Hematology CPC

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Hematology CPC

• Bao Le, DO
• Internal Medicine
• October 9 , 2007

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Objectives

• Presenting a case
• Bariatric surgery
• Neurologic complications of Bariatric surgery
• Peripheral neuropathy
• Macrocytic anemia
• Myelodysplastic syndrome
• Conclusion

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Case

• CC Sore throat.
• HPI A 43 y/o man presents to the ER with
• A 3-day history of mouth and throat pain
  associated with a white coating.
• Temperature of 102 F at home with chills.
• Progressively fatigued over past 5 months.
• Overt dyspnea on exertion with walking 10 yards.
• Progressive numbness of his fingers and toes
  ascending to mid shin and mid forearm over one
  year.
• He denies
• Changes in mentation or tongue soreness.
• Bright red blood per rectum or black tarry
  stools.

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Case (Cont)

• ? PMH
• Bariatric surgery at the age of 25, in 1987.
• Weighed 541 lbs prior to the surgery.
• PSH
• Bariatric surgery.
• Family hx
• No blood dyscrasias.
• Positive for obesity.

• Social hx
• Worked as a laborer.
• No heavy metal exposure.
• 10 pack/year tobac history.
• Less than 1 drink EtOH/day.
• Medications
• B12 injections.
• Iron 325 mg BID.
• MVI.
• ROS
• Pertinent per HPI.

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Case (Cont)

• Physical Exam
• VS 110/75, 105, 97 RA, 101.2 F, 240 lbs, 61
• GEN toxic, uncomfortable, no dyspnea with
  conversation.
• HEENT oral mucosa coated with thrush, tongue
  appears normal, non-icteric sclera, conjuctiva
  was pale.
• NECK prominent carotid pulse, no thrill or
  bruit, no lymphadenopathy.
• CV tachycardic, S1 S2, no m/g/rubs.
• RESP clear.
• ABD mod obese, no TTP, no organomegaly.

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Case (Cont)

• Physical Exam (cont)
• EXT chronic venous insufficiency changes.
• DERM no rashes.
• PSYCH appropriate.
• NEURO
• distal reflexes decreased.
• distal sensation decreased.
• able to ambulate.
• normal speech pattern.

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Case (Cont)

• LAB
• G 20, M 15, L 65
• MCV 108, RDW 13
• Ferritin lt 10 (39-150)
• B12 gt 700 pg/mL
• MMA not elevated
• Folic acid normal
• LDH 210 (60-200)
• Liver and Renal normal

• PBS
• Severe leukopenia
• Few (lt 1 per HPF/avg) hypersegmented neutrophils
• No blasts
• Macrocytic RBC without fragmentation
• Bone Marrow
• Hypercellular 70
• Trilineage dysplasia
• Ringed sideroblasts
• lt 5 blasts
• Cytogenetics normal

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Case Overview
Neurological deficits
Sore throat DOE/Fatigue
43 y/o man
Constitutional symptoms
Hematologic abnormalities Pancytopenia
Bariatric surgery
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Obesity and Bariatric Surgery

• According to 2000 US Census 63 million adult
  Americans with obesity, BMI 30, and 10.5
  million with morbid obesity, BMI 40.
• Annual obesity-related medical expenditures were
  substantial.
• The rise in the prevalence of obesity is
  associated with increases in the prevalence of
  obesity comorbidities.
• The loss of life expectancy due to obesity is
  profound.
• In 1991, NIH established bariatric surgery
  guidelines BMI 40 or 35 in the presence of
  significant comorbidities.

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Gastrointestinal Tract
Calcium Iron, Phosphorus, zinc Copper, Vitamins
B12, Zinc Copper, Phosphorus Vitamins
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Bariatric surgery techniques
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• The prospective, controlled Swedish Obese
  Subjects study involved 4047 obese subjects.
• Age 37-60, BMI gt 34 for male, BMI gt 38 for
  female.
• Conventional treatment 2037
• Bariatric surgery 2010
• Average follow-up 10.9 years
• Surgical group had a hazard ratio of 0.76
  compared to control group ( 95 confidence
  interval, 0.59 0.99, P 0.04)

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• 136 articles and 22094 patients.
• JAMA, October 13, 2004 - Vol 292.
• Results
• Resolution of DM 76.8
• Resolution of HTN 61.7
• Improvement of lipid 83
• Resolution of OSA 85.7

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Neurologic Complication of Bariatric
Surgery

• Encephalopathy
• Behavior abnormalities
• Cranial nerve palsies
• Ataxia
• Seizure
• Myelopathy
• Plexopathy
• Mononeuropathy
• Myopathy
• Myotonia
• Peripheral neuropathy

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• Department of Neurology, Mayo Clinic and Mayo
  Foundation, Rochester, MN.
• Neurology 2004 631462-1470.
• Retrospective review study, 1985 - 2001.
• Open Cholecystectomy 300 BS 435.
• 
  BS 16
• Peripheral Neuropathy P lt 0.001
• 
  Open Chol 3

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• Neuropathic characteristics of PN after BS

Sensory-predominant PN Insidious onset Chronic
course Distal LE/UE
Mononeuropathy Carpal Tunnel Syndrome
Radiculoplexus neuropathy Lumbosacral Cervical
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• Risk factors for PN after BS
• A greater absolute weight loss
• A faster rate of weight loss
• A lower postsurgery BMI
• Lower serum albumin
• Lower transferrin concentrations
• Prolonged postsurgery GI symptoms
• Less MVI and Ca supplement
• Not attending nutritional clinics

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Symmetric Polyneuropathies

• Inflammatory/Immune-Mediated Neuropathies
• Guillain-Barre syndrome
• Chronic inflammatory demyelinating
  polyradiculoneuropathy
• Vasculitic neuropathy
• Sarcoid neuropathy
• Neuropathies associated with connective tissue
  disease

• Toxic Neuropathies
• Drugs, metals, alcohol
• Neuropathies Associated with Cancer
• Remote effects of cancer
• Direct tumor infiltration

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Symmetric Polyneuropathies

• Inherited Neuropathies
• Hereditary motor sensory neuropathies
• Giant axonal neuropathy
• Porphyric neuropathies
• Lysosomal enzyme deficiency (Fabry disease)
• Lipoprotein disorders
• Neuropathies Associated with Infection
• HIV
• Leprosy
• Lyme disease

• Neuropathies Associated with Organ System Failure
• Kidney, lung, liver
• Critical illness polyneuropathy
• Organ transplantation
• Diabetic Polyneuropathy
• Vitamin Deficiencies
• Cobalamin (B12)
• Vitamin E
• Thiamine (B1)
• Pyridoxine (B6)

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Neurologic Manifestations of Cobalamin (B12)
Deficiency

• Distal paresthesias
• Unsteady gait
• Deficit in vibratory sensation and proprioception
• Diffuse hyperreflexia
• Loss of reflex at ankle
• Neurobehavioral changes apathy, irritability,
  memory loss.

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Neurologic Manifestations of Vitamin E Deficiency

• Progressive gait ataxia
• Night blindness
• Loss of vibratory sensation and proprioception
• Absent reflexes
• Ptosis/Ophthalmoplegia
• Dysarthric speech
• Intention tremor

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Neurologic Manifestations of Thiamine (B1)
Deficiency

• Fatigue/Irritability
• Distal paresthesias affecting feet with burning
  pain
• Distal sensory loss
• Hyporeflexia
• Wernicke-Korsakoff syndrome mental confusion,
  ataxia, ophthalmoplegia
• Cerebellar degeneration

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Neurologic Manifestations of Pyridoxine (B6)
Deficiency

• Paresthesias in distal limbs
• Gait instability
• Distal areflexia with normal muscle strength
• Lhermitte sign (Barber Chair Phenomenon)
• EMG
• Absent or reduced sensory nerve potentials
• Normal motor nerve conduction

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Gastrointestinal Tract
Calcium Iron, Phosphorus, zinc Copper, Vitamins
B12, Zinc Copper, Phosphorus Vitamins
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• Department of Neurology and Division of
  Gastroenterology and Hepatology, Mayo Clinic,
  Rochester, MN.
• Neurology 20046333-39
• Chart review of 13 patients with known copper
  deficiency and neurologic deficits.

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• 45 y/o woman
• Persistent LE paresthesias and difficulty
  ambulating
• PE Marked pallor and palpable spleen
• Neuro
• Hyperactive reflexes
• Markedly decreased vibratory sense LE
• Extremely ataxic gait
• Cognition normal
• BM
• Hypercellular
• Ringed sideroblasts

• 45 y/o man
• 4-month hands and feet paresthesias
• Progressive weakness, exertional dyspnea,
  difficulty ambulating
• PE Marked pallor and mild hepatosplenomegaly
• Neuro
• Slow and clumsy toe tapping
• Decreased vibratory sensation and proprioception
• Marked truncal ataxia
• Brisk reflexes

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Copper Deficiency Causes Demyelination
2 Atoms of Copper
O2
?
Superoxide Dismutase
O2
H2O2
Oxidadive damages DNA Proteins Lipids
Demyelination
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Macrocytic Anemia

• Drugs
• Alcoholism
• Reticulocytosis
• Liver disease
• Hypothyroidism
• Vitamin B12 deficiency

• Folate deficiency
• Multiple myeloma
• Aplastic anemia
• Acute leukemia
• Myelodysplastic syndrome

Chemotherapeutic agents
Diuretics Cyclophosphamide
Triamterene Hydroxyurea
Anticonvulsant agents Methotrexate
Phenytoin Azathioprine
Primidone Mercaptopurine
Valproic acid 5-Fluoracil
Anti-inflammatory Antiretroviral
Sulfasalazine Zidovudine

Stavudine Hypoglycemia Metformin Antimicrobials
Pyrimethamine Sulfamethoxazole Trimethoprim V
alacyclovir
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Myelodysplastic Syndrome

• MDS comprises a heterogeneous group of malignant
  stem cell disorders characterized by dysplastic
  and ineffective blood cell production.
• These disorders may occur de novo or arise years
  after exposure to potentially mutagenic therapy.
• The precise incidence of de novo MDS is not
  known.
• MDS manifests as symptomatic anemia (60-80),
  neutropenia (50-60), and thrombocytopenia
  (40-60).
• Clinical presentations
• Incidental findings on routine laboratory
  studies.
• Fatigue, malaise, and a general sense of
  tiredness.
• Petechiae, ecchymoses, nose and gum bleeding.
• Fever or shock.

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Myelodysplastic Syndrome

• Physical Exam
• Pale, petechiae, purpura
• Hepatomegaly, splenomegaly, LN
• Tachycardia, fever
• PBS
• Macrocytic with oval-shaped RBC
• Basophilic stippling, Howell-Jolly bodies
• Neutropenia
• Thrombocytopenia
• Bone Marrow
• Hypercellularity with trilineage dysplastic
  changes
• Ringed sideroblasts
• Cytogenetics
• Normal, 5q-, 7q-, 20q-, trisomy 8

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FAB Criteria for MDS Subgroups
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Myelodysplastic Syndrome
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Myelodysplastic Syndrome
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Myelodysplastic Syndrome

• Treatment
• Supportive care
• Transfusion as needed
• Iron chelation
• Low-intensity therapy
• Anemia EPO G-CSF (ringed sideroblast and serum
  Epo levels lt 500 mU/mL)
• Neutropenia G-CSF or GM-CSF
• Thrompocytopenia IL-11, thrombopoietin, danazol
• 5-azacytidine
• Immunosuppressive therapy ATG and cyclosporine
• Anti-TNF, anti-angiogenesis agents
• High-intensity therapy
• Chemotherapy
• Hemopoietic stem cell transplantation (HSCT)

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Copper Deficiency
Central/peripheral neuropathy
Copper Deficiency
?
MDS
Anemia Leukopenia
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• Baylor College of Medicine, Houston, Tx and the
  Department of Pathology, University of Alabama at
  Birmingham.
• Blood, 15 August 2002. Vol 22, number 4
  1493-1495.
• 44 y/o woman with h/o gastric resection with
  Billroth II for peptic ulcer who presents with
  macrocytic anemia and leukopenia.
• WBC 1.5 with 19 neutrophils, hemoglobin 6.4
  g/dl, MCV 102, platelet count 192.
• B12, folate, and ferritin were elevated.
• PBS macrocytic, oval shaped RBC
• Bone marrow dyserythropoiesis, dysmyelopoiesis,
  ringed sideroblasts, and prominent hemosiderin in
  plasma cell.
• Cytogenetic studies were normal.

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• She was diagnosed with MDS, FAB subtype
  refractory anemia with ringed sideroblasts
  (RARS).
• Treated with G-CSF and EPO.
• Referred for BM transplantation.
• Treated with 6 weeks of IV copper chloride.
• Normalized hematologic abnormalities and bone
  marrow aspiration.

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• Department of Neurology, University of Michigan,
  MI.
• Arch Neurol 2003 601303-1306.
• 46 y/o male c/o
• CP/SOB
• Progressive numbness and weakness of both LE
• Poor balance
• Neurologic Exam
• Intact cranial nerves
• Normal mentation
• Brisk DTRs in LEs
• Bilateral plantar flexor response
• Markedly reduced vibratory sensation and
  propioception
• Wide based gait

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• Lab
• Hemoglobin 7.9 g/dL
• Copper lt 10 ug/dL (80 120 ug/dL)
• Zinc 184 ug/dL (80 120 ug/dL)
• 24-hour urine copper 0.04 mg/d ( 0.03 0.05
  mg/d)
• 24-hour urine zinc 5.01 mg/d ( 0.24 0.4 mg/d)
• Treatment
• Started copper supplement 2 mg/d
• Normalize hematologic abnormalities
• Worsening neurologic deficits
• Increased to 8 mg/d
• Improving neurologic deficits

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Hyperzincemia Induces Copper Deficiency

• ? Zinc
• ? Metallothionein
• Metallothionein competes
  Copper receptors in GI
• ? GI Copper Absorption
• Copper Deficiency

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Iron Metabolism Depends on Copper
Copper (6 atoms)
Ceruloplasmin
Ferrous Iron Fe
Ferric Iron Fe
Transferrin
Apotransferrin Apo Tf
Abnormal iron metabolism
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• 82 of 3-5 day-old pigs
• Control with no iron
• Control with PO iron
• Control with IM iron
• Exp with PO iron
• Exp with IM iron
• Study over 14 weeks

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Conclusion
Abnormal iron metabolism
Copper deficiency
Peripheral polyneuropathy
Myelodysplastic syndrome RARS
Neutropenia
Macrocytic anemia
Thrombocytopenia
Neutropenic fever
Fatigue, DOE
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Lab/Study
Blood and Urine Culture

• Dr. Hurley
• Dr. Starr
• Copper and Ceruloplasmin Level
• Complete iron panel
• Dr. Clark

Rectal Exam!!!
EMG
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References

• Xylina T. Gregg, Vishnu Reddy, and Josef T.
  Prchal. Copper deficiency masquerading as
  myelodysplastic syndrome. Blood 2002 100
  1493-1495.
• P. Thaisetthawatkul, M.L. Collazo-Clavell, M.G.
  Sarr, J.E. Norell, and P.J.B. Dyck. A controlled
  study of peripheral neuropathy after bariatric
  surgery. Neurology 2004 63 1462-1470.
• Katalin Juhasz-Pocsine, Stacy A. Rudnicki, Robert
  L. Archer, Sami I. Harik. Neurlogic complications
  of gastric bypass surgery for morbid obesity.
  Neurology 2007681843-1850.
• Jerry R. Mendell, John T. Kissel, David R.
  Cornblath. Diagnosis and Management of Peripheral
  Nerve Disorders. Oxford University Press, Inc.
  New York, NY, 2001.
• Henry Buchwald, Yoav Avidor, Eugene Braunwald,
  Michael K. Jensen, Walter Pories, Kyle Fahrbach,
  Karen Schoelles. Bariatric Surgery. JAMA
  20042921724-1728.
• Neeraj Kumar, John B. Gross, and Eric Ahlskog.
  Copper deficiency myelopathy porduces a clinical
  picture like subacute combined degeneration.
  Neurology 20046333-39.
• P Peter L. Greenberg, Neal S. Young, and Norbert
  Gattermann. Myelodysplastic Syndromes. Hematology
  2002 136-161.
• G. Richard Lee, Sergio Nacht, John N. Lukens, and
  G. E. Cartwright. Iron Metabolism in
  Copper-Deficient Swine. The Journal of Clinical
  Investigation 1968 472058-2069.
• Florence Aslinia, Joseph J. Mazza, Steven H.
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  Macrocytosis. Clinical Medicine Research
  20064 236-241.
• Edward H. Livingston. Complications of Bariatric
  Surgery. Surgical clinics of North America
  200585853-868.
• C.I. Prodan, N.R. Holland, P.J. Wisdom, S.A.
  Burstein, S.S. Bottomley. CNS Demyelination
  Associated with copper Deficiency and
  Hyperzincemia. Neurology 2002591453-1456.
• Neeraj Kumar, John B. Gross, J. Eric Ahlskog.
  Myelopathy due to Copper Deficiency. Neurology
  200361 273-274.
• Peter Hedera, John K. Fink, Paula L. Bockenstedt,
  George J. Brewer. Myelopolyneuropathy and
  Pancytopenia due to copper Deficiency and High
  Zinc Levels of Unknown Origin. Arch Neurol
  2003601303-1306.

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Thank you! Questions?
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Trivia

• Jon Brower Minnoch (USA, 1941-1983).
• Weights 1397 lbs (635 kg).
• Heaviest person.

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Trivia

• Manuel Uribe from Monterrey, Mexico.
• 40 years old and weights 1225 lbs.
• In March 2006, underwent most extreme BS in
  Italy.

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