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Clin path test 4 > Chem lect 21: Eval musculoskeletal and hepatic systems > Flashcards

Chem lect 21: Eval musculoskeletal and hepatic systems Flashcards

1
Q

Reference intervals (RI) for enzymatic assays

A
  • RI’s needed to interpret results of patient
  • Different instruments/reagents produce different results for enzymes
    • eg temperature of assay
  • Best to RI’s for your lab especially for enzymes
    • not as much difference for hematology assays
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2
Q

Why would enzymes increase in the blood?

A
  • cellular leakage of enzyme
    • cytoplasmic release following plasma membrane damage or fragmmentation
      • blebosomes
    • release of cytosol or organelles following necrosis
  • increased synthesis of enzyme (induction)
    • by existing cells
    • by hyperplastic/neoplastic cells
  • decreased inactivation or clearance of enzymes
    • ex: renal excretion of amylase
  • absorption of maternal enzymes in colostrum
    • (ALP and GGT in certain neonates)
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3
Q

Physiochemical features that influence diagnostic use

(i.e. lead to inc enzyme activity in blood)

A
  • enzyme activity in target cell > blood
  • long enough half-life (hours) so enzyme accumulates in blood prior to activation
  • access to blood vs fate of enzyme from luminal epithelium
    • directly
    • lymphatics
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4
Q

Biometrics of ‘ideal’ diagnostic test

(ENZYMES)

A
  • want high sensitivity
    • test detects sick patients
  • Want high specificity
    • normal results when disease is absent
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5
Q

Exceptions to clinical significance

A
  • Certain enzymes
    • ALP in cats
    • GGT in dogs and cats
    • SDH
  • Low grade inflammatory lesion (vs acute ‘flare up’)
  • decreased number of target cells
    • necrosis or fibrosis
    • decreasing enzye activity may be a bad sign
    • organ function tests more reliable than enzyes
  • Inhibitors of enzye activity
    • pancreatic lipase

* dec enzyme activity below RI is not clinically significant

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6
Q

Muscle-origin enzymes

A
  • CK, AST, LDH
  • increases attributed to ‘leakage’ from injured skeletal myocytes
    • reversible vs irreversible injury
  • increased enzyme activity correlates with number of injured cells
    • not type of injury (mild, necrotic, etc)

* can’t tell if damage is reversible or irreversible

* can’t tell if cells are damaged or dead

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7
Q

Causes of myopathies

A
  • Traumatic
    • HBC, downer, post-op, IM injections
  • Exertional
    • exercise, endurance, seizures, trailering
  • Degenerative
    • rhabdomyolysis, Senna, capture mypathy
  • Inflammation
    • clostridial myositis
  • Nutritional
    • Vit E/Se deficiency
  • Ischemic
    • Saddle thrombus
  • Metabolic
    • equine glycogen storage
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8
Q

Creatine kinase

CK

A
  • Leakage
  • Source
    • skeletal (+ cardiac/smooth)
      • muscle, brain
      • Isoenzyes not used
  • Serum half life
    • very short (hours)
  • Clinical application
    • highly specific and sensitive for myopathies
  • Overly sensitive
    • inc (>3X) in animals w/o significant myopathy
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9
Q

Aspartate aminotransferase

AST

A
  • Leakage
  • Source
    • sk muscle
    • hepatocytes
    • other cells (Incl RBCs)
  • Serum half life: hours to days
  • Clinical applications
    • sensitive, but low specificity (muscle vs. liver origin)
      • need other specific enzymes (CK, ALT) to ID tissue source of leakage
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10
Q

Lactate dehydrogenase

LDH

Not a test question

A
  • Leakage
  • Sources: multiple
    • skeletal muscle
    • liver
    • WBCs
    • RBCs
  • Serum half-life: varies
  • Clinical application: not much
  • Not includedin chem panels
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11
Q

ALT in muscle damage

A
  • Mild elevations of ALT may be seen in dogs and cats
  • liver disease is most usual cause of increases in these enzymes
  • young dogs with muscular dystrophy
    • inc CK, ALT
  • dystrophic deficient cats
    • inc CK, ALT
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12
Q

Uncommon blood changes in massive rhabdomyolysis

A
  • release of intracellular analytes from myocytes
    • hyperkalemia
    • hyperphosphatemia
    • creatine => inc creatine
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13
Q

Muscle Disease beyond routine chem panel

A
  • Urine myoglobin (skeletal)
  • Plasma troponins (skeletal, cardiac)
  • Pro-BNP, Pro-ANP (cardiac)
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14
Q

Muscle Disease

A
  • Myoglobin
    • muscle necrosis releases myoglobin
    • freely filters into urine > myoglobinuria
    • Urine ‘dipstick’ reacts to blood, hemoblobin and myoglobin
    • Clinical signs
      • enzymes
      • urinalysis
      • CBC can help differentiate
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15
Q

Troponin

Not on test

A
  • Cytosolic myofibrillar protein (not an enzyme) released from damaged cardiac and skeletal muscle
  • Cardia troponin (cTI) specific for detecting myocardial disease
  • Measured by immunoassay
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16
Q

Natriuretic peptides

A
  • released in response to cardiac myocyte stretch
    • vasodilation
    • natiuresis
  • Inc blood levels with inc cardiac myocyte stretch/stress
  • Commercially available (IDEXX)
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17
Q

Natriuretic Peptides

Pro-BNP

A

Preliminary investigations in veterinary medicine

  • causes of dyspnea
  • Screen occult heart disease
  • Predict morbidity/mortality with cardiac disease
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18
Q

Liver physiology

What can go wrong

A
  • Makes most proteins (albumin)
  • Makes most coagulation factors
  • Makes fuel
    • glucose, glycogen, lipoproteins
  • Makes cholesterol
    • membranes and hormones (cortisol and testosterone)
  • Makes tihngs to eliminate
    • urea and bilirubin
  • Processes RBCs and hemoglobin
  • Detoxifies endogenous and exogenous chemicals and drugs
  • Filters bacteria from portal blood
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19
Q

Serum/plasma chemistry tests for detection of liver disease

A
  • hepatic damage
    • hepatocellular injury
      • leakage enzyme
    • cholestasis
      • induced enzymes
  • Decreased hepatic function
    • synthetic function tests (albumin)
    • Excretory function tests (bilirubin)
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20
Q

Liver tests

A
  • Hepatocyte injury or ‘leakage’
    • ALT, AST, SDH
  • Cholestasis
    • ALP, GGT
  • Liver function
    • direct tests: bile acids, ammonia
      • in healthy animals, 95% of bile acids are removed from portal blood and recycled by liver
    • indirect tests
      • total bilirubin, albumin, glucose, BUN, cholestasis, coagulation factors
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21
Q

Enzyme Abbreviations

  • ALT
  • AST
  • SDH
  • LDH
  • CK
  • GGT
  • ALP
A
  • ALT: (Almost) Always Liver Test
  • AST: A Sometimes (liver) Test
    • could be from muscle or lysed RBCs
  • SDH: Sick Depressed Horse (test)
  • LDH: Lotta Darn Help (not)
  • CK: Cramp Knot (test)
    • muscle
  • GGT: Grungy Gall Test
  • ALP: A Liver Possibility
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22
Q

ALT

Alanine aminotransferase

A
  • Leakage
  • Source:
    • hepatocytes
    • skeletal muscle in dogs/cats
  • Serum half-life: hours/days
  • Clinical application:
    • sensitive and specific for hepatocellular injury in dogs/cats
    • not used in ruminants, horses, swine
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23
Q

AST

Aspartate aminotransferase

A
  • Leakage
  • Source
    • skeletal muscle
    • hepatocytes
    • other tissues incl RBCs
  • Serum half life: hours/days
  • Clinical application
    • sensitive, but low specificity
      • muscle vs liver
      • need ALT and CK for comparison
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24
Q

SDH

Sorbitol dehydrogenase

A
  • Leakage
  • Source
    • hepatocytes
  • Half life: hours
  • Clinical application
    • very sensitive and specific for hepatocellular injury
    • used mostly for horses, ruminants and swine
    • increases not very marked
  • limited availability of test, ustable storage
25
Q

Comparison of enzyme activities in blood during active liver vs. muscle disease

A
26
Q

Cholestasis (impaired biliary flow)

A
  • between hepatocytes and duodenum
  • Intrahepatic
    • canaliculi and hepatic biliary duct flow affected
  • Extrahepatic
    • gall bladder and common bile duct flow affected
  • Markers: Tbili, Chol, Bile Acids, ALP, GGT
  • Distinction not possible with chemistry tests
    • need imaging or surgery
27
Q

Bile acids made from

A
  • cholesterol backbone
28
Q

Examples of cholestatic dzs

A
  • hepatocellular swelling from accumulatin of lipid or glycogen
  • inflammation (hepatitis, cholangiohepatitis, cholangitis)
  • Neoplastic cell infiltration
  • Common bile duct obstruction (colethiasis, pancreatitis) or leakage
  • Disruption of hepatocellular bilirubin excretion
    • functional cholestasis (e.g. sepsis)
29
Q

Cholestatic enzymes

ALP, GGT

A
  • Cholestatis induces synthesis of ALP and GGT which are bound to cell membranes
  • ALP on canalicular surface of hepatocytes is cleaved by phopholipase
    • activated by increased bile acids during cholestasis
    • crosses cell to sinusoidal slurface and enters blood
  • Cholestasis causes biliary epithelium to undergo hyperplasia
    • then synthesizes more GGT
  • requires days for inc in induced inzyme activity vs immediate release of leakage enzyes
30
Q

ALP mostly comes from

A

Hepatocytes

31
Q

GGT mostly comes from

A

biliary epithelium

32
Q

Alkaline phosphatase

ALP

A
  • Source
    • Hepatocytes
    • biliary epithelium
    • osteoblasts
    • colostrum
  • half-life
    • varies with isoform and species
      • 3 days dog
      • 6 hours cat
  • Variable sensitivity for cholestasis and low specificity
    • depends on species
    • many sources of ALP
33
Q

Inc ALP activity

A
  • Cholestasis Dog > Cattle > Cat, horse
    • inc ALP precedes hyperbilirubinemia
    • Feline ALP: any inc is important
  • Iatrogenic elevation in dogs
    • glucocorticoid induction
    • phenobarb
  • Young animals have inc ALP from bone or bone abnormalities
    • non-healing fractures
    • osteosarcoma
    • animals
  • Colostrum ingestion (dog, cats) few days
  • Late pregnancy of cats (placental ALP)
  • Mammary neoplasms
34
Q

Gamma glutamyltransferase

GGT

A
  • Source
    • biliary epithelium
    • renal tubules
      • renal tubular GGT detected in urine not blood
  • Half-life: 3 days
35
Q

Increased GGT activity

A
  • Cholestasis
    • more specific (vs ALP) for cholestasis
    • More sensitive (vs ALP) in cats, horses, cattle
    • bottom line: assay ALP and GGT?
  • Colostrum ingestion of mammary GGT a few days postnatal
    • puppies, calves
  • Drug induction in dogs
    • less effect vs ALP
    • Steroids
    • phenobarbital
36
Q

Overview of liver function tests

Excretory

Synthetic

A
  • Excretory
    • bilirubin
    • bile acids
    • ammonia
  • Synthetic
    • albumin
    • urea (BUN)
    • cholesterol
    • glucose
    • coagulation factors

*tests (n=5) on routine chemistry panels

* notice missing hepatic tests….

37
Q

BIlirubin as a hepatic function test

A
  • Routinely available
    • less sensitive for hepatic function vs bile acids
    • variable sensitivity for cholestasis
      • less so in dogs
38
Q

Metabolic pathway of bilirubin

A
  • Hemoglobin degraded to unconjugated bilirubin
  • Unconjugated bilirubin binds to albumin in plasma, travels to liver
  • Liver conjugates bilirubin to make it more soluble for excretion
  • Excretion through biliary tract into intestine
39
Q

Categories of hyperbilirubinemia

Pre-hepatic

hepatic

post hepatic

A
  • Pre-hepatic
    • mostly unconjugated
  • Hepatic
    • mix of unconjugated/conjugated
  • Post-hepatic
    • mostly conjugated

*icterus clinically evident when total bilirubin > 1.5 mg/dL

40
Q

Tests for bilirubin

Blood and urine

Total bilirubin

bilirubin splits

urinary bilirubin

urinary urobilinogen

A
  • Total bilirubin (plasma/serum)
    • routine chem panel
  • Bilirubin ‘splits’ (plasma/serum)
    • special request
    • direct
      • conjucated (including delta bili)
    • indirect
      • unconjugated (calculated)
  • Urinary bilirubin (urine dipstick)
    • interpretation for bilirubinuria in dogs vs cats
  • Urinary urobilinogen (urine dipstick)
    • not clinically imp
41
Q

Bilirubin tests in the real world

A
  • Typically just inc total bilirubin, don’t request splits
  • Best candidate for determining splits
    • anorectic horses with suspected liver dz
  • Categorize ‘pre-hepatic’ or ‘hepatic/post-hepatic’ using other data
    • PCV for anemia
    • ches for liver dz
    • leukograms for sepsis
42
Q

Metabolism of bile acids

A
  • Synthesized from cholesterol in hepatocytes
  • conjugated and excreted into bile
  • ‘stored’ in gall bladder
    • CCK causes release into small intestine from gall bladder
    • Aids in fat digestion
  • Reabsorbed in ileum, enters portal circulation
  • uptake/clearance by hepatocytes from portal veins
    • highly efficient clearance (90% 1st pass)
  • Enterohepatic cycle re-starts (95% overall recovery)
    • small losses in feces, urine

*not on routine panels

43
Q

Bile acids excreted into….

Should not be inc in….

A

Duodenum

Peripheral blood samples

44
Q

Basis for bile acid testing

A
  • Evaluates excretion and subsequent clearance of bile acids by hepatocytes
  • Requires healthy
    • hepatocytes
    • intestinal absorption
    • portal circulation
  • Detects
    • hepatocellular dz
      • shunting vessel concerns…
    • cholestasis
    • hepatic circulation disorders (+malabsorption?)
  • Very sensitive and specific for liver dz in all species
45
Q

Bile acid testing

Indications and procedure

A
  • Not a routine test ($$)
  • Indicated when hepatic enzymes/function tests are minimally altered but liver dz still suspected
  • NOT indicated if hyperbilirubinemia of hepatic origin is present
    • redundant
  • Fasting (8-12 hours)
  • postprandial (2 hrs post small meal) serum samples in dogs/cats
    • postprandial more sensitive
    • single test in ruminants and horses
46
Q

Increased bile acids

A
  • Decreased hepatic clearance
    • portosystemic shunts
    • hepatocellular disease
  • Decreased hepatic biliary excretion
    • intrahepatic and extrahepatic cholestasis
    • functional cholestasis
      • e.g. extrahepatic sepsis
47
Q

Maltese dog bile acid results

Fasting: 36 ug/dL H [0-10]

Postprandial: 45 ug/dL H [0-20]

A
  • maltese dog thing:
    • we don’t no what the hell goes on with them
    • not indicative of active liver dz
48
Q

Mixed breed bile acid results

Fasting 25 ug/dL H [0-10]

Postprandial 18 ub/dL [0-20]

A
  • Considerations
    • Event during fasting
    • spontaneous gall bladder contraction
    • bile flow bypassed gall bladder
      • gall bladder contracts whenever it wants (CCK contracts gall bladder)
      • postprandial more sensitive for liver dz
  • Technique
    • dog vomited fat meal before stimulating gallbladder release…?
49
Q

Problems with sensitivity/specificity

A
  • excess fat
    • induces post-prandial lipemia that intereferes with absorbance
  • therapeutic use of bile acids
    • ursodeoxycholic acid….? may or may not affect assay
  • falsly decreased results if severe intestinal dz
    • PLE: decreases intestinal reabsorption of bile into protal circulation
50
Q

‘Ammonia’

(ammonium, NH4)

Significance

A
  • Produced from protein degradation by enteric bacteria
  • absorbed by intestines and cleared from protal circulation by hepatocytes
    • enters urea cycle
      • hepatic detoxification
  • SIgnificance
    • accumulates during liver disease
      • >60% loss of functional mass
    • role in hepatic encephalophathy
      • causes neurologic signs => these make us want to run ammonia tests
51
Q

Ammonia test procedure

A
  • ammonia can be generated in tube after collection
    • must send on ice
    • must analyze within a couple of hours
  • should maybe send a normal sample too to rule out handling problems
  • bile acids much less complicated
52
Q

Hyperammonemia

rule outs

A

*typically run on fasted blood sample

  • hepatocellular dz (dec uptake)
  • Hepatic vascular shunts (PSS)
  • urea cycle disorders (rare)
  • urea toxicosis in ruminants
    • ​non protein nitrogen
53
Q

Decreased concentrations of analytes synthesized by hepatocytes

A

* not sensitive or specific but useful in concluding liver disease

  • albumin
  • urea
  • cholesterol
  • glucose
  • clotting factors
54
Q

Effects of decreased hepatic synthesis

Hypoalbuminemia

Dec BUN

Hypocholesterolemia

Hypoglycemia

Coagulopathy

A
  • Hypoalbuminemia
    • Late event in liver disease (80% loss function)
    • Other causes
      • inflammation
      • renal or intestinal loss + hyperglobulinemia?
  • Dec BUN
    • Polyuria from inabilty to conc urine
  • Hypocholesterolemia
    • also from cholestasis
  • Hypoglycemia (late, 80% loss, least likely?)
    • hyperglycemia with decreased hepatic uptake
  • Coagulopathy
55
Q

Coagulation disorders in liver dz

A
  • Dec synthesis of coagulation factors
  • Dec activation of Vit K dependant factors (II, VII, IX, X)
  • Liver necrosis causes DIC
  • Dec clearance of FDPs, activated coagulation factors
56
Q

Bilirubin on urine dipstick….

A

Always bad in cats

Shows up in urine before it shows up in blood… I think

57
Q
A

Ammonium biurates and bilirubin crystals

58
Q

Microcytosis

Microcytosis in absence of anemia

A
  • decreased liver function could mean less processing of cholesterol to make the lipid bilayer of cell wall membrane
  • something about processing iron

Microcytosis in absence of anemia

  • shunts
  • dec liver function
  • japanese breeds

*microcytosis not very sensitive

Clin path test 4 (9 decks)

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