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The Liver & Tests of Hepatic Function

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1 The Liver & Tests of Hepatic Function
Study Guide Pg 90

2 Module Focus It is the primary site for the metabolism of carbohydrates, proteins, lipids, and bile acids. It is the major site for the storage of iron, glycogen and lipids.

3 The liver also plays an important role in the detoxification of molecules foreign to the body & the excretion of waste products such as bilirubin, ammonia & urea. Lab tests are generally used as a nonspecific index of liver function.

4 Summary of Lab Tests of Liver Function
Total protein, albumin, bilirubin, ALT, AST, GGT, ALP AFP, ammonia, iron Urine bilirubin & urobilinogen Hepatitis markers CBC, retic counts, PT, hemoglobin electrophoresis

5 Hepatic Function Metabolic/Synthesis:
Proteins, carbos, lipids, coag factors Detoxification (protective): Convert ammonia to urea, bilirubin, drugs Storage: Lipids, glycogen, vitamins, hormones Excretory: Bilirubin Hemoglobin to bilirubin to urobilinogen

6 Diseases of the Liver Tumors, cirrhosis, drugs, alcohol
Hepatitis A, B, C Cholestatic or obstructive jaundice Reye’s syndrome Hemochromatosis Wilson’s disease

7 Indicators of Metabolic Function (for severity, not diagnosis)
Albumin:  values due to  synthesis by the liver, causes ascites (the accumulation of fluid in the abdominal cavity)  Prothrombin time: =  clotting time

8 Indicators of Hepatic Detoxification & Excretory
 Ammonia: Ammonia is very toxic to the brain Normally, it is converted to urea by the liver  levels may indicate impending hepatic coma  Bilirubin: derived from breakdown of hemoglobin & excreted in feces as urobilinogen/urobilin

9 Enzymes Determinations
The majority of enzymes are intracellular When tissue damage occurs, enzymes are released into the plasma. Enzyme tests are the most sensitive tests. Liver enzymes = ALP, GGT, AST, ALT We will study these tests in the next unit.

10 Normal Bilirubin Metabolism pg 94
After 120 days, RBCs are typically broken down by the RE System. The hemoglobin in the RBCs forms heme + iron + protein The heme is converted to unconjugated (indirect) bilirubin

11 4. Since the unconjugated (indirect) bilirubin is insoluble, it will attach to albumin to be transported to the liver. unconjugated cannot be excreted in the urine in this form.

12 Metabolism in the LIVER
5. Bilirubin is transported into the liver cell. In the liver cell, it combines with glucuronic acid by the enzyme glucuronyl transferase to form conjugated bilirubin. The conjugated bilirubin is now water soluble. glucuronyl transferase Unconjugated + Glucuronic Conjugated Bilirubin acid Bilirubin

13 Bile Ducts The majority of the conjugated bilirubin that is produced in the liver, is transported into the bile ducts & the intestinal tract. In the GI tract, bacterial enzymes convert the conjugated bilirubin to Urobilinogen. The urobilinogen then forms UROBILIN which gives the feces its brown color.

14 Expected Normal Values pg 93
Analyte Reference Range Total Bilirubin < 1.0 mg/dl Direct (conjugated) Bilirubin 0 – 0.2 mg/dl Indirect (unconjugated) Bilirubin <0.8 mg/dl Urine Bilirubin Negative Urine Urobilinogen 1 – 4 mg/day Fecal Urobilinogen 50 – 250 mg/dl

15 Clinical Applications Jaundice pg 92
Signs & Symptoms Bilirubin = > 3mg/dl Causes yellowish discoloration of skin and sclera Serum appearance = “icteric”

16 Causes of Altered Bilirubin Levels
Prehepatic jaundice = “hemolytic jaundice” Excessive hemolysis of RBCs =  bilirubin Hepatic jaundice  conversion of unconjugated bilirubin to conjugated bilirubin by the liver. Posthepatic jaundice = “obstructive jaundice” Impairment of bile excretion Gall stones, pancreatic tumor Note: in both pre & post, the function of the liver is not impaired.

17 Prehepatic Jaundice pgs 95 & 96
Problem:  RBC destruction exceeds the ability of the liver to conjugate & excrete bilirubin. Causes: Hemolytic anemias, transfusion reactions, HDN Lab Findings: Increased total bilirubin Increased (indirect) bilirubin Urine bilirubin negative  fecal urobilinigen &  retic count

18 Hemolytic Disease of the Newborn (HDN) pg 95
Cause = Usually due to Rh incompatibility of mother & child (mother is Rh – and baby is Rh +)  levels of indirect bilirubin due to excessive breakdown of baby’s RBCs. When the baby’s unconjugated bilirubin levels reach >15 – 20 mg/dl, the bilirubin is either unbound or loosely bound to albumin.

19 HDN Continued Loosely bound or unbound unconjugated bilirubin has a high affinity for brain & CNS tissue. Bilirubin that deposits in brain tissue may cause irreversible brain damage “kernicterus”. May need to perform an exchange transfusion before this occurs. Monitor baby’s albumin as well as bilirubin levels very closely.

20 Causes of Hepatic Jaundice
Failure to conjugate Defective transport system in or out of hepatocyte Hepatitis, cirrhosis Lab values vary depending on disease process.

21 Hepatic Retention Jaundice
Defective transport of bilirubin into hepatocyte or impaired conjugation. Causes: Physiologic jaundice of the newborn. The baby’s glucuronyl transferase system is not fully developed, especially in premies. Chronic liver diseases since lever eventually loses its ability to conjugate. Lab Findings:  indirect bilirubin, urine bilirubin negative

22 Hepatic Regurgitation Jaundice
Defective transport of conjugated bilirubin out of bile ducts. Causes: Acute viral hepatitis Neoplasms, cirrhosis Lab Findings:  in direct bilirubin Urine bilirubin +

23 Posthepatic Jaundice Problem: Blockage of bile duct which causes blockage of bile (conjugated bilirubin) flow into intestinal tract “cholestasis” & conjugated backs-up into plasma. Causes: Gall stones, neoplasms of pancreas. Lab Findings: Increases in direct bilirubin, urine bilirubin = +, Clay colored stools.

24 Causes of Post hepatic jaundice “Cholestasis”
Gall stones, tumors Increases in conjugated bilirubin as it backs up into plasma Urine bilirubin is + since conjugated is water soluble. Decrease in fecal urobilinogen = clay colored stools.

25 Typical Lab Findings in Jaundice
Review summary on pg 93

26 Prehepatic Jaundice “Hemolytic Anemia”
Total Bilirubin Indirect Direct Bilirubin Urine Bilirubin Fecal Urobilinogen  Initially Normal Negative  In hemolytic anemia, the indirect or unconjugated portion is increased due to the excessive breakdown of RBCs. Indirect bilirubin is insoluble & can’t be excreted in the urine.

27 Hepatic Jaundice    0 or  
Total Bilirubin Direct Bilirubin Indirect Bilirubin Urine Bilirubin Fecal Urobilinogen   0 or  In hepatic jaundice, results will be variable Results are dependent on the type of disease & whether it is an acute or chronic condition. Typically, the liver will first lose its ability to transport bilirubin into the bile ducts after it is conjugated.. As the disease progresses, the liver will lose it’s ability to conjugate.

28 Post Hepatic Jaundice    Normal    Total Bilirubin
Direct Bilirubin Indirect Bilirubin Urine Bilirubin Fecal Urobilinogen    Normal    In obstructive jaundice, bilirubin is conjugated by the liver, but if the bile ducts are blocked, bilirubin will back up into the serum. Because it is soluble, it will be excreted in the urine. Bile ducts are blocked. Therfore, urobiliogen is not being formed & stools will appear clay colored.

29 REMEMBER pg 96 Prehepatic:  indirect bilirubin
Urine bilirubin negative Caused by excessive breakdown of RBCs Posthepatic:  direct bilirubin Urine bilirubin positive Fecal urobilinogen will be decreased due to blockage of bile ducts.

30 Bilirubin Methods Jendrassik-Grof Evelyn-Malloy
Direct Spectrophotometric – only performed on newborns.

31 Jendrassik-Grof Principle: Bilirubin couples with diazo to form a colored complex (azobilirubin) Conjugated bilirubin is water soluble and reacts directly with the color-producing agent DIAZO. Unconjugated Bilirubin is attached to albumin and is NOT water soluble and cannot react with DIAZO directly.

32 = Sulfanilic acid + Sodium Nitrate + HCl
Diazo reagent = Sulfanilic acid + Sodium Nitrate + HCl

33 Direct Bilirubin Procedure
Conjugated + DIAZO Azobilirubin (DIRECT) Bilirubin Pink Conjugated bilirubin is water soluble and reacts directly with the color-producing agent DIAZO to produce a pink compound (azobilirubin).

34 Jendrassik-Grof Total Bilirubin Procedure
Caffeine Benzoate Conjugated + Unconjugated + Diazo Azobilirubin Bilirubin Bilirubin Accelerator A dissociating agent (accelerator), caffeine benzoate, is added to the reaction to release unconjugated bilirubin from albumin and make it soluble so that it can react with diazo.

35 Indirect Bilirubin Measure the total & direct bilirubin.
Subtract the direct bilirubin from the total to obtain the direct measurement. Example: Total bilirubin = 7.0 mg/dl Direct bilirubin = 2.5 mg/dl Total Direct Indirect 7.0 mg/dl – 2.5 mg/dl = 4.5 mg/dl

36 Reference Ranges Total serum bilirubin = 0.2 – 1.0 mg/dl
Direct bilirubin = 0.2 mg/dl Approximately 80% of bilirubin is unconjugated in a normal individual.

37 Specimen Precautions Bilirubin is photosensitive
Serum and urine specimens should be stored in the dark. Approximately 10% of bilirubin loss per 30 minutes. Remember: Protect specimens from light!

NEWBORNS ONLY: (Cannot be performed on adults due to carotenes & other pigments in serum)   1. Dilute serum & measure absorbance at 445 nm 3. Measure absorbance at 575 nm to correct for hemoglobin interference 4. Subtract Abs. at 575 nm from Abs at 455 nm

39 Compare ALBUMIN levels to bilirubin levels to assess the ability to transport unconjugated bilirubin to the liver. If albumin levels are insufficient, unconjugated bilirubin will deposit in CNS tissue and may cause brain damage (KERNICTERUS) in newborns.

40 PLASMA AMMONIA Source of ammonia:
Breakdown of amino-acids obtained from dietary proteins in intestine Metabolized by liver (ammonia + CO UREA) Urea excreted by kidneys

41 Purpose Ammonia levels provide indicators of hepatic detoxification and excretory ability of the liver. Ammonia levels reflect the ability of the liver to convert toxic ammonia byproducts into urea so that they can be excreted by the kidneys.

42 SPECIMEN COLLECTION EDTA plasma, place on ice & analyze ASAP to prevent ammonia contamination SOE = poor venipuncture technique, probing, ammonia contamination from handling  Method: alpha-ketoglutarate + NH4 + NADPH >glutamate + NADP (measure decrease in absorbance at 340 nm)

43 Clinical Interpretation
Reference range = 20 – 80 ug/dl or 11 – 35 umol/L   levels of ammonia are toxic to CNS - Reye’s syndrome ( if < 5x normal = 100 % survival), hepatic encephalopathy, hereditary disorder of urea cycle

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