JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

September 2024

D-M11 (NP)

 

Signalment (JPC Accession # 2287584): 6-year-old female donkey

 

HISTORY: 1-week history of anorexia, depression, and weakness; in late gestation. On physical exam: increased heart and respiration rates, dehydration, and dependent edema. The serum was grossly lipemic.

 

HISTOPATHOLOGIC DESCRIPTION: Liver: Diffusely the hepatocytes are markedly enlarged by a discrete clear cytoplasmic vacuole (lipid) up to 20µm in diameter that flattens and peripheralizes the nucleus (vacuolar degeneration, lipid type). Multifocally, vacuoles of adjacent hepatocytes coalesce. There are few hepatocytes that are shrunken and hypereosinophilic with nuclear pyknosis (single cell death). Diffusely, sinusoids are collapsed. Multifocally, portal areas contain few lymphocytes, plasma cells, and rare neutrophils. The capsule is minimally thickened by fibrous connective tissue, and the liver has a rounded contour.

 

MORPHOLOGIC DIAGNOSIS: Liver, hepatocytes: Vacuolar change, lipid-type, diffuse, severe, breed unspecified, donkey (Equus asinus), equine.

 

CONDITION: Hepatic lipidosis, hyperlipemia syndrome, equine hyperlipidemia, fatty liver disease 

 

GENERAL DISCUSSION:

• Hepatic lipidosis (steatosis) is the abnormal accumulation of triglycerides within hepatocytes 
• Hepatic lipidosis most often affects ponies (Shetland ponies are predisposed), donkeys, miniature horses, cattle, cats, sheep (pregnant, obese, or lactating), and is a characteristic finding in rabbits with gastric trichobezoar 
• Usually secondary to an event that causes anorexia
• Rapid clinical course with high mortality in ponies
• Obesity is an important risk factor, primarily in felines

 

PATHOGENESIS:

• Hepatic lipidosis occurs when triglycerides, neutral fats, and cholesterol accumulate faster than their metabolic degradation or release as lipoproteins; these excess lipids are deposited as intra hepatocellular droplets; VLDL is the primary lipoprotein in the blood of hyperlipemic ponies 
• Hepatic lipidosis can occur as the result of one or a combination of the following mechanisms:

• Excessive delivery of free fatty acids either from the gut or from adipose tissue 

• Increased mobilization of fat is the most common cause of lipidosis in domestic animals

• Decreased beta-oxidation of fatty acids to ketones and other substances because of mitochondrial injury (toxins, hypoxia)
• Impaired synthesis of apoprotein (e.g. CCL₄ toxicity, aflatoxicosis)
• Impaired combination of triglycerides and protein from lipoprotein (uncommon)
• Impaired secretion of lipoproteins from the hepatocyte (uncommon)

• Insulin resistance: Proposed underlying cause in ponies; increased steroid hormones interfere with insulin function; stress (increased cortisol) and increased progesterone during pregnancy may exacerbate the problem; insulin resistance results in increased lipolysis and free fatty acids, leading to hypertriglyceridemia

TYPICAL CLINICAL FINDINGS:

• Depression, anorexia, weakness, colic, pasty feces, icterus
• Hepatic rupture is a frequent cause of death
• Ponies may also manifest signs of hepatic encephalopathy or terminal DIC
• Clinical pathology: Increased plasma triglycerides (primarily VLDL), increased alkaline phosphatase, GGT, LDH, and SDH, lipemic serum and blood, metabolic acidosis, DIC in severe cases, increased ammonia (Azevedo, J Vet Diagn Invest. 2019)

TYPICAL GROSS FINDINGS:

• Enlarged greasy yellow liver, bulges on cut surface, floats in formalin
• Enlargement of the liver may cause rupture of the liver capsule
• Lipidosis may also involve the heart, skeletal muscle, kidney, adrenal cortex
• Hemorrhage and infarction if DIC is present

TYPICAL LIGHT MICROSCOPIC FINDINGS:

ADDITIONAL DIAGNOSTICS:

• Cytology: Hepatocytes demonstrate marked fatty change with mixture of microvesicular (relatively uniform discrete vacuoles smaller than the centrally placed nucleus) and macrovesicular lipid vacuolation (variably sized discrete vacuoles larger than the often-displaced nucleus)
• Plasma triglyceride levels > 500 mg/dl
• Special stains: Oil red-O, Sudan IV on frozen tissues

 

DIFFERENTIAL DIAGNOSIS:

• Endocrinopathies: Hyperlipidemia and fatty liver may occur with diabetes mellitus, hypothyroidism, hyperadrenocorticism
• Hepatotoxins: Usually cause necrosis in addition to fatty change

 

COMPARATIVE PATHOLOGY:

• Cats: Feline fatty liver syndrome is an idiopathic syndrome of hepatic lipidosis that typically affects obese and anorectic cats; these cats develop hepatic failure, icterus, and hepatic encephalopathy; elevated ALP is more severe than GGT; adipokine concentrations are altered: increased concentrations of adiponectin (related to liver disease) and leptin (specifically related to hepatic lipidosis)
• Chickens: Fatty liver hemorrhagic syndrome (FLHS) is a common noninfectious cause of mortality in laying backyard chickens; abundant coelomic fat reserves and an enlarged, pale, tan to yellow, friable liver with subcapsular and parenchymal hematomas and hemorrhages.
• Parrots: Hepatic lipidosis in pet species is commonly associated with excessive dietary fat intake, adults usually die with no premonitory signs
• Small ruminants: White liver disease caused by dietary deficiencies of vitamin B12 and cobalt; hepatic lipidosis and ceroid deposition start in the centrilobular areas; anemia and icterus are common
• Ox, bison: Ketosis results from impaired carbohydrate and volatile fatty acid metabolism; in pregnant and lactating ruminants, the continual demand for glucose and amino acids may result in ketosis when fat metabolism becomes excessive; bovine fatty liver syndrome (physiologic fatty liver/fat cow syndrome) occurs most often in obese, periparturient dairy cattle and rarely beef cattle and is precipitated by an event that causes anorexia 
•  Rabbits: Watanabe rabbits have a single-gene defect in the gene encoding for low-density lipoprotein receptor; develop hypercholesterolemia on a low-cholesterol diet; hepatic lipidosis is a characteristic finding in rabbits with gastric trichobezoar (hairballs)
• Non-human primates: Fatal fasting syndrome of older, obese macaques that are stressed and anorectic 
• Reptiles: Captive bearded dragons commonly have hepatic lipidosis at necropsy, but pathogenesis remains unclear; underlying disease is found to reduce hepatic lipid changes due to normal reptile lipid metabolism primarily occurring in the liver; reptiles can also have physiologic hepatic lipidosis in preparation for hibernation, or reproductive seasonality, especially in vitellogenic females. 
• Other periparturient animals: Due to negative energy balance and mobilization of fatty acids; hepatic pathways for oxidation of fatty acids and VLDL formation are overwhelmed, and fat accumulates in the liver
• Neonates: Fatty liver is normal in neonates of species in which the milk is rich in fat
• Hepatic lipodystrophy of Galloway calves: fatal liver disease affected a small portion of the breed; histologic findings include fibrosis, lipidosis, and bile duct hyperplasia
• American pikas may not be pathologically affected by periportal hepatic lipidosis 
• Cetacea: Hepatic lipidosis in very young animals is normal, in adults it is associated with starvation or metabolic disorders
• Fish (especially salmonids): Excessive fat deposition can lead to fatty infiltration of the liver

 

REFERENCES:

1. Abdul-Aziz T, Fletcher OJ. Chapter 8: Hepatobiliary System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016: 356 – 367, 373 – 374. 
2. Barboza T, Susta L, Reavill D, Beaufrère H. Prevalence and risk factors of hepatic lipid changes in bearded dragons (Pogona vitticeps). Vet Pathol. 2023;60(1):133-138. 
3. Barrett A, Holder K, Knowles S, LaDouceur EEB. Retrospective review of the pathology of American pikas. J Vet Diagn Invest. 2024. doi: 10.1177/10406387241256907. Epub ahead of print.
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