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Dr. Larry Thornburg’s research on CAH (Chronic Active Hepatitis) One of the more interesting observations is tabulated in column eight -The Gross Appearance of the Liver at the time of Death. Several of the dogs had a normal appearing liver in that the surface of the liver was smooth rather than nodular. Yet these dogs had continual elevation in the liver enzymes and developed ascites with liver failure. Other investigators have made the same observation, but the common misconception is that all of the Dobermans with chronic active hepatitis have a nodular, cirrhotic liver when they die. This observation along with other evidence that I have accumulated to date points to the idea that CAH is not hepatitis" (i.e., not a primary inflammatory disease of the liver). Chronic active hepatitis of Dobermans does not appear to be an autoimmune disease of the liver at all. The inflammation that is found in some cases appears to be a secondary phenomenon. This may be the reason why anti-inflammatory drugs (steroids) do not cure the disease, even when the disease is first detected in the very early stage. The most consistent finding in the liver tissue from among the dogs (although, not found in the liver from all 14 dogs), was the changes in the blood vessels in the liver. The liver receives blood from two different sources. One source is the portal vein. The portal vein is the vessel that brings blood from all of the intestines (containing digested nutrients) into the liver. In some of the affected dogs there were a decreased number of portal vein branches within the liver. Several of the dogs had portal veins with markedly thickened walls. Thickened walls are the usual response of veins to increased blood pressure. The other change that I found in several of the dogs was the hepatic artery (artery that brings heart blood to the liver). There were numerous new branches of the hepatic artery throughout the liver tissue. This is the usual response of the artery (increase in the number of branches) when the blood flow through the portal vein is significantly decreased. It is my interpretation from the results to date that the primary disease among this group of dogs appears to be a form of congenital vascular disease. It appears that the liver tissue is secondarily affected as a result of the vascular disease. The vascular disease results in liver cell death and replacement by scar tissue (ie., cirrhosis of the liver). The vascular disease may result in persistently high, abnormal blood pressure in the portal vein over a long period of time. And, it may be the high blood pressure that results in the elevated ALT on the blood test and causes the ensuing liver damage. However, the microscopic changes in the liver tissue suggest an alternative possibility. Some (may be all) of these dogs had a malformation of the portal vein when they were born (hypoplasia of the portal win). A congenital malformation of the portal vein would result in a decreased number of portal vein branches and a decreased blood flow to the liver. Although this could result in portal hypertension over time, it could cause insufficient blood flow to the liver and liver cell death (and elevated ALT) as the dog grows in size. It is possible that different degrees of malformation of the portal vein could explain why some dogs have more severe disease than other dogs. The more severe the malformation, the more severe the liver disease. Finally, the research has turned up the fact that not all of the Doberman Pinschers with CAH will die from the disease. CAH progresses at different rates in all affected dogs. There are apparently three factors that suggest which dogs will suffer severe disease. One is the sex of the dog. Females are at higher risk. A second is the ALT level over time. Consistent ALT values in the 500 to 1000 range are often associated with relatively rapid disease progression. The third prognostic factor is the amount of excess copper in the liver at the time of disease diagnosis. Copper values greater than 1000 parts per million on a dry weight basis seem to be associated with fairly rapid disease progression. However, removing the copper does not stop disease progression. There is no treatment that will cure the disease. Success of treatment is being evaluated by the effect on the ALT value. Unless the ALT value is within the normal range there are still liver cells dying. In some of the affected Dobermans 10 mg of prednisone every other day has lowered the ALT from the >500 range into the 100-200 range. Numerous other treatments have been evaluated and none have consistently lowered the ALT values in affected dogs. DIAGNOSIS: The diagnosis of CAH is not easy. The diagnosis must be based upon a combination of ALL of the following: laboratory data (blood tests), liver biopsy, liver copper concentration and elimination of other liver diseases. 1. Laboratory tests: The ALT is the most reliable laboratory indicator of CAH. The ALT must be elevated on at least two blood tests taken a minimum of two weeks apart before the diagnosis of CAH should even be considered. Several liver diseases cause an elevation in the ALT and CAH is only one of them. At this time there is no treatment that will cure CAH. Therefore, the ALT will remain elevated over the dog's entire lifetime. Although other liver tests may be abnormal in Dobermans with CAH, persistently elevated ALT is the hallmark of the disease. 2. Liver biopsy: There are NO histological features that are diagnostic of CAH. Certain drug reactions, acute and chronic bile duct obstruction, congenital vascular anomalies, copper toxicosis and liver necrosis secondary to hemolytic anemia can all resemble CAH in a liver biopsy. A pathology report can only SUGGEST the presence of CAH. 3. Liver copper concentration: Normal dogs have a liver copper concentration less than 400 parts per million on a dry weight basis. The majority of Dobermans with CAH have increased hepatic copper concentration in the range of 500 to 2000. When the copper concentration in the liver is greater than 2000 ppm dw the diagnosis of copper toxicosis must be considered as opposed to CAH. Copper toxicosis is a treatable disease. Quantitative copper determination is a must in any Doberman Pinscher with liver disease. Histochemical methods are inadequate for accurate assessment of hepatic copper concentration. 4. Elimination of other diseases: The one disease that could confuse the diagnosis of CAH is congenital portocaval shunt. Dogs with congenital portocaval shunt can have a persistently elevated ALT. And, the changes in the liver biopsy may very closely resemble the changes found in chronic active hepatitis. Some dogs with congenital portocaval shunt have abnormal portal tracts in the liver tissue. The portal tracts do not contain a branch of the portal vein. Frequently, needle liver biopsy does not provide adequate tissue for correct evaluation of the liver histology. Ultrasound or dye injection studies are necessary for conformation of the shunt. Also, the veterinarian should take great care to eliminate all long-term drug treatments (heartworm preventatives, dewormers, etc), as a cause of the elevated ALT. 5. Special care must be taken to eliminate the possibility of cardiomyopathy. Heart disease can cause secondary effects on the liver. The changes in the liver that are caused by heart disease (cardiomyopathy) can closely resemble the changes found in the liver of dogs with chronic active hepatitis. Therefore, cardiomyopathy must be ruled out before the diagnosis of CAH is made. FUTURE: Currently there is no treatment that will stop the disease progression as measured by reducing the ALT value into the normal range. Anti-inflammatory drugs have been tested since the late 70's and have never been shown to stop disease progression regardless of the stage of the disease. The failure of these drugs to stop the disease is additional proof that CAH is not an immune-mediated inflammatory disease. Removal of the excess hepatic copper does not stop the disease progression. No special diets, herbal or vitamin supplements have been found effective for reducing the ALT in affected dogs.



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