FRANK J. MILNE STATE-OF-THE-ART LECTURE


chromatosis. The reason for the high serum iron in those horses with liver failure is unknown but one possible theory is that during severe liver disease iron might be released from the iron storage protein and iron detoxicant, ferritin, or from the consider- able hemosiderin that seems to normally accumu- late in horse liver. In my experience, after evaluating serum iron and saturation values in adult horses for more than 15 years, extremely high serum iron and nearly 100% saturation is most com- monly seen in adult horses with liver disease and may be seen in up to 20% of horses with severe liver disease. This does not apply to newborn foals, who normally have very high serum iron for the first few days of life.148 There is a recent abstract conclud- ing that horses drinking heavily iron-contaminated water (72.5 mg/L, or 150 times acceptable levels) for a prolonged period can result in hemochromatosis and liver failure.149 Iron toxicity has been well documented in new-


born foals. In the spring of 1983, more than 60 foals died at 2–5 days of age in association with the administration of a probiotic/nutritional supplement paste containing only 64 mg of ferrous fumar- ate.150,151 Foals that died were always adminis- tered the product before nursing colostrum. Iron toxicity in these foals was likely related to the direct passage of iron to the liver in foals that had not received the antioxidant benefits of colostrum. Foals were most commonly observed to be ill at 2 days of age with variable degrees of icterus and neurological signs.150 Hypoglycemia was almost always present; this is common in foals with hepatic failure and may reflect the relatively low glycogen content of foals. Both total and conjugated biliru- bins were increased with conjugated bilirubin less than 10% of total. Foals were severely acidotic, also characteristic of liver failure in foals. GGT and AST were moderately elevated in all foals and, amazingly, SDH was normal in 3- and 5-day-old foals, likely reflecting massive hepatic necrosis on day 1 and the very short half-life of SDH. Interest- ingly, a small amount of liver on the periphery seemed normal, allowing some function to occur. This was believed to be a result of dilution of the iron toxin between the central area of the liver and main entry point of the iron, the portal vein. Three sur- prising findings were discovered from these unfor- tunate cases: bile ductule proliferation can be rapid and pronounced in the equine, Alzheimer type II cells associated with hyperammonemia can de- velop in 48 hours or less, and detectable fibrosis may be seen within 5 days.13 It was hard to fathom that 64 mg of ferrous fumarate would kill a newborn foal when 50 mg/kg could be given to adult ponies with- out evidence of liver disease (clinical, biochemical, or microscopic), but it did and we learned. All poten- tial toxins, even in small amounts, administered to foals prior to colostrum consumption could be harm- ful and should be routinely avoided.


Another less-well-understood hepatic failure pos-


sibly associated with iron overload has occurred in foals with neonatal isoerythrolysis that required one or more blood transfusions.152 Affected foals may have progressive liver disease (increasing liver en- zymes) within days after they receive one or more transfusions and these foals may exhibit liver fail- ure as soon as 5 days following transfusion or up to 3 months later. Histologic lesions in the liver con- sist of hepatocellular necrosis with extensive biliary proliferation. A greater number of transfusions and lower packed cell volume (PCV) on hospital admission were risk factors for liver failure. Histo- logic findings are similar to those seen in the new- born foals that received ferrous fumarate, suggesting that a combination of hepatic hypoxia and iron overload from transfusions may have caused the severe liver disease. It is unlikely that either one alone would have caused the disease in so many foals. Regardless, liver failure is one of the most common complications seen in foals with ex- tremely low PCVs who have been transfused. Re- gardless of the etiology of liver failure in those foals, treatment with subcutaneous deferoxamine should be considered because this drug increases iron elimination.153 The liver is not only the key organ for iron homeo-


stasis and storage but is also the main producer of acute phase proteins. Acute phase proteins include the iron-regulating protein hepcidin, serum amyloid A, and fibrinogen. A decrease in serum iron (a neg- ative phase reactant) is known to occur quickly in many species following an acute inflammatory re- sponse and is believed to be an evolved method for decreasing the iron available to invading bacteria. Except for a few bacteria exceptions such as my nemesis Borrelia spp., iron is the most important element required for bacterial growth.154 Dr. Alex- andre Borges, while on sabbatical at Cornell, dem- onstrated that low serum iron was a better predictor of systemic inflammation than plasma fibrinogen.155 Hepcidin is known to be the key regulator of iron metabolism that leads to hypoferremia during in- flammation. Dr. Borges was further able to clone and sequence the equine hepcidin gene and perform expression analysis from different equine tissue.156 That work has shown that equine hepcidin is pre- dominantly expressed in the liver of horses. When horses were challenged with endotoxin, plasma iron concentration was decreased significantly from the pre-infusion level by 8 hours and relative real-time RT-PCR analysis showed that liver hepcidin and IL-6 mRNA expression was up-regulated at 6 hours post lipopolysaccharide (endotoxin) infusion.157 The totality of Dr. Borges’ work suggests that hepcidin acts as an acute-phase protein in horses, its regula- tion of iron (hypoferitenemia) is more rapid than most other markers of inflammation and the serum concentration of iron is correlated with the severity or course of inflammation, with a return to normal as the inflammation resolved.


AAEP PROCEEDINGS  Vol. 61  2015 83


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