26,27,28 Flashcards
Why do we get metabolic acidosis
Increased H+ formation
Acid ingestion
Reduced renal H+ Excretion
Loss of bicarbonate
H+, pCO2 and pO2 in metabolic acidosis
High H+ and pO2
Low CO2
Why do we get metabolic alkalosis?
Generation of bicarbonate by gastric mucosa
Renal generation of HCO3- in hypokalaemia
Administration of bicarbonate
H+, pCO2 and pO2 in metabolic alkalosis
Low H+ and pO2
High CO2
Consequences of metabolic alkalosis
K+ goes into cell and urine
PO4 goes into cells
Get respiratory suppression
Causes of respiratory acidosis
CO2 retention due to:
a) Inadequate ventilation
b) Parenchymal lung disease
c) Inadequate perfusion
H+, pCO2 and pO2 in respiratory acidosis
H+ and CO2 High
pO2 low
Cause of respiratory alkalosis
Increased CO2 excretion due to excessive ventilation producing alkalosis (e.g. fast heavy breathing)
H+, pCO2 and pO2 in respiratory alkalosis
Low H+ and low CO2
High pO2
Why do we get increased H+ formation
Ketoacidosis, diabetic or alcoholic
Lactic acidosis
Poisoning
Inherited organic acidoses
When would we suspect metabolic acidosis
Tiredness and weight loss
What happens in keto-acidosis
Hyperglycaemia
Osmotix diuresis - due to pre-renal uraemia
Hyperketonaemia
Increased FFA
ALL of these lead to acidosis
Two types of lactic acidosis
Type a - shock
Type b - metabolic and toxic causes
Why do we get acidosis in an alcoholic
NAD+ depletino (thiamine)
Thiamine deficiency (which is a pyruvate dehydrogenase Co-factor, hence without it can’t make acetyl-CoA)
Enhanced glycolysis for ATP formation
FFA Made into acetyl-coA which then also produces ketones
Keto-acids secondary to counter-regulatory hormones
Get profuse vommiting
How does high lactate = lactic acidosis
In alkalosis: Increased glycolysis, reduced oxygen delivery due to shift in oxygen dissociation curve, lactate induced vasoconstriction, impaired mitochondrial respiration
OR Oxygen debt due to further anaerobic lactate production causing hyperventilation
What causes reduced H+ Excretion
Renal tubular acidosis
Generalised renal failure
What happens in renal failure
Reduced volume of nephrons
Increased bicarbonate loss, reduced NH4+ excretion
NH4+ to liver for urea + H+ synthesis
Only fraction of NH4+ derived from glutamine (normally approx 100%)
How much co2 do we produce daily
25mol/day
how much unmetabolised acid do we produce a day
50mmol/day
What is normal plasma concentration of acid
40nmol/L
What are the buffering systems
Haemoglobin Bicarbonate Phosphate Protein Ammonia Organic acids
Only Hb and bicarbonate are of real important
What is normal blood pH
7.35 to 7.45
What are the sites for acid base metabolism
Lungs, kidneys, liver, GI
What happens in tissue gas exchange with CO2
Co2 non-polar diffuses into cell
Forms HCO3- and H+
H+ binds with HbO2
Forms H+HB and releases O2 from the cell
What causes a right shift in the oxygen dissociation curve
Increased temperature
Increased 2,3-DPG
Decreased pH (acidosis)
What happens in renal reclamation of bicarbonate
HCO3- is small so gets lost by the kidneys
Na+/H+ pump, pumps Na+ out of the kidney and H+ in
H+ binds with HCO3- –> forms H2) and CO2
CO2 reabsorbed and reforms HCO3-
Renal Regeneration of bicarbonate
Glutamine converted to NH3 and NH4+
NH4+ then excreted –> allows us to excrete more H+
Also HPO4 can be turned into H2PO4- allowing us to remove more H+
Where do mineral corticoids (aldosterone) act on the kindey
Distal tubule
What happens if alkalotic in the distal tubule
K+ lost, H+ retained
What happens if acidotic in the distal tubule
K+ retained H+ lost
Discuss acid/base balance in the GI tract
Stomach excretes acid for digestion
Pancreatic juice contains HCO3- to neutralise the stomach acid
Where is the dominant site for lactate production
The liver
Where is the only site of urea synthesis
The liver
Is acid-base disorders due to the liver common
No as the liver has such an excess capacity for dealing with it
What are protein and amino acids broken down into
Carbon skeleton and NH4+
What is stimulated by alkalosis
NH4+ to NH3 to be lost in the urine
What is inhibited by acidosis
the formatin of H+ and urea
What happens in sever liver failure
Metabolic acidosis
NH4+ toxicity as:
NH4+ and oxo-glutamate can’t be made into glutamine
and
NH4+ and CO2 can’t be made into urea and H+
why do cells need to adapt
due to changes in the environment or the demand
Which cells don’t need to adapt
Fibroblasts - survive severe metabolic stress without harm e.g. oxygen absence
Which cells adapt easily
Epithelial cells
Lable cell population that can adapt easily with an active stem cell population
Highly adaptive
Which cells do not adapt easily
Cerebral neurons
Permanent cell population - terminally differentiated, highly specialised and easily damage
What is physiological adaptation
Response to normal changes
What is pathological adaptation
Response to disease related changes
What happens in hypertrophy
Increased size of existing cells, increased functional capacity, increased synthesis of structural components, increased metabolism
Where does hypertrophy particularly occur
In cardiac and skeletal muscle
Physiological hypertrophy
Utero in pregancy
Marathon runners
Pathological hypertrophy
LV hypertrophy, aortic stenosis, urinary bladder with adenymyotamous hyperplasia of prostate
How to diagnose LV Hypertrophy
Clinical examination, ECG and imaging
Consequences of LV hypertrophy
Ventricular tachycardia, can be so large it can be functionally ischamic
What is subcelular hypertrophy and hyperplasia
Increase in size and number of sub cellular organelles
e.g. hepatocytes due to barbituates (increased P450 enzymes)
What cell populations does hyperplasia occur in
Lable and stable
Physiological hyperplasia
Hormonal
Compensatory (particularly kidneys if one is small)
Pathological hyperplasia
Excess hormones or growth factors
Describe gynocomastia
Increase in male breast size due to increased oestrogen (hyperplasia)
Can be pathological or physiological
What is graves disease
Auto-antibody to TSH receptor
Causes hyperplasia with an enlarged pale thyroid
What is adenymomoatous hyperplasia of the prostate
Hyperplasia of the the prostate which occurs normally as age related
What are hyper plastic nodleuls in the liver
When liver cells try to return back to normal but function is never fully restored
What is atrophy
Reduction in cell size and number
Physiological atrophy examples
Embryogenesis, uterus after pregnancy, menopause (decreased oestrogen decreases the size of the uterus)
Pathological atrophy examples
Deceased work load, loss of innervation, inadequeate nutrition/blood supply/endocrine stimulation
Pressure
What happens in renal artery stenosis
One kidney atrophies due to reduced blood flow
What is hydronephrosis
Increased pressure in kidney due to obstructed bladder outflow causes atrophy
Describe physiological atrophy in the thymus
Very big in child but replaced by fat in the adults
What is sub cellular atrophy
Reduction in the volume of specific cells
What is involution
Physiological atrophy by apoptosis (requires energy)
What is brown pigment
Non-digestible part of the cell membrane
What is ageneis
failure of formation of embryonic cell mass
What is aplasia
failure of differentiation into organ specific tissue
what is dysgenesis
failure of structural organisation of tissue into organs
what is hypoplasia
Failure of growth of organ to full size
Developmental causes of reduced cell mass
Agenesis
Aplasia
Dysgenesis
Hypoplasia
What is significant about dysplasia
Earliest morphological manifestation of multistage neoplasia (irreversible)
Want to try and spot before it invades the basement membrane
What is metaplasia
the transformation of one cell type to another caused by the transdifferentiation of stem cells
Epithelium in vagina
straified squamous
epihtleium in endocervix
squamocolumnar
Describe metaplasia in cervix
In puberty increased oestrogen causes stromal bulk of cervix
The squamocolumnar junction moves into the vagina (cervical ectopic)
Columnar epithelium becomes squamous (squamous metaplasia) due to the acidic vaginal environment
Where does HPV cause cervical cancer
Squamocolumnar junction
What happens to the squamocolumnar junction in menopaure
THE Squamocolumnar junction moves back up the cervix but no metaplasia occurs
Makes screening less effective as the SCJ is in the cervical canal so can’t swab it but cervical cancer is likely to occur here
Pathological metaplasia in the bronci
Smoking causes change from pseudo stratified ciliated to squamous
Pathological metaplasia in bladder urothelium
Urothelium changes to squamous due schistosomiasis, long standing catheter and bladder calculous
Pathological metaplasia in fibrocollagenous tissu
Changes to bone due to chronic trauma
Pathological metaplasia oesophagus
Changes from squamous to columnar due to acid reflux
This is barretts oesophagus - predisposes us to adenomas carcinoma
What is squamous metaplasia in the cervix linked to
CIN and squamous cell carcinoma
What is endometrial hyperplasia due to increased oestrogen linked to
Adenocarcinomas
Common due to obesity as fat cells produce oestrogen
What is parathyroid hyperplasia linked to
Chronic renal failure due to adenoma
What is squamous metaplasia in bronchi linked to
Dysplasia and squamous cell carcinoma
What is squamous metaplasia in the bladder linked to
squamous cell carcinoma
what is glandular metaplasia in the oesophagus linked to
adenocarcinoma
What is a neoplasm
a lesion resulting from the autonomous growth of cells that persist in the absence of the initiating stimulus
cancer from epithelial cells
carcinoma
cancer from connective tissue
sarcoma
cancer from lymphoid or haematopoietic organs
lymphomas/leukaemias
Commonest cancer for mortality
lung cancer
4 main characteristics of tumours
Differentiation
Rate of growth - malignant tumours tend to grow more rapidly
local invasion
metastasis
What is differentiation
the extent that neoplastic cells resemble the corresponding normal parenchymal cells, morphologically and functionally
How differentiated are benign tummours
usually well -differentiated
mitoses rare
how differentiated are malignant tumours
Wide range of differentiation
most exhibit morphological alterations showing malignant nature
What is anaplasia
Poorly differntiated cells in a neoplasm
Do not resemble original cells
likely to be malignant
What is pleomorphism
Variations in size and shape
What is abnormal nuclear morphology
I.e. nuclei too large (normally want a 1:4/1:6 ratio to cytoplasm)
Irregular shape/pattern
Chormosome coarsely clumped along cell membrane (in more malignant tumours)
Hyper chromatin - dark colour
What are mitoses
Indicative of high proliferation
Seen in hyperplasia and cells with high turnovers
Can see trip, quad or multipolar spindles in malignancy
What is loss of polarity
When the cells orientation is disturbed (normally the nucleus is at the bottom of the cell)
Disorganised growth
Grading of differentiation
1 = well differentiated 3= poorly differntiated
Indicative of prognosis
What do some tumours express not normally seen in adults
Some tumours express foetal proteins
What happens in bronchogenic carcinoma
Corticotropin
Parathyroid like hormones
Insulin
Glucagon
Benign tumours local invasion
Adhesive expansile masses
Localised to the site of origin
No capacity to infiltrate, invade or metastasise
What can surround benign tumours
Encapsulation
ECM deposited by stromal cells - activated by hypoxia and from pressure of tumours
Forms a rim around the tumours formed of fibrous tissue
What can surround malignant tumours
Pseudoencapsulation
Usually slow-growing
Microscopically rows of cells are penetrating the margin in a crab-like fashion
Do malignant tumours respect anatomical boundaries?
No
Most penetrate organ surfaces and skin
Surgical resection difference as requires resection of adjacent normal tissue too
What is metastasis
Spread of tumour to sites physically discontinuous with the primary tumour
Generally in malignant
What is metastasis associated with
Lack of differentiation
Local invasion
Rapid growth
Large size
Pathways of metastasis
Direct
Lymphatic
Haematgenous
How does direct seeding occur
Neoplasm penetrates natural open field without physical barriers e.g. peritoneal cavity
BUT can remain confined to surface of peritoneal structures without penetrating e.g. pseudomyxoma peritoneal
What is the most common pathway of seeding
Lymphatic spread
Do tumours have lymphatic channels
NO - lymph vessels are at the tumour margin
Pattern of lymph node involvement follows the route of lymph drainage
Where do breast cancers present lymphatically
Presents in the upper outer quadrant
Affects axillae node first
Then infra and supra clavicular nodes become involved
Significance of axillary node in breast cancer
First site of spread of breast cancer
Determination of axillary node status determines future course of disease and what therapy is most suitable
What is the sentinel node
The first node in regional lymphatic basin that receives lymph flow from the primary tumour
How do we identify sentinel node
Inject radioactivelly labelled dyes
Frozen section during surgery can lead/guide surgeon to appropriate therapy
Are regional barriers good at preventing further tumour dissemination
Usually they are effective
Cells arrest within node - can be destroyed by a tumour specific immune response
Do all enlarged nodes have cancer in?
No - drainage of tumour cell debris and tumour antigens can cause reactive change in nodes
What is haematogenous spread typical of
Sarcomas
BUT not strictly confined to this method
What is lymphatic spread typical of?
carcinoma
BUT not strictly confined to this method
What vessels are more easily penetrated by cancer
Veins due to their thinner walls
Blood borne cells then follow the venous flow draining the site of the neoplasm
Where do metastasis via haematogenous spread usually come to a rest
In the first encountered capillary bed
Commonly Liver (portal circulation) Lungs (caval) most
What are the most frequent sites of haematgeonous spread to
Liver (portal)
Lungs (caval)
What is stroma
The connective tissue framework that neoplastic cells are embedded in
Provides mechanical support, intercellular signalling, nutrition
What is a desmoplastic reaction
Fibrous stroma formation due to induction of connective tissue proliferation by growth factors from the tumour cells
Clinical complications of tumours
Compression
Destruction
Metabolic
Non specific metabolic effects of tumours
Cachexia Wardburg effect Neuropathies Myopathies Venous thrombosis
Compression complications of tumours
Displacement of adjacent tumours
I.e. benign pituitary tumours can compress the pituitary gland obliteration the function causing hypopituitarism
Destruction complications of tumours
Invasion - rapidly fatal if it invades vital structures e.g. arteries
Or mucosal surfaces invaded causeing ulceration e.g. GI leading to anaemia
Metabolic complications of tumours
Well differentiated tumours can retain functional propertios
But thyrotoxicosis in thyroid adenoma
Inappropriate metabolic response in tumours
Called paraneoplastic
I.e. ACTH/ADH in small cell lung cancer
What is the wardburg effect
Produces energy by high rate of glycolysis with fermentation of lactic acid
How do we detect the ward burg fefect
Used in imaging PET scanning (FDG Uptake)
Summary of benign tumours
Well differentiated
Slow rate of growth
No local invasion
No metastasis
Summary of malignant tumours
Variable differentiation
Fast rate of growth
Local invasion
Metastasis
