Mairi Speeti, opening words.
Dissertation Defense on the 22nd of June 2004
Classification of liver diseases
Dogs could suffer from different types of liver disease that can be divided by primary and secondary illnesses. In primary illness cases, the liver itself is sick and in secondary illness cases, the liver reacts to some other illness in another organ. The common feature for both diseases is that the concentration of the liver enzymes, alanin aminotransferase (ALAT) and alkaline phosphatase (AP) in blood serum will increase.
The classification of different types of liver diseases according to pathological changes has been traditionally very subjective and therefore it has been very hard to make an exact diagnosis of the disease. At the same time, it has made the follow up of the disease and the planning of the appropriate treatment very difficult. Luckily, there will be changes to this situation in the near future. A professional group of internationally recognized researchers, including Professor David Twedt who has been working in the field of clinical hepatology, have tried to collate the terminology of the diseases and establish guidelines on how to classify the changes based on chronic conditions. The group is creating recommendations on histological staining methods, which have to be used to analyze different types of liver diseases and to develop guidelines on the sizes of the tissue samples that are needed in investigate the nature of liver diseases. The ideal situation for the pathologist is that the tissue sample is as big as possible. But in some cases the health condition of the pet doesn't allow for safe sedation need to perform surgical procedures. In many cases, the owner of the pet is unwilling to pay for expensive examinations and treatments.
Today, it is possible to take the tissue sample from the liver using many methods. The fine needle biopsy has been used when taking a small sample (as a thin needle biopsy), that mainly consists of single cells. A bigger but still small tissue sample is obtained by using a special cutting needle technique. For both of these procedures, the pet is usually only sedated. In order to collect a larger tissue sample, the pet has to be anesthetized and the abdominal cavity must be opened (laparotomy). University hospitals normally are equipped with special instruments so that opening of the stomach cavity is not needed (laparoscopy). The recommendations given by an expert panel of researchers will be very helpful to assist the clinician in deciding the right method of how the sample tissue will be taken.
The primary target for the research group is to develop a universally accepted classification system of how to histologically divide liver diseases in dogs and cats. As the diagnosis of the liver condition is based on the histological changes, classifications will assist in the development of guidelines that pathologists and clinicians will refer to during the treatment of liver conditions.
Based on the classification, liver diseases will be divided in to four (4) different main groups being vascular liver disorders, biliary tract disorders, parenchymal disorders and tumors.
1. VASCULAR DISORDERS
Normally the blood will go from the intestinal tract, spleen and pancreas through the portal artery to the liver. The liver functions like a big filter removing the toxic material and the microbes from the blood before the blood goes to the general circulation. Congenital portosystemic shunts are according to their name, inborn constructional defects of the liver blood vessels. There is a passage by which blood flow going directly into the general circulation without entering the liver. The shunt will carry all the toxic materials and microbes into the body which will result in complications. Adverse effects in dogs are seen as neurological signs. Often only one abnormal shunt is involved. The shunt is located either inside or outside the liver
One vascular liver disorder is a condition, in which the departure of the blood from the liver has become hindered. In these cases, the most common cause in dogs is a heart failure or a pericardial disease. As a result, congestion in the liver will develop and fluid will accumulate in the abdomen (ascites).
The blood circulation inside the liver might also be hindered. As a result, the portal blood pressure will increase. The most common diagnosis for dogs having this condition is chronic liver disease. When liver disease progresses over a long period of time, the blood circulation, especially in small blood veins of the liver (sinusoids) will become difficult.
2. BILIARY TRACT DISORDERS
The biliary tract consist both the gall bladder and biliary tract problems. They are more common in cats than in dogs.
3. PARENCHYMAL DISORDERS
Reversible injury: The histological changes in the basic cell tissue of the liver could be temporary, and the changes can be a result of a problem situated somewhere elsewhere in the body. After the original disease has been cured, the changes in the liver will improve.
In the storage disorders group, the best known liver disease is the primary copper metabolism malfunction of Bedlington terriers.
Changes in the liver parenchyme can be targeted mainly to hepatocytes, Kupffer cells, and Ito cells. Hepatocytes are mainly responsible for the function of the liver. They have many vital tasks and because of this, a malfunction in the cells can lead to problems in normal bodily functions. The Kupffer cells are liver's local macrophages and belong to the defense system of the body. They clean the blood which is flowing through the liver to the other parts of the body, from the harmful material and microbes. Ito cells normally store vitamin A, but are activated by outside attacks like infections and start to make connective tissue. These cells have a primary role in a development of the liver cirrhosis.
When formulating a diagnosis, the pathologist also evaluates the severity of the cell death (necrosis) in the parenchyma and examines where necrosis is situated. In addition to the above, the pathologist will develop a statement regarding the degree and location of the inflammation.
Tumors of the liver can be benign or malign. This distinction can't be done by outlook. Ultrasound examination doesn't separate them either. If the surgeon is able to remove the changed liver tissue, it is very important for the dog's prognosis, to be evaluated based on the type of tumor involved. Malignant tumors, are further divided either to the primary liver tumors where the origin is in the liver itself, or to metastasis to the liver. When talking about metastasis, the original primary tumor is somewhere else in the body and the tumor cells immigrate to the liver through the circulation. Metastasis is more common than primary liver tumors.
CHRONIC HEPATITIS IN PEOPLE
Chronic hepatitis, belongs to the category of parenchymal disorders. The mononuclear cell infiltration is a typical feature. In people, chronic hepatitis can be divided based on etiology. The division is mainly based either on anti virus antibodies or autoantibodies found in the patient's serum. Even though the diagnosis of the hepatitis is based on the evaluation of the blood sample, the diagnosis is always confirmed with the tissue sample. With the help of this, the pathologist will confirm the diagnoses of the chronic hepatitis. The pathologist also will determine the degree of the infection, severity of the cell necrosis as well as how much the normal liver tissue has been replaced with the connective tissue. Based on the evaluation of the pathologist, the clinician will determine the seriousness of the illness and plan the proper medication. The effect of the medication will be evaluated by repeated biopsies. The same will be the goal in veterinary hepatology too.
CHRONIC HEPATITIS IN DOGS
Any dog breed is able to develop chronic hepatitis, but the most common breeds that will be infected include Bedlington terriers, West Highland White Terriers, Labrador Retrievers, English Cocker Spaniels, Skyterriers, and Dobermans. The disease will very often lead to the individual's death because of the infection and the damage to the liver cells. The dead liver cells will be replaced with connective tissue leading to liver cirrhosis. At the moment, the diagnosis of chronic hepatitis in dogs has been mainly done based on the results of liver biopsies. Currently, veterinary science is unable to divide chronic hepatitis to separate groups based on etiology. The etiology is only known in Bedlington terriers in which the cause is a primary metabolic copper disorder.
In Dobermans, the disorder is called chronic hepatitis, copper associated hepatitis or Doberman hepatitis (DH). The name copper associated hepatitis is used since copper typically accumulates into the liver cells. Doberman hepatitis is the term which I have used in my own research.
First, articles about Doberman hepatitis were published already during the 1970's and after that, there have publications regarding this topic have come out on a regular basis. Even though there has been a lot of research, much of the details of the disease are still unknown. We know that females are more often affected than males, so there is an obvious sex predisposition. The reason for that is unknown. Clinically, the dog will get sick between 4 to 6 years of age - at the dog's best age. The dog is already trained Typically, Doberman hepatitis is very aggressive. The clinical condition of the dog will decline normally very fast after the first symptoms of the liver malfunction have appeared. Currently there is no cure or control of the disease after it has been diagnosed, showing how aggressive the disease is. Normally the clinically affected individual has to be euthanized either immediately or soon after the diagnosis. The treatment used today is mainly corticosteroids and other immunosuppressive drugs such as azathioprine. As a supportive treatment it is advisable to check the dog's diet. Today, there are multiple choices of special commercial diets for dogs having liver disorders.
The etiology of the disease is not known today. Researchers have tried to find autoantibodies typical to human autoimmune based chronic hepatitis also from affected Dobermans. Nothing significant has been found yet. Some kind of immunological malfunction is said to cause this disorder. This is based on the role of mononuclear cell infiltration observed in the liver samples.
Since the etiology is unknown, an effective treatment is missing today.
THE PURPOSE OF MY RESEARCH
As the prognosis of the Doberman with clinical chronic hepatitis is poor at the time of the diagnosis, one of my goals was to diagnose the disease before the first symptoms appear. ALAT and AP blood values are taken when the Doberman is suspected to have a liver malfunction. These two liver enzymes were earlier equally important without a priority of one over the other. Based on my research, I found out that measuring ALAT values on a regular basis is the best way to indentify those individuals without symptoms (subclinical). The ALAT value will be the first to increase, followed later by the AP value. Also, I examined which blood parameter is the best to predict the progression of the disease from the subclinical to the clinical stage. This information has never been published anywhere before. For the progression of the disease, the liver enzyme values, ALAT and AP are not informative. Instead, the follow up of the serum bilirubin values in subclinical individual is advisable. During the subclinical stage, the values stay normal but when the disease is in the clinical stage, bilirubin values are elevated.
Since the prognosis in the clinical stage is very poor, detection of affected individuals in the asymptomatic stage is essential. The dog itself will benefit from an early diagnosis of DH because it will probably prolong survival time. Environmental factors may affect DH development. Improving the living conditions of the dog and avoiding unnecessary stress is advised. It is advisable that the female Doberman with DH should not be bred. Pregnancy and giving birth is a great strain for a female and its liver. If the female dog is in a subclinical stage, the pregnancy could advance the dog to the clinical stage.
Since hepatitis is more common among this breed than others, it is possible there is a hereditary component involved. That is why breeding with sick individuals should be avoided. At the moment in Finland , all females and males, who are planned to be used in breeding, are screened for hepatitis by blood tests before mating. This testing is obligatory for the registration of the litter by the Finnish Kennel Club. This will not resolve the problem but hopefully will inhibit the use of affected dogs in breeding.
Earlier publications have mainly described the dogs which already have had clear symptoms of liver malfunction and die quickly. There have been no publications about the criteria how Dobermans with the early hepatitis and in subclinical stage could be found among within a population of healthy dogs. What type of histological changes are typical for the dog in subclinical stage? One of the targets of this research was to create the criteria for the subclinical stage. Since the histology is very essential for the diagnosis, and the subclinical histology is very different from the clinical stage, I describe in my research, how the histology in the subclinical stage looks like. In addition I described what are the differences between these two stages. I used a new valuation scale in my research that allowed me to compare the tissue samples from the same dog from the beginning of the DH to the end. With this new valuation scale, I was able to show that the disease is progressive. The same method is used when humans are examined for chronic hepatitis.
It has been a known fact for a long time that an unusually large amount of copper is accumulated in the liver at the Doberman hepatitis. At present the most common theory is that the copper accumulation to the liver is caused by chronic disturbance in the bile flow (cholestasis). Based on my own research, I found out the chronic cholestasis is not the reason for the increased amount of the copper.
According to another theory, which I disagree, there is a primary disorder in the metabolism of copper. I will present evidence that chronic hepatitis will disturb the normal exit of copper from the hepatocytes. This will cause an accumulation of copper to the liver.
In my last article, I explained the etiology of the disease, why Dobermans develop liver infection. In my research I discovered that liver cells of affected individuals are producing protein that healthy dogs' hepatocytes won't produce. Normally, this protein has been produced only by the cells that belong to the body's own defense mechanism. Based on my findings I suggested that this is an autoimmune disease and genetically predisposed Dobermans will be prone to this disorder. Also, I presented my own theory about how the disease will start and progress at the cell level. My theory is obviously just a rough framework and demands a lot of additional research, so that all the small and different details will be understood.
© Mairi Speeti
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