Dr Stefanie Mitze
DVM MRCVS DipECVIM-CA Internal Medicine
EBVS® European Veterinary Specialist in Small Animal Internal Medicine
We would like to introduce “Paddy” an 11y old male neutered Border Collie who presented as an emergency with severe sudden onset lethargy, weakness and anorexia. Paddy had never travelled abroad and was up to date with his vaccinations and worming protocols. There was no history of trauma and up until this episode of sudden onset lethargy and weakness his owners reported that his day had been unremarkable. His owners were aware that he had had a heart murmur for a number of years. Initial blood tests found Paddy to have very low blood glucose (<2mmol/L); this result was repeatable on subsequent blood samples.
On examination, Paddy was very weak, reluctant to get up and was showing intermittent lateral recumbency. He was however fully alert and responsive. Paddy’s temperature was 37.7°C. Respiratory rate and heart rate were WNL, a systolic heart murmur II/IV was auscultated with Point of Maximum Intensity (PMI) at the left heart base. Paddy’s blood pressure was very low, with a mean arterial pulse of 50mmHG.
Emergency therapy was administered: Paddy was immediately put on fluids and dextrose boluses administered.
What problems have you identified? And what are the differential diagnoses?
Problem List and Broad Differential Diagnoses
- Lethargy
- Anorexia
- Weakness
- Hypoglycemia
- Artefact (e.g. erythrocytosis, lab error)
- Hepatic dysfunction (e.g. PSS, hepatic cirrhosis)
- Excess glucose utilization (e.g. hunting dogs, starvation, pregnancy)
- Infectious causes (e.g. Babesia, parvovirosis, sepsis)
- Toxins (e.g. xylitol, ethanol)
- Decreased glucose production (e.g. neonatal, toy breeds, hypoadrenocorticisis)
- Excess insulin or insulin-like factors (e.g. insulin overdose, insulinoma, leiomyosarcoma, hepatic carcinoma)
- Hormone deficiencies (e.g. thyroid hormone/catecholamine/cortisol/growth hormone/glucagon deficiencies)
- Hypotension
- Drug induced (e.g. anesthesia)
- Sepsis, SIRS
- Anaphylaxis
- Blood loss
- Cardiac dysfunction
- Hypovolemia
- Heart murmur: not reason of presentation, known for years
Since hypoglycemia and hypotension can lead to lethargy, anorexia and weakness the focus was on differentials of these two life-threatening findings in this emergency situation:
- Hypoglycemia
- Hypotension
What tests would you like to perform next?
The most important first step is to rule out life-threatening underlying reasons for the hypoglycemia and hypotension, i.e. sepsis/Systemic Inflammatory Response Syndrome (SIRS), drugs, anaphylaxis, blood loss and hypovolaemia. Since the heart rate was normal and the heart murmur had not changed over the preceding years, a cardiac aetiology for this presentation was considered unlikely.
This patient needed urgent attention with fluid therapy and dextrose boluses, however several investigative steps did take place at the same time.
As an initial first step full bloods and urine (cystocentesis, with ultrasound guidance) were taken, see below. Further imaging was also performed.
Results
Haematology Results
| WBC | 11.59 | 6-17×10^9/L |
| Neut | 7.91 | 3.5-12×10^9/L |
| Lym | 1.62 | 0.9-5.0×10^9/L |
| Mono | 1.31 H | 0.16-1.12×10^9/L |
| Eos | 0.74 | 0.1-1.5×10^9/L |
| %Eos | 6.4 | |
| %Lym | 14 | |
| %Mono | 11.3 | |
| RBC | 5.28 L | 5.65-8.87×10^12/L |
| HGB | 117 L | 131-205g/dL |
| HCT | 33 L | 37-61% |
| MCV | 73.3 | 60-80fL |
| MCH | 23.6 | 19-25pg |
| MCHC | 32.2 | 30-36.5g/dL |
| Reticulocytes | 70.2 | 10-110 K/uL |
| Reticulocytes Hb | 20.3 L | 22.3-29.6pg |
| Platelets | 235 | 200-500×10^9/L |
| MPV | 9.3 | 5.5-10.5fL |
Biochemistry:
| TP | 64 | 52-82g/L |
| Albumin | 20 L | 22-39 g/L |
| Globulin | 44 | 25-45 g/L |
| ALT | 304 H | 10-125 U/L |
| ALP | 328 H | 32-212U/L |
| GGT | 1 | 0-11 U/L |
| Bilirubin | 16 H | 0-15µmol/L |
| Cholesterol | 1.06 L | 2.84-8.26mmol/L |
| Bile acids | 92.4 H | 0-10 umol/L |
| Amylase | 935 | 500-1500 U/L |
| Lipase | 265 | 200-1800 U/L |
| Osmolality | 301 | mmol/L |
| CRP | 100 H | 0.0-10.0mg/L |
| Glucose | 1.52 L | 3.89-7.95mmol/L |
| Crea | 114 | 44-159umol/L |
| Urea | 2.5 | 2.5-9.6mmol/L |
| Phosphorus | 1.63 | 0.81-2.20mmol/L |
| Calcium | 1.95 L | 1.98-3.00mmol/L |
| iCa | 1.21 | 1.21-1.40mmol/L |
| Sodium | 156 | 144-160mmol/L |
| Potassium | 3.6 | 3.5-5.8mmol/L |
| Na/K ratio | 43 | |
| Chloride | 117 | 109-122mmol/L |
cPLI SNAP: WNL
APTT,PT: WNL
Urinalysis (sample collected post glucose bolus and infusion)
| Glucose | Trace |
| Bil | marked |
| Ketones | neg |
| Blood | neg |
| pH | 6 |
| Protein | neg |
| Uro | neg |
| Nit | neg |
| Leu | neg |
| USG | 1.006 |
The sediment was unremarkable, UPC was WNL. The urine culture later came back negative.
Additional findings included a mild monocytosis, a mild non-regenerative anaemia, a mild hypalbuminaemia, a mild (total) hypocalcaemia, a mild hypocholesterolaemia, mild increased liver parameters and a severely increased CRP. The latter confirming a severe inflammatory process of yet unknown origin.
The liver reacts to many stimuli in the body. We usually take liver parameters seriously if they are elevated 5-10 times over the upper normal limit. However, it is important to note that in end stage liver disease (e.g cirrhosis) liver parameters might drop or even go back to normal due to the loss of functional tissue. It is important to look at other “functional liver parameters” as well e.g. coagulation parameters, which in Paddy’s case were normal. This means a severe acute on chronic hepatopathy, which was also a potential differential, was a possibility although not very likely.
Albumin is an important parameter to monitor and a low albumin result should be carefully considered. If albumin is being lost then other proteins including proteins desperately needed for coagulation or for an appropriate immune response, may also be being lost. Since calcium is bound to albumin the mild hypocalcemia in Paddy’s case is linked to the loss of the latter and is not considered a true hypocalcemia, especially because iCa was WNL.
Albumin loss usually occurs due to renal or intestinal loss or as a result of an inflammatory state. Since the UPC was WNL on the urine examination, a renal loss has been ruled out. Loss due to an inflammatory state remained a possibility, with the CRP elevation. However, since cholesterol was also low, enteral loss was considered the most likely explanation.
Thoracic radiographs 2 views: Clinical findings were consistent with hypovolaemia, with a small cardiac silhouette (microcardia) and a small caudal vena cava. The liver appeared rather small as well. Otherwise the findings were within normal limits for his age.
Figure 1: Right lateral chest radiograph.
Abdominal ultrasound: The liver was decreased in size and there was a suspicion of a chronic hepatopathy. Mild pancreatic changes were apparent (acute vs chronic), mildly thickened small intestinal walls, very mild peritoneal effusion (anechoic, not possible to sample) and the adrenal glands were mildly decreased on both sides (3.8mm and 3.6mm caudal pole). A FNA of the liver was taken at the same time.
Figure 2: Ultrasound of right adrenal.
Given the results above, what is your interpretation? Have you updated or refined your differential diagnosis?
So, in summary in all these findings there are clues as to what might be going on for this patient, but they do not provide a definitive diagnosis to account for this acute presentation.
The hepatic cytology results indicated a moderate mixed, predominantly neutrophilic inflammation, a mild cholestasis and a marked lipid and non-lipid hepatopathy. This was most likely secondary to another pathology, rather than primary. So overall the cytology was consistent with an acute on chronic hepatopathy.
Let’s have a look what we have ruled out on our differential list so far:
- Hypoglycemia
Artefact (e.g. erythrocytosis, lab error)Hepatic dysfunction (e.g. PSS, hepatic cirrhosis)Excess glucose utilization (e.g. hunting dogs, starvation, pregnancy)Infectious causes (e.g. Babesia, parvovirosis, sepsis)Toxins (e.g. xylitol, ethanol)- Decreased glucose production (e.g. neonatal, toy breeds, hypoadrenocorticism)
Excess insulin or insulin-like factors (e.g. insulin overdose, insulinoma, leiomyosarcoma, hepatic carcinoma)- Hormone deficiencies (e.g. thyroid hormone/catecholamine/cortisol/growth hormone/glucagon deficiencies)
- Hypotension
Drug induced (e.g. anesthesia)Sepsis, SIRSAnaphylaxisBlood lossCardiac dysfunction- Hypovolemia
Considering all these rule outs, what is left? Yes, hormones! Remember that in dogs the cut off for the caudal pole thickness of the adrenal gland is 4 mm to rule out a hypofunction. Paddy’s caudal adrenal pole thickness was reduced on ultrasound! What would you do next?
It is important to remember the following: The adrenal cortex has 3 layers and secretes glucocorticoids (GC) and mineralocorticoids (MC). GC can be secreted from all 3 layers, however MC from the Zona glomerulosa only, which is the only zone with the enzyme called aldosterone synthesises.
When a patient is in a hypoglycemic state, the whole hormonal task force is activated, and this includes within minutes, adrenaline and glucagon (excreted by the α cells of the pancreas). If the hypoglycaemia lasts longer than a few hours then growth hormone and cortisol are also increased.
So, what do we need to do for Paddy now? Yes, an ACTH Stim!
ACTH Stim of Paddy:
Pre- < 27.6nmol/L (50-250)
Post- <27.6nmol/L (50-250)
We have a diagnosis!
- Atypical primary Addison’s disease (atypical, because electrolytes are still normal).
- Severe hypotension with Addisonian crisis.
- Possible hypotensive related hepatopathy vs acute on chronic.
- Suspicion of anemia of inflammatory disease.
How would you like to manage the patient?
The treatment of severe hypotension and hypoglycemia must not be delayed. Logically, a patient with low glucose can just be fed, or dextrose can be given slowly IV. Hypotension is usually treated with (aggressive) fluid therapy. Vasopressors are indicated if the patient is non-responsive (e.g. noradrenalin, vasopressin or dopamine).
To treat the addisonian crisis, any steroid IV is indicated, for instance dexadreson or hydrocortisone, or methylprednisolone sodium succinate IV. Otherwise treatment is symptomatic.
What is the long-term prognosis for atypical Addison’s disease?
The prognosis is excellent if they survive the acute crisis. The long-term therapy consists of oral prednisolone. Please do not forget that progression to “true” Addison’s is possible for atypical cases, so monitoring of electrolytes is recommended regularly.
What happened to Paddy?
Paddy initially improved quickly, however the hypotension despite all interventions remained refractory and he finally developed kidney and hepatic failure. This was thought to be due to the persistent secondary hypoperfusion and he was sadly put to sleep. Do remember aggressive fluid management is the keystone in management of an Addisonian crisis.
Other potential differentials that were considered for this case include:
- Secondary hypoadrenocorticism – Na/K normal.
- Low pituitary endogenous ACTH. Renin and angiotensin control primarily Na/K. Neuro/other hormonal signs.
- Isolated hypoaldosteronism – K high, Na low.
- ACTH stimualation test: Cortisol normal. Low renin and aldosterone pre-/post ACTH stimulation.
- Critical illness-related corticosteroid insufficiency (CIRCI).
- HPA axis disturbance. Vasopressor-resistant hypotensive condition.