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Home , Hypoalbuminemia, Liver function tests

LIVER FUNCTION TESTS.

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Color index: Important | Doctors notes | Further explanation. (Extra/ circulation system of the )

Unlike most organs, which have a single supply, the liver is an extremely vascular that receives its blood supply from two sources: 1. The hepatic artery A branch of the aorta, supplies oxygen-rich blood from the heart to the liver and is responsible for providing approximately 25% of the total blood supply to the liver 2. The portal vein Supplies nutrient-rich blood (collected as food is digested) from the digestive tract, and it is responsible for providing approximately 75% of the total blood supply to the liver. The two blood supplies eventually merge and flow into the  The excretory system of the liver: sinusoids, which course b tween individual . Bile canaliculi  intrahepatic ducts  the right and left hepatic ducts  the common hepatic duct The liver is drained by a collecting system of veins that the common hepatic duct is eventually joined with empties into the hepatic veins and ultimately into the the cystic duct of the to form the inferior vena cava . Combined digestive secretions are then expelled into the duodenum 435 Biochemistry Team OBJECTIVES:   as liver enzymes, , and the liver and causes ofliver dysfunction. injury. that can diagnose hepatic Discuss markers Discuss markers of such Understand the metabolicmajor functions of 435 Biochemistry Team Biochemistry Extra (for better understanding)

 Liver function tests: • We can say that “liver function tests” is a It is a group of blood tests for liver functions misnomer because we are not really measuring  What is the liver functions? liver functions, instead we are measuring its The liver performs 4 major functions: dysfunctions 1. Excretion/secretion 2. Synthesis • There is no one test which can tell you about all 3. Detoxification the liver functions. Because the liver is a large 4. Storage. organ and it has too many functions . The liver is so important that if the liver becomes nonfunctional, death will occur with 24 hours due • So in order to see the whole picture we take a to . Although the liver is responsible series of tests “battery of tests” to see if there is for too many functions here we are focusing on any dysfunction. LFTs can detect how much the 4 major functions mentioned previously. damage is their + what is being damaged

 Indications of liver function tests - Alcoholics - The use of some medications that can cause a liver damage - General symptoms  Anorexia / / nausea / vomiting

435 Biochemistry Team Major Metabolic Functions of the Liver Production Synthesis Detoxification storage and excretion of bile salts • Plasma • Ammonia to urea (urea Vitamins A, D, E, K Helps in digestion (albumin/) cycle) , bilirubin , and B12 • , cholesterol , and lipoproteins metabolite

Some example of liver dysfunction

Genetic Disorders Hepatocellular  (obstruction of (increased Liver Hemochromatosis disease bile flow) bilirubin) (iron storage)

Steatosis (fatty liver) Liver

435 Biochemistry Team Liver function tests

 What’s “Liver function tests”? “screening” is not a diagnosis ( • Noninvasive methods for screening of liver dysfunction. because it’s not fully accurate), so we  When they’re performed? need to do an another test for • They’re performed after a simple . confirmation or search for other markers.  Benefits: • Help in identifying general type of disorder • Assess severity and allow prediction of outcome - For dose adjustment • Disease and treatment follow up - To know if the patient is responding to the treatment or not

They’re broadly classified as

Tests to detect hepatic injury Tests to assess hepatic function • Mild or severe; acute or chronic • Nature of liver injury (hepatocellular or cholestasis) مقطع نصحت د.سمبل اننا liver function tests نشيك عليه 435 Biochemistry Team LFTs Common liver chemistry tests Liver chemistry test: Clinical implication of abnormality: Alanine aminotransferase Hepatocellular damage. Aspartate aminotransferase Bilirubin Cholestasis, impaired conjugation, or biliary obstruction. Alkaline phosphate Cholestasis, infiltrative diseases, or biliary obstruction. Prothrombin time Synthetic function. Albumin g-glutamyltransferase Cholestasis or biliary obstruction. Bile acids

Normal LFT values do not because the liver has very always indicate absence of large reserve capacity Limitations of liver function tests So the diagnosis should be people may based on clinical have abnormal LFT results. examination Liver functions tests

Group II: Markers of Group I: Markers of liver Group III: Markers of hepatocellular injury dysfunction cholestasis

Serum bilirubin: total  What is “Bilirubin”? and conjugated. • A byproduct of red blood cell breakdown. • It is the yellowish pigment observed in jaundice.  High bilirubin levels are observed in: o gallstones : bile salts and o acute and chronic hepatitis urobilinogen Normal serum bilirubin levels Total bilirubin 0.2 to 0.8 mg/dL Prothrombin Time Unconjugated/free/indirect (bilirubin-albumin complex) 0.2 to 0.7 mg/dL (clotting time) Conjugated/direct 0.1 to 0.4 mg/dL Abnormal serum bilirubin levels Total , serum albumin and Latent jaundice Above 1 mg/dL albumin/ Jaundice Above 2 mg/dL ratio 435 Biochemistry Team Liver functions tests

Group II: Markers of Group I: Markers of liver Group III: Markers of hepatocellular injury dysfunction cholestasis

Serum bilirubin: total Bilirubin levels and jaundice and conjugated. Class of Jaundice Raised Bilirubin Causes Pre-hepatic Unconjugated • Abnormal red cells  “Hemolytic jaundice”. ONLY! • ; and ; Urine: bile salts and Thalessemia.Hemoglobinopathies . urobilinogen Gilbert’s, Crigler-Naajjar syndrome Hepatic or Hepatocellular Unconjugated & • Viral hepatitis, toxic hepatitis  ”Hepatocellular jaundice“. conjugated • Intrahepatic cholestasis Prothrombin Time Post-hepatic Conjugated ONLY! • Extrahepatic cholestasis; gallstones; (clotting time)  “Obstructive jaundice”. tumors of the bile duct • carcinoma of

Total protein, serum Preheated and post hepatic jaundice, as the names imply, are caused by abnormalities outside of the liver, either albumin and before, as in “pre hepatic,” or after, as in “post hepatic.” In these conditions, liver function is normal or it may be functioning at a maximum to compensate for abnormalities occurring elsewhere. albumin/globulin This is not the case with hepatic jaundice, where the jaundice is due to a problem with the liver itself—an intrinsic ratio liver defect or disease. 435 Biochemistry Team الساليدات فيها صور بس بدون شرح، الشرح اللي بساليدز 10، 11 عبارة عن الكالم اللي قالوه الدكاتره بأسلوب لبنكوت – الشرح بعد معاد بالفزيولوجي بمحاضرة البليروبين. Bilirubin  Degradation of : After approximately 120 days in the circulation, red blood cells are taken up and degraded by the reticuloendothelial system, particularly in the liver and spleen (RBCS  heme + globin + iron). 3.Conjugation of the bilirubin . 1. Formation of bilirubin In the , the solubility of bilirubin is In the macrophages of the increased by the addition of 2 reticuloendothelial system, molecules of glucuronic acid. the heme  bilirubin. . by microsomal bilirubin glucuronyl- transferase using 2.Uptake of unconjugated uridine diphosphate- bilirubin by the liver: glucuronic acid (2-UDP-GA) as . Bilirubin is only slightly the glucuronate donor. soluble in plasma so it is transported to the liver by binding non-covalently to 4. Secretion of bilirubin into albumin. bile . Bilirubin dissociates from the conjugated bilirubin is carrier albumin molecule, actively transported against a enters a hepatocyte via concentration gradient into facilitated diffusion, and the bile canaliculi and then binds the protein ligandin. the bile and then the intestine. Bilirubin

5. Formation urobilins in the intestine Conjugated bilirubin is hydrolyzed and reduced by bacteria in the gut to yield urobilinogen “colorless”.

o Feces: Most of the urobilinogen is oxidized by intestinal bacteria to stercobilin, which gives feces the characteristic brown color.

o Portal blood: However, some of the urobilinogen is reabsorbed from the gut and enters the portal blood.

o Liver: A portion of this urobilinogen participates in the enterohepatic urobilinogen cycle in which it is taken up by the liver, and then resecreted into the bile.

o Kidneys: The remainder of the urobilinogen is transported by the blood to the , where it is converted to yellow urobilin and excreted, giving urine its characteristic color.

Note: Fate of urobilinogen (3): What is the purpose of conjugation? 1. Gets metabolized in the large Makes bilirubin soluble. intestine and then excreted in feces. Where it happens? (stercobilin). Liver’s ER. 2. Reabsorbed through intestinal What’s the form of bilirubin which comes to the bile? mucosa into  Portal vein  Liver Conjugated. “enterohepatic circulation” Bilirubin has the ability to function as 3. Excreted in urine “as urobilin”. an antioxidant. Liver functions tests

Group II: Markers of Group I: Markers of liver Group III: Markers of hepatocellular injury dysfunction cholestasis

Serum bilirubin: total Urobilinogen (UBG) and bile salts and conjugated.  Most UBG is metabolized in the large intestine, a fraction is excreted in urine (less than 4 (احفظوه) .(mg/day  Normally bile salts are NOT present in urine.  Obstruction in the biliary passages causes: Urine: bile salts and • leakage of bile salts into circulation. urobilinogen • leading to its excretion in urine.

Prothrombin time Prothrombin Time  Prothrombin: synthesized by the liver, a marker of liver function. (clotting time)  Half-life: 6 hrs. (indicates the present function of the liver).  Prolonged PT: • PT is prolonged ONLY when liver loses more than 80% of its reserve capacity. Total protein, serum • deficiency also causes prolonged PT. albumin and • Intake of vitamin K does not affect PT in liver disease (because the liver can’t produce PT albumin/globulin to be activated by vit K). كيف نعرف ان سبب هالزيادة هو فايتمن كاي او مشكلة بالكبد؟ ratio نعطي الشخص فايتمن كاي اذا تحسن خالل 24 ساعة فالسبب هو فايتمن كاي واذا ماتحسن فالمشكلة بالكبد. Liver functions tests

Group II: Markers of Group I: Markers of liver Group III: Markers of hepatocellular injury dysfunction cholestasis Serum albumin Serum bilirubin: total  The most abundant protein synthesized by the liver and conjugated.  Normal serum levels: 3.5 – 5 g/dL  Synthesis depends on: the extent of functioning liver cell mass البروثرومبن كان 6 ساعات فتقريبا يعلمنا عن حالة الكبد الحالية، هنا 20 يوم فيعطينا كفاءة الكبد على اللونق ترم . Longer half-life: 20 days Urine: bile salts and  Its levels decrease in all chronic liver diseases. urobilinogen Serum globulin  Normal serum levels: 2.5 – 3.5g/dL  a and b-globulins mainly synthesized by the liver. Note: a and b-globulins are for transport while g-globulins are for immunity Prothrombin Time  They constitute immunoglobulins (antibodies). (clotting time)  High serum g-globulins are observed in chronic hepatitis and cirrhosis: . IgG in . . IgA in .. Total protein, serum albumin and Albumin to globulin (A/G) ratio albumin/globulin • Normal A/G ratio: 1.2/1 – 1.5/1 For every 1 globulin molecule there are 1.2-1.5 albumin molecules • ratio Globulin levels increase in as a compensation. Hypoalbuminemia indicates a chronic diseases, whenever albumin levels are low globulins increase to maintain Liver functions tests

Group II: Markers of Group I: Markers of liver Group III: Markers of hepatocellular injury dysfunction cholestasis

Alanine aminotransferase Aspartate (ALT). aminotransferase (AST). • More liver-specific than AST.  Normal range: 8 – 20 U/L • Appears in plasma many days before clinical signs appear.  A marker of: hepatocellular • A normal value DOES NOT always indicate absence of liver damage damage. (reserve)  High serum levels are observed in: • Obese but otherwise normal individuals may have elevated ALT levels. • Chronic hepatitis. • Cirrhosis. NORMAL Male: 13-35 Female: 10-30 • Liver cancer. HIGH SERUM LEVELS acute hepatitis (300-1000U/L) Moderate elevation (100-300U/L) Minor elevation cirrhosis, and non-alcoholic (NASH) (Fatty liver) (50- 100U/L) Liver functions tests

Group II: Markers of Group I: Markers of liver Group III: Markers of hepatocellular injury dysfunction cholestasis

Alkaline phosphatase (ALP): • A non-specific marker of liver disease.  Produced by bone osteoblasts (for bone calcification) (ALP).  Present on: hepatocyte membrane.

40 – 125 U/L. Normal range

Infective hepatitis, alcoholic hepatitis and hepatocellular Moderate elevation γ- glutamyl carcinoma. transferase (GGT). Extrahepatic obstruction (obstructive jaundice) and High levels intrahepatic cholestasis. Bone diseases. Very high levels

Note: ALP is elevated in pregnancy because it is produced in placenta. (. فما نعتمد عليه لحاله not specific or liver, but it’s specific for bones) 435 Biochemistry Team AST & ALT Liver functions tests

Group II: Markers of Group I: Markers of liver Group III: Markers of hepatocellular injury dysfunction cholestasis

γ- glutamyl transferase (GGT).  Used for: synthesis Alkaline phosphatase  Normal range: 10 – 30U/L (ALP).  Moderate elevation observed in:  Infective hepatitis and prostate • GGT is increased in alcoholics despite normal liver function tests  Highly sensitive to detecting alcohol abuse. γ- glutamyl • Is a polypeptide of 3 amino acids. Active side chain of serine has an SH group (thiol) to transferase (GGT). obtain oxygen. • It’s related to Biliary ducts obstruction. • Don’t get confused between GGT and GTT ( tolerance test) !!

AST & ALT 435 Biochemistry Team "الملخص الشامل موجود بالداونلود سنتر" SUMMARY Serum bilirubin: total and conjugated. o gallstones o acute and chronic hepatitis Urine: bile salts and urobilinogen Obstruction in biliary passage  Bile salts in urine. Group I: Total protein, serum albumin and o Albumin is the most abundant protein synthesized by the liver. Markers of liver albumin/globulin ratio o Serum albumin is decrease in all chronic liver diseases. dysfunction o IgA is elevated in alcoholic liver disease. Prothrombin Time (clotting time) • Prolonged in: 1. Liver disease: when liver loses 80% of its reserve capacity - Vit. K intake doen’t affect it. 2. Vitamin K deficiency: Vit. K intake affects it. • indicates the present function of the liver (Shorter half life than serum albumin). Alanine aminotransferase (ALT). o More liver specific than AST. Group II: o Elevated in : Markers of - Obese individuals. hepatocellular - Moderately elevated in alcoholic hepatitis. injury Aspartate aminotransferase (AST). o A marker of: hepatocellular damage. o Less specific than ALT. Group III: Alkaline phosphatase (ALP). o Produced by bone osteoblasts . Markers of o Moderately elevated in alcoholic hepatitis cholestasis γ- glutamyl transferase (GGT). o Increased in alcoholics despite normal liver function tests Biochemical markers used in diagnosis of alcoholic liver disease (ALD) . IMPORTANT!!! . γ- glutamyl transferase (GGT). . Alkaline phosphatase (ALP). . Alanine aminotransferase (ALT). . Serum globulin (IgA). 435 Biochemistry Team Check your understanding!

Q1: which one of the following compounds can be Q5: where we could find the Unconjugated Bilirubin: Detoxified and excreted by liver : A. bile. A. cholesterol. B. Blood “ plasma”. B. Vitamins A. C. Small intestine. C. Ammonia. D. Kidney. D. A+C. Q6: in which form dose the Bilirubin excreted in the feces: Q2: Which of the following LFTs is more liver-specific? A. Unconjugated Bilirubin. A. Alanine aminotransferase B. conjugated Bilirubin. B. Alkaline phosphatase. C. Urobilin stercobilin. C. Serum bilirubin. Q7: which form of the Bilirubin that can be found D. Alpha fetoprotein . normally in the kidney in small amount: Q3: one of the reason behind LFTs limitation is: A. Urobilinogen. A. Liver a has very large reserve capacity. B. bile salts. B. It’s not useful because it’s noninvasive test. C. Indirect Bilirubin. C. Doesn’t asses the hepatic function. Q8.Increased conjugated bilirubin only is due to? D. All of the above. Hemolytic. Q4: Unconjugated is : Hepatic. A. Result of breaking down RBCs. Pre hepatic. B. Cause of yellowish pigment in jaundice. D) Post hepatic C. Its level goes up in chronic hepatitis. D. All of the above. 1.D, 2.A , 3.A, 4.D, 5.B, 6.C. 7,A, 8.D Check your understanding!

Q12: which of the following is Produced by bone Q9: in which of the following condition the Globulin levels osteoblasts? increase as a compensation: A. Alanine aminotransferase A. hypoalbuminemia. B. Alkaline phosphatase. B. autoimmune hepatitis. C. Serum bilirubin. C. alcoholic liver disease. D. Alpha fetoprotein . Q10: which of the following indicates the present function of the liver: A. Albumin. SAQ: B. Globulin. Biochemical markers used in diagnosis of alcoholic C. (A/G) ratio. D. Prothrombin. liver disease (ALD) . . γ- glutamyl transferase (GGT). Q11: deficiency in which of the following vitamins will . cause prolonged PT : Alkaline phosphatase (ALP). A. vitamin A. . Alanine aminotransferase (ALT). B. vitamin B12. . Serum globulin (IgA). C. vitamin K. D. vitamin E.

9.A, 10.D, 11.C, 12.B. Done by: - شهد العنزي. - عبداهلل الغزي. - عال النهري. - خالد النعيم. - دالل احلزميي. - رغد املنصور. - أمحد الرويلي. Revised by: -نوف الرشيد.

Resources: @435biochemteam . 435’s slides and notes. . Lippincott’s illustrated reviews: Biochemistry – sixth edition [email protected] . Clinical Chemistry - Techniques, Principals and Correlations: 6th edition. . Liver fibrosis markers in alcoholic liver disease - National Center for @biochemteam435 Biotechnology Information (NCBI) Search database.