MET Flashcards
Rectus sheath above and below arcuate line
Above Arcuate Line:
EO passes anteriorly, IO splits and half goes anterior while half goes posterior, TA and transversalis fascia go posteriorly.
Below Arcuate Line:
EO, IO, TA all move anteriorly, TF goes posteriorly.
Blood supply to Abdominal Wall
Superior epigastric artery: below the costal margin the internal thoracic artery becomes the SEA
Inferior epigastric artery: comes from the external iliac.
Lateral side supplied by lower IC and lumbar arteries.
Kwashiorkor
Protein-wasting malnutrition, micronutrient & anti-oxidant deficiencies
Marasmus
Severe malnutrition, muscle wasting, protein loss.
Iron Function, Deficiency and Excess
Function • O2 transport • Myoglobin function • Absorbed in upper small bowel. o Transferrin o Stored as ferritin
Deficiency
• Microcytic anaemia
• Lethargy/fatigue
• Cognitive impairment
Excess
• Haemochromatosis: lethargy, fatigue, diabetes, cirrhosis.
Osteomalacia & rickets
Vitamin D Deficiency
Osteomalacia = reduced bone strength, increase in bone fracture, bone pain, bending of bones
Rickets = prior to epiphyseal fusion –> expansion of growth plate and growth retardation
Function of Vitamin D
Increases absorption of calcium in the gut
Has two different sources.
o Intake in diet
Salmon, tuna fish, milk, liver, egg etc…
o Intake through UV sunlight
Through 7-dehydrocholesterol –> Generates vitamin D3.
If one intake compromised other can compensate.
Wernicke’s Encephalopathy & Korsakoff’s Psychosis
Thiamine Deficiency (Vitamin B1)
Wernicke’s Encephalopathy
o Horizontal nystagmus
o Opthalmoplegia
o Cerebellar ataxia
Korsakoff’s Psychosis
o Additional loss of memory and confabulatory psychosis (disturbance of memory)
Beri-Beri
Thiamine Deficiency (Vitamin B1)
Dry: peripheral neuropathy (motor and sensory)
Wet: enlarged heart, tachycardia, peripheral oedema, peripheral neuritis
Shoshin: lactic acidosis, cardiac failure
Function of Thiamine (Vitamin B1)
Involved in:
o Glycolysis and Krebs cycle
o Branched-chain amino acids metabolism
o Pentose Phosphate Cycle Metabolism
Absorbed in the jejunum.
Pellagra
Niacin Deficiency (Vitamin B3)
Early: loss of appetite, irritability, vomiting, abdominal pain
Late: vaginitis, oesophagitis, diarrhoea, depression.
o Casal’s necklace = skin rash (especially in areas exposed to sunlight)
FOUR Ds = dermatitis, diarrhoea, dementia, death.
Function of Niacin (Vitamin B3)
Generic form for two forms: nicotinic acid and nicotinamide
o Forms NAD and NADP/NADH and NADPH.
Absorbed in the jejunum.
Types of Feeding
Enteral –> oral, nasogastric, orogastric, gastrostomy etc…
• Gastrostomy brain injury, Parkinson’s disease, motor neurone disease
Parenteral –> Peripheral and Central
• Short bowel, small bowel, acute pancreatitis
Blood glucose range before and after meals
Kept within range of 3.5-5.5 mmol/L (before meals)
Less than 8mmol/L (2 hours after meals).
Cell in Islets of Langerhans
- Alpha Cells: producing glucagon
- Beta Cells: producing insulin
- Delta Cells: producing somatostatin
- PP Cells: producing pancreatic polypeptide
- Epsilon Cells: producing ghrelin.
Mechanism of Insulin Secretion
- If glucose is higher than 5 millimoles it can go through the transporter in the cell.
a. Ensured by Km of glucokinase (affinity for glucose molecules) - Glucose –> Glucose-6-phosphate –> pyruvate
- Generates ATP (rise in ATP: ADP ratio).
a. Closure of potassium-ATP channels –> Membrane depolarization - Voltage-gated calcium channels open –> Trigger insulin secretion.
Two phases of insulin secretion
First phase: rapidly triggered in response to increase glucose
Second phase: sustained, slow release of nearby formed vesicles.
What other substances can trigger insulin release
• AAs: arginine and leucine
- Arginine directly depolarises beta cell membrane
- Leucine causes allosteric activation activation of GDH
- Glucagon like peptide-1 (GLP-1)
- Fatty acids.
- Acetylcholine.
- CCK.
Actions of Insulin
Glycogen synthesis in muscles (G6P –> G1P –> UDP-glucose –> glycogen)
o Translocation of GLUT4 transporters to plasma membrane
Glucose uptake and lipogenesis (synthesises alpha-glyceryl phosphate –> TGs)
Inhibits lipolysis
How can the liver affect K+ levels
Promotes potassium intracellular uptake
Albumin Functions and regular level
Large protein synthesised in the liver
o Most abundant protein in plasma and is usually trapped within capillaries (35-50g/l)
Functions to maintain oncotic pressure.
Good indicator of mortality risk
o As inflammation falls albumin level should normalise.
Hypoalbuminemia
Arises from inadequate protein intake
In hospital: major cause is inflammation and sepsis associated with infection
Increased C-reactive protein, white cell count.
Capillary walls become more porous and albumin drifts out.
NOTE: low albumin DOES NOT reflect poor nutritional status (poor intake).
Blood Supply to the Liver
25% through celiac trunk
75% through hepatic portal vein.
What vessels contribute to the portal vein
Splenic (inferior mesenteric veins joins here) and superior mesenteric veins meet posterior to head of pancreas to form portal vein
Porto-Systemic Anastomoses
Oesophagus:
(P) Left gastric vein and (S) Azygous and hemiazygos
- Sign/Symptom: Oesophageal varices, hematemesis
Rectum:
(P) Superior rectal vein and (S) Inferior Rectal Vein
- Sign/Symptom: Recto-anal varices
Anterior Abdominal Wall:
(P) Paraumbilical veins* and (S) Intercostal and inferior epigastric
- Sign/Symptom: Caput medusa.
Retro-Peritoneal:
(P) Duodenal, pancreatic, right and left colic veins and (S) Lumbar veins
- Sign/Symptom: Retroperitoneal haemorrhage.
Causes of Ascites
fluid in peritoneal space caused by:
• Porta Hypertension, Hypoalbuminaemia
• Aldosterone related renal sodium retention
Venous Drainage of the Oesophagus
Oesophageal veins (azygos vein branches)
Left gastric veins (portal vein).
What anatomical structure does the common hepatic duct lie in
free margin of lesser omentum
Stimulation of Glucagon Secretion
Low blood glucose concentration: 80-90mg/100ml
Increased blood amino acids (alanine and arginine)
Exercise (exhaustive blood concentration of glucagon increases)
What receptor does Glucagon react with
G protein-coupled receptor (GPCR)
Process of Glycogenolysis
Glucagon activates cAMP which activates PKA
–> Mediates production of glucose from glycogen
Glycogen stores depleted in 24 hours
Process of gluconeogenesis
Uses AAs, glycerol and lactate.
Inhibition of phosphofructokinase-1 and pyruvate kinase are critical
Enzymes in glycolysis.
Increased amino acid uptake into the liver
Process of lipolysis
Glucagon activates hormone sensitive lipase
Allows triglycerides to be broken down.
• Glycerol used in gluconeogenesis.
• Fatty acids used in beta oxidation –> Generate ketone bodies when in excess (Occurs because C substrates in the Kreb’s cycle are used up in prolonged fasting)
Also, involves the activation of the carnitine shuttle
Transport fatty acids into the mitochondria
• Mediated by CPT-1
Regulation of Glucagon
Inhibited: by insulin and somastatin
- Insulin converts cAMP to 5’AMP through phosphodiesterase –> This switches signalling OFF (does not stimulate PKA).
Catecholamines and Glucocorticoids
Both released from the adrenal cortex
Catecholamines = QUICK RESPONSE –> Released in response to stress and hypoglycaemia.
o Synthesized from phenylalanine and tyrosine
Glucocorticoids = LONGER RESPONSE
Cortex cells = have many LDL receptors, enabling cholesterol uptake.
o Enables steroid hormone synthesis
Epinephrine in metabolism
Catecholamine • Inhibits insulin secretion • Stimulates glycogenolysis in the liver and muscle. o Produce cyclic AMP and PKA • Stimulates glucagon secretion • Increases lipolysis in adipose tissue
Cortisol in metabolism
Glucocorticoid
secreted in response to ACTH from pituitary (Negative feedback loop)
o Functions in metabolism
Enhances gluconeogenesis
Inhibits glucose uptake
Stimulates muscle proteolysis
Stimulates adipose-tissue lipolysis.
= rapid mobilisation of AAs and FAs from cellular stores
o Resisting Stress and Inflammation
Maintains blood pressure, suppresses inflammation.
If prolonged = can induce muscle wasting.
Why do glucocorticoids take longer to cause response
It passes through the plasma membrane and binds to nuclear receptor in cell.
• Goes into the nucleus and stimulates transcription of genes.
Thyroid Hormones
T4 (thyroxine) and Triiodothyronine (T3)
Activate nuclear receptors and transcription of large number of genes:
Increases in the number and activity of mitochondria
Stimulation of carbohydrate metabolism
Stimulation of fat metabolism
Increased basal metabolic rate
Incretins
Group of GI hormones including glucagon-like peptide-1 and gastric inhibitory peptide:
o Enhancement of insulin secretion.
Diabetic causes
Obesity:
o Accumulation of lipids and their metabolites
o Increased concentration of circulating FFAs
o Chronic inflammation –> Altered adipokine levels
• Cytokines secreted by adipose tissue
• Lead to chronic inflammation
• Hyperinsulinemia
o Increased lipid synthesis worsens Insulin Resistance
When a tissue is insulin resistant the pancreas tries to create more insulin however the cell doesn’t respond. This increases the synthesis of lipids which makes the whole thing worse.
Both lead to increased insulin resistance –> Diabetes T2
Hyperglucagonaemia in diabetes
Occurs even when glucose is high because = alpha cells become resistant to high levels of glucose/insulin through glucolipotoxicity.
OR defect in insulin secretion.
Nothing to tell cells to stop secreting glucagon
Treatments for:
Decreases Glucose and Gluconeogenesis
Stimulation of Insulin Secretion
Glucagon Peptide 1 Stimulation
Decreases Glucose and Gluconeogenesis
• TZD = increases level of transcription of genes.
• Biguanides (Metformin).
Stimulation of Insulin Secretion
• Sulfonylureas
• Meglitidines
o Stimulates closure of potassium channels in beta cells –> increase in calcium –> secretion of insulin.
Glucagon Peptide 1 Stimulation
• Metformin: inhibits DD-4 (molecule usually inhibits G1P) increasing GL1P activation
• Sitagliptin: increases GL1P (stimulates insulin secretion).
What pathway in glucose can excess alcohol inhibit
gluconeogenesis is inhibited
Signs and Symptoms for acute hypoglycaemia (only T1D)
Mild –> Autonomic: Trembling, sweating, anxiety, hunger
Moderate –> Neuroglycopaenic: Confusion, disorientation, weakness, tiredness
Severe –> confusion, fitting, seizures, coma - Diabetes emergency (mainly for T1D)
Occurs in patients using blood glucose lowering medication (insulin)
• Missed meal
• Overdose medication.
• Alcohol consumption.
Prolonged Hypoglycaemia
Growth hormone and cortisol secreted
o Decrease glucose utilisation and convert to fat utilisation
Leads to: Neuroglycopaenic (shortage of glucose or brain) symptoms
Hyperglycaemia complications
Macrovascular
Microvascular
Due to Protein Kinase C Pathway Stimulation
Macrovascular complications of Hyperglycaemia
Atherosclerosis
Increases uptake of LDLs by modification of low LDLD receptor.
Pro-inflammatory cytokine production
Microvascular complications of Hyperglycaemia
o Kidney disease (nephropathy) –> Damage to blood vessels in glomerulus
• Proteinuria, glomerular hypertrophy, decreased glomerular filtration
o Nerve disease (neuropathy) –> 4 types
Peripheral: pain or loss of feeling in hands, arms, feets and legs
Autonomic: change in digestion/bowel and bladder control (branches supplying autonomic nerves are affected).
• Also, means don’t have pain (15-20%)
Proximal: causes pain in thing and hips
Focal: affect any nerve in the body
o Blindness (retinopathy)
Non-proliferative: dilation of veins and micro aneurysms
Proliferative: fragile new blood vessels near optic disk (tend to bleed).
Dyslipidaemia
Fat deposition in skeletal muscle –> Worsens insulin resistance
Maturity Onset Diabetes of the Young
Pancreatic beta cell dysfunction.
• Inherited (autosomal dominant).
Gestational Diabetes
Diabetes in pregnancy
• Increased complications during the second half of pregnancy
• Increased risk of developing T2D
Latent Autoimmune Diabetes of Adults (LADA
Antibodies to beta cells.
• Like T1D, Patients become insulin dependent.
Type 3c Diabetes
Due to disease of exocrine pancreas
What state of K+ do acidemia and alkalosis lead to
acidemia leads to hyperkalaemia
alkalosis leads to hypokalemia
- H+ enters tissue and binds to protein displacing potassium which exits the cell.
- H+ leaves cells and potassium enters.
Hyperchloremic metabolic acidosis
Loss of bicarbonate: CL- compensates (HCO3-/Cl- symporter) for loss Causes include: Severe diarrhoea Losses via NG tubes Administration of Acidifying Salts.
Reduced Kidney H+ Excretion:
If kidneys do not excrete acids efficiently, bicarbonate is needed to buffer them.
Bicarbonate travels into the blood and combines with H+
Exchanged with Cl- to keep charge neutral –> CL- then also exists into the blood (along with K+).
Leads to hyperchloremic metabolic acidosis
Elevated Gap Acidosis
Increase in unmeasured anions and decrease in bicarbonate
Causes include:
o Ketoacidosis
o Lactic acidosis
o Renal failure
Low Gap Acidosis
Hypoalbuminemia
o Albumin is a negatively charged protein
o Its loss causes retention of bicarbonate and CL to compensate electrical charge.
Causes include: o Haemorrhage (loss of albumin through blood) o Nephrotic Syndrome o Intestinal Obstruction o Liver Cirrhosis
Ammonium production (kidney)
titratable acids –> H+ + HPO42- –> H2PO4- and ammonium (NH4+)
Action of these kidney cells:
Alpha-intercalated
Beta-intercalated
Alpha-intercalated = secrete acid, reabsorb bicarbonate
Beta-intercalated = secrete bicarbonate, secrete acid
Glutamate Pathway in acidosis
Allows to produce bicarbonate (production of alpha-ketoglutarate to glucose = side products are NH4+, HCO3-)
Hormonal Regulation of the Acid/Base Status
Aldosterone = increases pH
Angiotensin II = increases PH
Parathyroid = prevents reabsorption of HPO42 and increases pH
Orexigenic peptide and neurons
Agouti Related Peptide (AgRP)
NPY Neuron
Melanocortin receptor antagonists –> Inhibit the satiety centre.
o Appetite stimulating
Anorexigenic peptide and neurons
Proopiomelanocortin (POMC)
(Cocaine, Amphetamine Regulate Transcript (CART) Neuron
Melanocortin receptor agonists –> POMC undergoes post-translational modification –> melanocortins (Stimulate satiety centre)
o Appetite inhibiting.
Alpha-melanocyte-stimulating hormone (MSH)
Predominant POMC derived products
If deficient will result in hyperphagic (abnormally great desire for food) obesity
Anorexigenic peptides
Serotonin (5HT) = anorexigenic
• Acts through Htr1b and HTr2c receptors that increase signalling from POMC neurons
• Htr1b decreases AgRP neuron signalling
o These receptors interact with ARC (arcuate nucleus)
PPY 3-36 = anorexigenic • Synthesized in gut. • Mechanism of action o Inhibits NYP neurons (Y2 receptors) o Stimulates POMC neurons o Decreases food intake.
GLP-1 and PPY = anorexigenic
• Released by cells in the gut lining
o Inhibits NYP and stimulates POMC.
Cholecystokinin = anorexigenic
• Secreted from I-type enteroendocrine cells in duodenum and SI
Leptin = long acting anorexigenic
• Secreted by adipose tissue (amount of leptin = amount of adipose tissue).
o Indicates total energy storage.
• Pattern: start with relatively low leptin during the day. It rises and starts to fall at night.
o Fasting causes a decrease in leptin
ALSO Drop AGRP levels
Malonyl CoA
Potent controller of appetite
o Inhibits lipolysis (carnitine shuttle) at high levels
o Lipolysis is stimulated at low levels.
Not Hungry = result of malonyl-CoA increased in cytoplasm (for FA synthesis) –> High levels sensed by hypothalamus
• Turns down AgRP and NPY
• Decreases appetite.
Hungry = less malonyl-CoA in cytoplasm (no FA synthesis) –> Sensed by hypothalamus
• Increases AgRP and NPY.
Insulin contribution to Obesity
It decreases the rate of lipolysis in adipose tissue (and lowers plasma fatty acid level).
o Increases uptake of TGs from blood into adipose tissue
Stimulates FA and TG synthesis in tissues.
Decreases rate of fatty acid oxidation in muscle and liver.
T2D Drugs on Insulin Levels:
Increase
Stable
Decrease
Increase:
insulin injections, sulfonylureas – increases insulin release
TZD – increases level of transcription of genes
Stable:
metformin
DPP IV inhibitors
Decrease:
SGLT-2 inhibitor – SGLT-2 in the kidney to help reabsorb glucose
Thrifty gene hypothesis
Selective advantage of obesity in populations with frequent starvation
Syndromic Monogenic Obesity
Mental retardation, dysmorphic features in addition to obesity
Bardet-Biedl Syndrome - Ciliopathy
Cilia mediate leptin receptor signalling
Polygenic Obesity
Involves CNS, food sensing and digestion, insulin signalling, lipid metabolism, muscle and liver biology, gut microbiota as well as:
Adipocyte Differentiation
• Ciliopathies
• Mutations in PPARy2.
o Targeted by TZD drugs.
Main site of adaptive thermogenesis
Brown Adipose Tissue
Orlistat
lipase inhibitor
o Reduces amount of fat absorbed from food
Wolffian and Mullerian ducts
Mesonephric = Wolffian Ducts (precursor male internal sex organ)
Paramesonephric = Mullerian Ducts (precursor female internal sex organ)
Embryonic Kidneys
Pronephric
Mesonephric
Metanephric
Ascent of the Kidney
Metanephros located in the sacral region (S1)
Ascends as the embryo unfolds –> To the lumbar region (T12)
Function of the Kidney Within Foetus
Involved in generation of amniotic fluid
Functional at the end of the first trimester.
Kidney Agenesis
Failure of kidney to form
unilateral
bilateral (baby will not survive after birth)
Oligohydramnios = reduction in amniotic fluid.
Birth defects = lung development and club foot
Polycystic Kidney
Kidney develop fluid filled cysts
Cysts originates as dilations of intact tubule
Cysts enlarges and loses contact with nephron
Cysts epithelium becomes secretory resulting in increased fluid secretion.
Increased proliferation of cyst epithelium.
Types of Polycystic Kidney
Autosomal dominant (polycystin mutation):
85-90% are polycystin (PKD-1) mutations
10-15% are polycystin-2 (PKD-2) mutations.
• Polycystin = localised to primary cilia –> Involved in cell adhesion, calcium transport, cell cycle
Autosomal recessive (fibrocystic mutation)
Vessels in Drainage of Urine
Collecting ducts –> renal papilla –> minor calyx –> major calyx –> renal pelvis –> ureter
Internal Vasculature of the kidneys
Renal artery –> 5 segmental arteries (each supply renal segments)
Segmental arteries –> interlobar arteries –> arcuate –> interlobular arteries –> afferent arterioles –> glomerular capillaries
Capillaries –> interlobular veins –> arcuate veins –> interlobar veins –> renal vein.
Blood Supply to the Kidney
Renal arteries (L1/L2): o ¼ of cardiac output. o RRA passes posteriorly to IVC
Renal veins (L2) o Anterior to aorta LRV longer than right due to right --> Receives left suprarenal and gonadal veins
Lymph drainage from the kidneys
Lateral aortic lymph nodes
Nerve Supply and pain in the kidneys
Via the renal plexus
o MOTOR
Sympathetic (visceral afferent)
Blood Supply to Ureters
Renal arteries
Testicular arteries
Common iliac arteries.
Structure of Ureter
Tri-layered wall:
o Transitional epithelial mucosa.
o Smooth muscle muscularis.
o Fibrous connective tissue adventitia
Muscle for peristalsis
Pain in Ureter/Kidney stones)
Referred along ilioinguinal and Iliohypogastric nerves (L1)
Descent –> may start to feel pain over groin
- nerve change –> Pain referred to genitofemoral (L1/L2)
Trigone
Area between ureters and urethra
infections persist in this region
Structure of Bladder
- Transitional epithelial mucosa
- Thick muscular layer
- Fibrous adventitia
Urethra Sphincters
Urethra = Muscular tube
o IUS = involuntary sphincter (male) - prevents retrograde ejaculation
o EUS = voluntary sphincter
o Levator ani = voluntary urethral sphincter
four sections of Urethra in males
Intramural (pre-prostatic) = length varies on bladder filling
Prostatic = contains ejaculatory ducts
Intermediate (membranous) = penetrates perineal membrane
• Surrounded by EUS.
Spongy = final part in corpus spongiosum of penis.
Micronutrition (Voiding or Urination)
Distension of bladder walls initiates spinal/sympathetic reflexes:
o Stimulate contraction of EUS.
o Inhibit detrusor muscle and IUS
Voiding reflex: parasympathetic
o Stimulate detrusor muscles to contract
o Inhibit internal and external sphincters.
SYMPATHETIC STOPS PEE
PARASYMPATHETIC PERMITS PEE
Measurement of GFR
Done by creatinine = completely filtered and none is reabsorbed.
o Break-down produce of Creatine Phosphate found in muscle
Cr Clearance
(urine concentration x urine volume)/plasma concentration
Creatinine is also actively secreted leading to an overestimation of 10-20%
Misleading in:
• Muscular individuals (naturally raised serum creatinine)
• Malnourished individuals = low serum creatinine.
• Drugs = may inhibit tubular secretion of creatinine (e.g. Trimethoprin)
Gold standard of GFR
A nuclear medicine scan (e.g. Cr51-EDTA)
Renal Disease and Transport Proteins
Proximal tubule:
o Apical Na/cysteine cotransporter = cystinuria
o Apical Na/glucose cotransporter = renal glycosuria
o Basolateral Na/HCO3 = proximal RTA
Thick Ascending Loop = Bartter Type 1
Distal Tubule = Gitelman’s
Reabsorption of Proximal, distal Tubule and loop
Proximal Tubule:
Bulk reabsorption of solutes to 80%, water 65%, AAs, low molecular weight Ps (100%)
Loop of Henle:
• Descending - many aquaporins - allow water to move out –> more conc.
• Ascending - active transport of sodium and chloride out of the tubule
Secondary Active Transport = Na, K and CL
Paracellular Transport: Na, Ca Mg down concentration gradient
Distal Nephron:
Excrete potassium, regulate sodium delivery to collecting duct as well as urine acidification
Effects of Glucose Presence in Urine
Osmotic diuresis
o Water and urine attracted into collecting duct due to increased solute –> leads to polyuria.
Glucose renal threshold
> 10 mmol/L.
Cushing’s Syndrome/Disease
Syndrome: high cortisol
Disease: high cortisol caused by tumour that causes increased ACTH secretion
Symptoms: o Loss of peripheral vision o Progressive Opthalmoplegia Paralysis of muscles within/surrounding eyes. o Weight gain (truncal obesity) o Abdominal striae.
Sella turcica
Depression in the sphenoid where Pituitary sits
Anterior Lobe Hormones
o ACTH = adrenocorticotrophic hormone
EXCESS = Cushing’s syndrome/disease.
o TSH = thyroid-stimulating hormone
EXCESS = hyperthyroidism, weight loss, rapid heart rate, tremors.
o LH = luteinising hormone
o FSH = follicle-stimulating hormone
EXCESS = irregular menstrual periods and decreased interest in sex
o PRL = prolactin
EXCESS = irregular menstrual periods, abnormal milk production.
o GH = growth hormone
EXCESS = gigantism, acromegaly in adults.
o MSH = melanocyte-stimulating hormone.
Posterior Lobe Hormones
Extension of the hypothalamus (made up of neural tissue)
Two nuclei = cell bodies extend down into the Posterior Pituitary o Supraoptic (above the optic chiasm) ADH o Paraventricular nuclei. Oxytocin
Adrenal Gland shapes
Right AD = pyramidal shaped right (contact with liver and IVC)
Left AD = crescent shaped left (spleen, stomach, pancreas).
Blood Supply
Superior suprarenal artery (6-8) = inferior phrenic
Middle suprarenal artery (1+) = abdominal aorta
Inferior suprarenal artery (1+) = renal artery.
Venous drainage on the left is into the renal vein, on the right on the IVC
Damage to what in surgery causes tetany
Parathyroid glands
Level of Thyroid Gland
C5-T1
Arterial Blood Supply to Thyroid Gland
ECA = superior thyroid artery
Subclavian –> thyrocervical trunk = inferior thyroid artery
Common variant: thyroid IMA artery (10%)
Venous Blood Supply
IJV = Superior, middle thyroid vein.
BCV = Inferior thyroid vein.
Blood Supply to pancreas
Coeliac Trunk
Splenic artery
Gastroduodenal –> superior pancreatoduodenal (when it gives of its final gastric branch)
Superior Mesenteric Artery
Inferior pancreatoduodenal.
Iodine required in diets
1mg
Synthesis of Thyroid Hormones
- Iodide taken up by NIS (sodium-iodine symporter on basolateral membrane of thyroid follicular cell) Release tyrosine molecules from structure.
b. Causes T3 and T4 to separate.
c. DIT and MIT release iodine to restart process
Action of Thyroid Hormones
T3 enters the nucleus (converted from T4) and enters target cells
• In the nucleus = thyroid hormone receptor.
Initiates transcription for specific mRNAs.
• This increases the metabolic rate.
Thyroid Deiodinases
D1 = rT3 –> T4 –> T3
D2 = provide T3 to the nucleus
• T4 levels fall = D2 is upregulated –> T3 levels are maintained
• (If no longer able to compensate = rise in TRSH/TSH).
• Excess T4 = decrease D2 to protect from excess thyroid hormone
D3 = activated by ischemia/hypoxia, slowing down metabolism of affected tissues by reducing T3 levels.
Hyperthyroidism (hyper function of the thyroid gland)/ Thyrotoxicosis symptoms
CV
• Atrial fibrillation (dissipate heat)
NS
• Nervousness seizures
Eyes
• Eyelid retraction
• Inflammation of orbital soft tissue (buldging).
Skin
• Plummer’s Nails
• Pretibial myxoedema
Bones
• Accelerated osteoclast activity
• Hypercalcemia
• Osteoporosis
Metabolism • Increased protein and lipid degradation • Increased appetite • Heat intolerance • Hyperglycaemia.
Haematological
• Pernicious anaemia – RBC deficiency
• B12 deficiency
Reproduction
• Oligomenorrhea – infrequent periods
• Gynecomastia – enlargement of male breast’s
• ED
Grave’s Disease
An autoimmune thyroid disease
Positive antibodies against TPO, thyroglobulin and most significantly the TSH receptor
Causes of Hyperthyroidism (hyper function of the thyroid gland)/ Thyrotoxicosis
- Grave’s Disease
- Toxic multinodular goitre – swelling in the thyroid gland
- Toxic adenoma – noncancerous tumour
- Excess iodine
- HCG
Diagnosis and Management of Hyperthyroidism
Diagnosis: High T3 and T4
Treatment: Thionamide drugs
• Propylthiouracil.
• Carbimazole.
Primary and secondary Hypothyroidism
Primary - loss of thyroid
Central or secondary - insufficient pituitary stimulation (commonly pituitary macroadenoma affecting anterior pitruitary)
Hypothyroidism symptoms
CV
• Reduced cutaneous circulation = sensitivity to cold
o J waves (wave directly after S) of hypothermia
• Sinus bradycardia
GI Tract
• Reduced appetite constipation.
• Weight gain
Nerves, muscle, bone
• Impaired fetal brain development
• Dementia
• Growth retardation
Endocrine
• Delayed puberty
• Erectile dysfunction
Metabolism
• Reduced BMR
• Decreased GLUT4 stimulation
Renal
• Reduced GFR
• Mild hyponatraemia
Haematological
• Normochromic/normocytic anaemia
Causes of hypothyroidism
Hashimoto’s disease
Infiltrative disease
Hypopituitarism – pituitary doesn’t produce sufficient (if any) hormones
Cabbage – in iodine deficiency
Lithium.
Diagnosis and Management
Diagnosis = high TSH, low T4
Treatment
• Levothyroxine
• Liothyronine
Embryonic structure origins
Endoderm = lung cells, thyroid, digestive cells.
Mesoderm = cardiac muscle, skeletal muscle, tubule of the kidney, RBCs
• Visceral mesoderm wraps around gut tube.
o Forms mesenteries (suspend the gut tube in body cavity).
Ectoderm = skin cells, neurons of the brain pigment.
What is Hirschsprungs Disease and symptoms
Congenital megacolon due to lack of enteric neurons (ENS)
o Affected segments can’t relax (don’t allow stools to pass) – no peristalsis
Symptoms:
o Failing to pass meconium within 48 hours
o A swollen belly
o Vomiting green fluid.
Anal Sphincters
Internal Anal Sphincter (IAS):
• Involuntary and thickened muscle
External Anal Sphincter (EAS):
• Voluntary muscle which encircles the IAS
o Lies just below and laterally to the lower edge of the IAS
• Defers defecation until a socially opportune moment.
Nerve supply to Pelvic Floor Muscle
S2-S4 give parasympathetic supply through the pudendal nerve.
o Keeps the 3Ps off the floor (penis, poo and pee).
Anal sphincter nerve supply
External Anal Sphincter:
Supplied by the inferior rectal branch of the pudendal nerve. Further divides to form the
o The perineal nerve and dorsal nerve of the penis.
o Dorsal nerve of the clitoris
Internal Anal Sphincter:
Innervated by the enteric nervous system (ANS)
o Sympathetic: L1, L2 via hypogastric nerves
EXCITATORY (STOP)
o Parasympathetic: S2-S4 pelvic nerves
INHIBITORY (LET GO)
In a continuous tonic state
Constipation types
Primary and secondary
Primary Constipation
Normal Transit
• Patient feels constipated.
Slow Transit
• Infrequency and slow movement of stool.
• Bloating, abdominal pain and infrequent urge to defecate
Disordered Defecation
• Dysfunction of pelvic floor and anal sphincters (due to structural abnormalities).
Secondary Constipation
Endocrine = diabetes (high blood sugar damages vessels), hypothyroidism
Neurological = spinal injury: Parkinson’s disease
Psychogenic = eating disorders
Metabolic = hypercalcaemia etc…
Passive Incontinence
Structural/functional lesion to the internal sphincter.
Urge Incontinence
• Structure/functional lesion to the external sphincter
Acidotic State and Ca2+
less calcium binds to albumin (replaced by H+): increase in ionized Ca2+.
Alkalotic State and Ca2+
More calcium binds to albumin, decrease in ionized Ca2+
• Causes tingling of the lips (hypocalcaemia due to blowing of Co2).
is Hypocalcaemia or hypercalcaemia more dangerous
Hypocalcaemia = causes uncontrolled firing of nerves across the body (more dangerous than hyper).
o Can cause cardiac arrhythmia’s/cardiac arrest.
Calcium role in signalling
Intracellular circulating molecule that is also involved in stabilizing Na+ pumps
o Sits within these channels to prevent them from firing.
Where is phosphate mineralised
85% is mineralised in bone.
PARATHYROID HORMONE
Secreted PTH in response to low calcium.
o PTH Secreted by Chief Cells
Causes an increase in extracellular calcium through:
o Bone = increases activity of osteoclasts (bone reabsorption –> releases more Ca2+/PO43)
o Kidney = increases Ca2+ reabsorption, decreases phosphate reabsorption –> Phosphate forms salts with calcium and decreases the amount that is ionized
o Intestine = increased hydroxylation of vit. D to produce calcitriol (1,25-dihydroxyvitamin D) –> Calcitriol promotes reabsorption of calcium through gut by stimulating CBP.
PTH Regulation
High levels of calcium inhibit PTH (minor change)
However a basal amount secreted.
Familial Hypocalciuric Hypercalcemia
Inactivating mutations of CaSR.
o Parathyroid can’t sense high calcium
o PTH not supressed.
High serum Ca, low urine Ca (reabsorption not stopped)
Determinants of PTH Secretion
Decrease Secretion:
• High Calcium
• Activated vitamin D (1,25D/calcitriol) from 25 (OH) D3: supresses PTH transcription.
o Negative feedback loop
• Cinacalcet activates Calcium Signalling Receptors = restrains PTH
Increase Secretion
• Phosphate (increased secretion).
Where does PTH act
PTH only acts on distal tubule
o Upregulates TRV calcium channels/calcium ATPase and Na/Ca exchanger.
Osteoblasts
Contain and produce RANKL.
o PTH and 1,25D stimulate RANKL production.
Osteoclasts
Have RANKL receptors
o RANKL activation: forms seals over bone and cause its breakdown (release H+) –> Release Ca2+
OPG (osteoprotegerin) inhibits this process and is therefore downregulated by PTH
Further factors of bone Remodelling
Glucocorticoid = reduce osteoblast number, increase RANKL.
Estrogen = inhibits bone remodeling.
How is 1,25 (OH)D made
Vitamin D (Absorbed by diet or UV light) o Undergoes hepatic conversion to 25(OH)D.
Conversion to 1,25 (OH)D is highly regulated.
Function of 1,25 (OH)D
Increase Ca2+ and phosphate absorption from the gut.
o And from kidney
Stimulates bone reabsorption and remodeling
Other Effects
• Increases levels of osteocalcin and RANKL
• Increases amino acid uptake.
FGF23
Secreted by osteoblasts in response to high phosphate levels.
Decreases Ca2+ and phosphate levels.
Calcitonin
Thyroid C-cells (secrete calcitonin)
Medullary thyroid cancer (levels of calcitonin increase –> marker)
PTHrP
Physiological role in lactation
HYPERPARATHYROIDISM Complications
stones (renal calculi)
bones (osteoporosis)
groans (dyspepsia – indigestion pain in upper abdomen after eating)
moans (depression, confusion)
polyuria and polydipsia (increased thirst)
Primary, secondary and tertiary HYPERPARATHYROIDISM
Primary disease (parathyroid adenoma, carcinoma hyperplasia) hypercalcemia (no lack of Ca2+)
Secondary disease (compensates for decreased Ca2+ by increasing PTH)
Tertiary disease is caused by successful compensation of chronic secondary hyperparathyroidism.
HYPOPARATHYROIDISM symptoms
Features:
o Convulsions.
o Arrhythmias.
o Seizures.
Rathke’s pouch
Ectoderm that grows from the roof of the mouth (forms anterior pitruitary)
Posterior pituitary formation
from the diencephalon of the brain
Oxytocin
Stimulates milk synthesis
ADH/Vasopressin
Increases water absorption through the opening aquaporins in the collecting duct
Desmopressin = drug that mimics it.
Iliothyronine
synthetic form of T3
What stimulates GH
GHRH as well as ghrelin
o Inhibited by SS (negative feedback = secreted when there are high levels of GH)
What does GH stimulate
Stimulates IGF (insulin-like growth factor) production.
o Inhibits GF and GFHRH via negative feedback.
o Stimulates secretion of SS.
McCune-Albright Syndrome
Spontaneous mutation in the embryo.
o Prevents downregulation of cAMP in GCPRs
Results in:
o Hyper functioning endocrine organs (goitre)
o Bone deformities.
o Skin discolorations (often to café au lait [orange] color).
More common in females.
Hypothalamo-Pituitary-Adrenal Axis
CHR–> ACTH –> cortisol
negative feedback
Circadian Rhythm of Cortisol
Rise at about 3am
Peak at 6-9am
Levels decline throughout the day
Cushing’s Syndrome and types
Increased cortisol levels
Two types:
ACTH Independent:
ACTH not being impact.
Adrenal tumour may be the cause
• Cause of raised cortisol downstream from the pituitary gland.
ACT Dependent:
ACTH levels raised primarily.
Issue due to a pituitary defect (e.g. adenoma).
• Increased ACTH leads to increased cortisol.
Cushing’s Syndrome symptoms
Weight gain
muscle weakness
skin changes
Gonadal Axis
Kisspeptin stimulates GnRH (gonadotropic releasing hormone) in the hypothalamus
GnRH stimulates LH and FSH in the pituitary glands
This causes oestrogen and testosterone production in the gonads.
o Inhibit Kisspeptin and LH/FSH via negative feedback
in puberty oestrogen causes positive feedback to Kisspeptin
Classes of Diuretics
Carbonic anhydrase inhibitors - Proximal Convoluted Tubule (bicarbonate ions are not reabsorbed)
Thiazide Diuretics - Distal Convoluted Tubule
(block the Na+/Cl- –> decreases Na+ reabsorption to cause diuresis)
Loop Diuretics - Ascending Limb of Loop of Henle (inhibits the Na/K/2CL co-transporter –> K+ excretion)
Potassium Sparing Diuretics - Collecting Tubules (Lose Na+ and gain K+)
- Amiloride/Triamterene
Na+ channel antagonists –> Na+ loss - diuresis - Spironolactone/Eplerenone
Aldosterone antagonists therefore deregulates Epithelial Sodium Channels (ENaCs) –> Na+ loss - diuresis
Mannitol
Osmotic Diuretic
• Na+, K+ and water are all dragged out from the interstitial space
Clinical Use:
• Cerebral oedema / raised intracranial pressure.
Side Effects:
• Pulmonary oedema.
Micturition Reflex
Micturition centre activated
• (1) Stimulation of parasympathetic efferents (stimulate detrusor muscle to contract).
o Action continued through positive feedback.
o Release acetylcholine which stimulate muscarinic receptors on smooth muscle.
• (2) Inhibition of somatic efferents (pudendal nerve) and sympathetic efferents (hypogastric nerve)
o Relaxation of sphincters and detrusor muscle
International Prostate Symptoms Score
Involves frequency, urgency, nocturia etc… o Mild (0-7) = reassure, watch and wait o Moderate (8-19) to Severe (20-35)
Lower Urinary Tract Symptoms (LUTS)
Storage (Irritative) Symptoms = frequency, nocturia, urge incontinence
Voiding (Obstructive) Symptoms = hesitance, straining, poor flow, incomplete emptying (also = terminal dribbling, haematuria)
Overactive Bladder Syndrome (OAB) = urgency, with or without incontinence (usually with frequency and nocturia).
Medical Therapy for Lower Urinary Tract Symptoms (LUTS)
Alpha blockers (stretchers)
o Prevent activation of alpha receptors (which activate smooth muscle).
Enlarges lumen of urethra.
5-alpha reductase inhibitors (shrinkers)
o Reduce growth of prostate.
Enlarges lumen of urethra
PDE5 inhibitors.
Antimuscarinics.
Surgery for Lower Urinary Tract Symptoms (LUTS)
TURP = transurethral resection of the prostate
HoLEP = laser to remove prostate
UroLIFT = holds prostate gland out of the way
Urge Incontinence
Stress Incontinence
Urge Incontinence = overactive waves (overactive bladder)
Stress Incontinence = urine leaks due to weakened pelvic muscles
Treatment for Urge Incontinence
Anticholinergics = block Ach in parasympathetic nerves (as well as in other places)
Beta adrenergics = beta receptors upregulated in OAB. Decrease this but hypertension.
Botulinum Toxin A = fuses synaptic vessels with end plate.
Issues with hyper continence.
Mineralocorticoids
Involved in electrolyte and water balance.
Glucocorticoids
Affects metabolism, fights infection (anti-inflammatory), prevents fluid loss, affects neurochemistry etc…
Side Effects of Glucocorticoids
- Oedema
- Weight gain
- Hypertension
- Osteoporosis (increases activity of osteoclasts, decreases activity of osteoblasts).
- Hyperglycaemia
- Glaucoma
- Jaundice
- Peptic ulcers (sore on lining of stomach/SI/eosophagus)
- Avascular necrosis
Use of Glucocorticoids
- Hypersensitivity such as asthma, atrophic dermatitis (eczema) and allergic rhinitis (nose allergy)
- Adrenal deficiencies
- Chron’s disease or ulcerative colitis
- Arthritis
- Multiple sclerosis.
Glucocorticoid Receptors
Alpha and beta are the two main forms
Found within nucleus and cytoplasm
o Can enter through cell membrane as they are lipid.
Synthetic Forms of Glucocorticoids
- Dexamethasone
- Betamethasone
- Prednisone
- Prednisolone.
Acute Cellular Rejection
CD4+ activate cytotoxic T lymphocytes (CD8+).
o “Cell-mediated”
Acute Antibody-Mediated (Humoral) Rejection
CD4+ activate B lymphocytes that produce antibodies
o Gives a different type of pathology.
what is used to identify rejection.
C4d levels
Cellular vs Antibody Rejection
Cellular: More c4d between cells/connecting cells
Antibody: around the blood vessels (peritubular)
Hyperacute Rejection
Minutes to hours.
Antibodies in the circulation before the transplant occurs.
Chronic Rejection
Occurs from months to years
Immunosuppression in Rejection
Acts to prevent activation of helper T cells.
Activated T cells secrete IL to cause clonal expansion
Corticosteroids: prevent cytokine gene activation
Chromaffin cells
Release catecholamines (80% secrete adrenaline, 20% noradrenaline)
Steroid production
Cholesterol conversion through cytochrome p450 to pregnenolone initiates pathway.
Hyperaldosteronism signs
low potassium, high blood pressure and alkalosis
Functions of Aldosterone
Stimulates Na/K ATPase and increases its expression.
Inserts additional ENaC.
Stimulates the H+ ATPase
Liddle’s Syndrome
Increased expression of ENaC:
• Hypertension
• Hypokalemia
• Metabolic Alkalosis
Addison’s Disease
Primary Adrenal failure: can be autoimmune and tuberculosis
Vague symptoms initially
o Fatigue, weakness, myalgia
o Anorexia, weight loss
o Hyperpigmentation.
Chromaffin Cell Tumours
Phaeochromocytoma: arising from within adrenal medulla
Paraganglioma: extra-adrenal tumours.
Known as PPGL
