9/27 - Weebly
Labdx test 1
9/27
-under age 12, alkaline phosphatase levels are normal under 300, otherwise 30-115 is normal
-you can’t eat your glucose much above 200 unless you’re a diabetic
-confirm diabetes with FBG above 126 on 2 or more occasions
-onset of type I diabetes usually occurs under age 12
-suddenness of onset is very acute with type I
-high osmolarity from high glucose levels pulls water out of cells and into urine – polyuria
-polyuria and polydypsia are consequences of hyperosmolarity
-onset of type I diabetes: 70-80% of kids have antecedent history of flu/cold (up to 6 months prior)
-IgM anticoxakie B virus (as opposed to IgG in normal people)
-also will find antibodies to own Beta cells
Labdx test 2 10/15/07
4 Types of Clinical Laboratories
-commercial/reference
-Hospital
-Clinic
-Office (physician’s office lab)
Commercial / Reference Laboratories
-A commercial lab is usually a privately owned, decentralized facility which performs lab test for private physicians, nursing homes, out-patient health centers, and which serves as a reference lab for smaller hospitals
-may be local, regional or national
-purpose is profit (they sell service and good work)
-potential advantages:
-full service (will order any test that is needed)
-if they don’t provide a certain test, either nobody ever orders that test or…
-cost
-quality (in general, they do really good work)
-supplies (doctor doesn’t have to buy supplies)
-information source
-continuing education (an educated consumer is the best customer)
-they send you reprints of current literature
-potential disadvantages:
-availability (lab may be 100 miles away)
-inconvenience
-cost
-quality (possible fraud)
-turn around time (time it takes to order test and get results; from hours to months)
Selecting a commercial lab
-doctors often buy lab services with far less scrutiny that they would use to buy a car
-key points to think about:
-Do they actually want your business?
-sometimes commercial labs don’t do tests for chiropractors
-Service
-Do they offer all the tests you require?
-What are the specimen/results logistics?
-What is the usual turn around time?
10/15/07[2]
-Price
-How does the price per test compare?
-Are there volume discounts?
-Is the laboratory accredited? (state licensed, Medicare, ASCP)
-Is there ongoing quality assurance programs? (yes, if they’re accredited)
-Do they offer professional discounts?
-Do they offer billing options?
-What is the repeat testing policy?
-Do they offer customized profiles?
-Do they furnish any/ all supplies?
-Are there consultation services?
10/22/07
Hospital Laboratories
-A centralized facility that primarily performs tests on in-patients and serves the needs of the medical staff.
Advantages:
Increased accessibility, quality, info source
Disadvantages:
-Lack of interest in taking care of your patients
-Limited testing
-Patient-sample-results logistics
-cost
Clinic Laboratories
-a centralized facility which performs tests on patients while they are at the Doctor’s office
-Clinic labs are a type of shared facility, which is utilized by the doctors within the clinic
-Clinic labs have essentially the same advantages and disadvantages as the hospital lab for the referring doc
-however, unlike the commercial or hospital labs, clinic labs may be a potential source of revenue for the clinic physician
Office Laboratories
-An office lab is a facility that is in the doctor’s office and usually performs tests only on the patients of that doctor
-doctor’s office lab may be nothing more than a small table with a bottle of urine dipsticks or it may be an entire room
with a chemistry analyzer, automated blood cell counter, microscopes, incubators, centrifuges, blood drawing chairs,
and a registered Medical Technologist
Advantages:
-Convenience
-Control of quality
-Decreased cost
-Potential source of revenue
-Improved patient care
Disadvantages:
-Time and space restrictions
-Capital expenses
-Increased cost ?
-Lack of quality ? (doctors don’t know what they’re doing)
-Prohibitive regulations ?
The decision as to whether or not, to use laboratory tests in your practice is in part based on personal philosophy and in part based on legal considerations.
The decision as to whether or not to perform laboratory test in your office should be based on practicality and cost.
There are many factors that must be considered in the evaluation of test practicality and cost, and these factors will differ for each type of practice and practitioner.
In office testing
In general there are a few laboratory tests that are appropriate for most out-patient based office practices.
Urinanalysis
• pH • Sp. gravity
• glucose • bile/bilirubin
• protein • blood
• ketones • nitrates
(microscopic exam of urine sediment)
Stool exam for occult blood
Blood glucose
Culture collection supplies for throat and urine cultures
Blood drawing supplies for tests that are sent out
Do Urinalysis if patient…
-has symptoms suggestive of possible kidney/urinary tract disorder (ie dysuria, frequency, urgency, etc)
-exhibits signs of UT disorder such as hematuria, discoloration, urine, edema
-has been recently treated for a UT disorder
-has a know condition to effect the kidneys (ie HTN)
-is undergoing treatment with a medication know to affect kidneys
-has sustained trauma affecting GU system
-has unexplained fever
-is pregnant and a urinalysis is performed as part of the prenatal care if appropriate
Serology
pregnancy test
mononucleosis screen
rheumatoid factor screen
lupus/ANA screen
rheumatic fever/ ASO screen
10/23/07[1]
Screening
-general term that indicates the performance of a variety of tests on healthy or sick people
Criteria for Effective Screening
-technically reliable, cost effective
-is there an effective therapy for what you’re screening
-at risk population must be identified
-represent a significant health problem
Multiphasic Screening
-groups of tests performed on healthy subjects for baseline data, risk assessment, or pre-admission (to hospitals)
-split opinion as to the value of this screening (b/n physicians and insurance companies)
-the more tests ordered, the more false positives found
Targeted Screening
-Designed to confirm or exclude a specific condition
-organ profiles
-4-8 tests per profile
-considered to be cost effective
-5 LDH isoenzymes
-LDH 2 is the highest
-if LDH 5 is high, indicates RBC or liver issue
-protein electrophoresis
-albumin, alpha1, alpha2, beta, and gamma globulins
-gamma globulins are made up of 5 immunoglobulins
-“M-spike” is when gamma spikes on the electrophoresis graph (Multiple Myeloma)
-Bence-Jones proteins in urine are light chains
10/23/07[2]
-important to know type of Hgb if anemic, otherwise it is not important
-if find protein in urine, then two things we need to know:
what type of protein and how much is there?
-electrophoresis reveals the type
-24 hour urine protein to determine how much
-albumin is the protein most associated with kidney disease
-if multiple myeloma, then no albumin, but rather gamma-globulin spike (M-spike)
-if no protein, electrophoresis would be a straight flat-line
Targeted screenings
-renal panel, diabetic panel, bone/joint panel, anemia panel, etc
-performed on someone who has a related dysfunction
Renal Panel
-BUN/creatinine
-dehydration inflates BUN (but not creatinine)
-creatinine clearance
-the semi-gold standard for kidney function (esp. glomerular filtration rate)
-ml of serum that is completely cleared of creatinine per minute
-total protein (serum & urine)
-electrolytes (Na, K, Cl)
-glucose
Pancreatic Panel
Amylase
Lipase – more sensitive to longer term pancreatitis
Calcium – 55% bound and the rest available for biological function
Glucose
Diabetic Panel
Glucose-fasting
Glucose 2-hr
BUN/creatinine
Cholesterol trigs – if high sugar, this is also high
Glycosylated hemoglobin (measure of glycemic control) – not diagnostic for diabetes
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10/29/07
CBC
One of the most commonly ordered clinical laboratory tests, the complete blood count (CBC), is a basic evaluation of the cells (red blood cells, white blood cells, and platelets) suspended in the liquid part of the blood (plasma).
The CBC is a useful screening and diagnostic test that is often done as part of a routine physical examination.
It can provide valuable information about the blood and blood-forming tissues (especially the bone marrow), as well as other body systems.
Abnormal results can indicate the presence of a variety of conditions-including anemias, leukemias, and infections-sometimes before the patient experiences symptoms of the disease.
A complete blood count is actually a series of tests
number of red blood cells
number white blood cells
number of platelets
hemoglobin
hematocrit (packed cell volume)
RBC indices and morphology
WBC differential (types & percentages)
Components of the complete blood count (hemoglobin, hematocrit, white blood cells, platelets, etc.) can also be tested separately, and are sometimes done to monitor a specific condition
The blood count is performed relatively inexpensively and quickly.
Most laboratories routinely use some type of automated equipment to dilute the blood, sample a measured volume of the diluted suspension, and count the cells in that volume.
RBC Count
The number of RBC's per unit volume is measured directly and given in millions per microliter.
Hemoglobin (Hgb)
The Hgb content is measured directly and given in grams per deciliter. This value, along with Hct, provides the most useful measure of the oxygen carrying capacity of the blood.
Hematocrit (Hct)
The packed cell volume expressed as % of RBC per volume of whole blood
OR
The Hct is a calculated value (RBC count x MCV) and provides a measure of the oxygen carrying capacity of the blood.
[pic][pic]
-usually hgb is 1/3 the hct
Hemoglobin (Hgb) concentration corresponds closely to the RBC count.
Also closely tied to the RBC and hemoglobin values is the hematocrit (Hct), which measures the percentage of red blood cells in the total blood volume.
The hematocrit (expressed as percentage) is normally about three times the hemoglobin concentration (reported as grams per deciliter).
Red Cell Indices
Mean Corpuscular Volume (MCV)
The MCV is measured directly; the unit is a femtoliter. The MCV measures the size of RBC's and is the most important index for classification of anemias into "macrocytic" with higher than normal MCV and "microcytic" with low MCV.
Mean Corpuscular Hemoglobin (MCH)
The MCH is calculated (Hgb ÷ RBC count) and gives the average mass of Hgb in an individual RBC; the unit is a picogram.
Mean Corpuscular Hemoglobin (MCHC)
The MCHC is calculated (Hgb ÷ Hct)
MCV 82-98 fl (femtoliters ( 10-15)
MCHC 31-37 g/dl
MCH 26-34 pg (picograms ( 10-12)
RDW 11.5-14.5% (The RDW is the coefficient of variation of the MCV)
Red blood cell indices are useful in differentiating types of anemias.
most common causes of macrocytic anemia (high MCV):
vitamin B12 and folic acid deficiencies
most common causes of microcytic anemia (low MCV):
iron deficit, thalassemia, and chronic illness
most common causes of normocytic anemia (normal MCV):
kidney and liver disease, bone marrow disorders, or excessive bleeding or hemolysis of the RBC’s
RDW is increased in anemias caused by deficiencies of iron, vitamin B12, or folic acid.
Abnormal hemoglobins, such as in sickle cell anemia, can change the shape of red blood cells as well as cause them to hemolyze.
The abnormal shape and the cell fragments resulting from hemolysis increase the RDW.
Conditions that cause more immature cells to be released into the bloodstream, such as severe blood loss, will increase the RDW. The larger size of immature cells creates a distinct size variation.
A platelet count is a diagnostic test that determines the number of platelets in the patient's blood.
Platelets, which are also called thrombocytes, are small disk-shaped blood cells produced in the bone marrow and involved in the process of blood clotting.
There are normally between 150,000-450,000 platelets in each microliter of blood.
Low platelet counts or abnormally shaped platelets are associated with bleeding disorders.
High platelet counts sometimes indicate disorders of the bone marrow.
The primary functions of platelet counts are to assist in the diagnosis of bleeding disorders and to monitor patients who are being treated for any disease involving bone marrow failure.
Leukemia
polycythemia vera
aplastic anemia
An abnormally low platelet level (thrombocytopenia) may result from:
-increased destruction of platelets
idiopathic thrombocytopenic purpura (ITP)
Hypersplenism
-decreased production
Aplastic anemia (no RBC’s, no granulocytes, no platelets)
-increased usage of platelets
Disseminated intravascular coagulation (DIC)
Abnormally high platelet levels (thrombocytosis) may indicate benign reaction to an infection, surgery, or certain medications
polycythemia vera, in which the bone marrow produces too many platelets too quickly.
White Blood Cells
Leukocytes
Normal WBC = 4,500 - 11,000/cmm
Leukocytosis = an increased number of WBC
Leukopenia = a decreased number of WBC
[pic]
-eosinophils – stain red/pink
-basophils – granules stain blue/purple
-neutrophils – neither pink nor blue
10/30
Case impression:
-petechiae and large bruise on back
-no RBC’s, no WBC’s and no platelets
-infections due to lack of WBC’s
-bruises due to lack of platelets
-fatigued due to low RBC’s
-isoniazide is a hepatotoxin and marrow toxin, causing marrow suppression
-drug-induced agranulocytosis (marrow toxicity)
-in most anemias, the WBC’s and platelets are not affected
11/1/07
RBC loses its nucleus as it matures, but retains a reticulo-stroma
-proteins stain pink, and nuclear material stains blue
-normally, 0.5-1.5% of RBC’s are reticulocytes (slightly immature RBC)
-reticulocyte is the lab test value used to make decision about hypo vs hyperproliferative anemia
-anemia: either losing too many RBC’s or not making enough
-can tell by reticulocyte count
-if slow bleed, then reticulocyte count is increased
-if not making enough RBC’s, reticulocyte count is decreased (?)
White Cell Differential
-Diagnosis of myeloproliferative disorders, myelodysplasias, various other hematologic disorders
-Support diagnosis of various infections and inflammation
White Cell Differential
A determination of the relative (%) proportion of the different types of WBC
Normal Adult WBC Differential
Segs 50-75%
Bands 0-7%
Meta 0-1%
Myelo 0%
Eos 0-4%
Baso 0-2%
Lymph 20-40%
Mono 0-5%
Differential Count vs Absolute Count
-The differential count is a relative count (%), while the absolute is the actual number of cells/cmm of blood
-Absolute = % cells x the total WBC
-thus, Lymphocytosis, Lymphopenia, Lymphocytopenia, Neutrophilia, Neutropenia, Monocytosis, Eosinophilia, Basophilia … all refer to the absolute counts NOT the differential
Leukocytosis affects all types of white blood cells:
neutrophilia, lymphocytosis, and granulocytosis
-leukocytosis is normally when there is a disproportionate elevation of one of the cell types
-eosinophils & allergies
-IgE binds mast cell and causes degranulation releasing histamine and ECF, which recruits eosinophils
Normal white blood cell counts are 4,300-10,800 white blood cells per microliter.
Leukocyte or white blood cell levels are considered elevated when they are between 12,000-20,000 per microliter.
The most common and important causes of leukocytosis is inflammation and infection
-most infections cause neutrophilia.
Tissue damage from other causes:
burns
infarction
crush injuries
inflammatory diseases
poisonings
severe diseases -kidney failure and diabetic ketoacidosis
-correlation (in lab testing) – if know one thing then know another thing
-ie good correlation b/n the presence of an embryo and levels of HCG
-good correlation b/n ALT and liver cell necrosis
-correlations are quantifiable (via a coefficient)
-never implies cause and effect
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11/5/07
Diseases of the RBC, WBC, and Hemostasis
RBC morphology
If RBC’s are smaller than normal and have an increases zone of central pallor. This is indicative of a hypochromic (less Hgb in each RBC) microcytic (smaller size) anemia. There is also increased anisocytosis (variation in size) and poikilocytosis (variation in shape)
Basophilic stippling in nucleated RBC
RBC’s have stacked together in long chains. This is known as “rouleaux formation” and it happens with increased serum proteins, particularly fibrinogen and globulins. Such long chains of RBC’s sediment more readily. This is the mechanism for the sedimentation rate, which increases non-specifically with inflammation and increased “acute phase” serum proteins.
-rouleaux formation does not happen in vitro. Any kind of movement or vibration will cause the cells to dissipate apart
-indicative of a plasma protein issue
“helmet cells” aka “schistocytes”
-indicate the RBC’s are being destroyed (microangiopathic hemolytic anemia – MAHA)
-typical for disseminated intravascular coagulopathy (DIC)
Features common to all types of anemia are mainly related to chronic tissue hypoxia
-air hunger, easy fatigability, and pale skin and mucous membranes
-Brittle and concave nails (spooning), especially in iron deficiency anemia
-fatty change of parenchymatous organs (heart, liver)
-expansion of red cell marrow associated with accelerated formation of RBCs
Anemias are classified etiologically according to:
1) Increased blood loss, due to either hemorrhage or hemolysis (hemolytic anemias)
2) Decreased red cell production, due to either bone marrow failure (aplastic anemia) or deficiency of important factors (ie iron, B12, folate)
-half life of RBCs = 120 days
Hemorrhagic Anemia
-Acute post-hemorrhagic anemia
-chronic blood loss anemia
-hemolytic anemias
Acute posthemorrhagic anemia
Manifestation of hypovolemia, hypotension, shock, and tachycardia are present in the first few hours following acute blood loss. Later, a compensatory increase in the plasma volume occurs (hemodilution). The bone marrow actively compensates for the loss, and the reticulocyte count increases
Chronic blood loss anemia
It leads to iron deficiency anemia when the iron stores are depleted. It can be due to gynecologic problems with vaginal bleeding or gastrointestinal bleeding (ie peptic ulcer or colon cancer)
Hemolytic anemia
Hemolytic anemias have three main features common to all of them:
-reduction in survival time of the erythrocytes
-retention of the destroyed erythrocytes and their iron within the body
-functionally active bone marrow
General manifestations of hemolysis
-hyperbilirubinemia leads to jaundice
-pigmented gallstones may form
-intravascular hemolysis leads to hemoglobinemia with consequent hemoglobinuria
-decreased serum haptoglobin – a hemoglobin binding serum protein found
-excessive iron deposition leads to systemic hemosiderosis
-splenomegaly and hepatomegaly occur as the destroyed red cells are carried out by the reticuloendothelial system
-incr’d erythropoietic activity leads to expansion of the bone marrow. This results in thickening of the flat bones (skull)
Types of hemolysis
-Intravascular hemolysis, which occurs when hemolysis takes place inside blood vessels owing to mechanical injury (microangiopathic hemolytic anemia), or to a complement-mediated mechanism (mismatched blood transfusion)
-Extravascular hemolysis, which occurs in the mononuclear phagocyte cells of the liver and spleen. This can be due to opsonizaiton of the red cells or a red cell membrane defect. It differs from intravascular hemolysis by the lack of hemoglobinemia and hemoglobinuria
Intrinsic (intracorpuscular) hemolytic anemia
-hereditary spherocytosis
-Glucose-6-phosphate dehydrogenase (G6PD) deficiency
-Hemoglobinopathies
-Thalassemias
I. Hereditary spherocytosis
-It is an autosomal dominant disorder characterized by sphere-shaped red cells (spherocytes)
-It is due to deficiency of the red cell membrane protein termed spectrin.
This results in an unstable, deficient cell membrane. The red cells acquire a spheroidal shape.
-Spherocytes are trapped and sequestered in the spleen with consequent splenomegaly.
The spleen shows congested red pulp and erythrophagocytosis
-Clinically, it manifests with microcytic anemia, splenomegaly, and hemolytic jaundice
-infection may precipitate a hemolytic crisis or an aplastic crisis
-characteristically, there is increased red cell osmotic fragility
II. Glucose-6-phosphate dehydrogenase (G6PD) deficiency
This is an X-linked condition affecting 10% of African-Americans and is also commonly seen in persons of Mediterranean origin.
Oxidative stimuli (antimalarial drugs, infection, or fava beans) oxidize hemoglobin, creating denatured hemoglobin that precipitates in erythrocytes as Heinz bodies.
The latter attach to the cell membrane, decreasing its flexibility and predisposing the red cells to destruction in the spleen.
Clinically, it manifests with acute mild hemolytic anemia.
G6PD deficiency protects individuals from falciparum malaria.
III. Hemoglobinopathies
These are a group of hemolytic anemias resulting from genetically determined hemoglobin (Hb) structure abnormalities
The normal hemoglobin molecule consists of two parts:
-Heme moiety, which is the pigment containing iron (porphyrin with four pyrole rings).
-Globin moiety, which is a protein with two pairs of polypeptide chains.
The heme moiety
Its iron is present in the ferrous state, which is essential to oxygen transport.
Hemoglobin oxidation into the ferric state renders it unable to carry oxygen.
This occurs in methemoglobinemia (due to some drugs such as sulfonamides, nitrites, and phenacetin).
Sulfohemoglobinemia occurs when sulfides combine with hemoglobin in inorganic sulfide poisoning.
The globin moiety
There are many types of polypeptide chains that can be present in the globin moiety alpha, beta, gamma, delta, and epsilon, thus a number of types of hemoglobin
Normal types of hemoglobin
Hb A (adult hemoglobin) has two alpha chains and two beta chains
Hb A2 accounts for less than 3% of normal adult hemoglobin. It has two alpha chains and two delta chains (a282)
Hb F (fetal hemoglobin) is the normal hemoglobin in the fetus and newborn.
It has two alpha chains and two gamma chains (cx2y2).
Hemoglobin S disorders
This is a hereditary hemoglobinopathy resulting from a point mutation of the globin gene with consequent substitution of valine for glutamic acid at the sixth codon of the 3 globin chain.
This creates hemoglobin S
It is present in approximately 7% of African Americans.
It protects against malarial infection.
Deoxygenation polymerizes hemoglobin S, forming rigid sickle cells that obstruct small vessels and that may produce microinfarcts.
Hemoglobin S disorders - Consequences of sickling
-Chronic hemolysis
-Sickle cells possess rigid membranes, which facilitate their sequestration in the spleen
-The life span of the sickle cells is markedly decreased
-Microvascular occlusion
-This results in widespread micro-infarction
-In the spleen, this may result in auto-splenectomy- markedly shrunken spleen
-Vaso-occlusive crisis: painful attacks of ischemic necrosis, often occurring in bones, lungs, liver, penis, spleen
-Aplastic crisis is temporary bone marrow suppression caused by infection or folate deficiency.
This leads to a fall in hemoglobin level.
-Infection: Increased susceptibility to infection occurs, especially to Salmonella osteomyelitis.
This is probably due to splenic fibrosis and an impaired alternate complement pathway
Hemoglobin C disorder- This is seen mainly in African Americans, Heterozygous forms are usually asymptomatic unless co-inherited with hemoglobin S, Homozygous forms produce mild hemolytic anemia, splenomegaly, target cells, and red cell crystals.
Hemoglobin E disorder- It is the second most prevalent form of abnormal hemoglobin worldwide and the third most prevalent form in the United States- It resembles thalassemia trait and produces microcytosis.
Hemoglobin SC disease- It occurs as frequently as hemoglobin SS in African Americans- It gives the manifestations of sickle cell anemia in a milder form.
The RBC's may sickle, but not as commonly as with Hemoglobin SS disease. The hemoglobin C leads to the formation of "target" cells--RBC's that have a central reddish dot.
11/6/07
IV. Thalassemias
These comprise a heterogenous group of hereditary disorders resulting from deficiency of production of one of the two globin polypeptide chains of hemoglobin. They predominantly occur in persons of Mediterranean, Asian, or African ancestry.
Beta-thalassemias
They are the most common type of thalassemias.
They are due to reduced synthesis of the beta-globin chain.
-there are excess alpha chains when reduction in beta chains
The lack of beta chains results in free unbound alpha chains, which produce unstable aggregates with consequent membrane damage, hemolysis, loss of potassium, and deficient DNA synthesis. This produces inefficient erythropoiesis, a chronic hemolytic state, and marked splenomegaly.
Bone marrow expansion leads to thinning of the cortical bone and new bone formation on the outer aspect. This may create mongoloid facies in children when it involves the skull.
Ineffective erythropoiesis is associated with excessive iron absorption.
This, as well as repeated blood transfusions and hemolysis, creates iron overload and generalized hemosiderosis.
2 Types of Beta-thalassemias
(1) Thalassemia major
Aka = Cooley's anemia, Mediterranean anemia
Homozygous form
It results in a severe transfusion-dependent form of hemolytic anemia. Peripheral blood smear shows microcytic hypochromic red cells with anisocytosis (variability of red cell size), target cells, red cell stippling, and schistocytes (fragmented red cells).
(2) Thalassemia minor
Heterozygous form
It is more common than thalassemia major.
It is usually asymptomatic but may produce mild microcytic hypochromic anemia.
Alpha-thalassemias
These results from reduced synthesis of alpha-globin chains due to deletions of one or more of the four alpha-globin genes
Alpha-thalassemias-4 forms
(1) Silent carrier-
It is asymptomatic.
(2) Alpha-thalassemia trait-
It results in manifestations resembling Beta-thalassemia minor.
(3) Hemoglobin H (Hb H) disease-
It results from deletion of three of the alpha-globin genes.
It leads to the formation of unstable tetramers of beta-globin (Hb H).
(4) Hydrops fetalis
It results from deletion of all four alpha-globin genes
It leads to the formation of gamma-globin tetramers (Hb Bart's), which have a high affinity for oxygen and do not deliver it to tissues.
It is lethal in utero.
Paroxysmal nocturnal hemoglobinuria
It is a rare acquired intracorpuscular membrane defect that leads to a hemolytic disorder.
It results from deficiency of a membrane protein termed decay-accelerating factor (DAF).
This leads to increased sensitivity to complement mediated red cell lysis.
DAF is also deficient in granulocytes and platelets.
Consequently, these patients are predisposed to infections and thrombosis.
The morning urine sample usually shows hemoglobinuria.
Extrinsic (extracorpuscular) hemolytic anemias
Autoimmune hemolytic anemia
(1) Warm-antibody AHA
This is an IgG-mediated immune hemolytic anemia that is not associated with complement fixation.
It is mostly idiopathic but can be secondary to the Lymphoproliferative tumors (Hodgkin's lymphoma, leukemias),
autoimmune conditions (SLE)
Drugs (alpha methyl dopa).
Direct Coombs' test is positive, which indicates that the patient's red cells are coated with IgG.
The IgG-coated (opsonized) red cells acquire a spheroidal shape (spherocytosis),
owing to partial loss of their membranes in the spleen.
(2) Cold agglutinin AHA
This an IgM-mediated immune hemolytic anemia.
Cold-agglutinin IgM fixes complement at warmer temperatures and agglutinates red cells with the help of complement
in peripheral cool parts of the body
It can be acute or chronic. Chronic cold-agglutinin manifests with Raynaud's phenomenon, pallor,
and cyanosis of peripheral body parts when the temperature drops below 30
Isoimmune hemolytic anemias (Rh &ABO incompatibility)
Hemolytic disease of the newborn (HDN) (aka erythroblastosis fetalis)
It results from maternal alloimmunization against fetal red blood cell antigens, mainly the Rh system (if the mother is Rh negative) or from ABO incompatibility between the mother and the fetus (if the mother has blood group 0).
Antibodies are of the IgG type and can cross the placenta, leading to fetal hemolysis, stillbirth, and heart failure with anasarca (hydrops fetalis).
It can lead to ictherus gravis neonatorum, which may be complicated by kernicterus=permanent damage to the basal ganglia and CNS structures due to deposition of unconjugated bilirubin.
Microangiopathic hemolytic anemia
It is a hemolytic state associated with widespread capillary thrombosis and thrombocytopenia. (a component of DIC)
It is observed in malignant hypertension, eclampsia, and septic shock.
Toxic and infective hemolytic conditions
Diseases such as malaria, clostridial and streptococcal infections may be associated with hemolysis.
Chemical toxins such as lead, arsenic, and nitrobenzene may lead to hemolysis.
Anemias of Decreased Red Cell Production
-Iron deficiency -Vitamin B12 deficiency
-Folic acid deficiency -Anemia of chronic disease
-Marrow failure (aplastic) -Marrow replacement (myelophthisic)
-Sideroblastic
-about 7% of people are classified as anemic, and 1% have Hgb values that produce symptoms
Iron deficiency anemia
It is the most common type of anemia encountered clinically.
It can be due to:
-Increased demands- Pregnancy, Infancy and preadolescence.
-Decreased intake (rare)- Infancy (Human milk is iron deficient, Prematurity, Malabsorption)
-ferric sulfate is used as a preservative in numerous junk foods
Chronic blood loss (the most common cause of iron deficiency in adults)
It can be due to
-gynecologic causes (menorrhagia)
-gastrointestinal causes (colon cancer, peptic ulcer) ( most silent form of blood loss
-patient can have 40-50% loss of Hgb and not be aware of it
-hemorrhoids
-parasitic infestations
Clinical picture
Dyspnea, pallor, and easy fatigability.
Glossitis and alopecia.
Koilonychia (nail spooning).
Plummer-Vinson syndrome: Iron deficiency associated with an upper esophageal web and atrophic glossitis.
It is associated with an increased incidence of pharyngeal carcinoma. It is more common in women.
Laboratory findings
Peripheral smear: Hypochromic microcytic red cells
Decreased mean corpuscular volume (MCV) and MCHC
Diminished red cell count, hemoglobin level, and hematocrit.
Diminished serum iron level and increased total iron-binding capacity (TIBC).
Decreased serum ferritin level.
11/12/07
Anemia of chronic disease
It occurs secondary to many chronic diseases such as rheumatoid arthritis and chronic renal diseases.
It may be due to:
Defective iron transport and reutilization.
Defects in erythropoietin production.
Shortened red cell survival
It is usually normochromic normocytic; however, in chronic inflammatory conditions, it can be microcytic hypochromic.
Administration of iron is usually not effective if the cause is not treated.
Sideroblastic anemia
It can be hereditary or acquired owing to drug use (e.g., isoniazid) or lead ingestion.
It is associated with bone marrow changes, including erythroid hyperplasia and ringed sideroblasts.
It is characterized by increased serum ferritin, iron, and transferrin saturation. TIBC is decreased.
It is considered preleukemic and may lead to acute leukemia.
Megaloblastic anemia
It is due to deficiency of vitamin B12 or folic acid and is associated with large megaloblasts (erythroid precursors) in the bone marrow.
There is impaired DNA synthesis leading to impaired red cell production and early red cell destruction in the marrow (ineffective erythropoiesis). This creates a mild hemolytic tendency and results in mild hemosiderosis and elevated serum lactate dehydrogenase (LDH) level.
Nuclear maturation lags behind cytoplasmic maturation.
There is abnormal granulopoiesis, leading to giant metamyelocytes and hypersegmented neutrophils.
The peripheral blood smear shows macro-ovalocytes, pancytopenia, and hypersegmented neutrophils.
2 Types of megaloblastic anemia
B-12 Deficiency
Folate Deficiency
Vitamin B12 deficiency-Pernicious anemia
It is an autoimmune disease caused by chronic atrophic gastritis which is associated with achlorhydria and an
increased incidence of gastric carcinoma.
Antibodies
Blocking antibody, which blocks the binding of intrinsic factor with vitamin B12
Parietal antibody which binds to parietal cells.
Binding antibody, which reacts with intrinsic factor or vitamin B12
Clinical picture
Pale yellow skin & Glossitis (atrophic glazed tongue)
Atrophic gastritis with absent parietal cells that are replaced by mucus goblet cells (intestinalization).
Subacute combined degeneration of the spinal cord (in 75% of cases), leading to sensory ataxia, spastic
paraparesis, hyperreflexia, paresthesias, and an impaired sense of position and vibration.
Schilling test characterized by deficient vitamin B12 absorption, which is corrected by intrinsic factor
administration.
Pernicious anemia-like vitamin B1 deficiency
Causes
Gastrectomy
Terminal ileum disorders (Crohn's disease)
Malabsorption syndromes (sprue and celiac disease)
Diphyllobothrium latum, a fish tapeworm from improperly cooked freshwater fish
Broad-spectrum antibiotics an
Folate deficiency
It produces megaloblastic anemia without neurologic manifestations or gastritis.
Folate deficiency due to:
Pregnancy
Inadequate intake as in alcoholism or in geriatrics
Malabsorption due to sprue or Giardia lamblia infection
Drugs, dilantin and methotrexate (a chemotherapeutic agent that interferes with folic acid metabolism).
Aplastic anemia
It is due to bone marrow depression. Characterized by hypocellular bone marrow = decreased erythroid, granulocytic,
and megakaryocytic elements producing:
Pancytopenia:
Anemia
Leukopenia
thrombocytopenia
Aplastic anemia can be due to
1. Toxic chemicals and drugs
2. Broadspectrum antibiotics (e.g., chloramphenicol).
3. Irradiation.
4. Viruses (hepatitis C and Parvoviruses).
Myelophthisic anemia
It is a bone marrow replacement anemia (metastases).
It results in a leukoerythroblastic reaction:
myeloid precursors (e.g., myelocytes) and erythroid precursors (e.g., nucleated red cells) in the peripheral blood
Summary
[pic]
POLYCYTHEMIA
Polycythemia denotes an increase in the red blood cell number that may be relative or absolute (primary or secondary)
Relative polycythemia
Associated with diminished plasma volume = dehydration
Absolute polycythemia
1. Primary (polycythemia rubra vera): A myeloproliferative syndrome characterized by marked erythrocytosis, moderate granulocytosis and thrombocytosis, splenomegaly, and decreased erythropoietin (due to negative feedback).
2. Secondary polycythemia: Caused by increased erythropoietin due to chronic hypoxia as in:
-Chronic obstructive lung disease - Cyanotic heart diseases
-High altitudes - Erythropoietin secreting tumors
BLEEDING DISORDERS
Excessive bleeding may result from
(1) increased fragility of vessels
(2) platelet deficiency or dysfunction
(3) derangements in the coagulation mechanism
(4) combinations of these
Primary Disorders of Hemostasis
These are hemorrhagic disorders resulting from defects of initial platelet plug formation.
They are characterized by petechial hemorrhages in skin and mucous membranes and bleeding from the gums, nose, and
gastrointestinal tract.
They result from increased vascular fragility or platelet dysfunction
Increased vascular fragility
a. Senile purpura. It occurs on the dorsal aspects of the hands and is possibly due to age-dependent atrophy of the
connective tissues supporting blood vessels.
b. Simple purpura: It occurs mainly in the thighs of otherwise healthy women.
c. Scurvy-vitamin C deficiency, resulting in bleeding gums and cutaneous petechiae.
d. Ehler-Danlos syndrome-a connective tissue disorder due to collagen (or elastin) abnormalities, characterized by
bleeding, deformities, articular hyperextensibility, and cutaneous hyperelasticity
e. Henoch-Schönlein purpura-an allergic purpura due to leukocytoclastic vasculitis, characterized by purpuric rash,
colicky abdominal pain, polyarthralgia, and acute glomerulonephritis
f. Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome): characterized by abnormal capillaries and
venules that lead to hemorrhages of the skin and mucous membranes
g. Meningococcemia and Rickettsial diseases: They affect the endothelium of small vessels, resulting in their rupture.
Disorders of platelets
These result from quantitative platelet dysfunction (thrombocytopenia)
or
qualitative platelet dysfunction (thrombasthenia)
Platelet counts normally range between 150,000 to 300,000/mm3,
Below 100,000/mm3 is generally considered to constitute thrombocytopenia.
Spontaneous bleeding does not become evident until the count falls below 20,000/mm3
Thrombocytopenia can result from
-decreased production (aplastic anemia, ineffective megakaryopoiesis [vitamin B12 or folate deficiency],
or myelophthisic anemia)
-decreased survival (drugs such as methyldopa and quinine, infections, and mechanical reasons)
-sequestration (hypersplenism)
-dilution (massive blood transfusion)
Idiopathic thrombocytopenic purpura (ITP)
It results from immunologically mediated platelet destruction.
In children, it is usually an acute self-limited condition, probably related to viral infections (rubella, cytomegalovirus).
In adults, it is usually chronic and is associated with platelet autoantibodies. The platelets are destroyed in the spleen;
however, splenomegaly is not a feature of ITP - Splenectomy may be curative in some cases.
Chronic ITP is more common in women, especially in those having autoimmune hemolytic anemia, SLE, or lymphomas.
Clinically, it manifests with easy bruisability; purpura, epistaxis, and sometimes hematuria or melena.
Thrombotic thrombocytopenic purpura (TIP)
It is characterized by microangiopathic hemolytic anemia, thrombocytopenia, neurologic manifestations, renal failure,
and fever.
It is caused by widespread hyaline microthrombi.
It is more common in young women and is managed with corticosteroids and exchange transfusions.
The cause of hyaline microthrombus formation is not clear, but it may be due to:
-Immunologic reaction to vascular endothelium
-Platelet-aggregating protein
Unlike DIC, activation of the coagulation cascade is not a feature of TTP
Isoimmune thrombocytopenia
It is caused by antibodies against platelets (ABO incompatibility)
Post-transfusion thrombocytopenia
Occurs when PL-Al positive blood is given to a PL-Al negative patient who was previously sensitized
(by pregnancy or transfusion). This results in antibody mediated destruction of platelets.
Other causes of thrombocytopenia
Disseminated intravascular coagulation (DIC)
Systemic lupus erythematosus
Acquired immunodeficiency syndrome
Acute leukemias
Irradiation, drugs, and chemicals
Hypersplenism
Multiple transfusions
Qualitative platelet dysfunction - thrombasthenia
Characterized by a normal platelet count and prolonged bleeding time
Defective platelet adhesion:
Bernard-Soulier disease, - deficiency of a platelet surface glycoprotein
Defective platelet aggregation,
acquired - aspirin inhibits thromboxane A2 formation
inherited - Glanzmann's thrombasthenia, deficiency of the platelet membrane glycoproteins necessary for aggregation
Secondary Disorders of Hemostasis
These are caused by defects or deficiency of the coagulation factors.
Associated with large ecchymoses or hematomas, hemarthrosis, and prolonged bleeding after trauma
Hemophilia A (classic hemophilia)
It is an X-linked recessive trait characterized by factor VIII
Hemophilia B (Christmas disease)
It is an X-linked recessive disorder characterized by deficiency of factor IX.
Acquired coagulation factor deficiency
Vitamin K deficiency results from malabsorption syndromes
Combined Primary and Secondary Disorders of Hemostasis
Von-Willebrand's disease
It is an autosomal dominant disorder characterized by deficiency of von Willebrand's factor (vWF).
VWF is synthesized by endothelial cells and megakaryocytes, and acts as a carrier for factor VIII
Consequently, deficiency of vWF results in, deficient platelet adhesion and VIII dysfunction
Disseminated intravascular coagulation - DIC (consumption coagulopathy)
It is characterized by
-widespread microthrombi in the microcirculation, resulting Microvascular obstruction, leading to infarcts
-Consumption of coagulation factors and platelets, leading to bleeding
Microthrombus formation is probably due to Release of thromboplastic substances (tissue factor) during or from
widespread endothelial injury.
50% of DIC cases occur in complicated obstetric conditions such as eclampsia, amniotic fluid embolism,
abruptio placentae, intrauterine fetal death, septic abortion, or puerperal sepsis.
Around 33% of those with DIC have carcinomatosis.
Other causes of DIC include sepsis (especially Gram-negative septicemia) and major trauma.
Hallmark finding of DIC: schistocytes (helmet cells – fragmented RBC’s)
Manifestations of DIC
Microangiopathic hemolytic anemia
Hypofibrinogenemia, fibrin split products
Dyspnea and cyanosis
Convulsions and coma
Oliguria and acute renal failure
Shock
Acute DIC is associated mainly with obstetric complications or severe hemorrhage and manifests mainly with bleeding.
Chronic DIC is associated mainly with carcinomatosis and manifests with thrombotic complications (e.g., infarctions).
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Liver coagulopathy
The liver synthesizes all coagulation factors except vWF (which is produced by endothelial cells and megakaryocytes).
Consequently, hepatocellular failure is associated with prolonged PT, aPTT, and thrombin time.
Platelet dysfunction and thrombocytopenia due to hepatocellular failure lead to a prolonged bleeding time.
Diseases of the White Blood Cells and Lymphoid Tissues
LEUKOPENIA
Leukopenia is a decrease in the total number of circulating peripheral white blood cells. The most common form is a decrease in the number of neutrophils (neutropenia, also called agranulocytosis).
Agranulocytosis (Neutropenia) is a severe decrease in the number of granulocytes, predisposing the patient to serious infections.
Causes:
Ineffective granulopoiesis
Aplastic anemia (due to bone marrow suppression).
Myelophthisic anemia.
Acute leukemia.
Drugs (anticancer drugs and broad-spectrum antibiotics).
Megaloblastic anemia.
Infections (typhoid fever and influenza).
Other causes:
Enhanced destruction of granulocytes
Hypersplenism.
Autoimmune disease (e.g., SLE, Felty's syndrome).
Drugs (e.g., anticancer drugs and broad-spectrum antibiotics).
The neutrophil count may be normal, but the function may be abnormal.
The functional defect may involve chemotaxis and phagocytosis (lazy leukocyte syndrome), or it may be mixed and involve intracellular digestion of organisms (Chronic Granulomatous Disease and Chediak-Higashi syndrome).
Felty’s syndrome (in RA) – drop in white cell count in blood (white cell sequestration)
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Diabetes: high blood glucose, high urine glucose and ketones
Renal failure: high BUN, potassium, and creatinine, low protein and albumin (blood), protein in urine
UTI: bacteria, WBC, leukocytes, and nitrates in urine
Liver failure: bilirubin elevated, elevated ALT and Alkaline phosphatase
Anemia: low RBC, HGB and HCT
Heart disease: cholesterol and trigs are elevated (esp in diabetic), possibly elevated LD
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LEUKOCYTOSIS
This is a reactive increase in the number of white blood cells, usually in response to inflammatory conditions
Neutrophilia (Polymorphonuclear Leukocytosis)
It is associated with acute forms of inflammation, especially the suppurative types.
It may be associated with neutrophilic
Döhle bodies, toxic granules, or cytoplasmic vacuolation.
More premature forms appear in peripheral blood (e.g., bands, metamyelocytes) and may be myelocytes (shift to the left).
Monocytosis: Increased number of monocytes occurs
Granulomas (tuberculosis).
Systemic lupus erythematosus.
Rheumatoid arthritis.
Inflammatory bowel diseases.
Eosinophilia: Increased number of eosinophils occurs (6 or more is unusual)
Allergic conditions (bronchial asthma)
Parasitic infestations
Some skin diseases (psoriasis)
Hodgkin's disease and eosinophilic leukemia
Lymphocytosis: Reactive increase in the number of lymphocytes occurs
Chronic infections (tuberculosis, brucellosis, syphilis).
Some viral infections (cytomegalovirus, Epstein-Barr virus, viral hepatitis)
Leukemoid reactions:
Rare severe reactive leukocytosis that mimics chronic myeloid leukemia or chronic lymphoid leukemias
REACTIVE LYMPHADENOPATHY
Acute Reactive Lymphadenitis
Localized forms occur in nodes draining areas of acute inflammation (cervical lymphadenitis in acute tonsillitis).
Generalized forms occur in bacteremia and viral infections.
Clinically, acute lymphadenitis may be a painful, tender, soft lymphadenopathy.
Granulomatous Lymphadenopathy (Chronic)
Tuberculosis
Sarcoidosis
Toxoplasmosis
Cat scratch disease: Gram negative bacteria
Histoplasmosis
Lymphogranuloma venereum: a chlamydial STD
Tularemia: Francisella tularensis. It produces severe acute lymphadenopathy (with history of contact with rabbits).
AIDS Related Lymphadenopathy
Labdx test 3 11/19/07
LEUKEMIAS
Leukemias are malignant neoplasms of the hematopoietic stem cells of the bone marrow characterized by:
-the appearance of abnormal immature white cells in the peripheral blood
-bone marrow replacement with leukemic cells
-widespread infiltration of the spleen, liver, and other organs by the leukemic cells
Leukemias are classified on the basis of:
1. Type of cell series involved:
Myeloid (myelogenous = granulocytic), lymphocytic, and monocytic.
2. Level of peripheral white cell count:
Leukemic (flooding into peripheral blood) and aleukemic (into the bone marrow only).
3. Progression of the clinical course:
Acute leukemia, characterized by immature (blast) cells in peripheral blood and a rapid fatal course, and
Chronic leukemia, characterized by mature well differentiated leukocytes and an indolent course.
Chronic leukemias are associated with the highest white cell counts, and the circulating white cells tend to be of the mature forms.
Acute leukemias usually have mild to moderate elevation of the white cell count, but the cells tend to be of the primitive forms (blasts).
In some cases of lymphoma, cells flood into the blood and create a leukemic phase. In these cases, the type of leukemia usually corresponds to the histologic picture of lymphoma.
-lymphocytic lymphoma may be associated with lymphocytic leukemia
-plasma cell (multiple) myeloma may give rise to plasma cell leukemia
-acute myeloblastic (granuloblastic) leukemia may give rise to granulocytic sarcoma (chloroma).
The bony infiltrates of acute myeloblastic leukemia form tumor masses that usually occur in facial bones and are termed chloromas (granulocytic sarcomas). The latter usually occur in facial bones and may lead to exophthalmos.
They are called chloromas because when they are freshly cut, they have a greenish color that fades rapidly upon exposure to air
Subperiosteal infiltrates in acute leukemia result in bone pains and tenderness
The lymph nodes are generally enlarged in most forms of leukemia.
The most striking enlargement occurs in lymphoid leukemias
Lymph nodes are usually discrete, rubbery; and painless
The spleen is enlarged in most types of leukemia. The most striking enlargement is encountered in chronic myeloid leukemia.
The liver is enlarged in most types of leukemia.
Secondary changes include anemia, and thrombocytopenia with hemorrhages in skin, mucous membranes, and other sites.
Infection is common because the leukemic cells express little defensive capacity.
Acute lymphocytic leukemia (ALL)
Chronic lymphocytic leukemia (CLL)
Acute myelocytic (myeloblastic) leukemia (AML)
Chronic myelocytic leukemia (CML)
Acute leukemias
Acute leukemias are characterized by a rapidly fatal course and predominance of immature (blast) cells in the peripheral circulation and bone marrow.
They represent the most common malignant tumor in children.
The blasts suppress the normal hematopoietic stem cells and result in pancytopenia.
Abrupt stormy onset: Most patients present within 3 months of the onset of symptoms.
Symptoms related to depression of normal marrow function: fatigue due mainly to anemia; fever, reflecting an infection due to absence of mature leukocytes; bleeding (petechiae, ecchymoses, epistaxis, gum bleeding) secondary to thrombocytopenia.
Acute lymphoblastic leukemia (ALL)
It constitutes more than 80% of childhood acute leukemias.
B cells (CD19 B-cell marker) comprises about 80% of cases of ALL
ALL has the best response to chemotherapy among the acute leukemias
Acute myeloblastic leukemia (ANL)
It is also termed acute granulocytic leukemia and acute nonlymphoblastic leukemia
It most commonly affects young adults
It shows a predominance of myeloblasts and promyelocytes.
The cytoplasm shows fine azurophilic granules with red rodlike structures (Auer bodies)
The prognosis is worse than for ALL
Chronic leukemias
These are characterized by more mature forms and less blasts than in acute leukemias.
They follow a longer course than acute leukemias and usually express remissions and exacerbations.
Chronic myeloid (myelocytic; granulocytic) leukemia (CML)
It is a myeloproliferative disorder that affects young adults and is characterized by neoplastic clonal proliferation of myeloid stem cells.
Leukocyte count is markedly elevated (usually more than 100,000/mm3) with many neutrophils, metamyelocytes, myelocytes, basophils, and eosinophils. Thrombocytosis can be encountered early in the disease.
Approximately 90% of cases express Philadelphia chromosome
Splenomegaly is usually severe, while hepatomegaly and generalized lymphadenopathy are mild.
CML expresses an accelerated phase with severe anemia, thrombocytopenia, and excess blasts (blastic crisis) with transformation into acute leukemia.
In contrast to ALL, the presence of Philadelphia chromosome in CML carries a good prognosis.
Chronic lymphoid (lymphocytic) leukemia (CLL)
It occurs in old age (usually older than 60), is more common in men, and runs an indolent course.
Leukemic lymphoid cells are usually of the B-cells that are unable to differentiate into plasma cells. This leads to hypogammaglobulinemia and predisposes the patient to bacterial infections.
Lymphadenopathy is marked
Hairy cell leukemia
It is a rare chronic B-cell lymphocytic leukemia occurring in old age.
Cells have hair-like surface projections.
It is associated with marked splenomegaly and pancytopenia (due to marrow failure and hypersplenism).
Splenectomy may be of benefit
MYELODYSPLASTIC SYNDROMES
It is a group of bone marrow disorders characterized by ineffective or disordered maturation and hypercellular or
normocellular bone marrow.
There are usually megaloblastoid erythroid precursors, hypogranular myeloid precursors, and an increased number of
bone marrow blasts.
The peripheral smear shows micromegakaryocytes and agranular platelets.
Refractory anemia and Chronic myelomonocytic leukemia
It usually affects elderly males. The median survival ranges from 1 to 15 years.
PLASMA CELL DYSCRASIAS
These are monoclonal neoplastic proliferations of immunoglobulin-secreting plasma cells.
They secrete monoclonal immunoglobulin, which is usually a complete immunoglobulin, light Bence Jones protein
or heavy chains, or both.
The light chains include lambda or kappa (Bence Jones proteins).
If only light chains are produced (without complete immunoglobulin), the condition is referred to as light chain disease.
MYELOPROLIFERATIVE SYNDROMES
These are clonal neoplastic proliferations of multipotent bone marrow stem cells
Polycythemia Rubra Vera
-an absolute increase in the red cell mass (severe erythrocytosis).
-moderate granulocytosis as well as thrombocytosis and splenomegaly.
-erythropoietin level is decreased. This distinguishes it from secondary polycythemia, which is associated with
increased erythropoietin level.
-Clinically, in patients with polycythemia rubra vera, there is increased viscosity, thrombosis, hemorrhagic diathesis,
vascular stasis and cyanosis.
-Headaches, dizziness, infarcts, and hyperuricemia are also present
Multiple (plasma cell) myeloma
It is the most common gammopathy.
It is a malignant neoplasm of plasma cells involving multiple sites in bones.
It produces a monoclonal immunoglobulin, termed M protein, that appears in the serum and urine on electrophotometry
as an M spike. The total serum protein level is increased with hyperglobulinemia.
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The M component is usually IgG, less commonly, it may be IgA, IgD, or IgE
It may be associated with a free light chain either lambda or kappa (Bence Jones proteins), which may appear in the
urine)
Clinical pathologic features
Bone lesions
1.They are due to an osteoclast-activating factor released by the tumor cells.
2. They are multiple osteolytic punched-out (with a clearly defined sharp border) lesions involving mainly the skull
and axial bones.
3. Osteopenia (diffuse bony rarefaction due to demineralization) may be present.
4. They produce pain, pathologic fracture, and hypercalcemia due to bone resorption.
5. Hypercalcemia leads to confusion, lethargy, depression, constipation and metastatic calcification.
Multiple myeloma presents most often as multifocal destructive bone lesions throughout the skeletal system
vertebral column, 66%; ribs, 44%; skull, 41%;
Pathologic fractures are most common in the vertebral column.
Hyperglobulinemia results in hyperviscosity syndrome and rouleaux formation (stacking of RBCs in blood smear)
Pancytopenia (incr RBCs, WBCs, and platelets) is due to bone marrow replacement by the neoplastic plasma cells.
Recurrent encapsulated bacterial infection (pneumococcal) occurs owing to suppression of normal immunoglobulin.
Myeloma kidney occurs due to tubular casts of Bence Jones proteins and tubular atrophy
Renal amyloidosis
Metastatic calcification
Recurrent pyelonephritis (due to decreased immunity)
It results in azotemia and renal failure.
The most common causes of death are renal failure and infection.
Waldenstrom’s macroglobulinemia
It is a malignant proliferation of monoclonal IgM-producing cells
It most commonly affects elderly males.
The M protein is an IgM of either lambda or kappa specificity.
It produces hyperglobulinemia and
hyperviscosity syndrome. which may lead to dizziness, headache, stupor, and retinal vasodilatation with hemorrhage.
It is a slowly progressive condition with generalized lymphadenopathy, anemia, and hepatosplenomegaly
The average survival rate is 2-5 years with chemotherapy
Heavy-chain diseases
These are rare gammopathies associated with an increased level of one of the heavy chains in the blood or urine, or both.
Alpha heavy-chain disease is the most common type of heavy chain disease and occurs mainly in young adults
Gamma-chain disease, encountered most often in the elderly, resembles a malignant lymphoma
Mu-chain disease is the rarest of these entities, most often encountered in patients with chronic lymphocytic leukemia
Histiocytosis
This is a proliferative disorder of the Langerhans' cell, a phagocytic cell present normally in the epidermis and has three variants
Letterer-Siwe Disease
It is also termed acute disseminated Langerhans' cell histiocytosis.It affects infants and young children and has an aggressive fatal course. It is characterized by widespread histiocytic proliferation with hepatosplenomegaly, lymphadenopathy, pancytopenia, and recurrent infections.
Hand-Schüller-Christian Disease
It is also termed multifocal Langerhans' cell histiocytosis.
It affects children younger than the age of five and has a better prognosis than Letterer-Siwe disease.It is characterized by histiocytic proliferation with inflammatory cells leading to hepatosplenomegaly, lymphadenopathy, calvarial bone involvement, posterior pituitary involvement, diabetes insipidus, and exophthalmos.
Eosinophilic Granuloma
It is also termed unifocal Langerhans' cell histiocytosis.
It affects children and young adults and carries the best prognosis of all histiocytosis variants.It is characterized by many eosinophils and by histiocytic proliferation mixed with inflammatory cells.
It is usually a solitary asymptomatic bone lesion
LYMPHOMAS
Lymphomas are malignant neoplasms (monoclonal) of lymphoid tissues (lymphocytes and histiocytes)
The term “lymphoma” is something of a misnomer, since these disorders are lethal unless controlled or eradicated through therapy. There are no “benign” lymphomas. Two broad categories include Hodgkin's and non-Hodgkin's lymphomas.
Hodgkin’s Disease
This is a malignant lymphoid neoplasm that may occur at any age but shows two peaks of incidence: one at the third
decade of life and the other at the seventh decade.
It is the most common type of lymphoma and predominantly affects men
Clinical features of Hodgkin’s
It presents with painless enlargement of the lymph nodes, which spreads to anatomically contiguous nodes
It is uncommon for Hodgkin's disease to involve extranodal structures (liver)
Fever (recurring fever), pruritus, diaphoresis, and leukocytosis.
Ann Arbor classification
1. Stage I: Disease involves a single node or a group of nodes.
2. Stage II: Disease involves more than one group of nodes along one side of the diaphragm.
3. Stage III: Disease involves nodes on both sides of the diaphragm.
4. Stage IV: Widespread involvement of extralymphoid sites is seen with or without nodal involvement.
Clinical staging is better correlated with the prognosis than is the histologic variant
Histologic classification: The characteristic cell is the Reed-Sternberg cell, a large binucleated or multinucleated) cell
with eosinophilic nucleoli surrounded by a clear halo (owl-eye appearance),
The more Reed-Sternberg cells, the more aggressive the disease and the worse the prognosis
Non-Hodgkin’s Lymphomas
-These are malignant tumors of lymphoid tissues that are characterized by more frequent involvement of multiple
peripheral nodes than in Hodgkin's disease. They commonly involve extranodal tissues.
-The usual presentation of NHL is as a localized or generalized lymphadenopathy.
-Although variable, all forms of lymphoma have the potential to spread from their origin in a single node or chain of
nodes to other nodes, and eventually to disseminate to the spleen, liver, and bone marrow
Burkitt's lymphoma
It is B cell lymphoma usually affecting children.
It occurs sporadically in the United States, where it usually presents with an abdominal mass.
It is endemic in some parts of Africa and usually presents with a facial bone mass.
It is related etiologically to Epstein-Barr virus infection.
DISEASES OF THE SPLEEN
Hypersplenism
It is associated with splenomegaly
Blood cells are sequestered at an increased rate in the enlarged spleen, leading to pancytopenia
Reactive hyperplasia of the bone marrow occurs
Splenectomy leads to clinical and hematologic improvement
Hyposplenism
Lack of splenic function is encountered in:
-Splenectomy
-Sickle cell disease (autosplenectomy due to repeated infarctions)
-Celiac disease (splenic atrophy
It predisposes patients to recurrent bacterial infections, especially by capsulated bacteria (Streptococcus pneumoniae, Hemophilus influenzae, Neisseria meningitidis, and Escherichea coli).
Septicemia and multi-organ failure may develop eventually.
Splenomegaly
Causes include:
-Infective
-Neoplastic: Lymphomas & Leukemias, especially chronic leukemia (the spleen is largest in CAM)
-Immunologic:
-Sarcoidosis (noncaseating granulomas).
-Felty's syndrome: Follicular hyperplasia of the spleen associated with hypersplenism and leukopenia in an adult
with rheumatoid arthritis.
-Systemic lupus erythematosus
INFLAMMATION
Inflammation IS NOT Infection. Inflammation is a reaction of the microcirculation characterized by movement of fluid and leukocytes from the blood into the extravascular tissues. Inflammation is a process which attempts to localize and eliminate metabolically altered cells, foreign particles, micoorganisms, or antigens. Under normal conditions the inflammatory response eliminates the pathogenic insult and removes the injured tissue components
An inflammatory reaction or response leads to one of three possible outcomes:
1) The source of the tissue injury is eliminated, the inflammatory response resolves, and normal tissue architecture and
physiologic function are restored
2) The tissue is irreversibly injured despite elimination of the initial pathogenic insult, the affected tissue’s architecture
Is altered (scarred), and varying degrees of function are retained
3) The inflammatory response fails to eliminate the pathologic insult, the inflammatory response continues, the tissue’s
architecture is continually altered, and function is eventually lost
Inflammations is almost always accompanied by some degree of cellular necrosis. It is the final common pathway of almost all pathological processes. The characteristics of an inflammatory reaction are swelling, heat, redness, and pain and the systemic presentation of inflammation includes fever, tachycardia, malaise, and anorexia.
Depending on the site of inflammation (liver, kidney, muscle) a number of laboratory tests may be abnormal, and reflect the associated cellular necrosis
CPK - increased due to tissue destruction
LDH - increased due to tissue destruction
ALT/AST - increased due to tissue destruction
Despite the location or the etiology of the inflammation one or more of the following supports the presence of an inflammatory reaction:
Increased WBC ( >12,00/cmm)
WBC Left Shift (> 10% bands)
Increased ESR (> 20 mm/hr)
Increased C-Reactive protein(>10ug/ml)
Increased alpha and beta globulins
LEUKOCYTOSIS
Leukocytosis can be a false positive indicator of inflammation as it occurs in a number of non-inflammatory conditions, such as:
Pregnancy
Acute bleeding
Following severe exercise
Daily circadian fluctuation of about 2x
Additionally, some infections typically do not produce an elevation of the WBC
Bacterial - Brucellosis, Chlamydial, Diptheria, Typhoid
Fungal - Histoplasmosis
Parasitic - Malaria, Toxoplasmosis, Leishmaniasis
Rickettsial - Typhus, Rocky Mountain Spotted Fever
Viral - Chickenpox, Measles, Rubella, Smallpox
LEFT SHIFT - An increase in the number of immature granulocytes
Immature granulocytes: Basophilic, Eosinophilic, or Neutrophilic
Bands or stabs
Metamyelocytes or Juvenile
Myelocyte
Promyelocyte
“Right Shift” - An increase in the number of mononuclear cells : lymphocytes or monocytes
“Left Shift” - The increase number of immature cells in the peripheral circulation occurs because cells are recruited out, before they have fully matured
Left shift = increased number of baso, eos, and neutrophils
Right shift = increased number of lymphocytes and monocytes
SED RATE - ERYTHOCYTE SEDIMENTATION RATE
When well mixed venous blood is placed in a vertical tube, the RBC will tend to fall toward the bottom. The length of fall of the top of the column of RBC in a give time is the Erythrocyte Sedimentation Rate (ESR). ESR is usually expressed in mm/hr.
ESR – let tube set for an hour, the sed rate is the mm distance that the top of the cells are from the original top
-if inflammation, sed rate is elevated
What is the maximum possible Sed Rate?
First, it depends on the length of the tube
Second , it depends on the Hematocrit
V = 2r2 (d1- d2) g
9n
r = radius of the sphere
d1= density of the sphere
d2= density of the fluid
g = force of gravity
n = Viscosity of the fluid
What’s being measured?
How does this relate to inflammation?
Plasma Composition
RBC are negatively charged and normally repel each other.
The negative charge is expressed as the Zeta potential
The Zeta potential is a function of the:
-sialic acid groups on the RBC membrane
-pH of the medium
-ionic strength of the medium
-dielectric effect of the protein molecules in the medium.
All proteins and other macromolecules decrease the zeta potential of the RBC
During an inflammatory response acute phase proteins are produced, which contribute to lowering the zeta potential
Decreased Zeta potentials allow for RBC to undergo rouleaux formation (pseudoagglutination), thus causing the RBC to fall at a greater rate (i.e.; to increase SEDIMENTATION rate)
Rouleaux formation (pseudoagglutination)
The proteins that contribute the most lowering the Zeta potential are:
Fibrinogen
Gamma globulin
alpha 1 globulin
beta globulin
haptoglobin
Acute Phase Protein Effect on Sed Rate
Inflammatory response ( acute phase proteins ( rouleaux formation
*Zeta potential is the net negative charge (of plasma?)
-zeta potential allows for Rouleaux formation which promotes the sed rate
-elevated sed rate is indicative of an increase in acute phase proteins in patients plasma
Sed Rate and “Artifacts”
There are times when Sed Rate results are meaningless and thus the Sed Rate can not be used
Artifacts: NUMBER OF ERYTHOCYTES
When the number of erythrocytes per unit volume of blood is greater or less than normal, the true sedimentation rate is modified.
Hematocrit values greater than 42±5 for females and 47±5 for males will, by them selves, produce clinically significant sedimentation rates.
Example:
A patient has a Hematocrit of 30%, has no inflammatory reaction or process, yet has a Sed Rate of 36mm/hr
This is a false positive result (an abnormal Sed Rate in the absence of inflammation) due to the decr numbers of RBC
Conversely, a patient has a Hematocrit of 60%, has a severe inflammatory reaction or process, yet has a Sed Rate of 5 mm/hr. This is a false negative result (an normal Sed Rate in the presence of inflammation) due to the incr numbers of RBC
With Hct normally 45%,
-an Hct of 30% would FALSELY INCREASE erythrocyte number
-an Hct of 60% would FALSELY DECREASE erythrocyte number
Artifacts: SIZE OF ERYTHROCYTES
Macrocytosis (MCV>96) or Microcytosis (MCV 8.0)
-In addition, precipitation of urine crystals in supersaturated urine is highly dependent on urine pH
-Although the kidneys play a central role in the control of acid/base metabolism, the pH of a random urine sample is not a reliable indicator of total body acid/base status.
-In some conditions, impaired renal tubular function in fact causes or perpetuates the underlying acid/base derangement.
-Meaningful evaluation of acid-base status requires blood gas analysis and consideration of clinical signs.
-The test is specific for the detection of hydronium ions, the pH being the negative common logarithm of the hydronium ion concentration. The test pad contains the indicators methyl red, phenolphthalein and bromthymol blue.
Specific Gravity (USG)
-tells fluid intake
-Urine specific gravity is a measurement of the density of urine compared to pure water
-The USG is influenced by the number of molecules in urine, as well as their molecular weight and size, therefore it only approximates solute concentration.
-It is also affected by temperature, with urine density decreasing with increasing temperatures.
-The presence of large amounts of protein and glucose will alter the USG & should be considered when interpreting USG results
-Urine osmolality is directly related to the number of particles in solution and is unaffected by molecular weight and size.
-Osmolality can be measured by freezing point depression
-Urine osmolality can be approximated from the USG, by multiplying the last 2 digits of the USG by 36
-Specific gravity between 1.002 and 1.035 on a random sample should be considered normal if kidney function is normal.
- Since the USG of the glomerular filtrate in Bowman's space ranges from 1.007 to 1.010, any
measurement below this range indicates hydration and any measurement above it indicates relative dehydration.
-If USG is not > 1.022 after a 12 hour period without food or water, renal concentrating ability is impaired and the patient either has generalized renal impairment or nephrogenic diabetes insipidus.
- In end-stage renal disease, USG tends to become 1.007 to 1.010.
-Any urine having a specific gravity over 1.035 is either contaminated, contains very high levels of glucose, or the patient may have recently received high density radiopaque dyes intravenously for radiographic studies or low molecular weight dextran solutions.
The test detects the ion concentration of the urine. In the presence of cations, protons are released by a complexing agent and produce a color change in the indicator bromthymol blue from blue via blue-green to yellow.
(This test is based on the apparent pKa change of certain pretreated polyelectrolytes, poly(methyl-vinyl-ether/maleic anhydride), in relation to ionic concentration. In the presence of bromthymol blue, colors range deep blue-green in urine of low ionic concentration through green and yellow-green in urines of increasing ionic concentration.)
Protein
Dipstick screening for protein is done on whole urine, but semi-quantitative tests for urine protein should be performed on the supernatant of centrifuged urine since the cells suspended in normal urine can produce a falsely high estimation of protein.
-The urine protein results should always be interpreted in context with the urine specific gravity and pH.
-A trace to 1+ reaction in a very dilute urine is suggestive of significant proteinuria.
-A dipstick protein reaction > 2+ in dilute urine indicates significant proteinuria.
-Normal total protein excretion does not usually exceed 150 mg/24 hours or 10 mg/100 ml in any single specimen.
-More than 150 mg/day is defined as proteinuria.
-Proteinuria > 3.5 gm/24 hours is severe and known as nephrotic syndrome.
-The test is based on the "protein error of pH indicator dyes".
-Basically, the test is dependent on the ability of amino groups in proteins to bind to and alter the color of acid-base indicators, even though the pH is unchanged
-The reaction is extremely sensitive to albumin (as it contains the most amino groups), but is much less sensitive to globulins.
-It is insensitive to Bence-Jones proteins.
-Generally this differential sensitivity is not a significant problem (nearly all cases of significant proteinuria involve albuminuria)
Protein - False positive results
Alkaline urine: False positives occur rarely in highly buffered or alkaline urine samples as the citrate buffer is overcome, resulting in a shift in pH.
Contact time: Leaching of the citrate buffer occurs if the urine remains in contact with the pad for a long time.
Detergents: Quaternary ammonium compounds and chlorhexidine can result in false positives.
In rough terms: trace positive results (which represent a slightly hazy appearance in urine) are equivalent to 10 mg/100 ml or about 150 mg/24 hours (the upper limit of normal).
1+ corresponds to about 200-500 mg/24 hours,
2+ to 0.5-1.5 gm/24 hours
3+ to 2-5 gm/24 hours,
4+ represents 7 gm/24 hours or greater.
The most accurate measurement of urine protein output is measurement of urine protein excretion over 24-hours
Things beside kidney disease can cause proteinuria:
-Postural proteinuria (orthostatic, etc): 3-5% of healthy young adults pass excess protein during the day, not at night.
-Functional proteinuria (albuminuria): occurs with fever, cold exposure, stress, pregnancy, eclampsia, CHF, shock, severe exercise
-Drugs that can increase measurements include acetazolamide, aminoglycosides, amphotericin B, cephalosporins, colistin, griseofulvin, lithium, methicillin, nafcillin, nephrotoxic drugs (such as arsenicals, gold salts), oxacillin, penicillamine, penicillin G, phenazopyridine, polymyxin B, salicylates, sulfonamides, tolbutamide, and viomycin.
Glucose
-In nearly all cases, glucosuria is a result of prior (often, continuing) hyperglycemia to a level in excess of the renal threshold for reabsorption
-Glycosuria generally means diabetes mellitus.
-Benign low renal glucose threshold (the kidneys excrete glucose in the urine at a relatively low blood glucose level)
-Cushing's syndrome
-Severe stress (for example, trauma or surgery)
-Drugs that may increase urine glucose measurements include: aminosalicylic acid, cephalosporins, chloral hydrate, chloramphenicol, dextrothyroxine, diazoxide, diuretics (loop and thiazides), estrogens, isoniazid, levodopa, lithium, nafcillin, nalidixic acid, and nicotinic acid (large doses).
-Glucose is measured on the Multistix by a glucose oxidase method. The reaction of glucose with glucose oxidase forms nascent oxygen (O), which converts potassium iodide in the dipstick pad to iodine, forming a brown color change. Normal urinary glucose is below the level of sensitivity of the commonly used detection techniques. Therefore, glucose is an abnormal finding in urine.
-Drugs that may increase urine glucose measurements include: aminosalicylic acid, cephalosporins, chloral hydrate, chloramphenicol, dextrothyroxine, diazoxide, diuretics (loop and thiazides), estrogens, isoniazid, levodopa, lithium, nafcillin, nalidixic acid, and nicotinic acid (large doses).
False positives (trace to +1)
dipstick jar being left uncapped for a few days hypochlorite( bleach)
Drugs that may give false negative results
ascorbic acid
levodopa
Phenothiazines
Tetracycline
Ketones
Ketonuria indicates deranged energy metabolism such that fat is used in excess of carbohydrate. This can result in production of the ketone bodies (acetone, aceotacetic acid, beta-hydroxybutyric acid) in amounts greater than can be metabolized by peripheral tissue and filtration into urine in excess of tubular reabsorption
Test is based on the principle of Legal's test Acetone and acetoacetic acid react with sodium nitroprusside in alkaline solution to give a violet colored complex
Phenylketones and phthalein compounds produce red colors on the test area.
Captopril, MESNA (2-mercaptoethanesulfonic acid sodium salt) and other substances containing sulfhydryl groups may produce false-positive results
metabolic abnormalities
uncontrolled diabetes or glycogen storage disease
abnormal nutritional conditions
starvation, fasting, anorexia, high protein or low carbohydrate diets
protracted vomiting
disorders of increased metabolism
hyperthyroidism, fever, acute or severe illness, burns, pregnancy, lactation or following surgery
-Because the color change on the dipstick can be quite subtle, positive reactions can confirmed with the Acetest.
-This comes in tablet form and contains lactulose to enhance the color change.
-The Acetest is useful for semi-quantitatively measuring ketones in other fluids, such as plasma, serum and milk.
Nitrite
-The reaction thus indirectly detects the presence of nitrite-forming organisms in the urine..
-The test is based on the principle of Griess' test and is specific for nitrite
-The most common organisms causing urinary tract infections, E. coli, and most urinary pathogens, convert dietary nitrate to nitrite, which produces a pink coloration of the test area .
-This assay determines total nitric oxide based on the enzymatic conversion of nitrate to nitrite by nitrate reductase. The reaction is followed by a colorimetric detection of nitrite as an azo dye product of the Griess Reaction. The Griess Reaction is based on the two-step diazotization reaction in which acidified NO2 produces a nitrosating agent, which reacts with sulfanilic acid to produce the diazonium ion. This ion is then coupled toN-(1-naphthyl) ethylenediamine to form the chromophoric azo-derivative
-Negative results do not exclude significant bacteriuria
-A negative result even in the presence of bacteriuria can have the following reasons:
-bacteria not containing nitrate reductase, diet with low nitrate content, high diuresis, high content of ascorbic acid or insufficient incubation of the urine in the bladder.
-False positive results may occur in stale urines, in which nitrite has been formed by contamination of the specimen and in urines containing dyes (derivatives of pyridinium, beetroot).
-Just how to check people, especially children, for urinary tract infections is a subject of much discussion today
-more than 105 colony-forming units / mL of clean-catch voided urine
-more than 104 colony-forming units / mL of catheter-obtained voided urine
-more than 103 colony-forming units / mL of urine obtained by suprapubic aspiration
Leukocyte
-The reaction detects the presence of esterases that occur in granulocytes.
-These enzymes cleave an indoxyl ester and the indoxyl so liberated reacts with a diazonium salt to produce a violet dye.
-Pyuria can be detected even if the urine sample contains damaged or lysed WBC's.
Bilirubin
-Bilirubin metabolism begins with the breakdown of red blood cells (RBCs) by phagocytic cells (cells that consume and digest other cells).
-Hemoglobin is broken down to heme and globin.
-Heme is converted to bilirubin, which is then carried by albumin in the blood to the liver.
-In the liver, most of the bilirubin is conjugated with glucuronic acid before it is excreted in the bile.
Conjugated bilirubin is called direct bilirubin
Unconjugated bilirubin is called indirect bilirubin
Total bilirubin = DB + IB.
-Conjugated bilirubin is excreted into the bile by the liver and stored in the gall bladder or transferred directly to the small intestines.
-Bilirubin is further metabolized by bacteria in the intestines to urobilins, which contribute to the color of the feces.
-A small percentage of these compounds are reabsorbed and eventually appear in the urine, where they are referred to as urobilinogen.
-If the bile ducts are obstructed, direct bilirubin will build up to a high enough level that some of it will escape from the liver into the blood.
-If the levels are high enough, some of it will also appear in the urine.
-Only direct bilirubin appears in the urine.
-Increased direct bilirubin usually means that the biliary (liver secretion) ducts are obstructed.
-Hepatobiliary disease:
Bilirubinuria generally results when conjugated bilirubin levels in blood are elevated as a result of hepatobiliary disease, bilirubinuria indicates cholestasis.
-In some cases of hemolytic anemia, bilirubinuria may be secondary to the hemolysis without any evidence of cholestasis. The renal tubular epithelium is capable of absorbing hemoglobin from the glomerular filtrate and converting it to conjugated bilirubin, which is then excreted in the urine. This will only occur with intravascular hemolysis, when free hemoglobin is filtered by the glomerulus.
-The bilirubin pad on the multireagent dipstick detects bilirubin using a specific diazotization reaction and is sensitive to 0.2-0.4 mg/dL of conjugated bilirubin.
-The color change indicating a positive reaction, however, is a rather subtle transition among shades of beige, and sometimes is obscured by color inherent in the urine itself (e.g., marked hemoglobinuria).
False negative results
-large amounts of vitamin C or Nitrite
-long exposure of the sample to direct light
This test is based on detection of the "peroxidase-like" activity inherent in molecules of heme Hemoglobin and myoglobin catalyze the oxidation of the indicator by an organic peroxide contained in the test pad
|Hematuria |Hemoglobinuria |Myoglobinuria |
|Mechanism - RBCs lyse on contact with |Mechanism - free Hb filtered into |Mechanism - free Mb filtered into |
|the reagent pad, causing a positive |urine as a result of hemoglobinemia |urine as a result of myoglobinemia |
|reaction (speckled pattern may result |(usually detectable as visibly red |(not visually detectable in plasma).|
|if low-grade) |plasma) | |
|Clinical - Bleeding into urinary |Clinical - Intravascular hemolysis of |Clinical - Myocyte injury allowing |
|space; can occur at any level of the |any cause: immune-mediated, toxic, |release of myoglobin which reaches |
|tract). Commonly due to inflammation, |mechanical, infectious, etc. |bloodstream and is readily filtered |
|trauma, neoplasia, hemostatic | |at the glomeruli. |
|disorders | | |
Hematuria: RBC will be present on urine sediment examination (if hematuria is marked, a red precipitate forms after centrifugation of urine).
Hemoglobinuria: There will be no RBC on the urine sediment and the urine supernatant will be red (remember that RBC will lyse in very dilute or alkaline urine).
Myoglobinuria: high CK and (maybe) high AST, reflecting muscle injury.• In rare instances, myoglobinuria and hemoglobinuria can pre-exist in a single patient
Urine Microscopy 12/4
Under normal conditions, the urine of healthy people contains a number of erythrocytes, leukocytes and hyaline casts, yet there is no precise information as to the upper limit of the normal cell range counts in urine excreted daily.
This lack of data is due in part to technical problems and to the wide variation from one individual to another, and in part to the considerable variability in the percentage of cells and casts that are destroyed and consequently not counted; the extent of this loss depends on the physicochemical conditions of the urine and the length of time these elements remain in it.
Quantitative assessment is therefore only empirical and approximate; nonetheless, for conventional volumes of 1250 ml of urine voided per day, it is generally agreed that the approximate, acceptable maximum limits for normal urine are:
500 erythrocytes/ml
2000 leukocytes/ml
> 15 hyaline casts/ml.
Since the various techniques for obtaining total counts are too time-consuming for routine examination, they have not come into common use and an estimate of the average number of elements in highly magnified microscopic fields (generally 400x) is preferred.
This is more approximate and even less reliable assessment since it is based on a technique which introduces an additional number of variables, partly determined by chance (e g. dilution ot the urine) and partly connected with the execution of the test.
The latter is often be no means standardized: there may be variations in the volume of urine centrifuged, the time and speed of centrifugation, the volume of the supernatant, the drop of urine examined, etc.
If, however, one does not intend to fix precise limits for normal and abnormal values, or to inaccurate comparisons of the different examinations, this type of semi-quantative test does provide quite a good practical basis for assessment.
Erythrocytes and leukocytes are not found in the sediment of some healthy people; yet, although opinions differ, one red cell, one to two leukocytes and only an occasional hyaline cast are generally taken, in a rather arbitrary way, to indicate the upper normal limit for each high magnified microscopic field observed (400x).
Before drawing any definite conclusion, all borderline results require careful critical assessment, bearing in mind that the urinary sediment in certain nephropathies may, at least in some stages, be basically normal.
Quantitative or semi-quantitative assessment must be considered as only approximate, especially if successive observations are being compared.
Erythrocytes
-The morphology of the blood red cells found in urinary sediment is extremely variable.
-There correlations between certain pathological conditions of the kidney and the urinary tract and the morphology of the red cells in the sediment.
-Using a morphological classification, a first category may include the following elements, typical of hematuria, generally caused by 'urologic' diseases
-Urinary red cell morphology can be assessed best by Phase-contrast microscopy.
-A second category of red cells in the urinary sediment includes damaged, irregularly shaped cells, showing fractured membranes, extrusion of cytoplasm, or fragmentation = 'glomerular' red cells
-Extensive fragmentation of the red cells is typical of hematuria in glomerulonephritis and in vascular nephropathies, proliferative glomerulonephritis or cortical necrosis.
-The few red cells found in the urinary sediment of healthy people are very rarely normal. The red cells from the so-called 'exercise-induced hematuria' are generally abnormal in appearance, which indicates that they have come from the glomerulus rather than from the bladder
Some elements in the sediment may be mistaken for RBC
-fungi
-calcium carbonate crystals
-small air bubbles.
-fat droplets
-small leukocytes
Leukocytes
Granulocytes, lymphocytes, and monocytes may be found in the urine. However, in routine clinical practice no great interest is being shown in the accurate identification of these cells. They are taken simply as a non-specific indication of an inflammatory process in the urinary tract.
Epithelial Cells
Renal tubular epithelial cells, Cells of this kind are found in varying numbers in 90% of glomerular diseases
Epithelial cells from the urinary tract used to be defined as "cells from the upper, middle or lower tracts", according to their morphology
However, except for the urethra, the excretory system is lined with an epithelium of several layers (transitional or urothelial epithelium). The characteristics of these layers are common throughout, so that the morphological differences depend on the layers from which they come and not on the part of the tract where exfoliation took place
Casts
Casts are made up of protein material that has been precipitated into the tubular lumen.
Some of this material is the Tamm-Horsfall urinary protein, produced primarily by the renal tubule in the ascending limb of the loop of Henle.
This endotubular precipitation is favored by highly concentrated urine with a low pH. With an alkaline pH the hyaline matrix of the casts either does not form at all or dissolves.
In advanced chronic renal failure, with polyuria and a urinary pH tending to be alkaline, the number of casts decreases, irrespective of the extent of the damage to the parenchyma.
It is also possible for there to be a large number of casts in the renal parenchyma, and yet a very low number of casts in the urine. This happens in chronic pyelonephritis and in other interstitial nephropathies in which these elements are blocked in the kidney and only a small number are passed out in the urine
On the basis of their structure, casts can be classified as:
-hyaline
-cellular (red blood cell, epithelial or granulocytic)
-granular
-waxy
-mixed and with inclusions
1) Hyaline casts
The transitory presence of small delicate hyaline casts in urine has no specific significance; casts of this kind can occasionally be found in the urinary sediment of healthy people under normal conditions, and they are frequently found, even in healthy people, after strenuous physical exercise or acute dehydration. Hyaline casts are neither specific nor differential for kidney disease.
-Hyaline casts increase in the following disorders:
-heart failure
-Hyperthermia
-all nephropathies, with or without proteinuria.
-the presence of cells or fat droplets always indicates some renal damage.
2) Granular casts
-Granular casts may be made up of granules of very varied diameter; these granules are believed to be mainly derived from cellular debris and tend to become progressively more homogeneous. Granular casts are more specific that hyaline casts.
-Casts of small diameter and with small granules can be found in rapidly reversible pathological conditions (e.g. febrile diseases with increased catabolism) and, very rarely, also in healthy people. For these reasons, no precise pathological significance can be attributed to the occasional finding of a few such granular casts
-In contrast, however, persistent granular casts, particularly if the granules are large, always have a pathological significance
3) Hemoglobin cast
-Hemoglobin casts appear in acute hemolysis, transfusion of incompatible blood.
-acquired hemolytic disorders (DIC) inherited hemolytic diseases (glucose-6-phosphate dehydrogenase deficiency)
4) Red cell casts
-Glomerular diseases, in the active stages, are the most frequent cause of red cell casts in the urine, but they can be found in all the nephropathies that cause hematuria.
5) Waxy casts
-Considered to be the final transformation of all kinds of cast: cellular, granular and hyaline and they always point to severe renal impairment in at least one area.
-Their significance as markers of severe damage is still greater if they are of medium size or large diameter.
6) Epithelial casts
-These casts are made up of desquamated tubular cells, included in a protein matrix
-indicate active or acute renal disorders
-glomerulonephritis, in interstitial nephritis, in 'acute tubular necrosis'
Crystals
-crystals usually only form in extreme urine pH
1) Uric acid crystals
-Uric acid crystals are characteristic of acidic urine
-their repeated appearance demonstrates the existence of a habitually low urinary pH, which may create a predisposition
to precipitation in vivo
-Calcium oxalate are a characteristic of acid urine (calcium phosphate in an alkaline urine)
-The presence is generally due to urine having been kept for some time at room temperature, or at low temperature
-Calcium oxalate crystals may be observed in urine of healthy people, especially after they have eaten food rich in oxalic
acid, such as spinach or cocoa (calcium oxalate is seen in vegetarian diet)
-Generally there is no connection between this crystalluria and urinary calculi, but if the crystals are large or clustered, or
if they appear very frequently in the freshly voided urine examined immediately at body temperature, they should be considered an abnormal finding.
2) Phosphate crystals
-Only the presence of magnesium ammonium phosphate in freshly voided urine is now regarded as significant.
-This finding suggests infection with urease-producing bacteria
3) Cystine crystals
-The presence of cystine crystals in the sediment is always a very important diagnostic feature, as they are a definite sign
of urolithiasis or a predisposition to it.
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