Using a problem-orientated approach in an 8-year-old Labrador with abdominal distention.

Professor Rob Foale

VVS Small Animal Internal Medicine Specialist

Follow through this case blog and answer the questions posed by Professor Rob Foale. Discover how he would encourage you to approach a challenging internal medicine case, in a problem-orientated way.

“Billy” is an 8-year-old MN Labrador who had been in his owners’ possession since he was a puppy.  He had been regularly vaccinated, he had no travel history, and no past history of illness at all.  However, he presented to his vet due his owner starting to become concerned that he was “putting on weight”, he was more lethargic than normal and he seemed to get tired much more quickly than he used to when he was out on a walk. 

What more might you want to know?

Establishing the timeline of these changes is really important so we can work out whether Billy has become unwell very quickly and has an acute pathology or whether he has a more chronic condition/s.  We also need to know, with his history of gaining weight if his appetite has increased or not?  Furthermore, what actually do his owners mean by “gaining weight”?  Understanding exactly what the owners’ concerns are is really important to help them build trust in us, to help us understand what the underlying problems may be and to help us avoid any misunderstandings.  Lastly, we ought to establish some indicators of general health for Billy, so whether or not his water intake has changed (and if so, by how much?), are his faeces normal, is his breathing normal and has his character changed in any way?

On clinical examination, Billy’s “weight gain” was actually abdominal enlargement with palpable muscle loss over his dorsum.  Accurate abdominal palpation was difficult but a ballotable fluid thrill was present.  His pulmonary auscultation and percussion were normal, and he had a regular heart rate of 120bpm with synchronous pulses, but possibly slightly quiet heart sounds and slightly pale mucous membranes, but his CRT was normal.

So, what do you want to do now?

It is very tempting to say “I’ll run some bloods”, but this is an answer that although sometimes will lead us to the answer, most referral clinicians can cite dozens and dozens of cases they will have seen because a colleague did exactly this without thinking about what might be wrong with the patient. In these cases the blood results led the attending clinician down completely the wrong path.  To avoid this, we should always ask ourselves, “what questions am I trying to answer by performing this test?”; to be able to do this we must create a differential diagnosis list we are investigating and to do this, we firstly need to create a problem list:

His ascites is really the most important clinical problem, so the potential differential diagnosis list for this is:

Pathophysiological grouping:

• Increased hydrostatic pressure
• Reduced plasma oncotic pressure
• Increased endothelial permeability
• Reduced lymphatic uptake

Clinical grouping

We could also list the differential diagnoses for lethargy and muscle/weight loss, but these lists are long and we already have a reasonably lengthy list of possible causes for Billy’s ascites. We need to work to narrow this list down as quickly as we can and the best way to do this is to sample the ascitic fluid, not to take bloods as a first step!

Billy therefore had a 5ml ascitic fluid sample obtained via a sterile mid-line aspiration and the fluid analysis results were as follows:

How would you interpret these results?  Is there any further information you would like to have?

These results indicate that Billy’s ascites is a moderately low protein modified transudate.  Taking a problem orientated medicine approach, if we deem this as a new problem we can then consider the possible differential diagnoses that may be responsible:

• Hepatic disease
• Cardiac/pericardial disease
• Venous thrombosis
• Neoplasia (carcinomatosis)
• Urine leakage

This immediately indicates that a biochemical and cell count analysis on the fluid on its own is not enough and what is vital in all fluid analysis is a microscopic analysis of the sample too, in this case to investigate the possibility of there being an underlying neoplastic cause.  The microscopy on Billy’s ascitic fluid sample revealed:

CYTOLOGICAL FINDINGS

A cytospin and direct smear are examined. There is a mixed population of cells, comprising  40% neutrophils, 40% macrophages and 20% small lymphocytes with occasional mesothelial cells. The neutrophils are non-degenerate, the macrophages are moderately activated and mesothelial cells show mild reactive change

Interpretation:  moderate cellularity with moderate to low protein indicates a modified transudate.

This result rules out an exfoliating neoplasia such as a mesothelioma or carcinomatosis and further biochemical evaluation proved the fluid not to be urine, so we have been able to markedly reduce the main differential diagnosis list to:

• Hepatic disease
• Cardiac/pericardial disease
• Venous thrombosis
• Neoplasia (carcinomatosis)
• Urine leakage

Right-sided heart failure (either due to myocardial disease, pericardial disease or thrombotic/parasitic disease) can cause marked elevations in hepatocellular parameters due to stress and hypoxia. Problem-orientated medicine indicates that ruling out cardiac disease is the next logical step and this will also probably make interpreting any serum biochemistry results more simple.  Note: we have got this far without any blood sampling, sedation or anaesthesia or diagnostic imaging being required. If we do move to using such techniques, we will have a much clearer idea of why we are doing the tests, what we are looking to diagnose (or rule out) and how to interpret our findings.

An echocardiogram was performed which revealed no evidence of myocardial or pericardial disease and no evidence of intravascular obstruction.

What would you do now?

We are now in the position where our main differential diagnosis for Billy is that he has some form of hepatic pathology. We cannot completely rule out a protein-losing nephropathy or the presence of a portal venous thrombus but if one does exist, we don’t yet have an indication of what pathology could cause this.  As his owners described that there was no sudden change in Billy but that rather he had changed his body shape and become more lethargic over a period of several weeks, a chronic hepatopathy would definitely fit with his clinical signs (as would his age and breed), but so would a renal pathology such as glomerulonephritis. We also cannot rule out the more worrying possibility of him having an hepatic neoplasia.  

A venous blood sample was obtained for serum biochemistry analysis and a complete blood count, but with the very specific aim of seeing if there was evidence to support hepatocellular and/or renal pathology and also to look for evidence to possibly support a coagulopathy.

His haematology results were:

What abnormalities can you identify here and how do you interpret them?  Do these results fit with our main possible differential diagnoses?

The CBC results show that Billy has a mild non-regenerative anaemia with evidence of some microcytosis.  If we again consider this to be a new problem and then consider the differential diagnoses for microcytosis:

• Iron deficiency
  • Young patients
  • Diet
  • Intestinal parasites
• GI blood loss
  • Ulceration
  • Parasites
  • Inflammation
  • Neoplasia
• Portosystemic shunts
• Chronic hepatitis/hepatic cirrhosis
  • Can sometimes also see target cells
  • Note: Microcytosis due to liver disease caused by abnormal iron transport, not necessarily iron deficiency

Billy isn’t a young dog but all of the other differentials listed here are possible, so this has increased the need to obtain serum biochemistry results and look for evidence of hepatocellular and renal pathology and then to plan possible diagnostic imaging depending on these results. 

Billy’s serum biochemistry results revealed:

What abnormalities can you see here and how do you interpret them?  Is there any further data you would like to see?

The major abnormalities are the marked elevation in ALT and ALP, with a reduction in total protein, albumin and urea.  Serum creatinine is normal, so significant renal compromise can be ruled out, but we still require a urine sample to investigate the possibility of Billy having a protein-losing nephropathy (and we also need to consider the possibility that he may have more than one pathology!).  However, the pattern of change here is most consistent with Billy having significant hepatocellular damage and possibly reduced hepatic function (as both albumin and urea are synthesised in the liver). 

ALT and AST (although the main source of AST is skeletal muscle, so if AST is assessed we need to measure CK concurrently) can be considered as hepatocellular/leakage enzymes that are released from hepatocytes following damage, cell necrosis or changes in membrane permeability that cause enzyme leakage.  It is important to remember that in acute disease the degree of elevation increases roughly proportional to number of hepatocytes damaged but the level of elevation does not indicate prognosis, reversibility, or the nature of disease.  Increases are usually more marked in acute than chronic disease and actually, in end stage liver disease there may be only a small increase or even normal levels of these enzymes, due to there being such a small cell mass left to release their contents. 

ALP and GGT on the other hand are cholestatic enzymes that a found on the bile canalicular membrane and small amounts normally secreted into bile.  These markers therefore reflect biliary inflammation and cholestasis; it is really important to remember that ALP is not a hepatocellular marker!  It is also important to remember that dogs are unique and have a cortisol-induced isomer of ALP, so ALP will often rise (albeit mildly) is any dog that is stressed due to illness or pain, so ALP always needs to be interpreted with this in mind.

Cholesterol and bilirubin are also synthesised in the liver and their levels are within normal limits, so these results are giving a slightly mixed message with regard to liver function.  Performing a bile acid stimulation would help establish whether Billy has normal liver function, so this was subsequently performed:

• Bile acids (fasting):                 158 mmol/l  (0.1 – 5.0)
• Bile acids (pp):                        181 mmol/l (0.1 – 10.0)

Billy’s serum albumin-ascites gradient was also calculated to be 1.5, which is potentially consistent with him having portal hypertension, which can occur secondary to significant inflammatory or fibrosing hepatopathies (Pembleton-Corbett et al (2000), JVIM, 14(6), 613 – 618).

So, what would you like to do now?

The basis of problem-orientated medicine is to use the differential diagnosis list to inform us of the most likely pathology/ies that are present and to investigate these in a logical and efficient manner.  Therefore, if we review the differential list we had and see how it has narrowed down:

Billy’s bile acid stimulation in conjunction with his serum biochemistry is very strongly indicative that he has a significant hepatopathy. Bile acid levels in excess of 100 mmol/l are highly suggestive of porto-systemic shunting, which at his age is most likely to be secondary to a significant, long-standing primary hepatopathy.  In the absence of diarrhoea and with normal cholesterol levels, a protein-losing enteropathy can be considered to be unlikely, so a good urinalysis will enable us to rule a PLN in or out before moving forwards to investigate his liver in more detail:

A mid-stream free-catch urine sample was obtained and the results were as follows:

How do interpret these results?  What would you like to do next?

The normal UPCR means we can rule out Billy having a PLN, but the presence of isosthenuria with normal serum renal parameters would be potentially further supportive of him having a significant hepatopathy.

All of the clinical data we have is now strongly suggestive that Billy has a significant hepatic pathology as the root cause of his problems.  In a dog of his age and breed, chronic hepatitis is the most likely diagnosis but neoplasia cannot be ruled out. So diagnostic imaging in the form of abdominal ultrasound is now indicated.  Ultrasound is generally considered preferable to CT in this situation.

Billy’s abdominal ultrasound revealed:

• Liver: multiple hypoechoic nodules throughout the parenchyma leading to an heterogeneous echogenicity of the parenchyma. The size of this organ is within normal limits/slightly small. The capsule is generally smooth but with occasion areas of deformation due to nodular change
• Portal vein: large vessel in the splenic vein site which contains blood flow with hepatofugal direction. The termination site of this vessel could not be determined. The renal veins and other mesenteric vessels are relatively enlarged. In the caudodorsal part of the abdomen there are vessels with relatively large diameter that follow a zigzag direction; one of these vessels exits the splenic vein and another one the left renal vein however the end-point of these vessels is not seen
• Urinary bladder: small echogenic foci on the dependent side of the wall with associated distal acoustic shadow.

How do you interpret these findings and what would you like to do now?

If we consider our main differential diagnoses, the ultrasound is potentially consistent with an infiltrative neoplasia, but it is much more consistent with a chronic inflammatory, now fibrosing, hepatitis; alongside the heterogenous appearance to the liver. The key finding is the abnormal blood flow with several blood vessels appearing to be aberrant because this description is consistent with multiple acquired portosystemic shunts, which develop as a consequence of hepatic inflammation, fibrosis and increased portal pressure over a prolonged period of time.  This is not a feature of neoplastic disease but it is a feature of chronic hepatic inflammation.  If this is correct, fine needle aspirate samples will not be diagnostic and what is required is a histological diagnosis.  Billy was therefore taken to surgery and laparoscopic liver biopsies were obtained.  What was really interesting was how much worse his liver looked at laparoscopy compared to ultrasound (!):

Histological Diagnosis:

• Neutrophilic to lymphocytic-plasmacytic, chronic, multifocal, moderate interface hepatitis with fibrosis

Billy’s diagnosis of chronic hepatitis with fibrosis was therefore confirmed and he was treated with:

• Prednisolone, starting at 1mg/kg SID, tapered to 0.5mg/kg EOD over 6 weeks and then maintained
• Denamarin 425mg SID
• Destolit 300mg SID
• Spironolactone 80mg SID, stopped after two months treatment

Although his prognosis was guarded in light of the fibrosis, he actually responded better than expected and remained well for over a year before being lost to follow-up!

One of the fundamental ways we teach on the VVS internal medicine mentorship programme is to use real case examples and to present them in a problem-orientated fashion, as we have done with Billy. This helps to show how helpful this thought process can be when undertaking clinical investigations, particularly with challenging patients. It also enables us to discuss a wider variety of different differential diagnoses than we might otherwise do if we just focused solely on a single type of pathology. 

Interested in the VVS Internal Medicine Mentorship? – Find out more.