Laboratory Interpretation: A Focus on WBC’s, RBC’s, and LFT’s Wendy L. Wright, MS, ANP-BC, FNP-BC, FAANP, FAAN, FNAP Adult/Family Nurse Practitioner Owner - Wright & Associates Family Healthcare Amherst, NH Owner – Wright & Associates Family Healthcare Concord, NH Owner – Partners in Healthcare Education, LLC
Wright, 2019 1
1
Relevant Financial Relationship Disclosure Statement
Title of talk
• I will not discuss off label use and/or investigational use of any drugs/devices.
• I don’t have the following relevant financial relationships to report in relationship to this presentation.
Wright, 2019 2
2
Objectives
• Upon completion of this lecture, the participant will be able to: – Identify a step approach to the interpretation of a cbc – rbc’s and wbc’s, and hepatic function tests – Discuss various laboratory abnormalities identified on an individual throughout the lifespan – Systematically interpret laboratory findings using case studies Wright, 2019 3
3
Wright, 2019 1 Red Blood Cell Formation
• Formed in bone marrow (erythropoiesis) • When mature, the rbc is released into circulation • Mature rbc has a life span of approximately 120 days – Many factors trigger an increase in the production of rbc’s by the bone marrow, but a decrease in O2 is the most common. – Low tissue oxygen levels trigger the endothelial cells in the kidneys to secrete erythropoietin – which in turn, stimulates bone marrow red cell production
Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and erythropoiesis. Blood. 2000;96:823-833. Wright, 2019 4
4
Anemia: Defined
• Anemia – comes from the Greek word “Anaimia” – meaning “without blood”
• A decrease in the number of red blood cells, hemoglobin, or hematocrit OR A decrease in the oxygen carrying capacity of the blood
Wright, 2019 5
5
Statistics
• Approximately 3.5 million Americans have some form of anemia • Approximately 17.5/1000 individuals in primary care practice have anemia • Approximately 20% of all women have anemia – Iron deficiency anemia is by far the most common anemia, particularly in the women – Most common anemia in the older adult: • Anemia of Chronic Disease
Wright, 2019 6
6
Wright, 2019 2 Step Approach is Essential
Wright, 2019 7
7
The CBC - A Blessing or a Curse • RBC – 4.1-5.1 m/mm3 • Hemoglobin – 12-16 g/dl • Hematocrit – 36-46%
**1 hemoglobin:every 3 hematocrit
Wright, 2019 8
8
The Indices - Your Most Important Tools
• MCV - Mean Corpuscular Volume 80 - 100: Normocytic <80: Microcytic: defect in hgb synthesis >100: Macrocytic
The MCV allows you to classify the type of anemia to further determine the etiology
Wright, 2019 9
9
Wright, 2019 3 MCHC - Mean Corpuscular Hemoglobin Concentration
• Average concentration of hemoglobin in red blood cells – Much more helpful than the MCH – Provides you with information regarding the color of the cells • Normal: – 32-37: Normochronic – <32: Hypochromic Wright, 2019 10
10
Classifications/Causes of Anemia
Macrocytic, Normochromic (↑MCV, Normal MCHC) Vitamin B12 Deficiency Folate Deficiency
Wright, 2019 11
11
Classifications/Causes of Anemia
Normocytic, Normochromic (Normal MCV and Normal MCHC) Anemia of Chronic Disease Acute Blood Loss Early Iron Deficiency
Wright, 2019 12
12
Wright, 2019 4 Classifications/Causes of Anemia
Microcytic, Hypochromic (↓ MCV and ↓ MCHC) Iron deficiency Anemia Thalassemia Lead Poisoning Sideroblastic Anemia Aluminum Toxicity G6PD (Occasionally: Anemia of Chronic Disease) Wright, 2019 13
13
RDW
• Red Cell Distribution Width – Normally all red cells are about equal in size – RDW is the degree of anisocytosis or the variability of the red cell size – Helps to differentiate between various causes of microcytic, hypochromic anemia • IDA, Thalassemia, and Anemia of Chronic Disease – Increased RDW - IDA – Normal RDW-Anemia of Chronic Disease – Normal or slightly increased RDW- Thalassemia
Wright, 2019 14
14
Reticulocyte Count
• The number of new, young, red blood cells found in 100 rbc’s in circulation – It is expressed as a percentage with normal being approximately 1-2 % – It is an index of the bone marrow’s health and response to the anemia
Wright, 2019 15
15
Wright, 2019 5 What Does an Elevated Reticulocyte Count Indicate?
ELEVATED RETICULOCYTE COUNT MEANS THAT THE BONE MARROW IS HEALTHY and/or YOUR TREATMENT IS WORKING BUT…Blood loss or destruction is likely occurring
Wright, 2019 16
16
Anemia is not a diagnosis; it is a sign of an underlying problem.
Wright, 2019 17
17
Krepzek Study
• Pathology was found in 50% of individuals diagnosed with iron deficiency anemia. Diagnoses included: • Cancer Adenomas • Gastritis Vas Malformations • Esophagitis Hemorrhoids • Gastric Ulcer • Duodenal Ulcer • Crohn’s (Journal of DigestiveWright, 2019 Diseases, June 1995) 18
18
Wright, 2019 6 Macrocytic, Normochromic Anemia
Wright, 2019 19
19
Macrocytic Anemia
Wright, 2019 20
20
Vitamin B12 Deficiency
Wright, 2019 21
21
Wright, 2019 7 Megaloblastic Anemia
• Vitamin B12 (cobalamin) is essential for the production of DNA • Deficiency in Vitamin B12 results in the alteration in the production of DNA – Decreased rate of production – Enlarged red cell
Wright, 2019 22
22
General Causes of Vitamin B12 Deficiency • Inadequate intake • Decreased absorption • Inadequate utilization • Most common cause: – Inadequate absorption
Wright, 2019 23
23
Other Potential Causes
• Inadequate absorption or utilization – Crohn’s disease – Celiac disease – S/p Gastrectomy or Bariatric surgery • Medications – Methotrexate or Fluorouracil • Altered gastric acid production – PPI’s
Wright, 2019 24
24
Wright, 2019 8 Vitamin B12
• Food sources: animal products • Amount provided in average diet’ – 5 – 15 ug/day (RDA – 2ug/day) • Storage amount – 2 – 5 mg is stored mainly in the liver – Takes 2 – 5 years to develop a deficiency even in the setting of severe malabsorption
Wright, 2019 25
25
Pernicious Anemia
• Most common cause of a vitamin B12 deficiency • Autoimmune disease characterized by the presence of autoantibodies to the parietal cells in the stomach and their secretory product called intrinsic factor – Remember – intrinsic factor is essential for the absorption of vitamin B12 in the terminal ileum of the bowel
Wright, 2019 26
26
Pernicious Anemia
• Very commonly seen in the setting of other autoimmune conditions such as: – Hashimoto’s thyroiditis – Vitiligo
Wright, 2019 27
27
Wright, 2019 9 Pernicious Anemia
• Onset is usually insidious • Begins in the 5th –6th decade of life • Women > men
Wright, 2019 28
28
Important History Questions
• Dietary intake • Alcohol consumption • Medication history – Chemotherapeutics – PPI’s • PMH – Surgeries – Conditions affecting ileum/stomach
Wright, 2019 29
29
Signs and Symptoms of Pernicious Anemia • Anemia with elevated MCV • Smooth and beefy red tongue – Tongue is frequently very sore • Diarrhea • Anorexia
Wright, 2019 30
30
Wright, 2019 10 Neurologic Manifestations
• Neurologic manifestations are related to the inability to maintain myelin integrity • Paresthesias – Pins and needles – stocking/glove distribution – Weakness in extremities • Delirium/psychosis may occur • Decreased position and vibratory sense • Incoordination • Depression
Wright, 2019 31
31
Diagnosis of Pernicious Anemia
• CBC • Peripheral smear • Vitamin B12 level • Schilling test – This test will confirm that the Vitamin B12 deficiency is caused by an intestinal malabsorption due to a deficiency in the intrinsic factor rather than other malabsorptive conditions
Wright, 2019 32
32
Treatment of Vitamin B12 Deficiency
• Vitamin B12 Deficiency – Cyanocobalamin: 1000 iu/day x 5 days • Weekly until hemoglobin normal • 1000 ug/month for life • Reticulocytosis within 1 week • Increase in hemoglobin and hematocrit with 1 week • Normalization of h/h within 2 months • Rapid improvement in symptoms; however may take 12 – 18 months for all neurologic symptoms to improve
Wright, 2019 33
33
Wright, 2019 11 Words of Warning
• Patients who are severely vitamin B12 deficient can develop severe hypokalemia • Monitor potassium levels as vitamin B12 is administered
Wright, 2019 34
34
Treatment of Vitamin B12 Deficiency
• Vitamin B12 Deficiency – Nascobal (cyanocobalamin) • 500 micrograms/0.1ml nasal gel • Maintenance of Vitamin B12 deficiency • Used after IM B12 has resolved the anemia • 1 spray into 1 nostril each week
Wright, 2019 35
35
Folate Deficiency
Wright, 2019 36
36
Wright, 2019 12 Folate Deficiency
• Most often results from an inadequate intake of folic acid – Poor dietary intake such as the elderly, chronically ill, alcoholics, fad diets • Occasionally – Increased need – Impaired absorption – Inadequate utilization
Wright, 2019 37
37
Reasons for Folate Deficiency
• Body has very little folate in storage – Very different from vitamin B12 where 3 – 5 years of B12 is held in storage • Impaired absorption – Celiac disease – Giardia infection – Phenytoin
Wright, 2019 38
38
Reasons for Folate Deficiency
• Increased need – Pregnancy – Hyperthyroidism – Malignancy – Chronic inflammatory disorders – Crohn’s • Impaired utilization – Methotrexate – Metformin – Trimethoprim Wright, 2019 39
39
Wright, 2019 13 Important Information
• Source – Green, leafy vegetables, beans, grains, liver, wheat • RDA: 100 ug/day • Amount in diet: 200 – 300 ug/day • Storage amount: 5 – 10 mg
Wright, 2019 40
40
Clinical Presentation
• May be asymptomatic • Glossitis • Similar presentation to vitamin B12, when severe
Wright, 2019 41
41
Diagnosis
• Serum folate level • Additional tests – MMA (methylmalonic acid) – Homocysteine (Hcy) – Both will be elevated in vitamin B12 deficiency – Only homocysteine will be elevated in folate deficiency
Wright, 2019 42
42
Wright, 2019 14 Treatment of Folic Acid Deficiency
• Folic Acid Deficiency – 1mg po qd – May increase to 5 mg/day – Review cause with patient – i.e. dietary sources – Reticulocytosis within 1 week – Hematocrit and hemglobin should improve within 1 week – Hematocrit should normalize in 2 months
Wright, 2019 43
43
Treatment of Vitamin B12 or Folic Acid Deficiency
• If anemia fails to resolve, remember IDA coexists in 1/3 of patients with these types of anemia
Wright, 2019 44
44
Microcytic Anemia
Wright, 2019 45
45
Wright, 2019 15 Iron Deficiency Anemia
Blood loss is the number ONE cause for IDA in individuals > 4 Wright, 2019 46
46
Iron Deficiency Anemia
• Most prevalent anemia worldwide • Causes –Increased iron loss – Dietary inadequacy – Malabsorption – Increased iron needs
Wright, 2019 47
47
Important History
• Medications? Dietary Intake? • Any Blood Loss? Alcohol Intake? – Menorrhagia Any Chronic Disease? – Black or Blood Stools Any Surgeries? – Hematuria •Gastric bypass – Hemoptysis – Blood Donation • Family History of Anemia? – Celiac disease (sprue)
Wright, 2019 48
48
Wright, 2019 16 However…
• Signs and symptoms of iron deficiency anemia are determined by… – Degree of anemia – Acuteness of the anemia – Presence of underlying disease states
Wright, 2019 49
49
Diagnosis of Iron Deficiency Anemia • Ferritin – Measurement of iron stores – Level < 16 is diagnostic of IDA – Normal: 10 - 210 – Keep in mind that this can be falsely elevated in the individual with febrile illness, malignancy, liver disease, inflammatory diseases • Iron – Normal: 50 - 160 – Amount of circulating iron – Low level coupled with an elevated TIBC is suggestive if IDA
Wright, 2019 50
50
Diagnosis of Iron Deficiency Anemia • TIBC – Normal: 250 - 350 – Number of cells not bound with iron – Higher the iron, lower the TIBC – Lower the iron, higher the TIBC • Peripheral Blood Smear – Anisocytosis – Poikoilocytosis – Microcytosis, hypochromia •
Wright, 2019 51
51
Wright, 2019 17 Red Cell Morphology
• Spherocyte – hereditary condition; hemolytic anemia • Schistocyte – prosthetic heart valve • Elliptocyte or ovalocyte – iron deficiency anemia • Teardrop cells – Iron deficiency anemia • Sickle cells – sickle cell disease • Target cells – thalassemia • Basophilic stippling – Thalassemia, lead toxicity • Bite cells – G6PD deficiency
Wright, 2019 52
52
Most Important Take Away Message! • Find out why – Colonoscopy – UGI/Endoscopy – Chest X-ray – Urinalysis – Endometrial biopsy
Wright, 2019 53
53
Treatment of IDA
• Increase Iron Rich Food Intake – liver, beef, lamb, pork, veal, chicken, eggs, fish, beans, prunes, green leafy vegetables • Iron Supplements – Ferrous Sulfate 325mg: 1 po tid – Ferrous Sequel: 1 po tid
Wright, 2019 54
54
Wright, 2019 18 Treatment of IDA
• Chromagen Forte – Capsules – 1 capsule daily – Iron, plus folic acid
Wright, 2019 55
55
Treatment of IDA
• If the bone marrow is healthy – Within 5 days, the reticulocyte count will increase • With adequate treatment – The hematocrit should rise 1 point each week • For instance, if someone’s hematocrit is 28 – Goal is 36-40 – It will take 8-12 weeks to correct
Wright, 2019 56
56
Treatment of IDA
• Once hematocrit has normalized, it takes 3-6 months to replenish iron stores – This is provided that the bleeding or dietary issue is corrected • Many providers stop the iron too quickly
Wright, 2019 57
57
Wright, 2019 19 Treatment of IDA
• Intravenous Iron Dextran may be necessary if the individual is unable to absorb the iron or when the rate of blood loss exceeds absorption – Increased risk of anaphylaxis • Should be performed in setting capable of handling this potentially life-threatening emergency Wright, 2019 58
58
Normocytic Anemia
Wright, 2019 59
59
Chronic Disease
• Frequently accompanies chronic disorders – Acute and chronic infections – Malignancy – Inflammatory disorders – HIV disease • Hypoproliferative state • Commonly confused with iron deficiency
Wright, 2019 60
60
Wright, 2019 20 Pathophysiology
• Usually caused when there is a trapping of iron by macrophages • Renders iron unavailable for erythropoesis • Inflammatory processes also suppress erythropoesis leading to diminished production of rbc’s
Wright, 2019 61
61
Clinical Presentation
• Asymptomatic • Fatigue • Tachycardia • Pallor • Similar presentation to an IDA
Wright, 2019 62
62
Laboratory Diagnosis
• Anemia – Normal MCV, normal MCHC • Rarely will the hematocrit go below 25% with an ACD • Serum iron is often low • TIBC is also often low – differentiates it from IDA Ferritin will be normal or even increased – very helpful to differentiate ACD from early IDA
Wright, 2019 63
63
Wright, 2019 21 Treatment of Normocytic Anemia
• Renal disease – Erythropoietin, Procrit, Aranesp • Malignancies – Chemotherapy • Inflammatory disease – Optimal control • Hypothyroidism – Goal: TSH = 1.5
Wright, 2019 64
64
Treatment
• Severity of anemia determines treatment – Blood – Epoetin alfa – Darbepoetin alfa
• FDA, American Red Cross recommend treating early and conservatively using blood as last resort.
Wright, 2019 65
65
Treatment: Blood
• Benefits – Immediate elevation of Hgb and HCT – Immediate improvement in energy level • Drawbacks – Temporary – Risk of reaction – Risk of transmission of blood-borne infections – Administered in hospital or outpatient facility – Limited supply – Religious beliefs may influence willingness to receive blood
Wright, 2019 66
66
Wright, 2019 22 Epoetin Alfa
• Dosing – CKD: 50-100 units/kg 1x/week – every two weeks – Cancer: 150 units/kg 1x/week – HIV: 50-100 units/kg 1x/week • Administered IV or subcutaneously • Less frequent dosing if often performed • No known drug interactions
Wright, 2019 67
67
Aranesp (darbepoetin alfa)
• Indications – Anemia: related to CRF – Chemotherapy induced anemia • Advantages – 3 fold longer half life than Epoetin alfa – Early and sustained effect – Less frequent dosing
Wright, 2019 68
68
Aranesp
• Dosing – Once weekly dosing may be needed initially – CRF: 0.435 mcg/kg of body weight – Maintenance dosing: q 4 weeks
Wright, 2019 69
69
Wright, 2019 23 Recent Warnings
• Caution regarding increasing hemoglobin > 12 in individuals using any of these products • Goal: hemoglobin at 10 - 12 • Increased risk of MI
Wright, 2019 70
70
Case - 1
86 year old woman in for a complete physical. Labs: wbc 7.1, rbc 4.64, hgb 8.8, hct 28.1, MCV 84, MCHC 32.8, RDW 13.0, normal diff. What type of anemia? What would you order?
Wright, 2019 71
71
IL – 69 year old male
• Presents with complaints of numbness of fingers /toes and fatigue. No additional neuro symptoms – Labs: Vitamin B12: 182 (211-911) Folate: 6.0 (2.5 – 10.0)
– Treatment initiated: Now – 489 – Resolution of symptoms
Wright, 2019 72
72
Wright, 2019 24 Case Study - 3
18 year old female presents with fatigue and sob while cheerleading. +Increase in ice consumption. PE-pallor, pale conjunctiva, systolic murmur, and tachycardia. CBC:wbc 7.58, rbc-3.02, hbg 5.4, hct 18.7, MCV 61.9, MCHC 28.9, RDW 18.7, Normal diff. Peripheral Smear: aniso, microcytes, hypochromia, teardrop cells, few ovalocytes, elliptocytes. What type of anemia does she have? What would you order? Wright, 2019 73
73
Case Study-4
26 year old male presents for a complete physical. He is asymptomatic. Routine labs reveal the following: CBC: wbc 7.78, rbc 5.84, hgb 11.5, hct 38.5, MCV 68.2, MCHC 28.1, RDW 14.9; Normal diff. Peripheral Smear: 1+microcytes, ovalocytes, target cells, and basophilic stippling. Remainder of labs normal. What type of anemia does she have? What would you order next?
Wright,. 2019 74
74
Liver Function Tests
Wright, 2019 75
75
Wright, 2019 25 Function of the Liver
• Numerous functions – Production of plasma proteins – Glucose homeostasis • Production occurs significantly at night – Lipoprotein synthesis • Necessary for sex hormones – Bile acid production • LDL production – Vitamin B12, A, D, E, K storage
Wright, 2019 76
76
Additional Functions
• Detoxification of medications and endogenous substances – Primarily through the CY P450 enzyme – Purpose: take fat soluble medication and convert to water soluble for purposes of renal excretion • Production of clotting factors
Wright, 2019 77
77
Liver Function Tests: Are They Really? • Although we do monitor liver functioning (LFT’s)… – It is important to remember that these enzymes are really not good indicators of functioning but more…markers of liver damage and abnormalities in bile flow…. • Normal liver enzymes can be present in the setting of liver damage – We see this frequently in patients with chronic hepatitis C – 33% of patients with chronic hepatitis C have Wright, 2019normal LFT’s 78
78
Wright, 2019 26 Most Important LFT’s: These Do Provide Information on Function • Albumin • Bilirubin • Prothrombin Test
• All provide best information on function of the liver • Whereas….AST, ALT – provide information re: liver injury or damage
Wright, 2019 79
79
Albumin
• Albumin – serves as an index of the liver functioning/synthesis ability • Synthesized exclusively by the liver • Essential for the transportation of endogenous and exogenous substances • Not completely sensitive or specific
Wright, 2019 80
80
Albumin
• Half-life: 3 weeks • Provides better information regarding chronic liver disease than acute liver injury/function
Wright, 2019 81
81
Wright, 2019 27 Low Albumin (Liver Causes)
• Cirrhosis – Up to 80% of patients with cirrhosis will have normal albumin • Malignancy • Chronic Liver Disease
Wright, 2019 82
82
Low Albumin with Normal LFT’s
• Consider – Non-hepatic causes • Protein loss: Proteinuria • Acute or chronic inflammatory states • Burns • Sepsis • Trauma • Rheumatic disorders • Intravenous fluids
Wright, 2019 83
83
Bilirubin
• Results from the enzymatic breakdown of heme in the body • Unconjungated (indirect) and conjungated (Direct) = total bilirubin – If total bilirubin is elevated – ask for breakdown
Wright, 2019 84
84
Wright, 2019 28 Bilirubin
• Conjugated (Direct) levels do not become elevated until the liver has lost at least ½ of its excretory capacity – Conjugated bilirubin is rarely present in the blood in healthy individuals – Thus – when conjugated bilirubin is elevated – there is a marked decrease in secretion into the bile • Increase in bilirubin in serum and urine • Hepatobiliary disease is very common
Wright, 2019 85
85
Causes of Elevated Bilirubin
• Common to see slight elevation in bilirubin after fasting – 12 – 24 hours • Elevated bilirubin – – Elevated unconjungated (indirect) with normal CBC • Gilbert’s syndrome • Neonatal jaundice – Elevated conjugated (direct) • Hepatobiliary disease is almost always seen • Cholestasis/hepatocellular diseases of all types Wright, 2019 86
86
Causes of Increased AST or ALT in Asymptomatic Patients • A - Autoimmune • F – Fatty Liver Hepatitis • G – Growths (tumor) • B – Hepatitis B • H – Hemodynamic • C – Hepatitis C disorders (CHF) • D – Drugs or Toxins • I – Iron • E - Ethanol – Copper • M – Muscle injury
Adapted from http://www.aafp.org/afp/990415ap/2223.html accessed Wright,February 2019 9, 2006 87
87
Wright, 2019 29 Narrowing It Down
• ¾ of all elevated AST and ALT values are caused by: – Alcohol – Hepatitis B – Hepatitis C
– I would add – fatty liver (NASH)
Adapted from http://www.aafp.org/afp/990415ap/2223.html accessed FebruaryWright, 2019 9, 2006 88
88
AST (Formerly SGOT)
• Enzyme found within the liver cell • Rises rapidly with hepatic injury • Resolves very quickly – Half life – 17 hours • Not as specific to the liver as ALT – Found also in heart muscle, skeletal muscle, pancreas, kidney, brain, lung, white and red blood cells • Alcohol • Statin medications • Tylenol www.fhea.com Wright, 2019 89
89
ALT (Formerly SGPT)
• More specific than AST to liver • Half life - 47 hours • Avandia or Actos • Liver infection or diseases • Toxic agents
www.fhea.com
Wright, 2019 90
90
Wright, 2019 30 Approach to Patient with Asymptomatic Elevation
• Person asymptomatic and picked up on screening or monitoring for various medications – Repeat enzymes in next 2 weeks – Avoid alcohol, acetaminophen, ibuprofen – 50% of individuals will have normal LFT’s upon repeat – Remember – • Hepatitis C patients do have fluctuating LFT’s and you may be falsely assured Wright, 2019 91
91
Degree of Elevation
• Degree of Transaminase elevation provides significant clues as to the etiology of the liver problem – < 5 times – mild – 5 – 10 times ULN – moderate – > 10 times ULN – marked/severe • For instance: – > 1000 units/L: hepatitis, drugs or toxins, acute biliary obstruction – Another way to look at this: moderate – marked increase – acute hepatic injury Wright, 2019 92
92
Gary
• 48 year-old male who presents for routine annual examination (new patient to practice) • Complaining of increased abdominal bloating and on further questioning – breast enlargement • Social history: 8 – 16 beers daily; Cigarette abuse – 1 ppd x 30 years • PMH: Asthma - childhood Wright, 2019 93
93
Wright, 2019 31 Laboratory Evaluation
• CBC with differential – Hgb: 13.2 – Hct: 40.0 – MCV: 108 – MCHC: 33 – RDW: 16%
Wright, 2019 94
94
Gary’s Lipid Panel
• Total cholesterol: 208 •HDL: 62 •LDL: 110 • Triglycerides: 284
Wright, 2019 95
95
Liver Function Tests
• AST: 178 – (normal 0 – 40) • ALT: 86 – (normal 0 – 40) • AST/ALT > 1 – If AST/ALT is > 1 – Consider: AST
Wright, 2019 96
96
Wright, 2019 32 AST/ALT > 1
• Highly suggestive of alcoholic liver disease • If ratio is > 2: VERY suggestive of alcoholic liver disease – One study showed that 90% of individuals who presented with an AST/ALT ratio > 2 had alcoholic liver disease on biopsy – This percentage is 96% when AST/ALT ratio is > 3
Wright,– 2019 Gary’s Ratio: > 2 (178/86) 97
97
The Good News
• With sobriety – AST – normalize within 3 months – GGT – normalize within 1 – 2 weeks – Triglycerides – normalize in 1 month – MCV – normalize within 4 months – But remember…these are not liver function tests, they are liver injury tests – Normalization does not mean that there is NO
Wright, 2019damage 98
98
CW
• CW is a 52-year-old woman who presents to discuss her recent cholesterol profile – Lab results are as follows: • Total cholesterol: 286 • HDL: 46 • LDL: 199 • Triglycerides: 154 • Risk ratio: 6.22 • LFT’s: normal
Wright, 2019 99
99
Wright, 2019 33 Treatment • CW has been on a diet and exercise plan for the last 3 months attempting to lower her cholesterol without pharmacotherapy • At today’s visit, atorvastatin therapy initiated • Dosage: 20 mg qhs
Wright, 2019 100
100
6 Months Later
• CW calls complaining of cramping in her feet only at night • It is occurring every night • This is new; she has never had anything like this before and because of our discussion regarding potential side effects of the statin class, she decided to call • She was advised to stop atorvastatin and come into the office for an evaluation and a few additional laboratory tests Wright, 2019 101
101
Labs
• Physical examination: normal; no evidence of tender or edematous muscles • AST: 102 • ALT: 75 • Ratio: AST/ALT - > 1 • CPK: 3305 (normal level: 20-170) • Remainder of Chemistry panel: normal • Urinalysis: normal • CBC with differential: normal
Wright, 2019 102
102
Wright, 2019 34 Rhabdomyolysis
• Laboratory Features: – Elevated CK-MM** Most sensitive test • With rhabdo, range is often: 500 - >100,000 units/L • Degree of elevation roughly correlates with the risk of renal failure – BUN/Creatinine ratio <5 • Normally, this ratio is 10 • With rhabdomyolysis, creatine phosphate is released from damaged muscle and is converted into creatinine – Increased serum uric acid • Often times, the uric acid levels are markedly elevated • Can be > 40 mg/dL Wright, 2019 103
103
What Changed?
• Why did this happen? • CW went to a walk-in center • Diagnosed with “walking pneumonia” • Given a prescription for clarithromycin
Wright, 2019 104
104
Remember CY P450 3A4
• Atorvastatin is a substrate • Clarithromycin is an inhibitor • Blocks 3A4 enzyme causing atorvastatin levels to increase significantly (50%)
Wright, 2019 105
105
Wright, 2019 35 AST/ ALT < 1
• This is the most commonly encountered abnormality – Consider Avandia/Actos – Liver infection or disease (NASH) – Toxic agents
Wright, 2019 106
106
NASH
• Fatty liver is thought to be present in up to 23% of Americans • Typical Picture: Obese, hyperlipidemia, hypertension, diabetes – AST/ALT ratio < 1 is most common initially • Ratio can shift – AST/ALT > 1 • Indicative of advanced fibrosis – 61% of patients with advanced fibrosis will have this ratio – Increased GGT – up to 3x ULN Wright, 2019 107
107
Other Differentials: AST/ALT < 1 Hepatitis
• Hepatitis A IgM • Hepatitis B sAg • Anti Hep C – Hepatitis C RNA • Hepatitis D IgM • Alpha1 Antitrypsin
Wright, 2019 108
108
Wright, 2019 36 Other Differential AST/ALT < 1: Hemochromatosis
• Autosomal recessive condition • Abnormal deposition of iron in the liver, heart and pancreas • Labs: – AST/ALT < 1 – often seen – Elevated ferritin (> 300+) – Transferrin saturation index • > 45% is highly suggestive of this condition Wright, 2019 109
109
White Blood Cells
Wright, 2019 110
110
Earl • 66 year old man employed by the town presents with a 6-day history of a cough, worsening sob, fever, chills, pain in back with inspiration, and yellow-brown sputum. – PMH: Nonsmoker, Hx: MI age 51, Type 2 Diabetes – PE: T: 103.8; P: 148; R: 32; BP: 138/90; HEENT: unremarkable; Tired appearing; Lethargic; Crackles in right lower lobe; Do not clear with coughing – Finger stick: 188 – Xray: Consolidation-RLL – Sputum Gram Stain: Pending Wright, 2019 111
111
Wright, 2019 37 Community Acquired Pneumonia • Acute infection of the pulmonary parenchyma that is associated with symptoms of an infection such as fever, chills, shortness of breath and physical examination findings – Found in a person not hospitalized or residing in a long-term care facility for > 14 days before the onset of symptoms
Wright, 2019 112
112
Community Acquired Pneumonia 4 million Americans yearly are diagnosed with Community Acquired Pneumonia – 1 million hospital admissions yearly – 75% of CAP’s are managed on an outpatient basis Billions of dollars are spent yearly on the care of patients with Community Acquired Pneumonia; most inpatient care
www. cdc.gov accessed 02-01-2010 Wright, 2019 113
113
Community Acquired Pneumonia Leading cause of death from an infectious disease 6th leading cause of death – 55,000 deaths in the US yearly 1.2 million hospitalizations yearly Highest incidence: winter months
www. cdc.gov accessed 02-01-2010 Wright, 2019 114
114
Wright, 2019 38 Symptoms of Pneumonia
Cough Fever (almost always accompanied by a fever) – Yet-elders may not mount a fever Sputum production Shortness of breath Pleurisy Fatigue Malaise Anorexia
Wright, 2019 115
115
Signs
Fever Tachypnea Tachycardia Crackles or decreased breath sounds Egophony, Bronchophony, Whispered Pectoriloquy Increased tactile fremitus Pleural rub
Wright, 2019 116
116
Streptococcus Pneumoniae
Gram positive diplococci Most common cause of Community Acquired Pneumonia – Most common in individuals 50 years of age and older – Also the most common bacterial cause of OM and sinusitis 70% of children and 30% of adults have nasopharyngeal colonization Disease results from a microaspiration
Wright, 2019 117
117
Wright, 2019 39 Earl
66 year old man employed by the town presents with a 6 day history of a cough, worsening sob, fever, chills, pain in back with inspiration, and yellow-brown sputum. – CBC: WBC 16,500; Bands 7%, Neuts: 83% – What does this mean to you? – What is the likely etiology?
Wright, 2019 118
118
Let’s Talk About White Blood Cells and the Differential: What Do Each of the Components Mean?
Wright, 2019 119
119
Leukocytes or WBC’s
Heterogeneous group of cells – Arise from single stem cell Differentiation occurs during stem cell maturation
Fischbach, F.T. 2004. A Manual of Laboratory and Diagnostic Tests. Ed 7. Philadelphia, PA: Lippincott Williams & Wilkins.Wright, 2019 120 120
Wright, 2019 40 Leukocytosis
Elevated white blood cell count – Generally > 10,500/mm3 Very commonly encountered abnormality Words of warning – Must look at the cells that are present in excess in the differential to determine relevancy and importance of this elevated wbc count!!
Wright, 2019 121
121
White Blood Cells
WBC’s or leukocytes are divided into 2 groups – granulocytes and agranulocytes Granulocytes: receive their name from the granules that are present in the cytoplasm of the cell Agranulocytes – absence of granules
Wright, 2019 122
122
Leukocyte Forms
Granulocytes –Neutrophils Also known as polys or segs –Eosinophils –Basophils
Wright, 2019 123
123
Wright, 2019 41 Agranulocytes
Do not have the granules in the cytoplasm –Lymphocytes –Monocytes
Wright, 2019 124
124
Endocrine System
Important regulator of the number of leukocytes in the blood Hormones affect the production of leukocytes in the blood-forming organs, their storage, release from tissue, and their destruction
Wright, 2019 125
125
Infection/Inflammatory Response
Inflammatory process occurs in response to exposure to an infection and/or an acute inflammatory process – Results in the release of inflammatory mediators Causes the mobilization of leukocytes Leukocyte released and lives for 13 – 20 days Destroyed by the lymphatic system Excreted from the body in fecal matter
Wright, 2019 126
126
Wright, 2019 42 Action of Leukocytes
Leukocytes fight infection and defend body by a process called phagocytosis – Leukocytes encapsulate the foreign organism and destroy it Leukocytes: produce, transport and distribute antibodies in response to the foreign organism
Wright, 2019 127
127
Interpreting the WBC Count
Useful guide as to severity of the infection, however, can be fooled by this as well Normal Leukocyte count: – Adult: 4,500 – 10,500/mm3 – Children: 6 – 18 years 4,800 – 10,800/mm3
Wright, 2019 128
128
Leukocytosis
Elevated WBC count: > 10,500/mm3 Usually elevated by one type of leukocyte and it is the type that shows the biggest increase that will give the condition it’s name – For instance: Neutrophilic leukocytosis: neutrophilia Lymphocytic leukocytosis: lymphocytosis Monocytic leukocytosis: monocytosis Basophilic leukocytosis: basophilia Eosinophilic leukocytosis: eosinophilia Wright, 2019 129
129
Wright, 2019 43 Leukocytosis
Often occurs in response to acute infections Degree of response is determined by the severity, patient’s resistance, patient’s age and marrow efficiency and reserve
Wright, 2019 130
130
But…Not Always Related to Infections Leukemia Trauma Bronchogenic carcinomas Uremia Drugs (quinine, epinephrine) Acute hemolysis Hemorrhage S/P splenectomy Polycythemia Vera Pregnancy
Wright, 2019 131
131
Earl
66 year old man employed by the town presents with a 6 day history of a cough, worsening sob, fever, chills, pain in back with inspiration, and yellow-brown sputum. – PMH: Nonsmoker, MI-age 51; Type 2 Diabetes – PE: Crackles in right lower lobe; Do not clear with coughing. RR - 32 – Xray: Consolidation-RLL – Sputum Gram Stain: Pending –CBC: wbc 16,500; Bands 7%, Neuts: 83% – Blood cultures pending
Wright, 2019 132
132
Wright, 2019 44 Physiologic Leukocytosis
Leukocytosis with a Healthy 30 year old normal differential Just exercised x 1 – Stress response hour vigorously – Labor TWBC-16,100 – Menstruation – Neuts-50% – Exercise – Bands-1% – Lymphs-40%
Wright, 2019 133
133
Differential
Differential: expressed as a percentage of the total number of leukocytes The distribution of cells in the differential along with the degree of increase and decrease are very significant and can help the clinician diagnostically Absolute count: obtained mathematically by multiplying percentage by the total wbc count – % x WBC count = Absolute count
Wright, 2019 134
134
Differential: Functions of Circulating WBC’s Neutrophils: bacterial infections Eosinophils: allergic disorders and parasitic infections Basophils: parasitic infections, some allergic disorders (store histamine); inflammation Lymphocytes: viral infections Monocytes: Share vacuum cleaner function with neutrophils, severe infections Bands/stabs: severe bacterial infections
Wright, 2019 135
135
Wright, 2019 45 Normals
WBC Type Percentage Neutrophils 30% - 70% Lymphs 15% - 40% Monocytes 2% – 8% Eosinophils 0% - 5% Bands 0% – 4% Basophils 0% - 3%
Wright, 2019 136
136
Earl
66 year old man employed by the town presents with a 6 day history of a cough, worsening sob, fever, chills, pain in back with inspiration, and yellow-brown sputum. – PMH: Nonsmoker, Type 2 Diabetes – PE: Crackles in right lower lobe; Do not clear with coughing. RR - 32 – Xray: Consolidation-RLL – Sputum Gram Stain: Pending Neuts: 83% – Blood cultures pending
Wright, 2019 137
137
Neutrophils
Most numerous and most important leukocytes in the body Polys/segs often used interchangeably Constitute our body’s primary defense against infection through the process of phagocytosis – Immature neutrophils: stabs or bands
Wright, 2019 138
138
Wright, 2019 46 Neutrophils
First responders to a bacterial infection Life span – 10-hours in circulation – 4-5 days in tissue Highly mobile Death of neutrophils in large numbers forms pus
Wright, 2019 139
139
Neutrophilia
Normal: 30% – 70% Neutrophilia: > 70%
Wright, 2019 140
140
Neutrophilia
Causes of Neutrophilia Bacterial Infection Inflammatory causes – RA, Pancreatitis, Gout Burns Acute hemorrhage Uremia, DKA Tumor necrosis – Significant elevation
Wright, 2019 141
141
Wright, 2019 47 Neutrophil Morphology: Additional Information
Seen in inflammation and infections –Toxic granulation Coarse black or purple granules found in the cytoplasm –Dohle bodies Small blue cytoplasmic inclusions Infections, inflammation, burns
Wright, 2019 142
142
Neutrophil Morphology: Additional Information Hypersegmented neutrophils – Mature neutrophil – > 5 distinct lobes IDA - severe Megaloblastic anemia Long-term chronic infections
Wright, 2019 143
143
Earl
66 year old man employed by the town presents with a 6 day history of a cough, worsening sob, fever, chills, pain in back with inspiration, and yellow-brown sputum. – PMH: Nonsmoker, Type 2 Diabetes – PE: Crackles in right lower lobe; Do not clear with coughing. RR - 32 – Xray: Consolidation-RLL – Sputum Gram Stain: Pending –CBC: wbc 16,500; Bands 7%, Neuts: 83% – Blood cultures pending Wright, 2019 144
144
Wright, 2019 48 Bands
Bands (0% - 4%) – Immature neutrophils – Neutrophil form with banded nucleus, and distinctive granules – Termed band because of the appearance of the nucleus. It has not developed into the lobed shape that is present in a mature neutrophil
Wright, 2019 145
145
Order of Leukocyte Migration and Elevation in a Bacterial Infection
Increased neutrophils Elevated WBC count Elevated bands Further increase in WBC count
Wright, 2019 146
146
Earl 66 year old man employed by the town presents with a 6 day history of a cough, worsening sob, fever, chills, pain in back with inspiration, and yellow-brown sputum. – PMH: Nonsmoker, Type 2 Diabetes – PE: Crackles in right lower lobe; Do not clear with coughing. RR - 32 – Xray: Consolidation-RLL – Sputum Gram Stain: Pending –CBC: wbc 16,500; Bands 7%, Neuts: 83% –BUN - 42 – Blood cultures pending
Wright, 2019 147
147
Wright, 2019 49 What Does Earl Have?
Wright, 2019 148
148
“Left Shift” Pulling up of less mature granulocyte forms from various pools in response to overwhelming infection Sign of a significant bacterial infection What do you need present in order to have a left shift?
Wright, 2019 149
149
Left Shift
Elevated wbc count Elevated neutrophil count Elevated band count
Wright, 2019 150
150
Wright, 2019 50 What Do We Do With Earl?
Hospitalization based on CURB-65 criteria IV Antibiotics IV Fluids Awaiting Sputum
Wright, 2019 151
151
Most Important Decision!!!
Decision to hospitalize or not Single most important decision in the course of the illness – Can determine life or death – Average mortality for hospitalized patients: 14% compared with non-hospitalized: <1% Average cost of treatment for CAP in the hospitalized patient vs. non-hospitalized – $7500 (20x more than non-hospitalized)
Wright, 2019 152
152
CURB-65 Score
Confusion Urea > 7 mmol/L (BUN > 19 mg/dL) Respiratory rate > 30/min Systolic blood pressure < 90 mm and Diastolic blood pressure < 60 mm Hg Age > 65 years of age
http://www.mdcalc.com/curb-65-severity-score-community-acquired-pneumonia accessed 01-28-2010
Wright, 2019 153
153
Wright, 2019 51 Remember Earl...
Age: 66 Confusion 0 Urea 1 Respiratory rate 1 Blood pressure 0 Age 1
CURB Score 3 -
Wright, 2019 154
154
CURB-65 Score CURB > 4 – ICU management – (27.8% 30-day mortality) CURB = 3 – Hospital admission (consider ICU) – (14% 30-day mortality) CURB = 2: Hospital admission or outpatient management with very close follow-up – (6.8% 30-day mortality) CURB = 0 – 1: Outpatient management – (2.7% 30-day mortality)
http://www.mdcalc.com/curb-65-severity-score-community-acquired-pneumonia accessedWright, 2019 01-28-2010 155
155
Next Day: Repeat CBC with Differential
Earl seems to be worsening –Temp still 102-103; –RR: 34 labored More lethargic; seems confused Moved to intensive care unit
Wright, 2019 156
156
Wright, 2019 52 CBC with differential
WBC count: 12,100/mm3 (↓) Neuts: 58% (↓) Bands: 20% (↑) Now we see the presence of: – Metas: 3% (↑) – Metamyelocytes: 2% (↑)
Wright, 2019 157
157
Cells typically found in bone marrow
Metamyelocyte – Crescent-shaped nucleus Myelocyte – Round nucleus, small number of granules These cells are typically recruited when circulating wbc’s i.e. neutrophils and bands have been exhausted
Wright, 2019 158
158
Granulopoiesis Process of differentiation from earliest form to mature neutrophil – 7 - 11 days in health When demand is increased, maturation period will shorten – 48 - 72 hours in illness
Wright, 2019 159
159
Wright, 2019 53 Degenerative Left Shift
When available and more mature neutrophils forms are exhausted – Less mature forms accessed Total number of wbc’s begin to fall General supply is less
Wright, 2019 160
160
The sign of….
A desperate attempt to control infection…..
Often associated with a very poor prognosis
Wright, 2019 161
161
Earl: CBC with differential
WBC count: 12,100 (↓): Was 16,500 Neuts: 58% (↓): Was 83% Bands: 20% (↑): Was 7% Metas: 3% (↑) Metamyelocytes: 2% (↑)
Wright, 2019 162
162
Wright, 2019 54 Unfortunately, Earl…
Continued to worsen Grew out: DRSP and despite multiple antibiotics/ventilator assistance etc, he did not survive the pneumonia and died within 48 hours of presentation
Wright, 2019 163
163
Had Earl Recovered…This is What We Would Have Seen!
Wright, 2019 164
164
Sean
14 month-old w/ 5-day hx fever, irritability, no wet diaper in >6 h – H/ H= 11g / 37% – WBC= 2,600 mm3 – Neuts= 35% – Bands= 48% – Metas= 2% Degenerative Shift
Wright, 2019 165
165
Wright, 2019 55 Sean
After initiation of antimicrobial therapy and rehydration – WBC= 7,200 mm3 –Neuts= 59% –Bands= 10% – Monos= 10% (>5%)
Wright, 2019 166
166
Regenerative Left Shift
Rise in total WBC Drop in immature forms Rise in monocytes – Predictor of recovery
Wright, 2019 167
167
MA
19 year-old male who presents with a sore throat, low-grade fever, achiness, fatigue x 5 days Decreased appetite No other family members ill Has missed 3 days of school Denies medications
Wright, 2019 168
168
Wright, 2019 56 Physical examination
VSS: T:99.2; RR – 18; Pulse - 104 Skin: p/w/d; no jaundice Ears: Canals/TM’s normal Nose: Turb/mucosa pink; no discharge Mouth: Tonsils erythem; +exudate; no petecchiae
Wright, 2019 169
169
Physical examination
Nodes: .5 cm tonsillar, occipital, posterior cervical nodes Lungs: clear bilaterally; no c/w/r Heart: S1S2: RRR; no murmurs Abdomen: +BS; +hsm; R&L UQ tenderness; no masses, rebound, guarding Eyes: no icterus
Wright, 2019 170
170
Michael
WBC = 3,900 (4,500- 10,500/mm3) Neuts = 25% (40% - 70%) Bands = 3% (0 - 4%) Lymphs = 64% (20% - 42%) Downey cells
Wright, 2019 171
171
Wright, 2019 57 Labs
Mono: + CMP: – AST: 48 (0-40) – ALT: 89 (0-40) – Otherwise normal
Wright, 2019 172
172
Leukopenia
Leukopenia: WBC < 4500 – Viral infections, some bacterial infections, (overwhelming bacterial infections) – Primary bone marrow disorders Leukemia, aplastic anemia, pernicious anemia – Pernicious anemia – Mononucleosis – Medications (antibiotics, anticonvulsants, chemotherapy, diuretics)
Wright, 2019 173
173
Lymphocyte
2nd most numerous WBC in circulation
15% - 40% of total WBC count
Wright, 2019 174
174
Wright, 2019 58 Lymphocytosis
>4000 mm3 in adult >7200 mm3 in child 1st cell to enter viral infected tissue – Increases common in viral infection May be seen with leukocytosis, normal wbc count or leukopenia
Wright, 2019 175
175
Lymphocytes
Small, mononuclear cells without granules Very motile cells Migrate to areas of inflammation in early and late stages of the process Manufactured in the bone marrow – B Lymphocytes: mature in the bone marrow – T Lymphocytes: mature in the thymus
Wright, 2019 176
176
Other Differentials: Lymphocytosis
Lymphatic leukemia –Acute and chronic Inflammatory bowel disease –Crohn’s and Colitis Addison’s disease Thyrotoxicosis
Wright, 2019 177
177
Wright, 2019 59 Atypical Lymphocytes or Downey Cells… Atypical/ reactive lymphs = 14% Atypical lymphs: also called Downey cells, Reactive lymphs Large, deeply indented with deep blue cytoplasm
Wright, 2019 178
178
Downey Cells
. Commonly seen with: . Mononucleosis . Viral hepatitis . Tuberculosis . Drug reactions
Wright, 2019 179
179
Eosinophils
Eosinophils –Increase in response to worms, wheezes and weird diseases –Variability in the eosinophil count Highest between 12:00am – 4:00am It decreases as the day progresses
Wright, 2019 180
180
Wright, 2019 60 Most Common Causes of Eosinophilia Allergic Rhinitis Asthma Parasitic infection Atopic disorders Acute eosinophilic leukemias
Wright, 2019 181
181
Basophils
Responsible for antigen response and allergic response Release histamine causing inflammation
Wright, 2019 182
182
Monday, September 25
17 year old male presents with a 3 week history of fatigue, nasal discharge-clear; seen by MD 1 week prior and started on Augmentin. Not feeling any better. PE: pallor, tachycardia, diaphoretic; Lungs clear, HEENT-normal; CBC: wbc: 8.9; rbc: 1.54; hgb: 5.5, hct: 17.2, MCV: 112, MCHC: 32; platelet: 32; Bands: 0; Segs: 5 (L) Monocytes: 21, Abnormal lymphocytes: 33.
Wright, 2019 183
183
Wright, 2019 61 Thank You!!
I Would Be Happy to Answer Any Questions You May Have
Wright, 2019 184
184
Wendy L. Wright, MS, RN, ARNP, FNP Amherst, New Hampshire
(W) 603 249-8883 email: [email protected]
Wright, 2019 185
185
Wright, 2019 62