Peggy, the inappetent Persian cat
Professor Rob Foale
VVS Internal Medicine Specialist
Read this engaging case by Professor Rob Foale as he shares his thoughts and problem-oriented approach to Peggy, the inappetant Persian cat.
Peggy is a 7-year old neutered female Persian cat who presented with a five day history of progressively worsening inappetence leading to anorexia in the 24 hours prior to presentation. She also vomited up some white frothy material just before being brought to the clinic. The owners report that she has become lethargic and appears to just want to sleep at home, but that a week ago she was completely normal. Peggy is an indoor-outdoor cat who is fully vaccinated and wormed every three months with a prescription product.
On examination, Peggy was quiet and in reasonable body condition. Her heart rate was 168bpm with a sinus rhythm, cardiopulmonary auscultation was unremarkable and her rectal temperature was within normal range at 38.20C. Abdominal palpation revealed her liver to be a little more easily palpable on the right-hand side than expected but she showed no sign of pain or discomfort. Intestinal and renal palpation was unremarkable.
What would you like to do next?
It is very easy with patients like Peggy to jump to conclusions about what she may have or what treatment to give, so the best way forward with her, and actually with any patient with what appear to be non-specific signs, is to construct a problem list and then to list the main possible differential diagnoses for each problem. From this, it is likely that there will be at least one, often several, differential diagnoses that become apparent and we can then specifically investigate and/or test for these having prioritised the list based on the history and clinical examination findings.
If we reach a conclusive answer, then we can treat the diagnosis/diagnoses reached. However, if no definitive diagnosis is reached, we then need to return to the problem list and expand the possible differential diagnosis list and start the investigative process again to rule in or to rule out the less common possibilities. This is the essence of “problem-orientated medicine” and it is really useful because it creates a logical, reproducible framework that can be applied to any patient, meaning that we can always create a plan when we are not sure of the best thing to do.
Peggy does not appear to require emergency treatment, although if she hasn’t eaten properly for nearly a week and not at all for 24 hours, it is likely she will require fluid therapy support in the very near future. We therefore need to commence an investigation into her condition quickly. Adopting a problem-orientated approach, as explained above, her problem list is:
From this, we can create an initial differential diagnosis list, which at this stage can be quite broad in nature:
- Oral cavity pathology (dental disease, foreign body, fracture, ulceration, neoplasia)
- Nasal disease (causing inability to smell food; fungal disease, neoplasia, foreign body)
- Cardiothoracic disease (cardiac failure due to myocardial or pericardial disease, pulmonary disease, pleural effusion, intra-thoracic neoplasia)
- Gastro-intestinal disease (non-infectious gastritis/enteritis, pancreatitis, foreign body, parasitic or bacteriological infection, neoplasia)
- Metabolic disease (renal failure, diabetes mellitus resulting in DKA, hepatic disease such as cholangiohepatitis, hepatic neoplasia)
- Infectious disease (FIP, TB, pyelonephritis, toxoplasmosis)
- CNS disease
- Almost any pathology can cause lethargy(!), so as this is less specific, it is probably better to concentrate on the problems that create a more focused differential list at this stage
- Gastric disease (foreign body, inflammation, neoplasia)
- Intestinal disease (foreign body, inflammation, parasitic disease, neoplasia)
- Metabolic disease (pancreatitis, renal disease, hepatic disease, DKA)
- Toxic (xylitol, ethylene glycol)
- CNS disease
- Infectious disease (FIP)
- Inflammatory disease (hepatitis/cholangiohepatitis, amyloidosis)
- Hepatic lipidosis
- Neoplasia (lymphoma, hepatocellular carcinoma)
This is obviously a large list of potential differential diagnoses, so we need to refine this list based on the clinical findings to make it manageable. The only real physical abnormality identified was the mild enlargement of her liver, so if we take this abnormality along with the possible gastrointestinal differential diagnoses in light of her inappetence and vomiting, at this stage it would be reasonable to say we can refine the differential list down to:
- Obstructive, inflammatory or infiltrative gastro-intestinal disease
- Inflammatory, infectious or infiltrative hepatic disease or secondary hepatic lipidosis
- Other metabolic disease, thinking mainly of acute renal failure and DKA
This is a much more manageable list and has created a framework for us to now start a proactive investigation into Peggy’s diagnosis, because we now have possible diagnoses that we need to try to either rule in or rule out, and this is a crucial part of how to advance her diagnosis; when we are performing a diagnostic test we need to know what question(s) we are asking by performing the test and therefore to understand why we are doing the test.
What investigations would you like to do next?
In Peggy’s case:
- A serum biochemistry or a complete blood count (CBC) are unlikely to establish if she has inflammatory, obstructive or infiltrative gastrointestinal disease, but a serum biochemistry will rule in or rule out renal failure and diabetes, it will indicate if there is hepatocellular inflammation or dysfunction and along with a CBC, will help indicate her level of dehydration. As a minimum we therefore need to assess:
- Urea (as a marker of renal function, hydration status and may possibly also indicate gastrointestinal haemorrhage)
- Creatinine (as a marker of renal function)
- ALT (as a marker of hepatocellular inflammation)
- AST (as a marker of hepatocellular inflammation if CK is also assessed concurrently)
- ALP (as a marker of biliary inflammation)
- GGT (as a marker of biliary inflammation and potentially useful when interpreted in conjunction with ALP to help indicate the possibility of hepatic lipidosis)
- Albumin (as an indicator of hepatic function)
- Globulins (as indicators of hepatic function and also of a potential immune response)
- RBCC (as a marker of dehydration and to possibly support a diagnosis of GI or hepatic disease if for example, a microcytic anaemia was identified)
- WBCC (in particular her neutrophil count as a marker of inflammation)
- PLT count (to help know how safe or not obtaining a fine needle aspirate of an organ will be in required)
- Assessment of her electrolytes will establish if we need to supplement her potassium (which can fall quickly in inappetant cats, especially if we start intravenous fluid therapy), so we need to assess her Na+, K+ and Cl–
- An fPLI or DGGR lipase analysis will be very helpful to rule in pancreatitis
- Performing diagnostic imaging in the form of abdominal radiographs will be useful to investigate the possibility of a GI obstructive lesion, whilst abdominal ultrasound can also be used to look for obstructive lesions whilst also enabling us to assess the hepatic parenchyma and pancreas, but knowledge of the serum biochemistry results before we perform an ultrasound will help inform where we should be particularly focusing our scan
A decision was therefore made to obtain blood samples for a serum biochemistry assessment to include the parameters detailed above, an fPLI analysis, a complete blood count, an electrolyte assessment and an intravenous catheter was placed in anticipation of commencing intravenous fluid therapy as soon as the electrolyte results became available, with the hypothesis being that we were performing these analyses to try to rule in or rule out hepatic disease, renal disease, diabetes mellitus and pancreatitis before considering diagnostic imaging. The results obtained were:
|Albumin||22 g/l||25 – 40|
|Globulin||55 g/l||20 – 45|
|Urea||8.6 mmol/l||2.5 – 7.5|
|Creatinine||68 umol/l||40 – 145|
|Glucose||5.4 mmol/l||4.3 – 6.6|
|ALT||257 iu/l||13 – 88|
|AST||290 iu/l||13 – 60|
|ALKP||443 iu/l||14 – 105|
|GGT||22 iu/l||0 – 10|
|Bilirubin||9 umol/l||0 – 15|
|Creatine kinase||172 iu/l||110 – 257|
|Na+||152 mmol/l||150 – 161|
|K+||3.7 mmol/l||3.3 – 4.8|
|Cl–||122 mmol/l||120 – 127|
|HCT||0.22 l/l||0.24 – 0.45|
|MCV||38 fl||40 – 52|
|MCHC||31 pg/ml||32 – 35|
|WBCC||23 x 10e9/l||5.5 – 19.5|
|Neutrophils||19.9 x 10e9/l||5.5 – 12.5|
|Lymphocytes||1.4 x 10e9/l||1.5 – 5.0|
|PLT||220 x 10e9/l||200 – 500|
Film Comment: Mild left shift, occasional polychromasia
Considering our differential diagnosis list and rationale for performing these blood tests, how do you interpret these results and what would you want to do next?
Interpretating the results:
- The normal creatinine means that overt renal failure has been ruled out
- The marginal elevation in urea is almost certainly pre-renal in nature, so most likely to be due to dehydration or low-grade GI haemorrhage, but at this level is unlikely to be clinically significant
- The normal blood glucose means that diabetes mellitus (and therefore DKA) has been ruled out
- The low albumin and high globulins are most likely to reflect an inflammatory response in which the low albumin is a negative acute phase protein marker, but the low albumin could also indicate reduced hepatic function, renal protein loss or GI protein loss. However, as her urea concentration is slightly higher than normal and urea is also made by the liver, hypoalbuminaemia as a consequence of reduced liver function is less likely. Further investigation may therefore require a urine protein: creatinine ratio assessment. However, as renal failure has been ruled out as a cause of Peggy’s presenting signs, it is more sensible at this stage to concentrate on the potential hepatic causes of hypoalbuminaemia and reserve further investigations of this to if we do not find a hepatic explanation
- A serum albumin of 22g/l is highly unlikely to cause any physiological difficulties so does not need to be treated specifically
- Her electrolytes are unremarkable so there is no need to supplement her with potassium, but this will require regular re-assessments if she remains inappetent and we start intravenous fluid therapy. As she hasn’t eaten, it is now appropriate to provide her with fluid therapy support using 0.9% saline or Hartmann’s at a maintenance rate
- The negative fPLi indicates that Peggy does not have pancreatitis
- The main abnormalities present are the ALT and AST elevations, which considering we had inflammatory or infiltrative disease as a major differential diagnosis, are significant. ALT is predominately located within hepatocytes and the serum half-life of ALT in cats at approximately 6 – 10 hours is considerably shorter than the 60 hours it is in dogs. A five-times elevation in ALT in a cat should therefore always be taken as being significant, and indicative of active hepatocellular damage at the time the blood sample was obtained. AST is also located within hepatocytes, but there are larger volumes located within skeletal muscle, so if there is a proportional increase in CK and AST concurrently, it is more likely that the AST source is damaged skeletal muscle. However, in Peggy’s case, the fact that her CK level is within normal limits is indicative that the elevated AST she displays is probably of hepatic origin
- These two results therefore support Peggy having a diagnosis of an inflammatory, infectious or infiltrative hepatopathy
- ALKP and GGT are both markers of biliary inflammation or other pathology, which may of course be linked to hepatic pathology. Hepatic lipidosis was on our differential diagnosis list and in this condition, ALKP is often elevated by a significantly higher degree than GGT, so this remains a possible differential diagnosis. However, hepatic lipidosis is a secondary condition with a primary underlying pathology, so this will not be a diagnosis on its own
Therefore, if we take these results with reference to our initial differential diagnosis list, we can further refine our list, such that:
- Obstructive, inflammatory or infiltrative gastro-intestinal disease – still possible, but less likely as a primary pathology
- Pancreatitis – highly unlikely/ruled out
- Inflammatory, infectious or infiltrative hepatic disease or secondary hepatic lipidosis – most likely and requires further investigation to confirm and establish the exact nature of the pathology
- Other metabolic disease, thinking mainly of acute renal failure and DKA – ruled out
Considering our refined differential diagnosis list, what would you want to do next?
In light of this refinement, it is now clear that performing diagnostic imaging with a particular focus to investigate the possibility of inflammatory, infectious or infiltrative hepatic disease is the next and most appropriate action. Radiography will give us information on the general hepatic size and shape and would also reveal the presence of abnormal gas if Peggy had emphysematous cholangitis, and we would probably also be able to establish the presence of a gastrointestinal foreign body if one was present. However, radiography cannot give us detail on the appearance of her hepatic parenchyma, and the use of ultrasound also facilitates diagnostic samples being obtained through fine needle aspiration or Tru-cut biopsy, whilst also facilitating visualisation of the pylorus and the whole of the intestinal tract. A CT scan at this stage does not offer any significant advantages over an ultrasound scan, so moving forward with an abdominal ultrasound is the most appropriate action to take.
An abdominal ultrasound examination was performed under sedation with dexmedetomidine and butorphanol. This confirmed her liver to be moderately enlarged throughout with an accompanying diffuse increase in echogenicity, but with a normal appearance to her common bile duct, gall bladder and biliary tree. No vascular abnormalities were noted. Examination of her pylorus, pancreas, intestinal tract, spleen, kidneys, adrenal glands and urinary bladder were all unremarkable:
All of our clinicopathological evidence is pointing towards an inflammatory, infectious or infiltrative condition of the liver and our new and refined differential diagnosis list therefore is:
- Inflammatory hepatic condition
- Infectious hepatic condition
- Infiltrative hepatic condition
- Hepatic neoplasia, lymphoma more likely than adenoma or carcinoma in light of ultrasound appearance and statistical occurrence
- Hepatic lipidosis
We have therefore now reached the point where we require a cellular sample to be able to drive her diagnosis forwards. Obtaining a liver biopsy via laparotomy, laparoscopy or Tru-cut biopsy is very much an option here, as fine needle aspirates will not be diagnostic for hepatitis or FIP, but such a procedure requires a full general anaesthetic and full assessment of her coagulation status before proceeding.
Furthermore, whilst FIP remains a distinct possible diagnosis, the fact that Peggy’s biliary system appears completely normal and most cats have cholangiohepatitis as a complex rather than just idiopathic hepatitis like dogs. It was the view of the attending clinician that an infiltrative condition was more likely than an inflammatory one. Ultrasound-guided fine needle aspirates of the liver in the hands of an experienced ultrasonographer are reasonably safe to perform, as long as the platelet count is normal and the liver does not appear shrunken (as this indicates that the normal hepatic flexibility and capsule elasticity is likely to be compromised). Fine needle aspirate samples are generally excellent for diagnosing lymphoproliferative disease and lipidosis. The fact that they can also be obtained with good sedation also justifies attempting this first and resorting to obtaining histological biopsy samples if FNA’s fail to generate a diagnosis.
Two fine needle aspirates from the right lateral liver lobe were therefore obtained and the cytological appearance of the cells seen is as shown below. Can you describe these cells? Does this give us a diagnosis?
The slides reveal a significant population of abnormally large round cells of lymphoid origin, with each cell being 2 – 3 times the size of adjacent erythrocytes. The nuclear to cytoplasmic ratio is increased, the shape and size of the nuclei are variable and within each nucleus there are variable numbers of variably shaped and sized nucleoli. There is one mitotic figure visible at the very top (just to the right of centre) of the slide, one cell at the bottom of the slide that looks like it is in the very early stages of mitosis due to two areas of chromatin clumping and a small number of the cells exhibit nuclear moulding. A few of the cells exhibit vacuolation within their cytoplasm, which could be consistent with them being of B-cell origin.
These cells therefore display the hallmark signs of neoplastic change. A neoplastic proliferation of lymphocytes (possibly B cells) within the liver is consistent with a diagnosis of HEPATIC LYMPHOMA.
Lymphoma is considered to be more common in the cat than the dog, but the multi-centric form of the disease is more common in dogs than cats. Lymphoma was historically linked to FeLV infection but it is still a relevant clinical diagnosis even though FeLV infection rates have fallen markedly over the past 20-30 years. Indeed, there is one study showing that feline lymphoma case numbers presenting to an American veterinary teaching hospital have actually risen over the past 30 years, not fallen.
In Peggy’s case, we performed a PARR analysis on the samples obtained which confirmed her lymphoma to be of B-cell origin and we also ran an FeLV/FIV screen, which proved to be negative. After consultation with her owners, she was then treated with a modified 17-week Madison-Wisconsin chemotherapy protocol using vincristine, cyclophosphamide, prednisolone and doxorubicin which was well tolerated and she returned to normal health. Monitoring her for remission was difficult, as it was cytology that confirmed the diagnosis, so a repeat abdominal ultrasound was performed before her week 11 vincristine treatment (i.e.: after she had been off prednisolone for more than one month) which revealed her liver to have a normal size and sonographic appearance and no further assessments were performed at the owners’ request.
She remained well for nine months post-diagnosis, but then her clinical signs of inappetence and lethargy returned, her liver was found to be significantly enlarged and an abdominal ultrasound at that time revealed a general increase in hepatic echogenicity along with nodular lesions in her spleen and enlargement of her hypogastric lymph nodes. A provisional diagnosis of lymphoma relapse was made, Peggy’s owners then opted for euthanasia at this time.
Hepatic lymphoma as a sole site is not a common diagnosis, so it was not high on the original differential diagnosis list. This illustrates how useful developing a problem-orientated approach to cases can be, and how focusing on what the most likely differential diagnoses are, and sensibly testing for these, can really help in real-life clinical settings.
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