| | Iron Overload A common and easily treatable cause of early death and disability Clinical information on iron overload: Every doctor who treats patients with arthritis, fatigue, diabetes, liver disease, frequent infections, heart disease, cancer, HIV and mental disease needs to be very familiar with iron overload.
IRON OVERLOAD: A polyetiologic condition characterized by a moderate or severe increase in body iron levels that has or will have negative effects on health. The severity of iron overload can range from moderate to severe.
SEVERE IRON OVERLOAD:
· causes organ failure (cardiomyopathy, diabetes, liver failure, pituitary failure) and death.
· Generally speaking, severe iron overload can be caused by several different diseases and disorders (see list). In any one patient, however, the cause of severe iron overload may have one cause (e.g., homozygous hereditary hemochromatosis) or may have several causes (e.g., heterozygous hemochromatosis, alcoholism, and dietary excess).
· Clinical manifestations are diverse and range from severe to nonexistent (i.e., patients with sever iron overload can be completely asymptomatic).
· Treatment for severe iron overload is iron-removal therapy. Since blood is high in iron, removal of blood--therapeutic phlebotomy--is the treatment of choice. Deferoxamine chelation can be administered to patients who refuse or cannot withstand phlebotomy (i.e., patients with cardiomyopathy, severe anemia, hypoproteinemia) but is much less effective, much more expensive, and with side effects such as neurotoxicity.
· Hereditary iron overload disorders are now recognized as being among the most common genetic diseases in the human population.
· Always, when a hereditary iron overload disorder is diagnosed, all (first-degree) blood relatives must be screened for iron overload.
· Severe iron overload is not a clinical diagnosis; you cannot look at or clinically examine a patient and determine whether he or she has severe iron overload-it can only be detected with laboratory tests, and these tests must later be conformed with a diagnostic procedure such as liver biopsy, diagnostic phlebotomy, or, perhaps, MRI.
CLINICAL FEATURES AND MANIFESTATIONS OF SEVERE IRON OVERLOAD - High levels of iron as indicated by laboratory tests: elevated transferrin saturation and serum ferritin.
- Asymptomaticity: no symptoms.
- Fatigue, lethargy, weakness
- Chronic abdominal pain
- Liver damage: hepatomegally, elevated serum levels of liver enzymes and alkaline phosphatase, fibrosis and cirrhosis, hepatocellular carcinoma, or other findings such as hematemesis and melena, ascites, hyperbilirubenemia and jaundice, hypoalbuminemia, hepatic encephalopathy, clotting dysfunction, anemia, liver abscess, increased incidence of esophageal carcinoma.
- Abnormal glucose metabolism or diabetes mellitus: elevated glucose levels. Usually asymptomatic, yet can cause weight loss, polyuria, polyphagia, polydypsia.
- Musculoskeletal disorders: arthritis and arthralgia, generalized osteoporosis, bone pain, myalgia. Especially arthropathy of the hands and wrists, hips, and knees.
- Cardiac dysfunction: cardiomyopathy, arrhythmia, fibrillation, congestive heart failure; shortness of breath or dyspnea on exertion, fatigue.
- Cutaneous manifestations: 'slate-gray' or ashen coloration, increased pigmentation ('tan') of the skin, atrophy of the skin, ichthyosis, koilonychia, loss of body hair, increased incidence of malignant melanoma.
- Endocrine disorders: hypogonadotrophic hypogonadism, (autoimmune) hypothyroidism, hyperthyroidism; manifest as decreased libido, impotence, testicular atrophy, or sterility in males, amenorrhea or difficulty conceiving in females, loss of body hair.
- Increased susceptibility to infections, especially infections due to Yersinia enterocolitica, Vibrio vulnificus, and Mycobacterium tuberculosis
- Neurologic symptoms: blurred vision, sensorineural hearing loss, hyperactivity, dementia, attention deficit disorder, ataxia, lightheadedness, dizziness, anxiety, depression, tinnitus, confusion, lethargy, memory loss, disorientation, headaches and migraine headaches, personality changes, hallucinations, paranoia, chronic treatment-resistant psychiatric illness such as schizophrenia, compulsive disorders, bipolar affective disorder
- 'Alcoholism'
- Any race, nationality, or ethnic background
- A family history of, or suggestive of, a hereditary iron overload condition: family history of iron overload, hereditary anemia or iron-loading anemia, cardiac disorders or "heart disease", arthritis, diabetes, neurologic disorders, liver disease, impotence, amenorrhea, sterility.
What lab tests should be used? Test with transferrin saturation and serum ferritin.
TS is considered the best test for genetic hemochromatosis, while other primary and secondary forms of iron overload are more commonly associated with increased serum ferritin. Either test can have normal results even in patients with documented iron overload. Therefore, for the most accurate evaluation possible, both transferrin saturation and serum ferritin should be assessed. If you must use only one test, I'd vote for serum ferritin.
· Wands JR, Rowe JA, Mezey SE, et al. Normal serum ferritin concentrations in precirrhotic hemochromatosis. N Engl J Med 1976; 294: 302-5
· Barton JC, Bertoli LF, Janich MR, Arthur MW, Alford TJ. Normal transferrin saturation in hemochromatosis. Hosp Pract (Off Ed). 1991;26 Suppl 3:46-8
Transferrin saturation The best test for GH
>40% is high-normal and should be repeated; associated with increased risk of cancer,
>45% "A fasting TS of 45% or more is typically used as the screening threshold because it identifies 98% of affected persons while producing relatively few false-positive results." Ann Intern Med 1998 Dec 1;129(11):925-31
Serum ferritin The best test for secondary and non-GH iron overload; best single test for iron deficiency
>120 may be unhealthy
>160 abnormal for women
>200 with increased risk of myocardial infarction in men; begin iron-removal therapy.
>300 strongly suggests iron overload and/or the need for additional investigation,
"...in otherwise healthy persons, a fasting transferrin saturation greater than 60% in males and 50% in females strongly suggests homozygosity for hemochromatosis. If either the transferrin saturation or serum ferritin is abnormal, liver biopsy should be considered."
Welch FJ. Recognizing genetic hemochromatosis. Journal of the Louisiana State Medical Society 1994; 46: 531-3 "…[treatment] should be initiated in men with SF levels of 300 or more and in women with SF levels of 200 or more, regardless of the presence or absence of symptoms." Barton JC, McDonnell SM, Adams PC, Brissot P, Powell LW, Edwards CQ, Cook JD, Kowdley KV. Management of hemochromatosis. Ann Intern Med 1998 Dec 1;129(11):932-9 In a recent study, 11/78 (14%) of patients with TS 45-55% and SF <200 were diagnosed with hemochromatosis. This is amazing, since these lab values have traditionally been regarded as normal--the implications are that many people with TS 45-55% and SF <200 have hemochromatosis and that previous studies which used a TS of 60% missed large numbers of patients and thus greatly underestimated the true prevalance of hereditary iron overload disorders.
Phatak PD, Sham RL, Raubertas RF, Dunnigan K, O'Leary MT, Braggins C, Cappuccio JD. Prevalence of hereditary hemochromatosis in 16031 primary care patients. Ann Intern Med 1998 Dec 1;129(11):954-61 High-risk patients These are patients who should be screened for iron overload. Remember, "high-risk" is a two-way street: patients who have one or more manifestations of a common life-threatening disease are at higher risk of having that disease and are at higher risk of dying of that disease if they are not diagnosed early; physicians who fail to accurately assess for the presence of a life-threatening disease when the patient presents with signs and symptoms of the disease not only place the patient at risk for health complications but also place themselves at risk for medicolegal complications.
PATIENTS WITH A CAUSE OF IRON OVERLOAD Homozygous genetic hemochromatosis, Heterozygous genetic hemochromatosis, African hemochromatosis, African-American hemochromatosis, non-HLA linked hemochromatosis, Juvenile hemochromatosis, Neonatal hemochromatosis, Dietary excess of iron, Parenteral administration of iron in the form of iron injections and blood transfusions, Porphyria cutanea tarda, Portacaval shunt, Hepatic cirrhosis, portal hypertension, and splenomegally, AIDS, Inherited red blood abnormalities: "iron-loading anemias", hemoglobinopathies: Alpha-thalassemia, Beta-thalassemia, Thalassemia intermedia, Sideroblastic anemia, Aplastic anemia, Anemia associated with pyruvate kinase deficiency, AC hemoglobinopathy, AS hemoglobinopathy, X-linked hypochromic anemia, Pyridoxine-responsive anemia, Atransferrinemia
MEN OVER AGE 30: This is the group with the highest prevalence of clinically important iron overload. Read these articles for more information about the importance of screeing for moderate iron overload and hemochromatosis in this group.
DIABETES Remember that the classic presentation of hemochromatosis is "bronze diabetes with cirrhosis".
· Czink E, Tamas G. Screening for idiopathic hemochromatosis among diabetic patients. Diabetes Care 1991; 14: 929-30
· Phelps G, Chapman I, Hall P, Braund W, Mackinnon M. Prevalence of genetic haemochromatosis among diabetic patients. Lancet 1989; 2: 233-4
"ARTHRITIS" and PERIPHERAL POLYARTHROPATHY This may be the only manifestation of the disease and may mimic rheumatoid arthritis, osteoarthritis, and other conditions.
· Vasquez A. Musculoskeletal disorders and iron overload disease: comment on the American College of Rheumatology guidelines for the initial evaluation of the adult patient with acute musculoskeletal symptoms [letter/ comment]. Arthritis Rheum 1996;39:1767-8
· Olynyk J, Hall P, Ahern M, Kwiatek R, Mackinnon M. Screening for hemochromatosis in a rheumatology clinic. Aust NZ J Med 1994; 24: 22-5
· Bywaters EGL, Hamilton EBD, Williams R. The spine in idiopathic hemochromatosis. Ann Rheum Dis 1971; 30: 453-65
· M'Seffar AM, Fornasier VL, Fox IH. Arthropathy as the major clinical indicator of occult iron storage disease. JAMA 1977; 238: 1825-8
CONGESTIVE HEART FAILURE The cause of death in 30% of hemochromatoics.
· Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 31-1994. A 25-year-old man with the recent onset of diabetes mellitus and congestive heart failure [clinical conference]. N Engl J Med 1994; 331: 460-6
IDIOPATHIC ELEVATION OF LIVER ENZYMES Iron overload is one of the most important rule-outs. Liver biopsy may be indicated to assess condition and disease co-existence. · Herrera JL. Abnormal liver enzyme levels: clinical evaluation in asymptomatic patients. Postgrad Med 1993; 93: 119-32
· Mild liver enzyme abnormalities: eliminating hemochromatosis as cause. Clin Chem. 1997 Aug;43(8 Pt 2):1535-8.
ENDOCRINE DYSFUNCTION Hypogonadotrophic hypogonadism, hypothyroidism, hyperthyroidism; manifest as decreased libido, impotence, testicular atrophy, or sterility in males, amenorrhea or difficulty conceiving in females, loss of body hair. Remember, the pituitary is often injured by iron overload, therefore, the entire endocrine system can be affected.
· Haemochromatosis as an endocrine cause of subfertility. BMJ. 1998 Mar 21;316(7135):915-6
· Edwards CQ, Kelly TM, Ellwein G, Kushner JP. Thyroid disease in hemochromatosis. Increased incidence in homozygous men. Arch Intern Med 1983 Oct;143(10):1890-3 Autoimmune hypothyroidism was found in >10% of men with hemochromatosis.
· Phillips G Jr, Becker B, Keller VA, Hartman J 4th. Hypothyroidism in adults with sickle cell anemia. Am J Med 1992 May;92(5):567-70
PORPHYRIA CUTANEA TARDA "Virtually all patients have increased iron stores; serum iron, iron saturation, and ferritin values."
· Rich MW. Porphyria cutanea tarda. Don't forget to look at the urine. Postgrad Med. 1999;105: 208-10, 213-4
SIDEROBLASTIC ANEMIAS Bottomley SS. Sideroblastic anemia. Hosp Pract (Off Ed). 1991; Suppl 3:37-40
Bottomley SS. Sideroblastic anemia: death from iron overload. Hosp Pract (Off Ed). 1991; Suppl 3:55-6
Medicolegal considerations
Are there situations in which failing to assess for iron overload (hemochromatosis) could 1) leave the patient undiagnosed, and 2) leave the physician in a situation where the chances of adverse medicolegal actions are greater than zero? YES! "When assessing and managing patients with iron disorders, avoidance of medicolegal complications is essentially no different from that of other diseases: Diagnose responsibly, treat responsibly, and record responsibly." Herbert V. Introduction and medicolegal considerations. Hosp Pract (Off Ed). 1991 Apr;26 Suppl 3:4-6 What if the patient shows up being iron deficient, rather than iron overloaded? Iron-deficiency anemia in adults: mandatory evaluation
"We conclude that substantial gastrointestinal lesions, particularly those of the upper gastrointestinal tract, are common [62%] in patients with iron-deficiency anemia. Therefore thorough evaluation of all such patients is mandatory."
"Among the 10 patients with colon cancer who had valid stool guaiac tests, 8 had positive tests." (In other words: according to this study, stool guaiac tests for occult blood as a test for the presence of colon cancer missed 20% of the patients with colon cancer!) Rockey DC, Cello JP. Evaluation of the gastrointestinal tract in patients with iron-deficiency anemia. N Engl J Med 1993; 329: 1691-5
RATIONALE FOR SCREENING ALL PATIENTS:
1. Hereditary iron-accumulation disorders occur in a large percentage of the population. 2. Persons with the disease usually have no symptoms. 3. Clinical manifestations are often indicative of irreversible organ damage or organ failure. 4. Iron overload can cause death if not treated early. 5. Early treatment ensures normal life expectancy. 6. Therefore, early detection (before the onset of symptoms and organ damage) requires screening asymptomatic patients.
LITERATURE SUPPORT FOR THE ROUTINE SCREENING OF ALL PATIENTS FOR IRON OVERLOAD "In view of the high prevalence of hereditary hemochromatosis, its dire consequences when untreated, and its treatability, screening for the disorder should be performed routinely." Fairbanks VF. Laboratory testing for iron status. Hosp Pract (Off Ed) 1991 Suppl 3:17-24
"CONCLUSIONS: Hemochromatosis is relatively common among white persons. Routine screening of white persons for hemochromatosis should be considered by primary care physicians."
Phatak PD, Sham RL, Raubertas RF, Dunnigan K, O'Leary MT, Braggins C, Cappuccio JD. Prevalence of hereditary hemochromatosis in 16031 primary care patients. Ann Intern Med 1998 Dec 1;129(11):954-61
"Conclusions: Screening blood donors for hemochromatosis has the potential to improve overall societal health status and decrease third-party payer health care costs over the long-term."
Adams PC, Gregor JC, Kertesz AE, Valberg LS. Screening blood donors for hereditary hemochromatosis:
decision analysis model based on a 30-year database. Gastroenterology 1995; 109: 177-88
"Screening for hemochromatosis is both feasible and cost-effective, and we recommend its use in patients seeking medical care."
Balan V, Baldus W, Fairbanks V, Michels V, Burritt M, Klee G. Screening for hemochromatosis:
a cost-effectiveness study based on 12, 258 patients. Gastroenterology 1994; 107: 453-9
"The high gene frequency in the general population warrants routine screening tests in asymptomatic healthy young adults."
Gushusrt TP, Triest WE. Diagnosis and management of precirrhotic hemochromatosis. W Virginia Med J 1990; 86: 91-5
"Summary: In view of the incidence of hereditary hemochromatosis being close to one individual per 500 and the observation that the incidence of liver cancer in patients with HH is 219 times that of control populations, the diagnosis of HH and its subsequent treatment in the pre-cirrhotic stage in imperative..."
Bryan CF. The immunogenetics of hereditary hemochromatosis. Am J Med Sci 1991; 301: 47-9
"First, hemochromatosis is not rare. It is probably among the most common inherited metabolic abnormalities. Second, hemochromatosis can be detected before any clinical signs or symptoms of the disease develop and even before hepatic iron loading occurs."
Edwards CQ, Kushner JP. Screening for hemochromatosis. N Engl J Med 1993; 328: 1616-20
"Conclusion: We recommend that practitioners consider including a serum transferrin saturation test in their routine screening for asymptomatic white men."
Phatak PD, Guzman G, Woll JE, Robeson A, Phelps CE. Cost-effectiveness of screening for hereditary hemochromatosis. Arch Intern Med 1994; 154: 769-76
"Conclusions: Our observations support routine screening with transferrin saturation for white men [30 years of age and older]."
Baer DM, Simmons JL, Staples RL, Runmore GJ, Morton CJ. Hemochromatosis screening in asymptomatic
ambulatory men 30 years of age and older. Am J Med 1995; 98: 464-8
"A case could be made for screening all white children, given the high frequency of the hemochromatosis gene. Totally asymptomatic patients, such as ours, were discovered with standard iron profiles."
Kaikov Y, Wadsworth LD, Hassall E, Dimmick JE, Rogers PCJ. Primary hemochromatosis in children:
report of three newly diagnosed cases and review of the pediatric literature. Pediatrics 1992; 90: 37-42 "Routine health practice profile chemistries must include a serum iron and iron saturation, and if high followed by a serum ferritin." Flexner JM. Hemochromatosis: diagnosis and treatment. Compr Ther 1991; 17: 7-9
"Routinely measuring iron status is necessary because about 6% of Americans have negative iron balance, about 10% have a gene for positive balance, and about 1% have iron overload."
Herbert V. Everyone should be tested for iron disorders. J Am Diet Assoc 1992; 92: 1502-9
MODERATE IRON OVERLOAD Intermediate between normal/healthy iron status and severe iron overload, moderate iron overload is associated with increased incidence of cancer and heart disease (heart attack and stroke). The causes of moderate iron overload are related to heredity (i.e., hemochromatosis heterozygosity) and/or lifestyle (alcoholism, high-meat diet) and of course include all of the causes of severe iron overload. T These patients have no symptoms which can be attributed to iron overload and have iron status that is well within the reference range according to most medical laboratories. Periodic blood donation is the recommended preventive treatment, but is not mandatory.
"There is evidence in this data set, however, of elevations of cancer occurrence and of death in subjects with baseline transferrin saturations in the range of 40-60% as well, a level which may include many heterozygotes for hemochromatosis."
Stevens RG, Graubard BI, Micozzi MS, Neriishi K, Blumberg SB. Moderate elevation of body iron level and increased risk of cancer occurrence and death. International Journal of Cancer 1994; 56: 364-9
"… men with serum ferritin > 200 mcg/L had a 2.2 fold risk factor-adjusted risk of acute myocardial infarction compared with men with a lower serum ferritin."
Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Seppanen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 1992; 86: 803-11
Iron Overload can be thought of as a location. There are many ways to arrive at this location. However, once someone has arrived here, there are only 2 routes for leaving. 
TREATMENTS: Early treatment prevents organ failure and early death. - Therapeutic phlebotomy-the treatment of choice for the majority of patients. Generally, one unit of blood is removed once or twice per week. Treatment on a less frequent basis can be counterproductive due to increased iron absorption secondary to hypoxia/anemia.
- Deferoxamine chelation-deferoxamine is a chelating agent that is specific for iron. It is administered by 24-hour subcutaneous infusion; it can be painful and can predispose to infection, and it is more expensive than phlebotomy and can be neurotoxic. It is much less effective than phlebotomy, and is generally reserved for patients with severe anemia, hypoproteinemia, cardiomyopathy, or acute iron toxicity.
- Orally administered chelating agents-the most researched drug is deferiprone. As great as an orally administered drug might sound, these have been generally unsatisfactory for the removal of iron in iron overloaded patients and are associated with bone marrow toxicity and significantly increased risk of liver damage.
THE "TAKE-HOME" MESSAGES: Things to remember with regard to iron overload Severe iron overload occurs in persons of either gender at any age of any hereditary background and can become clinically manifest as several "different" disorders, such as diabetes, arthritis, fatigue, endocrine problems, liver and heart disease.
Moderate iron overload is associated with increased risk for heart attack and cancer.
Iron-status testing with both transferrin saturation and serum ferritin is essential for the identification of affected patients.
Given the high prevalence of the disease and the effectiveness and cost-effectiveness of testing and treatment, screening any and all patients--even patients without symptoms--is justifiable.
Patients with diabetes, porphyria, idiopathic congestive heart failure, peripheral arthropathy (widespread arthritis), idiopathic hepatopathy (liver disease of unknown origin) must be tested for iron overload.
"You will never find what you don't look for." Additional information can be obtained from the Iron Overload Disorders Institute. |
