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Hemochromatosis gene (HFE)-associated hereditary hemochromatosis (HH) is a genetic predisposition to iron overload and subsequent signs and symptoms of disease that potentially affects approximately 80,000 persons in Australia and almost 1 million persons in the United States. Most clinical cases are homozygous for the Cys282Tyr (C282Y) mutation in the HFE gene, with serum ferritin (SF) concentration >1000 lg/L as the strongest predictor of cirrhosis. The optimal treatment regimen for those with SF concentrations above the normal range but <1000 lg/L is unknown. We assessed HFE mutations in a prospective cohort of 31,192 participants of northern European descent, aged 40-69 years. An HFE-stratified random sample of 1438 participants including all C282Y homozygotes with iron studies 12 years apart were examined by physicians blinded to participants' HFE genotype. All previously undiagnosed C282Y homozygotes (35 male, 67 female) and all HFE wild-types (131 male, 160 female) with baseline and follow-up SF concentrations <1000 lg/L were assessed for HH-associated signs and symptoms including abnormal second/third metacarpophalangeal joints (MCP2/3), raised liver enzymes, hepatomegaly, and self-reported liver disease, fatigue, diabetes mellitus, and use of arthritis medication. The prevalence of HH-associated signs and symptoms was similar for C282Y homozygotes and HFE wild-types for both normal and moderately elevated SF concentrations. The maximum prevalence difference between HFE genotype groups with moderately elevated SF was 11% (MCP2/3, 95% confidence interval 5 26%, 29%; P 5 0.22) and for normal SF was 6% (arthritis medicine use, 95% confidence interval 5 23%, 16%; P 5 0.11). Conclusion: Previously undiagnosed C282Y homozygotes with SF concentrations that remain below 1000 lg/L are at low risk of developing HH-associated signs and symptoms at an age when disease would be expected to have developed. These observations have implications for the management of C282Y homozygotes. (HEPATOLOGY 2010;52:925-933)

Maternal thyrotoxicosis, predominantly secondary to Graves' disease, affects 0.2% of all pregnancies. The Endocrine Society guidelines recommend the use of propylthiouracil as a first-line drug for thyrotoxicosis in pregnancy because of associations between carbimazole or methimazole and congenital anomalies. However, recent studies have highlighted the risk of severe liver injury with propylthiouracil. Here, we report another case with multiple congenital anomalies following in utero exposure to carbimazole and review the literature to consider the risks and benefits of available pharmacological treatments for thyrotoxicosis in pregnancy.

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