Hereditary Haemochromatosis: Hepatic and Cardiac Iron content and cardiac function at baseline and after a treatment course of venesection.

Abstract

Background Hereditary haemochromatosis (HH) is the most common inherited genetic disorder in Europe1. Although there are several genetic mutations which can lead to the development of HH, the p.C282Y mutation (tyrosine substitution for cysteine at amino acid 282) in the HFE (high Fe 2+) gene on the short arm of chromosome 6 is the most commonly implicated mutation2. Approximately 1 in 200 Northern Europeans are homozygous for the disorder3.

In HH, inappropriately low secretion of hepcidin, which negatively regulates iron absorption, results in increased absorption of iron and iron overload4. Increased plasma iron results in progressive parenchymal iron loading particularly in the liver, pancreas and heart5 which may result in end organ dysfunction including cirrhosis, diabetes and heart failure if untreated.

Phlebotomy is the cornerstone of treatment with limited experience of chelation therapy in a minority of patients6. Treatment of HH is guided by serum ferritin measurements with a target serum ferritin of <50mcg/L. Serum ferritin remains an accurate parameter in measuring total body iron stores. However, ferritin is an acute phase reactant and it has been shown that serum ferritin does not correlate accurately with myocardial iron content7,8.

The diagnosis of HH is non-invasive encompassing clinical examination, genetic testing, serum iron measurements and imaging. T2* MRI is the mainstay radiological investigation for the quantification of parenchymal iron overload in the liver and heart. Early in the disease, patients with HH may have subclinical cardiac impairment manifested by diastolic dysfunction and be asymptomatic. Echocardiography cannot directly quantify cardiac iron overload, but can be performed to assess cardiac function. Higher resolution 3T MRI is becoming more commonly used clinically and has been studied in other clinical cohorts. Cardiac and hepatic iron content has been evaluated at 1.5T MRI, but there is a paucity of data on the measurement of hepatic and cardiac iron content at 3T in patients with HH and the effect of venesection on hepatic and myocardial iron loading.

Aims The aim of this study was to utilize different imaging modalities in patients with newly diagnosed HH to assess for organ dysfunction namely 3T MRI for hepatic assessment, 3T MRI and echocardiography for cardiac assessment and to determine if there was any change in parenchymal iron content and cardiac function after a treatment course of venesection. We aimed to establish baseline markers of diastolic function with echocardiography and cardiac MRI and to determine if there was an improvement after a treatment course with venesection.

Methods: Two separate prospective cohort studies were performed.

1st cohort study: Cardiac function as measured with echocardiography before and after venesection in Hereditary Haemochromatosis: a prospective cohort study Baseline echocardiography was performed on 25 consecutive patients with newly diagnosed hereditary haemochromatosis with elevated serum ferritin levels. The test was repeated after one year of treatment with venesection. Tissue Doppler Imaging (TDI) and deformation (strain) imaging using speckle tracking (a newer echocardiographic technique) were performed.

2nd cohort study: Cardiac and hepatic assessment with 3T MRI before and after venesection in C282Y Hereditary Haemochromatosis: a prospective cohort study Baseline cardiac and hepatic MRI at 3T was performed on 28 consecutive C282Y homozygous patients with newly diagnosed HH, with elevated serum ferritin levels and repeated after a course of treatment with venesection. Quantitative cardiac and hepatic T2* mapping and cardiac strain analysis were performed offline using dedicated relaxometry fitting and feature tracking software.

Results 1st cohort study: Radial strain showed a significant improvement after 1 year of venesection (increase from 38.8 to 52.6). Left atrial ejection force showed a significant decrease after 1 year of venesection (median decrease=0.6, (IQR 0, 1.60), p=0.0004). IVRT decreased significantly in patients after 1 year of venesection (decrease from 107.4 +/- 16.2ms to 97.68 +/-15.4 ms, p (0.0187).

2nd cohort study: The majority (84%) of patients had normal baseline myocardial T2* values (25.8ms, range 8.9-31.2ms) which did not change significantly after venesection (23.2ms, range 11-38.1ms). Median global radial strain significantly increased from 26.6 (range: 15.6-32.9) to 28.3 (range: 19.8-35.8) (p=0.003) and median global circumferential strain decreased from -16.3 (range: -11.1 to -19.2) to -17.5 (range: -13.0 to -20.1) (p=0.002). Median hepatic T2* values increased from a median of 3.09ms at baseline to 7.02ms after a treatment course of venesection consistent with a reduction in hepatic iron content.

Conclusion 1st cohort study: Among all measurements, radial strain, iso-volumetric relaxation time and left atrial force were shown to significantly improve following a 1 year course of venesection suggesting that these parameters could be used to identify subclinical cardiac dysfunction in patients with iron overload secondary to hereditary haemochromatosis and to guide intensification of venesection therapy. 2nd cohort study: In patients with HH, normal cardiac T2 * is insensitive as patients may have subclinical LV dysfunction which can be detected by impaired radial and circumferential strain. Strain imaging can detect sub-clinical LV dysfunction in patients and as it improves following venesection in HH, may serve as a useful biomarker to guide treatment. Hepatic T2* values demonstrated a significant increase following venesection, in keeping with a decrease in hepatic iron concentration.