The Case: Sequelae to Addison’s Disease

History
A 2-year-old, spayed female Alaskan malamute weighing 68 pounds was presented on an emergency basis for evaluation of vomiting, lethargy, and ataxia. The night prior to presentation the dog vomited multiple times and appeared uncoordinated and ataxic. The morning of presentation she had not eaten and was unable to rise. The dog had been treated by another veterinarian a week prior for presumptive gastroenteritis, with clinical signs of lethargy, hematochezia, inappetence, and restlessness. In-hospital therapy had included metronidazole, a single dose of carprofen, maropitant, intravenous fluids, and a bland diet. Blood analysis from the primary veterinarian revealed elevated liver values, azotemia, electrolyte abnormalities, and hypoglycemia:

• Total protein: 7.8 g/dL (range, 5.0–7.4)
• Globulin: 4.2 g/dL (range, 1.6–3.6)
• Aspartate aminotransferase: 864 U/L (range,15–66)
• Alanine aminotransferase: 177 U/L (range,12–118)
• Alkaline phosphatase: 3 U/L (range, 5–131)
• Blood urea nitrogen: 63 mg/dL (range, 6–31)
• Creatinine: 3.2 mg/dL (range, 0.5–1.6)
• Phosphorus: 10.2 mg/dL (range, 2.5–6.0)
• Glucose: 66 mg/dL (range, 70–138)
• Calcium: 12.6 mg/dL (range, 8.9–11.4)
• Potassium: 7.7 mEq/L (range, 3.6–5.5)
• Sodium: 135 mmol/L (range, 139–150)
• Amylase: 1467 U/L (range, 290–1125)
• Lipase: 936 U/L (range, 77–695)
• Creatine phosphokinase: 23,682 U/L (range, 59–895)

Imaging

• Abdominal radiography: unremarkable
• Skull radiography: unremarkable (Dog had vocalized when her mouth was touched and had been reluctant to play with toys.)
• Abdominal ultrasonography: unremarkable

PRESENTATION 1
Physical Examination
The dog was quiet but alert/responsive and had tacky gingivae with a capillary refill time of about 2.5 seconds. No heart murmur was noted, but bradycardia (68 bpm) was present; pulses were moderate and synchronous. She was ambulatory but exhibited weakness when rising and fell when walking. Stools were normal with no melena or hematochezia. The rectum was dilated and dry. Findings of the examination were otherwise unremarkable.

Diagnostics

• Blood analysis
• Glucose: 66 mg/dL (range, 60–115)
• Sodium: 127 mmol/L (range, 139–150)
• Potassium: 9.0 mmol/L (range, 3.4–4.9)
• Ionized calcium: 1.47 mmol/L (range, 1.12–1.40)
• Hematocrit: 62% (range, 35–50)
• pH: 7.173, metabolic acidosis
• ACTH stimulation test: prestimulation <0.7 μg/dL (range, 1.0–5.0), poststimulation <0.7 μg/dL (range, 8.0–17.0)
• Urinalysis (abnormal value): specific gravity 1.007 (range, 1.015–1.050)

Treatment

• Fluids
• 1 L 0.9% sodium chloride, followed by 3.2 g calcium gluconate (for cardioprotection against hyperkalemia) IV boluses
• Insulin (regular): 16 U with dextrose 50% (100 mL bolus), followed by 5% dextrose CRI in 0.9% sodium chloride (160 mL/hr)

Repeat blood analysis after treatment revealed improvement in hyperkalemia and hyponatremia (sodium 131, potassium 6.5, glucose 138). The patient appeared brighter after treatment as well. The ACTH stimulation test confirmed the suspected diagnosis of hypoadrenocortocism.  

• Prednisone (10 mg q12h PO)
• Desoxycorticosterone pivalate (70 mg IM)

Another blood recheck showed resolution of azotemia. The dog was bright, active, and eating well, with no additional vomiting or diarrhea noted during the 2-day hospitalization. Her electrolytes were evaluated shortly prior to discharge and were normal (sodium 145 mmol/L [range, 144–160], potassium 5.6 mmol/L [range, 3.5–5.8]).

At-Home Treatment

• Prednisone (10 mg q12h PO)

Initial Outcome
Shortly after discharge, the dog was noted to vomit a single time. A streak of frank blood was noted in the vomitus. She was otherwise behaving normally at home. Gastroprotectants (famotidine [30 mg q24h PO], sucralfate slurry [1 g q8h PO]) were then prescribed.

PRESENTATION 2
Four days after discharge, the patient was re-presented. The dog’s appetite had decreased (~ 30% of normal, eating only chicken and beef). The night prior to presentation, she vomited 5 times; the first vomitus contained abnormal material resembling "black spaghetti." Two days prior to presentation, the dog also developed diarrhea (liquidy, with frank blood); her stools were initially normal after discharge. On the day of presentation she was very lethargic. She had last received her medications that morning.

Physical Examination

• Quiet, alert, responsive
• Mild dehydration, eyes sunken in orbits bilaterally, slightly tacky mucous membranes, CRT <2 sec
• BCS 4/9 with marked temporal and epaxial muscle wasting
• Minimal aural debris bilaterally  
• No cardiac murmur, normal sinus rhythm. Moderate femoral pulse quality 
• Eupneic. Appropriate bronchovesicular sounds over all fields   
• Full palpation of abdomen performed without discomfort. Uncomfortable and vocalizing during ultrasound examination. 
• Ambulatory × 4, coordinated gait but tired easily
• Liquid stool in colon. Defecated after examination: moderate amount of mucus with tinge of frank blood

Diagnostics

• Blood analysis
• White blood cells: 18.6/μL (range, 6–7,000)
• Glucose: 185 mg/dL (range, 74–143)
• Blood urea nitrogen: 31 mg/dL (range, 7–27)
• Alanine aminotransferase: 588 U/L (range, 10–100)
• Sodium: 138 mmol/L (range, 144–160)
• Potassium: 4.0 mmol/L (range, 3.5–5.8)
• Chloride: 106 mmol/L (range, 109–122)

• FAST*: Poor ultrasound detail, somewhat concerned about free gas; small amount of free fluid noted
• Abdominal fluid: turbid and serosanguineous; in-house cytology: predominant degenerative neutrophils with intracellular bacteria (rods). Culture & sensitivity: Escherichia  coli 
• Blood pressure: 90 mmHg

Based on all available diagnostics, septic peritonitis was highly suspected. Potential causes as discussed with her owner included gastrointestinal perforation secondary to ulceration caused by hypoadrenocorticism or previous use of NSAIDs or steroids. A surgical estimate was given, and her owners consented to surgery that day.

Treatment

• 500 mL Plasma-lyte† bolus
• Exploratory laparotomy: duodenal perforation identified and repaired; Jackson-Pratt drain placed
• Abdominal drain fluid collection/analysis postoperatively

Postoperative Course
Day 1

• Abdominal fluid from drain: occasional red blood cells, very few inflammatory cells, no bacteria
• Packed cell volume: 35% (range, 37-55)
• Total solids: 4.0 g/dL (5.0–7.4)
• Blood analysis
• pH: 7.37 (range, 5.5–7.0)
• Sodium: 144 mEq/L (range, 139–154)
• Potassium: 4.4 mEq/L (range, 3.6–5.5)
• Chloride: 105 mEq/L (range, 102–120)

Day 2

• Abdominal fluid from drain: moderate number of neutrophils; no toxic changes/bacteria
• Blood analysis with liver panel
• Packed cell volume: 35% (range, 37–55)
• Total solids: 4.2 g/dL (range, 5.0–7.4)
• Blood urea nitogen: 4 mg/dL (range, 6–31)
• Albumin: 1.4 g/dL (range, 2.7–4.4)
• Alanine aminotransferase: 116 U/L (range, 10–100)
• Alkaline phosphatase: 245 U/L (range, 5–131)
• Cholesterol: 75 mg/dL (range, 92–324)  
• Blood Smear: Adequate number of platelets, few neutrophils

Day 3

• Abdominal fluid from drain: moderate number of neutrophils without toxic changes/bacteria; low number of lymphocytes
• Packed cell volume: 38% (range, 37–55)
• Total solids: 4.8 g/dL (range, 5.0–7.4)

Day 4

• Blood analysis: albumin 2.6 g/dL (range, 2.7–4.4), otherwise unremarkable
• Drain removed

Postoperative Treatment

• Amoxicillin/clavulanate: 375 mg q12h × 14 days PO, based on culture & sensitivity results
• Metronidazole: 250 mg q12h × 14 days PO with food
• Famotidine: 20 mg q24h × 14 days PO
• Sucralfate: 1 g in slurry q8h × 14 days PO 
• Misoprostol: 100 μg q12h × 14 days PO
• Prednisone: 5 mg (1/2 10-mg tablet) q12h × 3 days; then q24h thereafter

Based on the patient’s weight, the "physiologic" prednisone dosage was estimated between 3 and 6 mg per day with the possibility of it being lowered in future based on control of signs of Addison's disease and presence of signs of steroid excess, such as excessive thirst and urination. The clients were advised that mineralocorticoids and glucocorticoids would be required for the rest of the dog’s life.

Outcome 
Response to desoxycorticosterone pivalate was evaluated after 14 days of treatment via blood analysis. Electrolytes were within normal range, indicating the dose was appropriate at that time. The incision healed well and the sutures were removed on postoperative day 16. The dog was bright, alert, and responsive and had a healthy appetite, with no vomiting, diarrhea, melena, hematochezia, or hematemesis noted.

*FAST = fast abdominal ultrasonography for trauma; †Plasma-lyte is a multiple electrolyte solution.

 The Specialist’s Opinion
Gretchen Statz, DVM, DACVECC

Hypoadrenocorticism is typically a rewarding disease to diagnose and treat because it carries an excellent long-term prognosis, with treatment producing complete resolution of clinical signs. In general, this case was handled well. Here are my thoughts.

Diagnostic Suggestions
The laboratory analysis performed by the primary veterinarian showed abnormalities that are fairly classic for hypoadrenocorticism––azotemia, hypoglycemia, and electrolyte abnormalities (hyponatremia, hyperkalemia, hypercalcemia).  When coupled with the history, these findings indicated a high probability of hypoadrenocorticism and should have prompted the clinician to perform further testing. At the very least, a resting cortisol study should have been performed as a rule out test (if >2 μg/dL, hypoadrenocorticism is extremely unlikely).  In the interest of obtaining a timely diagnosis when hypoadrenocorticism is strongly suspected, however, it is most appropriate to go straight to the ACTH stimulation test.
 
Differential diagnoses include acute renal failure (possibly leptospirosis given the liver changes) or gastrointestinal disease (whipworms, for example). A urinalysis is always indicated in patients with azotemia; it is useful in further assessing kidney function and should have been performed at the original veterinary visit. 

Unusual Laboratory Findings
The elevated creatine phosphokinase and aspartate aminotransferase values are indicative of muscle cell damage and are not typical of hypoadrenocorticism. Possibly more than one disease process was active at the time of initial presentation:  The oral pain and elevated muscle enzymes suggest masticatory muscle myositis or trauma. It isn’t entirely clear whether the muscle enzymes were rechecked after the initial visit. Results of such testing would have been interesting to see. It appears that the oral pain resolved by the time the dog was presented to the referral clinic. 

Treatment Discussion
It is not clear whether the carprofen was given before or after the initial laboratory results were obtained. Carprofen can worsen azotemia (via changes in renal blood flow) and should not be used in azotemic animals. Moreover, the use of carprofen was questionable given the history of hematochezia and inappetence.

Because the hyponatremia was not severe and the hyperkalemia was, I think sodium chloride was a reasonable initial fluid. However, it could be argued that lactated Ringer’s or Normosol R may have been better choices.  Sodium chloride has the potential to increase sodium too rapidly (especially with starting values of <120 mEq/L) and can make metabolic acidosis worse.  A rapid increase in sodium can also cause myelinolysis, which results in neurologic signs that may not be evident immediately.  In general, sodium should not be increased more than 0.5 to 1 mEq/L per hour.  It is not stated how much time elapsed between obtaining the values 127 and 145 mEq/L, so it is difficult to say whether the sodium increased at an appropriate rate.

Duodenal Perforation
The gastrointestinal perforation may have had a multifactorial cause. Gastrointestinal ulceration is common and sometimes severe in dogs with hypoadrenocorticism.  A basal amount of cortisol is necessary for normal function of the enterocytes; without it there is high risk for ulceration.  I do not believe that gastrointestinal perforation is a common sequela of hypoadrenocorticism but it seems reasonable that perforation could occur with severe ulceration.  Although it seems unlikely that one dose of carprofen in itself would cause a duodenal perforation, it could contribute in a case where the gastrointestinal tract is compromised. In general, the use of carprofen and prednisone together are contraindicated and a wash-out period (5–7 days) is recommended between these medications.  In this case, the prednisone was necessary for survival of the dog and there was an appropriate length of time between them.  It seems likely that that underlying disease was the main contributor to the perforation. 

Gretchen Statz, DVM, DACVECC, is an internal medicine consultant for Antech Diagnostics and a VIN consultant on the internal medicine boards. A graduate of University of Wisconsin – Madison, Dr. Statz interned at VCA West Los Angeles and then worked for several years at two emergency/referral hospitals in the Boston area. After completing a residency at VCA Veterinary Referral Associates in Gaithersburg, Maryland, she became boarded in emergency and critical care. Having a strong interest in internal medicine, she has been practicing in that field for the past several years. 

The Generalist’s Opinion
Barak Benaryeh, DVM, DABVP
The error that was made in this case lies in the history. The patient’s initial blood values indicate a sodium:potassium ratio of 17.5 that was never pursued. Any sodium:potassium ratio less than 27 needs to be investigated, and a rule-out list should include hypoadrenocorticism, severe gastrointestinal disturbances, and parasitism (namely with Trichuris vulpis or whipworm). According to some studies, any ratio less than 20 is practically pathognomonic for hypoadrenocorticism, with a specificity approaching 100%.1 Not only was the sodium: potassium ratio overlooked, but none of the other blood abnormalities were pursued. Even given a normal ratio, the abnormal hepatic and renal values should have been investigated.

Prednisone Dose
It is difficult to find areas of improvement with any of the treatment the dog received at the emergency hospital.  An ACTH stimulation test was run immediately and measures were taken to protect the dog from the effects of the severe hyperkalemia (9.0 mmol/L). The departing 10-mg dose of prednisone was slightly higher than the patient’s physiologic dose (0.1–0.2 mg/kg or 3–6 mg q24h), but it is common and appropriate practice after an Addisonian crisis to start with a slightly higher dose and titrate down.
 
Opting for Surgery
The decision to perform surgery was based on findings of intracellular bacteria in free abdominal fluid and the possibility of free gas in the abdomen. A pneumoperitoneum without a history of abdominal surgery is always an indication for an abdominal exploratory. Whether the perforating ulcer developed secondary to the initial single carprofen dose or from the slightly higher prednisone dose is impossible to say. Neither of these treatments should have ordinarily precipitated an ulcer. Furthermore, gastrointestinal ulceration, though reported, is not a common sequela of hypoadrenocortocism, and subsequent perforation is even less common. In any case, the treatment course was appropriate and lifesaving.

Hypoadrenocorticism is also sometimes referred to as “the great pretender” because presenting signs can be nearly anything. A common medical axiom is “If nothing else turns up, be sure to perform an ACTH stim test,” which applies regardless of the sodium:potassium ratio. This dog’s presentation fits the classic profile for canine hypoadrenocorticism: young female dog with gastrointestinal clinical signs and a low sodium:potassium ratio.  Had the disease been recognized sooner, further complications might have been avoided.

Reference
1.    Combining white blood cell counts and the sodium to potassium ratio to screen for canine hypoadrenocorticism. Seth M, Drobatz KJ, Church DB, et al. ACVIM Proc, 2011.

Barak Benaryeh, DVM, DABVP, is the owner of Spicewood Springs Animal Hospital. He graduated from University of California–Davis School of Veterinary Medicine in 1997 and completed an internship in Small Animal Medicine, Surgery, and Emergency at University of Pennsylvania. Dr. Benaryeh has also taught practical coursework to first-year veterinary students and was a primary veterinary surgeon for the Helping Hands Program, which trains assistance monkeys for quadriplegic people. Dr. Benaryeh is certified by the American Board of Veterinary Practitioners in Canine and Feline Practice.