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What is Hepatitis?
Hepatitis is a catch-all diagnosis for a number of diseases where there is inflammation and death of liver tissue. The liver is a vital organ that performs many different functions, including the digestion and conversion of nutrients, the removal of toxic substances from the blood and the storage of vitamins and minerals. Because the liver is involved in so many processes, it can be vulnerable to damage from a variety of sources. Liver function can also be affected by other diseases elsewhere in the body. The term ‘hepatitis’ therefore is not, in itself, a single disease - there are many different causes and types of hepatitis.
Hepatitis can be acute or chronic. In acute hepatitis, liver inflammation will have arisen quite suddenly, or over a short period, for example if a dog has ingested something poisonous or contracted a serious infection. If the damage is not too far advanced, when given supportive medications and a little time, the liver will frequently recover completely, due to its amazing and unique ability to regenerate. However, in some cases, acute hepatitis can become chronic hepatitis.
In chronic hepatitis, the damaging process of liver inflammation will have been going on for some time and is associated with progressive scarring (cirrhosis) or the formation of excessive fibrous tissue in the liver (fibrosis). In some cases, chronic hepatitis can be effectively managed, with dogs living for a considerable time (sometimes years) after their diagnosis. Sadly, in other cases it can lead to progressive loss of liver function, as healthy liver cells are replaced by scar tissue, resulting in end-stage liver failure and death.
What causes Chronic Hepatitis?
Chronic hepatitis has a variety of causes, not least because it describes a number of different diseases and because the liver can be affected by so many other internal organs and systems as well as a host of external factors. The following list includes many of the possible causes of chronic hepatitis in dogs.
Bacterial and viral infections: For example, the bacteria that causes leptospirosis and the canine adenovirus that causes infectious canine hepatitis. Even common sources of infection, such as chronic tooth decay, could eventually lead to chronic liver disease.
Toxins: Liver damage can be caused by poisons ingested by the dog or by accumulation of substances made by the body. Examples of chemical, plant-based or other toxic substances include pesticides, insecticides, bleach, household cleaners, fungal toxins (e.g. aflatoxin), sago palm (cycasin), Xylitol (used as a sweetener).
Medications: Certain drugs can cause side effects of liver damage that may progress to chronic hepatitis. They include nonsteroidal anti-inflammatory drugs (NSAIDs), pain medications, antibiotics, anaesthetics, de-wormers, corticosteroids and anticonvulsants.
Parasitic infestations: For example, heartworm and roundworm.
Copper-storage disease: A genetic disease that predisposes dogs in certain breeds (e.g. Bedlington Terriers) to an abnormal accumulation of copper in the liver, leading to progressive damage and scarring (cirrhosis). It is not known to be a genetic risk in English Springer Spaniels.
Lifestyle and environmental factors: For example, a diet that is too high in fats.
Immune-mediated (autoimmune) disease: Many experts believe that some forms of chronic hepatitis may have an autoimmune component, which means that a weakened or overactive immune system may play a leading role. Research is ongoing to try to establish whether this may be relevant in a severe form of chronic hepatitis that has been identified in some English Springer Spaniels. Scroll down for further information about this research.
Idiopathic (unknown cause): As the symptoms of chronic hepatitis are unpredictable and may not be specific, diagnosing and treating the disease can be exceedingly difficult. In many (if not most) cases, it is simply not possible to identify the cause.
What are the symptoms?
The liver has a large reserve capacity, meaning there must be damage to a significant portion of it (as much as 80%) before any signs of illness are usually noticed. The first signs are generally vague and non-specific, and can include loss of appetite, vomiting or diarrhoea, weight loss, depression, lethargy, increased drinking (polydipsia) and increased urination (polyuria). As the disease becomes advanced, there will be signs more specific to liver failure such as jaundice (yellowing of the skin and whites of the eyes, pale gums), fluid accumulation in the abdomen (ascites), dark coloured urine, weight loss, coagulation (thickening/clotting of the blood) and neurological abnormalities such as circling, lack of co-ordination or behavioural changes, due to the build-up of toxins normally metabolised by the liver.
How is Chronic Hepatitis diagnosed?
A vet will firstly consider the dog’s symptoms and carry out a physical examination. If liver disease is suspected, they will undertake routine diagnostic blood tests - these will show elevated levels of liver enzymes (ALTs) if the dog is indeed affected by abnormal liver function. Imaging techniques such as x-ray and abdominal ultrasound are also commonly used to assess the size and appearance of the liver. Dogs with chronic hepatitis can have small, irregular livers and some dogs develop blood vessels that allow blood to bypass the liver and free fluid to accumulate in the abdomen.
A liver biopsy is the only definitive way to diagnose chronic hepatitis. This is necessary in order to differentiate chronic hepatitis from other categories of liver disease (such as liver cancer) and to determine the type, pattern, severity, extent and possible cause of the problem, enabling an assessment of the dog’s prognosis and the planning of appropriate treatment options.
What is the treatment and prognosis?
Depending on the type and stage of a dog's illness when it is diagnosed, treatment may involve antibiotics, corticosteroids, antioxidants, ursodeoxycholic acid, dietary management and other support medications.
The prognosis for chronic hepatitis is quite variable. Dogs with end-stage disease have a poor prognosis, while dogs diagnosed earlier can live for many months, if not years after diagnosis. Unfortunately, liver damage is often advanced by the time the disease is recognised.
Further help and information:
If any ESS owner and/or breeder would like any help or further information about chronic hepatitis, the Breed Health Co-ordinators would be happy to hear from you (click on the link below for contact details). All information you provide will be treated in the strictest confidence.
We would also be extremely grateful if ESS owners would help us to monitor CH in ESS by reporting online any confirmed diagnosis of CH or the death of your ESS from the disease.
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ENGLISH SPRINGER SPANIEL CHRONIC HEPATITIS RESEARCH
ENGLISH SPRINGER SPANIEL CHRONIC HEPATITIS RESEARCH
Introduction
Research has been ongoing for a number of years at The Queen's Veterinary School Hospital, University of Cambridge, led by Principal Investigators Dr. Penny Watson and Dr. Nick Bexfield, to find the cause of a particular type of chronic hepatitis (CH) seen in English Springer Spaniels (ESS) and to establish whether there is any evidence that it may be inherited. The study was originally initiated in 2006, in response to an apparent marked increase in the number of reports of ESS suffering from a severe form of the disease.
Affected dogs are typically young to middle-aged, more often female (although males are also affected), and they usually present with sudden-onset jaundice, vomiting, lethargy and often a marked high temperature. Their disease becomes ‘chronic’, with periodic relapses, and unfortunately there is a very high mortality rate.
Summary of the research
The researchers began by gathering information on as many ESS as possible with CH. Their initial task was to classify the disease better histopathologically (i.e. by examining the microscopic structure of liver tissue in dogs with CH). This enabled them to ensure as far as possible that only ESS with the type of CH under investigation would be included in the research studies and dogs with unrelated forms of the disease could be excluded.
The primary aim initially was to find out if the disease is caused by a virus. The researchers looked for known viruses (including canine adenovirus-1, canine parvovirus, canine herpesvirus, canine hepacivirus and the human hepatitis viruses A, B, C and E), and used state of the art techniques (high throughput sequencing and bioinformatics) to look for previously unrecognised (novel) viruses. Some genetic material was detected which looked like it came from viruses, but unfortunately, when comparing samples from ESS with CH alongside healthy ESS, it was not possible to identify any virus which was more common in the diseased ESS than in the healthy ones. To date, no virus has been found which is associated with CH in ESS.
Studies have also been undertaken to determine if bacteria play a role, but these too have not yielded any new discoveries.
Two genetic studies have been performed. A component of one study suggested that some of the genes involved in the control of the immune system, known as dog leucocyte antigens (DLA), may be a reason why some dogs develop CH and others are protected. A larger, far more powerful genome wide association study (GWAS) has also been undertaken, to look for specific genes that may be involved in the development of CH in ESS. Genomes from nearly 100 affected and 300 healthy dogs have been screened – the analysis of such a huge amount of genetic data is extremely time consuming and technically demanding. It is currently on hold while the researchers identify someone with the skillset to continue this work. To date, no specific genes have been identified as being associated with the development of CH in ESS.
A corticosteroid (prednisolone) treatment trial in ESS with CH has now been completed. Although this study only looked at limited numbers of dogs, it demonstrated that treatment with steroids improves clinical signs and reduces the level of liver enzymes on blood tests. However, it is important to stress that this should never be used without a biopsy because some dogs have infectious or other causes of their liver disease which would get worse rather than better with steroid treatment.
The full results of this study have been written up by veterinary specialist-in-training Will Bayton and are published in the Veterinary Record (see link #6 in the list of publications at the end of this page), where they are available for vets to read and should lead to improved treatment of ESS with biopsy confirmed CH.
The researchers are currently working on laboratory analysis of blood samples to identify markers that suggest ESS with CH are attacking their livers (i.e. immune-mediated or autoimmune disease). This study is being funded by the BSAVA PetSavers and will continue during 2023. Preliminary data generated in 2022 shows great promise. Work will continue in the coming months to validate these results, with the hope that in future a blood test can be developed to identify ESS with immune-mediated CH. Further updates will follow when available.
In an exciting development during 2018, the team successfully obtained funding from the Kennel Club Charitable Trust to study ageing changes in the liver and pancreas in dogs of a number of breeds, including ESS. Human studies indicate that fundamental aspects of the ageing process may predispose to chronic diseases such as chronic hepatitis. Dogs age much faster than humans and larger breeds tend to age faster than smaller dogs. As cells age or become damaged, they generally stop dividing and adopt a state known as ‘senescence’, but far from being inactive bystanders, these cells release a variety of factors that can cause surrounding cells to dysfunction, therefore contributing to ageing and disease. Little is currently known about senescence in the canine ageing process. The new project explores normal healthy ageing of the canine liver, as this may give insight into why breeds such as ESS suffer CH at an earlier age than other breeds. As yet, no direct links have been revealed. Additionally, the project will look at a specific ageing change in liver biopsies from canine patients with CH, in the hope of finding new predictive markers on biopsy samples to aid with clinical management (see link #5 in the list of publications at the end of this page).
In terms of its overall prevalence in the ESS, chronic hepatitis is uncommon and, anecdotally, it appears the incidence may even have decreased in more recent times. Sadly, however, its cause has still not been established and it remains an utterly devastating disease for both dogs and owners. Frustratingly and painfully for all those affected, this project continues to demonstrate that research is a long and complex process, and finding answers is never guaranteed. On the positive side, the understanding of CH in ESS has increased greatly since the researchers first started studying it, and they remain hopeful that ongoing studies will lead to prevention or effective treatment of this heartbreaking disease. They have published several papers on their work – see links below.
Advice and contact details
Although Penny Watson has recently retired from the University of Cambridge, she still maintains a keen interest in ongoing research. Nick or Penny are happy to be contacted by owners of dogs with a biopsy diagnosis of CH to help the antibody research to progress.
If you have an ESS affected with chronic hepatitis, we would encourage you to ask your vet to contact the researchers (details below). They can then discuss the best treatment for your dog with your vet.
Nick Bexfield Tel: 01223 337621 Email: nb289@cam.ac.uk
Penny Watson Email: pjw36@cam.ac.uk
Published Papers and Further Reading
1. Breed, age and gender distribution of dogs with Chronic Hepatitis in the United Kingdom (2011):
The Veterinary Journal 193(1),124-128
2. Chronic Hepatitis in the English Springer Spaniel: clinical presentation, histological description and outcome (2011):
The Veterinary Journal. 169(16),415
3. DLA Class II Alleles and Haplotypes are Associated with Risk for and Protection from Chronic Hepatitis in the English Springer Spaniel (2012):
4. Canine hepacivirus is not associated with chronic liver disease in dogs:
Journal of Viral Hepatitis 2014
5. Hepatocyte expression and prognostic importance of senescence marker p21 in liver histopathology samples from dogs with chronic hepatitis:
Journal of Veterinary Internal Medicine 2018
6. Prednisolone therapy for chronic hepatitis in English springer spaniels: a prospective study of 12 cases:
The Veterinary Record - June 2020
7. Chronic Hepatitis in the English Springer Spaniel:
Abstract presented at ECVIM Congress - Budapest (2007)
8. Chronic Hepatitis ESS Research Project:
Original proposal and project overview (2007)
9. ACVIM consensus statement on the diagnosis and treatment of chronic hepatitis in dogs:
Journal of Veterinary Internal Medicine 2019
10. Breed-related expression patterns of Ki67, γH2AX, and p21 during ageing in the canine liver:
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