Iron overload and the genetic hemochromatosis: diagnosis and management guidelines from inflammation to mastery 2014.
* Hereditary iron overload disorders are now recognized as being among the most common genetic diseases in the human population.Iron overload is a phenotypic state to which a patient arrives by either genetic or environmental/iatrogenic routes. The severity of iron overload can range from moderate to severe. Excess iron catalyzes oxidative stress which damages body tissues and structures in which the iron is stored. In patients with genetic hemochromatosis, two problems exist simultaneously: I) a disproportionately large amount of iron is absorbed from the gastrointestinal tract (i.e., these patients' iron absorption is "too efficient"), and 2) iron is preferentially deposited in parenchymal tissues such as the heart, liver, pancreas, pituitary gland, and joints rather than being stored safely within the reticuloendothelial system. The deposition of excess iron in parenchymal tissues promotes destruction of these organs/tissues via oxidative mechanisms and subsequent tissue necrosis and fibrosis, leading to the protean manifestations of the disease dependent upon which organs are most affected in the individual patient: heart failure, hepatic fibrosis, hypoinsulinemic diabetes, hypopituarism, and hemochromatoic arthropathy. Iron overload can be defined as a state of "iron toxicity" similar to mercury toxicity or poisoning with any other heavy metal or toxin, except that the mechanism is more related to the quantity of the iron rather than the unique characteristics or quality of iron itself. In other words, whereas the toxicity of mercury can be seen even when only small amounts of the metal are present, the toxicity of iron is directly related to the amount of the excess iron, rather than the inherent toxicity of the iron itself.
* Many patients are asymptomatic; when symptoms present, most patients' problems will be erroneously attributed to another disorder:
* Diabetes: Patients may present with diabetes, which is erroneously attributed to metabolic syndrome or type-2 diabetes.(9)
* Musculoskeletal pain: Patients may present with joint pain that is erroneously attributed to osteoarthritis(10), rheumatoid arthritis(11), or some other musculoskeletal syndrome.(12)
* Cardiomyopathy: Patients may present with heart failure that is written off as "idiopathic cardiomyopathy.(13)
* Liver disease: Hemochromatosis liver disease resembles and exacerbates viral hepatitis, alcoholic hepatitis, and porphyria.
* Fatigue, lethargy, weakness
* Chronic abdominal pain
* Liver damage: Hepatomegaly, 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 ofthe skin, ichthyosis, koilonychia, loss ofbody hair, increased incidence of malignant melanoma.
* Endocrine disorders: Hypogonadotrophic hypogonadism, (autoimm tine) hypothyroidism, hyperthyroidism; manifest as decreased libido, impotence, testicular atrophy, or sterility in males, amenorrhea or difficulty conceiving in females, loss of body hair.
* Susceptibility to increased frequency and severity of infections: Especially infections due to Yersinia enterocolitica, Vihrio vulnificus, HIV, 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, hall-ucinations, paranoia, chronic treatment-resistant psychiatric illness such as schizophrenia, compulsive disorders, bipolar affective disorder.
* 'Alcoholism': Alcoholism can cause elevated liver enzymes and liver damage, and many iron overload patients are erroneously diagnosed as alcoholics despite their abstinence from alcohol when the clinician fails to consider iron overload as the cause for the hepatopathy.
* Any race, nationality, or ethnic background: Hereditary iron overload conditions have been identified in people of all ethnic backgrounds and nationalities. Secondary iron overload conditions can occur irrespective of genetic predisposition.
* Either gender: Iron overload conditions occur in both men and women.
* A family history of, or suggestive of, a hereditary iron overload condition: Family history of iron overloads hereditary anemia oriron-loading anemia, cardiac disorders or -heart disease", arthritis, diabetes, neurologic disorders, liver disease, impotence, amenorrhea, sterility.
* Diabetes mellitus: Remember that the classic presentation of hemochromatosis is "bronze diabetes with cirrhosis." All patients with diabetes should be tested for iron overload. (14),(15)
Conditions causally associated with iron overload Primary/genetic disorders
1. Homozygous genetic hemochromatosis
2. Heterozygous genetic hemochromatosis
3. African iron overload
4. African-American hemochromatosis (African-American iron overload) .
5. Non-HLA-1inked hemochromatosis
6. Juvenile hemochromatosis
7. Neonatal hemochromatosis Secondary and metabolic disorders
8. Dietary excess of iron
9. Parenteral administration of iron in the form of iron injections and blood transfusions
10. Porphyria cutanea tarda
11. Portacaval shunt
12. Hepatic cirrhosis, portal hypertension, and spleno-megally
14. Sudden infant death syndrome
16. Metabolic syndrome Inherited red blood cell abnormalities ("iron-loading anemias", hemoglobinopathies)
19. Thalassemia intermedia
20. Sideroblastic anemia
21. Aplastic anemia
22. Anemia associated with pyruvate kinase deficiency
23. AC hemoglobinopathy
24. AS hemoglobinopathy
25. X-linked hypochromic anemia
26. Pyridoxine-responsive anemia
* Hepatopathy: Iron overload is one of the most important rule-outs in patients with liver disease. 16 Liver biopsy is often indicated to assess condition and disease co-existence.
* Musculoskeletal disorders: Patients with polyarthropathy should be tested for iron overload. (17)
* Degenerative arthritis or osteoarthritis
* Pseudogout, calcium pyrophosphate dihydrate deposition disease
* Rheumatoid arthritis(18)
* Ankylosing spondylitis: The resemblance here is only superficial, related primarily to calcification of the intervertebral discs and ligaments.(19)
* Hyperthyroidism and hypothyroidism(20),(21)
* Hypogonadotrophic hypogonadism: Erecti le dysfunction in men, subfertility in women (22)
* Porphyria cutanea tarda: "Virtually all patients have increased iron stores; serum iron, iron saturation, and ferritin values.(23) All patients with porphyria cutanea tarda must be tested for iron overload.
* Themanifestationsoftheconditionaresoprotean that history is generally non-sensitive and non-specific for the disorder. Rarely, a patient will mention that a relative was diagnosed with iron overload or that a relative had an unusual heart or liver disease, and this clue may lead to a diagnosis or iron overload in unsuspecting family members.
* Physical examination/objective:
* Theclassicpresentationofthcfullydevelopeddisease is "bronze diabetes with arthritis and cirrhosis."
* Physical examination should be specif-ic for the patient's complaint(s) of arthritis. cardiomyopathy, diabetes, etc.
* Imaging & laboratory assessments:
* Routine screening with serum ferritin for iron overload among all patients should be the standard of care in clinical practice.
* "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."(24)
* -Screening for hemochromatosis is both feasible and cost-effective, and we recommend its use in patients seeking medical care."(25)
* "The high gene frequency in the general population warrants routine screening tests in asymptomatic healthy young adults. "(26)
* "Primary iron overload occurs in African Americans... Clinicians should look for this condition."(27)
* Imaging: The radiographic findings are nearly identical to those of osteoarthritis, except more joints are typically involved and that the distribution is typically symmetric (both due to the systemic/metabolic nature of the disease). Hooklike osteophytes at the metacarpal heads--with the "hooks" pointing proximally (rather than distally, as in rheumatoid arthritis) may be the only finding that could be called pathognomonic. Flattened or -squared-off" metacarpal heads are also seen. See previous table labeled Musculoskeletal manifestations of iron overload" for more details.
* Laboratory evaluation: Serum ferritin is the test of choice when looking for primary iron overload, secondary iron overload, and/or iron deficiency and should be a component of each new patient's evaluation, just as are CBC and the chemistry/metabolic panel. Transferrin saturation is a common test used for the detection of genetic hemochromatosis in research studies because it measures both iron levels but also disordered iron handling; this is why this test is best used in research screening of large populations. For clinicians, serum ferritin is very obviously the superior lab test for iron overload and deficiency.
* Transferrin saturation: Good test for detecting genetic hemochromatosis before iron overload has occurred; values greater than 40% should be repeated in conjunction with a measurement of serum .ferritin. Guidelines for screening for genetic hemochromatosis advocate the transferrin saturation test because it is a more sensitive assessment (compared to serum ferritin) for the hemochromatosis genotype which manifests phenotypically not simply as increased iron absorption and accumulation but also as an abnormality in iron handling which preferentially alters the transferrin saturation value, which is the ratio of serum iron to serum transferrin; the former rises due to increased iron absorption while the latter declines due to impaired hepatic synthetic function secondary to the preferential intraparenchymal deposition of iron in genetic hemochromatosis. Thus, genetic hemochromatosis is not simply a disorder characterized by increased iron absorption; it is also a disorder of iron handling/metabolism wherein iron is stored intracellularly in tissue parenchyma rather than (as in non-GH persons) in the reticuloendothelial system.
* Ferritin: Routine use of serum ferritin is the most reasonable and cost-effective means for diagnosing this condition in symptomatic and asymptomatic patients. Elevations of ferritin (i.e., >200 mcg/L in women and >300 mcg/L in men) need to be retested along with CRP (to rule out false elevation due to excessive inflammation) before making the presumptive diagnosis of iron overload. In the absence of significant inflammation, ferritin values >200 mcg/L in women and >300 mcg/L in men indicate iron overload and the need for treatment/ phlebotomy regardless of the absence of symptoms or end-stage complications.' Another benefit to the use of serum ferritin is the frequent detection of iron deficiency.
Guide to Patient Management Based on Iron Status:
* Deficiency: Adult patients with iron deficiency must generally be presumed to have occult gastrointestinal blood loss and should therefore be referred for gastrointestinal endoscopy; this is consistent with the standard of care in medicine.
* Optimal: Ferritin levels between 40-70 mcg/L are generally optimal for most men and women; up to 120 mcg/L is reasonable for subsets of patients with restless leg syndrome, perhaps also those with recalcitrant depression and/or Parkinsonian features to allow sufficient iron entry into the brain for maximal dopamine production.
* Excess: Levels greater than 200 mcg/L in a woman or 300 mcg/L in a man are suggestive of iron overload and/or tendency toward accumulation and are physiologically unnecessary and medically unjustifiable, particularly as increased iron stores correlate with increased cancer mortality, increased cardiovascular mor-tality, and increased all-cause mortality. Image used with permission Copyright c 2014 Vasquez A, Inflammation Mastery, Volume 1
* Overload: Diagnosis and treatment for iron overload can occur simultaneously with diagnostic/therapeutic phlebotomy. Genetic testing and liver biopsy are generally inefficient expenditures of financial and medial resources; genetic testing is largely irrelevant in the presence of the hemochromatosis phenotype (i.e., otherwise inexplicable iron accumulation) while liver biopsy exposes the patient to unnecessary treatment delays, risk, and expenses. Identification of idiopathic or genotropic iron overload requires testing of genetic relatives.
Musculoskeletal findings in genetic hemochromatosis: The only specific finding is the retrograde hook-like osteophytes at the metacarpal heads; other findings of intervertebral disc calcification, osteophytosis of the humeral head, and meniscal chondrocalcinosis are nonspecific and therefore easily nondiagnosed or misdiagnosed.
* CRP: Should be relatively normal as iron overload is not inflammatory, per se. If the ferritin is elevated and the CRP is markedly elevated, then inflammatory and hepatic diseases must be considered, namely advanced cancer, viral hepatitis or other hepatopathy, and alcoholic liver disease. If the ferritin is elevated and the CRP is normal, then the most likely diagnosis is iron overload, which should be confirmed either with liver biopsy or diagnostic/therapeutic phlebotomy.
* CSC: may show anemia, but the findings here are nonspecific
* Chemistry panel: may show evidence of diabetes and hepatopathy
* Thyroid assessment: may show hyper- thyroidism or hypothyroidism, both of which are more common in patients with iron overload.
* Bone marrow biopsy: unnecessary and archaic in this setting, now that serum ferritin is widely available.
* Liver biopsy: traditionally considered the "gold standard" for diagnosing iron overload but is now clearly unnecessary for the diagnosis, which can be established by monitoring the response to therapeutic phlebotomy, which is the treatment of choice. Life-saving diagnostic and therapeutic phlebotomy should never be denied or delayed for lack of liver biopsy in patients with laboratory indicators of iron overload.(42)
* Genetic testing, such as for the HFE mutation: This is a waste of time and money in most clinical situations; these tests should be reserved for research purposes and for evaluation of affected relatives--especially children--of index cases. The only value these tests may have in clinical practice is that of supporting a diagnosis in a patient with elevated serum ferritin who refuses biopsy, liver MRI, or phlebotomy; however, a negative result is meaningless if the ferritin is high and the clinical picture is compatible with iron overload. If the diagnosis is established, genetic relatives must be tested.
Establishing the diagnosis: Any one of the following three is sufficient:
* Diagnostic liver biopsy shows heavy iron deposits.
* Characteristic laboratory findings (ferritin >200 in women or >300 in men) and the ability to resist intractable anemia with serial/weekly phlebotomies.
* Characteristic MRI of liver and the ability to tolerate serial/weekly phlebotomies.
* Patients diagnosed and effectively treated before the onset of signs and symptoms have normal life expectancy.
* The most common causes of premature mortality in undiagnosed and untreated patients are related to heart failure, liver failure, infections and/or complications of diabetes.
* Treatment for severe iron overload is iron-removal therapy. Since blood is high in iron, the 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. Adjunctive nutritional and lifestyle modifications are no substitute for iron-removal therapy, and weekly phlebotomy is the treatment of choice.
* When a hereditary iron overload disorder is diagnosed, all (first-degree) blood relatives must be screened for iron overload.
* Medical standard: Iron-removal is accomplished by weekly phlebotomy of 1-2 units (250-500 mL of blood, each of which removes 250 mg of iron), and deferoxamine chelation is used in patients who cannot tolerate phlebotomy. Complications of the disease, such as arthritis, heart failure, hypogonadism, and diabetes are treated appropriately. Cirrhotic patients must be monitored for hepatoma with twice-yearly liver ultrasound and measurement of serum alpha-fetoprotein. Always, when a hereditary iron overload disorder is diagnosed, all (first-degree) blood relatives must be screened for iron overload.
* Diet modifications: These are no substitute for iron-removal therapy with phlebotomy and are weak in their effectiveness by comparison.
* Decrease consumption of foods and nutritional supplements which are significant sources of iron: Iron supplements, iron-fortified foods and supplements, liver, beef, pork, Iamb.
* Increase consumption of foods that will decrease intestinal absorption of iron from ingested food: tannins in tea, phytates (in whole-grain products, bran, legumes, nuts, and seeds), soy protein, egg, calcium supplements.
* Ensure adequate protein intake to replace protein lost during phlebotomy.
* Decrease consumption of excess ascorbic acid (vitamin C); high-dose vitamin C supplementation is clearly contraindicated. (43)
* Alcohol consumption should be avoided because ethanol exacerbates liver damage and increases iron absorption from the gut.
* Silymarin: Milk thistle has proved benefit in an animal model of iron overload (44) and is probably suitable for use in patients with iron overload, particularly given its ability to reverse cirrhosis."
* Antioxidant supplementation (excluding high-dose ascorbate): Oxidative stress is increased and antioxidant reserves are decreased in patients with iron overload.
* Coenzyme Q10: C0Q-10 probably has a role in the treatment of hemochromatoic cardiomyopathy given its safety and efficacy in other cardiomyopathies.(46),(47),(48),(49),(50),(51).(52),(53)
Iron overload disorders are common in all ethnic/racial populations
Genetic hemochromatosis is considered one of the most common hereditary disorders in the Caucasian population with a homozygote frequency of 1 per 200-250 (approx 0.5%) and a heterozygote frequency of about 1 in 7 (approx 14%); the condition is at least as common in other ethnic groups except that this predisposition toward iron overload is more common in Africans (as high as 1 in 20) and African-Americans (as high as about 1 in 80 in some series among hospitalized patients). Of course, the expected frequency would be even higher among symptomatic patients than among the general population. Thus, for a clinician in full-time practice, the only reason for not appreciating this condition among one's patient population several times per year is because one is simply not sufficiently looking and testing for this condition.
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.
Test of choice: Serum ferritin, shows the best correlation with body iron stores and thus prognosis and need for treatment.
Musculoskeletal manifestations of iron overload
Clinical findings may include:
* Joint pain
* Bone pain
* Joint swelling
* Loss of motion
* Subcutaneous nodules Sites of involvement
* Metacarpophalangeal joints
* Metatarsophalangeal joints
* Symphysis pubis
* Achilles tendon
* Plantar fascia Radiographic findings
* Joint space narrowing
* Hook-like osteophytes at the metacarpal heads (high specificity)
* Flattened or "squared-off" metacarpal heads
* Generalized osteopenia
* Generalized osteoporosis
* Subchondral cysts
* Carpal erosions
* Calcific tendonitis
Initiation of therapeutic phlebotomy is based on serum ferritin and does not require liver biopsy
"Therapeutic phlebotomy is used to remove excess iron and maintain low normal body iron stores, and it should be initiated in men with serum ferritin levels of 300 microg/L or more and in women with serum ferritin levels of 200 microg/L 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. Hemochromatosis Management Working Group. Ann Intern Med. 1998 Dec (41)
(1.) 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. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 1996; 39:1767-8
(2.) Olynyk JK, Bacon BR. Hereditary hemochromatosis: detecting and correcting iron overload. Postgrad Med 1994; 96: 151-65
(3.) Phatak PD, Cappuccio JD. Management of hereditary hemochromatosis. Blood Rev 1994; 8: 193-8
(4.) Rouault TA. Hereditary hemochromatosis. JAMA 1993; 269: 3152-4
(5.) Crosby WH. Hemochromatosis: current concepts and management. Hosp Pract 1987; 22:173-92
(6.) Bloom PD, Gordeuk VR, MacPhail AP. HLA-linked hemochromatosis and other forms of iron overload. Dermatol Clin 1995; 13: 57-63
(7.) Barton JC, Berton LF. Hemochromatosis: the genetic disorder of the twenty-first century. Nat Med 1996; 2: 394-5
(8.) Lauffer, RB. Iron and Your Heart. New York: St. Martin's Press, 1991
(9.) "Most ofthe patients (95%) had one or more ofthe following conditions; obesity, hyperlipidaemia, abnormal glucose metabolism, or hypertension. INTERPRETATION: We have found a new non-HLA-linked iron-overload syndrome which suggests a link between iron excess and metabolic disorders." Moirand R, Mortaji AM, Loreal 0, Pai 1 lard F, Brissot P, Deugnier Y. Anew syndrome of liver iron overload with normal transferrin saturation. Lancet. 1997 Jan 11;349(9045):95-7
(10.) Axford JS, Bomford A, Revell P. et al. Hip arthropathy in genetic hemochromatosis: radiographic and histologic features. Arthritis Rheum 1991; 34: 357-61
(11.) Bensen et al. Hemochromatoic arthropathy mimicking rheumatoid arthritis. A case with subcutaneous nodules, tenosynovitis, and bursitis Arthritis Rheum 1978; 21: 844-8
(12.) Olynyk J, Flail P. et al. Screening for genetic hemochromatosis in a rheumatology clinic. Australian and New Zealand Journal of Medicine 1994; 24: 22-25
(13.) [No authors listed] 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. N Engl J Med. 1994 Aug l8;331(7):460-6
(14.) Czink E, Tamas G. Screening for idiopathic hemochromatosis among diabetic patients. Diabetes Care 1991; 14: 929-30
(15.) Phelps G, Chapman I, Hall P. Braund W, Mackinnon M. Prevalence of genetic haemochromatosis among diabetic patients. Lancet 1989; 2: 233-4
(16.) Herrera JL. Abnormal liver enzyme levels: clinical evaluation in asymptomatic patients. Postgrad Med 1993; 93: 119-32
(17.) M'Seffar AM, Fornasier VL, Fox 1H. Arthropathy as the major clinical indicator of occult iron storage disease. JAMA 1977; 238: 1825-8
(18.) Bensen WG, Laskin CA, Little HA, Fam AG. Hemochromatoic arthropathy mimicking rheumatoid arthritis. Arthritis Rheum 1978; 21: 844-8
(19.) Bywaters EGL, Hamilton EBD, Williams R. The spine in. idiopathic hemochromatosis. Ann Rheum. Dis 1971; 30: 453-65
(20.) 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-
(21.) 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
(22.) Tweed MJ, Roland JM. Haemochromatosis as an endocrine cause of subfertility. BMJ. 1998 Mar 21;316(7135):915-6 bmj.bmjjournals.com/cgi/content/ful1/316/7135/915
(23.) "Virtually all patients have increased iron stores; serum iron, iron saturation, and ferritin values." Rich MW. Porphyria cutanea tarda. Postgrad Med. 1999;105: 20810, 213-4
(24.) Fairbanks VF. Laboratory testing for iron status. Hosp Pract (Off Ed) 1991 Suppl 3:17-24
(25.) Balan V, Baldus W, Fairbanks V. et al. Screening for hemochromatosis: a cost-effectiveness study based on 12, 258 patients. Gastroenterology 1994; 107: 453-9
(26.) Gushusrt TP, Triest WE. Diagnosis and management of precirrhotic hemochromatosis. W Virginia Med J 1990; 86: 91-5
(27.) Wurapa RK, Gordeuk VR, Brittenham GM, Khiyami A, Schechter GP, Edwards CQ. Primary iron overload in African Americans. Am J Med. 1996 Jul;101(1):9-18
(28.) Barton JC, McDonnell SM, Adams PC, Brissot P, Powell LW, Edwards CQ, Cook JD, Kowdley KV. Management of hemochromatosis. Hemochromatosis Management Working Group. Ann Intern Med. 1998 Dec 1;129(11):932-9
(29.) Milman N, Albeck Mi. Distinction between homozygous and heterozygous subjects with hemochromatosis using iron status markers and receiver operating characteristic (ROC) analysis. Eur J Clin Biochem 1995; 33: 95-8. See also Milman N. Iron status markers in hereditary hemochromatosis: distinction between individuals being homozygous and heterozygous for the hemochromatosis allele. Eur J Haematol 1991;47:292-8
(30.) Olynyk JK, Bacon BR. Hereditary hemochromatosis: detecting and correcting iron overload. Postgrad Med 1994;96: 151-65
(31.) "Therapeutic phlebotomy is used to remove excess iron and maintain low normal body iron stores, ... initiated in men with serum ferritin levels of 300 microg/L or more and in women with serum ferritin levels of 200 microg/L 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. Hemochromatosis Management Working Group. Ann Intern Med. 1998 Dec 1;129(11):932-9
(32.) Barton JC, Edwards CQ, Bertoli LF, Shroyer TW, Hudson SL. Iron overload in African Americans. Am J Med 1995; 99: 616-23
(33.) Barton JC, McDonnell SM, Adams PC, et al. Management of hemochromatosis. Ann Intern Med. 1998 Dec 1;129(11):932-9
(34.) Salonen JT, Nyyssonen K, Korpela [-Let al. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 1992; 86: 803-11
(35.) Nicoll D. Therapeutic drug monitoring and laboratory reference ranges. In: Tierney LM, et al. Current Medical Diagnosis and Treatment. Appleton and Lange, 1996: 1442
(36.) Sullivan JL. Iron and the sex difference in heart disease risk. Lancet. 1981 Jun 13;1(8233):1293-4
(37.) Lauffer, RB. Iron and Your Heart. New York: St. Martin's Press, 1991: 79-8, 83-88, 162
(38.) Vasquez A. High body iron stores: causes, effects, diagnosis, and treatment. Nutritional Perspectives 1994; 17: 13, 15-7, 19, 21,28 and Vasquez A. Men's Health: Iron in men: why men store this nutrient in their bodies and the harm that it does. MEN Magazine 1997; Jan:11,21-23 vix. com/menmag/alexiron.htm
(39.) Rockey DC, Cello JR Evaluation of the gastrointestinal tract in patients with iron-deficiency anemia. N Engl J Med. 1993329(23):1691-5
(40.) "Endoscopy revealed a clinically important lesion in 23 (12%) of 186 patients. ... CONCLUSIONS: Endoscopy yields important findings in premenopausal women with iron deficiency anemia, which should not be attributed solely to menstrual blood loss." Bini EJ, Micale PL, Weinshel EH. Evaluation of the gastrointestinal tract in premenopausal women with iron deficiency anemia. Am J Med. 1998 Oct;105(4):281-6
(41.) "Therapeutic phlebotomy is used to remove excess iron and maintain low normal body iron stores, and it should be initiated in men with serum ferritin levels of 300 microg/L or more and in women with serum ferritin levels of 200 microg/L 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. Hemochromatosis Management Working Group. Ann Intern Med. 1998 Dec 1;129:932-9
(42.) Sullivan JL, as quoted in Crawford R, ed. "The debate." In: Ironic Blood: information on iron overload. West Palm Beach: Iron Overload Diseases Association. 1996; 16 (2)
(43.) Mclarlan et al. Congestive cardiomyopathy and hemochromatosis: rapid progression possibly accelerated by excessive ingestion of ascorbic acid. Aust NZ J Med 1982;12:187-8
(44.) "CONCLUSIONS: Oral administration of silybin protects against iron-induced hepatic toxicity in vivo. This effect seems to be caused by the prominent antioxidant activity of this compound." Pietrangelo A, et al. Antioxidant activity of silybin in vivo during long-term iron overload in rats. Gastroentemlogv. 1995 Dec;109(6):1941-9
(45.) Salmi et al. Effect of silymarin and chemical, functional, and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 1982;17:517-21
(46.) Greenberg S. Frishman WH. Co-enzyme Q-10: a new drug for cardiovascular disease. J Clin Pharmacy' 1990; 30: 596-608
(47.) Langsjoen P11, Langsjoen PH, Folkers K. Long-term efficacy and safety of coenzyme Q-10 therapy for idiopathic dilated cardiomyopathy. AM J Cardiol 1990; 65: 521-3
(48.) Manzoli U, Rossi E, Littarru GP, et al. Coenzyme Q-10 in dilated cardiomyopathy. Intl Tiss Reac 1990; 12: 173-8
(49.) Langsjoen et al. Pronounced increase ofsurvival of patients with cardiomyopathy when treated with coenzyme Q-10 and conventional therapy. Intl Tiss Reac 1990;12:163-8
(50.) Folkers K. Heart failure is a dominant deficiency of coenzyme Q-10 and challenges for future clinical research on CoQ-10. Investig 1993; 71: s51-s54
(51.) Folkers K, et al. Therapy with coenzyme Q-10 of patients in heart failure who are eligible or ineligible for a transplant. Biochem Biaphys Res COMIMM 1992 ;182:24753
(52.) Mortensen SA, et al. Coenzyme Q-10: clinical benefits with biochemical correlates suggesting a scientific breakthrough.... Intl Tiss Reac 1990;12:155-62
(53.) Langsjoen PH, Langsjoen PH., Folkers K. A six-year clinical study of therapy of cardiomyopathy with coenzyme Q-10. hill Tiss Reac 1990; 12: 169-71
by: Alex Vasquez, DC, ND, DO
Interuretalion of iron status hascd on serum ferritin (in descending order) Ferritin Categorization and Management [greater than or equal to] 800 mcg/L Practically diagnostic of severe iron overload(29): Repeat tests: rule out inflammation or occult pathology. Initiate phlebotomy and consider liver biopsy or MRI. [greater than or equal to] 300 mcg/L Probable iron overload; clear predisposition to iron accumulation(30): Repeat tests; rule out inflam-mation or occult pathology. In men. initiate phlebotomy and consider liver biopsy or MRI. [greater than or equal to] 200 mcg/L In women: Probable iron overload; clear predisposition to iron accumulation(32): Repeat tests, rule out inflammation or occult pathology. In women, initiate phlebotomy and consider liver biopsy or MRI.(33) In men: High-normal unhealthv iron status with increased risk of myocardial infarction-: Rule out inflammation or occult pathology. No follow-up is mandated, yet blood donation and/or abstention from dietary iron are recommended preventative healthcare measures. [greater than or equal to] 160 mcg/L In women: Abnormal iron status(35): Repeat tests, rule out inflammation or occult pathology. Consider phlebotomy and liver biopsy or MRI. [greater than or equal to] 80-120 mcg/L High-normal unhealthy iron status(36): No follow-up is mandated: blood donation and abstention from dietary iron are suggested preventative healthcare measures. A subset of patients with rest-less leg syndrome (RLS, a condition also causally associated with intestinal bacterial overgrowth dysbiosis) have impaired transport of iron into the brain and therefore require slightly elevated ferritin/iron levels (up to 120) to enhance cerebral iron uptake. 40-70 mcg/L Optimal iron status for most people(37),(38) < 20 mcg/L Iron deficiency: Search for occult gastrointestinal blood loss with endoscopy or imaging assess-ments in adults; refer to gastroenteroliogist.(39), (40)
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|Article Type:||Disease/Disorder overview|
|Date:||Sep 1, 2014|
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