EASL Clinical Practice Guidelines

What is the penetrance of C282Y homozygosity?

Differences in inclusion criteria and in the definition of biochemical and disease penetrance have produced a range of estimates for the penetrance of C282Y homozygosity. The disease penetrance of C282Y homozygosity was 13.5% (95% confidence interval 13.4–13.6%) when 19 studies were included in the meta-analysis and the results of individual studies weighted on the inverse variance of the results of the individual study (Fig. 2) [[134], [135]].

Fig. 2 Forest plot of studies on the penetrance of hemochromatosis. Studies are weighted on the inverse of the confidence interval. (For detailed information see Table 6).
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Excess iron

Although the majority of C282Y homozygotes may have a raised serum ferritin and transferrin saturation, this cannot be relied upon as secure evidence of iron overload. An individual patient data meta-analysis including 1382 C282Y homozygous individuals reported in 16 studies showed that 26% of females and 32% of males have increased serum ferritin concentrations (>200 μg/L for females and >300 μg/L in males) (Table 6). The prevalence of excess tissue iron (>25 μmoles/g liver tissue or increased siderosis score) in 626 C282Y homozygotes who underwent liver biopsy was 52% in females and 75% in males as reported in 13 studies. The higher penetrance of tissue iron overload is due to the selection of patients for liver biopsy, which is more likely to be carried out in patients with clinical or biochemical evidence of iron overload.

Table 6
Data from studies addressing the penetrance of C282Y homozygotes.

Authors Ref. Study type C282Y homozygotes (females) Definition of penetrant disease Affected individuals Penetrance Comments
Burt et al. (1998) [ 10] Cross-sectional 5 (4) Hepatic iron index >1.9 upon liver biopsy 3 60% No liver biopsy in unaffected individuals because of normal serum iron parameters
Distante et al. (1999) [ 13] Cross-sectional 2 (1) Iron removed >5 g or HII >1.9 or histological iron grade >2+ 1 50% Unaffected patient had Pearl's stain Grade 2 and HII of 1.7
McDonnell et al. (1999) [ 127] Cross-sectional 4 (3) Iron removed >5 g or HII >1.9 or histological iron grade >2+ 3 75% One unaffected patient had elevated serum iron parameters
Olynyk et al. (1999) [ 14] Cross-sectional 16 (9) HII >1.9 or histological iron grade >2 9 56.3% Two additional patients had serum ferritin of 1200 μg/L and 805 μg/L respectively, but did not undergo liver biopsy. Cirrhosis was found in 1 patient, fibrosis in 3 patients, and arthritis in 6 patients
Distante et al. (2000) [ 136] Cross-sectional & short term follow up 14 (9) HII>1.9 or histological iron grade >2 or congestive heart failure + marked and persistent hyperferritinemia and TS >55% 3 21.4% Liver biopsy available only in 5 patients; a total of 5 patients of whom 4 had no biopsy had persistent hyperferritinemia
Bulaj et al. (2000) [ 137] Cross-sectional – affected individuals 184 (48) At least one disease-related condition (cirrhosis, fibrosis, elevated ALT or AST, arthropathy) 137 74.5%
Cross-sectional – family members 214 (101) 33 15.4%
Cross-sectional – unselected 107 (41) 7 6.5%
Barton et al. (1999) [ 138] Cross-sectional – family based 25 (n.d.) Cirrhosis or diabetes attributable to iron overload 6–23 24–79% Ill-defined HC phenotype was present in a total of 23 patients
Beutler et al. (2002) [ 21] Cross-sectional 152 (79) 'liver problems' (assessed in 124) 10 8.1% Signs and symptoms that would suggest a diagnosis of HC in only one patient
Waalen et al. (2002) [ 139] Cross-sectional 141 (80) Only symptoms and serum iron parameters reported 92 patients had elevated serum ferritin concentrations, disease-associated symptoms were equal in control group and C282Y homozygotes
Deugnier et al. (2002) [ 23] Cross-sectional 54 (44) At least one disease-related symptom (fatigue, arthralgia, diabetes, increased ALT) 35 64.8% 21 patients had increased serum iron parameters
Phatak et al. (2002) [ 26] Cross-sectional 12 (8) Iron removed >5 g for males and >3 g for females 5 42% Increased serum ferritin in 50% of patients
Poullis et al. (2003) [ 98] Cross-sectional 12 (5) Histological iron grade >2 7 58% Increased serum ferritin in 11 out of 12 patients, but coincidence of significant co-morbidities (HCV and iron in 5 patients)
Olynyk et al. (2004) [ 140] Longitudinal 10 (6) Hepatic iron >25 μmol/g 6 60% Gradual increase in TS over 10 year observation – no biopsy in 4 patients
Andersen et al. (2004) [ 141] Longitudinal 23 (16) At least one disease-related condition (cirrhosis, fibrosis, elevated ALT or AST, arthropathy) 3 13.0% Increased serum ferritin in 16 patients
Gleeson et al. (2004) [ 142] Family based study 71 (25) Histological iron grade >3+ 26 36.6% Only 71 out of 209 C282Y homozygote patients who underwent liver biopsy were included
Rossi et al. (2004) [ 143] Cross-sectional 2 0 0% No clinical symptoms
Delatycki et al. (2005) [ 128] Cross-sectional 51 (26) Disease-associated symptoms 45 88% 45 patients had disease-associated symptoms (tiredness, abdominal pain, joint pain)
Powell et al. (2006) [ 144] Cross-sectional – family based 401 (201) Histological iron grade >2 128 32% At least one disease related condition 17%
Cross-sectional – population based 271 (112) Histological iron grade >2 135 50% At least one disease related condition 27%
Asberg et al. (2007) [ 145] Cross-sectional 319 (0) Cirrhosis 11–16 3.4–5% Predicted/calculated penetrance
Allen et al. (2008) [ 146] Longitudinal 203 (108) Serum ferritin >1000 μg/L 40 19.7% In persons homozygous for the C282Y mutation, iron overload-related disease developed in a substantial proportion of men but in a small proportion of women

When all 1382 patients with reported iron parameters were included in the meta-analysis, the penetrance of excess liver iron was then 19% for females and 42% for males.

Clinical penetrance and progression

Disease penetrance based on symptoms (e.g. fatigue, arthralgia) is difficult to assess due to the non-specific nature and high frequency of such symptoms in control populations [21].

Disease penetrance based on hepatic histology has been studied but is biased by the fact that liver biopsy is usually reserved for patients with a high pre-test likelihood for liver damage. However, these studies give an estimate of disease expression in C282Y homozygotes. Elevated liver enzymes were found in 30% of males in one study [142]. Liver fibrosis was present in 18% of males and 5% in females homozygous for C282Y; cirrhosis was present in 6% of males and 2% of females [[66], [144]]. A recent meta-analysis concludes that 10–33% of C282Y homozygotes eventually would develop hemochromatosis-associated morbidity [147].

Penetrance is generally higher in male than in female C282Y homozygotes. C282Y homozygotes identified during family screening have a higher risk of expressing the disease (32–35%) when compared with C282Y homozygotes identified during population based studies (27–29%).

Three longitudinal (population screening) studies are available and show disease progression in only a minority of C282Y homozygotes [[140], [141], [146]]. Available data suggest that up to 38–50% of C282Y homozygotes may develop iron overload, with (as already stated) 10–33% eventually developing hemochromatosis-associated morbidity [147]. The proportion of C282Y homozygotes with iron overload-related disease is substantially higher for men than for women (28% vs. 1%) [146].

The prevalence and predictive value of abnormal serum iron indices for C282Y homozygosity in an unselected population

Serum iron studies are usually used as the first screening test when hemochromatosis is suspected. The predictive value of screening for serum iron parameters in the general population is highlighted by two studies [[131], [145]].

The prevalence of persistently increased serum transferrin saturation upon repeated testing was 1% (622 of over 60,000). Of these individuals ∼50% also had hyperferritinemia (342 of 622). Homozygosity for C282Y could be detected in ∼90% of men and ∼75% of women with a persistently elevated transferrin saturation and increased serum ferritin. From a cross-sectional point of view, the disease penetrance of the C282Y/C282Y genotype in this study cohort, defined as the prevalence of liver cirrhosis, was ∼5.0% in men and <0.5% in women [145].