Hepatic encephalopathy (HE) is a complex clinical syndrome characterized by abnormal mental conditions accompanied by severe hepatic insufficiency (4,10). HE is also defined as a clinical syndrome frequently observed in animals with hepatic dysfunction and is characterized by changes in mental state, inappropriate behaviors, and impaired motor function, which occur secondary to liver failure or portosystemic vascular shunting (9). In horses, HE is associated with several forms of liver disease (10). Clinical signs are widely variable, ranging from a slightly altered mental status to coma (4). The most common clinical signs of hepatic insufficiency in horses include depression, anorexia, colic, weight loss, orange-colored urine, and icterus (3,11). Some authors have classified the clinical stages of mental status into four stages (5,8). Diagnosis is based on history, clinical signs, physical examination, laboratory and diagnostic imaging results, and its presence is confirmed by evidence of hyperammonemia and other indicators of impaired liver function (10). Differential diagnosis from other neurologic diseases such as equine protozoal myeloencephalitis (EPM), Wobblers syndrome, motor neuron disease, or encephalopathies is accomplished via a rule-out process. The options for treatment are diverse, mostly supportive, and aim to reduce potentially toxic protein metabolites that may be absorbed into the bloodstream (4). The prognosis for HE is generally poor, but if maintained properly, it can be controlled to sustain life (3,12).

The purpose of this case report is to describe the clinical findings, diagnosis, management, progress, and necropsy and histopathologic findings of HE in a young Connemara pony.

A 3-year-old female Connemara pony was referred to Jeju National University Equine Hospital (JNUEH) with reported weight loss and intermittent inappetence. The pony was presented a reduced appetite and weight loss to a local veterinary clinician several months ago, but the cause was not diagnosed clearly. Removal of one dental cap and some supportive treatments were given, but no improvement of clinical signs was observed before referring to our hospital. The patient was presented to JNUEH after transportation for more than 18 h, including a 6 h overnight boarding in a ferry without a supply of feed or drinking water (Fig. 1).

Figure 1. The pony on arrival. Remarkable muscular atrophy of the body with prominent bony marks on shoulder, thorax, and pelvic area can be seen.

At admission (day 0), the pony had a body weight of 270 kg, a rectal temperature of 38.5°C, a heart rate of 48 beats per minute, and a respiratory rate of 20 breaths per minute; both rates were slightly higher than the normal ranges. The pony was in poor nutritional condition (body condition score 2/9) and was dehydrated by approximately 6-8%. Initial hematological and blood chemical analyses using Vet Scan HM5 (Abaxis Inc., Union City, USA) and Vet Scan VS2 (Abaxis Inc., Union City, USA), respectively, revealed high, but within the normal range, packed cell volume of 43.76%, normal total protein (TP) of 7.2 g/dL, remarkably elevated total bilirubin (t-BIL) of 6.5 mg/dL, and remarkably increased enzyme activities of aspartate aminotransferase (AST) of 425 U/L and gamma-glutamyl transferase (GGT) of 234 U/L. In contrast, plasma creatinine (Cre) concentration was decreased to 0.6 mg/dL. Other parameters, including blood urea nitrogen (BUN), were within normal ranges (Table 1). The pony’s conjunctival and oral mucosal membranes were yellowish. Based on the results of diagnostic procedures on day 0, including CBC, blood chemistry, dental exam, and gastric endoscopy, the pony was tentatively diagnosed with chronic hepatitis and icterus, then provided with rest and feed in a box with bedding.

Table 1 . Hematology and blood chemistry results on day 0.

	At admission (day 0)	Reference range (horse)	Unit
Hematology
RBC	9.90	6.8-12.9	106/μL
WBC	11.04	5.4-14.3	103/μL
LYM%	11.5	17-68	%
MON%	6.3	0-14	%
NEU%	82.0	22-80	%
EOS%	0.1	0-10	%
BAS%	0.0		%
HCT	43.76	32-53	%
MCV	44	37-59	fL
PLT	146	100-400	103/μL
MPV	7.9		fL
HGB	18.1	12.0-17.0	g/dL
Blood chemistry
Na+	131	126-146	mmol/L
K+	4.0	2.5-5.2	mmol/L
Ca++	13.1	11.5-14.2	mmol/L
tCO2	29	20-33	mmol/L
Glu	101	65-110	mg/dL
Cre	0.6	0.6-2.2	mg/dL
t-BIL	6.5	0.5-2.3	mg/dL
BUN	10	7-25	mg/dL
ALB	3.1	2.2-3.7	g/dL
GLOB	4.1	2.7-5.0	g/dL
TP	7.2	5.7-8.0	g/dL
CK	259	120-470	U/L
AST	425	175-340	U/L
GGT	234	5-24	U/L

Moderate dehydration and chronic hepatic problems were strongly suspected. The total bilirubin concentration and the AST and GGT enzyme activities were abnormally elevated (reference ranges from VetScan® equine profile, 2015)..

On day 1, a low dose of medetomidine (0.005 mg/kg, IV) was administered for thoracic radiology and abdominal ultrasonography. On transcutaneous abdominal ultrasound using a convex probe (Aloka Arietta 60, Hitachi, Japan), the caudal margin of the right liver lobe was observed to be bluntly thickened and the parenchyma showed remarkably decreased vascular markings and increased echogenicity (Fig. 2). On day 2, gait evaluation and more diagnostic considerations were added to differentiate chronic hepatic failure, liver cirrhosis, EPM, wobblers syndrome, and HE. The pony exhibited unstable movement of the hind limbs with reduced resistance to side forces; hind limbs paresis was considered for the differential diagnosis, but the pony did not yet exhibit any specific cranial nerve signs. Due to reduced appetite and poor body condition, supportive fluid (lactated Ringer’s solution; total volume of 2 L at 1 L/h) and a low dose of amino acids and vitamins were given on days 2 and 3. Although the pony showed mild to moderate depression and abnormal gait on day 0, its clinical signs aggravated from day 2, showing remarkable hind limbs paresis and more cranial nerve signs such as circling, drooping, jerking, and head pressing against the obstacles and walls. HE was the most suspected diagnosis, but there were limited options to manage it due to its fast progress. Recumbency and ataxia were seen at night on day 3. With the agreement of the person responsible, the pony was euthanized humanely. Plasma ammonia concentration on day 3 was as high as 656 μmol/L. Both EPM and wobblers were ruled out by cervical radiology and postmortem evaluation of cerebrospinal fluid (CSF) aspirated from the atlantooccipital space.

Figure 2. Ultrasonographic images. Both left and right lobes of the liver show significantly reduced hepatic vascular pattern and hyper-echogenicity. (A) Margin of right liver lobe is thickened and rounded (yellow arrowhead). (B-D) The parenchyma of the liver shows hyper-echogenicity and reduced vascular patterns compared to normal image; features like that of the spleen (red arrow).

Necropsy and histopathologic examinations confirmed HE. At necropsy, subcutaneous tissues and skeletal muscles showed severe diffuse yellowish discoloration. There were about 100 mL of bright, reddish-colored turbid fluid in the abdominal cavity. The liver was firm with muscle consistency, diffusely yellowish green in color, and bluntly thickened on the edges. In the lower abdominal areas of the liver and mesentery, multiple enlarged tortuous blood vessels were observed (Fig. 3). Histopathologically, mild vacuolation in white matters and mild perivascular edema were observed in the thalamus. Most astrocytes in the brain presented as Alzheimer type II cells, characterized by single, double, or triple cells with clear, swollen vesicular nuclei in the gray matter of the cerebrum. The liver showed severe fibrosis and chronic inflammation in the portal triads (Fig. 4). Many newly formed capillaries and hyperplasia of bile ducts were observed in fibrotic hepatic lesions.

Figure 3. Gross findings of pony. (A) Subcutaneous tissue and muscle had a yellowish discoloration. (B) Note enlarged tortuous blood vessels on the serosa of the abdominal organs (yellow arrowhead).

Figure 4. Histopathologic findings. (A) Severe fibrosis around the portal triad (red arrowhead). H&E, ×100. (B) Hyperplasia of bile ducts (blue arrowheads) and newly formed vascular channels in fibrotic lesions. H&E, ×200. (C) Mild vacuolations in the white matter of cerebrum (red arrowheads). H&E, ×100. (D) Note single or double Alzheimer type II cells with clear swollen nuclei (blue arrowheads). H&E, ×400.

There have been many reports of chronic liver disease or HE in horses, but few reports of HE in 3-year-old ponies. Beech et al. (1977) reported a case of HE related to portal vein anomaly in 1-year-old Thoroughbred gelding (1). Durham et al. (2003) retrospectively analyzed 116 cases of mature horses over two years old with suspected liver diseases to evaluate their diagnostic data, assess their 6-month liabilities and predict their prognosis. Johns et al. (2007) reported a case of a pregnant mare to describe histopathological changes in the mare and fetus. Peek et al. (1997) reported a clinical case of a 3-year-old Paso Fino filly. The present case is a rare occurrence of HE in a young Connemara pony.

The cause of the original liver disease remains uncertain in this case. Based on communication with the referring veterinarian, earlier toxic effects to the liver might be suspected, but there was no definitive finding. Based on the author’s experience, the weak body condition, long-distance transport without a supply of feed or water, and the unfamiliar environment could act as stress factors to trigger HE. In addition, a small amount of fluid and supportive medication, even in low doses, might increase the load on hepatic function.

Usually, more than 80% of the liver mass must be lost, or obstruction of the common bile duct occur before clinical signs become apparent, regardless of the cause of hepatic disease (8). Most of the common relevant clinical signs were exhibited in this pony. As the concentration of ammonia in the blood increases, neurological signs become prominent; therefore, measuring the plasma ammonia concentration is important to diagnose HE. In this case, the patient was diagnosed with HE because there were negative clues related to fever or infection, cervical stenosis in radiologic exams, and CSF abnormalities, and because there were positive clues to associated with gradual changes in neurologic signs, functional insufficiency of the liver in blood chemistry, morphologic abnormalities of the liver in ultrasonography, and high ammonia concentration in the blood.

The normal echogenicity of the liver is lower than that of the spleen. The enlarged liver often shows round margins (17). Durham et al. (2003) examined 89 cases of ultrasonography out of 116 horses with liver diseases and observed that 33% of the patients had evidence of hepatic abnormalities such as generalized hyperechogenicity, hepatic atrophy, hepatomegaly, dilated vessels, focal hyperechogenicity, focal anechogenicity, and rounded liver margins (3). In this case, the rounded margin, reduced hepatic vascular pattern, and hyper-echogenicity of the liver were consistent with the referred abnormalities.

Usually, HE is considered a potentially reversible metabolic encephalopathy, and it is uncertain whether HE can lead to irreversible neuronal damage (8). But in this case, the pony had little sustainability during hospitalization and showed dramatic changes of metabolic and neurologic signs, which seemed to be irreversible, especially on day 3.

Necropsy to find any anomalies in the liver or portal vein, and histopathologic examinations to find Alzheimer type II cells in the brain can be elected after euthanasia (6,7,12,13). In this case, the gross and histopathological findings coincided with previously referred evidence of HE.

Ammonia has a toxic effect on cell membrane neurons by inhibiting Na/K-dependent adenosine triphosphatase activity in nerve cell membranes, thereby depleting adenosine triphosphate (14). Hyperammonemia is also associated with impairment of CNS energy production due to changes in the tricarboxylic acid cycle, which reduce α-ketoglutarate formation and increase glutamine synthesis (2,10). Plasma ammonia concentration is closely related to plasma urea concentration, but an increment in plasma ammonia concentration is not always accompanied by a decline of BUN (16). In this case, plasma ammonia concentration was as high as 656 μmol/L on day 3, remarkably higher than the reference value of 17.8 ± 3.8 μmol/L, mean plasma ammonia concentration after 8 hours of fasting in normal horses (15).

A 3-year-old female Connemara pony was diagnosed with HE based on history, clinical exams, diagnostic imaging, and gross and histopathologic examinations. Due to the disease’s rapid and irreversible progress and poor prognosis, treatment options were limited. However, the well-established data from this case could be helpful in the diagnosis of patients with HE, and hopefully improve their sustainability.

The authors have no conflicting interests.