CMS Pub. 100-03, ch. 1, § 190.14

Diagnosis of HIV infection is primarily made through the use of serologic assays. These

assays take one of two forms: antibody detection assays and specific HIV antigen (p24)

procedures. The antibody assays are usually enzyme immunoassays (EIA), which are

used to confirm exposure of an individual’s immune system to specific viral antigens.

These assays may be formatted to detect HIV-1, HIV-2, or HIV-1 and 2 simultaneously,

and to detect both IgM and IgG. When the initial EIA test is repeatedly positive or

indeterminant, an alternative test is used to confirm the specificity of the antibodies to

individual viral components. The most commonly used method is the Western Blot.

The HIV-1 core antigen (p24) test detects circulating viral antigen which may be found

prior to the development of antibodies and may also be present in later stages of illness in

the form of recurrent or persistent antigenemia. Its prognostic utility in HIV infection has

been diminished as a result of development of sensitive viral RNA assays, and its primary

use today is as a routine screening tool in potential blood donors.

In several unique situations, serologic testing alone may not reliably establish an HIV

infection. This may occur because the antibody response (particularly the IgG response

detected by Western Blot) has not yet developed (that is, acute retroviral syndrome) or is

persistently equivocal because of inherent viral antigen variability. It is also an issue in

perinatal HIV infection due to transplacental passage of maternal HIV antibody. In these

situations, laboratory evidence of HIV in blood by culture, antigen assays, or proviral

DNA or viral RNA assays, is required to establish a definitive determination of HIV

infection.

Indications

Diagnostic testing to establish HIV infection may be indicated when there is a strong

clinical suspicion supported by one or more of the following clinical findings:

1. The patient has a documented, otherwise unexplained, AIDS-defining or AIDS-associated opportunistic infection.

2. The patient has another documented sexually transmitted disease, which identifies

significant risk of exposure to HIV and the potential for an early or subclinical infection.

3. The patient has documented acute or chronic hepatitis B or C infection that

identifies a significant risk of exposure to HIV and the potential for an early or

subclinical infection.

4. The patient has a documented AIDS-defining or AIDS-associated neoplasm.

5. The patient has a documented AIDS-associated neurologic disorder or otherwise

unexplained dementia.

6. The patient has another documented AIDS-defining clinical condition, or a history

of other severe, recurrent, or persistent conditions which suggest an underlying immune

deficiency (for example, cutaneous or mucosal disorders).

7. The patient has otherwise unexplained generalized signs and symptoms suggestive

of a chronic process with an underlying immune deficiency (for example, fever, weight

loss, malaise, fatigue, chronic diarrhea, failure to thrive, chronic cough, hemoptysis,

shortness of breath, or lymphadenopathy).

8. The patient has otherwise unexplained laboratory evidence of a chronic disease

process with an underlying immune deficiency (for example, anemia, leukopenia,

pancytopenia, lymphopenia, or low CD4+ lymphocyte count).

9. The patient has signs and symptoms of acute retroviral syndrome with fever,

malaise, lymphadenopathy, and skin rash.

10. The patient has documented exposure to blood or body fluids known to be capable

of transmitting HIV (for example, needle sticks and other significant blood exposures)

and antiviral therapy is initiated or anticipated to be initiated.

11. The patient is undergoing treatment for rape. (HIV testing is part of the rape

treatment protocol.)

Limitations

1. HIV antibody testing in the United States is usually performed using HIV-1 or HIV-

1/2 combination tests. HIV-2 testing is indicated if clinical circumstances suggest HIV-2

is likely (that is, compatible clinical finding and HIV-1 test negative). HIV-2 testing may

also be indicated in areas of the country where there is greater prevalence of HIV-2

infections.

2. The Western Blot test should be performed only after documentation that the initial

EIA tests are repeatedly positive or equivocal on a single sample.

3. The HIV antigen tests currently have no defined diagnostic usage.

4. Direct viral RNA detection may be performed in those situations where serologic

testing does not establish a diagnosis but strong clinical suspicion persists (for example,

acute retroviral syndrome, nonspecific serologic evidence of HIV, or perinatal HIV

infection).

5. If initial serologic tests confirm an HIV infection, repeat testing is not indicated.

6. If initial serologic tests are HIV EIA negative and there is no indication for

confirmation of infection by viral RNA detection, the interval prior to retesting is 3-6

months.

7. Testing for evidence of HIV infection using serologic methods may be medically

appropriate in situations where there is a risk of exposure to HIV.

8. The CPT Editorial Panel has issued a number of codes for infectious agent detection

by direct antigen or nucleic acid probe techniques that have not yet been developed or are

only being used on an investigational basis. Laboratory providers are advised to remain

current on FDA-approved status for these tests.

190.15 - Blood Counts

(Rev. 17, Issued: 07-02-04) (Effective/Implementation: Not Applicable)

PM AB-02-110

Blood counts are used to evaluate and diagnose diseases relating to abnormalities of the

blood or bone marrow. These include primary disorders such as anemia, leukemia,

polycythemia, thrombocytosis and thrombocytopenia. Many other conditions secondarily

affect the blood or bone marrow, including reaction to inflammation and infections,

coagulopathies, neoplasms and exposure to toxic substances. Many treatments and

therapies affect the blood or bone marrow, and blood counts may be used to monitor

treatment effects.

The complete blood count (CBC) includes a hemogram and differential white blood

count (WBC). The hemogram includes enumeration of red blood cells, white blood cells,

and platelets, as well as the determination of hemoglobin, hematocrit, and indices.

The symptoms of hematological disorders are often nonspecific, and are commonly

encountered in patients who may or may not prove to have a disorder of the blood or

bone marrow. Furthermore, many medical conditions that are not primarily due to

abnormalities of blood or bone marrow may have hematological manifestations that

result from the disease or its treatment. As a result, the CBC is one of the most

commonly indicated laboratory tests.

Inpatients with possible hematological abnormalities, it may be necessary to determine

the hemoglobin and hematocrit, to calculate the red cell indices, and to measure the

concentration of white blood cells and platelets. These measurements are usually

performed on a multichannel analyzer that measures all of the parameters on every

sample. Therefore, laboratory assessments routinely include these measurements.

Indications

Indications for a CBC or hemogram include red cell, platelet, and white cell disorders.

Examples of these indications are enumerated individually below.

1. Indications for a CBC generally include the evaluation of bone marrow dysfunction

as a result of neoplasms, therapeutic agents, exposure to toxic substances, or pregnancy.

The CBC is also useful in assessing peripheral destruction of blood cells, suspected bone

marrow failure or bone marrow infiltrate, suspected myeloproliferative, myelodysplastic,

or lymphoproliferative processes, and immune disorders.

2. Indications for hemogram or CBC related to red cell (RBC) parameters of the

hemogram include signs, symptoms, test results, illness, or disease that can be associated

with anemia or other red blood cell disorder (e.g., pallor, weakness, fatigue, weight loss,

bleeding, acute injury associated with blood loss or suspected blood loss, abnormal

menstrual bleeding, hematuria, hematemesis, hematochezia, positive fecal occult blood

test, malnutrition, vitamin deficiency, malabsorption, neuropathy, known malignancy,

presence of acute or chronic disease that may have associated anemia, coagulation or

hemostatic disorders, postural dizziness, syncope, abdominal pain, change in bowel

habits, chronic marrow hypoplasia or decreased RBC production, tachycardia, systolic

heart murmur, congestive heart failure dyspnea, angina, nailbed deformities, growth

retardation, jaundice, hepatomegaly, splenomegaly, lmphadenopathy, ulcers on the lower

extremities).

3. Indications for hemogram or CBC related to red cell (RBC) parameters of the

hemogram include signs, symptoms test results illness, or disease that can be associated

with polycythemia (for example, fever, chills, ruddy skin, conjunctival redness, cough,

wheezing, cyanosis, clubbing of the fingers, orthopnea, heart murmur, headache, vague

cognitive changes including memory changes, sleep apnea, weakness, pruritus, dizziness,

excessive sweating, visual symptoms, weight loss, massive obesity, gastrointestinal

bleeding, paresthesias, dyspnea, joint symptoms, epigastric distress, pain and erythema of

the fingers or toes, venous or arterial thrombosis, thromboembolism, myocardial

infarction, stroke, transient ischemic attacks, congenital heart disease, chronic obstructive

pulmonary disease, increased erythropoietin production associated with neoplastic, renal

or hepatic disorders, androgen or diuretic use, splenomegaly, hepatomegaly, diastolic

hypertension.)

4. Specific indication for CBC with differential count related to the WBC include signs,

symptoms, test results, illness, or disease associated with leukemia, infections or

inflammatory processes, suspected bone marrow failure or bone marrow infiltrate,

suspected myeloproliferative, myelodysplastic or lymphoproliferative disorder, use of

drugs that may cause leukopenia, and immune disorders (e.g., fever, chills, sweats, shock,

fatigue, malaise, tachycardia, tachypnea, heart murmur, seizures, alterations of

consciousness, meningismus, pain such as headache, abdominal pain, arthralgia,

odynophagia, or dysuria, redness or swelling of skin, soft tissue bone, or joint, ulcers or

the skin or mucous membranes, gangrene, mucous membrane discharge, bleeding,

thrombosis, respiratory failure, pulmonary infiltrate, jaundice, diarrhea, vomiting,

hepatomegaly, splenomegaly, lymphadenopathy, opportunistic infection such as oral

candidiasis.)

5. Specific indication for CBC related to the platelet count include signs, symptoms, test

results, illness, or disease associated with increased or decreased platelet production and

destruction, or platelet dysfunction (e.g., gastrointestinal bleeding, genitourinary tract

bleeding, bilateral epistaxis, thrombosis, ecchymosis, purpura, jaundice, petechiae, fever,

heparin therapy, suspected DIC, shock, pre-eclampsia, neonate with maternal ITP,

massive transfusions, recent platelet transfusion, cardiopulmonary bypass, hemolytic

uremic syndrome, renal diseases, lymphadenopathy, hepatomegaly, splenomegaly,

hypersplenism, neurologic abnormalities, viral or other infection, myeloproliferative,

myelodysplastic, or lymphoproliferative disorder, thrombosis, exposure to toxic agents,

excessive alcohol ingestion, autoimmune disorders (SLE, RA and other).

6. Indications for hemogram or CBC related to red cell (RBC) parameters of the

hemogram include, in addition to those already listed, thalassemia, suspected

hemoglobinopathy, lead poisoning, arsenic poisoning, and spherocytosis.]

7. Specific indications for CBC related to differential count related to the WBC include,

in addition to those already listed, storage diseases; mucopolysaccharidoses, and use of

drugs that case leukocytosis such as G-CSF or CM-CSF.

8. Specific indications for CBC related to platelet count include, in addition to those

already listed, May-Hegglin syndrome and Wiskott-Aldrich syndrome.

Limitations

1. Testing of patients who are asymptomatic, or who do not have a condition that could

be expected to result in a hematological abnormality, is screening and is not a covered

service.

2. In some circumstances it may be appropriate to perform only a hemoglobin or

hematocrit to assess the oxygen carrying capacity of the blood. When the ordering

provider requests only hemoglobin or hematocrit, the remaining components of the CBC

are not covered.

3. When a blood count is performed for an end-stage renal disease (ESRD) patient, and

is billed outside the ESRD rate, documentation of the medical necessity for the blood

count must be submitted with the claim.

4. In some patients presenting with certain signs, symptoms, or diseases, a single CBC

may be appropriate. Repeat testing may not be indicated unless abnormal results are

found, or unless there is a change in clinical condition. If repeat testing is performed, a

more descriptive diagnosis code (e.g., anemia) should be reported to support medical

necessity. However, repeat testing may be indicated where results are normal in patients

with conditions where there is a continued risk for the development of hematologic

abnormality.

190.16 - Partial Thromboplastin Time (PTT)

(Rev. 17, Issued: 07-02-04) (Effective/Implementation: Not Applicable)

PM AB-02-110

Basic plasma coagulation function is readily assessed with a few simple laboratory tests:

The PTT, prothrombin time (PT), thrombin time (TT), or a quantitative fibrinogen

determination. The PTT test is an in vitro laboratory test used to assess the intrinsic

coagulation pathway and monitor heparin therapy.

Indications

1. The PTT is most commonly used to quantitate the effect of therapeutic unfractionated

heparin and to regulate its dosing. Except during transitions between heparin and

warfarin therapy, in general both the PTT and PT are not necessary together to assess the

effect of anticoagulation therapy. PT and PTT must be justified separately.

2. A PTT may be used to assess patients with signs or symptoms of hemorrhage or

thrombosis. For example: Abnormal bleeding, hemorrhage or hematoma petechiae or

other signs of thrombocytopenia that could be dues to disseminated intravascular

coagulation; swollen extremity with or without prior trauma.

3. A PTT may be useful in evaluating patients who have a history of a condition known

to be associated with the risk of hemorrhage or thrombosis that is related to the intrinsic

coagulation pathway. Such abnormalities may be genetic or acquired. For example:

dysfibrinogenemia; afibrinogenemia (complete); acute or chronic liver dysfunction or

failure, including Wilson’s disease; hemophilia; liver disease and failure; infectious

processes; bleeding disorders; disseminated intravascular coagulation; lupus

erythematosus or other conditions associated with circulating inhibitors e.g., factor VIII

inhibitor, lupus-like anticoagulant; sepsis; vonWillebrand’s disease; arterial and venous

thrombosis, including the evaluation of hypercoagulable states; clinical conditions

associated with nephrosis or renal failure; other acquired and congenital coagulopathies

as well as thrombotic states.

4. A PTT may be used to assess the risk of thrombosis or hemorrhage in patients who

are going to have a medical intervention known to be associated with increased risk of

bleeding or thrombosis. An example is as follows: evaluation prior to invasive

procedures or operations of patients with personal or family history of bleeding or who

are on heparin therapy.

Limitations

1. The PTT is not useful in monitoring the effects of warfarin on a patient’s coagulation

routinely. However, a PTT may be ordered on a patient being treated with warfarin as

heparin therapy is being discontinued. A PTT may also be indicated when the PT is

markedly prolonged due to warfarin toxicity.

2. The need to repeat this test is determined by changes in the underlying medical

condition and/or dosing of heparin.

3. Testing prior to any medical intervention associated with a risk of bleeding and

thrombosis (other than thrombolytic therapy) will generally be considered medically

necessary only where there are signs or symptoms of a bleeding or thrombotic

abnormality or a personal history of bleeding, thrombosis or a condition associated with a

coagulopathy. Hospital/clinical-specific policies, protocols, etc., in and of themselves,

cannot alone justify coverage.

190.17 - Prothrombin Time (PT)

(Rev. 17, Issued: 07-02-04) (Effective/Implementation: Not Applicable)

PM AB-02-110

Basic plasma coagulation function is readily assessed with a few simple laboratory tests:

the partial thromboplastin time (PTT), PT, thrombin time, or a quantitative fibrinogen

determination. The PT test is one in-vitro laboratory test used to assess coagulation.

While the PTT assesses the intrinsic limb of the coagulation system, the PT assesses the

extrinsic or tissue factor dependent pathway. Both tests also evaluate the common

coagulation pathway involving all the reactions that occur after the activation of factor X.

Extrinsic pathway factors are produced in the liver and their production is dependent on

adequate vitamin K activity. Deficiencies of factors may be related to decreased

production of increased consumption of coagulation factors. The PR/INR is most

commonly used to measure the effect of warfarin and regulate its dosing. Warfarin

blocks the effect of vitamin K on hepatic production of extrinsic pathway factors.

A PT is expressed in seconds and/or as an international normalized ration (INR). The

INR is the PT ration that would result if the WHO reference thromboplastin had been

used in performing the test.

Current medical information does not clarify the role of laboratory PT testing in patients

who are self monitoring. Therefore, the indications for testing apply regardless of

whether or not the patient is also PT self-testing.

Indications

1. A PT may be used to assess patients taking warfarin. The PT is generally not useful

in monitoring patients receiving heparin who are not taking warfarin.

2. A PT may be used to assess patients with signs or symptoms of abnormal bleeding or

thrombosis. For example: swollen extremity with or without prior trauma; unexplained

bruising; abnormal bleeding, hemorrhage, or hematoma; petechiae or other signs or

thrombocytopenia that could be due to disseminated intravascular coagulation.

3. A PT may be useful in evaluating patients who have a history of a condition known to

be associated with the risk of bleeding or thrombosis that is related to the extrinsic

coagulation pathway. Such abnormalities may be genetic or acquires. For example:

dysfibrinogenemia; afibrinogenemia (complete); acute or chronic liver dysfunction or

failure, including Wilson’s disease and hemochromatosis; disseminated intravascular

coagulation (DIC); congenital and acquired deficiencies of factors II, V, VII, X; vitamin

K deficiency; lupus erythematosus; hypercoagulable state; paraproteinemia; lymphoma;

amyloidosis; acute and chronic leukemias; plasma cell dyscrasia; HIV infection;

malignant neoplasms; hemorrhagic fever; salicylate poisoning; obstructive jaundice;

intestinal fistula; malabsorption syndrome; colitis; chronic diarrhea; presence of

peripheral venous or arterial thrombosis or pulmonary emboli or myocardial infarction;

patients with bleeding or clotting tendencies; organ transplantation; presence of

circulating coagulation inhibitors.

4. APT may be used to assess the risk of hemorrhage or thrombosis in patients who are

going to have a medical intervention known to be associated with increased risk of

bleeding or thrombosis. For example: evaluation prior to invasive procedures or

operations of patients with personal history of bleeding of a condition associated with

coagulopathy; prior to the use of thrombolytic medication.

Limitations

1. When an ESRD patient is tested for PT, testing more frequently than weekly requires

documentation of medical necessity, e.g., other than chronic renal failure or renal failure

unspecified.

2. The need to repeat this test is determined by changes in the underlying medical

condition and/or the dosing of warfarin. In a patient on stable warfarin therapy, it is

ordinarily not necessary to repeat testing more than every two to three weeks. When

testing is performed to evaluate a patient with signs or symptoms of abnormal bleeding or

thrombosis and the initial test result is normal, it is ordinarily not necessary to repeat

testing unless there is a change in the patient’s medical status.

3. Since the INR is a calculation, it will not be paid in addition to the PT when

expressed in seconds, and is considered part of the conventional PT test.

4. Testing prior to any medical intervention associated with a risk of bleeding and

thrombosis (other that thrombolytic therapy) will generally be considered medically

necessary only where there are signs or symptoms of a bleeding or thrombotic

abnormality of a personal history of bleeding, thrombosis or a condition associated with a

coagulopathy. Hospital/clinic-specific policies, protocols, etc., in and of themselves,

cannot alone justify coverage.

190.18 - Serum Iron Studies

(Rev. 17, Issued: 07-02-04) (Effective/Implementation: Not Applicable)

PM AB-02-110

Serum iron studies are useful in the evaluation of disorders of iron metabolism,

particularly iron deficiency and iron excess. Iron studies are best performed when the

patients is fasting in the morning and has abstained form medications that may influence

iron balance.

Iron deficiency is the most common cause of anemia. In young children on a milk diet,

iron deficiency is often secondary to dietary deficiency. In adults, iron deficiency is

usually the result of blood loss and is only occasionally secondary to dietary deficiency or

malabsorption.

Following major surgery the patient may have iron deficient erythropoiesis for months or

years if adequate iron replacement has not been given. High doses of supplemental iron

may cause the serum iron to be elevated. Serum iron may also be altered in acute and

chronic inflammatory and neoplastic conditions.

Total iron binding capacity (TIBC) is an indirect measure of transferring, a protein that

binds and transports iron. TIBC quantifies transferring by the amount of iron that it can

bind. TIBC and transferrin are elevated in iron deficiency, and with oral contraceptive

use, and during pregnancy. TIBC and transferrin may be decreased in malabsorption

syndromes or in those affected with chronic diseases. The percent saturation represents

the ratio of iron to the TIBC.

Assays for ferritin are also useful in assessing iron balance. Low concentrations are

associated with iron deficiency and are highly specific. High concentrations are found in

hemosiderosis (iron overload without associated tissue injury) and hemochromatosis

(iron overload with associated tissue injury). In these conditions the iron is elevated, the

TIBC and transferring are within the reference range or low, and the percent saturation is

elevated. Serum ferritin can be useful for both initiating and monitoring treatment for

iron overload.

Transferrin and ferritin belong to a group of serum proteins known as acute phase

reactants, and are increased in response to stressful or inflammatory conditions and also

can occur with infection and tissue injury due to surgery, trauma or necrosis. Ferritin and

iron/TIBC (or transferrin) are affected by acute and chronic inflammatory conditions, and

in patients with these disorders, tests of iron status may be difficult to interpret.

Indications

1. Ferritin, iron and either iron binding capacity or transferrin are useful in the

differential diagnosis or iron deficiency, anemia and for iron overload conditions.

a. The following presentations are examples that may support the use of these

studies for elevating iron deficiency: Certain abnormal blood count values (i.e.,

decreased mean corpuscular volume (MCV), decreased hemoglobin/hematocrit when the

MCV is low or normal, or increased red cell distribution with width (RDW) and low or

normal MCV); abnormal appetite (pica); acute or chronic gastrointestinal blood loss;

hematuria; menorrhagia; malabsorption; status post-gastrectomy; status port-

gastrojejunostomy; malnutrition; preoperative autologous blood collection(s); malignant,

chronic inflammatory and infectious conditions associated with anemia which may

present in a similar manner to iron deficiency anemia; following a significant surgical

procedure where blood loss had occurred and had not been repaired with adequate iron

replacement.

b. The following presentations are example that may support the se of these

studies for evaluating iron overload: chronic hepatitis; diabetes; hyperpigmentation of

skin; arthropathy; cirrhosis; hypogonadism; hypopituitarism; impaired porphyrin

metabolism; heart failure; multiple transfusions; sideroblastic anemia; thalassemia major;

cardiomyopathy, cardiac dysrhythmias and conduction disturbances.

2. Follow-up testing may be appropriate to monitor response to therapy, e.g., oral

or parenteral iron, ascorbic acid, and erythropoietin.

3. Iron studies may be appropriate in patients after treatment for other nutritional

deficiency anemia, such as folate and vitamin B12, because iron deficiency may not be

revealed until such a nutritional deficiency is treated.

4. Serum ferritin may be appropriate for monitoring iron status in patients with

chronic renal disease with or without dialysis.

5. Serum iron may also be indicated for evaluation of toxic effects of iron and

other metals (e.g., nickel, cadmium, aluminum, lead) whether due to accidental,

intentional exposure or metabolic causes.

Limitations

1. Iron studies should be used to diagnose and manage iron deficiency or ion overload

states. These tests are not to be used solely to assess acute phase reactants where disease

management will be unchanged. For example, infections and malignancies are associated

with elevations in acute phase reactants such as ferritin, and decreases in serum iron

concentration, but iron studies would only be medically necessary if results or iron

studies might alter the management of the primary diagnosis or might warrant direct

treatment of an iron disorder or condition.

2. If a normal serum ferritin level is documented, repeat testing would not ordinarily be

medically necessary unless there is a change in the patient’s condition, and ferritin

assessment is needed for the ongoing management of the patient. For example, a patient

presents with new onset insulin-dependent diabetes mellitus and has a serum ferritin level

performed for the suspicion of hemochromatosis. If the ferritin level is normal, the repeat

ferritin for diabetes mellitus would not be medically necessary.

3. When an end stage renal disease (ESRD) patient is tested for ferritin, testing more

frequently than every three months requires documentation of medical necessity (e.g.,

other than chronic renal failure or renal failure, unspecified).

4. It is ordinarily not necessary to measure both transferring and TIBC at the same time

because TIBC is an indirect measure of transferrin. When transferrin is ordered as part of

the nutritional assessment for evaluating malnutrition, it is not necessary to order other

iron studies unless iron deficiency or iron overload is suspected as well.

5. It is not ordinarily necessary to measure both iron/TIBC (or transferrin) and ferritin in

initial patient testing. If clinically indicated after evaluation of the initial iron studies, it

may be appropriate to perform additional iron studies either on the initial specimen of on

a subsequently obtained specimen. After a diagnosis of iron deficiency or iron overload

is established, either iron/TIBC (or transferring) or ferritin may be medically necessary

for monitoring, but not both.

6. It would not ordinarily be considered medically necessary to do a ferritin as a

preoperative test except in the presence of anemia or recent autologous blood collections

prior to the surgery.

190.19 - Collagen Crosslinks, Any Method

(Rev. 17, Issued: 07-02-04) (Effective/Implementation: Not Applicable)

PM AB-02-110

Collagen crosslinks, part of the matrix of bone upon which bone mineral is deposited, are

biochemical markers the excretion of which provides a quantitative measurement of bone

resorption. Elevated levels of urinary collagen crosslinks indicate elevated bone

resorption. Elevated bone resorption contributes to age-related and postmenopausal loss

of bone leading to osteoporosis and increased risk of fracture. The collagen crosslinks

assay can be performed by immunoassay or by high performance liquid chromatography

(HPLC). Collagen crosslink immunoassays measure the pyridinoline crosslinks and

associated telopeptides in urine.

Bone is constantly undergoing a metabolic process called turnover or remodeling. This

includes a degradation process, bone resorption, mediated by the action of osteoclasts,

and a building process, bone formation, mediated by the action of osteoblasts.

Remodeling is required for the maintenance and overall health of bone and is tightly

coupled; that is, resorption and formation must be in balance. In abnormal states of bone

remodeling, when resorption exceeds formation, it results in a net loss of bone. The

measurement of specific, bone-derived resorption products provides analytical data about

the rate of bone resorption.

Osteoporosis is a condition characterized by low bone mass and structural deterioration

of bone tissue, leading to bone fragility and an increased susceptibility to fractures of the

hip, spine, and wrist. The term primary osteoporosis is applied where the causal factor in

the disease is menopause or aging. The term secondary osteoporosis is applied where the

causal factor is something other than menopause or aging, such as long-term

administration of glucocorticosteroids, endocrine-related disorders (other than loss of

estrogen due to menopause), and certain bone diseases such as cancer of the bone.

With respect to quantifying bone resorption, collagen crosslink tests can provide adjunct

diagnostic information in concert with bone mass measurements. Bone mass

measurements and biochemical markers may have complementary roles to play in

assessing effectiveness of osteoporosis treatment. Proper management of osteoporosis

patients, who are on long-term therapeutic regimens, may include laboratory testing of

biochemical markers of bone turnover, such as collagen crosslinks, that provide a profile

of bone turnover responses within weeks of therapy. Changes in collagen crosslinks are

determined following commencement of antiresorptive therapy. These can be measured

over a shorter time interval, such as three months, when compared to bone mass density.

If bone resorption is not elevated, repeat testing is not medically necessary.

Indications

Generally speaking, collagen crosslink testing is useful mostly in “fast losers” of bone.

The age when these bone markers can help direct therapy is often pre-Medicare. By the

time a fast loser of bone reaches age 65, she will most likely have been stabilized by

appropriate therapy or have lost so much bone mass that further testing is useless.

Coverage for bone marker assays may be established, however, for younger Medicare

beneficiaries and for those men and women who might become fast losers because of

some other therapy such as glucocorticoids. Safeguards should be incorporated to

prevent excessive use of tests in patients for whom they have no clinical relevance.

Collagen crosslinks testing is used to:

1. Identify individuals with elevated bone resorption, who have osteoporosis in whom

response to treatment is being monitored.

2. Predict response (as assessed by bone mass measurements) to FDA approved

antiresorptive therapy in postmenopausal women.

3. Assess response to treatment of patients with osteoporosis, Paget’s disease or the

bone, or risk for osteoporosis where treatment may include FDA approved antiresorptive

agents, anti-estrogens or selective estrogens receptor moderators.

Limitations

Because of significant specimen to specimen collagen crosslink physiologic variability

(15-20 percent), current recommendations for appropriate utilization include: one or two

base-line assays from specified urine collections on separate days; followed by a repeat

assay about 3 months after starting anti-resorptive therapy; followed by a repeat assay in

12 months after the 3-month assay; and thereafter not more than annually, unless there is

a change in therapy in which circumstance an additional test may be indicated 3 months

after the initiation of new therapy.

Some collagen crosslink assays may not be appropriate for use in some disorders,

according to FDA labeling restrictions.