Abstract
Jaundice is a yellow discolouration of the skin, mucous membranes and schlerae caused by an increased concentration of bilirubin in serum and tissues. Jaundice generally becomes visible when serum bilirubin concentration exceeds 2 mg/dl (35 μmol/l), or greater than five to ten-fold above normal. Unlike most other clinical signs of hepatobiliary disease which are non-specific (for example, inappetence, lethargy, weight loss, vomiting, diarrhoea, dehydration), jaundice correlates with hyperbilirubinaemia and is therefore a highly specific sign of either hepatobiliary disease or acute haemolysis. However, jaundice has low sensitivity as an indicator of liver disease, because less than 50% of cats with liver disease manifest jaundice.
Normal bilirubin metabolism
The principal source of bilirubin is the degradation of haemoglobin from senescent erythrocytes. To a lesser extent, bilirubin also is derived from the breakdown of myoglobin, cytochromes and other haeme-containing proteins within the liver. In macrophages of the liver and spleen, haeme from phagocytised senescent erythrocytes is cleaved by haeme oxygenase to form biliverdin, a green pigment. Biliverdin is reduced to bilirubin by biliverdin reductase. Unconjugated (indirect reacting) bilirubin, a yellow-orange pigment, is released into the circulation where it is bound to albumin. Plasma bilirubin (unconjugated) is removed from the circulation by the liver (uptake), converted to conjugated (direct reacting) bilirubin by hepatocytes, secreted from the hepatocyte into the biliary system, and then excreted into the intestines with bile. Thus, normal bilirubin metabolism depends upon the processes of uptake, conjugation, secretion, and excretion. A small amount of bilirubin within the intestine can be deconjugated by bacteria and reabsorbed and returned to the liver in enterohepatic circulation. Most bilirubin within the intestinal tract is converted by intestinal bacteria to colourless urobilins, such as urobilinogen which, when oxidised, contribute to the normal brown colour of the faeces. Failure of bile to enter the intestinal tract, as in extrahepatic bile duct obstruction, can result in pale gray acholic faeces. A small amount of intestinal urobilinogen is reabsorbed by the intestine and efficiently re-excreted by the liver (enterohepatic circulation), except for a small portion that is excreted into the urine by the kidneys. The formation of urobilinogen is affected by the amount of conjugated bilirubin entering the intestine, the intestinal flora, and intestinal transit time; thus, urine dip stick determinations of urobilinogen are very imprecise measures of bilirubin metabolism.
Bilirubin is not detectable in normal feline urine. A small amount of bilirubin may be found in the urine of healthy dogs, especially males, because canine kidneys have the unique ability to produce bilirubin from haeme and can conjugate bilirubin and excrete it. In cats, the presence of bilirubin in the urine is indicative of conjugated hyperbilirubinaemia and liver disease. When cholestasis causes increased circulating conjugated bilirubin, a small portion that is not protein bound can pass into the urine by glomerular filtration to be detected as a positive urine bilirubin dipstick reaction. Severe bilirubinuria in concentrated urine can also cause green or orange-brown discolouration of the urine.
Jaundice and hyperbilirubinaemia may persist beyond recovery of an animal from hepatobiliary disease. Bilirubin is normally reversibly bound to albumin in plasma and cleared by the liver; however, in animals with cholestasis and jaundice, especially when chronic, up to 80% of conjugated bilirubin can form irreversible covalent bonds to albumin. The disappearance of this form of bilirubin from the circulation depends on the half-life of albumin (12 to 14 days). This tightly-bound form of conjugated bilirubin is not filterable by the kidney and does not contribute to bilirubinuria.
Pathophysiological classification of jaundice
The pathophysiological mechanisms of hyperbilirubinaemia and jaundice are: (1) increased bilirubin production from destruction of erythrocytes (haemolysis); (2) decreased hepatocyte uptake, conjugation, and secretion of bilirubin; and (3) impaired biliary excretion. These correspond to the three traditional categories of jaundice—pre-hepatic, hepatic and post-hepatic. This classification helps explain how different categories of disease can impair bilirubin metabolism and produce jaundice; however, overlap and blending of these categories frequently limit the application of this classification to individual patients.
Pre-hepatic jaundice
Jaundice is characterised as pre-hepatic when the primary abnormality is haemolysis. Increased erythrocyte destruction causes increased formation of bilirubin, but haemolysis by itself is unlikely to cause jaundice because of the large reserve capacity of the normal liver for uptake, conjugation and excretion of bilirubin. When haemolysis is acute and severe, however, hypoxia involving the centrolobular zones of the liver can secondarily impair liver function and cause intrahepatic cholestasis as well. Thus, the jaundice associated with acute severe haemolysis results from the combination of increased production of bilirubin and intrahepatic cholestasis caused by the secondary effects of hypoxia. The hyperbilirubinaemia is mixed.
Hepatic jaundice
Jaundice is characterised as hepatic when the primary abnormality is intrahepatic cholestasis associated with hepatocyte destruction and dysfunction. Severe liver disease, such as cholangiohepatitis, lipidosis or lymphoma, may impair various steps in bilirubin metabolism and produce intrahepatic cholestasis at the level of the canaliculi. Intrahepatic cholestasis causes regurgitation of conjugated bilirubin into the circulation, while increased bilirubin accumulation within hepatocytes interferes with the conjugation process and bile retention may damage hepatocytes. Thus, the hyperbilirubinaemia that occurs in liver disease is a mixture of conjugated and unconjugated bilirubin in varying proportions, usually with the conjugated fraction predominating.
Post-hepatic jaundice
Jaundice is characterised as post-hepatic when the primary abnormality is impaired excretion of bilirubin caused by extrahepatic biliary disease. This is associated with various diseases in the extrahepatic biliary system that obstruct the flow of bile causing extrahepatic cholestasis. Extra-hepatic cholestasis directly causes conjugated bilirubinaemia, while bile retention interferes with conjugation and injures hepatocytes, causing unconjugated bilirubinaemia. Thus, the hyperbilirubinaemia is mixed, with the conjugated fraction usually predominating.
The fallacy of bilirubin fractionation
Total serum bilirubin can be fractionated into indirect-reacting unconjugated bilirubin and direct-reacting conjugated bilirubin by means of the VandenBergh reaction; however, bilirubin fractionation has limited diagnostic usefulness in small animals. In all three categories of jaundice—pre-hepatic, hepatic and post-hepatic, hyperbilirubinaemia is both conjugated and unconjugated, usually with the conjugated form predominating. In pre-hepatic jaundice, severe acute haemolysis is usually accompanied by intrahepatic cholestasis secondary to hypoxia; thus, unconjugated and conjugated bilirubin are increased in plasma. Both intra- and extra-hepatic cholestasis decrease bile flow in canaliculi and cause regurgitation of accumulated conjugated bilirubin into the plasma. In cholestasis, accumulation of conjugated bilirubin in hepatocytes can decrease the conjugation process. This coupled with hepatocyte loss or dysfunction can cause increased plasma uncon-jugated bilirubin as well. In jaundiced animals with primary hepatobiliary disease, erythrocyte turnover and bilirubin production may be increased two- to five-fold because of shortened erythrocyte survival time in the circulation. This secondary form of low-grade haemolysis may be related to instability of erythrocyte membranes in animals with hepatobiliary disease and, in some cases, hypersplenism related to portal hypertension.
The difficulties with interpreting bilirubin fractions is compounded by variable reactivity of bilirubin conjugates in the test procedure. In animals with cholestatic disease, the liver produces a mixture of various bilirubin conjugates that have different polarities, rather than only the diglucuronide conjugate produced under normal conditions. The colorimetric reaction for fractionating bilirubin depends on the polarity of the bilirubin molecule such that bilirubin conjugated as diglucuronide reacts rapidly as ‘direct-reacting’ bilirubin, whereas unconjugated bilirubin is mostly ‘indirect-reacting’ after an accelerator is added. Animals with cholestasis have a mixture of conjugates with variable polarities, and so this difference in reactivity between direct and indirect bilirubin is not well delineated.
Diagnostic approach for the jaundiced cat
Jaundice is a frequent clinical sign of liver disease in cats and can occasionally be observed in cats with severe acute haemolytic anaemia. Other clinical manifestations of feline liver disease can include inappetence, lethargy, weight loss, vomiting, diarrhoea, dehydration, hepatic encephalopathy, abnormal bleeding, hepatomegaly and, rarely, ascites.
Exclusion of haemolytic (pre-hepatic) jaundice
The first step in evaluating the cause of jaundice in a cat is to determine whether it is pre-hepatic as a result of haemolysis. To produce jaundice, haemolysis must be acute and severe enough to cause moderate to severe anaemia. Other typical manifestations of haemolytic anaemia can include mucous membrane pallor, lethargy, weakness or collapse, tachypnea, tachycardia, anaemic murmur and hepatosplenomegaly. Severe pallor and other clinical signs of anaemia with a haematocrit of less than 20% suggest further evaluation for causes of haemolysis, including immune-mediated haemolysis, infectious disease (haemobartonella), hypophosphataemia, and Heinz body anaemia (various oxidant drugs or toxins such as zinc, onion or propylene glycol).
Serum chemistry evaluations
The jaundiced cat without indications of severe haemolysis should be evaluated for causes of primary hepatobiliary disease. Hepatic disease that frequently cause jaundice in cats include hepatic lipidosis, cholangiohepatitis, portal hepatitis, lymphoma, feline infectious peritonitis and hepatotoxicity Laboratory evaluation should include a complete blood count, urinalysis, routine serum biochemistry determinations, serum bile acid liver function tests and haemostasis evaluations. Cats with liver disease often have poikilocytosis (abnormally-shaped erythrocytes) related to cell membrane instability. Hyperbilirubinaemia and bilirubinuria confirm jaundice. Increased serum liver enzyme levels are expected in most cats with jaundice. The transaminases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are increased in hepatocellular injury, whereas alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT) are increased in response to cholestasis. Generally, both ALP and GGT increase to comparable levels in cats with jaundice; however, cats with idiopathic lipidosis often have increased ALP while the GGT remains normal or minimally increased. Thus, discordancy of these two enzymes may have diagnostic significance. Non-specific abnormalities in hepatobiliary disease can include hypoalbuminaemia, low BUN, hypo- or hyperglycaemia, hypo- or hypercholesterolaemia, and electrolyte abnormalities.
The serum bile acid (SBA) determination (12-h fasted and 2-h post-prandial) is the test of choice for liver function in cats; however, this test may not be necessary in cats with overt jaundice because the presence of hyperbilirubinaemia provides similar information. Elevation of either the fasted or post-prandial SBA above 20 μmol is considered highly indicative of liver disease and provides justification for considering liver biopsy.
All middle-aged and older cats with evidence of liver disease should have a baseline serum thyroxin level to check for underlying hyperthyroidism. A feline-specific serum trypsinlike immunoassay (fTLI) is indicated when pancreatitis is suspected. Subclinical chronic pancreatitis often accompanies a cholangiohepatitis in cats, presumably because the pancreas and biliary system share ducts, lymphatics and microcirculation.
Other laboratory evaluations
Depending on the circumstances, other laboratory evaluations that might be indicated include serologic tests for infectious agents (eg, FeLV, FIPV, FIV, toxoplasma) and faecal examinations (smears, flotation, sedimentation) for liver fluke ova.
Diagnostic imaging
Diagnostic imaging of the liver, especially ultrasonography, is very useful in jaundiced cats. Survey abdominal radiographs can evaluate liver size and detect calcified choleliths that might be the cause of extrahepatic biliary obstruction. The use of contrast cholangiography has been reported in the cat, but the technique is difficult and the results are often inconclusive.
Ultrasonography is the most useful imaging technique in the jaundiced cat. Ultrasonography helps to differentiate extrahepatic biliary obstruction from intrahepatic disease. Biliary obstruction, bile sludging, gall bladder disease and cholelithiasis can be identified. Hepatic neoplasms, cysts and abscesses can also be detected. Parenchymal abnormalities (such as lipidosis, cholangiohepatitis, cirrhosis and lymphoma) can sometimes be differentiated. Ultrasonography can also detect abnormalities in adjacent organs and structures such as the pancreas (pancreatitis), spleen, kidneys, GI tract and lymph nodes.
Liver biopsy
Liver biopsy is the single most informative test in cats with hepatic disease and is usually required for definitive diagnosis of diseases such as lipidosis, cholangiohepatitis and neoplasia. Biopsy methods include: fine-needle aspiration (for cytologic differentiation of lipidosis, inflammatory diseases and lymphoma); percutaneous needle biopsy (‘blind’ or ultrasound guided); needle or forceps biopsy by laparoscopy; and excisional biopsy by laparotomy.
Idiopathic hepatic lipidosis
Idiopathic hepatic lipidosis is a unique syndrome of progressive hepatic failure in cats and associated with severe diffuse lipidosis involving nearly all hepatocytes. This is the most common liver lesion in surveys of cats in North America, accounting for half of all cats with liver disease. Persistent anorexia, rapid weight loss and intrahepatic cholestasis are hallmarks of the disease. Aggressive nutritional support therapy for a few weeks can resolve the disorder in most cats.
Feline inflammatory liver disease: Cholangiohepatitis and portal hepatitis
Hepatic inflammation is the second most common form of liver disease in cats based on liver biopsy surveys, accounting for approximately 25% of all cases. There are two histologically distinct types of chronic inflammatory liver disease in cats—suppurative (neutrophilic or mixed) and non-suppurative (lymphocytic or lympho-plasmacytic). Both are characterised by inflammatory infiltrates in the portal triad areas and have been referred to as different forms or stages of cholangiohepatitis syndrome. Suppurative cholangiohepatitis is characterised by inflammation and degeneration of the bile ducts, infiltration of inflammatory cells into the adjacent parenchyma (lobular invasion), and periportal necrosis. Portal infiltrates may consist of neutrophils or neutrophils mixed with lymphocytes and plasma cells. It has been suggested that the lesion in many cats with nonsuppurative portal inflammatory disease would be better described as lymphocytic portal hepatitis. In addition to portal inflammation with lymphocytes, there is a variable degree of bile duct proliferation and fibrosis, but an absence of bile duct infiltration or periportal necrosis. In some cats, small intrahepatic bile ducts are decreased in number and replaced by lipogranulomatous foci.
Clinical signs are similar in both forms of feline inflammatory liver disease, and include jaundice, anorexia, lethargy, weight loss and intermittent vomiting. The clinical course may be acute or chronic and signs may be episodic or insidious. Cats with neutrophilic cholangiohepatitis are generally younger and have more acute presentation (days or weeks), whereas cats with the lymphocytic form are usually middle-aged or older and have a chronic history of weeks or months in duration. Jaundice and dehydration are the most consistent physical findings. Cats with the suppurative form sometimes have fever or abdominal pain. Hepatomegaly is found in less than 50% of cats with the suppurative form, but is common in cats (est. 70%) with the lymphocytic form.
Frequent concurrent disorders in cholangiohepatitis cats include extrahepatic bile duct obstruction, cholelithiasis, gall bladder abnormalities (sludge, cholecystitis), chronic subclinical pancreatitis and inflammatory bowel disease. The triple combination of idiopathic inflammatory disease in adjacent areas of the biliary tract, duodenum, and pancreas has been called ‘triaditis’ (ie, cholangiohepatitis, duodenitis and pancreatitis).
Cholangiohepatitis generally responds to corticosteroid therapy (oral prednisolone) to control inflammation. Adjunctive treatments that have been recommended empirically include antibiotics (especially metronidazole), ursodiol (ursodeoxycholic acid) to improve the bile acid composition and water content of bile, vitamin E (alpha-tocopherol) to provide an antioxidant effect in the liver, and S-adenosylmethionine (SAMe), a neutraceutical with various proposed beneficial effects on liver metabolism.