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Hereditary Hemochromatosis: Early Detection of a Common Yet Elusive Disease


Although widely regarded as a raredisorder, hereditary hemochromatosisis the most common genetic disease inCaucasians. In certain populations ofnorthern European descent, 1 of every200 persons is homozygous for thecausative mutation.1

Although widely regarded as a raredisorder, hereditary hemochromatosisis the most common genetic disease inCaucasians. In certain populations ofnorthern European descent, 1 of every200 persons is homozygous for thecausative mutation.1

Hereditary hemochromatosis isalso the most common cause of primaryiron overload. Persons with thisdisease are predisposed to absorb excessiron from the GI tract; the excessiron deposits in the parenchyma of organsand produces such clinical manifestationsas diabetes, cirrhosis, andheart failure. (In secondary iron overload,excess iron results from cirrhosis,sideroblastic anemias that cause ineffectiveerythropoiesis, multiple transfusions,or other exogenous sources.)

The diagnosis is frequently overlookedbecause:

  • Affected patients may have no obvioussymptoms.
  • The clinical manifestations are protean;they include osteoarthritis (OA)and diabetes.
  • Hereditary hemochromatosis is oftennot considered in the differentialdiagnosis because of its perceivedrarity.

Early diagnosis is crucial--beforeirreversible tissue damage occurs.Here, I highlight the symptoms, laboratoryresults, and biopsy findings thatsuggest hereditary hemochromatosis,even in its early stages. I also outline atreatment approach and explore thepros and cons of screening.

In North America, it has been estimatedthat a physician will see a patientwith hereditary hemochromatosisapproximately every 3 weeks.2 Thisestimate may be conservative.

In population studies, the prevalenceof hereditary hemochromatosisis surprisingly high. Of 16,031 asymptomaticpatients from 22 ambulatorypractices in Rochester, NY, who werescreened with iron studies, 25 hadbiopsy-proven hereditary hemochromatosis.Another 22 patients met clinicalcriteria for the disease but declinedbiopsy.3 The prevalence was 4.5 per1000 patients, which is consistent withthe known frequency of the hereditaryhemochromatosis mutation. Routinescreening of the general population forhereditary hemochromatosis is controversial(Box).

How does the prevalence ofhereditary hemochromatosis comparewith that of a relatively common entitysuch as iron deficiency anemia? In aWest German study, 3027 outpatientsand 3012 employees of industrial companieswere screened for both conditions.4 All participants were asymptomatic.Among the outpatients, 1.6%of the men had hemochromatosis, andonly 1.5% had iron deficiency anemia.In the employee group, 1% of the menhad hemochromatosis, and only 0.3%had iron deficiency anemia. Amongthe women, iron deficiency was morecommon than iron overload; however,1.9% of the female outpatients and1.1% of the female employees hadhemochromatosis.

These 2 studies included onlyasymptomatic patients. Populationstudies in patients with disorders thatmight be related to iron overload revealan even greater prevalence ofhereditary hemochromatosis. For example,the prevalence may be as highas 5% in patients with peripheral arthritis,6% in those with chronic liver diseaseor cirrhosis, and 15% in thosewith hepatocellular carcinoma.5

When persons with 2 or more disordersthat may be related to iron excessare screened, the prevalence ofhereditary hemochromatosis skyrockets.Persons with both liver diseaseand diabetes are 43 times more likelyto have hereditary hemochromatosisthan are those with neither disease.Patients who have diabetes and liverneoplasia are 83 times more likely tohave hereditary hemochromatosis.6

During the past decade, the candidategene for hemochromatosis wasidentified. The gene is found on chromosome6 and encodes a major histocompatabilitycomplex class I-likeprotein that, like a typical HLA molecule,spans cell membranes. Becauseof this similarity, the gene was initiallynamed HLA-H, but was later renamedHFE.7 Although the HFE protein isfound in many human cells, it is mostabundant in the duodenum--whichsuggests a prominent role in the absorptionof iron. The mechanism bywhich HFE regulates iron absorptionis not fully understood. Studies withmonoclonal antibodies have also confirmedthe presence of the protein incrypt cells, where it is associated withthe transferrin receptor.8

Major mutation. Two missensemutations of the HFE gene play an importantrole in hereditary hemochromatosis.The major HFE mutation,C282Y, results in a cysteine to tyrosinechange at amino acid 282. Dependingon the population studied, between69% and 100% of patients with hemochromatosisexhibit this majormutation on both chromosomes in apair--that is, are homozygotes.7,9-11This is a significant percentage; of Caucasianpatients who have cystic fibrosis,for example, only 70% exhibit themost common mutation associatedwith that disease (CFTR, or delta 508mutation). It is estimated that 1 in 385Americans is homozygous for themajor mutation associated with hereditaryhemochromatosis (C282Y).12

Minor mutation. Another significantmutation, the "minor mutation,"or H63D, also has a role in some patients.Between 4% and 7% of patientswith hereditary hemochromatosis arecompound heterozygotes (personswho exhibit both C282Y and H63Dmutations).7,11,13 Nearly 1 in 50 Americansmay be a compound heterozygote.12 "Simple" heterozygotes (patientswho have either the C282Y orH63D mutation but not both) may accountfor 3% to 4% of cases of hereditaryhemochromatosis; these patientsmay have other HFE mutations aswell.13,14 However, iron overload rarelydevelops in simple heterozygotes unlessthey have another concurrentliver disease.

Although the HFE gene plays animportant role in hemochromatosis,this role is still not clearly understoodor well-defined. Up to 7% of patientswith hereditary hemochromatosis exhibitneither the major nor the minorHFE mutation.9,13,15 Moreover, somepatients who are homozygous for themajor mutation or who are compoundheterozygotes have no clinical or biochemicalevidence of iron overload.Thus, environmental or other geneticinfluences also appear to have a role inthe disease.1

Most patients with hereditary hemochromatosisdo not present withthe classic finding of "bronze diabetes,"which is a late manifestation ofthe disease; many have nonspecificsymptoms. The 3 most common complaintsare fatigue, arthralgia, and libidoloss.16 Symptoms are often attributedto other diseases or to functionalentities and are usually present for anaverage of 10 years before a diagnosisis made.

GI system. Hereditary hemochromatosiscommonly involves theGI system; the liver is most frequentlyaffected. Excess iron deposits, inthe form of ferritin and hemosiderin,cause hepatomegaly and ultimatelylead to fibrosis and cirrhosis. Patientsmay present with abdominal pain,particularly in the right upper quadrant.Aminotransferase levels are typicallyelevated. However, only 60% ofpatients with hereditary hemochromatosishave abnormal liver functiontest results at the time of diagnosis,17so normal results cannot reliably excludethe disease. Ultimately, cirrhosisand its attendant problems, suchas varices and ascites, develop in untreatedpatients. Hepatocellular carcinomais one of the most serious complicationsof hemochromatosis and isa frequent cause of death.

Musculoskeletal system. Morethan 50% of patients with hereditaryhemochromatosis have musculoskeletalcomplaints; arthralgia is themost common of these symptoms.The arthritis of hereditary hemochromatosisresults from calcium pyrophosphatedeposition in the joints.The joints most frequently involvedare the wrists, distal interphalangeals,and metacarpals (particularly the secondand third); however, it is not un-usual to see knee, hip, or even shoulderarthritis.

Radiographic findings are similarto those of OA--joint-space narrowing,subchondral cysts, and sclerosis.Sometimes distinctive hook-like orbeak-like osteophytes are seen on theradial aspects of the metacarpal heads.Despite the fact that the radiographicfindings mimic those of classic OA,osteoarthritic changes in the metacarpalsand wrist joints are rarely seen.Thus, OA in unusual sites, such as thewrist, elbow, or ankle, is a clue to hereditaryhemochromatosis--especiallywhen there is no history of traumato these joints.

Another clue that suggests hereditaryhemochromatosis is OA in largenon-weight-bearing joints--particularlythe shoulder--when there is no historyof trauma. Patients in whomarthritis develops before age 50 years,especially those who require early jointreplacement, may also have underlyinghereditary hemochromatosis.

Finally, hereditary hemochromatosisshould be included in the differentialdiagnosis of unexplainedchondrocalcinosis.

Cardiovascular system. Cardiacmanifestations occur in about 15% of affectedpatients. Bradyarrhythmias arecommon; of patients who have thesearrhythmias, up to 2% have underlyinghereditary hemochromatosis.18 Diastolicdysfunction with restriction occursearly in the disease; systolic dysfunctionwith dilated cardiomyopathyoccurs later.19

Up to 5% of patients referred toThe Johns Hopkins Hospital for "idio-pathic" cardiomyopathy had previouslyundiagnosed infiltrative diseasesof the heart, including hereditaryhemochromatosis.20 Considerroutinely testing patients with heartfailure for hereditary hemochromatosisonce you have excluded ischemiaand other obvious causes. Congestiveheart failure (CHF) is a commoncause of death in patients who havehereditary hemochromatosis.

Endocrine system. Endocrineproblems are also common in patientswith hereditary hemochromatosis.These include decreased libido(one of the most common complaints),erectile dysfunction,testicular atrophy, amenorrhea, sterility,and even osteoporosis secondaryto gonadal failure. Such problems aremost likely the result of hypogonadotrophichypogonadism causedby iron deposition in the pituitarygland; patients have low or normalfollicle-stimulating hormone andluteinizing hormone levels with lowsex hormone levels.

Diabetes mellitus occurs in up to50% of symptomatic patients withhereditary hemochromatosis.17Hyperglycemia results from iron depositionin pancreatic parenchymaand seems to be selective for the pancreaticbeta cell.

Other endocrine problems includehypoparathyroidism and adrenalinsufficiency secondary to infiltrativedisease. Hypothyroidism canalso occur; iron deposits cause glandfibrosis.

Figure 1

Skin. The classic dermatologicpresentation--hyperpigmentation--isseen late in the course of hereditaryhemochromatosis (Figure 1). Hemosiderindeposition and direct iron stimulationof melanocytes result in darkeningof the skin.21 Although the classicdescription of this phenomenon isbronzing, in early stages it resemblestanning.

Nervous system. Neuropsychiatricsymptoms can also occur; depressionis the most common. In patientswith advanced hereditary hemochromatosis,a dementia-like illness and peripheralneuropathy have been seen.

Immune system. Affected patientsare more susceptible to severeVibrio, Yersinia, and Listeria infections.22 The increased susceptibilityprobably results from the increasedavailability of iron for the bacteria'smetabolism.

DIAGNOSTIC TESTSTransferrin saturation. The firstphenotypic expression of the disease isan elevated transferrin saturation (TS).(To calculate TS, divide the serum ironlevel by the total iron-binding capacity.)An elevated TS correlates with increasedGI iron absorption. A commonmisconception is that measurement offerritin or serum iron is the most appropriatescreening test for hereditaryhemochromatosis. However, ferritinlevels rise only after parenchymal cellsare overloaded. Asymptomatic patientsor those with arthralgia or other earlysymptoms may have normal serumferritin levels.


I consider any TS greater than 45%as indicative of hereditary hemochromatosis.Different authorities use differentcutoffs. The problem with usinghigher cutoffs is that you may miss disease;using lower cutoffs results in morefalse-positive readings.23

A random blood sample may beused for the initial TS; however, if thispercentage is high, obtain a second TSlevel after fasting. Iron levels are highestafter meals; thus, a postprandial TSlevel may be falsely elevated. If the second(fasting) TS is elevated, measurethe serum ferritin level and test for theHFE mutation (Algorithm).

Serum ferritin. Ferritin levelsgreater than 300 μg/L (200 μg/L forpremenopausal women) are suspect.However, ferritin is an acute phase reactantand may be elevated because ofan unrelated systemic inflammatoryprocess. Ferritin concentration is alsoincreased in other liver diseases, suchas chronic viral hepatitis, alcoholicliver disease, and nonalcoholic steatohepatitis.Genetic testing may helpclarify the source of iron overload.

HFE mutations. Biochemicalevidence of iron overload along withC282Y homozygosity confirms thediagnosis of hereditary hemochromatosis.If a homozygous patient hasa normal serum ferritin level but anelevated fasting TS, two explanationsare possible. The patient may have afrustrated (clinically nonpenetrant)form of hereditary hemochromatosis,and clinical manifestations of the diseasemay never develop. Alternatively,the patient may be in an earlystage of the disease, in which caseperiodic ferritin monitoring is required.Once the ferritin level reachesa critical threshold (300 μg/L, or200 μg/L for premenopausal women),treatment can be started. Becauseit is impossible to distinguishbetween these 2 forms of the disease,ferritin levels must be monitoredindefinitely.

Liver biopsy. Results help you ruleout other causes of liver disease. Also,in the absence of known causes of secondaryiron overload, the diagnosis ofhereditary hemochromatosis is confirmedwhen at least one of the followingcriteria is met:

  • Hepatic iron concentration of morethan 71 μmol/g.
  • Hepatic iron index (HII) of 1.9 orgreater. The HII is calculated by dividingthe hepatic iron concentration (expressedin μmol/g) by the patient'sage in years. The 1.9 cutoff helps distinguishalcohol-related and othertypes of liver disease from hereditaryhemochromatosis.24

The HII is not a perfect indicator;if a patient with hereditary hemochromatosisloses iron because of GI bleeding,the value may drop below 1.9.However, genetic testing has made itpossible to diagnose this condition inpatients whose index is between 1.5and 1.9 (for example, by differentiatingbetween heterozygotes and homozygoteswho had donated blood).

Figure 2

Figure 3

The location of hepatic iron onlight microscopy also aids in the diagnosisof hereditary hemochromatosis.When iron overload results from a secondarycause, iron tends to accumulatein macrophages or Kupffer cells,and thus appears in the liver sinusoids(Figure 2). If a patient demonstratesiron accumulation of this type, it isprobably not necessary to quantitatethe hepatic iron concentration and calculatethe HII. The excess iron that resultsfrom hereditary hemochromatosisaccumulates mostly in the periportalhepatocytes and generally sparesthe sinusoids (Figure 3).

A genetic test for C282Y homozygositymay obviate the need for liverbiopsy in patients whose TS and ferritinlevels are consistent with the diagnosis.If the patient has normal liverfunction tests, normal liver size, aserum ferritin level less than 1000μg/L--and is homozygous--cirrhosisis extremely unlikely.25 Heterozygotesare at lower risk for iron overload thanhomozygotes; in fact, liver diseasecaused solely by hereditary hemochromatosisis rare in heterozygotes.26 Investigate concomitant causesof liver disease--such as hepatitisC--in heterozygous patients.

Liver biopsy can be used prognosticallyas well as diagnostically. Ifcirrhosis is found, aggressive screeningfor hepatocellular carcinoma iswarranted.

Table – Results of phlebotomy
Problems improved by phlebotomy

Problems not improved by phlebotomy

TREATMENTPhlebotomy. The most widelyused treatment is therapeutic phlebotomy,which is safer, more effective,and less expensive than chelation. Thelatter is used only in patients who cannottolerate or who refuse blooddraws. Although many problems relatedto hereditary hemochromatosiscan be reversed by phlebotomy, severalare irreversible (Table).

Initiate phlebotomy when theserum ferritin level is greater than 300μg/L (200 μg/L for premenopausalwomen). Do not delay treatment untilsymptoms develop, because symptomscorrelate with organ damage.Draw 1 unit of blood per week untilmild hypoferritinemia occurs (approximately10 μg/L to 20 μg/L). Patientswith a high body mass index may toleratehaving up to 2 units drawn weekly,while frail or elderly patients maytolerate the drawing of only half a unitper week. Continue phlebotomy forthe patient's lifetime, with a ferritingoal of less than 50 μg/L.27 After thetarget level has been achieved, phlebotomiesmay be needed only 2 to 6times per year.21

Dietary restrictions and othermeasures. Adherence to dietaryguidelines is important. Patients withhereditary hemochromatosis need tolimit their intake of red meat becauseit is one of the richest sources ofbioavailable iron. Although avoidingiron supplements seems obvious, remindpatients that most multivitaminscontain at least some iron. Vitamin Csupplements must also be limited becauseascorbic acid increases intestinaliron absorption. Abstaining fromalcohol is crucial for those with hepaticdisease. Have patients avoid shellfish,or at least cook it thoroughly; severalfatal cases of Vibrio vulnificus infectionhave been reported in patientswith hereditary hemochromatosiswho ate contaminated seafood.22

Finally, vaccinate all patients withhereditary hemochromatosis againsthepatitis A and B if they are not alreadyimmune.

Expected outcomes. Decreasingand maintaining iron stores atnearly normal levels through phlebotomysignificantly improves the lifeexpectancy of patients with hereditaryhemochromatosis. With therapy,5-year survival increases from roughly30% to nearly 90%. Furthermore,life expectancy is normal if patientsbegin treatment before the developmentof cirrhosis or cardiomyopathy.28 In untreated patients, CHF andhepatocellular carcinoma are themost frequent causes of death.


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26. Bulaj ZJ, Griffin LM, Jorde LB, et al. Clinicaland biochemical abnormalities in people heterozygousfor hemochromatosis. N Engl J Med. 1996;335:1799-1805.
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