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GEM > Module 9 Integrative > Flashcards

Module 9 Integrative Flashcards

1
Q

Aciclovir

A

Aciclovir a faulty base.
Mimics the real purine, guanosine
When incorporated into the elongating DNA chain causes “chain termination”, therefore viral DNA unable to be properly synthesised

Only activated in infected cells (requires both human cellular enzymes and viral enzymes thymidine kinase to activate it into active form)
Higher affinity for viral DNA polymerase than cellular enzymes

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2
Q

Aciclovir: Resistance

A

Absence of thymidine kinase – TK- variants
Alteration of thymidine kinase – TK mutants
Altered DNA polymerase

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3
Q

Valaciclovir

A

Valaciclovir - Addition of valine tail to acyclovir to improve half life and oral bioavailability
Means less frequent dosing can be used eg twice a day rather than 5 times per day

Mimics the real purine, guanosine
When incorporated into the elongating DNA chain causes “chain termination”, therefore viral DNA unable to be properly synthesised

Only activated in infected cells (requires both human cellular enzymes and viral enzymes thymidine kinase to activate it into active form)
Higher affinity for viral DNA polymerase than cellular enzymes

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4
Q

Ganciclovir

A

Anti-cytomegalovirus drugs: Ganciclovir

Acyclic guanosine analogue
Requires phosphorylation – by the viral enzyme UL97
Ganciclovir triphosphate acts as DNA polymerase inhibitor
Active against all herpesviruses
Poorly absorbed orally – valganciclovir
Toxic eg bone marrow

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5
Q

Cidofovir

A

Anti-cytomegalovirus drugs: Cidofovir

Acyclic phosphonate nucleotide analogue
Non-viral dependent phosphorylation
Inhibits viral DNA polymerase
Broader spectrum – potentially all DNA viruses
Given by intravenous infusion
Toxicity - nephrotoxic

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6
Q

Foscarnet

A

Anti-cytomegalovirus drugs: Foscarnet

Pyrophosphate analogue
Viral DNA polymerase inhibitor
Poor oral availability
Nephrotoxic

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7
Q

Ribavirin

A

Interferes with mRNA processing
Broad spectrum of activity in vitro, incl both DNA and RNA viruses
Clinical use mostly disappointing except
Severe RSV infection
Lassa fever

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8
Q

Amantadine

A

Inhibits uncoating of influenza A virus
Effective, BUT:
Poorly tolerated because of CNS stimulation
Resistance rapidly emerges
No longer recommended

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9
Q

Zanamavir

A

Viral release inhibitors
Neuraminidase inhibitor

Work against all known influenza NA
Licensed for treatment of severe infection, or infection in high risk individuals
Resistance to oseltamivir in H5N1 ‘flu has now been reported – H275Y Still uncommon

Neuraminadases found to be effective against avian influenza strains

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10
Q

Disease-causing human retroviruses - which is worse

A

HIV-1
HIV-2

HIV-1 more potent, transmissible, is found worldwide

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11
Q

HIV Routes of transmission

A

Sexual
Homosexual – highest risk - receptive anal sex
Heterosexual - now account for roughly same number of current infections

Mother-to-baby
Antenatally: transplacental
Perinatally: in birth canal, exposure to maternal blood
Postnatally: in breast milk

Blood or blood products
Transfusion contaminated blood and blood products
IVDU
Needle-stick injury

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12
Q

HIV lifetime presentation

A

Initial increase in viral load, followed by decrease -> Seroconversion illness:
Flu like symptoms
Lymphadenopathy
Rash

As viral load increases over time:
Opportunistic infections:
- Pneumocystis pneumonia
- Oral/oesophageal candidiasis
- Herpes infection/shingles
- Cryptococcus
AIDS related cancers
- Kaposis sarcoma, cervical cancer
Wasting

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13
Q

Elite controllers HIV

A

An elite controller is a person living with HIV who is able to maintain undetectable viral loads for at least 12 months despite not having started antiretroviral therapy (ART)
Elite controllers are rare: ~ 0.5% of those infected
T cell-mediated immune responses different from other patients

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14
Q

AIDS CD4+ threshold

A

<200

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15
Q

HIV life cycle

A

HIV attachment
Reverse transcription of RNA to DNA
HIV integration
Transcription and translation
Viral release and proteases

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16
Q

HIV attachment - proteins involved

A

HIV binds to white cells including lymphocytes and macrophages which express CD4 on their surfaces. Gp120 binds to CD4 and co-recptors –CCR5 or CXCR4

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17
Q

PEPSE, PREP for HIV

A

PEPSE
Post exposure prophylaxis after Sexual exposure
Must be started within 72 hours of unsafe sex
4 weeks treatment

PREP
Pre-exposure prophylaxis
86% effective
Truvada (tenofovir/emtricitabine) once a day
Either on-demand or continuous
Requires monitoring

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18
Q

Common drug interactions with antivirals

A

Via enzyme induction of cytochrome p450 – which effects metabolism of many drugs and can cause reduction and elevation of drug levels
Eg :
Decreased Rifampicin
Increased Midazolam

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19
Q

Expected CD4 Counts for OI in HIV

A

No cut-off Kaposi’s sarcoma, Pulmonary TB, Herpes Zoster, Bact. pneumonia, Non Hodgkin’s Lymphoma

<250/ul Pneumocystis pneumonia, Oesophageal Candida, HSV, PML

<100/ul Cerebral toxoplasmosis, Cryptococcosis, Miliary TB

<50/ul CMV retinitis, Atypical mycobacteriosis

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20
Q

PCP (pneumocystis jirovecii) presentation diagnosis xray treatment; if not treated

A

History
Dyspnoea on exertion
Dry cough
Sub febrile temperature, malaise

Diagnosis
Induced sputum (Sens 50-90%)
Broncho-alveolar lavage (Sens 90%)
PCR/ Immunofluorescence/Silver stain

Xray
CXR- perihilar haze, interstitial infiltrates, sparing apices,

Treatment
Co-trimoxazole (high dose)
Pentamidine
Clindamycin and primaquine
Steroids

If not treated -> pnueuomothorax

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21
Q

TB - presentation diagnosis xray treatment; if not treated

A

History
SOB, dry cough, haemoptysis
Weight loss, night sweats, lymphadenopathy
Headache, eye symptoms, fits, focal neurology
Diagnosis
CD4 any
BAL, Induced sputum, Biopsy, CSF
Smear, PCR, T-spot test (past exposure)
CT imaging
Treatment
Quadruple therapy +/- steroids

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22
Q

Cryptosporidium

A

Protozoan parasite
Faeco-oral route transmission, contaminated water
Sub acute profuse, non bloody diarrhoea affects small intestine
Malabsorption
HAART

Paromomycin
Azithromycin
Nitazoxanide

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23
Q

Isosporiasis Microsporidiosis

A

Parasites

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24
Q

HIV Neurological Conditions

A

Presentation Main Causes

Space occupying lesions Toxoplasmosis, primary CNS
lymphoma, PML, TB, cryptococcus, NHL, syphilitic gummae

Encephalitis HIV, varicella zoster virus, herpes simplex virus, syphilis

Meningitis HIV seroconversion, cryptococcus, TB, syphilis, bacteria (strep pneumoniae)

Spastic paraparesis HIV vacuolar myelopathy, transverse myelitis – VZV/HSV/HTLV-1/toxo/syphilis

Polyradiculitis CMV, NHL

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25
Q

Cerebral toxoplasmosis

A

Toxoplasma gondii - cat poo parasite
Most common cause mass lesion
CD4 <200- reactivation
Confusion/headache/hemiparesis/fits/fever

Ring enhancing lesions- cortex/grey matter

Sulphadiazine, pyrimethamine, folic acid
Clindamycin 2nd line
Septrin prophylaxis

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26
Q

Cryptococcal Meningitis

A

Cryptococcus neoformans- encapsulated yeast
CD4<100
Sub acute meningitis, headache, fever
Raised CSF pressure, positive serum CRAG
Scan normal or Cryptococcomas - basal ganglia
Daily LP- to reduce pressure, IV amphotericin B, flucytosine
Can also cause lung infection

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27
Q

Progressive Multifocal Leucoencephalopathy

A

Demyelinating disease
JC Virus
Advanced HIV
Sub acute/chronic
Personality change/aphasia/hemiparesis/
White matter changes- parieto- occipital, no mass effect

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28
Q

CMV Disease

A

Seroprevalence of 50-70%
Human herpes virus
CD4 <100
Retinitis
Colitis
Pneumonitis
Encephalitis
Ganciclovir +/- Foscarnet
HAART

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29
Q

X-linked (inherited) agammaglobulinemia also called Bruton’s disease/Bruton’s agammaglobulinemia

A

X-linked (inherited) agammaglobulinemia also called Bruton’s disease/Bruton’s agammaglobulinemia, related to a dysfunctional tyrosine kinase, rare, 1:200,000 people, caused by an inability to produce antibodies due to lack of maturation between pre-B-cell and formation of a B-cell.

All classes of immunoglobulins depleted.

Recurrent infections that may be evidenced in neonate.

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30
Q

Hyper IgM syndrome

A

Lack of T-helper cell mediated isotype class switching, hence predominantly produce IgM.

Often X-linked, autosomal recessive.

Characterized by normal or elevated serum IgM levels and decreased levels or absence of other serum immunoglobulins, resulting in susceptibility to bacterial infections.

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31
Q

Common variable immune deficiency (CVID)

A

Characterized by a low level of antibody production, hence susceptibility to bacterial infections.
Low circulatory IgG and IgA, diagnosed as hypogammaglobulineamia, arises from a number of genetic causes.
Relatively rare, affecting ≈1:25,000.

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32
Q

DiGeorge syndrome

A

Developmental, arising from a microdeletion on the long arm of chromosome 22.
Affects facial regions and the thymus, can result in a thymic hypoplasia.
Deficiency in T-cell production and maturation, vulnerable to viral and fungal infections.

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33
Q

Acquired Immunodeficiency Syndrome (AIDS)

A

Caused by human immunodeficiency virus (HIV), HIV-1 and HIV-2. HIV-1 is more virulent and the cause of most AIDS.
Spread by exchange of bodily fluids, via sexual intercourse and blood products such as infected needles or blood (transfusions), and vertical transmission (mother to offspring).
HIV displays cellular tropism via binding of HIV gp120 to CD4 receptors (present on T-cells, DC, Mθ). Of these, CD4+ T cells are the major source of HIV throughout infection and can lead to their depletion.

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34
Q

Severe combined immune deficiency (SCID)

A

Inherited stem cell defect that results in loss of B-cells or T-cells or both.
Typically presents in first year of life with persistent infections of all types (bacterial, viral, fungal, protozoan eg pneumocystis) and diarrhoea and faltering growth.
Generally fatal if untreated without a bone marrow transplant – ‘life in a bubble’.

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35
Q

Kostmann’s syndrome

A

(severe congenital neutropenia (SCN)), lack of production of mature neutrophil within bone marrow, results in life-threatening bacterial infections in infancy. Treatment with G-CSF.

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36
Q

cyclical neutropenia

A

(cyclical reductions in neutrophil count), rare (~1:1x10^6), such as germline mutation in neutrophil elastase, patients vulnerable to recurrent infections.

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37
Q

Chronic granulomatous disease (CGD),

A

lack of neutrophil phagocytotic activity, patients with persistent bacterial and fungal infections.

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38
Q

Complement deficits

A

Regulatory components eg. C1q inhibitor deficiency results in acquired angioedema.
Complement proteins: eg. immune complex disease (unable to remove used up immune complexes) which can cause vascular damage; MAC complex loss results in bacterial infection.

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39
Q

urticaria

A

Erythematous papules and plaques
Prominent on trunk and extremities
Perivascular inflammatory infiltrates involving neutrophils, lymphocytes and eosinophils
Can result from an exposure to food, drugs, temperature, pressure and pollens

Microscopic features include:
Superficial dermal oedema
Dilated blood vessels with perivascular inflammatory cells
Normal epidermis (no spongiosis or hyperplasia)

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40
Q

erythema multiforme

A

Self-limited hypersensitivity to infections, drugs like penicillin, malignancy

Clinical features: formation of bull’s eyes (hallmark)
Rash tends to be symmetrical

Types: erythema multiform minor (less severe) and erythema multiform major (severe)
Leads to intense itching or burning sensation

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41
Q

eczema

A

Group of diseases: red, itchy (pruritic) skin with tiny blisters (vesicles). Scaly, cracking, bleeding. It could be acute or chronic

Failure of the skin barrier: water lost (dry), influx of allergens: hypersensitivity and inflammation (lymphocytic)

Different distribution suggests causes
Swelling or cracking in the epidermis: spongiosis
Persistent scratching of blisters can lead to skin thickening
Redness – dilated blood vessels

Thickened skin from prolonged rubbing/itching: (hyperkeratosis and acanthosis)
Chronic inflammation in the dermis: oedema and fibrosis
Long rete ridges

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42
Q

psoriasis

A

Chronic dermatitis
Excessive growth of skin cells
Neutrophilic
Red raised plaques covered by thick white scale which bleeds on removal
Epidermis: Rapid rate of epidermal cell renewal. Thin with parakeratosis
Dermis: oedema and numerous dilated capillaries
Long rete ridges

Pink plaques, itching and intense burning, silvery scales and sometimes arthritis
“Oil slick” nail discolouration with nail pitting
Histologically: diminished granular layer, elongation of the Rete ridges

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43
Q

lichen planus

A

Chronic condition

Mainly affect mucus membrane and extremities
Purple, polygonal, planar, pruritic papules and plaques

Abnormal T cell mediated immune reaction against body’s own tissue

Skin lesions are small, flat topped and itching (common)
Can involve the skin, genitals and oral cavity
Patients may experience nail pitting
Severe cases can lead to scarring

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44
Q

Skin infection agents

A

Bacterial: superficial (epidermal), deep (epidermis, dermis and hypodermis)
Viral:
Direct: Pox virus (molluscum), Herpes simplex (oral herpes), varicella-zoster (chicken pox and shingles). Human papilloma virus (HPV): warts and verrucae (papillary epidermal growth)
Indirect: measles, rubella
Fungal: Superficial (athlete’s foot, ringworm), deep (rare) or systemic (immunocompromised: aspergillus)
Mycobacteria: TB, Leprosy
Protozoa: Leishmania
Parasites: scabies, schistosomiasis

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45
Q

Impetigo

A

Staph/strep
Sub corneal bullae +/- neutrophils
Burst and spread: yellow crusting
Scratching encourages spreading
Highly contagious, children

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46
Q

Cellulitis

A

Strep pyogenes/staph
Superficial dermis, spreading factor
Risk factors: weak immune system, lymph edema, eczema, previous episode
Can lead to necrotising fasciitis (mixed bacteria)

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47
Q

Acne

A

over production of sebum. infected follicle blocked with keratin plug. Can be triggered/worsened by hormonal changes

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48
Q

Boil

A

infection in a hair follicle

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49
Q

actinic keratosis

A

Premalignant dysplastic lesion in upper epidermis

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50
Q

carcinoma in situ

A

Premalignant dysplastic lesion in full thickness epidermis

51
Q

Basal cell carcinoma

A

Most common: 75-80% of skin cancer
Less common in dark skinned people
Linked to total cumulative sun exposure
Common on head and neck, chest and back, forearms and hands
Diagnosed by biopsy, removed and monitored for recurrence. Curable

Nodular - Smooth translucent nodule with telangiectatic vessels under surface / Pigmented with pearly appearance
Can also be flat, scaly erythematous plaque with vessels and nodular borders mimicking other dermatological conditions
Extends wide and deep, central depression and ulceration

52
Q

Squamous cell carcinoma

A

10-20% of skin cancer
Linked to total sun exposure and occupational exposure (arsenic/coal)
Men x2 prevalence than women

Malignancy of upper epidermal layers

Intraepidermal (years) or Invasive (breach of BM and metastases to regional LNs) Metastases 0.5-16%
Invasion can be from intraepidermal or other pre-malignant lesion e.g actinic keratosis
Curable. Diagnose by biopsy, remove and monitor recurrence
5yr survival with metastases: 25%

Red, scaly, slightly elevated with irregular border
Ulcerates with raised red border and crusts (chronic) (no BVs or rolled border)
Common on nose, forehead, ear, lip and hand (exposed areas, lighter skin), unexposed areas (darker skin)

53
Q

hyper- or hypo- pigmentation

A

Hyperpigmentation: excess melanin. Causes include melasma, post-inflammatory, sun damage, medications like antibiotics
Hypopigmentation: loss of melanin activity. Causes include vitiligo (auto-immune disorder against melanocytes), albinism (genetic condition), tinea versicolor (fungal)

54
Q

Nevocellular nevi:

A

Proliferation of melanocytes in the epidermis and dermis
Tan-deep brown, Uniformally pigmented papules with well defined borders

55
Q

Junctional nevi:

A

Nests of rounded melanocytes at E:D junction. Flat or slightly raised.

56
Q

Compound nevi:

A

Grow into dermis as nests/cords
More elevated. Can have different shapes

57
Q

Dermal nevi:

A

Situated primarily within the dermis. Disappearance of nests in epidermis
More elevated, pinkish brown growth. Can vary in shape with well defined borders

58
Q

Dysplastic Nevi

A

Atypical groups of melanocytes at epidermal-dermal junction: pleiomorphism, mitoses

59
Q

Seborrheic keratosis

A

Affects people of middle age (>40 years)
Round, flat, velvety plaques or patches
Growth are waxy and attempt to pick the off can cause bleeding.
Number of growth increases with age
Could be hereditary
Exposure to direct sunlight may influence development of seborrheic keratosis

60
Q

Melanoma and types

A

Originate in the melanocyte
Aggressive, rapidly progressive, metastatic
Arise from pre-existing or new nevi
Uneven surface, irregular borders, slightly raised, black/brown colour
Most common on areas exposed intermittently (back, legs) and in indoor workers

Superficial spreading (most common)
Nodular: aggressive - vertical dermal invasion
Lentigo malignant melanoma: more prevalent in older individuals - atypical basal melanocytes
Thin malignant melanoma - clumps of atypical melanocytes and microinvasion of dermis

61
Q

Kaposi sarcoma

A

Kaposi sarcoma - endothelial cells of dermal blood vessels. Several places at once

62
Q

Histiocytosis X

A

Langerhans cell histiocytosis

63
Q

Merkel cell carcinoma

A

Merkel cell carcinoma-neuroendocrine

64
Q

Haemopoiesis location embryo to adult

A

Yolk sac, then liver, then
In adults, haemopoiesis, the production of blood cells, takes place in the red marrow of long bones such as vertebrae, ribs, sternum, proximal ends of femur as well as tibia

65
Q

Bone marrow (BM) niche supports growth of BM stem cells

A

Various BM residential cell types such as macrophages, fibroblasts, fat cells interact with stem cells either via growth factor release or direct contact. Extracellular matrix also plays an important role in supporting BM stem cells

Major growth factors and cytokines involved in haemopoiesis:
Stem cell factor, interleukin-3, Granulocyte Monocyte-colony stimulating factor (GM-CSF), Thrombopoietin, Erythropoietin

66
Q

Blasts – differentiating progenitor cells - (6)

A

Myeloid (aka GEMM) progenitors:
Myeloblast – Granulocytic (Neutrophilic, eosinophilic and basophilic) lineage
Erythroblast – Erythroid lineage
Monoblast – Monocytic lineage
Megakaryblast - Megakaryocytic lineage

Lymphoid progenitor:
B / T lymphocytes
Natural Killers

67
Q

Proliferation and differentiation in blood cell development

A

Haemopoietic stem cells and lineage committed progenitors actively proliferate to maintain the pool.

Proliferation of early stage immature blood cells continues till cells have nearly completed their maturation pathway

68
Q

Erythropoietin (EPO) and Hypoxia-inducible factor (HIF)

A

EPO is one of the major erythropoiesis stimulation growth factors. When there are insufficient circulating RBC hypoxia occurs in local tissue microenvironment

HIF produced by interstitial fibroblasts in kidneys is sensitive to oxygen and undergoes continuous degradation. In hypoxia, HIF degradation is suppressed.

HIF acts as a transcription factor for EPO production

EPO stimulates erythropoiesis in BM. Increase in RBCs will restore oxygen tension, HIF degradation resumes. This acts as a negative feedback loop for haemopoiesis

69
Q

anisocytosis

A

RBC size variation

70
Q

B12 folate deficiency leads to what microscopic features?

A

Macrocytic, megaloblastic anaemia
Not only RBCs affected, WBCs also show hypersegmentation

71
Q

Megaloblastic anaemia

A

Erythroblast maturation affected
Many megaloblasts undergo apoptosis
Red blood cell synthesis decreases due to apoptosis of defective megaloblasts
Decrease in number of RBC in peripheral blood

Red cell derived from surviving megaloblast mature with larger nuclei affecting cell sizes - macrocytosis
Often presents with oval macrocytes
Non-oval macrocytes found in liver diseases

Hyper-segmented neutrophils also found but not exclusively in megaloblastic anaemia

72
Q

Clinical presentation of megaloblastic anaemia

A

Gradual progression of symptoms

Mild jaundice due to increased apoptosis of RBC precursors in bone marrow
Pallor, glossitis (Beefy tongue)

Peripheral neuropathy (Affecting mainly lower than upper limbs) – Ataxia, paraesthesia, muscle weakness

Laboratory findings
FBC marked macrocytosis, mild anaemia
Blood smear – oval macrocytes, neutrophil hyper-segmentation
Bone marrow (if performed in some cases) – megaloblastic changes

Diagnostic testing – serum B12 folate levels

73
Q

Absorption of dietary B12 and folate

A

Folate absorbed as Methyl TetraHydroFolate (THF) in duodenum and jejunum

B12 forms a complex with intrinsic factor (IF) produced by gastric parietal cells

IFB12 complex binds to IF receptors in ileum
B12 transported by Transcobalamin (TC) out from gut lumen

Both MetTHF and B12 carried away by portal vein

74
Q

Pernicious anaemia

A

Autoantibodies against intrinsic factor (IF)
Neutralising IF or compete with B12 for binding sites

Autoantibodies against gastric parietal cells
Decrease in IF level due to less parietal cells producing IF

Both affects B12 absorption leading to megaloblastic anaemia

75
Q

Chromosomes for globins

A

Genes encoded by loci on Chromosome 11 and 16

76
Q

Alpha thalassaemia

A

4 copies of ‘a’ gene

Lose one - carrier, asymptomatic

Lose two - a Thal minor - asymptomatic, mild microcytic

Lose three - Hb H Disease/intermediate - symptomatic, haemolytic and microcytic anaemia, splenomegaly

Lose 4 - fatal in utero - foetus depends on 2a2y Hb; Foetal development impossible without alpha chain

77
Q

beta thalassaemia

A

More than 200 variants / mutations (as opposed to locus deletion in a-thalassaemia)

Beta thalassaemia trait (minor)
Asymptomatic or mild microcytic hypochromic anaemia

Beta thalassaemia intermediate
Variable severity, mild to moderate anaemia, possibility of extramedullary haemopoiesis

Beta thalassaemia major (Cooley’s anaemia) Severe anaemia, transfusion dependent (leading to iron overload), extramedullary haemopoiesis

78
Q

b-thalassaemia major clinical signs

A

Bone marrow compensation – extramedullary erythropoiesis

Maxilla, bossed skull with prominent frontal and parietal bones
bone marrow expansion into cortical bone ‘hair on end’ X ray

79
Q

Sickle cell signs

A

Crescent shaped red blood cells lose flexibility when passing through narrow channels such as the branches of small blood vessels
These shapes cause red blood cells to interlock each other occluding the micro-circulation

Leading to clinical symptoms:
crisis pain
hands or feet (particularly in young children)
ribs and sternum, spine
pelvis
tummy
legs and arms

vision loss

Infections

Transient ischaemic attack

80
Q

Normocytic normochromic anaemia

A

Red blood cell synthesis defects
Bone marrow failure
Myelodysplastic syndrome
Myelofibrosis (may also see pear-shaped RBCs / poikilocytes when cells squeeze through fibrotic marrow space when released from bone marrow)
Chemo- / radio-therapy

Chronic blood loss – internal bleeding. Plasma volume restored by anti-diuretic feedback. Continuous loss of normal RBCs

81
Q

Haemolytic anaemia

A

Intrinsic RBC defects
Unstable Hb
HbC, HbE
Hereditary membrane structural defects
Hereditary elliptocytosis,spherocytosis
Enzymes deficiency
Some enzymes responsible for membrane integrity and redox balance
e.g. Glucose-6-phosphate dehydrogenase

Antibody (Ab) binding to RBC
Ab against own antigens (auto-antibodies)
Warm or cold reacting autoantibodies e.g. cold agglutinins – autoimmune haemolytic anaemia
Ab against RBC membrane modified by drugs

82
Q

Other causes of haemolytic anaemia

A

Mechanical / Physical insults
March haemoglobinuria - Continuous excessive impacts on soles. Used to be military-associated but now also sports

Thermal – burns

Artificial heart valves, arterial grafts

Coagulation defects
thrombosis, Disseminated Intravascular coagulation

Infections
Malarial parasite (red cell lysis when parasites erupt from RBCs)

Toxin from bacteria

83
Q

Leukaemia definition

A

Leukaemia is a malignant disease of blood forming organs
Malignancies of immature haematopoietic cells that are present in the blood and bone marrow
- increased number of circulating leucocytes is usually seen

84
Q

Diagnosis techniques for leukaemia

A

bone marrow aspirate

Immunophenotyping
Fluorescent-labelled antibodies identify the proteins expressed by the leukaemic cells
Identifies the lineage (myeloid or lymphoid)
Demonstrates that the leukemic cells are abnormal and clonal

Cytogenetics
Missing or extra chromosomes
Structural abnormalities
Abnormal karyotype (number/appearance of chromosomes)

Molecular tests
Screen the leukaemic cells for specific abnormalities using PCR

85
Q

Acute Leukaemias - examples, Characterised by, pathophys, symptons

A

Acute Myeloid Leukaemia (AML)
Acute Lymphoblastic Leukaemia (ALL)

Characterised by
increased immature cells (blasts) in marrow
short survival (weeks to months) if untreated

A myeloid or lymphoid precursor becomes malignant, resulting in
uncontrolled proliferation
limited potential for progeny to differentiate
resistance to programmed cell death (apoptosis)

Leukaemic cells proliferate so much that production of healthy blood cells is compromised resulting in bone marrow failure
Anaemia – tiredness, fatigue, pallor
Thrombocytopenia – bleeding, bruising
Neutropenia - infections

86
Q

Acute Myeloid Leukaemia (AML) def, RF, Clinical Features, diagnosis, treatment

A

A malignancy of an early myeloid cell
80% acute leukaemias in adults are AML

Risk Factors
Age, Male
Pre-existing haematological disorders (myelodysplasia, myeloproliferative disorders)
Occupational exposure to benzene, smoking tobacco
Down’s Syndrome
Previous chemo/radio
Environmental factors e.g. exposure to formaldehyde, herbicides
First degree relative with AML

Symptoms for weeks to few months only
Reduced production of red cells leads to anaemia
- Breathlessness, dizzy, fatigued
- Pale skin
Low platelet count
- Bleeding (skin, gums, nose, gut)
Reduced production of mature myeloid cells / weakened immune system
- susceptible to bacterial or fungal infection,
Bone pain especially in arms and legs
Splenomegaly, hepatomegaly, weight loss due to decreased appetite

Diagnosis may be made from blood count and film
Blast cells seen, Auer rods (pathognomy of AML)

Definitive diagnosis made through bone marrow aspiration.
Cytogenic analysis to examine chromosomes of AML cells

Potentially curable if can withstand intensive chemotherapy; Allo-SCT if donor available
Relapse is common
15% in some ‘good risk’ patients, >90% in ‘poor risk’ patients

87
Q

Acute Lymphoblastic Leukaemia (ALL); def, RF, Clinical Features, diagnosis, treatment

A

A malignancy of B or T cell lymphoid precursor

Commonest malignancy of children (80% acute leukaemias in children are ALL)
peak age at diagnosis is 4-5 years old
rare in adults

Risk Factors: Down’s Syndrome

Reduced production of red cells leads to anaemia
- Breathlessness, dizzy, fatigued
- Pale skin
Low platelet count
- Bleeding (skin, gums, nose, gut)
Reduced production of mature myeloid cells / weakened immune system
- susceptible to bacterial or fungal infection,
Bone pain especially in arms and legs
Splenomegaly, hepatomegaly, weight loss due to decreased appetite

Bone pain is very common in children with ALL
limping, refusing to walk
sclerotic or lytic bony lesions on X Ray
Hepatosplenomegaly or lymphadenopathy is common

88
Q

Where can ALL also occur>

A

ALL can also occur in testes, CNS or ovary
These are also ‘sanctuary sites’ where relapse may occur
conventional chemotherapy is not good at eradicating ALL from these sites

89
Q

Chronic Leukaemias; examples, Characterised by

A

Chronic Myeloid Leukaemia (CML)
Chronic Lymphocytic Leukaemia (CLL)

Characterised by
increased numbers of mature cells in the blood but not usually bone marrow failure
potential for prolonged survival (years) even if untreated

90
Q

Chronic Myeloid Leukaemia (CML) def, RF, Clinical Features, diagnosis, treatment

A

malignant proliferation of myeloid cells

A mutation is acquired in a haematopoietic stem cell which results in uncontrolled proliferation of the progeny
Differentiation still occurs i.e. marked increase in mature myeloid cells in blood and BM

Diagnosis
Cytogenetics
95% will be ‘Philadelphia positive’
Molecular testing
BCR-ABL translocation

The Philadelphia chromosome/ BCR-ABL translocation; Fusion of chromosome 9 and 22 leads to formation of the BCR-ABL genes which have a constitutively active tyrosine kinase domain

Development of targeted therapies that specifically inhibit the activity of the abnormal protein produced by the BCR-ABL1 fusion gene
Primary goal of treatment is to reduce the number of leukemic cells in the blood and bone marrow, achieve complete cytogenetic response (CCyR), and prevent disease progression
Tyrosine kinase inhibitors (TKIs) – inhibit the activity of the abnormal protein.
Stem cell transplant (also known as bone marrow transplant)

Staging:
Chronic phase: characterized by the presence of a relatively small number of immature white blood cells (blasts) in the blood and bone marrow. Mild or no symptoms. Prescence of Philadelphia chromosomes is a defining characteristics.

Accelerated phase: intermediate phase between chronic and blast phases. characterized by a higher risk of disease progression and a decreased response to TKIs. Stem cell transplant may be considered.

Blast phase: most advanced/ most aggressive phase. a large number of immature blast cells are present in the blood and bone marrow. Patient experience severe symptoms. Survival rate is significantly reduced. Treatment options are limited as patients may not respond well to TKIs

91
Q

The Philadelphia chromosome

A

Philadelphia chromosome identified in the 1960’s by Peter and David results from reciprocal translocation between chromosome 9 and chromosome 22.
In a normal cell, these chromosomes are separate entities. They become fused in chronic myeloid leukaemia.
Fusion of chromosome 9 and 22 leads to formation of the BCR-ABL genes which have a constitutively active tyrosine kinase domain

92
Q

Chronic Lymphocytic Leukaemia (CLL)

A

A malignancy of mature B cells

Relatively common ( 3000 cases/year in UK )
Increases with age
Majority of patients die of unrelated conditions
Treatment is only required for troublesome symptoms, bulk disease or marrow failure
Reproductive rate of most CLL is less than ordinary blood cells, but defective apoptosis means they don’t die normally

70% are diagnosed as an incidental finding - high lymphocyte count on routine FBC
Lymphadenopathy
Hepatosplenomegaly
Infections
shingles
recurrent bacterial infections

Bone marrow failure if advanced disease

93
Q

Aetiology and mechanisms of lymphomagenesis

A

Highly complex process.
Four main mechanisms recognised:
Stimulation and selection of tumour cells by an antigen
Auto-immune disorders, infections e.g. H. Pylori, HCV, Chlamydia Psittaci
Infection by an oncogenic virus
EBV – Burkitt’s lymphoma, Hodgkin’s disease
Immunodeficiency of the host
Congenital; AIDS; severe iatrogenic immune suppression
Genetics
Family history increases the risk of disease

94
Q

Cell types giving rise to lymphoma

A

Hodgkin and Non-Hodgkin lymphoma
Could be B-cell or T-cell lymphoma
Examples of B- cell lymphoma
a) diffuse large B cell lymphoma (DLBCL) - most common
b) Follicular lymphoma - lymph nodes
c) Mantle cell lymphoma (from mantle zone B cells)
d) Chronic lymphocytic lymphoma (CLL) involves blood and bone marrow - blood and bone
e) Marginal zone lymphoma - associated with chronic inflamm conditions
f) Burkitt’s lymphoma (an aggressive form)
g)Primary central nervous system lymphoma
Examples of T-cell and NK cell lymphoma
a) Peripheral T cell lymphoma (can be aggressive and arise from mature T cells)
b) Cutaneous T cell lymphoma (involves the skin)
c) Anaplastic large cell lymphoma
d) Enteropathy associated T cell lymphoma (affect the GIT)
e) Nature killer cell lymphoma - URTI and those of Asian descent

95
Q

Lymphoma diagnosis

A

First include it in the differential - almost impossible to say any mystery illness is not lymphoma
Blood test, blood chemistry
History of weight loss, fevers, night sweats (B symptoms)
Elevated lactate dehydrogenase in blood tests
CT Scan or examination suggests lymphadenopathy or any enlarged organ, Ultrasound scan
Positron emission tomography
Lymph node biopsy or bone marrow biopsy is vital – no biopsy = no diagnosis
Immunohistochemical diagnosis: biopsy of lymph node or extranodal mass

B-cell markers (CD19, 20, 22, 79a)
T-cell lymphocyte markers (CD2, 3, 5,7)
Reed-Sternberg cells (CD15, 30)

In CNS involvement, lumbar puncture may be performed

96
Q

Hodgkin Lymphoma

A

Two peaks in the age-specific incidence: 15-29 60-79

Weight Loss > 10% in 6 months
Drenching night sweats (enough to change nightclothes / bed linen)
Fevers > 38c
Generalised pruritus

The bulk of the tumour in HD are ‘normal’ white cells reacting to the presence of tumour cells – Reed Sternberg cells
Related to Epstein-Barr virus (EBV) infection - 40%

97
Q

Non-Hodgkin lymphoma

A

Originate from B (more common-85%) or T cells

Risk factors: age, immunodeficiency, exposure to chemicals, genetics

Types: diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (arises in extra nodal sites), Burkitt’s lymphoma (very aggressive), T cell and NK-cell lymphoma (originate from either T cells or NK cells)

98
Q

Sezary’s syndrome

A

Sezary’s cells infiltrate the skin. Symptoms include hair loss, nail pitting.
Slow growing, affecting skin and draining lymph nodes – lymphadenopathy
Malignant T cells in the dermis of skin giving a red rash that becomes plaques in later stages.
Malignant cells can be in blood stream causing abnormal blood count (lymphocytosis) - nuclei resemble
Diagnosis: Biopsies, blood test, molecular testing

99
Q

Low grade lymphoma

A

Slow growing, small cells
An example is Follicular lymphoma
Most common type of low-grade lymphoma
Accounts for 19% of all NHLs
Enlarged and painless lymph nodes and patients may experience the B symptoms (fever night sweat and unintentional weight loss)

Other examples: Small lymphocytic lymphoma / Chronic lymphocytic leukaemia
Same condition
SLL if mainly involves lymph nodes
CLL if mainly in the blood

100
Q

High grade lymphoma

A

Large cells, aggressive growth
Aggressive course, require prompt treatment.
An example is the diffuse Large B cell Lymphoma –40% of NHL in adults. Can occur in lymph node and extra nodal sites
Another example is Burkitt Lymphoma (extremely aggressive).can be endemic or sporadic – 2% of total NHL, but most common NHL in children in UK. Involves jaw, face and abdomen.
Another example is the anaplastic large cell lymphoma: associated with genetic abnormalities
Another example is the Lymphoblastic lymphoma: common in children and adolescents

Rapidly growing lymphadenopathy. Patient may experience B symptoms
Extra lymphatic spread – bone marrow, testes, skin, liver, kidneys, paranasal sinuses, CNS
Generally good response to chemotherapy - curable disease in >50% of cases

101
Q

Burkitt lymphoma (BL) - Endemic

A

Endemic BL – Equatorial Africa (Uganda, Kenya, Nigeria) and Papua New Guinea
Primary affects children and adolescents.
Association to malaria incidence
EBV ( a member of the herpes virus) DNA detectable in malignant B cells
Presents with rapidly growing jaw/facial tumours, abdominal masses, fever, night sweats and weigh loss
Histologically – sheets of small round blue lymphoma cells inspersed with macrophages
Transcription factor for cell proliferation up- regulated (Oncogene c-MYC)

102
Q

Burkitt lymphoma - Sporadic

A

Can occur anywhere and affects individuals of all ages
Less common but it is very aggressive
Characterised by rapid growing tumours and abdominal masses
Patients experience the B symptoms
Same histologically as endemic Burkitt lymphoma
EBV less associated (5-10%)
Transcription factor for cell proliferation up- regulated (Oncogene c-MYC)
Can be cured with high dose chemotherapy in up to 80%

103
Q

Treatment of NHL

A

Low grade Lymphoma
Localised disease - involved field radiotherapy can be tried and may be curative in a minority of cases;
Advanced disease - ‘Watch and wait’ - no survival advantage shown for immediate treatment compared with expectant management in asymptomatic patients
Treatment is palliative, and therapies are usually administered intermittently over a period of several years
The illness will pursue a remitting - recurring course

High grade lymphoma – usually treated with intensive combination chemo-immunotherapy, good chance of cure

104
Q

Lymphoma Staging

A

Non-Hodgkin lymphoma is divided into four stages based on how far the disease has spread.
Stage 1: localised/involvement of a single lymph node
Stage 2: involve 2 or more lymph node regions.
Stage 3: signifies that lymphoma is present on both sides (above and below) the diaghpram
Stage 4: generalised

105
Q

Cystic fibrosis carrier rate

A

1 in 25

106
Q

What is the inheritance pattern of cystic fibrosis?
2 carrier parents?

A

Autosomal recessive
50% carrier
25% unaffected
25% CF

107
Q

What is the cystic fibrosis gene?

A

Cystic fibrosis transmembrane conductance regulator (CFTR)
Member of the ABC (ATP binding cassette) superfamily of transporters

CFTR is a chloride channel found in membranes of cells that line passageways of the lungs, liver, pancreas, intestines, reproductive tract, and skin.

108
Q

Four mutations account for >80% of CF in the UK

A

DF508 (or DF508, F508del) – Deletion of codon 508 for phenylalanine (1st NBD of protein) results in misfolding and the protein being retained in the endoplasmic reticulum

G551D – Mis-sense mutation of codon 551 resulting in aspartate rather than glycine (1st NBD) results in normal trafficking of the protein, but the protein has reduced nucleotide binding and ATPase activity

G542X – Mutation of codon 542 results in a stop codon in this position. No mature full-length protein is produced

621 + 1G>T – mRNA splicing mutation in intron 4, results in
loss of an exon

109
Q

6 classes of CF mutations

A

Protein production mutations (Class 1)
Protein processing mutations (Class 2)
Improper regulation (Class 3)
Improper cl transport (Class 4)
Improper synthesis - splicing defect (Class 5)
Increased degradation (Class 6)

I,II,V,VI - not enough protein
III, IV - not enough function

110
Q

CF modulator treatments

A

Potentiatorsincrease the flow of Cl–through CFTR (e.g. fix theme II i.e. III, IV)

Correctorsincrease the synthesis, processing and/or delivery of CFTR proteins to the cell surface (e.g. fix theme I i.e. I,II,V,VI)

111
Q

Cystic fibrosis affect on fertility

A

Females with CF are generally fertile
Menstrual cycle may be irregular
If good lung function (e.g. over 50%), no liver disease more straightforward
Sometimes fertility treatment required

Males often infertile
Males usually have absent vas deferens
Sperm can be aspirated

112
Q

Common causative agents of lung infections in children and adults with CF

A

Children: staph aureus
Adults: pseudomonas

113
Q

Perinatal signs of CF

A

Echogenic Bowel

114
Q

Presentation of CF at birth

A

10-15% of CF presents with Meconium Ileus
90% of Meconium Ileus will have CF
failure to pass meconium
bile stained vomiting
abdominal distension - peristalsis
echogenic bowel - antenatal US
AXR - distended bowel loops mottled inspissated meconium
Peritoneal calcification - IU perforation
Gastrograffin enema - diagnostic & therapeutic
Acetylcysteine
Surgery - defunctioning ileostomy

115
Q

CF presentation after birth

A

Failure to thrive

116
Q

CF Diagnosis

A

Day 5 heel prick - immunoreactive trypsin levels
Sweat Test - +ve if Cl >60mmol/L, Na >60mmol/L

117
Q

CF - Lung disease Pseudomonas aeruginosa

A

Milestone in clinical course of CF
80% adults chronically infected
Chronic infection associated with serious disease & reduced survival
Initial strains - non-mucoid phenotype
Early aggressive treatment may delay chronic infection
3 week treatment nebulised Colomycin & oral Ciprofloxacin
Parenteral antibiotics - Aminoglycosides, Ceftazidime, Pipericillin, Meropenem, Aztreonam
Indwelling vascular device - “Portacath”
Reduce Cross Infection - segregation

118
Q

DNase in CF

A

Mucolytic

119
Q

CF - GI Tract

A

Pancreatic Insufficiency -> Malabsorption -> Steatorrhea -> FTT

Test for Faecal Elastase

Higher energy expenditure
Calorie requirement 120-150% of recommended daily allowance; high protein & high fat
Pancreatic enzymes - (Creon) enteric coated microspheres
Vitamin supplements - Vit A, D & E
High calorie nutritional supplements
NG feeding
Gastrostomy feeding

120
Q

Distal Intestinal Obstruction Syndrome

A

Distal Intestinal Obstruction Syndrome (Meconium Ileus equivalent)
faecal retention
abdominal pain
Right Iliac fossa mass
Insufficient enzymes

121
Q

CF - Liver disease

A

Hyperviscus bile -> focal fibrosis -> multilobular cirrhosis

122
Q

CF - Renal disease

A

Rare - CFTR expressed in kidney
Renal handling of drugs
Nephrotoxic drugs
Renal stones & Nephrocalcinosis
Pseudo- Barters syndrome - metabolic alkalosis associated with Na & K depletion

123
Q

Refeeding syndrome

A

Previously low electrolytes and/or B1 deficiency
Following reintroduction of food -> glucose increases -> increase in anabolic pathways -> decreases micronutrients even more -> organ failure

124
Q
A

GEM (18 decks)

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