Case 1 -
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The patient was a 40 year old dentist with a history of alcoholic liver disease and decompensated
cirrhosis. He was transplanted and the section is from the explant. Apart from some acquired red cell
spurring requiring 2 transfusions in the preceding 12 months, there was no history of recurrent
transfusions or iron supplementation. Testing for HFE mutations was performed at a later time.
Case 1 - Figure 1
Low power view showing established cirrhosis.
Case 1 - Figure 2
Medium power view showing pigment in hepatocytes
Case 1 - Figure 3
Medium power view showing an area of nodular dropout, indicating that active parechymal refashioning is ongoing in this liver. The lost nodule is replaced by a ductular reaction. Small clusters of hepatocytes remain focally.
Case 1 - Figure 6
Perls stain showing iron accumulation in bile ducts and ductules.
Case 1 - Figure 7
PAS stain after diastase digestion showing globules of alpha-1-antitrypsin. The patient was PiMZ. The globules were irregularly distributed.
The case demonstrates heavy siderosis, predominantly hepatocellular and in biliary ductules, in the
context of end-stage cirrhosis. The pattern is certainly similar to that seen in hereditary
hemochromatosis (HH), but when genotyping became routinely available several years later and was
performed, the patient did not have either of the typical mutations in the HFE gene (C282Y or H63D). This commentary will discuss hepatocellular iron
overload when HH due to HFE mutation has been excluded.
i. Other forms of hereditary hemochromatosis
Recent advances in the understanding of iron transport have clarified the genetic basis of the rarer
forms of HH. Central to the control of iron homeostasis is the iron downregulator hepcidin, produced by
hepatocytes. Its expression is modified by HFE protein and transferrin receptor 2 (TfR2) but the
mechanisms underlying this are still under investigation. Another protein, hemojuvelin (HJV), is a
crucial co-receptor for hepcidin transcription. Therefore, mutation of any of these can cause HH .
Hepcidin expression is increased when iron is replete in the hepatocytes and circulating iron pool.
Thus, Pietrangelo has pointed out that hepcidin is a little like insulin, increasing in response to
increased iron (analogous to insulin in the case of glucose). Conversely, when hepcidin is deficient,
iron absorption is allowed to occur unchecked. Circulating hepcidin binds to ferroportin in mucosal and
reticuloendothelial cells, leading to its degradation. As ferroportin is the chief iron exporter protein
from cells, this leads to retention of iron in the mucosal or reticuloendothelial cell. Iron loading
disorders result when there are inappropriately low levels of hepcidin (eg mutations in HFE, TfR2, HAMP
(the hepcidin gene) or HJV), or if ferroportin mutation prevents iron export from cells, mainly
macrophages (Table 1).
Thus, although HFE mutation is the major cause of iron overload, mutation of the above proteins gives
a similar histological picture, dominated by hepatocellular deposition as well as iron loading throughout
the body. An exception is ferroportin mutation, causing hemochromatosis type 4. With an autosomal
dominant inheritance, ferroportin mutation can produce two phenotypic patterns of iron deposition
depending on the specific mutation, which governs the activity and location of ferroportin in the cell.
As this protein controls iron transport out of enteric mucosal cells and also other cells such as
macrophages, one pattern resembles classical HH and the other, more common, shows a mixed deposition in
hepatocytes, reticuloendothelial cells (Kupffer cells, bone marrow and splenic macrophages, and
enterocytes. The latter pattern is associated with low transferrin saturation and resistance to
Although mutation of one or the proteins listed in Table 1 is a possible cause of the changes seen in
this case, with the exception of HFE mutation these disorders are very rare. However, data from the last
decade suggest that heavy hepatic iron overload mimicking HH, that is grade 3-4 siderosis or hepatic iron
index >1.9, occurs in about 8-12% of patients with end-stage cirrhosis coming to liver transplantation
Clearly, other mechanisms must be responsible.
ii. Iron overload in cirrhosis
Although overlooked, hepatic iron accumulation is common in late cirrhosis; this was initially
pointed out by Ludwig in 1997 . Studies published to date have had similar results, describing some
degree of iron deposition in many livers removed at the time of transplantation (around 30-40% of
explants), but also heavy siderosis mimicking HH in about 10% of explants. The mimicry can be striking,
including heavy hepatocellular deposition, relative sparing of kupffer cells, and deposition in
structures such as ductules, endothelial cells and vessel walls. An analysis of prior biopsies suggests
that the iron accumulation may occur relatively rapidly over a period of only 12-18 months. The current
case showed only patchy grade 1 iron in a biopsy taken 15 months earlier.
iii. Spur cell anemia as a potential cause or cofactor of marked siderosis
It is pertinent to ask why this marked siderosis occurs. Non-HH siderosis is described in a number
of scenarios (hereditary haematological disorders, dietary, parenteral/transfusional, acquired anemias,
porphyria cutanea tarda, African siderosis). Parenteral iron overload typically produces siderosis that
is prominent in reticuloendothelial cells, and in most of the causes above the clinical history will be
In the case of end-stage cirrhosis, the predominantly hepatocellular loading is likely to reflect a
relationship between decreasing liver mass, abnormal hepcidin homeostasis and stepwise deterioration of
hepatic function related to sepsis and intrahepatic vascular events. As hepcidin is produced by the
hepatocytes, reduced liver mass in cirrhosis may translate into reduced hepcidin expression.
Additionally, the progression of cirrhosis from early to late phases is a reflection of intrahepatic
vascular events leading to zonal ischemia and dropout of nodules (parenchymal "extinction")
is another cause of reduced hepcidin expression.
Finally, several studies found an association between spur cell anemia, severe end-stage liver
disease and heavy siderosis in liver explants
Red cell spurring is seen in advanced cirrhosis and
occurs because of abnormal cholesterol metabolism by the diseased liver, resulting in red cell membrane
spurring and hemolysis. It occurs in bouts that correlate with episodes of functional deterioration; in
some cases it requires transfusion. The combined hypoxia as well as erythropoietic drive is probably an
additional cause of reduced hepcidin expression. Thus, in late cirrhosis, as nodules progressively drop
out and liver function deteriorates, it seems likely that multifactorial suppression of hepcidin allows
free mucosal absorption of iron and deposition in tissues. This can lead to grade 4 iron deposition in
under 12 months, and gives a predominantly hepatocellular accumulation (rather than Kupffer cells as
would be expected) that is strikingly similar to HH. A diagnostic clue is the deposition of iron in
hepatocytes, ductules, vessels and endothelium but not in larger anatomical bile ducts.
iv. Alpha-1 antitrypsin (a1AT) globules
PAS-positive, diastase-resistant globules are present in conspicuous numbers in some parts of the
liver explant. The patient was heterozygous (PiMZ) and this demonstrates how a1AT globules can be
relatively prominent in some heterozygous patients. There were no globules in an earlier biopsy. The
jury is still out on the role of heterozygosity for a1AT deficiency in exacerbating another chronic liver
disease. It is tempting to speculate that there may have been a role for ATZ in accelerating the
deterioration of liver function, precipitating the red cell spurring and indirectly contributing to the
iron loading in this patient.
1. Non-HFE hereditary hemochromatosis occurs when the genes for hepcidin, hemojuvelin, ferroportin,
transferrin receptor-2 or caeruloplasmin are mutated. Others may remain to be discovered. These genes
encode proteins that are intimately involved in iron transport and regulation. However, the mutations
are very rare.
2. Heavy siderosis can be seen in end-stage cirrhosis due to hepatocellular (but generally not
biliary) disease. It is likely that multifactorial inhibition of hepcidin expression (by liver hypoxia,
reduced liver mass and increased erythropoiesis in the face of red cell spurring) leads to unregulated
transport of iron across the enteric mucosal cells and heavy siderosis within 12-18 months.
3. Cirrhosis-associated siderosis occurs only late in the disease and is probably stimulated by
post-cirrhotic remodeling that occurs when intrahepatic vascular events lead to nodular dropout and
Table 1. Classification of hereditary hemochromatosis and related disorders
| ||Disorder || ||Mutation ||Histological pattern|
|Type 1 ||HFE-associated HC ||Rec ||HFE|
- C282Y homozy
|Hepatocellular with periportal accentuation|
|Type 2 ||Juvenile HC ||Rec ||2A - hemojuvelin|
2B - hepcidin
|Hepatocellular with periportal accentuation|
|Type 3 ||Transferrin R2 HC ||Rec ||Transferrin receptor 2 ||Hepatocellular with periportal accentuation|
|Type 4 ||Ferroportin-assoc HC ||Dom ||Ferroportin ||2 patterns occur (mutation-site dependent) |
a. macrophage (K cell) & hepatocyte loading
b. predominantly hepatocyte loading
| || || || |
| ||Atransferrinemia ||Rec ||Transferrin ||Hepatocellular with periportal accentuation|
| ||Acaerulplasminemia ||Rec ||Caeruloplasmin ||Hepatocellular with periportal accentuation|
Abbreviations: HC - hemochromatosis; Rec - autosomal recessive; Dom - autosomal dominant; K cell - Kupffer cell
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