A 9-year-old male intact mixed-breed dog was presented to The Ohio State University Veterinary Medical Center for evaluation of two days’ duration of weakness, lethargy, inappetence, and one episode of vomiting the day of presentation. On presentation, the dog was depressed and tetraparetic. He was noted to be icteric and dehydrated. Obesity and truncal alopecia with a “rat tail” appearance were observed. Diagnostic testing revealed evidence of an acute hepatopathy and peritonitis. Given the dog’s neurologic status, physical examination abnormalities, including a “tragic facial expression”, and hyperlipidemia, there was concern for possible myxedema coma. A thyroid panel was consistent with hypothyroidism. The dog experienced respiratory arrest prior to initiation of therapy, and an autopsy confirmed the presence of subacute necrotizing cholangiohepatitis, marked atherosclerosis, and severe thyroid atrophy. These clinical and pathologic changes were supportive of myxedema coma.
Acute liver injury is an important cause of morbidity in dogs. There are many possible causes of acute liver injury and subsequent liver failure, with hepatotoxicity, infection, inflammatory disease, trauma, and hypoxemia accounting for most presentations [
Acquired primary hypothyroidism most commonly results either from immune-mediated lymphocytic thyroiditis or idiopathic atrophy; the latter is often presumed to represent the end-stage of the former. The disease is characterized by a deficiency of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). The most common clinical signs include lethargy, weight gain, endocrine alopecia, and other dermatologic conditions [
Myxedema coma is a rare syndrome that can be seen with severe hypothyroidism. In addition to the typical signs of hypothyroidism, dogs with myxedema coma may present with dullness, myxedema (nonpitting edema of the skin), hypothermia, bradycardia, hypotension, and hypoventilation. This can progress to stupor and coma.
A 9-year-old male intact mixed-breed dog was presented to The Ohio State University Veterinary Medical Center for evaluation of two days’ duration of weakness, lethargy, inappetence, and one episode of vomiting the day of presentation. Seven months prior to evaluation, the dog was evaluated by an emergency clinic for acute vomiting and lethargy. Diagnostic evaluation was declined by the owner at that visit, and the dog received subcutaneous fluids and an antiemetic (maropitant, 1 mg/kg SQ once).
Upon presentation to The Ohio State University Veterinary Medical Center (OSU-VMC), the dog weighed 25.6 kg and had a body condition score of 8/9 (obesity) with normal muscle condition. The dog was estimated to be approximately 7-8% dehydrated, and the mucus membranes were tacky, pale pink, and icteric. Temperature (
Initial diagnostics performed included a packed cell volume/total protein (PCV/TP), venous blood gas, and blood pressure measurement. The blood pressure via oscillometric measurement was 125/70 mmHg (systolic/diastolic). The PCV/TP were 40% and 11 g/dL, respectively. The blood gas revealed a mild hyponatremia (138.4 mmol/L; reference range, 143.0-150.0 mmol/L), hypochloremia (106.4 mmol/L; reference range, 111.0-119.0 mmol/L), and hyperlactatemia (5.5 mmol/L; reference range, 0.5-3.5 mmol/L). BUN and creatinine at presentation were 21 and 1.5 mg/dL, respectively.
The dog was admitted to the hospital for further diagnostic evaluation and supportive care including intravenous fluids (Plasmalyte), to correct for dehydration, as well as an antiemetic (ondansetron, 0.3 mg/kg IV q8h).
The CBC (Table
Serial CBC results.
Variable | Day 1 | Day 2 | Reference interval |
---|---|---|---|
Hematocrit | 33 | 27 | 40-59% |
MCV | 57 | 68 | 62-77 FL |
MCHC | 38.8 | 36.2 | 33-36.1 g/dL |
RBC morphology | Target cells | Target cells | |
Total leukocytes | 23.7 | 17.8 | |
Segmented neutrophils | 20.6 | 16 | |
Band neutrophils | 2.6 | 0.4 | |
Lymphocytes | 0.2 | 0.5 | |
Monocytes | 0.2 | 0.9 | |
WBC morphology | Döhle bodies | Döhle bodies, reactive lymphocytes | |
Platelets | 311 | 259 |
Serial biochemistry results. Variables denoted with an asterisk were from blood gas analyzer.
Variable | Day 1 | Day 2 | Day 2 | Day 2 | Reference interval |
---|---|---|---|---|---|
BUN | 21 | 28 | 33 | 9-33 mg/dL | |
Creatinine | 1.5 | 1.4 | 1.9 | 0.7-1.8 mg/dL | |
Phosphorus | 6.3 | 2.2-6.3 mg/dL | |||
Total calcium | 10.8 | 9.3-11.3 mg/dL | |||
Sodium | 138.4 | 144 | 144.1 | 145.9 | 143-150 mmol/L |
Potassium | 3.97 | 2.86 | 3.47 | 3.8 | 3.5-4.8 mmol/L |
Chloride | 106.4 | 104.8 | 115.8 | 109.3 | 111-119 mmol/L |
pH | 7.296 | 7.495 | 7.378 | 7.508 | 7.38-7.48 |
Bicarbonate | 16.8 | 28 | 14 | 26.5 | 16.9-24.2 mmol/L |
Ionized calcium | 5.6 | 5.5 | 5.5 | 5.5 | 4.9-5.8 mg/dL |
Magnesium | 1.1 | 1.2 | 1.0 | 1.3 | 1.11-1.53 mg/dL |
ALT | 4,563 | 18-108 IU/L | |||
AST | 1,585 | 16-51 IU/L | |||
ALP | 2,341 | 12-133 IU/L | |||
CK | 449 | 53-372 IU/L | |||
Cholesterol | 1,272 | 122-345 mg/dL | |||
Triglycerides | 1,118 | 34-265 mg/dL | |||
Total bilirubin | 4.24 | 0.05-0.2 mg/dL | |||
Albumin | 3.1 | 3.3-4.2 g/dL | |||
Globulin | 4.1 | 1.7-3.4 g/dL | |||
Glucose | 88 | 147 | 107 | 112 | 78-126 mg/dL |
Lactate | 5.5 | 1.3 | 3.1 | 3.8 | 0.5-3.5 mmol/L |
Urine was obtained via cystocentesis and submitted for urinalysis. Urine specific gravity was 1.011 (after dog had received IV fluids for at least four hours). Hematuria (blood 3+), proteinuria (3+), and bilirubinuria (2+) were noted.
Both prothrombin time (PT) and partial thromboplastin time (PTT) were increased above reference intervals (20.7 seconds; reference range, 14-19 seconds and >200 seconds; reference range, 75-105 seconds, respectively). A point-of-care immunoglobulin detection test was negative for leptospirosis.
Thoracic radiographs revealed a diffuse unstructured interstitial pattern consistent with pulmonary hypoinflation. Mineralization of the principal bronchi and multiple pinpoint mineral foci throughout the lungs were observed. The cardiac silhouette was unremarkable, and there was no evidence of pulmonary neoplasia.
Abdominal ultrasound revealed hepatomegaly; the liver was diffusely hyperechoic with a fine echotexture. The gallbladder contained a large amount of echogenic material. The gallbladder wall was thickened and hypoechoic, consistent with edema, and the fat surrounding the gallbladder was hyperechoic (Figure
Ultrasonographic image of the gallbladder, demonstrating a thickened and hypoechoic wall, consistent with edema. The surrounding fat is hyperechoic.
There was a scant amount of anechoic to mildly echogenic peritoneal effusion present. Abdominocentesis was performed, and fluid analysis was consistent with an exudative process (white blood cells 69,000 IU/L: 85% neutrophils (degenerative neutrophils present), 15% large mononuclear cells; total protein 8 g/dL). Abdominal fluid glucose and lactate (69 mg/dL and 5.1 mmol/L) were compared to peripheral blood glucose and lactate (76 mg/dL and 3.6 mmol/L); results were not consistent with abdominal sepsis. Aerobic and anaerobic bacterial cultures of the peritoneal fluid were ultimately negative.
The dog was diagnosed with an acute hepatopathy of unknown etiology. Differential diagnoses considered included bacterial cholangiohepatitis, acute pancreatitis, previous gallbladder perforation, and neoplasia. Broad-spectrum antibiotic management of ampicillin-sulbactam (30 mg/kg IV q8 h) and enrofloxacin (10 mg/kg IV q24 h) was instituted. N-Acetyl cysteine was administered (140 mg/kg IV once, followed by 70 mg/kg IV q6 h) for antioxidant support.
A nasogastric tube (NGT) was placed to remove gastric residual volume (GRV) due to suspected ileus. Approximately 540 mL fluid was removed in the first 4 hours (20 mL/kg/hr). An IV continuous-rate infusion (CRI) of metoclopramide was administered (0.08 mg/kg/hr), and GRV declined. Antiemetic therapy was continued (ondansetron 0.3 mg/kg IV q8 h), and analgesia was provided (fentanyl 2
On day 2 of hospitalization, the dog was stable; however, mentation remained abnormal. Vital parameters (rectal temperature, heart rate, and respiratory rate) and blood pressure remained normal. There was minimal GRV present. A low-fat veterinary therapeutic liquid enteral diet was provided via the NGT at a CRI to provide approximately 25% resting energy requirement (RER). Serial monitoring via blood gas analysis (NOVA) showed elevations in BUN and creatinine indicative of an IRIS Stage II acute kidney injury (Table
Given concern for possible myxedema coma, including hyperlipidemia, dermatologic signs consistent with an endocrinopathy, abnormal mentation, and “tragic” facial expression (Figure
The dog in the ICU with a nasogastric tube (NGT) in place. Note the “tragic” facial expression.
Thyroid panel results.
Variable | Result | Reference interval |
---|---|---|
Total thyroxine (TT4) | 0 | 9-45 nmol/L |
Total triiodothyronine (TT3) | 0.4 | 0.8-2.1 nmol/L |
Free T4 | 9 | 6-42 pmol/L |
T4 autoantibody | 10 | 0-20% |
T3 autoantibody | 11 | 0-10% |
TSH | 0.97 | 0-0.58 ng/mL |
Thyroglobulin autoantibody | 11 | 0-35% |
The patient had multiple instances of inappropriate vocalization overnight and throughout his second day of treatment in the hospital. These vocalizations occurred both while receiving fentanyl CRI (2 mcg/kg/hr) and while not.
The patient became agonal in the evening of his second day in the hospital. Cardiopulmonary resuscitation was initiated, and the patient was intubated. Naloxone and epinephrine were administered IV. Resuscitation efforts were unsuccessful, and the owner elected for humane euthanasia.
At postmortem examination, there was marked icterus of the abdomen, pinna, and mucous membranes; generalized hypotrichosis; and diffuse subcutaneous edema that most significantly affected the face. There was widespread atherosclerosis, grossly apparent in multiple organ systems, including the gastrointestinal tract, kidneys, heart, testes, and brain; affected arteries were firm and tortuous, thickened by friable but cohesive, yellow-tan material (Figure
Marked atherosclerotic changes of multiple organs including the (a) brain, (b) gastrointestinal tract, (c) kidney, and (d) heart.
Histologic examination of the skin revealed marked epidermal and adnexal atrophy; superficial dermal collagen fibers were separated by increased clear space containing scant amorphous amphophilic material, supportive of edema and mucinosis, respectively (Figure
Histopathology of haired skin (hematoxylin and eosin stain, 10x). There is epidermal and adnexal atrophy. Dermal collagen layers are separated by white space (edema) with intervening amorphous amphophilic to basophilic material (mucinosis), changes supportive of cutaneous myxedema.
Histopathology of the right thyroid gland (hematoxylin and eosin stain, 10x). Histologically normal parathyroid tissue is seen in the top left. No thyroid follicular epithelium is noted (severe atrophy/loss). The tunica media of this artery is markedly expanded by foam cells, cholesterol clefts, and eosinophilic proteinaceous debris. The tunica adventitia is expanded by fibrous connective tissue, and there is mild lymphoplasmacytic infiltration within the vessel wall and extending into the adjacent fibrofatty tissue.
Histopathology of the liver (hematoxylin and eosin stain, 10x). There is complete loss of hepatic cord architecture with widespread biliary and periportal hepatocellular necrosis. Multifocally, hepatocytes are expanded by cytoplasmic vacuolation (hepatocellular lipidosis and/or glycogenosis).
The patient presented with signs of acute hepatopathy (mixed hepatocellular-cholestatic pattern) characterized at postmortem examination as necrotizing portal hepatitis, fibrinosuppurative peritonitis, and suspected cholecystic rupture. The widespread acute necrotizing cholangiohepatitis was most likely attributable to cholecystic rupture and associated peritonitis [
Other significant pathologic findings included widespread atherosclerosis and severe thyroid atrophy, supportive of severely unregulated hypothyroidism; the cutaneous changes were suggestive of myxedema. Based on these findings, we hypothesize that uncontrolled hypothyroidism resulting in atherosclerosis and concurrent hepatobiliary disease together ultimately culminated in myxedema coma (crisis). The presence of these two coexisting pathological processes resulted in a clinical presentation not entirely consistent with either individual condition (e.g., tachypnea, likely resultant from peritonitis associated visceral pain, rather than bradypnea expected with a myxedema crisis). The clinical presentation of the patient and the dual pathological processes thereby complicated disease diagnosis and management.
Based on the absence of microscopic changes in the cerebral tissue, hypothyroidism and atherosclerosis were considered to result in the neurologic signs. Atherosclerosis is the most common cause of arteriosclerosis in humans, but it occurs less frequently in dogs and is characterized mostly by lipid deposition in the tunica media rather than in the tunica intima [
Although the aforementioned case reports highlight the association between hypothyroidism and neurologic deficits, the physiologic pathway for these deficits is unclear. The association between hypothyroidism, hyperlipidemia, and atherosclerosis is well-documented in dogs, and it is hypothesized that aberrant lipid metabolism and deposition may be linked to neurologic deficits in some patients [
Aside from occasionally mildly elevated liver enzymes (ALP, ALT), a specific association between hypothyroidism and clinically apparent hepatopathy has not been extensively described in the veterinary literature; however, an association between hypothyroidism and gallbladder mucoceles is well described in dogs [
Myxedema coma (crisis) is a rare variant of severe uncontrolled hypothyroidism that has a mortality rate as high as 25-60% in humans [
In human literature, the leading precipitating events to myxedema crises are infection and septicemia [
Treatment of myxedema coma involves establishing an airway and maintaining adequate ventilation, initiating intravenous fluid and levothyroxine therapy, and passive warming to manage hypothermia [
The authors have no conflicts of interest to disclose.