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Episode based on:
Lidbury JA, Cook AK, Steiner JM. Hepatic encephalopathy in dogs and cats. J Vet Emerg Crit Care 2016. 26 (4):471-487.
“The aims of this article are to comparatively review the pathogenesis, clinical presentation, diagnosis, and management of HE in dogs and cats. Gaps in the understanding of HE in dogs and cats and areas worthy of future study are also highlighted.”
What is Hepatic Encephalopathy?
“the spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain disease” from Hepatic encephalopathy – definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna 1998 (Hepatology, 2002).
Hepatic Encephalopathy – Classification
Three types in human medicine:
- Type A: due to acute liver failure in the absence of pre-existing liver disease.
- Type B: associated with portal systemic bypass without intrinsic hepatocellular disease; e.g. congenital portosystemic shunting in dogs and cats.
- Type C: associated with cirrhosis and portal hypertension or acquired portal systemic shunting. Subcategorised according to duration and characteristics. Distinction made in people between ‘overt HE’ (signs of impaired mental status) and ‘covert HE’ (no altered mental status).
“can be applied to dogs and cats if the definition of type C HE is broadened to include cases associated with all intrinsic hepatocellular disease and portal hypertension or acquired portal systemic shunting.”
Covert HE currently not recognised in dogs and cats – likely exists but challenging to diagnose.
Schemes for grading severity exist in human medicine. No universally accepted guidelines to grading in dogs or cats. Some authors have adapted human grading schemes for use in dogs, e.g. Proot et al, 2009.
Hepatic Encephalopathy – Pathogenesis
Evidence (more and better quality in people) for central role of ammonia dysmetabolism.
Gastrointestinal tract is main source of ammonia. Especially via breakdown of nitrogenous products (e.g. urea) by urease producing gastrointestinal microbial organisms; but also via conversion of glutamine to ammonia within intestinal mucosa.
Ammonia and the liver:
Liver is main site of ammonia detoxification (kidneys and skeletal muscle much less so): failure of hepatic detoxification leads to hyperammonaemia and higher cerebral exposure.
Main causes of inadequate hepatic detoxification:
1) Portosystemic shunting (PSS):
Most common reason in dogs and cats
Ammonia-rich splanchnic blood from the gastrointestinal tract bypasses hepatic uptake and flows directly into systemic circulation.
Two types of portosystemic shunt, extrahepatic and intrahepatic
Congenital vascular anomalies or acquired collateral blood vessels secondary to prehepatic or hepatic portal hypertension
2) Intrinsic liver dysfunction despite receiving ammonia-rich blood:
Due to acute liver failure or potentially chronic cirrhotic changes
Ammonia and the brain:
Brain is involved and active in ammonia handling
Ammonia passes freely across the blood brain barrier (BBB) in healthy individuals
Ammonia and pathogenesis of hepatic encephalopathy:
- One of the most appealing theories is ammonia causes astrocyte swelling
- Other potential mechanisms too
- May also contribute to neurological dysfunction by increasing BBB permeability
“Dogs and cats with HE are often hyperammonemic, and successful treatment of HE is usually associated with a reduction in serum ammonia concentrations. However, patients may have HE despite a blood ammonia concentration within the reference interval suggesting that other mechanisms also play a role in the pathogenesis of HE.” (authors cite Rothuizen, van den Ingh, 1982).
Other pathogenic mechanisms of HE:
Infection and inflammation may play a role:
Clinical evidence in people
Non-infectious or infection systemic inflammatory response syndrome (SIRS) is common in people with both acute liver failure and cirrhosis
Inflammatory mediators may trigger HE by exacerbating cerebral effects of ammonia
Systemic inflammation also a potential phenomenon in dogs and cats with acute liver failure…“However, the relationship between inflammation and canine HE needs to be better defined. To the authors’ knowledge, this relationship has not been studied at all in cats.”
Neurosteroids found in high concentrations in the brain
Amino acid balance
Hepatic Encephalopathy – Precipitating factors
At least one trigger identified in 88 to 90% of those affected
Individuals with one or more triggers have a worse prognosis than those without
Most commonly reported include: gastrointestinal bleeding, constipation, diarrhoea, infection, hypokalaemia, hyponatraemia, and excess dietary protein.
Number of same factors can potentially precipitate HE in dogs and cats; some have been described in the veterinary literature. “However, the evidence base to support the role of many of these factors in veterinary species is weak or nonexistent.” Further investigation of the factors that may predispose dogs and cats to HE is needed.
Hepatic Encephalopathy – Clinical presentation
Signalment reflects most common causes of HE in dogs and cats, namely congenital or acquired portosystemic shunts.
Canine breeds most likely to be have congenital PSS (in descending order): Havanese, Yorkshire Terrier, Maltese, Dandy Dinmont Terrier, Pug, Miniature Schnauzer, Standard Schnauzer, and Shi Tzu. (Tobias, Rohrbach, 2003)
No studies evaluating which breeds are most likely to develop acquired shunting. Probably most likely in breeds predisposed to chronic hepatitis. Wide age range but typically older than dogs presenting for congenital PSS.
Congenital PSS reported in several cat breeds; unclear which – if any – are predisposed.
The authors say that although congenital shunts have been reported in a number of cat breeds, it is not clear which if any cat breeds are predisposed to HE and large-scale epidemiological studies will be needed to ascertain this.
Initially often subtle and episodic; can progress in intensity and frequency
May be exacerbated by eating
In one study (Lidbury et al, 2012)):
- Most common historical findings: obtundation, altered behaviour, head pressing, ataxia, apparent seizures, vomiting, lethargy, ptyalism, apparent blindness, and shaking.
- Most common neurological findings: obtundation, ataxia, weakness, conscious proprioceptive deficits, seizures, circling, cranial nerve deficits, stupor, and tremor.
Signs of HE in cats reportedly broadly similar to those in dogs.
Hepatic Encephalopathy – Diagnosis
In veterinary medicine, based on:
- Presence of consistent clinical signs
- Exclusion of other causes of encephalopathy
- Laboratory findings
- Imaging studies, and
- Response to treatment
Currently no way to evaluate dogs and cats that have HE but without impaired mental status.
Measuring blood ammonia concentration:
May or may not be elevated in dogs with HE
“In individual dogs, fasting ammonia concentrations poorly predict the severity of HE.” (Rothuizen, van den Ingh, 1982)
When accessible, seems to be performed routinely or at least commonly in veterinary patients suspected of having HE; not the case in human medicine.
Appropriate sample handling is critical:
- Ammonium ions are extremely labile in plasma and ammonia may be released by red blood cells ex vivo.
- Samples should be collected in a lithium heparin or EDTA tube, placed immediately on ice, and the plasma separated from the red blood cells as soon as possible.
- Plasma must be kept cooled and should be analysed within 30 minutes of collection.
In-house and point of care analysers available: Reliability? Validation in dogs and cats?
“Measurement of pre- and postprandial serum bile acid concentrations is a useful test for diagnosing hepatobiliary disease, including portosystemic shunting, in dogs and cats. A definitive diagnosis of portosystemic-shunting requires diagnostic imaging or surgical exploration. Several imaging modalities are useful for this purpose, including angiography, abdominal ultrasonography, portal scintigraphy, computed tomography angiography, and MRI angiography. These imaging modalities, apart from portal scintigraphy, frequently allow the anatomic characterization of the shunt vessel(s)….For patients with acquired liver disease, a histological diagnosis is often necessary to define the underlying cause.”
Hepatic Encephalopathy – Treatment
Treating the underlying cause:
Various techniques for attenuation of congenital PSS
“Generally, signs related to HE improve after shunt attenuation…although incomplete closure can lead to persistent compromise. Dogs with a poorly developed portal vasculature may develop portal hypertension after shunt closure. This triggers the development of [acquired collateral circulation] with possible recurrence of HE. Postoperative seizures can also occur, the pathogenesis of which is unknown.”
Post-attenuation seizures “can occur in dogs and cats that do not have HE or other metabolic causes of seizures….Typical histological changes of the cerebrum in animals undergoing necropsy include selective “ischemic” neuronal necrosis and other changes that are consistent with ischemia or hypoxia. Withdrawal of endogenous benzodiazepines [post-congenital shunt] attenuation has also been proposed as a potential mechanism.”
Attenuation of acquired shunts contraindicated; these shunts are a compensatory response to portal hypertension and closure results in an acute exacerbation of portal hypertension.
General supportive care and treatment of precipitating factors:
Standard practice around:
- Maintenance of fluid and electrolyte balance
- Routine care of the comatose or stuporous patient
- Management of suspected intracranial hypertension
- Antimicrobial therapy for confirmed or highly suspected infection
- Gastroduodenal ulcer treatment and prophylaxis
Warm water enemas:
Advised in this review to be performed in severely affected dogs and cats with HE until signs improve (reference is a single author book chapter).
Help remove blood and faecal matter from colon; therefore decrease bacterial ammonia production.
Also indicated for constipated patients with HE of all severity grades.
Typical recommendation is protein-restricted diet containing specific types of protein sources.
Cats reportedly have a higher dietary protein requirement than dogs.
Diets recommended for HE also tend to have other modifications including reduction in some substances and supplementation with others.
“Although several commercially available diets are marketed for dogs and cats with HE, the optimal diet formulation has not been established.”
A non-absorbable disaccharide
Potential beneficial effects:
- Trapping of ammonium ions within the colon leading to decreased absorption of ammonia into the portal circulation
- Inhibition of ammonia production by colonic bacteria
- Stimulation of incorporation of ammonia within bacterial proteins
- Reduced intestinal transit times leading to decreased bacterial ammonia release
- Increased faecal excretion of nitrogenous compounds
Placebo controlled studies in humans support efficacy for treating overt HE. While lactulose is “commonly used to treat HE in dogs and cats [both acutely and chronically]…there are no studies that have critically evaluated the efficacy of this drug.”
Can be given per rectum after a cleansing warm water enema in acutely compromised patients but “it has not been proven that this has any benefits over a plain warm water enema.”
Aim to reduce ammonia production by altering intestinal microbiome
- Poor gastrointestinal absorption
- Use no longer recommended in people as inadequate evidence of efficacy and risk of serious renal injury and ototoxicity
- No good quality information about its use for HE in dogs and cats.
Metronidazole and vancomycin have also been used to treat HE in people; may be better tolerated in people than neomycin but their efficacy has not been rigorously established. Clinical trials have not been reported describing the efficacy of metronidazole for HE in dogs and cats.
Rifaximin (semisynthetic derivative of rifampicin) is US Food and Drug Administration approved for maintaining remission of HE in people. “The pharmacokinetics of rifaximin has been reported for dogs and this drug has been reported to be well tolerated in this species…The lack of apparent adverse effects is a potential benefit compared to neomycin and metronidazole. However, the safety and efficacy of this drug in dogs and cats with HE have not been established. Current costs are also likely to be prohibitive.”
Intravenous ampicillin (or potentiated amoxicillin) may be used in dogs or cats that cannot receive oral medications
Use of oral ampicillin also been reported
“Anticonvulsant drugs should be administered to patients with HE if seizures occur and in patients that seizure after attenuation of a congenital portosystemic shunt. Additionally, they are sometimes given to patients prior to shunt attenuation in an attempt to reduce the occurrence of postoperative seizures.”
“The use of diazepam and midazolam to treat seizures due to HE is controversial and there are no clinical trials that have evaluated the efficacy of these drugs in this setting. As diazepam is hepatically metabolized its half-life may be prolonged in dogs and cats with HE. Therefore, the dose and frequency that is used should be reduced in order to avoid causing profound sedation…In people benzodiazepine administration is considered to be a precipitating factor for HE.”
- Rapidly acting anticonvulsant with few side effects identified so far
- Can be given intravenously or orally to dogs and cats
- Principal route of excretion is renal so suitable for patients with hepatic compromise.
- Use in dogs undergoing congenital PSS attenuation may be well tolerated and may reduce occurrence of postoperative seizures (Fryer et al, 2011).
Phenobarbital and propofol may also be used if required in acute situations
Potassium bromide can be used as an adjunct to other anticonvulsant drugs in dogs; of little use in emergency scenario due to very long half-life and delayed onset of action.
Other potential treatment options in people:
- Flumazenil (intravenous benzodiazepine receptor antagonist): role of endogenous benzodiazepines in the pathogenesis of HE is controversial; only consensus is that flumazenil is useful when treating human patients with HE who have taken benzodiazepines.
- L-ornithine-L-aspartate (or LOLA): thought to increase the rate of ammonia detoxification; early positive findings with clinical use in people with overt HE but further work is needed.
- L-carnitine: several potentially beneficial mechanisms of action have been proposed in ammonia toxicity; some positive early findings in people but more work is needed.
- Prebiotics, probiotics and synbiotics: controversy in the evidence base in people and further well-designed large-scale clinical trials are needed.
Application to veterinary emergency and critical care
“HE is a relatively common but potentially life-threatening complication of hepatobiliary disease in dogs and cats. Veterinarians working in emergency or critical care settings must be able to promptly recognize, diagnose, and manage this condition. Although increased blood ammonia concentrations strongly suggest HE, it is important for clinicians to be aware of the limitations of this diagnostic tool. It is also essential that predisposing factors are quickly identified and addressed and that appropriate supportive care is provided.”
“Although there are several well-established treatments for HE in dogs, none of them are supported by robust scientific evidence. Clinical trials of the drugs currently used to treat HE are needed to help optimize treatment protocols.”
Papers mentioned in this episode:
Fryer KJ, Levine JM, Peycke LE, et al. Incidence of postoperative seizures with and without levetiracetam pretreatment in dogs undergoing portosystemic shunt attenuation. J Vet Int Med 2011. 25(6):1379–1384.
Lidbury JA, Cook AK, Steiner JM. Hepatic encephalopathy in dogs and cats. J Vet Emerg Crit Care 2016. 26 (4):471-487.
Lidbury JA, Ivanek R, Suchodolski JS, Steiner JM. Clinical feature of hepatic encephalopathy in dogs: 80 cases (1991–2011). J Vet Int Med 2012. 26(3):781 (Abstract).
Mehl ML, Kyles AE, Hardie EM, et al. Evaluation of ameroid ring constrictors for treatment for single extrahepatic portosystemic shunts in dogs: 168 cases (1995–2001). J Am Vet Med Assoc 2005. 226(12):2020–2030.
Proot S, Biourge V, Teske E, Rothuizen. Soy Protein Isolate versus Meat-Based Low-Protein Diet for Dogs with Congenital Portosystemic Shunts. J Vet Int Med 2009. 23(4):794-800.
Rothuizen J, van den Ingh TS. Arterial and venous ammonia concentrations in the diagnosis of canine hepato-encephalopathy. Res Vet Sci 1982. 33(1):17-21.
Taboada J, Dimski DS. Hepatic encephalopathy: clinical signs, pathogenesis, and treatment. Vet Clin North Am Small Anim Pract 1995. 25(2):337–355.
Tobias KM, Rohrbach BW. Association of breed with the diagnosis of congenital portosystemic shunts in dogs: 2,400 cases (1980–2002). J Am Vet Med Assoc 2003. 223(11):1636–1639.
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