Feline liver disease

Question 1

What are the pecularities of the feline liver

Answer 1

1/ Limited conjugation capabilities
- can only conjugate to cholic acid with taurine
- deficiency in glucuronyl transferase limits glucuronide conjugation

2/ Inability to synthesize certain amino acids, fatty acids and vitamins
- Vitamin A and niacin are essential vitamins
- taurine and arginine are essential amino acids
- arachidonic acid is an essential fatty acid

3/ High activity of hepatic transaminases and deaminases
- have high dietary protein requirement
- unable to down-regulate these enzymes in response to decreased protein intake

4/ Major pancreatic duct joins the common bile duct before it enters the duodenum

Question 2

What can you interfere from serum bilirubin concentration

Answer 2

Tissue jaundice will only generally be evident when serum bilirubin exceeds 50 µmol/l

When serum bilirubin is > 200 µmol/l, this is most often caused by either hepatic lipidosis or post-hepatic obstruction
- generally the higher the serum bilirubin, the more likely that complete post-hepatic biliary obstruction is present

If serum bilirubin is > 100 µmol/l, abdominal ultrasound is critical in identifying whether extra-hepatic biliary duct obstruction is present

Question 3

What are the four histologic variants of cholangitis in the cat

Answer 3

Neutrophilic cholangitis (acute or chronic)

Lymphocytic cholangitis

Chronic cholangitis due to flukes

Question 4

What is the histopathological lesion in acute neutrophilic cholangitis

Answer 4

In ANC, histopathology reveals primarily neutrophils within the portal areas and the wall and lumen of intrahepatic bile ducts with accompanying bile duct epithelial degeneration and necrosis
- concurrnt periportal parenchymal inflammation is common

Question 5

What is the suspected cause of acute neutrophilic cholangitis

Answer 5

ANC is believed to be associated with infection
- this may be a primary biliary tract infection ascending from the GI tract or secondary to the spread of a distant infection

Question 6

What factors may predispose cats to acute neutrophilic cholangitis

Answer 6

Many cats with ANC have biliary tree abnormalities predisposing them to ascending bacterial infections
- IBD
- pancreatitis
- abnormalities of gall bladder structure and function
- cholelithiasis
- biliary parasites
- extrahepatic bile duct obstruction

Question 7

What are the most commonly isolated organisms in cats with ANC

Answer 7

Escherichia coli

Enterococcus

Question 8

Explain why in many reported cases of ANC, even if a bacterial etiology is suspected, cultures are negative

Answer 8

Reasons speculated for the failure to isolate bacteria include:
- lack of anaerobic culture submission
- difficulty in growing anaerobic organisms in vitro
- prior treatment with antibiotics

Question 9

What are signalement and clinical findings in cats with ANC

Answer 9

Cats with ANC tend to be young (median age 3 years)
- a predisposition in male cats has been noted

An acute presentation, with short duration of clinical signs (< 5 days) is common
- history may include anorexia, lethargy, vomiting and diarrhea

Physical examination findings include a typical triad of signs
- jaundice
- abdominal pain
- fever

Question 10

What are the histological lesions associated with chronic neutrophilic cholangitis

Answer 10

Chronic neutrophilic cholangitis is associates with infiltration of portal areas and/or bile ducts with plasma cells, lymphocytes and lesser number of neutrophils and macrophages
- bile duct hyperplasia is typically present and there may be periductal fibrosis

Question 11

What is the suspected cause for CNC

Answer 11

CNC may represent tissue response to chronic, non-septic injury, although some cases may represent progression from the acute form

An association between CNC and chronic inflammatory disease in the GI tract and pancreas has been reported
- CNC may be one manifestation of a systemic autoimmune disorder
- or chronic vomiting secondary to IBD may lead to reflux of gastrointestinal contents into the common duct and perfusion of the pancreatic and biliary systems
- the result of this reflux is a low-grade bacteremia/inflammation that leads to the development of chronic neutrophilic cholangitis

Question 12

What are the histological lesion in lymphocytic cholangitis

Answer 12

In lymphocytic cholangitis, there is moderate to marked infiltration of portal areas by small lymphocytes
- depending on chronicity varying degrees of portal to bridging lobular fibrosis or periductal fibrosis is noted

Question 13

What are the signalement and clinical findings in cats with CNC and lymphocytic cholangitis

Answer 13

Cats with CNC or lymphocytic cholangitis are hard to distinguish clinically or biochemically
- most cats are middle aged or older
- no sex predisposition
- commonly, cats have been ill for greater than 2 months, often with a waxing and waning course of clinical illness

Signs are subtle and may include vomiting, diarrhea and rarely anorexia and lethargy
- some cats may have surprisingly good appetite and appear clinically like cats with hyperthyroidism

On physical examination, most cats have hepatomegaly and may be jaundiced

Question 14

What are the lesions associated with chronic cholangitis secondary to liver fluke infestation

Answer 14

Cats with chronic fluke infestation have severe ectasia and hyperplasia of bile ducts and severe concenttric periductal fibrosis
- a mixed inflammatory infiltrate including eosinophils is frequently present in portal areas

Question 15

What are the clinical signs associated with chronic cholangitis secondary to liver fluke

Answer 15

Most cases are asymptomatic
- with heavy infections cats can present with weight loss, anorexia, vomiting, diarrhea, jaundicee, hepatomegaly and abdominal distension

Question 16

How is made a definitive diagnosis for feline cholangitis

Answer 16

DEfinitive diagnosis of feline cholangitis requires examination of a hepatic biopsy

Hepatic biopsy will confirm an inflammatory etiology and permits determination of disease stage (acute vs chronic) and grade (severity of inflammation and degeneration)

Question 17

Explain why taurine is considered an essential dietary component for cats

Answer 17

Taurine is the only nutrient used by cats to conjugate bile acids and, because cats have limited taurine production capacity, it is considered an essential dietary component for cats
- thus taurine availability is a limiting factor in the production of conjugated bile acids

Question 18

What are the two types of cholestasis

Answer 18

Intrahepatic cholestasis
- occurs predominantely at the level of hepatocytes, bile canaliculi or bile ductuli
- it is linked to the destruction of bile ductuli and hepatic fibrosis secondary to cholangitis
- some cholestatic drugs (e.g., methimazole, ciclosporin) have been associated with reduced bile flow at the canalicular level
- endotoxins represent a major cause of intrahepatic cholestasis by impairement of the canalicular bile flow

Extrahepatic cholestasis
- it is caused by obstruction of the common bile duct

Question 19

What are the most common causes of EHBDO

Answer 19

Bile sludge and choleliths, associated with cholangitis, cholecystitis and impaired contractility of the gallbladder, have been implicated as the most common causes of EHBDO

Question 20

What ultrasonographic sign is considered diagnostic for EHBDO

Answer 20

A dimater of more than 5 mm for the CBD is a useful parameter in diagnosing EHBDO

Question 21

Explain the metabolism of bilirubin

Answer 21

Bilirubin is a waste product of haemprotein degradation
- the primary source of haem proteins is senescent erythrocytes
- myoglobin and haem containing enzyme systems in the liver are additional sources

Mononuclear phagocytic cells engulf old erythrocytes and form biliverdin through the action of haem oxygenase

Biliverdin is converted to fat-soluble bilirubin IXa, which is then released into the circulation where it is bound by albumin

Hepatocytes take up the bilirubin and conjugate it with various carbohydrates, making bilirubin water-soluble

Conjugated bilirubin is excreted into bile canaliculi and travels in the bile ducts with other bile constituents to the gall bladder, where it is stored until it is expelled into the duodenum

In the intestine, conjugated bilirubin undergoes bacterial deconjugation and then reduction to urobilinogen, which is mostly resorbed into the portal system and returned to the liver

A small fraction of urobilinogen is excreted in the urine and the remainder stays in the intestinal tract where it is converted to stercobilin, which impacts normal fecal color

Question 22

Explain bile acid metabolism

Answer 22

Bile acids are synthesized from cholesterol in the liver
- there is a vast reserve capacity for the production of bile acids and, hence, insufficient production is never a concern

Bile acids are conjugated to taurine and stored in the gall bladder

After a period of fasting, bile acids are low in the serum of normal cats
- ingestion of food results in the release of cholecystokinin, which stimulates the gall bladder to contract and release bile acids into the duodenum

Question 23

What are the pathomechanisms leading to hyperbilirubinemia

Answer 23

Hyperbilirubinemia develops because of one of three possible causes:
- excessive hemolysis of RBCs (pre-hepatic icteurs)
- high bilirubin in blood occurs because of an overload of the mononuclear/phagocyte system with heme pigments from RBC destruction

- hepatic parenchymal disease or insufficiency (hepatic icterus)
    - results in lack of normal bilirubin metabolism in hepatocytes and reflux of the pigments into the blood stream when they are not taken up into cells and excreted in bile

- disease of gallbladder, biliary tract or pancreatic duct (posthepatic icterus) resulting in obstruction of the bile ducts or loss of bile into the abdomen

Because the normal feline liver has high capacity to process large amounts of bilirubin, jaundice only occurs when there is overwhelming hemolysis, significantly decrese in hepatic function and/or obstruction to normal bile flow

Question 24

Explain why jaundice may be visible on physical examination even after resolution of the underlying disease

Answer 24

A fraction of conjugated bilirubin can bind irreversibly to albumin (as delta-bilirubin)
- if that happens, that fraction of bilirubin may remain in circulation for the same length of time as albumin (approximately 2 weeks), so the jaundice might be visible on physical examination even after resolution of the underlying disease

Question 25

Explain what is cholestasis of sepsis in cats

Answer 25

A septic cat may have hyperbilirubinemia (although often no visible jaundice) without having a structural hepatobiliary disease or hemolysis - it happens because of complex changes in bilirubin metabolism within the hepatocytes due to cytokines and endotoxins, nutritional changes, and cats intrinsic low concentration of glucuronosyltransferase (liver enzyme needed to conjugate bilirubin)

Question 26

What is the pathomechanism explaining hepatic lipidosis in cats

Answer 26

The inciting event is a period of anorexia, which is most often caused by an underlying disease, such as IBD, neoplasia? pancreatitis, or cholangitis - obese cats are especially at risk Mobilization of fatty acids from peripheral adipose tissue leads to triglycerides accumulating in the liver more quickly than they can be utilized or secreted, resulting in a massive increase in the organ's lipid content The depletion of hepatic glutathione (an important antioxydant) and the presence of Heinz body anemia confirm the importance of secondary oxidative injury in this disease A variety of other derangements of metabolism occur due to protein-calorie malnutrition - for example, arginine deficiency can lead to impairement of the urea cycle with subsequent development of hyperammoniemic encephalopathy

Question 27

What is the typical diet for nutritional support in hepatic lipidosis

Answer 27

Diets for cats with hepatic lipidosis should ideally be: - high in protein (> 40% ME) - have lower amounts of carbohydrates (< 20% ME) - with the remaining calories coming from fat The diets that best fit this profile are the diets formulated for diabetic cats

Question 28

Explain how portosystemic shunts can lead to hepatic encephalopathy and liver atrophy

Answer 28

Portosystemic shunts are vascular anomalies that connect the splanchnic and systemic circulations - they can be either congenital or acquired - single or multiple in number - extrahepatic or intrahepatic - the two most common veins that serve as the connection point for the shunting portal venous blood are the caudal vena cava and the azygous vein The shunting of ammonia-rich blood from the splanchnic circulation to the systemic circulation, bypassing the liver, can lead to hepatic encephalopathy Hepatic atrophy or hypoplasia can also occur because the liver is not exposed to trophic factors that are normally present in the portal circulation, which can compromise the liver function

Question 29

What is the most common form of portosystemic shunt? congenital or acquired?

Answer 29

Congenital portosystemic shunts are more common - in cats a single, extrahepatic, portocaval shunt is the most common form (75 % of cases)

Question 30

What is the suspected mechanism for hepatic encephalopathy

Answer 30

The pathogenesis of HE is poorly understood and it is likely that multiple factors are involved The syndrome results from failure of the liver to remove toxic products of gut metabolism from the portal blood and also from failure of the liver to produce factors important for normal brain function - one of the major factors contributing to HE is ammonia, which is often increased in cats with PSS The principal source of ammonia is the gastrointestinal tract, in particular the colon - anaerobic bacteria and coliforms degrade proteins and produce urease, which converts urea to ammonia - ammonia is normally removed from the portal circulation by the liver and converted into urea - in cats with PSS, the ammonia is not metabolized by the liver because it enters the systemic circulation directly Various other fators have been implicated in the pathogenesis of HE including: - increased aromatic amino acids (e.g., tyrosine, tryptophane, methionine) - increased central nervous system inhibitors (GABA) - increased mercaptans - increased short-chain fatty acids

Question 31

What would be your medical plan for hepatic encephalopathy

Answer 31

Decrease bacterial production of ammonia - acute: enemas with warm water or lactulose - chronic: lactulose (0.5-1 ml/kg, PO, q8 h; dosage based on stool softness) and antibiotics (metronidazole (5-10 mg/kg, PO, q 12h) or ampicillin (20 mg/kg, PO, q8h Gastrointestinal ulcers and erosions - omeprazole 1 mg/kg, PO, q12h Seizures - levetiracetam (20 mg/kg, PO or IV, q8h) - or phenobarbital (1-3 mg/kg, PO, q12h) Nutritional support - place esophagostomy tube if needed - protein at least 35% (dry matter basis) - B vitamin supplementation (1 ml/l, in fluids or 0.25 ml, SC, q24h)

Question 32

What are the most common complications of surgical attenuation of congenital portosystemic shunts

Answer 32

Continued shunting due to incomplete closure of the shunt vessel or the formation of acquired portosystemic collateral blood vessels Post-attenuation seizures, amaurosis, and portal hypertension are possible and occur more commonly than in dogs