Hypercalcaemia - next steps?

Re: Hypercalcaemia - next steps?

Martin Atkinson — Wed, 03 Sep 2014 08:57:22 GMT

It seems to me that you are spending an awful lot of the clients money doing pointless further investigations when it is as Andrew says most likely to be renal.

Re: Hypercalcaemia - next steps?

Andrew Kent — Tue, 02 Sep 2014 21:56:00 GMT

Hi Beats,

Thanks for the update - what a frustrating case.

I think with the results you have that renal disease seems the most likely scenario and so unless you find anything very different I would continue to focus on treating that.

But, as you are doing, if the calcium comes up again then repeating your calcium testing sounds good. I would also check again with them that there is no source of vitamin D to give a waxing and waning hypercalcaemia.

Andy

Re: Hypercalcaemia - next steps?

Beats — Tue, 02 Sep 2014 21:14:21 GMT

OK hypercalcaemia fans, here's the latest installment in what is becoming a particularly tedious saga!

Post-ACTH cortisol fine (say 400-ish) so addisons ruled out.

Serum protein electrophoresis unexciting and non-specific (I can report full findings), so bye-bye suspicions of myeloma.

Total calcium levels on vet test heparainzed plasma have been well within normal limits both yesterday and today, so have not taken samples for repeat PTH/PTHrp or vitaminD metabolites.

No further weight loss and appetite improved (either as result of daily cerenia or waxing and waning nature of disease process), and without a hypercalcaemia, I couldn't see much advantage to short-term hospitalisation, so is coming back tomorrow morning to see if is a high calcium day in which case will do PTH etc samples.

Some large intestinal D+, so have stopped the renal food and back to normal rations.

Kidneys scanned yesterday and no "lesion here" motif graffittied into either of them; other than noting them to look symmetrical and kidney-like my amateur attempts at ultrasonography probably haven't helped, but here's some piccies to brighten up an otherwise dry update

I assume my differential list reads something like this at this stage?

1) Neoplasia

2) Primary structural kidney disease

3) HyperPTH

4) 'Other'

Once again, really appreciate the all the advice to date

Re: Hypercalcaemia - next steps?

Stephen Courtney — Sat, 30 Aug 2014 10:49:55 GMT

Try mirtazapine to help with appetite, and give oral cerenia against nausea - very likely with azotaemia.

It looks very like renal failure to me, an ACTH stim would show addisons but you would struggle to interpret a cushingoid response in an animal that is unwell.

Re: Hypercalcaemia - next steps?

Beats — Fri, 29 Aug 2014 23:15:16 GMT

Thanks Andrew - that's very helpful.

The in-house bloods taken were:

Lab Result date: 27 Aug 2014

Cl 112 mmol/L 109 122

LaserCyte

Run date: 27/08/14 17:13:00

RBC 6.00 x10^12/L 5.50 8.50

HCT 43.0 % 37.0 55.0

HGB 14.2 g/dL 12.0 18.0

MCV 71.6 fL 60.0 77.0

MCH 23.7 pg 18.5 30.0

MCHC 33.1 g/dL 30.0 37.5

RDW 16.6 % 14.7 17.9

%RETIC 0.3 %

RETIC 18.9 K/Î¼L 10.0 110.0

WBC 7.73 x10^9/L 5.50 16.90

%NEU 69.3 %

%LYM 13.6 %

%MONO 10.0 %

%EOS 6.7 %

%BASO 0.4 %

NEU 5.36 x10^9/L 2.00 12.00

LYM 1.05 x10^9/L 0.50 4.90

MONO 0.77 x10^9/L 0.30 2.00

EOS 0.52 x10^9/L 0.10 1.49

BASO 0.03 x10^9/L 0.00 0.10

PLT 220 K/Î¼L 175 500

MPV 11.4 fL

PDW 16.2 %

PCT 0.25 %

VetTest

Diagnostic set ID: 20140827_170254_3381

Run date: 27/08/14 17:16:35

GLU 5.59 mmol/L 4.11 7.94

UREA 22.0 mmol/L 2.5 9.6 ***HIGH***

CREA 242 Î¼mol/L 44 159 ***HIGH***

PHOS 2.45 mmol/L 0.81 2.19 ***HIGH***

CA 3.57 mmol/L 1.98 3.00 ***HIGH***

TP 75 g/L 52 82

ALB 32 g/L 23 40

GLOB 44 g/L 25 45

ALT < 10 U/L 10 100 ***LOW***

ALKP 48 U/L 23 212

TBIL 3 Î¼mol/L 0 15

CHOL 5.11 mmol/L 2.84 8.27

AMYL 1027 U/L 500 1500

I will do an ACTH stim on Monday - I agree would be good to rule-out addison's more conclusively.

I can request serum protein electrophoresis to be set up tomorrow morning on the serum already submitted and at the lab; is there any point in requesting any actue phase proteins (eg CRP/haptoglobin)?

Dietary history is unremarkable other than chocolate ingestion 8 weeks ago. No known sources of vitamin D.

I can ultrasound the kidneys on Monday, though I have a basic machine and even more basic skills so subtle changes won't be seen.

[quote user="Andrew Kent"]Whilst I am usually loathe to suggest repeating PTH/PTHrp due to the cost it could help here to see if the PTHrp is increasing and to see what the PTH is doing at the time an iCa is abnormal.[/quote]

I'm already regretting not freezing some EDTA plasma on Wednesday - I just know that on Monday the ionized calcium will turn out to be normal again! I guess all I can do is take an EDTA plasma sample on Monday and freeze it as if will be testing and then get the ionized calcium checked first (assuming the total calcium which I can check easily is, say, 3.4 or more) - I might try to get that done via a local clinic on Monday if feasible. Otherwise I can just repeat daily until get a suitably high calcium day.

I've had this headache before - the PTH sample arrived "cold" having been sent at 3pm Royal Mail Special Delivery for 9am in the labs freezer pack well insulated etc etc. I have resorted to dry ice before, but Royal Mail don't take that and finding a reliable courier that takes both dry ice AND diagnostic samples is a nightmare.

[quote user="Andrew Kent"]Measuring vitamin D metabolites would also allow you to look at this potential mechanism.[/quote]

I can do this via Nationwide Specialist Labs at same time as PTH/PTHrp testing I think. I assume this is something to wait for a day with a high calcium for as well.

I forgot to mention clinical signs: Has lost significant weight and appetite is picky. Ate great today, but poor last couple of days. Took on long walk at weekend as had been in great form and was lethargic for days afterwards. I think after Monday's round of testing I'll keep in on saline drip, so I guess I'll maybe just have to repeat PTH/PTHrp off Monday's samples then otherwise my treatment will mess with future day's sampling... Is there any other treatment I should be suggesting at the minute? The owners have various renal diets at home to try but I don't think has taken much of any of them presently.

Re: Hypercalcaemia - next steps?

Andrew Kent — Fri, 29 Aug 2014 22:00:22 GMT

Hi Beats,

These cases are sometimes difficult when things like iCa, PTH etc are difficult to measure reliably in postal samples. And there are certainly some conflicting results here, especially with regards to calcium which has fluctuated in and out of the normal range. What was the total calcium on your in house bloods? And what were the globulins?

Firstly I think with that basal cortisol I would do an ACTH stim. It is still an unlikely diagnosis but I think with that kind of level you have to follow up.

Did you manage to find out any more about the dogs diet? And in addition it would be worth asking the owners about sources of Vitamin D.

Clearly the dog is now azotaemic but whether this is a result of hypercalcaemia or a cause of hypercalcaemia its difficult to know. Most dogs with renal disease have high total calcium but normal iCa so it may suggest still a primary cause of hypercalcaemia. Would you be able to ultrasound the dog's kidneys?

If the globulins are persistently high then a myeloma would be a differential. Serum protein electrophoresis might help in that case to see if this is monoclonal.

Whilst I am usually loathe to suggest repeating PTH/PTHrp due to the cost it could help here to see if the PTHrp is increasing and to see what the PTH is doing at the time an iCa is abnormal. Measuring vitamin D metabolites would also allow you to look at this potential mechanism.

Re: Hypercalcaemia - next steps?

Beats — Fri, 29 Aug 2014 20:07:32 GMT

[quote user="Michael Woodhouse"]

In the UK QCR/Trio diagnostics distribute the I-stat and Woodley the Epoc machine. Both will do iCa. We have an I-stat and would happily do a blood sample for a neighbouring practice in similar situation. Either ring around and see what kit is available locally or ask the companies if they know of any local machine installs.

How close are you to a human hospital lab? You can ask them.

[/quote]

The local Vets Now have kindly obliged in the past. As long as I book the dog in for our closing time and then take a completely-filled heparin tube round to them (about a 10min drive at most) they will run an epoc which gives venous blood gases and ionized calcium - they also have done coags for me before and are generally very helpful. I'm just a little uncomfortable how long this work-up is taking and wonder if a clinic with better in-house diagnostics mightn't do a better job than me if I just sent the whole dog.

Re: Hypercalcaemia - next steps?

Michael Woodhouse — Fri, 29 Aug 2014 19:56:08 GMT

How close are you to a human hospital lab? You can ask them.

Re: Hypercalcaemia - next steps?

Beats — Fri, 29 Aug 2014 19:45:51 GMT

The plot thickens...

Longer timeline than hoped for, but here we are:

Came in on Wedensday evening and blood and cystocentesis samples taken and run in-house as follows:

SG (human medical refractometer): 1.015
Mulitick: pH6, prot-trace, otherwsie unremarkable
Sediment exam: sperm++, rbcs+, epithelial cells+, small refractile crystalline material+

[I can type out in-house bloods if wanted, but effectively showed persistent hypercalcaemia and azotaemia, so elected to send whole lot to an external lab]

Here is external lab report:

Ionised Calcium	H	1.64	mmol/l	1.25 - 1.45

pH		7.5

CK		183	u/l@37C	20 - 230

Early Renal profile
Full Blood Count
WBC		8.8	x109/L	6.0 - 15.0

RBC		5.95	x1012/L	5.00 - 8.50

Haemoglobin		14.7	g/dl	12.0 - 18.0

PCV		46.0	%	37.0 - 55.0

MCV		77.3	fl	60.0 - 80.0

MCH	H	24.7	pg	19.0 - 23.0

MCHC		32.0	g/dl	31.0 - 34.0

Platelets		304	x109/L	200 - 500


Differential		%	Abs	Interval

Neutrophils		73 %	6.4 x109/L	3.0 - 11.5


Bd Neutrophils		0 %	0.0 x109/L	0.0 - 0.3


Lymphocytes		16 %	1.4 x109/L	1.0 - 4.8


Monocytes		1 %	0.1 x109/L	0.0 - 1.3


Eosinophils		10 %	0.9 x109/L	0.1 - 1.2


Basophils		0 %	0.0 x109/L


Film :
Platelet count appears normal in film


Urea	H	24.5	mmol/l	1.7 - 7.4

Phosphate	H	2.31	mmol/l	0.80 - 1.60

Potassium		4.72	mmol/l	3.60 - 5.60


Sodium		142	mmol/l	139 - 154

Creatinine	H	265	umol/l	20 - 124

Urine Sodium		63.0	mmo/l

Urine Creatinine		6.30	mmol/l

Fractional Sodium	H	1.87		0.00 - 1.00


Urine NAG		3176	umol/hr/l

Urine NAG : Creatinine	H	504		0 - 50

Urine Protein		637.0	mg/l

Urine Protein : Creatinine	H	0.89		0.00 - 0.50

Urine Microscopy
WBC		Less than 10 cells/mm3

RBC		+/-

Epithelial Cells		+/-

Bacteria		Not Seen

Crystals		+++ Triple phosphate

Casts		Not Seen

Urine Biochemistry
pH		6.0

Specific Gravity		1.010

Protein		Trace

Urine Glucose		Negative

Ketones		Negative

Urobilinogen		Negative

Bilirubin		Negative

Haemoglobin		Negative


Albumin		29.5	g/l	26.0 - 40.0

Total Protein	H	75.3	g/l	50.0 - 72.0

Total Globulin		45.8	g/l	19.0 - 46.0

Albumin : Globulin		0.6		0.5 - 1.6

Cortisol Basal	L	35.6	nmol/l	50.0 - 250.0

Comment

iCa serum filled to brim.

Physiological pH is 7.4, so this more alkaline pH is an indicator of sampling/transit artefact (e.g. aerobic handling, although the sample arrived with no air bubbles) which will affect the iCa result. iCa drops as pH rises, so iCa may actually be higher in vivo than it appears here. Hypercalcaemia can be caused by malignancy (e.g. lymphoma, apocrine gland carcinomas of the anal sacs), primary hyperparathyroidism, acute oliguric renal failure, hypervitaminosis D, hypoadrenocorticism (Addison's disease) or granulomatous disease. Basal cortisol is not high enough to rule out hypoadrenocorticism here. An ACTH stimulation test would clarify, although K and Na are both within ranges here.

No significant haematological abnormalities are noted. TP could suggest some dehydration at sampling but azotaemia, isosthenuria and raised FENa are all consistent with renal disease and reduced glomerular filtration function. NAG:Cr is also high, suggesting renal tubular damage.dysfunction too, but trends over time are more informative than a single result. UPCR suggests some renal protein loss, since sediment is mostly inactive (only scant red cell presence, likely artefact of cysto sampling). Struvite crystals can be seen in urine from clinically normal dogs and can also precipitate in transit. Significance (if any) depends on clinical signs and presence/absence of crystals in a fresh urine sample exam examined in-house.

Urine culture to follow.

I'm guessing I need an ACTH Stim to rule-out addison's at this point, but I remain unsure how to approach this case further and would appreciate further suggestions :-)

I can send the dog to another veterinary clinic to get ionized calcium done on a fresh epoc sample if that is of help (I can only post away from my clinic), though I'm inclined to go with there being a genuine physiologically-active hypercalcaemia based on this result? Thoughts?

Re: Hypercalcaemia - next steps?

Andrew Kent — Fri, 22 Aug 2014 23:24:19 GMT

I agree that some of the results are a bit conflicting but in most of the samples the calcium has only been mildly abnormal, and based on the external sample the calcium is basically normal. So I wouldn't expect it to have a big effect on the USG or really to make the dog PUPD.

I'm happy with basal cortisol as an initial screening test for Addison's, with the potential to follow up with an ACTH stim if less than about 55.

Re: Hypercalcaemia - next steps?

Beats — Fri, 22 Aug 2014 21:44:13 GMT

[quote user="Andrew Kent"]This really isn't classic for neoplasia, both because the ionised calcium is normal and PTHrp is really not that exciting. The primary mechanism for the high Ca Phos product is the hyperphosphataemia which makes renal likely (I might also want to exclude addisons ideally).

I would get a urinalysis firstly and most importantly to assess concentration and ideally do this at the same time as a biochemistry. You could also looks at UPC etc yes.

[/quote]

Thanks Andrew, that's very helpful.

I see what you are saying from most recent results. Does the phos and calcium levels on the in-house first set of results:

PHOS 1.49 mmol/L 0.81 2.19

CA 3.04 mmol/L 1.98 3.00 ***HIGH***

not look a bit atypical for renal disease to you or might it just be poor analytics or actually typical enough for kidney disease?

I'll get a cysto sample on Monday and repeat (in-house?) blds for basic bioschemistry. In terms of interpreting this: the refractivity of the urine will likely be low with the hypercalcaemia anyway will it so how will I know if there is genuine kidney disease? I'll do a dipstick and a spin-down for sediment and save some for culture and UPC and report back? Anything else I'm not thinking of?

Would you be happy with a basal cortisol to rule out addison's (I froze some serum the last day in case needed more tests and could post it tomorrow if the lab don't have any left), or should I get pre- and post-ACTH samples to be sure?

Really appreciate all the advice

Re: Hypercalcaemia - next steps?

Beats — Fri, 22 Aug 2014 21:32:34 GMT

[quote user="Michael Woodhouse"]Have you checked anal sacks?[/quote]

I should confess that other than taking a blood sample (and then being left to report the results!), I've not laid hands on the dog yet - I rang the owners with results this evening (they'd got mislaid somewhere) and said I wasn't too sure what to make of them and would call back after getting some advice with a view to getting the dog in for whatever needed done on Monday. That can include a thorough examination (and any pertinent history questions brought up)

... but to try to answer your question in meantime, assume yes - the dog has been examined by a colleague who knew it to be hypercalcaemic and described a symmetrical non-painful enlarged prostate, so I'm pretty conifdent that the anal sacs have been checked.

Re: Hypercalcaemia - next steps?

Andrew Kent — Fri, 22 Aug 2014 21:28:13 GMT

This really isn't classic for neoplasia, both because the ionised calcium is normal and PTHrp is really not that exciting (that doesn't mean it definitely isn't, just that it hasn't read the rule book if it is!). The primary mechanism for the high Ca Phos product is the hyperphosphataemia which makes renal likely (I might also want to exclude addisons ideally).

I would get a urinalysis firstly and most importantly to assess concentration and ideally do this at the same time as a biochemistry. You could also looks at UPC etc yes.

Re: Hypercalcaemia - next steps?

Beats — Fri, 22 Aug 2014 21:24:12 GMT

[quote user="Andrew Kent"]do you have any urinalysis results?[/quote]

No.

[quote user="Andrew Kent"]And is the dog on a normal diet?[/quote]

I'll have to check with owners.

Re investigating possibly renal, what would you recommend? Is a UPC ratio and kidney ultrasound the most useful approach? I agree with what makes you suspicious of renal, but the marginally high total calcium with no azotaemia in the first blood sample raised an eyebrow for me. Also the PUPD having "resolved" for now?

The raised globulins and PTHrp level made me think more neoplasia, like Robb.

I really can't decide though... so I'm finding it hard to know where best to go next - I guess can investigate for neoplasia and kidney disease simultaneously?

Re: Hypercalcaemia - next steps?

Michael Woodhouse — Fri, 22 Aug 2014 21:19:09 GMT

Have you checked anal sacks?

Re: Hypercalcaemia - next steps?

Beats — Fri, 22 Aug 2014 21:15:03 GMT

[quote user="robloxley"]Have you scanned that prostate?[/quote]

No.

[quote user="robloxley"]Given the Ca/Phos product I'd want to get the calcium down with some drugs while I hunt the tumor[/quote]

What would you use? Any risk of making the hunt harder?

Re: Hypercalcaemia - next steps?

Andrew Kent — Fri, 22 Aug 2014 21:03:58 GMT

The normal ionised calcium with high total, high phosphate and episode of azotaemia would make me suspicious of a renal cause. Generally if the mechanism is PTH related the phosphate will be low so renal seems more likely.

do you have any urinalysis results? And is the dog on a normal diet?

the PTHrp is in the grey area, but many labs require it to be over 2 to be convincing. The globulins are interesting and I guess could be associated with a malignancy, this could be investigated further with electrophoresis.

but I would want to be sure this isn't renal before searching for the weirder things.

Re: Hypercalcaemia - next steps?

Rob Loxley — Fri, 22 Aug 2014 20:35:23 GMT

Have you scanned that prostate?

Given the Ca/Phos product I'd want to get the calcium down with some drugs while I hunt the tumor