Icterus (or jaundice) is defined as the clinical state in which hyperbilirubinemia is detectable as a yellowish discoloration of the plasma or soft tissues. Icterus results when the rate of bilirubin production exceeds its rate of elimination. The intensity and distribution of tissue bile pigment staining depends on 4 factors: 1) the total serum bilirubin concentration; 2) the form of bilirubin (unconjugated or conjugated); 3) capillary perfusion and the ability to detect a yellow hue through normal pink mucous membranes; and 4) tissue composition, i.e., tissue high in fat is predisposed to deposition of lipid soluble unconjugated bilirubin while tissue high in elastic fibers, such as sclera and skin, is predisposed to deposition of water soluble conjugated bilirubin.

BILIRUBIN METABOLISM

The bulk of bilirubin (approximately 80%) is produced as a result of the breakdown of senescent red cells. The remainder comes from catabolism of other pigments (e.g., cytochromes and catalases, particularly cytochrome p450). Reduction of heme occurs primarily in the liver and spleen where hemoglobin released from senescent red cells is phagocytosed by cells of the mononuclear phagocytic system. Globin is enzymatically degraded to amino acids, iron is bound to transferrin and transported to the bone marrow, and the heme is converted to biliverdin by heme oxygenase and subsequently to bilirubin by biliverdin reductase. Bilirubin is the only major breakdown product that requires excretion since the globin and heme molecules are reused.

Bilirubin is released from the mononuclear phagocyte system into the circulation where it circulates bound to albumin. Bilirubin is insoluble in water and the binding to albumin allows it to be transported and inhibits its diffusion into the tissues. This type of albumin-bound bilirubin is referred to as unconjugated, indirect reading, or lipid soluble bilirubin. Binding of bilirubin to albumin is disrupted by a low serum albumin concentration and competition from a variety of drugs such as sulfonamides, thyroxine and salicylates. Transport of bilirubin by albumin ends with its disassociation at the hepatic sinusoidal membrane.

Hepatocyte Uptake

Hepatocyte uptake of unconjugated bilirubin is a carrier mediated process. The process may exhibit saturation as the carrier is shared by conjugated bilirubin and a variety of organic anions including bile acids and bacterial endotoxin. Within the hepatocytes bilirubin is bound by two proteins called y and z binding proteins which allow the process of conjugation to take place.

Conjugation

Conjugation renders bilirubin more water soluble, thereby facilitating the secretion of bilirubin into the bile. Bilirubin is conjugated to glucuronic acid, taurine (and to a lesser extent glucose) primarily via glucuronosyltransferase to form bilirubin monoglyceride and diglucuronide. This form of bilirubin is called conjugated, direct reacting or water soluble bilirubin.

Biliary Secretion

Secretion of bilirubin across the hepatocyte canaliculus membrane is the rate limiting step in bilirubin metabolism. This active transport process occurs against a large concentration gradient and is ordinarily not disrupted in hepatic disease.

Post Hepatic Bilirubin Metabolism

Bilirubin flows in the bile from the biliary canaliculi down the bile ducts into the gallbladder where it is stored until feeding initiates gallbladder contraction. Conjugated bilirubin in bile then flows into the duodenum via the common bile duct. In the distal small intestine and colon bacteria reduce most of the conjugated bilirubin to a group of colorless compounds known as urobilinogens that are readily absorbed by the intestinal and colonic mucosa. Most reabsorbed urobilinogen is re-secreted into the bile, but a small amount is excreted in the urine. Some urobilinogen is not reabsorbed but is instead passed in the feces either unchanged or further degraded into stercobilins, which are believed to impart color to the feces.

A PRACTICAL APPROACH

Jaundice is clinically detectable when the plasma concentration of bilirubin exceeds 30 mmol (2 mg/dl). The discoloration of jaundice is most noticeable in the sclera, the nonpigmented thin skin such as the inner pinnae and caudal portion of the hard palate.

Jaundice may be classified as: 1) prehepatic or hemolytic (increased bilirubin production); 2) hepatic (liver disease); and 3) post-hepatic (bile duct obstruction).

When a jaundiced patient is presented for evaluation it is important for the clinician to estimate the severity of the jaundice and try to correlate this with other physical findings. The question must then be asked is the jaundice due to increased bilirubin production or to decreased secretion? This question is best answered by measuring the packed cell volume. If the packed cell volume is normal, then hemolysis can be eliminated as the cause of jaundice and attention focused on disease of the liver or biliary system.

History in the Jaundiced Patient

A complete and detailed history is crucial to the diagnostic evaluation of the icteric patient. The client should be questioned about the time of onset and chronicity of icterus. Signs related to hemolytic icterus may occur acutely and include weakness, anorexia, and hematuria and bilirubinuria in patients with intravascular hemolysis. Obstructive icterus is more likely to be chronic and progressive over several weeks, with signs varying from vague inappetence and depression to severe vomiting and diarrhea.

A history of exposure or the possibility of exposure to toxins, medications, and such agents as methylene blue, lead, copper, benzocaine derivatives, propylthiouracil (in cats). Exposure to agents associated with chronic hepatobiliary disease (anticonvulsants, inhalation anesthetics and acetaminophen) should be ruled out in the history if possible. The frequency and severity of any vomiting and diarrhea should be characterized by more detailed questioning. The presence of vomiting and/or diarrhea is more suggestive of hepatocellular or obstructive icterus, although both dogs and cats with acute hemolysis are also known to vomit occasionally.

Physical Examination

A complete and thorough physical examination should be carried out in all icteric patients, with particular attention being paid to assessment of the liver during abdominal palpation. The size and shape and surface texture of the liver should be noted along with the presence or absence of ascites.

Any evidence of a hematological disorder should also be noted during examination. Clinical findings vary with the specific disease involved, as well as with its clinical course. General signs of anemia include lethargy, weakness, and pale mucous membranes. Fever is an occasional clinical feature of hemolytic anemia. Splenomegaly and hepatomegaly could provide evidence of increased reticuloendothelial activity in an animal with immune mediated hemolytic anemia. However, hepatomegaly is often a sign of primary liver dysfunction.

HEMOLYTIC ANEMIA

The differential diagnosis of hemolytic anemia in the dog and cat is listed in Table 1.

Table 1. Differential diagnosis of hemolytic anemia

Hemolytic anemia may be acute or chronic, intravascular or extravascular, with the signs varying accordingly. The degree of jaundice will range from mild to profound. Mucous membranes may be pale with superimposed icterus and there is often a smooth generalized splenic and/or hepatic enlargement.

A complete hematological evaluation is the key to the diagnosis and appropriate treatment of the patient with hemolytic anemia. This should include a complete blood count, which may reveal one or more of the following signs: 1) marked reduction in red cell count and packed cell volume, and hemoglobin, 2) signs of hemolysis (increased icterus index or agglutination), 3) an increase in MCV, 4) reticulocytosis, and 5) a leukocytosis with neutrophilia and a left shift. It is important to also assess red blood cell morphology which may reveal anisocytosis, polychromasia, and possibly, evidence of blood parasites. If the packed cell volume is less than 20% it is customary to evaluate the reticulocyte count for signs of an appropriate response. This usually does not appear before the 4-5th day. A platelet count should also be done because it is possible that thrombocytopenia may accompany the anemia. It occasionally happens that the blood will be seen coagulating in the collection tube. Cold agglutinins cause red cell aggregation if a drop of cold saline is added to a drop of blood on a slide and the red cells examined under a low power field. A Coombs test should be done if agglutination does not occur. It is also customary to carry out an antinuclear antibody (ANA) test to check for the presence of more widespread immune-mediated disease.

A complete biochemical evaluation should also be performed in patients presenting with hemolytic anemia. This will usually reveal an increase in serum ALT and bilirubin concentration. Increased creatinine and BUN suggests either dehydration or the hemolytic uremic syndrome with associated severe renal damage. A urinalysis is mandatory in all jaundiced patients. Hemoglobinuria is not an uncommon presentation in severe hemolysis. Decreased fibrinogen and early signs of disseminated intravascular coagulation may be present in severely afflicted patients.

Treatment

If the packed cell volume is extremely low <10% and the animal is dyspneic, then immediate transfusion should be performed. This should however, never be done without first cross-matching to ensure compatibility. Treatment with a blood substitute is also appropriate if fresh blood or packed red cells are not available. If there is a possibility that hemolysis is caused by Haemobartonella, treatment with tetracycline or doxycycline should be initiated immediately. Also, if results of laboratory studies are not immediately available then it is appropriate to begin treatment with prednisone at a dose of 2 mg/kg per day initially, and if the treatment is successful, tapering by 50% every 2 weeks. Prednisone inhibits the binding of monocyte FC receptors to IgG sensitized lymphocytes. In severe hemolysis it is not uncommon to add azathioprine at a dose of 1-2 mg/kg per day in the dog and 0.3 mg/kg in the cat. It may also be appropriate to start treatment with danazol at a dose of 5-10 mg/kg twice daily at this time. Other drugs that should be considered are cyclophosphamide (2 mg/kg for 4 days/week) and cyclosporine (10 mg/kg for 5 days, rest for 2 days then 5 mg/kg for 5 days). Cyclosporine, which is being used with increasing frequency in patients refractory to routine therapy, decreases IgG and complement and may also be useful. If all treatments are unsuccessful and repeated transfusions are needed to keep the patient alive, then splenectomy is appropriate as a last resort. The prognosis is always guarded to grave in severe hemolytic anemia.

HEPATIC AND POST-HEPATIC ICTERUS

Liver disease is the most common cause of icterus in the dog and cat, accounting for approximately 85% of nonhemolytic icterus, while extrahepatic bile duct obstruction accounts for only 15% of cases. As with other types of disease the evaluation of the patient with liver disease or potential bile obstruction should include a thorough history and physical examination. Complete hematologic, biochemical and urinalyses are also essential. This should be followed by radiographic or ultrasonographic studies. A liver biopsy is essential to obtain a specific diagnosis and prescribe appropriate treatment.

A small percentage of patients (~ 2%) may present with jaundice caused by mechanisms other than hemolysis or liver disease. Such patients may be icteric as a result of bile peritonitis, sepsis or rarely, hyperthyroidism (cats). The differential diagnosis for causes of intrahepatic jaundice is shown in Table 2.

Table 2. Intrahepatic causes of jaundice DOG

Specific treatment of liver disease will depend upon the results of the biopsy. Causes of extrahepatic jaundice include pancreatitis (especially in the cat), severe fibrosing duodenitis, bile duct trauma, tumor, calculus, or stricture. In some parts of the world liver flukes which invade the biliary system and cause obstruction must be included in the differential diagnoses.