Ferritin AHS – G2011

Description of Procedure or Service

Ferritin is a high molecular weight iron compound consisting of protein shell with a molecular weight of 450,000 and a variable amount of hydrated ferric phosphate which forms a central core within the protein shell. Iron may comprise up to 20% of the molecule which may have a molecular weight as high as 900,000.

Ferritin is found mainly in the cytoplasma of reticuloendothelial cells, liver cells, and to a lesser extent in the developing red cell precursors in the bone marrow. It has normally been considered as a storage compound from which iron is readily mobilized either into the transferrin-bound plasma pool or for intracellular haemsynthesis. It has not been thought to appear in the plasma or extracellular fluid under normal conditions (Addison GM, 1972).

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for measurement of serum ferritin levels when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When measurement of serum ferritin levels is covered

Measurement of serum ferritin levels is considered medically necessary in any of the following situations:

• In the evaluation of an individual with abnormal hemoglobin and/or hematocrit levels.
• In the evaluation and monitoring of iron overload disorders.
• In the evaluation of individuals with liver disease. 
• In the evaluation and monitoring of patients with chronic kidney disease who are being considered for, or are receiving treatment for, anemia at a frequency of every 1 to 3 months. 
• In the evaluation of HLH and Still’s Disease.
• For individuals on iron therapy, at a frequency of every 1 to 3 months.

When measurement of serum ferritin levels is not covered

The use of ferritin measurement as a screening test for iron deficiency is not considered medically necessary.

Policy Guidelines

Ferritin is the major iron-storage compound: its production increases in cells as iron supplies increase. Although all cells are capable of storing iron, the liver, spleen, and bone marrow cells are primary iron-storage sites in people (Institute of Medicine, 2001). Ferritin is a protein that stores iron, releasing it when body needs it. Ferritin usually lives in body cells, with very little actually circulating in the blood. According to the Mayo Medical Laboratories, ferritin contains 20 percent iron. The greatest concentrations of ferritin are typically in the cells of the liver (known as hepatocytes) and immune system (known as reticuloendothelial cells).

Ferritin is stored in the body’s cells until it’s time to make more red blood cells. The body will signal the cells to release ferritin. The ferritin then binds to another substance called transferrin.

Iron deficiency and iron overload are the two major disorders of iron metabolism. Iron-deficiency anemia is the most severe form of iron deficiency. It is linked to many adverse consequences of iron deficiency, such as reduced physical capacity (Haas 2001) and poor pregnancy outcomes (Schorr 1994). Iron deficiency without anemia, however, has been linked to negative effects on cognitive development among infants and adolescents (Grantham-McGregor 2001). Iron overload is the accumulation of excess iron in body tissues, and it usually occurs as a result of a genetic predisposition to absorb iron in excess of normal but can also be caused by excessive ingestion of iron supplements or multiple blood transfusions (Pietrangelo 2004). In advanced stages of iron overload disease (hemochromatosis), the iron accumulates in the parenchymal cells of several organs, but particularly the liver, followed by the heart and pancreas; this condition can lead to organ dysfunction and even death (Pietrangelo 2004).

Ferritin is present in the blood in very low concentrations. Plasma ferritin is in equilibrium with body stores, and its concentration declines early in the development of iron deficiency. Low serum ferritin concentrations thus are sensitive indicators of iron deficiency. Ferritin is also an acute-phase protein; acute and chronic diseases can result in increased ferritin concentration, potentially masking an iron-deficiency diagnosis. The generally accepted cut-off level for serum ferritin below which iron stores are considered to be depleted is 15 ng/mL for people aged 5 years and older and 12 ng/mL for people younger than 5 years of age (World Health Organization 2001).

Among all age groups, 1–5-year-old children have the lowest ferritin concentrations. Children up to age 11 have lower transferrin saturation levels than do adolescents or adults.

Women 12 years and older are more likely to be defined as iron deficient than are men. These women have lower concentrations of serum ferritin, lower transferrin saturation, and higher EPP concentrations.

Mexican Americans have lower serum ferritin and higher EPP concentrations than do either nonHispanic whites or non-Hispanic blacks.

Non-Hispanic blacks have lower serum transferrin saturation levels than do non-Hispanic whites.

Mexican-American and non-Hispanic white children (aged 1–5 years) have lower serum ferritin concentrations than do non-Hispanic black children.

Mexican-American children (aged 1–5 years) have higher EPP concentrations than do nonHispanic black or non-Hispanic white children.

Mexican-American women of childbearing age (aged 20–39 years) have lower serum ferritin concentrations than do non-Hispanic white women. Concentrations for non-Hispanic black women of childbearing age fall between those of Mexican-American and non-Hispanic white women.

Non-Hispanic black women of childbearing age (aged 20–39 years) have lower serum transferrin saturation levels than do non-Hispanic white women. Serum transferrin saturation levels for Mexican-American women of childbearing age fall between levels for non-Hispanic white and Mexican-American women of childbearing age.

Because children and women have lower serum ferritin and transferrin saturation levels than do men and older people (≥ 60 years), children and women are at greater risk for iron deficiency.

Two minority groups, non-Hispanic blacks and Mexican Americans, typically are at greater risk for iron deficiency than are non-Hispanic whites.

At least 5 percent of persons in each age group, except for older people (≥ 60 years), have low serum ferritin concentrations (< 12 ng/mL for children younger than 5 years and < 15 ng/mL for people aged 5 years and older) that are consistent with depleted iron storage.

At least 10 percent of persons in each age group have low transferrin saturation levels (< 16 percent), which are indicative of iron deficiency (Iron-Status Indicators - CDC 2008).

Ferritin Test

• A ferritin test is a laboratory blood test that measures the amount of ferritin in a person's blood stream.
• Ferritin is the major iron storage protein in the body, so the ferritin test is ordered as an indirect way to measure the iron stores in the body.
• The ferritin test is often ordered as part of a panel of tests that examine the levels of body iron and the effects of abnormalities in iron storage.
• It may be ordered together with an iron level, a total iron binding capacity test, or blood cell counts.

Preparation for the Ferritin Test

The ferritin test is measured in a blood sample withdrawn from a vein as for any routine blood test. It can be performed at any time of day, and no special preparation for the test is necessary.

Per Mayo Clinic lab, 2016), A ferritin test measures the amount of ferritin in the blood. Ferritin is a blood cell protein that contains iron. A ferritin test helps the doctor understand how much iron your body is storing.

If a ferritin test reveals that blood ferritin level is lower than normal, it indicates that body's iron stores are low, and one has iron deficiency.

• If a ferritin test shows higher than normal levels, it could indicate a condition that causes that body is storing too much iron. It could also point to liver disease, rheumatoid arthritis, other inflammatory conditions or hyperthyroidism. Some types of cancer also may cause blood ferritin level to be high. 

Tests to diagnose a medical condition. The doctor may suggest a ferritin test if other blood tests have shown that the level of oxygen-carrying protein in red blood cells (hemoglobin) is low, or if the proportion of red blood cells to the fluid component in the blood (hematocrit) is low. These may indicate that one has iron deficiency anemia. A ferritin test can help confirm that diagnosis. Ferritin may also be measured in someone with restless legs syndrome. Ferritin test may also be used to help diagnose conditions such as hemochromatosis, liver disease and adult Still's disease, among others.

When used to diagnose a medical condition, a ferritin test may be done in conjunction with an iron test and a total iron-binding capacity (TIBC) and transferrin test. These tests provide additional information about how much iron is in the body.

• To monitor a medical condition. If one has been diagnosed with a disorder that results in too much iron in the body, such as hemochromatosis or hemosiderosis, the doctor may use a ferritin test to monitor the condition and guide treatment.

Guidelines and Recommendations

While there are guidelines and recommendations related to screening for anemia in certain populations, none of them recommend use of ferritin as a first-line test in asymptomatic individuals. Use of ferritin is recommended as a follow-up to abnormal hemoglobin or hematocrit screening results.

The National Kidney Foundation

The National Kidney Foundation’s KDOQI guidelines recommend use of ferritin testing as part of the evaluation of iron status in individuals with chronic kidney disease who are being treated for anemia. They recommend testing prior to initiation of treatment, once per month during initial treatment, and at least every 3 months after a stable hemoglobin level is reached.

2016 The American College of Gastroenterology (ACG)

In their practice guideline on the evaluation of abnormal liver chemistries, ACG recommends use of ferritin testing as part of the workup of individuals with suspected iron overload, those with a family history of hereditary hemochromatosis, and those with liver disease (Kwo et al, 2017).

Bethesda (2015)

In collaboration with the International Micronutrient Malnutrition Prevention and Control (IMMPaCt) Program, Centers for Disease Control and Prevention (CDC), USA and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA: Based on the data analysis and the consultation, participants concluded that the concentration of hemoglobin should be measured for the assessment of iron status, even though not all anemia is caused by iron deficiency, and that the assessment of serum ferritin and transferrin receptor would be the best approach for measuring the iron status of populations. The committee concluded:

• Serum/plasma ferritin as a marker of iron deficiency and overload in populations.
• Response on ferritin concentration from nutrition-specific and nutrition-sensitive interventions in children and women of reproductive age 

International consensus statement on the peri-operative management of anemia and iron deficiency by Munoz et al (2017)

Expert workshop, including a number of experienced researchers and clinicians, was conducted to develop a guidance for the diagnosis and management of anemia in surgical patients. They have developed a series of best-practice and evidence-based statements to advise on patient care with respect to anemia. Their statements included serum ferritin measurement as the most sensitive and specific test used for the identification of absolute iron deficiency (Munoz et al, 2017).

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page. 

Scientific Background and Reference Sources

Allen , X Yu, CA Kozinetz, KL McClain. “Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis,” Pediatr Blood Cancer. 2008 Jun;50(6):1227-35

Anemia or Iron Deficiency. FastStats, Centers for Disease Control and Prevention. Accessed 1.2014 

Bethesda, 2015; 

Bruce R. Bacon, Paul C. Adams, Kris V. Kowdley, Lawrie W. Powell, and Anthony S. Tavill “Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases” Hepatology, Vol. 54, No. 1, 2011

Emedicine health, 2016; 

Ferritin LabTestsOnline, Accessed 1.2014

Grantham-McGregor S, Ani C. A review of studies on the effect of iron deficiency on cognitive development in children. J Nutr. 2001;131(2S-2):649S-6S.

Haas JD, Brownlie T 4th. Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship. J Nutr. 2001;131:691S-6S.

Institute of Medicine, Food and Nutrition Board. Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium and zinc. Washington, D.C.: National Academy Press; 2001.

Iron Deficiency Anemia National Heart Lung and Blood Institute. Accessed 1.2014

Iron-Status Indicators - CDC, National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population 1999-2002, reported 2008 

KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. National Kidney Foundation. Accessed 1.2014

Kwo, P.Y., Cohen, S.M., and Lim, J.K. ACG Practice Guideline: Evaluation of Abnormal Liver Chemistries. (2016). Am J Gastroenterol 112:18-35; doi:10.1038/ajg.2016.517 Mayo Clinic Lab, accessed Nov, 2016; 

Pietrangelo A. Hereditary hemochromatosis – a new look at an old disease. N Engl J Med. 2004;350:2382-97.

Recommendations to Prevent and Control Iron Deficiency in the United States, MMWR 1998; 47 (No. RR-3) p. 5. Accessed 1.2014

SCA Meijvis, H Endeman, ABM Geers, EJ ter Borg. “Extremely high serum ferritin levels as diagnostic tool in adult-onset still’s disease” The Netherlands Journal of Medicine, vol. 65, no. 6, June 2007.CE

Screening for Iron Deficiency Anemia--Including Iron Supplementation for Children and Pregnant Women. Retrieved on 1.17.2014

Shersten Killip, John M. Bennett, Mara D. Chambers, “Iron Deficiency Anemia” Am Fam Physician 2007;75:671-8.

U.S. Department of Health and Human Services. Healthy people 2010: understanding and improving health. 2nd ed. Washington, D.C.: U.S. Government Printing Office; November 2000. Link

USPSTF 2006, “Screening for Iron Deficiency Anemia in Childhood and Pregnancy; Update of the 1996 U.S. Preventive Task Force Review.” Evidence Syntheses, No. 40 Agency for Healthcare Research and Quality (US); April 21, 2006. Report No.: 06-0590-EF-1. Accessed 1.2014

World Health Organization (WHO). Iron deficiency anaemia – Assessment, prevention, and control. A guide for program managers. Geneva: World Health Organization; 2015, (WHO/NHD/01.3) [cited 2008].

Policy Implementation/Update Information

1/1/2018 New policy developed. BCBSNC will provide coverage for measurement of serum ferritin levels when it is determined to be medically necessary because the medical criteria and guidelines are met. Medical Director review. Policy noticed 1/1/2019 for effective date 4/1/2019. (mco)