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91

What are the clinical and lab findings of sideroblastic anaemia?

Clinical findings
- anaemia

Labs
- sideroblastic MDS:  Normal or slightly elevated MCV
- all others: low
- HCT of 20-30% (moderate anaemia)
- elevated serum iron and transferrin saturation
- smear:  dimorphic RBCs (normal and hypo chromic), in lead poisoning:  basophilic stippling, elevated serum lead
- BMBx is diagnostic:  marked erythroid hyperplasia with ringed sideroblasts (erythroid cells with iron deposits in mitochondria encircling nucleus) on Prussian blue iron stain.

92

What is the treatment of sideroblastic anaemia?

Treatment
- occasionally transfusions
- do NOT respond to EPO therapy
- occasionally pyridoxine
- remove offending toxin/drug in secondary forms

93

What is required for diagnosis of sideroblastic anaemia?

BMBx is diagnostic:  marked erythroid hyperplasia with ringed sideroblasts (erythroid cells with iron deposits in mitochondria encircling nucleus) on Prussian blue iron stain.

94

What are the causes of B12 deficiency?

Dietary deficiency (rare)
Decreased production of intrinsic factor
- Pernicious anemia
- Gastrectomy
Helicobacter pylori infection Competition for vitamin B12 in gut
- Blind loop syndrome
- Fish tapeworm (rare)
Pancreatic insufficiency
Decreased ileal absorption of vitamin B12
- Surgical resection
- Crohn disease
Transcobalamin II deficiency (rare)

95

What are the essentials of diagnosis for B12 deficiency?

- Macrocytic anemia.
- Megaloblastic blood smear (macro-ovalocytes and hypersegmented neutrophils).
- Low serum vitamin B12 level.

96

What is the physiology of B12 absorption and utilisation?

Physiology
B12 a cofactor in conversion of homocysteine to methionine, and for conversion of methylmalonylcoenzyme A (CoA) to succinyl CoA —> annulment of Okazaki fragments during DNA synthesis of erythroid progenitor cells

Dietary B12 is animal in origin —> —> absorbed by ileum —> liver stores 2-5mg while daily utilisation is 3-5mcg —> takes 3 years for iron deficiency to occur

97

What are the clinical findings of B12 deficiency?

Clinical findings
Slow onset mod-severe anaemia
May be asymptomatic
Later:  leukopaenia and thrombocytoapaenia
Mucosal disturbance —> glossitis
Anorexia and diarrhoea
Neurology - peripheral nerves 1st —> parasthesia —> posterior column involvement —> loss of balance or proprioception or both  —> later: dementia, neuropsychiatric abnormalities, decreased vibration and position sense
Non-hematologic complications can occur w/ NORMAL FBC

98

What are the lab findings in B12 deficiency?

Labs
Low serum B12 (cobalamin <170, symptomatic <100
Best confirmed with an elevated level of serum methylmalonic acid (can also be elevated i kidney disease
MCV >110 (but can have normal MCV, esp with Fe deficiency or thalassaemia)
Smear:  Macro-ovalocytes (megaloblastic), hyper segmented neutrophils, reduced reticulocyte count, in severe cases: reduced WCC and PLTs (B12 deficiency affects all cell lines
Elevated LDH and indirect bilirubin due to intramedullary destruction of abnormal RBCs, similar to peripheral haemolytic anaemias
BMBx - erythroid hyperplasia, megaloblastic changes in erythroid precursors:  abnormally large cell size, asynchronous maturation of the nucleus and cytoplasm (normal cytoplasm maturation, impaired DNA synthesis —> abnormal nucleus)

99

What is the ddx of B12 deficiency anaemia?

DDx
Other megaloblastic anaemias —> but B12 will be normal
MDS - different morphology, normal B12 and methylmalonic acid levels

100

What is the treatment of B12 anaemia?

Treatment
IM daily for first week, weekly for first month, monthly for life
Oral when corrected, even if pernicious anaemia as will be passively diffused if unable to be actively transported - continue indefinitely
Concurrent folic acid required due to intestinal mucosal disruption for several months
Hypokalemia may occur in first few days esp if anaemia severe
Neurology reversible if <6 months duration

101

A 46-year-old man with hypertension and previous end stage renal failure due to glomerulonephritis,
received a kidney transplant 15 years ago. His creatinine has been stable at 110-130 μmol/L
[60 - 120 μmol/L] for the last five years. During this time his immunosuppression has been unchanged
and consists of azathioprine 100 mg daily and prednisolone 5 mg daily.
His general practitioner is concerned about his reported mean corpuscular volume (MCV) of 106 fL
[80 – 96 fL]. Which of the following is the most likely cause?
A. Folate deficiency.
B. Azathioprine.
C. Myelodysplasia.
D. Haemolysis.
E. Hypothyroidism.

B

102

What is the differential diagnosis in B12 deficiency?

Other megaloblastic anaemias —> but B12 will be normal
MDS - different morphology, normal B12 and methylmalonic acid levels

103

What is the treatment of B12 deficiency anaemia?

Treatment
IM daily for first week, weekly for first month, monthly for life
Oral when corrected, even if pernicious anaemia as will be passively diffused if unable to be actively transported - continue indefinitely
Concurrent folic acid required due to intestinal mucosal disruption for several months
Hypokalemia may occur in first few days esp if anaemia severe
Neurology reversible if <6 months duration

104

A 42-year-old woman presents with several weeks of lethargy and is found to be clinically anaemic and mildly icteric.  There is no history or clinical evidence of overt blood loss.  She has a normal varied diet and is on no medication. 
 
Her full blood count shows: 

  

The blood film shows macrocytosis and a hypersegmented neutrophil
 
 
The most likely diagnosis is: 
 
A. pernicious anaemia. 
 
B. Evans’ syndrome (autoimmune haemolytic anaemia and thrombocytopenia). 
 
C. aplastic anaemia. 
 
D. hypothyroidism. 
 
E. alcoholic liver disease. 

A.  Results in B12 deficiency --> megaloblastic anaemia

105

What are the causes of folate deficiency?

Dietary deficiency 
Decreased absorption
- Tropical sprue
- Drugs: phenytoin, sulfasalazine, trimethoprim-sulfamethoxazole Concurrent vitamin B12 deficiency
Increased requirement 
- Chronic hemolytic anemia 
- Pregnancy
- Exfoliative skin disease
Excess loss: 
- hemodialysis
Inhibition of reduction to active form
- Methotrexate

106

What are the essentials for diagnosis of folate deficiency?

- macrocytic anaemia
- megaloblastic smear (macro-ovalocytes and hypersegmented neutrophils
- normal serum B12 levels
- reduced serum folic acid levels

107

What is the physiology of folate?

Physiology
- real name: pteroylmonoglutamic acid
- citrus and leafy greens
- stored for 2-3 months
- absorbed throughout entire GI tract
- absorption impaired by drugs or full length mucosal disruption
- increased requirements in pregnancy, haemolytic anaemia and exfoliative skin disease

108

What are the signs and symptoms of folate deficiency?

Signs and symptoms
- anaemia
- mucosal megaloblastic changes
- NO neurological abnormalities

109

What are the lab findings in folate deficiency?

Macrocytic anemia.
Megaloblastic blood smear (macro-ovalocytes and hypersegmented neutrophils).
Normal serum vitamin B12
Low red blood cell folate (preferred as reflects stores over lifespan of RBC)

110

What is the ddx of folate deficiency?

- B12 deficiency - check level
- alcoholic nutritional deficiency —> no megaloblastic changes but TARGET cells
- hypothyroidism assoc w/ pernicious anaemia

111

What is the treatment of folic acid deficiency?

Tx
Daily PO folic acid, similar response as in B12 replacement
- MUST check B12, large doses of folic acid will correct bloods but will allow ongoing neurologic damage.

112

Graft-versus-host disease is a major complication of allogeneic stem cell transplantation for haematological malignancy in adults. 
 
Which one of the following has the least influence on the risk of developing graft-versus-host disease? 
 
A. Age of recipient. 
 
B. Donor-recipient ABO blood group incompatibility. 
 
C. In vitro T cell depletion of the graft. 
 
D. Type of HLA-matched donor (sibling versus unrelated). 
 
E. Donor-recipient HLA mismatch. 

B. Donor-recipient ABO blood group incompatibility. 

113

The major cause of death in patients more than six months following cardiac transplantation is:
A. graft-versus-host reaction.
B. opportunistic infection.
C. rejection.
D. malignancy.
E. coronary artery disease.

E

114

A 42-year-old man with acute myeloid leukaemia undergoes allogeneic stem cell transplantation from a human leucocyte antigen (HLA)-matched sibling.  He is progressing well for the first 10 days, but then complains of abdominal pain and leg swelling. 
 
He is noted to have marked ascites, moderate peripheral oedema and jaundice. 
 
Liver function tests are as follows: 

  

An abdominal ultrasound confirms large volume ascites with an enlarged liver (span 18 cm).  The spleen is normal in size. 
 
The most likely explanation for his condition is: 
 
A. graft-versus-host disease. 
 
B. cytomegalovirus hepatitis. 
 
C. hepatosplenic candidiasis. 
 
D. portal vein thrombosis. 
 
E. veno-occlusive disease. 

E. veno-occlusive disease. 

115

Which of the following is the greatest cause of mortality occurring more than 100 days following allogeneic peripheral blood cell stem transplantation for acute leukaemia? 
 
A. Hepatic veno-occlusive disease. 
 
B. Graft-versus-host disease. 
 
C. Transplantation-related lung injury. 
 
D. Transplantation-related infection.  
 
E. Recurrent leukaemia.

E

116

What are the early post hematopoetic stem cell transplant complications?

Mucositis (most common)
Haemorrhagic cystitis
Prolonged and severe pancytopaenia
Infections
CMV
EBV
Viral hepatitis
Acute GVHD
Graft failure
Transplant related lung injury
Hepatic veno-occlusive disease
Transplant related MAHA

117

What is the most common early HSCT transplant complication?
What causes it?
How do you treat it?

Mucositis
- most common short-term complication
- etoposide and MTx
- can be oropharyngeal and intestinal
- intubation if supraglottic
- may need TPN
- topical and systemic analgesia and opioids

118

When does severe pancytopaenia occur in HSCT?  How is it managed? When do infections occur?

Prolonged & severe pancytopaenia
- common, lasts up to 4 weeks
- empiric anti fungal tx if persistent unexplained fever in setting of use of broad-spectrum abc
- antiviral prophylaxis usually given
- serious infections (pneumonia, bacteraemia, fungaemia, viraemia) in up to 50% - more common in matched unrelated donors (MUDS) than auto or sibling allografts.
- recombinant growth factors (filgrastim) started 24-72 hours post stem cell infusion reduce neutrophil recovery time
- severe thrombocytopaenia —> transfuse <10, or 50 if surgery required.
- severe anaemia —> transfuse, sometimes EPO

119

What is the timeline of infection in HSCT?

Infections
Early (0-30 days) - mucosal and skin injury —> aerobic bacteria (esp coag -ve staph, viridans step, gram -ve’s candida and HSV).
Mid 1-3 months: T-cell dysfunction, hypogammaglobulinaemia —> encapsulated bacteria (pneumococcus, H.influenzae), viruses (CMV, PHP), molds and candida
Later 3-12 months - t-cell reconstitution, chronic GVHD —> encapsulated bacteria, CMV, PJP, HZV, EBV and hepatitis

120

What causes CMV and EBV infection in HSCT?

CMV
- due to impaired viral immunity in first year, acute or chronic GVHD
- CMV positivity = higher peritransplanatation mortality rate. - treated prophylactically and preemptively to prevent pneumonitis and viraemia but can still occur

EBV
- most common in patients who are EBV naive, in patients receiving T-cell depleted grafts, or receiving ATG for in-vivo t-cell depletion.
- causes posttrantplant lymphoproliferative disorder (PTLD) in HSCT, t-cell depleted grafts, and those undergoing intensive tx for GVHD