Basic Science

Basic Science Dr. Vijay Sharma Consultant Histopathologist and Honorary Senior Lecturer Liverpool Clinical Laboratories Royal Liverpool Hospital.

Topics covered (briefly)     

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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      

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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 – 

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myopericarditis

Motor neurons of spinal cord – muscular paralysis

Virus 

West Nile Virus    

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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  

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DNA Skin, mucous membrane HSV-1  

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HSV-2 

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Gingivo-stomatitis Corneal blindness Genital sore

Glassy intranuclear inclusion

Herpes virus - CMV   

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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  

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Dew drop on rose petal Torso – head and neck

Shingles 

Dorsal root ganglia –   

sensory nerve reactivation Painful vesicular lesion Trigeminal nerve

EBV 

Infectious mononucleosis  

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Fever, sore throat Generalised lymphadenopathy

B-cell lymphoma Burkitt lymphoma  

8:14 translocation c-myc oncogene

HPV    

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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 

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Progessive multifocal leucoencephalopathy (JC virus) -HIV Merkel cell cancer

HHV-8  

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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 

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S. epidermidis 

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IV drug abuser, prosthetic valve

S. saprophyticus 

Urinary tract infection

Streptococcal infection 

Group A β haemolytic : 

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Group B β haemolytic : 

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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: 

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Meningitis in elderly & immunosuppressed patient

Anthrax Cutaneous: black eschar  Inhalation: rapid sepsis  Gastrointestinal: contaminated meat, bloody diarrhoea 

Gram negative bacteria 

N. meningitidis –diplococci 

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5-15 years

N. gonorrhoeae STI  Urethritis, PID 

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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  

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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 

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Lepromatous Numerous bacteria  Skin nodules  Disfigurement  Testis - sterility 

Syphilis 

Delayed type hypersensitivity 

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Primary syphilis (3 week)   

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Chancre Plasma cells Obilliterative endarteritis

Secondary syphilis (210weeks) 

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reinfection

Skin, mucocutaneous lesions

Tertiary syphilis (>5years)  

Aortitis neurosyphilis

Clostridium  

Anaerobic bacteria C. perfringens 

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C. tetani  

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Umbilical stump Neurotoxin – convulsive contraction of skeletal muscle

C. botulinum 

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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   

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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  

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Encapsulated yeast Negative stain with India ink Meningoencephalitis Soap bubble lesion

Fungal infection 

Mucormycosis Diabetics  Non-septate  Right-angle branching 

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Aspergillosis Septate hyphae  Invasive disease  Non-invasive 

Parasites 

Malaria Plasmodium falciparum – severe disease  Sickle cell trait – lessen severity  Anopheles mosquito 

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Leishmaniasis Sandfly  Cutaneous, mucocutaneous, visceral disease 

Parasites 

African Trypanosomiasis Sleeping sickness  Tsetse flies 

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Chagas disease Trypanosoma cruzi  Cats, dogs  Myocardial inflammation 

Cell injury and cell death    

Necrosis Apoptosis Mitochondria Calcification

Necrosis 

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Coagulative necrosis  Protein denaturation  Tissue framework maintained  Hypoxic (ischaemic) death (all organs except brain) Liquefactive necrosis  Autolysis predominates  Brain, Abscess

Necrosis 

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Caseous necrosis  Tuberculosis Fat necrosis  Adipose tissue  Lipase activation  Complex with calcium - saponification  Acute pancreatitis

Apoptosis – programmed death   

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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 

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Megamitochondria  Alcoholic liver disease Increased mitochondria  Oncocytoma  Mitochondrial myopathy

Pathologic calcification 

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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  

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Liquefactive necrosis Coagulative necrosis Fat necrosis P53 Bcl-2 Metastatic calcification Dystrophic calcification Caseous necrosis

EMQ 

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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 

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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 

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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 

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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 

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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 

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Heart  

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Coagulative necrosis Contraction band necrosis

Kidney 

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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  

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Autosomal recessive  

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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 

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95% - a complete extra chromosome 21 4%- Translocation 1% - Mosaicism 

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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    

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Marfan syndrome Cystic fibrosis Fragile X syndrome Huntington disease Haemophilia Edward syndrome

EMQ 

Marfan syndrome – 

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Cystic fibrosis 

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Autosomal dominant inheritance

Haemophilia 

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X-linked recessive inheritance

Huntington disease 

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Autosomal recessive inheritance

Fragile X syndrome

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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 

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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 

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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 

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t(14,18) translocation 

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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  

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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 

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Small round blue cells with neurofibrillary background Produce catecholamine N-myc amplification

Wilms tumour 

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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