Clinical Biochemistry > Year 3 > Flashcards

Year 3 Flashcards

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1
Q

What is clinical biochemistry?

A

• Study of the chemical processes of the body in health and disease
Or
• Measurement of chemicals in the body to aid diagnosis, monitoring and treatment of disease

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2
Q

What level does imaging allow you to see?

A

Macro

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3
Q

What are some examples of external body imaging?

A
  • MRI
  • X-ray
  • CT scans
  • Whole body imaging
  • Bone scan
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4
Q

When is imaging not useful?

A
  • When there is no physical abnormality

* When it is at the molecular level

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5
Q

What does diagnostic tests inform us?

A

Identification of disease when patients simply feel “unwell”

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6
Q

What does prognostic tests inform us?

A
  • Disease progression

* Possible treatment

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7
Q

What does monitoring tests inform us?

A
  • How they are responding to treatment

* Informs on any changes necessary

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8
Q

What does screen tests inform us?

A

• If it is a condition that is present sub-clinically by the use of biomarkers

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9
Q

Why are emergency tests important?

A

Patients rushed to hospital with unknown cause requires emergency diagnosis

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10
Q

What do biomarkers do?

A

Inform clinicians on diagnosis and how to proceed with treatment and monitoring of patients

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11
Q

What are some examples of requested samples?

A
  • Blood
  • Urine
  • Ascitic fluid (in abdomen)
  • Gastric fluid
  • Amniotic fluid
  • Cerebrospinal fluid
  • Sweat
  • Saliva (limited use)
  • Faecal material
  • Solid tissues (tumour)
  • Analytes
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12
Q

What are analytes?

A

Substance whose nature and/or concentration is determined by a clinical test

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13
Q

What are the specific conditions that need to be taken into account when collecting a sample?

A
  • Time sample was taken
  • Volume collected
  • Specific diet
  • Fasting/not fasting
  • How is it preserved?
  • How is it transported?
  • Is it immediately analysed or is it stored first?
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14
Q

Why do we need to be aware of how the sample was collected?

A

Can affect biochemistry

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15
Q

What needs to be on the label of a sample?

A
  • Name
  • Date
  • Time of sampling
  • Patient identifier
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16
Q

What does a plasma sample contain?

A
  • Yellow liquid that blood cells are suspended in
  • Contains dissolved proteins (serum albumins, globulins and fibrinogen)
  • Glucose
  • Clotting factors
  • Electrolytes (Na+, Ca2+, Mg2+, HCO3-, Cl- etc)
  • Hormones
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17
Q

What does serum contain?

A

The same as plasma but without the clotting factors (and blood cells)

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18
Q

What are the advantages of simple laboratory tests?

A

• Highly reproducible
• Easy to replicate
• Reduces false positives and false negatives
• Can be done by automation
High throughput – does lots of samples at once (but can be limited when reading low concentration samples)

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19
Q

What test detects samples with low concentrations?

A

Immunoassay analysers

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20
Q

What is the workflow of a chemistry analyser?

A
  • Sample pipetted into cuvette
  • Reagent pipetted into cuvette
  • Reaction mixture mixed and incubated
  • Absorbance monitored
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21
Q

What do general chemistry analysers do?

A

initiate and measure defined reactions

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22
Q

What are the advantages of general chemistry analysers?

A
  • Larger machines can process thousands of samples per hour (may have to wait in queues)
  • Can analyse the same sample 7-10 times
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23
Q

Which general chemistry analysers are typically used?

A
  • Spectrophotometry
  • Potentiometry (ion specific electrodes)
  • Immune-assays
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24
Q

What level of training is required for point of care testing?

A
  • For sophisticated analysers in diabetes or epilepsy clinics there needs to be trained lab staff
  • For glucose testing, blood gases, ITU and GP clinic there needs to be a nurse or medical staff
  • For blood or urine (diabetes) the patient can do it (no training)
  • For glucose, cholesterol, PSA it can be done in pharmacies, supermarkets or internet vendors
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25
How can a clinical biochemistry lab be standardised?
* Standard Operating Procedures (SOPs) – validated protocol followed every time * Training Log Books – staff training procedures * Analyser Maintenance – machines routinely serviced * Reagent logs – storage temp/in-date/batch ID * Calibration Log – machines calibrated, analyte controls * Serum Indices * Quality Control Management System(s)
26
What are the tests done for a urea and electrolyte profile?
* Sodium * Potassium * Chloride * Bicarbonate * Urea * Creatinine
27
What are the tests done for a liver function test profile?
* Aspartate transferase (AST) * Alanine aminotransferase * Alkaline phosphatase (ALP) * Gamma glutamyl transferase (GGT) * Bilirubin * Total protein
28
What are the tests done for a bone profile?
* Calcium * Phosphate * Alkaline phosphatase * Albumin
29
What are the tests done for thyroid function test profile?
* Thyroid simulating hormone | * “free” T4
30
What are some examples of disease influencing electrolyte imbalances?
* Hypernatremia * Hyperkalaemia * Diabetes insipidus * Conn’s disease (involved in excess production of aldosterone)
31
What does a urea and electrolyte profile give an indication of?
* Kidney function * Overall health * Useful in diagnosing many diseases
32
In a 70kg male with 42L of water (60% of the body is water) how much would the intra and extracellular fluid have?
• 66% ICF – 28L (fluid in tissues) • 33% ECF – 14L o 3.5L intravascular fluid – blood plasma o 10.5L interstitial fluid – pleural, pericardial, peritoneal, cerebrospinal and GI fluid
33
What can cause the water levels to fluctuate?
* Eating * Drinking * Exercise * Passing urine/faeces * Sweating * Chemical reactions liberating water * Diuretics
34
What treatment uses water balance on the ward?
IV drip
35
What are the features of dehydration?
* Increased pulse * Decreased blood pressure * Decreased skin turgor * Soft/sunken eyeballs * Dry mucus membranes * Decreased urine output * Decreased consciousness
36
What are the features of over-hydration
* Normal pulse * Normal to increased blood pressure * Increased skin turgor * Normal eyeballs * Normal mucus membranes * Normal urine output * Decreased consciousness
37
What does dehydration do to osmolality of plasma?
* Increases * Less water = increased salt concentration * Increased salts initiates mechanisms to control water and salt levels
38
What usually causes over-hydration?
Problems with excretion by the kidneys
39
What is over-hydration typically not caused by?
Excessive intake, except if compulsive drinking disorder
40
What is osmolality?
It is the measure of osmotically active particles in solution
41
What are the units of osmolality?
mOsm/kg
42
What is the osmolality of a healthy person?
285-295 mOsm/kg
43
How is the osmolality of different body compartments (ICF/ECF) kept equal?
• The movement of water across semipermeable membranes in response to concentration changes (except in water controlling cells such as nephrons and sweat glands)
44
What does osmolality affect in solution?
The freezing point which is used to measure osmolality
45
How do you calculate the calculated plasma osmolality?
Calculated Plasma osmolality = 2x [Na+] + 2x [K+] + [urea] + [glucose]
46
What is the difference between plasma osmolality and urine osmolality?
Plasma osmolality remains constant, urine osmolality dramatically changes
47
Why does urine osmolality change?
Absorption or excretion of excess electrolytes
48
What is the osmolar gap?
This is the difference between measured and calculated osmolality
49
How do you calculate the osmolar gap?
Osmolar gap = measured osmolality – calculated osmolality
50
What does an osmolar gap greater than 10 indicate?
* It is considered abnormal | * Caused by toxins/poisons such as ethanol, methanol, ethylene glycol (antifreeze) as they supress the freezing point
51
When is the osmolar gap test extremely useful?
When the patient is unconscious
52
How does water deprivation affect plasma osmolality?
Increases
53
How is raised plasma osmolality due to water deprivation corrected?
Either by drinking more or urinating less
54
What is the flow of drinking more occur from the detection of raised plasma osmolality in water deprivation?
* Stimulating thirst * Increasing liquid consumption * Increased total body volume
55
What is the flow of urinating less occur from the detection of raised plasma osmolality in water deprivation?
* ADH release * Water retention * Reduced urine output
56
How is water deprivation detected?
Raised plasma osmolality
57
What does antidiuretic hormone (ADH) activate in kidney function?
* Renal collecting ducts * Permits water reabsorption back into the body and urine concentration * At high levels leads to vasoconstriction= increased blood pressure and increased blood volume * Also controlled by the renin angiotensin-aldosterone system (RAA system)
58
What causes ADH increase?
* High ECF osmolality * Dehydration/fever * Exercise * Drugs
59
What causes ADH decrease?
* Low ECF osmolality * Overhydration * Alcohol
60
What occurs if cells are not water balanced?
* Water will move out/move in | * The cell will either swell and rupture or shrink
61
What are electrolytes?
Electrolytes are substances that dissociate into ions in solution and so acquire the ability to conduct electricity
62
What is the normal amount of sodium within the cellular fluid?
* In plasma (ECF) 142mmol/kg * In interstitial fluid (ECF) 145mm/kg * In ICF 12mmol/kg
63
What is the normal amount of potassium within the cellular fluid?
* In plasma (ECF) 4mmol/kg * In interstitial fluid (ECF) 4mmol/kg * In ICF 156mmol/kg
64
What are the most requested biochemical profiles?
* Serum sodium * Potassium * Chloride * Urea * Creatinine * Bicarbonate
65
What is the major mechanism of transport for sodium and potassium?
Na/K pump
66
What are the functions of sodium?
* Establishes osmotic gradients/fluid balance (hydration of the body in vessels and cells) * Blood pressure regulation (hydration of vessels) * Aid movement of solutes/nutrients in/out of cells (hydration in cells) * Muscle/nerve contractions
67
What colour blood tube is lithium heparin?
Green
68
Why must blood not be collected from the same arm that has IV drip saline (150 mm NaCl)?
* Artefact | * Can disturb the results
69
How does temperature affect potassium in a blood sample?
Potassium moves out of the cells creating an artificial rise in potassium in ECF
70
How much sodium should be in a lithium heparin tube?
140 mmol/kg
71
How much potassium should be in a lithium heparin tube?
4 mmol/kg
72
How are electrolytes measured?
Either direct (undiluted sample) or indirect (diluted sample) ion-selective electrodes (ISE)
73
What can be a problem of a diluted sample when conducting indirect ISE?
Can result in false values
74
What does hypovolaemia (low body water) lead to?
Decreased blood pressure
75
What does hypovolaemia activate?
Activates mechanism such as renin angiotensin-aldosterone system (RAA system) to regulate water/electrolytes
76
What is the overview of the RAA system?
• Hypovolaemia detected by kidneys in the Juxtaglomerular apparatus • Release of Renin converts angiotensinogen -> angiotensin I • Angiotensin Converting Enzyme converts angiotensin I -> angiotensin II • Stimulates Adrenal cortex • Aldosterone release o Kidneys re-absorb sodium and water o Blood pressure rises o Potassium is excreted (to balance the sodium increase)
77
What is aldosterone?
A steroid hormone produced by the Adrenal cortex in response to a drop in blood volume (ECF) and a drop in pressure detected in renal juxtaglomerular
78
What does aldosterone act on?
* Nuclear mineralocorticoid receptors (MR) within the principal cells of the renal distal tubule activating Na/K pump * Action is to decrease urinary sodium excretion (exchanging Na with K)
79
How does aldosterone affect Conn's disease?
* Primary hyperaldosteronism | * Low renin, high aldosterone
80
How does aldosterone affect Addision's disease?
* Hypoaldosteronism | * Low aldosterone
81
What is atrial natriuretic peptide (ANP)?
A powerful vasodilator
82
Where is atrial natriuretic peptide (ANP) synthesised and released?
The heart
83
What is the purpose of atrial natriuretic peptide (ANP)?
* To oppose the RAA system | * Inhibits production of aldosterone and renin (reduces Na reabsorption – more in the urine)
84
What affect does atrial natiuretic peptide (ANP) on the body?
* Reduced blood pressure | * Reduced blood volume
85
What does aldosterone stimulate?
Reabsorption of potassium
86
What is the dietary intake of potassium per day?
Approximately 75-150 mmol/day
87
Where is potassium secreted?
* Kidney and lesser by the gastrointestinal tract * At distal nephron in exchange from sodium using the sodium potassium pump, controlled by aldosterone – triggering the secretion of potassium
88
What does potassium imbalance refer to?
Localisation as well as overall concentration
89
What is hyponatraemia?
* Low sodium serum | * Both low sodium or high water
90
What are the symptoms of hyponatraemia?
* Mild confusion * Fatigue * Muscle cramps * Oedema * Death
91
When dealing with electrolytes what must be considered?
The hydration status of the patient
92
What are the three categories of blood volume tests depending upon total body fluid that help diagnose disease?
* Low fluid = hypovolaemia * Normal fluid = normovolaemia * High fluid = hypervolaemia
93
If blood sodium is low (hyponatraemia) where should be checked?
Urine
94
What does concentrated urine (polyuria) suggest with regards to sodium?
It suggests that the cause is due to osmotic diuretic or may also indicate renal failure
95
What does dilute urine suggest with regards to sodium?
Polydipsia (excess thirst) which can lead to hypovolaemia or diabetes insipidus
96
If sodium levels in urine are still low after fluid replacement what should be examined for?
* Congestive cardiac failure * Liver disease * Cushing’s syndrome * Conn syndrome
97
What concentration is classed high urine [Na+]?
>20 mmol/L
98
What are conditions with high urine [Na+]?
* Acute renal failure (no longer absorbing Na+) * Addison’s disease (normal renal function but altered hypothalamus/pituitary/adrenal axis * SIADH
99
How should hyponatraemia be examined?
* Blood sodium * ECF volume * Urine sodium
100
What is the cause of hyponatraemia?
Due to reduced water in the body rather than increased sodium intake (dehydration) although there can be cases of sodium overdose (in children)
101
What is an example of disease with hypernatraemia?
* Conn’s syndrome (excess aldosterone = sodium retention) | * Diabetes insipidus (production of high volumes of dilute urine caused by either cranial or nephrogenic)
102
What are the main causes of diabetes insipidus?
• Cranial o Failure to secrete ADH from pituitary gland o Congenital, following head injury or tumour • Nephrogenic o Kidneys fail to respond to ADH
103
What are the symptoms of diabetes insipidus?
* Polyuria (excess urine output) * Polydipsia (excessive thirst) * Don’t always develop hypernatraemia if water intake matches loss
104
What are the possible ways of artefact measurement of sodium?
* Artefact hyponatraemia – blood taken too close to vein with IV fluid * Surgical patients – increased ADH (stress), opiate analgesics, IV fluids * Dilutional hyponatraemia – significant water retention * Syndrome of inappropriate antidiuretic hormone (SIAD) * Sick cell syndrome – possible faulty Na+ pump
105
What is pseudohyponatraemia caused by?
* Incorrect sampling * Occurs due to increased protein or lipid concentration in original plasma leading to an erroneously low sodium concentration if diluted – less water and sodium in initial sample * Occurs in diluted ISE with a non-genuine sodium measurement of <135-145mmol/L
106
When is the general term syndrome of inappropriate antidiuretic hormone (SIADH)
• When cause of hyponatraemia is not immediately apparent o Common in elderly, ADH production continues for no reason o Water retention with multiple causes – ADH secreting tumours, pulmonary disease, CNS, drug side effects ->SIAD OR high water in ECF -> hyponatraemia
107
What is the diagnosis of SIADH?
* Lack of disease-causing renal leakage of sodium into urine * Low plasma osmolality but still producing ADH * Loss of sodium in urine * Normal renal function * Exclusive thyroid, pituitary, adrenal, renal disease or taking diuretics * So called as “inappropriate” levels of ADH in blood for water and electrolyte levels
108
How is sodium imbalance treated?
* Isotonic fluid replacement (increase salts) * Reduced fluid intake to reduce water overload * Treat primary cause if more serious underlying problem (liver/kidneys/heart) * Diuretics * Kidney dialysis
109
What is hypokalaemia?
``` • Low potassium in serum • Not just K+ depletion (slow) but also relates to K+ relocalisation (fast) o Depleted intake o Drugs o Loss through gut or kidneys ```
110
What is the clinical reference range of hypokalaemia?
3.3-4.7 mmol/L
111
What is the acute shift of K+ into cells in hypokalaemia?
* Insulin in high doses (cardiac arrest patients) induces hypokalaemia * Adrenaline * Cellular incorporation of potassium
112
What are the principle causes of hypokalaemia?
* Decreased potassium intake * Transcellular potassium movement * Increased potassium excretion
113
What are the clinical features of hypokalaemia?
* Even severe hypokalaemia can be asymptomatic * Muscle weakness * Depression * Constipation * Paralytic ileus (blocked intestine due to nerves/muscle NOT actual blockage) * Cardiac arrythmias * Polydipsia/polyuria
114
What is the management of hypokalaemia?
* Locate the cause * Careful with IV potassium fluid replacement therapy * Remember potassium enters ECF prior to ICF * ECG monitoring * Can induce hyperkalaemia (far worse clinical outcome)
115
What is hyperkalaemia?
* Potassium excess by increased intake, decreased excretion (renal failure), drugs and spurious * Defined as potassium excess and localisation * More serious than hypokalaemia
116
What does hyperkalaemia do to cardiac tissue?
Lowers membrane potential in cardiac tissue and shortens cardiac potential
117
What are the symptoms of hyperkalaemia?
Slow ventricular fibrillation or cardiac arrest
118
What is the clinical reference for significant risk of cardiac arrest with hyperkalaemia?
6.5 mmol/L
119
What is the clinical reference for an emergency of a cardiac arrest with hyperkalaemia?
>7 mmol/L
120
What is the treatment of hyperkalaemia?
* Calcium gluconate competes with potassium giving some protection * Glucose and insulin will initiate potassium uptake into cells * If kidney failure – requires kidney treatment strategy * ECG monitoring
121
What is the most advantageous of point of care testing?
Shortened turn-around time
122
How is osmolality measured?
By freezing it
123
Where is ADH released from?
Pituitray gland
124
Where is ADH produced from ?
Hypothalamus
125
What is the impact of exercise training on ADH?
Decreases
126
What is a common poison that makes people drunk, which is often responsible for changes in the osmolar gap?
Ethanol
127
What is a false biochemical change caused by an error in sampling or analysis?
Artefact
128
What is a disorder characterised by reduced body fluid?
Dehydration
129
What is a part of the brain known as the thirst centre containing osmoreceptors?
Hypothalamus
130
What is a hormone released in response to hypertonicity of the extracellular fluid (aka antidiuretic hormon)?
Vasopressin
131
What is the difference in osmotic potential across a membrane?
Tonicity
132
What does arterial blood gases (ABG) enable the measurement of?
Measurement of effectiveness of blood exchange of oxygen and carbon dioxide
133
What is Dalton's law of partial pressure?
* Dalton’s law states that the total pressure of a mixture of gases is the sum of the partial pressures of its components * P total = Pgas1 + Pgas2 + Pgas3
134
How do gases move in pressure?
Gases move from areas of high pressure to areas of low pressure
135
What is the main waste product from respiration?
Carbon dioxide
136
What does carbon dioxide in the blood relate to?
* Acidity * High CO2 = acidity * Low CO2 = basic
137
What is PCO2?
Partial pressure of carbon dioxide
138
What is PaCO2?
Partial pressure of carbon dioxide in arterial blood
139
What can the brainstem detect with its respiratory centre?
Acidity
140
What is the role of the respiratory centre in the brainstem?
* System initiates diaphragm and ribs to increase ventilation * Removal of CO2 when detect too acidic environment * Once rise in PCO2 is detected the equilibrium shifts to the right favouring bicarbonate buffer * HCO3 moves to the central chemoreceptor to the respiratory control centre to increase ventilation
141
How does increased ventilation affect PaCO2?
PaCO2 increased
142
How does decreased ventilation affect PaCO2?
PaCO2 decreased
143
What is PO2?
Partial pressure of oxygen
144
What is PaO2?
Partial pressure of oxygen in arterial blood
145
What is sO2?
Oxygen saturation of Hb
146
What SaO2?
Oxygen saturation of Hb in arterial blood
147
How can SaO2 be simply measured?
Using a finger probe called a pulse oximeter
148
What is hypoxaemia?
Oxygen content in arterial blood is reduced
149
What does hypoxaemia cause?
* Impaired oxygenation * Low Hb (anaemia) * Reduced affinity of Hb to O2 (CO poisoning)
150
What is hypoxia?
Tissues receive inadequate supply of O2 to support aerobic respiration
151
What does hypoxia cause?
* Impaired oxygenation * Low Hb (anaemia) * Reduced affinity of Hb to O2 (CO poisoning)
152
What is hypoxia often associated with?
* Lactic acidosis | * Cells resorting to anaerobic respiration
153
What are the types of respiratory impairments?
* Type 1 * Type 2 acute * Type 2 chronic * Hyperventilation
154
What are the features of type 1 respiratory impairment?
* Defective oxygenation | * Normal ventilation
155
What are the features of type 2 acute and chronic respiratory impairment?
Defective ventilation
156
What are the gas levels associated with type 1 respiratory impairment?
* Low PaO2 | * Normal/low PaCO2
157
What are the gas levels associated with type 2 acute respiratory impairment?
* Low PaO2 | * High PaCO2
158
What are the gas levels associated with type 2 chronic respiratory impairment?
* Low PaO2 * High PaCO2 * High HCO3
159
What are the gas levels associated with hyperventilation respiratory impairment?
* Normal PaO2 | * Low PaCO2
160
What are the causes of type 1 respiratory impairment?
* Acute asthma * Pneumonia * Alveolitis * COPD
161
What are the causes of type 2 acute respiratory impairment?
* Inhaled foreign body * Benzodiazepine toxicity * Exhaustion * COPD * Neuromuscular disorder
162
What are the causes of type 2 chronic respiratory impairment?
When chronic disease, HCO3 will compensate high PCO2
163
What are the causes of hyperventilation respiratory impairment?
* Anxiety * Fear * Pain * Acidosis * Drug toxicity * Central nervous system
164
What processes is H+ critical for to maintain concentration/function of?
* Mitochondria – oxidative phosphorylation * Protein conformation * Ionisation of weak acids-bases * Enzymatic function * Chemical reactions
165
What is the [H+] of a healthy individual?
35-46 nmol/L
166
What can acid-base disorders lead to?
Impaired tissue oxygenation
167
What is an acid?
Produces H+ in solution
168
What is a base?
Compound which combined with H+ in solution
169
What is a buffer?
A weak acid (HA) in solution combined with its conjugate base (A)
170
What is the acid-base equation of Bronsted and Lowery?
HA H+ + A-
171
What is the equation of the Henderson-Hasselbach equation?
pH = pKa + log [base]/[acid] --> pH = pKa + log [A- ]/[HA]
172
What does pKa indicate about an acid?
Strength
173
What is pKa?
A dissociation constant
174
What can H+ be produced by?
* Metabolic acids | * Respiratory acids
175
What metabolic acids can H+ be produced by?
* Anaerobic metabolism of glucose to lactate and pyruvate * Anaerobic metabolism of fatty acids * Oxidation of sulphur containing amino acids (cysteine and methionine) * Diets rich in protein often give rise to acidic urine
176
What respiratory acids can H+ be produced by?
Carbon dioxide generated by respiration
177
What does the bicarbonate buffer equation look like if acidic conditions are promoted?
CO2 + H2O --> H2CO3 (carbonic acid) --> HCO3
178
What promotes acidic conditions in the bicarbonate buffer equation?
Increased CO2
179
What does the bicarbonate buffer equation look like if alkaline conditions are promoted?
HCO3 --> H2CO3 (carbonic acid) --> CO2 + H20
180
What promotes alkaline conditions in the bicarbonate buffer equation?
Increased bicarbonate
181
What are the main mechanisms of acid excretion?
* Bicarbonate (buffer) * Ammonia (buffer) * Phosphate (buffer)
182
Where is ammonia generated?
NH4+ generated in the renal tubular cells
183
What pH is favoured for ammonia buffer?
7.4
184
What is the equation of ammonia buffer?
NH4 + NH3 + H+ pH = 9.2 + Log [NH3] / [NH4 +]
185
At which pH does phosphate exist as the mono form (HPO4)2-?
7.4
186
At which pH is phosphate buffer effective at?
* 6.8 | * Low concentration in ECF, high in bone and ICF
187
What is the equation of phosphate buffer?
• H2PO4 - HPO4 2- + H+ pH = 6.8 + log [HPO4 2- ] / [H2PO4 -]
188
What is the reference range for pH in urine?
4.8-7.8
189
What does a blood gas analyser measure?
* pH * PCO2 * HCO3
190
What must the blood be like to be used as a sample in a blood gas analyser?
* Arterial blood * Heparinised (prevents clotting) * Free of bubbles (effects PCO2) * Chilled (reduces glycolysis/lactate)
191
What is the reference range of pH in blood gas analysis?
7.35-7.45
192
What is the reference range of [H+] in blood gas analysis?
35-45 nmol/L
193
What is the reference range of PCO2 in blood gas analysis?
35-45 mmHg
194
What is the reference range of PO2 in blood gas analysis?
12-14.6 kPa
195
What is the reference range of serum [HCO3-} in blood gas analysis?
24-29 mmol/L
196
In acid-base disorders, what does an increased PCO2 mean ?
Respiratory acidosis
197
In acid-base disorders, what does a decrese in PCO2 mean?
Respiratory alkalosis
198
In acid-base disorders, what does a decrease in [HCO3] mean?
Metabolic acidosis
199
In acid-base disorders, what does an increase in [HCO3] mean?
Metabolic alkalosis
200
What is the equation for the anion gap?
Anion Gap = [Na+] + [K+] – [Cl- ] – [HCO3 - ] = 10-18mmol/L
201
What happens to the anion gap if there is an increase in H+?
* We see a decrease in [HCO3-] | * Anion gap increases
202
What other "unmeasured" anions are present in the solution making it electroneutral in the anion gap?
* Lactate anion (lactate acidosis) | * Acetoacetate and hydroxybutyrate (Diabetic ketoacidosis)
203
What may simple electrolyte tests indicate?
Metabolic acidosis
204
What is acid-base compensation?
Physiological mechanisms which try to return disordered [H+] (hence pH) back to normal
205
What type of acid-base compensation is there?
* Plasma buffer compensation * Renal compensation * Respiratory compensation
206
How fast is plasma buffer compensation?
Immediate response
207
How fast is renal compensation?
Slow response (12-24 hrs)
208
How fast is respiratory compensation?
Quick response (minutes)
209
What does renal compensation compensate?
Impaired lung function
210
What does respiratory compensation compensate?
Metabolic disorders
211
What is the difference between acute and chronic disorders with regards to how they effect HCO3?
* Acute disorders do not have time to effect HCO3 | * Chronic disorders do have time to effect HCO3
212
What is the pH level in metabolic acidosis?
Low (acidic)
213
What is the pH level in metabolic alkalosis?
High (basic)
214
What is the pH level in respiratory acidosis?
Low (acidic)
215
What is the pH level in respiratory alkalosis?
High (basic)
216
What is the primary change in metabolic acidosis?
Decreased HCO3 (acidic)
217
What is the primary change in metabolic alkalosis?
Increased HCO3 (basic)
218
What is the primary change in respiratory acidosis?
Increased PCO2 (acidic)
219
What is the primary change in respiratory alkalosis?
Decreased PCO2 (basic)
220
What is the compensation in metabolic acidosis?
Decreased PCO2 (basic)
221
What is the compensation in metabolic alkalosis?
Increased PCO2 (acidic)
222
What is the compensation in respiratory acidosis?
Increased HCO3 (basic)
223
What is the compensation in respiratory alkalosis?
Decreased HCO3 (acidic)
224
What are some clinical causes of respiratory acidosis?
* Lung disease, COAD (hypoventilation) = increased [PCO2] * Neuromuscular disease e.g. polio, Guillian Barre = chronic breathing problems * Drugs = decrease lungs ability to eliminate CO2 * H+ retained and K+ secreted at kidneys so can present as hypokalaemia
225
What are some features of the compensation mechanism for respiratory acidosis?
* Buffered by carbonic acid system initially * Hyperventilation (main compensation) – decreased [PCO2] but lung function typically impaired * Renal system will increase recycling/reclamation of HCO3- * Critically requires functioning renal system, urinary system (to accept H+) and no renal tubular acidosis
226
What are the symptoms of mild to moderate respiratory acidosis?
* Cardiovascular effects, arrhythmia, warm skin, sweating | * CNS depression
227
What are the symptoms of severe respiratory acidosis?
* Seizures | * Coma
228
What is the treatment of respiratory acidosis?
* Determine underlying cause | * Correct ventilation
229
What can be used to determine the underlying cause of respiratory acidosis?
* Sodium, potassium, urea, albumin, calcium and creatinine | * Hydration, electrolytes, calcium levels, kidneys
230
What can be used to correct ventilation for patients with respiratory acidosis?
* Drug therapy | * Medical oxygen
231
What are some clinical causes of metabolic acidosis?
* Renal disease – [H+] retained * Chronic diarrhoea/intestinal fistula – fluid loss [HCO3-] * Renal tubular acidosis – tubular cells cannot excrete [H+] but are losing [HCO3-] * Overdose/poisoning – acid metabolites product – e.g. salicylate poisoning
232
What are some features of the compensation mechanism for metabolic acidosis?
* Buffered by carbonic acid system initially * Hyperventilation (main compensation): reduces pCO2, which reduces [H+] * Renal system will slowly increase [HCO3-] to bind H+ and push equilibrium to the left
233
What are some common causes of metabolic acidosis?
* Lactic acidosis (most common) | * Diabetic ketoacidosis
234
What are some features of lactic acidosis causing metabolic acidosis?
* Low HCO3 and high lactic acid due to low O2 delivered to tissues * Leads to anaerobic respiration * Blood supply, cardiac, shock/blood pressure * Serum lactate is significant predictor of death * Can be life threatening
235
What are some features of diabetic ketoacidosis causing metabolic acidosis?
* Caused by insulin deficiency, no glucose metabolism -> metabolism of fats * Fat metabolism generates ketones (organic acids) -> acidosis * Diagnosis = high plasma glucose, ketones, anion gap * Can be life threatening
236
What are the symptoms of mild to moderate metabolic acidosis?
* H+ secreted not K+ at kidneys so presented as acidosis and hyperkalaemia * May result in release of catacholamines, neuromuscular irritability, arrythmia and tachycardia
237
What are the symptoms of severe metabolic acidosis?
* Decreased blood pressure, loss of consciousness, coma | * Movement of potassium from ICF to ECF – cardiac arrest (acute hyperkalaemia)
238
What treatment is given for a patient with metabolic acidosis?
* Determine underlying cause | * I.V. sodium bicarbonate – in life threatening cases
239
What can be used to determine the underlying cause of metabolic acidosis?
* Blood glucose (diabetes) * Blood lactate (acidosis) * Urea and creatinine (renal failure)
240
What are some clinical causes of respiratory alkalosis?
* Hyperventilation, anxiety * Pain, sepsis, stroke, meningitis, pulmonary embolism * Excess mechanical ventilation
241
What are features of the compensation mechanism against respiratory alkalosis?
* Buffered by carbonic acid system initially * Renal system will decrease ammonia – formation and decrease H+/sodium exchange * Decreased reabsorption of HCO3-
242
What are the symptoms of respiratory alkalosis?
* May cause cardiovascular and neurological symptoms * Blood vessels in the brain may constrict * Dizziness, confusion, loss of consciousness
243
What is the treatment for respiratory alkalosis?
* Determine underlying cause | * Correct ventilation
244
What can be used to determine the underlying cause of respiratory alkalosis?
Potassium measurements may indicate hyperkalaemia
245
What can be used to correct ventilation in a patient with respiratory alkalosis?
Rebreathing (paper bag)
246
What is metabolic alkalosis?
* Increased plasma pH due to loss of H+ or gain of HCO3 | * Net result
247
What are some features of the compensation mechanism of metabolic alkalosis?
* Buffered by carbonic system initially * Hypoventilation (main compensation) – increases pCO2, which decreases [HCO3-] (consider lung disease) * Renal system will decrease recycling/reclamation of HCO3-
248
What are some clinical causes of metabolic alkalosis?
* Loss of [H+] in gastric fluid – pyloric stenosis prevents HCO3- rich secretions from duodenum * Ingestion of alkali sources – very unlikely cause unless coupled with renal impairment * Potassium deficiency – e.g. diuretic therapy * Primary adrenal adenoma – excess production of aldosterone * Glucocorticoid excess
249
What are the symptoms of mild to moderate metabolic alkalosis?
* Non-specific symptoms | * Cramps, hypokalaemia -> muscle weakness, confusion, hypovolaemia
250
What are the symptoms of severe metabolic alkalosis?
Severe hypokalaemia, hypocalcaemia, confusion, coma
251
What treatment is given to a patient with metabolic alkalosis?
* Determine underlying cause * Correction of any volume depletion * Potassium and chloride depletion management
252
What is used to determine the underlying cause of metabolic alkalosis?
* Sodium, potassium, urea, albumin, calcium and creatinine | * Hydration, electrolytes, calcium levels, kidneys
253
What type of cation is calcium?
Divalent cation
254
What percentage of the earth's crust is calcium?
3%
255
In the body, what is the most abundant fixed form of calcium?
• Hydroxyapatite (Ca10(PO4)6(OH)2)
256
Where is hydroxyapatite most present in the body?
* Bones * Teeth * Little in the cytoplasm of cells
257
How much of the body's calcium is in the bones?
Approximately 98%
258
What other molecules does calcium bind to?
* Albumin | * Globulin
259
What free form of calcium is in the body?
* Ca++ | * Physiologically active found in miniscule portion circulating
260
What is the dietary intake of calcium per day?
25 mmol/day or 10mg/100mL
261
Where is calcium distributed?
* Bone from the ECF * Kidney from plasma * GIT from ECF
262
How is calcium excreted?
* Faeces | * Renal loss
263
How much calcium is excreted in faeces per day?
20 mmol/day
264
How much calcium is excreted through renal loss per day?
5 mmol/day
265
What is classed as ultra-filterable calcium which is 53% of plasma calcium distribution?
* Complexed calcium (0.13-0.16 mmol/L) | * Ionised calcium (free) (1.03-1.22 mmol/L)
266
What is classed as protein-bound calcium which is 47% of plasma calcium distribution?
* Albumin bound calcium (0.81 – 0.96 mmol/L) | * Globulin bound calcium (0.22 – 0.26 mmol/L)
267
How does protein bound calcium affect pH?
Protein binding decreases as pH decreases resulting in acidosis
268
In acidosis, how is calcium effected?
* Decreased calcium binding to protein, increased ionised fraction * As pH decreases, [Ca] increases – less calcium is bound to proteins * More H+ binds to albumin, displacing calcium, therefore increases ionised Ca
269
In alkalosis, how is calcium affected?
* Increased calcium binding to protein, decreased ionised fraction * As pH increases, [Ca] decreases – more calcium is bound to proteins * There are more binding sites available for Ca reducing the ionised calcium
270
What is the amount that ionised calcium increases by when pH decreases by 0.1?
0.05 mmol/L
271
Does [H+] of acidosis or alkalosis affect the total calcium within the body?
No
272
What do osteoclasts do?
Dissolve (resorb) bone material (releasing calcium)
273
What do osteoblasts do?
Reform bone (requires calcium)
274
What do osteocytes do?
Help maintain bone (requires calcium)
275
What cells cover the surface of the bone?
Lining cells
276
How is calcium regulated?
By 3 molecules
277
What are the molecules controlling calcium regulation?
* Parathyroid hormone (PTH) * Vitamin D (calcitriol or 1,25-dihydroxycholeciferol) * Calcitonin
278
What are the principle organs involved with regulation of calcium?
* Gut * Kidney * Bone * Skin, liver and parathyroid glands
279
How does PTH affect calcium and phosphate?
* Increased calcium | * Decreased phosphate
280
How does vitamin D affect calcium and phosphate?
* Increased calcium | * Increased phosphate
281
How does calcitonin affect calcium and phosphate?
* Decreased calcium | * Decreased phosphate
282
What cells secrete PTH?
Chief cells of the parathyroid gland
283
Where is the parathyroid gland located?
4 tiny glands located posteriorly on the thyroid at the back of the neck
284
When is PTH secreted?
In response to decreasing ionised calcium
285
What does PTH do?
* Causes increased osteoblast maturation and thus increased bone turnover * Acts on PTH receptors of target cells of bone and kidney * Activate vitamin D to increase calcium absorption
286
What is the flow order of PTH?
* Low plasma calcium * Parathyroid glands * Increased PTH to bone and kidney * Kidney * Increased calcitriol to small intestine (increased absorption of dietary Ca and PO4) and bone (Ca released) * Increased plasma calcium * Parathyroid
287
What is PTH?
Peptide hormone with activity in the N-terminus
288
What effect does PTH have on bone?
* Increased reabsorption of Ca | * Osteoclast activity
289
What effect does PTH have on the renal system?
* Decreased reabsorption of urinary PO4 | * Decreased reabsorption of urinary HCO3-
290
What effect does PTH have on the GIT?
* Increased reabsorption of dietary PO4 | * Increased reabsorption of dietary Ca
291
What does vitamin D do in the intestine?
* Stimulates calbindin-D | * Binds calcium and promotes absorption along with PO4
292
What does vitamin D do in the bone?
* Mineralisation and reabsorption * Increased availability of Ca and PO4 * Promotes osteoblast activity – osteoclasts do not have a vitamin D receptor * Longer term (days) enhance maturation of osteoclasts – osteoblasts release paracrine hormone stimulating osteoclast activity * Inhibits calcitonin release
293
What does vitamin D do in the kidneys?
Renal tubular calcium reabsorption
294
What is the flow order of active vitamin D in calcium regulation?
* Sunlight (UV) to skin * 7-dehydrocholestrol (provitamin D) * Pre-vitamin D3 * Cholecalciferol (vitamin D3 * Liver
295
What is calcitonin secreted by?
Parafollicular or C cells of the thyroid
296
What is the effect of calcitonin?
* Opposing actions to PTH * Reduces Ca reabsorption * Reduces renal calcium (and PO4) reabsorption and increases renal excretion * Reduces bone reabsorption (supress osteoclast activity) * Not clinically relevant other than as a tumour marker
297
What disease is calcitonin used as a tumour marker for?
Medullary thyroid carcinoma (MTC)
298
How can calcium be measured?
* Spectrophotometry using calcium bound to NMBAPTA shining UV light to get a spectral shift depending on the amount of calcium * EDTA is not used as much as it is not specific to calcium * Laboratory testing with calcium bund to albumin calculating corrected calcium (<15g/L)
299
Which sample tubes are used for measuring calcium?
* Lithium heparin (green) * Plain serum (red) * Serum separator (yellow)
300
Which sample tubes are not used for measuring calcium and why?
* Sodium citrate (blue) – prevents clotting by binding Ca * EDTA (pink) or potassium EDTA (purple) – binds calcium to potassium * Fluoride oxalate (grey) – prevents clotting by precipitating Ca and is used more for blood glucose analysis
301
What type of sample is used to measure calcium?
* Venous * Ionised calcium + protein bound + anion bound * 2.1-2.6 mmol/L
302
What occurs to calcium when albumin is low?
* Protein bound calcium will be low | * Ionised calcium is unaffected and remains unchanged
303
What is the reference range for albumin adjusted in measuring calcium?
34-50 g/L
304
What is the calculation for corrected [Ca] in mmol/L when albumin is <40g/L?
Measured total [Ca] (mmol/L) + 0.02 x (40 – serum albumin (g/L))
305
What is the calculation for corrected [Ca] in mmol/L when albumin is >45g/L?
Measured total [Ca] (mmol/L) – 0.02x (serum albumin (g/L) -45)
306
What are the features of ABG calcium?
* Measures the ionised fraction only * Is under very close homeostatic control * Measured with precise ion selective electrode * Gives an accurate measurement of calcium homeostasis
307
What is a disadvantage of only measuring the ionised fraction in ABG calcium?
* Labour intensive process | * Can’t be done in a high throughput manner
308
When is ABG calcium recommended?
* TPN – total parenteral nutrition * Acidosis * ICU patients * End stage renal failure * Some cases of hyperparathyroidism * Citrated blood products
309
What sample is used for measuring PTH?
Plasma EDTA sample - increased stability
310
How is PTH measured?
* Analysed immediately/frozen for storage due to instability of the molecule * Immunoassay-photometric detection of free electron post formation of an immune complex
311
What is the reference range of PTH?
1.1-5.5 pmol/L
312
What sample is used for measuring calcitriol?
SST (gel separator tube) or tube without preservative
313
What method is used to measure PTH?
* Immunoassay-photometric detection of free electron post formation of an immune complex * Stable molecule – long ½ life * Doesn’t need to be frozen * UPLC-MS/MS (low throughput laboratories)
314
What is the reference range of calcitriol?
48-145 nmol/L
315
What are some features of hypercalcaemia?
• High albumin adjusted (>2/6 mmol/L) or ionised calcium (>1.23 mmol/L) • Occurs when rate of entry of calcium to ECF > capacity of kidney to excrete it o Increased absorption from GIT o Increased bone loss o Decreased renal excretion
316
What are the most common causes of hypercalcaemia?
* Primary hyperparathyroidism – sporadic, familial, PTH mediated * Malignant disease – disrupts calcium homeostasis – PTHrP, skeletal metastasis, haematological malignancy
317
What are some less common causes of hypercalcaemia?
* Granulomatous disease – sarcoidosis, TB, histoplasmosis, berrylliosis, leprosy * Vitamin D toxicity * Persistent hyperparathyroidism after renal transplant – PTH mediated * Severe thyrotoxicosis
318
What systems are affected by hypercalcaemia?
* CNS * Gastrointestinal tract * Cardiovascular * Renal * Muscles and bones
319
What symptoms of hypercalcaemia are due to the CNS?
* Lethargy * Depression * Confusion * Coma
320
What symptoms of hypercalcaemia are due to the GIT?
* Anorexia * Nausea * Vomiting * Abdominal pain * Constipation * Pancreatitis
321
What symptoms of hypercalcaemia effect the cardiovascular system?
* Hypertension * ECG changes (reduced QT, prolonged PR) * Arrhythmias (severe hypercalcaemia)
322
What symptoms of hypercalcaemia effect the renal system?
* Polyuria * Polydipsia * Volume depletion * Reduced GFR * Calculi * Nephrocalcinosis
323
What symptoms of hypercalcaemia effect muscles and bones?
* Bone pain * Fractures * Hypotonia * Hyporeflexia * Muscle weakness
324
What are some rare causes of hypercalcaemia?
* Thiazides * Lithium * Anti-oestrogens/Tamoxifen * Vitamin A toxicity * Immobilization * Acute renal failure-diuretic phase * Islet cell tumours/phaeochromocytoma * Addison’s disease * Milk-alkali syndrome
325
What are some features of primary hyperparathyroidism?
* Most common cause of hypercalcaemia * More common in women * Parathyroid carcinoma very rare (<1%) * Often symptom free – increased prevalence of osteoporosis and 15% have renal complication (stones)
326
What is the laboratory investigation of calcium disorders?
``` • Plasma o Calcium o Albumin o Creatinine o Phosphate o ALP o PTH o GGT o Vitamin D • Urine o Calcium o Phosphate ```
327
Hypercalcaemia usually means hypercalciuria except in which condition?
* Familial benign hypocalciuric hypercalcaemia (FBHH) | * Sometimes known as just FHH
328
What is the reference range of having FHH?
<0.01
329
If the Ca:Cr ratio is >0.03, what condition does the patient have?
Primary hyperthyroidism
330
If the Ca:Cr ratio is <0.01, what condition does the patient have?
Familial hypocaliuric hypercalcaemia
331
What treatment is required in a patient with FBHH?
No treatment required
332
How is hypercalcaemia treated?
* If severe (>3mmol/L) would have to treat each separately * Mild to moderate (up to 2.8-3 mmol/L) needs no treatment if asymptomatic * Mild to moderate with symptoms would have a low calcium diet – avoid thiazide diuretics, lithium and volume depletion
333
In acute hypercalcaemia what can be used as treatment?
* Rehydration – normal saline/5% dex will reduce Ca within 24-48 hrs * Biphosphates – if it is due to increased bone reabsorption (may take 1 week to respond) * Calcitonin for severe refractory hypercalcaemia * Dialysis – last resort
334
In chronic hypercalcaemia what can be used as treatment?
* Identify and treat underlying cause | * Cinacalcet – lowers PTH secretion and therefore lowers [Ca]
335
What are some features of hypocalcaemia?
* Less common * Important to assess albumin – ionised Ca required in patients with very low albumin * Common causes relate to secretion and/or action of PTH and vitamin D * Increased excitability of neuromuscular tissue * Chronic hypocalcaemia has calcification of basal ganglia
336
What occurs with hypocalcaemia and excited neuromuscular tisse?
* Tetany or carpopedal spasm or paraesthesia (perioral and fingers) * Laryngeal stridor and seizures * Prolonged QT and ST intervals * Arrhythmias, heart block and congestive heart failure
337
What occurs in calcification of basal ganglia in chronic hypocalcaemia?
* Psychiatric (depression, memory loss, anxiety and hallucinations * Cataracts may occur
338
What are the main causes of hypocalcaemia?
``` • Hypoparathyroidism o Post-surgery o Hypomagnesaemia o Malignancy • Abnormal vitamin D metabolism o Deficiency o Deficiency 1α-hydroxylation (RIMP) • Acute pancreatitis • Hyperphosphataemia – PO4 administration • Acute rhabdomyolysis • Abrupt inhibition of bone reabsorption – hungry bones ```
339
What are some other less common causes of hypocalcaemia?
* Parathyroid hormone resistance * Sepsis * Osteoblast metastasis * Vitamin D resistance * Pseudohypoparathyroidism
340
What is investigated in hypocalcaemia?
* Serum calcium * Albumin * PTH * Urea and creatinine * Magnesium * Vitamin D * Phosphate
341
How can false results be generated in the laboratory when measuring hypocalcaemia?
* EDTA contamination – decrease/undetectable Ca, increased K+ (decrease Mg, decreased Zn, decreased ALP) * Improper blood taking/contamination
342
What is the flow order of diagnosis in suspected hypocalcaemia?
* Suspected hypocalcaemia * Determine corrected calcium (<2.2 mmol/L) * Assess renal function (if evidence of renal function stop) * No renal disease * Measure the PTH * If low PTH or undetectable can be post-surgery, magnesium deficiency or idiopathic * If high PTH then either vitamin D deficiency, pseudohypoparathyroidism or rare cause of hypocalcaemia
343
What must be considered with suspected hypocalcaemia?
* Consider ionised calcium (check albumin) * Check creatinine * Serum Mg * Phosphate – low in vitamin D, raised in cell lysis and pseudohypoparathyroidism * Vitamin D
344
What is the treatment of hypocalcaemia?
* Depends on symptoms and cause * Give calcium if necessary IV – 10-20ml 10% gluconate over 5 mins – continuous infusion of 9-19 mmol Ca in 2L over 24 hrs * Vitamin D deficiency – give vitamin D-25(OH)D not 1(OH)D unless required
345
What type of anion is phosphate?
Trivalent anion
346
What percentage of the earth's crust is phosphate?
0.1%
347
How much phosphate is in a 70kg adult?
23 mol
348
How much of the body's phosphate is in skeleton and teeth?
85%
349
How much of the body's phosphate is within cells and soft tissues?
14%
350
How much of the body's phosphate is within the ECF?
1%
351
How is phosphate present within the body?
* Organic (phosphoproteins and phospholipids) | * Inorganic (phosphate)
352
How much of phosphate is non-covalently bound to proteins?
15-20%
353
What are the roles of phosphate?
* Phospholipids, nucleic acids, enzyme cofactors etc * Cellular energy source (ATP, ADP, creatinine phosphate and diphosphoglycerate, electron transport chain) * Second messenger systems (cAMP, IP3) * 2,3-diphosphoglycerate – oxygen dissociation from OxHb * Buffer of H+ and therefore important in acid-base balance
354
What does severe hypophosphataemia do to intracellular (PO4)3-?
Deplete
355
What regulates (PO4)3-?
* PTH * Calcitriol * Fibroblast growth factor (FGF-23)
356
What does PTH do to regulate phosphate?
Increases renal excretion
357
What does calcitriol do to regulate phosphate?
Increased absorption from GIT
358
What does FGF-23 do to regulate phosphate?
Decreases phosphate reabsorption
359
What is the reference range of plasma phosphate?
* 0.8-1.4 mmol/L | * Higher in infancy and childhood
360
How is phosphate regulated in acid-base balance?
* Acidaemia increases [PTH] – PTH stimulate kidneys to excrete more phosphate from the urine and increases absorption of phosphate from the GIT * Acidaemia reduces [Calcitriol] – proximal tubule cells reduce 1α-hydroxylase
361
What are the main causes of hyperphosphataemia?
* Pseudohyperphosphataemia * Increased phosphate input * Reduced renal excretion * Cellular shifts
362
What are the consequences of hyperphosphataemia?
* No specific symptoms but can cause hypocalcaemia (tetany) * Complexes with calcium and calcification in soft tissue (blood vessels, skin, heart, lungs, kidneys, conjunctivae and joints) – renal failure
363
What is renal failure as a consequence of hyperphosphataemia treated with?
Parathyroidectomy
364
What is the flow order of diagnosis in suspected hyperphosphataemia?
* Laboratory artefact – if yes repeat analysis, if no carry on * Increased phosphate intake – if yes phosphate elimination, if no carry on * Renal failure – if yes treat renal disease, if no carry on * Phosphate moving from ICF to ECF – if yes treat cause, if no carry on * Hypoparathyroidism or acromegaly – if yes treat cause, if no rare causes of hyperphosphataemia
365
What investigations need to be conducted when diagnosing hyperphosphataemia?
* PTH * Calcium * Vitamin D * Creatinine * CK * Urinary phosphate and TmP/GFR
366
What is the therapeutic approach in hyperphosphataemia?
* Medication rarely required if cause is due to altered renal handling * Important in RIMP – avoid calcification and hyperparathyroidism * Phosphate binding salts, reduce absorption * Prevention – saline diuresis prior to chemo (TLS)
367
What are some binding salts with phosphate in hyperphosphataemia?
* Ca * Mg * Aluminium (issues -toxic) * Lanthanum carbonate * Sevelamer alternatives
368
What are the causes of hypophosphataemia?
* Decreased absorption * Increased renal loss * Cellular shifts * Alcoholism * Liver failure
369
What causes of hypophosphataemia is due to decreased absorption?
* Starvation * Parenteral * Vitamin D deficiency * Phosphate binders
370
What causes of hypophosphataemia is due to increased renal loss?
* Diuretics * Hyperparathyroidism (primary and secondary) * Renal tubular defects (e.g. Fanconi)
371
What causes of hypophosphataemia is due to cellular shifts?
* Rx of DKA * Alkalosis * Long distance running * Small amount of PO4 in ECF therefore small shift = large change in serum (PO4)3-
372
What is an example of cellular shifts of (PO4)3-?
* Re-feeding | * Respiratory alkalosis
373
What is re-feeding a response to?
Starvation
374
What are the risks of re-feeding?
* DKA | * Parenteral nutrition
375
What are the potential consequences of re-feeding?
* Organ failure * Cardiac arrest * Respiratory arrest
376
How is respiratory alkalosis involved in cellular shifts of (PO4)3-?
* Stimulus to hyperventilate * Decrease in blood [CO2] * Decreased intracellular [H+] * Increased phosphofructokinase (drives glycolysis) activity = increased phosphorylation of glucose
377
What might respiratory alkalosis occur, with cellular shifts of (PO4)3-?
* Liver failure * Burns * Salicylate poisoning * Alcoholic ketoacidosis * Alcohol withdrawal * Sepsis
378
What are the consequences of decreased (PO4)3-?
• Mild 0.35-0.8 mmol/L o Not harmful in short term o Chronic = osteomalacia/rickets • Severe <0.35 mmol/L o Acute phosphate deficiency – citically ill, decreased metal function, tremor and irritability o Attempt to predict (PO4)3- deficiency and be alert
379
What is acute phosphate deficiency with tremor and irritability often confused with?
Alcoholism
380
What is acute phosphate deficiency with decreased mental function often confused with?
Liver disease
381
What systems are affected by acute phosphate deficiency syndrome?
* Haematopoeitic * Straited muscle * Nervous system * GIT
382
How is the haematopoetic system affected by acute phosphate deficiency syndrome?
* Tissue hypoxia * Haemolysis * Decreased resistance to infection * Decreased platelet survival and abnormal clotting
383
How is the striated muscle system affected by acute phosphate deficiency syndrome?
* Respiratory failure * Decreased stroke work (Heart Failure) * Stiffness * Weakness * Debility * Muscle pain, weakness
384
How is the nervous system affected by acute phosphate deficiency syndrome?
* Lethargy * Confusion * Irritability * Tremor * Seizure * Coma * Parasthesia – peripheral nerves (decreased conduction velocity)
385
How is the GIT affected by acute phosphate deficiency syndrome?
Gastric stasis - smooth muscle
386
What is the flow order of diagnosis for suspected hypophosphataemia?
* Medication causing hypophosphataemia – if yes change medication, if no continue * Phosphate moving from ECF to ICF – if yes treat cause, if no continue * Investigate urinary phosphate excretion – if high excessive renal loss, if low or normal inadequate phosphate intake
387
What is the laboratory investigation of suspected hypophosphataemia?
* Clinical Hx more important * Assessment of blood gas/respiration * Chronic hypophosphataemia – determination of renal phosphate handling/wasting – FGF-23
388
What is the treatment for hyperphosphataemia?
• Mild to moderate – usually transient and no treatment is required • Replace o Orally - Na or K-hydrogen phosphate o IV – K-phosphate, 50-100mmol/L kg in ½ N saline over 12 hrs – repeat as required while monitoring K, Ca and (PO4)3- - stop when PO4 >0.35 mmol/L and replace orally
389
What type of cation is magnesium?
Divalent cation
390
What percentage of the earth's crust id magnesium?
2.4%
391
What are the features of magnesium metabolism?
* Majority within the bone * 2nd most abundant intracellular cation * Important co-factor for enzymes, control of ion channels, protein and nucleic acid synthesis and oxidative phosphorylation * Is essential in all enzyme reactions using ATP
392
How much magnesium is present within the plasma?
0.5-1%
393
What are the features of magnesium distribution?
* Magnesium in food: green vegetables (principle ion in chlorophyll) * Absorbed by both active and passive mechanisms, large bowel can absorb magnesium * Magnesium deficiency increases absorption by the GIT * Intake=output (bowel and kidney)
394
What is the dietary intake of magnesium per day?
15 mmol/day
395
How much magnesium is in ECF?
15 mmol
396
How much magnesium is in bone?
750 mmol
397
How much is excreted?
* 10 mmol/day in faeces | * 5-10 mmol/day in renal loss
398
How much plasma magnesium is filtered by the kidneys?
75%
399
Where in the kidneys is plasma magnesium filtered?
* Approximately 20% in proximal tubules (paracellular) * Approximately 65% in cortical thick ascending limb of the loop of Henle (passive) * Approximately 5-10% in the distal convoluted tubule (active) * No significant reabsorption in the collecting duct
400
What are the features of regulation of magnesium?
* Filtered by the kidneys * Magnesium reabsorption is saturable * Reabsorption requires sodium to drive it (Na/K-ATPase pumps) * In magnesium deprivation – 24hr UMg can be <1 mmol * Increased renal Mg loss – osmotic diuretics, thiazides and loop diuretics
401
What is the relation between PTH and magnesium?
* Magnesium has calcium-like effects on PTH secretion (1/3 potency) * Increased Mg inhibits PTH * Deceased Mg stimulates PTH (PTH increases rate of reabsorption of Mg) * However profound decreased [Mg] inhibits PTH secretion and action
402
What are the causes of hypermagnesaemia?
* Increased intake (rare unless CRF) * Cellular release * Decreased excretion
403
What are causes of increased intake of magnesium?
* Oral * Parenteral * Antacids * Laxatives * Bladder irrigation * Dialysis
404
What are causes of cellular release of magnesium?
* Cell necrosis * DKA * Hypoxia
405
What are causes of decreased excretion?
* Renal failure * Mineralocorticoid deficiency * Hypothyroidism * FHH
406
What is the treatment for mild hypermagnesaemia?
* 1.5-2.5 mmol/L | * Asymptomatic but can decrease blood pressure
407
What is the treatment for moderate hypermagnesaemia?
* 2.5-5.0 mmol/L * Absent reflexes * ECG changes (prolonged PR, QRS and peaked T waves
408
What is the treatment for severe hypermagnesaemia?
* >5 mmol/L * Respiratory paralysis and cardiac arrest * Mg >8 mmol/L = almost always fatal – inhibition of acetylcholine release
409
What is the flow order of diagnosis for suspected hypermagnesaemia?
* Medication causing hypermagnesaemia – if yes change medication, if no continue * Renal failure – if yes treat renal disease, if no continue * Hypothyroidism – if yes treat hypothyroidism, if no continue * Addison’s disease – if yes treat Addison’s disease, if no possibly hypocaloric hypercalcaemia
410
What are the causes of hypomagnesaemia?
* Inadequate intake/absorption * Malabsorption * Renal tubular dysfunction * Intracellular shift
411
What are the causes of inadequate intake/absorption in hypomagnesaemia?
* Alcoholism * Protein calorie malnutrition * Prolonged infusion or ingestion of low Mg solution or diet
412
What are the causes of malabsorption in hypomagnesaemia?
* IBD (diarrhoea) * Proton pump inhibitor (omeprazole) * Gluten enteropathy (diarrhoea) * Intestinal bypass/fistula * Radiation enteritis * Laxative abuse
413
What are the causes of renal tubular dysfunction in hypomagnesaemia?
* Alcoholism * Hyperaldosteronism * Hyperparathyroidism * Hypoparathyroidism * Nephrotic drugs (cisplatin, ciclosporin, gentamicin, FK506) * Diuretics * Osmotic diuresis * Rare familial disorders
414
What are the causes of intracellular shift in hypomagnesaemia?
* Post MI * Post parathyroidectomy * Recovery from DKA * Refeeding * Acute pancreatitis
415
What systems are affected as a consequence of hypomagnesaemia?
* Neuromuscular * GIT * Neurological * Biochemical * Cardiovascular
416
What are the neuromuscular consequences of hypomagnesaemia?
* Tremor * Muscle weakness * Twitching * Cramps * Arrythmia
417
What are the gastrointestinal consequences of hypomagnesaemia?
* Anorexia * Nausea * Vomiting
418
What are the neurological consequences of hypomagnesaemia?
* Apathy * Depression * Agitation * Confusion * Delirium * Convulsions * Coma
419
What are the biochemical consequences of hypomagnesaemia?
* Hypokalaemia | * Hypocalcaemia
420
What are the cardiovascular consequences of hypomagnesaemia?
Arrythymia (secondary to hypokalaemia)
421
What is the serum magnesium reference range for hypomagnesaemia?
<0.5 mmol/L
422
Most patients with hypomagnesaemia will also have what other low molecule?
Albumin - only 25% have low ionised magnesium
423
What is the reference range of normal urinary magnesium (uMg)?
2-7 mmol/24hrs
424
What is the calculation of uMg fractional excretion of Mg?
FEMg (%) = (uMg x plasma creatinine)/((0.75x plamsa magnesium)x urea creatinine)X 100
425
What does FEMg >2% mean?
Renal magnesium wasting
426
How would magnesium deficit be determined?
* Combine urinary Mg fractional excretion with Mg infusion test * UMg <0.7mmol/24hrs = inadequate intake or malabsorption
427
What is the flow of diagnosis for suspected hypomagnesaemia?
* Medication causing hypomagnesaemia – if yes change medication, if no continue * Magnesium moving from ECF to ICF – if yes treat cause, if no continue * Urinary magnesium excretion – if normal consider GIT losses, if high consider renal losses
428
When should hypomagnesaemia be treated?
* Ventricular tachycardia * Hypokalaemia unresponsive to K supplements * Neurological symptoms * Diuretic therapy (stop/change) * Hypocalcaemia unresponsive to Ca supplementation * Asymptomatic hypomagnesaemia
429
What should hypomagnesaemia be treated with?
* IV MgSO4 in saline or dextrose for symptomatic deficiency * Requires repeat treatment over several days * Oral supplements where suitable
430
When calcium levels are too high or too low, which body systems is primarily affected?
Nervous system
431
What is likely to be released when blood calcium levels are elevated?
Calcitonin
432
An individual with very low levels of vitamin D presents themselves to you complaining of seemingly fragile bones. explain how these might be connected
Vitamin D is required for calcium absorption by the gut. Low vitamin D could lead to insufficient levels of calcium in the blood so the calcium is being released from the bones. The reduction of calcium from the bones can make them weak and subject to fracture
433
Describe the effects caused when the parathyroid gland fails to respond to calcium bound to its receptors
Under “normal” conditions, receptors in the parathyroid glands bind blood calcium. When the receptors are full, the parathyroid gland stops secreting PTH. In the condition described, the parathyroid glands are not responding to the signal that there is sufficient calcium in the blood and they keep releasing PTH, which causes the bone to release more calcium into the blood. Ultimately, the bones become fragile and hypercalcaemia can result
434
When blood calcium levels are low, what does PTH stimulate?
The activity of osteoclasts
435
What can result from hyperparathyroidism?
Fractures
436
Describe the role of negative feedback in the function of the parathyroid gland
The production and secretion of PTH is regulated by a negative feedback loop. Low blood calcium levels initiate the production and secretion of PTH. PTH increases bone reabsorption, calcium absorption from the intestines and calcium reabsorption by the kidneys. As a result, blood calcium levels begin to rise. This, in turn, inhibits the further production and secretion of PTH
437
Explain why someone with a parathyroid gland tumour might develop kidney stones
A parathyroid gland tumour can prompt hypersecretion of PTH. This can raise blood calcium levels so excessively that calcium deposits begin to accumulate throughout the body, including the kidney tubules, where they are referred to as kidney stones
438
What happens to the total serum calcium values when blood is drawn from a patient who is supine?
Lowered compared to a patient in an upright position
439
What does the renal system include?
* Kidneys * Ureter * Bladder * Urethra
440
What are the roles of the renal system?
* Critical homeostasis of electrolytes and acid-base status * Excretion of waste * Endocrine role * Degradation/synthesis of hormones such as insulin and aldosterone
441
What is the primary role of the renal system?
Homeostasis to maintain composition of the blood and interstitial and intracellular fluids
442
What does the excretory function of the kidney get rid of?
* Non-protein nitrogenous compounds | * Excess inorganic substances ingested in the diet
443
What non-protein nitrogenous compounds are excreted by the kidneys?
* Urea * Creatinine * Uric acid
444
What excess inorganic substances that are ingested in the diet are excreted by the kidneys?
* Sodium * Potassium * Chloride * Calcium * Phosphate * Magnesium
445
What is the functional unit of the kidney?
Nephron
446
What is the anatomy of the nephron?
* Bowman’s Capsule containing Glomerus * Proximal convoluted tubule * Proximal straight tubule * Loop of Henle descending * Loop of Henle ascending * Ascending thick limb * Macula densa * Distal convoluted tubule * Connecting tubule * Cortical connecting duct * Outer medullary collecting duct * Inner medullary collecting duct
447
What are the 4 stages of urine formation?
* Filtration * Reabsorption * Secretion * Excretion
448
What occurs in filtration stage of urine formation?
Distal tubule collects a filtrate from the blood containing water and low Mr solutes
449
What occurs in reabsorption stage of urine formation?
Reclaims valuable substances from the filtrate returning them to the body fluids
450
?What occurs in secretion stage of urine formation
Toxins and excess ions, for example, are secreted into the distal tubule
451
What occurs in excretion stage of urine formation?
Urine leaves the system and the body
452
What are the features of urine formation?
* Useful metabolites are reabsorbed * Waste products excreted in urine * Continuous process – 99% of filtrate is reabsorbed, approximately 200L per day filtered but only produces 1L of urine * Requires good blood flow and perfusion in kidneys * Renal vascular tone is modulated by multiple mechanisms * Renal hypoperfusion results in renin release * At rest 25% of all cardiac output is to the kidneys
453
What does renal hypoperfusion that results in renin release, trigger?
* Triggers RAA system | * Vasoconstriction, increased blood pressure and increased blood flow to kidneys
454
What are the features of the glomerulus?
* Afferent arteriole brings blood into the glomerulus and efferent arteriole flows blood away * Ultrafiltrate – water and small molecules * Filtrate from blood drain into the bowman’s capsule space * Hypovolaemia detected by kidneys in the juxtaglomerular apparatus * Renin is secreted from this region
455
What is the physiology of the glomerulus?
* Juxtalomerular apparatus * Bowman’s capsule * Proximal tubule
456
What cells are found within the glomerulus?
* Podocytes * Endothelium * Glomerular basement membrane * Mesangium
457
What is the filtrate contents in the proximal convoluted tubule?
* Approximately 70% of Na+ is reclaimed here * Nearly all of K+ is claimed here * HCO3- is reabsorbed here * H+ >90% into urine * Glucose and uric acid are in a Na+ dependant manner * Creatinine is excreted at a constant rate
458
What are the features of the proximal convoluted tubule?
* Most metabolically active region * Contains ion transport channels and pumps * These tubes are “convoluted” to increase length and therefore filtration area
459
What is the renal physiology of the Loop of Henle?
* The concentration of the filtrate is greatly increased as it passes through the Loop of Henle * Water leaves the tubule by osmosis and the filtrate increases in concentration * The ascending loop is permeable to salts but impermeable to water * Water, sodium and urea diffuse out of the collecting ducts into the interstitial fluid * Loss of water = osmotic loop
460
How is the permeability of the ascending Loop of Henle?
Permeable to salts but impermeable to water
461
What are the features of the distal convoluted tubule?
* They are the fine-tuning apparatus * Of 200L plasma filtered/24hrs only 1-2 L of urine is formed * Aldosterone mediates reabsorption of Na+ at distal convoluted tubule via sodium pumps * Leads H+/K+ balance and excreted - critical function in acid-base homeostasis * Urine then passes into collecting ducted
462
How is the permeability of the collecting ducts?
Impermeable to water but can permit reabsorption of solute-free water via ADH regulation
463
What is the endocrine function of the kidneys?
* Erythropoietin into bone marrow * 1,25 Dihydroxycholecalciferol into the gut * Renin to convert angiotensinogen to angiotensin I and angiotensin converting enzyme to convert angiotensin I to angiotensin II * Angiotensin II stimulates aldosterone from the adrenal cortex * Parathyroids release PTH into the kidneys * Post-pituitary releases arginine vasopressin (ADH) into the kidneys
464
How is the renal system involved in controlling acid-base balance?
* Recycling of HCO3 | * Generation of HCO3- and phosphate/ammonia removal of H+
465
How is HCO3- recycled in renal control of acid-base balance?
From the blood into the glomerulus to the renal tubular cell and out into the interstitial fluid – going through molecular changes
466
How is HCO3- generated and phosphate/ammonia removal of H+ in renal control of acid-base balance?
Phosphate from blood into glomerulus filtered with ammonia. H+ from renal tubular cell to glomerulus in exchange for Na+ pulls the bicarbonate buffer equation to the right as H+ is being produced from carbonic anhydrase. Generated HCO3- goes out into the interstitial fluid
467
What type of simple urinalysis is there?
* Physical exam * Chemical exam * Microscopic exam
468
What is the physical exam of simple urinalysis?
Colour and clarity of sample
469
What is the chemical exam of simple urinalysis?
Dipstick
470
What is the microscopic exam of simple urinalysis?
* Cells, bacteria, yeast | * Casts and crystals
471
What does a dipstick test analyse?
* Glucose * Ketones * Bilirubin/urobilinogen * Proteinuria * Haemoglobin * Ph * Nitrites * Leukocyte esterase (pyuria) * Specific gravity
472
What is glucose analysed for in a dipstick test?
Diabetes
473
What are ketones analysed for in a dipstick test?
Ketoacidosis
474
What is bilirubin/urobilinogen analysed for in a dipstick test?
Liver damage
475
What is proteinuria analysed for in a dipstick test?
Kidney function
476
What is haemoglobin analysed for in a dipstick test?
Blood levels in urine
477
What is pH analysed for in a dipstick test?
Renal tubular acidosis
478
What are nitrites analysed for in a dipstick test?
Absent in urine unless bacteria present
479
What is leukocyte esterase (polyuria) analysed for in a dipstick test?
UTI
480
What is specific gravity analysed for in a dipstick test?
Osmolality
481
What measurement on the dipstick test is mandatory in kidney disease classification?
* Protein measurement | * >450 mg/L per 24hrs is usually pathological
482
What are the different types of proteinuria?
* Glomerular * Tubular * Overflow
483
What are the causes of glomerular proteinuria?
* Glomerular * Tubular * Overflow
484
What are the causes of tubular proteinuria?
* Decreased tubular capacity, heavy metals, anoxia – due to low molecular weight protein such as B2M, alkaline phosphatase * Decreased nephron number due to kidney disease – due to low molecular weight protein such as B2M and alkaline phosphatase * Distal tubular damage (secreted proteinuria) – due to Tamm Horsfall glycoprotein
485
What are the causes of overflow proteinuria?
Increased plasma concentration: multiple myeloma, rhabdomylosis – due to Bence Jones protein
486
What is renal proteinuria caused by?
* Damage to nephrons – e.g. inflammation of glomerulonephritis or nephrosis * Need to eliminate urinary tract disease and infections – high protein in urine with infections
487
What can kidney function be affected by in the glomerulus?
* Net pressure across glomerular membrane * Physical nature of the glomerular membrane * Number of functioning glomerular
488
What is the amount of blood getting to the kidneys measured by?
Renal plasma flow (RPF)
489
What is the number of functioning glomerular estimated by?
Glomerular filtration rate (GFR)
490
What can indicate the degree of renal impairment by disease?
RPF and GFR
491
What molecule is used to be able to calculate the renal plasma flow?
Para-aminohippuric acid (PAH)
492
What are the features of PAH in renal plasma flow?
* Injected IV, not produced endogenously * PAH doesn’t affect renal flow in any way * PAH entering the nephron is totally cleared by filtration (20-30%) and secretion (70-80%) * However, PAH clearance is about 90% of total RPF
493
What is the gold standard to produce accurate GFR?
* Inulin (plant carbohydrate) | * Administered by IV – can be “tracked”. Inulin is NOT reabsorbed but the kidneys
494
What is the silver standard to produce accurate GFR?
* 51Cr-EDTA | * GFR can be accurately calculated by clearance of Chromium 51 injected into the blood
495
What is the main issue of accurate GFR?
* Very specialist * Time consuming * Labour intensive * Expensive * Requires urine collection at late time point
496
What is the bronze standard to produce accurate GFR?
* Creatinine * Muscle mass will not rapidly change and creatinine secretion constant * Creatinine is not significantly reabsorbed by the kidneys * Creatinine is ultimately excreted in urine and measured
497
How is creatinine measured?
* Creatinine clearance | * Widely accepted as the standard in measurement of kidney function
498
What is the calculation of GFR?
GFR= (UxV (ml/min))/P
499
How is creatinine clearance done?
* Determine [substrate] in blood vs urine – clearance by kidneys * GFR= (U x V)/P * U is [substance in urine] * V is volume excreted per time unit (ml/min) * P is [substance in plasma] * Corrected against body surface area of 1.73 m2 * Requires timed urine collection
500
How is GFR corrected?
GFR corrected = GFR measured x 1.73/BSA m2
501
What is the reference range of serum creatinine in adults?
60-120 µmol/L
502
What does a progressive rise on serial creatinine measurement, even within the reference range, indicate?
* Declining renal function | * Can be part of the definition of acute kidney injury
503
Does estimated GFR (eGFR) require timed urine collection?
No, only serum creatinine
504
What Cockcroft and Gualt creatinine clearance equation?
• GFRcockcroft = ((140-age) x mass(kg) [x 1.23 if male] [x1.04 if female])/serum creatinine (µmol/l)
505
What is the clinical reference range for males with GFRcockcroft?
90-125
506
What is the clinical reference range for females with GFRcockcroft?
85-120
507
What can cause a decrease in plasma creatinine in the creatinine clearance equation?
* Pregnancy | * Reduced muscle bulk through starvation or steroid therapy
508
What can cause an increase in plasma creatinine in the creatinine clearance equation?
* High meat intake, strenuous exercise * Drug effects (salicylates) * Analytical interference (due to cephalosporin antibiotics) * Renal causes (acute or chronic)
509
Where is urea formed?
Liver from ammonia
510
How is urea released by the liver?
Released by deamination of amino acids
511
What excretes urea?
Kidneys
512
What are plasma urea measurements accepted as?
Giving a measure of renal function
513
How relevant to clinical tests is urea?
* Inferior to plasma creatinine as it is passively reabsorbed through tubules * But when coupled to creatinine, increasing plasma urea remains an indicator of renal impairment
514
What are the causes of low plasma urea?
* Malabsorption/starvation * Liver disease – less production * Water retention associated with SIADH
515
What are the pre-renal causes of high plasma urea?
* Hypovolaemia * Impaired renal perfusion * Congestive heart failure * Haemorrhage * High protein diet * Increased protein catabolism
516
What are the intra-renal causes of high plasma urea?
* Renal failure | * Reduced GFR
517
What are the post-renal causes of high plasma urea?
* Obstruction of urine flow * Benign prostate disease * Bladder blockage
518
What does next generation testing of GFR include?
Cystatin C
519
What is cystatin C?
GFR marker
520
What are some features of cystatin C?
* Produced by all cells * Not reabsorbed * Secreted by kidneys
521
When would cystatin C be a more appropriate choice as an alternative to creatinine measurement?
* Liver cirrhosis * Morbidly obese * Malnourished * Reduced muscle mass
522
What is conducted in a renal test?
* Urinalysis * Proteinuria * Electrolyte panel * Acid-base panel * BUN * Creatinine * Glucose * Cystatin C
523
Why is a urinalysis conducted in a renal test?
* General inspection * UTI * Crystals
524
Why are proteinuria tests conducted in a renal test?
High levels of protein due to kidney damage
525
Why is an electrolyte panel done in a renal test?
Check for kidney function in relation to Na+, K+, Cl- and HCO3-
526
Why is an acid-base panel done in a renal test?
* Renal acid-base regulation * pH * acidosis/alkalosis
527
Why is BUN tested in a renal test?
Blood urea
528
Why is creatinine tested in a renal test?
Kidney function - clearance of creatinine from serum to urine
529
Why is glucose tested in a renal test?
Diabetes associated kidney disease
530
Why is cystatin C tested in a renal test?
If available - kidney marker
531
What does BUN stand for?
Blood urea nitrogen
532
What calculations are performed in a renal test?
* eGFR | * Anion gap
533
Where is erythropoietin produced?
Kidneys
534
What does erythropoietin stimulate?
Red blood cell production
535
How does kidney disease affect erythropoietin?
* Causes reduced production of erythropoietin * Fewer RBCs leads to anaemia * Reduced iron following kidney dialysis can impair haemoglobin production causing anaemia
536
What excretes potassium?
Kidneys
537
How does kidney disease affect potassium?
* Reduces potassium excretion leading to hyperkalaemia | * Can lead to cardiac arrythmias
538
How does kidney disease affect vitamin D?
Lowers vitamin D activation
539
What is the knock-on effect of lowered vitamin D activation by kidney disease?
* Lower calcium absorption * Hypocalcaemia which causes PTH release * PTH stimulates bone demineralisation to replace calcium in the blood making bones brittle (renal osteodystrophy)
540
In impaired renal function, what type of causes are there?
* Pre-renal * Renal * Post-renal
541
What are the pre-renal causes of impaired renal function?
* Reduced renal blood flow due to drop in blood pressure * Overstimulation of ADH/RAA system * Renal blood flow (congestive heart failure)
542
What are the renal causes of impaired renal function?
* Acute kidney injury or chronic kidney disease | * Reduced GFR
543
What are the post-renal causes of impaired renal function?
* Outflow obstructions anywhere in the renal system * Stones, prostate causes, various genitourinary cancers * Blockage may progress to actual kidney damage
544
Where can the outflow obstructions in the renal system occur in post-renal causes of impaired renal function?
* Ureter * Bladder * Urethra
545
What is acute kidney injury (AKI) also known as?
Acute tubular necrosis
546
What is the mortality of AKI if uncomplicated?
5-10%
547
What is the mortality of AKI if complicated?
50-70%
548
What are the pre-renal causes of AKI?
* Dehydration * Haemorrhage * Diarrhoea * Sepsis * Cardiac failure
549
What are the intra-renal causes of AKI?
* Drugs * Nephropathy * Many kidney related diseases * Embolism/thrombosis * Injury/accident (myoglobin)
550
What are the post-renal causes of AKI?
* Bladder obstruction * Fibrosis * Benign/malignant bladder or prostate cancer
551
What is the treatment for AKI?
* Surgical if blockage * Electrolyte management to correct biochemical abnormalities * Renal replacement therapy
552
What are the stages of AKI?
* Oliguric phase (initial stage) * Diuretic phase (clinical improvement) * Recovery stage (not always)
553
What occurs in the oliguric phase of AKI?
* Urine has high osmolality (mainly Na+) * Hyponatraemia – water retention due to low GFR * Metabolic acidosis which can lead to hyperkalaemia (can be life threatening) * High plasma creatinine and urea * Daily measurements of plasma creatinine, Urea and K+ required
554
What occurs in the diuretic phase of AKI?
* Urine volume increases but plasma [creatinine] and [Urea] do not * Plasma [K+] falls * Urine [Na+] and [K+] may increase and electrolyte replacement is required
555
How much urine is in the oliguric phase of AKI?
<400 ml due to reduced GFR
556
How is AKI managed?
* Ensure that there is no renal blockage * IV fluids (balancing electrolytes) * Close eye on acid-base levels * Diuretics – furosemide a loop diuretic
557
What is the management of persistent AKI?
* Control sodium in diet * Examine fluids and nutrition * Renal replacement therapy
558
Is AKI reversible?
Yes
559
Is chronic kidney disease (CKD) reversible?
No
560
What does CKD indicate?
Decrease in functioning nephrons which leads to impaired filtration
561
What are the causes of CKD
* Hypertension * Diabetes * Glomerular disease * Polycystic kidney disease * Kidney stones * Toxic neuropathy (drugs)
562
How is hypertension and the kidney linked?
• Fluid and salt retention lead to increased blood pressure which is activated by the RAA system
563
What is usually an additional worry with hypertension and CKD?
Renal artery stenosis
564
What is the impact of CKD as it progresses?
* Inability to regenerate HCO3- (leads to metabolic acidosis) * Loss of the ability to excrete H+ (leads to metabolic acidosis)
565
What does advanced CKD lead to?
* Hyperkalaemia | * End-stage renal disease – eventual loss of reserve function with a need for dialysis or kidney transplant
566
What is overworking caused by in CKD?
In the early stages of CKD, the remaining functioning nephrons workload is increased to compensate for the loss of nephrons
567
What is the GFR clinical reference range for CKD?
<60 ml/min for >3 months
568
How many stages are there of CKD?
5
569
What are the 5 stages of CKD?
1) Kidney damage with normal or increased GFR 2) Kidney damage with mild decrease in GFR 3) Moderate decreased GFR 4) Severe decreased GFR 5) Kidney failure
570
What are the practical complications of reduced GFR?
* Anaemia – iron deficiency * Blood pressure increases * Calcium absorption decreases * Dyslipidaemia/heart failure/volume overload * Hyperkalaemia * Hyperparathyroidism * Left ventricular hypertrophy * Metabolic acidosis * Malnutrition
571
What is nephrotic syndrome?
Destruction of the filtration membrane of nephrons
572
What is the primary cause of nephrotic syndrome?
* Inflamed * Damaged glomerulus – glomerular nephritis * Renal transplant rejection
573
What does chronic glomerular nephritis do to the filtration membrane?
Causes it to thicken
574
When does acute glomerular nephritis often occur?
1-3 weeks after a severe bacterial infection
575
What are the secondary causes of nephrotic syndrome?
* Diabetes mellitus * Drugs * Heavy metals * Hypothyroidism * Hypertension
576
What is nephrotic syndrome characterized by?
* Large proteinuria >0.5 g/24hrs (x5 normal) * Hypoalbuminemia * Oedema (water retention)
577
What is diabetic nephropathy?
* Progressive kidney disease caused by damage to the capillaries in the kidney glomeruli * Later stage disease leads to increased proteinuria * Chronic hyperglycaemia has been implicated with nephropathy
578
What percentage of diabetics may develop diabetic nephropathy?
30-40%
579
When is kidney damage more likely in diabetic nephropathy?
``` When one or more of the following is present: • Poor control of blood glucose • High blood pressure • Type 1 diabetes mellitus • A family history of kidney disease ```
580
What can help with diabetic nephropathy?
ACE inhibitors
581
How is renal tubular disease acquired?
Can be inherited or acquired
582
What do renal tubular diseases affect?
Proximal or distal tubules
583
What is renal tubular acidosis (RTA)?
Syndrome due to either a defect in proximal tubule bicarbonate reabsorption, or a defect in distal hydrogen ion secretion, or both
584
How many types of renal tubular diseases are there?
4
585
What is type I renal tubular disease?
Defective hydrogen ion secretion in distal tubule
586
What is type II renal tubular disease?
Absorption of HCO3 in the proximal tubule is reduced
587
What is type IV renal tubular disease?
HCO3 reabsorption in the renal tubule impaired as a consequence of aldosterone deficiency
588
What is hepato-renal syndrome?
* The development of renal failure in patients with advanced chronic liver disease * Kidneys are histologically normal and functioning (no tubular necrosis) * Severe vasoconstriction of the blood vessels of the kidneys
589
What is the main theory of hepato-renal syndrome?
* The liver controls intestinal blood flow, drop in pressure leads to decreased blood flow to the kidneys – activation of RAA system * But cannot outcompete liver effects
590
What is the biochemistry of hepato-renal syndrome in patients with cirrhosis?
* Low urine flow * Increasing creatinine * Urea is common
591
What happens to the condition when the patient has a liver transplant?
It is reversed
592
How high is the risk of death with hepato-renal syndrome?
Very high
593
What might environmental chemicals and poisons do to the kidneys?
Injure kidney by increasing large blood flow and filtration
594
What do heavy metals do to the kidney?
Such as mercury and cadmium, target the kidney after glutathione/cysteine conjugation
595
How do paraquat or diquat (weed killers) damage the kidney?
Damage the kidney via production of reactive oxygen species (ROS)
596
What does low solubility of poisons such as ethylene glycol metabolites do to kidneys?
Causes crystal formation within tubular lumen and nephrotoxicity
597
How are electrolytes managed in CKD?
* Prevent sodium overload (restriction/diuretics) | * Control hyperkalaemia
598
How is diet managed in CKD?
* Restrict protein intake * Limit lipids and restrict non-complex CHO * Restrict potassium
599
How are drugs managed in CKD?
* Administer vitamin D, calcium and iron supplements | * Erythropoietin
600
When is dialysis used for patients with CKD?
If ESKD
601
What are some inherited kidney disorders?
* Polycystic kidney disease * Alport syndrome * Inherited Tubulopathology
602
What are the features of polycystic kidney disease?
* Enlargement of kidneys and cyst formation * Autosomal dominant polycystic kidney disease most common * It effects 1:400 – 1:1000 births * PKD1 and PKD2 gene mutations
603
What are the features of Alport syndrome?
* Genetic mutation in collagen genes found in glomerular (COL4A5) * It effects 1 in 5,00-10,000 people
604
What are some inherited Tubulopathology disorders
* Dents disease - defects in proximal tubule * Bartters syndrome - Loop of Henle defects * Gitelmans syndrome - distal tubule
605
What is ESKD?
* When kidneys can no longer support life | * Kidneys require assistance
606
What stage of CKD will enter ESKD?
Most stage 5 patients
607
What is the typical GFR for ESKD?
<15 ml/min
608
What therapy is used in patients with ESKD?
Renal replacement therapy
609
What are some diuretics used to treat ESK?
* Carbonic anhydrase inhibitors * Loop or high-ceiling diuretics * Thiazide and thiazide-like diuretics * Potassium-sparing diuretics * Osmotics
610
What is the site of action of carbonic anhydrase inhibitors?
Proximal convoluted tubules
611
What is the site of action of Loop or high-ceiling diuretics?
Thick ascending limb (Loop of Henle)
612
What is the site of action of thiazide and thiazide-like diuretics?
* Thick ascending limb (Loop of Henle) | * Distal tubules
613
What is the site of action of potassium-sparing diuretics?
* Distal tubule | * Collecting duct
614
What is the site of action of osmotics?
* Proximal tubule * Loop of Henle * Collecting tubule
615
What is the mechanism of action of carbonic anhydrase inhibitor?
* Inhibition of renal carbonic anhydrase | * Decreases HCO3- reabsorption
616
What is the mechanism of action of Loop or high-ceiling diuretics?
Inhibition of the luminal Na+/K+/2Cl- reabsorption
617
What is the mechanism of action of thiazide and thaizide-like diuretics?
Inhibition of sodium reabsorption
618
What is the mechanism of action of potassium-sparing diuretics?
* Inhibition of Na and H20 reabsorption (competes with aldosterone) * Blockade of Na+ uptake at the luminal membrane
619
What is the mechanism of action of osmotics?
* Decrease Na and H2O reabsorption * Decease medullary hypertonicity * Elevated urinary flow rate
620
When should renal replacement therapy be done?
* Pulmonary oedema – fluid overload * Severe/persistent hyperkalaemia * Severe acidosis * Renal system can no longer fully support patients’ needs * Other major complications such as pericarditis or neuropathy
621
What is renal replacement therapy?
* Haemodialysis through peritoneal dialysis and hemofiltration * Renal transplantation
622
What are the types of dialysis?
* Haemodialysis | * Peritoneal dialysis
623
What are the features of haemodialysis?
* Artificial membrane (dialysis tubing) * Blood and dialysis solutions * Small molecules diffuse from blood into rinsing fluid * “cleansed” blood returned to patient
624
What are the features of peritoneal dialysis?
* Permanent catheter * Membrane is now the peritoneal membrane * Place rinsing fluid into peritoneal cavity * Discard fluid every 6 hours
625
What does the type of dialysis depend on?
Patient condition and choice
626
What are the features of a renal transplant?
* Ideal solution, providing donor can be found * Restores renal function * Requires lifelong immunosuppression * Immunosuppressants can be nephrotoxic * Must monitor and routinely check creatinine levels
627
What is used as immunosuppressants for renal transplants?
Cyclosporin or tacrolimus
628
What is autocrine?
Cells releases hormone that acts on the same cell
629
What is an example of an autocrine hormone?
Numerous growth hormones
630
What is paracrine?
Cell releases hormone that acts on the adjacent/local cell
631
What is an example of a paracrine hormone?
Nuerotransmitter
632
What is endocrine?
Cell releases hormone into circulation with a systemic effect on cell types at a distant site
633
What are some examples of endocrine hormones?
* Insulin | * Cortisol
634
What are types of stimulus in hormone function?
* Humoral * Hormonal * Neuronal
635
What is an example of humoral?
* Ions | * Nutrition
636
What does hormonal do?
Hormone that acts on another hormone
637
What is an example of neuronal?
Nervous system - adrenaline
638
What is the action of hormones?
* Affect growth and development * Homeostatic control of metabolic pathways * Regulate production, use and storage of energy
639
What are hormones?
* Signalling molecules produced by glands * Regulate many processes * Tightly regulated by positive and negative feedback
640
What is the endocrine system defined as?
The collection of glans that produce hormones that can regulate metabolism, growth of tissues, reproduction, mood, sleep, and most physiological responses
641
What type of hormones are there?
* Water soluble | * Lipid soluble
642
What are the three general classes of water-soluble hormones?
* Amines * Peptide/protein hormones * Eicosanoids
643
What are amine hormones derived from?
Amino acids
644
What are peptide/protein hormones derived from?
Amino acids
645
What are eicosanoids derived from?
Arachidonic acid
646
What are some examples of amine hormones?
* Epinephrine (adrenaline) | * Dopamine
647
What are some examples of peptide/protein hormones?
* Antidiuretic hormone (ADH) * Insulin * Growth Hormone (GH) * Adrenocorticotrophic hormone (ACTH) * Follicle stimulating hormone (FSH) * Luteinizing hormone (LH) * Thyroid stimulating hormone (TSH) * Renin
648
What is an example of eicosanoids?
Prostaglandins
649
How are water soluble hormones present within the body?
Freely available
650
Where are water soluble hormones situated?
ECF
651
What is the action of water-soluble hormones?
* Does not enter cell * Binds to cell surface receptor – G protein-coupled receptor (GPCR) * Triggers a signal cascade
652
What is a lipid soluble hormone?
* Broad class of compounds with the same basic structure * Hydrophobic * Either natural or synthetic * Need a carrier molecule to move
653
What is the same basic structure that all lipid soluble hormones have?
Common 4 aromatic ring structure
654
What are the types of steroid lipid soluble hormones?
* Glucocorticoids * Mineralocorticoids * Oestrogens * Androgens * Progestogens
655
What are some examples of glucocorticoids?
* Cortisol | * Dexamethasone – synthetic used to treat some inflammatory conditions
656
What is an example of a mineralocorticoid?
Aldosterone
657
What is an example of oestrogens?
Oestrogen
658
What is an example of androgens?
Testosterone
659
What is an example of progestogens?
Progesterone
660
How is water and lipid soluble hormones transported in the blood?
* Water soluble hormones circulate freely | * Lipid soluble hormone are bound to a transport protein
661
What type of receptor does water soluble hormones interact with?
Cell surface receptor
662
What type of receptor does lipid soluble hormones interact with?
Internal receptor
663
What is the exception to the rule with water and lipid soluble hormones?
* Some water-soluble hormones can interact with internal receptors * Some lipid soluble hormones can interact with cell surface receptors
664
What are the features of nuclear hormone receptors?
* Non-membrane bound receptors form a complex with hormones in the cytoplasm * This complex is transported into the nucleus where it directly binds DNA * Hormone/receptor complexes activate gene transcription
665
What is the main precursor hormone?
Cholesterol
666
What are the main enzymes in converting hormones?
* 17α-hydrolase * 21-hydrolase * 11β-hydrolase * 5α-reductase * Aromatase
667
Which converting enzyme of hormones occurs in the mitochondria?
* Cholesterol side-chain cleavage enzyme * 11β-hydrolase * Aldosterone synthase
668
Where does the converting of the hormones mainly take place?
Smooth endoplasmic reticulum
669
What happens if the converting enzymes for hormone production are deficient?
Hormones won't be produced
670
What is the HPA axis?
Hypothalamus, anterior pituitary gland, and the adrenal cortex
671
What does the HPA axis do?
Controls and coordinates the endocrine system through secretion of inhibitory, releasing, and trophic hormones
672
What is the generic mechanism for controlling/inhibiting production of too many hormones?
Negative feedback
673
How might the secretion of anterior pituitary and hypothalamic hormones be inhibited?
By the circulating hormones, whose release they stimulate
674
What are trophic hormones?
Hormones which target other endocrine glands
675
What are the higher centres of the brain responsible for?
* Speech * Emotion * Consciousness * Awareness * Feelings * etc
676
What can impact on hormone production?
Heightened states such as stress, anxiety, euphoria, and fear
677
Where is the hypothalamus located?
At the base of the brain, just below the thalamus
678
How is the hypothalamus linked to the pituitary gland?
* Infundibulum also known as the pituitary stalk | * It is a hypothalamic channel
679
What is the main function of the hypothalamus?
* To respond to homeostatic changes * Maintain homeostasis * Stimulate the pituitary gland
680
What hormones does the hypothalamus produce?
* Thyrotropin Releasing Hormone (TRH) * Gonadotrophin-Releasing Hormone (GnRH) * Growth Hormone Releasing Hormone (GHRH) * Growth Hormone Inhibiting Hormone (GHIH) * Corticotrophin-Releasing Hormone (CRH) * Dopamine
681
What does Thyrotropin Releasing Hormone (TRH) stimulate in the anterior pituitary gland to release?
* Thyroid Stimulating Hormone (TSH) | * Prolactin (PRL)
682
What does Gonadotropin Releasing Hormone (GnRH) stimulate the anterior pituitary gland to release?
* Luteinising Hormone (LH) | * Follicle Stimulating Hormone (FSH)
683
What does Growth Hormone Releasing Hormone (GHRH) stimulate the anterior pituitary gland to do?
Release Growth Hormone (GH)
684
What does Growth Hormone Inhibiting Hormone (GHIH) stimulate the anterior pituitary gland to do?
Inhibit Growth Hormone (GH)
685
What does Corticotrophin-Releasing Hormone (CRH) stimulate the anterior pituitary gland to release?
Adrenocorticotrophic hormone
686
What does dopamine stimulate in the anterior pituitary gland to do?
Inhibit prolactin releasing factor (PRL)
687
What are the hormones that the anterior pituitary gland releases?
* Adrenocorticotrophic Hormone (ACTH) * Follicle stimulating Hormone (FSH) * Luteinising Hormone (LH) * Growth Hormone (GH) * Thyroid Stimulating Hormone (TSH)
688
What hormones are released from the posterior pituitary gland?
* Antidiuretic Hormone (ADH) | * Oxytocin
689
How is ADH and oxytocin activated for synthesis?
Activated by osmoreceptors
690
Where is antidiuretic hormone (ADH) synthesised?
Supraoptic nucleus
691
Where is oxytocin synthesised?
Paraventricular nucleus
692
How is the posterior pituitary gland stimulated?
Neurological signals are passed down the nerve axons of the supraoptic and paraventricular nucleus into the posterior pituitary
693
What is the role of oxytocin in the body?
Reproduction
694
What is oxytocin medically used for?
To induce uterine contraction -> labour
695
Why is oxytocin known as the happy hormone?
Pregnancy amnesia - forget the stress associated with giving birth
696
What is the target organ of adrenocorticotrophic hormone?
Adrenal cortex
697
What is the action stimulated on the adrenal cortex by adrenoocorticotrophic hormone?
* Glucocorticoid synthesis | * Pigmentation
698
What is the target organ of follicle stimulating hormone?
* Ovary | * Testis
699
What is the action stimulated by the ovaries by the follicle stimulating hormone?
* Oestrogen synthesis | * Oogenesis
700
What is the action stimulated by the testis by the follicle stimulating hormone?
Spermatogenesis
701
What is the target organ of growth hormone?
* Liver | * Other
702
What is the action stimulated on the target organ by the growth hormone?
IGF-1 synthesis - liver only
703
What is the target organ of luteinising hormone?
* Ovary | * Testis
704
What is the action stimulated on the ovaries by luteinising hormone?
* Ovulation | * Progesterone synthesis
705
What is the action stimulated on the testis by luteinising hormone?
Testosterone
706
What is the target organ of prolactin?
Breast
707
What is the action stimulated on the breast by prolactin?
Lactation
708
What is the target organ of thyroid stimulating hormone?
Thyroid
709
What is the action stimulated on the thyroid by thyroid stimulating hormone?
Synthesis of thyroid hormone - T3 and T4
710
What is the target organ of antidiuretic hormone?
Kidneys
711
What is the action stimulated on the kidneys by antidiuretic hormone?
Osmolality regulation
712
What is the target organ of of oxytoxcin?
* Uterus | * Breast
713
What is the action stimulated on the uterus by oxytocin?
Uterine contractility
714
What is the action stimulated on the breasts by oxytocin?
Lactation
715
When is growth hormone produced?
In pulses during the night/while sleeping
716
What is the role of GH?
* Produce IGF-1 | * Glycogenesis – breakdown of glycogen
717
How does GH and insulin interact?
Antagonistic function with insulin as it inhibits it, preventing insulin induced absorption of glucose to try to regain normal serum [glucose]
718
What does IGF-1 do?
* Stimulates cell growth * Increase protein synthesis * Enhance lipolysis of adipose tissue * Decrease glucose uptake
719
What negatively regulates GH?
IGF-1, which inhibits both the hypothalamus and pituitary
720
What stops the hypothalamus and anterior pituitary gland from producing more hormones when activated by GHRH?
* IGF-1 | * GH – before reaching the liver
721
What glucocorticoids are released under the control of adrenocorticotrophic hormone (ACTH)?
Cortisol from adrenal cortex
722
When is cortisol secreted?
* Secreted in a circadian rhythm | * High at 8am, low at 12pm
723
How is adrenocorticotrophic hormone important in pigmentation?
Stimulates melanocytes to produce melanin
724
What are the functions of glucocorticoids?
* Increase protein concentration * Increase hepatic glycogenolysis * Increase hepatic gluconeogenesis * Permissive effect on water excretion
725
What triggers adrenocorticotrophic hormone?
* Stress * Fear * Illness
726
What stops the hypothalamus and the anterior pituitary gland from producing more hormone when activated by corticotrophin releasing hormone?
Cortisol
727
What stops the hypothalamus and the pituitary gland from producing more hormones when activated by thyrotropin releasing hormone?
* Free thyroid hormones – T3 and T4 | * Main exertion is towards TSH secretion
728
What are gonadotrophins?
* Follicle stimulating hormone (FSH) | * Luteinising hormone (LH)
729
What stops the hypothalamus and the anterior pituitary from producing more hormones when activated by gonadotropin releasing hormone in females?
* Oestradiol | * Progesterone
730
What stops the hypothalamus and the anterior pituitary from producing more hormones when activated by gonadotropin releasing hormone in males?
* Testosterone | * Inhibin
731
What is the process of ovarian follicular development?
* FSH and LH rise and fall in the follicle maturation * They fall in response to rising oestradiol * Once near ovulation LH and FSH rise and oestradiol falls * Once ovulation occurs LH and FSH drop and oestradiol and progesterone rise
732
What produces oestradiol in ovarian follicular development?
* Follicle cell | * Corpus luteum
733
What produces progesterone in ovarian follicular development?
Corpus luteum
734
What produces follicle stimulating hormone in ovarian follicular development?
Follicle cell
735
What produces luteinising hormone in ovarian follicular development?
Follicle cell
736
What can occur if [prolactin] is high?
Can inhibit GnRH in the hypothalamus and LH/FSH in the pituitary - inhibits ovulation
737
What is a feature of prolactin releasing factor?
* It is hypothetical * All other hormones have known positive regulators, none has yet been determined for prolactin * Dopamine is thought to negatively regulate prolactin
738
What are some pituitary disorders?
* Hypopituitarism * Growth hormone deficiency * Acromegaly/Gigantism * Pituitary tumours * Anorexia Nervosa
739
What is hypopituitarism?
* Reduced (or no production) of 1 or more of the pituitary hormones * Can be pronounced in children, less so in adults
740
What are the most common causes of hypopituitarism?
• Pituitary tumours – destructive is hypopituitarism, functional is hyperpituitarism
741
What are the causes of hypopituitarism?
* Hypothalamus disorder * Genetic/congenital * Trauma/haemorrhage * Infection * Surgery * Cerebral tumours * Pituitary tumours
742
What are the symptoms of hypopituitarism?
* Fatigue * Weight loss * Decreased sex drive * Decreased appetite * Facial puffiness * Anaemia * Infertility * Irregular or no periods * Loss of pubic hair * Inability to produce milk for breast-feeding in women * Decreased facial or body hair in mean * Short stature in children * Diabetes insipidus (posterior)
743
What is the relation of GH deficiency with morbidity and mortality?
In adults - significant
744
What are the symptoms of growth hormone deficiency?
* Non-specific – may be asymptomatic * Reduced bone mineral density * Increased risk of bone fractures * Impaired cardiac function * Accelerated cardiovascular disease * Central obesity * Increased insulin sensitivity * Reduced exercise capacity * Emotional disturbances * Decreased quality of life * Reduced life expectancy
745
What are the causes of growth hormone deficiency?
* Pituitary tumours * Surgical/radiation treatment for pituitary tumours * Head injury * Hemochromatosis * Lymphocytic hypophysitis * Sarcoidosis
746
What is anorexia nervosa when the BMI falls below 20 kg/m2?
* The secretion of GnRH often impaired | * Causing low levels of LH, FSH and oestradiol
747
What are the thyroid levels in anorexia nervosa?
* T4 often falls below normal values | * T3 nearly always subnormal
748
What are the cortisol and growth hormone levels in anorexia nervosa?
Often increased because of starvation
749
Can anorexia nervosa be reversed?
Yes, once normal eating patterns and normal weight has been restored
750
What re the features of baseline investigations of growth hormone disorder?
* GH levels are usually undetectable during the day | * IGF-1 is stable so is used as a marker of GH function
751
What is the IGF-1 level that is consistent with GH deficiency?
Low serum [IGF-1]
752
What are the features of glucose administration to measure GH disorder?
* Administering glucose will lead to suppression of GH * Patient fasts for 12hrs and given glucose * GH levels monitored over time to detect excess
753
What does an insulin stress test, test?
HPA axis
754
What are the features of the insulin stress test?
* Induced hypoglycaemia leads to an increase in GH, ACTH, and cortisol * If the hypothalamus or pituitary are affected this will not happen * Emergency glucose must be available in case of hypoglycaemia
755
What is a treatment of hypopituitarism?
Replacement hormone therapy - stimulation of affected pathway
756
If deficient in ACTH what would be the replacemnet hormone?
Hydrocortisone
757
If deficient in TSH what would be the replacement hormone?
Thyroxine
758
If deficient in LH/FSH in males what would be the replacement hormone?
Testosterone
759
If deficient in LH/FSH in females what would be the replacement hormone?
Oestrogen
760
If deficient in GH what would be the replacement hormone?
GH
761
If deficient in ADH what would be the replacement hormone?
DDAVP - desmopressin
762
If deficient in prolactin what would be the replacement hormone?
None
763
Who is the most famous with gigantism?
* Robert Wadlow * Nearly 9 feet tall – 10’9” coffin * Died aged 22 – septic blister on ankle
764
What are the symptoms of acromegaly?
* Pronounced/coarse facial features * Protruding brow and jaw * Enlarged hands and feet * Abnormal height (tall)
765
What percentage of acromegaly cases are due to adenomas of the anterior pituitary gland?
99%
766
What is the biochemistry of acromegaly?
* Increased GH | * Increased IGF-1
767
What is the test used to diagnose acromegaly?
Oral glucose tolerance test (OGTT)
768
What are the features of OGTT?
* Response of plasma [GH] to an oral glucose tolerance test | * Blood samples are taken measuring [GH] and [glucose]
769
In patients with acromegaly what does the OGTT look like?
Plasma [GH] does not fall in response to stimulus of hyperglycaemia - may even increase
770
What does OGTT used to diagnose?
* Diabetes mellitus * Renal failure * Anorexia * Liver disease
771
What is the treatment of acromegaly?
* Surgery to remove adenoma | * Medication
772
What medication is used to treat acromegaly?
* Dopamine agonists * Somatostatin analogues such as octreotide * Pegvisomant
773
What does dopamine agonists do to treat acromegaly?
Can supress GH production (not always effective)
774
What does somatostatin do to treat acromegaly?
* Injection into muscle once a month | * Controls GH release and lead to tumour shrinkage in some people
775
What does pegvisomant do to treat acromegaly?
* Daily injection | * Lowers IGF-1 but not GH
776
What are the three zones of the adrenal cortex?
* Zona glomerulosa * Zona fasciculata * Zona reticularis
777
Where in the adrenal cortex is aldosterone produced?
Zona glomerulosa
778
Where in the adrenal cortex are glucocorticoids produced?
Zona fasciculata and zona reticularis
779
Where in the adrenal cortex are androgens produced?
Zona reticularis and to some extent zona fasciculata
780
Where does adrenaline bind?
Adrenergic receptors – α1, α2 or β
781
Where do beta blockers target?
Adrenergic receptors to tamper down adrenaline
782
What does binding of adrenaline do?
* Activates adrenergic receptors * GPCR receptors * Increases blood pressure, heart rate, constrict blood vessels and pupil dilation * Increased oxygen and glucose to muscles * Fight or flight
783
What enzymes is adrenaline metabolised by?
* Catechol-o-methyl transferase (COMT) | * Mono amine oxidase (MAO)
784
What is the flow of adrenaline metabolism?
* Epinephrine is metabolised by catechol-o-methyl transferase into metanephrine * Metanephrine is metabolised by mono amine oxidase to vanillylmandelic acid
785
In what condition is large amounts of vanillylmandelic acid found?
Neuroblastoma - abdominal swelling
786
What does the mechanism of adrenaline (catecholamine) metabolism prevent?
Prevents negative effects of adrenaline - fear, trembling
787
How is cortisol activated?
* Protein bound to cortisol binding globulin * Binds to glucocorticoid receptor (GR) in the nucleus * Gene transcription * Activating many pathways
788
What percentage of glucocorticoid activity is cortisol?
95%
789
What does glucocorticoid secretion effect?
* Carbohydrate metabolism * Fat metabolism * Protein metabolism
790
What does cortisol do in the liver?
* Stimulates gluconeogenesis * Amino acid uptake * Degradation
791
What are the effects of glucocorticoid secretion?
* Lipolysis is increased in adipose tissue * Proteolysis and amino acid release promoted in muscle * Glucocorticoids are mainly protein bound (90%)
792
What are glucocorticoids chiefly bound to?
Cortisol-binding globulin or transcortin (CBG)
793
What are the three factors that regulate adrenocorticotrophic acid and therefore cortisol secretion?
* Negative feedback control * Stress * Diurnal rhythm of plasma [cortisol]
794
How does negative feedback regulate adrenocorticotrophic acid?
* ACTH release from anterior pituitary is stimulated by hypothalamic secretion of CRH * Increased plasma [cortisol] or synthetic glucocorticoids supress secretion of CRH and ATCH
795
How does stress regulate adrenocorticotrophic acid?
* Sudden large increase in CRH (and ACTH) secretion | * Due to major surgery or emotional stress
796
How does diurnal rhythm of plasma [cortisol] regulate adrenocorticotrophic acid?
Relates to the individuals sleeping/waking cycle
797
What does aldosterone regulate?
* Water * Electrolyte balance * Blood pressure
798
What converting enzyme converts androstenedione to testosterone?
Aromatase
799
What do patients presenting with acute adrenal failure require?
Immediate treatment
800
What samples should be taken with adrenal hypofunction?
* Blood – electrolytes and glucose measurement | * Later plasma [cortisol]
801
What is Addison's disease caused by?
* Destruction of adrenal cortex * Tuberculosis * Idiopathic atrophy * Trauma * Drugs * Infection * Medication (iatrogenic)
802
What is autoimmune Addison's disease caused by?
Adrenal enzyme antibodies block 21-hydroxylase
803
What are most clinical features due to in Addison's disease?
* Lack of glucocorticoids and mineralocorticoids | * Due to cortisol deficiency
804
What are the symptoms of Addison's disease?
* Bronze pigmentation of skin * Changes in distribution of body hair * GI disturbances * Weakness * Weight loss * Postural hypotension * Hypoglycaemia
805
What is the adrenal crisis of Addison's disease?
* Profound fatigue * Dehydration * Vascular collapse (decreased blood pressure) * Renal shut down * Decreased serum [Na] * Increased serum [K]
806
What is hyperpigmentation due to?
* High [ACTH] * No cortisol so pituitary continue to signal ACTH * Caused by melanocyte hormone production
807
How is hyperpigmentation tested?
* Synacthen test (synthetic ACTH) * Inject synthetic ACTH – measure cortisol * If no change this indicates adrenal failure
808
What are the symptoms of Cushing's syndrome?
* Central obesity * Urinary free glucose and cortisol increased * Suppressed immunity * Hypercortisolism, hypertension and hyperglycaemia * Increased corticosteroids * Neoplasms * Glucose intolerance, growth retardation
809
What can hyperfunction of the adrenal cortex lead to overproduction of?
* Cortisol | * Aldosterone
810
What is Cushing's syndrome an overproduction of?
Cortisol
811
What is Conn's syndrome an overproduction of?
Aldosterone
812
What are the clinical features of Cushing's syndrome?
* Women 3x more likely to develop * Prolonged cortisol production and exposure * Obesity * Thinning of skin * Purple striae * Excessive bruising * Hirsutism * Skin pigmentation * Glucose intolerance * Hypertension * Muscle weakness and wasting * Menstrual irregularities * Back pain * Psychiatric disturbances
813
What are the causes of Cushing's syndrome?
* ACTH treatment * Pituitary hypersecretion of ACTH * Adrenal adenoma * Adrenal carcinoma * Ectopic ACTH secretion by tumours
814
What is the main cause of Cushing's syndrome?
Pituitary tumour - approximately 70% of cases
815
What is the difference between Cushing's syndrome and disease?
* Syndrome – excessive medication or tumour leads to excess cortisol by adrenal glands * Disease – cause is pituitary tumour effecting ACTH
816
What is the treatment of Cushing's?
* If drug related withdraw medication slowly * Tumours are surgically removed * Glucocorticoid antagonists/agonists depending on level * In severe cases of tumours removal of entire adrenal glands
817
What is used to diagnose Cushing's?
Dexamethasone - synthetic cortisol
818
How is dexamethasone used to diagnose Cushing's?
* Dexamethasone supresses the secretion of CRH, ACTH, and cortisol * Therefore, cortisol levels fall below 50 nmol/L * Cortisol is metabolised before excretion into urine, high cortisol in urine indicate Cushing’s
819
What is the biochemistry of Cushing's in a diagnostic positive test?
* Serum [cortisol] is increased at 10pm * Urinary [cortisol] is increased * Diurnal rhythm is lost * Plasma [ACTH] is normal or increased * Dexamethasone, high dose is suppressed * CRH increased response
820
What is the biochemistry of adrenal tumour in a diagnostic positive test?
* Serum [cortisol] is increased at 10pm * Urinary [cortisol] is increased * Diurnal rhythm is lost * Plasma [ACTH] is not detectable * Dexamethasone, high dose is not suppressed * CRH no response
821
What is the biochemistry of ectopic ACTH-secreting tumour in a diagnostic positive test?
* Increased serum [cortisol] at 10pm * Increased urinary [cortisol] * Diurnal rhythm is lost * Plasma [ACTH] is often much increased * Dexamethasone, high dose is not supressed * CRH test no response
Clinical Biochemistry
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