: The Permanente Journal FYI-----hemochromatosis

[Guest guest]

Clinical FeaturesIts broad clinical spectrum is part of the reason why hemochromatosis is so infrequently diagnosed: Each of its manifestations has other, more common explanations. Indeed, to cardiologists, hemochromatosis is unexplained cardiomegaly; to orthopedists, it is a need for hip replacement; to gynecologists, it is infertility; to urologists, impotence; and to family practitioners, the disease is identified as fatigue with depression. The situation is reminiscent of a fable: three blind men each try to identify an elephant by feeling a different part of the creature, thereby missing its essence. Dr. Funke's case illustrates this point. Notwithstanding the need to understand hemochromatosis in its totality, for purposes of discussion the diverse clinical features of this disease are conveniently grouped by organ system affected.

MusculoskeletalUnlike the description of the "classic triad," arthralgia is the most common symptom of hemochromatosis. However, nothing is distinctive about this symptom. Arthritis is common and often misdiagnosed as seronegative rheumatoid arthritis. A pattern of arthritis involving the metacarpophalangeal and proximal interphalangeal joints of the second and third fingers suggests hemochromatosis.14 However, its appearance can be indistinguishable from osteoarthritis, gout, or pseudogout. In addition, because iron overload disease underlies many cases of chondrocalcinosis, a radiographic finding of chondrocalcinosis should prompt evaluation for hemochromatosis.15 Occasionally, joint cartilage is rust-colored, but this finding is not specifically diagnostic. Many persons having joint replacement, particularly at younger ages, have hemochromatosis that remains unrecognized. The KPSD orthopedics department is currently collaborating with our clinic in an effort to determine the prevalence of hemochromatosis appearing initially as arthritis requiring joint replacement.

Typically, phlebotomy does not improve the arthritic symptoms of hemochromatosis; they sometimes worsen despite phlebotomy, illustrating the importance of diagnosing and treating hemochromatosis in its presymptomatic stage. However, Cutler16 has described great improvement of arthritic symptoms from use of deferoxamine. Many agree that arthritic symptoms can be reliably prevented if phlebotomy is done before their onset. However, much remains to be learned about the arthritis of hemochromatosis: Crosby17 pointed out that arthritis was not described as a complication of this disease before 1962. Moreover, the detailed monograph by Sheldon3 reported no cases of arthritis among 311 untreated, advanced cases of hemochromatosis, although joints were examined grossly and microscopically. The implications of this are unclear but suggest that some other factor, possibly dietary, may help to explain the current prevalence of arthritis in hemochromatosis. The videotape, "Hemochromatosis in Orthopedics and Rheumatology," illustrates the experience of four KPSD members who have hemochromatosis with extensive skeletal involvement.18

GastrointestinalAlthough hemochromatosis is typically conceived as a hepatic disorder, the classic triad of cirrhosis with darkened skin and diabetes actually defines an uncommon combination found only in advanced disease; the diagnosis of hemochromatosis is thus usually overlooked. Hepatomegaly is common in hemochromatosis, but transaminase values are frequently normal in uncomplicated disease, particularly if the patient's medical history does not include alcoholism or hepatitis B or C. Indeed, as Dr. Funke's case illustrates, normal liver enzyme levels do not preclude the need to consider hemochromatosis as a possible diagnosis.

In hereditary hemochromatosis, iron accumulates distinctively in periportal hepatocytes. By contrast, in secondary hemochromatosis (eg, resulting from transfusional iron overload or thalassemia), macrophages process out large numbers of red blood cells, and iron is deposited in the reticuloendothelial macrophages (which, in the liver, are termed Kupffer cells). Those cases of alcoholic cirrhosis in which minor deposits of iron are found in the hepatocytes could be due to the confounding influence of a coincident heterozygous state for hemochromatosis. When other processes like alcoholism or chronic hepatitis are present with hemochromatosis, the threshold for cirrhosis is lowered.

Once viewed as the standard procedure for diagnosing hemochromatosis, liver biopsy is increasingly being seen as unsuitable for this purpose because its results are frequently normal at early stages of the disease. Heavily iron-laden liver specimens taken at biopsy certainly provide meaningful information for diagnosing iron overload disease; however, as the pathophysiology of hemochromatosis shows, the earlier a biopsy is done in the disease, the more likely are the results to be normal or equivocal. For instance, half of liver biopsies done in presymptomatic cases have shown normal results. Even in symptomatic cases, about 8% of liver biopsies do not produce diagnostic results (ie, grade 3 or 4 when Perls' stain is used).19 Thus, liver biopsy results and their derivative measures (eg, the Hepatic Iron Index) are often misleadingly normal at precisely the stages of hemochromatosis where therapeutic opportunity is greatest.

The same logic applies to use of magnetic resonance imaging (MRI) and magnetic susceptometry (SQUID) to evaluate liver iron stores because these techniques also show normal stores of iron in the liver early in the disease. No matter how sophisticated the approach, any diagnostic technique focused on liver iron stores is limited to diagnosis of advanced cases only; worse yet, early cases will predictably be missed. On the other hand, because hepatoma is a potential outcome of untreated hemochromatosis, those who favor liver biopsy argue that it has a role in demonstrating cirrhosis with its implications for development of hepatocellular carcinoma. Others see little purpose in attempting this prediction.

Splenomegaly occurs in hemochromatosis and should suggest that disease as a possible diagnosis. Abdominal pain is common in hemochromatosis: the pain is often located low in the abdomen, suggesting mechanisms other than simple stretching of Glisson's capsule. Chronic diarrhea also occurs commonly in hemochromatosis and has an episodic quality that is easily confused with irritable bowel syndrome.

EndocrineThe endocrine manifestations of iron overload are all disorders of hypofunction. Excess iron deposited selectively in the pituitary gland causes gonadal failure (hypogonadotrophic hypogonadism): impotence and bilateral testicular atrophy occur in men, whereas menstrual irregularity, infertility, and premature menopause occur in women. Both sexes commonly manifest loss of axillary, pubic, and limb hair. Secondary osteoporosis can also be expected. Hypothyroidism is more common in iron overload disease than in the general population and results from end organ fibrosis and thyroid autoantibodies.20 By contrast, hyperthyroidism has sometimes provided false evidence of hemochromatosis by causing elevated iron saturation and serum ferritin levels.21 Iron overload disease has rarely been reported to cause hypoparathyroidism22 and adrenal failure.23

If deposited in the pancreas, excess iron induces diabetes mellitus. Conflicting reports on the prevalence of iron overload disease in diabetes probably reflect the stage at which hemochromatosis was diagnosed: late (ie, because suggested by clinical appearance) or early (eg, through screening). Neither Type 1 nor Type 2 diabetes characterizes the diabetes mellitus seen in hemochromatosis; multiple causative mechanisms seem possible, perhaps depending on the stage of the disease.24 Early treatment of hemochromatosis has been shown to reverse some cases of diabetes.25 In addition, treatment with deferoxamine greatly improved glycemic control in some cases of hyperferritinemic diabetes.26 Hemochromatosis should be treated early to prevent diabetes, and all diabetic patients should be screened once for underlying iron overload disease.

CardiacBoth the conduction and the pumping systems of the heart can be damaged by iron overload. Cardiomegaly, bradycardia, arrhythmia, and congestive heart failure result. Cardiomyopathy of hemochromatosis may be either dilated or restrictive and is usually alleviated greatly by phlebotomy. Iron overload is therefore an important diagnosis to consider for all patients who have cardiomyopathy, congestive heart failure,27 atrial fibrillation, or nonathletic bradycardia. When hemochromatosis manifests in adolescence, as it occasionally does, the heart is the organ most affected--and cardiac death from arrhythmia or congestive heart failure is the typical outcome. Such an adolescent case with cardiac death is illustrated in our videotape, "Hemochromatosis at Autopsy: A Mother's Story."28 What portion of cases of "idiopathic cardiomyopathy" actually represent undiagnosed hemochromatosis is yet to be determined. Cardiomyopathy and arrhythmia are well-documented outcomes of iron overload,27 but a currently contested hypothesis proposes that elevated iron stores are related to coronary artery disease in heterozygotes.29-31

HematologicContrary to popular expectation, anemia can result from iron overload. This point is important to remember lest a patient's anemia lead the physician to avoid diagnostic consideration of hemochromatosis. Indeed, many cases of iron overload disease are worsened by repeated prescription of ferrous sulfate for nonresponsive forms of anemia caused by unrecognized hemochromatosis. In this anemia, which typically resolves as iron is removed from the patient, excess iron causes toxic suppression of marrow function. We recently treated a middle-aged KPSD member whose hematocrit level rose from 32 to 43 as 40 units of blood were removed! Marrow iron stores correlate poorly with total body iron and may be low in presence of major iron overload; marrow examination is therefore not diagnostically helpful.

DermatologicSkin changes (classically described as bronzing) are most readily recognized as axillary tanning, which occurs at a relatively late stage in the disease. Two mechanisms are involved: 1) iron stimulates melanin, producing a tan color, and 2) direct iron deposition adds a greyish hue. Loss of body hair (already described here as an endocrine process) is another dermatologic effect. An uncommon blistering lesion of areas exposed to sunlight, porphyria cutanea tarda, is associated with underlying iron overload as well as with chronic hepatitis C. Porphyria cutanea tarda responds well to treatment of the underlying iron overload.32 All patients with porphyria cutanea tarda should be tested for hemochromatosis, and all patients with hemochromatosis should be examined for presence of photosensitive, vesiculating dermatitis.

NeuropsychiatricThe biomedical literature contains little discussion of nervous system effects caused by systemic iron overload disease. However, clinical depression that is out of character for the individual occasionally occurs and is reversed by phlebotomy.33 Mild dementia not confounded by coincident alcoholism or liver failure may develop rapidly and is reversed by phlebotomy.34 Profound fatigue, too, may develop suddenly and is reversed by phlebotomy.34 The brain in hemochromatosis contains a large amount of iron, and a prominent neuropeptide-like distribution pattern of transferrin receptors in the brain suggests that transferrin may have a neuromodulating function.35 Deafness is well known to be associated with hemochromatosis.3 Less clear is whether peripheral neuropathy, in the absence of diabetes, and tinnitus are also associated with hemochromatosis.

Infection and MalignancyHemochromatosis lowers the threshold for development of chronic active viral hepatitis, whose coincidence with iron overload disease is distinctly higher than expected. Any patient with this condition should therefore be screened for hemochromatosis. In addition, reduction of iron levels in chronic hepatitis C might improve the effectiveness of interferon treatment. Patients with Vibrio vulnificus, Listeria monocytogenes, and Yersinia infections should also be screened for hemochromatosis because iron overload predisposes patients to infection by these organisms.36-38 Hepatoma, too, is well known to have higher prevalence in hemochromatosis.39

Comparison of Diagnostic MethodsSaturation of TIBCCurrently, hemochromatosis is most reliably diagnosed by "transferrin saturation" testing, which costs only about $2 per test and is required only once per lifetime. The test, which indicates whether excess iron is being absorbed, gives reliable results for patients aged 1 year but not for neonates.39 For both sexes, excess iron absorption is suggested by >50% saturation in randomly drawn specimens. Some researchers have recommended a threshold of 55% saturation for men, but 8% of our homozygous male patients with hemochromatosis would have received misdiagnoses if the higher value had been selected as the diagnostic. To assure a reliable conclusion free of confounding influences, any initial test showing elevated iron levels should be repeated after the patient has fasted overnight and consumed no vitamin or mineral supplements for at least 24 hours; vitamin C (ascorbic acid) supplementation is particularly responsible for raising serum iron levels (especially in heterozygotes) because it increases intestinal absorption and releases iron from ferritin. Moreover, diurnal transferrin saturation levels vary: fasting morning specimens have higher saturation. Our experience with tens of thousands of randomly drawn specimens shows that 2.5% of KPSD members have saturation 50% at initial random testing, whereas the rate of abnormal results drops to 0.4% for patients who are retested after they have fasted overnight and ingested no dietary supplements for at least 24 hours. Fasting saturation values persistently >62% are highly likely to indicate hemochromatosis.

Illness, infection, and other factors can alter serum iron levels or TIBC, but these alterations balance each other, causing transferrin saturation to remain relatively unaffected.

Serum Ferritin LevelMeasurement of serum ferritin level gives useful--though imperfect--estimates of total body load but is not as useful as serum iron saturation for screening hemochromatosis. For instance, serum ferritin levels remain normal in all patients at the early stages of hemochromatosis, whereas serum ferritin levels are commonly elevated in alcoholism and in unrecognized chronic hepatitis--conditions which routine testing has shown to be more common than we may think. Infrequently, serum ferritin level is normal in symptomatic iron overload disease, possibly indicating increased density of iron packing in the ferritin latticework.40

Liver Biopsy and Other Tests http://www.kaiserpermanente.org/medicine/permjournal/winter99pj/winter99pjhemochromatosis.html

Webb Osterlohgroup co-owner http://groups.yahoo.com/group/The_Thyroid_Support_Group/ATP Board Member,Thyroid Patient Advocate