Hematology CPC

Bao Le, DO

Internal Medicine

October 9 , 2007

Objectives

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

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.

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.

Case (Cont’)

Physical Exam: VS: 110/75, 105, 97% RA, 101.2 F, 240 lbs, 6’1” 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.

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.

Case (Cont’)

LAB:

G: 20%, M: 15%, L: 65%MCV: 108, RDW: 13

Ferritin: < 10 (39-150) B12: > 700 pg/mL MMA: not elevated Folic acid: normal LDH: 210 (60-200) Liver and Renal: normal

PBS: Severe leukopenia Few (< 1 per HPF/avg)

hypersegmented neutrophils No blasts Macrocytic RBC without

fragmentation

Bone Marrow: Hypercellular: 70% Trilineage dysplasia Ringed sideroblasts < 5% blasts

Cytogenetics: normal

5.61000 65000

Case Overview

Bariatric surgeryHematologic abnormalities

Pancytopenia

Neurological deficits

Constitutional symptoms

Sore throatDOE/Fatigue

43 y/o man

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.

Gastrointestinal Tract

B12, ZincCopper, Phosphorus

Vitamins

CalciumIron, Phosphorus, zinc

Copper, Vitamins

Bariatric surgery techniques

The prospective, controlled Swedish Obese Subjects study involved 4047 obese subjects.

Age 37-60, BMI > 34 for male, BMI > 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)

University of Oklahoma Health Science Center. Neurology 2002;59:1953-1456

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 %

Neurologic Complication of Bariatric Surgery

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

Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, MN.

Neurology 2004; 63:1462-1470. Retrospective review study, 1985 - 2001. Open Cholecystectomy: 300; BS: 435.

BS: 16 % Peripheral Neuropathy: P < 0.001

Open Chol: 3 %

Neuropathic characteristics of PN after BS

Sensory-predominant PNInsidious onsetChronic course

Distal LE/UE

MononeuropathyCarpal Tunnel Syndrome

Radiculoplexus neuropathyLumbosacral

Cervical

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

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

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)

Neurologic Manifestations of Cobalamin (B12) Deficiency

Distal paresthesiasUnsteady gaitDeficit in vibratory sensation and

proprioceptionDiffuse hyperreflexiaLoss of reflex at ankleNeurobehavioral changes: apathy,

irritability, memory loss.

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

Neurologic Manifestations of Thiamine (B1) Deficiency

Fatigue/IrritabilityDistal paresthesias affecting feet with

burning painDistal sensory lossHyporeflexiaWernicke-Korsakoff syndrome: mental

confusion, ataxia, ophthalmoplegiaCerebellar degeneration

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

Gastrointestinal Tract

B12, ZincCopper, Phosphorus

Vitamins

CalciumIron, Phosphorus, zinc

Copper, Vitamins

Department of Neurology and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.

Neurology 2004;63:33-39 Chart review of 13

patients with known copper deficiency and neurologic deficits.

University of Oklahoma Health Science Center. Neurology 2002;59:1953-1456

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

Copper Deficiency Causes Demyelination

O2

O2

H2O2

Superoxide Dismutase

2 Atoms of Copper

↑Oxidadive damages

DNAProteinsLipids

Demyelination

Macrocytic Anemia

Drugs Alcoholism Reticulocytosis Liver disease Hypothyroidism Vitamin B12

deficiency

Folate deficiency Multiple myeloma Aplastic anemia Acute leukemia Myelodysplastic

syndrome

Chemotherapeutic agents DiureticsCyclophosphamide TriamtereneHydroxyurea Anticonvulsant

agentsMethotrexate PhenytoinAzathioprine PrimidoneMercaptopurine Valproic acid5-Fluoracil Anti-inflammatory

Antiretroviral SulfasalazineZidovudine Stavudine

HypoglycemiaMetformin

AntimicrobialsPyrimethamineSulfamethoxazoleTrimethoprimValacyclovir

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.

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+

FAB Criteria for MDS Subgroups

Type BM blasts (%)

Peripheral blood

blasts (%)

Auer rods

Monocytes > 1000/ul

Ringed sideroblasts

> 15% of nucleated erythroid cells

RA (21%) <5 ≤1 No No No

RARS (17%) <5 ≤1 No No Yes

RAEB (37%) 5-20 <5 No No ±

CMML (13%) ≤ 20 <5 No Yes ±

RAEB-T (12%)

(AML)

21-30 or ≥5 ± ± ±

Myelodysplastic Syndrome

Myelodysplastic Syndrome

Myelodysplastic Syndrome

Treatment: Supportive care:

Transfusion as needed Iron chelation

Low-intensity therapy: Anemia: EPO ± G-CSF (ringed sideroblast and serum Epo levels < 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)

Copper Deficiency

Copper Deficiency

Central/peripheralneuropathy

AnemiaLeukopenia

MDS?

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.

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.

Department of Neurology, University of Michigan, MI. Arch Neurol 2003: 60;1303-1306.

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 DTR’s in LE’s Bilateral plantar flexor response Markedly reduced vibratory sensation and propioception Wide based gait

Lab: Hemoglobin: 7.9 g/dL Copper: < 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

Hyperzincemia Induces Copper Deficiency

↑ Zinc

↑ Metallothionein

Metallothionein competes Copper receptors in GI

↓ GI Copper Absorption

Copper Deficiency

Iron Metabolism Depends on Copper

Ferrous IronFe++

ApotransferrinApo Tf

Ferric IronFe+++ Transferrin

Ceruloplasmin

Copper (6 atoms)

Abnormal iron metabolism

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

Conclusion

Copper deficiency

Peripheral polyneuropathyMyelodysplastic syndrome

RARS

Neutropenia

Neutropenic fever

Macrocytic anemia

Fatigue, DOE

Thrombocytopenia

Abnormal iron metabolism

Lab/Study

Dr. Hurley:

Dr. Starr:

Copper and Ceruloplasmin LevelComplete iron panelDr. Clark:

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 2007:68:1843-1850.

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 2004;292:1724-1728.

Neeraj Kumar, John B. Gross, and Eric Ahlskog. Copper deficiency myelopathy porduces a clinical picture like subacute combined degeneration. Neurology 2004;63:33-39.

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; 47:2058-2069.

Florence Aslinia, Joseph J. Mazza, Steven H. Yale. Megaloblastic Anemia and Other Causes of Macrocytosis. Clinical Medicine & Research 2006;4: 236-241.

Edward H. Livingston. Complications of Bariatric Surgery. Surgical clinics of North America 2005;85:853-868. C.I. Prodan, N.R. Holland, P.J. Wisdom, S.A. Burstein, S.S. Bottomley. CNS Demyelination Associated with

copper Deficiency and Hyperzincemia. Neurology 2002;59:1453-1456. Neeraj Kumar, John B. Gross, J. Eric Ahlskog. Myelopathy due to Copper Deficiency. Neurology 2003;61: 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 2003;60:1303-1306.

Trivia

Jon Brower Minnoch (USA, 1941-1983).

Weights 1397 lbs (635 kg).

Heaviest person.

Trivia

Manuel Uribe from Monterrey, Mexico.

40 years old and weights 1225 lbs.

In March 2006, underwent most extreme BS in Italy.