Journal of Feline Medicine and Surgery (2011) 13, 614e617
doi:10.1016/j.jfms.2011.05.001
CASE REPORT
Refeeding syndrome in a cat with hepatic lipidosis
Karen Brenner
BVSc,
Kate S KuKanich
Department of Clinical Sciences,
Kansas State University, College of
Veterinary Medicine, Manhattan,
KS 66506, USA
Date accepted: 29 April 2011
DVM, PhD, DACVIM*,
DVM
Refeeding syndrome is characterized by severe hypophosphatemia occurring in
patients given enteral or parenteral nutrition after severe weight loss. There are
few veterinary reports that describe this syndrome but it is well documented in
human medicine. This report describes a case of a domestic shorthair cat
diagnosed with hepatic lipidosis following a 4-week history of decreased
appetite and weight loss and in whom refeeding syndrome was documented
after initiation of enteral nutrition. Clinical findings, blood work abnormalities
and disease progression in this patient are described from the time of diagnosis
through to recovery. A review of the current literature pertinent to this clinical
syndrome is included.
Ó 2011 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.
A
14-year-old, spayed female domestic shorthair cat was presented for evaluation of
weight loss and decreased appetite of 4 weeks
duration. The patient had been evaluated 8 weeks earlier for intermittent episodes of mixed bowel diarrhea.
A minimum database (complete blood count, serum
biochemistry, urinanalysis and qualitative fecal flotation) was completed and hypoalbuminemia (2.5 g/dl,
reference interval [RI] 3.2e4.7 g/dl) was the only documented abnormality. Abdominal imaging and endoscopy were declined and no definitive diagnosis was
established. Nonetheless, resolution was noted following institution of metronidazole therapy and a highly
digestible diet (Prescription Diet i/d; Hill’s Pet
Nutrition).
On physical examination, the patient was alert and
displayed icteric mucous membranes. There was loss of
lean tissue, and the body condition score was 1/5. The
patient’s body weight (4.22 kg) had decreased 0.9 kg
(18%) from the previous visit (5.12 kg). A grade II/VI
left, parasternal, systolic heart murmur was auscultated.
Pertinent abnormalities from the complete blood
count and serum biochemistry are displayed as day
0 in Table 1. Serum hypocobalaminemia was also documented (<150 ng/l, RI 290e1499 ng/l). Ultrasoundguided liver aspirates demonstrated hepatic lipidosis.
Aerobic and anaerobic bacterial cultures of liver aspirates
were negative.
The patient was diagnosed with hepatic lipidosis,
most likely secondary to gastrointestinal disease. Supportive treatment was instituted with intravenous
*Corresponding author. E-mail: kstenske@ksu.edu
1098-612X/11/080614+04 $36.00/0
Nicole M Smee
lactated Ringers solution (LRS; Hospira, 480 ml/24 h),
famotidine (Famotidine; Baxter Healthcare, 0.5 mg/kg
IV q 24 h), phytonadione (Vitamin K1; MWI, 2.5 mg/kg
SC q 24 h), s-adenosylmethionine (Denosyl; Nutramax
Laboratories, 24 mg/kg PO q 24 h) and mirtazapine (Mirtazapine; Aurobindo, 3.75 mg PO q 72 h). Modest voluntary alimentation was observed, and 3 days after
admission an esophageal feeding tube was routinely
placed under general anesthesia, using thiopental (Thiopental; Hospira, 13.6 mg/kg IV) and isoflurane (IsoFlo;
Abbott Animal Health); the decision to postpone tube
placement was made to ensure optimal anesthetic monitoring and support was available in light of the cat’s
comorbidities. No immediate post-procedural complications were observed.
The patient’s resting energy requirement (RER) was
calculated using the standard formulation, RER
(kcal) ¼ 30 body weight (kg) þ 70.1 The patient’s
body weight (4.3 kg) at the time of tube placement was
employed in this calculation. A canned, high protein,
high energy recovery diet (Prescription Diet a/d; Hill’s
Pet Nutrition) was provided. The volume of food was increased by 1/3 RER over 3 days to achieve the total RER.
The patient was discharged from the hospital 48 h after
initiating nutritional support. Over the next 2 days,
communications with the owner suggested that the cat
was in stable condition.
Three days after discharge, nausea, profuse diarrhea,
lethargy and an increased respiratory rate were observed.
Upon re-examination, the patient was icteric, tachypneic,
markedly depressed, and had generalized muscle weakness. Systolic hypotension (64 mmHg) (Doppler; Parks
Medicinal Electrical), relative bradycardia (140 beats
Ó 2011 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.
Refeeding syndrome in a cat with hepatic lipidosis
615
Table 1. Complete blood count and serum biochemistry abnormalities. Values given in bold are outside
the RI.
Parameter
White blood cell count
Hematocrit, spun
Glucose
Creatinine
Blood urea nitrogen
Albumin
Sodium
Potassium
Chloride
Phosphorus
Magnesium, free
Alanine transaminase
Alkaline phosphatase
Bilirubin
Cholesterol
RI
RI*
Day 0
Day 8
Day 9*
Day 10
5.5e19.5 K/ml
30e45%
60e133 mg/dl
0.8e2.1 mg/dl
16e35 mg/dl
3.2e4.7 g/dl
150e163 mmol/l
3.6e5.5 mmol/l
116e130 mmol/l
2.7e6.5 mg/dl
0.77e1.28 mg/dl
45e217 U/l
11e95 U/l
0e0.4 mg/dl
75e271 mg/dl
e
e
70e119 mg/dl
e
17e37 mg/dl
e
152e162 nmol/l
3.2e5.0 nmol/l
113e126 nmol/l
e
0.77e1.28 mg/dl
e
e
e
e
4.9
36
99
1
16
2.8
149
4.4
120
3.5
np
71
607
4.6
168
25.3
22
303
1.3
51
2.8
129
3.3
84
6.0
np
76
522
10.8
256
np
19
175*
0.9
17*
np
136.4*
3.5*
108.9*
np
1.1*
np
np
np
np
10.9
17
234
0.5
9
2.1
138
4.2
107
1.7
np
81
490
8.6
196
*Indicates different RI for sample. np ¼ not performed.
per min) with weak femoral pulses and mild hypothermia (98.1 F) were documented. Oxygen responsive
hypoxemia (90%) was recorded with pulse oximetry.
A moderate normocytic, normochromic anemia and
acute inflammatory leukogram with mild toxic change
were recorded. Pre-regenerative hemolysis due to oxidative damage or gastrointestinal ulceration was considered a plausible explanation for the anemia as well as
anemia of chronic inflammatory disease.2 Gastrointestinal bacterial translocation, bacterial cholangiohepatitis,
and pneumonia were considered for the inflammatory
leukogram. Moderate hyperglycemia was suspected to
have been induced by stress, and the marked hyperbilirubinemia was considered to be a consequence of hemolysis and/or hepatic dysfunction. Despite the absence of
urine evaluation, it was hypothesized that the azotemia
was most likely a reflection of hypovolemia. The remaining abnormalities on day 8 (Table 1), hyponatremia and
hypochloremia, were attributed to loss of electrolyterich gastrointestinal fluid. Thoracic radiographs were
unremarkable, and echocardiography suggested senile
remodelling or mild hypertrophic cardiomyopathy as
well as mild diastolic abnormalities.
Active surface rewarming was undertaken and the
patient was treated with intravenous lactated Ringers
solution (LRS; Hospira); potassium chloride (KCl; Hospira) supplementation was adjusted based on serial
serum values (Table 1). Maropitant (Cerenia; Pfizer
Animal Health, 1 mg/kg SC q 24 h) was administered
to control nausea. Famotidine (Famotidine; Baxter
Healthcare, 0.5 mg/kg IV q 24 h) was initiated because
of the possibility of gastrointestinal ulceration suggested
by the increased blood urea nitrogen to creatinine ratio as
well as moderate anemia. Furthermore, ampicillin/sulbactam (Unasyn; Pfizer Animal Health, 22 mg/kg IV q
8 h) was provided because despite negative culture
results, bacterial cholangiohepatitis was still considered
a relevant differential diagnosis and the patient’s history
documented a positive response to antibiotic therapy.
Cyanocobalamin (Vitamin B12; APP Pharmaceuticals,
250 mg SC q 7 days) was also administered. An inspired
oxygen fraction of 40% was provided using an oxygen
cage. Nutritional supplementation was withheld for
19 h by which time the patient’s potassium was within
the RI and the hyponatremia and hypochloremia were
improved.
Approximately 38 h after re-admission, marked hypophosphatemia and hemolytic anemia were recorded (day
10, Table 1). The anemia was characterized by moderate
Heinz bodies, basophilic stippling, and occasional polychromasia. Weight gain (200 g, 5%) and resolution of azotemia were also documented at this time. Although
severe lipidosis and other primary liver diseases were initially considered differentials for the increasing bilirubin
and oxidative damage, the combination of the patient’s
nutritional history, hypophosphatemia, hypokalemia
and hemolytic anemia was most consistent with a diagnosis of refeeding syndrome. Supplemental phosphorus
was provided using potassium phosphate (KPO4; American Regent). Feeding began at 1/5 RER and was increased gradually over 5 days to achieve the total RER.
Again, a canned, high protein, high energy recovery
diet was employed (Prescription Diet a/d; Hill’s Pet Nutrition). The patient was weaned off oxygen and discharged on day 15. The esophageal feeding tube was
removed on day 46 when a complete recovery was
achieved. The patient is currently fed ad libitum with
a dry, high protein, low carbohydrate diet (DM Dietetic
Management Feline Formula; Nestlé Purina PetCare
Company); this dietary choice was dictated by the needs
of another cat in the household. Since the time of discharge an isolated episode of acute vomiting and
616
K Brenner et al
inappetence has been recorded; a highly digestible diet
was provided at this time (Prescription Diet i/d; Hill’s
Pet Nutrition) and the signs resolved in 2 days.
Refeeding syndrome is defined as the constellation of
metabolic and physiologic derangements associated
with caloric repletion of the starved patient.311 Classically, refeeding syndrome is characterized by the development of severe hypophosphatemia following the
introduction of enteral or parenteral nutrition. Refeeding
syndrome can also variably include hypokalemia, hypomagnesemia, vitamin deficiencies, fluid intolerance and
glucose intolerance.512
It is believed that refeeding syndrome is a consequence
of the body’s inability to rapidly adapt from a chronically
catabolic state to an anabolic state. Starvation can lead to
villous atrophy and compromised absorptive capacity
may explain the severe diarrhea observed in the patient
described here.
In response to anabolism and heightened by the
release of insulin, cellular uptake of phosphorus and
inorganic phosphates occurs, leading to hypophosphatemia. Phosphorus and phosphates are required for the
synthesis of ATP, DNA, RNA, proteins and 2,3-DPG, as
well as for phosphorylation of glucose. Phosphorus
depletion leads to a reduction in erythrocyte ATP concentration, failure of actin and myosin, altered erythrocyte
membrane lipids and consequently, hemolytic anemia.13,14 Heinz body formation contributes to anemia
and occurs due to impaired phosphorylation of glucose
in the pentose monophosphate pathway.14 The patient
described herein showed evidence of hemolytic anemia
and Heinz body formation, and although these changes
can result directly from lipidosis and toxin or drug exposure, such etiologies were considered less likely than
refeeding syndrome. Additional manifestations of hypophosphatemia may include increased susceptibility to infection, inadequate oxygen delivery to tissues,
rhabdomyolysis, impaired diaphragmatic contractility,
decreased sarcomere contractility and encephalopathy.
Impaired oxygen delivery from anemia and diaphragmatic contractility may have led to this patient’s tachypnea and hypoxemia. In this case, hypophosphatemia was
not apparent until 38 h after presentation; however, the
presence of a hypophosphatemic state was arguably
masked by the reduction in glomerular filtration rate
that accompanies volume contraction, which this patient
had. This interpretation is supported by the 60% reduction in creatinine that was documented between the
value recorded on admission for refeeding syndrome
(day 8, Table 1) and the value on the day that volume
repletion was accomplished, when hypophosphatemia
became biochemically apparent (day 10, Table 1). Ideally,
direct estimation of the patient’s glomerular filtration rate
would have been conducted to confirm this hypothesis.
The provision of carbohydrates and amino acids to
starved patients promotes anabolism and glycosis leading to intracellular translocation of phosphorus, potassium and magnesium and this is further augmented by
the increased release of insulin which is suppressed during states of weight loss and hepatic lipidosis.4,15 For
these reasons, a low carbohydrate, high protein and
high energy diet is recommended.
Hypokalemia may provoke glucose intolerance, neuromuscular weakness, ileus, polyuria and polydipsia,
respiratory depression and cardiac arrhythmias. Our
case demonstrated hypokalemia, and this derangement
may have contributed to the neuromuscular weakness
and respiratory depression observed; this was supported
by the notable clinical response to aggressive potassium
supplementation. Magnesium is mandatory for cellular
processes involving ATP, and hypomagnesemia is an
important mediator of hypocalcemia, refractory hypokalemia, cardiac arrhythmias and neuromuscular weakness.5 Hypomagnesemia is a variable finding in
patients with refeeding syndrome.
The remaining electrolyte abnormalities, marked
hyponatremia and hypochloremia, were most likely the
consequence of electrolyte-rich insensible fluid loss in
diarrhea. These abnormalities improved with intravenous fluid therapy; however, more aggressive therapy
may have been indicated because such derangements
can contribute substantially to generalized weakness.
Thiamine (vitamin B1) is an essential cofactor in a number of reactions involved in carbohydrate metabolism,
and it may become depleted when cellular demand increases in response to refeeding with carbohydrates.6,8,10,11 Thiamine deficiency can be objectively
diagnosed by demonstrating deficiencies of erythrocyte
transketolase or thiamine-phosphorylated esters;
however, thiamine deficiency is more commonly diagnosed by subjectively documenting signs consistent
with Wernicke’s encephalopathy and a response to
supplementation. Many features of thiamine
deficiency-associated-encephalopathy (ataxia, vestibular
dysfunction and visual disturbances) are indistinguishable from those induced by hypophosphatemia and hypokalemia, rendering it difficult to define its
contribution to refeeding syndrome. It’s important to
note that thiamine supplementation is common in commercial pet foods1 and clinical deficiency is rarely documented in companion animals.
Hyperglycemia documented in patients with refeeding syndrome may reflect the introduction of glucose
into a system adapted to fat metabolism. Hyperglycemia
can lead to disrupted neutrophil function and hyperosmolar hyperglycemic non-ketotic coma. The cat in this
report had only moderate and transient hyperglycemia
and although this abnormality was initially attributed
to stress it may also be an illustration of the pathophysiology of refeeding syndrome in play.
There is a paucity of reports documenting refeeding
syndrome in the veterinary literature, and the incidence
is currently unknown. Veterinary literature describing
the metabolic complications associated with parenteral
feeding is available;12,16,17 however, similar reports
focused on enteral nutrition are limited. One publication
describes hypophosphatemia associated with enteral alimentation in 2% of feline patients during an 18-month
period.13 To the authors’ knowledge, the three manuscripts that specifically identify refeeding syndrome in
Refeeding syndrome in a cat with hepatic lipidosis
companion animals are restricted to feline patients.12,13,18
The authors suggest that this may reflect the highly specific nutritional requirements of this species, such as the
need for high dietary protein and thiamine as well as essential amino acids. Furthermore, due to their low level of
hepatic glucokinase, cats may be more susceptible to the
development of hyperglycemia and subsequent insulin
release after nutritional support is instituted.
Early identification of patients at risk for refeeding syndrome is a major focus in human nutrition,10,13,15,19 and
experts advocate for correction of electrolyte deficiencies
prior to initiating feeding as well as administration of
a loading dose of thiamine.3,5,11 When nutritional support
is instituted, no greater than 20% of the basal energy expenditure is provided on the first day and supplementation is increased over 4e10 days.5,11 Recommended daily
monitoring parameters include body weight, urine output, plasma electrolytes, electrocardiographic changes
and maintenance of serum glucose within a narrow
range.5,11
One veterinary report specifically lists hepatic lipidosis as a risk factor for the development of refeeding syndrome.10 Interestingly, in the study describing enteral
nutrition induced hypophosphatemia in cats, 5/9 cases
were diagnosed with hepatic lipidosis.13 Similarly, humans with cirrhosis and hepatic insufficiency are more
likely to develop hypophosphatemia with glucose
infusions.13
Why the patient in this report developed refeeding
syndrome is unknown. The nutritional plan that was implemented adhered to contemporary recommendations
not to exceed the patient’s RER and to increase the daily
caloric load slowly over 72 h.1 Perhaps following recommendations from the human literature whereby the patient’s basal energy requirement rather than the RER is
used in addition to increasing the daily caloric intake
over 4e10 days instead of 3 days, would have prevented
this complication. Finally, high risk patients should be
identified prior to initiating nutritional support and electrolyte values (potassium, phosphorus, magnesium) and
packed red cell volume monitoring should be performed
daily until total RER is achieved in order to minimize the
risk of refeeding syndrome.
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