Understand 2nd year medicine

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Endocrine System

 
Anterior pituitary relies on (portal) vessels: A   P

Posterior pituitary relies on axons (nerves) : P   A

 

Anterior A pituitary: AP: Portal hypophyseal vessels, ABC cells (acidophil, basophil, chromophobe) SAT (sex - FSH & LH, acth, tsh)

  • blue basophil makes the SAT (FSH follicular stimulating hormone and LH luteinizing hormone) hormones (see below for pathway)FSH and LH stimulates the testes in the male (FSH --> Sertoli cells --> Inhibin, LH --> Leydig cells --> Testosterone) and ovaries in the female (FSH --> Ovary --> Inhibin, LH --> Ovary --> Oestrogen)
  • red acidophil: gh and prolactin (GPA)
  • clear chromophobe
Posterior pituitary PA: Axons, PAO (adh, oxytocin)
  • Supraoptic nucleus and paraventricular nucleus
  • Continuous with the hypothalamus via the pituitary stalk
  • Terminal of hypothalamic neurosecretory neurones and Pituicyte

Parafollicular cells aka C cells make calcitonin (decrease serum calcium levels)
Single layer cuboidal epithelium makes T3/4 which is stored in colloid

Hypothalamus: TRH thyroid releasing hormone → Anterior pituitary: TSH thyroid stimulating hormone → Thyroid gland: T3/4 (exert negative feedback to hypothalamus)
Iodine-deficient Goitre: No negative feedback so constant stimuli!

T3: Triiodothyronine (active)
T4: Tetraiodothyronine or Thyroxine (inactive, long t1/2) → Deiodination to T3 in peripheral tissues

Na+/I- cotransporter (secondary active transport): TSH sensitive

TSH thyroid stimulating hormone
  • Increase iodine uptake
  • Increase thyroglobulin production
  • Stimulate thyroid peroxidase
  • Stimulate T3/4 release

Thyroid peroxidase
  • I- oxidation to I*
  • Iodination of tyrosine residue in thyroglobulin to form MIT and DIT
  • Coupling
    • MIT+DIT → T3
    • DIT + DIT → T4

T3/4 (70% T4, 30%T3) and...
  • 70% bound to TBG (thyroid binding globulin)
  • 29% albumin
  • 1% free

Mechanism of T3
  • Crosses membrane of all cells
  • Binds to receptors in nucleus and activate genes for enzyme synthesis (Na/K+ pump: ATP → ADP + Pi + Heat)

Functions of T3/4
  • 4 B’s
    • B-adrenoceptor upregulated: Tachycardia, Increased contractility
    • Bone catabolism: Osteoporosis, hypercalcemia
    • Brain maturation
    • BMR +
      • Lipolysis: Weight loss
      • Proteolysis: Decrease muscle mass
      • Gluconeogesnsis, glycogenolysis: Increase glucose → Diabetes
Iodine deficiency goitre
  • Low iodine thus no iodination of tyrosine in TG thus no MIT and DIT made thus no T3/4 made
  • Instead of making T4 (normal 70%) which consumes more iodine (DIT x 2), it switches to making T3 (DIT + MIT only) to maintain normal function
  • Less negative feedback of TSH and TRH -> More TSh and TRH → More t3/4 release → Follicular enlargement therefore goitre

Hyperthyroidism: Increased ATP (energy).... more heat generated (see below equation)

Symptoms
  • Tremor, Sweating
  • Increased appetite, Weight loss
  • Heat intolerance - (Na/K+ pump: ATP → ADP + Pi + Heat)
  • Tachycardia
  • Goitre (enlarged neck)
  • Exopthalmos
    • Mucopolysaccharide
    • Lymphocytic infiltration

Treatment
  • Surgery - remove thyroid
  • Radioactive iodine
  • Carbimazole: Inhibit thyroid peroxidase (no coupling, iodination, oxidation)

Drug-induced hyperthyroidism
  • Levothyroxine: T4

Grave’s disease: IgG bind to TSH-R (type 2 hypersentivity) → Constant stimulation to produce T3/4
  • Most common cause of hyperthyroidism
  • Diffuse hypertrophy due to hyperplasia of acinar epithelium
    • so increased vascularity of tissue
  • Less stored colloid
  • Lymphocyte
  • Secondary follicle
  • Ptosis due to inflammation of the eye muscles and orbital fat

Thyroiditis: De Quervain’s thyroid
  • Virus: Mumps
  • Short duration
  • Painful enlargement
  • Granuloma
  • Inflammatory cells
  • Fibrosis

Toxic adenoma
  • Solitary nodule

Toxic multinodular goitre


Hypothyroidism
  • At birth: Crtenism
    • Endemic: Iodine deficient
    • Sporadic: Congenital absence/hypoplastic
    • Dyshormonogenesis: Recessive defect in thyroid peroxidase
  • Adulthood: Myxdema
  1. Low O2 consumption: hypoxia, hypercapnia
    1. low epo
    2. hypoventilate
  2. Low lipolysis
    1. weight gain
    2. hyperlipidemia
  3. less gluconeogesnsis and glycogenolysis → hypoglycemia
  4. less HR and contractility → heart failure
  5. Less sympathetic (less upregulation of B-adrenoceptor) → less sweating
  6. Cretinism
    1. irreversible brain damage (t3/4 needed for glial, myelin formation)
    2. no bone growth - short and fat


Causes
  • Hashimoto’s thyroiditis (Autoimmune thyroiditis): Initial rise in T3/4 (follicular rupture → thyrotoxicosis) then low (no colloid!)
    • Diffusely enlarged non-tender thyroid
    • antibodies vs Thyroid peroxidase, thyroglobulin
    • Lymphocyte, germinal center
    • Low colloid
  • Grave’s disease (hyperthyroid → hypothyroid due to lymphocytic infiltration)
  • Treatment for hyperthyroidism e.g. carbimazole to inhibit thyroid peroxidase
  • iodine deficiency

Treatment: Levothyroxine (T4)

Primary hypothyroid: Low T3/4 despite high tsh
Secondy hypothyroid: Low t3/4 due to low tsh



Diabetes

Normal insulin action
  • K+ and glucose go in!!!
    • hypoglycemia
    • hypokalemia
  • ANABOLIC!
    • Increase


Type
  1. Insulin not produced (absolute) - IDDM
  2. Insulin resistance (relative) - NIDDM

GLUT transporters (1-3: not insulin dependent)
  1. RBC, BBB, Kidney
  2. B-cells in pancreas
  3. Testes, placenta
  4. Liver, muscle, adipose

Pancreatic cells

Endocrine cells in Islets of Langerhans

Cell type

Secretory product

% of endocrine cells

a  (A)

Glucagon

20 %

b  (B)

Insulin

70 %

d  (D)

Somatostatin: inhibit insulin and glucagon secretion

5-10 %

pp (F)

Pancreatic polypeptide: inhibition of pancreatic enzyme secretion from the surrounding acinar cells (exocrine)

1-2 %



Collagen types
  1. Bone
  2. Cartilage
  3. ?
  4. Vessel basement membrane

Hyperglycaemia → Hyperosmolarity → Osmotic diuresis → Polyuria (Na+ and K+ follow so hyponatremia and hypokalemia) → Dehydration → Sympathetic → Aldosterone  (further decrease K+) and catetcholamine release → Catabolic (f’a’ release) and vasoconstriction (Decreased GFR) → Hyperglycemia


Effects of hyperglycemia
  1. Glucose into cell and metabolized into sorbitol → can’t diffuse out → osmotic pressure increase → water to lens → cataracts
  2. Diabetic glomerulosclerosis: Thicker BM but High permeability → Microalbuminuria and later proteinuria → Chronic kidney diseases
    1. Less EPO made → Anemia
    2. Hyperkalemia (Failing Na/K+ in collecting duct) → Cardiac arrythmia
    3. Less active Vit-D3 made (7-dehydroxycholesterol + UV → Hydroxycholcalciferol + 25-hydroxylase in liver → Calcidiol + 1-alphahydroxylase in kidney → calcitriol (active vitamin D))
      1. Vitamin D: Increases calcium levels in blood by increasing calcium (and phosphate) absorption in gut and increase bone resorption
      2. Hypocalcemia
  3. Glucose bind to protein → AGE form (advanced glycation end-product) → AGE binds to BV receptor and increase collagen made → Retinal BV: BM increase thickness, decreased permeability, luminal narrowing → Eye ischemia → Blindness and VEGF made (fragile BV formation - dots (microaneurysm - dots, hemorrhage - blots, exudate - cotton wool)
  4. Hypertension due to
    1. Dehydration → Sympathetic → RAAS (sympathetic: NE release further complicates hyperglycemia)


Symptoms of diabetes: 3 Poly's
  • Polydipsia (dehydration!)
  • Polyuria (frequent urination)
  • Polyphagia (frequent eating)


Diagnosis
  • Hyperkalemia (due to H+ into protein and K+ out protein), depleted K+ in cell because no insulin!
  • High ketone: Fruit breath, Kussmaul breathing (deep and labored breathing pattern often associated with severe metabolic acidosis)
    • Fat breakdown (lipolysis): FFA → Ketogenesis (B-hydroxybutyrate and acetoacetate)
  • Dehydration
  • High H+
  • Hyperglycemia
    • Fasting glucose > 7mmol/L
    • 2 hr oral glucose tolerance test (OGTT) >11mmol/L
      • Overnight fast
      • Ingest glucose
      • Wait 2 hours
      • Sample blood
      • HbA1c% >7% - long term monitoring

Type 1 IDDMType 2 NIDDM
Autoimmune disorder: B cells, Viral infection: Mumps, measles
<30
Not obesity
No genetics
Severe glucose intolerance
DKA is COMMON

Histology: Lymphocytic infiltration
Treatment: Pancreas transplant
Insulin resistance
>40
Obesity
Strong genetics
Mild glucose intolerance
DKA is rare




  • Diabetic retinopathy
    • Background: Dots (microaneurysm) and blots (haemorrhage)
    • Preproliferative (cotton wool spots - microinfarct of retina)
    • Proliferate (Neovascularization due to ischemia)
    • Maculopathy (affects macula)
  • Diabetic nephropathy
    • Affect glomeruli
    • Mesangial expansion due to AGE (advanced glycation end-product)
    • Thicken GBM (glomerular basement membrane) with less heparan sulfate
      • Heparin sulfate is negative: less heparan sulfate in GBM--> less heparin to repel albumin (negative) so albumin passes through, causing proteinuria


Drug mechanisms for DM
  • Sulfonylurea: Close ATP-sensitive K+ channel so no K+ efflux → depolarization in B cell → VDCC (voltage-dependent calcium channel) open → Insulin release
  • Biguanide: Metformin - decrease gluconeogenesis
    • sfx: Lactic acidosis
Diabetes insipidus
  • Central: Lack of ADH made (e.g. [posterior] pituitary surgery)
  • Nephrogenic: Lack of response to ADH e.g. lithium, hypercalcaemia
  • Intense thirst, polyuria
Parathyroid Gland
  • Pea size
  • Behind thyroid gland
  • 2 superior parathyroid gland: from 4th branchial pouch
  • 2 inferior: from 3rd branchial pouch
  • Blood supply: Inferior thyroid artery (from thyrocervical trunk)

Chief cells: Dark, many, small - produce PTH
Oxyphil cells: Large, light, few

PTH has 2 actions in the kidney
  • Inhibit apical Hpo-/na+ symporter in PCT
    • phosphate dumping!
  • stimulate basolateral ca2+/na+ antiporter in DCT
    • more calcium absorption!

Hyperparathyroid causes high PTH → High serum calcium (bone resorption, gut and renal absorption) and low phosphate
  • Stones, bones, moans, psychic overtones

Causes of Hyperparathyroidism
Primary: Adenoma/hyperplasia
Secondary: Hypocalcemia
Tertiary: Autonomous chronic secondary

Adrenal cortex
  • produces steroid hormones
  • GFR: Salt sugar sex (mineralocorticoid - aldosterone, glucocorticoid - cortisol, androgenic steroids)

Adrenal medulla
  • embryologically same origin as the sympathetic nervous system
  • chromaffin cells secrete the catecholamine hormones adrenaline and noradrenaline in response to input from sympathetic preganglionic fibres.

 

Hunger hormones:

Ghrelin : Made by stomach - Receptors for ghrelin hormone in lateral hypothalamus - NPY neuron

  • Late night snacking - ghrelin (stomach grumbling.... hunger)

Leptin (satiety - full) - Leptin made by white adipose tissue acts on ventromedial hypothalamus - POMC neuron (a bit like Lipton tea... makes you FULL)


Arcuate nucleus
  • neurons contain NPY, AGRP and the inhibitory GABA projects to lateral hypothalamus. When activated, these neurons can produce eating. These neurons are inhibited by leptin, insulin and peptide YY and activated by ghrelin.
  • neurons contain POMC projects to ventromedial hypothalamus. When activated by leptin and insulin, they inhibit feeding. It is inhibited by NPY neuron.

Gastrointestinal System

Phases of digestion

  1. Cephalc (head) stimuli due to though, sight, taste, smell, chewing to medulla oblongata
    1. Causes medulla PS (vagal ACh) output to stomach - Parietal cells secrete acid, G cells secrete gastrin, chief cells make pepsin
  2. Gastric stimuli due to food distention and chemoreceptor (peptide)
    1. Causes medulla PS (vagal ACh) output to stomach - further chief cell, parietal cell, G cell stimulation
  3. Intestinal phase due to chyme
    1. Duodenal CCK: Gall bladder contract, make more pancreatic enzyme, relax sphincter of oddi
    2. Duodenal Secretin: Make more pancreatic bicarbonate

Main enzymes
  • Carbohydrate
    • Salivary amylase: Starch → Dissaccharide
    • Pancreatic amylase: alpha-amylase (Starch → Oligosaccharide)
    • Intestinal brush border enzymes on enterocyte: Dissacharide/oligosaccharide → Monosaccharide
      • Absorption as monosaccharide via enterocyte
        • Glucose, galactose: Na+ dependent SGLT
        • Fructose: GLUT 5 transpoter
          • Glut1: BBB, RBC, kidney
          • Glut2: B cells
          • Glut3: Testes, placenta
          • Glut4: Muscle, fat, liver
          • Glut5: Fructose transporter in enterocyte
  • Fat: Lipase, phospholipase A
  • Protease: As proenzymes
    • Trypsinogen → via enteropeptidase of duodenal mucosa → Trypsin stimulate more trypsinogen (positive feedback loop
    • Trypsin activates other proteases (chymotrypsin, amino/carboxy-peptidase)
  • Mineral absorption
    • Iron: Duodenum
    • Folic: Jejunum
    • B12: Ileum

Enzyme markers
  1. AST - Skeletal muscle, cardiac muscle (MI)
  2. ALT - Liver
  3. GGT - Alcohol
  4. ALP - Bone, bile duct
  5. Amylase, lipase

Alcohol screening

CAGE questionnaire
  • C: Felt need to cut down?
  • A: Felt annoyed by people asking you about drinking?
  • G: Guilty?
  • E: Eye opener - need to have one in the morning

Units:
Male 21 units/wk
Female 14 units/wk
1 unit: ½ pint beer, 1 small glass of wine, 1 short spirit

3 pathways for alcohol metabolism
  1. Cytosol: Ethanol -(Alcohol dehydrogenase) → Acetaldehyde
  2. Mitochondria: Acetaldehyde -(Acetaldehyde dehydrogenase)→ Acetate  
  3. Disulfram inhibits acetaldhyde dehydrogenase so acetaladehyde increases → nausea...

Peroxisome: Catalase
Microsome (MEOS): CYP2E1 aka cytochrome P450 (abbreviations...)

Dehydrogenase: Enzyme that oxidizes a substrate by stealing its hydrogen and transferring it to NAD+ or FAD → NADH or FADH2

Alcohol has hypoglycemic properties
  • The dehydrogenase enzymes use up NAD+ and produce more NADH!!!
  • Pyruvate + NADH<-(LDH)-> Lactate + NAD+
  • More NADH so more lactate made and less routed to gluconeogesnesis



Alcohol is FAT
  1. Microvesicle
  2. Macrovesicle: When many small vesicle fuse together, fat pushes nucleus to periphery
    1. Cause portal hypertension: Increased resistance in sinusoid!

Acetaldehyde is TOXIC to cells
  1. Chromosome cleavage between nucleosome by endonuclease
  2. Condense  (pyknosis)
  3. Fragmentation (karyorrhexis)
  4. membrane enclosed apoptotic bodies

Glucocorticoid-induced apoptosis: elimination of lymphocytes
  1. GR are expressed in cell cytoplasm. Normally heatshock proteins are bound to it as chaperones (hold GR in conformation)
  2. When Glucorcorticoid enters cell and binds to GR, heat shock proteins fall off and conformation changes.
  3. The dimer enters nucleus.
  4. Dimer interacts with DNA to upregulate Bax which travels to mitochondria
  5. Bax causes pore formation in mitochondria and releases cytochrome c (respiratory enzyme...) → No respiration and activate caspase (cytochrome c + apaf-1)
    1. Caspase activates endonuclease.
    2. Caspase deregulates structural protein cytoskeleton -- breaks up and membrane bulges outwards taking a portion of cytoplasm.
    3. Phosphatidyl serine (normally on inside of membrane) flipped to the outside (probably by cytochrome c.) → Macrophages recognizes and engulfs and digest blebs (NO INFLAMMATION)




Alcoholic hepatitis
  • Cause: High [alcohol] → Damage hepatotocytes → Neutrophil infiltration
  • Acute
  • Histology: Mallory body
    • Focal necrosis
    • Mallory body: eosinophilic damaged cytokeratin filaments
    • Fibrosis around CV → cirrhosis
    • Neutrophil


Pericyte: Undifferentiated cell that can transform into CT (e.g. fibroblast)
Alcohol -> Acetaldehyde -> Necrosis -> Cell burst -> Enzyme leak -> Cell debris -> Activate Kupffer cells (macrophage) -> Cytokine release stimulates
  1. Fibroblast proliferation
  2. Ito/stellate cells (pericyte that stores vitamin A) change to fibroblast


Sinusoidal lumen: Hepatic artery and portal vein to central vein
Bile canaliculi: From central vein to bile duct (opposite direction)

Fibroblast makes collagen -> Fibrosis (if moderate, architecture of matrix is sustained - reversible functional regeneration; if extensive - CIRRHOSIS - matrix continually degraded by MMP and reform - nodules - irreversible no full functional regeneration) -> High resistance in sinusoid -> Portal hypertension

Portal hypertension
Normal: <10mmhg
Portal HT: >12mmHg

Prehepatic: Portal vein thrombosis
Intrahepatic:
  • Enlarged hepatocyte: Sinusoidal obstruction
    • fat deposition
    • hyperplasia
    • cell swelling
  • increased CT: Cirrhosis
Posthepatic:RSHF
Complications of portal hypertension
  • Splenomegaly (increased size): Hypersplenism (increased spleen function)
    • spleen stores blood, platelet → if splenomegaly, even more storage so less in blood
    • anemia (RBC), thrombocytopenia (WBC), bruising (platelet)
  • portosystemic anastamosis
    • esophageal varices
    • paraumbilical vein: caput medusae
    • hemorrhoid: superior rectal vein

Treatment for portal hypertension
TIPS: Transjugular intrahepatic portosystemic shunt (connect portal vein to IVC inferior vena cava)


Liver failure
  • Hyperammonia (thus alkalosis): NH3 + CO2 -> Carbamoyl -> Urea (urea synthesis in liver)
  • Hepatocyte necrosis: No HDL (LCAT to pick up cholesterol into CE) made so hypercholesterolemia
  • hepatic encephalopathy: false transmitters - flapping tremor
  • less clotting factor synthesis!

Alcoholic cirrhosis
  • High GGT if recent alcohol intake
  • Low albumin (Liver failure → Less albumin production)
  • Diffusely nodular (chaotic architecture - e.g. Central vein has fibrotic tissue - normally none)
  • Hard liver
  • Inflammation






Treatment for Complications of alcoholic cirrhosis
  • Liver transplant
    • 6 months abstinence
    • good family support
    • advanced diseases with complication
  • varices
    • obliterate
    • B-blocker (B1? because to lessen the symp. vasoconstriction thus portal HT from AT2)
  • ascities
    • diuretic: spironolactone (aldosterone antagonist)
      • Liver failure → less albumin produced → less oncotic pressure → ascities (less plasma protein to grab back that tissue fluid!) and lower BP (though higher portal pressure) → RAAS system →  Angiotensin → Aldosterone (K+ secretion hypokalemia and Na+ absorbed hypernatremia) → More water reabsorbed
    • less fluid intake
  • encephalopathy: all the toxins bypass/not metabolized liver
    • laxative (e.g. lactulose: increase water content to draw nh3)

Jaundice (aka icterus: yellow discoloration due to high [bilirubin])

Breakdown in Spleen: Hemoglobin -> Heme and globin (Globin to a’a’) -> Heme to biliverdin
Conjugation in Liver: unconj bilirubin + albumin in blood -> conj bilirubin (by glucuronic acid) -> Stercobiliin in feces and urobilinogen in urine




Bile canaliculi → Bile duct → Hepatic duct → common hepatic duct fuses with cystic duct to form common bile duct, CBD fuses with pancreatic duct → Sphincter of Oddi and through duodenal papilla

Acini zones
1 - periportal (close to portal vein!)
  • drug, toxin prone
2 - midzone
3 - centriolobar
  • viral (yellow fever), hypoxic

Types of jaundice
1. prehepatic
  • high unconjugated (i.e. does not involve liver) bilirubin
    • hemolytic anemia, gilvert’s syndrome: failed conjugation
2. intrahepatic
3. posthepatic: blocked post-hepatic duct e.g. pancreatic head tumor, gallstone
  • high conjugated bilirubin
  • less bile in GI → can’t emulsify and no pancreatic enzymes
    • steatorrhea (STINKY!!!!), no fat absorption (Vit ADEK deficiency), pale stool (no stercobilin because no bilirubin)


Collateral circulation
  1. Internal thoracic artery (from subclavian) to superior epigastric to inferior epigastric (from external iliac)
  2. Superior PancreaticoDuodenal PD artery (from celiac) to inferior PD artery (from SMA)
  3. Middle colic (SMA superior mesenteric artery) to left colic (IMA inferior mesenteric artery) via marginal artery

A represents an internal hemorrhoid, B represents an external prolapsed hemorrhoid, C is a mixed hemorrhoid (both internal and external), D is a thrombosed hemorrhoid and E is an external hemorrhoid.
Above pectinate lineBelow pectinate line
Internal hemorrhoid
Simple columnar
Superior rectal → IMV → Portal vein
No pain

External hemorrhoid
Stratified squamous
Middle/inferior rectal → pudendal → internal iliac vein → IVC

Pain



Portal systemic

RectumInternal hemorrhoidSuperior rectal (P: IMA) x middle/inferior rectal (S: Pudendal → internal iliac)
EsophagusEsophageal varicesLeft gastric (P: Portal vein) x Esophageal (S: azygos)
UmbilicusCaput medusaeParaumbilical (P: Portal vein) x Superior/Inferior epigastric (S: Femoral → external iliac)


Barrett’s esophagus:
Affects DISTAL esophagus
Chronic GERD → Glandular metaplasia (turn to glandular) i.e. from stratified squamous to columnar epithelium


Esophagus histology
Mucosa: Non-keratinized stratified squamous, lamina propria
Submucosa: Seromucous glands
Muscularis externa: Proximal ⅓ (skeletal muscle), distal ⅔ (smooth muscle - Inner circular, outer longitudinal)

Esophageal cancer
  • Progressive dysphagia: Solid → Liquid (weight loss)
  • Risk factors
    • A: ALCOHOL
    • B: BARRET’S ESOPHAGUS
    • C: CIGARETTE
    • D: DIVERTICULI
    • E: ESOPHAGITIS
    • F: FAMILIAL

Coeliac disease
  • HLADQ2
  • Atrophy of small intestine villi, crypt hypertrophy
  • Malabsorption
  • Gluten associated
  • Diagnosis
    • High IgA endomyseal
    • Tissue transglutaminase antibody
    • Antigliadin antibodies

 

Inflammatory bowel disease

Crohn’s
(Fat granny skipping on all cobblestone road causing fistula)
Crohn’s (constriction)Ulcerlative colitis (dilation)
Any GI especially terminal ileum; Rectal sparing

Skip lesions

Transmural  inflammation

Cobblestone mucosa
String sign lesion (narrowed lesion with poststenotic lesion)
Fistula

Noncaseating granuloma

Stricture
Fistula
Malabsorption


Sulfasalazine: Prodrug into 5-ASA Aminosalicyclic acid
Infliximab - TNF-alpha antagonist
Retrograde from rectum to colon

Continuous

Mucosal inflammation only

Pseudopolyp
Loss of haustra (leadpipe appearance)



Crypt abscess

Toxic megacolon
Colorectal cancer
Malabsorption
Bloody diarrhea

Colectomy
Infliximab




Granuloma

Aggregate of epitheloid macrophage, giant cell, lymphocytes seen in chronic inflammation

Macrophage → Epitheloid cell (larger nuclei due to activation) → Fuse to form Langhan giant cell

Acute pancreatitis
  • Autodigestion by pancreatic enzyme
  • Causes
    • GALL STONE
    • ETHANOL
    • TRAUMA
    • STEROID
    • MUMPS
    • AUTOIMMUNE
    • SCORPION STING
    • HYPERLIPIDEMIA
    • ERCP
    • DRUG
  • Presentation
    • Epigastric pain radiate to back
    • High serum amylase and lipase and autolysis!!!
      • Diffuse fat necrosis
      • Hypocalcemia (calcium soap deposits!)
      • DM (B-cells killed!)
      • Steatorrhea (no lipase to digest fat)
      • Fat soluble vitamin deficiency


Gastric Glands
Mucous neck cell
Parietal (oxyntic cell): HCl and Intrinsic factor
Chief (Zymogenic) cell: Pepsinogen
G cell: Gastrin

 

Respiratory System

 

Anatomic Dead Space
Conducting zones e.g. mouth where no gas exchange occurs.
Alveolar dead space: Where gas exchange could occur but can't because no blood flow (e.g. PE)

Lung anatomy

Right Lung


A PALM Seed Makes ALP


RUL

A - Apical

Palm - Posterior

pAlm - Anterior


RML

paLm - Lateral

palM - Medial


RLL

Seed - Superior

Makes - Medial basal (closest to heart)

A - Anterior basal

L - Lateral basal

P - Posterior basal (behind everything)

Left Lung


Astute anatomists share inside secrets ALP


LUL

Astute - Apico-posterior

Anatomists - Anterior



Lingular

Share - Superior ling.

Inside - Inferior ling.


LLL

Secrets - Superior

A - Antero-medial basal

L - Lateral basal

P - Posterior basal



Trachea -> Primary bronchus -> Secondary (lobar) bronchus -> Tertiary (segmental) bronchus -> Bronchiole (Lobular -> Terminal -> Respiratory) -> Alveolar duct -> Alveolar sacs (alveoli)

Up to terminal bronchiole: Conducting zone
Respiratory zone: Respiratory bronchiole - Alveolar sac
  • Respiratory bronchioles and the alveolar ducts: 10% gas exchange
  • Alveoli are responsible for 90% gas exchange


Layers of respiratory tract


Epithelium (Mucosa) > Lamina propria (mucosa) > Submocsa (+
submucosal glands - seromucous glands) > Cartilage

http://www.meddean.luc.edu/lumen/meded/MEDICINE/PULMONAR/images/hussain3/Scan15.jpg


 

COPD chronic obstructive pulmonary disease
- Chronic bronchitis (blue bloater)
  • Wheezing
  • Crackle
  • Cyanosis
  • Dyspnea

Asthma.. allergy th2!!! - small aireways affected

in terms of digestion phase: cephalic -> gastric (2) -> duodenal

thus histamine: H2!!!!... asthma is H1 - type 1H ypersensitivity)

M1 (parietal) H2 CCK-B -



TSLP (Thymic stromal lymphopoietin); Airway epithelium expresses PRR (e.g. TLRs). When insult, epithelium releases TSLP into lumen. The antigen peptide and TSLP together activates DC and promote Th2 inflammatory response. Th2 produce IL4 (IgE) & 5 (Eosinophil) & 13 (3 things...)- induces airway hypersensitivity, goblet cell metaplasia, mucus hypersecretion.

http://www.nature.com/icb/journal/v85/n6/images/7100104f1.jpg

Allergen
- Cold-induced
- Exercise
- HDM
- Cockroach feces
- Glutaldehyde: Found in sterilization fluid
Binds to body protein (e.g. albumin) -> to APC antigen presenting cell-> Th2 mediated attack (allergy!)

3  important ILs InterLeurkin (il 4 IgE, il5 - eosinophil, and il13 - 3 effects), 2 preformed stuff from mast (histamine binds to h1, leukotriene cause bronchoconstriction), 2 encounters (first, subsequent -> immediate and late), 2 things in eosinophil (ecp, and mbp)

Pathophysiology
- Affect BRONCHIOLE (small airawy with NO CARTILAGE) - BRONCHOCONSTRICTION and increased airway resistance
- Variable airway reactivity (more at night and early morning - unlike COPD - progressive dyspnea)
- First encounter - Sensitization to antigen: APC x antigen -> MHCII, IL4 and 10 and TSLP (from airway epithelium) -> Naive to Th2 -> Th2 release IL4 (IgE) and IL3 (Bcell), 13 -> IgE bounds to mast cell / basophil
- Subsequent Encounter: Immediate and late response (if chronic exposure -> irreversible airway remodelling - fibrosis,
  1. Immediate response: Antigen (Irritant: Smoking, pollutant, dustmite) x 2IgE -> Mast cell releases PREFORMED mediators -> Leukotriene: Bronchospasm and mucus hypersecretion; Histamine: +vascular permeability. (bronchoconstriction - bronchoconstriction, BV leak, mucus)
  2. Late response: Arrival of eosinophil (cause further damage - eosinophil cationic protein a RNAse, and major basic protein induce damage), macrophage, Th2
    1. Th2: IL13 induces airway hypersensitivity, goblet cell metaplasia, mucus hypersecretion, IL3 - mast cell survival, IL4: +IgE synthesis, IL5 - eosinophil survival

Hypoxia, hypercapnia, respiratory alkalosis


Use of accessory muscles
Wheezing on expiration
Prolonged expiration (when inhale: lungs expand, when exhale: diameter of airway decreases dramatically because of the bronchoconstriction and mucus plugs)

ECG findings of pulmonary hypertension (V:Q mismatch - paradoxical vasoconstriction of pulmonary vessels when hypoxic to divert blood to better ventilated parts of the lung), thus, RVH right ventricular hypertrophy and

Aspirin-induced asthma
Aspirin: COX inhibitor, pathway diverted to 5-lipoxygenase -> Leukotriene D4) -> Bronchospasm and mucus

Symptoms
Dyspnea
Wheezing
Cough

Morphology (very similar to chronic bronchitis except that it is found in smokers only)
Bronchial remodelling....
EOSINOPHILIA - IL5, Th2 - IL13
Goblet cell hyerpplasia in epithelium
Thickened BM beneath mucosal epithelium
SM hypertrophy and submucosal gland hyperplasia
Bronchial hyperactivity
3 C’s
  • Creola bodies - sloughed off epithelium (damage by eosinophil granules - ECP and MBP)
  • Curshmann’s spirals: Mucus

http://www.nikonsmallworld.com/images/gallery1996/fourbythree/14th1996large.jpg
  • Charchot Leyden crystals: Needle-shaped crystals made of breakdown products of eosinophil



http://nursingpharmacology.info/Pulmonary/respiratory_anesthesiology/Charcot-Leyden_Crystals.jpg

Reid index>1/3: Thickness of mucous gland layer/Thickness from bronchial epithelium to perichondrium
Diagnosis
  • Bronchial challenge test - test for asthma
    • Breathe in nebulized methacholine (act on M3 receptor) or histamine (act on H1 receptor) and cause bronchoconstriction
      • Asthma - HYPERsensitivity - greater degree of bronchoconstriction
    • Reversibly/post-bronchodilator test: Reversibility of bronchoconstriction by administering bronchodilator before repating spirometry test
      • Distinguish between COPD and asthma
histamine
h2 in gastric acid secretion
h1 in allergy (type 1) - e.g. asthma

Complication
- Mucus plugging -> atelectasis (collapsed lung)
  • Primary: Lungs fail to expand at birth (e.g. premature birth - the type 2 pneumocytes not yet developed to produce surfactant to reduce alveolar surface tension (intermolecular force that pulls stuff together)
  • Secondary: Caused by obstruction/compression
    • Obstructive: Most common (as in mucus plugging!)
      • Obstruction of large bronchus
        • Secretions accumulate -> Infxn -> Pul. FIBROSIS
        • Absorption atelectasis
          • Air in collapsed lung absorbed: As O2 distal to obstruction gets absorbed to alveolar blood vessel, [N2] in the obstruction rises, therefore, N2 (VERY SLOWLY due to being poorly soluble) diffuses to blood until entire alveolar volume gets reabsorbed. this process occurs SLOWLY. there is a v:q mismatch so vascular constriction, making absorption even slower.... but...... if oxygen therapy is used.... atelectasis occurs even faster!
          • Oxygen therapy: No V:Q mismatch so no constriction... nitrogen absorption occurs even faster! another factor is combining oxygen with nitrogen to form the more soluble nitrous oxide … FASTER ATELECTASIS!!!
    • Compressive
      • Mucus free to drain -> Less mucus -> Less/no fibrosis
      • External lung compression - e.g. pneumothorax



Bronchiectasis (bronchiec.... bronchi affected)

Permanent dilation of proximal bronchi (>2mm) caused by weakening or destruction of the muscular and elastic components of its walls
- Cause: Mucus accumulation................ -> chronic infection
  • Infection damages the cilia i.e. Loss of muco-ciliary clearance, also seen in foreign body or primary ciliary dyskinesia (autosomal recessive defect in the action of the cilia lining the respiratory tract (lower and upper, sinuses, Eustachian tube and fallopian tube.)
    • accumulation of secretions, bacterial overgrowth, infection and atelectasis (obstructive)

    The mucus that accumulates become a site to infection. Further infection damages the clearance mechanism hence more mucus and the cycle of infection and bronchi damage continues.

End result: Chronic infection -> Chronic inflammation (neutrophil - protease, eosinophil - MBP, ECP)-> Dilation of proximal bronchi

Xray: Cysts are actually dilated air-fluid (crescent-shaped) bronchi
http://www.youtube.com/watch?v=Kk4x7DPJtRI


HRCT high resolution ct [computed tomography]: Signet ring (bronchi (black) larger than pulmonary artery which appears white (normally pul. artery is bigger than bronchi )
http://www.youtube.com/watch?v=Kk4x7DPJtRI

Features
- Postural cough: Bronchiectatic segments are insensitive and do not provoke cough. When the patient bends down the gravity moves the pus to proximal normal bronchi evoking a cough response
- Large amounts of foul-smelling sputum (3 layers)
http://www.meddean.luc.edu/lumen/MedEd/MEDICINE/PULMONAR/images/sputum2.jpg
- Recurrent pneumonia
- Fever


Cough reflex

Pulmonary irritant receptors in posterior wall of airway up to resp. bronchiole. When triggered, impulse travel via int. laryngeal n of vagus n. to medulla. (coughing is internal laryngeal nerve... inside mouth!!!)

The efferent: From cerebral cortex and medulla  (aim to create a high velocity)
  1. Diaphragm (innervated by phrenic nerve) and external intercostal muscles (innervated by intercostal nerves) contract -> Air rushes into the lungs .
  2. Glottis closes (innervated by recurrent laryngeal nerve) and the vocal cords contract -> shutting the larynx.
  3. Abdominal muscles and other expiratory muscles contract to increase pressure of air in lungs
  4. Vocal cords relax and the glottis opens, releasing air at over 100 mph.

Stimulation of the auricular branch of the vagus nerve supplying the ear may also elicit a cough. This is known as Arnold's reflex. (e.g. using cotton wool spud in ear)




Lung volume analysis in asthmatics, COPD
  1. Decreased FEV (forced expiratory volume), VC (vital capacity)
  2. Increased RV, FRC (air trapping)
  3. Lung hyperinflation
  4. Increased TLC (COPD: hyperinflation, asthma: trapped air behind occluded)

Diff dx for asthma
  • Bronchial challenge test - test for asthma
    • Breathe in nebulized methacholine (act on M3 receptor) or histamine (act on H1 receptor) and cause bronchoconstriction
      • Asthma - HYPERsensitivity - greater degree of bronchoconstriction
    • Reversibly/post-bronchodilator test: Reversibility of bronchoconstriction by administering bronchodilator before repating spirometry test
      • Distinguish between COPD and asthma
        • asthma: reversibl
        • copd: irreversible



Obstructive lung diseases

FEV1:FVC ratio < 80% (reduced flow rate) and normal lung volume

SitePathologySymptoms
Asthma
(not chronic b/c variable)

COPD

Bronchiectasis
Chronic bronchitis
Emphysema
Small airway (bronchiole)




Proximal bronchi
Bronchus
Distal to terminal bronchiole
centroacinar - resp. bronchiole
panacinar - entire acini (resp bronchiole - alveoli
paraseptal (alveolar duct and alveoli)




SM hyperplasia, mucous gland hyperplasiaWheeze, cough, dyspnea





Restrictive lung disease e.g. fibrosis, weak resp. muscles: FEV1/FVC is normal, but decreased lung volume)

COPD - chronic obstructive pul. disease
Cause: SMOKING
Blue bloater (chronic bronchitis on the left): Emphysema (Pink puffer)
http://pic90.picturetrail.com/VOL2258/10277444/18441070/292334005.jpg

- Progressive dyspnea

- Prolonged expiration

Bronchitis - mucus trapping
Emphysema -  Alveolar damage - radial traction (elastic recoil in airway that keeps airway OPEN during expiration) decreases, air trapped... actually hunched over to squeeze air out

Do not give 100% O2 as patient will lose their hypoxic drive
- Hypoxic drive: The PCO2 in peripheral and central receptors are adaptive. In COPD patients, the chronically high CO2 levels turn it unresponsive. The main drive for ventilation turns to O2, sensed by peripheral chemoreceptors which are not adaptive. When O2 supplement is provided, it removes the hypoxemic drive. THe increasing PO2 decreases ventilation

Chemoreceptor:
1. Peripheral —carotid and aortic bodies respond to low PO2, (< 60 mmHg), high pCO2 and low pH in blood. (3 things)
2. Central — in floor of 4th ventricle (medullary) responds to changes in CSF pH (H+ can’t diffuse directly into CSF... CO2 diffuses freely → CO2 + H20 -> H2CO3 -> H+ → Decrease pH

Outflow to heart (S and PS), vasomotor (S) center in medulla (solitary nucleus)

Sinus for baroreceptor
  • Carotid sinus: Dilation of ORIGIN of ICA (internal carotid artery)
Body for chemoreceptor (b can’t pair with b!)
  • carotid body: bifurcation of carotid artery

Cushing’s reflex:

Fall -> Edema compresses BV to brain (ischemia -> Brain vessels dilate -> Further increease in capillary pressure; ischemia also lessens Na/K+ activity, thus, Na+ accumulate) -> Raised ICP (paradox...) -> cerebral ischemia -> Sympathetic stimulation - alpha1 in arteries cause vasoconstriction - hypertension in attempt to restore perfusion to brain (so MAP is greater than ICP to push the blood and perfuse brain) -> Baroreceptors in carotid artery detect and stimulate reflex bradycardia via vagal nerve

Cerebral Perfusion Pressure (CPP) = Intracranial Pressure (ICP) – Mean Arterial Pressure (MAP)

Cushing’s triad:  hypertension, bradycardia and irregular respirations in a patient with increased intracranial pressure.


Increasing ICP can cause brainstem herniation -> irregular respiration.


(A) Cingulate herniation. (B) Uncal herniation. Most common. (C) Tonsillar herniation through foramen magnum and compress medulla -> cushing's response






Pursed lips breathing for COPD
- Increase pressure in lungs to prevent collapse




Key differentiating ones: PaCO2, pH, Cyanosis, Cor pulmonale


- Chronic bronchitis (blue bloater)
  • Disease of large airway (asthma - small airway)
  • Low respiratory drive: Hypoxic
  • Productive cough for at least 3 successive months for at least 2 successive years

http://www.meddean.luc.edu/lumen/meded/mech/cases/case8/scan8.jpg

  • Purulent sputum
  • Recurrent infection
  • Less respiratory drive

Morphology (same as asthma... without the 3C’s)
Thickened BM beneath mucosal epithelium
SM (smooth muscle) hypertrophy, submucosal gland hyperplasia
Goblet cell hyerplasia in epithelium
Reid index > 1/3
Bronchial remodelling?

- Emphysema: Dilation of airspace distal to terminal bronchiole (bronchiectasis: dilation of bronchi that is >2mm) - pink puffer
  • Pink puffer - much efforts to hyperventilate to rid CO2 therefore normal ABG
    • Weight loss: Energy used in breathing (remember accessory muscles!)
  • Barrel chest due to increased lung compliance (antioxidant-oxidant and protease-antiprotease imbalance)
  • Respiratory acinus: Respiratory bronchiole -> Alveolar duct -> Alveoli
  • Types of emphyema (distal to terminal bronchiole i.e. acini)
    • Centroacinar (say s..c...): Smoker, upper lobe, involves respiratory bronchiole
    • Panacinar (entireacinar): alpha1-antitrypsin deficiency (1% of emphysema patients), lower lobe, involves respiratory bronchiole to alveoli
    • Distal acinar (Paraseptal): Cause pneumothorax, involve alveolar duct and alveoli
      • Alveoli fuse to form bulla (Bulla: Air-filled space in lung ( !@#$%^&*. with alveolar destruction); Bleb air in layer of visceral pleura)


http://www.meddean.luc.edu/lumen/MedEd/MEDICINE/PULMONAR/images/hussain3/Scan10.jpg

Pathogenesis of emphysema


SMOKING causes
  • oxidant-antioxidant imbalance
    • Smoking creates ROS which inactivate antiprotease
    • ROS activates NF-KB gene
      • Pro-inflammatory cytokines IL2 and IL8 (chemotactic - neutrophil elastase!), TNF-alpha
  • Protease-antiprotease imbalance
    • Protease: Neutrophil elastase
      • damages alveolar tissue causing alveoli to enlarge
      • destroys alveolar wall - increased compliance (ability to stretch) and decreased radial traction (the recoil that keeps small airways open –> collapse during expiration)
      • destroys capillary bed - hypoxia
    • Antiprotease: alpha1-antitrypsin inactivate protease
      • Inactivated by the ROS created by smoking
      • Congenital alpha-1 antitrypsin deficiency (1% emphysema)



Grading breathlessness

MRC dyspnea scale
1 - None except strenous exercise
5 - When walking upstairs/dressing



Summary of GPCRs (KISS QUICK til your SIQ of SQS - sick of sex)
alpha1=Q (eyes, BV)
alpha2=I
beta1=S (heart)
beta2=S (lungs)
beta3=S
M1=Q (stomach)
M2=I
M3=Q
m4 - eye
D1=S
D2=I
H1=Q
H2=S (stomach)
V1=Q
V2=S

Subtypes of GPCR
  • Gq: PLC turns PIP2 (phospholipid on cell membrane) into IP3 and DAG.
    • IP3 binds to IP3 receptors on ER (RER make protein, SER make lipids) and SR (SER in smooth and striated muscle) -> open calcium channel and causing calcium release -> Calcium-induced calcium release via Ryanodine receptor
    • DAG activates PKC
  • Gs: Activate AC -> + cAMP -> +PKA
  • Gi: Inhibits AC -> less cAMP -> less PKA

m1 neuroparietal - i.e. parietal cells of stomach AND neuro....  CNS
m2  - neurocardiac

Muscarinic
M1 - Gq - Neuroparietal (h2 in stomach, cck-B [gastrin] in stomach) 1, 2, 3
M2 - Gi - Neurocardiac  (b1 in heart)
M3 - Gq - Smooth muscle (constriction) and glands (secretion)

Treatment
- COPD
  • Corticosteroid: Inhibit NFKB pathway
  • o2 therapy
  • prevention (cessation, vaccine for infxn)
  • dilator (short-acting: salbutamol, long-acting: salmeterol)
    • antimuscarinic
      • Antagonist at M3 receptor (Gq), therefore no PLC activated to convert PIP2 to DAG and IP3, therefore low calcium -> no bronchoconstriction  (Ca-CAM complex interact with MLCK -> MLCK phosphorylate myosin head on MLC so myosin can interact with actin) and mucus secretion
      • Sfx: Dry mouth (inhibit M3 glandular secretion!)
    • Methylxanthine e.g. theophylline (a xanthine)
      • two routes for camp metabolism
        • cAMP -PDE (Phosphodiesterase)-> AMP -> Bronchoconstriction
        • cAMP -> PKA -> PKA phosphorylates MLCK -> MLCK can’t phosphorylate myosin light chain in head-> Myosin head can’t form crossbridge with actin  -> Muscle can’t contract -> Bronchodilation
      • Theophylline inhibits PDE, therefore cAMP metabolism is directed to making more PKA -> bronchodilation
    • b2 agonist: Act on b2 receptors in bronchial SM
      • Gs linked GPCR: +AC -> +cAMP -> +PKA -> Bronchodilation
      • long acting: salmeterol
      • short acting: salbutamol

Gs-alpha subunit activates AC

http://www.nature.com/scitable/content/ne0000/ne0000/ne0000/ne0000/14673543/U4.cp2.1_nature01307-f1.2.jpg


Calcium-induced calcium release
Calcium-induced: DHP (dihydropyridine - remember the drug which is a calcium blocker!!!!!!!!!) receptor (L-type voltage-gated calcium channel) allows calcium entry to cytosol
Calcium release: Cytosol calcium binquds to ryanodine receptor on SR, releasing calcium through the channel from its SR stores


Phospholamban; inhibitor of cardiac muscle sarcoplasmic reticulum Ca++-ATPase (SERCA) in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein.


Phospholamban; inhibitor of cardiac muscle sarcoplasmic reticulum Ca++-ATPase (SERCA) in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. When phospholamban is phosphorylated by PKA its ability to inhibit the sarcoplasmic reticulum calcium pump (SERCA) is lost.[4] Thus, activators of PKA, such as the beta-adrenergic agonist epinephrine (released by sympathetic stimulation), may enhance the rate of cardiac myocyte relaxation. In addition, since SERCA is more active, the next action potential will cause an increased release of calcium, resulting in increased contraction (positive inotropic effect). When phospholamban is not phosphorylated, such as when PKA is inactive, it can interact with and inhibit SERCA. The overall effect of phospholamban is to decrease the rate of muscle relaxation and contractility, thereby decreasing heart rate and stroke volume, respectively



Mast cell stabalizer
- Sodium cromoglicate
- Block IgE-regulated calcium channel (needed for mast cell degranulation) -> No Ca influx -> No histamine vesicle fuse with cell membrane to degranulate
- Route of administration: Asthma (inhaler), hay fever (nasal spray), allergic rhinitis (eye drop)

Leukotriene receptor antagonist
  • Montelukast, Zafirlukast
    • CysLT1 antagonist - block action of leukotriene D4 acting on CysLT1 receptors in bronchial tube
      • Leukotriene D4 causes Bronchospasm and mucus hypersecretion
  • Zileuton
    • Inhibit leukotriene formation by inhibiting 5-lipoxygenase

Acid secretion in stomach
Stimiuli: ACh (M1 - Gq linked), Histamine released from ECL (H2 receptor: Gs-linked - +cAMP -> PKA),  Gastrin from G cells (CCK-B receptor - Gq linked -> +Ca -> PKC); 1, 2, 3
The protein kinases phosphorylates H+/K+ ATPAse proton pump - activating it? H+ out parietal cell and K+ in
Inhibitory: PGE2 - Gi linked - inactivate AC (Less ACh - M1)


NSAID
- Inhibit NFKB pathway - less pro-inflammatory e.g. TNF-alpha in asthma!

PGI2: Inhibit platelet agg.
PGE2: Uterus contraction, platelet agg.
Different receptor types cause either bronchoconstriction or dilation.




Test

Normal

Low

High

pH

pCO2

pO2

O2 sat

HCO3

Base excess

7.35-7.45

40 mmHg (35-45)

80 mmHg (drops significantly after 60)

95%

23 (MJ)

+- 2

acidosis

alkalosis

hypoxemia

hypoxemia

acidosis

(i.e. -) acidosis

alkalosis

acidosis

-

-

alkalosis

(i.e. +) alkalosis




Henderson Hasselbalch equation
pH = 6.1 + log  ([HCO3-] / [0.03 x pCO2)]........................ pH ~ HCO3- / PaCO2

Respiratory: pCO2 +/- slow renal compensation


Respiratory acidosis
pCO2 > 40 mm Hg (hypercapnia -> decrease [hco3]/pCO2 -> decreased pH) due to:
  • Decrease in minute ventilation (hypoventilation) e.g. from brain injury, opioid, sleep apnea, muscle weakness, airway obstruction (asthma, COPD - decreased responsiveness to hypoxia and hypercapnia, decreased diaphragmatic function due to fatigue or hyperinflation)
  • acute: paco2 >45 mmHg with acidemia
  • chronic: paco2>45mmHg with near/normal pH due to renal compensation and elevated serum bicarb
    • initial: cellular buffering (increase bicarb)l
    • later: renal compensation - excrete carbonic acid and increase bicarb absorption
  • little effect on electrolyte
    • normal: ca2+ to protein and h+ out protein, k+ out protein and h+ in protein
    • acidic: more ca2+ stay in blood, k+ out protein

Respiratory alkalosis
pCO2 < 40 mm Hg (hypocapnia) due to
  • Increase in minute ventilation (hyperventilation) usually due to anxiety or severe asthma, PE (V:Q abnormality -> Hypoxia -> Hyperventilation)

Davenport diagram



The normal blood buffer line goes through (pH = 7.4, [HCO3-] = 24, PCO2 = 40 mm Hg). If we add or eliminate HCO3 we move only up and down the 40mmHg.

BE (Base excess)

RESPiratory

Respiratory acidosis:
- 1a: Elevated pCO2 to 60mmHg
- 1b: Renal compensation to increase [HCO3-] to 32
- Resulting pH: 7.35
- Predicted HCO3: 24.5
Thus BE is 32 - 24.5 -> +7.5 mmoles/L (height difference)


Metabolic alkalosis: Given: base excess of +4.7, an arterial PCO2 of 48 mmHg, and an arterial pH of 7.4
- 2a: Move along 40mmHg to +5 BE (e.g. if example gives BE as 5)
- 2b: Respiratory Compensatory - hypoventilation PCO2 to 48 mmHg
arterial pH of 7.4


Metabolic: Along normal isobar
- Alkalosis: Positive base excess, resp. compensation moves it back to normal pH
- Acidosis: Negative base excess, resp. compensation moves it back to normal pH

Controlling [H+]
  1. Blood: Buffer systems
    1. bicarbonate
    2. proteins: albumin - contain weak acidic and basic groups
    3. Hemoglobin: binds to both CO2 (Hb + CO2 -> HbCO2 carbaminohemoglobin) and H+ (H+ + Hb- <-> HHb)
  2. Respiratory: co2 elimination - alveolar ventilation inverse to arterial pressure of CO2 paCO2 (i.e. if fast ventilation, low PacO2)
  3. Electrolyte
    1. Sodium/potassium: Potassium-exchanger ATP (K+ in and H+ out to lumen)
      1. Aldosterone: More Na/K+ atpase in principal cell of collecting duct so more K+ in principal cell so more K+ diffuse out from principal cell to lumen → so more principal cell Potassium-H+ exchanger in intercalated duct (i.e. aldosterone stimulates H+ secretion in intercalated cell)
  4. Renal: Handling of Bicarbonate and Hydrogen Ions
    1. Regenerate bicarb: Bicarbonate ions are freely filtered by the glomerulus. The concentration of bicarbonate in the tubular fluid is equivalent to that of plasma. If bicarbonate were not reabsorbed the buffering capacity of the blood would rapidly be depleted. reabsorption mostly in PCT (basolateral hco3-/na+ in PCT and hco3-/cl- in intercalated cell)
    2. excrete H+ especially in collecting duct intercalated cell (apical H+ atpase, h+/k in intercalated)
    3. buffers in urine: phosphate and ammonia
      1. Hydrogen phosphate (HPO4 2-)
      2. ammonia - produced in PCT by glutaminase acting on glutamine
        1. glutaminase works optimally in acidic conditions, thus, more ammonia produced during acidosis

unonized ammonia easily diffuses down its concentration gradient and combines with H+ to form ammonium ion (ionised so doesn't go back) -> Ammonium gets lost, losing H+ with it!

  1. PCT makes ammonia (glutamine -(glutaminase)-> NH3 + glutamate -> NH3 to blood + H+ -> NH4+ ammonium ion)
  2. Ammonium ion reabsorbed in thick ascending limb by substituting K+ in Na/K/2Cl- cotransporter. The less acidic tubular cell then causes NH4+ to dissociate into NH3 and H+.
  3. The NH3 diffuses into medullary interstitum.
  4. Luminal membrane of thick ascending limb impermeable to NH3 so NH3 can't diffuse back to lumen but diffuses  to PCT -> interstitial NH3 recycling.
  5. NH3 re-enters the lumen where it is protonated back to NH4 and is again recycled back into the medullary interstitium via reabsorption at the thick ascending limb... cyclical causing high concentration of NH3 in the medullary interstitium.
  6. Low NH3 concentration (removal in the loop of Henle) and a maximally acidic urine pH in the collecting duct (reduces NH3 -> Nh4+) means that there is a large gradient for NH3 to diffuse into the collecting duct
  7. NH3 secretion into the collecting duct lumen leads to “ammonium trapping” as NH4+ formed from the very acidic urine is unable to diffuse back into the cell
  8. NH4+ is then excreted in the urine, usually with a Cl- anion.

NH4+ <-> NH3 + H+ thus NH4+ is acidic

It all depends on acidification of urine by intercalated cell
  • acidotic: hydrogen secretion is high → greater ammonia trapping (NH4+ in lumen) -> acidic urine
  • alkalosis: hydrogen secretion is less → less ammonia trapping → alkalemic urine

Metabolic: BE changes (HCO3-) +/- fast lung compensation


Base excess - amount of acid to turn 1L of blood to normal pH at standard pCO2
  • Highly + base excess (i.e. much acid needed to restore blood to normal pH, thus, metabolic alkalosis - HCO3>23)
    • due to Less acid (acid loss), HCO3 retention
  • Highly - base excess (metabolic acidosis - HCO3 <23)
    • due to more acid (e.g. lactic, failure of renal acid secretion), less HCO3 (loss)
  • Respiratory compensation: Responds to CSF pH


ignore the bottom carbamino bit... just CO2 + Hb <-> HbCO2

70% bicarb, 20% carbamino, 10% dissolved


Respiratory faliure: when pO2 is less than 60mmHg or pCO2 is greater than 40mmHg
  • Type 1: Hypoxemia but no hypercapnia
    • v:q mismatch e.g. PE
    • PE
  • Type 2: Hypoxemia AND hypercapnia
    • reduced breathing effort (e.g. LMN)
    • reduced SA for gas exchange (e.g. emphysema)
  • Type 3: Atelectasis
  • Type 4: Shock (hypoperfusion)

after drinking vodka
pH     7.16 (acidosis)
Pco2     80 mmHg (hypercapnia)
Po2     40 mmHg (hypoxia)
Base excess    +1.0 mmol.l-1 (normal)
diagnosis: respiratory acidosis, respiratory failure  type 2

after stroke and intubation
    pH     7.63 (alkalotic)
   Pco2     20 mmHg (hypocapnic)
   Po2     265 mmHg (high.........)
   Base excess     -1.2 mmol.l-1 (normal)
diagnosis: respiratory alkalosis

after vomiting and taking in much sodium bicarb:
    pH    7.54 (alkalotic)
Pco2    50 mmHg (hypercapnia)
   Po2    83 mmHg (not hypoxic)
   Base excess     + 17 mmol.l-1 (high...)
diagnosis: metabolic alkalosis (see base excess...) with respiratory compensation

diabetic, stopped insulin, unrousable
    pH    7.19 (acidotic)
   Pco2    30 mmHg (hypocapnic)
   Po2    100 mmHg (normal o2)
   Base excess     -16.5 mmol.l-1 (low!)
diagnosis: metabolic acidosis with resp compensation

COPD
pH    7.39 (normal)
   Pco2    42 mmHg (normal)
   Po2    35 mmHg (hypoxic)
   Base excess    0 mmol-1 (normal)
diagnosis: type 1 resp. failure (hypoxic but everything else is normal)

COPD

pH    7.36 (normal)

   Pco2    60 mmHg (high)
   Po2    40 mmHg (hypoxic)
   Base excess    +7 mmol.l-1 (high)
diagnosis: type 2 resp. failure (hypoxic and hypercapnic) with renal compensation (high h+, so renal secretes less h+ thus produce less actual hco3!)

A 70 year old man is admitted to the intensive car unit with acute pancreatitis. He is hypotensive, hypoxic and in acute renal failure. He has a respiratory rate of 50 breaths per minute.
pH 7.1 acidic
PCO2 3.0kPa (22mmHg) hypocapnic
BE -21.0mmol metabolic acidosis

metabolic acidosis with respiratory compensation (hyperventilate)

A 6 week old male child is admitted with a few days history of projectile vomiting.
pH 7.50 alkalotic
PCO2 6.5kPa (48mmHg) hypercapnia
BE +11.0mmol metabolic alkalosis

metabolic alkalosis with respiratory compensation (hypoventilate)

pH -> pCO2 -> Base excess -> Interpretation



HCO3 is amphoteric but for practical purposes, assume it is a base.

OH- + HCO3- <==> HOH + CO3=
H+ + HCO3- <==> H2O + CO2(g)

VIRhow’s Triad: Vascular trauma (damaged endothelium), Increased coagulability
Reduced blood flow (stasis)

Pulmonary Embolism: Occluded pulmonary artery - NOT  a disease... but caused by DVT (the actual disease)

Types of PE
  1. Minor: Most common, blocked small vessel by small emboli
  2. Major: Blocked middle sized pul. artery, lung infarct is common (thus hemoptysis, pleuritic chest pain)
  3. Massive: Sudden blockage of >60% pulmonary vasculature  (e.g. saddle embolus - bifurcation of R&L pulmonary artery) → circulatory collapse (heart pumping but no output!!!!)
    1. hypotensive
    2. cold periphery
    3. sudden increase in pul. a. pressure
    4. acute right ventricular strain
  • Most common cause: DVT embolism in lower extremities
  • high fatality rate
  • 60% clinically silent until 60% of pulmonary circulation is obstructed!
  • Clinical
    • Triad of symptoms: Hemoptysis, pleuritic chest pain, dyspnea
      • pleuritic chest pain: due to pulmonary infarction.... Chest pain on inspiration → inflammed pleura rub when inhale ( → less surfactant → atelectasis → inflammed pleura)
      • hemoptysis: lung die → inflammatory exudate
    • hyperventilate
    • tachycardic
    • hypoxia and respiratory alkalosis
    • Pulmonary infarction causing
      • pleural effusion: Low percussion note, with vocal resonance
      • pleuritic chest pain
      • fever
  • complications
    • Pulmonary hypertension → Right sided heart failure
      • Dilated right ventricle
      • Displaced IV septum → impair filling of left ventri
    • lung infarction (though rare because lung has dual blood supply - brachial artery provides oxygenated!)
  • Diagnosis
    • gold standard: Computed Tomography pulmonary angiography [CTPA] (distended pulmonary artery bigger than aorta!)
    • cxr elevated hemidaphragm (Elevation of half of the diaphragm)
    • v:q scan
      • V: Inhaled krypton
      • Q: Macroaggregated albumin x radioactive - stick to pulmonary artery
      • PE: Normal V, Low Q!
    • d-dimer (Fibrin mesh + Plasmin → FDP + D-dimer)
      • not useful (e.g. also found in DIC) but if very low, definitely not PE
    • ct
    • ultrasound of vein legs
    • ecg: Right ventricular strain (Increased JVP), sinus tachycardia,  S1q3t3
  • a large S wave in lead I
  • large Q wave in lead 3
  • inverted T wave in lead 3
  • Treatment
    • Mandatory (even if just suspected) heparin, warfarin (NOT with ASPIRIN!!! → hemorrhage..)
    • NOT plasmin... cleave fibrin and cause massive disseminated clots to pul...
    • mobilize early after surgery
    • stocking
    • analgesia
    • IV filter to stop clots going to heart


Possible emboli
  • Fat from bone fracture
  • amniotic fluid during labor
  • air after surgery
  • decompression sickness → releases nitrogen bubbles
  • foreign bodies
  • tumor embolism