The Newcastle Hospital’s NHS Trust serves a local population of around 270 000 and is a tertiary referral centre for up to 4 million people. Among other services it provides the regional renal transplant, liver and haematology service.

All patients aged over 18 years who had serum ferritin assayed between January 2002 and September 2002 were identified. All those with a ferritin level of ≥ 1500 micrograms/litre (μg/L) (normal range 12-200 μg/L) were included in the study. Demographic data, medical histories (including blood transfusion history and documented weight loss), biochemical markers and histopathological data were collected for each patient. The medical notes of patients with specific diagnoses, such as Hereditary Haemochromatosis (HHC), were scrutinised to ensure diagnostic criteria had been met before the patients were classified[3] (Table 1).

Of the 150 patients evaluated in detail, 81 had one single identifiable cause for their hyperferritinaemia, with only 3 patients having none of the listed potential causes (Table 1) recorded in their medical records as well as no significant weight loss. Table 2 gives details of the frequency of conditions associated with a markedly elevated serum ferritin level. Table 3 lists the 10 most common causes for hyperferritinaemia in all patients studied as well as for patients who lived locally.

Renal failure was the most common cause for hyperferritinaemia in the overall patient population of the hospital trust that provides significant tertiary care, however, alcoholic liver disease was the most common cause of a raised ferritin level in the local population. 51% of patients in our study had only one cause identified for their hyperferritinaemia, with alcoholic liver disease being the most common single cause for a raised ferritin level. Hereditary haemochromatosis accounted for only 9% of cases, ranking as the 10^th commonest cause of hyperferritinaemia. Liver disease (alone) accounted for 25% of cases, but contributed to raised ferritin levels in 44%.

The median ferritin level was 2613 μg/L. Those with liver diseases had the highest ferritin levels (Table 4). Patients with haematological disease (or repeated blood transfusion) as the single cause of a ferritin level ≥ 1500 μg/L also had very high median ferritin level results. Patients with renal failure had relatively lower median ferritin level results.

Dying red blood cells in macrophages are broken down to release iron to serum transferrin, which is then taken up by transferrin receptors on parenchymal tissues and in the bone marrow. In HHC, it is thought the binding of transferrin receptor 1 is inhibited in crypt and reticuloendothelial cells via the protein hepcidin[4]. This leads to raised ferritin, high transferrin saturation and high liver iron concentration.

HHC is a relatively rare cause of markedly raised ferritin ranking as the 8^th most common cause in the local population. Local guidelines for the diagnosis of HHC suggest that unless the transferrin saturation is > 45% genotyping is not indicated[3]. A serum ferritin greater than 300 μg/L (for men and post-menopausal women) is regarded as requiring further investigation for HHC. Our cut-off of 1500 μg/L is likely to have missed a large proportion of patients with HHC, which would include both those with a mild degree of iron overload and patients with HHC undergoing successful venesection treatment. HHC has a prevalence of 1/300 (which should be 900 patients locally). Clearly, if stable patients are having their ferritin levels checked twice yearly as recommended, our study would have missed a large proportion of these patients, suggesting that local venesection therapy is working.

It is well-known now that patients who are homozygous for HHC and who drink more than 60 g alcohol per day are approximately 9 times more likely to develop cirrhosis than those who drink less. This is associated with a massive rise in iron concentrations on biopsy[5]. All eight patients with HHC who had more than one identifiable risk factor for hyperferritinaemia were heavy drinkers.

The liver diseases (particularly HHC) produce the most markedly raised ferritin levels, especially in those with no other contributing factors (Table 4). There is evidence now of an association between iron excess on liver biopsy with other metabolic disorders[6]. A study in 2001 confirmed that an increased ferritin level with normal transferrin saturation is frequently found in patients with hepatic steatosis[7] but reflects iron overload only in those in whom it persists despite an appropriate diet. We did not include non-alcoholic steatohepatitis or fatty liver disease as separate diagnoses, nor did we look at associated metabolic disease, other than HHC, but it seems likely given the above evidence, that some of the patients in the “other liver disease” category had these conditions.

Investigating patients who were referred with abnormal liver function tests who were found to have a raised serum ferritin level is potentially time-consuming and costly. Time and resources could be reduced if cut-off levels for serum ferritin, above which specific diagnoses could be included or excluded from the differential diagnosis, were available. To do this most effectively, we would need to look at median ferritin levels at diagnosis for all patients with each of the liver diseases (e.g., ALD, HHC, fatty liver, autoimmune hepatitis) and not just at those patients identified with marked hyperferritinaemia. This may then enable greater targeting in subsequent investigations. From our limited study, it seems likely that patients with massively raised ferritin levels (e.g. > 5000 μg/L) are more likely to have HHC than any of the other chronic liver diseases or conditions commonly associated with hyperferritinaemia.

More patients had weight loss as an identifiable potential cause of their hyperferritinaemia than had haemo-chromatosis. The weight loss in the majority of these patients was associated with neoplasia or chronic inflammatory disease. It is not possible to determine whether this was a significant factor in the development of hyperferritinaemia. Only two patients seemed to have weight loss alone as a cause for their hyperferritinaemia.

Patients with anorexia nervosa may be found to have increased ferritin and abnormal liver biopsies with high iron content. A study looking at malnourished children demonstrated abundant iron stores in the liver despite evidence of iron deficiency [personal communication, Professor Alan Jackson, University of Southampton]. The causes for this are unclear but it is postulated that the demand for oxygen carriage is reduced in the face of a diminished lean body mass, and hence red cell mass is lower due to the release of iron to be stored. It is also thought that bone marrow activity may be directly or indirectly suppressed due to ongoing stress or infection-related challenge, thus reducing demand on stored iron. Limited nutrient availability may also suppress marrow activity[8]. These possible explanations are not mutually exclusive.

Usual tests to diagnose iron deficient anaemia and measure iron stores are suspect in those with chronic renal failure, who are plagued by poor nutrition, multiple medications and acute and chronic inflammatory processes[9]. Iron replacement therapy in chronic renal failure is common and these patients frequently undergo ferritin checks as a measure of their iron stores. There may be therefore a disproportionately high number of patients with chronic renal failure included in our study. The median ferritin level in patients with renal failure was 1959 μg/L (1954 μg/L in those with RF as a single cause). 52% (22/42) of patients with renal failure had a ferritin level < 2000 μg/L making up 38% of all those with ferritin levels < 2000 μg/L in this study.