Pathology Flashcards
Pyknosis
Nuclear shrinkage and increased basophilia
Karyorrhexis
Nuclear fragmentation
Karyolysis
Nuclear lysis and reduced basophilia
Cadherins
Component of adherens junctions (link to anchoring proteins)
Catenins
Catenins (anchoring proteins), link to actin or cytokeratin
Collagen (I, II, III, IV, VII)
3 polypeptide alpha chains forming triple helix
I: connective tissue proper, bone, tendon, ligament
II: cartilage, intervertebral disc
III: reticular fibres (supporting framework)
IV: basement membrane
VII: anchoring fibrils linking to basement membrane
Reticulin
Delicate supporting framework (bone marrow, liver)
Elastin
Branching fibre sheets (aorta, lung, skin)
Central core of elastin surrounded by fibrillin microfibrils
Related to Marfans Syndrome
Ground Substance
Glycosaminoglycans (GAGs)
- Hyaluronic Acid (unbranched polysaccharide) in loose CT
- Proteoglycans (GAGs linked to proteins)
- Na+ and H2O
Glycoproteins (glycosylated proteins)
- Fibronectin, fibrillin, laminin
- Link between cells and matrix
Basement Membrane
GAG : Heparan sulphate
Glycoproteins : fibronectin, laminin
Ectoderm
Gives rise to Skin & Nervous System & Epithelium
Mesoderm
Gives rise to Muscle & Connective Tissue & Epithelium
Endoderm
Gives rise to Epithelium
Simple Squamus
Mesothelium (lining of body cavities), endothelium, lining of alveoli, glomeruli
Simple Cuboidal
Thyroid follicles, renal tubules
Simple Columnar
Stomach, intestines, gallbladder, bileducts, endometrium, endocervix
Ciliated : Fallopian tubes, bronchioles
Pseudostratified Cliliated Columnar
Respitory tract
Stratified Squamous
Skin (keratinising)
Oral cavity, oesophagus, anus, vagina, ectocervix
Stratified Cuboidal
Some ducts
Stratified Columnar
Breast glands / sweat glands / prostate
Transitional
Renal pelvis, ureters, bladder
C-Reactive Protein (CRP)
Binds to phosphocoline to activate classical complement pathway
Serum Amyloid A (SAA)
Recruit immune cells to site of inflammation
An acute phase protein produced in excess by the liver in inflammatory states.
Prolonged excess occurs in chronic inflammatory disease states.
Related Diseases:
- rheumatoid arthritis
- tuberculosis
- inflammatory bowel disease
- bronchiectasis
- chronic osteomyelitis
- certain malignancies).
Fibrinogen
Converted to fibrin by thrombin
Bind to RBCs -> stack together in long chains (rouleaux formation)
Epidermal Growth Factor (EGF)
Epithelial and fibroblast proliferation
Vascular Endothelial Growth Factor (VEGF)
Blood vessel proliferation
Fibroblast Growth Factor (FGF)
Fibroblast proliferation
Platelet Derived Growth Factor (PDGF)
Blood vessel proliferation, fibroblast proliferation
GM-CSF
Growth factor for myeloid cell production (induced maturation of granulocytes and monocytes)
Infarct Timelines (histological)
4-12 hours - early coagulative necrosis, oedema, haemorrhage
12-24 hours - pyknosis, early neutrophil infiltration
1-3 days - coagulative necrosis, loss of striations, infiltatre of neutrophils
3-7 days - dying neutrophils, phagocytosis by macrophages
7-10 days - phagocytosis of dead cells, early fibrovascular granulation tissue at margins
10-14 days - granulation tissue, angiogenesis, collagen deposition
2-8 weeks - increased collagen with decreased cellularity
>2months - dense collagenous scar
Inflammation Timelines
Coagulation
Neutrophils (6-72 hours)
Macrophages / Lymphocytes
Fibroblasts
Endocrine vs Exocrine
Endocrine: secrete into blood
Exocrine: secrete onto epithelial surface or duct
Chronic bronchitis
Productive cough for 3 months for 2 consecutive years
Respiratory effects of smoking
Increase in volume of seromucinous glands (half wall thickness)
squamous metaplasia
cilial damage
increased number of goblet cells
increased presence of macrophages and lymphocytes
Types of necrosis
Coagulative Caseous Liquefactive (+calcium = saponification) Fibrinoid (typical of immune reactions) Fat
Apoptosis pathway
Extrinsic (death-receptor)
FasL -> Fas
pro-caspase 8 -> caspase 8
Intrinsic (cell stress)
UV, chemicals, etc.
Pathologic Calcification
Dystrophic - calcification occurring in degenerate or necrotic tissues
Metastatic - high blood Ca2+
Cardinal features of acute inflammation
Redness Swelling Heat Pain Loss of Function
Types of Acute Inflammatory Exudate
Purulent / suppurative (neutrophil rich)
Fibrinous (fibrin rich)
Serous (fluid rich)
Granulation Tissue
Macrophages, fibroblasts, lymphocytes, capillaries, ECM
Granulomatous Inflammation
Epithelioid Macrophages, Multinucleate Giant Cells, well circumscribed, necrosis
Infarct Timelines (gross)
4-12 hours - occasional dark mottling
12-24 hours - dark mottling
1-3 days - infarct centre becomes yellow-tan
3-7 days - hyperemia at border, yellow-tan centre
7-10 days - soft and yellow-tan, red-tan margins
10-14 days - red-grey and depressed boreders
2-8 weeks - grey-white granulation tissue
>2months - completed scarring
Sudden Cardiac Death
Unexpected event occurring within 1 hour of onset of symptoms in an apparently healthy subject
- arrhythmia (VF, asystole, VT, atherosclerosis, tamponade)
Neoplasia
Cancer
Tumour
Dysplasia
N - abnormal uncontrolled cell growth (includes cancer and benign lesions)
C - Malignant lesions (can metastasize)
T - mass lesion (e.g. inflammatory) term for neoplastic lesions
D - abnormality of development, alteration in size, shapr, organisation
Features of neoplasia
Evade growth suppressors Sustain proliferative signal Activate invasion and metastasis Enable replicative immortality Induce angiogenesis Resist cell death
BRCA1, BRCA2
Breast cancer associated DNA repair genes
dysfunction may mean cell unable to correct DNA errors
Myc, Ras, Her2-neu, Bcr-Abl, WNT
Oncogenes
Dominant (only 1 allele needs to be activated/mutated)
P53, Rb, APC, PTEN, BRCA1/2
Tumour Suppressor
Recessive (both alleles need to be deactivated/mutated)
GI Common Structural Features
MUCOSA
- Mucosal epithelium (columnar/stratified squamous)
- Lamina Propria (connective tissue, nerves, vessels, immune, lymph)
- Muscularis mucosae (facilitates mixing)
SUBMUCOSA (cholera acts here)
- dense irregular connective tissue (vessels, nerves, ganglia - regulate absorption/secretion)
MUSCULARIS EXTERNA
- Inner circular
(ganglia - myenteric plexus - cells of Cajal)
- Outer longitudinal
SEROSA (simple squamous) /ADVENTITA
GI Glands
Gastric - foveolar (mucous) - parietal (Hydrochloric Acid, H+, intrinsic factor) - chief cells (pepsinogen) - G-cells (gastrin) - D-Cells (somatostatin) Small Intestine (including crypts of lieberkuhn) - mucous - paneth (defensins, lysosome) - brunners glands (alkaline mucus) DUODENUM - peyers patches (submucosa) ILEUM - I-Cells (CKK) - S-Cells (secretin) - D-Cells (somatostatin) - L-Cells (GLP-1)
GI tract differentials
Duodenum - brunners glands, short plica (valves of kerkring), long villi,
Jejunum - larger in diameter / thicker walls, less fat in mesentery
Ileum - peyer’s patches, short villi, more goblet cells, lots of arcades, short vasa recta
Large intestine - teniae coli, haustra, no villi, more goblet cells in rectum, immune cells, rare paneth cells
Rectum - no tenia
Gallblader Epithelium
Simple Columnar
No Mucous or Goblet Cells
Absorbative (remove water and concentrate bile)
Oesophegus Epithelium
Non-keratinised simple stratified squamous
striated muscle superior (conscious control)
smooth muscle inferior
Acute Gastritis
Due to breakdown of gastric barrier or microcirculatory changes accompanying shock/sepsis
Release of inflammatory mediators (oedema & erosion)
Healing by regeneration
Can progress to Chronic gastritis
Erosion
Acute Ulcer
Chronic Ulcer
Erosion - Mucosa
Acute Ulcer - Submucosa
Chronic Ulcer - Serosa w/ sharply punched out fibrotic floor
Chronic Peptic Ulcer Layers
- exudate of fibrin, neutrophils and necrotic debris
- narrow zone of fibrinoid necrosis
- zone of cellular granulation tissue
- zone of fibrosis
Can lead to: perforation haemorrhage penetration (gastro-colic fistula) stenosis
Chronic Gastritis - Autoimmune
destruction of acid secreting tubules
= achlorhydria & anaemia
confined to gastric body (corpus)
goblet cell metaplasia hypergastrinaemia
ciruculating antibodies to
- parietal H+/K+ ATPase
- intrinsic factor
- gastrin receptor
Chronic Gastritis - Chemical
Bile reflux or aspirin/NSAIDs
disruption of mucus layer causing epithelial desquamation
foveolar hyperplasia
gastric pit elongation and toruosity
vasodilation, oedema, fibromuscular hyperplasia
Chronic Gastritis - Helicobacter pylori
live in intracellular junctions of foveolar epithelium
Urea breakdown -> amonia
positively charged amonia can neutralise HCl and are toxic to cells
Neutrophilic gastritis
IL-8
Antibodies appear @ 4 weeks
intestinal metaplasia
peptic ulcers (primary cause)
adenocarcinoma
B-Cell lymphoma of MALT
Iron deficiency Anaemia
B-cell lymphoma of MALT or marginal zone lymphoma
Infiltration of neoplastic lymphocytes into gastric gland causing epithelial damage
Expansion of mucosa eventually replacing entire wall
Helicobacter pylori gastritis patterns
ANTRUM DOMINANT
- chronic gastric inflam
- gastric polymorphs
- increased acid
- gastric metaplasia of duodenum
- chronic inflammation of duodenum
- duodenal ulcer
PAN-GASTRITIS \+ gastric atrophy \+ gastric intestinal metaplasia - reduced acid - normal duodenum - gastric ulcers possible b-cell lymphoma of MALT
Coeliac
1:100 Prevalence
HLA-DQ2, HLA-DQ8 + CD4 + IFN-gamma
MIC A & B + IL15 + CD8 w/NKG2D
Pathogenesis Stage 1. Lots of IELs on surface (2-3 per enterocyte) Stage 2. Crypt hyperplasia / elongation Stage 4. Flat mucosa, no villi Lots of plasma cells in lamina propria Submucosa is normal
Presentations
GI: diarrhoea, bloating, cramps, flatulence
Anaemia (microcytic hypocrhomic), vitamin deficiency
Malabsorption
Osteoporosis (Vit D + Ca2+)
Lethargy, Infertility
Increased prevalence of autoimmune diseases
Long term:
Enteropathy associated T-cell lymphoma
adenocarcinoma
oesophageal cancer
Anorexia Nervosa
Symptoms:
- Amenorrhoea
- Lanugo (fine) hair
- Bradycardia
- Anaemia
Causes:
- Stress
- Personality
- Genetics (Serotonin 1D, Delta Opioid Receptor, 5HT2A Receptor reduced binding)
Cancer Staging
A - invades beyond muscularis mucosae
B - invades beyond muscularis propria
C - lymph node metastases
D - distant metastases
Cancer Terminology:
Premalignant
Malignant
Premalignant:
- Dysplasia (intraepithelial neoplasia)
- Carcinoma in situ
Malignant:
- Carcinoma (epithelium)
- Sarcoma (stroma)
- Lymphoma/leukaemia (haematopoietic)
HPV
Sexually Transmitted
High risk types 16 & 18
- moderate to severe squamous dysplasia (CIN2-3)
- major cause of squamous cell carcinoma
Integration with cellular genome
- loss of p53 (E6 Binds) & Rb (E7 Binds) tumour suppression
Adenomatous (dysplastic) polyps
Precursors for colorectal cancer
TUBULAR ADENOMA: sessile or pedunculated
VILLOUS ADENOMA: often large & sessile (shag carpet)
TUBULOVILLOIS ADENOMA: mixed features
Lynch Syndrome (NHPCC)
Hereditary Non Polyposis Colorectal Cancer
Autosomal Dominant (80-85% penetrance)
Assocaited with extracolonic cancers
Most common familial colorectal cancer syndrome
Familial Adenomatous Polyposis
Autosomal Dominant
APC gene mutation
>100 adenomatous polyps in large bowel
Colorectal Cancer Genetic Pathways
Chromosomal Instability - 75-85% CRC Microsatellite Instability (MSI) - 15% CRC CpG island methylator phenotype (CIMP) - 15% CRC
Common genetic changes in dysplastic carcinoma sequence
Proto-oncogenes - K-RAS in 50% - B-RAF in 10% Tumour suppressor genes - SMAD2/SMAD4 - p53 Telomerase activation
Kwashiorkor
Malnutrition due to severe protein lack
Enlarged fatty liver, low albumin, oedema (ascites)
Alfatoxin -(P450)-> Aflatoxin Expoxide (reactes with guanine in DNA causing cell death or cancer)
- Kwashiorkor microbiota generated products that resulted in selective inhibition of TCA cycle enzymes.
Bruise Timeframe (Days)
0 - reddish - blood trapped in interstitual tissue 1-2 - blue/purple/black - deoxy & met-Hb 5-10 - green/yellow - biliverdin 10-14 - yellow/brown - bilirubin >14 - fades
Acute Hepatitis Pattern
Lubular Disarray and Apoptosis
Acute Viral Hep A & B)
- Hepatocyte swelling, size variation, plate disruption
- Lymphocytes surrounding infected hepatocytes
- Kupfer cells containing bile & lipofuschin (cell breakdown products)
- Councilman bodies - hepatocyte apoptosis
Acute Hepatitis Pattern
Zonal Coagulative Necrosis
Toxins e.g Paracetemol - Zone 3
- liver injury caused by metabolite NAPQI -> depletion of glutathione
- no inflammation, macrophages may come in later to clean up necrotic debris
Acute Hepatitis Pattern
Acute hepatitis with Mallory bodies
Alcoholic Hepatitis
Mallory Bodies
- chemotactic for neutrophils
- massive collapse of cytoskeleton (intermediate fillaments cytokeratin 18 and ubiquitin)
- pink ropey material in c-shape around nucleus
Hepatocellular ballooning
Large fat vacuoles (Macrovesicular steatosis)
Pericellular fibrosis (hepatocytes) and sclerosing hyaline necrosis (central vein).
Neutrophils
Patient presents with Jaundice, Fever, RUQ tenderness, fever
Acute Hepatitis Presenting Features
Jaundice
Raised ALT < 6 months
No previous history of liver disease
Primarily CD8 T Cells and no neutrophils (except alcoholic)
Chronic Hepatitis Presenting Features
Pt usually not overtly unwell
Raised ALT/AST > 6 months
Apoptosis is hallmark feature of acute and chronic hepatitis
Periportal Inflammation (portal tract with lymphocytes extending irregularly into adjacent tissue)
- aka INTERFACE HEPATITIS
- degree is defined as GRADE
- leads to fibrosis over time and distortion of hepatic architecture
Fibrous septa
- degree of fibrosis is defined as STAGE
Common causes: HBV, HCV, autoimmune, drugs
Non Alcoholic Fatty Liver Disease
STEATOSIS with or without STEATOHEPATITIS (NASH) and FIBROSIS
Macrovesicular steatosis caused by increased triglyceride synthesis or decreased excretion
Steatohepatitis has hallmark feature of hepatocellular ballooning degeneration
Pericellular Fibrosis (around hepatocytes)
Associated with obesity, metabolic syndrome, diabetes
Associated with mildly elevated ALT,AST, GGT
Wernicke Korsakoff Syndrome
Alcohol metabolism leading to Thiamine destruction
Affects 2% of Australians
Symptoms: Eyes uncoordinated (nystagmus) Wide step Confusion Hypothermia Amnesia Confabulation
Foetal Alcohol Syndrome
Small heads, eyes, facial features
Indistinct philtrum, flat midface, thin upper lip
Trouble with abstract concepts like time and money
Difficulty generalizing, concentrating, or learning from example
Pancreas Structure
EXOCRINE (bicarb & digestive)
Acinar cells
basophilic base
eosinophilic apex
ENDOCRINE Islets of langerhans (rich vascular) - Alpha Cell - Glucagon - Beta Cell - Insulin - Delta Cell
Pancreatitis
Alcohol Abuse and Gallstones account for 90% of cases
Decrease in pain may signal advanced destruction of pancreas
Serum amylase and/or lipase are elevated in pancreatitis
Haemolytic Jaundice
Pre-Hepatic
Unconjugated bilirubin (3x normal level)
AST slightly increased
Urine urobilinogen increased
Increased reticulocytes
Decreased haemoglobin
Neonatal Jaundice
Caused by increased haem catabolism (changeover from Hb-F to Hb-A)
Normal for neonatal bilirubin to be up to 100umol/L
can be caused by
- haemolytic disorders (Rh factor incompatibility)
- birth trauma
- reaction to breastmilk
- premature (liver not developed)
- hepatic inflammation
Gilbert’s Syndrome
Decreased conjugation of bilirubin
Unconjugated bilirubin fluctuations
Hyperbilirubinaemia increases on fasting
Crigler Najjar Syndrome
Absence of bilirubin conjugating enzyme
Severe unconjugated hyperbilirubinaemia
Dubin Johnson Syndrome
Decreased excretion of bilirubin
Fluctuating conjugated hyperbilirubinaemia
Rotors Syndrome
Similar to Dubin Johnson but no hepatic pigmentation
Chronic Liver Diseases
Chronic Hepatitis (B,C,AIH)
NASH, ALD (steatohepatitis, pericellular fibrosis),
Metabolic Diseases (Wilsons - copper, Haemochromatosis - iron)
Chronic inflmmation of bile dicts (scleorisng cholangitis, biliary cirrhosis),
Drugs (methotrexate, methyldopa)
Cirrhosis (Fibrosis Stage 4)
Nodules of regenerating hepatocytes surrounded by bands of fibrous (scar tissue)
Nodules appear green as a result of marked cholsestasis
Pathogenesis:
persistent hepatocyte APOPTOSIS stimulates activation of STELLATE CELLS (‘myofibroblast differentiation’), deposition of increased collagenous extracellular matrix
KUPFFER CELLS secrete TGF-b (stimulate fibrogenesis), chemotactants and proliferants for stellate cells
Remodelling of vascular supply leads to ischaemia and progression of cirrhosis
Complications:
- Parenchymal Liver Failure (Hepatic encephalopathy, Jaundice, Hypoalbuminaemia, Coagulopathy)
- Endocrine (Gynecomastia, Spider Naevi, Female hair patterns, Gonadotrophy)
- Portal Hypertension (Encephalopathy, Varices, shunts, Ascites, Renal failure)
- Hepatocellular Carcinoma
Hepatocellular Carcinoma
Most occur in patients with cirrhosis
Risk relates to cause of cirrhosis as well as cirrhosis itself
Mostly seen due to alcohol, Chronic Hep B/C, haemochromatosis
Metasteses to cirrhotic livers are exceptionally rare
Portal Hypertension
Increase in portal BP or gradient between portal vein and hepatic vein
Pathogenesis:
- Splanchnic circulation in cirrhosis is hyperdynamic resulting in increased portal and hepatic arterial blood flow
- Hepatic vein directly compressed by regenerating nodules
- small portal veins are trapped/narrowed by scar tissue
- hepatic arterial blood shunts into portal and increases pressure
Complications: Splenic enlargement Ascites Varices at sites of porto-systemic anastamoses (oesophegus, rectum, umbilicus) Encephalopathy Jaundice others ...
Acute Renal Failure
- definition
- pre-renal
- intra-renal
- post-renal
Acute reduction in GFR w/ increased serum creatinine & urea
Sudden (one - several days)
Often reversible
Urine flow < 500ml/day (but oliguria not always present)
RAAS activation
Anuria (rare) - usually due to other causes
PRE-RENAL
- Systemic Perfusion Pressure < 70mmHg
- Glomerular hydrostatic pressure < 45mmHg
- Stasis & anoxia = casts & death of tubular cells (ATN)
- Causes: shock, sepsis, haemolysis, rhabdomyolysis, nephrotoxicity, renal artery stenosis, dehydration
INTRA-RENAL
- Glomerulonephritis (post-strep group A)
- Interstitial nephritis (inflammatory reaction)
- Acute Tubular Necrosis (ischaemia, toxins - e.g. aminoglycosides, rhabdo, ) - MOST COMMON CAUSE
- Acute on chronic (e.g. drugs
POST-RENAL
- Obstruction (ureteric, cystic, urethral), (stones, clots, fibrosis, tumors)
Chronic Renal Failure
Gradual (6months - years)
RAAS, VitD, Erythropooeitin activation
Common Causes:
- Diabetes
- Hypertension
- Chronic glomerulonephritis
- Cystic disease (polycystic kidney)
- Reflux nephropathy
[K+] increase pH falls rise in [PO4] reduction in [Ca2+] decrease in [VitD] High PTH
Normal GFR 120ml/min
GFR @ 65yo 100ml/min
GFR @ 80yo 75ml/min
CRF < 50ml/min
Acute Tubular Necrosis
Most common cause of Acute Renal failure
oliguria (<400mL/d)
+/- acidosis
increased K+
can be caused by severe or prolonged pre-renal causes
Reversible if patient supported
Ischaemic or Toxic damage of tubular cells leading to death or detachment and tubular dysfunction
Glomerular vs Tubular Disease
Glomerular
- Na+ retention and hypertension
Tubular:
- Na+ wasting and low BP
- Impaired concentrating ability & polyuria
Layers of glomerulus
Fenestrated epithelium (capiliaries) Basal Lamina Endothelium (Podocytes, contiunous with wall of Bowman's capsule)
Epithelium in Kidney
Proximal Tubule: Simple Cuboidal Epithelium w/ microvilli (dense staining - mitochondria)
Thin loop: squamous cells
Distal Tubule: Simple Cuboidal Epithelium (smaller, larger lumen, paler cytoplasm)
Collecting duct: Simple Cuboidal Epithelium becoming Columnar
Ureter/Bladder - Transitional Epithelium (surrounded by smooth muscle)
Urethra - Transitional Epithelium then Stratified Squamous
IBD:
Ulcerative Collitis vs Crohn’s
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Hepatocyte
Prominent RER & Golgi - protein synthesis
Prominent smooth ER - fat / steroid metabolism
Many Mitochondria
One/Two nuclei
150 day lifecycle
collagen types I/III (reticular)
Space of Disse between hepatocyte and sinusoid, contain Kupfer & stellate cells
Familial Cold Urticaria
Signs of acute inflammation when exposed to cold
single nucleotide mutation of cryopyrin (NLRP3) gene
Gout
Painful acute inflammation of a a single joint
Men, age, menopause
Genetics
Obesity, hypertension, metabolic syndrome
SIGNS/SYMPTOMS:
Painful distal joints (early morning)
Gouty nephropathy & kidney stones
Tophi (foreign body type granulatomatous inflammation)
PATHOPHYSIOLOGY Purine rich foods Asymptomatic for 20-30 years Monosodium-urate formation exceeds renal clearance capacity Precipitation (pH, temp, dehydration) Urate crystal phagocytosis Phagolysosome destabilisation ROS, Protease lowered cytosolic K+ NLRP3 inflammasome activation caspase 1 cleavage IL-1b cleavage and secretion Promotion of acute inflammation
TREATMENT:
Anti-inflammatory (anakinra), urate lowering (allopurinol)
Causes of pancreatitis
I GET SMASHED
Idiopathic (no obvious cause) Gallstones Ethanol Trauma or surgery Steroids Mumps & other viruses Auto-immune Scorpion bites Hypercalcaemia or Hyperlipidaemia ERCP Drugs, toxins, medications that trigger inflammation
Alcohol induced Pancreatitis
Acute episodes of pancreatitis progressing to chronic pancreatitis
Hypertriglyceridaemia Pancreattis
Lipid abnormalities + poorly controlled diabetes, alcohol, or medication.
Drug / Medication induced Pancreatitis
Asparaginase, Azathioprine, 6-Mercaptopurine, Pentamidine, Saquinavir, Ritonavir
Autoimmune Pancreatitis
Obstructive Jaundice Focal mass (difficult to distinguish from cancer) Abdominal Pain Biliary disease Usually presents with other autoimmune diseases (diabetes, lupus)
Gallstones & Pancreatitis
Obstruct enzyme flow Epigastric pain radiating to the back Nausea Vomiting 3-5x serum amylase & lipase Elevated ALP and bilirubin = ductal obstruction Elevated ALT
Hypertension Definition (BP)
140/90
Age related arterial changes
AORTA:
- loss of elasticity, hardening, arteriosclerosis
- media: framentation of elastin, increased collagen
- intima: increased collagen
ARTERIES:
- media: fragmentation of elastin, increased collagen, calcification
- intima: increased collagen -> thickening
ARTERIOLES:
- hyaline sclerosis (deposition of plasma proteins in wall)
- smooth muscle atrophy
- increased collagen
Alport Syndrome
Abnormal Gene coding for collagen subtype in glomerular basement membrane
Protein loss through urine
Finnish Type Nephrotic Syndrome
Mutation in gene for nephrin (protein in fine filtration pore between podocytes)
Protein loss through urine
Glomerulonephritis
Typically immune mediated depositions and compliment activation
- Post-Strep GN
- IgA Nephropathy (most common in AUS)
- Membranous Nephropathy
- Diabetic Nephropathy
may have CRESCENTS: clumps of monocytes, fibrin, and epithelial cells (podocytes)
Leads to renal impairment
- decreased GFR
- increased serum creatinine
- heamaturia
- nephrotic syndrome
Post-Strep GN
haematuria / nephritic syndrome
similar mechanism to rheumatic fever (1-4 weeks after infection)
Diffuse (every glomerulus) and Global (most of glomerulus) GN
Abundant neutrophils
IgG clumps on EXTERNAL surface of basement membrane (below podocyte foot processes) - lumpy bumpy
IgA Nephropathy
haematuria / nephritic syndrome
most common GN in AUS
Dark (electron-dense) deposits of abundant immune complexes in MESANGIUM
Mesangial expansion reduces blood flow leading to sclerosis/ischaemia. Tubules become atrophic w/ interstitial fibrosis. Small & atrophied macroscopically macroscopically.
Membranous Nephropathy
proteinurea / nephrotic syndrome
Dark (electron-dense) deposits of abundant immune complexes along OUTER (epithelial) aspect of basement membrane
Diabetic Nephropathy
Most common cause of ESRF nephrotic syndrome (proteinurea) & CRF
Nodular balls of collagen in glomerulus (diffuse and local)
Caused primarily by microangiopathy:
Formation of AGEs in endothelium leads to thickening and concurrent weakening of vascular basement membranes.
Three key histological features:
- Thickened glomerular basement membrane
- Glomerulosclerosis (kimmelsteil-Wilson nodules)
- Mesangial expansion
Tubulointerstitial Diseases
More common than glomerulonephritis
- ATN (ischaemia)
- Interstitial Nephritis
- Pyelonephritis (infection)
Interstitial Nephritis
Presents as Acute Renal Failure Interstitum and tubules infiltrated by inflammatory cells (MANY EOSINOPHILS) Tubules not necrotic Often fever, possible rash Often due to drug allergy
Pyelonephritis
Bacterial infection of parenchyma, calyces, or renal pelvis
Acute: Acute inflammation Fever, chills, lumbar tenderness and pain Discomfort when urinating Renal function preserved
Chronic:
May be associated with obstruction
Results in interstitial scarring, tubular atrophy, ‘saddle’ scars on renal surface
Cells of CNS
NEURON
- high levels of protein synthesis (Nissl bodies - RER blobs)
- actin (dynamic shape changes), microtubles (dynamic transport within axon), intermediate filaments (permanent)
ASTROCYTE
- neurotransmitter uptake and degredation (GABA, glutamate)
- K+ homeostasis
- BBB maintenance
- Modulate blood flow and neuronal function
- intercommunication via Ca2+ waves / exocytosis (Ca2+ waves inhibit neuronal activity, and causes vasoconstriction)
OLIGODENDROCYTE / SCHWANN
- O: wrap around many axons, S: wrap one axon only
- insulate and increase speed of conduction
- Nodes of Ranvier
EPENDYMAL
- line central canal and ventricle
- low columnar / cuboidal, some ciliated
- no basal laminar (basal projections into spinal cord)
SATELLITE
MICROGLIA
- phagocytic (macrophages)
Parkinson’s
Idiopathic degeneration of dopaminergic pathways
Affects basal ganglia (substantia nigra - 80% dead before symptoms present)
α-synuclein in presence of DA & metal oligomerises, becomes insoluble, and forms lewy-bodies
Rx (symptomatic relief):
- L-Dopa & peripheral Dopadecarboxylase inhibitor (Levidopa + Cabidopa/Benserazide)
- MAO inhibitors (Selegiline)
- Dopamine receptor agonists (bromocriptine, cabergoline)
- Muscarinic receptor antagonists (ACh in striatum)
Symptoms: tremor at rest muscle rigitidy stooped posture slow movement (bradykinesia) poor balance and co-ordination reduced/lost sense of smell (first loss) microhandwriting Depression/anxiety (low dopamine) Fatigue/Pain/Bladder Problems
(contrast with huntingtons -> degeneration of striatum)
Huntington’s
Degeneration of striatum & GABA deficiency
Autosomal Dominant unstable repeat expansion (CAG) in coding region - protein gain’s new function and toxicity in basal ganglia*
Symptoms: Disinhibition Apathy Involuntary movements Chorea (trouble with balance and walking) Weakness Dysarthria Rigidity Bradykinesia (late)
Rx:
GABA agonist - e.g. Baclofen
Dopamine antagonist - e.g. Chlorpromazine
*old function was transcription, intracellular transport, signalling, reduction of apoptosis
Fragile X Syndrome
Most common cause of male Autism
Mutation of FMR1 (Fragile X Mental Retardation gene 1)
Affects synaptic and dendritic development
X-linked
Unstable repeat expansion in 5’ untranslated region
Loss of protein function
Epidural/Extradural Haematoma
Pterion Fracture Middle Meningeal Artery Bleed Can cause fast increase in ICP Dura more adherent with age so less likely Egg shaped on MRI Lucid interval (50%)
Subdural Haematoma
Low pressure bleed from veins (superior cerebral bridging veins)
Brain shrinkage with age so more likely
Crescent shaped on MRI
Diffuse Axonal Injury
Damage to individual axons / tearing
Corpus Callosum is highly susceptible
Diffuse vascular injury
Swelling of axon with axonal spheroid (collection of axonal intracellular structures)
Long term effects:
- atrophy of cerebrum
- enlarged lateral/third ventricles
- thin corpus callosum
- thin white matter compared to grey matter
Primary Essential Hypertension
Complex, multifactorial disorder involving environmental and genetic polymorphisms influencing sodium resorption and RAAS
- no identifiable cause
- most common (cf. secondary)
- high BP (slow rise)
- no evidence of acute end organ damage (acute renal failure or hypotensive encephalopathy)
- proteinuria indicates kidney involvement
- silver wiring & AV nipping indicates retinopathy
[Renovascular relates to secondary hypertension caused by renal artery stenosis - usually atherosclerosis]
Benign Nephrosclerosis Microscopic Features
Patchy tubular atrophy
Interstitial chronic inflammation and fibrosis
Hyalinised arterioles
Glomerulosclerosis
PNS regeneration timeline
NORMAL
Central Nucleus, Dense Nissl substance
2 WEEKS
Peripheral Nucleus, Loss of Nissl substance
Degeneration of axon and myelin sheath (phagocytosed), muscle atrophy
3 WEEKS
Schwann cell proliferation, axons penetrate cord (guidance of schwann cells) (grow at 0.5-3mm/day)
3 MONTHS
Successful regeneration, Muscle fibre regen
NEUROMA
Unsuccessful regeneration, painful/unwanted sensation
Inhibitory factors to CNS regeneration
More complex than CNS Oligodendrocytes inhibitory Myelin Astrocytic gliosis & scarring Central canal swelling and obstruction
CNS injury treatment
INHIBIT DAMAGE
- Minimise primary damage (e.g. tPA for stroke)
- Corticosteroids reduce inflammation
- EPO
REGROWITH
- Promote axonal regeneration (neurotrophins NGF & BDNF)
- Prevent Astrocytic gliosis (block ECM - collagen IV and CS proteoglycans)^^
- Prevent myelin inhibitors (Nogo, MAG, OMGp, NgR)
- assist axonal guidance (EphA4, ephrinA5)
- Stem cells (induced & differentiated)
^^ reduces wound healing ad BBB repair
CNS injury timeline
IMMEDIATE:
Physical damage & cell loss
MINUTES/HOURS:
Ischaemia, Ca2+ influx, glutamate toxicity, BBB breakdown, free radicals
HOURS/DAYS
Immune cell infiltration (microglial)
Cytokines, chemokines, metalloproteases
DAYS/WEEKS Axonal degeneration Demyelination Apoptosis (neural and oligodendrocyte) Astrocytic gliosis & scar Meningeal Fibroblast migration Central canal swell & obstruction
Presbyopia
Loss of ability to focus (accomodation)
Caused by reduction in lens capsule and zonules
Varies with age
LMNL
Weakness or paralysis Decreased superficial reflexes Hypoactive deep reflexes Decreased tone Fasiculations and fibrillations Severe muscle atrophy
UMNL
Weakness Spasticity - Increased tone - Hyperactive deep reflexes - Clonus Babinski's sign Loss of fine voluntary movements
Hemiparetic Gait
Unilateral weakness
Arm flexed
Plantar flexion of foot
Drags leg in semicircle
Sign of Cerebellar damage
Medial Medullary Syndrome
Anterior Spinal Artery damage
- > Hypoglossal nucleus (tongue deviation towards lesion)
- > Medial Lemniscus (contralateral somatosensory hemidefect)
- > Medullary Pyramids (contralateral hemiparesis)
Stroke
- types
- causes
- pathophysiology
TYPES:
75% - infarction
20% - haemorrhage (multifocal -> leukaemia?)
5% - subarachnoid haemorrhage
CAUSES: Cardiac - valve vegetations - patent interatrial septum Large artery occlusion (thrombotic/embolic) - atherosclerosis Small vessel occlusion (thrombotic/embolic) - hyaline arteriolosclerosis - amyloid deposition in superficial blood vessels Venous occlusion (thrombotic) Atriovenous malformation haemorrhage Coagulopathy (Leukaemia) Berry Aneurysm Coarctation of Aorta
PATHOPHYSIOLOGY
- ischaemia
- decreased aerobic respiration -> no ATP (metabolic cells die first)
- ion channel pump failure
- Na+/Ca2+ retention -> water retention -> cytotoxic oedema (first hour) -> raised ICP -> herniation
- ROS -> caspase -> apoptosis
- penumbra (glutamate toxicity)
- support cell death (astrocyte, endothelial) -> vasogenic oedema (36 hours)
- reperfusion (haemorrhage), macrophages, liquefactive necrosis (days/weeks)
- cystic space (months years)
Hypokinesia (Parkinson Gait)
Bradykinesia Tremor Rigidity Stooped Posture Short Shuffling Steps
Hyperkinesia (Huntingtons)
Quick irregular muscle jerks and twitches
Like a dance
Chorea (Gait)
Abnormal
Varying cadence of walk
Wobble from side to side (upset balance)
Arms don’t swing
Alzheimer’s Disease
APP, Aβ Amyloid, ApoE
β-secretase cleaves APP forming insoluble β-sheets (amyloids plaques), damage occurs before plaque formation while oligomer is embedded in membrane upsetting synapse
Age major risk factor
Diagnosis only if there is a decrease in daily living activity
Symptoms (reduced): Working Memory Anterograde Episodic Memory Semantic Memory Attention and executive abilities (distractible, muddled) Language (syntax and phonology) Visuospatial and perceptual Praxis Depression, Apathy Delusions, hallucinations
BRAAK AND BRAAK STAGING
I-II - transtentorhinal - asymptomatic
III-IV - limbic system - symptoms begin
V-VI - neocortical association cortex - fully developed
Freidrich Ataxia
Autosomal Recessive
Unstable repeat expansion in intron (thought to form triple helix, or induciton of heterochromatin resulting in reduced protein production)
Loss of protein function
Onset around puberty
Mitochondrial iron accumulation leads to oxidative damage
Progressive limb and gait ataxia with cardiomyopathy & diabetes mellitus
Spinocerebellar Ataxia
Autosomal Dominant
Unstable repeat expansion confers ‘novel’ protein function
Progressive degeneration of CNS & spinocerebellar tracts (gait, coordination, speech, eye movement)
Different variants based on chromosome involved
Indigenous Australians highly affected
Epilepsy
Excessive hyper-synchronous activity of neurons (inhibitory / excitatory) GENETIC (primary) - usually generalized seizures - onset in childhood - respond well to medication STRUCTURAL/METABOLIC (secondary) - e.g. tumor/slecrosis - usually partial/focal - uncommonly remit UNKNOWN (cryptogenic)
Higher mortality
SUDEP (sudden unexplained death in epilepsy)
Due to alterations in neuronal network components, intrinsic neuronal cellular excitability, synaptic transmission, extraneuronal environment (glia)
Mesial Temporal Sclerosis
Cell loss in hippocampus
Mossy fibre sprouting
Excessive proliferation of glial cells
Need to remove hippocampus to stop seizures due to MTS in epileptics
Seizure -> MTS -> seizures -> etc.
Increased T2 signal, decreased T1 signal
Schizophrenia
Problem with synaptic formation and pruning
decreased neuronal size (DLPFC)
decreased neuronal connections
decreased glial density (DLPFC)
altered cell cytoskeleton (wnt pathway)
increased calprotectin (microglial protein upregulated during inflammation)
Autism
Overgrowth of DLPFC early in development
Enlargement doe snot persist into late childhood
Activated microglia (retracted processes, plumped up amoeboid) w/o pro inflammatory cytokines
Protective & Risk SNPs conferred from parents
Atherosclerosis Mechanism
COMPLETE THIS LATER
• risk factors: smoking, age, hypertension, hypercholesterolaemia
• Sympathetic stimulation on exertion -> increased heart rate and contractility thus
myocardium needs more oxygen
• Narrowing of at least one coronary artery by >70% and reduced release of vasodilators by
dysfunctional endothelium don’t allow sufficient oxygen delivery -> myocardial ischaemia
with generation of lactate, adenosine etc -> pain
Asthma Mechanism
Increased responsiveness of airways to various stimuli leading to episodic bronchoconstriction which is partly reversible.
Type I hypersensitivity
Sensitisation Phase
Th2
IgE switching (high affinity binding)
IL-4, IL-5 Response Phase - IgE histamine leukotrienes Tnf-alpha cytokines growth factors remodelling
Immediate response - increased vascular permeability -> odema - increased mucus production - bronchospasm Late phase (4-8 hours) - chemotaxis of eosinophils, lymphocytes, macrophages - ongoing inflammation - epithelial damage
Supplementary Oxygen Maintain Airways Adrenaline Gluco-corticosteroids, B2-agonists Antihistamines
Guillain-Barre Syndrome
Acute inflammatory post-infective demyelinating disease (EBV, CMV, HIV)
Partial or total paralysis (glove and stocking)
Frailty
- Definition
- Pathology
- Fried’s Criteria
Vulnerable state
Diminished ability to carry out practical and social aspects of daily living
Balance easily perterbed
Unable to bounce back in response to stress
Low grade chronic immune activation:
increased IL-6 & TNFα (cachexia, atrophy, sarcopenia)
increased CRP
decreased CNS & PNS innervation
decreased GH, IGF-1, sex hormones
decreased caloric/protein intake
muscle disuse (Type 2 loss»_space; Type 1 - slow)
Fried’s Criteria
- Unintentional Weight Loss (3-4kg w/o trying)
- Weakness
- Exhaustion
- Slow walking speed
- Low physical activity
Prefrail: 1 or 2 criteria
Frail: 3+
cf. disability - impairment limiting 1+ major ADL
cf. co-morbidity - presence of 2+ chronic diseases
Spongiform Encephalopathies
kuru, CJD, BSE
Cannibalism
Spongiform - small fluid filled vacuoles - classical reaction to toxin
Conversion of Prion Protein to abnormal β-sheet Prion Protein and autocatalysis
Codon at 129 determines susceptibility to disease (homozygous Methionine = susceptibility to vCJD)
Cushings Syndrome
Inappropriately high cortisol levels
SYMPTOMS: Hypertension Weight gain (trunk) hyperhidrosis (sweating) Striae Hirsuitism/Baldness
CAUSES:
Pituitary adenoma
paraneoplastic
iatrogenic (prescribed drug)
TESTS: Dexamethasone Suppression (competitive w/ cortisol) - should inhibit ACTH release of pituitary if feedback loop is working
Hypothyroidism
Primary (thyroid failure or low iodine, hashimotos)
↓T3 & ↓T4, ↑TSH -> goiter
Secondary (tumor, axis failure)
↓T3 & ↓T4, ↓TSH +/- ↓TRH -> no goiter
Decreased BMR, O2 consumption, energy, HR, reflexes, protein synthesis (puffy myxoedema), appetite, bowel motility (constipation)
Increased weight, thickened skin
Cold intolerance
Alopecia
Hyperthyroidism
Primary (graves, autoimmune, hypersecreting tumor)
↑T3 & ↑T4, ↓TSH -> goiter
Secondary (axis excess)
↑T3 & ↑T4, ↑TSH +/- ↑TRH -> goiter
Increased BMR, O2 consumption, energy, HR, reflexes, appetite, alertness, exopthalmosis (water retained behind eyes), cardiomegaly, insomnia, bowel motility (diarrhoea)
Decreased weight, flushed skin
Heat intolerance
Diffuse Nontoxic (“Simple”) Goitre
Impaired synthesis of throid hormone (hypothyroidism or euthyroid)
Normal T3 & T4, ↑TSH -> goiter
Involutes if normal thyroids levels are returned
Causes: Iodine deficiency, goitrogens
Histopathology:
- hyperplastic follicles (crowded)
- some follicles larger than others, may have colloid filled cysts
- with persistant ↑TSH some follicles rupture or haemorrhage
- can become multinodular with cycles of hyperplasia and involution
Thyroid Histopathology
Round/oval follicles lined by cuboidal eppithelial cells
Filled with colloid (thyroglobulin & GAGs)
Rich blood supply
When active follicle cells become taller and colloid becomes scalloped
Toxic Multinodular Goitre
Nodules rupture and fibrose
Nodules become autonomous
Patient may be hyperthyroid (if they suddenly get iodine out of diet)
Nodule appears ‘hot’ on PET scan
Cause ‘pemberton’s sign’ - mass effect compression of SVC
Less than 1/3 regress,
Graves Disease
Type II Hypersensitivity
Hyperthyroidism due to diffuse (no nodules), enlargement of thyroid
↑T3 & ↑T4, ↓TSH -> goiter
↑Anti-TPO, ↑Thyroid Stimulating Immunoglobulin*
Exopthalmosis
Fibroblasts (TSHR) produce more GAGs, transform into adipocytes: retro-orbital hydrophilic mycopolysaccharides, oedema, lymphocytes, fibrosis, fat.
Myxoedema
SYMPTOMS: Muscle Wasting Fine Hair Goiter Sweating Tachycardia Weight Loss Oligomenorrhea Tremor Proptosis Heat intolerance Frequent bowl movements
TREATMENT:
Radioactive Iodine
Surgery
Inhibition of Thyroperoxidase (carbimazole)
beta-blockers - reduce sympathetic overactivity
Female Predominant 20-50yo
* Can have TSH-binding inhibitor immunoglobulins and present with hypothyroidism
Hashimotos Thyroiditis
Type IV Hypersensitivity
Hypothyroid
↓T3 & ↓T4, ↑TSH
↑Anti-TPO, ↑Anti-Thyroglobulin
CD8+ cytotoxic cell-mediated cell death
Cytokine mediated cell death (IFN-γ, FAS)
Mononuclear Inflammatory infiltrate (T&B cells, plasma cells, germinal centres)
Abundant eosinophilic granular cytoplasm (‘Hurthle cells’)
Increased interstitial connective tissue (chronic inflammation - fibrosis/scarring)
Macro: enlarged at first then atrophic, firm, tan-yellow, pale (fibrotic), nodular, ‘unripe pear’
Treatment:
Thyroxine Replacement
Can precipitate AF (especially in elderly / pregnant)
Associated risk of B-cell non-Hodgkin lymphoma
Female Predominant 45-65yo
Associated with other autoimmune conditions & HLA-DQ3,4,5
Cushing’s Syndrome
Inappropriately high cortisol levels
CAUSES: Pituitary adenoma Primary: Adrenal Tumor Secondary: Pituitary Tumor (Cushings Disease) paraneoplastic iatrogenic (prescribed drug)
TESTS: Dexamethasone Suppression (competitive w/ cortisol) - should inhibit ACTH release of pituitary if feedback loop is working
SYMPTOMS: Present with: Hyperglycaemia (mimics diabetes) Protein shortage (muscle wasting) Abnormal fat distribition (moon face, trunk obesity, stretch marks - striae) Increased appetite Hypertension (salt retention) Osteoporosis (disrupted plasma [Ca2+]+ balance) Mood and memory changes Oligomenorrhoea Hirsutism Acne Red cheeks Poor wound healing Inhibition of growth (children)
Addison’s Disease
Autoimmune destruction of adrenal cortex
Hyposecretion of ALL adrenal steroid hormones
decreased Aldosterone
- K+ retention -> cardiac arrythmia
- Na+ depletion -> hypotension
decreased Cortisol
- decreased stress response
- hypoglycaemia
high ACTH = darkening of skin (MSH) - joints & gums
muscle weakness
GI symptoms (anorexia, nausea, vomiting, diarrhoea, weight loss)
(Secondary hypocortisolism may be caused by abnormal hypothalamus or pituitary - ↓ACTH & ↓cortisol )
Hyperaldosteronism
Primary Aldosteronism - Conn's Syndrome Secondary hyperaldosteronism (RAAS)
Hyernatremia
Hypokalemia (= muscle weakness)
Hypertension
Adrenogenital Syndrome / Congenital Adrenal Hyperplasia
Excess Androgen & Estrogen
Low Cortisol & Aldosterone
Lack enzyme in cortisol steroidogenic pathway (21 hydroxylase) - CAH is autosomal recessive
Premature masculinisation & pubic hair acne & hirsutism enlargement of penis/clitoris ambiguous genatalia growth spurt epiphyseal fusion voice deepening
Treatment:
Glucocorticoids
Galactosaemia
inability to epimerise the galactose to glucose due failing enzymes
- galactokinase
- galactose-1-phosphate uridylyltransferase
- uridine diphosphogalactose-4-epimerase
Pompes Disease
Lysosomes engorge with glycogen due to lack of α-1,4-glucosidase. Respiratory failure (diaphragm) causes death before age 2
Starvation Energy Sources
0-2 days
use up glycogen
ketones steadily rise
2-10 days
protein breakdown and gluconeogenesis
10+ days
glycerol and FFAs
ketones begin to plateau
Pellagra
Niacin deficiency / lack of tryptophan (niacin precursor)
Attributable to high corn diet
Photosensitive Dermatitis
Diarrhoea
Demetia
Death
Malignant Hyperthermia
Triggered by exposure to general anaesthesia (typically halothane)
Susceptibility based on 6 genes particularly RYR1 (ryanodine receptor gene)
Uncontrolled oxidative phosphorylation overwhelms body’s ability to supply oxygen and regulate temp.
Dantrolene stops Ca2+ coupling in contraction cycle of muscle.
Menke’s Disease
X-linked disorder
Mutation of ATP7A copper transporter results in storage (not release) of copper in enterocytes leading to copper deficiency
Mental deterioration, aortic elastin defects, and defective keratinization leading to wiry sparse hair
Wilson’s Disease
Genetic - ATP7A copper transporter overactivity
High serum copper & toxicity (liver)
Kayser-fleischer ring around iris
Beriberi
Thiamine (B1) deficiency Weakness Paralysis Anaemia Pitting oedema (low serum albumin)
Type 1 Insulin Dependent Diabetes Mellitus
Incidence 0.5%
Organ specific, T cell mediated (CD4 & CD8)
Autoimmune destruction of pancreatic beta-cells (insulin producing) -> glucose intolerance
HLA DR3-DQ2 & HLA DR4-DQ8
T cells recognise region within C-peptide (not a chain or b chain)
Diagnosis/Symptoms/Complications: Polyuria/polydypsia Hyperglycaemia Lipolysis/proteolysis Weight Loss Elevated HbA1c Ketoacidosis Increased risk of Infection (kidney, LL) Autoantibodies (GAD, IA-2) Hypoglycaemia - Rapid - sympathetic drive - tachycardia, anxiety, dry mouth, tremor - absolute - brain malfunction, paralysis, coma, death
Macroangiopathy - atherosclerosis
- leg amputations
- IHD, cerebrovascular disease, peripheral vascular disease
Microangiopathy - basement membrane thickening
- Retinopathy
- Nephropathy (w/ kimmelsteil wilson nodules)
- Neuropathy
Pathophysiology
Formation of Advanced Glycation End products (AGEs) (glucose acting on proteins)
- modified collagen IV, elastin (BM)
- protein crosslinking & resistance to turnover
- trapping of proteins and lipids
- altered signalling, gene transcription, free radial formation (VEGF, TGFβ)
- increased pro-coagulant activity of endothelial cells & ROS
- release of pro-inflammatory cytokines from macrophages (via RAGE receptor)
T1DM shows lymphocytic infiltrate in islands of langerhans
T2DM shows amyloid deposits
Advanced Glycation End Products (AGEs)
Result of interactions between molecules derived from glucose and the amino groups of proteins.
Causes:
- modified collagen IV, elastin (BM)
- protein crosslinking & resistance to turnover
- trapping of proteins and lipids
- altered signalling, gene transcription, free radial formation (VEGF, TGFβ)
- increased pro-coagulant activity of endothelial cells & ROS
- release of pro-inflammatory cytokines from macrophages (via RAGE receptor)
Hyperparathyroidism
Tumor (parathyroid or neoplastic)
Renal osteodystrophy
Hypercalcaemia & hypophosphataemia
Variable effects
Hypoparathyroidism
Rare Autoimmune?, Parathyroidectomy (during thyroidectomy) Hypocalcaemia & hyperphosphataemia Neuromuscular excitability Increased RANKL & osteoclastic activity
Osteoporosis
Reduced mass (<2.5SD) of otherwise normal bone w/ increased risk of fracture
Causes:
- low peak bone mass (30yo) & aging
- low physical activity
- Ca2+/VitD deficiency
- endocrine (PTH)
- genetic
- menopause (IL-1, IL-6, decreased oestrogen)
Hyaline Cartilage
Common in ribs, trachea, joints (articular cartilage)
Collagen Type II
Aggrecans (large GAGs - chondroitin sulphate, heparan sulphate)
Hyaluronic Acid
Condronectin (glycopritein that binds collagen and aggrecans)
Chondrocytes (build and breakdown matrix)
No blood vessels - perfusion by compression/decompression of cartilage
Elastic Cartialge
Common in ears, ear canals, epiglottis, larynx
Collagen Type II
same as Hyaline Cartilage
+ Elastin
Fibrocartilage
Binds solid joints, forms meniscus and intervertebral discs*
Dense connective tissue and islands of cartilage
No perichondrium
Type I collagen
Chondrocytes differentiate from fibroblasts
*originally collagen Type II in nucleus pulposus, replaced by fibrocartilage by 20yo
Synovial Membrane
Not an epithelium (no BM, tight juctions, desmosomes) - leaky
Surface layer (intima) - 2-3 cells thick, fibroblast-like and macrophage-like
Sub-intimal layer - fibrous connective tissue
Synovial fluid:
- ultrafilrate of synovial blood vessels
- proteoglycans
Stages of Bone Repair
Inflammatory phase (~1week)
- haematoma
- fibrin mesh
- platelets & leukocytes release cytokines
- granulation tissue (fibroblasts)
Soft Callus (fibrocartilage) (days-weeks)
- cartilage formation (chondrocytes from periosteum)
- no structural rigidity
- periosteum repairs over outside
- skip this step if ends have ‘union’
Hard Callus (bone) (weeks-months)
- osteoblasts form woven bone (cellular, collagen, no Haversian systems)
- thickened woven bone (rigid but not strong)
Remodelling (months-years)
- woven to lamellar bone
- along lines of stress
Factors That Slow Bone Repair
Age (>40) Comorbidities (e.g. diabetes) Meds (NSAIDs, corticosteroids) Smoking Poor Nutrition Open fracture w/ poor blood supply Multiple traumatic injuries Infection
Paget’s Disease
“osteitis deformans”
Overactive osteoclasts (osteolytic)
Increased osteoblastic activity (osteosclerotic)
= thick soft cortex, course trabeculae, easily fractures, nerve compression
Osteomalacia & Rickets
Inadequate vitamin D
- higher PTH required
- loss of phosphate in urine
Impaired bone mineralisation
Adults: generalised muscle weakness weightloss bone pain limb bowing
Children: Impaired growth Dental defects Cough Pigeon breast Kyphosis Bowleg Enlarged ends of long bones
Primay sites of bone metastases
Breast Bronchus (lung) Byroid (thyroid) Bidney (kidney) Brostate (prostate) <----- major (rarely, bowel)
Osteomyelitis
Slow flow through looped capillaries and venous sinusoids
Bacteria seed metaphyseal-epiphyseal junction
Protected from immune response (low WBC & immune mediators)
Pressure from pus further limits blood supply
Infection spreads to subperiosteal space, lifts periosteum (10-20days), invades shaft
Acute Fever
Infection most common (mostly self limiting virus)
Idenitfy serious illness (shock, impaired consciousness, tachypnea, cyanosis)
Identify ‘at risk’ patinets (elderly, immunocompromised, OS travel)
Warning bells:
- Rapid onset
- Rigors
- Severe muscle pain
- Impaired consciousness
- Vomiting
- Severe headache
- Rash
- Jaundice
Investigations:
FBE, CRP, renal function, liver function
blood culture, urine culture, CXR
Treatment:
IV antibiotic if infection likely
ED stay
Prolonged Fever
TB, CMV, bacterial endocarditis, STI, meds, malaria, psittacosis (birds), coxiella burnetii (farms)
Investigations: FBE - high lymphocyte or neutrophil count (left shift) CRP (high w/ bacterial infection) CXR - atypical pneumonia Serology & cultures
Pyrexia of Unknown Origin
Fever above 38.3 for 2-3 weeks with no diagnosis
Infection
- bacterial endocarditis - viridians strep
- TB
- intraabdominal abcess
- HIV opportunisitc infections (cryptococcus, MAC)
- CMV, EBV, brucella, Q fever, psittacosis, malaria
Connective Tissue Diseases
- Polymyalgia rheumatica
- Giant cell arteritis
- Vasculitis
- SLE
- Thyroiditis
- Sarcoidosis, Chron’s, Idiopathic Hepatitis
Malignancy
- Lymphoma
- Leukemia
- Renal Cell Carcinoma
- Hepatoma
- Need to worry about opportunistic infections of immunocompromised patients!
Sarcopaenia
Age-associated loss of skeletal muscle and function w/ increased connective tissue (fibronectin)
- disuse
- endocrine changes
- chronic disease
- insulin resistance
- nutritional deficiencies
- neuromuscular changes
Cachexia may be a component of sarcopaenia (but conditions are not the same)
Diagnosis (1 + 2or3)
- Low muscle mass
- Low muscle strength
- Low physical performance
Treatment:
Strength training
GH not shown to be effective
Duchenne Muscular Dystrophy
Onset: Early Childhood (3-6yo), X-linked recessive
Prevalence: 1 in 3500 newborn males
Symptoms: Generalised weakness, falls, enlarged calves, gowers sign (crawling up legs)
Progression: Slowly affects all voluntary muscles, cardiorespiratory failure by age 20
Pathology: Mutation in dystrophin gene on Xp21
Dystrophin important in stabilizing sarcolemma during muscle contraction (especially lengthening)
Deletion causes ‘frame shift’ resulting in premature mRNA translation and synthesis of unstable fragments
Loss of dystrophin results in disorganised costameres, fibre branching, and enhanced membrane leak.
Increased oedema and inappropriate cytosolic Ca2+ and ROS generation causes further muscle dysfunction, hypercontraction, and necrosis. This is particularly important when muscles are stretched forcibly.
Treatment: Primarily corticosteroids Anabolic steroids beta-2 agonists IGF-1
Becker Muscular Dystrophy
Onset: Adolescence or adulthood, X-linked recessive
Symptoms: Generalised weakness, falls, enlarged calves. Less severe than DMD
Progression: Slowly affects all voluntary muscles. Survival well into mid to late adulthood.
Pathology: Mutation in dystrophin gene on Xp21
Dystrophin important in stabilizing sarcolemma during muscle contraction (especially lengthening)
Mutation results in significant amounts of abnormal proteins
Compartment Syndrome
Injury Oedema Increased Pressure (Pain, Pale, Pulseless, Paraesthetic, Paralysed) Decreased Blood Flow Ischaemia - 2-4 hours for nerve - 6-8 hours for muscle (never recovers beyond)
Varicose Veins
Incompetent valves (especially at termination of Greater Saphenous and Superficial Saphenous, and perforating)
Dilated tortuous superficial veins
Increased Capillary Pressure
Extrusion of blood / blood products into soft tissue
Brown pigmentation, venous eczema, ulceration
Osteoarthritis
Chronic degeneration of few joints (especially hard working / weight bearing / injured) > 70yo Obesity Prior injury Heavy joint use Genetics
SIGNS/SYMPTOMS: Deep pain (worse with use) Reduced ROM Crepitus (grinding) Insidious onset Loss of cartilage Osteophyes Subchondral thickening Subarticular cysts NO SYSTEMIC SYMPTOMS!
TREATMENT:
Physiotherapy
PATHOPHYSIOLOGY:
Damage stimulates chondrocyte proliferation, enzymes (collagenases, MMPs), and cytokines (IL-1)
Unravelling of cartilage matrix reduces function and releases more enzymes and cytokines
Regenerative process leads to hypertrophy of cartilage and bone w/ thickening and microfractures
Shedding of cartilage - ‘fibrillation’, erosions
Bone-on-bone eburnation, cysts, osteophytes
Rheumatoid Arthritis
Autoimmune inflammatory w/ systemic involvement
Starts symmetrically in small joints of hands and feet
Genetic (HLA-DRB1)
Female
25-55
Smokers
SYMPTOMS: Morning stiffness (1 hour) Warm, swollen joints Systemic symptoms (fever, weight loss, anaemia) Progressive Villous hyperplasia mononuclear infiltrate germinal centres Juxta-articular Osteopaenia Subchondral Erosions Uniform! joint space loss
TREATMENT:
Disease modifying anti-rheumatic drugs
PATHOPHYSIOLOGY
Autoimmune
Th1, Th17, IL-1, IL-6, IL-17, TNF-a
Induced fibroblasts, macrophages, osteoclasts, B cells, neutrophils, fibrin
Germinal centres
Granulation tissue-like pannus (hyperplasia of synovium w/ villus formation)
Invasion of pannus
Collagenases and MMPs
Breakdown of catilage and bone
Fibrosis and bony union of joints
Serum Amyloid Associated (SAA) protein may deposit in joints
Neonatal gonoccoal opthalmia
- conjunctivitis day 2-5 after birth
- neisseria gonorrhoea at birth
- IV cefotaxime and eye irrigation
Congenital varicella
VSV infection first trimester primary infection limb hypoplasia scarring (dermatomal) increased risk of shingles in infancy treatment: prophylactic VZIg and/or acyclovir varicella vaccine
‘Preterm’ delivery
- labour before 37 weeks gestation
- occurs in 5-8% of deliveries
- responsible for 80% perinatal mortality and morbidity
- possible causes: infection, membrane rupture
Pre-eclampsia
- most common serious disorder of pregnancy
- high maternal BP
- proteinuria w/ generalised oedema
- placental dysfunction (growth restriction)
- common in first pregnancy
- occurs in 5-10% (mild) 1-2% (severe)
- responsible for 15% of maternal mortality (cerebral complications, cardiac failure)
- responsible for 10% of perinatal mortal
- increased risk of long term CVD complications
- possible causes: unknown, pregnancy specific, inadequate endometrium, vasculature of placenta?
- treatment: Magnesium sulphate (MgSO4), labetalol
Interuterine Growth Restriction (IUGR)
- low birth weight (<2SD below mean) (approx 10% babies)
- placental insufficiency
- predisposition to adult disease
- occurs in 2-10% of babies
- 2-3x perinatal mortality
- possible causes: malformations, fetal infection, lack of amniotic fluid, maternal diseases, pre-eclampsia, oxygen deprivation, smoking, malnutrition, placental insufficiency
Ovary Structure
held in place by ovarian ligament and suspensory ligament behind broad ligament
Surface
- simple squamous/cuboidal mesothelium
- 70% of ovarian tumors start in this layer
Tunica Albuginia
- thick dense connective tissue layer
Oocytes
Structure of fallopian/uterine tube
Surrounded by serosa (mesothelium + thin connective tissue)
Smooth muscle (muscularis)
mucosa (connective tissue + columnar ciliated epithelium)
Ampulla
- outer 2/3, wide diameter
- thin smooth muscle wall (peristalsis)
- folded mucosa (produces secretions - nutrients)
- fertilisation occurs here
Isthmus
- thin diameter
- thick muscular wall
Structure of Uterus
Endometrium (mucosa)
- ciliated and secretory simple columnar epithelium
- secretory glands penetrate into lamina propria (dense connective tissue)
- lamina propria / basal lamina rebuilds endometrium after sloughing
- supplied by helical (tortuous) arteries
myometrium (muscularis)
- 2 longitudinal
- middle circular (highly vascular)
Perimetrium (mesothelium and underlying elastic connective tissue)
After pregnancy thickened myometrium is retained
Structure of Cervix
Endocervix (uterine)
- simple columnar epithelium
- glandular (serous during ovulation, thick otherwise)
- lymphocytes
Squamocolumnar Junction / Transformation Zone
- site of metaplasia
- susceptible to HPV infection
Ectocervix (vaginal)
- stratified squamous epithelium (filled with glycoprotein)
- non-glandular
Structure of Vagina
Stratified squamous epithelium (w/ erectile lamina propria)
- superficial cells still nucleated
- non-keratinising
thin inner and thick outer muscular layers
no glands (lubricated by cervical glands or vestibular glands)
Structure of Breast
Mammary glands -> lactiferous sinus -> ducts
- ‘terminal duct lobular units (TDLUs)’
- cuboidal epithelium becomes more columnar during luteal phase
- surrounding myoeopithelial cells proliferate during pregnancy
- during menstruation glands involute
dense connective tissue
- plasma cells infiltrate during pregnancy to produce IgA
- loss of connective tissue (elastin/fibroblasts) during involution
abundant adipose tissue
Composition of Breast Milk
mixture of lipid, carbohydrate, protein initially colostrum (premilk) - high protein, low lipid/carb high in IgA prolactin stimulates milk production
Structure of Testis
Surrounded by thick tunica albuginea (connective tissue)
septa from tunica seperate testis into ~250 compartments
seminiferous tubles winthin compartments
- 40cm long
- stratified epithelium (spermatogonia & sertoli cells)
- tunica (lamina) propria contains myoid cells (contractile)
- tunica (lamina) propria contains leydig cells (steroid secreting)
tubuli recti
- lined only with sertoli cells and finally simple cuboidal epithelium
rete testis
- interconnected cavities
- ciliated cuboidal epithelium
epididymis
- 20 mesonephric tubules join (efferent ductules)
- ciliated pseudostratified columnar epithelium
- epithelium surrounded by smooth msucle
- 4-6m long and highly coiled
- head -> body -> tail
- decapacitates sperm and absorbs fluid
ductus/vas deferens
- ciliated pseudostratified columnar epithelium
- thick smooth muscle coat (ejaculation)
Structure of Seminal vesicles
- thick mucosa
- thin smooth msucle
- alkaline secretion
- fructose
- prostaglandin
- neutralises acidic vagina (pH 4)
Structure of prostate
- lobular with septa
- columnar and cuboidal pseudostraified epithelium
- connective tissue w/ smooth muscle
- 30-50 tubuloalveolar glands
- prostatic glands (drain via long ducts)
- submucosal glands (drain via prostatic sinuses)
- secretion (phosphatase, fibrolysin, coagulating)
- clots ejaculate
- fibrolysin disolves clot
Zones of prostate
central zone - surrounds ejaculatory ducts Peripheral zone - surrounds central zone Transitional zone - surrounds prostatic urethra (periurethral zone) Periurethral zone - immediately adjacent to urethra
Structure of Penis
tunica albuginiea surrounds cavernous tissue
1x corpus spongiosum (surrounds urethra)
2x corpus cavernosa (superior)
cavernous tissues
- ‘potential’ vascular spaces (sinuses)
- surrounding smooth muscle & elastic connective tissue
Structure of Clitoris
glans body - bilateral cavernous tissue - surrounded by tunica albuginea crus - extends inferiorly along pelvis bulbs - bilateral cavernous tissue deep to labia
Structure of Primordial Oocytes
smallest oocytes
large nucleus arrested in prophase of meiosis 1
surrounded by squamous follicle cells and basal lamina
develop into primary oocytes
Structure of Primary Oocytes
oocyte enlarges
cell becomes surrounded by zona pellucida
follicular cells become cuboidal multilayed granulosa cells and form ‘stratum granulosum’
surrounding stromal cells start to form theca interna and externa
Structure of Secondary Follicle
stratum granulosum thickens
fluid filled cavity (antrum) appears
oocyte suspended on stalk (cumulus oophorus)
granulosa cells around oocyte form ‘corona radiata’ after release
when mature it is called a Graafian follicle
under LH surge oocyte completes meiosis 1 and follicle ruptures (stromal smooth muscle contraction)
Structure of Corpus luteum
follicle which has lost oocyte
stromal, granulosa and thecal cells invade cavity (antrum)
becomes endocrine organ producing estrogen and progesterone
lasts 14 days - if no fertilisation become corpus albicans and involutes
Down Syndrome
Chromosome 21 trisomy
Major cause: Non-disjunction in Meiosis I during maternal gametogenesis
1 in 600
Major cause of intellectual disability and congenital heart defects
associated with increased GI anomoly, leukaemia, immune defects, reduced fertility, thryoid defects, hypotonia, and alzheimer like dementia
increased risk with increased maternal age (1 in 355 at 35yo)
familial down syndrome = carrier with balanced translocation
Edwards Syndrome
Chromosome 18 trisomy
incidence 1 in 3000
often fatal before or after birth
overlapping fingers, club foot, heart defects
Turner Syndrome
Female having only one X chromosome
short stature
infertility due to absent or immature gonadal and sexual development
impaired neurocognitive function
Beckwith-Wiedemann Syndrome
epimutation of region 11p15.5
1 in 15000
natal overgrowth
hypoglycaemia
anterior abdominal wall defects
9x increased risk with IVF
Prader-willi syndrome
deletion of paternal 15q11-13 or maternal
uniparental disomy
1 in 10000
obesity w/ hypotonia
hypogonadism
small hands and feet
Angelman syndrome
deletion of maternal 15q11-13 or paternal
uniparental disomy
severe intellectual disability
absent speech, inappropriate laughter, ataxic movements
large mouth, protruding tongue
How common are birth defects?
4% of babies have a ‘birth defect’
Cerivcal Condyloma
due to HPV
thickened epithelium
papilomatosis (stromal core poking up into epithelium)
Flat Condyloma
due to HPV
normal epithelium thickness
superficial squamous epithelium shows enlargement and increase numbers of nuclei
pleomorphic nuclei
abundant cytoplasm
koilocytes - perinuclear cave and odd shaped nucleus (presence of HPV virus)
typically present in asymptomatic patient
10-15% may go onto form cancer
Cervical Intraepithelial Neoplasia 1 (CIN1)
- similar to flat condyloma HPV infection
- may show disorded and expanded parabasal cells (dysplastic)
- CIN1 = dysplasia confined to lower 1/3 of epithelium
- superficial squamous epithelium shows enlargement and increase numbers of nuclei
- pleomorphic nuclei
- abundant cytoplasm
- typically asymptomatic (no visible lesion)
Cervical Intraepithelial Neoplasia 2 (CIN2)
- CIN2 = dysplasia up to lower 2/3 of epithelium
- superficial squamous epithelium shows enlargement and increase numbers of nuclei
- pleomorphic nuclei
- abundant cytoplasm
- typically asymptomatic (no visible lesion)
Cervical Intraepithelial Neoplasia 3 (CIN3)
- surface of sratified squamous epithelium looks teh same as base (no maturation)
- enlargement and increase numbers of nuclei
- pleomorphic nuclei
- abundant cytoplasm
- risk of progression to invasive cancer
- typically asymptomatic (no visible lesion)
Cervical Squamous Cell Carcinoma
- malignant cervical cancer with squamous differentiation
- most common cervical cancer
- infiltrating solid nests of squamous cells
- intercellular bridges
- pleomorphic nuclei
- mitotic bodies
- desmoplastic stroma
- possible keratin pearls
Cervical Adenocarcinoma in situ
- related mainly to HPV18
- may progress to invasive adenocarcinoma
- nuclear enlargement
- stratified nuclei and crowding
- mitotic bodies
- pleomorphic nuclei
- cribriform/papillae due to hyperplasia of glands
- less common than squamous carcinoma
Cytological grading of cervical squamous lesions
low grade vs high grade (risk of progressing to cancer)
nuclear to cytoplasmic ratio higher than normal (less squamous maturation)
polymorphic nuclei
Skin histological structure
EPIDERMIS
- keratinising stratified squamous epithelium
- stratum corneum (dead keratinized cells)
- stratum granulosum (blue granules - keratinizing)
- stratum spinosum (polygonal w/ prominent intercellular bridges & langerhans cells)
- stratum basale (cuboidal/columnar w/ stem cells and melanocytes)
- basement membrane
- dermo-epidermal junction
DERMIS
- corrigated (dermal papillae & rete ridges)
- connective tissue (papillary - fine collagen, reticular - course collagen) & clevage lines
- capillaries (from papillary plexus)
- sebacious glands (lipid rich, pale staining cells)
- hair folliocles
HYPODERMIS
- vascular (cutaneous plexus from arterial/venous supply)
- adipose tissue (‘subcutaneous’)
- sweat glands (layer of secretory cells with outer myoepithelial cells)
- sweat ducts (stratified cuboidal)
- hair follicles
eccrine vs apocrine sweat glands
ECCRINE - pale blueish staining APOCRINE - pinker - secrete hormones and pheremones - gential and axillae
skin healing (primary intention)
No significant loss of tissue Closely opposed would 24 hours (inflammation) - bleeding - clot/platelets - scab - acute inflammation (neutrophils) 3 to 7 days (proliferation) - fibroblasts - angiogenesis - granulatioon tissue 7 - 8 weeks (maturation) - fibrous union (scar)
skin healing (secondary intention)
Significant loss of tissue Lengthy healing time 24 hours (inflammation) - bleeding - clot - scab - acute inflammation (neutrophils) 3 to 7 days (proliferation) - fibroblasts - angiogenesis - granulatioon tissue - myofibroblasts 7 - 8 weeks (maturation) - wound contration (myofibroblasts) - fibrous union (scar)
Impetigo
Infection of epidermis
bullous, crusted, or pustular lesions
Most common cause S. aureus (bullous) and S. pyogenes
Soap & water
treat with flucloxacillin or dicloxacillin
Erysipelas and cellulitas
rapid spreading erythematous infection
usually face, legs, feet
well defined border
pain & fever
often caused by Strep pyogenes
erysipelas is superficial
cellulitis includes subcutaneous fat and may be caused by wider range of bacteria (S. aureus, vibrio, H. influenzae)
treat with flucloxacillin or dicloxacillin
Necrotising fasciitis
'flesh-eating bacteria syndrome' rapidly spreading along fascial planes disrupts blood supply = necrosis if severe - myonecrosis and gangrene S. pyogenes and anaerobes (Clostridium species)
treat with surgery, penicillin G + hyperbaric oxygen
Anaemias
Hb below that which is normal for age and gender
Increased production
- reticulocytes & polychromasia
Increased destruction
- jaundice, haptoglobins, LDH, rapid
- haemolysis: spherocytes, sickle cells, G6PD, malaria, sepsis, HUS, autoimmune
Microcoytic - Iron deficiency - Thalassaemia - lead poisoning Macrocytic - b12 - folate - liver disease - congenital anaemia
Polychromasia
- has RNA in it due to left shift
Alpha & Beta Thalassaemias
- decreased synthesis of one or more globin chains
- therefore get homotetramers instead of heterotetramers
ALPHA
- south east asia
- majority caused by large deletions
- overexpression of beta globins
- affects both fetal and adult Hb
BETA
- europe, middle east, africa
- majority caused by point mutations
(e. g. promoter regions, transcription) - overexpression of alpha and gamma globins
- homotetramers precipitate out
- RBCs die
- secondary haemochromotosis
- hepatomegaly / splenomegaly
- intra/extramedullary erythropoeisis
- anaemia (microcytic, hypochromic)
Leukaemia
Somatic mutation in multipotential stem cell or progenitor
chromosomal translocation encoding fusion protein disrupting normal pathway
acute: usually blastic
chronic: usually progenitors
- lymph swelling
- hepato/splenomegaly
- weightloss/loss of appetite
- fever/infections
- weakness/fatigue
- pain/tenderness
- easy bruising and bleeding
DIAGNOSIS:
FBE, bone marrow
biochemical (Ca2+, uric acid, LDH, liver function)
Imaging (xray, CT)
TREATMENT:
Chemo, transplant (bone marrow)
Breast Histology
glands (acini) - secretory cells - myoepithelial cells - plasma cells duct - epithelial secretory cell - myoepithelial cells adippose tissue connective tissue
Breast pathology
- most lesions arise from epithelium of TDLUs
- calcification (mamography)
Breast fibrocystic change
- commen in older women
- bilateral, multifocal
- scarring (fibrosis)
- dilated ducts
- cyst formation
- epithelial hyperplasia (adenosis)
- aprocrine metaplasia
- bilateral & multifocal
- asymptomatic (may produce lumps / discomfort)
Breast fibroadenoma
- common in young women
- well circumscribed lesions
- neoplastic/hyperplastic STROMAL tumor with epithelial component
Breast Carcinoma
- increased risk w/ age and family history
- increased risk w/ long oestrogen exposure
- increased risk w/ obesity and alcohol
- increased risk w/ histoy of breast diseases
- mutations in p53, BRCA1, BRCA2 (cell cycle arrest & DNA repair)
- autosomal dominant, cancer onset at younger age
- HER2, neu, c-erbB-2
(epidermal growth factor receptor) - begins in TDLU
-spread - skin, nipple, muscle, chest wall
- metastatic to lymph (axillary & mammary) and blood
(lung, bone, liver, brain)
Histology of Ductal Carcinoma in Situ
- large dilated ducts
- necrotic debris
- hyperplasia of endothelium
- pleomorphic nuclei
- dystrophic calcification (due to necrosis)
- intact basement membrane w/ no invasion
- usually asymptomatic
- if it extends to nipple - Paget’s
Invasive Ductal carcinoma of breast
mostly upper outer quadrant of breast
'scirrhous' - firm due to fibroblasts & collagen
infiltration of parenchyma
macroscopically
- irregular edges
- pale ('schirrous')
histologically
- desmoplastic stroma
- lymphocytic infiltration
- large pleomorphic nuclei
- acini formation (adenocarcinoma)Hodgkins lymphoma
- disease of lymph nodes (rarely extra-nodal)
- rarely invovles waldeyer’s ring
- more common in males than females
- typically disease of young people
- commonly cervical lymph nodes (and axial)
- bimodal age spread
- characterised by isolated tumor cells (Reed-Sternberg)
- large nuclei, prominant pale cytoplasm
- T cell rosettes (t cells surrounding lymphoma cell)
Chronic Myeloid Leukaemia
Philadelphia chromosome t(22;9) - Bcr-Abl
Bcr-Abl - autonomous growth signal
thought to originate from pluripotent stem cell
many mature neutrophils
less mature myelocytes
slow progression then accelerated phase and blast crisis
Treatment: imatinib (gleevec) - binds to tyrosine kinase domian and inactivates Bcr-abl
Chronic Lymphocytic Leukaemia
Naive B cell or memory B cell mutation
most are excessive B cells (with same Ig)
- because of antibody diversity (AID)
most common adult leukaemia (males>females)
loss of miRNA (miRNA15a/16-1) allow increased Bcl-2
elevated Bcl-2 (elevated level prevents apoptosis)
ZAP-70 / p53 mutations (indicate poorer survival)
lymph node - lots of small lymphocytes
blood - lots of small lymphocytes
- smudge cells (ruptured tumor cells)
associated with immune abnormality & autoimmunity
treatment: BH3-only mimetic ABT-199 (proapoptotic)
- block bcl-2 and allow mitochondria to release cytochrome c
Average age of diagnosis - 60yo
Slow, non-specific, non-agressive presentation (lymphadenopathy)
Not usually curable
Burkitt’s Lymphoma
viral infection (EBV) & chronic inflammation t(18;14) overexpression of transcription factor MYC longevitiy of B-cells
HER2
Epidermal growth factor receptor in breast tissue
Tyrosine kinase Receprot
Overexpressed in breast cancers
Inhibited by herceptin
MYC
Transcription factor
Bcr-Abl
autonomous growth signal
abl normally located on chromosome 9
translocation to chromosome 22 (philadelphia chromosome) with bcr region added abl can no longer be inhibited
Associated with CML
CyclinD-CDK4
- activation of transcription factors in
replciation
- inhibited by CDKIs (e.g. p16) stimulated by p53
- detatches Rb from E2F to produce S phase enzymes
Rb
Tumor supressor
p53
Growth inhibition signal
Control over cell cycle
Stimulates DNA repair
Can promote apoptosis
APC
Tumor supressor
Hallmarks of cancer
- evasion of apoptosis
- autonomous growth signalling
- evading growth inhibitiory signals
- activation of invasion and metastasis
- immortality (telomeres)
- angiogenesis
- avoiding immune destruction
- tumor-promoting inflammation
- deregulation of cellular energetics (increase
glucose) - genome instability & mutation
Folliculitis
Infection of hair follicle
ususally due to blockage
may progess to abcess
Most comon cause is S. aureus
Nephrotic Syndrome
- Massive proteinuria (3.5g/day)
- Hypoalbuminemia
- Oedema (whole body)
- Hyperlipidemia/hyperlipiduria
Primary causes Diabetes Mellitus Membranous Glomerulonephritis Amyloid Deposition Inherited Abnormalities (Alport, Finnish Type) Hep B & C HIV Malignancy
Nephritic Syndrome
- Hematuria (due to capillary wall damage)
- Oliguria
- Azotemia (high Urea/Creatinine in blood)
- Hypertension
(some proteinuria and oedema)
Causes
Post streptococcal Glomerulonephritis – appears weeks after URTI
IgA Nephropathy – appears within a day or two after URTI
Rapidly progressive Glomerulonephritis (crescentic glomerulonephritis)
Goodpastures - anti GBM antibodies against basal membrane antigens
Acute Lymphocytic Leukaemia
Bone Pain (diffuse bone marrow involvement) Pancytopaenia (low cell count) - Fatigue (anaemia) - Infection/Fever (leukocytes) - Bleeding/Bruising (platelets)
Average age 3 yrs
Most common cancer of children - 80% cure rate
Poorer diagnosis in adults
Acute Myeloid Leukaemia
Bone Pain (diffuse bone marrow involvement) Pancytopaenia - Fatigue (anaemia) - Infection/Fever (leukocytes) - Bleeding/Bruising (platelets)
Auer rods
Cells with bilobed nuclei and granular cytoplasm
Burn Gradings
Superficial
- epidermis only
- RED and HOT
- no blisters
- full sensation
- blanches
- no scarring
- heals in 7 days
Partial Thickness
- Involves dermix
- Pink
- blistering at dermo-epidermal junction
- PAINFUL!
- blanches
- risk of infection
- scarring
Full Thickness
- Into hypodermis
- WHITE and DRY
- no pain
- no blisters
- no blanching
- months to heal (Contractures)
Restrictive Lung Diseases
Idiopathic Pulmonary Fibrosis
Pneumoconiosis (asbestosis)
Sarcoidosis
“Honey-comb lung”
Increased elastic WOB (inspiration) Short/shallow fast breaths Reduced FEV1 Reduced FVC Normal FEV1/FVC Abnormal gas exchange (due to A-C membrane thickening)
Obstructive Lung Diseases
Asthma
COPD
- bronchitis (productive cough 3 months for 2 years, mucosal hypertrophy, lymphocytes, fibrosis +/- squamous metaplasia)
- emphysema (↑proteases/elastases, ↓α1AT = alveolar septa loss w/o fibrosis)
- small airways disease (chronic inflammation, fibrosis, obstruction of terminal bronch4xhoioles)
Bronchiectasis
Reduced FEV1
Normal FVC
Reduced FEV1/FVC
Stages of Lobar Pneumonia
- Congestion
- exudate and PMN infiltration - Red Hepatization
- haemorrhage into air spaces - Grey Hepatization
- fibrin and macrophages - Resolution
- Clearance by cough or macrophages
Atypical Pneumonia
Viral or mycoplasma pneumoniae
Interstitial immune response
Systemic symptoms predominate (malaise, aches, pains, diarrhoea)
Dry cough
Reticulonodular infiltrate on XRAY
Patient ambulatory but ‘look like they should be dead’
TB
Ghon complex
- parenchymal focus and hilar lymph node
Granulatomous inflammation
- epitheliod macrophages
- multinucleated giant cells
- central caseous necrosis
May be dystrophy calcification
Clinically:
- insidious weight loss, malaise, fevers, night sweats, haemoptysis, dyspnoea, couch
Reactivation often involves upper lobe
miliary Tb to liver, spleen, bone, spine (potts), marrow, brain
Chronic Hypercapnea
Usually due to
- severe airways disease
- severe obesity
- motor-neurone disease
- interstitial lung disease
Patients are dependant on O2 drive (rather than CO2) so don’t give supplemental oxygen!!
Respiratory causes of Dyspnea
AIRWAYS
Upper - tumor, foreign body, croup
Lower - asthma, COPD, bronchitits
ALVEOLAR
Pneumonia, collapsed lung, pulmonary odema, pulmonary fibrosis
PULMONARY VASCULAR DISEASE
Pulmonary embolism, vasculitis, primary pulmonary hypertension
PLEURAL and CHEST WALL DISEASE
Pleural effusion, pneumothorax, chest wall deformity
RESPIRATORY MUSCLE DISEASE
weakness, phrenic nerve paulsy
DVT Risk factors
Post op Post trauma / burns Post MI Malignancy High oestrogen Nephrotic syndrome Obesity (cytokines Inflammatory diseases Factor V Leiden mutation (anticoagulant) Prothrombin mutation (excessive clotting)
DVT/PE Clinical features and Pathophys
<50% present with features Dyspnoea Haemoptysis Cough Syncope (LV output to brain reduced) Pleuritic Pain (infarct)
Pathophys
- haemoptysis & loss of surfactant
- V/Q mismatch
- pulmonary hypertension
- decreased pulmonary compliance
- wedge shaped infarct (haemorrhagic due to collateral supply)
Layers of Chronic Peptic Ulcer
1 exudate (fibrin, neutrophils) and necrotic debris
2 fibrinous necrosis
3 zone of granulation tissue
4 zone of fibrosis
