SUGER Flashcards
1
Q
3 categories of genetic disease
A
Mendelian genetics - single faulty gene (rare)
Complex trait genetics - multiple genes (common)
Somatic genetics - cancer
2
Q
Summarise the human genome project
A
2001 - 90% complete
2004 - 99.7% complete
2011 - found less expected genes (21000), RNA, non-coding sequences, splicing allows more proteins to be coded for, regulatory sequences
2022 - only 5 gaps left
3
Q
Define rare
A
1/2000 (Europe) or 1/1250 (USA)
-> 3 million in UK affected
4
Q
What is ADPKD?
(Autosomal Dominant Polycystic Kidney Disease)
A
= Enlarged kidney with lots of holes
Disease Incidence - 1/500-1000
- Polycystin 1 + 2 genes mainly
-4th most common cause of kidney failure
-Has extrarenal manifestations e.g. intracranial aneurysms, pancreatic cysts, liver cysts etc
Treatment - vasopressin-2 receptor antagonist (ADH inhibitor)
5
Q
What is tuberous sclerosis?
A
Develops kidney cysts, mixed tissue tumours, brain lesions, epilepsy, renal cysts, mental retardation
Very variable expressivity!
2 main genes - TSC1, TSC2
Treatment - everolimus
6
Q
4 Functions of the kidney
A
Endocrine (secreting hormones)
Excreting waste + excess fluid
Maintain balance of salt, water, pH
Filtration + removal of drugs
7
Q
Name the components of the kidneys
A
Cortex - glomerullus, proximal, distal convoluted tubules
Medulla - loop of Henle, collecting ducts
8
Q
How much renal blood and urine flow per minute?
A
(Cardiac output ~ 5L/min)
Renal blood flow = 1.25L/min
Urine flow ~ 1ml/min
9
Q
Describe arteries in kidneys
A
Renal -> Interlobar -> Arcuate -> Interlobular -> Afferent -> Glomerular -> Peritubular
10
Q
How is juxtaglomerular specialised?
A
Contains macula dense and modified layer of afferent arteriole (increased smooth muscle , granules containing renin and acts as barometers to decreased change in bp)
11
Q
What are the 2 mechanisms for intrinsic auto regulation of the kidneys?
A
Tubuloglomerular feedback- macula dense release prostaglandins to reduce NaCl and activate renin-angiotensin system
Moygenic mechanism - increased bp stretches vessel wall = triggers contraction and increases resistance so lowers bp. Vice versa
= Maintains GFR and excretion of water/waste
12
Q
What are the 3 layers of glomerulus filtration barrier?
A
Capillary endothelium
Basement membrane
Foot processes of podocytes
(Fluid from blood to Bowman’s capsule to form filtrate)
13
Q
What 5 factors determine filtration (of glomerullus)?
A
- Pressure (Hydostatic>osmotic)
- Size of molecule < 10kDa
- Charge of molecule (-ve harder to pass)
- Rate of blood flow (slow allows more)
- Binding to plasma proteins e.g. ca, thyroxine (protein/albumin don’t normally pass)
14
Q
Define glomerular filtration rate
A
= Filtration volume per unit time (120ml/min)
(Kf is filtration coefficient)
15
Q
What 3 factors is GFR determined by?
A
- Net filtration pressure (Back flow due to constriction of efferent increases vice Vera)
- Permeability of filtration barrier
- Surface area
16
Q
How does sympathetic innervation affects GFR?
A
Strong sympathetic to arterioles = constrict = decrease renal blood flow = decrease GFR
Important in bleeding, shock ..
17
Q
How is GFR measured?
A
(NOT measured directly)
Marker = filtered freely, not metabolised/absorbed/secreted
= creatinine (natural)
= Cystatin C
= Inulin infusion
18
Q
Define renal clearance
A
All plasma that is filtered of marker
= 125ml/min (=GFR)
Clearance = urine conc x volume
——————————
Plasma conc
19
Q
Describe the function of proximal tubules
A
Actively reabsorbs all glucose, amino acids, phosphate, HCO3
Na gradient generated by Na/K ATPase
Metabolically active - lots of mitochondria
Vulnerable to hypoxia(low O2) and toxicity(filtering toxins)
20
Q
What is renal glycosuria disorder?
A
Sodium glucose transporters (SGLT2) is defect so glucose is not reabsorbed in proximal tubules = sugar in urine
SGLT2 inhibitor used for treating type 2 diabetes, heart failure and Chronic kidney disease
21
Q
What are aminoacidurias disorders (e.g. cystinuria)
A
Renal basic amino acid transported (rBAT) is defect so amino acid is not reabsorbed = clumps of AA= cystine crystals and kidney stones form
Treatment
= High fluid intake - High urine flow
= Alkaline urine - increases solubility
= Chelation - binds to cystine
22
Q
What is hypophosphataemic rickets?
A
Commonest form is XLH
Zinc dependent metalloprotease (PHEX) defect means phosphate cannot be reabsorbed = passed out
Treatment = phosphate replacement
23
Q
Describe bicarbonate reabsorption in proximal tubules
A
H20 + CO2 form carbonic acid and splits via carbonic anhydrase to form H+ and HCO3- in tubular cells
H+ is exchanged with Na+ in tubular lumen
Na+ and HCO3- move into the blood from the tubular cells
24
Q
What is proximal renal tubular acidosis (type 2)
A
Na/H anti Porter between tubular cell and lumen is defected = Bicarbonate is not reabsorbed
Treatment = supplementation
25
What does a defect in carbonic anhydrase affect?
= Mixed proximal / distal renal tubular acidoses
Inhibited by acetazolamide (mild diuretic and induces metabolic acidosis)
Also used to treat altitude sickness
26
What is the Fanconi syndrome?
All solutes not reabsorbed in proximal tubules may be due to Na/K ATPase failure
27
What is the function of the loop of Henle?
Generates medullary concentration gradient
= ascending actively reabsorb Na+ and cl- in but is impermeable to water so lumen osmolality decreases.
= Water from permeable descending limb moves into lumen
= continuous flow pushes hyperosmotic fluid to ascending limb.
Also voltage dependent ca2+ and Mg2+ absorption
28
What is Barters syndrome?
Defect in Na+/K+/Cl- transporters in ascending limb of loop of Henle = salt wasting
Treatment = block Na+ transporters due to Na+ overload
29
Describe the functions of distal tubule and collecting ducts
Fine tuning of Na+, K+ reabsorption and acid-base balance.
Collecting ducts mediates water reabsorption (principal cells) + acid secretion (intercalated cell)
30
Name some distal tubular and collecting ducts disorders
Gitelmans syndrome
Distal (type 1) renal tubular acidosis
Hyperaldosternosim
Type 4 renal tubular acidosis
Nephrogenic diabetes insipidus (failure of water reabsorption)
Liddle’s (More Na+, less K+ absorption due to mutation)
31
Describe different pathways for fall in bp
Aorta: baroreceptors increase sympathetic to increase HA and vasoconstriction
Kidney: JGA secretes renin which convert angiotensinogen to angiotensin 1->2. Causes vasoconstriction and releases aldosterone
32
Describe actions of aldosterone
(Steroid hormone acts on transcription)
Clings onto Na+ and exchanges it for K+ or carbonic acid
= more Na+ in blood so more water
33
What is distal (type 1) renal tubular acidosis?
H+ATPase or H+/K+ ATPase defect in distal/collecting ducts so failure of urinary acidification
(Due to high aldosterone)
34
What is glucocorticoid remediate aldosteronism?
Too much aldosterone
Treatment = ATCH suppressors stops producing aldosterone
35
What is Liddell syndrome?
Mutated epithelial Na+ channels so constant aldosterone effect
36
What is syndrome of apparent mineralcorticoid excess?
Cortisol not broken down so activates mineralcorticoid receptors
37
What is hyperkalaemic distal (type 4) renal tubular acidosis
Low aldosterone levels due to reduced electrochemical gradient
38
What is nephrogenic diabetes insipidus?
Vasopressin 2 or Aquaporin 2 channels defect so water is not reabsorbed = very dilute urine
39
Acidosis vs Alkalosis
Acidosis - makes blood more acidic
Alkalosis - makes blood more alkaline
40
Consequences of acidosis vs alkalosis
Acidosis - Hyperkalaemia, bone growth disorder, neurological, arrhythmia etc
Alkalosis - Hypokalaemia, myocardial depression, tetany etc
41
Factors affecting pH
CO2 conc
Intrinsic (metabolic products)
Extrinsic acid (diet, toxins)
Buffers (HCO3-)
42
Give 3 forms of the Henderson-Hasselbalch equation
pH = pKa + log([A-]/[HA])
pH = pKaH2CO3 + log([HCO3-]/[H2CO3])
pH = 6.1 + log([HCO3-]/0.03xpCO2)
43
Describe Stewart’s strong ion principle
pH and HCO3- are dependent variables governed by:
pCO2
Weak acid (ATOT) conc
Strong ion difference (SID) - Na+, K+ e.g.
44
What do we measure in ABG?
pH
pCO2
pO2
HCO3-
Base excess
45
What is standard bicarbonate?
Affected by both respiratory and metabolic so measure acid-base.
Standardised at temp 37, 5.3kPa pCO2
46
What is base excess?
Quantity of acid required to return pH to normal under standard conditions
(Negative in acidosis)
47
Describe metabolic acidosis
= Renal failure, HCO3- loss, H+ retention
= Low pH, HCO3-, CO2
Sighing respirations, tachypnoea
Hyperventilating to increase CO2 output
Long term - muscle wasting, growth retardation
48
How can we investigate acid-base disorders?
Anion gap = [Na+] + [K+] - [Cl-] - [HCO3-]
= difference between anions - and cations +
Normal = 10-16
49
Disorders with high anion gap
Renal failure
Lactic acidosis
Ketoacidosis
Acid ingestion
50
Disorders with normal anion gap
Diarrhoea
Renal tubular acidosis
Urinary diversion
51
Describe metabolic alkalosis
Causes - alkali ingestion, GI acid loss (vomiting), Renal acid loss
= Hypoventilation and renal bicarbonate excretion
= High pH, HCO3-, CO2
52
Describe respiratory acidosis
CO2 retention (hypoventilation, COPD) leads to increased carbonic dissociation
Causes - any respiratory failure
= Increased renal H+ excretion and HCO3- retention
= Low pH, High HCO3-, Co2
53
Describe respiratory alkalosis
CO2 depletion due to hyperventilation, hypoxia
Causes - type 1 respiratory failure, anxiety
= increased Renal bicarbonate loss, H+ retention
= High pH, Low HCO3-, CO2
54
Where do renal and genital systems develop from? (Embryology)
The intermediate mesoderm form metanephric tissue (genital) and gonad tissue (renal)
55
What are the 3 stages of kidney development?
(Cranial to caudal)
1. Pronephros forms and regresses at week 4 (non-functional)
2. Meseonephros- appears week 4, regresses in females but persists in males = vas deferents
3. Metanephros - week 5 (definitive kidney)
56
Describe the mesenephros stage
Excretory tubules develop (to bowman’s capsule) with capillaries (to glomerulus)
(Collecting duct called the mesonephric duct)
Gonad starts to develop
Females - all degenerate
Males - tubules = duct of testes
Mesonephric duct = vas deferens
57
Describe the metanephros stage
Definitive kidney develops in pelvic region and functions at week 12 gestation
58
What does ureteric bud develop to?
Grows out from the mesonephric duct and covered by cap of metanephric tissue.
Bud grows into renal pelvis -> major and minor calyx and Collecting tubules
59
What does the metanephric bud develop to?
Development promoted by cell clusters and renal vesicles
= forms nephrons
60
Why is the ureteric bud and metanephric tissue dependent of each other?
They signal each other to continue developing
61
Do foetal kidneys ascend or descend in utero?
Ascend
62
What is it called if kidneys don’t develop?
Renal a genesis
(Unilateral if one not developed or bilateral if two)
If signalling between ureteric bud and metanephric tissue fails so nephrons and collecting ducts don’t develop
63
Horseshoe vs pancake kidney
H - Lower poles of kidneys fuse
P - Both upper and lower poles fuse medially
Usually asymptomatic
64
Is polycystic kidney disease genetic or environmental?
Genetic (autosomal / recessive)
Cysts form large kidneys
65
How do polar arteries form?
As kidneys ascend lower vessels normally regres.
However these vessels persist = polar
66
Describe development of the bladder
Cloaca = common terminal cavity for urogenital system and gut
Urorectal septum tissue grows down and separates urogenital sinus and anal canal.
67
What does the urogenital sinus form?
1. Upper part = bladder
2. Pelvic part = urethra
3. Phallic part = penile urethra in males/ vestibular vagina in females
68
Describe development of the ureter
Ureteric bud and mesonephric duct connect to bladder wall
(Ureteric bud forms ureter)
69
Double vs ectopic ureter anomalies
D - ureteric bud splits early
E - development of two ureteric bud (one enters urethra, vagina or epididymis)
70
Describe embryology of the pancreas
At junction of forest and midgut, 2 pancreatic ducts are generated and fuse to form a pancreas
Exocrine functions begin after birth
Endocrine functions from 10-15 weeks
71
What does the pancreas consist of?
Small clusters of glandular epithelial cells
98-99% = acini cells- manufacture and secrete fluid digestive enzymes in the pancreatic juice (exocrine)
2-3% = Islet cells - manufacture and release peptide hormones (endocrine)
72
Name 3 types of cells in islets of langerhans
Beta - secrete insulin (51 amino acids)
= glucose uptake, lipid + protein synthesis
Alpha - secret glucagon (29 aa)
= glycogenolysis, gluconeogenesis, lipolysis
Delta - secret somatostatin (inhibitor)
73
Describe insulin secretion in the Beta cells
GLUT2 transporters uptake varies with the glucose concentration outside.
Phosphorylated by glucokinase to glucose 6-phosphate
Rate of glycolysis is increased
ATP generated closes KATP channel, stopping efflux of K+
depolarises the membrane, opening voltage-dependent Ca2+ channels, allowing influx of calcium
This triggers insulin exocytosis from primed secretory granules
74
Describe structure of insulin
Pro insulin is released
Contains A chain (21) and B chain (30 amino acids) is joined by C peptide
(If C peptide not present = not made body)
75
Describe biphasic insulin release
B- cells sense rise in glucose and rapid release of stored products
Second phase response is slower and releases newly synthesised hormones
= Exocytosis of GLUT4 vesicles, increases glucose transporters in the cell membrane and rapid uptake of glucose
76
What is normal blood glucose levels?
~5mmol/mol
Short term response - glycogenesis/ glycogenolysis
Long term response - lipogenesis/ gluconeoenesis
77
Where are glucose sensors?
Primary - pancreatic islets
Also in medulla, hypothalamus, carotid bodies
Sensory cells in gut wall stimulate insulin increase = incretins
78
What do incretins cause and how do we turn it off?
Gastric delaying stimulates insulin release
DPPIV turns off incretins and prevents hypoglycaemia
79
What is diabetes?
A disorder characterised by hyperglycaemia
Type 1 - mutation means K+ channels don’t close so insulin isnt released
Type 2 - insensitivity to insulin
80
What is the genital ridge?
= ridge of mesenchyme + epithelium
(Develops from intermediate mesoderm)
81
What do primordial germ cells do (PCGs)?
Migrate to genital ridges in week 6 and crucial for gonads to develop + forming primitive sex cords.
82
What happens to primitive sex cords in males?
Continue to develop and form Sertoli cells + germ cells (to form testis cords) + leydig cells (produces testosterone at week 8)
83
What happens to primitive sex cords in females?
Primitive sex chord regresses and cortical cord develops instead. These divide and surround germ cells = primordial follicle
84
What is an indifferent gonad?
Sex is determined at fertilisation but gonad is identical in males and females until week 7.
= two pairs of ducts (mesonephric + paramesonephric)
85
What does SRY stand for?
Sex Coding region on Y chromosome
86
Describe male differentiation of gonads at week 7
Sertoli cells release Anti-mullerian hormone = paramesonephric duct regresses
SRY = testes develop
Testosterone = forms vas deferens
87
Describe female differentiation of gonads at week 7
Less understood
Absence of SRY, but WNT4 gene for ovarian development
Oestrogen = female differentiation and paramesonephric ducts develop
88
Describe development of mesonephric ducts in males
Duct opens into prostatic urethra = ejaculatory duct
Prostate develops around ejaculatory duct and seminal vesicles develop from vas deferens
89
Describe development of paramesonephric ducts in females
Upper parts = form uterine tubes
Caudal parts fuse = form uterus, cervix, upper vagina
Urogenital sinus = lower vagina
Growth of sinovagial bulbs = lumen develops
90
What is atresia?
Lower vagina doesn’t form if sinovial bulbs don’t develop
91
How does oestrogen influence female external genitalia
Genital tubercle = clitoris
Urethral folds = labia Minorca
Urethral groove = vestibule
Genital swelling = labia majors
92
How does testosterone influence male external genitalia
Genital tubercle = glans
Urethral folds = fuse to form penile urethra
Genital swellings= scrotum
93
What are produced in the testes?
Spermatozoa by seminiferous tubules
Testosterone by leydig cells
94
Describe the structure of the testes
Covered by extension of peritoneum = tunica vaginalis
White fibrous capsule = tunica albuginea
Septa divides testes into compartments containing seminiferous tubules which drain into rete testis. Leydig cells lay between tubules.
Sertoli cells promote sperm development and separate it from immune system = blood brain barrier
95
Why is scrotum outside the body?
Testicular thermoregulation is necessary since sperm is produced at lower than body core temperatures
(Arteriole blood cools as it descends)
96
Why does meiosis occur?
To keep chromosome number constant after fertilisation from generation to generation
(= 4 haploid cells prevents polyploidy)
Also increases genetic variability and chromosomal combinations
97
Type A vs type B cells in spermatogenesis
A - mitosis and remains outside blood-testis barrier
B - differentiate into primary spermatocytes and pass BTB to enter lumen. Meiosis 1 = secondary spermatocytes. Meiosis 2 = spermatids
98
What is spermiogenesis
Transforms spermatids (haploids) into spermatozoa (sprouts tail and discards cytoplasm to become lighter)
99
Difference between male and female gamete production
Male - mass production but not perfect process (75million in an hour)
Female - 1 egg per month per perfect
100
What is the blood testes barrier formed from?
Sertoli cells (if not present = infertile)
101
How long does spermatogenesis take?
64 days
102
Describe the hypothalamo-pituitary-testicular axis
Hypothalamus produces GnRH
-> Anterior pituitary gland release FSH (so Sertoli cells inhibit HP) and LSH (so leydig cells produce testosterone= inhibits)
= For spermatogenesis
103
Describe the structure of a spermatozoon
Head
Tail
104
Describe spermatic ducts
Efferent ductules
- 12 small ciliated ducts from rete teste
Epididymis
- 6m long tube site of maturation and storage on (fertile for 40-60 days)
Vas deferens
- from scrotum to bladder
Ejaculatory duct
-from vas deferens and seminal vesicles to urethra
105
Describe composition of semen
10% sperm
30% prostatic fluid
60% seminal vesicles fluid
(Fructose, fibrinogen e.g.)
106
Describe the menstrual cycle
1. Hypothalamus- GnRH to AP
2. Anterior Pituitary- FSH (matures follicles in ovary and thickening of uterus)
3. Oestrogen released (thickens endometrial and causes LH release)
4. Anterior pituitary- LH (causes ovulation at day 14)
5. Empty follicle releases progesterone= endometrium stays thick
107
Describe fallopian tube cells
Keep spermatozoa alive for 5 days
108
What is capacitation?
Spermatozoa need to stay near egg or female tract for some time before they gain the ability to fertilise the oocyte.
109
Describe fertilisation
Proteins in Zona-pellucida (surrounds oocyte)
ZP1 attaches sperm
ZP2 reacts acrosome
ZP3 allows head to penetrate
= Through perivitelline space and binds to cortical granule (stops any more sperm entering Zona-pellucida)
= Surge of Ca2+ activates genome
= Male and female pronucleus develop and fuse to form a zygote. (Day 1)
= Mitosis + specialisation so blastocyst leaves Zona-pellucida
110
Describe day 1 fertilisation
(Just outside ovary)
Oocyte activation triggered by sperm protein PLCz = releases Ca2+
= syngamy (pronucleus fuse)
111
Describe day 2 of fertilisation
Moves through fallopian tubes
After 24 hours, ooplasm divide into blastomeres (cleavage)
112
What is embryonic genome activation?
Before day 3 = mother genes do work
After day 3 = fathers genes do work
113
Describe day 3 of fertilisation
= totipotent cells
114
Describe day 4 of fertilisation
Cells flatten, tight junctions form, polarisation of outer cell
115
Describe day 5 of fertilisation
= Pluripotent cells
Cavity expands and fluid fills
116
Describe day 6 of fertilisation
Blastocyst expands and causes embryo to hatch from ZP
= implanted into uterus
117
Energy requirements pre implantation vs blastocyst
Pre = pyruvate (simple)
B = glucose (complex)
118
Describe the 3 stages of embryo implantation
1. Apposition - Unstable adhesion + orientates
2. Attachment - stronger adhesion
3. Invasion- penetrates endothelium
119
What is Human Chorionic Gonadotropin?
hCG sustains early preganacy by repelling immune cells of mother to protect the foetus
(Levels used to test pregnancy)
120
What is the Barker Early Origins Hypothesis?
Small baby body size = greater risk of cardiovascular disease, 2 diabetes, stroke, hypertension
(Due to poor nutrition in womb)
Large baby body size = greater risk of cancer
121
Some ethical complications of IVF
Multiple pregnancy risks
Increased incidence of disorders in IVF babies that wouldn’t have been able to be passed down in normal birth.
122
Describe the hypothalamus-pituitary-gonad feedback loop
Hypothalamus release GnRH to anterior pituitary
Pituitary gland releases FSH and LH to ovaries
Ovaries release estrogen (activates cycle) and progesterone (inhibits cycle) to thicken endometrium of uterus.
123
Describe meiosis in females
Meiosis 1:
Starts in utero before week 12 and arrests at metaphase 1
Resumes by LH surge at puberty
Meiosis 2:
Arrested at metaphase 2 until fertilisation
124
Oogenesis vs spermatogenesis
O - in utero Meiosis 1 = polar body + primary oocyte
Meiosis 2 = polar body + secondary oocyte
S - 2 meiosis cycles in puberty = 4 spermatocytes
125
What is gonadal dysgeneses?
Anomaly of primary sex development due to missing or extra sex chromosome
126
Before vs after puberty
B - Low pulse amplitude of GnRH and low levels of FSH, LH and sex steroids
A - Increase amplitude and levels
(Influenced by many other factors)
Precococious puberty due to lesions, tumours, hypothyroidism etc
127
What is normal body pH?
pH 7.35 - 7.45
[H+] 45- 35 nmol/L
128
How is body pH managed?
Lugs mediate CO2
CO2 + H2O = H+ + HCO3-
Kidneys excrete acid and reabsorbed bicarbonate
Also diet of acids and lactate
129
What is urine pH?
pH 4.5 (min) - 8
130
What is the urinary buffer?
Alkaline Phosphate
131
Describe movement of ammonia buffer
Responsive to acid load
NH3 synthesised from glutamine and diffuses into lumen at proximal tubules. Add H+ to form NH4+ and reabsorbed at loop of Henle or collecting ducts.
132
Where in the kidney is Erythropoietin formed?
Peritibular cells in interstitial space of renal cortex
(O2 sensitive)
133
Can renal compensation occur?
Yes - very fast, but never overcompensates
(Many renal conditions can happen at the same time)
134
What is incontinence?
Unintentional passing of urine
(Failure to bladder store or void)
135
Name 3 bladder storage incontinence problems?
Stress - Leak when coughing due to weak sphincter
Urge - Leak with urgency due to bladder detrusor overactivity
Mixed - both
136
Name 2 bladder void incontinence problems
Overflow - continuous dribbling due to retention
Total - complaint of continuous leakage e.g. due to fistula
137
What is needed for normal urinary tract function?
Storage - low pressure
(Sphincter active)
Emptying - periodic urine expulsion
(Detrusor muscle active)
138
Describe neural control of lower urinary tract
(Young and old can’t control)
Pelvic = Bladder contraction
Hypogastric = Bladder relaxation
Pudendal = External sphincter control
139
Describe bladder filling
Hypogastric nerve - sympathetic (NorE) on,
Pelvic nerve - parasympathetic (M2,3) off
Pudendal - voluntary sphincter on
140
Describe bladder storage reflex
Distention produces low bladder afferent firing.
Triggers guarding reflex = sympathetic and pudendal
141
Describe bladder voiding reflex
Intense bladder afferent firing in pelvic nerve triggers spinobulbospinal reflex = To PAG in brain.
This turns PMC on = parasympathetic outflow and inhibits sympathetic + pudendal
142
Name some LUTS symptoms
High frequency
Nocturnal (wake up multiple time)
Urgency
Hesitancy
Slow flow
143
Conservative management of incontinence
Weight loss
Avoid triggers: smoking, coffee
Pelvic floor muscle excercise
Containment exercise
Bladder re-training
144
What % of cardiac output do kidneys receive?
20-25%
145
Proximal vs distal tubules
P = bulk absorption (leaky)
D = fine tuning (impermeable)
146
Describe posterior pituitary
Hormones vasopressin (antidiuretic) and oxytocin (labour and suckling stimulates milk ejection) Produced in hypothalamus, transported down nerve axons and stored in posterior pituitary
147
Anterior vs posterior pituitary
A - formed from glandular tissue
P - formed from neuro tisssue (glial cells)
148
Describe function of vasopressin
Regulates water balance:
Water ingestion decreases plasma osmolality = cells hydrated and no thirst so vasopressin decreases. Water intakes decreases and renal water increases (osmolality decreases)
149
What is max urine concentration?
1200Osm/L
150
How does vasopressin work?
Vasopressin bind to receptors and activate cAMP second messenger. This increases Aquaporin2 water channels into membrane = more water absorbed into the blood.
151
When is vasopressin released?
Osmoreceptors in hypothalamus detect change in osmolality, basoreceptors detect bp change.
Increases stimulation so anterior pituitary release V1, posterior pituitary releases V2, V3.
152
Vasopressin 1 vs 2 vs 3
1 - Vasoconstriction, platelet aggregation, glycogenolysis
2 - AQP2 channels reabsorb more water
3 - Acts on anterior pituitary to release ACTH
153
What is diabetes insipidus?
Extreme thirst, high Na+ and high urine
= Stopped producing ADH or kidney can’t sense vasopressin
= high Na+ means more water should be reabsorbed but
= Inability to concentrate urine
154
What is SIADH (Syndrome of antidiuretic hormone secretion)
ADH being produced when it shouldn’t be
= Concentrated urine, low osmolality, low plasma Na+, high Na+ excretion
155
How many layers in the skin?
3:
Epidermis
Dermis
Subcutis
156
What is the largest organ of the body?
Skin
(3.6kg, 2m squared)
157
Describe functions of epidermis
Tight cell junctions of stratum granulosum, stratum corneal and oil layer form waterproof barrier
Vit D synthesis
Immune function
Uv protection
Thermoregulation
158
Describe function of dermis
Thermoregulation
Vit D synthesis
Sensory organ
159
Describe function of subcutis
Thermoregulation
Endocrine
Vit D storage
Energy reserve
Shock absorber
160
Why does skin wrinkle when wet?
Sympathetic nervous system causes vasoconstriction in dermis to improve grip
161
Why does skin wrinkle after death?
Washerwomen’s change due to water logging (has laid in wet for long time) so epidermis sloughs away
162
How is skin a physical barrier?
Stratified squamous epithelium helps resist abrasive force
Fat in subcutis acts as shock absorber
163
How does skin synthesise Vit D?
7-dehydrocholestrol present in plasma membranes of epidermal keratinocytes and fibroblasts is converted to (cholecalciferol) previtamin D3 by UV(B).
= Stored in subcutis or diffuse into bloodstream in dermis
164
How is skin an endocrine organ?
Androgens acts on follicles and sebaceous glands (spotty)
Vit D3 synthesis
Thyroid acts on dermal fibroblasts, follicles etc (dry)
MSH increases skin pigments
Hormones in sebocytes and dermal adipocytes convert DHEA to androgens
Dermal fibroblasts form IGFBP-3
165
How is skin a barrier to ultraviolet?
UV A is most common (B is shorter and directly damages)
Can burn, kill, photo-age collagen, DNA damage and suppress immune Langerhan cells.
166
What does skin colour depend on?
Melanin
Carotenoids (from vegetables)
Oxy/deoxyhaemoglobin
167
Describe synthesis of melanin
Synthesised in melanocytes from tyrosine (by melanosomes)
Transported to keratinocytes
= Photoprotective of UV
Two types:
Pheomelanin (red/yellow constant in everyone)
Eumelanin (brown/black vary)
168
Do different skin colours have same conc of melanocytes?
Yes - same conc melanocytes, different conc melanin
(However varies in different body sites)
169
How does skin respond to sunlight?
Immediate pigment darkening = photooxidation of melanin
Photodegredation = generates reactive oxygen species which kills cells
= increases release of melanin (delayed tanning)
= increases histamine release (vasodilation + swollen = sunburn)
170
How is skin a barrier to function?
Granular layer keratinocytes secretes cytokines which recruite immune cells to site.
Also peptides synthesised have antimicrobial properties
171
How is skin a sensory organ?
Merkle cells (basal epidermis) for light touch
Encapsulated mechanoreceptors in dermis - pressure, touch
Myelinated and unmyelinated sensory nerve endings - pain, itch, temperature
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How does skin regulate body temperature? (37degrees)
Subcutaneous fat
Cutaneous blood flow (sympathetic cholinergic = vasodilation)
1-3L per hour Eccrine sweating
Hair
Piloerection (goosebumps by sympathetic adrenergic fibres)
Metabolism
Evaporation, radiation, convection, conduction etc
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How is skin an energy store?
Subcutaneous fat
White adipose connective tissue
174
How are sexes determined?
Migration of primordial germ cells from dorsal endoderm to urogenital ridge week 6-8 and development of bipotential gonad.
- Presence of SRY gene on Y chromosome = testes differentiation week 9
- Absence = ovaries week 11-12
175
What affects sex differentiation?
Adrenal and germ cells develop from the same tissue and hormones affect sex differentiation
176
Which hormone factors differentiate female week 11-12
WNT4
RSP01
FOXL2
(Suppresses formation of testis)
AMH (stabilises mullerian duct)
Lack of testosterone (regresses wolffian duct)
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Which hormone factors differentiate males
SRY + SOX9 differentiate testis
AMH (sertoli cells -> mullerian regressions week 7)
Testosterone + DHT (leydig cells release week 8)
178
What does DSD stand for?
Disorder of Sex Develeopment
179
What is the adrenal glands regulated by?
Hypothalamic-pituitary-adrenal axis
(CRH - ACTH - Cortisol -> Androstenedione)
180
46, XX DSD vs 46, XY DSD
XY= Mineralocorticoid excess, sex hormone deficiency, glucocorticoid deficiency (female genitalia turn to male)
XX = opposite
181
How many patients with DSD have a definitive diagnosis and why is this dangerous?
Only 40-50%
Carriers a risk of malignancy
(Also fertility problems, urological, sexual function, social and cultural circumstances)
182
Why measure growth in children?
Sensitive and early indication of health with adequate nutrition and emotionally supportive environment
183
Describe the infancy-childhood-puberty model
2-4yrs - rapid but decelerating growth determined by nutrition
4-11yrs - hormonal dependence with height velocity
11-15yrs - growth and height velocity spurt due to GH and sex hormones
Growth ends with fusion of epiphyses due to oestrogen in girls and boys (convert testosterone to oestrogen in fatty tissue)
184
Name some determinants of growth
Parental phenotype + genotype
Quality + duration of pregnancy
Nutrition
Psycho-social environment
Growth promoting hormones + factors:
Leptin - regulates appetite
Adrenarche - maturation of adrenal gland
185
All growth disorders originate from or affect the…
Growth plate (chondrogenesis)
186
Regulators of growth
Nutrition
Extracellular fluids
Inflammatory cytokines
Endocrine signals
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Regulation of growth hormone secretion
GHRH: Growth Hormone Releasing Hormone (regulated by food, sleep, steroids)
SST: Somatostatin
Released from hypothalamus affects release of GH from anterior pituitary
-> Liver releases IGF-1
-> Opposite to insulin effect on growth plate and cortical bone
All a negative feedback loop
188
Where is GH synthesised?
40-50% anterior pituitary synthesised by somatroph cells
(Most abundant hormone)
Pulsation secretion max at night
189
Influences on GH secretion
Stimulation: Exercise, stress, fasting, high protein meals, puberty, hypoglycaemia
Suppression: hypothyroidism, aging, high carbohydrate meals
190
Definitive signs of puberty
(Don’t significantly fertility)
Girls - Menarche (first period)
Boys - first ejaculation
191
Describe development of secondary sexual characteristics
Girls:
Oestrogen and androgens develop breasts, pubic hair and genitalia
Boys:
Testicular androgens develop genitalia, pubic hair, voice deepening
192
Precocious vs delayed puberty
Precocious- onset of secondary sexual characteristics before 8(girls), 9(boys)
= risk of brain tumour
Delayed - absence by 14(girls), 16(boys) may lead to reduced peak bone mass and osteoporosis
193
What is the hypothesis for puberty start?
Increased stimulatory glutamate and kisspeptin
Decreased inhibitory GABA and opioids
->Increase in hypothalamic GnRH
194
Primary vs secondary/tertiary hypogonadism
Primary (gonads) - Hypergonadotrophic hypogonadism (too much GnRH)
Secondary/ tertiary (pituitary/hypothalamus) - hypogonadotrophic hypogonadism (not enough GnRH)
195
Describe a healthy skin barrier
Cells full of natural moisturising factor containing acids.
Filaggrin breaks this down to keep surface at a low pH 5.
Protease inhibitors and low pH stop degratory proteases from breaking down corneodesmosomes (holds skin cells together)
Low pH enhances lipid processing enzymes
= Irritants bounce off skin and water is retained
196
Why are babies more at risk of developing atopic dermatitis?
Have a thinner skin barrier (layer)
-> Also why face is mostly affected
197
What happens in genetic predisposition to atopic dermatitis
Mutation means no filaggrin breakdown NWMF so surface pH increases.
This reduces lipid processing enzymes and degradatory proteases break down corneodesmosomes
198
How do skin and detergents break down skin barrier?
Raise surface pH
199
How does atopic dermatitis progress
Genetic predisposition - Environmental triggers - Allows irritants through skin
200
Describe some environmental triggers for atopic dermatitis
Raises pH:
Saliva, breast milk
Bed bug faeces
Food penetration through skin
201
Can inflammation of skin causes depression?
Yes
202
Define hormones
Substance secreted directly into the blood by specialised cells to bind specific receptors and influence cellular reactions
203
Name some endocrine glands
Hypothalamus
Pituitary
Thyroid
Parathyroid
Adrenal
Pancreas
Ovary / Testes
204
Name other endocrine organs
Heart
Liver
Skin (fat)
Kidney
Intestines
205
What are hormones synthesised from?
Steroid - cholesterol
Peptides - Amino acids (tyrosine)
Thyroid - tyrosine in thyroglobulin forms thyroxine (T4)
206
Which hormones bind to surface vs Intracellular receptors?
Surface - peptide
Intracellular - steroid, thyroid
(Deiodinases form T3 from T4)
207
How to measure hormones?
Bioassays
Immunoassays
Mass spectrometry
208
What are the anterior pituitary hormones?
Glycoproteins:
TSH - thyroid hormone synthesis
LH - ovulation
FSH - egg/ sperm development
Polypeptides:
Prolactin- breast milk production
GH - growth
ACTH - regulation of adrenal
209
What are posterior pituitary hormones?
ADH - Water regulation
Oxytocin - breast milk expression
210
Describe blood supply to anterior pituitary
Hormones released into portal venous circulation from hypothalamus
(No arterial supply)
211
Function of hypothalamus
Homeostasis + primitive functions e.g. appetite, thirst, sleep, Temperature
Controls endocrine via pituitary
212
Hypothalamus hormones
Thryotropin (TRH) - TSH
Corticotropin (CRH) - ACTH
Gonadotropin releasing hormone - LH/FSH
GH releasing hormone (GHRH) - GH
Somatostatin - inhibits GH
Dopamine - inhibits prolactin
213
Effect of ACTH
(Stress, cytokines, diurnal (when awake) -> CRH -> ACTH)
Causes adrenal glands to release cortisol
(negative feedback on CRH and ACTH)
214
Effect of growth hormone
Pulsation released through life
Stimulated by low glucose, sleep, exercise
= Protein synthesis, lipolysis, glycolysis, cartilage growth
215
Effect of thyroid stimulating hormone
Controls how much energy the body uses
216
Effect of LH and FSH in females
LH stimulates ovulation
FSH stimulates development of follicles (during ovulation)
217
Effect of prolactin
Synthesised by lactotrophs
Inhibited by tonic release of dopamine
Essential for lactation and suppresses GnRH therefore decreased LH/FSH
218
Pituitary tumours cause:
Pressure on local structures
E.g. optic chasm = bitemporal hemianopia
Pressure on pituitary - hypopituitarism
Functioning tumour e.g. Cushing
Chronically nerve damage etc
219
Describe some pituitary diseases
Hyperprolactinaemia - due to tumours, less dopamine
Benign pituitary adenoma
Craniopharyngioma - benign tumour
220
Excess pituitary hormones lead to:
ACTH - increased cortisol (Cushing’s disease)
GH - Acromegaly
LH/FSH - misgivings stop periods
TSH - thyrotoxicosis
Prolactin - galactorrheoea, prolactinomas
221
Deficiency of pituitary hormones (hypopituitarism) lead to:
GH - reduced linear growth
LH/FSH - hypogonadism
ACTH - adrenal insufficiency
TSH - hypothyroidism
222
Adrenal medulla vs cortex synthesis
Cortex - Effect of ACTH =
(Zona glomerulosa) mineralocorticoids - aldosterone
(Zona fasiculata)
Glucocorticoid - cortisol
(Zona reticularis)
adrenal androgens - DHEA
Medulla- Catecholamines
223
Describe cortisol structure
Cholesterol precursor
3 cyclohexane rings
1 cyclopentane ring
224
Classification of steroids
21 carbons = progesterone, corticoid
19 carbons = androgens
18 carbons = oestrogen
225
Glucocorticoid function
Permissive function so that other hormones can work
Important in homeostasis and stress
- increase glucose mobilisation
- Maintenance of circulation
- Dampens immune response
(Act on most tissue)
226
Transport of glucocorticoids
90% bound to CBG
5% bound to albumin
5% free - only one available
During inflammation, CBG decreases so more % free cortisol available
227
Define stress
Sum of the body’s response to adverse stimuli
E.g. infection, trauma, haemorrhage, exercise, medical illness
228
Describe effect of aldosterone
In collecting ducts, diffuse into cells and acts on nucleus to transcript Na+K+ATPase. So more Na+ and water is reabsorbed
229
Is endocrine salt loss primary or secondary adrenal insufficiency?
Primary = low Na+, high K+ in plasma
230
Describe adrenal androgens
Weak generated by adrenal gland.
Precursor of oestrogen and regulated by ACTH
DHEA most abundant
231
Adrenal medulla function
Specialised ganglia supplied by sympathetic preganglia synthesises noradrenaline
Synthesises adrenaline from noradrenaline when high cortisol
catecholamines = 80% adrenaline, 20% noradrenaline
232
Thyroid anatomy
Brownish-red in neck. Right and left lobes united by a narrow isthmus surrounded by a thin fibrous capsule of connective tissue
233
How may ectopic thyroid tissue, cysts and pyramidal lobes form?
If descent during embryology leaves behind tissue
234
Describe thyroid gland cells
Thyroid epithelial/ follicles produces hormones and surround colloid. Supporting c cells nearby all covered by basement membrane.
235
Function of thyroid hormones?
Control of metabolism: energy generation and use
Regulation of growth
Development
236
T3, T3 and TSH levels in hypothyroidism vs hyperthyroidism
Hypo: T3, T4 low, TSH high
(Underactivity)
Hyper: T3, T4 high, TSH low
(Overactivity)
Goitre = enlargement
237
Describe thyroid hormone synthesis
1. TSH binds to TSHR on basement membrane
2. Iodine- is uptake by NIS symporter
3. Iodisation of tyrosine residues and coupling by thyroperoxidase
4. Export of mature Tg to colloid where it is stored
(Tyrosine -> diiodotyrosine -> thyroxine)
238
T3 vs T4
Triiodothyronine = 3 iodines vs thyroxine = 4
(T3 is more biologically active by mono-deiodoination of T4)
239
How does thyroid hormone act?
Travels through transmembrane transporter to cell nucleus where transcription is induced = affects metabolism
240
Symptoms of hypo vs hyperthyroidism
Hyper:
Tachycardia, AF, shortness of breath, weight loss, tremor, myopathy, anxiety, double vision
Hypo:
Bradycardia, heart failure, weight gain, constipation, depression, carpal tunnel syndrome
241
Function of parathyroid glands
Regulates calcium and phosphate levels by secreting parathyroid hormone when low calcium or high phosphate.
= Increases Ca reabsorption in distal tubules, in intestine
= Increase calcium release from bone to soluble calcium
= Decrease phosphate reabsorption
C cells release calcitonin to raise calcium levels
(Vit D important)
242
What % of serum calcium is free?
50% of serum calcium is free
50% bound to albumin
243
Describe parathyroid hormone structure
84 amino acids cleaved to smaller peptides and assayed by two site assays. Binds to G protein coupled receptors in kidneys (production of active Vit D, reabsorption of calcium) and osteoblasts.
Also enhances osteoclasts for bone resorption
Normal adult referent = 1.6-6.9 pool/L
244
Different hyperthyroidism
= raised serum PTH
Primary - parathyroid tumour
Secondary - pituitary disease may cause renal disease
Tertiary - hypothalamus disease causes irreversible hyperplasia
245
Describe calcitonin
Produced by thyroid c-cells and released in hypercalcaemia. Not essential to life.
2 calcitonin genes products from a single gene and primary RNA transcription
246
Define ovary
1/2 female reproductive glands that contain ova or eggs that are released during ovulation
247
What scan is best for looking at reproductive organs?
Ultrasound
= sound waves bounce off fluids and tissues and recorded by transducers
= no ionising radiation
= helps guide needles
248
Why is a transvaginal ultrasound used?
With large obese patients, most waves deflected.
Allows view of endometrium lining, thickness, ovaries and myometrium
249
When would you do an ultrasound during pregnancy?
12 weeks = dating, heart beat and unchallenged thickness
20 week = anomaly scan
Additional if clinical problems
250
What may foetal maternal referral
Diagnosis
251
Define menopause
Cessation of menstruation
252
What is climacteric (perimenopause)
Period around menopause and at least the first year after it
253
Define post-menopause
12 months of no period
254
Average age of menopause?
51
(48-52)
255
Cause of menopause
= Depletion of primordial follicles in ovary
Decline of oestrogen production (fluctuates then gradual decline and affects other organs)
Gradual rise of FSH and LH (lack of negative feedback)
Age of menopause decided by size of primordial pool
256
Causes of premature menopause
Idiopathic
Iatrogenic e.g. Surgery, chemo
Chromosomal
Autoimmune
257
How are primordial follicles lost?
Atresia
258
How long does it take for primordial follicles to mature and ovulate?
2.5 months
259
Premature menopause increases risk of
Mortality
Heart disease
Cognitive dysfunction
Bone mineral density
Autoimmune and thyroid disease
260
Tests to confirm (pre-) menopause
Antral follicle test
Anti-mullerian hormone test
Stromatolites velocity
261
Menopause symptoms
4-12 years!
Vasomotor - hot flush, sweat, palpitation, headaches
Physiological - irritability, low mood, lethargy, emotional
Urogenital - vaginal dryness, urethral syndrome
Skin - dryness, brittle nails
Osteoporosis - bone remodelling is uncoupled
Cardiovascular disease - angina, myocardial infarction, cerebrovascular stroke
262
Treatment for menopause
Hormone replacement of oestrogen (+ progesterone reduce endometrial cancer)
Beta blockers
Sedatives
Clonidine
Lifestyle advice
Supplements e.g. calcium
Monitoring
Local steroids
Complementary therapies
263
Types of hormone replacement therapy
Oral
Skin patches
Signal cream
Skin cream
Nasal spray
Vaginal ring
264
Long term risks of hormone replacement therapy
Cardiovascular
Breast cancer (progesterone)
Cancer (oestrogen)
Venous thromboembolism
265
Contraindications of HRT
Abnormal liver function
Thromboembolic disease
Conginetsli lipid metabolism
Hormone dependent tumours
Sickle cell aenemia
