Clinical Pathology Conference

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Clinical Pathology Conference

• March 13, 2007
• Lisa L. Willett, MD

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The lonely journey of a CPC

• The first step towards knowledge is to know that
  we are ignorant.

-Richard Cecil
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Well known rules of a CPC

• TB is always in the differential
• Never read case reports
• Never trust a chief resident who doesnt follow
  the rules
• Never trust a chief resident who apologizes when
  handing you the case
• The answer is always in the title

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47 year old woman with paresthesias and anemia
1980s
1990

Lower GI bleed s/p hemicolectomy
PUD s/p Billroth 2 vagotomy
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47 year old woman with paresthesias and anemia
1980s
1990
1990s

Lower GI bleed s/p hemicolectomy
B12 deficiency Monthly IM B12
Fe deficiency Menorrhagia s/p hysterectomy Oral
Iron
PUD s/p Billroth 2 vagotomy
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47 year old woman with paresthesias and anemia
2000 (years)
1980s
1990
1990s

Lower GI bleed s/p hemicolectomy
B12 deficiency Monthly IM B12
Fe deficiency Menorrhagia s/p hysterectomy Oral
Iron
PUD s/p Billroth 2 vagotomy
Recurrent n/v Occasional hematemesis 7 weight
loss No diarrhea, abd pain
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47 year old woman with paresthesias and anemia
2006 (6 months)
2000 (years)
1980s
1990
1990s
Refractory anemia (po iron, IM B12,
darbo) Transfusion dependent 2 nondiagnostic BMs

Lower GI bleed s/p hemicolectomy
B12 deficiency Monthly IM B12
Fe deficiency Menorrhagia s/p hysterectomy Oral
Iron
PUD s/p Billroth 2 vagotomy
Recurrent n/v Occasional hematemesis 7 weight
loss No diarrhea, abd pain
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47 year old woman with paresthesias and anemia
2007 (weeks)
2006 (6 months)
2000 (years)
1980s
1990
1990s
Refractory anemia (po iron, IM B12,
darbo) Transfusion dependent 2 nondiagnostic BMs

Lower GI bleed s/p hemicolectomy
B12 deficiency Monthly IM B12
Fe deficiency Menorrhagia s/p hysterectomy Oral
Iron
PUD s/p Billroth 2 vagotomy
Recurrent n/v Occasional hematemesis 7 weight
loss No diarrhea, abd pain
Numbness Tingling Hands/feet
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47 year old woman with paresthesias and anemia

• Neurologic abnormalities
• Interesting physical exam findings

• Anemia
• Interesting hematological findings

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Neurologic Abnormalities

• Symptoms
• Numbness, tingling in hands, feet x wks
• Exam sensory deficits
• Normal light touch, 2 point discrimination
• Decreased vibratory sensation
• Decreased position sense first toe
• proprioception

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Neurology

• Location, location, location
• Pattern of nerve involvement
• Timing, duration
• Tests EMG/NCS, Imaging

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Location, location, location
Neuroanatomic Location
CNS
PNS
Brain
Cord
Focal lesion
Meningeal Process (meningitis)
Diffuse Process (encephalitis)
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Patterns of peripheral neuropathy
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Patterns of peripheral neuropathy
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Patterns of peripheral neuropathy
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Peripheral Neuropathies Pathophysiology

• Neuronopathies
• Axonopathies
• Myelinopathies

Poncelet, Amer Fam Phy, 1998
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Peripheral Neuropathies

• Neuronopathies (polio)
• Motor neuron or DRG
• Subsequent degeneration of peripheral process
• Recovery usually incomplete

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Peripheral Neuropathies

• Axonopathy
• Toxic or metabolic injury
• Distal axon degenerates
• Concomitant breakdown of myelin sheath
• Dying-back
• Length dependent
• Small fibers first

• Myelinopathies
• At myelin sheath, patchy and segmental
• Inflammatory
• Axons spared or later involved
• Usually full recovery
• Large fibers first

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Nerve fibers

• Large myelinated
• Touch
• Pressure
• Proprioception
• Vibratory sensation
• (Dorsal Column)

• Small unmyelinated
• Touch
• Pain
• Temperature

2 point discrimination higher cortical
function Graphesthesia (recognize
letters) Stereognosis (recognize objects)
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Subacute, symmetrical, polyneuropathy of large
myelinated nerves

• Diabetes
• Alcohol
• B12 deficiency
• Hypothyroidism
• Paraneoplastic
• HIV
• Arsenic poisoning

• Lyme disease
• Vasculitis
• Amyloidosis
• Uremia
• Drugs
• Syphilis
• And more

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Acute Arsenic Exposure

• Ingestions (water) or inhalation
• GI nausea, vomiting, abdominal pain, diarrhea
• Shock, ARDS, renal failure
• If survive
• Hepatitis, pancytopenia (1 week)
• Sensorimotor peripheral neuropathy (3 wks)

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Chronic Arsenic Exposure

• Longer exposure to lower levels
• Sensorimotor peripheral neuropathy
• Skin lesions
• Pigmentation changes
• Scaling
• Squamous cell carcinoma
• Hair, nails

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47 year old woman with paresthesias and anemia

• Neurologic abnormalities
• Interesting physical exam findings

• Anemia
• Interesting hematological findings

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The RBC Oxygenation

• Lifespan 120 days
• Travels 300 miles
• 780 ms in pulmonary capillary
• Erythropoiesis
• Functioning marrow
• Erythropoietin
• Hemoglobin substrates
• 300 million hgb/RBC

Bird, The Red Cell, British Medical J
19721293-7 Nature
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Causes of Anemia

• Decreased production (75)
• Maturation defects
• ineffective erythropoiesis
• Excess loss bleeding or hemolysis

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Our patient

• Hct 27
• MCV 98

anemia
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Our patient

• Hct 27
• MCV 98
• Reticulocytes 2
• Normal LDH

anemia
BM problem No hemolysis
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Our patient

• Hct 27
• MCV 98
• Reticulocytes 2
• Normal LDH
• Anisopoikilocytosis
• Variations in size (?RDW)
• Variations in shape
• Neutropenia ANC 378
• Monocytosis
• Eosinophilia

anemia
BM problem No hemolysis
Ineffective hematopoiesis
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Normal Erythroid Maturation
(hemoglobin accumulation)
Reticulocyte
UpToDate
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Ineffective Erythropoiesis

• Nuclear (macrocytosis)
• B12 deficient
• Folate deficient
• Drugs
• MTX
• chemo
• Myelodysplasia

• Cytoplasmic (microcytosis)
• Iron
• Heme synthesis
• Globin synthesis

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Myelodysplastic Syndrome

• Heterogeneous spectrum of stem cell malignancies
• Complications bone marrow failure
• Variable features, no biologic marker
• Diagnosis based on morphology
• Cytogenic studies helpful
• 40-70 chromosomal abnormalities

List et al, American Society of Hematology
Education Program Book, 2004
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WHO classification, revised 2001

• Refractory anemia (RA)
• RA with ringed sideroblasts (RARS)
• Refractory cytopenia with multilineage dysplasia
  (RCMD)
• RCMD-RS
• RA with excess blasts -1, and -2
• MDS Unclassified
• MDS with isolated deletion (5q)

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MDS mimickers

• Megaloblastic anemia B12 deficiency
• Toxins (arsenic)
• Alcohol
• Cytotoxic agents
• HIV
• and more

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47 year old woman with paresthesias and anemia

• Neurologic abnormalities
• Interesting physical exam findings

• Anemia
• History of iron and B12 deficiency
• Interesting hematological findings

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Our Patient Billroth procedure

• Billroth 2
• Distal partial gastrectomy
• Re-anastamosis jejunum
• Indications
• PUD
• Gastric cancer
• Similar to Roux en Y

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Post Gastrectomy Complications

• Iron deficiency
• B12 deficiency
• Folate deficiency
• Calcium, Vitamin D
• Other deficiencies
• Gastric cancer
• Stump cancer

• Recurrent ulceration
• Diarrhea
• Dumping
• Vomiting
• Malabsorption
• Dehydration

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Iron

• Essential for oxygen binding
• Sources
• Diet absorbed proximal small intestine
• Recycled from senescent red cells
• Deficiency
• increased demand (pregnancy, adolescence)
• blood loss (menses, GI bleed)
• Poor absorption (gastrectomy, sprue, diet)
• Ineffective erythropoiesis ? iron overload

Heme group
http//en.wikipedia.org/wiki/Hemoglobin
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Does our patient have iron deficiency?

• YES?
• s/p Billroth
• No proximal small bowel
• Recurrent GI bleeding
• Goodies powders
• Iron 13
• TIBC 373
• 3 saturation

• NO
• History
• Compliant w/ iron
• No picca
• Macroctyic anemia
• Ferritin 200
• BM biopsy
• Iron stores are normal
• Ringed sideroblasts

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What is a ringed sideroblast?

• Adequate total iron
• Iron uptake by mitochondria of developing
  erythroid cell,
• Cant incorporate into heme
• Mitochondria surround the nucleus ? ring

Sideroblastic anemia ineffective hematopoiesis
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Sideroblastic Anemia

• Hereditary
• Idiopathic
• Myelodysplastic syndrome
• Acquired
• Prolonged exposure alcohol, lead, drugs
• Nutritional ?folic acid, ? copper, ?zinc
• RA, heme malignancies, PCT, renal disease,
  hyperthyroidism

www.irondisorders.org/Disorders/Sideroblastic.asp
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Lead Toxicity

• Exposures
• Work (car batteries, cables), lead gas
• Paint
• Moonshine
• Ethnic medications
• Lead glazed cookware

UpToDate
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Lead Toxicity

• Respiratory (adults) or GI absorption (kids)
• adults have increased GI absorption if iron,
  calcium, or zinc deficient
• 99 bound to RBC
• Basophilic stippling
• Heme alterations
• 1 free in plasma
• kidneys, soft tissues, skeleton, neuropathy

UpToDate
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Lead Toxicity Symptoms

• GI abdominal pain
• CNS irritability, poor concentration
• Anemia
• Peripheral neuropathy
• Motor deficits
• Extensor weakness
• Wrist or ankle drop

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(No Transcript)
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Does our patient have lead toxicity?

• YES?
• Lives in older home
• Sideroblastic anemia
• GI symptoms
• Peripheral neuropathy

• NO
• No abdominal pain, constipation
• Mental status normal
• Sensory neuropathy

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Post Gastrectomy Complications

• Iron deficiency
• B12 deficiency
• Folate deficiency
• Calcium, Vitamin D
• Other deficiencies
• Gastric cancer
• Stump cancer

• Recurrent ulceration
• Diarrhea
• Dumping
• Vomiting
• Malabsorption
• Dehydration

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Folate Deficiency

• Causes of folate deficiency
• Poor diet
• elderly at risk
• Alcoholism
• Pregnancy
• Hemolysis
• Drugs MTX, trimethoprim, phenytoin

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Folate Deficiency

• Plasma levels easily corrected
• RBC level more accurate
• more expensive
• Macrocytic anemia
• like B12 deficiency
• Does not give neurologic symptoms

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B12 (Cobalamin) Absorption

• Dietary sources meat and dairy
• Acid and pepsin frees B12 from proteins
• Pancreatic proteases
• Intrinsic factor from gastric parietal cell
• Pernicious Anemia
• Ileum with Cbl-IF receptors

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Our Patient Billroth 2 ? B12 Deficiency

• Dietary sources meat and dairy
• Acid and pepsin frees B12 from proteins
• Pancreatic proteases
• Intrinsic factor from gastric parietal cell
• Pernicious anemia
• Ileum with Cbl-IF receptors
• Up to 70 of patients will develop B12 deficiency

Fujoika, Diabetes Care, Feb 2005
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B12 deficiency

• Heme ineffective erythropoiesis
• macrocytic anemia
• increased LDH
• low reticulocytes
• neutropenia (hypersegmented polys)
• Neurologic subacute combined degeneration
• symmetric polyneuropathy, legs arms
• ?proprioception, vibration, ataxia, spasticity

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B12 deficiency diagnosis

• Cbl level 300 pg/mL excludes deficiency
• Except in up to 5 of cases
• Homocysteine and methylmalonic acid
• B12 dependent metabolites
• Both elevated in B12 deficiency
• Only homocysteine elevated in folate deficiency

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Vitamin B12-dependent enzymes L-methylmalonyl-CoA
mutase (top) and methionine synthase (bottom)
folate
Sumner, AE, Ann Intern Med 1996124
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Does our patient have B12 deficiency?

• YES?
• HIBGIA
• Gastrectomy
• Macrocytic anemia
• Neutropenia
• Peripheral neuropathy

• Unlikely
• Not responding to IM replacement
• Normal LDH
• Hypercellular marrow
• B12 905
• Unless in that 5
• MMA, homocysteine

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So Whats Left?
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Copper
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Copper

• Essential cofactor in redox chemistry
• Similar to iron
• Required for many biological processes
• Delicate balance
• Dietary intake
• Stomach, small intestine absorption
• Liver metabolism
• Biliary excretion

Pena, Journal of Nutrition, 1999129
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Copper Deficiency

• Extremely rare
• Ubiquitous distribution
• Low daily requirements
• Prolonged parental nutrition without Cu
• Gastrectomy
• Malabsorption
• Zinc toxicity, competition

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Neurology 20046333-39
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Copper Deficiency Neurologic Manifestations

• Like subacute combined degeneration1
• marked dorsal column deficits
• First report 46 F previous gastrectomy2
• 13 cases to date3
• Average symptoms 2.9 yrs (0.17 10)
• 10/13 women
• 6/13 gastric surgery or malabsorption
• Residual neurologic deficits in all

1Everett, Neurology 2006, 2Schleper, J Neuro
2001, 3Kumar, Neurology 2004
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Copper Deficiency Hematologic Manifestations

• Anemia (micro, macro, normocytic)
• Bone Marrow
• Vacuolization
• Megaloblastic
• Ringed sideroblasts
• Animal models deficient cytochrome oxidase
  activity ? failed heme synthesis

Gregg, Blood 2002
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Copper Deficiency Hematologic Manifestations

• Neutropenia, unclear reasons
• Thrombocytopenia less common
• Often confused with MDS
• Neurologic manifestations can be present in
  absence of hematologic manifestations

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Swayback myelopathyMenkes disease
www.cda.org.uk/megab2/general/cuFarm/sec11.htm
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Does our patient have Copper deficiency?

• Differential Diagnosis
• Paraneoplastic
• HIV
• B12 deficiency
• Arsenic toxicity
• Lead toxicity
• MDS

• YES
• Gastrectomy
• Peripheral neuropathy
• Ineffective erythropoiesis
• Macrocytic anemia
• Neutropenia
• Ringed sideroblasts

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• Final Diagnosis Copper Deficiency
• Test Copper Level