The Case: Lethargy, Inappetence, & Neurologic Signs

An 8-year-old neutered male Irish setter was presented for 5 days of lethargy and decreased appetite as well as 2 weeks of strange head movements (intermittent bobbing). The patient was completely aware and responded to owners during the head bobbing episodes, which lasted several minutes. Pancreatitis had been diagnosed 2 months prior via abdominal ultrasound, which also showed a hypoechoic spleen. Blood analysis at that time reportedly revealed elevated alanine aminotransferase (ALT), aspartate aminotransferase (ASP), alkaline phosphatase (ALP), bilirubin, and globulin, but values were not available at the time of presentation. Urinalysis at that time showed trace protein, high bilirubin, and ammonium urate crystals with a specific gravity of 1.045. Patient recovered well from previous pancreatitis with outpatient therapy.

• Weight: 38.2 kg
• Temperature: 101.6⁰F
• Pulse:  120 bpm
• Respiration:  Panting
• Mucous membranes: Pink, moist
• Cardiopulmonary: No murmurs auscultated, lung sounds clear
• Abdomen: Soft, non-painful
• Neurologic: Normal mentation, mild conscious proprioceptive deficits of right hind limb, cranial nerves intact, mild neck pain elicited on palpation

• Abdominal ultrasound: Markedly hyperechoic and irregular peripancreatic fat of both limbs, most prominent around right limb. Pancreas hypoechoic and irregular. Diffusely hyperechoic mesentery. Mild anechoic free fluid.
• CBC: Mild monocytosis
• Serum chemistry:
• AST: 83 IU/L (range, 15–66)
• ALT: 181 IU/L (range, 12–118)
• All other values within normal limits
• T₄: Normal
• Urinalysis:  Urine specific gravity: 1.040, trace protein, bilirubinuria, ammonium urate crystals
• Abdominal fluid analysis: Transudate
• Prothrombin time/activated partial thromboplastin time: Within normal limits

Patient was discharged with

• Fentanyl: 100 mcg patch
• Maropitant: 60 mg q24h PO
• Metoclopramide: 10 mg q8h PO
• Famotidine: 10 mg q12h PO

Patient was presented again the following morning because of discomfort and panting the entire previous evening.

Patient was panting, hypersalivating, and exhibited apparent cranial abdominal pain as well as prayer position and hunched appearance. Occasionally lifted his left forelimb.

• Weight: 39.4 kg
• Temperature:  99.1⁰F
• Pulse: 140 bpm
• Neurologic: Normal, no neck pain noted at this time

• Bile acids test was recommended due to ammonium urate crystals, elevated liver enzymes, and abnormal head bobbing, but could not be completed due to extreme patient nausea. Systolic blood pressure was 130 mmHg (by Doppler).
• Thromboelastogram: No hypercoagulability

Hospitalization for pancreatitis with possible secondary vascular event contributing to neurologic signs

• IV fluids: 90 mL/kg/d
• Ampicillin: 20 mg/kg q8h IV
• Metoclopramide: 0.06 mg/kg/hr CRI
• Famotidine:  0.5 mg/kg  q12h IV
• Maropitant: 1 mg/kg  q24h SC
• Ondansetron: 0.2 mg/kg q8h IV
• Various pain medications: Hydromorphone (0.05 mg/kg q6h IV), fentanyl (100 mcg patch), buprenorphine (0.01 mg/kg q8h IV)

Neurologic status continued to decline over several days with patient being unable to stand or walk, displaying agitation, and beginning to shuffle to the left. Patient developed mild regurgitation, mild circling to left, hypermetric forelimbs, loss of conscious proprioception in both hind limbs, and inconsistent menace reflex OU. Head bobbing was appreciated when lifting head. Anorexia persisted. As patient’s neurologic status worsened, a vascular event was deemed less likely. Inflammatory disease was not ruled out.

• MRI: Within normal limits
• CSF tap: Normal
• Recheck abdominal ultrasound: Hyperechoic areas of pancreas, mesentery within normal limits, no free fluid visualized. Pancreatitis appeared resolved.
• Dexamethasone sodium phosphate: 0.2 mg/kg IV after MRI with no improvement
• Resting total serum bile acids: Elevated at 235.5 μM/L (range  <25)
• Abdominal ultrasound: No obvious hepatic shunt

For suspected hepatic encephalopathy

• Warm-water enemas q6h
• Lactulose: 15 mL q8h PO
• Metronidazole: 250 mg q8h PO
• S-adenosylmethionine + silybin (Denamarin): 425 mg q24h PO

Patient significantly improved, became ambulatory with support, much brighter, remained uninterested in food. On Day 6 of hospitalization, the patient ate small amounts of dry kibble.

Patient continued to improve; discharged on Day 7 with a poor long-term prognosis. Medications dispensed:

• Maropitant:  80 mg q24h PO
• Lactulose: 10 mL q8h PO
• Metronidazole: 250 mg q12h PO
• Denamarin: 425 mg q24h PO

Gretchen Statz, DVM, DACVECC

This case was handled well, with a very thorough workup. In retrospect, it would have been ideal to test for hepatic dysfunction prior to the advanced diagnostics (MRI and CSF tap). Although the testing was not harmful to the dog, it was likely expensive and ultimately unnecessary. It was stated that bile acids were recommended prior to the MRI and CSF tap but not performed because of nausea. A urine bile acids test would have been a good option in this case (see information below).

A number of laboratory indicators and clinical signs can accompany severe liver dysfunction. As shown by this case, not all dogs have all of the laboratory changes or clear-cut clinical signs.  

Laboratory changes that suggest hepatic dysfunction include:

• Elevated liver enzymes (indicates liver involvement, not really a test of function)
• Hypoalbuminemia
• Hypoglycemia
• Hyperbilirubinemia
• Hypocholesterolemia
• Elevated bile acids
• Urate crystals or stones in the urine
• Prolonged clotting times

Clinical signs of hepatic encephalopathy include:

• Ataxia
• Lethargy
• Disorientation, “spaciness,” acting “drunk”
• Pacing, circling
• Head pressing
• Seizures

This dog did have elevated liver enzymes and total bilirubin; however, it was reasonable to assume that these were a result of the pancreatitis found on ultrasound examination. There were no comments about the liver on the initial ultrasound examination, so my assumption is that the liver appeared normal.  

The neurologic signs seemed to vary. On initial presentation, the neck pain and conscious proprioception deficits with normal mentation may have led to spinal cord localization rather than the brain. As the clinical signs progressed, it became more obvious that there was brain involvement. Differentials for neurologic deficits originating from the brain include metabolic disease, toxicosis, infection, inflammation, and neoplasia. In many cases MRI and CSF tap are the first diagnostics we pursue in the presence of neurologic signs. In this case, the presence of urate crystalluria should have prompted further testing for liver function prior to advanced imaging (in retrospect, of course).

Pre- and postprandial serum bile acid testing is the most common way to diagnose liver dysfunction. Dogs with hepatic encephalopathy should have markedly elevated bile acids. Such testing is not always easy to perform: In small puppies it may be unsafe to initiate a fast for the recommended 12 hours or it may be difficult to obtain enough blood for both samples. In dogs that are nauseated or anorectic, it may be difficult to get them to eat enough to obtain an accurate postprandial sample. In other cases, owners are not willing to leave their pet in your care for 2 hours.

In these situations, a urine bile acid to creatinine ratio is another option. Urine bile acid testing requires 1 mL of random urine and does not require fasting or eating.  Levels obtained reflect the average serum bile acid concentrations during the time of urine formation. Sensitivity for liver disease is approximately 80% and specificity approximately 90%.

In young dogs, liver failure is often a result of a liver shunt (marked increase in bile acids) or microvascular dysplasia (mild to moderate increase in bile acids). In older animals, congenital hepatic shunt is less likely. Diseases such as fibrosis or cirrhosis due to a previous liver insult or chronic hepatic disease are more likely. Obtaining a definitive diagnosis would have necessitated a liver biopsy. 

Barak Benaryeh, DVM, DABVP

Although hepatic encephalopathy is not commonly encountered in general practice, this case serves as a good reminder of some of the difficulties involved in both its diagnosis and treatment. Many aspects are beyond what most general practitioners would deal with. The main learning points here are the general concepts surrounding hepatic encephalopathy. In addition, we can look at some alterations in strategy that could be considered.

The dog had been presented 2 months earlier with pancreatitis and had abnormal hepatic values at that time. After recovery, the values were not rechecked until this presentation. Most hepatic enzymes will decline after approximately 4 weeks, barring continuing liver damage.¹  It’s good medicine to follow up on cases and recheck any blood value abnormalities, even if they seem unrelated to the case at hand. It’s unlikely that this would have made a big difference in this particular case, but it might have led to an earlier diagnosis of liver disease.

A very thorough workup was performed, including complete blood analysis, an ultrasound, and finally an MRI and CSF fluid analysis. There is no definitive test for hepatic encephalopathy; it is a diagnosis of exclusion. A bile acid assay was not initially run as the dog was too nauseated to eat. Even without feeding, however, a resting bile acid can be measured (which is what was eventually done). Resting bile acid levels within the reference range do not rule out liver disease but an abnormal result is consistent with liver dysfunction.  

The final treatment choices for this dog included lactulose, metronidazole, and Denamarin. Lactulose helps reduce ammonia absorption from the gut. Metronidazole helps alter the profile of gut bacteria in favor of bacteria that reduce ammonia load. Finally, Denamarin functions as a general liver protective agent. Clearly, these treatments were beneficial and allowed the dog to go back home for some quality time.

Some additional treatment choices that could have been made include the following:  

• A change in diet to either Hill’s l/d or Royal Canin Hepatic, both of which are designed to reduce clinical signs of hepatic encephalopathy.
• Probiotics have been shown to decrease plasma ammonia levels in humans with hepatic encephalopathy¹ and are available in several forms for veterinary use.²
• Metronidazole is an excellent choice due to its low side effect profile. Consideration could be given to neomycin as an additional antibiotic, as it has been shown to lessen ammonia load.

This patient had a severe disease and, sadly, there is not much available to reverse its general course. These clinicians did a good job of managing a tough case. Strong consideration needs to be given to referral to a specialty facility in cases as complex as this one.