Download 4 Feeling Tired (Pernicious Anaemia)

DIFFERENTIALS
Tiredness:
Cardiovascular • Valvular disorders
• Cardiomyopathy/CHF
• Pericarditis
• Varicose veins
• CVA
• MI
• Anaemia
• Thalassemia Respiratory
• Pulmonary oedema
• COPD
• Interstitial disease / fibrosis
GIT:
• Liver disease (cirrhosis, fatty liver)
• Hypoglycaemia / Diabetes
• Obesity
• Metabolic / endocrine disorder
• Deficiency
Other:
• Infection
• Neoplastic
• Allergy
• Drugs / Poisons • Trauma • Pregnancy / Menopause
• Hypoxic environment
• Radiation exposure
• Psychogenic – depression, anxiety, ...
PBL Case – Feeling Tired
Agnes B, 92F — GP practice
• Tired, not eating, light‐headed, giddy, ↓wt
• Dx: Pernicious Anaemia HPC: • Light‐headedness: faintness, not vertigo
• Appetite: not interested in cooking, meat 2/7, fruit & veg
• Normal bowel movements
• Always thin, clothes now "hanging off" her
PMHx:
• Stomach ulcer operation 10 years ago
SHx:
• Ø smoking, Ø drinking, Ø medications
• Lives alone, ? able to care for herself, neighbor does shopping
EXAMINATION:
• Pale, slightly jaundiced, some vitiligo
• Refuses breast examination
• MMSE not indicated, no indication of depression
Examination Findings
110/70 sitting 105/70 standing 80 bpm, regular Vitals
47 kg (was 50kg) 1.58M → BMI 18.8
Cardioresp
HS dull, no murmur, chest clear
Tongue red & sore (?dentures)
Other
Conjunctival pallor
INVESTIGATIONS:
• Full blood count & film
Investigations
Haemoglobin
80
RCC
2.0
Haematocrit
0.24
MCV
117
HCH
40
HCHC
342
WCC
3.5
Neutrophils
1.75
Platelets
135
120 – 150
3.6 – 5.2
0.33 – 0.46
90 – 98
27 – 35
310 – 365
4.5 – 10.5
2.0 – 7.5
150 – 450
g/L
x 10¹²/L
fL
pg
g/L
x 10⁹/L
x 10⁹/L
x 10⁹/L
L
L
L
H
H
Causes of Tiredness in the Elderly
Sleep‐deprived: Non‐sleep‐deprived:
– OSA
– Endocrine (hypothyroidism, Adisons)
– Insomnia
– Metabolic (diabetes)
– Pain
– Anaemia
– Chronic disease – Diet
– Infection
– Drugs (benzos, antihistamines)
L
L
L
Oval macrocytes (sphereocytes) and hyper‐segmented neutrophils
Coagulation Tests:
‐ aPTT: intrinsic pathway
– PT: extrinsic pathway
– Thrombin time: fibrinogen → fibrin
Test
Serum Iron: Poor test of status
Blood film
Bilirubin
LD
Investigations
35
350
0 – 20 μmol/L
120 – 250 μmol/L
H
H
INITIAL MANAGEMENT:
• Stomach ulcer was malignant – partial gastrectomy
– no evidence of recurrance in 3 years
Investigations
Vitamin B12
50
130 – 660 pg/L
L
Red cell folate
520 360 – 1450 nmol/L
Intrinsic factor antibody Positive
• B12 injections initially, orally after Repeat FBC (10 days later)
Haemoglobin
92
110 – 160 g/L
L
Reticulocytosis
150
10 – 100 x 10⁹/L H
• Refuses gasteroenterologist referral for endoscopy
4 Feeling Tired (Pernicious Anaemia)
GERIATRIC GIANTS
Instability
Incontinence
Immobility
Intellectual deterioration
Iatrogenic IRON STUDIES
Elevated
TIBC (transferrin):
apotransferrin : transferrin
Ferritin:
Proportional to Fe stored inside cells
Low
Liver dz, hypoplastic Chronic disease, ↓Fe, anaemia, ↓erythropoesis, post‐surgery
↓Fe
↓Fe, pregnancy, OCP
↑Fe
↑Fe, liver disease, infection, inflammation, malignancy
↓Fe, hypothyroidism, ascorbate deficiency Hepsidin:
↑Fe
↓enterocyte Fe absorption ↓Fe
7 Masqueraders:
– Can present differently
• Diabetes
• Drugs
• Depression
• UTI
• Spinal dysfunction
• Thyroid
• Anaemia p1
PBL Case – Feeling Tired
Six Weeks Later:
• Worried health has deteriorated, ? can't live at home any more
• Requests weekly B12 injections
Repeated FBC (6 weeks)
Haemoglobin
100
120 – 150 g/L
L
MCV
84
80 – 100 fL
WCC
6.4
3.5 – 10.0 x 10⁹/L L
Platelets
350
150 – 400 x 10⁹/L
Vitamin B12
830
130 – 660 pg/L
H
Serum ferritin
5
10 – 200 μg/L
L
TIBC
90
15 – 55 μmol/L H
B12:Protein
pepsin
B12:R binder
proteases
B12:IF
IF receptor
@ terminal ileum
• Accepts GI endoscopy referral now
– Endoscopy: Atrophic gastritis in remaining stomach
– Colonoscopy: normal
• Started on iron supplements OUTCOME
• Recovered 2 months later, coping well
Repeated FBC (2 months)
Haemoglobin
125
120 – 150 g/L
MCV
86
80 – 100 fL
Vitamin B12
DNA Synthesis
Fatty acid synthesis
– Important for all cells
B12 (Cobalumin) Metabolism: — sources: meat, milk, eggs
• Absorption requires intrinsic factor (parietal cells)
1. Freed from binding proteins by pepsin
2. B12 binds to salivary proteins (cobalophilins / R‐binders)
3. B12 released by pancreatic proteases, binds to IF
4. B12‐IF endocytosed in terminal ileum
5. B12 bounds to transcobalumin II, secreted into plasma
6. Transcobalumin II‐B12 to liver, BM, GIT lining
B12 Deficiencies:
FOLATE: purine nucleotide synthesis
• ↓ Intake: inadequate / vegetarian One enzyme in purine pathway requires BOTH B12 & Folate
• ↓ absorption: Deficiency: pancytopenia, neural tube defects (pregnancy)
– Achlorhydria & loss of pepsin pdn
Methotrexate/Trimethoprim: block DHF reductase
– Loss of pancreatic exocrine fxn
→ similar effects as folate deficiency – IF deficiency: pernicious a., gastrectomy
– Malabsorption
– Intestinal disease (lymphoma, resection, ileitis)
– Competitive uptake (tapeworm)
• ↑ requirement: pregnancy, hyperthyroidism, disseminated cancer
Erythropoiesis: Sites: long bones → flat bones Extra‐medullary: liver, spleen
Stimulated: EPO (released from JGA @ Kidneys)
Proerythroblast: committed stem cell
Normoblast: expels nucleus → reticulocyte → RBC
Proerythroblast
Normoblast – expels nucleus
4 Feeling Tired (Pernicious Anaemia)
Anisocytosis: varied RBC size
Poikilocytosis: varied RBC shape
Abnormal Blood Cell Types: seen on blood smear
Hypersegmented nϕ: megaloblastic anaemia (>5 lobes)
Target cells: ↓Fe, liver disease (codocyte)
Acanthocyte: spiny, shar‐shaped – liver disease
Burr cell: blunt projections – chronic renal disease
Sickle cell: genetic disorder
Ovalocyte: genetic disorder
Spherocyte: auto‐hemolytic anaemia – genetic disorder
Sideroblast: ring of iron surrounding nucleus – genetic
Schisocytes: RBC fragments
Tear‐drop cells: ↓Fe, myelofibrosis, thalassemia major
p2
A reduction below normal limits of total circulating red cell mass
→ ↓ haematocrit or ↓ blood [Hb]
Anaemia
Mechanisms:
1. Blood loss (eg trauma, menses, haematochesia, malena, haematuria)
• Loss of intravascular volume → interstitial fluid shift → ↓Hct
– Leukocytosis, ↑ reticulocytes, thrombocytosis
• Chronic loss: anaemia only when no Fe or loss > pdn
2. ↑ destruction
• Intrinsic (RBC): membrane / enzyme / Hb problems
• Extrinsic: Ab's, mechanical, infection, chemicals, hypersplenism 3. ↓ production
• Stem cells: leukaemia, aplastic (all BM lines), renal failure, endocrine disorders
• Erythroblasts: defective DNA synth (B12/folate deficiencies), ↓Fe, thalassaemia
• Others: sideroblastic a. & a. of chronic disease, infection
➔ TICS & RACH = BLOOD
Anaemia Types
Microcytic
Normocytic
Macrocytic
Thalassaemia Renal failure
B12 deficnecy
Iron‐deficiency Aplastic Bone Marrow Liver disease
Chronic disease Chronic disease
FOlate deficiency
Sideroblastic
Haemorrhage
EtOH
Drugs
Aplastic a.: pancytopenia & hypocellular BM (aplasia)
Haemolytic a.: RBC destruction, acquired or inherited
Iron Deficiency a.: loss or insufficient uptake
– bleeding, pregnancy, growth, ↓ absorption, poor diet
A. of chronic disease: ↓ RBC proliferation + ↓ Fe utilization
• Infections: osteomyelitis, infective endocarditis, TB
• Neoplasm: Hodgkin's lymphoma, lung/breast carcinoma
• Immune: rheumatoid arthritis, SLE, enteritis, Crohn's
• Renal failure
– ↓Fe release from BM into RBCs + ↓ EPO from cytokines
Sideroblastic a.: protoporphyrin doesn't bind Fe
• (heme precursor) → Excess Fe + ring sideroblasts Megaloblastic a.: delayed nuclear maturation
• B12/folate deficiency: malabsorption, coeliac, pernicious a.
Normoblastic a.: EtOH, ↑ reticulocytes, hypothyroidism,
drugs (azathipine – immunosuppressant), pregnancy
dUMP
Folate‐B12‐DNA Synthesis
Folate
(diet)
DHF
Methionine
THF
B12
5,10‐MTHF
dTMP
5‐MTHF
Homocystine
DNA
Syndrome, not Dx!
Cell Indices:
• Haematrocrit (Hct): % of whole blood occupied by RBCs
• Red Cell Count (RCC): RBCs / L
• Mean Cell Volume (MCV): Hct / RCC (μm³)
• Mean Cell Hb (MCH): Average Hb mass per RBC (pg)
• Mean Cell [Hb] (MCHC): Average [Hb] per RBC (g/dL)
• RBC Distribution Width (RDW): measure of RBC size variation
• Reticulocyte count: immature RBCs / L • LD: abundant in RBCs — ↑ LD = haemolysis Cell Changes:
1. Cell size: {micro,normo,macro}cytic
2. Haemoglobinization: {normo,hypo}chromic
3. Special features: shape etc
CLINICAL FEATURES:
Compensations:
• Pallor
• ↑ CO: ↑ HR & ↑ SV – angina, dyspnoea, heart failure
• Tachycardia
• ↑ RR: ↑ O2 saturations
• Wide pulse pressure
• Peripheral vasodilation: ↓BP, postural hypotension
• Weakness
• ↑ 2,3‐BPG: ↑ intracellular pH / respiratory alkalosis • Malaise
• ↑ Erythropoesis: ↑ EPO
• Easily fatigued
• Dyspnoea on mild exertion
• Koilynichia (concave nails)
• Atrophic glossitis (B12,Folate & iron deficiencies)
• Angular stomatitis
• Fatty change: liver, myocardium, kidney
• Angina pectoris
• Headache, dimness of vision, faintness
• Organomegaly
FOLATE‐DEFICIENCY ANAEMIA
Folate: intermediate in one‐carbon transfers
Aetiology:
• ↓ intake: raw green vegies & some fruits; alcohism & infancy
• ↓ absorption: malabsorptive states, intrinsic intestinal dz, drugs
• ↑ loss: haemodialysis
• ↑ requirement: pregnancy, infancy, cancer, ↑↑ haematopoiesis
• Impaired use: folic acid antagonists (methotrexate)
Diagnosis: • Megaloblastic a., hypersegmented neutrophils
• Normal serum B12, ↓ serum folate
Management: • Folate therapy – B12 deficiency: folate may exacerbate neurological degeneration
PERNICIOUS ANAEMIA: B12 deficiency anaemia
Clinical Features:
• Immunologically‐mediated gastric mucosal destruction
• Insidious onset – often severe a. by presentation
• Results in achlorhydria & absence of IF F>M
• Moderate‐severe megaloblastic a.
• ↑: early graying, blue eyes, blood group A, FHx
• Leukopaenia, hypersegmented granulocytes
• Associated Dz: vitiligo, myxoedema, Hashimoto's, • Mild‐moderate thrombocytopaenia
Addison's & hypoparathyroidism
• Mild jaundice (ineffective erythropoiesis + peripheral haemolysis)
• Antibodies develop against IF‐secreting cells
• Neurological changes (posteriolateral spinal tracts)
– Type I: Blocks B12‐IF binding (75%)
– Ø methionine = CNS demyelination → parasthesia, peripheral neuropathy
– Type II: Prevents B12‐IF binding to ileal receptor
• Achlorhydria (even after histamine stimulation)
– Type III: bind to α & β units of gastric proton pump (90%)
• ↓ serum B12 / ↑ serum homocystine & methyl malonic acid
• Results:
• Striking reticulocyte response & Hct levels ~5 days after parenteral B12
1. Loss of parietal cells
Management:
ovalocytes
2. Infiltrate of plasma cells & lymphocytes
• Lifelong parenteral B12 administration (4/year)
3. Megaloblastic changes in mucosa similar to RBC precursors – Cure anaemia, reverse/halt neurological changes
• Pathology:
– Doesn't affect gastric mucosal changes
– Megaloblastic a., pancytopenia, BM hyperplasia
hypersegmented neutrophil
– Atrophic glossitis (shiny, glazed, beefy tongue)
– Chronic gastritis (fundic atrophy, intestinilization, ↑ GI cancer)
– CNS lesions: demyelination in dorsal & lateral tracts
Spastic paraparesis, sensory ataxis, severe parathesia in lower limbs
Unsteady gait, + Babinski, loss of deep tendon reflexes
4 Feeling Tired (Pernicious Anaemia)
p3
Medical Overservicing
Medicare: insurance to pay health costs – NOT to pay doctors
Medicare Australia Responsibilities:
1. Administer Medicare & PBS
2. Aust. Childhood immunization register
3. Aust. Organ Donor register
4. Practice incentives
5. Rural retention program
6. DVA (inc. repatriation‐PBS)
7. Family Assistance Office
8. Private health insurance rebates
Inappropriate practice:
• Conduct that would be unacceptable to members of that profession
• Allowing employed practitioner to engage in inappropriate conduct
Medical Overservicing: 1. Seeing too many patients
2. Ordering too many investigations
3. Ordering inappropriate medications
4. Accepting benefit for referral/recommendation
5. Offering benefit for referral/recommendation
6. Failure to disclose interest in referral/recommendation
7. Poor record keeping
8. Unnecessary medications
9. Unorthodox medicine
80/20 Rule: 80 consults in 20 days/month for 12 months is overservicing
Medicare's Role in Professional Service Review Scheme:
Negotiated Settlement:
1. Identify inappropriate practice
Disadvantages for Dr:
Advantages:
2. Practitioner Review Program
• Admission of guilt
• Matter remains private
– Advice practitioner in writing of concerns
• Repayment
• End of proceedings
– Interview: address concerns • Disqualification/sanctions (< 3 years)
→ dismiss case, offer counseling/opportunity to correct practice
• 2nd time: 5 year disqualification
3. Review period – after time, review by Medicare's Medical Director
4. Medical director can request Professional Services Review
Professional Services Review Independent statutory authority (Health Insurance Act 1973)
Role: examine health practitioner's conduct: inappropriate practice/prescription
• Protect Medicare & PBS
Determining Authority
• Protect patients & community from risks of inappropriate practice Statutory authority, independent from PSR & Medicare • Protect Commonwealth from costs of inappropriate practice
• Reviews PSR decisions & determining sanctions
5. Director of PSR reviews case
• Made up of medical practitioners & lay person
– Dismiss case
– Negotiate settlement: reprimand, partial/full disqualification from medicate (up to 3 years), repayment of benefits for services
– Establish Professional Services Review Committee to conduct inquiry
• Agreements must be ratified by Determining Authority (DA)
6. Professional Service Review Committee
• New committee formed for each case: chaired by Dr + 2 Drs from same discipline, includes other health practitioners
• Formal hearing (under oath), legal counsel allowed
• If "serious threat to life of health of any person" → referred to medical board
7. Federal Court: appeals against Final Determination
8. High Court: appeals against Federal Court Decision
Medicare Australia
Referrals
PSR Director
Not inappropriate
Inappropriate
Agreement with person
Determining Authority
(Impose sanctions /ratify agreement)
Inappropriate
Referral to PSRC
PSR Committee
4 Feeling Tired (Pernicious Anaemia)
Not inappropriate
Inappropriate
p4