Pathology Pathology General Pathology by hedongchenchen

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									                                  Pathology
General Pathology
Abscess and Pus
Pus

Composed of two phases

   1. Solid:
           o  live/dead polymorphs, macrophages
           o  Bacteria/causative agent (eg irritant chemicals)
           o  Dead human cells
   2. Fluid: contains exudate
          o Immunoglobulins (for opsonisation - 1IgG, 2IgM)
          o Complement - chemotaxis, anaphylaxis, opsonisation
          o Clotting factors
          o Inflammatory mediators

Abscess

      Localised collection of pus
      If loculated = pus, if free = empyema
      Wall composed of granulation tissue "pyogenic membrane"
      Natural history is to dischage through line of least resistance
            1. enzymes released from polymorphs/macrophagtes break down long
               chain molecules
            2. increases osmotic pressure (as more molecules)
            3. Swells pus collection
            4. Discharges


Agenesis Aplasia Atrophy
Agenesis

Complete failure of organ to develop (at all)

      Di George syndrome - failure of developement of third and fourth pharyngeal
       pouches (leads to no thymus and parathyroid glands)



Aplasia

Failure to attain size or function - recognizable tissue that has failed to fully develop
        Biliary atresia - failure to develop a lumen within the biliary tree!



Atrophy

Reduction in normal cell size or number. (Cf hypertrophy - increase in size,
hyperplasia - increase in number)

        Physiological
            1. Childhood: thymus, umbilical vessels
            2. Adulthood: Menopausal uterus/vagina
        Pathological
            1. Starvation, ischaemia, disuse (immobilization


Amyloidosis
Amyloid

        Family of extracellular proteins composed of B-pleated sheets
        Mammalian systems have no enzyme to degrade these compounds (similar to
         silk ligatures)
        Have apple-green birefringnce on polarised light after staining with Congo red

Classification

AL        Amyloid Lymphocyte origin: Primary amyloid
          Soluble precursor Ig light chains (esp from myeloma)

              1. Heart: restrictive cardiomyopathy
              2. Nerves: neuropathy
              3. Skin: may result in carpal tunnel syndrome


AA        Secondary/Reactive                                                                            a
          From chronic conditions - macrophages secrete ILs that stimulate hepatocytes to secrete serum a
          precursor protein (SAA)

              1. Kidney: walls renal arteries, GM, BM
              2. Liver: in sinusoidal space of Diss
              3. Spleen: forms"sago spleen



                 Chronic infection: TB, syphillis, leprosy
                 Chronic inflammatory diseases: RhA, Crohns, UC
                 Neoplasms: Hodgkin's, renal cell carcionoma
AH/AB Occurs with Alzheimer's disease with APP as precursor


Anaemia
Red cell precursors

      Myeloblasts
      Myelocytes
      Early normoblasts
      Late normoblasts
      Reticulocytes



Anaemia

Microcytic                  Normocytic               Macrocytic
   1. Iron deficiency          1. Haemolytic           1. B12 (3 year stores in
      anaemia                  2. Anaemia of chronic       liver - functions as
                                  disease                  co-enzyme) / Folate
                                                           (3 months stores -
                                                           used to produce
                                                           methionine from
                                                           homocysteine)
                                                       2. Alcoholism (leading
                                                           to B12, folate), liver
                                                           damage
                                                       3. Thyroid disease
                                                       4. Renal failure




Megaloblastic Anaemia

      Megaloblast = abnormal nucleated cell not usually found in the body, present
       in BM and occasionally found in peripheral blood

   1. B12
          o    Functions as co-enzyme to produce methionine from tetrahydrofolate
          o    3 years store
          o    Deficiency in (1) Pernicious anaemia GPC antibodies (2) partial/total
               gastrectomy (3) failure to absorp from terminal ileum
   2. Folate
          o    Tetrahydrofolate used to form methionine from homocysteine
          o    3 months store in liver
             o   Deficiency (1) inadequate intake or excess demand in pregnancy (2)
                 vegans (3) drugs which have an anti-folate action




Haemolytic anaemia

   1. Congenital
         o Membrane abnormalities: spherocytosis (spectrin), elliptocytosis,
             abetalipoproteinaemia
         o Abnormal Haemoglobinopathies: SCC, HbC, HbD, thalassaemia
         o Enzyme deficiency: G6PD, pyurvate kinase, glutathione synthetase
             deficiency
   2. Acquired
         o Immune
         o Mechanical - artificial heart valves, microangiopathic haemolytic
             anaemia

Diagnosis:

      low Hb, normochromic normocytic - macrocytic (raised Red cell distribution
       width)
      Raised reticulocyte count
      Excess unconjugated bilirubin



Haematocrit

Proportion of total blood volume that consists of red cells
Expressed as percentage / fraction
Normally = 0.4 - 0.45

Determines oxygen-carrying capacity of blood
Determines blood viscosity



Determinants

   1. Red cell volume
          o Blood loss
   2. Plasma volume
          o Loss of water
          o Plasma expansion - pregnancy


Asbestos
Occupations associated with asbestos exposure

      shipworkers
      Builders

Clinically significant asbestos

   1. White asbestos (Chrysotile)
         o 90% asbestos used in industy
         o Long woolly fibres: associated with fibrosis
   2. Blue asbestos (Crocidolite)
         o Straight short fibres: associated with malignancy, fibrosis (penetrate
             more deeply into lungs and are associated with greater pathology)
   3. Brown asbestos (Amosite)
         o Straight long fibres: associated with fibrosis

Asbestos-related diseases

      Ca Bronchus (esp blue/crocidolite)
      Malignant mesothelioma
      Asbesosis - fibrotic lung disease
      Chronic bronchitis


Ascities
Ascities

Abnormal free fluid within the peritoneal cavity



Transudate:

      Hydrostatic: cirrhosis, right heart failure, Budd-chiari (hepatic vein
       obstruction)
      Oncotic: loss of protein (starvation, liver failure, nephritic/nephrotic
       syndrome)

Exudate:

      Inflammatory: peritonitis, pancreatitis, malignancy


Atheroma / atherosclerosis
Atheroma

Accumulation of lipid within the intima of large and medium sized arteries
Aeitological factors:hypertension, smoking, hyperlipidaemia, DM, hereditary factors
   




Complications

   1. Ischaemia
   2. Infarction (from progressive occlusion, rupture of plaque leading to
      thrombosis, haemorrhage into plaque)
   3. Embolus
   4. Aneurysm


 Blood cells
Polymorphonuclear leucocytes are classed as neutrophils, basophils and oesinophils.

Neutrophils                        Polysegmented nuclei (hypersegmented in
                                    B12/folate deficiency)
                                   Clear cytoplasm with fine granules (contain
                                    elastase, protease, A1AT, lysosyme, lactoferrin)
                                   Close relation with acute inflammation

Basophils                          Unlobulated or bilobate nuclei
                                   Granules contain histamine, eosinophil
                                    chemotactic factor, slow-releasing substance of
                                    anaphylaxis
                                   Close relation with allergic reactions/anaphylaxis

Eosinophils                        Bilobed nuclei
                                   Bright eosinophilic granules contai: major basic
                                    protein, eosinophil cationic protein
                                   Close relation with parasitic infections



Platelets

      Adhese to vessel wall in presence of Von Willebrand factor leading to shape
       change and degranulation
      Aggregates with contraction to form solid mass in vessel
      Releases PGs, serotonin, TXs



Giant Cells

   1. Normal
         o Osteoclasts
         o Syncytiotrophoblasts
           oMegakaryocytes
           oSkeletal muscle cells
           oOocytes
   2. Abnormal
         o Macrophage and related giant cell
         o Virus induced
         o Tumour giant cells (Reed-sternberg cells in Hodgkin's = modified B
            lymphocytes)


Calcification
Calcification

   1. Orthotopic
         o Bone / teeth
         o Otoliths
   2. Heterotopic
         o Metastatic: occurs as a result of hypercalcaemia, in regions that secrete
             acid (lung CO2, Kidney, stomach)
         o Dystrophic: occurs in dead or damaged tissues in the presence of a
             normal circulating calcium concentration - atheroma, scars, aortic
             valve




 Calculi
Calculi

       Abnormal mass of precipitated solid material in a duct

   1.   Prostatic (commonest: most TURP and prostatectomy specimens have calculi)
   2.   Biliary
   3.   Urinary
   4.   Pancreatic
   5.   Salivary

Principles of formation

   1. Flow
           o    Stasis
   2. Wall
   3. Constituents
         o Nidus (desqumated cells, secretion, infection)
         o Increased colloid / reduced solvent
         o Change in pH
Complications of Calculi

(Depends on site and size)

Obstruction
Haemorrhage
Infection
Stricture
Perforation
Metaplasia/Malignant change


Cellulitis / Erysipelas / Nec fascititis
Clinical differentiation



Condition Pathology                  Organisms             Management
Cellulitis Infection of the skin         Staph aureus /   History
           and underlying                  epidermidis     Swab
           subcutaneous tissues          Streptoocci      IV antibiotics -
                                                           benpen/fluclox or
                                                           clindamycin/erythromycin
                                                           (if penicillin allergic)
Erysipelas A form of cellulitis            Lancefield A
            Occurs in                       B-haemolytic
            immunocompromised,              streptococci
            young, old
Necrotising Necrotising process of         Lancefield A Resuscitation
fascitits   the deep fascia                 B-haemolytic Blood cultures / wound
                                            streptococci swab
            Forms                                        Antibiotics
                                                         Radical tissue
                   Fournier's                           debridement
                    gangrene (of
                    the scrotum)




Complement Cascade
The Complement system

      Important mechanism to control infection
      Promotes phagocytosis
      Involved in bactericidal mechanisms
      Promotes lymphocyte function
      Mediates inflammation through mast cell degranulation and chemotaxis



Classical pathway                                       Alternate pathway
                                                             C3 activated directly
                                                               by endotoxins,
                                                               viruses, bacteria,
                                                               fungi
                                                             Does not need
                                                               immunoglobulin
                                                               activation




      IgG or 2 IgM fix to cell membrane
      C1q binds to long chains and then to C1r and
       C1s
      Whole activates C4 and C2. C2,4 cleaves C3
       into components
      C3a is chemotactic and anaphylactic. C3b is an
       opsonin and also acts with C2,4 to cleave C5
      C5a is chemotactic and anaphylactic. C5b binds
       with C6, C, C8 and C9 to form membrane attack
       complex




Coroner
Deaths that must be reported to the coroner

   1. Suspicious or Unnatural
         o Death unknown
         o Violent / unnatural
         o Suicide
         o Due to abortion
         o In detention / custody
           o  Ill treatment, starvation or neglect
   2. Medical
         o Death within 24 hours of hospital admission
         o Due to medical intervention (of any sort)
         o During operation or before recovery
         o Not been seen by certifying doctor after death or within 14 days before
              death
   3. Industrial
         o Industrial disease or related to deceased employment
         o Service disability pensioners


Cyst
Cyst

Abnormal fluid-fillled space (lined with epithelial cells) - cf pseudocyst (filled with
granulation tisse - pancreatic)



Pathological process involved

   1. Congenital
          o Thyroglossal
          o Branchial
          o Biliary
          o Polycystic kidney disease
   2. Inflammation
          o Infection - ameoba, cysticercosis, hydatid
          o Obstruction - spermatocoele, meiboniam cyst, epipdydimal
   3. Degeneration
          o Bone - osteoarthritis
          o Cerebral cysts post infarction
   4. Implantation
          o Epidermal / dermal
   5. Hyperplasia
          o Breast cysts
   6. Neoplastic
          o Ovarian cysts
          o Cystic neoplasms of the pancreas


Diverticula
Diverticulum

      Abnormal outpouching of a hollow visucs into surrounding tissues

Classification
   1. True and False
         o True: all components of the viscus (tend to be congenital)
         o False: Only part of wall represented (tend to be acquired) - eg. sigmoid
              colon diverticulum, pharyngeal diverticulum through Killian's
              dehiscence between thryopharyngeus and cricopharyngeus msucles
              (components of the inferior pharyngeal constrictor)
   2. Congenital or acquired
         o Eg. Meckel's diverticulum - 2inches long, 2ft from ileocaecal valve,
              2% population#
         o Duodenal diverticula
   3. Pulsation and traction

Complications

   1. General
         o Inflammation
         o Haemorrhage
         o Perforation
   2. Function
         o Ectopic secretion of peptic acid, as in Meckel's diverticulum
         o "Blind loop" syndrome - causing vitamin deficiencies secondary to
             bacterial overgrowth
   3. Cellular
         o Metaplasia, as a bladder diverticulum
         o Malignant change as in bladder diverticula


Erosion Ulcer
Erosion

       Partial loss of epithelial or mucosal surface that heals by resolution (ie.
        replacement by fully functional tissue)

Ulcer

       Full thickness loss of epithelial or mucosal surface which heals by repair
        (replacement with fibrous tissue) with or without resolution

Factors affecting rate of healing of ulcer

   1. Local
           oPersisting cause (acid secretion, continuing infection, continuing
            sepsis)
         o Persisting inability to detect damage (hypoasthesia, anaesthesia)
         o Poor blood supply - ischaemia
         o Neoplastic process (ulcerated carcinoma)
   2. Systemic
         o Malnutrition
         o Immune deficienc: diabetes, AIDS
Gout
Purines (adenine, guanine)

         are metabolised to hypoxanthine
         changed by xanthine oxidase to xanthine
         Further metabolised to uric acid

Pyrimidines (thymine, cytosine)

         are metabolised to ammonium salts + urea.

Nucleoside = Base + ribose: Eg. RNA
Nucleotide = Base + ribose + phosphate radical



Classification of hyperuricaemia

   1. Primary: absolute/relative abnormality of xanthine-hypoxanthine handling
         o Deficiency of PPRT (Lesch-Nyhan syndrome) leads to inability of
             xanthine/hypoxanthine to be recycled into purines
   2. Secondary: increased purine breakdown with increased formation of uric acid
         o Ingestion - caviar, roe
         o Increased cell turnover: psoriasis, sickle cell, leukaemia, malignancy
         o Decreased excretion: CRF, diuretics

Complications of gout

         Joints: destructive osteoarthropathy
         Renal tract - stones, renal failure from a big stone


Fistula
Fistula

         Abnormal connection between two epithelial surfaces



Classification

   1. Simple / Complex (associated with abscess cavity)
   2. Anatomy
         o Respiratory: Bronchopulmonary fistula, tracheo-oesophageal
         o GI tract: tracheo-oesophageal, enterocutaneous, perianal
         o Urinary tract: entero-vesical fistula, urethrocutaneous (in circumcision)
         o Reproductive tract: Entero-vaginal fistula
           o Circulation system: arterio-venous fistula, AAAs
           o Salivary gland fistula (following parotidectomy)
   3. High output (>500mls/day) or Low output
         o Associated electrolyte disturbance / fluid disturbance
         o Associated malnutrition & sepsis
   4. Aetiology
         o Trauma/iatrogenic (AV fistula, post surgery, tracheostomy, earings)
         o Inflammatory (IBD)
         o Sepsis (from anastamotic leaks, abscesses)
         o Malignancy
         o Radiotherapy

Examples

      Earings
      Perianal fistula
      Enteric fistula (Crohn's disease)

Factors controlling healing

   1. Local
           oPersisting cause / material
           oPersisting sepsis
           oPersisting flow through fistula
           oWidth of fistula
           oIschaemia
           oEpidermidisation of track
           oMalignant change
   2. Systemic
         o Nutrition, vitamin deficiency
         o Immunosuppression - DM, AID




Principles in Management

Hope Hospital protocol - SNAP - Sepsis / Nutrition / Anatomy / Proceed

   1. Sepsis
           o  Remove cause
           o  Drain abscess cavities
           o  Avoid antibiotics
           o  Skin protection
   2. Nutrition to promote healing
         o Restrict / control fluid intake (determines output of fistula)
         o Total Parenteral nutrition / distal enteral nutrition
   3. Anatomy
         o Fistulography
         o Bowel enema
         o CT / MRI: define abscess cavities
   4. Procedure (1) excision - karydakis procedure (2) laying open (3) seton to cut
      through tract


Haemoglobinopathies




Haemoglobinopa Pathology           Blood picture          Complications
thy
Sickle cell    Single amino acid       Normochromic         Haemolytic
disease        substitution on B-      Microcytic              anaemia results
               chain at position 6        anaemia               in cardiac
               of valine for           Sickled cells           failure
               glutamic acid           Reticulocytosis      Pigment
                                       Features of             gallstones
                    Autosomal            splenic atrophy    Thrombosis
                       co-                (target cells,        and infarction -
                       dominant:          acanthocytes,         abdomen,
                       homozygot          Howell-Jolly          chest, splene,
                       es have 90-        bodies)               bone
                       100% HbS,                             Infection -
                       heterozygot                              salmonella
                       es have 20-                              osteomyelitis,
                       40%                                      pneumococcal
                                                                sepsis

Thalassaemia      Defective globin           Hypochromic            Marrow
                  chain synthesis -           microcytic              hyperplasia
                  causes abnormal             anaemia                Iron overload
                  haemoglobin                Reticulocytosis         (cirrhosis,
                  production                 Target cells            endocrine
                                             Nucleated red           disturbance,
                        Alpha                cells                   pancreatitis)
                         Thalassaem          Increased              Hypersplenism
                         ia - China,          haemoglobin F           - decreased red
                         Asia,                                        cell survival
                         Africa                                       time,
                        Beta                                         leucopaenia,
                         Thalassaem                                   thrombocytope
                         ia -                                         nia
                         Mediterran
                         ean, Middle
                             East



Hamartoma
Hamartoma

        Tumour-like malformation composed of haphazard arrangement of different
         amounts of tissues normally found at that site ("error")
        No tendency for lesion to grow other than normal growth controls of the body



Examples

   1.    Haemangiomas
   2.    Peutz-Jegher's polyp of bowel
   3.    Bronchial hamartoma
   4.    Melanocytic naevi
   5.    Neurofibromatosis
   6.    Tuberous Sclerosis

Morbidity from Hamartoma

   1.    Obstruction
   2.    Pressure
   3.    Infection
   4.    Infarction
   5.    Haemorrhage
   6.    Fracture


Hernia
Hernia

        Protusion of a viscus or tissue from the body compartment in which it normally
         resides into another body compartment

Classification

   1. Congenital / acquired
   2. Complete / partial
         o Complete: inguinal, femoral
         o Partial: Richters, sliding gastric

Predisposing features

   1. Increased donor compartment pressure
             o
             Abdomen: inguinal, femoral, obturator, diaphragmatic, hiatus
             o
             Brain: ICP - brain herniation
    2. Weakness of tissues with normal pressure in donor compartment
          o Incisional hernia: poor technique, nutrition

Complications

    1.   Obstruction
    2.   Ischaemia / infarction
    3.   Pressure effects
    4.   rupture


Hyperplasia & hypertrophy
                 Hyperplasia                                   Hypertrophy

                 Increase in number, number, number, number,
Definition                                                   Increase in SIZE of cells
                 number of cells

              Breast in pregnancy
                                                             Uterus in pregnancy
Physiological Thyroid in pregnancy
                                                             Skeletal muscle with exercise
              Pituitary in pregnancy (cf Sheehan's syndrome)

                                                               Overstimulation
                 Overstimulation
Pathological                                                   Graves disease
                 Graves disease
                                                               Cardiomyopathies
                 Adrenals in Cushins
                                                               Congenital muscular
                 Endometrium in oestrogen excess
                                                               dystrophies


 Inflammatory Markers
Classification of inflammatory mediators

    1. Substances stored irrespective of need and released when required
          o Histamine
          o Serotonin
    2. Substances synthesized in cells as required when inflammatory events dictate
          o Leucotrines
          o Prostaglandins
          o Cytokines
    3. Cascades that are activated as part of the inflammatory response
          o Clotting cascade
          o Complement cascade - opsonins, chemoattractants, anaphylactic agents
          o Kinin cascade
Prime plasma-derived mediators in acute inflammation

       Fibrin-related peptides and plasmin
       Kallikrein and bradykinin
       C3a C5a



CRP

C-reactive protein
Half-life ~6hours
Marker of acute inflammation
Protein derived produced in liver
Functionally similar to IgG (but not specific)


 Ischaemia & Infarction
Ischaemia

       Abnormal reduction in blood supply to or drainage from an organ or tissue
       Infarction is the result of cessation of the blood supply to or drainage from an
        organ or tissue



Classification of causes

   1. Local
            o
            Arterial obstruction: thrombus, embolus, artheroma, pressure, spasm
            o
            Venous: thrombus, pressure, stasis
            o
            Capillary obstruction: vasculitis (meningococcal septicaemia, drugs),
            obstruction (sickle cell)
         o External pressure
   2. General
         o Hypoxaemia
         o Anaemia
         o V/Q defect
   3.



Factor determining the extent of ischaemic damage in arterial obstruction

   1.   Tissue involved - brain low reserve
   2.   Speed of onset
   3.   Degree of obstruction
   4.   Presence of collaterals
   5.   Level of oxygenation
   6. Presence of concomitant heart failure
   7. State of microcirculation




Metaplasia
Metaplasia

Change from one fully differentiated cell type to another

       Can become dysplastic if the agent that caused the metaplasia persists
       Can be misdiagnosed clinically



Classification

   1. Epithelial
         o Squamous - endocervix, bronchi, bladder, prostate
         o Glandular or columnar cell: intestinal with h.pylori; gastric with
             barrett's oesophagus
   2. Connective tissue
         o Osseous metaplasia (formation of metaplastic bone) in bladder,
             bronchus
         o Chondroid metaplasia (formation of metaplastic cartilage) in scars
         o Myeloid metaplasia (formation of metaplastic bone marrow) - liver,
             spleen, lymph nodes




 Metastasis
Metastatis

       Migration of cells from a malignant tumour to a site distant from the primary



Routes of Metastasis

   1.   Lymphatic
   2.   Haematogneous
   3.   Transcoelomic - stomach, ovary, colon, pancreas
   4.   Perineural - adenoid cystic carcinoma of salivary glands
   5.   CSF - medulloblastoma
   6.   Iatrogenic - implantation during surgery
Necrosis
Necrosis

      Abnormal tissue death during life
      Energy independent
      Occurs as a result of factors outside the cell
      Associated with inflammatory changes



Classification

   1. Coagulative
         o Tissue architecture preserved - kidney, heart, spleen
         o Proteins coagulate rapidly from heat
   2. Colliquative
         o Tissues rich in lipid, lysosomal enzymes denature fats and cause
             liquifaction - brain
   3. Caseous
         o Unstructured
         o Impossible to identify tissue affected by necrosis as architecture is
             destroyed - classical of TB



Fat Necrosis



Gangrene

   1. Dry: mummification of tissue without infection
   2. Wet: Necrosis with putrefaction caused by infection (anaerobic streptococci,
      bacteroides)



Autolysis

      Degradation of a cell by activation of enzymes presnet in the affected cell
       (self-digestion)
      May occur in necrosis or apoptosis

Heterolysis

      Degradation of a cell by activation of enzymes present in cells other than the
       affected cell
‹   Organisation resolution and repair
Organisation

       Transformation of inanimate material (clot, thrombus, pus) into living
        tissue responsive to growth control factors of the body
       Achieved by replacement with granulation tissue

Resolution

       Replacement of damaged tissue by fully functional tissue normally
        found at that site (no scar tissue)
       Found in liver, bone marrow, mucosal defects, minor injury to
        epidermis

Repair

       Replacement of damaged tissue by fibrosis or gliosis filling defect but
        has no intrinsic specialised function relevant to organ
       Occurs in most instances



    Pneumonia
Definition

Inflammatory condition of the lung



Classification

    1. Primary vs secondary
    2. Organism
           o Viral
           o Bacterial
           o Fungal
    3. Anatomy
           o Lobar pneumonia: exudate forms directly in bronchioles/aveoli
                   1. spills into adjacent segments via pores of Kohn
                   2. Confined to a lobe
                   3. Usually staph
                   4. Phases: (1) Congestion - inflammatory exudate (2) Red hepatisation
                      - Neutrophils and extravasated erythrocytes (3) Grey hepatisation -
                      Fibrin meshwork and degenerating erythrocytes (4) Resolution -
                      Macrophage release fibrinolytic enzymes
            o Bronchopneumonia: starts at bronchioles, extends to alveoli. Common in
              extremes of age
          o Interstitial pneumonia: chronic alveolar inflammation
   4. Aetiology
          o Hospital acquired: loss of barriers, instrumentation, impaired cough reflex,
              aspiration
                  1. Early: - OP organisms - staph aureus, strep pneumoniae
                  2. Late: Gram negative - pseudomonas, enterobacter, acinetobacter,
                      morganella
          o Community acquired

Severity score : CURB



Normal respiratory defences

   1.   Cough reflex
   2.   Mucociliary function
   3.   Aleolar macrophages
   4.   Secretory IgA




Complications of Pneumonia

   1.   Pleuritis - pleural effusion
   2.   Empyema
   3.   Lung abscess
   4.   Generalised sepsis




Prevention of pneumonia

   1.   Protection / isolation
   2.   Intermittent feeding
   3.   Controlled use of antibiotics
   4.   Regular suctioning / chest physio


Sinus
Pathological sinus

       Blind-ending tract that communicates with an epithelial surface
       Result of inflammatory process, usually lined with granulation tissue

Anatomical sinus

       Coronary sinus
       Intracranial venous sinus (cavernous sinus)
       Air sinuses


 Skin
Layers of the skin




Function of skin

   1.   Physical barrier
   2.   Filtration of light / ionising radiation
   3.   Secretion: sweat, contains Igs and is acidic due to lactic acid
   4.   Commensals - protects against pathogens
   5.   Immunological - Langerhan's cells
   6.   UV light generates vitamin D




Skin Cancer

   1.   Squamous cells
   2.   Malignant melanoma
   3.   Basal cell carcinoma
   4.   Merkel cell tumour

Risk factors for skin cancer

   1. Congenital
         o Familial syndromes - BK mole syndrome
         o xeroderma pigmentosum
   2. Acquired
         o UV light - skin grading (1) chalk white burns easily (2) fair tans difficulty (3)
             fair tans easily (4) olive (5) brown (6) black
         o Ionising radiation
         o Chemical carcinogens (tars, dyes, rubber products)
         o Viruses - HPV
         o Immunosuppression




         Subtypes                         Grading                Treatment

BCC             Nodular                                               Local excision with 3-
(above          Cystic                                                 7mm margin
lips)           Pigmented
                Superficial spreading

SCC                                                                    Local excision with 5-
(below                                                                  10mm margin +/-
lips)                                                                   block dissection of
                                                                        draining lymph nodes

MM              Superficial spreading    Breslow Thickness            Local excision with
                 (64%)                    <1mm                          10mm margin if 1mm
                Nodular (12-25%)         1 - 2mm                       depth
                Lentigo maligna (7-      2 - 4mm                      Local excision with
                 15%) with best           >4mm                          20mm margin if 2mm
                 prognosis                                              depth
                Acral lentiginous (10-   Clarke Levels                Local excision with
                 13%)                                                   30mm margin if 3mm
                Amelanotic               I: epidermis                  depth
                                          II: papillary dermis
                                          III:
                                          papillary/reticular
                                          junction
                                          IV: reticular dermis
                                          V: subcutanous fat




  Spread of infection
Sources of infection

   1. Animals
           o    Humans - TB, MM, influenza, neisseria, MRSA
           o    Animals - zoonoses, vets, mos
   2. Plants
           o Soil
   3. Environment
          o Soil
          o Air

Routes of infection - the "I"s

      Inhalation / droplet spread
      Ingestion
      Intercourse
      Innoculation - catherisation, injection, insects
      In-utero: trans

Endemic: Exists continously in a population, usually of low prevalence
Epidemic: Sporadic disease in a population, usually involves large numbers of people
Pandemic: Epidemic that affects many parts of the world


 Syndromes
 Lipoma
Lipoma

   1. Commonest benign tumour of mature fat cells (adipocytes)
          o Occur anywhere in body
          o Commonest in subcutaneous layer of skin (neck and trunk)
          o Malignant change is thought to not occur
   2. Multiple painful lipomas are known as adiposis dolorosa or Dercum's disease
      (associated with peripheral neuropathy)
   3. Variants
          o Liposarcomas arise de novo (and not via lipomas)
                  1. Classification
                          1. Well-differentiated: ring or long markers, chromosomes
                              derived from long arm of Chromosome 12
                          2. Myxoid and round cell (poorly differentiated)
                              liposarcoma
                          3. Pleomorphic liposarcoma: characterised by complex
                              karyotypes
          o Angiolipomas have prominent vascular component
          o Hibernomas: tumours of brown fat cells - seen in hibernating animals
          o Cowden's disease: association of lipoma, palmoplantar keratoses,
              multiple fascial papules, oral papillomatotis, vitiligo with involvement
              of the thyroid and disgestive tract
          o Bannayan-Zonana syndrome: rare AD hamartomatous disoder:
              multiple lipomas, macrocephaly, haemangiomas
   4. Treatment
          o Non-surgical: watch and wait
             o   Surgical: (indications are pain / cosmesis) - options: (1) suction
                 lipolysis via small remote incision (2) excision under LA

Inspection

   1. Discoid / hemispherical swelling
   2. May appear lobulated
   3. Look for scars (recurrent lipoma / Dercum's disease)

Palpation

   1. Lobulated
   2. Soft / firm depending on nature of fat in lipoma
   3. If soft and large may be fluctuant
   4. Slip sign: manner in which lipoma tends to slip away from examining finger
      on gentle pressure
   5. Skin freely mobile over the lipoma (compared to sebaceous cysts)
   6. Determine if lipoma is in skin or intramuscular (disappears on contraction of
      muscle)

Completion

   1. Life impact: cosmesis
   2. Similar lumps elsewhere (Dercum's disease)


Thrombosis / Clotting
Thrombus

       Solid material formed from constiuents in flowing blood
       (A blood clot inside a blood vessel when the patient is alive)
       Function of platelets + clotting cascade

Factors contributing to thrombosis (Virchow's triad)

   1. Wall
   2. Flow
   3. Constituents

Clot

       Solid material formed from constituents of stationary blood
       Primarily function of clotting cascade


Urinary tract calculi
Type                            Prevalence      Composition
Calcium oxalate              75%            Spiky / mulberry shaped
                                            Caused by hypercalciuria (moans, stones, psychic groans)
                                            Rare enzyme deficiency
                                            Increased oxalate absorption: coeliac, diverticulae of bowel,
Ammonium phosphate           15%            Associated with proteus infection
                                            "Staghorn calculi" (from urease)
Urate                        5%             Primary gout: HGPRT deficiency (Leesh-Nyhan)
                                            Secondary gout: increased purine breakdown - tumours, RT,
Cysteine                     3%             Results from primary cysteinuria, inborn error of metabolism

Management

   1. History: precipitants, family history, personal history
   2. Examination
   3. Investigations
         o Urine dipstick - blood, nitrates (UTI cause)
         o U/Es, serum electrolytes, WCC, CRP
         o KUB - 90% renal tract stones are radio-opaque (calcium, ammonium ,
              cysteine) - urate/xanthine stones radiolucent
         o IVU: determines degree / level of obstruction (hydronephrosis) - sites
              for blockage: (1) renal pelvis (2) pelvic brim (3) insertion into bladder
              - contrast contraindicated in pregnancy, allergy, anaphylaxis, raised
              serum creatinine
         o USS: - no contrast, detects stones >5mm, determines hydronephrosis
              and obstruction
         o CT Abdo: identifies radio-opaque and lucent stones, secondary signs of
              obstruction
   4. Analgesia - morphine, pethidine, NSAIDs
   5. Hydration

Definitive treatment

<4mm                        4-6mm                         >5mm
       Watch and wait             60% pass                    Extra-corporeal
       90% pass                    spontaneously                shockwave
        spontaneously                                            lithotripsy: stones <
                                                                 2cm in upper or
                                                                 lower 1/3 (middle
                                                                 difficult to visualise
                                                                 apparently) -
                                                                 contraindicated in
                                                                 pregnancy,
                                                                 aneurysms,
                                                                 pacemakers
                                                                Ureteroscopy
                                                                 +lithotripsy: stones
                                                                 in lower 1/3
                                                                 collected using
                                                                 stone basket or
                                                                     fragmented and
                                                                     pieces collected
                                                                    Percutaneous
                                                                     nephrolithotomy:
                                                                     stones > 2cm in
                                                                     renal pelvis - tract
                                                                     made
                                                                     percutaneously into
                                                                     renal collecting
                                                                     system and stone
                                                                     extracted (large
                                                                     stones can be broken
                                                                     up first)
                                                                    If obstructed -
                                                                     percutaneous
                                                                     decompression + JJ
                                                                     stenting
                                                                    Open surgery (less
                                                                     than 1% patients) -
                                                                     for stones that just
                                                                     are bad to the bone




Urinary tract infections
Urinary tract infection

      Infection of bladder, ureter, kidney (via renal pelvis)
      NB. Urethral infection is considered a STD




Predisposition

   1. Anatomy
          o Female anatomy: proximity of urethra to anus
          o Congenital abnormalities affecting flow: ectopic vesicae, ureteric
             duplication, urethral valves, congenital stricture, VUJ reflux
   2. Urine stasis
          o Mechanical obstruction: hydronephrosis, stricture, stone, neurogenic
             bladder, prostatic hypertrophy
          o Prostatic enlargement
   3. Instrumentation
          o Indwelling catheters
   4. Systemic disease
            o   Diabetes
            o   Immune deficiencies

Organisms

      Enterococci: E.coli, proteus, pseudomonas, klebsiella, staph aureus




Diagnosis

      Urine dipstick: RBCS, WCC, nitrates
      Microscopy
      Culture


GI pathology
Alcohol-related diseases
Metabolism of alcohol

      Microsomal ethanol oxidising system (MEOS)
      Alcohol dehydrogenase
      Catalase



Biochemistry/Haematology

      Raised GGT
      Macrocytosis



Laryngeal disease associations

      Laryngeal inflammation
      SCC larynx
      SCC pharynx / oesophagus

Hepatic effects of chronic alcohol

      Fatty liver
      Alcoholic hepatitis
      Cirrhosis: End stage of all chronic liver insults (1) nodules (2) fibrosis (3)
       distorted architecture
        Hepatocellular carcinoma

GI associations

        Gastritis/erosions
        Pancreatitis
        Carcinoma of pancreas

CNS effects

        Dis-inhibition, violence, trauma, chronic malnutrition
        Cerebellar degeneration
        Korsakov's psychosis
        Wernicke's: antegrade amnesia (?related to thiamine deficiency)


Colorectal pathology

Layers of the bowel wall

Mucosa
Muscularis mucosae
Submucosa
Muscularis propria
Subserosa
Serosa



Dukes staging

A:

B: Penetrating wall (including touching wall)

C1: Local nodes/peri-rectal nodes

C2: Apical nodes

D: Distant spread



Dukes staging system does not take into account the lesion that extends laterally
(rather than through wall). Therefore one can have a massive superficial tumour.


 Diverticular disease
Diverticulum [pathology]

Outpouching of colonic wall which results from herniation of mucosa through
muscular wall

     1. Occur at sites where mesenteric vessles penetrate bowel wall
     2. Lage of dietary fibre in western diets results in low stool bulk which
        stimulates increased segmentation of colonic musculature, resulting in
        hypertophy
     3. Increased intraluminal pressure results in herniation

Complications of diverticular disease

     1. Haemorrhage
     2. Inflammation - diverticulitis
     3. Obstruction from diverticular stricture
     4. Fistulation to bladder, vagina or skin
            o Pneumaturia
            o Faecaluria
            o Chronic urinary tract infections
     5. Perforation
     6. Pericolic or pelvic abscess


Hydatid disease
D: The result of infection with adult tapeworm (Echinoccocus granulosus)

G: Common in mediterranean

P: Large parasitic cyst grows slowly and asymptomatically

         Can have pressure effects on organs
         Can Rupture (can also release daughter cysts within them)
         Cysts can become infected with bacteria

Life Cycle

         Ingestion of canine tapeworm eggs (dogs are asymptomatic)
         Eggs hatch in duodenum + embryos cross mucosal membrane
         Travel via portal blood supply to liver
         Primary site of infection is the liver (can affect any organ in body)

S: Can present as acute abdomen from minor trauma from rupture

         Rupture: pain
         Into biliary tract: Obstructive jaundice, cholangitis

S:
I: Diagnosis is by serology and scans

       Serology/ELISA assay - Enzyme Linked ImmunoSorbent Assay for antibodies
        to hydatid antigen
       USS: Multiloculated cysts
       CT: "floating membrane"

T: Albendazole chemotherapy. Surgical enucleation is required occasionally.

       Chemotherapy: Albendazole/Mebendazole
       Percutaneous hypertonic saline and alcohol
       Surgery: (1) complete resection (2) local excision of cysts (3) de-roofing of
        cyst with evacuation of contents. Contamination of peritoneal cavity at time to
        surgery should be avoided by continuing drug therapy.


 Inflammatory bowel disease
Causes of Colitis

   1.   Infection
   2.   Inflammation - Crohn's, UC
   3.   Ischaemia
   4.   Radiation
   5.   Drugs (antibiotic induced pseudomembranous)

             Crohn's                            Ulcerative Colitis
Definition       Disease of inappropriate activation of gut mucosal immune
                   system
                 Driven by normal bowel flora
                 ?Defective barrier mechanism


Incidence 40/100,000                              80/100,000
Age                                               20 - 35 years
Sex
Geography
Aetiology     Genetics                                  Genetics
              Smoking                                   Smoking protective
              Diet: low fibre
              Immune mechanisms


Pathology           Transmural inflammation             Mucosal inflammation (with
                    Serositis common                     crypt abscesses
                                                         Serosa normal

Macroscopi          Anywhere along GIT (but             Starts at rectum and
c                    esp terminal ileum)                  progresses proximally
                    Patchy "skip lesions"                (ileum 10%)
                   "Cobblestone" appearance             Continous lesions
                    with fissuring                       No fissuring
                   Strictures common                    Strictures uncommon
                   Fistulae common                      Fistulae uncommon

Microscopi         Non-caseating granuloma              Inflammation - neutrophils,
c                   (aggregation of                       macrophages
                    macrophages)

Prognosis          Possible malignant change            Malignant change well
                                                          recognised

Symptoms                                                 Severe acute colitis

                                                     1.   Frequent stools >6/day
                                                     2.   Fever, tachcardia
                                                     3.   Systemically "unwell"
                                                     4.   Rectal bleeding
                                                     5.   Low albumin

                                                         Intermittent relapsing colitis
                                                         Chronic persistant colitis
                                                         Asymptomatic

Signs              Skin: Erythema nodosum,       Endoscopic grading
                    pyoderma gangrenosum
                   Eyes: iritis
                   Joints:

Investigatio
ns
Treatment Depends on                              Depends on

                1. Site of disease                   1. Site of disease
                2. Type of disease                   2. Type of disease
                3. Disease severity                  3. Disease severity

             Medical treatment                    Medical treatment

                1. 5-ASA (blocks                     1. 5-ASA (blocks
                   prostaglandins and                   prostaglandins and
                   leukotrienes)                        leukotrienes)
                2. Steroids                          2. Steroids
                3. Immunosuppressants -              3. Immunosuppressants -
                   Azathioprine                         Azathioprine
                   (mercaptopurine derivative),         (mercaptopurine derivative),
                   infliximab (anti TNF                 infliximab (anti TNF
                   antibody), methotrexate              antibody), methotrexate
                    (antimetabolite)                      (antimetabolite)



            Indications for sugery                Indications for sugery

                   Limited Resections                   Total colectomy + ileostomy
                   Strictureplasty                       + mucous fistula
                   Bypass procedures                    Proctocolectomy + ileoanal
                                                          pouch (depends on adequate
                1. Elective                               anal musculature)
                      o Chronic symptoms                 Types of pouch: S-pouch, J-
                          despite medical                 pouch, Four-loop W-pouch
                          therapy
                      o Malignancy                    1. Elective
                      o Fistulating disease                 o Chronic symptoms
                      o Chronic obstruction                     despite medical
                2. Emergency                                    therapy
                      o Clinical: Severe                    o Malignancy
                          colitis, haemorrhage        2. Emergency
                      o Biochemical: WCC,                   o Clinical: Severe
                          CRP                                   colitis, haemorrhage
                      o Radiographical:                     o Biochemical: WCC,
                          Perforation                           CRP
                                                            o Radiographical:
                                                                Perforation, toxic
                                                                megacolon



Peptic ulcer disease
Common aetiological factors

   1. H.pylori - 90% duodenal ulcers, 70% gastric ulcers
   2. NSAIDS - systemically suppress (protective) prostaglanding production
   3. Systemic illness - leading to stress ulcers: Curling's in burns / Cushing's in
      trauma
   4. Cigarette smoking
   5. Chronic disease

Complications of peptic ulceration

   1. Perforation (anterior wall ulcers - cause peritonitis): needs oversewing
   2. Haemorrahge (posterior wall ulcers - erode gastoduodenal artery): needs
      under-running
   3. Gastric outlet obstruction (duodenal ulcers - stricture of first part of
      duodenum)
   4. Recurrent ulceration
Confirmation of perforated peptic ulcer

   1. History - risk factors (smoking, medications)
   2. Examination - rigid abdomen, peritonitis, absent bowel sounds (may be no
      clinical signs in elderly)
   3. CXR - free air under diaphragm (85% of cases)
   4. Serum amylase to exclude pancreatitis
   5. ECG to exclude MI


Polyp
Polyp

Tumour protruding from the epithelium of an organ

Classification of Polyps

   1. Congenital acquired
   2. Shape
   3. Aeitiology
         o Metaplastic or hyperplastic
         o Inflammatory - UC
         o Hamartomatous - Peutz-Jegher's, juvenile retention polyps
         o Neoplastic




Complications

   1.   ulceration
   2.   haemorrhage
   3.   infection
   4.   intesussception
   5.   Function effects: protein loss, potassium loss
   6.   Malignant change




Bowel Polyp syndromes

   1. Peutz-Jehger's
   2. Familial adenomatous polyposis


Pyloric stenosis
Clinical features

      Familial tendency, 20% affected parents
      Especially male children



Pathophysiology of Alkalosis in Pyloric stenosis

   1. Stomach: Loss of gastric acid secretions (rich in protons and chloride)
   2. Pancreas: Reduced pancreatic juice secretion (reduced load in duodenum) -
      Pancreatic juice rich in bicarbonate which is retained
   3. Volume depletion maintains alkalosis by leading to bicarbonate absorption
      over chloride
   4. Kidneys: Increased uptake of bicarbonate at renal tubules (due to loss of
      chloride) to maintain electrochemical neutrality


Volvulus
Volvulus

Malrotation of a segment of intestine about its own mesenteric axis

Results in

   1. Partial / complete obstruction of lumen + proximal dilation
   2. Compromise of blood flow leading to ischaemia
   3. Infarction from venous congestion



Pre-disposing factors

   1. Anatomy - long narrow-based sigmoid mesentry prone to twisting
   2. High residue diet
   3. Chronic constipation

Areas affected

   1. Small bowel
   2. Caecum
   3. Sigmoid colon (75%)

Management

   1. History
   2. Examination
   3. Investigations
         o AXR - dilated loops of bowel extending diagonally
            o
            ABG - acidosis, lactate
   4. Treatment
         o Conservative: if no features of ischaemia (80% will resolve)
         o Sigmoidoscopy - diagnostic and therapeutic
         o Flatus tube insertion (can be left for 2-3 days)
         o Laparotomy for decompression (untwisting) with excision of
            redundant sigmoid colon (sigmoid colectomy + primary anastamosis)


Haematology
Disseminated intravascular
coagulopathy (DIC)
Cytokine-mediated disease

Causes

   1.    Tissue injury - burns, trauma, fat embolus
   2.    Infections
   3.    Vascular/perfusion disorders: vasculitis, PAN, ARDS
   4.    Haematological disorders
   5.    Neoplasms
   6.    Systemic: pancreatitis, burns, embolism, hypothermia

Recognition intraoperatively / clinically

   1.    Understand risk factors
   2.    Bleeding / oozing which is difficult to control
   3.    Hypotension
   4.    Tachycardia
   5.    Low oxygen saturations
   6.    Bleeding from ususual areas - venepuncture, cannulation sites, epistaxis,
         haematuria from uncomplicated bladder catheterisation

Diagnosis

   1.    Low platelets
   2.    Low plasma fibrinogen (used up in coagulating)
   3.    Increased PT and APTT (clotting factors used up)
   4.    Increased FDPs / D-dimers (more degradation products)
   5.    Haemolysed fragmented red cells


Lymphoma
Lymphoma
      Malignant tumour of lymphoid tissue

Presentation

   1. Primary Tumour
         o Painless progressive lymph node enlargement
         o SVC obstruction
   2. Systemic effects
         o Malaise
         o Weight loss
         o Splenomegaly / Hepatomegaly
   3. Metastatic features
         o Bone pain
   4. Paraneoplastic syndromes

Classification

                    Hodgkin's Lymphoma                 Non-Hodgkin's Lymphoma
                       Dorothy Reed-Sternberg
                                                                B-cell tumour
                          cells
Cellular                                                        Monomorphic
                       Polymorphic


                           Bimodal age distribution            Peak 50 years (older)
                           Step-by-step spread                 Random spread
Clinical features
                           80% curable                         Poor prognosis

                    Rye Classification

                       1.   Lymphocyte predominant
Classification
                       2.   Nodular sclerosing
(grading)
                       3.   Mixed cellularity
                       4.   Lymphocyte deplete



                    Ann Arbor System

                           A - Absence of systemic symptoms (wt loss, fever)
                           B - Presence
Staging

                           Stage I: one node
                           Stage II: many nodes (same side)
                           Stage III: Both sides of diaphragm
                           Stage IV: Metastatic spread

                       1. History
Diagnosis
                       2. Examination
                        3. Imaging
                               o CXR
                               o IVU - retroperitoneal nodes compress renal
                                  calyces
                               o CT scan
                        4. Tissue diagnosis
                               o Node excision biospy [Splenectomy previously]


Treatment          Radiotherapy + Chemotherapy


Platelets
Platelets

   1. Derived from megakaryocytes
   2. Functions - adhesion, activation, secretion, aggregation
   3. Release: serotonin, adrenalin, ADP, prostaglandins, thromboxanes



Classification of platelet abnormalities

   1. Disorders of number
         o Thrombocytopenia: bleeding - petechiae, ecchymosis, epistaxis
         o Thrombocythaemia: splenomegaly, haemorrhages, thrombotic episodes
   2. Disorders of function
         o Thrombasthenia


Polycythaemia
Classification

   1. Primary
         o Polycythaemia rubra vera: myeloproliferative disease
   2. Secondary
         o Appropriate EPO excess: hypoxia (emphysema, lung diseases), CCF,
             high altitude
         o Inappropriate EPO excess: renal neoplasms
   3. Relative
         o Apparent polycythaemia because of a reduction in plasma volume


AIDS
Human Immunodeficiency Virus

      RNA retrovirus
      requires reverse transcriptase
      Core protein RNA surrounded by glycoprotein envelope
      Infects cells via CD4 receptors (T-helper)




Neoplastic associations

   1. Lymphoma
         o B-cell NHL / T-cell NHL
         o Aggressive form HL
   2. Kaposi's sarcoma
   3. Skin cancer
         o SCP
         o SCC: anus, vulva
   4. Laryngeal neoplasm
         o SCC larynx

Surgical Relevance

      Bacterial enteritis
      Haemorrhage from KS of GIT
      CMV infection leading to megacolon
      GIT lymphoma


 Hypersensitivity reactions

Type         Immediate / Anaphylactic
I             IgE linkage by an antigen leads to release of mast cell contents
              (histamine, 5HT, heparin, PAF, chemokines)
             Minutes
             Eg. eczema, asthma, allergic rhinitis

Type         Cytotoxic
II            Antibody in serum reacts against tissue components resulting in cell
              death from (1) complement action (2) destruction by killer T-cells (3)
              phagocytosis by macrophages
             Minutes-hours
             Eg. transfusion reactions

Type         Immune complex
III           Immune complex formed that activates complement/platelets - cause
               damage by formation of membrane attack complex (MAC) and
               enzyme release from inflammatory cells
              Hours
              Eg.

Type          Delayed
IV             Mediated by sensitised T-lymphocytes
              Days TB, organ transplants



Immunodeficiency
Body's defences

   1. Innate
          o    Skin
          o    Complement
          o
   2. Interactive
          o Cellular
          o Antibody

Immunisation

   1. Active or Passive
         o Active: pre-formed antibodies (HBsAG, immunocompromised patients
             with shingles, botulism, rabies)
         o Passive: transplacental transfer of IgG protects for first 6 months of life
   2. Natural or artificial
         o Natural: following infection
         o Following vaccination

Different types of vaccinations

   1. Live attenuated: - BCG, sabine for polio, MMR
          o Long lasting immunity
          o Potentially dangerous in immunocompromised patients
   2. Killed organisms: typhoid, cholera, pertussis
          o Smaller immune response: usually boosters are required
   3. Toxoid
          o Not the infection but the effects of toxin that result from infection (eg.
              Tetanus toxoid)
   4. Other bacterial constiuents
          o Surface polysaccharides and proteins

Immunoglobulin

   1. Antigen binding sites (light and heavy chain regions)
     2.   Complement activation parts
     3.   Immune adherence
     4.   Heavy chains determine the class of immunoglobulin - GAMDE
     5.   Light chains are kappa- or lambda- irrespective of the immunoglobulin class

         IgG: most important Monomeric: activates complement, binds to killer t-cells
         IgA: present in secretions of BIT, respiratory tract; Dimer with J-chain
         IgM: Largest - Pentamer
         IgE: Monomer bound to mast cells

Immunodeficiency

     1. Acquired
           o Drugs
           o Infections
     2. Congenital
1.      Bruton's X-linked gammopathy
2.      T-cells: Thymic atrophy in Di-George anomaly
3.      SCID
4.      Lymphoma




Infections in Compromised patients

     1. Congenital
           o Bruton type hypogammaglobulinaemia
           o Di George type
           o Combined
           o Deficiency of neutrophil function in chronic granulomatous disease
     2. Acquired
           o Infections: AIDS
           o Drugs: steroids, cytotoxics
           o Diabetes (also because glucose as a culture medium in urine and on
               skin)
           o Instrumentation - lines, catheters, ventilation
           o Prosthesis: hips, knees, heart valves




Sources of infection

     1. Endogenous
           o Colonic bacteria
           o GIT
           o Skin
     2. Exogenous
           o Foamites
           o   Other people
           o   Transplanted tissues
           o   "Opportunist"


 Metabolic / Endocrine
Adrenal pathology
Layers of the adrenal gland

Glomerulosa: Salt: aldosterone

Fasiculata: Sugar: glucocorticoids

Reticularis: Sex hormones - dehydroepiandrosterone / oestradiol

Medulla - catecholamines



Mechanism of action of Steroid hormones

   1. Intracellular receptor binding
   2. Results in gene stimulation

Hormone release (RAS)

   1. Glucocorticoids
         o ACTH
   2. Aldosterone
         o Renin (stimulated by low BP, sympathetics); Low Na; Hyperkalaemia
         o Renin - activates Angiotensinogen
         o Angiotensinogen activates angiotensin I
         o Angiotensin I to Angiotensi II by ACE (in the lungs)
         o Stimulates aldosterone release




Cushing's syndrome / Disease

      Hypercortisolaemia (Cf disease - hypercortisolaemia secondary to pituitary
       adenoma secreting ACTH)

Causes:

   1. ACTH - pituitary tumours, ectopic ACTH from oat cell, carcinoid, pancreas
   2. Steroid secreting adenoma
   3. iatrogenic steroids
       Cushingoid features (1) Head and neck - moon face from fat and oedema, acne
        from testosterone effects, male pattern baldness, hisutism in ladies (2) Chest
        and trunk - buffalo hump from fat distribution, central obesity, striae,
        ecchymoses from capillary fragility (4) Limbs - muscle wasting from cortisol
        effect
       Endocrine effects

   1.   Fat / salt handling
   2.   Diabetes
   3.   Secondary osteoporosis
   4.   Amenorrhoea from suppression



Hyperaldosteronism

   1. Primary: Conn's syndrome - autonomic secretion from adenoma
         o Salt/water retention leads to hypertension
         o Hypernatraemia / hypokalaemia / metabolic alkalosis (in association
             with hypokalaemia)
         o Rx: Spironalactone (Aldosterone antagonist)
   2. Secondary: RAS activation following dehydration



Adrenocortical insufficiency / Addison's disease

       Bilateral destruction of the layers of the adrenal gland

   1.   Infection - TB, fungi, Friederichsen-Waterhouse (meningococcal emboli)
   2.   Deposition - haemochromatosis, amyloid, malignancy
   3.   Auto-immune
   4.   Drugs - adrenolytic drugs (ketoconazole), steroid withdrawal
   5.   Iatrogenic- Adrenalectomy

       Clinical features

   1. General: Weight loss, malaise
   2. Skin: - Hyperpigmentation due to POMC (pro-opio melano cortin) from
      anterior pituitary with increase in MSH and ACTH
   3. Biochemical: Hyponatraemia, hyperkalaemia, increased ACTH, decreased
      aldosterone and cortisol




Adrenal Medulla
Hormones produced

   1. Catecholamines: produced from tyrosine (tyrosine hydroxylase)> DOPA
      (Dopa decarboxylase)> Norad (Dopamine B-hydroxylase)> Dopamine
      (Phenylethanolamine-N-methyl-transferase)> Adrenaline
   2. From chromaffin cells: Dopamine, somatostatin, substance P, enkephalins

Innervation: Ach from pre-ganglionic sympathetic fibres



Effects of hormones:

   1. Cardiovascular effects
          o Hypertension, tachycardia
   2. Respiratory
   3. GI:
   4. Metabolic
          o Carbohydrate - cause hyperglycaemia (1) stimulates gluconeogenesis
             (2) glycolysis (3) inhibit release or insulin - mediated via alpha-
             receptors
          o Lipids - stimulates lipolysis




Diabetes
Diabetes Mellitus

Due to absolute / relative insulin resistance

[Pancreas]

Diagnosis

   1. History: polyuria, polydipsia, unexplained weight loss
   2. Plus:
         o RPG: >11.1
         o FPG: > 7.0
         o GTT: >11.1 2 hours after 75g oral glucose

Complications

   1. Arterial disease
   2. Renal disease
   3. Skin disease
   4. Anaesthetic complications
   5. Eye disease: cataracts, retinopathy, infections
   6. Bone/Joint disease - septic arthritis, osteomyelitis
   7. Systemic: immune deficiency

Clinical Features

   1. Skin
          o      Necrobiosis lipodica diabeticorum
          o      Leg ulcers
          o      Fat atrophy
          o      Skin infection
   2. Eyes
          o  Diabetic retinopathy
          o  Cataracts
   3. Peripheral vascular
          o Amputations
          o Gangrene
   4. Neurological
          o Charcot's joint
          o Diabetic neuropathy - dorsal column disease
   5. Renal disease
          o Skin pigmentation
          o Hypertension
          o AV fistulae


Hyperparathyroidism
Classification

                                              Serum
                    Causes/sources                         Complications
                                              biochemisty
                                                              Bone disease:
                                                                 pathological
                                                                 fractures
                          85% parathyroid    High calcium
                                                              Psychic effects
                           adenoma
Primary - tumour                                              Abdominal pains
                          15% parathyroid    Low
                                                              Renal effects:
                           hyperplasia        phoshate
                                                                 calculi,
                          1% carcinoma
                                                                 nephrocalcinosis



                                              Low calcium
                          Renal - decreased
Secondary - to
                           metabolism of
hypocalcaemia                                 High
                           vitamin D
                                              phosphate
                          Dietary deficiency
                          Decreased
                          sunlight
                         Pregancy -
                          increased demands

                                              High calcium
Tertiary -
autonomous
                                              Low
adenoma
                                              phosphate


Multiple Endocrine Neoplasia
Type I: pituitary, pancreas, parathyroid (PPP)



Type IIa: parathyroid, thyroid, phaeochromocytoma (PTP)



Type IIb: phaeochromocytoma, thyroid, neuroma (PTN)


Paget's disease of bone
Osteitis Deformans

      D: Second most common metabolic bone disease (first is osteoporosis)
       characterised by excessive / disorganised bone formation and resorption
      I/A: Increasing incidence with age - 3-4% over 40 years, 10% 85+
      S: More common in men than women
      G: More common in the west, less common in east asian countries
      A: Unknown but though to be persistent infection in bone from a virus
       (Measles, mumps, RSV)
      P: Alternating phases of rapid bone resorption/formation
      M: Long bones have thicked shafts/deformities, cysts and stress fractures seen.
       May be areas of localised softening - "osteoporosis circumscripta".
      M: (1) Osteolytic phase - clasts produce excavations which are filled with
       vascular fibrous tissue (2) Mixed lytic-sclerotic phase - blasts lay down woven
       bone which is subsequently resorbed by osteoclasts (3) Quiescent
       osteosclerotic stage - clasts less active, eroded areas filled with brittle woven
       bone
      P

Clinical features

      Usually asymptomatic
      Bone: 15% monostotic, 85% polyostotic
   1. Long bones - become bowed/deformed
   2. Cranium - compression of cranial nerves as pass through foramina (8th -
      leading to deafness), compression of nerve roots (causing pain)
   3. Pathological fractures
   4. Osteosarcoma (1%)

        Cardiac

   1. High output cardiac failure - most common in polyostotic disease (increased
      bone blood flow)

Investigations

        Radiology
        Increased ALP (reflects osteoblastic activity)
        Plasma calcium normal/raised

Treatment

        Control pain
        Suppress bone turnover - bisphosphonates, serum ALP for measuring disease
         progression
        Surgery - pathological fractures, joint replacement, nerve/cord decompression


 Pancreatitis
Acute Pancreatitis

Inflammation of the pancreas



[Functions of the pancreas]



Causes

   1.    Gallstones 45%
   2.    Ethanol 35%
   3.    Trauma
   4.    Steroids
   5.    Mumps, coxsackie
   6.    Autoimmune
   7.    Scorpion venom
   8.    Hypercalcaemia (activates enzymes), hyperlipidaemia
   9.    ERCP
   10.   Drugs (steroids, thiazides)
Pathophysiology

   1. Activation of proteolytic pro-enzymes contained within pancreas
   2. Triggers autodigestion
   3. Results in severe inflammatory reaction
          o Inflammed acinar cells and invading leucocytes produce cytokines (IL-1) and
               TNFalpha
          o Cytokines mediate systemic inflammatory response syndrome (SIRS)
   4. Persistant inflammation leads to "pancreatic pseudocyst"
          o Collection of fluid rich in pancreatic secretions enclosed within a cyst lined
               with granulation tissue (as opposed to epithelium)
          o If < 5cm will resolve spontaneously; if > 5cm may beed surgical intervention
               and drainage
          o Conservative therapy needed for 4-6 weeks to allow cyst wall to mature
          o Surgical treatment: - Radiology-guided percutaneous drainage; endoscopic
               drainage; internal drainage




Clinical presentation

   1. History
           o  severe epigastric pain radiating to back and eased by leaning forwards
           o  Accompanied by nausea and persistent vomiting
   2. Examination
          o tenderness with rigid abdomen and absent bowel sounds
          o Abdominal distension due to ileus
          o bleeding in fascial planes: Grey-Turner's sign (flanks); Cullen's sign (peri-
              umbilical)
   3. Investigations
          o Shock- tachycardia
          o Low pO2
          o High BM etc...
          o High serum amylase (>500U) or serum lipase
          o AXR: "sentinel loop", CXR - exclude perforation




Ranson Criteria

APACHE III score (acute physiology and chronic health evaluation)

Glasgow (Imrie) scoring system

      PaO2 < 8kPa
      Age > 55years
      Neutrophils > 15 x108/l
      Calcium <2.0 mmol/l - saponification
      Raised Urea >16mmol/l
        Enzymes: AST/ALT >600; LDH >600
        Albumin <32g/litre
        Sugar > 11mmol/l

Severe if score 3 or more
Should be managed in HDU setting



Complications

   1.    Pancreatic abscess
   2.    Pancreatic pseudocyst
   3.    Severe destructive pancreatic haemorrhage
   4.    Duodenal obstruction
   5.    Chylous ascites




Chronic Pancreatitis

   1. Chronic inflammatory disease of pancreas
   2. Irreversible glandular destruction
          o Early: may appear "normal"
          o Late: fibrosis and calcification
          o Cysts form within pancreas with duct dilation
   3. May occur as result of recurrent acute pancreatitis

Causes

   1.    Alcohol
   2.    Smoking
   3.    Hereditary
   4.    Hypercalcaemia
   5.    Duct obstruction
             o Strictures
             o Gallstones
             o Cystic fibrosis

Clinical features

        Amylase usually normal
        Interferes with life and leads to opiate abuse
        Loss of exocrine function - malabsorption, steatorrhoea
        Loss of endocrine function - diabetes
        Imaging (CT/MRI-pancreas protocol): demonstrates calcification

Management

   1. Dietary modification - low fat, alcohol abstention
   2. Avoid opiates
   3. Pancreatic enzyme supplements: -
   4. Correct endocrine disturbance


 Pituitary hormone disorders
The pituitary hormone disorders



Hormone        Excess                                                       Deficiency
Growth Hormone Acromegaly

                  Causes

                          GH secreting pituitary adenoma
                          Ectopic GH from pancreas/lung/intestine
                           carcinoma



                  Surgical Associations

                          Osteoporosis
                          Orthodontic procedures
                          Large bowel polyps/carcinoma
                          Gallstones/GB disease
                          Increased incidence of hernias
                          Diabetes mellitus



Sjogren's syndrome
Pathology

   1. Autoimmune disorder - 90% occur in women, average age 50 years
   2. Intermittent or constatn swelling of one or all of hte salivary glands
   3. Diagnosis (at least 2/3)
          o Keratoconjunctivitis sicca (dry eyes)
          o xerostomia (dry mouth)
          o associated connective tissue disorders
   4. If no associated connective tissue disorders are present, this is known as
      primary Sjogren's disease
   5. Pathology:
          o lymphocyte-mediated destruction of the exocrine glands secondary to
              B-cell hyper reactivity and associated loss of suppressor T-cell activity
          o x40 increased risk of developing lymphoma, usually B-cell non-
              Hodgkin's type
           o  Antibodies: anti-salivary Ab, rheumatoid factor, anti-SSA-Ro and anti-
              SSB-La
   6. Investigations
         o Schirmer's tests for xerophthalmia (strip of filter paper inserted into
              each fornix and hyposecretion confirmed by wetting of less than 5mm
              in 5 minutes - normal is 15 mm)
         o Slit-lamp examination of the cornea
         o Lip biopsy for histological examination of the minor salivary glands


Testicular cancer
Classification

   1. Primary 95%
         o Germ cell (seminoma, teratoma)
         o Non-germ cell
   2. Secondary 5%
         o Lymphoma
         o Metastatic (lymphoma, leukaemia, melanoma)

Risk factors

   1.   Testicular maldescent (1/20 have malignancy)
   2.   Mumps orchitis
   3.   Trauma
   4.   Maternal oestrogen exposure
   5.   Genetics: 12p chromosomal abnormalities



Royal Marsden Hospital Staging system

       I: Confined to testis
       II: Confined to testis but with persistently raised tumour markers
       III: Infradiaphragmatic node involvement
       IV: both sides of diaphragm
       V: Extralymphatic metastases




Management

   1. History
         o Risk factors - trauma, mumps, maledescent, maternal oestrogen
         o Genetics
   2. Examination
         o Regional nodes - drain to para-aortic
   3. Investigations
         o Blood tests: Tumour marker assay, aFP, LDH, HhcG
         o CXR: Pulmonary metastases
         o USS scrotum
         o Chest / abdominal CT - detection of metastases in retroperitoneum and
              mediastinum
   4. Treatment
         o Scrotal exploration: if diagnosis is uncertain; scrotum can be explored
              and possible tumour biopsy
         o Orchidectomy: if there is any doubt
         o Radiotherapy (seminomas highly radiosensitive)
         o Chemotherapy for advanced stage disease


Thyroid / Goitre
Functional unit of the thyroid




Follicle

      Epithelial cells surround central colloid
      Follicular cells lie adjacent to a vein / capillary
      Produces 80% T4 and 20% T3 (rest of T3 is converted in the peripheries)
      T3 is the active form

Parafollicular cells

      Secrete calcitonin
T3/T4 Physiology

   1. Iodine transported across cell membrane, transfered to colloid, then linked to
      tyrosine
   2. Tyrosine iodinated to mono-iodotyrosine + di-iodotyrosine (bound to
      thyroglobulin)
   3. Coupling results in T3 and T4
   4. T3/T4 + thyroglobulin transported into cell as colloid droplets; then separated
      from TG
   5. T3/T4 released into circulation (bound to albumin, thyroxine binding globulin
      [different from thyroglobulin])




Goitre

        Any enlargement of the thyroid gland
        Seen as midline swelling that moves with swallowing

Single                Multinodular         Diffuse
        Adenoma         Adenoma              1. Painful
      Carcinoma            Carcinoma                o De Quervain's thyroiditis
                                                2. Painless
                                                      o Iodine deficiency
                                                      o Goitrogens - in foodstuffs
                                                      o Thyroiditis
                                                      o Infiltration - sarcoid
                                                      o Dyshormogenesis



Hyperthyroidism

   1. Immune
         o Graves
         o Hashimoto's
   2. "Physiological"
         o Pregnancy
   3. Drugs
         o Thyroxine replacement (in block and replace)
         o Amiodarone
   4. Carcinoma
         o hyperactive nodule
         o Follicular carcinoma
         o Papillary carcinoma
         o Struma ovarii - thyroid tissue in dermoid cyst
         o Basophil adenoma of pituitary

Thyroid disease workup

   1.
   2. Radioactive scanning (not a very useful test really is it?!)
         o Hot nodule: 95% benign
         o Cold nodule: 80% benign


Microbiology
Amoebiasis
Diseases caused by amoebae

      GIT: Amoebic dysentry, inflammatory polyps, liver abscess
      Skin: anal/vulval ulceration
      CNS: abcesses, meningoencephalitis (Naegleria fowleri)


Antimicrobials
Tazocin: contains piperacillin + B-lactamase inhibitor tazobactam
For pseudomonas cover
Similar spectrum as imipenem/meropenem



Tigecyclin


Bacteria
Classification

       Shape

   1.   Cocci
   2.   Bacilli
   3.   Vibrios - comma shaped organisms
   4.   Spirilla - spiral rods that don't bend
   5.   Spirochetes - spiral rods that bend in the middle
   6.   Actinomycetes - complex branching dos

       Gram Stain

   1. Positive
   2. Negative

       Ziehl-Neelsen stain: for mycobacterium (which possess a waxy coat and don't
        stain)



Pathological Effects

       Proliferate in tissues
       Resist phagocytosis in somce cases
       Secrete exotoxins and release endotoxins
       Attach to cell membranes and damage them


Anaerobic organisms
Classification

       Obligate anaerobes: grow only in absence of oxygen
       Facultative anaerobe: grows in presence or absence of oxygen

        Gram positive Gram Negative
Cocci Clostridium
Bacilli               Bacteroides
                      Fusobacterium


Actinomycosis
Actinomyces organsisms

      Actinomyces israelii - Gram positive filamentous bacetrium
      Commensal of alimentary tract - tonsils, mouth, upper intestine
      Pathogenic when

   1. Immunocompromised - Drugs, diabetes, steroids, AIDS, neoplasia
   2. Mucosal damage - appendicits, perforation, radiotherapy

Diseases

      Infection of neck, thorax, abdomen
      May mimic malignancy



Diagnosis

      Index of suspicion
      Microscopy - "sulphur granules" / tissue histology


 Clostridia
Characteristics of Clostridia :Positive - Spore - Endotoxic - Anaerobic -
Saphrophtyic

   1. Gram positive
   2. Spore forming
         o Subterminal
         o Drumstick
   3. Exotoxin producing
         o Botulinum - causes spastic paralysis with release of botulinum toxin
             (inhibits acetylcholine release) opisthotonus + involvement of
             respiratory muscles
         o Perfringens (welchii) - proteolytic enzyme lecithinase causes gas
             production - gas gangrene (with characteristic smell)
         o Tetani - produces tetanospasmin (inhibits inhibitory processes of motor
             neurones) causing muscular spasm and paralysis; prevented by tetanus
             toxoid immunisation / human anti-tetanus immunoglobulin
         o Difficile - exotoxin produces cell membrane damage to epithelial cells
             leading to pseudomembranous colitis
   4. Anaerobic
         o Oxygen forms free radicals
         o Cells have little/no defence
   5. Saphrophytes - requires soil to protect them from dehydration


Helicobacter pylori
Classification

       Curved/spiral gram negative bacterium
       Present in gastric mucus in crypts and on the surface of gastric acid and
        duodenal biopsies
       More prevalent in the antrum than in the body of the stomach
       Microaerophilic, flourishing best in low oxygen and high CO2 / H2
        atmospheres

Disease associations

   1.   Gastric erosion and gastric ulcer
   2.   Duodenal erosion and ulceration
   3.   Chronic gastritis
   4.   Gastric lymphoma of mucosa-associated lymphoid tissue
   5.   Gastric adenocarcinoma

Diagnostic tests

   1. Gastric biopsy
         o Culture
         o Histology with modified Giemsa statin for helicobacter-like organisms
         o Urease test on a biopsy specimen in agar gel with indicator system
         o Urease test on biopsy specimen using detector strip that incorporates
             the indicator system
   2. Urease breath test
                             13     14
         o Radio-labelled C or C given by mouth and measuring the amount of
             radioactivity in the breath as a consequence of splitting of Urea
   3. Serum test
         o For H.pylori antibodies


 Mycobacteria
Classification

       Alcohol acid-fast bacilli
       Would be gram positive if Gram stain could penetrate walls



   1. Typical mycobacteria
         o Mycobacterium Tuberculosis
         o Mycobacterium leprae
   2. Atypical mycobacteria
      Resistant to standard antituberculosis drugs, different culture characteristics
      from MTB (eg pigment production, different growth rate in culture)
         o Mycobacterium avium intracellulare: - infection in AIDS
         o Mycobacterium marinum: - swimming pool granuloma
         o Mycobacterium ulcerans: - causes Buruli ulcer
         o Mycobacterium kansasii: - chronic pulmonary infection

Mycobacterium Tuberculosis

Clinical classification

   1. Primary TB: usually symptomless
         o Lung - primary focus is "Ghon focus" with involvement of lymphatics
              and enlargement of hilar lymph nodes. Ghon focus forms at periphery
              of lung in mid-zone on a chest X-ray
         o Tonsils with cervical lymph node involvement "scrofula"
         o Terminal ileum with mesenteric lymph node involvement "tabes
              mesenterica"
   2. Post-primary TB: cough, fever, weight loss. Spread of infection limited by
      severe local response with cavitation and fibrosis
         o Haematogenous spread: miliary TB in many organs, TB meningitis,
              bone/joint TB, renal TB
         o Spread by rupture into air spaces - TB bronchopneumonia


Staphyloccoci and streptococci
Species        Staphylococci                      Streptococci
Main type          Gram positive cocci arranged      Gram positive cocci
                    in clusters (hence "cocci")          arranged in chains or
                   Form colonies - golden, white        pairs
                    colonies                          Transparent colonies
                   Type by bacteriophage             Typed by API strips
                    (bacterium-specific virus)

Classification By presence of absence of coagulase By type of haemolysis on culture
                                                   on blood-agar plate
                  1. Coagulase positive
                         o Staph aureus                1. Partial haemolysis -
                  2. Coagulase negative                   alpha: strep pneumoniae
                         o Staph epidermidis           2. Complete haemolysis -
                         o Staph saprophyticus            Beta: strep pyogenes
                                                          (causes erysipelas/nec
                                                          fasc)
                                                       3. No haemolysis - Gamma:
                                                          enterococci
                                                           By Lancefield group antigens

                                                                 Group A: Strep pyogenes
                                                                 Group B: none (strep
                                                                  agalactiae)
                                                                 Group C: none (strep
                                                                  equisimilis)
                                                                 Group D: enterococcus
                                                                  faecalis
                                                                 Group F: Viridans group



Treponemal diseases
Motile spiral organisms (spirochetes) - flex in middle as they move



Classification

   1. Veneral
         o T.pallidum pallidum - syphilis
   2. Non veneral
         o T.pallidum pertenue - yaws
         o T.pallidum endemicum - bejel
         o T.pallidum carateum - pinta


Culture Media
Solid - Isolation of separate colonies (esp when mixed growths)

Liquid - grow some sensitive organisms using enrichment broths


Exotoxins and Endotoxins
           Exotoxin                                 Endotoxin
           Immunogenic protein secreted from        Lipopolysaccharide derived from the
Definition a living organism (that is heat labile   cell wall of an organism that is not
           and has a specific molecular target      usually immunogenic (is heat stable)
                                                    Cause
                    Enzymes: vibrio
                    Neurotoxins: clostridium               Cytokine formation
Examples            Disrupters of membranes:               Fibrin degredation
                     clostridium                            Activation of clotting cascade
                                                            Kinin formation
                                                            Nitric oxide formation
                                                       Prostaglanding formation
                                                       Complement activation
                                                       Platelet activating factor
                                                        formation
                                                       Leucotriene formation

                    Cholera (vibrio)                  Shock
                    Dipheri                           DIC
                    Gas gangrene: cl.perfringens      Hypotension
Diseases
                    Food poisioning                   Organ failure
                    Botulism                          Pyrexia




Fungi
Fungi are larger than bacteria
Have nuclei with multiple chromosomes and cytoplasm containing mitochondria and
ribosomes
Can reproduce sexually by meiosis
Pathological by (1) infection - superficial, subcutaneous, systemic (2) toxin
production (3) hypersensitivity reactions
Predisposition - Immunocompromise; premature, AIDS, indwelling lines



Classification

      Yeasts
      Filamentous fungi
      Dimorphic fungi



Candida

      Commonest human pathogen is candida albicans sp
      Affects mucous membranes (vagina, cervix, oropharynx), skin, respiratory
       tract, urinary tract
      Risk:

   1. Diabetes
   2. Immunocompromised
         1. Acquired: drugs (steroids, cytotoxics), AIDS, leukaemia
         2. Congenital
        Diagnosis: (1) Microscopy (2) Culture (3) Antigen detection in urine, blood
         (4) Antibody detection (5) Increased arabinitol - a metabolite of candida in
         serum



Pathogenic fungi

        Cryptococcus neoformans
        Malassezia furfur
        Dematophytes
        Toulosis glabrata
        Aspergillus fumigatus
        Microsporum audouinii
        Pneumocystis carinii


 Viruses
Classification

   1. RNA / DNA
          o RNA: Influenzae, HIV, Rubella
          o DNA: HSV, HPV, HIV
   2. Size: parvovirus, picornavirus
   3. Shape: rhabdovirus, small round virus
   4. Tissue - Adeno (glandular), enterovirus

Neoplastic viruses

1. Directly cause neoplasia
          o EBV: Burkitt's lymphoma (8:14), Nasopharyngeal carcinoma
          o HPV: Cervical carcinoma
2. Predispose to neoplasia
          o Chronic hepatitis: hepatocellular carcinoma
          o AIDS: Lymphoma

3.Musculoskeletal
Osteoarthritis
Degenerative joint disease



Causes

   1. Metabolic joint disease
         o Abnormal lipid handling
            o
            Inherited hypercholesterolaemia and related disroders
            o
            Gout
            o
            Pyrophosphate arthropathies
            o
            Diabetes mellitus
   2. Inflammatory joint disease
          o Infective arthritis - gonococcus, salmonella
          o Non-infective: RA, ank spond, psoriatic
   3. Trauma
          o Joint trauma
          o Repetitive strain
   4. Congenital
          o Achondroplasia




Joints affected

        Hip
        Knee
        Shoulder
        Elbow
        TMJ


Osteomyelitis
Osteomyelitis

Inflammation of bone and bone marrow



Causes

   1. Infective
          o Bacteria - staph aureus, ecoli, streptococci, bowel organisms
          o Viruses
          o Fungi
          o Parasites
   2. Non-infective
          o Radiotherapy




Pathological Sequlae

   1. Suppuration with pus in marrow cavity
   2. Sequestrum: dead bone within periosteum that forms inner part of infected
      bone marrow
   3. Involucrum: reaction of periosteum to form new bone that 'envelops' the
      infected site and contains it
   4. Cloacae "sewer": holes in the involucrum through which pus formed in the
      medulla discharges
   5. Sinus: drainage tract from the cloaca to skin
   6. Septicaemia and pyaemia



Late complications

   1.    Amyloidosis
   2.    Malignant change in the sinus - Marjolin's ulcer
   3.    Septicaemia and pyaemia
   4.    Suppurative arthritis




Pathological Fractures
Pathological Fracture

Fracture through previously abnormal bone



Causes

   1.    Osteoporosis
   2.    Metabolic bone disease
   3.    Radiotherapy
   4.    Primary neoplasia
   5.    Paget's disease of bone


Oncology
Apoptosis
Apoptosis

        Programmed cell death
        Energy dependent process, requires specific protein synthesis (p53.Chr17).
         Does not stimulate inflammatory response
        May be physiological or pathological

Physiological                                  Pathological
      Embryology: finger development,              Following cellular damage:
       development gut lumens                        virus, bacteria, RT, drugs
      Thymus: physiological degeneration           Reaction to normal cell cycle
      Endometrial cycle                            In response to tumours
      Menopause




Apoptosis Genes

Promotors           Un promotors
p53 - Chromosome 17 bcl-2
c-myc
BrCA1/2


Carcinogenesis
Carcinogenesis

   1. Remote carcinogen
          o Precursor of carcinogenic agent
   2. Proximate carcinogen
          o Metabolite of remote carcinogen with potential
          o Needs further modification into ultimate
   3. Ultimate carcinogen
          o DNA interaction causes cancer

B-naphthylamine - ingested and absorbed from small bowel, metabolised in liver,
made soluble, excreted by kidney and causes cancer in bladder (after being
gluconurated by bladder epithelium).



Initiator: Alters DNA making it abnormal

Promoter: Leads to altered gene expression (eg hormones)


Cell cycle
Cell tissue classification in terms of ability to regenerate

   1. Labile cells: - Bone marrow, testis, small, bowel (all contain stem cells)
   2. Stable cells: liver, kidney, adrenal, bone
   3. Permanent cells: CNS, skeletal muscle
       G1: Gap phase.
        Variation by lenght of cell's cycle is determined mostly by the lenght of time it
        spends in G1
        Retinoblastoma gene (Rb1) serves as restriction point (for cyclin dependent
        kinase)
        p53 gene produces p53 protein which arrests cell cycle by increasing
        concentration of p31 (cyclin-dependent kinase inhibitor)
        G0 - resting phase
       S: Synthesis phase
        Cell wall, cytoplasm, nuclear proteins made
       G2: Second gap phase
       M: Mitosis



Oncogene

Abberant genes which were previously important in the regulation of the cell cycle



Mechanisms of oncogenesis

   1. Amplification: increases copies of proto-oncogene result in excessive activity
   2. Point mutation: conversion of proto-oncogene into permanently active gene
   3. Incorporation of new promoter: viruses can insert promotor sequences into
      human DNA
   4. Incorpation of enhancers
   5. Translocation of chromosomal material



Mechanisms of action

   1.   Signal transduction pathway effects
   2.   Regulation of nuclear activity
   3.   Growth factors / receptors
   4.   Inhibition of apoptosis



Promotor                                 Inhibitor
Cyclin                                   p53, p27, p21
Cyclin-dependent Kinases                 Rb - restriction
Epidermal growth factor (EGF) / c-erbB-2 BrCA1, BrCA2
PDGF / c-sis                             APC gene
Insulin-like growth factor-1             Wilm's tumour gene
Transforming growth factor B
                                         Interferon-alpha
                                              Prostaglandin E2
                                              Heparin


Chromosomal abnormalities
Normal chromosomal arrangement

       Normal cells: 44 autosomes + 2 sex chromosomes
       0,23,46, 46(n) - normal number of chromosomes in a cell (eg. RBC has none, striated
        muscle 46n)

0                       23                     46                    46n

Erythrocytes            Haploid cells          Normal cells          Tetraploid - before
                        Gonads - sperm,                              division
                        oocytes                                      Multinucleated cells -
                                                                     osteoclasts,
                                                                     syncitiotrophoblasts,
                                                                     muscle cells


Classification Chromosome abnormalities



            Autosome               Sex chromosome

Structure         Translocations - one part onto another
                  Delections - loss of material

Number            Monosomy - loss of one pair of chromosomes
                       1. Turners XO
                  Trisomy - increase to three of one type of chromosom
                       1. Downs Chromosome 23
                       2. Edwards
                       3. Patau
                  Polyploidy - extra sets of entire chromosomes
                       1. Kleinfelter's

Location
Autosomal dominant            Autosomal recessive           X-linked

      Single copy of gene          Both copies of               Disease due to
       responsible for               abnormal gene must            abnormality on X-
       disease                       be present                    chromosome

      FAP                          Cystic fibrosis (7q          Haemophilia A/B
      APKD                          CFTR)                        G6PD
      Achondroplasia               Alpha-1-Anti-trypsin         Fragile X
      Marfan's (fibrillin)          deficiency                   Red-green colour
      Spherocytosis                                               blindness
       (spectrin)                                                 Red-green colour
                                                                   blindess (1/10)




Down's syndrome
Chromosomal abnormality

Three copies of chromosome 21

   1. Non-disjunction (esp mothers > 40 years)
         o Non-disjunction of a gamete: one progeny gets TWO chromosomes
             (and the other one gets none) which is then fertilised by a normal
             gamete from the other parent enduing up with THREE copies of
             chromosomes.
         o Usually maternally derived extra copy
   2. Translocation (rare)
         o Parents phenotypically normal but have a balanced translocation
         o Chr 23 +Chr 23 / Ab Cr 22; get's one Chr 23 from mum, one Chr23
             from dad and AbCr22+Down's shit
   3. Mosaism
         o 1/100 cases
         o Normal ovum
         o Non-disjunction after the blastocysts starts to develop




Associations

      Congenital heart defects: PDA, VSD, ASD
      Neoplasia
      Increased incidence glue ear


Kleinfelter's syndrome
XXY - Extra X chromosome

Phenotypic features

        Tall stature
        Small genitalia
        Gynaecomastia (same risk of breast cancer as women)
        Female distribution of hair


Turner's syndrome
XO

Associations

        Coarctation of the aorta
        Webbing of neck
        Wide carrying angle
        Shield chest
        Short stature
        Streak ovaries
        No learning difficulties



NB - normal X chromosome is inactivated by lyonisation. Lyonisation is incomplete
inactivation of X chromosomes.


Dysplasia
Dysplasia

        A degree of failure of maturation of a tissue associated with a tendency to
         aneuploidy and pleomorphism but without the capacity to spread
        An abnormality of development of tissue in which fibrous or other non-specialised
         tissue is present instead of the expected tissue




Causes of dysplasia

     1. Chemicals
            o Smoking
            o Alcohol (larynx, stomach)
     2. Viruses
            o HPV 16,18
     3. Specific chronic inflammation
            o UC
    4. Non-specific chronic inflammation
          o Cystitis leading to bladder carcinoma




Sites of Dysplasia

    1. Respiratory tract
          o Bronchus: in relation to smoking
    2. Gastrointestinal tract
          o Oesophagus - in relation to candidiasis or other chronic irritation with
               results in squamous dysplasia
          o Oesophagus: Barrett's oesophagus - glandular dysplasia
          o Stomach: H.pylori infection
          o Large bowel: ulcerative colitis
    3. Urogenital tract
          o Cervix: CIN

Histological featurs

    1.   Multilayering (of a columnar or cuboidal) epithelium
    2.   Mitotic figures - increased in number, presence of abnormal mitoses
    3.   Pleomorphism
    4.   Hyperchromatism
    5.   Loss of cell-cell adhesion resulting in shedding
    6.   No invasion of basement membrane

‹


Effects of tumours

Cachexia (IL1, TNFa related)

Primary / Local effects

        Pressure effects
        Obstruction/compression
        Haemorrhage
        Infection leading to septicaemia
        Infarction (torsion of polyp)
        Pathological fractures
        Biochemical/hormonal abnormalities

Metastatic effects
Paraneoplastic manifestations

      Syndrome in which there are symptoms and signs caused by a neoplasm other
       than by its direct involvement, metastatic spread

Classification

   1. Endocrine
         o Cushing's syndrome
         o ADH secretion
         o PTHrP
         o Carcinoid syndrome
   2. Haematological
         o Polycythaemia
         o DIC
         o Thrombocythaemia
   3. Dermatological
         o Acanthosis nigricans
         o Dermatomyositis
         o Erythema gyratum repens
         o Erythroderma
         o Clubbing
   4. Neuromuscular
         o Polymyositis
         o Myopathies - Myasthenia, GBS


Hormones & Neoplasia
Relationships with neoplasia

   1. Hormones cause neoplasms
         o Tamoxifen: endometrial adenocarcinoma (partial oestrogen agonist)
         o Oestrogen causes endometrial cancer
         o Methylated steroid hormones cause liver neoplasms
   2. Hormones treat neoplasms
         o Tamoxifen + breast
         o Progestogens + endometrial cancer
         o Antiandrogens + prostate cancer
         o Thyroid cancer with thyroxine
   3. Neoplasms secrete hormones
         o Eutopic (from tumour tissues that normally secrete hormones) -
            adrenal, ovarian, thyroid, pituitary, kidney
         o Ectopic (from tissues that do not normally secrete hormoneS) -
            carcinoid, neuroendocrine tumours
   4. Neoplasms may be hormone dependent
         o Papillary carcinoma of thyroid
         o Breast ca may be dependent on oestrogen
Nomenclature
Carcinoma

Malignant tumour of epithelial cells

   1.   Squamous epithelium - SCC, melanoma, hepatocellular carcinoma
   2.   Glandular epithelium - Adenocarcinoma
   3.   Transitional epithelium (urinary tract)
   4.   Undifferentiated (anaplastic)




Sarcoma

Malignant tumour composed of connective tissue cells (mesenchyme)

   1.   Ligament - chondrosarcoma
   2.   Fat - liposarcoma
   3.   Bone - osteosarcoma
   4.   Fibrous tissue - fibrosarcoma

Typed by tissue that forms the greatest volumne of the tumour



Blastoma

Characteristically childhood tumours

Eg. Retinoblastoma, nephroblastom (Wilm's tumour), Neuroblastoma,
Medulloblastoma, Hepatoblastoma



Teratoma

Neoplasm composed of cells with potential to form all three germ layers.
May benign or malignant
99% ovary benign, 99% testicular malignant



Grading

       Well differentiated
       Moderately differentiated
       Poorly differentiated
       Undifferentiated
Examples:

   1. Rye classification of lymphoma
   2. Bloom & Richardson grading system




Staging

Degree of spread

Examples:

   1.   Royal Marsden Testicular cancer
   2.   Ann-Arbor Lymphoma
   3.   Duke's staging of colorectal cancer
   4.   Breast Manchester / Columbia system


Testicular cancer
Classification

   1. Primary 95%
          o Germ cell (seminoma, teratoma)
          o Non-germ cell
   2. Secondary 5%
          o Lymphoma
          o Metastatic (lymphoma, leukaemia, melanoma)

Risk factors

   1.   Testicular maldescent (1/20 have malignancy)
   2.   Mumps orchitis
   3.   Trauma
   4.   Maternal oestrogen exposure
   5.   Genetics: 12p chromosomal abnormalities




Royal Marsden Hospital Staging system

       I: Confined to testis
       II: Confined to testis but with persistently raised tumour markers
       III: Infradiaphragmatic node involvement
       IV: both sides of diaphragm
       V: Extralymphatic metastases
Management

   1. History
          o   Risk factors - trauma, mumps, maledescent, maternal oestrogen
          o   Genetics
   2. Examination
          o Regional nodes - drain to para-aortic
   3. Investigations
          o Blood tests: Tumour marker assay, aFP, LDH, HhcG
          o CXR: Pulmonary metastases
          o USS scrotum
          o Chest / abdominal CT - detection of metastases in retroperitoneum and
              mediastinum
   4. Treatment
          o Scrotal exploration: if diagnosis is uncertain; scrotum can be explored and
              possible tumour biopsy
          o Orchidectomy: if there is any doubt
          o Radiotherapy (seminomas highly radiosensitive)
          o Chemotherapy for advanced stage disease


Radiation
Classification

   1. Electromagnetic
          1. Infra-red
          2. Ultraviolet
          3. X-ray
          4. Gamma-ray
          5. cosmic rays
   2. Particulate
          1. alpha particles (electron)
          2. beta particles(hydrogen nucleus)

Cellular damage mechanisms

      Direct DNA damage (TT dimers, base deletions, cross linkages)
      Indirect damage to proteins, membranes, enzymes (via free radicals - unpaired
       electron)



Rad     Effect
100,000 Death in minutes (nuclear bomb)
10,000 Death within hours from CNS effects
1000    Death in weeks from pancytopenia
100     Nausea & vomiting



Radiation sensitivity is not commensurate with a tissues capacity to regenerate.

Radiosensitive (radidly    Intermediate                   Resistant
growing)
Bone marrow
Gonads
Growing cartilage/bone
Lens of eye (risk from UV)
Bowel
Thyroid
Pituitary
Kidney
Heart
Lung
Liver
Brain
Skin (risk from UV)


Tumour Markers
Tumour Marker

   1. Substance found in circulation (or immunohistochemical marker)
   2. Directly related to presence of neoplasm
   3. Disappears when neoplasm treated, reappears when neoplasm recurs

Not usually stoichiometric - not in direct proportion to tumour bulk



Classification

   1. Hormones: Eutopical / ectopical
         o ACTH
         o hGH (pituitary adenoma)
         o EPO - renal cell carcinoma
         o B-hCG: teratomas, choriocarcinoma
   2. Enzymes
         o Prostatic acic phosphatase (not prostatic specific antigen) - Ca prostate
         o Placental alkaline phosphatase - ca bronchus, pancreas, colon
   3. Oncofetal antigens
         o a-fetoprotein (foetal albumin): germ cell tumours, hepatocellular
            carcinoma
           o     Carcioembryonic antigen (CEA): colorectal

   4.Urological
Renal cell carcinoma
Presenting features

   1. General / primary
         o Weight loss, cachexia
         o Mass in loin
         o New varicocoele on left (as left gonadal vein is longer and thus more
             easily compressed)
   2. Secondary
   3. Paraneoplastic manifestations

Investigations

       Urine dipstick
       FBC, LFTs
       Imaging: USS / CT
       CXR: cannonball pulmonary metastases


Rhabdomyolysis
Rhabdomyolysis

Clinical syndrome caused by release of potentially toxic muscle cell components into
circulation

Triggers

   1. Trauma
           o     Crush injury
           o     Burns
           o     Hypothermia
           o     Reperfusion
   2. Drugs
   3. Congenital

Complications

   1. Renal failure - ischaemic tubular injury
   2. DIC
   3. Compartment syndrome
   4. Electrolyte imbalances - hyperkalaemia, hypocalcaemia, hyperphosphataemia,
      hyperuricaemia
   5. Hypovolaemia
Diagnosis

   1.   Elevated CK (x5 normal)
   2.   Elevated creatinine
   3.   Elevated serum lactate dehydrogenase
   4.   Dark urine + positive urine dipstick

Management

   1.   Adequate hydration
   2.   Diuretics
   3.   Alkalinise urine
   4.   Manage electrolyte disturbances


Epistaxis
The Nose

   1. Bony and cartilaginous framework
   2. Overlied by skin and fibrofatty tissue
   3. Bones:
          o external: nasal bone + frontal process maxilla
          o Internal: nasal, frontal (crista galli), ethmoid, maxillary (palatine
             process), sphenoidal
          o Medial septum: vomer, ethmoid perpendicular plate
   4. Divided into left and right nasal cavities by nasal septum (perpendicular plate
      of ethmoid bone)
   5. Epithelium: respiratory (ciliated columnar)
   6. Conchae/meatus/turbinates
          o Superior meatus: opening of posterior ethmoidal air cells
          o Middle meatus: frontal, maxillary, anterior and middle ethmoidal
          o Inferior meatus: nasolacrimal duct from eye
Blood Supply to the nose

(All derived from external carotid artery)
   1.   Anterior ethmoidal
   2.   Posterior ethmoidal
   3.   Sphenopalatine
   4.   Greater palatine
   5.   External branches of labial

Epistaxis

Management

   1. Resuscitate
   2. History
         o Duration of bleeding
         o Preceding injuries: nose picking, nasal trauma, infection, neoplasia
         o Medications - anticoagulants, antiplatelet agents
         o PMHx of bleeding diathesis, family history
         o Perpetuating factors - hypertension
   3. Assess bleeding
         o FBC, U/Es, LFTs, Coag
   4. Examination (personal protection - gown/apron/gloves/visor)
         o Patient should attempt to clear their nose
         o Spray local anaesthetic (with adrenaline as vasoconstrictor)
         o Identify source of bleeding by anterior rhinoscopy with Thudicum's
             speculum
         o Look at kisselbach's plexus (anterior part of septum in Little's area)
       o  If bleeding not visible, may be posterior bleed
5. Emergency Treatment
       o Digital pressure to entire nose + cold compress/ice pack
       o Silver nitrate cautery / electrocautery coagulation of vessel (only one
          side of septum should be cauterised at once; small risk of septal
          perforation)
       o Pack nostril with nasal tampon (Merocel) / ribbon gauze (BIPP) - can
          pack both to increase tamponade effect; complications - sinusitism,
          airway obstruction, inhalation of pack, infection (risk of toxic shock
          syndrome)
       o Foley balloon catheter used for tamponade
6. Surgical treatment
       o Posterior nasal packing (under GA)
       o Submucosal resection which decreases blood flow to mucosa
       o Endoscopic visualisation of sphenopalatine artery and bipolar cautery/
          ligation
       o Arterial ligation
       o Angiogram and embolisation
7. Follow up
       o BP check with GP
       o Further nasal examination to exclude neoplasia

								
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