Chapter 13: Liver Function Tests Flashcards
Liver Response to Injury
- Initial response to injury is usually Metabolic changes –> fat and other deposits (reversible)
- If metabolic consequences of injury are serious enough, can cause hepatic failure
– Acute – chronic
- Jaundice(icterus)
- Hypoglycemia: due to loss of glycogen stores in liver
- Hyperammonemia: due to failure of liver to convert ammonia to Urea, can cause coma
- Ascites: edema in peritoneal cavity due to portal hypertension
- Cholestatsis: decreased bile deliver to duodeum with elevated bilirubin / heme catabolites in serum
– Chronic
- Hypoalbuminemia: can cause peripheral edema
- Clotting (bleeding) disorders
Assessing Liver Function: Serum Proteins
- One of the functions of the liver is to produce extracellular proteins including albumin and clotting factors
- One crude way to assess liver function is to check if these serum proteins are produced in normal amounts
- Testclotting
– Fibrin clot formation is another crude means of assessing hepatic protein synthesis (clotting factors).
– Reasons for increased “clotting times”, other than decreased clotting factors due to liver disease, are vitamin K deficiency and drugs (blood thinners)
• Albuminlevels
– Albumin may be decreased for a variety of reasons besides liver disease, e.g. poor nutrition, sepsis
– CHANGES TYPICALLY ONLY SEEN WITH CHRONIC LIVER FAILURE as Albumin has a long half-life
AST and ALT
- Cell injury results in the release of intracellular proteins
- Aminotransferases (AST and ALT) are very characteristic of hepatocytes and when aminotransferases increase in the serum this strongly suggests that hepatocytes have been damaged
- Note: Amino-transferases are also increased in cases of heart attacks and skeletal muscle injury. However, when muscle damage is the source of amino- transferases, other proteins such as CPK are elevated
• AST = Aspartate transaminase
• ALT = Alanine transaminase
Regions of Lobule
- Remember Hepatocytes located in different regions in liver lobule have varied functions due to O2 gradient
- Relative quantities of ALT differ in periportal and perivenous regions while AST is evenly distributed along the triad
- Periportal hepatocytes are metabolically very active
– Rich in ER, Golgi, and mitochondria for protein synthesis and metabolic pathways that require mitochondria and ATP energy
– Rich in ALT as this region is active in gluconeogenesis which uses the Glucose-Alanine cycle
• Perivenous region
– Contains 50% fewer mitochondria and a lot of smooth ER
– Drug detoxification
Hepatitis
- Hepatitis: swelling and inflammation of the liver hepatocyte damage and / or necrosis.
- Typical etiologies:
– Viral Hepatitis
- Viral infection –> lysis of hepatocytes –> release of liver enzymes
- Hepatitis viruses are an “equal opportunity killer” and lyses periportal and perivenous hepatocytes equally
- Usually, a large number of hepatocytes are affected so that AST levels are higher than with alcoholic hepatitis
– Drug metabolism (such as alcohol) –> toxic primarily to perivenous hepatocytes as this is the region of drug metabolism –> release of perivenous liver enzymes (e.g. around central vein)
- This region has little ALT and the lower levels of ALT released in alcoholic hepatitis is diagnostic
- Typically, fewer hepatocytes are affected & AST levels lower than with viral hepatitis
– Note: GGT is involved in drug metabolism. In cases of alcoholic hepatitis, GGT is typically elevated as well
Clinical Enzymes and Liver Disease
- The AST/ALT ratio differs between viral and alcoholic hepatitis
- Viral Hepatitis
– The immune system destroys infected hepatocytes –>
- Release of high levels of transaminase
- No specific area of the liver triad is preferentially involved –>
- AST/ALT ratio less than or equal to 1
- Alcoholic Hepatitis
- Associated with a smaller area of the liver –> -
- Release of lower levels of transaminases
- Cell necrosis is limited to hepatocytes around the central vein that are involved in drug metabolism
- ALT levels are not as high in this region –> -AST/ALT ratio > 2
Other Liver Enzymes
• AST and ALT are not the only enzymes released with liver necrosis, LDH, GGT, and ALK are released into serum as a result of liver damage. – Liver expresses LDH-5 which has a short half-life of ~10 hours and is not a good measure of hepatocyte necrosis
– GGT and ALK are both increased in with hepatocyte necrosis and their elevation is particularly associated with damage to the liver resulting from bile duct blockage
Bile Function and Composition
Two aspects of the bile synthesis and composition are relevant to assessing liver function
– Although bilirubin is only 0.3% of bile, it is diagnostically useful in assessing
- Heme catabolism and bilirubin conjugation
- The ability of liver to process and transport this waste product into the bile
– Gallstones form when ratios of bile salts/acids, cholesterol, and phospholipids are askew
• Gallstones can lead to liver damage which presents as post-hepatic jaundice
Abnormal Bilirubin Excretion –> Jaundice
- Bilirubin is a hydrophobic waste product which is eliminated in the bile by the liver and is used to assess hepatic anion transport
- Bilirubin is a yellowish-orange pigment
- In some disease states, bilirubin accumulates and leads to a yellow discoloration of the skin. This is termed jaundice or icterus
– Visible juandice > 3.0 mg/dL
– Chemical jaundice 1.5 – 3.0 mg/dL
- Discoloration of the sclera is termed scleral icterus
- Jaundice is not a disease but a sign or symptom of a disease
Overview of Heme Catabolism
• Most bilirubin comes from the heme in senescent erythrocytes
– Minor contributions from other heme containing proteins especially seen in mitochondria
- Bilirubin is water-insoluble (hydrophobic). Travels in blood bound to serum albumin and is delivered to the liver.
- Bilirubin is taken up by hepatocytes
- Bilirubin is made water-soluble by conjugating it with two glucuronic acid residues and then excreting it into the bile (anion transport)
- Gut bacteria deconjugate the bilirubin and degrade it to urobilinogens and eventually stercobilins which are excreted in the feces
Sources of Heme
- The heme that is degraded daily comes from several sources.
- Heme containing proteins found in all cells (~10%)
- Hemoglobin (90%)
- Macrophages in spleen phagocytize senescent RBCs and hydrolyze the globin to amino acids releasing the heme.
- With anemia, ineffective erythropoesis may be a major source of Heme – RBC production problems –> turnover of RBCs in the bone marrow that do not meet “quality control”
Bilirubin Formation
• Free heme is toxic.
-Although the majority of bilirubin is produced in macrophages from RBC breakdown, heme is degraded in every cell in the body to covert toxic heme to bilirubin
- Heme oxygenase catalyzes the oxidation of heme to biliverdin (a linear green molecule)
- Biliverdin reductase converts biliverdin into bilirubin aka unconjugated bilirubin (UCB) (a yellowish- orange substance)
- Unconjugated bilirubin is very water-insoluble and is avidly bound by albumin in the blood
Liver Formation of Conjugated Bilirubin
• Despite the fact that bilirubin is tightly bound to albumin, hepatocytes readily extract bilirubin from albumin.
– Transported into the hepatocyte by OATP, a Cl- coupled antiporter
- Bilirubin is conjugated to glucuronic acid making it relatively water- soluble (phase II reaction)
- Conjugated bilirubin is excreted into the bile caniliculus
– MRP2, primary active transporters, involved here
• In some cases of hepatitis, conjugated bilirubin accumulates because it cannot be excreted from the hepatocyte
Intestine: Colonic bacteria metabolize bilirubin
- The intestinal bacteria remove the glucuronic acid from the conjugated bilirubin and convert the bilirubin into urobilinogen
- Urobilinogen is autoxidized (does not require an enzyme) to stercobilins which account for the brown color of feces
Renal Excretion of Bilirubin
- Some of the urobilinogen produced in the colon is nonspecifically reabsorbed into the portal blood.
- Most of the urobilinogen is extracted by the liver and reexcreted into the bile without conjugation (urobilinogen is amphipathic and does not need conjugation to enter the bile)
- This enterohepatic recirculation is common for amphipathic substances such as urobilinogen and bile salts/acids
- The small amount of urobilinogen which is not extracted by the liver, is excreted in the urine and accounts for its yellow color.
Formation and Genetics
- Variations in any one of the three proteins pictured here can play a rate-limiting step in gallstone formation
- HMG CoA reductase catalyzes the rate-limiting step in the synthesis of cholesterol
– Increased activity –> increased cholesterol synthesis
• 7-α-Hydroxylase catalyzes the rate-limiting step in bile salt synthesis
– Decreased activity –> decreased bile salt synthesis
• Phospholipid export pump (MDR3) transfers phospholipid into bile from liver
– Decreased levels –> less solubilization of cholesterol
Cholestasis or Posthepatic Jaundice
- Like hepatic jaundice, posthepatic jaundice presents with elevated conjugated bilirubin in the serum
- In acute cases, limited hepatocyte damage and AST/ALT in serum. In chronic cases, detergent action of bile salts –> liver damage and release of these enzymes
- Posthepatic jaundice (acute or chronic) is also associated with high levels of serum alkaline phosphatase and gamma-glutamyl transferase which are used in the diagnosis
ALK and GGT Levels
• Backup of bile results in:
– (1) Enlarged hepatocytes with dilated canalicular spaces (2).
– (4) Kupffer cells with regurgitated bile pigments. Bile duct proliferation (5), edema, bile pigment retention (6) and eventually neutrophilic inflammation.
– Surrounding hepatocytes (7) become swollen & degenerate or undergo apoptosis (3).
- Acute cases: bile duct proliferation –> increase of ALK and GGT levels (these enzymes are in ducts)
- With increasing damage (chronic), AST / ALT levels also rise as detergent properties of bile –> hepatocyte damage
Liver Function: Heme Catabolism & Enterohepatic Recirculation
Summary: Liver Function Tests & Jaundice
