Liver

42 Liver



Anthony P. Carr



APPROACH TO THE DOG WITH ICTERUS


1. What is the difference between icterus and hyperbilirubinemia?

Icterus or jaundice are similar expressions and refer to visible hyperbilirubinemia. It is generally possible to see icterus when bilirubin concentrations exceed 2 mg/dl. Areas to inspect for jaundice include the sclera, soft palate, mucous membranes, and the ears. The serum will also be discolored as will urine.


2. Briefly describe bilirubin metabolism.

Bilirubin is a product formed during the degradation of porphyrins, predominantly hemoglobin. Other sources of hemoproteins include myoglobin and cytochromes. In most instances, hemoglobin is the major source of bilirubin in circulation.


Hemoglobin is liberated when senescent red blood cells are phagocytosed by the reticuloendothelial system, predominantly in the liver and spleen. Iron is removed and reused. The globin is degraded to amino acids that are also reused. Heme is converted to biliverdin. Biliverdin is converted to bilirubin by the enzyme biliverdin reductase. Bilirubin is lipid soluble and enters the circulation where it is bound to albumin (unconjugated bilirubin or indirect bilirubin). The unconjugated bilirubin binds to receptors on hepatocytes is internalized and then conjugated predominantly to glucuronic acid. This water-soluble product is now termed conjugated or direct bilirubin. This is then secreted into the bile canaliculus by means of an active transport process that is the rate-limiting step in bilirubin metabolism. A small percentage of conjugated bilirubin refluxes from the hepatocyte into the circulation. Because conjugated bilirubin is water soluble, it is readily filtered by the kidney and excreted via urine.


Most conjugated bilirubin collects in the gallbladder. On gallbladder contraction, the bilirubin enters the duodenum. The bacteria in the gut then deconjugate it and metabolize it to various other products, including urobilinogens and stercobilin. Some of the urobilinogens are reabsorbed from the gut. Most are returned to the liver, and a small part is excreted through urine.


3. Is it useful to differentiate between conjugated and unconjugated bilirubin in clinical cases?

It is tempting to think that this would be useful. Increased unconjugated bilirubin would be expected with hemolytic disease. Conjugated bilirubin would be increased with hepatic or posthepatic disease. Unfortunately, clinical experience has shown that in dogs these measurements are rarely useful in localizing the cause of icterus.


4. What is the significance of urobilinogen in the urine?

Urobilinogen is commonly tested for on urine test strips. Its presence has no specific meaning; a negative test could indicate bile duct obstruction (no bile gets to intestine to form urobilinogen). The clinical significance of this is minimal.


5. How are the common causes of icterus categorized?

Many times, icterus is compartmentalized into prehepatic, hepatic, and posthepatic icterus. Prehepatic icterus would be caused by hemolysis. This would lead to so much hemoglobin being presented to the liver, leading to increased bilirubin production, which eventually overwhelms the capacity of the liver to transport it into bile. Hepatic icterus would be caused by any process that interferes with bile flow. This can be primary liver disease (e.g., cirrhosis, chronic inflammatory liver disease). In rare cases, it can also be seen with inflammatory or infectious diseases outside the liver that inhibit bilirubin transport, such as occurs with sepsis. Posthepatic icterus refers to disease that interferes with bile flow in the larger bile ducts.


6. What are some potential causes of prehepatic icterus?

Prehepatic icterus is caused by hemolysis. The increased release of hemoglobin overpowers the reserve capacity of the liver to deal with this. In addition, if the anemia is marked enough, the liver will undergo hypoxia, which further reduces the capacity of the liver to deal with hemoglobin. The most common cause is immune-mediated hemolytic anemia. There are many other causes for hemolysis including infections (babesiosis), toxins (lead, zinc), and oxidative injury (onions).


7. What can cause hepatic icterus?

Almost any form of liver disease can cause icterus if damage is widespread enough.


8. What can cause posthepatic icterus?

Posthepatic icterus can be caused by a variety of diseases that affect the biliary tract or gallbladder. Common causes include pancreatitis, neoplasia, and gallbladder rupture (trauma or cholecystitis).


9. What would be a reasonable initial diagnostic plan for an icteric dog?

Initially a packed cell volume/total protein (PCV/TP) should be obtained to rule out prehepatic causes of icterus. Generally anemia has to be severe to be the sole cause of icterus. If anemia is not considered the cause, then it is necessary to determine if hepatic or posthepatic disease are present.


Differentiating hepatic from posthepatic icterus can be challenging. History, physical examination, and routine blood work may offer clues that point toward one cause, though it is not possible to establish a definitive answer in this manner. Abdominal ultrasound is an important part of working up icteric dogs. With posthepatic disease, the source of obstruction may become obvious or signs of obstruction (dilation of the biliary tree or common bile duct) may be seen. It is important, however, to remember that it may take 5 or more days to see these changes in acute bile duct obstruction. In addition, gallbladder disease can be visualized at times. With gallbladder perforation, abdominocentesis can be helpful. Ultimately, it may, however, require an abdominal exploratory to obtain liver biopsies and check the integrity of the biliary system.



BIBLIOGRAPHY



Anderson JG, Washabau RJ. Icterus. Compend Contin Edu Pract Vet. 1992;14:1045-1059.


Eddlestone SM. Jaundice. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 6, St. Louis: Elsevier, 2005.



LIVER DISEASE BASICS



10. What clinical signs are seen with liver disease?

Clinical signs with liver disease can be variable. In some cases, dogs may be severely affected and present in a coma as a result of hepatic encephalopathy. In other cases, the diagnosis may be fortuitous resulting from abnormalities detected on a biochemical profile or finding urate uroliths.


Common clinical findings include lethargy, weight loss, vomiting, anorexia, and diarrhea. With more advanced disease icterus, ascites and symptoms associated with hepatic encephalopathy predominate.


11. What changes on a biochemical profile are expected with liver disease?

Jaundice can be seen with advanced liver disease (see previous section about the dog with icterus). A variety of liver enzyme elevations can be seen with liver disease, though they do not necessarily have to occur. The degree of elevation does not necessarily relate to the severity of the disease. Serum alanine aminotransferase (ALT) is relatively liver specific in dogs. Elevations indicate hepatocellular leakage or necrosis. Marked elevations occur with hepatic necrosis, widespread hepatic neoplasia, and chronic hepatitis. Serum aspartate aminotransferase (AST) is similar to ALT; however, AST is also present in muscle and red blood cells. Alkaline phosphatase (ALP) is an enzyme induced by cholestasis. ALP activity will increase with biliary obstruction as well as with hepatocellular swelling (intrahepatic cholestasis). Isoenzymes occur in bone, liver, intestine, and kidney, though only the bone and liver isoenzymes have half-lives long enough to make them clinically relevant. A corticosteroid induced isoenzyme can also lead to significant ALP activity increases as can certain medications (phenobarbital, phenytoin, primidone). Gamma glutamyltranspeptidase is similar to ALP in its diagnostic importance.


12. Which components of a routine biochemical profile reflect liver function?

Liver enzyme activities do not correlate with hepatic function. Usually liver function tests such as serum bile acids or an ammonia tolerance test are needed to assess liver function properly. There are, however, four values on a biochemical profile that could provide information about liver function. Glucose is partially produced by the liver and with decreased liver function gluconeogenesis can decrease. In addition, dogs with liver disease are prone to sepsis, which could also decrease glucose concentrations.


Albumin is produced by the liver and represents around 25% of the proteins that the liver synthesizes. Hypoalbuminemia can result as a result of decreased liver function. In addition, albumin is a negative acute-phase reactant. If there is significant inflammation in association with the liver disease, this will reduce albumin synthesis. In many diseases hypoalbuminemia is associated with poorer outcome.


Blood urea nitrogen (BUN) is produced by the liver by conversion of ammonia from the portal circulation. Decreases in BUN occur with extensive liver disease or shunting. BUN concentration is dependent on a number of factors including hydration status (excreted via the kidney), polyuria (will decrease BUN), and nutritional status (increased by protein consumption, decreased by anorexia or consumption of a low-protein diet).


The liver also produces cholesterol. With severe, usually end-stage liver disease hypocholesterolemia can be seen. In many instances of liver disease, however, hypercholesterolemia is seen as a result of cholestasis.


13. How is liver disease confirmed in the dog?

There are a variety of ways to diagnose liver disease in dogs. Cytologic or histopathologic sampling of the liver is required for a definitive diagnosis. Aspirates, needle biopsies, and wedge biopsies are potential ways for obtaining diagnostic specimens. It has been shown that cytology is the least reliable of these techniques. Needle biopsies also often do not concur with results of wedge biopsies. Aspirates and needle biopsies are probably best reserved for cases in which neoplasia is suspected. With inflammatory liver disease, wedge biopsies will have a much higher diagnostic yield.


14. Before biopsy, what additional tests should be considered?

Because liver biopsy can be associated with hemorrhage, it is always advisable to obtain a coagulation panel before biopsy. Dogs with liver disease are prone to coagulopathies, usually because of an inability to produce coagulation proteins. In addition some degree of vitamin K deficiency may also exist. A buccal mucosal bleeding time should also be considered to make sure that primary hemostasis is not impaired.


15. What information can imaging techniques provide in the assessment of liver disease?

Radiography is a good way to assess liver size and to assess for uniform increases or decreases in liver size. On occasion, calcification or gas can be recognized in the liver. Ultrasonography is the most widely used technique to image the liver parenchyma. Ultrasound allows the echotexture of the liver to be assessed. In addition, it is possible to determine if changes are focal or diffuse. With focal lesions, ultrasound-guided biopsies or aspirates may be superior to surgically obtained samples.



CHRONIC INFLAMMATORY LIVER DISEASE



16. What causes chronic liver inflammation in the dog?

In humans, viruses (hepatitis A, B, and C) are the most common cause of inflammatory liver disease. Although there have been studies carried out to identify infectious agents in association with chronic inflammatory liver disease, none have been found that commonly cause disease. On occasion, Leptospira, Bartonella, and Histoplasma can cause significant liver disease, though often the presentation is more acute than chronic. Copper accumulation and drugs can also cause hepatic inflammation. An etiologic diagnosis for most chronic liver disease in dogs is usually not found. In some cases, an immune-mediated phenomenon is suspected. Genetic factors play a role, because certain breeds are more likely to have chronic liver inflammation.


17. What histopathologic changes are seen with chronic hepatitis?

Chronic hepatitis can have many causes, though the histologic changes are often similar. A variable inflammatory infiltrate will be present, with lymphocytes and plasma cells predominating, though neutrophils and macrophages can also be present. There will also be areas of hepatocyte necrosis. Initially, this can be near the limiting plate (piecemeal necrosis). This can extend from the portal vein to the central vein (bridging necrosis). With inflammation and necrosis, fibrosis will develop. This can be extensive enough to connect adjacent portal triads (bridging fibrosis). Biliary hyperplasia is also a common finding as are areas of regeneration (regenerative nodules). After fibrosis progresses sufficiently, cirrhosis develops.


18. Which breeds are predisposed to chronic hepatitis?

Doberman Pinschers, Bedlington Terriers, West Highland White Terriers, and Cocker Spaniels are overrepresented.


19. What treatments are indicated for chronic hepatitis in dogs?

Treatment is best guided by results of a liver biopsy. If an underlying cause is found for the liver disease it should be addressed (e.g., antibiotics for bacterial infections, discontinuation of drugs if toxic hepatopathy). If significant copper is detected, treatments to remove copper or prevent further copper absorption are indicated (see the section on copper storage hepatopathies).


If significant inflammation is observed, antiinflammatory medications are indicated. The most commonly used are glucocorticoids. These medications are effective and inexpensive, though clinical signs of iatrogenic hyperadrenocorticism can develop and their use can result in significant liver enzyme activity elevation. Corticosteroids also reduce fibrosis. Azathioprine is another commonly used antiinflammatory drug. Use of azathioprine reduces the dose of corticosteroids that are required and in can be used as a sole agent for controlling inflammation with hepatitis. Side effects such as bone marrow suppression, pancreatitis, and hepatotoxicity are rare, though they have to be monitored for.


Significant fibrosis would indicate the need for antifibrotic agents. Reduction of inflammation will partially help to reduce fibrosis; however, this may be inadequate. Colchicine (0.03 mg/kg/day) has been used frequently for its antifibrotic activity. It has been shown to be effective in humans; similar information is lacking in dogs. Many dogs treated with this medication will develop gastrointestinal signs such as vomiting and diarrhea. Reducing the dosage and gradually increasing if tolerated can address this. Rarely bone marrow suppression can occur. Zinc is used for minimizing copper absorption from the intestine. It also has some antifibrotic effects.


Several other drugs are used to help protect the hepatocytes from injury, often related to antioxidant effects. Vitamin E is suspected to have some benefits minimizing oxidative injury. S-adenosylmethionine has also been used in dogs. It helps to increase glutathione concentrations in the liver, which helps to reduce oxidative injury. It may be of benefit with toxic liver injury. Milk thistle (silymarin) also has antioxidant effects.


A drug that has multiple effects with liver disease is ursodiol. Ursodiol is a choleretic (increases bile flow) that limits the presence of toxic (hydrophobic) bile acids. Antiinflammatory and immune-modulating effects may also be present.

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Jul 31, 2016 | Posted by in INTERNAL MEDICINE | Comments Off on Liver

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