Severe Gastrointestinal Disease in a Dog Presenting With Hypoadrenocorticism‐Like Electrolyte Derangements Due to Protothecosis

ABSTRACT

Objective

To describe systemic protothecosis as a novel differential for hypoadrenocorticism‐like clinicopathologic findings.

Case Summary

A 3‐year‐old neutered female Labrador Retriever was evaluated for an episode of acute lethargy, hyporexia, and ataxia. The dog had a prior history of chronic gastrointestinal signs with no underlying cause determined. On presentation, the dog had several clinicopathologic changes similar to those seen in cases of hypoadrenocorticism, most notably a severe hyperkalemia and hyponatremia, with a sodium‐to‐potassium ratio of <14:1. A diagnosis of Prototheca bovis infection was made based on the histopathology of endoscopic biopsies and confirmatory polymerase chain reaction. The dog initially had a positive response to treatment with oral antifungals but was later euthanized due to the progression of ophthalmologic and neurologic signs.

New or Unique Information Provided

Based on a literature search and to the authors’ knowledge, this is the first time canine protothecosis has been associated with severe hyperkalemia and one of only a few reports of gastrointestinal disease resulting in severe hyperkalemia.

Abbreviations

AI

adrenal insufficiency

CIRCI

critical illness‐related corticosteroid insufficiency

DOCP

desoxycorticosterone pivalate

GI

gastrointestinal

RI

reference interval

1. Introduction

Canine gastrointestinal (GI) disease is among the most commonly presenting complaints in small animal practice [1]. Electrolyte derangements are a frequent clinicopathologic finding in people with GI disease due to intestinal inflammatory changes that alter the absorption and secretion of ions across the mucosal epithelium in the GI tract [2]. These changes are also a common finding in veterinary medicine in cases of GI distress [3]. In cases of chronic inflammatory enteropathy, this most commonly leads to decreased absorption of sodium and chloride ions and increased secretion of chloride and potassium ions, with derangements seen on blood work analysis of hypokalemia and hyponatremia [2, 3]. Alterations in electrolyte absorption and excretion have been shown in human medicine to subsequently affect intraluminal osmolality and ion‐coupled nutrient transport across the intestinal epithelium, clinically manifesting as diarrhea and weight loss [2].

When GI disease is caused by hypoadrenocorticism, hyperkalemia is a much more common finding than hypokalemia [4]. This is due to the immune‐mediated destruction of the adrenal cortex, resulting in subsequent inadequate secretion of aldosterone and other hormones [5, 6]. Reduced aldosterone, specifically, results in loss of sodium, subsequent natriuresis, and a decrease in effective circulating volume that impairs potassium excretion in the distal renal tubules. Volume depletion also decreases renal perfusion and causes prerenal azotemia and further potassium depletion [5, 6]. In classic cases of hypoadrenocorticism, the sodium‐to‐potassium ratio will be <27:1 [4].

Limited reports exist of other GI disease processes causing similar electrolyte derangements and marked decrease in the sodium‐to‐potassium ratio. The mechanism for these derangements is unknown but is thought to be attributed to the loss of sodium and bicarbonate ions from the GI tract and metabolic acidosis [4, 7]. Fluid lost from circulation is usually isotonic and, when replaced by enteral water, results in hyponatremia. Loss of bicarbonate ions contributes to metabolic acidosis, which can cause translocation of intracellular potassium to the extracellular space. These pseudo‐Addisonian or hypoadrenocorticism‐like electrolyte changes have been reported secondary to severe trichuriasis, salmonellosis, and duodenal perforation [7, 8, 9, 10].

This case report describes severe electrolyte abnormalities consistent with an Addisonian crisis but ultimately determined to be caused by severe GI disease due to protothecosis. This is also the first reported case of protothecosis in the region.

2. Case Summary

A 3‐year‐old neutered female Labrador Retriever was presented to an emergency and specialty referral clinic for lethargy, paraparesis, and hind limb ataxia. The dog had not traveled outside of the state of Massachusetts and had gone swimming in lakes 3–4 months before the onset of clinical signs. The dog had a 5‐month history of mild weight loss, chronic diarrhea, and chronic intermittent hematochezia that had been nonresponsive to probiotics¹, antimicrobials², anthelminthic drugs³, and dietary trials^{4 , 5 , 6 , 7}. Appetite and energy levels were reportedly normal throughout this timeframe. Prior diagnostic workup with the dog's primary care veterinarian included multiple negative fecal flotation examinations and negative antigen testing for Ancylostoma caninum, Dipylidium caninum, Trichuris vulpis, Toxocara canis, and Giardia spp. Repeat serum biochemistry panels performed over the course of the disease process revealed mild, intermittent hypoalbuminemia. Hematology, thyroid hormone testing, and serum concentrations of cobalamin, folate, and trypsin‐like immunoreactivity were unremarkable. Serum cortisol concentration, determined 3 months before presentation using a commercially available competitive chemiluminescent immunoassay⁸, was decreased at 16.6 nmol/L (0.6 µg/dL; reference interval [RI]: 27.6–165.5 nmol/L [1–6 µg/dL]). A subsequent ACTH stimulation test was performed with cosyntropin⁹ (0.5 mg/kg, IV) and was not consistent with hypoadrenocorticism, with pre‐stimulation cortisol concentration measured⁸ to be 30.3 nmol/L (1.1 µg/dL; RI: 27.6–165 nmol/L [1–6 µg/dL]) and post‐stimulation cortisol concentration determined⁸ to be 262 nmol/L (9.5 µg/dL; expected result <55 nmol/L [<2 µg/dL] for dogs with hypoadrenocorticism). An abdominal ultrasound performed by a board‐certified small animal internist 2 months before presentation revealed slightly increased cecal and caudal colic wall thickness and mildly enlarged caudal colonic and ileocecal lymph nodes. The adrenal glands were both normal in appearance with the following dimensions (cranial pole × caudal pole × length): left adrenal 0.44 cm × 0.55 cm × 2.75 cm, right adrenal 0.54 cm × 0.66 cm × 2.72 cm. Sampling of abnormal tissues was not performed at this time, as only mild changes were noted.

The dog was presented to a specialty referral facility via the emergency service after a 1‐day history of lethargy, decreased appetite, and progressively abnormal gait. On presentation, designated as Day 0 for the purposes of this report, the dog was dull and moderately dehydrated with tacky mucous membranes. The dog was bradycardic with a heart rate of 50/min (RI: 80–120/min). A minimally ambulatory paraparesis with proprioceptive ataxia and crossing over of the hindlimbs was demonstrated while walking. Proprioceptive positioning was delayed but consistently present in all four limbs. Cranial nerve testing (evaluating cranial nerves II, III, V, and VII) and other physical examination findings were within normal limits. Liquid diarrhea was present on rectal examination.

An initial point‐of‐care serum biochemistry panel revealed moderate hypoalbuminemia of 20 g/L (2.0 g/dL; RI: 25–44 g/L [2.5–4.4 g/dL]), moderate azotemia with a BUN of 4.7 mmol/L (132 mg/dL; RI: 2.5–8.9 mmol/L [7–25 mg/dL]) and a creatinine of 221 µmol/L (2.5 mg/dL; RI: 26.5–123.8 µmol/L [0.3–1.4 mg/dL]), marked hyperphosphatemia of 3.5 mmol/L (10.8 mg/dL; RI: 0.9–2.1 mmol/L [2.9–6.6 mg/dL]), marked hyponatremia of 119 mmol/L (119 mEq/L; RI: 138–160 mmol/L [138–160 mEq/L]), marked hyperkalemia of >8.5 mmol/L (>8.5 mEq/L; RI: 3.7–5.8 mmol/L [3.7–5.8 mEq/L]), and moderate hyperglycemia of 13.3 mmol/L (240 mg/dL; RI: 3.3–6.1 mmol/L [60–110 mg/dL]) (Table 1). The total carbon dioxide concentration was 14.5 mmol/L (14.5 mEq/L; RI: 19–26 mmol/L [19–26 mEq/L]).

TABLE 1.

Selected clinicopathologic values in a 3‐year‐old neutered female Labrador Retriever presenting with severe hyperkalemia associated with disseminated Protothecosis.

	Reference interval	Units	Day 0	Day 1	Day 2	Day 4	Day 21	Day 30*
ALB	25–44, 31–42	g/L	20	18	13	19	21	33
	2.5–4.4, 3.1–4.2	g/dL	2.0	1.8	1.3	1.9	2.1	3.3
BUN	2.5–8.9, 2.1–10.7	mmol/L	4.7	0.7	0.2	0.7	0.1	1.0
	7–25, 6–30	mg/dL	132	20	6.0	20	3.0	27
CREAT	26.5–123.8, 44–132.6	µmol/L	221	53	44.2	61.9	53	106.1
	0.3–1.4, 0.5–1.5	mg/dL	2.5	0.6	0.5	0.7	0.6	1.2
PHOS	0.9–2.1, 0.8–1.8	mmol/L	3.5	1.6	1.5	1.9	1.6	2.0
	2.9–6.6, 2.5–5.6	mg/dL	10.8	5.0	4.7	6.0	4.9	6.1
NA	138–160, 145–151	mmol/L	119	130	135	139	142	139
	138–160, 145–151	mEq/L	119	130	135	139	142	139
K	3.7–5.8, 3.7–5.1	mmol/L	>8.5	5.0	4.0	3.2	4.6	5.7
	3.7–5.8, 3.7–5.1	mEq/L	>8.5	5.0	4.0	3.2	4.6	5.7
GLU	3.3–6.1, 4.3–6.5	mmol/L	13.2	5.8	6.8	5.8	6.2	5.6
	60–110, 78–118	mg/dL	240	105	123	105	112	100
TP	54–82, 54–70	g/L	63	53	46	56	50	58
	5.4–8.2, 5.4–7.0	g/dL	6.3	5.3	4.6	5.6	5.0	5.8

Note: Table is organized by timepoint, with Day 0 as the day of initial emergency presentation. Abnormal values appear in bold. Values for Days 0–21 were obtained from a point‐of‐care chemistry analyzer, while values for Day 30 were obtained from a diagnostic laboratory (reference values denoted with *)

Abbreviations: ALB, albumin; BUN, blood urea nitrogen; CA, calcium; CREAT, creatinine; GLU, glucose; K, potassium; NA, sodium; PHOS, phosphorous; TP, total protein.

A CBC showed a leukocytosis of 22.9 × 10⁹/L (22.9 × 10³/µL; RI: 5.0–16.8 × 10⁹/L [5.0–16.8 × 10³/µL]) characterized by a neutrophilia of 22.2 × 10⁹/L (22.2 × 10³/µL; RI: 3.0–11.6 × 10⁹/L [3.0–11.6 × 10³/µL]), a monocytosis of 3.2 × 10⁹/L (3.2 × 10³/µL, RI: 0.2–1.1 × 10³/µL [0.2–1.1 × 10³/µL]), a normal lymphocyte count of 3.42 × 10⁹/L (3.42 × 10³/µL; RI: 1.05–5.10 × 10⁹/L [1.05–5.10 × 10³/µL]), and a mild eosinopenia of 0.02 × 10⁹/L (0.02 × 10³/µL, RI: 0.06–1.23 × 10³/µL [0.06–1.23 × 10³/µL]). The dog's weight had decreased from 30.6 kg, when clinical signs were first noticed 5 months prior, to 24.8 kg upon emergency presentation.

Blood was collected for a baseline cortisol measurement for suspected hypoadrenocorticism, and resuscitative measures were initiated. An IV fluid bolus (0.9% NaCl 24 mL/kg) was administered, and the dog was treated with Humulin R¹⁰ (1 unit, IV), dexamethasone sodium phosphate¹¹ (0.26 mg/kg, IV), and desoxycorticosterone pivalate (DOCP)¹² (2.2 mg/kg, IM). A slow IV infusion of calcium gluconate was started but was discontinued after 5 mL due to an increase in heart rate to 100/min and the development of ventricular cardiac arrhythmias on ECG. The dog was hospitalized on continuous IV 0.9% NaCl (75 mL/kg/day), dexamethasone sodium phosphate¹¹ (0.26 mg/kg, IV, q 24 h), methadone¹³ (0.2 mg/kg, IV, q 6 h), maropitant¹⁴ (1 mg/kg, IV, q 24 h), and probiotics¹ (1 capsule, PO, q 12 h). An ACTH stimulation test was performed with cosyntropin¹⁵ (0.5 mg/kg, IV). The dog was discharged on Day 2 after responding well to treatment.

Attitude and gait had normalized, and blood work was periodically rechecked, showing progressive improvement in electrolyte abnormalities (Table 1). Albumin decreased in the hospital and was 13 g/L (1.3 g/dL; RI: 25–44 g/L [2.5–4.4 g/dL]) before discharge. The ACTH stimulation test was not consistent with hypoadrenocorticism, with a pre‐stimulation cortisol concentration⁸ of 637 nmol/L (23.1 µg/dL; RI: 27.6–165 nmol/L [1–6 µg/dL]) and a post‐stimulation cortisol concentration⁸ of 582 nmol/L (21.1 µg/dL; expected value <55 nmol/L [<2 µg/dL] for dogs with hypoadrenocorticism). Fecal testing (zinc sulfate centrifugation and antigen testing for Ancylostoma caninum, Dipylidium caninum, Trichuris vulpis, Toxocara canis, and Giardia spp.) that had been submitted during hospitalization was negative. Serum aldosterone concentration determined using a commercially available radioimmunoassay kit¹⁶ was inconsistent with primary hypoaldosteronism, with pre‐stimulation aldosterone concentration >4.716 nmol/L (>170 ng/dL; RI: 0.014–0.958 nmol/L [0.5–34.5 ng/dL]) and post‐stimulation aldosterone concentration >4.716 nmol/L (>170 ng/dL; RI: <0.197–2.103 nmol/L [<7.1–75.8 ng/dL]). The dog was discharged with metronidazole² (10 mg/kg, PO, q 12 h, for 7 days), capromorelin¹⁷ (3 mg/kg, PO, q 24 h, as needed), prednisone¹⁸ (0.1 mg/kg, PO, q 24 h, to be given until otherwise instructed), maropitant¹⁴ (2.4 mg/kg, PO, q 24 h, for 5 days), fenbendazole³ (0.24 g/kg, PO q 24 h, for 3 days), and a probiotic¹ (1 capsule, PO, q 12 h, for 20 days). The cause of the electrolyte abnormalities remained unknown.

After discharge, the dog returned to normal activity and appetite but continued to have consistent diarrhea with intermittent hematochezia. A follow‐up abdominal ultrasound performed on Day 4 by a board‐certified small animal internist revealed static to mildly progressive thickening of the descending colon with mild wall layer alteration and static to mildly progressive caudal abdominal lymphadenopathy. Adrenal glands were still normal in appearance with a left adrenal diameter of 6.8 mm and a right adrenal diameter of 5.7 mm.

Blood work revealed persistent hypoalbuminemia of 19 g/L (1.9 g/dL; RI: 25–44 g/L [2.5–4.4 g/dL]) and hypokalemia of 3.2 mmol/L (3.2 mEq/L; RI: 3.7–5.8 mmol/L [3.7–5.8 mEq/L]). Urinalysis, urine protein:creatinine ratio, bile acids, and trypsin‐like immunoreactivity were submitted, and all returned within normal limits. Pancreatic lipase immunoreactivity was increased (788 µg/L; RI: ≤200 µg/L), consistent with pancreatitis. The dog developed hyporexia that improved with administration of capromorelin¹⁷ (3 mg/kg, PO, q 24 h). Endoscopy was performed on Day 21. Gastroscopy showed mild changes consistent with inflammation in the stomach and duodenum. Colonoscopy showed markedly decreased vascular markings. Point‐of‐care blood work at the time of endoscopy revealed normal electrolytes and improved hypoalbuminemia of 21 g/L (2.1 g/dL; RI: 25–44 g/L [2.5–4.4 g/dL]). Microscopically, endoscopic histopathology sections of the ileum and colon had variable architectural effacement by a mixed leukocytic to neutrophilic infiltrate associated with organisms most consistent with Prototheca sp. (Figure 1).

FIGURE 1.

Photomicrographs of endoscopic biopsies of the colon of a 3‐year‐old neutered female Labrador Retriever, showing marked expansion of the lamina propria and effacement of normal glandular architecture by sheets of Prototheca sp. organisms, characterized by round to ovoid basophilic bodies or multiple wedge‐shaped endospores delineated by a refractile wall. (A) Hematoxylin and eosin stain. (B) Periodic acid–Schiff (PAS)‐positive goblet cells (white arrows) and PAS‐positive organisms (black arrows).

Steroid administration had been discontinued on Day 12 before endoscopy. While awaiting histopathology results, the owners noted return of mild ataxia, and on Day 27, prednisone¹⁸ (0.1 mg/kg, PO, q 24 h) was restarted. Upon receiving histopathologic results, treatment for protothecosis was started with itraconazole¹⁹ (8 mg/kg, PO, q 24 h) and nystatin²⁰ (6000 U/kg, PO, q 8 h). Positive polymerase chain reaction results confirmed a diagnosis of Prototheca bovis. Treatment with amphotericin B was discussed but declined by the owner.

The dog initially showed a good response to treatment with some improvement in diarrhea and good appetite, attitude, and energy. However, a recheck appointment on Day 30 showed retinal detachment and decreased intraocular pressures of the left eye with an absent menace response on the affected side. A serum biochemistry panel at this visit revealed mild hyperphosphatemia of 2.0 mmol/L (6.1 mg/dL; RI: 0.8–1.8 mmol/L [2.5–5.6 mg/dL]), hyponatremia of 139 mmol/L (139 mEq/L; RI: 145–151 mmol/L [145–151 mEq/L]), hyperkalemia of 5.7 mmol/L (5.7 mEq/L; RI: 3.7–5.1 mmol/L [3.7–5.1 mEq/L]), and hypertriglyceridemia of 3.8 mmol/L (337 mg/dL; RI: 0.3–2.2 mmol/L [28–197 mg/dL]). Symmetric dimethylarginine was within normal limits but at the high end of the RI at 0.67 µmol/L (13.6 µg/dL, RI: <0.69 µmol/L [<14.0 µg /dL]). A repeat DOCP injection (2.2 mg/kg, IM) was given due to the recurrence of hyperkalemia.

Consultation with a board‐certified ophthalmologist on Day 46 revealed changes to the left retina consistent with subretinal granuloma from protothecosis (Figure 2). The right retina had subretinal granulomas in the inferior one‐third, with minor focal retinal hemorrhages. The left eye was noted to have light perception but no functional vision; vision in the right eye was apparently unaffected at the time of consultation. Mild anterior uveitis was also present in the left eye. Treatment was initiated with prednisolone acetate 1% suspension²¹ (1 drop, OS, q 12 h, 1 drop, OD, q 24 h) and dorzolamide 2% solution²² (1 drop, OS, q 12 h) for anterior uveitis. The owner reported the dog's vision at home progressively worsened, resulting in a systemic treatment change from itraconazole¹⁹ to voriconazole²³ (5 mg/kg, PO, q 12 h).

FIGURE 2.

Ophthalmologic changes noted during examination of a 3‐year‐old neutered female Labrador Retriever with disseminated protothecosis. (Left) Apparent retinal detachment in the left eye visible with the naked eye. (Right) Subretinal granulomas visible on fundoscopic examination.

The dog returned on Day 59 for euthanasia due to progressive blindness, disorientation, weakness, and incoordination at home. Necropsy was consistent with disseminated protothecosis. Protothecal organisms and associated inflammatory change were noted in the colon, regional lymph nodes, kidneys, globes, leptomeninges, and rare hepatic foci (Figure 3). The adrenal glands were grossly unremarkable with regard to size, shape, color, and corticomedullary ratio. There were few microscopic foci of adrenalitis, but no organisms were noted with periodic acid–Schiff, and there was no significant loss of adrenal cortex grossly or microscopically (Figure 4).

FIGURE 3.

Necropsy findings of a 3‐year‐old neutered female Labrador Retriever with disseminated protothecosis. (A) Partially incised colon showing multiple pale‐tan, raised mucosal nodules that are embedded within the mucosa and submucosa on a cut section of the wall. (B) Bisected left kidney showing tan, ovoid, radiating, mass‐like structures within the renal pelvis that bulge on the cut section. (C) Right (upper) and left (lower) globes after formalin fixation and sagittal sectioning through the optic nerve head. Opacity of the retina with partial (upper globe) or complete (lower globe) detachment and subretinal exudate. The lower globe also has opacity of the vitreous from the exudate. (D) Histopathology of one of the globes demonstrating presence of numerous Prototheca sp. organisms, stained with hematoxylin and eosin stain.

FIGURE 4.

Low‐magnification photomicrograph of the adrenal gland collected at the time of postmortem examination in a 3‐year‐old neutered female Labrador Retriever with disseminated protothecosis. The adrenal gland is grossly unremarkable with regard to size, color, and corticomedullary ratio. Cortical loss or layer disruption is not evident microscopically. Inset: High‐magnification photomicrograph demonstrating a rare focus of infiltrating leukocytes identified after careful inspection of the cortex, with no Prototheca sp. organisms found. The tissue was stained with hematoxylin and eosin stain.

3. Discussion

Protothecosis is a rare disease caused by achlorophyllous algal species of the genus Prototheca, which has been shown to infect a wide variety of species, including people, dogs, cats, cattle, and pigs [11, 12]. Although cutaneous infection appears to be the most common manifestation in most species, canine protothecosis appears to present more commonly as a disseminated process primarily affecting the GI tract, eyes, and nervous system [11, 13]. Protothecal organisms are ubiquitous in nature, and given the low incidence of disease, it has been theorized that protothecosis is a secondary infection associated with primary immunosuppression [11, 14]. This is more clearly demonstrated in human medicine, where more severe disseminated infections are typically found in immunocompromised individuals [15]. In the current case, no primary underlying disease was found. The dog was noted by the owners to have swum in multiple lakes during the summer 3–4 months before the initial onset of GI signs, which may be the origin point of infection as Prototheca spp. are known to thrive in warm, wet environments. Pathologic findings in other cases of systemic canine protothecosis have led to the conclusion that ingestion is likely the primary route of infection, followed by subsequent hematogenous and lymphatic dissemination [11]. To the authors’ knowledge, this is the first report of canine protothecosis in the state of Massachusetts, and because the dog had no history of travel, protothecosis was not initially considered as a differential diagnosis for this case.

Although canine protothecosis is a rare clinical diagnosis, many case reports exist in the literature. Prototheca wickerhamii, P. zopfii, P. bovis, and P. ciferrii have all been shown to be pathogenic in dogs [13, 14]. Prototheca bovis and P. ciferrii have been reported to be more invasive, with greater dissemination and tissue involvement [16]. In dogs, protothecosis has been reported to affect the GI tract, eyes, nervous system, lymph nodes, urinary tract, liver, spleen, skin, and heart [17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]. Blood work is unremarkable in most cases, but reported changes include leukocytosis, neutrophilia, and monocytosis, similar to the current case [17, 18, 21, 23, 24, 26, 35]. A few cases have reported anemia, which was not noted in this dog [18, 20, 26]. Other reports include increases in alkaline phosphatase, alanine aminotransferase, and gamma‐glutamyl transferase [17, 21, 27], and azotemia in a case series regarding renal protothecosis [24]. These signs were not seen in the current case despite the findings of organisms in the kidneys and inflammatory hepatic foci postmortem.

Increased albumin, globulin, and total protein concentrations have also been described in some cases [20, 21, 23, 28, 31, 36]. Dehydration is a common clinical finding that may result in some of these changes. Hypoalbuminemia has also been noted in previous cases of disseminated protothecosis, as was seen in the dog in this case [20, 31, 35]. This may be due in part to the role albumin plays as a negative acute‐phase protein, resulting in decreased production during periods of severe systemic inflammation [37]. Additionally, chronic intestinal inflammation frequently leads to loss of proteins through the GI tract [37].

The severe electrolyte abnormalities mimicking an Addisonian crisis seen on this dog's initial emergency presentation make this case unique. Severe hyperkalemia in dogs is most commonly reported secondary to disease of the urinary tract or hypoadrenocorticism [38]. The severe hyperkalemia observed in the current case, combined with marked hyponatremia, a sodium‐to‐potassium ratio of <14:1, and the presence of chronic GI signs, made hypoadrenocorticism a very likely differential for this case. However, normal ACTH stimulation test results and normal serum aldosterone concentrations ruled out hypoadrenocorticism in this dog. Secondary hypoadrenocorticism (i.e., disease of the hypothalamus or pituitary) was not considered the likely cause since electrolyte changes are typically only seen with primary hypoadrenocorticism affecting the adrenal glands; thus, functional testing of hypothalamus and pituitary was not performed. The pituitary gland was evaluated histologically on necropsy, and no abnormalities were noted.

Diagnostic standards for critical illness‐related corticosteroid insufficiency (CIRCI) have remained elusive in human and veterinary medicine; however, this problem was considered unlikely in this case. In human medicine, CIRCI has been documented as a complication in patients with sepsis, septic shock, acute respiratory distress syndrome, community‐acquired pneumonia, cardiac arrest, trauma, and burns, and those undergoing extensive surgical procedures [39]. CIRCI is characterized by dysfunction of hypothalamic–pituitary–adrenal axis, altered cortisol metabolism, and increased resistance of tissues to cortisol [39, 40]. In people, treatment for CIRCI with hydrocortisone is not recommended if hemodynamic stability is achieved with fluid resuscitation and vasopressor therapy. There is a lack of comprehensive research on CIRCI in human medicine, and the literature in veterinary medicine is even more sparse. A study in dogs evaluating cases of septic shock with suspected CIRCI showed a potential survival benefit in cases that were treated with glucocorticoids, as treated and nontreated groups were found to have similar survival rates despite animals in the treated group having more risk factors for mortality on initial presentation [41].

It is uncertain whether there was a degree of CIRCI present in the current case. Even in human medicine, there are variable approaches to testing for CIRCI, with no gold standard method for definitively confirming a diagnosis [39]. In people, CIRCI can present similarly to primary adrenal insufficiency (AI), with findings such as hypoalbuminemia, hyponatremia, and hyperkalemia [39, 40]. Encephalopathy, which can cause paraparesis and proprioceptive deficits similar to those noted in the current case, has also been reported in some human cases of CIRCI [40]. If present in the dog in this case, AI could explain the positive clinical response to treatment with low doses of glucocorticoids and the recurrence of clinical signs when treatment was discontinued. However, although shock with life‐threatening electrolyte abnormalities was exhibited, the dog stabilized rapidly with fluid therapy and did not require treatment with pressors; thus, it is unclear whether a true critical illness was present to trigger CIRCI. Hypoglycemia or eosinophilia should suggest the suspicion of AI, as these abnormalities are relatively rare in acute conditions [39, 42], but neither was noted on initial presentation in this case. The fact that this patient did not develop hypotension, a common characteristic of septic shock and CIRCI, also makes it less likely that CIRCI was playing a role.

In this dog, serum cortisol concentrations on Day 0 were increased before and after administration of ACTH, which is not suggestive of AI. However, the dog did initially have low baseline cortisol performed with the referring veterinarian. This could be the result of protein loss through the GI tract secondary to chronic enteropathy, as circulating plasma cortisol has been found to be ∼90% bound to cortisol‐binding protein [40]. Increased proinflammatory cytokines during acute conditions can inhibit adrenal cortisol synthesis and induce tissue resistance to corticosteroids; however, there is limited evaluation of this in chronic inflammation [39]. As with albumin, cortisol‐binding protein is also a negative acute‐phase protein that is decreased in critical conditions and enteropathies and can complicate the reliable measurement of free cortisol levels [43]. One study in human patients with CIRCI found an initial hypercortisolemia, followed by a decrease to near basal levels [44]. During the acute stages of illness, hypercortisolemia is hypothesized to be caused by increased production of ACTH, leading to adrenal production of cortisol and decreased cortisol breakdown in the liver and kidneys combined with increased release of protein‐bound cortisol within the circulation [39, 40]. Hypercortisolemia subsequently inhibits ACTH production via a negative feedback loop, resulting in AI [40]. Cortisol concentrations in the current case were not evaluated after initial presentation; therefore, it is unknown whether they remained increased, normalized, or showed evidence of insufficiency.

Even less is known about critical illness‐related mineralocorticoid insufficiency in the human literature; to the authors’ knowledge, this condition has not been reported in veterinary medicine. Similar to the hypercortisolemia noted on presentation, the dog also had significant hyperaldosteronism, appropriate for a dog with severe hyperkalemia. Mineralocorticoid insufficiency in human medicine has been associated with hypoaldosteronism rather than hyperaldosteronism, but the pathophysiology has not been clearly elucidated [45]. Although primary hypoaldosteronism could have been a potential cause for the observed electrolyte derangements, it was ruled out due to increased serum aldosterone levels. Pseudohypoaldosteronism, in which adrenal function is normal but aldosterone is unable to bind to mineralocorticoid receptors in tissue, is extremely rare in human medicine [46] and, to our knowledge, has not been reported in veterinary medicine. In people, pseudohypoaldosteronism is typically caused by either a genetic mutation to the mineralocorticoid receptor or resistance of renal tissue to aldosterone [46]. The disease usually presents during infancy in people, and exogenous mineralocorticoid administration is not effective for treatment, making this differential less likely for the dog in this case [46]. Serum potassium concentration in this dog responded positively to treatment with DOCP and fluid resuscitation, but there was a recurrence of hyperkalemia. DOCP injection was repeated; however, the clinical response to this treatment was not evaluated before euthanasia, so it is unknown whether this provided any benefit to the patient.

AI, if present in the current case, may have been compounded over the course of treatment with further adrenal suppression by azole antifungals [39]. Ketoconazole has been used as a treatment option for Cushing syndrome as it targets enzymes involved at various steps in the pathways for synthesis of both cortisol and aldosterone [39, 40]. Acute AI has also been seen in human patients treated with fluconazole, particularly in critically ill patients [39]. The impact of newer azoles on adrenal function is less well understood, but they have been implicated in the induction of iatrogenic adrenal suppression [40, 47]. Azoles are also potent inhibitors of CYP3A4 in the cytochrome P450 system, decreasing glucocorticoid clearance and causing an increase in systemic glucocorticoid half‐life that ultimately amplifies secondary adrenal suppression. AI caused by azoles could either be primary from inhibition of adrenal steroid synthesis or secondary to increased glucocorticoid half‐life [48]. Hepatic cortisol metabolism may also be accelerated or prolonged by selected drugs, such as azoles, which modify the activity of cytochrome CYP3A4 [39].

Although the presence or absence of adrenal suppression in this dog cannot be definitively determined, it is worth noting that the adrenal glands were unremarkable on ultrasound and gross necropsy, with no adrenal atrophy noted, even after treatment with steroids over the 2‐month time span before euthanasia. There were a few focal areas of inflammation within the adrenal glands on necropsy, but these would not be expected to cause hypoadrenocorticism as the majority of the cortex was normal in appearance grossly and microscopically (Figure 4).

Besides consideration of adrenal involvement in the current case, there are other factors that may have contributed to marked hyperkalemia. Physical examination findings showed evidence of marked dehydration and hypovolemia, which likely resulted in prerenal hyperkalemia via reduced glomerular filtration rate and subsequent impaired potassium excretion [4]. Metabolic acidosis is also a commonly cited mechanism by which hyperkalemia is observed as a result of potassium movement out of cells in exchange for excess hydrogen ions [49]. Complete blood gas analysis was not performed in this patient, but an acidemia was likely present given the low concentration of total carbon dioxide and the tendency for loss of bicarbonate ions through the GI tract due to chronic diarrhea [49]. Primary renal damage may also have been a contributing factor given the presence of numerous protothecal organisms and bilateral necrotizing granulomatous pyelitis in both kidneys post‐mortem. Interestingly, however, the dog's kidney values were normal other than at initial emergency presentation, which was likely prerenal (fluid‐responsive). GI disease has also been found to cause marked hyperkalemia, although the mechanism not fully understood. Hyperkalemia has been reported as a sequela of trichuriasis, salmonellosis, and duodenal perforation [7, 8, 9, 10]. A study evaluating causes of decreased sodium‐to‐potassium ratio in dogs cited inflammatory bowel disease, chronic hepatopathy, anal furunculosis, hepatic vascular anomalies, antibiotic‐responsive diarrhea, acute liver failure, dietary intolerance, and resected peptic ulcer, as well as other GI disorders [50]. The same study also found that decreased sodium‐to‐potassium ratio can result from urogenital, cardiorespiratory, and endocrine disorders, among others [50]. Only cases caused by endocrine disease were found to have a sodium‐to‐potassium ratio of <15:1 [51]. Hyperkalemia and low sodium‐to‐potassium ratio have also been reported secondary to chylothorax [51, 52], lung lobe torsion [53], neoplastic pleural effusion [54], and late‐term pregnancy [55]. Few other cases of protothecosis have noted hyperkalemia as a finding, although the reported increases were not as marked as those in the current case [20, 35].

Protothecosis is a severe progressive disease and is typically fatal in dogs. Increasing numbers of cases of protothecosis have been reported worldwide recently in human medicine [12, 56]. Despite this, protothecosis is a rare disease in both human and veterinary medicine and as such is often not considered a differential diagnosis until the microorganism is found on histopathologic evaluation [13]. Protothecosis is likely underreported because it may be confused with yeast species such as Candida or Cryptococcus on Gram stain [57]. Additionally, Prototheca can resemble some life stages of coccidial organisms. Protothecosis can also appear similar to Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, Pneumocystis jiroveci, and Rhinosporidium seeberi, which has the potential to further complicate diagnosis [58]. Without the use of special staining, the morphology of the organisms may be missed on tissue sections [57]. Insufficient cases of canine disseminated protothecosis have been diagnosed and treated to fully evaluate the efficacy of various treatment protocols. Amphotericin B has historically been recommended as the treatment of choice as protothecal cell membranes are composed of ∼4% ergosterol, which this medication targets [59]. In vitro studies have shown that Prototheca spp. are sensitive to amphotericin B, azoles, and a wide range of antimicrobial agents [23], but these have shown little efficacy in vivo in canine patients beyond temporary or partial remission [33, 60]. In the human literature, azole antifungals are helpful in some cases, but amphotericin B has been observed to be the most consistently effective [61]. This treatment was discussed but not elected in this case. Administration can be difficult in a veterinary setting and cost‐prohibitive, as it necessitates repeated hospital stays and IV infusions.

In conclusion, this case sheds light on protothecosis as a differential for chronic GI disease causing severe hypoadrenocorticism‐like electrolyte derangements without definitive evidence of AI. Validation of this important disease process as a differential diagnosis can prevent delays in diagnosis and increase the potential for earlier and possibly more effective treatment in the future.

Author Contributions

Rachel G. Angles: writing – original draft, investigation, conceptualization. Courtney M. Peck: writing – review and editing, supervision, investigation, conceptualization. Pamela Mouser: writing – review and editing, resources, data curation. Patty Ewing: writing – review and editing, resources, data curation. Daniela Ackley: supervision, conceptualization, investigation.

Ethics Statement

The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. No ethical approval was required as this is a case report with no original research data.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.