Featured in the February 2012 Diagnostic Edge

Hepatic Lipidosis

10-year-old, spayed female domestic shorthair, Missy

Submitted by John Christian, DVM, PhD, Associate Professor of Veterinary Clinical Pathology, Purdue University School of Veterinary Medicine and Dennis B. DeNicola, DVM, PhD, DACVP, Adjunct Professor of Veterinary Clinical Pathology, Purdue University School of Veterinary Medicine, and Chief Veterinary Educator, IDEXX Laboratories, Inc.

 

Presenting reason
Missy presented to Purdue University Veterinary Teaching Hospital because of decreased appetite, vomiting and polyuria. Clinical signs were relatively sudden, occurring over the previous 5–6 days.

 

History
Missy presented to the primary veterinarian because of recent vomiting. She had lost a lot of weight over the previous few weeks and was eating less and less until she became completely anorectic. Missy stopped eating soon after a recent change in diet. There was a dog and another cat in the household, and the two cats compete for food. Missy was several years overdue on immunizations.

 

Physical examination
Missy was thin but bright, alert and responsive. She weighed 8.5 lb (3 months previously she was 12 lb). Her temperature was 101.3ºF. Her pulse was 180 beats per minute and respiratory rate was 40 breaths per minute. The conjunctivae were icteric.

 

Referring veterinarian laboratory data
Laboratory data from a commercial reference laboratory submitted for evaluation on the day of presentation revealed a markedly increased alkaline phosphatase, a moderate increase in alanine aminotransferases as well as increased total and direct bilirubin.

 

Differential diagnoses
With the clinical presentation and laboratory data collected at initial presentation, the referring veterinarian suspected hepatic disease with hepatic lipidosis highest in the differential list. Potential biliary involvement was of concern also. Both primary and secondary hepatic disease, including metabolic, inflammatory (infectious and noninfectious) and neoplastic disease, all were to be considered.

 

Diagnostic plan
Because the clinical picture was relatively severe and no additional laboratory data was generated since the initial presentation at the referring veterinary hospital, reevaluation of a complete blood count (CBC), clinical chemistry profile and urinalysis was deemed essential to characterize the severity of the disease as well as to investigate if any other organ system was involved beyond the liver.

 

Laboratory data

 

Morphology comments: Adequate platelets, polychromasia noted, 1+ Heinz bodies, microcytes noted, few keratocytes, pincer cells and schistocytes, moderate icterus noted.

 




Figure 1: 100x oil objective field of view of the monolayer of the blood film, Wright’s stain. Note the mildly decreased erythrocyte density supporting the finding of mild anemia, the presence of easily identified polychromasia supporting a regenerative anemia, the single Howell-Jolly body (center left), the microcytes and the increased amount of central pallor compared to normal feline erythrocytes. Several poorly defined Heinz bodies and one pincer cell (top left) were present also.




Figure 2: 100x oil objective field of view of the monolayer of the blood film, Wright’s stain. Note the multiple Heinz bodies (black arrowheads), the tiny microcyte (black arrow) and the keratocyte (red arrow).




Figure 3: 100x oil objective field of view of the monolayer of the blood film, new methylene blue stain. Note the multiple Heinz bodies (black arrows), the aggregate reticulocytes (black arrowheads) and the punctate reticulocyte (red arrowhead).

 

Erythron—There was a mild normocytic, normochromic anemia with polychromasia, Heinz bodies and microcytes noted. Besides Heinz bodies, the presence of pincer cells and keratocytes also supported oxidant injury. The decreased hematocrit in the face of the findings of within reference values for hemoglobin and RBC was explained by the low normal MCV and observation of microcytes. The latter findings were in contradiction to the polychromasia noted and the mild reticulocytosis supporting a regenerative anemia. One typically anticipates the MCV to be in the upper reference interval or increased, and a decreasing MCHC in a classic regenerative profile; however, the microcytes in this case were bringing the MCV down. Although normal numbers of RBC were present, their tendency towards small size resulted in a low RBC mass (HCT). The absolute reticulocyte count proved essential in objectively characterizing this as a regenerative anemia. The morphologic changes suggested that the oxidant injury was directly related to the anemia in this case.

 

Leukon—There was a normal leukocyte count characterized by a mild neutrophilia with a lymphopenia. This is most consistent with a stress (glucocorticoid response) leukogram.

 

Thrombon—Normal.

 

 

Hepatobiliary profile—There was evidence for moderate hepatocellular injury (ALT) and cholestasis (ALP, GGT, conjugated bilirubin and urine bilirubin). The mixed bilirubin profile with a predominance of conjugated bilirubin, although subject to numerous explanations, was most consistent with intrahepatic cholestasis or a long-standing posthepatic cholestasis. The presence of detectable protein-free bilirubin (conjugated bilirubin) in the serum/plasma was highly supportive of current cholestasis. Importantly, the possibility of hepatic lipidosis was to be considered strongly given the characteristic large elevation in ALKP relative to GGT (figure 4). No significant evidence for decreased hepatic functional mass was present.

 

Kidney panel—The BUN, creatinine and urine specific gravity were within normal limits. The 1.022 specific gravity was relatively low and suggested possible diuresis. The urinalysis reveals a neutral pH (see acid-base profile), 2+ proteinuria associated with the presence of 1+ occult blood, mild pyuria, bacteruria and granular casts. These changes supported a urinary tract infection with associated mild hematuria, proteinuria and renal tubular degeneration. The concurrent presence of glucosuria and ketonuria indicated diabetes mellitus (see pancreas profile). Bilirubinuria in cats is consistent with cholestasis (see hepatobiliary profile).

 

Pancreas (exocrine/endocrine) profile—The concurrent presence of hyperglycemia, glucosuria and ketonuria, barring iatrogenic hyperglycemia, was diagnostic for diabetes mellitus (i.e., lipids are being metabolized for energy in the face of hyperglycemia). The approximately threefold increase in lipase indicated concurrent pancreatitis. Lipase in the cat is reported to be poorly sensitive (many cases of pancreatitis in the cat with no increase in lipase activity); however, when increased, lipase proves to be highly specific for active pancreatitis.

 

Electrolyte profile—The decreases in serum sodium, chloride and potassium were best explained in this case by osmotic diuresis. The decreases in sodium and chloride were proportional to one another, suggesting loss with total water loss. The presence of hypokalemia in an unregulated diabetic cat was a potentially critical finding because insulin administration will drive potassium intracellularly and may exacerbate the hypokalemia into a life-threatening crisis (figures 1 and 2). Similarly, phosphorus in the low end of the reference interval was of concern because it is also driven intracellularly with insulin administration, potentially leading to a hemolytic crisis (figure 3).

 

Acid-base profile—No specific abnormal patterns were observed even in the presence of ketonuria. Because small molecular weight ketone bodies are freely filtered by the kidney, ketonuria generally precedes significant ketonemia or acid-base abnormalities (e.g., titrational metabolic alkalosis).

 

Interpretations

 

  1. Diabetes mellitus with probable pancreatitis.
  2. Hepatocellular injury and cholestasis. Hepatic lipidosis was considered strongly.
  3. Generalized electrolyte depletion, probably secondary to osmotic diuresis. Special attention was given to the hypokalemia and low reference interval phosphorus in light of impending insulin therapy (figure 2).
  4. Urinary tract infection (with associated pyuria, hematuria and proteinuria) with tubular degeneration.
  5. Stress leukogram.
  6. Mild regenerative anemia most likely associated with oxidant injury.

 

Additional tests that were considered

 

  1. Imaging and fPLI to help confirm pancreatitis.
  2. Aspiration cytology/biopsy of liver to confirm lipidosis.
  3. Electrolyte therapy monitored serially in conjunction with insulin therapy.
  4. Urine culture and imaging (to aid localizing and characterizing renal involvement).
  5. Serial CBC to monitor anemia.

 

Further diagnostics


Diagnostic cytology—Fine-needle aspirates of the diffusely enlarged liver were collected for microscopic evaluation. The samples were highly cellular and primarily contained blood and many hepatocytes were present individually and in cohesive clusters of varying size. Cytoplasm was abundant and contained variably sized clear vacuoles consistent with lipid accumulation. Dark brown-black pigment material consistent with bile pigment was found between hepatocytes (within bile canaliculi) and intracytoplasmically within occasionally seen hepatocytes. Increased numbers of mature nondegenerate neutrophils and low numbers of normal-appearing small lymphocytes were present also; no associated infectious agents were seen or suggested.

Liver—Moderate vacuolar hepatopathy consistent with lipid accumulation. Changes were consistent with hepatic lipidosis. Mild neutrophilic inflammation was suggested also.

 




Figure 4: 50x oil objective field of view of fine-needle aspirate of liver, Wright’s stain. Note the multiple discrete clear cytoplasmic vacuoles within the cluster of hepatocytes (top left), cell-free lipid material and moderate numbers of neutrophils and erythrocytes.




Figure 5: 50x oil objective field of view of fine-needle aspirate of liver, Wright’s stain. Note the many vacuolated hepatocytes and the dark brown-black bile pigment material trapped between individual hepatocytes.

 

Clinical case outcome


The owners of Missy were informed of the severity of the disease process and were advised to pursue aggressive treatment immediately. Due to financial concerns and the projected length of hospitalization, the owners elected euthanasia.

 

Recommended reading
Adams LG, Hardy RM, Weiss DJ, Bartges JW. Hypophosphatemia and hemolytic anemia associated with diabetes mellitus and hepatic lipidosis in cats. J Vet Intern Med. 1993;7(5):266–271.
Bruskiewicz KA, Nelson RW, Feldman EC, Griffey SM. Diabetic ketosis and ketoacidosis in cats: 42 cases (1980–1995). JAVMA. 1997;211(2):188–192.
Center SA, Baldwin BH, Dillingham S, Erb HN, Tennant BC. Diagnostic value of serum gamma-glutamyl transferase and alkaline phosphatase activities in hepatobiliary disease in the cat. JAVMA. 1986;188(5):507–510.
Greco DS. Endocrine emergencies. Part I. Endocrine pancreatic disorders. Compend Contin Educ Pract Vet. 1997;19(1):15–21.


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