Buku Medicine

Easy bruising

Quick tip; The majority of cases of easy bruising are constitutional or medication-related

'Easy bruising' can be hugely variable in reporting by patients, therefore a through history is needed to identify nature of the bruising, and any associated significant bleeding history or family history of a bleeding disorder as these will increase the likelihood need for referral to haematology.

Common Causes

Constitutional
Platelet disorder
- Platelet deficiency (ITP, liver disease, consumption from trauma/sepsis)
- Dysfunction due to inherited problem (uncommon and usually mild)
- Acquired dysfunction due to medications (antiplatelets, SSRI antidepressants, anticonvulsants) or systemic disorders (liver failure or renal impairment)
Coagulation disorder
- Anticoagulant medication including DOACs
- Liver disease
- Inherited haemophilia or von Willebrand's disease
Vascular disorder
- Corticosteroids, senile purpura, scurvy
- Inherited disorder (Marfan, Ehlers-danlos, hereditary haemorrhagic telangiectasia)
Autoimmune disorder
- Thyroid disease
Non-accidental injury especially in vulnerable individuals

Workup

Full clinical history including
- History of bruising; frequency, locations, raised/flat, painful
- Bleeding history;
  - Prolonged bleeding after trauma, dental procedures, surgery, childbirth
  - Spontaneous gum bleeding or epistaxis
  - Menorrhagia
- Family history of bleeding disorder
- Medication history (NSAIDS, anti-platelets, SSRI antidepressants, anticonvulsants)
Examination;
- Nature of bruises (petechiae more likely to support thrombocytopenia or vascular problem)
- Lymphadenopathy or hepato-splenomegaly
Investigations;
- Full blood count (FBC) and blood film
- Coagulation screen (PT, APTT and fibrinogen initially)
- Renal, liver and thyroid function
- Urine dipstick

There are no absolutes for referral, but clinically concerning history or examination (especially features in bold), or abnormal FBC or coagulation screen would merit referral.

In cases where there are no concerning features from the history and there could be other aetiological factors such as medications consider the benefits vs risks of reducing those risks (e.g stopping medications) or simply observing the bruising.

Links: BMJ | NICE CKS

Haemolysis

Quick Tip; A positive DAT screen is sensitive but not always specific for haemolysis

Haemolysis should be considered in cases of anaemia when no source of bleeding is evident or there are clinical features to suspect a haemolytic process, either from patient history of laboratory findings. Almost all haemolysis is extravascular but around 15-20% will be intravascular (mechanical e.g metallic heart valves, or thrombotic microangiopathy e.g Thrombotic Thrombocytopenic Purpura (TTP))

Risk factors for haemolysis;

Immune
- History autoimmune disease
Mechanical
- Metallic heart valves, intra-aortic balloon pump
- Microangiopathy (TTP, HUS, DIC, malignancy, pre-eclampsia, HELLP syndrome)
Malignancy
Medication (not an exhaustive list)
- Cephalosporins
- Dapsone
- Nitrofurantoin
Recent infection (not an exhaustive list)
- Epstein-Barr Virus
- Mycoplasma
Inherited disorder (not an exhaustive list)
- Membrane disorder (hereditary spherocytosis/elliptocytosis)
- Metabolic disorder (G6PD, Pyruvate kinase deficiency)
- Haemoglobinopathy (sickle cell disease, haemoglobin C disease)

Workup

Full blood counts and blood film looking for fragments-although the majority (>80%) of autoimmune haemolysis is extravascular
Reticulocytes, spherocytes and polychromasia (raised in haemolysis)
LDH (raised in haemolysis)
Haptoglobin (reduced in haemolysis)
Bilirubin (raised in haemolysis (direct more than indirect))
Direct antigen testing (Coombs' test)
Autoimmune screen if history consistent with underlying autoimmune disorder
If new presentation consider investigation for underlying lymphoproliferative disorder

Management

Avoid transfusion when possible (BCSH guidance is for transfusion in life threatening situations only [see Guideline 1]) as 30% of autoimmune haemolysis patients with have alloantibodies to red cells
If transfusion required match for ABO, Rh and K as these are the most commonly identified alloantibodies
Consider underlying aetiology if no obvious trigger present
Thromboprophylaxis should be given for patients with acute haemaolysis as haemolysis is a risk factor for VTE
Folic acid should be replaced
Call haematology for advice if anaemia is severe, or written referral if milder anaemia or seemingly slow progression

Links: Guideline 1 (Primary AIHA) | Guideline 2 (Secondary AIHA)

Myeloma, paraprotein

Quick tip; When identifying a paraprotein, the most important step is to identify whether end organ damage from any possible underlying disease is present (bone pain, anaemia, new/progressive renal impairment)

Myeloma is a cancer of plasma cells. A plasma cell is a B cell which has been exposed to antigen, and has matured to produce antibody. In a healthy individual there are a mix of different plasma cells making a mix of immunoglobulin types (aka 'polyclonal').

It is worth remembering the structure of antibody to make sense of the pathophysiology, tests and results.

95% of all myeloma cases produce a monoclonal protein (either paraprotein, which includes a light chain element, or light chain only) and this can be used to diagnose myeloma and monitor response to treatments. Alongside diagnosing myeloma, it is critical to also look for end organ damage.

Myeloma is often considered in the case of; new unexplained normo- or macrocytic anaemia in an older person, back (or other bony) pain with red flag features, pathological fracture, weight loss, or new renal impairment or hypercalcaemia.

End organ damage	Symptoms/signs	Tests
Hypercalcaemia from calcium release due to myelomatous bone destruction	Confusion, constipation, abdominal pain, renal stones.	Bone profile.
Renal impairment from protein deposition in renal tubules	General symptoms such as fatigue through to uraemia.	Renal function tests (U & E).
Anaemia from marrow infiltration with myeloma	Lethargy, shortness of breath.	Normocytic or macrocytic anaemia.
Bony pain	Persistent pain, night pain or pain that wakes from sleep. Pathological fractures.	Xray of affected area (then systemic imaging e.g whole body MRI when under haematology).

Key points for the 2 blood tests used to diagnose myeloma (serum electrophoresis and serum free light chains) are as follows.

Serum electrophoresis

This is not uniformly reported by all labs and can be confusing to interpret. The question you need to ask is ‘Is there a paraprotein?’. If this is not clear from the report, speak to the immunology lab providing the result to ask whether one is present or not.
An IgM paraprotein is much more likely to be associated with lymphoplasmacytic lymphoma (LPL) rather than myeloma. IgM myeloma is very rare. Think of LPL as a cancer of a cell which has only partially matured from a normal lymphocyte to a plasma cell. It has some features of the lymphocyte, and so has some lymphoma-like features (sweats, weight loss, fevers, lymphadenopathy/splenomegaly). It also has features of myeloma however (makes a protein, likes inhabiting in the bone marrow).

Serum free light chains (SFLC)- a mild and balanced increase in both kappa and lambda light chains is common in patients with renal impairment or inflammation, but pathology is suggested with more significant increases (usually over 100mg/L) in only one of the results, leading to an abnormal ratio (see the SFLC module for information about light chains). This has predominantly replaced the Bence Jones protein (BJP) which is a less sensitive and specific test for light chains in the urine. When SFLC is available, use this in preference over BJP.

Once these tests have been performed, this table can help differentiate different conditions;

	Paraprotein present	SFLC abnormal	End organ damage
Myeloma	✔	✔ (almost always)	✔
Light chain only myeloma	X	✔	✔
MGUS	✔ OR	✔	X

(‘SFLC abnormal’ in this table refers to a result suggesting a plasma cell disorder e.g Kappa 1500, lambda 2, ratio 750)

Differential diagnosis of a paraprotein;

MGUS
Myeloma
Lymphoplasmacytic lymphoma (type of lymphoma which secretes a paraprotein, almost always IgM)
Rarely a transient feature from severe inflammation/infections but this is not common, so even if suspected still discuss cases with haematology
Amyloidosis

Amyloidosis is a plasma cell disorder like myeloma, but the problems related to it come more from the deposition of the amyloid proteins throughout the body rather than problems with the bones or bone marrow as in myeloma. Amyloidosis produce a paraprotein or light chains like myeloma does, but usually small volume e.g 3g/L IgA rather than 30g/L+ which you can see in myeloma.

If myeloma is suspected…

Workup;

History;
- Any history inflammatory or autoimmune disorder (secondary causes of paraprotein)?
- Any evidence of myelomatous end organ damage; bony pain
- Any B symptoms; weight loss, night sweats, fevers
Full blood count- normo/microcytic anaemia, thrombocytopenia or leukopenia
Renal function
Bone profile including calcium
Liver function tests including alkaline phosphatase
Serum free light chains
Urinary Bence Jones protein only if serum free light chains not available
Blood beta-2 microglobulin
- A useful prognostic marker in myeloma but not a diagnostic test
Consider Xray of a specific area of bony pain if this is causing clinical concern, but usually MRI/PET will be organised from clinic (as per British Society for Haematology guidelines, this has now replaced Xray skeletal surveys where feasible)

Different haematology services have different referral advice, but broadly speaking, if a paraprotein is identified and there is suspected end organ damage, this should be discussed with haematology who are likely to suggest an immediate review. If there is no end organ damage (and therefore MGUS is a differential), most centres would advise using the Haematology Advice and Guidance service to ‘triage’ the speed of referral.

For information, Haematology workup for suspected myeloma will include;

- Bone marrow biopsy
  - Morphology
  - Trephine
  - Flow cytometry
  - Cytogenetics- increasingly used in prognostication
- Imaging
  - MRI +- X-ray imaging most likely
- Assessment of co-morbidities and performance status
- MDT discussion

Links: BMJ BMJ Best Practice

MGUS

Quick tip; Overall progression of MGUS to myeloma at 20 years is around 20%

Monoclonal gammopathy of uncertain significance (MGUS) is an entity in the same family of conditions as myeloma. MGUS is an identified paraprotein in the absence of any end organ damage from myeloma. All cases of myeloma are thought to originate from an MGUS but not all cases of MGUS will progress to myeloma.

Priorities of management of an identified paraprotein to diagnose MGUS are to take a history for paraprotein-related clinical conditions, rule out myeloma end-organ damage and risk assess for transformation to myeloma to decide appropriate follow up. Note that MGUS can also progress to amyloid, plasmacytoma or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome.

History and examination should look for;

Bony pain
B symptoms; weight loss, night sweats, fevers
Lymphadenopathy or organomegaly
Neuropathy, hepatic, cardiac or renal dysfunction

Myelomatous end-organ damage can be;

Renal impairment
Anaemia or other bone marrow suppression
Bony pain, including back pain with any neurological insult (think cord compression)
Hypercalcaemia

Three main features seem to convey a higher risk of transformation to myeloma (Rajkumar);

Paraprotein over 15g/L
Non- IgG paraprotein
Abnormal serum free light chain ratio

With each of these features, the risk of progression to myeloma at 20 years increases by roughly 15%- if all 3 are present, the risk of progression to myeloma at 20 years is 58%. Although still relatively low, the aim of risk stratification is to refer patients who are at risk before end organ damage is present as this is often irreversible.

Referral to haematology is reasonable if any of the above 3 features are present, or critically if any evidence supporting a diagnosis of myeloma such as end organ damage is present. Local guidance should also be followed for referral policy for MGUS.

If no high risk features are present and there is no evidence of myeloma then patients can be monitored with 6-monthly and then annual community bloods tests (electrophoresis, serum light chain, urine Bence Jones protein, FBC, bone profile, and renal function) with referral to haematology if an increase in the paraprotein of over 25% or any indication of end organ damage (please check local referral policy for local practice).

Rajkumar SV, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005 Aug 1;106(3):812-7

Kyle R, et al. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. N Engl J Med 2018;378:241-9.

Links: BMJ

How to test for myeloma

The investigations of myeloma are often one of the biggest sources of confusion in the understanding of the disease. Below is a bare-bones process of how to investigate for myeloma if there is a clinical/biochemical suspicion. Complete all 3 steps for a thorough workup.

Check serum electrophoresis
- This will report the immunoglobulin levels and also tests for a paraprotein (the pathological immunoglobulin in myeloma which is clonal i.e the same protein produced again and again)
- If no paraprotein is detected, this should be reported on the lab report. For example; polyclonal increase in immunoglobulins, no paraprotein detected. If unclear, call the immunology lab.
- If a paraprotein is detected, the lab will perform serum electrophoresis to quantify it-this should be commented on on the report e.g IgGk paraprotein detected 4g/L
Check serum free light chains (SFLC) (blood test) ideally OR if not available urine Bence Jones protein (no need for both)
- Serum free light chains are reported as the level of kappa light chain, lambda light chain, and the ratio of the two. Myeloma is suggested if the ratio is deranged. Levels under 100 of either rarely indicate a myeloma-type disorder. Causes for a rise with retained, or only slightly abnormal, ratio include inflammation and renal failure. For example; Kappa 27 mg/L. Lambda 15 mg/L. Ratio 1.8. This ratio is slightly outside the normal range (usually 0.26-1.65), but still comfortably under 100 so likely to be due to inflammation or mild renal impairment. Results from myeloma or another plasma cell disorder would be more like; Kappa 272 mg/L. Lambda 2 mg/L. Ratio 136.
- Urine Bence Jones protein tests for free light chains (as above) in urine. However it is not as sensitive, or specific as SFLC, and cannot quantify the protein as you can with SFLC. The test should be used if SFLC cannot be accessed as a positive result may suggest a light chain only myeloma.
Check for end organ damage
- FBC for anaemia
- Bone profile for hypercalcaemia
- Renal function
- Xray of areas of bony pain (if other features suggest myeloma however, do not let this delay referral to haematology)

Interpretation

MGUS- Monoclonal gammopathy of uncertain significance- a PP or abnormal LC ratio but with no end organ damage

Therefore, if as on the top row, there is no paraprotein, the light chain ratio is normal/Bence Jones negative, and no end organ damage which cannot otherwise be explained, myeloma will be ruled out in almost all cases.

Non-secretory myeloma is a myeloma type which makes neither PP or abnormal LC. This is very rare however and only represents 3% of myeloma. Therefore, if clinical suspicion of myeloma is low or intermediate, and no PP or abnormal LC ratio detected, myeloma is incredibly unlikely. If clinical suspicion is high, because of lytic lesions on imaging for example, discuss with haematology as the way to diagnose could be a bone marrow biopsy or biopsy of affected area.

Paraprotein/MGUS pathway

Pathway for monitoring and referral regarding paraprotein and serum free light chain results. Courtesy of Dr Kartik Ramasamy, Dr Ross Sadler and Faouzi Djebbari at Oxford University Hospitals-Many thanks. This is purely for information and education- local protocols may differ.

MGUS pathway
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Night sweats

Quick tip; Night sweats are a presentation of malignant haematological disease but can be present in other systemic illness

Night sweats are a common symptom in people in community and hospital populations but correlate poorly with incidence of serious pathology. Data is limited, but one literature review of older patients in primary care reported subjective prevalence of at least 10%, and other populations up to 40%. The older patient cohort, when followed up, had no shortened life expectancy relative to those without sweats. This clearly does not imply that night sweats can be dismissed, but that their prevalence is incredibly common and thus the chance of a presentation of night sweats being associated with a serious underlying problem is low.

It is also challenging as national guidelines/protocols remain absent for investigation/management of night sweats (if no lymphadenopathy or splenomegaly- see NICE CKS guidance ref) because of the huge number of possible causes and poor association to 'pathological' causes.

A key point to note is that the night sweats we see associated with lymphoma or leukaemia are 'drenching', with patients needing to change the sheets or bed clothes, or a partner moving to a spare bed because of them.

The history is critical to try to identify a possible cause, even though there may often be no specific clues. It is important initially, especially with a short history of sweats, to rule out infection as the cause. This includes;

Bacterial infection, including less common infections such as infective endocarditis or bone and soft tissue infections
Viral infections of the upper respiratory tract, HIV
Mycobacterial infections in those at risk such as the immunosuppressed, individuals from endemic areas or travellers
Other infections associated with travel such as malaria
Fungal infections in those who are immunocompromised

Other causes of night sweats include;

Arthropathies/Connective tissue disorders
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Myositis
Endocrine causes
- Diabetes
- Hyperthyroidism
Haematological disorders
- Lymphoma (Hodgkin and non-Hodgkin types)
- Leukaemia
- Myelofibrosis
Inflammatory bowel disease
Obesity
Sarcoidosis
Drug reaction

If these conditions are not considered to be likely or there are other concerning features causing suspicion of underlying malignancy, it is important to recognise clues as to the malignancy causing the fevers as both solid organ (lung and renal for example) and haematological malignancies can cause fevers. Features that may hint more at a haematological malignancy such as lymphoma include regular daytime fevers (>38^o), weight loss (>10%) and lymphadenopathy, although these features are not exclusive to lymphoma. For conditions such as myelofibrosis you would expect splenomegaly and an abnormal full blood count with anaemia and often other cytopenias.

If there is suspicion of a specific malignancy after history and examination (a chronic cough or haematuria for example) then a referral to the appropriate specialty would be advised. If however there is ambiguity about the possible cause or a haematological disease is suspected the next recommended investigations would include;

Full blood count with blood film
Lactate dehydrogenase (LDH)
Immunoglobulins
Bone profile (calcium and phosphate)
HIV and Hepatitis B/C screening

Particular indications for Haematology referral would include lymphadenopathy or splenomegaly, significant full blood count abnormalities (although this is usually completely normal in lymphoma) or a paraprotein identified on serum immunoglobulin electrophoresis. NICE CKS advise referral for night sweats with lymphadenopathy or splenomegaly as a 2ww referral.

References

Literature search of prevalence of night sweats; https://www.jabfm.org/content/25/6/878.long
NICE CKS guidance on haematology referral for symptoms suggestive of haematological cancers; https://cks.nice.org.uk/topics/haematological-cancers-recognition-referral/diagnosis/symptoms-suggestive-of-haematological-cancers/

Pancytopenia

Quick tip; Pancytopenia can be due to one pathology, but consider whether it could be multifactorial

Pancytopenia is a reduction in all of the 3 main bone marrow cell lines (red cells, white cells and platelets). If only two are affected it can be called bicytopenia but this is rarely used. Pancytopenia has a few possible causes and this is one way to consider it;

Either bone marrow failure from decreased cell production
- This can be from external stressors such as severe sepsis or toxin such as medications, chemotherapy or alcohol decreasing marrow activity
Or from a primary failure of the marrow due to;
- Decreased cell synthesis mechanisms e.g aplastic anaemia/hypoplastic myelodysplastic syndrome
- Absent building blocks i.e haematinics-vitamin B12 and/or folate.
- Or bone marrow infiltration, removing the ‘space’ for normal haematopoiesis
- Myelodysplastic syndrome
  - Although this results in low bloods counts, counter-intuitively the marrow is actually hypercellular but with ineffective haematopoietic cells
- Metastatic solid organ cancer
- Acute leukaemia
  - There may be no leukaemia cells (blasts) in blood, but the marrow can be fully populated with them
- Chronic leukaemia
- Myelofibrosis
- Lymphoma less commonly
- Myeloma rare to cause pancytopenia until end stage disease
- Systemic Lupus erythematosus can cause pancytopenia but is rare
- Or it could be multifactorial e.g critically ill patient who has reactive neutropenia because of acute illness, thrombocytopenia from DIC and anaemia from blood loss and marrow suppression with acute illness.

Another approach is to use speed of cytopenia development to guide the differential diagnosis (not exhaustive);

Acute
Acute Leukaemia
Acute severe illness
Medications
Viral infections e.g CMV/EBV but rare in non-immunosuppressed patients
Aplastic anaemia

Chronic
Myelodysplastic syndrome
Haematinic deficiency
Chronic leukaemia e.g CLL
Alcohol abuse
Myelofibrosis

Workup

Thorough history of medications including over the counter or illicit substances
Blood film
- May see signs of haematinic deficiency, leukaemia, dysplasia or marrow infiltration
B12 and folate levels
- This may lead onto further screening such as coeliac screening if B12 low
- Low haematinics can cause significant pancytopenia, but if the B12/folate are only mildly reduced, other causes must be considered
ANA and DsDNA
- If considering SLE
Almost all patients with new, unexplained pancytopenia should be discussed with haematology to aid in further investigations (e.g bone marrow biopsy)

Links

https://bestpractice.bmj.com/topics/en-gb/1024

https://www.uptodate.com/contents/approach-to-the-adult-with-unexplained-pancytopenia

Splenomegaly

Quick Tip; Mild splenomegaly (up to 14cm) often has no identifiable cause

Splenomegaly can be a presenting symptom with traditionally an ache in the left upper quadrant, or an incidental finding on abdominal imaging. The approach to splenomegaly can be by pathogenesis or by size (conditions causing massive splenomegaly are identified in bold)

Common causes

Myeloproliferative disorders
- CML (cause of massive splenomegaly)
- Myelofibrosis (and other myeloproliferative disorders e.g PRV and ET) (cause of massive splenomegaly)
- Acute leukaemia
Lymphoproliferative disorders
- CLL
- Hodgkin/ Non-Hodgkin lymphoma
- Hairy Cell leukaemia (cause of massive splenomegaly)
Infective
- Viral- EBV/ CMV
- Bacterial - Endocarditis/ Tuberculosis
- Tropical - Malaria/ leishmaniasis/schistosomiasis
Autoimmune disease
- Rheumatoid arthritis/ Felty's syndrome
- Systemic lupus erythematosus
Haemolysis
- Hereditary spherocytosis (HS)/ elliptocytosis (HE)
- Thalassaemia
Portal hypertension
Amyloidosis
Gaucher's disease (cause of massive splenomegaly)
Sarcoidosis

Workup

History and examination to identify aetiology such as;
- Fevers or sweats, weight loss (e.g Infective/neoplastic)
- Recent foreign travel (e.g malaria/leishmaniasis)
- Arthropathy, rashes, hair loss (Autoimmune/connective tissue disorder)
- History of liver disease - alcohol intake, risk factors for hepatitis, fatty liver
- Examine for lymphadenopathy and splenic size (finger breadths/cm below costal margin)
Full blood count and blood film (for hereditary problems e.g thalassaemia, HS, HE or acquired e.g myelo/lymphoproliferative problems)
Liver function tests (for cirrhosis/ portal hypertension)
LDH
Viral screen (including HIV) / tropical infection investigations as appropriate
DAT test (for haemolysis)
Immunoglobulins

Spleen size is also dependent on height and gender, therefore consider using a tool such as the Calculate App by QxMD as this has a spleen size calculator for these variables. This is taken from data of a cohort study of 1200 individuals (see ref). This could avoid referral for what is actually a 'normal' spleen for taller patients.

NICE guidance (see links) recommends that all patients with splenomegaly be considered for 2WW referral taking into account associated symptoms. In patients with only borderline splenomegaly (<14cm) with no symptoms to indicate a possible myeloproliferative/lymphoproliferative diagnosis (and there are no features to suggest other aetiologies), it may be appropriate to repeat the ultrasound at 3-4 months to check for any change in size. If it increases then refer to haematology as a 2WW, whereas if it remains static it could have serial ultrasound scans until confident there is no increase in size.

Links; NICE 2WW guidance

References;

Chow KU et al. Spleen Size Is Significantly Influenced by Body Height and Sex: Establishment of Normal Values for Spleen Size at US with a Cohort of 1200 Healthy Individuals. Radiology 2016 Apr;279(1):306-13.