?
A Red cell folate
B Red blood cell transketolase
C Red blood cell glutathione reductase
D Red blood cell aspartate aminotransferase activity
E Carbohydrate deficient transferrin
B Red blood cell transketolase
This patient suffers from chronic alcohol abuse with signs of chronic
liver disease. He also exhibits the classical triad of Wernicke’s encephalopathy
caused by a thiamine (vitamin B1) deficiency. The test for this
is measuring red blood cell transketolase activity (B). Red cell transketolase
is a thiamine pyrophosphate requiring enzyme which catalyzes
reactions in the pentose phosphate pathway essential for regenerating
NADPH in erythrocytes. The test measures enzyme activity by adding
thiamine pyrophosphate to a sample of haemolyzed red blood cells
and measuring the effluent substances. By calculating the amount of
product made and substrates consumed, one is able to calculate the
increase of enzyme activity after thiamine addition. A marked increase
in activity implies a thiamine deficiency as the other substrate (ribose
5 phosphate) is supplied in excess. Thiamine deficiency has a number
of clinical sequelae including Wernicke’s encephalopathy, a reversible
neurological manifestation characterized pathologically by haemorrhage
in the mammillary bodies. If left untreated, this may progress to
Korsakoff’s syndrome, an irreversible neurological disease characterized
by severe memory loss, confabulation, lack of insight and apathy.
Thiamine deficiency can also lead to wet beriberi syndrome leading to
a high output cardiac failure.
Hyperkalaemia
A 75-year-old man presents with acute onset abdominal pain. The patient
has not passed stools for 3 days and looks unwell. His past medical history
includes bowel cancer which was treated with an abdominoperineal resection
and chemotherapy 6 years ago. On examination, there is a large parastomal
mass which is tender and irreducible. An arterial blood gas shows metabolic
acidosis with a rasied lactate. The on-call doctor immediately starts normal
saline fluids and prepares the patient for theatre. A strangulated hernia is diagnosed
by the registrar and an emergency laparotomy is performed to resect the
ischaemic bowel. One day postoperatively the patient has the following blood
results:
Hb 13.2 WCC 10.9 Platelets 234 Na 145 K 6.3 pH 7.38 Urea and creatinine normal
What is the most likely cause of hyperkalaemia?
A Acute kidney injury
B Tissue injury
C Resolving metabolic acidosis
D Adrenal failure from metastases
E Overhydration from intravenous fluids
B Tissue injury
The most likely cause of this patient’s hyperkalaemia is secondary to
tissue injury. Potassium is the principle intracellular cation whereas
sodium is the principle extracellular cation. Na–K exchange pumps
require a continuous supply of adenosine triphosphate (ATP) to supply
the energy required to maintain the transcellular gradient. In iscliaemic conditions, where oxygen supply is limited, ATP production fails to
meet demand via aerobic respiration alone. Therefore ATP is also generated
via anaerobic respiration. This can only occur for a limited period
as the anaerobic pathway is both less efficient and produces lactic acid,
thereby reducing the local pH and reducing the efficiency of enzymatic
activity. This patient has had a significant amount of infarcted bowel
removed with a raised lactate implying anaerobic metabolism has both
occurred and ultimately failed leading to cell necrosis. The cells are then
unable to maintain the Na–K transporter activity leading to potassium
release in the blood stream. Furthermore, surgery itself causing direct
cell damage increases the intracellular potassium leak into the plasma.
Hypernatraemia
A 54 year old with a background of hypertension, presents to the GP with a
2-week history of diarrhoea. He has been travelling in South East Asia recently
and developed symptoms of diarrhoea 3 weeks ago. He went to the local doctor
whilst in China who prescribed tetracycline, but his symptoms have persisted and
only improved slightly. His past medical history includes an undisplaced parietal
skull fracture he sustained when he was 10. He takes no other medications. The
GP orders blood tests which show the following:
Na 148
K 4.8
Urea 13
Creatinine 112
What is the most likely cause of his hypernatraemia?
A Conn’s syndrome
B Nephrogenic diabetes insipidus
C Cranial diabetes insipidus
D Tetracycline
E Dehydration
E Dehydration
The most likely cause of hypernatraemia in this man is dehydration (E).
Gastroenteritis with diarrhoea for 3 weeks causes a high rate of free
water loss resulting in increased concentration of sodium in the extracellular
compartment. Sodium and intravascular volume are closely
linked and controlled by the renin angiotensin system and antidiuretic
hormone. A reduction in renal blood flow through loss of intravascular
volume results in increased renin secretion from the juxtaglomerular
apparatus in the kidneys. Renin converts angiotensinogen to angiotensin
I which in turn is converted to angiotensin II by angiotensin
converting enzyme (which is constitutively expressed in the lungs).
Angiotensin II increases the release of aldosterone from the zona glomerulosa
in the adrenal cortex which acts to increase sodium retention.
Retained sodium increases plasma osmolality which stimulates antidiuretic
hormone (ADH) release from the posterior pituitary. ADH acts to
increase free water retention, the net result being an increased intravascular
volume with a normal osmolality.
Water deprivation test
A 42-year-old woman with persistent polyuria and polydipsia is admitted for a
water deprivation test. At the beginning of the test her weight, urine volume and
osmolality and serum osmolality are measured and hourly thereafter for 8 hours.
After 8 hours, she is given intramuscular desmopressin but drinks 3 L of water
before going to bed. Her blood is taken again the next morning (16 hours after
beginning the test) and the results are as follows:
Start 8 hours 16 hours
Weight 70 kg 67.8 kg 66.8 kg
Urine volume (total) 0 mL 2200 mL 4000 mL
Urine osmolality 278 mosmol/kg 872 mosmol/kg 980 mosmol/kg
What is the most likely diagnosis?
A Nephrogenic diabetes insipidus
B Craniogenic diabetes insipidus
C Psychogenic polydipsia
D Invalid test
E Normal
C Psychogenic polydipsia
This patient is most likely suffering from psychogenic polydipsia, an
uncommon condition where excessive water drinking occurs without the
physiological stimulus to drink. It was classically described in patients
with schizophrenia but also occurs in children. Chronic psychogenic
polydipsia can result in mineral washout of the renal interstitium resulting
in a physiological inability to concentrate urine, in other words a
form of nephrogenic diabetes insipidus.
Acute abdominal pain
A 24-year-old previously fit and well woman presents with sudden onset
abdominal pain the night after a party where she drank five units of alcohol. She
complains of central abdominal pain, with nausea and vomiting. She also finds
it difficult to control her bladder. On examination, she is tachycardic, hypertensive
and is beginning to become confused. On looking back at her previous
admissions, the doctor notices she has had similar episodes after drinking. This
was also true for when she started the oral contraceptive pill and when she had
tuberculosis which was treated with standard antibiotic treatments. She is also
seeing a neurologist for peripheral neuropathy of unknown cause. The admitting
doctor, an Imperial college graduate, suggests the possibility of acute intermittent
porphyria.
What enzyme deficiency is responsible for this disease?
A Porphobilinogen deaminase
B Uroporphyrinogen synthase
C Coproporphyrinogen oxidase
D Protoporphyrinogen oxidase
E Uroporphyrinogen decarboxylase
A Porphobilinogen deaminase
PBG deaminase deficiency (A) causes acute intermittent porphyria,
which this patient suffers from. The porphyrias are a group of seven
disorders caused by enzyme activity reduction in the haem biosynthetic
pathway. Haem is manufactured in both the liver and bone marrow
where branched chain amino acids together with succinyl CoA and
glycine are needed. The first step involves 5 aminolevulinic acid (ALA)
synthesis by ALA synthase. This is the rate limiting step which is under
negative feedback from haem itself.
Exacerbating factors for gout
A patient presents with an acutely painful, inflamed elbow. He has decreased range
of movement passively and actively and the joint is tender, erythematous and warm.
His past medical history includes hypertension, chronic lower back pain for which
he takes aspirin, lymphoma for which he has just completed a course of chemotherapy
and psoriasis which is well controlled. He is also a heavy drinker. A joint aspirate
shows weakly negative birefringent crystals confirming the diagnosis of acute
gout. Which factor in this patient is the least likely to contribute to this attack?
A Bendroflumethiazide
B Chemotherapy
C Alcohol
D Psoriasis
E Aspirin
D Psoriasis
Although all of these factors can contribute to hyperuricaeamia, well
controlled psoriasis (D) in this patient is unlikely to contribute to this
attack of gout. Gout may be acute or chronic and is caused by hyperuricaemia.
Hyperuricaemia is caused either by increased urate production
or decreased urate excretion.
Uric acid is a product of purine metabolism and is produced in three
main ways – metabolism of endogenous purines, exogenous dietary
nucleic acid and de novo production. De novo production involves
metabolizing purines to eventually produce hypoxanthine and xanthine.
The rate limiting enzyme in this pathway is called phosphoribosyl pyrophosphate aminotransferase (PAT) which is under negative feedback
by guanine and adenlyl monophosphate. The metabolism of exogenous
and endogenous purines, however, is the predominant pathway for
uric acid production. The serum concentration of urate is dependent
on sex, temperature and pH. A patient with acute gout does not necessarily
have an increased urate concentration, therefore making serum
urate levels an inaccurate method of diagnosis. The diagnosis of acute
gout, which most commonly affects the first metatarsophalangeal joint
(‘podagra’) is best made by observing weakly negatively birefringent
crystals in an aspirate of the affected joint. This test is performed with
polarized light – urate crystals are rhomboid and illuminate weakly
when polarized light is shone perpendicular to the orientation of the
crystal (hence negative birefringence). This is in contrast with pseudogout
which has positively birefringent, spindly crystals – these
illuminate best when the polarized light is aligned with the crystals.
X-ray of the affected joint shows soft tissue inflammation early on,
but as the disease progresses, well defined ‘punched out’ lesions in the
juxta-articular bone appear with a late loss of joint space. There is no
sclerotic reaction. Treatment is with a non-steroidal anti-iflammatory
(e.g. diclofenac) in the acute phase or colchicine.
Anion gap
A patient has the following blood results; calculate the anion gap:
Na 143 mmol/L K 4 mmol/L Cl 107 mmol/L HCO3 25 mmol/L PO4 1 mmol/L Glucose 8 mmol/L Urea 7 mmol/L
A 14 mmol/L
B 15 mmol/L
C 16 mmol/L
D 17 mmol/L
E Not enough information
A 14 mmol/L
The anion gap is calculated using the following equation:
Anion gap = [Na+] + [K+] − [HCO3] − [Cl−]
It is a method of assessing the contribution of unmeasured anions in
metabolic acidosis. The normal range varies between laboratories but
the upper limit is usually between 10 and 18 mmol/L. It is helpful to
estimate the unmeasured anions such as phosphate, ketones and lactate
which are difficult to measure normally.
Estimated plasma osmolarity
A patient has the following blood results:
Na 143 mmol/L K 4 mmol/L Cl 107 mmol/L HCO3 25 mmol/L PO4 1 mmol/L Glucose 8 mmol/L Urea 7 mmol/L
What is the estimated plasma osmolarity?
A 309
B 279
C 426
D 294
E Not enough information
A 309
Estimated plasma osmolarity is calculated using the following equation:
Estimated plasma osmolarity = {[Na+] + [K+]} × 2 + [glucose] + [urea]
The estimation of osmolarity is an approximation of the laboratory
plasma osmolality which is always higher. The difference between
osmolarity and osmolality is the quantity of solvent one is referring
to – the former describes the osmoles of solute in 1 kg, whereas the latter
describes the same solute in 1 L of solvent. Sodium and potassium
are the main plasma cations, they are doubled to take into account the
equal concentration of total anions present to maintain electrical neutrality.
Glucose and urea are the other main osmolites even though urea
has very little osmotic effect in the plasma. It is a very small molecule
that can pass easily through cell membranes without affecting osmotic
pressure.
Biochemical abnormalities in chronic renal failure
A 67-year–old man with chronic renal failure presents with fatigue. He has been on
haemodialysis three times per week for a decade. His past medical history includes
diabetes mellitus, hypertension and gout. He has been increasingly tired the last few
weeks although he cannot explain why. He has been attending his dialysis appointments
and is compliant with his medications. The GP takes some bloods to investigate.
Which of the following is NOT a common association with chronic renal failure?
A Acidosis
B Anaemia
C Hyperkalaemia
D Hypocalcaemia
E Hypophosphataemia
E Hypophosphataemia
Patients with chronic renal failure normally suffer from hyperphosphataemia,
not hypophosphataemia (E). This is due to renal impairment
of calcium metabolism which is under the control of parathyroid
hormone (PTH) and vitamin D. In the evolving stages of chronic renal
failure, a secondary hyperparathyroidism exists to compensate for
the inability
of the kidney to retain calcium and excrete phosphate.
Therefore hypocalcaemia
(D) is associated with chronic renal failure.
This stimulates a physiological secretion of PTH by the parathyroid
glands in an attempt to retain calcium. PTH is also responsible for
excreting phosphate in the kidney, which is impaired due to the failure.
Hyperphosphataemia also increases PTH levels as part of a negative
feedback loop designed to maintain its homeostasis. Patients with
chronic renal failure usually take phosphate binders (e.g. Sevelamer)
which act to reduce phosphate absorption. This reduces PTH production
which also reduces bone resorption thus improving renal osteodystrophy,
a complex metabolic bone pathology associated with chronic renal
failure. It is also important to reduce phosphate concentration to reduce
ectopic calcification – if this precipitates
in the tubules, this may reduce
what little function there is left.
Thyroid function tests
A 45-year-old woman presents feeling tired all of the time. She has been investigated
for anaemia which reveals macrocytosis. She denies drinking excessively.
She has recently moved house and the GP notices she has a croaky voice, peaches
and cream complexion and a slowed reaction to his questions. He examines
her and elicits slow relaxing ankle reflexes. He suspects hypothyroidism and
orders some thyroid function tests.
Which of the following results are consistent
with primary hypothyroidism?
A Low TSH, raised free T4 and T3
B Low or normal TSH with low free T4 and T3
C Raised TSH with normal free T4 and T3
D Normal or raised TSH with raised T4 and T3
E None of the above
E None of the above
Thyroid function tests are relatively easy to interpret with a basic
understanding of the hypothalamic–pituitary–thyroid axis of thyroid
hormone control. The pituitary produces TSH (thyroid stimulating
hormone) which is released from the anterior pituitary. It is under the
control of the hypothalamus which releases thyroid releasing hormone
(TRH) which signals to anterior pituitary cells to release TSH. TSH
travels
in the bloodstream and acts on thyrocytes in the thyroid gland
to stimulate production of T4 and T3 hormone. Specifically TSH controls
the rate of iodide uptake required for thyroid hormone production,
thyroid peroxidase activity, iodotyrosine reuptake into the thyrocyte
from colloid and iodotyrosine cleavage to form mature hormone. T4 is
the main circulatory hormone produced in about a 10:1 ratio compared
with T3. However, free T3 has greater efficacy; in fact circulating T4 is
converted into T3 within cells which then binds to its hormone receptor.
TSH release is under negative feedback control of T4. In primary
hypothyroidism,
the thyroid does not have the ability to produce sufficient
T4 or T3 to inhibit further TSH release. Therefore the biochemical
abnormality found in primary hypothyroidism is a raised TSH with low
T4 and T3, which is not one of the answer options (E).
Biochemical abnormalities of metabolic bone disease
An 86-year-old woman presents to accident and emergency after a fall. She is a
frequent faller but was unable to weight bear after the most recent incident. She
has a history of rheumatoid arthritis which is controlled with low dose prednisolone.
On examination her right leg is clinically shortened and externally rotated
and a pelvic X-ray confirms the presence of a fractured neck of femur. The patient’s
hip is fixed the next day. Her day one postoperative bloods show the following:
Corrected calcium normal Phosphate normal Alkaline phosphatase raised Parathyroid hormone level normal Vitamin D level low
What is the most likely diagnosis?
A Normal
B Osteoporosis
C Paget’s disease
D Osteomalacia
E Malignancy
B Osteoporosis
Osteoporosis (B) is a common disease which affects women more than
men. It is pathologically associated with a reduction in bone density
but normal mineralization of bone. There are usually no biochemical
abnormalities and therefore all of the parameters measured here should
be normal. Given the nature of the fracture, the raised alkaline phosphatase
is likely to be due to the fracture where osteoblast and osteoclast
activation for remodelling and bone healing is required for bone
union. Note osteoblasts produce alkaline phosphatase, not osteoclasts.
The activation of the two is usually simultaneous, therefore any bone remodelling will lead to a rise in alkaline phosphatase concentration.
An important exception is in myeloma where bone lysis occurs with no
rise in alkalaline phosphatase because osteoclasts are directly activated
without osteoblast activity. Recently the National Institute of Clinical
Excellence (NICE) have published guidelines regarding osteoporosis and
its management. The risk factors of osteoporosis include:
1 Genetic factors: woman, age, Caucasion/Asian, family history
2 Nutritional factors: excessive alcohol and caffeine, low body weight
3 Life style factors: inactivity, smoking
4 Hormonal factors: nulliparous women, late menarche/early menopause,
oophorectomy, post menopausal women, amenorrhoea
5 Iatrogenic factors: thyroxine replacement, steroids
