Introduction

Atherosclerosis is a multifocal vasculopathy characterized by fatty plaque formation involving the tunica intima and media of larger arterial blood vessels.^1,2 Despite the strong association with hypothyroidism and the extensive lesions found on histopathology in hypothyroid dogs, clinical manifestations directly related to atherosclerosis are rare.^2–4 When they occur, neurological signs are most common.^5–7 We report the first known canine case of hypothyroid-induced atherosclerosis resulting in a clinical hepatopathy.

Case Report

An 18.2 kg 7 yr old male beagle presented for a 4-day history of progressive lethargy and anorexia. No other clinical signs were present or developed during this brief period of illness. The dog was otherwise healthy, with no previous illness reported. The dog received yearly vaccinations and monthly heartworm prophylaxis. On physical examination, the dog was estimated to be 5% dehydrated and displayed discomfort on palpation of the cranial abdomen. Vital parameters were within normal limits. There were no dermatologic abnormalities nor history of weight gain.

A normocytic, normochromic nonregenerative anemia (packed cell volume 29.5% [31–56%] and reticulocyte production index 1.0% [>1.5% to be considered regenerative]) and mild leukocytosis (24.7 × 10³ cells/μL [6.0–17.0]) consisting of 21.7 × 10³ segmented neutrophils/μL (3.0–11.5) and 1.0 × 10³ band neutrophils/μL (0.0–0.3) were noted on complete blood count. Hypercholesterolemia (1,176 mg/dL [120–247]), elevated alanine aminotransferase (ALT) activity (2,925 U/L [10–130]), and elevated alkaline phosphatase (ALP) activity (1,201 U/L [24–147]) were present on serum biochemistries. Abnormalities on abdominal ultrasonography included multifocal hypoechoic areas lacking Doppler blood flow within the left lateral liver lobe and a hyperechoic, central stellate with fine radiating striations pattern to the gallbladder consistent with a mucocele. Abdominal computed tomography (CT) revealed a discrete, hypoattenuating area within the left lateral liver lobe containing no visible vasculature following IV contrast administration (Figure 1). No apparent cause for the hepatic changes was identified on either imaging study.

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Given concern for vascular compromise and subsequent necrosis of the left lateral liver lobe, the dog underwent an exploratory laparotomy. The left lateral liver lobe was diffusely swollen and purple, whereas the remainder of the liver appeared grossly normal. The gallbladder was distended, firm, and unable to be expressed. Consequently, a cholecystectomy, left lateral liver lobectomy, and wedge biopsy of the right medial liver lobe was performed without complication. Postsurgical care included the administration of IV fluids, fentanyl^a 3 μg/kg/hr IV as a constant rate infusion, and ampicillin-sulbactam^b 30 mg/kg IV q 8 hr. Three days after surgery, the dog’s clinical signs had markedly improved. Therefore, the dog was discharged with instructions to administer amoxicillinclavulanic acid^c 13.75 mg/kg per os (PO) q 12 hr, S-adenosylmethionine^d 425 mg PO q 24 hr, and tramadol^e 5.5 mg/kg PO q 8hr for 1 wk.

Marked, multifocal blood vessel lumen stenosis secondary to intimal expansion by lipid-laden macrophages (foam cells) and clear acicular zones (cholesterol clefts; Figure 2) was present on histopathologic examination of the left lateral liver lobe. Large, well-demarcated areas of pallor containing necrotic hepatocytes were present surrounding stenotic blood vessels (Figure 2). These histopathologic findings warranted a diagnosis of severe, multifocal mural atherosclerosis with secondary hepatic infarction and centrilobular necrosis. Identical histopathologic lesions, albeit of lesser severity, were found in the biopsy taken from the right medial liver lobe. Diffuse mucosal hyperplasia with a large amount of intraluminal mucin, consistent with a mucocele, was present on histopathologic examination of the gallbladder. Blood vessels in the gallbladder wall contained identical atherosclerotic lesions to those found in the left lateral liver lobe.

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Upon re-evaluation 1 wk after discharge (12 days after initial evaluation and 10 days after surgery), clinical signs had completely resolved. However, the dog still had a mild nonregenerative anemia (packed cell volume 29.0% [31–56%] and reticulocyte production index 0.4% [>1.5% to be considered regenerative]), elevated ALP (1,381 U/L [24–147]), and hypercholesterolemia (1,093 mg/dL [120–247]). The ALT was within reference interval (127 U/L [10–130]). Both the ALT and ALP were significantly improved when compared with initial presentation. Because of the association of atherosclerosis with hypothyroidism and diabetes mellitus, serum for measurement of total thyroxine (T₄), free T₄, thyroid-stimulating hormone, and blood glucose concentration was submitted.³ Likewise, urine for urinalysis and a cortisol:creatinine ratio was submitted given the association of biliary mucocele and hyperadrenocorticism.⁸

The urine cortisol:creatinine ratio was above the reference limits (45.93 × 10⁻⁶ [<10 × 10⁻⁶]);however,the dog had no clinical signs or physical examination findings consistent with hyperadrenocorticism. This result was likely a false positive due to concurrent illness and the stress associated with urine sampling at the hospital visit. The blood glucose concentration (115 mg/dL [60–135]) and urinalysis were within reference limits. Serum total T₄ (<0.5 μg/dL [1.61–3.60]), free T₄ by equilibrium dialysis (<0.3 ng/dL [0.6–3.70]), and thyroid stimulating hormone concentrations (3.41 ng/mL [0.05–0.42]) were consistent with a diagnosis of primary hypothyroidism. Levothyroxine^f 0.02 mg/kg PO q 12 hr was prescribed.

Two weeks after commencement of levothyroxine therapy (28 days after initial evaluation), the dog was returned for a second recheck examination. The dog was still reported to be normal at home. The packed cell volume (42.7% [31–56%]), cholesterol (232 mg/dL [120–247]), ALT (125 U/L [10–130]), and ALP (143 U/L [24–147]) were all within their respective reference intervals. The serum total T₄ concentration 4 hr after the last levothyroxine administration was also within reference interval (4.92 μg/dL [3.6–5.0]), consistent with appropriate supplementation. Therefore, the dog was maintained on the same levothyroxine dose. At the time of writing (57 mo after initial evaluation), the dog was reported to still be clinically normal and to have normal liver enzymes.

Discussion

Hypothyroidism is a common canine endocrine disorder resulting from inadequate circulating thyroid hormone concentrations. Hypercholesterolemia occurs because of decreased biliary cholesterol excretion and changes to the serum lipoprotein profile that favor the accumulation of cholesterol-rich molecules, such as high-density and low-density lipoproteins, in the blood.^9,10 Macrophage and smooth muscle cell uptake of large quantities of cholesterol can result in fatty plaque formation (atherosclerosis) involving the tunica intima and media of larger blood vessels.^1,2 As plaque lesions progress, vascular occlusive disease can occur, resulting in clinical signs consistent with the organ(s) involved. Because of these metabolic alterations and their secondary vascular effects, an association between atherosclerosis and hypothyroidism has been established despite the prevalence of spontaneous atherosclerosis in dogs undergoing necropsy being 0.5%.³ Interestingly, however, despite histopathologic evidence of extensive atherosclerosis in hypothyroid dogs, clinical signs associated with these changes are rare.^2,4 This is likely due, in part, to the common manifestations of hypothyroidism resulting in early diagnostic and therapeutic intervention as well as the marked severity and/or prolonged duration of hypercholesterolemia necessary to result in occlusive atherosclerotic lesions.^11,12 When present, the clinical signs directly related to hypothyroidism-induced atherosclerosis are largely neurologic in origin, namely, central vestibular dysfunction, cranial neuropathies, tetraparetic or paraparetic myelopathy, and seizures.^5–7 Additional, yet infrequent, clinical signs described include lameness, vomiting, and collapse.^10,13

This case report describes a dog with occlusive atherosclerosis secondary to hypothyroidism that contains several unique features. First, the dog’s clinical signs were not specific to a particular organ system, unlike most previous reports, and were directly related to atherosclerosis, not hypothyroidism.^5–7 Second, the atherosclerotic lesions induced a clinical hepatopathy, making this the first report detailing this rare manifestation of hypothyroidism in the liver. Lastly, unlike most canine vasculopathies, whereby surgery is often ineffective because of lesion location or extensiveness, the dog in this report successfully underwent surgery to remove the disease-inducing lesion.

Treatment of hypothyroidism consists of oral levothyroxine therapy, accompanied by general supportive care, depending on whatever associated conditions or sequalae are present.¹⁴ However, for the dog in this report, hypothyroidism was diagnosed only after atherosclerosis was found on histopathology of the liver, primarily because of the lack of overt clinical signs consistent with this endocrinopathy. Therefore, the diagnostic and treatment decisions made prior to histopathology findings were based on clinical acumen. A left lateral liver lobectomy was performed given the focal hepatic lesion on abdominal imaging studies and the high degree of certainty that this lesion represented an area of vascular compromise. During surgery, the left lateral liver lobe was enlarged, firm, and dark purple, consistent with necrosis, and histopathology confirmed large numbers of necrotic hepatocytes. These gross and microscopic findings, in conjunction with the marked improvement in the dog’s liver enzymes and clinical signs, confirmed that surgery was the most appropriate clinical decision. It also demonstrated that advanced imaging modalities, such as CT, are effective at diagnosing large, focal vascular lesions within the hepatic parenchyma, thereby suggesting utility in such cases.

Based on the biochemical abnormalities, thyroid function tests, and histopathologic findings, primary hypothyroidism was unequivocally diagnosed in this case. Twice daily oral levothyroxine therapy was promptly initiated. At the 2 wk recheck following diagnosis, both ALT and ALP were within their respective reference intervals. This is particularly interesting given that occlusive atherosclerosis was also found on histopathology of the grossly normal right medial liver lobe, indicating that the dog’s lesions were not confined only to the surgically removed left lateral liver lobe. As demonstrated by the liver enzyme normalization, restoration of euthyroidism appears to result in a reversal of hypothyroidism-induced atherosclerosis in the liver. Likewise, this positive response to thyroid hormone supplementation is described in dogs suffering from a multitude of neurologic signs secondary to hypothyroidism-induced occlusive atherosclerosis.^5,6 Unlike older reports, the findings of Vitale et al., Higgins et al., and this case report demonstrate that dogs with clinical signs related to atherosclerosis can survive with appropriate and prompt treatment.^2,5,6,10

In addition to the hepatic changes, a biliary mucocele was found on abdominal imaging studies. Based on the liver enzyme pattern and lack of hyperbilirubinemia, it was not suspected to have played a primary role in the dog’s clinical signs. However, given the ultrasonographic appearance, surgical removal was decided upon to prevent future clinical problems such as obstruction or rupture. In retrospect, the presence of a biliary mucocele was not surprising, because it is associated with hypothyroidism.^8,15

Conclusion

To the author’s knowledge, this is the first report of an acute hepatopathy secondary to vascular occlusive disease caused by hypothyroid-induced atherosclerosis. Thus, finding atherosclerosis on hepatic histopathology should prompt a diagnostic investigation for hypothyroidism, and likewise atherosclerosis should be included as a differential diagnosis for acute hepatocellular liver enzyme elevation. Prompt restoration of euthyroidism can lead to a full recovery and prolonged survival. Abdominal imaging studies can be particularly useful for identifying vascular compromise of a liver lobe, and surgery to remove such pathology is beneficial.