JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
September 2021
D-M20

 

 

Signalment (JPC #3102662):   Three year old spayed Collie dog

 

HISTORY:  Vomiting post feeding for a week.  Exploratory surgery revealed small nodular liver.

 

HISTOPATHOLOGIC DESCRIPTION:    Affecting 80% of the section, there is loss of hepatocytes with replacement by high number of macrophages, often arranged in sheets, with abundant amounts of golden-brown, irregular, intracytoplasmic, granular pigment (hemosiderin, hemosiderosis). Admixed with the hemosiderin-laden macrophages are fewer lymphocytes, moderate numbers of foreign body-type multinucleated giant cells rarely with greater than 80 nuclei, scant hemorrhage, fibrin, and edema, and hypertrophied fibroblasts and variably mature fibrous connective tissue that often center on and bridge between portal areas (portal bridging fibrosis).  Within areas of fibrosis, there are increased numbers of bile duct profiles; these are often lined by hyperplastic, hypertrophic epithelial cells that often pile up to 4 cell layers thick and are enlarged with swollen nuclei, respectively (biliary ductular reaction).  Small islands of hepatocytes remain within the sheets of hemosiderin-laden macrophages.  There are also variably sized, up to 4mm diameter, irregular nodules of hepatocytes that retain hepatic chord architecture (nodular regeneration).  Hepatocytes at the margin of regenerative lobules and islands are often either enlarged with vacuolated cytoplasm (degeneration) or are shrunken and angular with hypereosinophilic cytoplasm and pyknotic nuclei (necrosis).  Within remaining sinusoids there are numerous hemosiderin-laden Kupffer cells.  Individual hepatocytes often have abundant brown intracytolasmic pigment (hemosiderin or lipfuscin).  Collagen fibers are multifocally deeply basophilic (collagen ferrugination).  There is increased subcapsular clear space and multifocally the lymphatics are markedly dilated (edema).

 

MORPHOLOGIC DIAGNOSIS:  Liver: Hepatocellular degeneration and necrosis, multifocal to coalescing, chronic, severe, with nodular regeneration, marked hemosiderosis, portal bridging fibrosis, biliary ductular reaction, and collagen ferrugination, Collie dog, canine.

 

ETIOLOGIC DIAGNOSIS:  Hepatic hemochromatosis

 

CAUSE:  Iron overload

 

CONDITION:  Hemochromatosis

 

SYNONYM:  None

 

GENERAL DISCUSSION:

• Affects various mammals, including bats, primates, rhinoceros, marine mammals, and birds; affects sheep and cattle exposed to high levels of iron in pasture and water
• Hepatic iron overload is divided into two sub-categories:
  • Hemosiderosis: only excess accumulation of hepatocellular iron (no hepatic damage)
  • Hemochromatosis: excess iron storage leads to:
    • Fibrosis
    • Inflammation
    • Hepatic injury
  • Iron is stored predominantly in lysosomes

 

PATHOGENESIS:

• Pathogenesis of nutritional iron overload is unknown; suspect diet, environment, genetic, but not confirmed
• Hepatic damage due to excessive iron storage from excessive iron supplementation in animals:
  • Iron-dextran intoxication in piglets (for prevention of anemia)
  • Ferrous fumarate intoxication in newborn foals
• Has been described in horses, with animals displaying signs of liver failure and neurological impairment
• In human, the hereditary hemochromatosis is associated with point mutation in hfe gene

 

 

TYPICAL CLINICAL FINDINGS:

• Clinical symptoms of liver failure
• Weight loss, lethargy, and anorexia
• One case report of iron deficiency anemia in a ring-tailed lemur with concurrent chronic renal failure reported (Anderson, J Am Vet Med Assoc. 2014)

 

TYPICAL GROSS FINDINGS:

• Enlarged brown liver with diffuse fine nodules
• Dark-brown discolored, firm liver and adjacent lymph nodes
• Brown discoloration of bone marrow

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Massive hepatic necrosis, hyperplasia of bile ducts (possibly due to hepatic progenitor cell proliferation
• Hemosiderin accumulation in hepatocytes
• Periportal and perivenular bridging fibrosis, with nodular regeneration
• Hemosiderosis in Kupffer cells, lymph nodes, kidney, pancreas, spleen, other organs

 

DIAGNOSTIC TESTS:

• Histochemical stains:
  • For iron: Prussian blue, Perl’s
  • For fibrosis: Masson’s trichrome
• Liver iron concentration

 

DIFFERENTIAL DIAGNOSIS:

• None

 

COMPARATIVE PATHOLOGY:

• Form of heritable hemochromatosis reported in Salers or Salers-cross cattle
  • Develop a wasting disease < 2 years of age
  • 30-100 fold increase in liver iron content
  • Develop a dark brown, firm liver with accumulation of hemosiderin in hepatocytes and Kupffer cells, fibrosis, and nodular regeneration.
• Common in mynah bird (starling family)
• Hemosiderosis (iron seen in hepatocytes and Kupffer cells with no observable biochemical, cellular, or tissue damage) is common in toucans, mynahs, hornbills, aracaris, kingfishers, jays, hummingbirds, and birds-of-paradise
• Hemochromatosis can be seen in birds being fed iron rich diet or supplementsà similar histological findings to other species.  
• Black and sumatran rhinoceros: iron overload disorder can lead to organ dysfunction
• Serum ferritin concentration is not reliable marker for iron overload disorder progression (Roth, J Zoo Wildl Med. 2018)
• Excessive iron deposition observed only in captive animals due to diet with high iron bioavailability (in wild populations, their diet is rich in iron chelating compounds (tannins, phytates, etc) that bind to iron and then pass through the GI tract without being absorbed.
• Typically lesions are seen in the spleen, liver, small intestines, and lungs
  • Lesions in the liver are similar with canines: hepatic cellular degeneration, necrosis, and fibrosis
• Egyptian fruit bats (Rousettus aegyptiacus): frequently develop iron storage disease, with consistently large amounts in liver and spleen; less amounts in other organs (pancreas, kidney, skeletal muscle, and lung)
• Bottle-nose dolphins (Tursiops truncates)
• Mice with spontaneous genetic mutations associated with defective iron metabolism are available
• Deer and Reindeer: seasonal iron storage disease with hepatocellular necrosis and mild fibrosis and marked iron accumulation in hepatocytes
• Lemurs and marmosets
• Captive low-land gorilla and mountain gorilla: prone to iron storage disease, mostly in liver, spleen, lymph nodes, duodenum
• Brazilian sloths
• Brazilian anteaters
• Brazilian and Malayan tapirs held in captivity
• Captive cheetahs: frequent
• African Grey Parrots: fed a carnivorous bird diet or fruit that is high in ascorbic acid
• Hyrax: presumed to be diet related in combination with genetic influences.
• Captive Kori bustards: hemosiderosis and hemochromatosis with evidence of iron accumulation in the kidney, GI tract, adrenal gland, and spleen (Cudd, Vet Pathol. 2021)

 

REFERENCES:

1. Agnew D, Nofs S, Delaney MA, Rothenburger JL. Chapter 21 Xenartha, Erinacoemorpha, Some Afrotheria, and Phloidota. In: Terio KA, McAloose D, St. Leger J, ed. Pathology of Wildlife and Zoo Animals, Cambridge, MA Academic Press; 2018: 519-520.
2. Anderson KM, Wolf KN. Iron Deficiency Anemia in a Ring-tailed Lemur (Lemus catta) with Concurrent Chronic Renal Failure. J Am Vet Med Assoc. 2014; 15;244(4):471-5.
3. Arenales A, Gardiner CH, Miranda FR, et al. Pathology of Free-Ranging and Captive Brazilian Anteaters. J Comp Pathol. 2020; 180:55-68.
4. Arenales A, Silva FL, Miranda F, et al. Pathologic findings in 36 sloths from Brazil. J Zoo Wildl Med. 2020; 51(3): 672-677.
5. Cudd SK, Garner MM, Cartoceti AN, LaDouceur EEB. Hepatic lesions associated with iron accumulation in captive kori bustards (Ardeotis kori) [published online ahead of print]. Vet Pathol. 2021
6. Cullen JM, Stalker MJ. Liver and Biliary System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. 6th ed. St Louis, MO: Elsevier; 2016: 272.
7. Duncan M. Chapter 17 Perissodactyls. In: Terio KA, McAloose D, St. Leger J, ed. Pathology of Wildlife and Zoo Animals, Cambridge, MA Academic Press; 2018: 435-436.
8. Gelberg HB. Alimentary System and the Peritoneum, Omentum, Mesentery, and Peritoneal Cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:451.
9. Klopfleisch R, Olias P. The Pathology of Comparative Animal Models of Human Haemochromatosis. J Comp Pathol. 2012;147(4):460-78.
10. Leone AM, Crawshaw GL, Garner MM, et al. A Retrospective Study of the Lesions Associated with Iron Storage Disease in Captive Egyptian Fruit Bats (Rousettus aegytiacus). J Zoo Wildl Med. 2016;47(1):45-55.
11. O’Connor MR, Garner MM. Iron Storage Disease in African Grey Parrots (Psittacus Erithacus) Exposed to a Carnivorous Diet. J Zoo Wildl Med. 2018;49(1):172-177.
12. Trupklewlcz J, Garner MM, Juan-Salles C. Chapter 33 Passeriformes, Caprimulgiformes, Coraciiformes, Piciformes, Bucerotiformes, and Apodiformes. In: Terio KA, McAloose D, St. Leger J, ed. Pathology of Wildlife and Zoo Animals, Cambridge, MA Academic Press; 2018: 800.
13. Paglia DE, Tsu IH. Review of Laboratory and Necropsy Evidence for Iron Storage Disease Acquired by Browser Rhinoceros. J Zoo Wildl Med. 2012;43(3 Suppl):S92-104.
14. Phillips BE, Venn-Watson S, Archer LL, et al. Preliminary Investigation of Bottlenose Dolphins (Tursiops truncates) for HFE gene-related hemochromatosis. J Wildl Dis. 2014;50(4):891-5.
15. Roth TL, Reinhart PR, Kroll JL. Serum Ferritin Concentration is Not a Reliable Biomarker of Iron Overload Disorder Progression or Hemochromatosis in the Sumatran Rhinoceros (Dicerorhinus sumatrensis). J Zoo Wildl Med. 2018;48(3):645-658.
16. Wojtusik J, Roth TL. Investigation of Factors Potentially Associated with Serum Ferritin Concentrations in the Black Rhinoceros (Diceros bicornis) Using a Validated Rhinoceros-Specific Assay. J Zoo Wildl Med. 2018;49(2):297-306.

 

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