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Phenotypic and clinical manifestations of compound heterozygous genetic haemochromatosis (CHGH): a non-invasive approach to clinical management


  • Funding: None.
  • Conflict of interest: None.


Raj Ramakrishna, Southern Sydney Haematology, Suite 7, 1-5 Derby Street, Kogarah, NSW 2217, Australia.




The role of compound heterozygous genetic haemochromatosis (CHGH) (C282Y/H63D) mutations in the manifestations of iron overload is known; however, the extent of these manifestations and their associated management remain unclear.


This study evaluates the phenotypic manifestations of CHGH using laboratory and radiological biomarkers including serum ferritin/transferrin saturation, liver function tests (LFT), thyroid function tests, blood sugar level, and abdominal ultrasound (US) or computed tomography. The study also evaluates the effects of venesection therapy on these markers and its potential role in routine management of CHGH patients.


In this case-controlled study, 104 patients with HFE-C282Y/H63D compound mutations were subjected to laboratory investigations and imaging. Tests were repeated over a 4-year period before and after venesection. Data were compared between patient and control groups using paired t-tests.


Patients showed significantly higher serum ferritin and transferrin saturations compared with controls (P = 0.002, P = 0.003). Twenty-four patients (23%) demonstrated hyperferritinaemia ≥1000 mmol/L. Sixty-nine patients (68%) demonstrated biochemical abnormalities on initial testing (abnormal LFT (transaminases) (51 patients, 74%) and US/computed tomography (42 patients, 61%)). A significant number of LFT and US abnormalities normalised post-venesection (80%; P = 0.000 and 52%; P = 0.005 respectively).


Phenotypic manifestations displayed by CHGH patients can include biochemical and radiological abnormalities, which can occur at levels similar to C282Y homozygous disease (ferritin ≥1000 mmol/L). With venesection therapy, a large number of these abnormalities is reversible. Based on this, a non-invasive framework to assess and manage CHGH within a routine community-based clinical setting is proposed.