Haematological (lymphatic and bone marrow, inc anaemia) Signs, Causes And Differentials

Question 1

What are the two broad categories of cause of lymphadenopathy?

Answer 1

Inflammation - often accompanied by preceding infection, with fluctuation in size

Malignancy - progressive enlargement of the node

Question 2

What are the most common causes of inflammation of lymph nodes?

Answer 2

Bacterial or viral infection of head and neck
- scalp, ear, tonsils (palatine, lingual, nasopharyngeal), teeth

TB (think of this if from high risk population)

HIV

Question 3

What is a common tonsilar lymphadenopathy presentation?

Answer 3

Pyrexia

Upon examining the oral cavity - inflamed, enlarged tonsils (on the walls bordering the uvula)

Question 4

What is the most common bacterial cause of inflammatory lymphadenopathy?

Answer 4

Streptococcus group A

also staph. A, strep pneumoniae and anaerobes

Question 5

What are the most common viral causes of inflammatory lymphadenopathy?

Answer 5

Adenovirus

Rhinovirus

EBV

Coxsackie virus A and B

Question 6

TB can often lie latent in the lymph nodes, what is typical TB?

Answer 6

TB that is in the chest - lungs (most common)

This can become trapped in the cervical lymph nodes, most often dormant and apyrexial.

Normal presentation: painless swollen lymph nodes

Question 7

What are the two broad categories of malignant lymph nodes?

Answer 7

Lymphoma

Metastatic

Question 8

What are the two categories of lymphoma?

Answer 8

Hodgkin’s lymphoma - bimodal age distribution; younger people (15-30) and older people (>50)

Non-hodgkins lymphoma - any age, more likely older people

(Non-hodgkin’s is any lymphoma discovered after the time of Thomas Hodgkin)

Question 9

What are metastatic lymph nodes like on palpation?

Answer 9

Hard

Painless

Irregular

Sometimes fixed to surrounding tissues

Question 10

Where can mucosal squamous lymphoma originate?

Answer 10

Oral cavity (can be examined in primary care)

Oropharynx (can be examined in primary care)

Larynx (ENT)

Hypopharynx (ENT)

Nasopharyngeal (ENT)

Question 11

What are the most common symptoms of malignant lymphadenopathy?

Answer 11

Neck lump

Unilateral odynophagia (pain on eating)

Hoarseness - progressive for >3 weeks (2 week wait pathway) or fluctuating (non-urgent)

Dysphagia - liquids, solids (2 week wait pathway), (improve on eating - indicates globus sensation)

May have B symptoms:
Fever, night sweats and weight loss

May have cough (mediastinal lymph node spread causes coughing reflex)

Question 12

What are the differentials for a neck lump?

Answer 12

Malignant or inflammatory lymphadenopathy
(Inflammatory are painful normally, malignant are more often painless)

Goitre or thyroid cancer (cancer is rare)

Salivary gland lumps (most often parotid lump)

Lipoma

Question 13

What are the differentials for bilateral hilar lymphadenopathy?

Answer 13

Lymphoma

Sarcoidosis

Disseminated malignancies (metastases)

Glandular fever

TB

Question 14

Which organs metastasise to the cervical lymph nodes?

Answer 14

Thyroid

Breast

Lung

Stomach

Pancreas

Question 15

What is tuberculous lymphadenopathy?

Answer 15

The result of infection of the lymph nodes with TB bacteria.

Most commonly in immunocompromised patients.

Question 16

Which bacteria is most commonly the cause of tuberculous lymphadenopathy?

Answer 16

Mycobacterium tuberculosis in adults.

In the case of atypical bacteria, their pattern of presentation may be different for different age groups.

Question 17

What is the most common presentation of tuberculous lymphadenopathy?

Answer 17

A chronic painless mass in the neck (a cold abscess - no redness, pain or warmth)

The mass progresses to adhering to the overlying skin and may rupture.

In short:
Painless lump

(Not firm, discrete and rubbery like in lymphoma)

Question 18

Which kind of cells are unique to hodgkin’s lymphoma?

Answer 18

Reed Sternberg cells:

Large

Multinucleated/bilobed nuclei

• CD 15 and 30 +ve (unlike CD 20+ve B cells)
• they are seen under light microscopy and have an owl eyes appearance i.e. they look like a PAIR of owls eyes due to their large cell (must be T,B or plasma) and the bilobed nuclei

Question 19

What kind of cells are abnormal in non-Hodgkin’s lymphoma?

Answer 19

Abnormal lymphocytes

Question 20

When grading non-hodgkin’s lymphoma, there are two broad categories: indolent and high-grade, based on histology.

What is an indolent non-Hodgkin lymphoma?

Answer 20

A slow growing tumour.

e.g. follicular lymphoma

Often don’t require treatment immediately since they aren’t symptomatic until later stages.

They respond well to chemotherapy but are RARELY cured.

Question 21

When grading non-hodgkin’s lymphoma, there are two broad categories: indolent and high-grade, based on histology.

What is a high-grade lymphoma?

Answer 21

A fast-growing tumour, frequently symptomatic.

e.g. diffuse large B cell lymphoma and Burkett lymphoma (B = better outcome)

More likely to be totally cured than non-hodgkin’s lymphoma.

Question 22

Are lymphomas normally isolated to the lymph nodes?

Answer 22

No, they commonly involve other components of the reticuloendothelial system:

• spleen
• liver
• bone marrow

This is why a reticuloendothelial examination involves palpation/percussion of the liver and spleen.

Splenomegaly or hepatomegaly can occur in lymphadenopathy.

Question 23

What is a lymphoma?

Answer 23

A malignant tumour that involves lymphocytes.

Characteristically, they are solid tumours involving the lymph nodes.

Lymphoma is closely related to leukaemias (originates in bone marrow) since leukaemia typically also involves circulating lymphocytes

Question 24

In the context of lymphomas, what is extra-nodal involvement?

Answer 24

Extra-nodal involvement is when there is involvement of other organs - skin, brain, bowels, bone etc

Question 25

What are the four histological types of Hodgkin’s lymphoma?

Answer 25

Hodgkin’s lymphoma is a malignancy (most often) of B cells that change in to malignant Reed Sternburg cells.

Types are on a scale of increasing Reed-sternburg cell number, they progress from 1 up to 4:

1. Lymphocyte-predominant type (mostly Lymphocytes, only a few Reed-Sternburg cells)
2. Nodular sclerosis (Bands of collagen where the increasing number of RS cells are held)
3. Mixed cellularity (so many RS cells that they equal the lymphocytes)
4. Lymphocyte depletion (less than 10% of lymphocytes present) - the worst prognosis

Question 26

What is leukaemia?

Answer 26

A malignant neoplastic process involving one of the white blood cell lines - neutrophils, lymphocytes, monocytes etc

Question 27

What are the four main types of leukaemia?

Answer 27

1. Acute Myeloid leukaemia
2. Chronic Myeloid leukaemia
   - neutrophil cell line is affected
3. Acute Lymphocytic leukaemia
4. Chronic Lymphocytic leukaemia
   - lymphocyte cell like is affected

Question 28

What is an acute leukaemia?

Answer 28

Short: Immature cells proliferate in an uncontrolled manner and clog the bone marrow and causing BM failure.

Basically blasting cells have mutated prior to differentiation.

An acute leukaemia is distinguished by increased numbers of immature cells (blast cells) in the serum.

However these are just the spill-over, the vast majority are in the bone marrow, crowding out the normal function of the marrow. This prevents the marrow from producing healthy cells.

Effect: Reduced red blood cell production and reduced platelet production - anaemia and/or thrombocytopenia

Acute Myeloblastic leukaemia - immature neutrophils (AML)

Acute Lymphoblastic leukaemia- immature T/B cells (ALL)

Question 29

What is chronic leukaemia?

Answer 29

Chronic leukaemia - mature cells are seen in high concentration in the serum, however these cells are malignant and abnormal

Chronic myeloid leukaemia or chronic lymphocytic leukaemia

Basically: the myeloid/lymphoid cells have differentiated to mature cells but then have mutated and become cancerous

Question 30

What is purpura?

Answer 30

Non-blanching red spots on the skin.

They caused by small areas (<1cm) of bleeding under the skin.

Question 31

What are echymoses?

Answer 31

Non-blanching red spots on the skin.

They caused by large areas (>1cm) of bleeding under the skin.

Question 32

What are the differentials for purpurin/echymoses rash on an older person?

Answer 32

Often no underlying pathology, generally caused by increasingly fragile skin and blood vessels bleeding with relatively minor trauma.

Bleeding disorders are unlikely to present in older age.

Meningitis (less likely in older people).

Anticoagulants.

Question 33

What are the differentials for purpura/echymoses rash or gum bleeding on a young person?

Answer 33

Thrombotic thrombocytopenic purpura

Haemolytic uraemia syndrome

Infections (like sepsis, especially meningococcal sepsis)

Haematological malignancy (like leukaemia)

Question 34

What is thrombotic thrombocytopenic purpura (TTP)?

Answer 34

In short: Thrombus formation in small vessels, damages the vessels and causes anemia,

TTP is an autoimmune clinical syndrome, a pentad of:

1. Thrombocytopenic purpura (damaged blood vessels bleeding under skin and reduced platelet count)
2. Microangiopathic haemolytic anemia (damaged small vessels fragment and destroy RBC as they pass through them)
3. Neurological symptoms (cerebral microvasculature)
4. Renal disease (AKI In renal microvasculature)
5. Fever

Pathophysiology: Congenital or acquired deficiency of ADAMTS-13 occurs. When ADAMTS-13 enzyme is deficient/inactive Von willebrand factor multimers are not cleaved in to VWF monomers (which participate in normal haemostasis). The large multimers circulate and act as triggers for uncontrolled thrombus formation and fibrin deposition in the microvasculature in areas of high sheer stress.

Question 35

What is haemolytic uraemic syndrome (HUS)?

Answer 35

An autoimmune syndrome consisting of:

1. Microangiopathic haemolytic anaemia (I.e. anaemia)
2. Decreased platelet count
3. AKI

Pathophysiology: Damage to the glomerular capillary bed in the kidney caused by either; e.coli (most commonly), exposure to drugs, bone marrow transplant, pregnancy or defect in regulation/activation of the complement system (can be familial)

Question 36

What are the symptoms and signs of Thrombotic Thrombocytopenic purpura?

Answer 36

TTP symptoms:

Neuro symptoms (headache, palsy, seizure, confusion, coma)

Purpuric rash

Fever

Signs; anemia, low platelets and low eGFR (AKI)

Question 37

What are the signs and symptoms of haemolytic uraemic syndrome?

Answer 37

HUS symptoms:

Diarrhoea (often bloody)

Abdominal pain

Nausea and vomiting

Apyrexial

Signs; anemia, low platelets and low eGFR

Question 38

What are the symptoms and signs of acute leukaemia?

Answer 38

Reminder: Marrow failure means platelets,
white and red cells are affected regardless of myeloid or lymphoid origin

Acute illness, fast onset with rapid deterioration

Marrow failure symptoms:

1. Infection - fever, inflammation and fatigue
2. Spontaneous bleeding; GI/GU (lack of platelets)
3. Anaemia (loss of Hb)

Signs:
Infiltration - hepato/splenomegaly

Question 39

Which signs can differentiate acute Myeloid and Lymphoid leukaemia?

Answer 39

Lymphoblastic leukaemia can have:

1. Lymphadenopathy; superficial or mediastinal
2. Orchidomegaly
   - > Lymph nodes and testicles

Myeloid leukaemia can have:

1. Gum hypertrophy
2. Skin involvement
   - > Mouth and skin

Question 40

What are the signs and symptoms of chronic myeloid leukaemia?

Answer 40

Symptoms:
Weight loss
Fatigue
Fever
Sweats

Possibly: Gout (purine breakdown), bleeding and abdominal discomfort (splenomegaly)

Signs:
Splenomegaly, hepatomegaly, anaemia and bruising
Increased WCC - granulocyte and lymphocytes
Anaemia
Increased urate

Question 41

What are the signs and symptoms of chronic lymphocytic leukaemia?

Answer 41

Symptoms:
Often asymptomatic
If severe - weigh loss, sweats and anorexia

Signs: 
Enlarged, rubbery, painless lymph nodes
Splenomegaly
Hepatomegaly
Increased lymphocyte count
If late stage - marrow infiltration (pancytopenia)

Question 42

What are the two most common form of non-Hodgkin’s lymphoma?

Answer 42

Diffuse large B cell lymphoma is the most common.

The second most common is Follicular non-Hodgkin’s lymphoma.

Question 43

What is Diffuse large B cell lymphoma?

Answer 43

A malignancy of the B cells, that can occur anywhere in the stages of B-cell maturation, causing uncontrolled proliferation and since it is a disease of the immune system it is linked to autoimmune disorders (SLE, Coeliac disease).

This is the most common form of non-Hodgkin’s lymphoma.

Question 44

What are the signs and symptoms of non-Hodgkin’s lymphoma?

I.e. diffuse large B cell lymphoma, follicular lymphoma etc

Answer 44

Symptoms:
Systemic - fever, night sweats and weight loss

Pancytopenia - infection, bleeding and fatigue/Dyspnoea (anemia)

Palpable lymph nodes (superficial lymphadenopathy)

Extranodal disease - Gut MALT lymphoma (dyspepsia and GI symptoms), skin (e.g. erythroderma) and oropharynx lymphoma (sore throat an obstructed breathing)

Signs:
Anemia
Increased LDH (higher means worse prognosis - higher cell turnover)
Marrow/node cell biopsy finds large B cells

Question 45

What is follicular non-Hodgkin’s lymphoma?

Answer 45

A B-cell lymphoma, it is the second most common form of non-Hodgkin’s lymphoma.

It is normally indolent, responds well to treatment but has a natural history of recurrent relapses.

It is considered incurable.

Question 46

What is the most common presentation of T cell non-Hodgkin’s lymphoma?

Answer 46

The most common is in the skin: T-cell lymphoma will present as a patch, and will look like psoriasis or eczema.

T-cell lymphomas are rare.

Question 47

What is multiple myeloma?

Answer 47

In short: The main malignancy of plasma cells.

Myeloma AKA multiple myeloma:
A malignancy arising from plasma cells (transformed B cells), the plasma cells proliferate within the bone marrow and release immunoglobulins which cause dysfunction of organs most common: bones and kidneys.

This causes signs common to all bone marrow malignancies; reduced erythropoiesis and reduced production of platelets.

They may form osteolytic nests in the bone, causing excavations in the bone.

Question 48

What are the symptoms and signs of multiple myeloma?

Answer 48

Multiple myeloma is
Symptoms:
Bone lesions;Back ache, Fractures and Vertebral collapse

Hypercalcaemia; bones, stones, groans and psychic moans

Bone marrow failure;
Anaemia - Dyspnoea, Fatigue and paleness
Recurrent Infection
GI bleeding

Signs:
Hypercalcemia
Normocytic normochromic anaemia
Thrombocytopenia
High ALP
Lytic bone lesions on X-ray 
Rouleaux formation on blood film

Question 49

What are the causes of lymphoma and leukaemia?

Answer 49

The causes are undetermined currently, there are only risk factors.

Question 50

What is sideroblastic anaemia?

Answer 50

HAEM ISSUE: A type of microcytic anaemia which has associated endocrine, lung and heart damage due to iron deposition.

MOA: Porphyrin rings for formation of haem subunit are ineffective, causing failed erythropoiesis. The body increases its iron absorption to respond, and iron overload/deposition occurs.

Caused by x-linked genetic trait or acquired (chemo, anti-TB drugs etc)

Similar to haemochromatosis in effect, but not in the mechanism.

Question 51

What are the thalassemias?

Answer 51

GLOBIN ISSUE: Genetic diseases of haemoglobin production.

MOA: Underproduction of one of the haemoglobin chains (alpha or beta) creates unmatched chains. These unmatched chains precipitate within the RBC, and damage their RBC membrane. This causes haemolysis while the RBCs are still in the marrow. This induces extramedullary haematopoiesis, leading to iron overload and deposition in the liver, heart and endocrine organs.

Types:
Beta minor/trait - carrier, asymptomatic, Mild anaemia
Beta intermedia - moderate anaemia, possible splenomegaly
Beta major - presents in first year (4-6 months), severe anaemia, extramedullary erythropoiesis (characteristic head shape)

Alpha thalassemia: four types (four genes for alpha globin, four possible deletions
Four deleted - death in utero; Barts hydrops retails
Three deleted - moderate anaemia, hepatosplenomegaly, leg ulcers, jaundice (signs of haemolysis)
Two deleted - asymptomatic, carrier

On blood film: varied cell sizes (anisocytosis), oddly shaped cells (poikilocytosis), hypochromic and target cells (bullseye shape).

Question 52

What are the physiological (natural) causes of iron deficiency anaemia?

Answer 52

In adults:

Rapid growth
Menarche, menorrhagia
Pregnancy

In neonates :

Prematurity
Low birth weight
Blood loss in birth

Question 53

What are the disease states of the GI tract that cause iron deficiency anaemia?

Answer 53

Oesophageal varices
Hiatus hernia
Gastric cancer 
H. Pylori ulcers
Gastroduodenal ulcers
Coeliac disease
CRC
IBD
Polyposis coli (premalignant state, FAP)

Question 54

What are the nutritional causes of B12 deficiency anemia?

Answer 54

Vegan diet
Poor diet
Pregnancy

Question 55

What are the malabsorption causes of B12 deficiency anaemia?

Answer 55

Gastric surgery - parietal cells are lost, meaning loss of intrinsic factor

Ileal resection - no cubilin receptors for B12 absorption

Pernicious anaemia - gastritis means loss of intrinsic factor production

Question 56

What is pernicious anaemia?

Answer 56

A form of vitamin B12 deficiency anaemia, caused by atrophic gastritis.

Atrophic gastritis is chronic inflammation of the stomach, caused by H pylori (most commonly), which also causes other digestive problems (malabsorption of B12, iron and proteins - pepsin production loss). This means it can also cause iron deficiency anaemia.

Question 57

What are the commonest cause of macrocytosis?

Answer 57

Alcohol, pregnancy, chemotherapy, HIV drugs, hypothyroidism, myelodysplasia, hypoxia and myeloma

Macrocytosis is not anaemia in itself

NOT folate/B12 deficient anaemias!

Question 58

What are the causes of folate deficiency anaemia?

Answer 58

Nutrition - poor diet, alcohol excess
Jejeunal resection - where folate is absorbed
Autoimmune - coeliac disease
Dialysis
Chronic haemolysis
Physiological - pregnancy or prematurity
Drugs - methotrexate and anticonvulsants (valproate)

Question 59

What are the congenital forms of haemolytic anaemia?

Answer 59

Hereditary spherocytosis (membrane)
Hereditary eliptocytosis
G6PD (enzyme)
Thalassemia alpha and beta (globin)
Sickle cell disease (globin)

On blood film: Clumps of red cells (agglutinate by cold immunoglobulins)

Question 60

What are the acquired forms of haemolytic anaemia?

Answer 60

Autoimmune haemolytic
Microangiopathic 
Drug induced
Infection induced
Toxin induced
Wilson’s disease

Question 61

What is hereditary spherocytosis?

Answer 61

Autosomal dominant haemolytic anaemia caused by an RBC membrane defect, which creates sphere shaped RBCs.
These are more often captured and removed by the spleen due to their shape (haemolysis).
This drastically reduces RBC life span

Sign on blood film: Sphere like, no area of central pallor.

Question 62

What is G6PD?

Answer 62

Glucose-6 phosphate deficiency, an X-linked enzyme deficiency and cause of haemolytic anaemia.
Patients are asymptomatic until TRIGGERED during times of oxidative stress.

MOA: Glucose-6 phosphate protects the RBC from oxidative stress in plasma, so a deficiency means the RBC is at risk of becoming damaged earlier, and will become haemolysed intravascularly. (Unlike spherocytosis where the spleen causes haemolysis)

Signs - pale, jaundiced and dark coloured urine (because of haem escaping through the glomerular filtration unit)
Bite cells on blood film (“a bite taken out of them”)

Question 63

What are the triggers for G6PD?

Answer 63

Drugs (antimalarials, aspirin, chloramphenicol, phenylhydrazine, nalidixic acid, dapsone, nitrofurantoin, vitamin K)

Foods (fava beans and broad beans)

Henna tattoo ink

Question 64

What is sickle cell disease?

Answer 64

An autosomal recessive beta globinopathy(like thalassemias).

If only one of the sickle cell S genes is present, patient has sickle cell trait.

MOA: Beta globin variant occurs due to an amino acid substitution in SS gene pairing, this causes production of an HbS haemoglobin (replacing HbA).

The patient is asymptomatic until triggering (cold, dehydration, infection, hypoxia) occurs, deoxygenation of HbS causes polymerisation of the HbS haemoglobin, causing the RBC to change shape and ‘sickle’.

These sickle cells are fragile, haemolyse easily, and cause microvascular occlusion in the bone marrow, mesentary, CNS, Spleen and kidney - crises.

Types of crisis:
Painful crisis
Chest crisis
Abdominal crisis
Stroke

Vaso-occlusive crisis signs:

1. Splenic destruction occurs before age 2.
2. Dactylitis (hands and feet damage) occurs before age 3.
3. Stroke, seizure or cognitive defects.
4. Avascular necrosis of the femoral head.
5. Acute abdomen.
6. Diffuse bone pain.
7. Chest pain (RBCs blocking alveoli)

Question 65

What is autoimmune haemolytic anaemia? (AIHA)

Answer 65

Haemolytic anemia mediated by autoantibodies, causing extravascular haemolysis and spherocytosis.

Classified by type depending on the optimal temperature range at which antibodies bind to RBCs and cause haemolysis:

Warm AIHA - IgG mediated, >37 degrees binding temp
Cold AIHA - IgM mediated, <4 degrees binding temp

Mostly due to idiopathic causes.
Warm causes = chronic lymphoblastic leukaemia, lymphoma, rheumatoid diseases, drugs and ovarian teratoma
Cold causes = follows infection; mycoplasma, ulcerative colitis and EBV

Question 66

What is the cause of anemia of chronic disease?

Bare in mind: there isn’t any blood loss.

Answer 66

Inflammation causes production of interleukin 6, IL6 stimulates the production of hepcidin, hepcidin reduces iron absorption and also decreases RBC production in the bone marrow.

This results in normochromic, normocytic anemia
- because fewer blood cells are made, less iron is needed. So a microcytic anemia doesn’t occur.

Question 67

Why does iron overload occur in haemolytic anemia?

Answer 67

Release of iron due to increased haemolysis.

Increased release of growth differentiation factor 15 (GDF15), which inhibits hepcidin and causes increased iron absorption.

Question 68

What is pyruvate kinase deficiency?

Answer 68

A form of congenital haemolytic anemia.

Pyruvate kinase normally transfers phosphate to ADP to produce ATP. Without ATP, the red blood cell can’t run its ion pumps. This means the RBC loses its shape (Sputnik cells) due to leaked potassium and loss of water, and undergoes haemolysis.