The (II)logic of iron reduction therapy for steatohepatitis

Abstract

A tool in the technique of logic that dates back to Aristotle is the use of a syllogism to prove an arguable point. In the context of iron reduction for steatohepatitis, it could unfold as follows:Major premise: An elevated serum ferritin can be associated with liver iron overload.Minor premise: Steatohepatitis is often associated with an elevated serum ferritin.Conclusion: Steatohepatitis can be associated with liver iron overload.The strength of the conclusion depends on the power or accuracy of the major and minor premise. There is no doubt that steatohepatitis patients usually have an elevated serum ferritin. However, the major premise that a high serum ferritin is an indicator of liver iron overload is where the problem begins with steatohepatitis (Fig. 1A). The overinterpretation of serum ferritin is a major clinical problem that leads to the overdiagnosis of hemochromatosis and or iron overload. 1,2Therapeutic bleeding has a long tradition in medieval medicine, and previous studies have shown reductions in liver transaminases postphlebotomy in a variety of liver diseases not commonly associated with iron overload. The assessment of liver iron overload is traditionally done by liver biopsy and, ideally, liver iron concentration. Semiquantitative iron staining (Prussian Blue 0-4) has usually shown that only those with 3 or 41 staining will have elevations in liver iron concentration. Magnetic resonance imaging (MRI) scanning is a noninvasive indirect estimate of liver iron stores. In the study of Adams et al., 3 the treated patients had a mean serum ferritin of 255 mg/L, which is within the reference range. Estimates of liver iron concentration by MRI were in the middle of the normal range at 23 mmol/g. In the study of Hoki et al., 4 mean serum ferritin was 182 mg/L, and of the 40 patients reported, there were only 2 of 40 (5%) with 31 iron staining and none with 41 staining. Therefore, it may not be surprising that iron reduction therapy had no obvious benefits given that the patients did not have iron overload. There are still investigators that emphasize the regional distribution of iron in fatty liver disease in macrophages, rather than hepatocytes, and speculate that this could be contributing to oxidative stress. It is important to remember that it is very difficult to induce liver fibrosis in experimental animals with massive iron loading, and there are clinical patients with extreme iron overload without fibrosis or cirrhosis (Fig. 1B). The findings in these studies are similar to a study in 43 patients by Beaton et al.5 that did paired liver biopsies before and after phlebotomy therapy. Only 2 of 43 (5%) patients had an elevated liver iron concentration initially and there were no beneficial effects on a range of histological parameters, including fibrosis. Serum ferritin decreased with phlebotomy therapy as liver iron concentration decreased from the normal range to the low normal range. There was not a strong correlation between liver inflammation, Creactive protein, body mass index, and serum fe...

Iron and non-alcoholic fatty liver disease

“…Overall, although there are promising results from small studies, venesection cannot currently be recommended as a suitable therapy for the majority of patients with NAFLD[ 94 ]. However, whether there are sub-groups of non-hemochromatotic NAFLD patients with increased iron that would benefit from venesection, remains to be determined by further studies.…”

Outcome of phlebotomy for treating nonalcoholic fatty liver disease: A systematic review and meta-analysis

“…[41] Thus, iron concentration in the liver might be lower than expected for a given serum ferritin level. [42] Adams et al . [17] reported that the mean ferritin level for a treatment group was 225 μg/L, which is within the reference range, and the hepatic iron concentration of this group was 23 μmol/g, which is in the mid-normal range as measured by magnetic resonance imaging.…”

“…Thus, patients may not display obvious benefit because, in fact, they had no hepatic iron overload. [42]…”

Non-invasive measurement of liver iron concentration by magnetic resonance imaging and its clinical usefulness

“…The vast majority of patients with hyperferritinaemia do not present iron overload in the liver [28,29]. However, it is important to recognize which of them have iron overload in order to be treated by phlebotomy [19,[30][31][32][33]. This treatment does not offer any benefit to patients without iron overload and, moreover, it can generate some complications [19,34].…”