Ann Hematol. 2005 Jun;84(6):347-52. Epub 2005 Mar 4.
Recent advances in hereditary hemochromatosis.
Franchini M, Veneri D.
Servizio di Immunoematologia e Trasfusione, Azienda Ospedaliera di Verona, Verona, Italy.
Hereditary hemochromatosis, a very common genetic defect in the Caucasian population, is characterized by progressive tissue iron overload which leads to irreversible organ damage if it is not treated in a timely manner. Recent developments in the field o f molecular medicine have radically improved the understanding of the physiopathology and diagnosis of this disease. However, transferrin saturation and serum ferritin are still the most reliable tests for identifying subjects with hereditary hemochromato sis. Therapeutic phlebotomy is the mainstay of the treatment of this disease and the life expectancy of these patients is similar to that of the normal population if phlebotomy is started before the onset of irreversible organ damage. In this review we di scuss the genetics, pathophysiology, diagnosis, clinical features, and management of hereditary hemochromatosis.
N Engl J Med. 2005 Apr 28;352(17):1769-78.
Comment in: N Engl J Med. 2005 Apr 28;352(17):1741-4.
Hemochromatosis and iron-overload screening in a racially diverse population.
Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C, Speechley M, Snively BM, Holup JL, Thomson E, Sholinsky P; Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators.
Department of Medicine, London Health Sciences Centre, London, Ont, Canada. email@example.com
BACKGROUND: Iron overload and hemochromatosis are common, treatable conditions. HFE genotypes, levels of serum ferritin, transferrin saturation values, and self-reported medical history were studied in a multiethnic primary care population. METHODS: Parti cipants were recruited from primary care practices and blood-drawing laboratories. Blood samples were tested for transferrin saturation, serum ferritin, and C282Y and H63D mutations of the HFE gene. Before genetic screening, participants were asked whethe r they had a history of medical conditions related to iron overload. RESULTS: Of the 99,711 participants, 299 were homozygous for the C282Y mutation. The estimated prevalence of C282Y homozygotes was higher in non-Hispanic whites (0.44 percent) than in Na tive Americans (0.11 percent), Hispanics (0.027 percent), blacks (0.014 percent), Pacific Islanders (0.012 percent), or Asians (0.000039 percent). Among participants who were homozygous for the C282Y mutation but in whom iron overload had not been diagnos ed (227 participants), serum ferritin levels were greater than 300 mug per liter in 78 of 89 men (88 percent) and greater than 200 microg per liter in 79 of 138 women (57 percent). Pacific Islanders and Asians had the highest geometric mean levels of seru m ferritin and mean transferrin saturation despite having the lowest prevalence of C282Y homozygotes. There were 364 participants in whom iron overload had not been diagnosed (29 C282Y homozygotes) who had a serum ferritin level greater than 1000 microg p er liter. Among men, C282Y homozygotes and compound heterozygotes were more likely to report a history of liver disease than were participants without HFE mutations. CONCLUSIONS: The C282Y mutation is most common in whites, and most C282Y homozygotes have elevations in serum ferritin levels and transferrin saturation. The C282Y mutation does not account for high mean serum ferritin levels and transferrin saturation values in nonwhites. Copyright 2005 Massachusetts Medical Society.
Eur J Echocardiogr. 2004 Oct;5(5):356-66.
Biventricular diastolic behaviour in patients with hypertrophic and hereditary hemochromatosis cardiomyopathies.
Palka P, Lange A, Atherton J, Stafford WJ, Burstow DJ.
St Andrew's Heart Institute, Brisbane, Queensland, Australia. firstname.lastname@example.org
AIM: To define biventricular diastolic behaviour in patients with cardiomyopathies with predominant diastolic left ventricular (LV) dysfunction. METHODS AND RESULTS: Doppler tissue echocardiography and both mitral and tricuspid Doppler inflow profiles wer e investigated in hypertrophic (n = 17), hereditary hemochromatosis (n = 12) cardiomyopathies and age-matched normals (n = 31). The cardiomyopathy group had both lower early diastolic mitral lateral annular (El), cm/s (13.9 +/- 6.5) and medial (Em) (10.0 +/- 4.5) velocities compared with normals (19.5 +/- 5.5, 15.9 +/- 3.4, p < 0.01, respectively). In the cardiomyopathy group, late isovolumic relaxation myocardial velocity gradient (IVR-MVG) (s(-1)) was positive compared with negative in normals (1.3 +/- 1.3 vs. -0.7 +/- 1.4, p < 0.01, respectively). In both the cardiomyopathy group and in normals the onset of the tricuspid E-wave preceded the onset of the mitral E-wave. However, the onset of early diastolic tricuspid annular (Et) motion preceded the onse t of El (ms) only in normals, but not in the cardiomyopathies (43 +/- 26 vs. -8 +/- 44, p < 0.01, respectively). In the cardiomyopathy group there was a positive correlation between the onset of Et and abnormally positive late IVR-MVG (r = 0.51, p = 0.002 ). CONCLUSIONS: Biventricular early diastolic behaviour is abnormal in the selected group of cardiomyopathy patients. The delay in the Et (early diastolic longitudinal right ventricular relaxation) may have a negative effect on LV diastolic function.
J Am Soc Echocardiogr. 2002 Sep;15(9):884-90.
The role of Doppler left ventricular filling indexes and Doppler tissue echocardiography in the assessment of cardiac involvement in hereditary hemochromatosis.
Palka P, Macdonald G, Lange A, Burstow DJ.
Department of Echocardiography, The Prince Charles Hospital, The University of Queensland, Brisbane, Australia. email@example.com
Although cardiac dysfunction in hereditary hemochromatosis (HHC) can be evaluated by conventional echocardiography, findings are often not specific. To test the hypothesis that the assessment of (1) conventional Doppler left ventricular filling indexes an d (2) intrinsic elastic properties of the myocardium by Doppler tissue echocardiography can both enhance the accuracy of echocardiographic diagnosis of cardiac involvement in HHC, a group of 18 patients with HHC (mean age 50 +/- 17 years) and 22 age-match ed healthy subjects were studied. The following indexes were characteristic for HHC: (1) the duration of atrial reversal measured from pulmonary venous flow (ms) was longer (118 +/- 20 vs 90 +/- 16; P <.001); (2) systolic lateral mitral, early-diastolic m edial mitral, and early-diastolic lateral tricuspid annular velocities were reduced by 23%, 31%, and 13%, respectively; (3) late-diastolic mean myocardial velocity and myocardial velocity gradient (MVG) were also reduced by 22% and 34%, respectively. Late -isovolumic relaxation (late-IVR) MVG (s(-1)) was positive in HHC as opposed to negative in healthy subjects (1.72 +/- 0.85 vs -0.89 +/- 1.15; P <.001) indicating impaired early-diastolic subepicardial relaxation in HHC. The assessment of atrial reversal flow duration, the difference in duration between A-wave and atrial reversal flow, and the presence of positive late IVR-MVG findings were the most accurate variables to differentiate patients with HHC from healthy subjects (80%, 67%, 94% sensitivity and 90%, 95%, 86% specificity, respectively).
Am Heart J. 2001 Mar;141(3):428-34.
Right ventricular diastolic function in beta-thalassemia major: echocardiographic and clinical correlates.
Hahalis G, Manolis AS, Gerasimidou I, Alexopoulos D, Sitafidis G, Kourakli A, Korfer R, Koerner MM, Vagenakis AG, Zoumbos NC.
Divisions of Cardiology and Hematology, Department of Internal Medicine, Patras University Medical School, Rio, Patras, Greece.
BACKGROUND: Cardiac hemochromatosis remains the most frequent cause of death in beta-thalassemia major. Previous studies suggest an important right ventricular (RV) contribution to cardiac morbidity and mortality. Studies with Doppler echocardiography hav e shown contradictory results regarding left ventricular (LV) filling, whereas the RV filling characteristics have not been studied yet. We prospectively studied the pattern of RV filling and investigated echocardiographic and clinical correlates during b aseline and follow-up examinations in patients with beta-thalassemia major. METHODS AND RESULTS: The study included 79 patients, aged 24.2 +/- 8.0 years, with homozygous beta-thalassemia major without symptoms of heart failure with normal LV function and 51 healthy control subjects, matched for age, sex, and body surface area. Doppler echocardiographic indexes of systolic and diastolic ventricular function were assessed. Hemodynamic measurements were obtained in 8 patients by right heart catheterization. An abnormal RV relaxation pattern was evident in the patient group. The LV filling characteristics indicated increased preload without abnormal alteration, whereas catheterization findings were consistent with a high cardiac output state. Short tricuspid deceleration time (DT) had the best predictive value for subsequent cardiac events. Repeat echocardiographic study in 35 asymptomatic patients at 19 +/- 7 months demonstrated deterioration of LV systolic function, chamber enlargement, and shortening of DT of tricuspid and mitral inflow. CONCLUSIONS: In patients with homozygous beta-thalassemia major without cardiac disease, the pattern of RV filling is abnormally altered, indicating impaired relaxation. In contrast, the LV filling is compatible with incre ased preload, as in chronic anemia. Short DT of early tricuspid inflow carries important prognostic value. LV remodeling occurs over time along with transition toward a restrictive ventricular filling pattern.
Wien Klin Wochenschr. 2001 Jun 15;113(11-12):408-15.
Echocardiography in storage and neuromuscular disorders
Stollberger C, Finsterer J.
2. Medizinische Abteilung, Krankenanstalt Rudolfstiftung. firstname.lastname@example.org
Storage disorders and neuromuscular disorders may lead to cardiac involvement which can be visualized by echocardiography. In storage disorders like hypothyroidism, haemochromatosis, amyloidosis, mucopolysaccharidosis and Fabry's disease, myocardial thick ening and systolic dysfunction can be found. In amyloidosis, atrial enlargement and abnormal texture of the myocardium are additional findings. In advanced haemochromatosis all cardiac chambers may be dilated. In hypothyroidism and amyloidosis, a pericard ial effusion can be present. In haemochromatosis and amyloidosis, a restrictive filling pattern may be detected using Doppler-sonography. Mucopolysaccharidosis and Gaucher's disease may lead to aortic and mitral stenosis. In neuromuscular disorders like g lycogenosis, mitochondriopathy and myotonic dystrophy, myocardial thickening and systolic dysfunction are found, in spinal muscular atrophy myocardial thickening and in muscular dystrophy Becker/Duchenne systolic dysfunction. An abnormal myocardial textur e may be present in glycogenosis, isolated left ventricular abnormal trabeculation (ILVAT) in mitochondriopathy, myotonic dystrophy and muscular dystrophy Becker/Duchenne. Using Doppler-sonography an impaired relaxation of the left ventricle may be detect ed in mitochondriopathy, myotonic dystrophy and spinal muscular atrophy. Most of these echocardiographic findings are unspecific and may be overlooked, especially if the storage or neuromuscular disorder is yet unknown. Establishing a correct diagnosis is important, since healing or functional improvement is possible in many of these disorders.
Clin Cardiol. 2001 Apr;24(4):307-12.
Possible causes of symptoms in suspected coronary heart disease but normal angiograms.
Molzer G, Finsterer J, Krugluger W, Stanek G, Stollberger C.
Second Medical Department of Rudolfstiftung Hospital, Vienna, Austria.
BACKGROUND: In patients with suspected coronary heart disease and normal angiography, the causes of cardiac symptoms frequently remain undetermined. A correct diagnosis is desirable, however, since some of the underlying disorders may be curable, treatabl e, influence prognosis, or induce screening of the relatives. HYPOTHESIS: In such patients, the prevalence of arterial hypertension, hemochromatosis, hypothyroidism, hypoparathyroidism, tachycardiomyopathy, amyloidosis, and neuromuscular disorders as a po ssible cause for their symptoms and the seroprevalence of micro-organisms, known to cause myocardial damage, were assessed. METHODS: Consecutive patients with normal coronary angiograms were invited for two visits comprising clinical history and investiga tion, electrocardiograms, blood tests, and echocardiography. Patients were investigated neurologically if unexplained anginal chest pain or creatine kinase elevation persisted or if echocardiography showed isolated left ventricular abnormal trabeculations . RESULTS: In 71 patients (31 women, 40 men, mean age 60 years), the most common cause for cardiac symptoms was hypertension (66%), followed by neuromuscular disorders (13%), tachycardiomyopathy (9%), hypothyroidism (4%), and hemochromatosis (3%). The ser oprevalence for Chlamydia species was 90%, Helicobacter pylori 70%, Chlamydia pneumoniae 63%, Borrelia burgdorferi sensu lato 15%, and Rickettsia conorii 10%. No possible cause was found in 24% of the patients. CONCLUSIONS: In patients with suspected coro nary heart disease and normal angiograms, hypertension, neuromuscular disorders, tachycardiomyopathy, hypothyroidism, and hemochromatosis should be considered as possible causes.
J Interv Card Electrophysiol. 1999 Oct;3(3):225-9.
Syncope and inducible ventricular fibrillation in a woman with hemochromatosis.
Strobel JS, Fuisz AR, Epstein AE, Plumb VJ.
Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. email@example.com.
BACKGROUND: Hemochromatosis has been associated with atrial tachyarrhythmias and congestive heart failure as a consequence of dilated or restrictive cardiomyopathy. Inducible ventricular fibrillation has not been previously described.METHODS AND RESULTS: An electrophysiologic study was conducted in a woman after two episodes of syncope. Polymorphic ventricular tachycardia (PMVT) and ventricular fibrillation (VF) were induced with ventricular programmed stimulation. Magnetic resonance imaging demonstrated signal loss in the liver consistent with hemochromatosis, but normal cardiac size and function. Hematologic studies supported a diagnosis of hemochromatosis.CONCLUSION: Cardiac hemochromatosis may be associated with serious ventricular arrhythmias.
Echocardiography. 1996 Jan;13(1):9-20.
Quantitative Texture Analysis in Two-Dimensional Echocardiography: Application to the Diagnosis of Myocardial Hemochromatosis.
Lattanzi F, Bellotti P, Picano E, Chiarella F, Paterni M, Forni G, Landini L, Distante A, Vecchio C.
Istituto di Fisiologia Clinica-C.N.R., Via P. Savi, 8, 56100 Pisa, Italy.
BACKGROUND: Myocardial reflectivity is abnormally increased in patients with thalassemia major under transfusion treatment, probably due to myocardial iron deposits and/or secondary structural changes. Such increased reflectivity has been detected by both qualitative and subjective analysis of two-dimensional echocardiographic (2-D echo) images and quantitative assessment of integrated backscatter amplitude with noncommercially available ultrasound prototypes. The purpose of this study was to assess the a coustic properties of myocardium in patients with beta-thalassemia major and iron overload by means of quantitative computerized offline textural analysis of conventionally recorded 2-D echo images, and to compare textural data with other qualitative (vis ual assessment) and quantitative (ultrasound backscatter analysis) approaches for myocardial ultrasound tissue characterization simultaneously applied to these patients. METHODS AND RESULTS: Thirty-five young patients with thalassemia major, without clini cal signs of cardiac failure, and 20 age and sex matched normal controls were studied by echocardiography. Each patient was receiving blood transfusion every 2-3 weeks. Two-dimensional echo images, obtained with a commercially available echocardiograph us ing the parasternal long-axis view, were digitized off line and analyzed by first and second order texture algorithms applied to regions of interest in the myocardium (septal and posterior wall). The mean gray level value was higher in thalassemic patient s than in controls on both the septum (110 +/- 25 vs 57 +/- 13, arbitrary units on a 0-255 scale; P < 0.01) and posterior wall (91 +/- 25 vs 67 +/- 18; P < 0.01). Among second order statistical parameters, contrast and angular second moment significantly (P < 0.01) differentiated septal and posterior walls of patients and controls. In thalassemic patients, no consistent correlation was found between wall texture parameters and hematologic (years of transfusions and chelation, number of transfusions), 2-D echo (posterior wall thickness, left ventricular end-diastolic diameter), and Doppler (transmitral E/A waves ratio) parameters. Myocardial walls with visually assessed increased echo reflectivity showed a trend toward higher values of mean gray level when compared with myocardial segments with qualitatively assessed normal reflectivity (septum: 121 +/- 26 vs 106 +/- 24; posterior wall: 105 +/- 23 vs 87 +/- 23). Although radiofrequency integrated backscatter has been demonstrated to be capable of identifyi ng thalassemic patients, no significant correlation was found between mean gray level (by texture analysis) and radiofrequency data (septum: r = 0.03; posterior wall: r = 0.09; P = NS for both). CONCLUSIONS: Myocardial walls affected by hemochromatosis sh ow ultrasound image texture alterations that may be quantified with digital image analysis techniques and appear mostly unrelated to hematologic and conventional, as well as radiofrequency-based, echocardiographic parameters. These changes in quantitative ly evaluated echo reflectivity are present even before the development of clinical and echocardiographic signs of cardiac dysfunction. (ECHOCARDIOGRAPHY, Volume 13, January 1996)
Eur Heart J. 1991 Feb;12(2):224-30.
Cardiac alterations in 36 consecutive patients with idiopathic haemochromatosis: polygraphic and echocardiographic evaluation.
Cecchetti G, Binda A, Piperno A, Nador F, Fargion S, Fiorelli G.
Institute of Internal Medicine, University of Milan, Italy.
Thirty-six consecutive patients with idiopathic haemochromatosis (IH) were studied by electrocardiography (ECG), polygraphy, M-mode and 2-D echocardiography and Doppler-echocardiography. No significant correlations were found between ECG, PEP/LVET ratio a nd echocardiographic measurements. Left ventricular (LV) enlargement with impaired LV systolic function was present only in three patients (5.5%), of whom two died during iron-depleting therapy because of cardiovascular complications. Compared with contro ls, echocardiographic abnormalities were significantly more frequent and marked in subjects with higher iron overload than in those in whom it was lower. Ten patients were studied before and after iron depletion, nine of whom had only mild echocardiograph ic abnormalities at baseline examination. Significant reduction of end-diastolic thickness of the interventricular septum and LV mass (P less than 0.01 and less than 0.02 respectively) was observed. Also the end-diastolic thickness of the LV posterior wal l and the end-systolic diameter of the left atrium reduced although not to a significant degree. The increased thickness of ventricular walls without impairment of LV systolic function is probably the first and still reversible cardiac alteration due to i ron deposition in the myocardium. Later, with increasing iron overload, LV function becomes impaired and dilated cardiomyopathy develops. Early diagnosis and treatment of IH cardiopathy is needed before irreversible cardiac damage occurs.
J Am Coll Cardiol. 1989 Jan;13(1):116-20.
Endomyocardial biopsy in hemochromatosis: clinicopathologic correlates in six cases.
Olson LJ, Edwards WD, Holmes DR Jr, Miller FA Jr, Nordstrom LA, Baldus WP.
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905.
Clinical and pathologic features of cardiac hemochromatosis diagnosed by endomyocardial biopsy in six men, aged 32 to 75 years (mean 52), are described. Echocardiography demonstrated left ventricular enlargement and marked global systolic dysfunction in f ive. Cardiac catheterization demonstrated normal coronary arteries, increased left ventricular end-diastolic pressure and decreased left ventricular systolic function in all five so studied. Stainable iron was present in all endomyocardial biopsy specimen s from the five patients with decreased left ventricular systolic function. Histologically, iron was detected only within the sarcoplasm, and its extent varied inversely with ventricular function. Thus, cardiac hemochromatosis represents a storage rather than an infiltrative disease. These results indicate that stainable iron is consistently observed in endomyocardial biopsy specimens from patients with impaired left ventricular systolic function. Iron staining is recommended for endomyocardial biopsy spe cimens from patients with idiopathic cardiac dysfunction.
Am J Cardiol. 1987 Oct 1;60(10):885-9.
Echocardiographic features of idiopathic hemochromatosis.
Olson LJ, Baldus WP, Tajik AJ.
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905.
To characterize cardiac involvement in idiopathic hemochromatosis, clinical records and 2-dimensional (2-D) echocardiograms of 24 patients with idiopathic hemochromatosis were reviewed. The 17 men and 7 women were 24 to 80 years old (mean 48). Of 19 patie nts without valvular, ischemic, hypertensive or other known heart disease, 7 (37%) had structural and functional echocardiographic abnormalities attributed to idiopathic hemochromatosis (group 1) and 12 had normal echocardiographic findings (group 2). Age , gender and laboratory markers of iron overload did not differentiate patients with cardiac dysfunction (group 1) from those without cardiac dysfunction (group 2). In group 1, echocardiographic abnormalities included chamber dilatation and global systoli c dysfunction. Increased wall thickness was not a feature of idiopathic hemochromatosis. All group 1 patients had abnormal electrocardiographic findings and cardiomegaly on radiography. Despite therapeutic phlebotomy, 4 patients in this group died, betwee n 0.5 and 30 months after echocardiography, because of congestive heart failure. In conclusion, there is a spectrum of cardiac dysfunction in idiopathic hemochromatosis. In patients with idiopathic hemochromatosis and left ventricular dysfunction, absolut e wall thickness is normal. Survival is poor in patients with idiopathic hemochromatosis and severe left ventricular dysfunction.
Arch Mal Coeur Vaiss. 1983 Oct;76(10):1240-6.
Adiastole caused by a secondary cardiac hemochromatosis. Successful treatment with an iron chelating agent
Baudouy P, Lombrail P, Azancot I, Piekarski A, Martin E, Slama R.
Severe congestive cardiac failure developed in a few weeks in a 44 year old man who had undergone porto-caval anastamosis for post-hepatitis cirrhosis one year previously and then treated for anaemia by repeated blood transfusion and chronic daily oral ir on therapy. Infiltrative, congestive and restrictive cardiomyopathy was diagnosed in the presence of global cardiomegaly, electrocardiographic changes (microvoltage, diffuse ST-T wave changes), echocardiographic appearances (dilatation of the left ventric le, with hypertrophic and hypokinetic walls), and hemodynamic signs of adiastole with equalisation of filling pressures at 15 mmHg and a cardiac index of 1,88 l/min/m2. Cardiac haemochromatosis was confirmed by the laboratory (serum iron: 35 mumol/l; side rophilin saturation: 100 p. 100; serum ferritin: 1854 ng/ml; induced siderouria: 51 mg/24 hours) and histological findings (endomyocardial biopsy showing pigment overload). The absence of a family history, of homozygote A3 antigen, of diabetes, of iron ov erload on hepatic biopsy one year previously, excluded the diagnosis of familial idiopathic haemochromatosis. A secondary form of the disease was diagnosed on a possible genetic predisposition (heterozygote A3 antigen) and on environmental factors (blood transfusions, iron therapy, cirrhosis, alcoholism and perhaps the porto-caval anastamosis. Cardiac haemochromatosis was cured in this case by iron chelating therapy comprising daily subcutaneous infusions of 2 g of desferrioxamine for 2 months. The cure w as confirmed by regression of the signs of clinical cardiac failure and of cardiomegaly, the increase in QRS voltages and the near normalisation of the hemodynamic and laboratory findings.
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