11/19/07 - Logan Class of December 2011
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.
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
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.
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.
11/26/07
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
12/4
Urine Microscopy
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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