1. Haematology Case based discussions
Dr Nnenna Osuji
Dr Stella Appiah-Cubi
Dr Stella Kotsiopoulou
21/05/2014

2. Objectives Focus on primary/secondary care interface
Discuss cases encountered and practical lessons
Highlight diagnostic clues
Encourage confidence around community care of chronic stable haematological malignancies
Information gathering
Sickle vaccinations
USC referrals
Marker analysis/immunophenotyping
Serum free light chains

3. Quiz Name the current consultants.
How do you contact haematology for advice?
Blood film suggests CLL. How are you going to refer this patient?
Indications for 2WR Haematology Referrals

4. MALIGNANT HAEMATOLOGY
Monoclonal Protein
MGUS Vs Multiple Myeloma
Case Discussions
CLL
Case Discussion

5. Varies greatly with age.
What is an M protein?
It is a monoclonal immunoglobulin secreted by an abnormally expanded clone of plasma cells that can be detected by immunofixation of serum and/or urine.
Varies greatly with age.
1 - 2% of people in their 6th decade
2-4% in their 7th decade
4-5% in their eighth decade
14% over the age of 90
Racial variation
Twice as common in black people as white people

7. Incidence of M-proteins
Varies greatly with age.
1 - 2% of people in their 6th decade
2-4% in their 7th decade
4-5% in their eighth decade
14% over the age of 90
Racial variation
Twice as common in black people as white people

8. Monoclonal gammopathies occur in the following conditions
Haematological malignancies
Multiple myeloma
Solitary plasmacytoma (skeletal or extra- medullary)
Waldenstrom's macroglobulinaemia
Low grade non-Hodgkin’s lymphoma
Monoclonal gammopathy of undetermined significance ( MGUS)
AL amyloidosis
Connective tissue disorders
RA, SLE, scleroderma, polymyositis and ankylosing spondylitis.
Skin disorders
Infections
Hepatitis C virus (HCV)-related chronic liver disease
HIV
Helicobacter pylori

10. Predicting Progression
There were only 2 statistically significant risk factors for progression
The concentration of monoclonal protein
The type of monoclonal protein
IgA and IgM gammopathy more likely than IgG to progress
IgM rarely becoming myeloma

11. Monitoring in the low risk group
Low risk defined as
IgG M-protein <15g/l
IgA or IgM M-protein <10g/l
No symptoms/signs of myeloma, lymphoproliferative disorders or AL amyloidosis
This group forms the vast majority of M
proteins detected in routine practice

12. Acronym: CRAB

13. New International Staging System: ISS
Stage
Criteria
Median survival I
Beta2 microglobulin<3.5 mg/L and
Serum albumin >3.5 g/dl
62 mo. II
Neither I or III 45
III
Beta2 microglobulin >5.5 mg/L 29

14. Clinical presentation
Symptoms of bone disease, persistent unexplained backache
Impaired renal function
Anaemia
Hypercalcaemia
Recurrent or persistent bacterial infection
Hyperviscosity
Spinal cord/nerve root compression
Symptoms suggestive of amyloidosis (nephrotic syndrome, cardiac failure)
High ESR (incidental finding)

18. Case 1. - Patient G.R. 13/07/2005 67-year old Afro-Caribbean
Right hypochondrial pain
Fatigue
Recently treated for epistaxis

19. Patient G.R. FBC: Hb 6.6, WBC 5.0, plts 85 Urea 10.2, creatinine 128
Adj. Ca 4.38, albumin 28
ESR 138 mm/h

20. Patient G.R. Admit Anaemia due to 3 units of blood transfusion
? Malignancy
? Epistaxis
3 units of blood transfusion
i.v. fluids + Pamidronate

21. Patient G.R IgA λ paraprotein 75 g/l (t.prot 127 g/l)
β2 microglobulin 5.6mg/l
BM – plasma cells 40%
INR 1.32, APTTr 1.34, fibrinogen 1.67 g

22. Patient G.R Drowsy Transfer to ITU Bleeding from mouth
HD Methylprednisolone
Subsequent C-VAD, Z-Dex chemotherapy

23. EMERGENCY !!! Hyperviscosity
Treatment – plasmapheresis, HD steroids, iv hydration

24. Case 2. Patient B.B. 05/08/2005 49-year old Afro-Caribbean
Back pain - 9 mo. (6 mo. off work)
Not able to mobilize from bed without help

25. Patient B.B. FBC – clotted Urea 6.5, creatinine 150
Adj. Ca 2.68, albumin 19
Total protein 174 g/L
Paraprotein 141 g/L IgGκ

26. Patient B.B. Hb 3.4 (citrate blood)
INR 1.5, APTTr 1.25, fibrinogen 1.41

27. Patient B.B. 3 sessions of plasmapheresis at RMH
Blood transfusion after plasmapheresis
Z-Dex chemotherapy
Abnormal ECHO
CThal Dex chemotherapy

28. Case 3. Patient J.M. 01/08/2005 48-year old Afro-Caribbean
Sudden lower-back pain on sneezing 3 mo. prior to admission
5/7 history back pain and reduced power in left leg

29. Patient J.M. FBC: Hb 10.5, WBC 6.8, plts 278
Urea, creatinine, adj. Ca - N
T. protein 99
paraprotein 45 g/L IgGκ

30. Patient J.M. 05/08/2005 Left leg – no movement
Right leg – reduced power

31. EMERGENCY !!!
Spinal cord compression Treatment – radiotherapy, Dexamethasone

32. Patient J.M. 1st August – Lumbar spine X ray 2nd August – MRI
2nd August – CT- guided biopsy
4th August - diagnosis ?MM, ?NHL
4/5th August – referral to haematology
5th August - referral for radiotherapy
6th August - radiotherapy

33. Patient J.M. 20 Gy – 5 doses 1 course Z-Dex, 3 courses C-VAD
!! Able to take few steps with crutches
Right leg – back to normal
Left leg – much improvement

34. Case 4. Patient N.H. 12/08/2005 71-year old Caucasian 3/12 back pain
Spine X-ray – lytic lesion lumbar

35. Patient N.H. FBC: Hb 15.6, N 5.7, plts 237
Us&Es, Ca, t. protein – normal
Small IgG paraprotein
BM – 3% plasma cells
CT-guided biopsy – plasma cells

36. Patient N.H.
PLASMACYTOMA
Treatment 40 Gy in 20 fractions

37. Management of persistent pain
SURGERY
Contraindicated in the absence of structural instability
Management of persistent pain
Vertebroplasty – bone strengthening and pain relief but does not restore height
(polymethacrylate)
Kyphoplasty – vertebral height can be restored (small inflatable balloon)

40. Chronic Lymphocytic Leukaemia CLL

41. CLL Clonal B cell malignancy.
Progressive accumulation of long lived mature lymphocytes
Most common leukemia of Western world.
Male to female ratio is 2:1.
Median age at diagnosis is years.
Small proportion are familial
Aetiology unknown

42. Clinical features Mostly disease of elderly with Often asymptomatic.
Classic B symptoms
recurrent infections
Lymphadenopathy, hepatosplenomegaly.
Marrow failure
Autoimmune haemolytic anaemia/thrombocytopenia

43. Diagnosis Persistent lymphocytosis > 5 x 109/l.
Morphology Mature looking lymphocytes
-clumped chromatin
Immunophenotyping
BM not required for diagnosis.

44. Immunophenotyping
Majority score 4/5
Score < 3 not CLL

45. Staging- classification systems

46. CLL Complications Infection Autoimmune – ITP/Haemolytic anaemia
Bacterial – hypogammaglobulinaemi a
Viral – T-cell dysfunction (H. Zoster)
Autoimmune – ITP/Haemolytic anaemia
Other malignancies
Transformation
Richter’s, Hodgkin’s
Shingles
High dose therapy 800mg 5 x per day for 10 days then prophylactic dose 400mg tds
Neuropathic pain

47. CLL treatment Many watch and wait – stage A Chemotherapy
Bone marrow failure=stage progression
B symptoms – weight loss, sweats, fevers (unexplained)
Symptoms from enlarged lymph nodes/spleen
Transformation
Not for high WBC alone
Median survival 10 years
What?
Chemotherapy
FCR- fludarabine,
cyclophosphamide, rituximab
Chlorambucil - elderly
Steroids
Alemtuzumab – anti CD52

48. “Watch and wait” policy
When to refer back
B symptoms
Lymphadenopathy
Hepatosplenomegaly
Falling haemoglobin, platelets, rapidly rising lymphocyte count
Recurrent infections
Autoimmune complications
How often?
Every 3 months
Then reduce frequency if stable

49. Mrs ID
2004 Aged 80, Routine FBC- lymphs 8. Normal Hb/neutrophils/plats
Well , no B symptoms, lymphadenopathy or hepatosplenomegaly
Diagnosis CLL
‘Watch and wait ’ policy
Discharged 2011 – GP to monitor

50. BENIGN HAEMATOLOGY Anaemias B12 Deficiency Case Discussion
Iron Deficiency Vs Thalassaemia Trait
Elevated Ferritin

51. ANAEMIA
Definition
Categorized according to Red Cell indices MCV and MCH:
Hypochromic and Microcytic (low indices)
Normochromic and Normocytic (normal indices)
Macrocytic (high MCV)
Can you name one cause for each category?

52. MACROCYTIC ANAEMIA How do we investigate?
1st line tests: B12, Folate, TSH, reticulocyte count, LDH, LFTs, blood film: ? Any dysplastic features. ? History of alcohol consumption
2nd line tests: SPE, UPE, DAT/haemolysis screen
3rd Line: Bone Marrow investigations

53. A guide to the management of B12 deficiency in the primary care

54. Outline Sources of dietary vitamin B12 Vitamin B12 absorption
Causes of B12 deficiency
Indications for measuring B12 level
Clinical presentation of B12 deficiency
Investigations to help define the cause of B12 deficiency.
A guide to management

55. Sources
Foods of animal origin- meat, fish, eggs, milk, cheese but not in plants.
Recommended daily requirement is 1- 2µg/day
Total body stores of µg
Mainly stored in the liver( up to 2yrs stores)

56. Absorption

57. Who is at Risk

58. Causes of B12 deficiency • Inadequate vitamin B12 in diet
▪ strict vegans
• Vitamin B12 malabsorption
▪ Pernicious anaemia-loss of GP→IF↓( increased of CA stomach ~ 2-3%)
▪ Long term use of PPI or H2-antagonist
▪ Chronic alcoholism
▪ Coeliac disease
▪ Small bowel( esp. terminal ileal) surgery
▪ Generalised malabsorption e.g. Tropical sprue, IBD
▪ Blind loop syndrome +/- small bowel bacterial overgrowth
▪ Fish tapeworm
•Drugs
▪ Biguanides e.g.. Metformin
▪ Oral contraceptive pill
▪ Slow K, Cholestyramine

59. Indications for measuring serum vitamin B12 level
Haematological
▪ Isolated red cell macrocytosis
▪ Macrocytic anaemia ( esp. if MCV> 110fl)
▪ Pancytopenia ( esp. if MCV> 110fl)
Neurological or psychiatric
▪ Peripheral neuropathy
▪ Cognitive change e.g. dementia
▪ Optic neuritis
Gastrointestinal
▪ Investigation of possible malabsorption process
Other (rare)
▪ Angular stomatitis, glossitis (sore beefy red tongue)

60. Clinical features Slow onset – symptoms of mild anaemia
Pallor and mild Jaundice( ineffective erythropoesis)
Glossitis & angular stomatitis
Neurological changes( B12< 60ng/L)( SCDC)
▪ Glove and stocking parasthesia
▪ Early loss of vibration sense
▪ Progressive weakness and ataxia
▪ Dementia
SCDC: Subacute Combined Degeneration of the Spinal Cord

61. Investigations
FBC-Megaloblastic anaemia with hypersegmented neutrophils
Serum B12 level- low
Serum folate may be normal or high
Anti-intrinsic factor ( anti-IF)- highly specific but +ve in 50-60% of PA.
Parietal cell antibodies- +ve in 90%( PA) but less specific
TSH & anti-thyroid Ab
Test for coeliac disease
Test for generalised malabsorption
Endoscopy
Schilling test- obsolete

62. Treatment-Symptomatic
B12 deficiency without neurological involvement:
▪ 1mg Hydroxocobalamin 3 times a week for 2 weeks then every 3 months
B12 deficiency with neurological involvement:
▪ 1mg Hydroxocobalamin every other day until no further improvement then every 2 months
▪ Folic acid 5mg daily for 4 weeks

63. Treatment-Asymptomatic
Serum B12> 150ng/l- Confirm test
Significant proportion of these patients will go on to become symptomatic.
Treat with oral vitamin B12 supplements + monitor level every 2-3months
If no response then consideration given to parenteral B12 replacement

64. Case 1- Patient LS 53y old legal secretary Previously fit & well
A&E with RIF
3/12 general lethargy & inability to concentrate

65. Patient LS PMHx- Nil relevant
SHx-Single, good diet with mixture of animal & diary products
No alcohol or smoking

66. On examination Pale, mildly jaundiced, sore and smooth tongue.
No pedal oedema, no hepatosplenomegally
BP- 95/50, Pulse -110/min
RIF tenderness with guarding? appendicitis

67. Investigations FBC- Hb- 6.8g/dl, WBC- 2.5 Plt- 58, MCV- 130fl,
U&E- NAD, LFT-Normal except Bili=26( 21- …), LDH- 8498, TSH- Normal, Hepatitis, HIV –ve.

68. Blood film

71. What other investigations would you consider?
Folate- 9
B12- 72
GP & IF ab- Positive
Coeliac Screen Negative

72. What is the management Vitamin B12 replacement- 1mg X 3 for 2 weeks.
Then 3 monthly
Folic acid 5mg daily for 4 weeks

73. Case 2 - Patient MS 47yr man South East Asian origin
Saw GP with tiredness, SOBO
PMHz- II DM on metformin
SHx- Banker, strict vegetarian, Alcoholo, smokingo
O/E- Unremarkable

74. Investigations
Hb WBC- 3.2 Plt- 223, MCV- 120, LFT-NAD, LDH-640, U&E-NAD, TSH- Normal
Blood film- macrocytosis with occasional hypersegmented neutrophils seen
Serum B , Folate- 12, Ferritin 45
GP & IF ab, Coeliac screen- Negative

75. What is the management? Oral supplementation
Cyanocobalamin µg PO daily
Recheck serum B12 in 2-3 months.
Continue if replete
If not, consider parenteral B12 injections.

76. Case 3- Patient DT 48y old Female Long H/O bloatedness Good diet.
SHx- Research nurse, no smoking or alcohol

77. Patient DT O/E- Unremarkable Bloods- Hb-9.8 WBC- 7.8 Plt-350 MCV-86fl
Blood film unremarkable
U&E, LFT, TSH- NAD

78. Patient DT Ferritin- 6µ/dl, serum B12 – 160, Folate- 8
Tissue transglutaminase (tTG)

79. Patient DT Referred to gastroenterologist Given oral B12 and FeSO4
Recheck 3 monthly

80. MICROCYTIC HYPOCHROMIC ANAEMIA
What tests would you consider in the following cases: (Fer Vs Fer+HbEP)
25 y.o. lady, Norwegian, fatigued, Hb:100 g/l, RBC: 3000, MCV: 74fl, MCH: 26pg
50 y.o. lady , Cypriot, routine check, Hb:100 g/l, RBC 5000, MCV 70fl, MCH 24 pg

81. Hb structure

82. Beta-Thalassaemia inheritance

83. Alpha-Thalassaemia inheritance

84. Regarding Ferritin Low Ferritin = Iron Deficiency
Raised Ferritin = Too much iron??

85. Causes of raised ferritin
Iron overload( Primary & Secondary)
High Ferritin Without Iron Overload

86. Causes of Fe overload Primary ▪ Hereditary haemochromatosis Secondary
▪ Hereditary aceruloplasmin( Wilsons’ disease)
Secondary
▪ Transfusion overload
▪ Ineffective erythropoiesis( thalassemia, sideroblastic anaemia)
▪ Excess dietary iron

87. Causes of high ferritin without Fe overload
Liver disease
Alcohol excess
Chronic inflammatory conditions( RA, IBD, bacterial infection)
Malignancy

88. Evaluation of Fe loading tendency
FBC
LFT
Ferritin
Transferrin saturation

89. Patient FT
59yr old female
Severe RA
On immunosuppressive drugs

90. Patient FT Hb- 99 WBC- 13.5 Plt-420 ESR- 43 CRP- 35, Ferritin 400µg/l
U&E, LFT- NAD
Blood film Normochromic normocytic anaemia
Serum electrophoresis- polyclonal increase in immunoglobulin

91. Patient FT Cause of raised ferritin- acute phase response
No specific therapy/investigations required for this
Treat the RA

92. Patient GM 38yr old German ancestry Fit & well City Banker
Alcohol- 10u/week
Well man clinic

93. Patient GM Hb- 154 WBC- 8.7 Plt- 210 Ferritin- 200µg/l
B12/Folate- within normal range
U&E, LFT-NAD
O/E- Nicely tanned but unremarkable otherwise
Transferrin saturation ( serum Fe & TIBC)- 89%

94. What is the next specific test?
Test for HFE mutation
Homozygous for C282Y/C282Y
Diagnosis: Hereditary Haemochromatosis

95. Hereditary haemochromatosis
Elevated Fe with no obvious cause
Family history
TS > 55% for men & post menopausal women
TS > 50% in premenopausal woman
Test for HFE mutation
Refer patient to gastro-enterologist in CUH
Venesection will be done by haematologist

96. Other issues Sickle cell vaccination
Community follow up for long term haematological conditions
Any others?

97. Sickle cell vaccinations
Pneumococcal Vaccine every 5 years
Hib immunisation (once in lifetime)
Tetravalent Meningococcal vaccine ACWY (once in lifetime)
Hepatitis B vaccination
Seasonal Flu Vaccination (annually)
WHY????

98. Community Follow-up for long term haematological conditions
Can you name 2 (previously presented in this talk)?
Can you suggest others?

99. Any Questions??????

100. Thank you! Dr Stella Kotsiopoulou Haematology Specialty Doctor Croydon University Hospital