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 the surgery.

prior to  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, S 1  RESP: clear.

S 2 , no m/g/rubs.

 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.

 LAB: 1000 5.6

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

Case (Cont’)

65000  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

Sore throat DOE/Fatigue

Case Overview

Neurological deficits 43 y/o man Constitutional symptoms Bariatric surgery Hematologic abnormalities Pancytopenia

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

Calcium Iron, Phosphorus, zinc Copper, Vitamins B12, Zinc Copper, Phosphorus 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)

 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 PN Insidious onset Chronic course Distal LE/UE Mononeuropathy Carpal Tunnel Syndrome Radiculoplexus neuropathy Lumbosacral 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 paresthesias  Unsteady gait  Deficit in vibratory sensation and proprioception  Diffuse hyperreflexia  Loss of reflex at ankle  Neurobehavioral 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/Irritability  Distal paresthesias affecting feet with burning pain  Distal sensory loss  Hyporeflexia  Wernicke-Korsakoff syndrome: mental confusion, ataxia, ophthalmoplegia  Cerebellar 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

Calcium Iron, Phosphorus, zinc Copper, Vitamins

Gastrointestinal Tract

B12, Zinc Copper, Phosphorus 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.

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

Copper Deficiency Causes Demyelination

2 Atoms of Copper ↑ O 2 Superoxide Dismutase Oxidadive damages DNA Proteins Lipids Demyelination O 2 H 2 O 2

Macrocytic Anemia

      Drugs Alcoholism Reticulocytosis Liver disease Hypothyroidism Vitamin B12 deficiency      Folate deficiency Multiple myeloma Aplastic anemia Acute leukemia Myelodysplastic Zidovudine Stavudine Hypoglycemia Metformin Antimicrobials Pyrimethamine Sulfamethoxazole Trimethoprim Valacyclovir syndrome

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 RA (21%) RARS (17%) RAEB (37%) CMML (13%) BM blasts (%) <5 <5 5-20 ≤ 20 RAEB-T (12%) (AML) 21-30

or

Peripheral blood blasts (%) ≤1 Auer rods No Monocytes > 1000/ul No Ringed sideroblasts > 15% of nucleated erythroid cells No ≤1 <5 No No No No Yes ± <5 ≥5 No ± Yes ± ± ±

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)

Central/peripheral neuropathy

Copper Deficiency

Copper Deficiency ? MDS Anemia Leukopenia

  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

Ceruloplasmin Copper (6 atoms) Ferrous Iron Fe ++ Ferric Iron Fe +++ Apotransferrin Apo Tf Transferrin 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 Abnormal iron metabolism Peripheral polyneuropathy Myelodysplastic syndrome RARS Neutropenia Macrocytic anemia Thrombocytopenia Neutropenic fever Fatigue, DOE

Lab/Study

 Dr. Hurley:  Dr. Starr: 

Copper and Ceruloplasmin Level

 Complete iron panel  Dr. 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.

 Manuel Uribe from Monterrey, Mexico.

 40 years old and weights 1225 lbs.

 In March 2006, underwent most extreme BS in Italy.

Trivia