Liver Document - General presentation & Labwork

Most hepatobiliary diseases can present either sick or asymptomatic. What diseases almost always present sick?

lymphoma (neoplasia), hepatic lipidosis, suppurative cholangitis/cholangiohepatitis

What hepatobiliary diseases can present either sick or asymptomatic?

acute hepatopathy, chronic hepatitis, neoplasia, biliary mucocele, shunts, vacuolar hepatopathy, cholangitis/cholangiohepatitis 

Most hepatobiliary diseases can present either sick or asymptomatic. What diseases almost always present asymptomatic?

massive HCA (neoplasia), metastasis (neoplasia), reactive hepatopathy, nodular hyperplasia, lymphoplasmacytic cholangitis/cholangiohepatitis

What are some general clinical exam findings for hepatobiliary disease?

icterus (nonspecific), hepatomegaly, ascites

What are common CBC abnormalities in hepatobiliary disease?

1. anemia (chronic disease → non-regenerative, regenerative anemia, iron deficiency anemia → microcytic anemia)

2. poikilocytes

3. target cells

Microcytic anemia is often secondary to alterations in ____ from decreases in hepatic ___. 

iron metabolism, blood flow

What are some hepatic diseases that can result in microcytic anemia?

portosystemic vascular anomalies (PSVA),

cirrhosis,

hepatic lipidosis (cats),

portal hypertension can also cause chronic bleeding into GI

Poikilocytes are secondary to ___ and are common in ___.

increased RBC membrane fragility, 

cats

Target cells may be noted secondary to ___ or ___.

cell membrane abnormalities,

iron deficiency

Liver enzymes are highly ___ but carry low ___ for liver disaese.

sensitive, specificity

True or False? The degree of liver enzyme elevation correlates with severity of hepatobiliary damage and is predictive of hepatobiliary function/return to function.

False. It does NOT correlate with severity of damage or predictive of hepatobiliary function due to the its regenerative capacity and in end stage liver disease, functional mass of liver cells reduced so less enzymes produced.

What are differentials for both dogs and cats for increases in liver enzymes that is NOT primary liver disease?

Anticonvulsants, diabetes mellitus, hypoadrenocorticism, GI disease, systemic infection, neoplasia, shock, seizure, hypotension, inflammation, CHF, surgery

What are differentials for both dogs and cats for increases in ALT that is NOT primary liver disease?

muscle injury

What are differentials for both dogs and cats for increases in ALP that is NOT primary liver disease?

bone growth, osteomyelitis, osteosarcoma

What are some differentials for dogs for increases in liver enzymes that that is NOT primary liver disease?

Corticosteroids, hypothyroidism, hyperaldosteronism, colostrum feeding

What are some differentials for cats for increases in liver enzymes that is NOT primary liver disease?

Hyperthyroidism, pregnancy

ALT

alanine aminotransferase

ALT is a ___ enzyme found in ___.

leakage, liver and muscle

ALT increases are seen with:

• hepatic inflammation and necrosis (hepatocellular damage)

• severe muscle inflammation or necrosis

• Phenobarbital (typically only ALT 2-4x)

• neoplasia and nodular regeneration

What is the serum half-life of ALT?

dogs = 2.5d, cats = unknown

A drop in ALT of __% or greater over __ hours is a good prognostic indicator with acute liver disease.

50%, 48 hours

AST

Aspartate aminotransferase

AST is a ___ enzyme and is more __ but less __ than ALT because?

leakage, sensitive, specific

large amounts of AST are found in muscle

How can you tell if AST elevation is due to muscle damage and not liver damage?

check CK, if degree of AST elevation much more significant than ALT, suspect muscle origin

What is the serum half-life of AST?

Dogs = 5-12hours, Cats = 77 minutes

True or False? Because the half-life of ALT is much shorter than AST, ALT will decrease more quickly with recovery in acute liver disease.

False. Half-life of AST is much shorter than ALT, so AST will decrease more quickly with recovery. Think AST is SHORT whereas ALT is LONG

ALP

alkaline phosphatase

ALP is a ___ enzyme so specificity is affected by isoenzymes including:

induced/membrane-bound, 

liver, corticosteroid-induced (glucocorticoid in dogs), bone, kidney, intestine, placenta origin

What isoenyzmes do not contribute to the total serum ALP?

intestines, kidneys, placenta

*half-lives are too short, except pregnant late in gestation

Bone ALP contributes up to __ of total serum ALP and is increased in what situations?

1/3

increased with osteoblast activity of growing dogs, osteomyelitis, osteosarcoma

typically mild elevations 2-5x

What are the largest contributors to total serum ALP in the dog and cat?

Dog: liver ALP and corticosteroid ALP

Cat: liver ALP (cats do not have C-ALP)

True or False? If you can differentiate C-ALP and L-ALP, can determine if it is corticosteroid in origin (Cushing’s) or hepatobiliary.

False. Differentiating C-ALP and L-ALP is of little diagnostic utility in dog because corticosteroids can increase L-ALP and other disease can increase C-ALP 

What is the serum half-life of ALP?

Dogs = 70 hours

Cats = 6 hours

True or False? ALP elevations in the cat is not as dramatic as the dog because of the shorter half-life and lower hepatic stores.

True

What can cause ALP elevations generally?

Increased synthesis or release from hepatocellular membrane, generally with disease that have a cholestatic component 

What are differentials for ALP elevations in the dog?

Hepatic neoplasia, hepatobiliary disease,

corticosteroids, anticonvulsants,

chronic illness,

nodular regeneration

What are differentials for ALP elevations in the cat?

Hepatobiliary disease is the most common cause, e.g. hepatic lipidosis

GGT

gamma glutamyl-transpeptidase

GGT is an __ enzyme primarily derived from __ but also the __.

induced/membrane-bound,

liver,

pancreas, kidneys, intestines

Elevations in GGT are associated with disease with a ____ component.

cholestatic

Besides cholestatic causes, what causes GGT elevations in the dog?

certain drugs like phenobarbital, glucocorticoids

What are differentials for GGT elevation in the cat?

cholangitis, cirrhosis, pancreatitis, biliary obstruction

In the cat, what diseases usually present with a much more significant GGT increase compared to ALP?

cholangitis, cirrhosis, pancreatitis, biliary obstruction

In the cat, what diseases usually present with a much more significant ALP increase compared to GGT?

hepatic lipidosis, e.g. ALP might be 10x normal with GGT 2x normal

ALT + AST elevation = ?

cellular damage

ALP + GGT elevations = ?

cholestasis

AST > ALT = ?

muscle damage suspected

What differentials should you consider with drastic increased ALP and GGT?

glucocorticoids/vascular hepatopathy

An increased ALT generally indicates what?

acute liver injury/hepatitis

What will the liver enzyme pattern look like for cholangitis in cats?

GGT > ALP, ALT > ALP

What will the liver enzyme pattern look like for hepatic lipidosis?

ALP > ALT and GGT

What labwork values indicate liver function?

BUN, glucose, albumin, cholesterol, clotting factors, anticoagulatns, bile acids, bilirubin, ammonia

What labwork values indicate liver synthesis?

BUN, glucose, albumin, cholesterol, clotting factors, anticoagulantsW

Bilirubin and bile acids indicate what about liver function?

liver uptake and secretion,

bilirubin only - liver conjugation

Ammonia indicates what about liver function?

metabolism

Bile is composed of __ % __ kept in solution by formation of ___.

>90%, bile acids, micelles

Bile acids are formed from __ in the liver. In the liver they are __ to __ (dog) or __ (dog, cat) and excreted in bile and stored in the gallbladder

cholesterol,

conjugated, glycine, taurine

Describe how bile is released from the gallbladder and reabsorbed.

1. Dietary fat and protein in duodenum stimulate cholecystokinin

2. Cholecystokinin causes contraction of gall bladder, transports bile to duodenum

3. Bile acids solubilize fat in intestinal tract to aid absorption

4. Conjugated bile acids get absorbed into portal circulation in receptors in the ileum

   1. Bile acid transporters in hepatic sinusoids re-extract bile acids

Should you fast animals 12 hours to obtain a baseline bile acids to compare the postprandial bile acids to?

Historically done as normal range describes post prandial 2-3x baseline BUT prolonged fast is not neccessary because bile acids should never be above post-prandial reference range of 30 umol/L

Fasting bile acids may be normal in dogs with ___ so what test would increase the sensitivity for diagnosing this?

PSVA, post-prandial bile acids

What are causes to increased bile acids?

• Maltese dogs, other breeds may have increased bile acids normally

• Severe intestinal disease

• Hepatobiliary disease

  • Decreased extraction by liver from portal blood → shunting, hepatocellular failure

  • Reflux into bloodstream → cholestasis

What might cause bile acids to be artificially decreased?

• Inadequate fat or protein in test meal

• Severe ileal disease

• variations in gastric emptying, intestinal tract time, cholecystokinin release

Why might fasting bile acids be higher than post-prandial bile acids?

Inter-digestive gallbladder contractions as well as the same reasons the causes bile acids to be artificially decreased

Besides serum bile acids, how else can bile acids be evaulated?

urine bile acids in dogs, fairly sensitive for liver disease

What is the advantage of using urine bile acids? Advantage of serum bile acids?

Urine bile acids do not require fasting, venipuncture or multiple samples, BUT serum bile acids believed to be more sensitive for early liver disease

The liver synthesizes what proteins that are helpful markers of liver function?

albumin, non-immunoglobulins (alpha-globulins, beta-globulins), coagulation factors

Hypoalbuminemia can be seen with severe __ disease due to:

liver,

synthetic failure (most common), portal hypertension, sodium retention, water retention, inflammatory conditions (albumin negative APP)

Hypoalbuminemia seen with hypocholesteremia may be caused by:

liver - liver enzymes, synthetic failure, normal to increased globulins

GI - panhypoproteinemia

Hematopoietic system - anemia, biliruin

For non-immunoglobulins, hypoglobulinemia may be due to what?

due to hepatic failure

For non-immunoglobulins, hyperglobulinemia may be due to:

chronic inflammatory liver disease, esp in cat

What coagulation factors does the liver produce?

Hepatocytes synthesize all factors except VIII

Will PT or PTT be prolonged in severe liver disease?

Both PT (7, extrinsic pathway) and PTT (8, 9, 11, 12, intrinsic pathway) will be prolonged

What hepatobiliary disease impair vitamin K uptake and how does it cause coagulopathy?

severe cholestasis → inhibit bile flow → impaired uptake of fat soluble vitamins like vitamin K → cannot activate factors 2, 7, 9, 10

What anticoagulants do hepatocytes produce?

protein C, antithrombin III, antiplasmin, fibrinolytic proteins (plasminogen)

With severe liver disease, will animals be in a hypo or hypercoagulable state?

Can be either due to role of the liver in production of anticoagulants and procoagulants

What produces ammonia? How does it get to the liver?

produced in small intestines by bacterial degradation of purines, amino acids and amines and by bacterial ureases in colon (largest source)

ammonia diffuses readily through intestines into portal circulation

How is ammonia detoxified?

Metabolism in urea cycle or by consumption in production of glutamine in liver (kidneys, muscle, brain, intestines also detox via glutamine)

What are differentials for hyperammonia?

Some forms of portosystemic shunting, severe hepatitis, severe necrosis and cirrhosis

deficiencies in argininosuccinate synthetase in dogs // deficiencies in arginine in prolonged anorectic cats → needed for urea cycle

What are different ammonia tests?

Fasting ammonia levels, fed ammonia levels, ammonia tolerance test, ammonia challenge test

Fasting or fed ammonia levels are less sensitive and specific than __.

But fasting ammonia is used to assess successful __ and is the preferred single initial test.

bile acids,

extrahepatic shunt ligation 

True or False? Ammonia tolerance testing is rarely used now.

True.

Describe the breakdown of bilirubin

Heme → bilirubin → spleen/liver binds bilirubin to albumin → unconjugated bilirubin → liver extracts and conjugates with glucuronic acid → conjugated bilirubin secreted into bile → bilirubin excreted in feces OR intestinal bacteria converts to → urobilinogen → stercobolin to feces OR urobilinogen to urine

Bilirubin retention may result in __ and may be due to what 3 causes?

icterus,

pre-hepatic (hemolysis), hepatic (impaired uptake, conjugation, excretion), post-hepatic (biliary obstruction)

True or false? Measure of direct (conjugated) and indirect (unconjugated) bilirubin can differentiate prehepatic from hepatic or post-hepatic causes of hyperbilirubinemia.

False. There is significant overlap in types of bilirubin produced in different disease sates and there is no improved specificity in using direct vs indirect. 

What are differentials for hyperlipidemia?

• primary hyperlipidemia from defects in lipoprotein synthesis/metabolism (Briard’s, mini schnauzers, Shetlands, beagles)

• biliary obstruction (cholestasis) from increased synthesis (most common), back-diffusion

Will cholesterol be increased or decreased in liver disease?

Can be increased or decreased

What are differentials for decreased cholesterol?

CPSS and cirrhosis from synthetic failure/hepatic failure,

increased production of bile acids (cholesterol used for bile acids)

Hypoglycemia can be seen with __% functional liver mass.

<30%

What are differentials for hypoglycemia related to the liver?

severe acute or chronic liver failure, small breeds with vascular anomalies, paraneoplastic with some liver tumors (hepatoma, heptaocellular carcinoma), glycogen storage disease

True or False? Hyperglycemia is rare in cats.

False. HYPOglycemia is rare in cats.

What are differentials for hyperglycemia related to the liver?

hepatocutaneous disease (dog)

How is blood urea nitrogen affected by liver disease?

Liver detoxifies ammonia in urea cycle and generates urea for excretion

What are differentials for decreased BUN?

secondary to decreased production in failing liver, diet, medullary washout (increase in glomerular filtration rate and fluid diuresis)

What are differentials increased BUN?

dehydration, increased dietary protein, GI hemorrhage

Dr. R prefers to look at __ and __ to evaluate liver function instead of __ because it is not a very specific indicator of liver function.

cholesterol, albumin

BUN 

What crystals are detected in the urine of animals with liver disease?

ammonium biurate crystals

How does liver disease results in ammonium birurate in urine?

deficiency of hepatic urate oxidase (uricase) may cause hyperuricemia and hyperammonia from failure of urea cycle in blood → ammonium biurate

Crystals and uroliths secondary to liver disease are most common with ____.

congenital portosystemic shunts

True or False? Crystals in urine do not always mean stones , but some dogs with PSVA will present with lower urinary tract signs because of calculi.

True

What is protein C?

Produced in the liver and is a vitamin-dependent proenzyme that is activated when thrombin binds to trombomodulin in endothelial cels. It acts as anticoagulant by cleaving factors Va and VIIIa