A tutorial of blood vessel pathology for 5th year medical students at Cambridge University.

1. Histopath Tute 3:
Things to do with(blood)Vessels
Christiane Riedinger 21/03/14

2. Today’s Contents
● Introduction
○ What your revision should cover
○ Reminder of the structure of blood vessels
○ Acquired changes of arterial vessels
● Atherosclerosis
● Hypertension
● Interim Summary
● Vasculitides
● Tying it in with last week: effects on the Kidney

3. Today’s Contents
● Introduction
○ What your revision should cover
○ Reminder of the structure of blood vessels
○ Acquired changes of arterial vessels
● Atherosclerosis
● Hypertension
● Interim Summary
● Vasculitides
● Tying it in with last week: effects on the Kidney

4. Path: What your pathology revision should cover
● Definition
● Aetiology
● Risk factors
● Epidemiology
● Pathogenesis
● Macroscopic Features
● Microscopic Features
● Investigations
● Clinical Features
● Treatment
● Prognosis
● Cancer: also Staging and Routes of Spread

5. Back to Basics: The Structure of Blood Vessels
● Tunica intima
○ endothelium
○ basement membrane
○ connective tissue
● Internal elastic lamina
● Tunica media
○ smooth muscle (arterioles), collagen, elastin (large arteries)
● External elastic lamina
● Tunica adventitia
○ supporting tissue, innervation, vasa vasorum

6. !Acquired Changes of Arterial Vessels!
Arteriosclerosis = hardening of medium and large sized arteries by any
process. Subtypes:
● Atherosclerosis - chronic process of accumulation of fatty deposits in
intimal lesions of arterial vessels.
● Arteriolosclerosis - hardening and loss of elasticity in arterioles.
○ hyaline arteriolosclerosis* - hyaline (glassy) deposits in media.
(T2DM, hypertension, drugs)
○ hyperplastic arteriolosclerosis - large deposits => narrowing of
lumen
● Medial calcific sclerosis** - deposition of Calcium in the media.
○ clinical significance unclear

7. Today’s Contents
● Introduction
○ What your revision should cover
○ Reminder of the structure of blood vessels
○ Acquired changes of arterial vessels
● Atherosclerosis
● Hypertension
● Interim Summary
● Vasculitides
● Tying it in with last week: effects on the Kidney

8. Atherosclerosis:Contents
● Definition
● Risk factors
● Pathogenesis
● Macroscopic Features
● Microscopic Features
● Treatment

9. Atherosclerosis:Definition
Chronic acquisition of fatty deposits
in intimal lesions of arterial vessels.

10. Atherosclerosis: Risk factors
● genetic
○ FH (LDLR mutations) or common polygenic
○ gender
● acquired
○ age
○ hypertension
○ diabetes
○ smoking, lifestyle, stress
● measured in the lab
○ hyperlipidaemia/hypercholesterolaemia (LDL)
○ raised CRP
○ hyperhomocysteinaemia
○ procoagulants
● a good buzz word: metabolic syndrome

11. Atherosclerosis: Pathogenesis
Many theories:
● Response-to-injury hypothesis
○ injury causes chronic inflammatory response and sm.m. proliferation
● Encrustation hypothesis:
○ sm.m. reaction to mural thrombus
● Monoclonal hypothesis
○ mutation in sm.m. to increased proliferation / chronic inflammation
● ...
● Unifying hypothesis

12. Atherosclerosis: Pathogenesis
Toxins
Turbulence
Inflammation
Injury Macrophage
infiltration
Lipid
Insudation*
Foam cells ┼
lipid release
T-cell
infiltration
aneurysm
dissection
Sm.m. hyperplasia
Fibrous tissue
Platelet adhesion
remodelling
vascularisation
weakening of
vessel wall**
stenosis
rupture, embolisation
clotting, thrombus
occlusion

13. Atherosclerosis: Macroscopic Features
Common Locations
● Abdominal aorta
● Coronary arteries
● Popliteal arteries
● Internal carotid arteries
● Circle of Willis
● At any ostia and branching points

14. Atherosclerosis:Macroscopic Features
Increasingly severe lesions:
● fatty streaks - acquired by 10y, mainly IC lipids
● intermediate lesions - IC and EC lipid
● atheroma - core of EC lipid
● fibroatheroma - multiple lipid cores with fibrotic/calcific layers
● complicated lesions - haemorrhage/thrombosis at surface defects
70% occlusion means critical stenosis!

15. Atherosclerosis:Microscopic Features

16. Atherosclerosis:Treatment
● in order to prevent cardiovascular disease: ischaemia/infarcts, IHD, periph.
vascular disease, sudden cardiac death
● Lifestyle changes
● Statins
○ indication
○ action:
■ HMG-CoA reductase inhibitor (cholesterol synthesis in the liver)
■ anti-thrombotic, anti-inflammatory, plaque stabilising, endothelium
○ side-effects:
■ muscle aches, myositis, rhabdomyolysis (esp. if + fibrates)
■ abdominal discomfort
■ raised transaminases (e.g. ALT), CK

17. Today’s Contents
● Introduction
○ What your revision should cover
○ Reminder of the structure of blood vessels
○ Acquired changes of arterial vessels
● Atherosclerosis
● Hypertension
● Interim Summary
● Vasculitides
● Tying it in with last week: effects on the Kidney

18. Hypertension:Content
● Definition
● Aetiology
● Pathogenesis
● Macroscopic Features
● Microscopic Features
● Treatment

19. Hypertension: Definition
systolic >140mmHg - diastolic >85mmHg
Above these levels, medical intervention is of benefit.
25% of the population affected!!!
Distinguish:
● 1* (essential, idiopathic) vs. 2* hypertension
● benign (slow onset) vs. malignant hypertension (fast onset)
○ note: outdated terms
○ malignant hypertension = hypertensive crisis/emergency (>180/>110),
acute impairment of organs and potential irreversible organ damage.

20. Hypertension: Aetiology
● 1* essential, idiopathic - 90% of cases
○ complex multifactorial
○ genetic combination of polymorphisms
○ nutrition salt, caffeine, alcohol, obesity
○ lifestyle stress (=> increased sympathetic discharge?)
○ hormonal RAAS
○ environmental
● 2* - 10% of cases
○ renal 1* or 2* (e.g. renal artery stenosis)
○ adrenal Phaeo, Cushing’s, Conn’s, CAH
○ thyroid hyper AND hypo
○ pituitary acromegaly
○ parathyroid hyper (how ?)
○ cardiovascular AVM, coarctation
○ drugs OCP, steroids, sympathomimetic
○ pregnancy
○ genetic Liddle syndrome (ENaC), aldosterone metabolism

21. Hypertension: Pathogenesis of benign hypertension
increased
pressure
leakage of
plasma
components
across vessel
valls
sm.m.↑
ECM ↑
hypertrophy of
media
hyaline
arteriolo-
sclerosis
worsening of
atherosclerosis!*
rupture, embolisation
clotting, thrombus
occlusion
5% progress to malignant hypertension!

22. Hypertension: Macroscopic Features of benign hypertension
http://www.sclerodermasociety.co.uk/Theheartandscleroderma1.php
● nephrosclerosis
● “cobblestone” kidney

23. Hypertension: Pathogenesis of malignant hypertension
sudden increase in pressure
acute
destructive
forces in
vessels
fibrous
thickening of
intima*
heavy
arteriolosclerosis
thrombosis
fibrinoid
necrosis
in arterioles

24. Hypertension: Macroscopic features of malignant hypertension
http://www.sclerodermasociety.co.uk/Theheartandscleroderma1.php http://sweetclipart.com/womens-green-eyes-474
https://www.auanet.org/education/modules/pathology/renovascular-
disease/malignant-hypertension.cfm

25. Hypertension: Microscopic Features
hyaline arteriolosclerosis hyperplastic arteriolosclerosis fibrinoid necrosis

26. Hypertension: Treatment
● measure BP: if high in clinic AND during ambulatory/home blood pressure
monitoring A/HBPM (24h/>4d am)
● rule out 2* causes
● when to treat:
○ consider treatment if > 140(135 A/HBPM), treat if + IHD, TIA, CKD,
T2DM
○ start treatment if >160(150 A/HBPM)
○ immediate treatment if >180/110
● lifestyle modifications:
○ lower salt and alcohol intake
○ lose weight
○ increase exercise
○ stop smoking
○ healthier diet

27. Hypertension: Treatment ctnd.
● single agent unlikely to be sufficient
● aim for <140/90 unless comorbidities (then lower)
● drug choice depends on age and race
● 4 step therapy depending on when target is reached
1:
<55 non-black: ACE-i/ARB*
>55 or black: ACE-i/ARB* and Ca2+-channel blocker
2: ACE-i/ARB* and Ca2+-channel blocker
3: ACE-i/ARB* and Ca2+-channel blocker and
thiazide diuretic
4: optimise doses in resistant hypertension
● * beta blocker if younger, want children, IHD, LVF, intolerance

28. Today’s Contents
● Introduction
○ What your revision should cover
○ Reminder of the structure of blood vessels
○ Acquired changes of arterial vessels
● Atherosclerosis
● Hypertension
● Interim Summary
● Vasculitides
● Tying it in with last week: effects on the Kidney

29. Interim (extended) summary
Hyaline arteriolosclerosis ↔ Benign Hypertension
Hyperplastic arteriolosclerosis
Intimal Thickening
↔ Malignant Hypertension
↔ Malignant Hypertension (Atherosclerosis)
↔ Hypertension (Atherosclerosis)Hypertrophy of media
Fibrinoid necrosis ↔ Malignant Hypertension, Vasculitis
↔ Atherosclerosis, hypertension, aneurysm,
dissection (see supervision 1)
Thinning of media
This is up for discussion!

30. Today’s Contents
● Introduction
○ What your revision should cover
○ Reminder of the structure of blood vessels
○ Acquired changes of arterial vessels
● Atherosclerosis
● Hypertension
● Interim Summary
● Vasculitides
● Tying it in with last week: effects on the Kidney

31. Vasculitis
● Definition and Aetiology
● Organising Vasculitides
● Pathogenesis
● Clinical Features
● Overview

32. Vasculitis:Definition and Aetiology
Inflammation of blood vessels (or a vessel)
that is either non-infectious or infectious.
Non-infectious:
● mainly autoimmune, chronic inflammatory
● idiopathic
Infectious:
● bacterial e.g. treponema pallidum causing aortitis in syphilis!
● fungal e.g. Aspergillus, Mucor spp.
● 2* e.g. due to systemic infection, endocarditis

33. Vasculitis: Organising Vasculitides
BY SIZE!!!! (and not complete)
● Large: Giant cell arteritis, aortitis, Takayasu’s arteritis*
● Medium: Polyarteritis nodosum PAN, Kawasaki’s disease
● Medium-small: Wegener’s granulomatosis, Churg-Strauss
● Small: Henoch-Schoenlein purpura, microscopic
polyangiitis, (Goodpasteure’s) Behcet’s
● Any size: Immune complex deposition

34. Vasculitis: Pathogenesis
● Mechanisms in autoimmune reactions causing vasculitis
● Immune complex deposition
○ hypersensitivity (type 3 and type 4!)
● Antineutrophil cytoplasmic antibodies ANCAs (type 2 hypersensitivity?)
○ c-ANCA
■ against PR3 proteinase 3 granule of PMNLs
■ = critically important, specific for Wegener’s
○ p-ANCA
■ against MPO myeloperoxidase in PMNL granules
■ = pretty useless ANCA as unspecific
● Anti-endothelial antibodies (Kawasaki)
● Autoreactive T-cells

35. Vasculitis: Clinical Features
● generic, systemic => consider if any unidentified multisystem disorder
● myalgia, tiredness, loss of appetite
● fever
● arthritis
● specific symptoms see upcoming overview
○ kidneys: GN, kidney failure, hypertension!
○ lungs: haemoptysis
○ nerves: neuritis, pain
○ skin: rash, ulcers, purpura
○ .. and more!
● investigations:
○ ESR/CRP raised
○ ANCA?
○ U&E and creatinine
● FBC
● urinalysis
● angiography

36. Vasculitis: Overview

38. PAN
l Necrosis of blood vessels leads to formation of
characteristic nodules in the blood vessels of the kidney

39. Kawasaki’s
● mimics Scarlet Fever
● diagnostic criteria: fever > 5d + 4 out of
● conjunctivitis
● mouth changes: dry, swollen lips or
tongue, strawberry tongue
● cervical lymphadenopathy
● erythema and desquamation of palms
and soles of feet
● erythematous rash
● complications
● coronary aneurysm => MI (prevent
with aspirin)

40. Vasculitis: Summary
● Giant cell arteritis emergency, eyesight at risk
● PAN kidney nodules, part of HepB
● Kawasaki affects children, strawberry tongue, CA aneurysm
● Wegener’s midline, lung, kidneys, nose, c-ANCA
● Churg Strauss allergic, lung, p-ANCA
● Microscopic Polyangiitis many organs, necrotising, p-ANCA

41. Case
A 53y-old man presents with cough (ongoing for the past
few months), SOB, fever, weight loss, as well as
haemoptysis, joint pain, sinusitis and recent otitis media.
CXR shows cavitation, urinalysis shows red cells + casts.
No response to antibiotics and sputum cultures -ve.
What is the diagnosis? Why? What do you test for?

42. Casectnd.
What if there was multiorgan involvement, including CNS
and GI?
What if he had eosinophilia and asthma?
What if it was only lung and renal involvement?

43. Today’s Contents
● Introduction
○ What your revision should cover
○ Reminder of the structure of blood vessels
○ Acquired changes of arterial vessels
● Atherosclerosis
● Hypertension
● Interim Summary
● Vasculitides
● Tying it in with last week: effects on the Kidney

44. How this affects the kidney
● tying things in with the 2nd supervision (see http://www.dr-cee.net/?
page_id=1431)
● Atherosclerosis
○ renal artery stenosis
● Hypertension
○ arterionephrosclerosis
○ hyalinisation of glomeruli => renal failure
● Vasculitis
○ immunocomplex deposition => GN (can be severe)
○ infarctions

45. References
histological slides:
wheater’s histology
pathogenesis of atherosclerosis:
http://quizlet.com/7447571/hypotheses-for-atherosclerosis-flash-cards/
microscopic features of atherosclerosis:
http://www.drugdevelopment-technology.com/projects/prasugrel/prasugrel2.html
PAN contrast X-ray:
picture from http://www.learningradiology.com/notes/chestnotes/polyarteritisnodosapage.htm
also see:
http://www.dr-cee.net/?page_id=1438