Differential diagnoses for red water (haemoglobinuria and/ or haematuria) in cattle in New Zealand
Janice Thompson: BVSc, PhD, Clinical Pathologist, Gribbles Veterinary Pathology, Palmerston North, New Zealand
Questions to consider when reading the clinical pathology results
- Is anaemia present?
- Is there an inflammatory leucogram?
- What is the urine SG?
- What is the urinary sediment like?
- What is significant in the biochem?
- What further tests would be useful?
- What is the possible differential list?
- What further questions would you ask the practitioner, and what further information would be useful from the owner to help to narrow down your list?
- What follow up samples would you like to see and why?
Case 1 (calves)
History and clinical findings:
Two 14 month old Friesian calves showed non specific signs of illness and produced red urine for one day. Samples were taken for routine biochemistry, haematology and urinalysis.
Important clinical pathological features to consider
- There was no anaemia to accompany the haemolysis seen in the serum and the red urine.
- Heinz bodies or RBC abnormalities were not seen.
- Mature neutrophilia indicated inflammation is present.
- Both calves have moderate to severe hepatocellular damage present.
- Hyperkalaemia was present in one calf.
- No RBCs were seen in the urinary sediment despite the large amount of blood, so haemoglobinuria is present rather than haematuria
- There was no inflammatory response obvious in the urinary sediment.
- The urine was hyposthenuric.
- Note though that measurement of some analytes is affected by haemolysis – includes protein, creatinine, AST, potassium and CK.
- L. pomona was not present. L pomona causes hepatocellular damage and nephritis in young calves and may cause severe intravascular and extravascular RBC destruction. The resultant haemolysis following L. pomona infection is accompanied by severe anaemia, haemolysed serum/ plasma, haemoglobinuria and jaundice. The practitioner also later requested L pomona serology and this was negative.
- Chronic copper toxicity was not likely in such animals and there was no history of copper being administered to animals of this age. There was no anaemia.
- This was not the season in which sporidesmin toxicity is seen and with this condition serum GGT concentrations are high. Sporidesmin may cause intravascular haemolysis through unknown mechanisms in severely affected animals. It may also cause haemorrhagic cystitis.
- Onions, brassicas, kale had not been feed to the calves and there was no anaemia. see below for further discussion).
- There was no anaemia to accompany the increased liver enzymes re possibility of bacillary haemoglobinuria.
- All causes of haematuria were excluded because there were no RBCs seen in the sediment.
Most likely differential diagnosis and discussion
Water intoxication was the most likely possibility diagnosis given the haemoglobinuria rather than haematuria, lack of anaemia and hyposthenuric urine. This is also consistent with the history when the practitioner had further discussions with the owner. This diagnosis was confirmed by the return of the urine to normal by the following day.
Following discussion with the pathologist the practitioner went back discuss with the farmer and obtained the following further information re feeding. The calves were thirsty and just weaned so he gave them a large drink of cold water. One day later the urine had grossly returned to normal and pink tinges were not seen. With water intoxication, ingestion of a large amount of water causes hypotonicity, lyses some RBCs and causes a transient haemoglobinuria. The hypotonic urine indicates there is still adequate renal function because the kidney is able to dilute urine. It does not exclude the possibility of mild/ subclinical renal disease that was not affecting renal function. Renal failure/ insufficiency leads to an inability to concentrate or dilute urine. A lack of azotaemia does not exclude subclinical renal disease/ insufficiency because azotaemia does not occur until the majority of nephrons (> 75%) are non functional but concentrating ability is lost before this occurs.
The cause of the increases in serum GDH/ AST concentrations was not discovered.
The calves did have relatively low globulin concentrations (inaccurate because of haemolysis) so it is possible they received minimal colostrum and developed infections resulting in signs of illness, the liver enzyme increases and the neutrophilia.
(Note though that while the measurement of some analytes is affected by haemolysis – this includes protein, creatinine, AST, potassium and CK, analysis was carried out because no more sera was available. Ultimately the presence of haemolysis was useful in making a diagnosis as it was more than artefact ie it fitted with the eventual diagnosis).
Case 2 (cow)
History and clinical findings:
A six year old cow of mixed breed was found recumbent, hypothermic and showed extreme icterus of the mucus membranes. A urine sample was obtained but was heavily contaminated with a purulent uterine discharge. She was grazing pasture, with no additional supplements.
Important clinical pathological features to consider
- There was a severe anaemia showing a mild response in the form of reticulocytes.
- There is a marked acute inflammatory leucogram indicating severe tissue damage/ necrosis and very likely infection.
- Fibrinogen was normal
- There were marked increases in serum GDH and AST concentrations indicating marked hepatocellular damage/ necrosis.
- Increased serum GGT concentration indicated mild cholestatic disease/ biliary damage.
- Increased in serum CK concentration indicated muscle damage (AST may also be derived from muscle).
- There was a mild hypophosphataemia.
- RBCs were not seen in the sediment of the urine so haemoglobinuria is present rather than haematuria.
- Total protein concentrations were within the reference range.
- The urine was concentrated with SG > 1.025.
- Causes of haematuria were excluded because RBCs were not seen in the urinary sediment. The red urine was a result of haemoglobinuria.
- Total serum protein concentration was not decreased to support marked haemorrhage. Severe hepatic disease may cause decreased clotting factor production resulting in haemorrhage but haemorrhage was not seen clinically. The increased urea in this animal that may result from GI haemorrhage probably resulted from other causes of pre renal azotaemia (non specific causes of increased protein catabolism).
- Nutritional causes were not present. There were no Heinz bodies seen in the blood smear and there was no history of animals being fed turnips, brassicas or onions. The toxic principle in onions is the compound n-propyl disulphide. This affects the enzyme glucose-6-phosphate dehydrogenase and this leads to Heinz body formation. The toxic principle in brassicas is the compound S-methyl cysteine sulphoxide (SMCO). This is broken down to dimethyl disulphide in the rumen and this is the compound that causes anaemia and haemolysis. Ingestion of turnips and brassicas may cause hepatotoxicity resulting in increases in serum liver enzyme concentrations. This toxicity results from the accumulation of compounds (glucosinolates) within the plants as a result of some growing conditions such as droughts, and these compounds are broken down to a toxic compound within the rumen that is absorbed. While these compounds cause liver damage they do not cause anaemia.
- The hypophosphataemia in this cow was mild and such decreases are common in cattle around parturition and early lactation and not usually associated with RBC destruction. Phosphorus is needed for the formation of ATP and the maintenance of RBC shape and function. Another form of post parturient haemoglobinuria is seen with low selenium concentrations. Selenium is an essential component of glutathione peroxidase, an enzyme preventing oxidation, but haemolysis associated with low selenium is often associated with presence of Heinz bodies. Selenium was not measured in blood from this animal.L pomonadoes not cause RBC destruction in older cattle. Abortion is the most common clinical sign in adult cattle.
- Water intoxication was not present, the urine was concentrated (SG > 1.025) not dilute as seen with the calves.
- Sporidesmin toxicity was not present. It was not the time of year for growth of Pithomyces chartarum, and sporidesmin toxin causes cholestatic disease (often increases in serum GGT concentrations).
- There was no history of copper administration (information gained on further discussion with practitioner).
Probable diagnosis and discussion
No samples were received for histopathological examination so the exact cause of the anaemia, haemoglobinuria and severe hepatic disease were never established. However, on ruling out all of the above causes bacillary haemoglobinuria was very likely. This occurs when there is ischaemic hepatic damage/ necrosis allowing the germination of spores of Clostridium haemolyticum (or Clostridium oedematiens Type D) within the liver. Possible causes for damage includes migration of immature liver flukes through the hepatic parenchyma or damage resulting from liver biopsies. Toxins are released from the bacteria that then cause haemolysis. Severe hepatocellular damage and possible necrosis was indicated by the marked increases in GDH and also the marked acute inflammatory leucogram. Low fibrinogen may occur as a result of severe hepatic disease.
Many of the WBCs in the urine may have arisen from the uterine discharge in addition to possible cystitis. The urine was concentrated so primary renal disease was unlikely. Metritis was also very likely to be present and contributing to the inflammatory leucogram.
The cow was recumbent and this accounted for the increases in CK.