Basic Science Dr. Vijay Sharma Consultant Histopathologist and Honorary Senior Lecturer Liverpool Clinical Laboratories Royal Liverpool Hospital.
Topics covered (briefly)
Infectious disease Cell injury and cell death Acute and chronic inflammation Haemodynamic disorder Disease of immunity Neoplasia Environmental Pathology Genetic disorder Disease of infancy and childhood
Topics not covered
None of the topics are covered in detail
Infectious disease
Virus Bacteria Fungi Parasites
Virus - Measles
RNA paramyxovirus Respiratory droplet Koplik spot Lymphoid follicular hyperplasia Warthin-Finkeldey cells Pneumonia, diarrhoea, encephalitis Rash – T cell mediated SSPE
Virus - Mumps
Paramyxovirus Replication in lymph node Salivary gland - parotitis Testes, ovary, pancreas, aseptic meningitis
Virus-poliovirus
RNA enterovirus Faecal-oral route Coxsackievirus A – diarrhoea & rashes Coxsackievirus B –
myopericarditis
Motor neurons of spinal cord – muscular paralysis
Virus
West Nile Virus
Arbovirus Dengue fever, yellow fever –haemorrhagic manifestations Mosquito CNS infection - meningoencephalitis
Viral haemorrhagic fever
Ebola, Marburg, Lassa Transmission - insect, animal Haemorrhagic manifestation – thrombocytopenia, shock
Herpes virus - HSV
DNA Skin, mucous membrane HSV-1
HSV-2
Gingivo-stomatitis Corneal blindness Genital sore
Glassy intranuclear inclusion
Herpes virus - CMV
breast milk, transplacental. Opportunistic infection Cellular enlargement, Intranuclear inclusion, clear halo, smaller basophilic cytoplasmic inclusion Colitis, pneumonitis, hepatitis, chorioretinitis, meningoencephalitis Congenital infection – IUGR, deafness, smaller brain with foci of calcification
Herpes virus – Varicella Zoster Virus
Ckickenpox – macule to vesicle
Dew drop on rose petal Torso – head and neck
Shingles
Dorsal root ganglia –
sensory nerve reactivation Painful vesicular lesion Trigeminal nerve
EBV
Infectious mononucleosis
Fever, sore throat Generalised lymphadenopathy
B-cell lymphoma Burkitt lymphoma
8:14 translocation c-myc oncogene
HPV
Papovavirus family Increased p16 expression Skin or genital contact Subtype: 16, 18, 31 koilocytes
Polyoma virus
BK , JC, SV40 strains Nephropathy (BK virus) Immunosuppression Renal allograft recipient - Allograft failure Intranuclear inclusion – decoy cells
Progessive multifocal leucoencephalopathy (JC virus) -HIV Merkel cell cancer
HHV-8
HIV Kaposi sarcoma Multicentric castleman’s disease Primary effusion lymphoma
Bacteria Gram positive
Gram negative
No
Yes
Endotoxin No lipopolysaccharide
Yes
Phospholipid bilayer
Staphyloccocal infection
S. aureus Impetigo Osteomyelitis Toxic shock syndrome
S. epidermidis
IV drug abuser, prosthetic valve
S. saprophyticus
Urinary tract infection
Streptococcal infection
Group A β haemolytic :
Group B β haemolytic :
Post infectious glomerulonephritis Pharyngitis Neonatal sepsis
α haemolytic:
S. pneumoniae Pneumonia
Diptheria
Corynebacterium diptheria Gram positive rod Exotoxin Pseudomembrane pharyngitis
Other gram positive bacteria
Listeria monocytogens:
Meningitis in elderly & immunosuppressed patient
Anthrax Cutaneous: black eschar Inhalation: rapid sepsis Gastrointestinal: contaminated meat, bloody diarrhoea
Gram negative bacteria
N. meningitidis –diplococci
5-15 years
N. gonorrhoeae STI Urethritis, PID
Pseudomonas P. aeruginosa – cystic fibrosis, HAI P. pneumonia – vascular invasion, thrombosis, necrosis
Gram negative bacteria
Yersinia Y. enterocolitica – ileitis; mesentric lymphadenitis granulomatous inflammation Plague – massive lymphadenopathy (buboes), pneumonia & sepsis
Mycobacteria
Tuberculosis
No toxin Cell wall properties Obligate aerobe Apices of the lung Delayed hypersensitivity response
Mycobacterium Avium intracellulare
Immunocompromised host
Leprosy
Tuberculoid Few bacilli Skin anaesthesia Chronic ulcer, autoamputation
Lepromatous Numerous bacteria Skin nodules Disfigurement Testis - sterility
Syphilis
Delayed type hypersensitivity
Primary syphilis (3 week)
Chancre Plasma cells Obilliterative endarteritis
Secondary syphilis (210weeks)
reinfection
Skin, mucocutaneous lesions
Tertiary syphilis (>5years)
Aortitis neurosyphilis
Clostridium
Anaerobic bacteria C. perfringens
C. tetani
Umbilical stump Neurotoxin – convulsive contraction of skeletal muscle
C. botulinum
Gas gangrene
Neurotoxin – flaccid paralysis
C. difficle
Pseudomembranous colitis (antibiotic treated patient) Exotoxin- Toxin A & Toxin B (used for diagnosing the organism) Mushroom lesion
Obligate intracellular bacteria
Chlamydia
Trachoma STI Lymphogranuloma venereum
Genital infection Painful adenopathy Granulomatous and neutrophilic response
Rickettsia
Endemic typhus – lice Rocky Mountain spotted fever – dog tick Haemorrhagic rash Pulmonary oedema
Fungal infection
Cryptococcus neoformans
Encapsulated yeast Negative stain with India ink Meningoencephalitis Soap bubble lesion
Fungal infection
Mucormycosis Diabetics Non-septate Right-angle branching
Aspergillosis Septate hyphae Invasive disease Non-invasive
Parasites
Malaria Plasmodium falciparum – severe disease Sickle cell trait – lessen severity Anopheles mosquito
Leishmaniasis Sandfly Cutaneous, mucocutaneous, visceral disease
Parasites
African Trypanosomiasis Sleeping sickness Tsetse flies
Chagas disease Trypanosoma cruzi Cats, dogs Myocardial inflammation
Cell injury and cell death
Necrosis Apoptosis Mitochondria Calcification
Necrosis
Coagulative necrosis Protein denaturation Tissue framework maintained Hypoxic (ischaemic) death (all organs except brain) Liquefactive necrosis Autolysis predominates Brain, Abscess
Necrosis
Caseous necrosis Tuberculosis Fat necrosis Adipose tissue Lipase activation Complex with calcium - saponification Acute pancreatitis
Apoptosis – programmed death
Anti-apoptosis - Bcl-2 & Bcl-x Promotes apoptosis - P53, TNF, Bak, Bax, Bim Dysregulated apoptosis P53 mutation Li- Fraumeni syndrome Breast, brain cancer, sarcoma, leukaemia Increased apoptosis Neurodegenerative disorder, stroke, myocardial infarction
Mitochondria
Megamitochondria Alcoholic liver disease Increased mitochondria Oncocytoma Mitochondrial myopathy
Pathologic calcification
Dystrophic Site of prior injury or nonviable tissue Atherosclerosis, damaged heart valves, necrosis Metastatic Hypercalcaemia; causes Increase parathyroid hormone Bone destruction – multiple myeloma Vitamin D related disorder - sarcoidosis Renal failure
EMQ
Liquefactive necrosis Coagulative necrosis Fat necrosis P53 Bcl-2 Metastatic calcification Dystrophic calcification Caseous necrosis
EMQ
Necrosis pattern in Brain abscess Liquefactive necrosis Necrosis pattern in Myocardial infarction Coagulative necrosis Necrosis pattern in acute pancreatitis Fat necrosis Apoptosis promoter p53 Decreases apoptosis Bcl-2 Patient with Paget’s disease of bone showing foci of calcification in skin Metastatic calcification
MCQ
A kidney tumour shows histology of oncocytoma. The tumour cell have: Increased lipids Increased mitochondria Cytoskeleton abnormality Increased glycogen
Acute and chronic inflammation
Different mediators in inflammation
Inflammation
3 plasma derived factors Complement system Kinin system Clotting system
Complement system C1-C9
C3 – classic pathway (Ag-Ab complex), alternate pathway C3b – phagocytosis C3a & C5a Anaphylatoxin Stimulate mast cells – release histamine – vascular permeability and vasodilatation C1 inhibitor deficiency Hereditary angioneurotic oedema - episodic Life threatening oedema emotional stress, trauma
Kinin system
Kallikreins Generates Bradykinin Increase vascular permeability and vasodilation Hageman factor activation (factor XII) Produces clotting factor XIIa Chemotactic activity Neutrophils aggregation
Clotting system
Intrinsic pathway Activation of thrombin Cleavage of fibrinogen Formation of fibrin clot Extrinsic pathway Tissue factor Converts VII to VIIa Intrinsic and extrinsic pathway converge at factor X activation Factor XIIa – activate fibrinolytic system – plasmin – degrades fibrin
Arachidonic acid metabolites
Cyclooxygenase Produces thromboxane and prostaglandins Inhibited by aspirin Thromboxane A2 – vasoconstriction Prostaglandins - Vasodilation
Tumour necrosis factor (TNF)
TNF and IL1 Acute- phase response Fever Anorexia Lethargy Decrease appetite Cachexia
Role of different mediators in inflammation Reaction
Mediators
Vasodilatation Increase vascular permeability Chemotaxis
PG’s, NO, Histamine Bradykinin, C3a &C5a
Fever Pain Tissue damage
Chemokines, C5a, TNF, IL-1 TNF, IL-1 PG’s, bradykinin Neutrophils and macrophages
Chronic inflammation
Macrophages – plays an important role Activated by IFNγ, endotoxin Produces fibrosis, tissue injury
MCQ
A patient develops lung abscess. Which mediator is responsible for fever? Prostaglandins Macrophages C3a &C5a TNF and IL-1
Haemodynamic disorder
Odema Thrombosis Shock
Oedema
Increased hydrostatic pressure Congestive heart failure Reduced plasma osmotic pressure Nephrotic syndrome, Liver cirrhosis Lymphatic obstruction Neoplastic Postirradiation Inflammation
Thrombosis
Virchow’s triad Endothelial injury Bacteria, radiation Alteration in normal blood flow Stasis – aneurysm, bed ridden Hyperviscosity – polycythaemia Hypercoagulable state Factor V mutation
Shock
Types Septic
shock Microbial infection Peripheral vasodilation, Endothelial injury, Activation of cytokine cascade Cardiogenic shock Low cardiac output; failure of myocardial pump MI Cardiac tamponade
Types of shock Hypovolemic Haemorrhage, fluid loss Inadequate blood or plasma volume Anaphylactic Sytemic vasodilation and increased vascular permeability IgE-mediated Neurogenic Loss of vascular tone and peripheral pooling Spinal cord injury
Septic shock
Gram negative bacteria Endotoxin Lipopolysaccharides (LPS) Released on degradation of cell wall
Organs in shock
Brain
Heart
Coagulative necrosis Contraction band necrosis
Kidney
Hypoxic encephalopathy
Acute tubular necrosis
Lungs
Diffuse alveolar damage
MCQ
A patient suffers from pneumonia and develops septic shock. In majority of cases it is caused by endotoxin (lipopolysacchride) present on Gram positive bacteria Gram negative bacteria Fungi Parasite
Genetic disorder
Mutation Transmission pattern Down syndrome
Mutation
Trinucleotide repeat mutation Amplification of trinucloetide sequence Fragile X syndrome Mental retardation FMR-1 gene X-linked recessive disorder Huntington disease Autosomal dominant disorder Chorea
Transmission pattern
Autosomal dominant
Autosomal recessive
NF-1 and NF-2 Marfan syndrome Cystic fibrosis Alpha 1- antitrypsin deficiency
X-linked recessive disorder
Duchenne muscular dystrophy Haemophilia A and B
Down syndrome
Down syndrome
95% - a complete extra chromosome 21 4%- Translocation 1% - Mosaicism
Mixture of cells with normal chromosome and cells with extra chromosome 21
Premature Alzheimer disease
Edward syndrome: Trisomy 18 Patau syndrome: Trisomy 13
MCQ
Fragile X syndrome has which of these mutation Point mutation Frameshift mutation Missense mutation Trinucleotide repeat mutation
EMQ 1. 2. 3. 4.
Autosomal dominant inheritance Autosomal recessive inheritance X-linked recessive inheritance Trisomy
EMQ
Marfan syndrome Cystic fibrosis Fragile X syndrome Huntington disease Haemophilia Edward syndrome
EMQ
Marfan syndrome –
Cystic fibrosis
Autosomal dominant inheritance
Haemophilia
X-linked recessive inheritance
Huntington disease
Autosomal recessive inheritance
Fragile X syndrome
Autosomal dominant inheritance
X-linked recessive inheritance
Edward syndrome
Trisomy
Disease of immunity
Hypersensitivity reaction Amyloidosis
Disorder of immune system Hypersensitivity Autoimmune
(SLE) Immunodeficiency (AIDS)
Hypersensitivity reaction Types
Type 1- Immediate
Type IIantibody mediated
Allergy Asthma anaphylaxis
Autoimmune haemolytic Anaemia Goodpasture syndrome
Type-III Immune complex mediated
Type-IV Cell mediated
SLE
Tuberculosis Contact dermatitis
Type I
Skin allergy, Allergic rhinitis, Hay fever, Bronchial asthma (toluidine blue) Allergen
Vascular dilatation Oedema
Inflammation Eosinophils
Mast cells IgE
degranulation
Goodpasture syndrome- Type II
autoantibodies are directed against the basement membrane
Type III
SLE, glomerulonephritis, vasculitis inflammation Circulating antigenantibody complex
deposit
Target organ
Vasculitis – fibrinoid necrosis
Type IV
Contact dermatitis, transplant rejection, tuberculosis, type 1 diabetes mellitus, multiple sclerosis Delayed type hypersensitivity T cell mediated CD 4 CD 8
MCQ
Which type of hypersensitivity reaction is involved in systemic lupus erythematosus? Type I Type II Type III Type IV
Amyloidosis
Non-branching fibrils 7.5-10nm Types AL B-cell dyscrasia AA Inflammatory state; RA B2- amyloid Alzheimer disease Transthyretin Familial amyloid polyneuropathy aging B2-microglobulin Long-term haemodialysis
Neoplasia
Inherited predisposition to cancer Genetics and Neoplasia
Inherited predisposition to cancer Gene
Disease
p16INK4A
Melanoma
BRCA1, BRCA2
Breast, Ovarian tumour APC FAP MSH2, MLH1, MSH6 HNPCC RET MEN, type 2
MCQ
A person has medullary carcinoma of thyroid, phaeochromocytoma, parathyroid hyperplasia. Which gene mutation is present here?
MEN1 RET gene BRCA 1 APC
Genetics and Neoplasia
t(8,14) translocation
t(14,18) translocation
Burkitt’s lymphoma, myc oncogene
Follicular lymphoma, bcl-2 gene rearrangement
t(11,22) translocation
Ewing’s sarcoma
Environmental and nutritional pathology
Oral contraceptive therapy
Breast carcinoma Yes; small risk Cervical carcinoma – ? Ovarian, endometrial cancer – no; protective Thromboembolism – yes Hypertension – yes Cardiovascular disease – >45yrs; smoker Hepatic adenoma yes
Hormone replacement therapy
Endometrial cancer – yes Breast cancer – yes Thromboembolism - yes
Disease of Infancy and childhood
Neuroblastoma Wilms tumour Congenital anomalies
Neuroblastoma
Small round blue cells with neurofibrillary background Produce catecholamine N-myc amplification
Wilms tumour
Chromosome 11p commonly involved Triphasic
Blastema Immature stroma tubules
Congenital anomalies
Rubella 1st trimester Cataract Heart defects
PDA Tetralogy of Fallot VSD Pulmonary artery hypoplasia
Deafness Mental retardation
Congenital anomalies
CMV 2nd trimester Mental retardation Microcephaly Deafness
MCQ
A newborn developed congenital rubella infection. Which of the following is not a manifestion of rubella infection? Patent ductus arteriosus Tetralogy of Fallot Ventricular septal defect Atrial septal defect
Thank you