Medical Coverage Policy: 0568

Effective Date 4/15/2024

Coverage Policy

The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients.

Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based.

For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document.

Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Each coverage request should be reviewed on its own merits.

Medical directors are expected to exercise clinical judgment where appropriate and have discretion in making individual coverage determinations. Where coverage for care or services does not depend on specific circumstances, reimbursement will only be provided if a requested service(s) is submitted in accordance with the relevant criteria outlined in the applicable Coverage Policy, including covered diagnosis and/or procedure code(s).

Reimbursement is not allowed for services when billed for conditions or diagnoses that are not covered under this Coverage Policy (see “Coding Information” below). When billing, providers must use the most appropriate codes as of the effective date of the submission. Claims submitted for services that are not accompanied by covered code(s) under the applicable Coverage Policy

will be denied as not covered. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines.

In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

Coverage Policy

Ferritin

Serum ferritin testing (Current Procedural Terminology [CPT®] code 82728) is considered medically necessary for ANY of the following indications:

• Assessment of anemia not the result of acute blood loss
• Evaluation and monitoring of anemia secondary to chronic kidney disease
• Evaluation and monitoring of iron overload conditions, or in suspected conditions where an abnormal ferritin is a diagnostic criterion

As a screening tool in an individual with ANY of the following:

• Porphyria cutanea tarda
• Chondrocalcinosis
• Hepatocellular carcinoma
• Type 1 diabetes
• Family history of hereditary hemochromatosis

Serum ferritin testing for any other indication including screening in the general population is not covered or reimbursable.

Transferrin

Serum transferrin testing (CPT® code 84466) is considered medically necessary when performed together with serum iron testing for iron overload in an individual with ANY of the following indications:

• Porphyria cutanea tarda
• Chondrocalcinosis
• Hepatocellular carcinoma
• Type 1 diabetes
• Family history of hereditary hemochromatosis

Serum transferrin testing is considered medically necessary to determine transferrin saturation when performed on the same date of service (DOS) as serum iron.

Medical Coverage Policy: 0568

Effective Date 4/15/2024

Total iron binding capacity (TIBC) and transferrin performed on the same DOS is considered duplicate testing. Serum transferrin testing is not covered or reimbursable for EITHER of the following:

• when performed for any other indication including screening in the general population
• for an individual with a ferritin level of less than 12 µg/L

Iron

Serum iron testing (CPT® code 83540), is considered medically necessary when performed together with serum transferrin testing for suspected iron overload in an individual with ANY of the following:

• Porphyria cutanea tarda
• Chondrocalcinosis
• Hepatocellular carcinoma
• Type 1 diabetes
• Family history of hereditary hemochromatosis

Serum iron testing is considered medically necessary to determine transferrin saturation when performed on the same DOS as transferrin testing or total iron binding capacity testing when the evaluation of anemia may be complicated by an elevated ferritin. Serum iron testing is considered medically necessary in the evaluation of toxic iron exposure or iron poisoning. Serum iron testing is not covered or reimbursable for ANY of the following:

• for an individual with a ferritin level of less than 12 µg/L
• the evaluation of incidental or asymptomatic anemia not complicated by conditions that may cause an elevated ferritin
• when performed for any other indication including screening in the general population

Total Iron Binding Capacity

Serum total iron binding capacity (TIBC) testing (CPT® code 83550) is considered medically necessary when performed together with serum iron testing for suspected iron overload in an individual with ANY of the following:

• Porphyria cutanea tarda
• Chondrocalcinosis
• Hepatocellular carcinoma
• Type 1 diabetes
• Family history of hereditary hemochromatosis

Serum TIBC testing is considered medically necessary to determine transferrin saturation when performed on the same DOS as serum iron testing.

Serum TIBC testing is not covered or reimbursable for ANY of the following:

• an individual with a ferritin level of less than 12 µg/L
• when performed with serum transferrin testing on the same DOS (considered duplicate testing)
• when performed for any other indication including screening in the general population

Soluble Transferrin Receptor

Serum soluble transferrin receptor testing (CPT® code 84238) is considered medically necessary for any of the following suspected anemic states:

• myelodysplastic syndromes
• nutritional anemias
• hemolytic anemias
• acquired pure red blood cell aplasia (erythroblastopenia)
• other aplastic anemias and other bone marrow failure syndromes
• anemia in chronic diseases
• myelofibrosis
• disease with participation of lymphoreticular and reticulohistiocytic tissue
• hypertensive chronic kidney disease, kidney transplant, glomerular diseases, acute kidney iron deficiency and disorders of iron metabolism failure and chronic kidney disease intestinal malabsorption
• postgastric surgery syndromes and postgastric malabsorption
• anemia complicating pregnancy, childbirth and of the puerperium

Serum soluble transferrin receptor testing for any other indication including screening in the general population is not covered or reimbursable.

General Background

Iron is an essential mineral that plays a critical role in the transfer of oxygen to tissues, cellular function, physical growth, and neurological development. Approximately two-thirds of iron in the body is present in hemoglobin. Other iron-containing proteins include myoglobin and cytochromes, flavoproteins, iron transport and storage proteins (such as ferritin and transferrin), and non-heme enzymes. Another major source of iron storage and regulation is the liver. The liver produces proteins, such as hepcidin and ferroportin, that tightly regulate iron metabolism in the body (Meynard, et al., 2014). With the exception of bleeding or pregnancy, daily basal loss of iron is relatively small, requiring as little as one milligram in the diets of adult males and non-menstruating women, to maintain iron balance. Although in the United States most people have adequate dietary iron intake, certain groups are at risk for insufficient dietary iron, including infants and young children, pregnant women, blood donors, and those in food-insecure households.

Iron deficiency begins with a depletion of iron stores, as indicated by decreased serum ferritin, and then progresses to marginal iron deficiency, and then to iron deficiency anemia. Serum ferritin, in the absence of confounding variables, is a cost-effective and accurate test in assessing iron stores.

Laboratory Testing Ferritin

Ferritin is a primary storage protein consisting of 24 subunits comprised of two isoforms, L (light) and H (heavy) that surround an iron core. In the absence of inflammation, serum/plasma ferritin values correlate with body iron stores (World Health Organization, 2020). Although a ferritin level of less than 12 ng/mL is widely accepted as an indicator of decreased iron stores (Wang, et al., 2010), studies argue that this threshold is not appropriate for all age groups (Mei, et al., 2021). Therefore, age and assay specific reference intervals should be considered (Adeli, et al., 2015).

Serum measurements, such as ferritin determination, are more acceptable alternatives in assessing iron stores than more invasive and costly methods, such as liver or bone marrow biopsy. Ferritin is also an acute-phase reactant and may be elevated due to infection, inflammation, or malignancy (Garcia-Casal, et al., 2021). It is estimated that over 90% of cases of hyperferritinemia are due to secondary causes (European Association for the Study of the Liver, 2010). Various methods are used to measure ferritin in blood; these include agglutination, enzyme-linked immunosorbent, immunochemiluminescence, and immunoturbidometric assays. The World Health Organization (WHO) recommends calibration to a commutable material traceable to a WHO reference standard. Results among different methods may not be comparable, hence, the same method should be used for initial and follow-up testing (Dahman, et al., 2022).

Various approaches to adjusting ferritin values in the presence of inflammation have been proposed, including the use of correction factors and linear regression.

Serum Iron

Over 99% of serum iron is bound to transferrin (Pfeiffer, et al., 2017). The determination of serum iron in isolation is generally reserved for the assessment of iron poisoning (The Royal College of Pathologists of Australasia, 2020); however, serum iron measurements are commonly part of panels for total iron binding capacity or transferrin saturation. Serum iron exhibits diurnal variation in which levels are highest early in the day and then gradually fall until evening. Serum iron is decreased in both iron deficiency and anemia of chronic disease, and it is usually increased in iron overload states. Serum iron determination is commonly performed on chemistry analyzers using a colorimetric method of chromogen-binding to iron.

Transferrin

Most iron in serum is bound to a carrier protein, transferrin. Transferrin may exist as a non-iron bound form (apo-transferrin), mono-ferric form, or di-ferric (holo-transferrin) form (Kawabata, 2019). The proportion of iron binding sites occupied by iron is calculated as either the ratio of serum iron to total iron binding capacity (TIBC) or serum iron to transferrin (Pfeiffer, et al., 2017). Transferrin is commonly measured by immunoassays, which are standardized to certified reference material ERM-DA470 (Zegers, et al., 2010). It is increased in iron deficiency and in late pregnancy and can be decreased as a result of iron overload, malignancy, kidney disease, inflammatory bowel disease, malnutrition, as well as in hereditary atransferrinemia.

Total Iron Binding Capacity (TIBC)

TIBC is a measure of the maximum amount of iron needed to saturate serum or plasma transferrin. Using a predetermined amount of excess iron, transferrin is saturated, unbound iron is removed from the sample, and the amount of iron then dissociated from transferrin is measured (Yamanishi, et al., 2003). TIBC is high due to iron deficiency anemia, and low due to iron overload. TIBC may also be determined as the sum of serum iron and the unsaturated iron binding capacity (UIBC), both measured using colorimetric methods, or by using a theoretical relationship between TIBC and transferrin concentration (Yamanishi, et al., 2003 and Gambino, et al., 1997).

Soluble Transferrin Receptor

Soluble transferrin receptor (sTfR) is a truncated form of transferrin receptor 1 and circulates bound to transferrin (Pfeiffer, et al., 2017). It has been used as an indicator of iron deficiency with, or in place of, ferritin when inflammation is a contributing factor (Markovic, et al., 2005).

Testing platforms for sTfR that have demonstrated analytic validity include chemiluminescent, immunoturbidometric, and immunonephelometric assays (Hou, et al., 2020). The sTfR concentrations are inversely proportional to iron stores; therefore, high concentrations of sTfR are observed during iron deficiency anemia.

Literature Review

Iron Deficiency

Iron deficiency is the leading cause of anemia worldwide, with women and children being at the highest risk (Ning, et al., 2019). Mild or moderate iron deficiency may not result in symptoms, and screening for iron deficiency in the general population is not clinically indicated. Diagnosis of iron deficiency anemia requires laboratory confirmed evidence of anemia as well as evidence of low iron stores. Although serum ferritin is stated to be a useful marker for iron deficiency anemia (Snook, et al., 2021), in a Cochrane Review, serum/plasma ferritin was found to be essentially uninformative in screening healthy populations for iron deficiency (Garcia-Casal, et al., 2021).

In investigating the cause for anemia, serum ferritin is the preferred method for assessing the presence of iron deficiency. The British Columbia Ministry of Health stated: "Serum iron, iron binding capacity, and transferrin saturation/fraction saturation are not routinely useful for investigating iron deficiency anemia." The inclusion of serum iron with other tests in panels for iron assessment may lead to either over-diagnosis or under-diagnosis of iron deficiency (Sezgin, et al., 2021). In a comparison study, direct transferrin measurement outperformed serum iron in the determination of iron deficiency as defined by ferritin levels (Hawkins, 2007).

Professional Societies/Organizations

The American Academy of Pediatrics (AAP) concluded that universal screening of children for anemia should be performed at 1 year of age with hemoglobin concentration in conjunction with an assessment of risk factors (Baker, et al., 2010). For infants with a hemoglobin concentration less than 11.0 mg/dL or those at significant risk for iron deficiency, serum ferritin and C-reactive protein, or reticulocyte hemoglobin concentration should be performed (Baker, et al., 2010).

Medical Coverage Policy: 0568
Effective Date 4/15/2024

The United States Preventative Services Task Force (USPSTF) concluded that there was insufficient evidence to determine the harms and benefits of screening for iron deficiency in asymptomatic children ages 6 to 24 months who were not at risk, stating (Siu, 2015): "...More research is needed to determine whether routine screening for and early treatment of screen- detected, asymptomatic iron deficiency anemia in young children improves these outcomes."

Anemia in Pregnancy

Iron status determination is not a recommended first-line component of screening pregnant individuals for anemia, but instead should be informed by the results of a complete blood count.

Professional Societies/Organizations

An American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin stated: "All pregnant women should be screened for anemia with a complete blood count in the first trimester and again at 24 0/7-28 6/7 weeks of gestation. Patients who meet criteria for anemia based on hematocrit levels less than 33% in the first and third trimesters, and less than 32% in the second trimester should be evaluated to determine the cause." (ACOG, 2021)

The USPSTF found adequate evidence that iron supplementation during pregnancy improved serum ferritin and hemoglobin levels; however, the task force concluded that there was insufficient evidence to assess the risks and benefits of screening for iron deficiency in pregnant women. Given the findings, they did not recommend specific tests for screening pregnant individuals (Siu, 2015).

Anemia of Chronic Disease

Chronic disease is the second leading cause of anemia, with acute or chronic immune activation being a common pathophysiologic mechanism. Conditions associated with anemia of chronic disease (ACD) include infection, malignancy, autoimmune disorders, and chronic kidney disease (Weiss, et al., 2005). Whereas ferritin is typically decreased in classic iron deficiency anemia (IDA), ferritin is also an acute phase reactant and may therefore, be elevated in patients where IDA coexists with inflammation or chronic disease states. Serum iron, on the other hand, is decreased in both ACD and iron deficiency anemia (Weiss, et al., 2005). In such cases when ferritin is elevated, transferrin is often used to differentiate ACD from iron deficiency anemia; transferrin is elevated in IDA and decreased in ACD (Weiss, et al., 2005 and Knovich, et al., 2009).

Professional Societies/Organizations

The European Society of Cardiology recommended that all patients with heart failure be regularly screened for iron deficiency with serum ferritin and transferrin saturation (McDonagh, et al., 2021). In an inflammatory bowel disease study, combined testing of ferritin and transferrin saturation did not add any diagnostic value for iron deficiency versus either test alone, when using soluble transferrin receptor as a reference (Daude, et al., 2020). In a study of children with inflammatory bowel disease, the soluble transferrin receptor-ferritin index appeared to have superior area under the curve (AUC) compared to other tests. However, the AUC was not determined for serum ferritin alone in that study, although it demonstrated statistical significance (Krawiec, et al., 2020). The soluble transferrin receptor-ferritin index has also been proposed to differentiate ACD from iron deficiency anemia (IDA), where a value less than 1.0 would favor the IDA (Knovich, et al., 2009). However, the strength of evidence that these and other tests offer clinical utility as markers of iron deficiency in the setting of chronic kidney disease is generally low (Chung, et al., 2012). Clinical guideline recommendations of these tests also differ, partly reflecting the influence of inflammatory processes as a factor in determining appropriate cut-off values (Tomasz, et al., 2021). In the evaluation of anemia of chronic kidney disease, the Renal Association suggests that hemoglobin levels be measured annually in those with grade 3 chronic kidney disease (CKD) and at least two times per year in patients with more severe disease that are not on dialysis. Further laboratory evaluation, including serum ferritin and transferrin, should be performed when anemia is detected (Mikhail, et al., 2017).

Medical Coverage Policy: 0568

Effective Date 4/15/2024

Iron Overload

In a Cochrane Review, there was a low certainty of evidence that high ferritin levels provided a sensitive test for iron overload when there was a clinical suspicion for iron overload (Garcia-Casal, et al., 2021). In patients undergoing evaluation of suspected iron overload, transferrin saturation (TS) is the preferred initial test (Kowdley, et al., 2019).

Professional Societies/Organizations

Medical Coverage Policy: 0568
Effective Date 4/15/2024

The European Association for the Study of the Liver (EASL) clinical practice guidelines for HFE hemochromatosis had previously stated (EASL, 2010):

• "Patients with suspected iron overload should first receive measurement of fasting transferrin saturation and serum ferritin (1B), and HFE testing should be performed only in those with increased transferrin saturation (1A)"
• "Serum iron concentration and transferrin saturation do not quantitatively reflect body iron stores and should therefore not be used as surrogate markers of tissue iron overload."

The American Association for the Study of Liver Disease (AASLD) guideline for hemochromatosis stated:

• "In a patient with suggestive symptoms, physical findings, or family history, a combination of TS [transferrin saturation] and ferritin should be obtained rather than relying on a single test. (1B) If either is abnormal (TS ≥ 45% or ferritin above the upper limit of normal), then HFE mutation analysis should be performed. (1B)"
• "Diagnostic strategies using serum iron markers should target high-risk groups such as those with a family history of HH [hereditary hemochromatosis] or those with suspected organ involvement. (1B)"

There is no recommendation for patients with type II diabetes or unexplained arthritis to be screened for hereditary hemochromatosis (HH) (EASL, 2010 and Murphree, et al., 2020). However, screening for HH could be considered in patients with porphyria cutanea tarda, well-defined chondrocalcinosis, hepatocellular carcinoma, or type 1 diabetes (EASL, 2010).

In individuals with a diagnosis of hereditary hemochromatosis undergoing therapeutic phlebotomy

EASL stated: “Serum ferritin is measured and is sufficient to monitor iron depletion. The frequency of measurements depends upon the absolute concentration. When ferritin levels are high, measurement is required less frequently (every 3 months or so); however, as ferritin approaches the normal range, measurements should become more frequent.”

The American College of Gastroenterology (ACG) clinical guideline stated (Kowdley, et al., 2019): “SF [serum ferritin] level should be checked monthly during the course of phlebotomy until a goal SF level of 50–100 ng/mL is reached… After the SF has reached its goal level, the initial induction phase of treatment is complete, and the maintenance phase follows. The goal of this phase is to maintain SF levels near 50 ng/mL, and the frequency which phlebotomy occurs typically is 3–4 times per year.”

In the setting of myelodysplastic syndrome requiring chronic red blood cell transfusion

clinical guidelines recommend monitoring serum ferritin, with the goal of decreasing ferritin levels to less than 1000 mcg/L. Initiate iron chelation therapy after 20 red blood cell units have been received or if serum ferritin exceeds 1000 mcg/L (National Comprehensive Cancer Network, 2022, and Fenaux, et al., 2021, and Killick, et al., 2021).