MET2 Lecture Revision Notes

1. Metabolism Introduction
Learning Objectives
n/a

Components of the Body Fluid Compartments

The cell is an island.
● Extracellular fluid = the sea
o Contains NaCL
● Intracellular fluid = banana tree on island.
o Potassium and phosphate

1. Failures of Body Fluid Balance

Dehydration
● Water intake insufficient to cover water loss,
eventually water is lost from plasma and ISF.
o Weight loss, fever and confusion.

NOTE: excess urine production occurs in both forms of diabetes (excess sugar in the urine).
● Increase in osmolality and prevent water reabsorption.

Both the very young and elderly are prone to dehydration:

● Not fully developed kidney
● Decline of kidney function.

Water Intoxication
● Dilution of body fluids (sodium reduced)
o Cell swelling = osmotic shift of water into cells.
▪ Coma
▪ Death

Oedema
● Accumulation of fluid in extracellular fluid. Four main causes
o Increased capillary hydrostatic pressure.
▪ Greater than oncotic pressure
● Heart failure
● Venous obstruction
● Cirrhosis (liver failure).
o Slows blood flow increasing
pressure in the vein (portal
hypertension)
o Loss of plasma proteins.
▪ Severe malnutrition
o Obstruction of lymphatic circulation
o Increased capillary permeability (inflammation).

2.

Anterior Abdominal Wall and Inguinal Anatomy

Learning Objectives
• Review the anatomy of the anterior abdominal wall
• To be able to identify the surface anatomy of the anterior abdominal wall
• Describe the basic anatomy of the inguinal ligament
• Understand the origins of the layers of the spermatic cord
• Explain where inguinal hernias commonly from and why

1. The Abdominal Wall

External Oblique
● Most superficial, runs anterior inferiorly
o Superiorly attached to the ribs
o Inferiorly attached to the iliac crest and pubic tubercle
▪ Inguinal canal = free border created by the aponeurosis of this
● Muscle fibres run until mid-clavicular line ฀ aponeurosis.

Internal Oblique
● Runs anterior superiorly.
o Superiorly attached to the ribs
o Inferiorly attached to iliac crest.

Transversus Abdominis
● Transversely across the abdomen.
● Muscle fibres run until mid-clavicular line
o Also, true for IO

Rectus Abdominis
● Runs from the xiphoid process down to the pubic symphesis
o Tendinous Intersections: divide it into 8 blocks of muscular tissue.
o Linea Alba: midline of these intersections (superior to inferior).

● Rectus Sheath: derived from aponeuroses of EO, IO and TA and encloses RA.
o Above Arcuate Line: EO passes anteriorly, IO splits
and half goes anterior while half goes posterior, TA
and transversalis fascia go posteriorly.
o Below Arcuate Line: EO, IO, TA all move anteriorly,
TF goes posteriorly.

2. Blood Supply to AW
● Superior epigastric artery: below the costal margin the
internal thoracic artery becomes the SEA.
● Inferior epigastric artery: comes from the external iliac.

NOTE: epigastric supplies anterior portion.

● Lateral side supplied by lower IC and lumbar arteries.

3. Nerve Supply to AW
● Intercostal Nerves (most of the supply)
o T7: xiphoid
o T10: umbilicus
o T12 (not an intercostal but subcostal nerve)
▪ Lies below the 12th rib.
● Lumbar Plexus: L1 to L4
o L1: Splits into two nerves:
▪ Iliohypogastric
▪ Ilioinguinal nerve.

4. Inguinal Ligament
● Inguinal Canal: space that passes
obliquely through AW
 o Spermatic cord in the male and the round ligament of uterus in the female. Both = ilioinguinal
nerve.
● Inguinal Ligament: thickening of EO aponeurosis from ASIS to the pubic tubercle. Forms floor of
inguinal canal.
o Lies the NAVEL.

Spermatic Cord: contains the

● Testicular artery, testicular veins.
● Pampiniform venous plexus
● Genital branch of genitofemoral.

Surrounding the spermatic cord are layers derived from the layers
of the abdominal wall:
● External spermatic fascia (EO).
● Cremaster muscle (IO)
● Internal spermatic fascia.

Deep Inguinal ring: spermatic cord enters abdominal wall

● Midpoint of inguinal ligament.

Superficial Inguinal Ring: spermatic cord emerges from abdominal wall

5. Development of Inguinal Ligament

Testes develop on the posterior abdominal wall and descend through inguinal canal: reach scrotum.

1. Testes
develop
retroperoneally.
 a.
As soon as they move through the canal they take perineum with them.
i. Eventually becomes tunica vaginalis.
2. Pushes through the transversalis fascia and takes a layer with it
a. Internal spermatic fascia
3. Goes under the transverse abdominis
4. Pushes through internal oblique and takes a layer with it
a. Cremaster muscle
i. Responsible for elevation of the scrotum
ii. Genitofemoral nerve L1 and L2.
5. Pushes through external oblique
a. External spermatic fascia

6. Inguinal Hernia’s
● Protrusion of peritoneum and viscera (e.g. SI) through opening/weakness.
o Risk of having blood supply cut off (strangulated hernia) or can be obstructive (obstructed).
● Direct (through abdominal wall) and indirect (with processus vaginalis).

Causes: separated into:

● Raising abdominal pressure (excessive coughing, lifting heavy weights)
● Anything that weakens or stretches the abdominal wall.

Inferior epigastric is landmark for determining direct/indirect.

● Medial: Hasselbach’s triangle. Most weaknesses exist here.
● Lateral: indirect hernias enter through
the deep inguinal ring.

Femoral Hernia:
Herniation into the femoral canal (inferior to
the inguinal ligament). Mostly females.

3. Micronutrients
Learning Objectives
1. List the principal causes of vitamin deficiencies in
developed countries.
2. Give examples of the fat-soluble vitamins and describe their function within the context of clinical features of their deficiencies.
3. Discuss the role of vitamins (and trace elements) as antioxidants
4. Give examples of water-soluble vitamins and list the principal function common to B vitamins
5. Describe the clinical syndromes associated with deficiencies of the water-soluble vitamins B1 (thiamin), B6, B12 and folate
6. Give examples of important trace elements present in the diet within the context of clinical features of their deficiencies

Vitamins (organic) + trace elements (inorganic) = micronutrients.

● Essential compounds required in small amounts in the diet.
o Used for = cofactors, coenzymes, genetic control, structure
● Maintain homeostasis in adults.
 ● Majorly important in paediatric population
o Energy supply, Body Growth & Development.
▪ 3X more per KG body weight than adults.

Dietary vitamins
● A = fish, liver, fruit and vegetable.
● D = orange juice, dairy products
● E = oils, meats, cereal grains
● K = herbs and spices, chilli
● C = fruits, green vegetables, tomatoes, potatoes
● B1 = pork, beef and nuts, yeast
● B2 = bread and cereals, eggs, broccoli
● B3 = beans, milk, meat eggs
● B6 = tuna, poultry, bananas, avocado
● Biotin = liver, soy beans, yeast, egg yolk
● B12 = meat and dairy food
● Folate = fruits and vegetables.
Required intake is set by the Recommended Dietary Allowance (RDA).

Fat-Soluble Vitamins Water-Soluble Vitamins

A, D, E, K C, B, Folate, Biotin.
Stored Not Stored
● Occasionally toxic when in excess ● Often acts as coenzymes
● Excess is excreted in the urine
● Travels into lymph fluid. ● Travels into portal vein.
1. Fat-Soluble vs Water-Soluble

2. Causes of Vitamin Deficiency in Developed Countries

Decreased Intake
Condition/Cause Vitamin Impacted
Alcohol Dependency B Vitamins (especially B1): excessively used
Small Bowel Disease Folate (B9): unable to absorb
Vegans Vit D (no sunshine), Vit B12
Elderly with Poor Diet Vit D (no sunshine), Folate
Anorexia Folate (mainly amongst others).

Decreased Absorption
Condition/Cause Vitamin Impacted
Ileal Disease/Resection B Vitamins (especially B12):
Liver and Biliary Tract Disease Fat Soluble Vit
Intestinal Bacterial Overgrowth Vit B12
Oral Antibiotics Vit K
 Others
● Long term enteral or parenteral nutrition
o Enteral (through human GI tract)
o Parenteral (anywhere other than in the mouth/alimentary canal, usually IV)
● Renal disease (vitamin D)
● Drug antagonists (methotrexate interfering with folate metabolism)

3. Deficiencies
Fat Soluble
NOTE: fat malabsorption, alcoholism and liver disease will impact the levels of these.
Vitamin RDA Contributing Factors to Deficiency Clinical Features
A Vision, skin bones 700-900 micrograms/d Infection, measles, protein-energy Xeropthalmia (abnormally
malnutrition dryness conjunctiva/cornea).
D Calcium absorption 5-15 micrograms/d Aging, lack of sunlight exposure Rickets (defective calcification
of bones), osteomalacia
(softening of bones)
E Antioxidant 15 milligrams/d Antibiotic use Peripheral neuropathy (impair
sensation, movement)
K Coagulation factors 90-120 micrograms/d Antibiotic Use Coagulopathy

*RDA = recommended dietary allowance

Water Soluble
Vitamin RDA Contributing Factors to Deficiency Clinical Features
C (Antioxidant, 75-90 milligrams/d Smoking Scurvy
connective tissue form.)

B1 (Thiamine) 1.1-1.2 milligrams/d Associated: B6, B12, folate deficiency Berri Beri,
Carbs to glucose
Wernicke-Korsakoff’s
Sydnrome
B2 Protein breakdown 1.1-1.3 milligrams/d Malabsorption Angular Stomatitis

B3 Carbs to glucose 14-16 milligrams/d Associated: B6 deficiency Pellagra

B6 Makes neurotrans. 1.3-1.7 mg/d Isoniazid use (antibiotic TB). Neuropathy, anaemia

B12 2.4 micrograms/d Gastric atrophy (pernicious anaemia) Anaemia, neurologic disorders

Folate 400 micrograms/d Sulfasalazine, pyrimethamine Anaemia, depression

(antiparasitic)

4. Trace Elements
● Dietary minerals required in small quantities for normal function of an organism.

Trace Element Source Function Deficiency

Calcium Dairy products Mechanical stability of the skeleton, Osteoporosis, paresthesias
muscle spasms
Phosphorus Seeds, nuts, soya Structures proteins, enzymes, Bone pain, pseudofracture
transcription factors, ATP/nucleic acids (thickening of bone
periosteum), proximal muscle
weakness, rickets.
Iron Red meat, dark vegetables Part of the heme protein and enzymes Anaemia, impaired cognitive
development
Selenium Seafood, red meat, cereal Component of glutathione peroxidase Cardiomyopathy
and deiodinase enzymes.
Zinc Meat, nuts, shellfish Synthesis/stabilization of protein, DNA, Growth Retardation,
RNA, normal spermatogenesis, fetal Dermatitis, Diarrhoea
growth, embryonic development
Copper Shellfish, liver, nuts, bran Part of numerous enzymes for iron Growth Retardation
metabolism: melanin, elastin and
collagen synthesis, CNS function.

4. Malnutrition
● Contributes to 1/3 of all child deaths worldwide
o Diarrhoea, malaria, pneumonia

Kwashiorkor: protein-wasting malnutrition, micronutrient & anti-oxidant deficiencies

Marasmus: severe malnutrition, muscle wasting, protein loss.

5. Refeeding Syndrome
● Pathology not completely understood
● Severe electrolyte disturbance and metabolic
abnormalities in under-nourished patients going
refeeding (orally, enternally, parenternally).
o Associated with resp. failure, confusion,
coma, cardiac failure death.

Mechanism
● Upon feeding = increased insulin secretion means
increased glucose, phosphorus, magnesium,
potassium uptake into the cells.
● Blood levels therefore become even lower than they
already were causing for symptoms/uneven
distribution.

Management
● Aggressive electrolyte replacement
● Nutritional supplementation
o Simple Sip Drinks
o Vitamins
o Nasogastric tube feeding.

6. Nutrition Important
● Impaired wound healing
● Impaired immune response
● Reduced muscle strength
● Depression and self-neglect.

7. Specific Micronutrient Deficiencies

Iron
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.
Vitamin D
Osteomalacia & rickets
● 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/ Absorption
● 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.
o If one is compromised other can compensate.

Other Contributors to Deficiency:

● Lifestyle Factors: obesity, smoking, alcohol, exercise
● Disease Factors: reduced skin synthesis, decreased bioavailability, increased excretion, drug-related.

Recommended Intake (to prevent osteomalacia and rickets) is higher:

● Pregnant/breast feeding women
● Infants and toddlers (higher if mother is Vit.D deficient).
● Low exposure to sun
● Age >65 years.

Thiamine Deficiency (Vitamin B1)

Wernicke’s Encephalopathy & Korsakoff’s Psychosis
● 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
Has various forms depending on where people live:
● Dry: peripheral neuropathy (motor and sensory)
● Wet: enlarged heart, tachycardia, peripheral oedema, peripheral neuritis
● Shoshin: lactic acidosis, cardiac failure

Function/Absorption
● Involved in:
o Glycolysis and Krebs cycle
o Branched-chain amino acids metabolism
o Pentose Phosphate Cycle Metabolism
● Absorbed in the jejunum.

Niacin Deficiency (Vitamin B3)

Pellagra
● 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/Absorption
● Generic form for two forms: nicotinic acid and nicotinamide
o Forms NAD and NADP/NADH and NADPH.
 ● Absorbed in the jejunum.

Vitamin B12 Deficiency

(Done in CR)

4. Nutrients in Medicine (Undernutrition)

Learning Objectives
• Understand the difference between malnutrition & undernutrition
• Understand prevalence & causes of undernutrition in UK
• Describe how to identify those at risk of undernutrition.
• Understand the physical & psychological effect of undernutrition.
• Be aware of the different methods of nutritional assessment
• Understand the different methods of delivery of nutrition support
• Be aware of the ethical & medico-legal aspects of artificial nutrition support

Undernutrition: a form of malnutrition.

● Reduced supply of food/inability to digest/utilise necessary nutrients.
o Macronutrients.
o Micronutrients.

1. Addressing Hospital Undernutrition

● Identify NICE/MUST (malnutrition universal screening tool).

Repeat weekly
Assess Nutritional Status
● Subjective Global Assessment
o History = weight, BMI, BMI changes, diet history etc…
o Physical = muscle wasting, fat stores, ascites, oedema
● Clinical Measurements
o Skinfold thickness (fat)
o Mid Arm Circumference (muscle)
▪ If <23.5, BMI is likely to be <20.
▪ If >32, BMI is likely to be >30.
o Imaging: DEXA
o Handgrip Dynamometry (HGD) or Grip Strength
● Laboratory Tests
o Anaemia
o Plasma Proteins
o Vitamin and Mineral Concentrations
o Immune Response

2. 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
5. Insulin Secretion and Action
Learning Objectives
1. List the symptoms, causes and consequences of hypoglycaemia.
2. Describe the actions of glucagon on glucose and lipid metabolism in the post absorptive and fasting states.
3. Describe the hepatic glucoregulatory actions of glucagon.
 4. Outline how glucagon opposes insulin action as glucose levels fall.
5. Outline the action of glucagon on hepatic lipid homeostasis during fasting.
6. Understand the regulation of thyroid pathophysiology.
7. Outline the metabolic effects of thyroid hormones.
8. Describe the acute metabolic actions of adrenaline and noradrenaline.
9. Summarise the physiological actions of the glucocorticoids on metabolism.

● Blood glucose tightly maintained despite wide fluctuations (except for first few days of life).
o Kept within range of 3.5-5.5 mmol/L (before meals)
▪ Less than 8mmol/L (2 hours after meals).

1. Brain and Glucose

● Brain is highly dependent on extracellular glucose concentration because it cannot:
o Store glucose.
o Metabolise substrates (apart from ketones).

2. Pancreas and Glucose

Pancreatic Cell Types:
● Primarily Exocrine cells
● Endocrine cells (Islets of Langerhans).
o Secretes insulin and glucagon
o Accounts for only 2% of the
total mass of the pancreas.

Islets of Langerhans.
● Alpha Cells: producing glucagon
● Beta Cells: producing insulin
● Delta Cells: producing somatostatin
● PP Cells: producing pancreatic polypeptide
● Epsilon Cells: producing ghrelin.

3. Insulin Production and Secretion

● Monomer: active forms
o Two chains (21aa and 30 aa) linked by three disuflide linkages.
▪ Form dimers when increase in concentration
● Hexamer: storage form of insulin.

Mechanism of Production
1. Initially synthesized as preproinsulin in pancreatic beta-cells.
a. Long chain (110 aas)
2. Processed into proinsulin 5-10mins after assembly in ER.
3. Undergoes maturation into active insulin through action of cellular
endopeptidases within the Golgi apparatus.
a. Cleave of C-peptide by breaking bonds
b. 86 amino acids to 21 + 30 aas (insulin) and 35 aas (C-peptide).

Regulation of Production
● Transcription from insulin gene (mRNA stability and mRNA translation)
● Post-translation modifications

Mechanism of Insulin Secretion

NOTE: insulin synthesis and secretion are largely independent.
1. 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)
2. Glucose ฀ Glucose-6-phosphate ฀ pyruvate
3. Generates ATP (rise in ATP: ADP ratio).
a. Closure of potassium-ATP channels
i. Membrane depolarization
4. Voltage-gated calcium channels open.
a. 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.

Further Insulin Release

There are signals other than glucose that can cause the release of insulin release. Include:
● AAs: arginine and leucine.
● Glucagon like peptide-1 (GLP-1)
● Fatty acids.
● Acetylcholine.
● CCK.

Mechanisms that Amplify Insulin Secretion

● Intracellular release of AAs
● Leucine (allosteric activation of GDH)
● Arginine (directly depolarise plasma membrane)

4. Physiological Roles of Insulin

● IR receptor = transmembrane tyrosine kinase receptor.
● Activated by insulin, IGF-I, IGF-II

Mechanism of Action
● Insulin binds to extracellular portion of alpha subunits
● Phosphorylation of receptor
● Allows IRs to bind.
o Phosphorylation of downstream effectors.
▪ Glucose transporters travel to membrane

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

5. Insulin and Liver

● Enhances glucose uptake
● Increases glycogen synthesis
● Increases lipogenesis
o Exported as lipoproteins.
6. Other Functions of Liver
● Promotes protein synthesis and storage.
o Increases translation of messenger RNAs
o Inhibits catabolism of proteins
● Stimulates transport of amino acids in cells
● Promotes potassium intracellular uptake.

7. Post-Prandial vs Fasting vs Starvation

Post-Prandial
Fasting

Fatty Acids and Ketogenesis: accumulation of acetyl-coA from

oxidation of fatty acids cannot all be used in the Kreb’s cycle.
● This is because the end-product oxaloacetate is being
used by gluconeogenesis (and therefore cannot form
with acetyl-CoA to form citrate).
● Acetyl-CoA is therefore converted into ketone bodies.

Prolonged Fasting
8. Insulin Signalling Switch Off
● Endocytosis and degradation of the receptor bound to insulin.
● Dephosphorylation of the tyrosine residues.
o IRS possibly not phosphorylated by tyrosine but by another residue.
● Decrease in the number of receptors that leads to insulin signalling.

6. Nutrition and Diet

Learning Objectives
1. Assessment of patient's nutritional status
2. Planning nutritional intervention
3. Reviewing outcome of nutritional intervention
Malnutrition costs the NHS around 20 billion annually.

1. Albumin
● 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
o 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).

2. Refeeding Syndrome
● Covered mainly in PBL
 o “Potentially fatal condition characterised by severe fluid
and electrolyte shifts and related metabolic implications in
malnourish patients undergoing refeeding).

3. Summary (Nutritional Support

7. Liver Anatomy
Learning Objectives
1. Understand the relations and the basic structure of the liver.
2. Understand the peritoneal reflections surrounding the liver.
3. Describe the blood supply to the liver (both systemic and portal).
4. Explain the clinical importance of porto-systemic anastomosis.
5. Describe the biliary tree.

(NOTE: overlapping material with anatomy practical not covered).

1. Relations to the Liver

Anterior Relations of Liver
● Oesophagus lies underneath apex of left lobe (also overlies the fundus).
● On the right side the liver overlies the duodenum and part of the transverse colon (just below the
hepatic flexure).

Posterior Relations of Liver

● IVC and abdominal aorta run behind
● Superior mesenteric vein and artery (surrounded by head of pancreas).

2. Surfaces of the Liver

● It has a diaphragmatic surface (superior) and a visceral surface (inferior)
● Bare area: contains no peritoneum (large triangular area).

Subphrenic Recess: separates liver from diaphragm.

● Recess divided longitudinally by faliciform ligament
o Attaches to the diaphragm.

Hepatorenal Recess: separates liver from kidneys.

NOTE: These recesses meet anteriorly.

3. Lobes
● Contains four lobes
o Right lobe (two accessory lobes).
 ▪ Caudate Lobe: between fissure for ligamentum venosum and groove for IVC.
▪ Quadrate Lobe: between fissure for ligamentum teres and gall bladder.
o Left Lobe.
● Right and left = separated by fossa for gall bladder and vena cava

Attachments and Ligaments

● Attached anteriorly by faliciform ligament.
o Continues as the ligamentum teres (where the umbilical vein travelled)
o Divides subphrenic recess in 2 regions.

Coronary Ligament: reflection portion of visceral peritoneum.

● Attaches to diaphragm.
● Surround the bare area
o Also, surrounded by the gallbladder fossa and porta hepatis.
● Anterior and posterior layers (joins lesser omentum).

Right and Left Triangular Ligament

● Formed when anterior and posterior layers of coronary ligament join

Hepatoduodenal and Hepogastric Ligaments

● Hepogastric connects to lesser curvature of the stomach
● Hepatoduodenal attaches to the duodenum.
o Hepatic portal vein
o Hepatic artery
o Bile duct
PORTA HEPATIS: deep fissure of liver that contains these structures.

Couinaud’s Segments
● Hepatic artery and portal vein subdivide lobes = 8 segments.
o Flow through liver and return to IVC.
o Blood carried into sinusoids of the liver lobule.
 3. Blood Supply to the Liver
● 25% through celiac trunk
● 75% through hepatic portal vein.

Hepatic Portal System of Veins

● Splenic and superior mesenteric veins meet
posterior to head of pancreas to form portal vein.
o Inferior mesenteric veins drain to splenic.

Porto-Systemic Anastomoses
● Regions: drainage into hepatic or caval system.

Summary Table
Portal Venous Systemic Venous Sign/Symptom
Drainage Drainage
Oesophagus Left gastric vein Azygous and Oesophageal varices,
hemiazygos hematemesis
Rectum Superior rectal vein Inferior Rectal Vein Recto-anal varices

Anterior Paraumbiliac veins* Intercostal and Caput medusa.

Abdominal Wall inferior epigastric
Retro-Peritoneal Duodenal, Lumbar veins Retroperitoneal
pancreatic, right haemorrhage.
and left colic veins
*Occurs if paraumbilical veins are recanalised.

Ascites: fluid in peritoneal space caused by:

● Porta Hypertension, Hypalbuminaemia
● Aldosterone related renal sodium retention

Caput Medusa: recanalised umbilical vein within the faliciform ligament.

● Paraumbilical veins radiate superiorly to IC veins and inferiorly to epigastric vein.

4. Liver Cirrhosis
● Consequence of chronic liver disease
o Characterized by replacement of liver tissue (by fibrosis, scar tissue, regenerative nodules).
▪ Nodules: lumps occur because of damaged tissue regenerating.
● Lead to loss of liver function.

Portal Hypertension
Defined when portal pressure (Gradient between portal vein
and IVC pressures gradient is greater than 10mmHg)
▪ Normal portal pressure = 9mmHg.
▪ Inferior Vena Cava = 2-6mmHg.
● Can lead to splenomegaly.

5. Venous Drainage of the Oesophagus

● Oesophageal veins (azygos vein branches)
 ● Left gastric veins (portal vein).

Oesophageal Varices
● Occur at anastomoses of left gastric vein with oesophageal veins at gastro-oesophageal junction.

6. Biliary Tree
● Bile secreted by the liver at a constant rate (40ml/hour)
● Bile canaliculi drain into interlobular ducts
o Form right and left hepatic ducts (porta hepatis)
▪ Right hepatic duct: right lobe, caudate and
quadrate lobe.
▪ Left hepatic duct: left lobe
o Leave as common hepatic duct.
▪ Lies in free margin of lesser omentum.
● Joined by cystic duct = bile duct
o Anterior to hepatic
portal vein, right of the
hepatic artery.
● Joined by pancreatic duct.
Supplied by the cystic artery.
8. Insulin (2): Counter Regulatory Hormones
Learning Objectives
1. Describe the structure of the pancreatic islet of Langerhans; list the major cell types and the hormones that they secrete.
2. Describe the main structural features of the insulin molecule.
3. Outline how insulin secretion is regulated.
4. List the major metabolic actions of insulin on the metabolism of the major energy fuels, glucose and lipid, in the postprandial state.
5. Describe the main features of the insulin receptor.
6. Describe the main features of the intracellular insulin signalling pathway.
7. Define insulin resistance.
8. Describe the molecular basis of insulin resistance at the level of the insulin receptor.

1. Glucagon
● Alpha cells of the islets of Langerhans produce glucagon.
o 29aa peptide
o Synthesized just like insulin
▪ Preproglucagon ฀ proglucagon ฀ glucagon.

NOTE: cells in the islets of Langerhans interlink and interact with each other.
● Beta cells inhibit alpha cells and vice versa.

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).

Glucagon Receptor
● G protein-coupled receptor (GPCR).

Results of Glucagon Secretion

● Decreases glycogenesis.
● Increased glycogenolysis.
o Activates cAMP which activates
PKA
o Mediates production of
glucose from glycogen.
NOTE: glycogen stores depleted in 24 hours.

● Increases gluconeogenesis.
o Uses AAs, glycerol and lactate.
o Inhibition of
phosphofructokinase-1 and
pyruvate kinase are critical
▪ Enzymes in glycolysis.
o Increased amino acid uptake into the liver.
NOTE: to prevent muscle wasting.

● Increases lipolysis
o Glucagon activates hormone sensitive lipase
▪ Allows triglycerides to be broken down.
● Glycerol used in gluconeogenesis.
● Fatty acids used in beta oxidation.
o Generate ketone bodies when in excess
▪ Occurs because C substrates in the Kreb’s cycle are used
up in prolonged fasting.
o Also, involves the activation of the carnitine shuttle
▪ Transport fatty acids into the mitochondria
● Mediated by CPT-1.
NOTE: throughout: inhibition of glycogen and triglycerides synthesis is inhibited.
Regulation of Glucagon
● Inhibited: by insulin and somastatin.
o Insulin converts cAMP to 5’AMP through phosphodiesterase
▪ This switches signalling OFF (does not stimulate PKA).

2. 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.

Epinephrine
● Inhibits insulin secretion
● Stimulates glycogenolysis in the liver and muscle.
o Produce cyclic AMP and PKA
● Stimulates glucagon secretion
● xIncreases lipolysis in adipose tissue.

Glucocorticoids = LONGER RESPONSE

● Cortex cells = have many LDL receptors, enabling cholesterol uptake.
o Enables steroid hormone synthesis.
● Cortex cells secrete glucocorticoids and other steroids.

Cortisol: 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.

The reason is takes longer = it passes through the plasma membrane and binds to nuclear receptor in cell.
● Goes into the nucleus and stimulates transcription of genes.

Growth Hormone is another example.

3. Other Hormones involved in metabolism

Thyroid Hormones
● T4 (thyroxine) and Triiodothyronine (T4)
o 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
o Increased basal metabolic rate

Incretins
● Group of GI hormones including glucagon-like
peptide-1 and gastric inhibitory peptide.
o Enhancement of insulin secretion.

9. Clinical Skills
10. Diabetes
Learning Objectives
1. Outline the potential abnormalities of glucose homeostasis in diabetes mellitus.
2. Describe the principal forms of diabetes mellitus.
3. Outline the changes in glucose and insulin during an oral glucose tolerance test in normal, insulin resistant and diabetic subjects.
4. Outline how glucose tolerance can be maintained by the balance between insulin secretion and action.
5. Describe how beta-cell mass changes in type 2 diabetes
6. List mechanisms that can amplify insulin secretion
7. Summarise the effects of inadequate insulin secretion or action upon carbohydrate and fat metabolism, including the etiology of diabetic ketoacidosis.
8. List the long-term complications of diabetes mellitus.
9. Outline the effects of persistent hyperglycaemia.
10. Describe advanced glycation end products (AGEs) and AGE receptors (RAGEs)
11. Describe the Hb A1c test.
12. Outline the macrovascular complications of diabetes mellitus.
13. Outline how increased AGE promote atherosclerosis via low density lipoproteins (LDL).

● Chronic non-communicable/contagious disease

o Main characteristic is hyperglycaemia
● Causes: relative insulin deficiency or resistance (or both).
o Usually irreversible and ฀ reduced life expectancy
● Quadruples since 1980.

TYPE 1 DIABETES (T1D)

● Chronic autoimmune disease
● Insulitis (infiltration of mononuclear cells).
o Immune T-cell mediated destruction of beta cells in islets of Langerhans.
o Immunosuppression delays beta cell disruption.
● Leads to insulin deficiency (constant need for injections).

Heredity
● Prominent in young patients (before 30 years of age).
● Not genetically predetermined but there is inherited increased susceptibility.
o Genetic basis not fully understood.
o Incidence increasing ฀ environmental factors involved in pathogenesis.

TYPE 2 DIABETES
● Abnormal insulin and secretion.
● Often overweight and obese
● Genetic component is there but genes not known.

Risk Factors
● Obesity: BMI greater than 31 = 40 increases risk
● Family: skeletal muscle insulin resistance
● Age: increased mitochondrial dysfunction, inflammation.
● Ethnicity

Causes (Insulin Resistance)

● 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 IR.

NOTE: 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.

Example: FFAs, accumulated lipids or cytokines may induce phosphorylation of IRS when insulin binds but with
the wrong residue (i.e. not a tyrosine residue).

1. Insulin Resistance and Islet Compensation

Healthy
● IR is associated with physiological conditions
o E.g. pregnancy or body weight gain.
● Islets (beta cells) will increase in size and number in response, as well as elevating their function.
o Glucose tolerance maintained by increased secretion of insulin.

In Type 2 Diabetes
● Because of environmental factors/cytokines/genetic
components ฀ beta cell dysfunction (T2D)

Genetic Basis of Reduced Pancreatic Beta Cell Mass

● Genes susceptible are regulators of cell regeneration.
o In healthy populations, insulin secretion is
impaired more often than insulin action.
● Inherited abnormalities of beta cell function/mass are
critical in the development of T2D.

2. Deregulation of Glucagon
● Hyperglucagonaemia occurs in all types of diabetes.
o Occurs even when glucose is high.
o Because = alpha cells become resistant to high
levels of glucose/insulin through glucolipotoxicity.
▪ OR defect in insulin secretion.
o Nothing to tell cells to stop secreting glucagon.

3. Diagnosis of Diabetes
● One abnormal plasma glucose in presence of symptoms (random or fasting).
o Thirst, increased urination, recurrent infections, weight loss etc…
● Two abnormal glucose samples in asymptomatic patients when fasting.

Oral Glucose Tolerance

● Starve patient for a few hours.
● Levels of glucose measured before and after consuming sugary drink.

HbA1C
● Modified haemoglobin when glucose is attached to it (glycated).
o Measure percentage of glycated haemoglobin.
● Disadvantage: costs money.

4. Treatments (aims to lower blood glucose levels)

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).
5. Acute and Chronic Complications of Diabetes
ACUTE
Ketoacidosis (only for type 1).
● Lack of insulin ฀ body will switch to prolonged fasting.
o Ketone bodies production
● Blood urine acid levels rise, dehydration, coma, death.
● Potentially life-threating complication.

Hypoglycaemia (only for type 1).

● Low blood glucose

Causes
● Alcohol excess = gluconeogenesis is inhibited
● Insulinoma = a tumour of pancreatic beta cells.
● Excessive Exercise = increase glucose usage
● Reactive Hypoglycaemia = occur in response to high carbohydrate meal due to excessive insulin
secretion (pre-diabetic condition).
● Type 1 Diabetes = high insulin injections without meal

Signs and Symptoms

● Mild ฀Autonomic: Trembling, sweating, anxiety, hunger
● Moderate ฀ Neuroglycopaenic: Confusion, disorientation, weakness, tiredness.
● Severe ฀ confusion, fitting, seizures, coma.
o 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

CHRONIC
Hyperglycaemia
Protein Kinase C Pathway Stimulation
● Increased when excess glucose.
● Can damage blood vessels because:
o Increased permeability
o Increased occlusion
o Increased reactive O2 species
o Increased inflammation
o Mitochondrial dysfunction.
 ● Macrovascular
o Atherosclerosis
▪ Increases uptake of LDLs by modification of low LDLD receptor.
▪ Pro-inflammatory cytokine production.

● Microvascular
o Kidney disease (nephropathy)
▪ Damage to blood vessels in glomerulus
● Proteinuria, glomerular hypertrophy, decreased glomerular filtration.
o Nerve disease (neuropathy)
▪ 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.

OTHER FORMS OF DIABETES

Maturity Onset Diabetes of the Young = pancreatic beta cell dysfunction.
● Inherited (autosomal dominant).

Gestational Diabetes = diabetes in pregnancy (2-6% of pregnancies in Europe).

● 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

11. Acid-Base: The Metabolic Side

Learning Objectives
• Understand why Acid-Base homeostasis is essential for human physiology
• Learn how cell metabolism and environment are constantly challenging the pH of the human body
• Learn the how to calculate the anion gap and what type of metabolic disorders it is associated with
• Learn which organs are involved in pH regulation and by which mechanisms
• Learn the relationship between pH, [HCO3-] and PaCO2
• Learn the four forms of Acid-Base disturbance

1. Normal Blood Limits

● 7.35 to 7.45
● Death = 6.8 and above 8.0.

Formation of Acid
● Intake is normally neutral.
● Results from cellular metabolism.
 o Carbonic, sulphuric, phosphoric etc…
● H+ added continually.
o CO2 ฀ carbonic acid (@15 mol/d)
o Lactate @1,5 mol/d
o Acid in diet and acids produced by metabolism (@60 mmol/d).

2. Mechanisms Limiting Changes in pH

Buffer = solution that can maintain a nearly constant pH when strong acids or bases are added.
It is the mixture of a weak acid and is conjugate base (or a weak base and its conjugate acid).

Phosphate Buffer System:

● H+ + HPO42- <-> H2PO4-
● Part of renal regulation (minor role in ECF).

Protein Buffer System

● Acidic and basic side chains can give up or take up H+.
● If the pH rises: the carboxyl group of an amino acid acts as a weak acid
● If the pH falls: the amino group acts as a weak base.

Hemoglobin Buffer System

● Can buffer changes in H+ caused by CO2 levels.
o H+ + Hb ฀฀ HHb
● In tissues: CO2 + H2O ฀ H2CO3 ฀H+ + HCO3- (bicarbonate buffer system)
o H+ + Hb ฀฀ HHb
● In lungs: HHb releases H+ (and takes up O2)
o H+ + HCO3- ฀ H2CO3 ฀ H2O + CO2 (excreted)

Bicarbonate/carbon dioxide buffer system

● Abundant in ECF
o CO2 + H2O ฀ H2CO3 ฀H+ + HCO3-
● Means that it can buffer H+ from any other source than CO2.
● E.g. lactic acid, salicylic acid

NOTE = 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.

3. The Anion Gap

● [Na+] – [Cl-] + [HCO3-] = 8 to 12 mEq/L.
o K+ may be included but often not (small).

Normal Gap Acidosis

● Loss of bicarbonate
o CL- compensates (HCO3-/Cl- symporter).
o Leads to hyperchloremic metabolic acidosis
▪ Within cells and within plasma.
o Causes include:
▪ Severe diarrhoea
▪ Losses via NG tubes
▪ Administration of Acidifying Salts.
 ● Reduced Kidney H+ Excretion
o 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+).
o Leads to hyperchloremic metabolic acidosis

Elevated Gap Acidosis

● Increase in unmeasured anions and decrease in bicarbonate
o E.g. formic acid, lactic acid (for example in liver disease), acetoacetate (diabetes).
● 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
● Calculation: different to another anion gap. Need correct for loss of albumin.

4. Renal Control of pH
● Third line of defence and ultimate acid-base regulatory organ.
o Only kidneys can rid body of metabolic acids.
● Kidneys must do two things: reabsorb bicarbonate and excrete acid.
o Does this by hydrogen secretion, bicarb reabsorption and excretion of H ions with urinary
buffers (titratable acids ฀ H+ + HPO42- ฀ H2PO4- and ammonium (NH4+).

Reabsorption of all filtered

bicarbonate
 ● HCO3 converted to OH- and CO2. CO2 is absorbed directly by the cell and converted back to HCO3-
through addition of OH- (enters cell after forming H20 with H+). H+ is recycled.
● HCO3- is then pushed into the interstitial space.

Excrete the daily acid load

● Active extraction of H+ happens in various
parts of distal kidneys.

NOTE: intercalated cells have reversed polarity.

● Alpha-intercalated = secrete acid.
● Beta-intercalated = secrete bicarbonate and
reabsorb acid.

When
the
Body
is in
Acidosis
● Excrete H+ and retain more bicarbonate.
● Glutamate Pathway = also allows to produce
bicarbonate (production of alpha-ketoglutarate to glucose = side products are NH4+, HCO3-).

When the Body is in Alkalosis

● Tubular cells secrete bicarbonate and reclaim hydrogen ions. Uses ATP-ases
(secrete H+).
● Also = trading K+ ions with H+ ions.

Hormonal Regulation of the Acid/Base Status

● Aldosterone = increases pH
● Angiotensin II = increases PH

● Parathyroid = prevents reabsorption of

HPO32 and increases pH.

12. Appetite Regulation

Learning Objectives
• Define the terms anorexigen and orexigen.
• Outline the control of food intake by the hypothalamic leptin- melanocortin pathway.
• Describe the role of malonyl-CoA in the hypothalamus as a regulator of food intake.
• Understand the significance of leptin resistance in obesity.
• Summarise the impact of insulin on satiety.
• Summarise how hormones from the gut, ghrelin, affect food intake.
• Outline the role of serotonin in the regulation of appetite.

BMI is 30-70% heritable (regional adiposity is becoming consistently

more heritable). Various affected genes have been found.

1. Arcuate Nucleus
● Main centre for appetite regulation in the hypothalamus.
o Input from two systems:

Agouti Related Peptide (AgRP), NPY Neuron

● Orexigenic Signals
o Melanocortin receptor antagonists.
▪ Inhibit the satiety centre.
o Appetite stimulating

Proopiomelanocortin (POMC) and (Cocaine, Amphetamine Regulate Transcript (CART) Neuron

● Anorexigenic Signals
o Melanocortin receptor agonists.
▪ POMC undergoes post-translational modification ฀ melanocortins.
● Stimulate satiety centre
o Appetite inhibiting.

Alpha-melanocyte-stimulating hormone (MSH) = considered the predominant POMC derived products (control
energy balance). If deficient will result in hyperphagic (abnormally great desire for food) obesity.

2. Peptides Regulating Appetite

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.

Ghrelin = orexigenic
● Mainly produced in fundus, duodenum and ileum.
● Mechanism of action
o Stimulates NPY (and AGRP).
▪ Increases food intake directly and via CNX.
o Decreases after meal.

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.
● NOTE = interacts on same pathway as insulin (inhibits lipolysis).
o Drop AGRP levels (increased in ob/ob and db/db).

Summary

3. Malonyl CoA
● Potent controller of appetite.
o Inhibits lipolysis (carnitine shuttle) at high levels
o Lipolysis is stimulated at low levels.
● Malonyl CoA sensing drives whether we are hungry or not.
o Not Hungry = result of malonyl-CoA increased in cytoplasm (for FA synthesis).
▪ High levels sensed by hypothalamus
● Turns down AgRP and NPY
● Decreases appetite.
o Hungry = less malonyl-CoA in cytoplasm (no FA synthesis)
▪ Sensed by hypothalamus
● Increases AgRP and NPY.

4. Therapeutics
● Gut Microbes: different between obese and lean mice
o Transfer one to the other may have impact on obesity.
● Cannabinoids = increase appetite and consumption of food.
o High expression of CB1 receptor in hypothalamus.

13. Obesity
Learning Objectives
1. Describe the prevalence of obesity in the UK and its relationship with the population's intake of fat and carbohydrate and trends in physical exercise.
2. Discuss the pathological and psychosocial consequences of obesity.
3. Explain the links between obesity, insulin resistance and diabetes.
(Contains lots of epidemiology you don’t need to know).

“Abnormal or excessive fat accumulation sufficient to adversely affect health/reduce life expectancy.”
● Crude measurement = BMI (kg/m2)
● More accurate = waist circumference (or waist/hip ratio).
o Distinguishes muscular people.

1. Insulin and Obesity (insulin makes you fat).

● 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.

Impact of T2D Drugs on Insulin Levels

● Increase: insulin injections, sulfonylureas, TZD
● Stable: metformin, DPP IV inhibitors
● Decrease: SGLT-2 inhibitor

2. Heritability
● Obesity is highly heritable (>0.70).
▪ Comparable to schizophrenia (0.81) and autism (0.90).
▪ Higher than hypertension (0.29) and depression (0.50).
o Due to selective advantage in populations with frequent starvation.
▪ Thrifty gene hypothesis.

Syndromic Monogenic Obesity

● Exceptionally rare (e.g. fragile X, prader-willi etc…)
o Mental retardation, dysmorphic features in addition to obesity.
● Bardet-Biedl Syndrome
o Ciliopathy
▪ Cilia mediate leptin receptor signalling.

Non-Syndromic Monogenic Obesity

● Currently 12 genes identified that have roles in energy maintenance (leptin-melanocortin pathway).

Polygenic Obesity
● 227 genetic variants involved in different biological pathways.
o 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.

Epigenetic Variation.

3. Aetiology of Obesity
Brown Adipose Tissue = main site of adaptive thermogenesis.
● Associated with protection against obesity and
metabolic diseases (T2D mellitus and dyslipidaemia).

Major Risk Factor for:

 ● CV diseases
● Pulmonary disease
● Metabolic disease
● Osteoarticular diseases
● Serious psychiatric illness

NOTE = obesity could cut lifespan by 11 years.

Obesity and T2D

Obesity causes:
● Chronic inflammation of the fat tissue
● Altered adipokine levels
o Especially leptin = this causes tissue to become leptin resistant.
● Breakdown of fat metabolism
o Accumulation of lipids in tissue
● Breakdown of glucose metabolism.

Obesity and Non-Alcoholic Fatty Liver Disease

● Build-up of fat in the liver.
● Seen in people who are overweight or obese.

4. Treatment for Obesity

● Prevention is key
o Lifestyle changes
▪ Diet
▪ Exercise
▪ Drug treatments
▪ Surgery

Drug Treatments:
● Orlistat (acts as lipase inhibitor).
o Reduces amount of fat absorbed from food.

Surgery
● Nobody gets surgery without undertaking
weight management course.
● Performed laparoscopically in patients with:
o Morbid obesity (BMI >40)
o BMI >35 AND related complications.
● Include:
o Restrictive procedures
▪ Restrict ability to eat (e.g. adjustable gastric banding).
o Malabsorptive procedures
▪ Reduce ability to absorb nutrients.
● Gastric bypass.
o Restrictive and Malabsorptive procedures

14. Development of the Kidney

Learning Objectives
1. Appreciate the basic anatomy of the intermediate mesoderm, mesonephric and metanephric systems
2. Know that the kidney is composed of the collecting system and excretory system
3. That the embryonic origin of the collecting system is the ureteric bud
4. The origin of the excretory system is the metanephric mesoderm
5. Appreciate during development how these tissue combine to give rise to the fully developed kidney
6. Describe the ascent of the kidney
7. Understand from their knowledge of kidney development how some of the common defects in kidney development can arise
8. Understand the embryonic origin of the adrenal medulla and cortex and how they give rise to the adrenal gland
9. Describe the development of zonation within the adrenal gland
1. Embryonic Ducts
● Mesonephric (Wolffian Ducts)
● Paramesonephric (Mullerian Ducts)
● Immature Gonads.
● Mesenchyme.

Female
● Mesonephric duct degenerates
o Apart from lower portion: ureteric bud.
● Paramesophrenic ฀ oviduct.

Male
● Paramesonephric duct degenerates.
● Mesonephric duct ฀ male reproductive duct.
o Lower potion also forms uretic bud.

2. Embryonic Kidneys
Three exist but only one is functional:
● Pronephric
● Mesonephric
● Metanephric (develops from mesonphrenic ducts).
o Goes on to become a fully developed adult kidney.

3. Metanephric Kidney
● Formed from 2 embryonic structures.
o Ureteric bud.
▪ Ureter
▪ Renal Pelvis
▪ Major and Minor Calyces
▪ Collecting tubules
o Metanephric bud.
▪ Renal glomerulus and capillaries
▪ Bowman’s capsule
▪ PCT and DCT
▪ Loop of Henle.

4. Fate of Ureteric Bud

● Ureteric bud encounters mesenchyme that runs down the side of the embryo. This forms the
metanephric bud. Major calyces are formed as the bud bifurcates.
● Major calyces form minor calyces as they subdivide
● These subdivide again to form collecting tubules (surrounded by the mass of the mesenchyme).

5. Fate of Metanephric Bud

● Mesenchyme will fuse with collecting duct at distal tubule and forms the remaining parts of the
nephron. This occurs because as mesenchyme meets ureteric bud it elongates (though signals sent).
6. Ascent of the Kidney.
● Metanephros located in the sacral region (S1)
o It ascends as the embryo unfolds. To the lumbar region (T12)
● Renal Arteries
o Will degenerate in the sacral region.
o New ones will form when the kidneys have fully ascended.

7. Function of the Kidney (Within Foetus)

● Functional at the end of the first trimester.
o Not involved in the excretion of waste products
▪ This is done by the placenta.
o Involved in generation of amniotic fluid.
 1. Urine passed into the amniotic cavity mixes with amniotic fluid.
2. Swallowed by the fetus.
3. Passes through kidney and excreted back into amniotic fluid.

PATHOLOGY
1. Kidney Agenesis
● Failure of kidney to form.
o Can be unilateral or bilateral.
▪ Unilateral:
● Common = 1:1000 live births.
● Patients would never know they have it.
▪ Bilateral
● Very rare (1: 10 000 live births
o Baby will not survive after birth.
▪ Needed for generation of amniotic fluid
▪ Oligohydramnios = reduction in amniotic fluid.
▪ Birth defects = lung development and club foot.
● Mechanism = ureteric bud on one side/both sides of embryo does not form.
o Mesenchyme receives no signals so kidney does not form.

2. Bifid Ureter
● Ureter splits into two to form either:
o Duplicate kidneys.
o Duplicate ureter.
▪ Does not impact function of kidney
● Common (2% in the UK).

3. Ectopic-Pelvic Kidney
● Two things can happen
o One kidney remains in pelvic region.
o Both remain and fuse to form a pancake kidney.
▪ Still functional.

4. Horseshoe Kidney
● Kidneys fuse in pelvic region.
● Attempt ascend but are stopped by the inferior mesenteric artery
so they form around it (one lope on either side) = U-shaped.
● Also, common: 1:500 to 1:1290.
o Still functional.

5. 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.
o Causes kidney to fail in 50% of patients by age 60.
 ● Two different types (inherited)
o Autosomal dominant (polycystin mutation)
▪ 85-90% are polycystin (PKD-1) mutations
▪ 10-15% are polycystin-2 (PKD-2) mutations.
● Polycystin = localised to primary cilia.
o Involved in cell adhesion, calcium transport, cell cycle.
o Autosomal recessive (fibrocystic mutation)

15. Kidneys and the Urinary System

Learning Objectives
• Describe the gross anatomy of the urinary system and relations of kidneys and adrenal glands
• Understand the blood supply to the kidneys and adrenals and the distribution of the arteries within the kidney
• Describe the course of the ureters and the position and relations of the urinary bladder in both sexes
• Discuss the structure, position and importance of urinary sphincter muscles

1. Surface Anatomy of the Kidneys

● Located in paravertebral gutter on the posterior abdominal wall.
o Extend down below the inferior ribs.
o Renal Angle = junction of 12th rib and lateral border of the erector spinae.
▪ Examination for tenderness is done here.
● Normally not palpable unless:
o Low body fat or enlarged due to disease.

2. Location
Anterior Relations
 ● Right Kidney = the liver (which also pushes it down) and part of the duodenum.
o Lies behind the 12th rib
● Left Kidney = the tail of the pancreas.
o Lies behind the 11th rib.

NOTE = Hepatorenal recess (Pouch of Morison) = fluid can collect here in pathologies.
● Lies between kidney and liver.

Posterior Abdominal Wall

● Muscles:
o Transversus Abdominis M.
o Quadratus Lumborum M.
● Nerves:
o T12: subcostal nerve.
o L1 contains:
▪ Iliohypogastric n.
▪ Ilioinguinal n.

Surrounding the Kidneys

● Enclosed in a lot of fat and fascia
● Most distally to most superficial:
o Pararenal fat.
o Renal Fascia (GEROTA’s fascia)
o Perirenal fat.
o Renal Capsule.
● Muscles of the back also surround the kidney:
o TA, IO and EO.
o Latissimus Dorsi.
o Quadratus Lumborum.
o Deep Back Muscles.

3.

Renal Structure
The kidney contains an outer cortical region and inner medullary region.

Drainage of Urine
● Collecting ducts ฀ renal papilla ฀ minor calyx ฀ major calyx ฀ renal pelvis ฀ ureter

Internal Vasculature
● Renal artery ฀ 5 segmental arteries (each supply renal segments).
o Segmental arteries ฀ interlobar arteries ฀ arcuate ฀ interlobular arteries ฀ afferent
arterioles ฀ glomerular capillaries
o 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 t=o right lateral position of IVC.
● Receives left suprarenal and gonadal veins.
● Lymph drainage ฀ lateral aortic lymph nodes.

Nerve Supply
● Via the renal plexus
o MOTOR
▪ Sympathetic (visceral afferent)
● Thoracic and lumbar splanchnic
▪ Parasympathetic (vagus).
o SENSORY
▪ Afferent fibres = enter T10-T12.
● Pain
o Direct pain = region of kidneys
o Referred pain = groin.

4. Kidneys and Adrenal Glands

● Adrenal glands sit on superior pole.
o Cortical part (corticosteroids).
o Medullary (epinephrine)

5. Ureters
● Retroperitoneal, muscular tubes.
● Pass over the pelvic brim at bifurcation of
common iliac arteries.
o Curves forward and medially into
the ischial spines.
● Enters bladder at posterosuperior angles.
o Ends at urinary orifices.

Blood Supply
 ● Comes from the renal arteries, the testicular arteries and the common iliac arteries.

Structure
● Tri-layered wall.
o Transitional epithelial mucosa.
o Smooth muscle muscularis.
o Fibrous connective tissue adventitia.
● Ureters actively propel urine to the bladder via response to smooth muscle stretch.
o Peristalsis.

NOTE = curves/narrowing’s in the ureter can cause for ureter stones. Tested for through pyelogram.

Nerve Supply
● Visceral afferents enter at spinal levels T11-L1/L2.
● Pain (Ureter/Kidney Stones)
o Referred along ilioinguinal and Iliohypogastric nerves (L1).
▪ As stone descends patient may start to feel pain over groin.
▪ Because of changing nerve segments (pain referred to genitofemoral (L1/L2).

5. Urinary Bladder
● Lies retroperitoneally on the pelvic floor (posterior to pubic symphysis).
o Apex = connected to umbilicus (median umbilical ligament)
o Base = inverted triangle
▪ Trigone = area between ureters and urethra.
● Clinical = infections persist in this region.

Structure
The bladder wall has three layers:
● Transitional epithelial mucosa
● Thick muscular layer
● Fibrous adventitia

6. Urethra
● Muscular tube that:
o Drains urine from the bladder.
● Sphincters keep the urethra closed when urine is not being passed:
o IUS = involuntary sphincter (male).
▪ Bladder-urethra (prevents retrograde ejaculation).
o EUS = voluntary sphincter.
▪ Voluntary sphincter surrounding urethra.
o Levator ani = voluntary urethral sphincter.

Females
Urethra tightly bound to anterior vaginal wall.
● External opening lies anterior to vaginal opening/posterior to clitoris.

Males
Double curvature and divided into four sections:
● Intramural (pre-prostatic) = length varies on bladder filling.
● Prostatic = contains ejaculatory ducts.
● Intermediate (membranous) = penetrates perineal membrane.
o Surrounded by EUS.
● Spongy = final part in corpus spongiosum of penis.
7. Micronutrition (Voiding or Urination)
● Act of emptying the bladder
● 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

16. Renal Excretory Function

Learning Objectives
1. Outline renal handling of important electrolytes
2. Show the effects of molecular size and charge on
the composition of glomerular filtrate.
3. Compare the reabsorption of sodium, glucose,
amino acids and hydrogen carbonate in the
proximal tubule of the nephron.
4. Regarding the renal reabsorption of glucose, define the terms: ‘renal threshold' and
'transport maximum'. What may be the effects of glucose presence in the final urine?
1. Glomerulus
● Structure enclosed by the Bowman’s capsule that filters plasma.
o Has an afferent and efferent arteriole
▪ Afferent arteriole has larger diameter vs efferent which generates a filtration
pressure.
● Allows fluid to be forced through endothelium
Podocytes
● Cells that cover the capillaries of the glomerulus and allow filtration of selected material.
● Capillaries are also fenestrated.
o Proteinuria ฀ if inflamed = proteins can enter urine.

Factors That Determine the Filtrate

● Net filtration pressure.
● Podocyte slit pores.
● Size of molecule.
● Charge of molecule.
o E.g. negative charge of large proteins will not allow them through.

Therefore, at the glomerulus there is:

● Free movement of small solutes/molecules (water, electrolytes, urea, amino acid).
● Restriction of larger solutes (proteins).

2. Glomerular Filtration Rate (GFR)

● Total amount of fluid filtered through the glomerulus
o 120ml/min (from C.O of 1.2l/min).
● Measurement is a parameter of kidney function.

Measurement of GFR
● Done by creatinine = completely filtered and none is reabsorbed.
o Break-down produce of CP found in muscle
● GFR = clearance of creatinine.
o Cr Clearance = (urine concentration x urine volume)/plasma concentration.
▪ Amount of substance cleared from plasma (i.e in urine) can be compared to the
plasma concentration/l to determine the glomerular filtration rate.
o (!) Creatinine is also actively secreted leading to an overestimation of 10-20%.

NOTE = creatinine clearance often takes place over a 24-hour period which can sometimes be difficult
● Gold standard = is therefore a nuclear medicine scan (e.g. Cr51-EDTA)
● Estimated GFR = MDRD equation or cockroft gault equation.

3. Relationship of GFR and Creatinine

● When creatinine is in normal range (60-100) small changes lead to a significant drop in GFR.
o Although relevant clinically, this can
sometimes be misleading
▪ A fall in GFR decreases creatinine
filtration and produces a
proportionate rise in serum
creatinine.
For example, it will be misleading in:
● Muscular individuals (naturally raised serum
creatinine)
● Malnourished individuals = low serum creatinine.
● Drugs = may inhibit tubular secretion of creatinine (e.g. Trimethoprin).

4. Loop of Henle and Osmolarity in the Kidney

Primary Active Transport = sodium absorbed through Na+/K+ pumps on the
basolateral membrane of the tubular cell.
Secondary Active Transport = because of gradient generated by Na+/K+, sodium can come into the cell and
co-transport phosphate, glucose and amino acids.

Renal Disease and Transport Proteins

Defects in transport proteins = renal disease.
● Proximal tubule (just be aware of these).
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

Proximal Tubule
● Proximal convoluted (2/3) and Proximal straight (1/3).
● Function = bulk reabsorption of solutes to 80%, water 65%, AAs, low molecular weight Ps (100%).

Counter current Mechanism

● Filtrate that leaves the proximal tubule = iso-osmolar to plasma (normal conditions).
o Excess water overload = urine is dilated (hypo-osmolar).
o Water Restriction = urine is concentrated (hyper-osmotic).

Loop of Henle Mechanism

Loop of Henle consists of ascending and descending loop:
● Descending Loop: receives fluid from PCT. Has many aquaporins that allow water
to leave the tubule and the fluid to become more and more concentrated.
● Ascending Loop: 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.
o Keeps ECF of medulla highly concentrated in lower regions while
returning it back to normal before it enters the collecting duct.
▪ It has a thinner and thicker part.
o Allows free movement of water from the descending limb to the interstitium.

Distal Nephron
Functions to excrete potassium, regulate sodium delivery to collecting duct as well as urine acidification.
● Presence of ADH = aquaporins become permeable to water.
o Moves down concentration gradient to interstitium.

5. Renal Absorption of Glucose

Renal Threshold = concentration of a substance dissolved in the blood above which the kidneys begin to
remove it from the urine. If exceeded, reabsorption in PCT is incomplete = substance remains in urine.
● Varies between substances
o E.g. urine is removed at a much lower concentration that glucose.
Glucose Levels
● Normal: 5.0 mmol/L
● Past Glucose Threshold = greater than 10 mmol/L.
o Glucose appears in urine because amount of glucose exceeds the reabsorption capacity of
tubules ฀ all glucose carriers are saturated.
o Rate of transportation depends on transport maximum for glucose.

Effects of Glucose Presence in Urine

● Induces osmotic diuresis.
o Water and urine attracted into collecting duct due to increased solute.
▪ Leads to polyuria.

18. Endocrine Anatomy

Learning Objectives
• Describe the structural and functional relationships between the hypothalamus and both the anterior and posterior lobes of the pituitary gland
• Describe the blood supply and venous drainage of the pituitary gland
• Discuss the anatomy and list the structures that pass through the cavernous sinus
• Describe the position, the anatomical relations and the blood supply of the adrenal glands
• Describe the position, the anatomical relations and the blood supply of the thyroid and parathyroid glands
• Describe the position, the anatomical relations and the blood supply of the pancreas

1. The Endocrine Glands Overview

● Network of glands found in cranium, neck, thorax, abdomen and pelvis.
o Are involved in maintaining homeostasis (growth and metabolism).
● Endo ฀ do not have ducts and secrete directly into the bloodstream.
● Diseases: occur when glands produce incorrect number of hormones.

Cushing’s Syndrome/Disease
Syndrome: high cortisol (e.g. caused by exogenous administration of glucocorticoids (CORTISOL) or tumour).
(Part of Syndrome) Disease: caused by tumour (pituitary oedema) 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.

PITUITARY GLAND
● Pituitary sits in the sella turcica (depression
in the sphenoid).

Anterior Lobe (Adenohyphosis)

● ICA = runs either side of the pituitary gland (in the cavernous sinus)
o Superior hypophyseal artery is a branch of this.
▪ Forms the primary plexus at the top of the
infundibulum.
● Hormones secreted as a result of releasing hormones into this
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.
● Drains via to hypophyseal portal veins to the anterior pituitary
where it is supplied into the cavernous sinus.

Low Levels of T3 and T4 = hypothalamus responds by releasing

thyrotropin releasing hormone which travels to secondary plexus and
thyroid-stimulating hormone ฀ increases T3 and T4.
Posterior Lobe (Neurohypophysis)
● Extension of the hypothalamus (made up of neural tissue)
● Two nuclei = cell bodies extend down into the PP
o Supraoptic (above the optic chiasm)
 ▪ ADH
o Paraventricular nuclei.
▪ Oxytocin
Cavernous Sinus

THE ADRENAL GLANDS

▪ Effectively a specialised sympathetic ganglion with
preganglionic sympathetic fibres (travel through pre-vertebral
aortic ganglion but don’t synapse).
o Synapse in ADs and release adrenaline.

Adrenal Gland Position

▪ Between superomedial aspects of the kidney and crura of the diaphragm (within perineal fat).
o Right AD = pyramidal shaped right (contact with liver and IVC).
o 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.

NOTE = venous drainage on the left is into the renal vein, on the right on the IVC.

THYROID AND PARATHYROID GLANDS

Scenario: be careful of not damaging these in surgery:
▪ Parathyroid glands (causes tetany)
▪ Thyroid IMA Artery
▪ Recurrent Laryngeal Nerve (dysphonia)
Infrahyoid muscles (four muscles)
▪ Thyrohyoid
▪ Sternohyoid
▪ Omohyoid
▪ Sternothyroid

1. Thyroid Gland
Lies at the level of C5-T1.
▪ Consists of left and right lobe connected by a thin thymus.

Arterial Blood Supply

▪ Highly vascular
o ECA = superior thyroid artery
o Subclavian ฀ thyrocervical
trunk = inferior thyroid artery
▪ Common variant: thyroid IMA artery
(10% of people have this).

Venous Blood Supply

▪ IJV = Superior, middle thyroid vein.
▪ BCV = Inferior thyroid vein.

2. Parathyroid Gland
▪ Located in the posterior aspect of the thyroid gland
o Variation between people.
▪ Function: involved in increasing blood calcium.

NOTE = recurrently laryngeal nerve also lies behind the thyroid gland.

PANCREAS
▪ Exocrine: secretion of powerful digestive enzymes into the SI.
▪ Endocrine: secretion of insulin and glucagon in to the bloodstream.

Blood Supply
▪ From both the foregut and the midgut.
o Coeliac Trunk
▪ Splenic artery
▪ Gastroduodenal ฀ superior pancreatoduodenal
(when it gives of its final gastric branch)
o Superior Mesenteric Artery
▪ Inferior pancreatoduodenal.

Anatomy and Gall Stones

Contains accessory
pancreatic duct and major
pancreatic duct.

20. Thyroid Gland

Learning Objectives
1. Outline the synthesis, storage and release of thyroid hormones
2. Describe the effects of thyroid stimulating hormone on the thyroid gland
3. Outline the actions of thyroid hormones
4. Briefly explain the pathophysiology of hypo- and hyperthyroidism
5. List the effects of excess and deficiency of thyroid hormones
6. Describe the detection and treatment of hyperthyroidism and hypothyroidism

Two main types of thyroid hormones

● Thyroxine = T4
 ● Triiodothyronine = T3
Essentially these increase metabolic activity.

(NOTE: lobule = 20-40 evenly dispersed follicular cells with colloid in the middle).

Diet
1mg of iodine required in diets per week (1/5th of this used for synthesis of thyroid hormones).
Follicular cells secrete hormones depending on secretion of TSH from the anterior pituitary gland. TSH:
● Stimulates expression of NIS, TOP, Tg which increase formation of T3 relative to T4.

1. Synthesis of Thyroid Hormones

1. Iodide taken up by NIS of the thyroid follicular cell (sodium-iodine symporter on basolateral
membrane) due to TSH increase (made possible by gradient created through Na+/k+ cells).
2. Iodide is transported to the colloid (this is where the synthesis
of thyroid hormones occurs through the pendrin transporter.
a. Follicular cell also secretes thyroglobulin.
3. Iodide oxidised to iodine.
4. Iodine binds to tyrosine rings of thyroglobulin.
a. One iodine binds = MIT
b. Two iodine binds = DIT
5. MIT and DIT can bind together forming T3.
6. DIT and DIT can bind together forming T4.
a. These are still linked to thyroglobulin.
7. These molecules will move back into the follicular cells.
a. Contains lysosomes = bind together with endosome
containing thyroglobulin
i. Release tyrosine molecules from structure.
b. Causes T3 and T4 to separate.
c. DIT and MIT release iodine to restart process.

T3 enters the nucleus (converted from T4) and enters target cells.
● In the nucleus = thyroid hormone receptor.
o Initiates transcription for specific mRNAs.
● This increases the metabolic rate.

Thyroid Deiodinases
● T4 is converted to T3 (active form) when it reaches the target
cell by thyroid deiodinases.

D1 = rT3 ฀ T4 ฀ T3
● Mechanism not fully understood.
D2 = provide T3 to the nucleus (particularly in the brain).
● 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.

2. Control of Thyroid Function

● Negative feedback
o The higher the iodine level the lower the rate of hormone formation.
o Control at intracellular level through D enzymes.

Hyperthyroidism/Thyrotoxicosis
Hyperthyroidism = hyper function of the thyroid gland.
● May cause thyrotoxicosis
o This can also be caused by the release of a hormone from a damaged gland.

Cardiovascular System
 ● Need to dissipate the excess heat.
● Causes atrial fibrillation

Metabolism
● Increased protein and lipid degradation
● Increased appetite
● Heat intolerance
● Hyperglycaemia.

Reproduction
● Oligomenorrhea
● Gynecomastia
● ED

Grave’s Disease
● An autoimmune thyroid disease
● Positive antibodies against TPO, thyroglobulin and most significantly the TSH receptor

Risk Factors: infection, stress, female.

Other causes of Hyperthyroidism/Thyrotoxicosis

● Toxic multinodular goitre
● Toxic adenoma
● Excess iodine
● HCG

Diagnosis Management of Hyperthyroidism

Diagnosis: High T3 and T4

Treatment: Thionamide drugs

● Propylthiouracil.
● Carbimazole.
Radioactive Iodine I-131
Thyroidectomy

Hypothyroidism
● Primary hypothyroidism: permanent loss or destruction of the thyroid.
● Central or secondary hypothyroidism: is caused by insufficient pituitary stimulation of a normal gland,
most commonly caused by damage to thyrotroph cells from a pituitary macroadenoma.

Cardiovascular System
● Reduced cutaneous circulation = sensitivity to cold
o J waves of hypothermia
● Sinus bradycardia.

GI Tract
● Reduced appetite constipation.
● Weight gain
Nerves, muscle, bone
● Impaired fetal brain development
● Dementia
● Growth retardation

Causes of hypothyroidism
● Hashimoto’s disease
● Infiltrative disease
● Hypopituitarism
● Cabbage
● Lithium.

Diagnosis and Management

Diagnosis = high TSH, low T4
Treatment
● Levothyroxine
● Liothyronine

21. Anatomy and Physiology of the Anorectum

(NO Learning Objectives)

INTRODUCTION
Review of Endoderm
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.

1. Embryology
● Imperforate anus or anorectal malformation.
o Failure/rupture of the anal membrane.
▪ Rectal fistulae may be found.
Hirschsprungs Disease
● Congenital megacolon due to lack of enteric neurons (ENS).
o Affected segments can’t relax (don’t allow stools to pass).
● Symptoms:
o Failing to pass meconium within 48 hours
o A swollen belly
o Vomiting green fluid.

2. Fluid and Electrolyte Absorption

● Small intestine receives 7-9L from different secretion and diet.
● LI = absorbs about 90% of the remaining volume.

3. Microbiota in the Gut

● Colonization occurs during a critical time window for immune and GI development.

ANATOMY AND PHYSIOLOGY OF CONTINENCE

● Normally faecal continence is maintained by:
o Anal canal
o Pelvic floor musculature
o Rectum

1. Anal Sphincters
Internal Anal Sphincter (IAS)
● Involuntary and thickened muscle
o Downward continuation of the inner circular muscle coat of the rectum.

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.

2. Pelvic Floor Muscle

Levator Ani
● Ischiococcygeus
● Iliococcygeus
● Pubococcygeus.
o MALE = pubourethralis and puborectalis
o FEMALE = pubovaginais and puborectalis

Puborectalis
● Passes backwards from the back of the pubic
symphysis (U-shape loop).
o Supports the EAS and assists in creating
the anorectal angle.

Flap Valve
● Tonic contraction produced by PC muscle
o Anterior rectal wall pushed down into canal during rise in
intra-abdominal pressure.

Nerves
● S2-S4 give parasympathetic supply through the pudendal nerve.
o Keeps the 3Ps off the floor (penis, poo and pee).

External Anal Sphincter

● Supplied by the inferior rectal branch of the pudnedal 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
o Parasympathetic: S2-S4 pelvic nerves
▪ INHIBITORY
● In a continuous tonic state.

DEFECAETION AND CONTINENCE

1. Continence
Dependent on an awareness of rectal filling.
o Impaired sensory function can affect these processes.
● Faecal continence is maintained by the:
o IAS and EAS (contraction)
o Puborectalis muscle (contraction)

Reservoir Continence
● Ability of the rectum to retain stool.

Renal Compliance
● Ability of rectum to adapt to imposed stretch.
o Mechanoreceptors activate sensation of urgency

2. Defaecation
Ano-Rectal Reflex (initiation of reflex = URGE).
Stretch of rectal afferents causes this reflex to occur:
● Causes relaxation of the internal sphincter
(due to inhibition of sympathetic hypogastric
nerve that causes tightening of IA).
o If conditions are not right: voluntary
effort increases external sphincter.
● Gradually afferents adapt and IAS contracts
again (reflex).
o Pressure goes back to normal as
faeces is pushed back up.

EXTENT of relaxation ฀ degree of distension.

Relaxation of IAS ฀ allows for sampling.
Defecation reflex (i.e. voiding reflex).
Defecation involves relaxation of the EAS and
puborectalis muscle.
● Individual also holds breath and creates a
pushing down effect (expiration against
closed glottis). Increases abdominal pressure.

Closure Reflex
● Last bolus of stool is passed = EAS is stimulated.
o Ampulli recti removes inhibitory drive to IAS.
o Voluntary contraction of EAS closes anus off.

CONSTIPTATION
● Purely symptomatic (not at diagnosis).
o Infrequent stools (<3 weeks)
o Passage of hard stools > 25% of the time
o Sensation of incomplete evacuation >25% of the time.
1. 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).

2. Secondary Constipation
Many other causes (quite straightforward).
● Endocrine = diabetes, hypothyroidism
● Neurological = spinal injury: Parkinson’s disease
● Psychogenic = eating disorders
● Metabolic = hypercalcaemia etc…

FAECAL INCONTINENCE
1. Passive Incontinence
● Structural/functional lesion to the internal sphincter.

2. Urge Incontinence
● Structure/functional lesion to the external sphincter.

RECTAL SENSATION
1. Hyper Sensitive
● Reduced sensory threshold to volumetric rectal distension

2. Hypo Sensitive
● Increased sensory threshold to volumetric rectal distension.

22. Bone and Calcium

Learning Objectives
1. Explain the relationship between the various forms of circulating calcium in blood
2. Describe the transformation of vitamin D3 into an active hormone and explain how this is regulated
3. Recognise the structure of vitamin D3 and describe the sources of this vitamin in the body
4. Describe the source of parathyroid hormone and explain how its secretion is regulated.
5. Describe the actions of parathyroid hormone and 1, 25-dihydroxyvitamin D3 and account for the effects of vitamin D3 deficiency, and for hypo- and
hyper-secretion of parathyroid hormone.
6. Outline the source and actions of calcitonin and explain its role in calcium metabolism.
7. Briefly explain how the body excretes excess calcium
8. Briefly explain the relationship between calcium and phosphate metabolism.

CALCIUM AND PHOSPHATE

[Link]
● 99% of body calcium is in the bone.
Blood Calcium
● 50% is bound to albumin
● 40% is ionised
o 10% bound to complexes with phosphate/citrate.

Acidotic State = less calcium binds to albumin (replaced by H+): increase in ionized Ca2+.
Alkalotic State = more calcium binds to albumin, decrease in ionized Ca2+
● Causes tingling of the lips (hypocalcaemia due to blowing of Co2).

Calcium Signalling
● Intracellular circulating molecule that is also involved in stabilizing Na+ pumps
o Sits within these channels to prevent them from firing.
● Hypocalcaemia = causes uncontrolled firing of nerves across the body (more dangerous than hyper).
o Can cause cardiac arrhythmia’s/cardiac arrest.

2. Phosphate
● 85% is mineralised in bone.
● Serum phosphate.
● Found in structural/informational/effector molecules.

PARATHYROID HORMONE
● Secretes 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.

1. Histology

2. PTH Regulation
High Levels of Calcium
● High levels of calcium inhibit PTH.
o However, it is not fully suppressible and there is always a basal amount secreted.
o Also, there is no major change in secretion (slightly decreased).

Low Levels of Calcium

● Dramatic increase in PTH secretion
o Lack of calcium picked up by calcium sensing receptor.

Calcium Sensing Receptor (CaSR)

● Reduces PTH Secretion
 ● Increases breakdown of stored PTH
● Supresses transcription of PTH gene.

Other Determinants of PTH Secretion

Decrease Secretion
● Activated vitamin D (1,25D/calcitriol) from 25 (OH) D3: supresses PTH transcription.
o Negative feedback loop
● Cinacalcet activates CaSR = restrains PTH

Increase Secretion
● Phosphate (increased secretion).

3. PTH and Renal Calcium Handling

● PTH only acts on distal tubule and is
only involved in 10% of calcium
reabsorption. Acts on:
o Upregulates TRV calcium
channels/calcium ATPase
and Na/CA exchanger.

Proximal Tubule: 65% of Ca2+ reabsorption

● Paracellular
● Driven by voltage gradient.

Loop of Henle: 20% reabsorption

● Paracellular
● Driven by voltage gradient.
● Inhibited by loop diuretics.

BONE PHYSIOLOGY
● Consists of collagen + hydroxyapatite (calcium and phosphate)
o Mineralisation = calcium + phosphate + alkaline phosphatase.

1. Bone Remodelling
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+.

NOTE = OPG (osteoprotegerin) inhibits this process and is therefore downregulated by PTH.
Further factors:
● Glucocorticoid = reduce osteoblast number, increase RANKL.
● Estrogen = inhibits bone remodeling.

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.

1. Vitamin D Receptor:
● Both nuclear and membrane bound.
o Negative feedback inhibition

2. Function
 ● Increase Ca2+ and phosphate absorption from the gut.
o And form kidney
● Stimulates bone reabsorption and remodeling.

Other Effects
● Increases levels of osteocalcin and RANKL
● Increases amino acid uptake.

3. Vitamin D Deficiency
● Caused by poor diet and lack of sunlight.
o Rickets
o Osteomalacia
o Osteoporosis

4. FGF23
● Secreted by osteoblasts in response to high phosphate levels.
● Decreases Ca2+ and phosphate levels.

5. Calcitonin and PTHrP

Calcitonin
● Thyroid C-cells
● Medullary thyroid cancer
o Role in humans unclear.

PTHrP
● Physiological role in lactation
● Everywhere in fetal life.

HYPERPARATHYROIDISM
● Increased PTH Levels = stones (renal calculi) bones (osteoporosis) groans (dyspepsia) moans
(depression, confusion), polyuria and polydipsia.
yPrimary 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
● Most commonly iatrogenic. Decreased PTH levels.
● Features:
o Convulsions.
o Arrhythmias.
o Seizures.
o Paraesthesia (tingling)
24. The Hypothalamo-Pituitary Axis
Learning Objectives
● Describe the structure/origins of the pituitary gland and explain the relationship between the hypothalamus and both the anterior and posterior pituitary.
● Use the concept of negative feedback to explain the principles underlying clinical tests for pituitary hormone secretion
● List the hormones secreted by both the anterior and posterior pituitary and in each case, explain the role of the hypothalamus in regulating their secretion
● Briefly outline the actions of the hormones of the posterior and anterior pituitary.

(First few slides are revision from endocrine anatomy lecture).

● NOTE: posterior pituitary: Hormones secreted into the
inferior hypophyseal artery.

Bitemporal
Hemianopia
Optic chiasm
compression by
pituitary adenoma:
causes loss of peripheral vision.

1. Pituitary Development
● Anterior pituitary = ectoderm
that grows from the roof of the
mouth (Rathke’s pouch).
o Upwards movement
● Posterior pituitary = forms from
the diencephalon of the brain

Transcription Factors
● Form a very important part of pituitary development.

2. Pituitary Hormones
● GH, TSH, PRL, ACTH, FSH and LH

Posterior Pituitary
ADH/Vasopressin
● Increases water absorption through the opening
aquaporins in the collecting duct.
● Desmopressin = drug that mimics it.

Oxytocin
● Stimulates milk synthesis

3. Thyroid Axis
● T4 inhibits TSH and TRH via negative feedback.
● TSH is also inhibited by somatostatin (SS).
● TRH can also stimulate prolactin release.

Thyroxine = T4
Iliothyronine = synthetic form of T3

Primary Underactivity: defect of thyroid organs (e.g.

Hasmimoto’s action on the thyroid gland).
Secondary Underactivity: problem with pituitary gland.
3. GH Axis
● GH is stimulated by GHRH as well as ghrelin.
o Inhibited by SS (negative feedback = secreted
when there are high levels of GH).
● Stimulates IGF (insulin-like growth factor) production.
o Inhibits GF and GFHRH via negative feedback.
o Stimulates secretion of SS.

Role of GHRH
● Promotes GH cell clusters (coordinated responses)
● Increase GH cell number.
● Increase GH synthesis.
● Stimulates GH release.

G-Protein Coupled Receptor

1. Ligand binding to the GPCR causes phosphorylation.
2. Activates G protein.
3. Alpha unit detaches from G protein and binds to AC (adenylate cyclase)
4. This increases cAMP activity which increases PKA levels.
 5. Causes a cellular response.

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 color).
● More common in females.

4. Adrenal Axis (Hypothalamo-Pituitary-Adrenal Axis.

● CHR (corticotrophin releasing hormone and ADH
stimulate ACTH (adrenocorticotrophic hormone).
● Stimulates cortisol production from the adrenal gland.
o Inhibits CRH, ADH, ACTH via negative feedback.

Circadian Rhythm of Cortisol

● Levels start to rise at about 3am.
● Peak in the morning between 6-9am.
● Levels decline throughout the day.

Cushing’s Syndrome
● Increased cortisol levels.
● Two types of Cushing’s syndrome:
o ACTH Independent:
▪ ACTH not being impact.
▪ Adrenal tumour may be the cause
● Cause of raised cortisol downstream from the pituitary gland.
o ACT Dependent:
▪ ACTH levels raised primarily.
▪ Issue due to a pituitary defect (e.g. adenoma).
● Increased ACTH leads to increased
cortisol.
● Symptoms:
o Weight gain, muscle weakness and skin changes.
Addison’s Disease: decreased levels of cortisol, lack of adrenal gland
steroid production.

5. Gonadal Axis
● Kisspeptin stimulates GnRH 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.

NOTE: in puberty oestrogen causes positive feedback to Kisspeptin.

Continuous GnRH Drive.

● Decreases LH pulse fertility.
25. Diuretics
Learning Objectives
1. Show, by means of a labelled diagram, the proportions of sodium reabsorbed from tubular fluid in: the proximal tubule; the loop of Henle; the distal tubule;
the collecting duct.
2. Compare the different mechanisms for sodium re-absorption found in different parts of the nephron.
3. Describe the actions of aldosterone on the distal tubule and collecting duct which maintain the sodium balance of the body. State the fraction of the total
sodium re-absorption which is subject to regulation by aldosterone.
4. List the major clinical indications of the uses of a diuretic.
5. Give the primary sites of action of thiazide, loop diuretics, and spironolactone, and rank them in order of their efficacy.
6. Explain why diuretics increase potassium excretion, and how this may be reduced.
7. Explain the use of mannitol as a 'diuretic'.

● Diuretics are a common medication used to cause increased water loss from the kidneys.
● This is achieved by decreasing Na+ reabsorption at different sites.
● 120ml solute / minute are filtered through the kidneys.
1. Classes of Diuretics
There are five classes of diuretics:

Carbonic anhydrase inhibitors

Proximal Convoluted Tubule
● Carbon anhydrase converts H2CO3 (formed from bicarbonate and hydrogen) to H2 and CO2 which is
absorbed by the PCT.
● CA also acts within the cell to transform H2CO3 (formed from CO2 and H2O absorbed) to H+ and
HCO3-. HCO3- is absorbed into the blood while H+ is excreted to restart the process.
Carbonic anhydrase inhibits CA: bicarbonate ions are not reabsorbed.

Clinical Use:
● CA inhibitors reduce bicarbonate absorption, leading to metabolic acidosis.
● This can be used to counter mountain and altitude sickness, as it counters the respirator alkalosis due
to hyperventilation.

Side Effects:
● Metabolic acidosis.
● Sedation.
● Bone marrow suppression.

Example: Acetazolamide

Thiazide Diuretics
Distal Convoluted Tubule
● Normally:
o Na+/K+ ATPase pumps Na+ out of cells and K+ into cells.
o Na+ and Cl- are then reabsorbed from the DCT lumen
due to the potential created by the ATPase.
● Thiazide diuretics block the Na+/Cl- symport transporter.
● This decreases Na+ reabsorption to cause diuresis.

Clinical Indications
● Hypertension.
● Blood volume reduction.
Side Effects
● Hypokalaemia.
● Hyponatraemia.
● Hypercalcaemia.
● Hyperglycaemia.

Example: Bendroflumethiazide, hydrochlorothiazide.

Loop Diuretics
Ascending Limb of Loop of Henle.
● Inhibits the Na/K/2CL co-transporter.
● Furthermore, it decreases absorption of magnesium and calcium.
o Normally potassium is excreted to generate a positive voltage
o This excretion is balanced by the entry of magnesium and
calcium
o However, potassium is not excreted when Na/K/2CL is inhibited
this renders Na/ dysfunctional and therefore there is no K+ that
enters the cell.

Clinical Indications
● Most potent diuretic.
● Hypertension.
● Heart failure.
● Volume overload from CKD.

Side Effects
● Hypokalaemia (due to K+ excretion).
● Dehydration.
● Kidney stones.
● Deafness.

Examples = frusemide and bumetanide.

Potassium Sparing Diuretics

Collecting Tubules

Amiloride/Triamterene
● Epithelial Na+ channel antagonists.
o Blocks Na+ channels in the collecting tube.
o Does not affect K+ channels.
o Increased Na+ loss causes diuresis.

Clinical Use:
● Heart failure.
● Hypokalaemia.
● Cirrhosis.

Side Effects:
● Hyperkalaemia.
● Hyponatraemia.

Spironolactone/Eplerenone
● Aldosterone antagonists.
o Aldosterone upregulates Epithelial Sodium Channels (ENaCs) in the collecting ducts.
o Decreased Na+ reabsorption causes diuresis.
o K+ is not affected.
Clinical Use:
● Hyperaldosteronism.
● Heart failure.
● Hypokalaemia.
● Cirrhosis.

Side Effects:
● Hyperkalaemia.
● Hyponatraemia.
● Gynecomastia.

Osmotic Diuretics
● Mannitol.

Mechanism:
● Any osmotically active molecule freely filtered in the glomerulus, and not reabsorbed in the tubules.
● Na+, K+ and water are all dragged out from the interstitial space.

Clinical Use:
● Cerebral oedema / raised intracranial pressure.

Side Effects:
● Pulmonary oedema.

27. Micturition
Learning Objectives

1. Micturition Physiology
Storage Phase
● Sympathetic efferents through hypogastric nerve
maintain a tonic contraction (in internal urethral
sphincter) in storage face/inhibit contraction of the
detrusor muscle. (SYMPATHETIC STOPS PEE).

Inhibition of Diuresis
● As bladder fills it activates pelvic afferents (S2-S4)
which signal to the micturition centre.
Parasympathetic are activated
 ● If not socially acceptable = tightening of external urethral sphincter (pudendal) and detrusor muscle
(hypogastric). This is voluntary.

Micturition Reflex
Micturition centre is 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

2. The Bladder Cycle.

● Bladder mostly in storage mode
o Normal 70kg adult = 4 times/24 hours.
▪ ~1500ml of urine.

PATHOLOGY
1. Diagnosis
History, personal history, past medical history, physical examination.
● I-PSS: 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).
▪ Low QofL = watch and wait
▪ Med/High QofL = medication, surgery etc…
o Quality of Life due to Urinary Symptoms.
▪ 0-6.

Lower Urinary Tract Symptoms

(!) Symptoms are not always clear cut.
● 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).

Investigations: inspect (colour and smell), urine dipstick, uroflowmetry (decreases

with age), urodynamic, ultrasound KUB, CT urograms, nuclear imaging etc...
2. Disorders
● Anatomic Disorders: obstruction (cancer, BPH), incontinence (stress, urge,
mixed incontinence)
● Functional Disorders: stroke, spinal cord injury, neurological disease,
idiopathic.
● Medical Disorders: cardiac, hepatic and renal failure.

3. Lifestyle Changes
● Fluid = type and amounts.
o Use a voiding diary.
o Caffeine = bladder contraction more likely
o Acidification = irritates the bladder.
● Bladder drill (storage for 3-4 hours).
● Food and Smoking
● Urethra milking
● Pads and Convenes
4. Medical Theraphy
● 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.

5. Surgery for LUTS (symptoms)

● TURP = transurethral resection of the prostate
● HoLEP = laser to remove prostate
● UroLIFT = holds prostate gland out of the way.

6. The Overactive Bladder

● Urinary urgency (with/without incontinence)
● Urinary frequency
● Nocturia (sometimes).

7. Urinary Incontinence
● Urge Incontinence = overactive waves (overactive bladder)
● Stress Incontinence = urine leaks due to weakened pelvic muscles.

Treatment for Urge Incontinence

● Conservative measures (i.e. fluid intake, caffeine, pads, timed voiding), pelvic floor exercises.
● Tablets, Botox, surgery.
o Anticholinergics = block Ach in parasympathetic nerves (as well as in other places)
o Beta adrenergics = beta receptors upregulated in OAB. Decrease this but hypertension.
o Botulinum Toxin A = fuses synaptic vessels with end plate.
▪ Issues with hyper continence.

Treatment for Stress Incontinence: pads, fluid intake, treat OAB, pelvic floor, vaginal cones etc…
NOTE = anything between micturition center and T12 are not safe lesions (high pressure = kidney failure)>
28. Imaging & Endoscopy of the Urinary Tract
Learning Objectives
1. Define endoscopy
2. Outline requirements for a successful endoscopic system
3. Give examples of the use of endoscopy in diagnosis and therapy

1. Tests in Urology
Static Imaging
● X-Rays: stones.
● Ultrasound: urine is liquid
● USS.
● CT: cancer.
● PET: cancer
● MRI: cancer, stones, cysts

Dynamic Imaging
● Nuclear medicine
2. Endoscopy in Urology
Endoscopy = examination of inner body using long, thin flexible tube with light source and camera at one end.
There are two types:
1. Natural orifice
2. Make a new hole (laparoscopy).

Laparoscopy
● Inflated abdomen = lens inserted (excellent view for nephrectomy).

3. Routes of Entry
● PNCL (Percutaneous nephrolithotomy): needle into kidney.
● URS and FURS (ureterorenoscopy and flexible ureterorenoscopy).
● Cystoscopy.

Cystoscopy: endoscopy of the urinary bladder through urethra

Ureterorenoscopy: endoscopy of ureters and kidneys through urethra.

29. Corticosteroids
Learning Objectives
1. Describe other unwanted effects arising from long-term therapy with glucocorticoids
2. Describe the mechanisms of action contributing to anti-inflammatory and immunosuppressive effects of corticosteroids.
3. Clinical uses of corticosteroids
4. Explain how long-term corticosteroid therapy disrupts endogenous corticosteroid secretion
5. List some synthetic steroids with mainly glucocorticoid activity. Explain the reason for the development of such compounds.

● Steroid hormones produced in the adrenal cortex.

o Used in treatment of inflammatory and autoimmune diseases.
● Two main classes: mineralocorticoids and glucocorticoids.
o Both permissive (allowing reactions to occur) and suppressive.

1. Mineralocorticoids
● Zona glomerulosa of the kidneys
o Most outer layer.
● Involved in electrolyte and water balance.

2. Glucocorticoids
● Produced in the zona Fasciculata of the kidneys
 o Middle layer
● Affects metabolism, fights infection (anti-inflammatory), prevents fluid loss, affects neurochemistry
etc…

Cortisol:
● Cortisol = highest when we wake up and lowest in the evenings (circadian rhythm ฀ normal diurnal
rhythm).
● This is because in the morning we are active and need higher immune protection, whereas in the
evening we are often in a protected environment.

NOTE: it is a natural homeostatic mechanism that controls the immune

system, but cortisol levels that are too high (i.e. stress
induced/administered) various side effects occur.

3. Side Effects of Glucocorticoids

Either stress induced/poor (excess) administration:
● Oedema
● Weight gain
● Hypertension
● Osteoporosis (increases activity of osteoclasts, decreases activity
of osteoblasts).
● Hyperglycaemia
● Glaucoma
● Jaundice
● Peptic ulcers
● Avascular necrosis

Cushing’s Syndrome
● High cortisol levels due to administration of corticosteroids.

4. Use of Glucocorticoids
● Hypersensitivity such as asthma, atrophic dermatitis and allergic rhinitis
● Adrenal deficiencies
● Chron’s disease or ulcerative colitis
● Arthritis
● Multiple sclerosis.
5. Glucocorticoid Receptors
● Found within nucleus and cytoplasm
o Can enter through cell membrane as they are lipid.
● Alpha and beta are the two main forms

Genomic Activities (slow)

Transactivation
● Alpha: ligand binds to alpha to activate receptors.
o Translocated to nucleus.
o Regulate gene expression.

Transrepression
● GC binds to DNA where pro-inflammatory transcription factors would:
o Prevention of gene expression.

Non-Genomic Actvities (fast)

● Activated GR bind to proteins in the cytoplasm/membranes to cause immediate effect.

NOTE = beta receptors does not bind steroid and is high in patients that are resistant to steroid drugs.

6. Synthetic Forms
● Dexamethasone
 ● Betamethasone
● Prednisone
● Prednisolone.

31. Transplantation Immunology

Learning Objectives
• Understanding the difference between types of rejection: hyperacute, acute and chronic
• Understanding the mechanisms that are important in mediating immunological rejection: lymphocytes, antibodies, complement and coagulation cascade
• Understanding non-immunological processes that damage transplanted organs, including "ischaemia-reperfusion injury”
• Understanding how the recognition of transplanted tissue is compatible with our understanding of how the immune system differentiates self from non-self
• Understanding how we can disrupt the immune response to transplanted tissue therapeutically

1. Rejection Classification
● Based on how long it takes for rejection to occur.

a. Acute
● From 1 week to 6 months after transplantation.

i. Acute Cellular Rejection

● CD4+ activate cytotoxic T lymphocytes (CD8+).
o “Cell-mediated”
 ● Lymphocyte infiltration, interstitial tubulitis (above) primarily peripheral lymphoid tissue.
● Also, causes endarteritis (inflammation of tunica intima/inner lining of artery (right).

ii. Acute Antibody-Mediated (Humoral) Rejection

● CD4+ activate B lymphocytes that produce antibodies
o Gives a different type of pathology.
● Antibodies are against any non-self-molecules
o ABO Antigens
o MCH Antigens (class I, II)
o MHC Class-I-related chain A (MICA)
● Primarily targets endothelium of arteries and capillaries.

Mechanism of Action: C4d is deposited in the endothelium as a product of the antibody-antigen

complex. This forms parts of the complement activation.
● C4d levels can be detected to identify rejection.

iii. Cellular vs Antibody Rejection

● Cellular: More c4d between
cells/connecting cells
● Antibody: around the blood vessels
(peritubular)

iv. Criteria for acute antibody MR

● Evidence of acute renal injury on histology
● Evidence of antibody activity (c4d I peritubular
capillaries).
● Circulating anti-donor specific antibodies.

b. Hyperacute
● Minutes to hours.
● Happens due to previous transplant, transfusion or pregnancy.
o There are preformed antibodies in the circulation before the transplant occurs.

Mechanism of Action
● Preformed antibody binds to endothelial cells and
activates complement.
● Normally endothelium is constituently anticoagulant
o Complement thrombosis which leads to
breakdown of tissue and infarction downstream.
1 hours: neutrophils in peritubular capillaries/glomeruli.
12-24 hours: intravascular coagulation/cortical necrosis.

c. Chronic
● Occurs from months to years
● Chronic rejection can come from:
 o Pre-transplantation damage of graft
o Recurrence of original disease
o Rejection.

2. Rejection Prevention
Hyperacute
ABO compatibility.
● Recipient A: can receive A or O
● Recipient B: can receive B or O
● Recipient O: O only
● Recipient AB: A, B or O.

Presence of Pre-Formed Antibodies

Chronic
● Choosing best organ
● Minimizing surgical damage, acute rejection and drug toxicity.

The immune system vs graft

Evolving relationship: aggressive early on but much less with time due to:
● Loss of BM-derived cells of donor
● Development of active regulation.
33. The Adrenal Gland
Learning Objectives
1. Principles of diagnostic endocrine and radiological tests for Acromegaly
2. Principles, benefits and risks of medical, surgical and radiotherapy treatments for
Acromegaly
3. Social and emotional impact of pituitary disease
4. Signs and symptoms of acromegaly (consequences of growth hormone
over-secretion)
5. Origin and natural history of pituitary adenomas
6. Effect of a pituitary mass on normal pituitary physiology
7. Physiology of the growth hormone axis and the pathophysiology of over-secretion
of growth hormone
8. Anatomical relations of the pituitary gland and the surgical anatomy of a pituitary
mass

1. Adrenal Anatomy
Adrenal gland is about 90% cortex.
Cortex
● Zona Glomerulosa.
o Typical steroidogenic cells
o Mainly produces aldosterone
(mineralocorticoids)
● Zona Fasciculata.
o Paler staining properties (clear
cells). Laid out in columns of two
cells wide (seen in diagram).
o Produces glucocorticoid.
● Zona Reticularis.
o Branching network of smaller
compact cells
o Also, secretes glucocorticoid
o Primary: secretes adrenal
androgens (androstenedione,
DHEA)

Medulla
● Separated from cortex by thin layer of
connective tissue.
 o Chromaffin cells release catecholamines (80% secrete adrenaline, 20% noradrenaline).
▪ Response to sympathetic nerve terminals.

Right gland is pyramidal in shape; the left is more crescentic.

● Vessels from subscapular plexus give rise to
fenestrated sinusoids throughout the gland.
o Most cells: one or two cells away from a
vascular endothelial cell: efficient delivery.

Adrenal Histology

2. Stress
● Starvation.
● Infection
● Severe Volume Loss.

ADRENAL CORTEX
1. Functional Zonation of the Adrenal Cortex
● In all cortical cells: steroid production
begins with cholesterol uptake.
o Conversion through cytochrome
p450 to pregnenolone initiates
pathway.

I. Mineralocorticoids
Hyperaldosteronism: low potassium, high blood
pressure and alkalosis
● Aldosterone has the opposite effect of ANH.

Primary Hyperaldosteronism
Mineralocorticoid Receptor
Aldosterone binds to MR receptors expressed in the nucleus.
● NOTE: cortisol can also bind to MR. However, this binding is inactivated by cortisone.
o Except in overwhelming conditions.

Functions of Aldosterone
● Stimulates Na/K ATPase and increases its expression.
● Inserts additional ENaC.
● Stimulates the H+ ATPase

Therefore, in excess: loss of H+ causing metabolic alkalosis and loss of K+ to balance concentration gradient
generated by intake of Na+.

Liddle’s Syndrome: increased expression of ENaC:

● Hypertension
● Hypokalemia
● Metabolic Alkalosis

II. Glucocorticoids

Function of Glucocorticoids

Cushing’s Syndrome

Addison’s Disease
Primary Adrenal failure: can be autoimmune and tuberculosis.
● Vague symptoms initially
o Fatigue, weakness, myalgia
o Anorexia, weight loss
o Hyperpigmentation.

When something stressful happens; cannot respond to it.

 ● Low blood pressure, low glucose, low sodium, high potassium.

Congenital Adrenal Hyperplasia:

● If defect in conversion to aldosterone and cortisol (due to 21-hydroxylase deficiency) excess ACTH will
be secreted (no negative feedback).
● Stimulate cholesterol uptake in adrenal gland. Converted to cortisol it is converted to testosterone.

ADRENAL MEDULLA
Catecholamines are made up of L-tyrosine

1. Chromaffin Cells

Chromaffin Cell Tumours:

Phaeochromocytoma: arising from within adrenal medulla.
Paraganglioma: extra-adrenal tumours.

Known as PPGL

2. Adrenoceptors

α1 vascular and smooth muscle contraction

α2 presynaptic, inhibitory to noradrenaline release - suppresses BP
β1 positive inotropic and chronotropic in the heart; increased renin; lipolysis
β2 bronchial, vascular, uterine smooth muscle relaxation; glycogenolysis
β3 Lipolysis, energy expenditure, e.g at brown fat tissue
D1 cerebral, renal, mesenteric, coronary vasculature dilatation
D2 presynaptic inhibition of noradrenaline and prolactin release
3. Symptoms of Catecholamine Excess (PPGL)

Treating Phaeochromocytoma with Beta Blockers

● Will lead to more vasoconstriction (beta adrenergic receptors cause vasodilation).