Liver and Renal Function Tests

1. Liver and Renal Function Tests Dr Amal Baalash

2. Hepatic Physiology Liver: Largest solid organ in the body Performs over 500 chemical processes Produces over 160 different proteins Makes clotting factors for the blood Stores & releases sugar as glycogen Metabolizes, detoxifies, synthesizes

3. Defining Terms Hepatitis: refers to any swelling, inflammation, or irritation of the liver Over 100 causes including: Viruses, alcohol, enzyme deficiencies Iron or copper overload Genetic disorders, drugs, toxins Fatty infiltrations

4. Defining Terms Inflammation that lasts long enough will create fibrosis Extreme fibrosis is called cirrhosis??? Cirrhosis can be either compensated or decompensated Compensated cirrhosis can be subtle Decompensated cirrhosis is more obvious

5. Hepatomegaly Common Causes: Congestive Cardiac Failure Cirrhosis (although end-stage typically small) Secondary cancers (liver metastases) Other Causes: Infections (Hepatitis A, B and C, EBV, amoebic abscess) Primary Tumours (Benign and malignant) Lymphoproliferative disorders Primary Biliary Cirrhosis Haemochromatosis Hepatosplenomegaly-other causes on worldwide basis: Malaria Kala-azar Schistosomiasis

6. Normal Liver

7. Cirrhotic Liver

8. Liver function tests Noninvasive method of screening for the presence of liver dysfunction Pattern of lab test abnormality allows recognition of general type of disorder To assess the severity and occasionally allow prediction of outcome To follow the course of the disease, evaluate response to treatment, and adjust treatment when necessary

9. Limitations Lack of sensitivity (may be normal in cirrhosis or HCC) Lack of specificity (aminotransferase levels may be elevated in musculoskeletal or cardiac disease) Results suggest general category of liver disease, not a specific diagnosis Essential to use LFT as a battery of tests and repeat them over time Probability of liver disease is high when more than one test is abnormal or the findings are persistently abnormal on serial testing

10. Liver Function Tests Liver function tests (LFTs), are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. Most liver diseases cause only mild symptoms initially, but it is vital that these diseases be detected early. Hepatic involvement in some diseases can be of crucial importance. Some tests are associated with synthetic functions (eg. Albumin); some with cellular integrity (eg. transaminase,) and some with conditions linked to the biliary tract (gamma-glutamyl transferase and alkaline phosphatase).

11. Common serum liver chemistry tests

12. Alanine Aminotransferase (ALT): Alanine transaminase (ALT), [also called Serum Glutamic Pyruvate Transaminase (SGPT)] is the enzyme produced within the cells of the liver (hepatocytes). It is an enzyme that plays a role in proteins metabolism. The level of ALT abnormality is increased in conditions where cells of the liver have been inflamed or undergone cell death. As the cells are damaged, the ALT leaks into the blood stream leading to a rise in the serum levels. Any form of hepatic cell damage can result in an elevation in the ALT. ALT rises dramatically in acute liver damage, such as viral hepatitis or paracetamol (acetaminophen) overdose. ALT is the most sensitive marker for liver cell damage.

13. Aspartate Aminotransferase (AST): Aspartate aminotransferase; [also called Serum Glutamic-Oxaloacetic Transaminase; (GOT) ] is similar to ALT in that it is another enzyme associated with liver parenchymal cells, therefore, it also reflects damage to the hepatic cell. However, it is less specific for liver disease. AST is also present in red cells, and cardiac and skeletal muscle and is therefore not specific to the liver. AST may be elevated in other conditions such as a myocardial infarct (heart attack). Although AST is not a specific for liver as the ALT, ratios between ALT and AST are useful to physicians in assessing the aetiology of liver enzyme abnormalities.

14. Alkaline Phosphatase (ALP): This enzyme occurs mainly in liver cells next to bile ducts. This enzyme occurs in the cells lining the biliary ducts of the liver. Alkaline phosphatase is also found in bone and the placenta. Renal or intestinal damage can also cause the alkaline phosphatase to rise. If the alkaline phosphatase is elevated, biliary tract damage and inflammation should be considered. One way to assess the aetiology of the alkaline phosphatase is to perform a serologic evaluation called isoenzymes. Another more common method to asses the aetiology of the elevated alkaline phosphatase is to determine whether the GGT is elevated or whether other function tests are abnormal (such as bilirubin) Alkaline phosphatase may be elevated in primary biliary cirrhosis, alcoholic hepatitis, gallstones in choledocholithiasis.

15. Gamma Glutamic Transpeptidase (GGT): This enzyme is also produced by the bile ducts. Although reasonably specific to the liver and a more sensitive marker for cholestatic damage than ALP, Gamma glutamyl transpeptidase (GGT) may be elevated with even minor, sub-clinical levels of liver dysfunction. It can also be helpful in identifying the cause of an isolated elevation in ALP. Medications commonly cause GGT to be elevated. Liver toxins such as alcohol can cause increases in the GGT.

16. 5�-Nucleotidase Normal 0.3 to 3.2 Bodansky units Spectrum of abnormality similar to that of ALP Specificity for hepatobiliary disease May be used to confirm hepatic origin of elevated ALP

18. Bilirubin: Bilirubin is a major breakdown product of haemoglobin. Haemoglobin is derived from red cells that have outlived their natural life and subsequently have been removed by the spleen. During splenic degradation of red blood cells, haemoglobin is separated out from iron and cell membrane components. Haemobilirubin is transferred to the liver where it undergoes further metabolism in a process called conjugation. Conjugation allows bilirubin to become more water-soluble. The water solubility of bilirubin allows the bilirubin to be excreted into bile. Bilirubin is the substance that gives bile its yellow-green color

19. Bilirubin: As the liver becomes irritated, the total bilirubin may rise. It is then important to understand the difference between conjugated bilirubin, which has undergone conjugation (that is hepatic cell metabolism), and that portion of bilirubin which has not been conjugated (nonconjugated). These two components are called total bilirubin. The direct bilirubin fraction is that portion of bilirubin that has undergone metabolism by the liver. When this fraction is elevated, the cause of elevated bilirubin (hyperbilirubinemia) is usually outside the liver. These types of causes are typically gallstones. This type of abnormality is usually treated with surgery (such as a gallbladder removal or cholecystectomy).

20. Albumin: Albumin is the major protein present within the blood. Albumin is synthesized by the liver. As such, it represents a major synthetic protein and is a marker for the ability of the liver to synthesize proteins. It is only one of many proteins that are synthesized by the liver. However, since it is easy to measure, it represents a reliable and inexpensive laboratory test for physicians to assess the degree of liver damage present in any particular patient. When the liver has been chronically damaged, the albumin may be low. This would indicate that the synthetic function of the liver has been markedly diminished. Such findings suggest a diagnosis of cirrhosis. Malnutrition can also cause low albumin (hypoalbuminaemia) with no associated liver disease. Albumin is also decreased in nephrotic syndrome, where it is lost through the urine.

21. Prothrombin time (PT): Another measure of hepatic synthetic function is the prothrombin time. Prothrombin time is affected by proteins synthesized by the liver. Particularly, these proteins are associated with the incorporation of vitamin K metabolites into a protein. This allows normal coagulation (clotting of blood). Thus, in patients who have prolonged prothrombin times, liver disease may be present. Since a prolonged PT is not a specific test for liver disease, confirmation of other abnormal liver tests is essential. This may include reviewing other liver function tests or radiology studies of the liver. Diseases such as malnutrition, in which decreased vitamin K ingestion is present, may result in a prolonged PT time.

22. Prothrombin time (PT): An indirect test of hepatic synthetic function includes administration of vitamin K (10mg) subcutaneously over three days. Several days later, the prothrombin time may be measured. If the prothrombin time becomes normal, then hepatic synthetic function is intact. This test does not indicate that there is no liver disease, but is suggestive that malnutrition or mal absorption may coexist with (or without) liver disease.

23. Initial approach to the evaluation of abnormal liver enzyme tests Asymtomatic or symptomatic History and physical

24. Patterns of Abnormal Elevations in ALT & AST only: suggests cellular injury Elevations in Alk Phos & Bilirubin: suggests cholestasis or obstruction Mixed pattern: ALT, AST, AP & Bili: probably the most common scenario Consider degree of elevation: Very high ALT and AST usually only come from: - Acute viral hepatitis (A,B,C, HSV) - Acetominophen toxicity / overdose

25. Ascites Definition: fluid in the peritonial cavity

26. Spider Angiomata

27. Spider Nevi

28. Nail Clubbing

29. Jaundice or Scleral Icterus

30. Flapping Tremor

31. Renal Function Tests The kidneys are vital organs that perform a variety of important functions. Urine formation, fluid and electrolyte balance, regulation of acid base balance, excretion of the waste products of protein metabolism, secretion of hormones, formation of Vit. D, Erythrobiotien, �etc

32. Renal function tests detect renal damage monitor functional damage help determine etiology From a clinical perspective it is important to have test which would have these characteristics. No such test exists. An early test to detect renal damage, for instance a simple strip test for haematuria is important in screening for heavy metal poisoning. There is a clinical need to monitor a patient with renal disease and this is achieved by serial plasma measurements. We need to know when to start dialysis in renal failure and laboratory tests assist the clinical decision making. There are about a million nephrons in each kidney and this represents a considerable functional reserve. In renal disease about half the nephrons have to lose their functioning before the abnormality can be detected by conventional laboratory tests.From a clinical perspective it is important to have test which would have these characteristics. No such test exists. An early test to detect renal damage, for instance a simple strip test for haematuria is important in screening for heavy metal poisoning. There is a clinical need to monitor a patient with renal disease and this is achieved by serial plasma measurements. We need to know when to start dialysis in renal failure and laboratory tests assist the clinical decision making. There are about a million nephrons in each kidney and this represents a considerable functional reserve. In renal disease about half the nephrons have to lose their functioning before the abnormality can be detected by conventional laboratory tests.

33. Laboratory tests of renal function glomerular filtration rate (GFR) plasma creatinine plasma urea urine volume urine urea minerals in urine urine protein urine glucose hematuria osmolality I shall review the tests in the left column today. The measurement of urine protein is important in certain conditions, e.g.diabetes. The detection of substances such as red cells or glucose could be an early indicator of renal damage. I shall review the tests in the left column today. The measurement of urine protein is important in certain conditions, e.g.diabetes. The detection of substances such as red cells or glucose could be an early indicator of renal damage.

34. Where can it break? Pre-renal Renal (intrarenal) Post-renal (obstructio)

35. Renal Function Tests- Urine volumes Adults: 1.5 L/24 htypical in health, oliguria < 400 mL, anuria < 100 mL, polyuria > 3000 mL Children: ca 1.5 ml/Kg of b.w./1 hour! Urine volume depends on how much you drink and sweat. In health it is closely matched to water balance by the hormone ADH or vasopressin, AVP. We define abnormally low urine volume as a 24 hour volume less than 400 mL. This is known as oliguria. A patient is considered anuric when there is no or little urine, less than 100 mL/24 h. There is no absolute definition for polyuria as some people can drink an awful lot and match it with a high urine output. If a patient has a urine volume greater than 3 litres per day and is not drinking then this is polyuria.Urine volume depends on how much you drink and sweat. In health it is closely matched to water balance by the hormone ADH or vasopressin, AVP. We define abnormally low urine volume as a 24 hour volume less than 400 mL. This is known as oliguria. A patient is considered anuric when there is no or little urine, less than 100 mL/24 h. There is no absolute definition for polyuria as some people can drink an awful lot and match it with a high urine output. If a patient has a urine volume greater than 3 litres per day and is not drinking then this is polyuria.

36. Blood Urea Nitrogen (BUN) Urea is the major end product of protein and amino acid catabolism and is generated in the liver through the urea cycle. Most of the urea is ultimately excreted by the kidneys. Urea is freely filtered by the glomeruli. Depending on the state of hydration and therefore the rate of urine flow, 40% to 80% of the filtered urea is passively reabsorbed with water, mostly in the proximal tubules.

37. The serum concentration of urea varies rather widely in health and is influenced by such diverse factors as dietary intake of protein and the state of hydration. BUN will ordinarily not be significantly increased until the glomerular filtration is decreased by at least 50%. Normal BUN 10-20 mg/dl

38. Creatinine (Cr) Creatinine is formed as a result of nonenzymatic dehydration of muscle creatine. Creatinine formation has a direct relationship to muscle mass. Creatinine is also freely filtered by the glomeruli but is not reabsorbed to any appreciable extent under normal circumstances. A substantial fraction of creatinine excretion by the kidney is the result of proximal tubular secretion. Serum creatinine concentration is often interpreted as a measure of glomeurlar filtration rate and is used as an index of renal function in clinical practice. Normal serum level 1�2 mg/dl 24 hour creatinine excretion 20 mg/kg/day for males 15 mg/kg/day for females Children, females, elderly, spinal cord injured have low serum and urine creatinine

39. A better index would related creatinine to muscle mass or lean body weight By virtue of its relative independence from such factors as diet (protein intake), degree of hydration, and protein metabolism, the plasma creatinine is a significantly more reliable screening test or index of renal function than is the BUN. The plasma creatinine tends to increase somewhat more slowly than the BUN in renal disease but also decreases more slowly with hemodialysis.

40. BUN/Creatinine (B/C) ratio Ordinary the B/C ratio is about 10 to 20. A high B/C ratio is typically associated with prerenal azotemia because of augmented tubular reabsorption of urea in the presence of diminished glomerular filtration. Postrenal azotemia also results in a high B/C ratio because urea is reabsorbed to a much greater extent than creatinine. Decreased B/C: low protein diet, muscular individuals, renal dialysis causes a decreased ratio because urea is more readily dialyzed than creatinine.

41. Glomerular Filtration Rate Glomerular filtration= major physiologic responsibility of kidney, GFR used as index of overall excretory function Methods: Clearence of inulin, creatinine, EDTA, Cystatin C GFR= Ux x V (V=volum of urine/ 1 minute or 1 second) P x x= clearence of substance used Urea is easily measured. It has a wide reference range and the value increases after a meal. Its concentration is increased in many different conditions which makes it sensitive to the presence of disease but a non-specific test.Urea is easily measured. It has a wide reference range and the value increases after a meal. Its concentration is increased in many different conditions which makes it sensitive to the presence of disease but a non-specific test.

42. Creatinine Clearance ?? Measure serum and urine creatinine levels and urine volume and calculate serum volume cleared of creatinine ?? Same issues as with serum creatinine, except muscle mass ?? Requirements for 24 hour urine collection adds variability and inconvenience

43. Estimated Glomerular Filtration Rate (eGFR) eGFR by MDRD Formula ?? Mathematically modified serum creatinine with additional information from patients age, sex and ethnicity eGFR = 30849.2 x (serum creatinine)-1.154 x (age)-0.203 (if female x (0.742))

44. Cystatin C ?? Cystatin C is a 13 KD protein produced by all cells at a constant rate ?? Freely filtered ?? Re-absorbed and catabolized by the kidney and does not appear in the urine

45. Uric Acid Uric acid is the end product of the metabolism of purines Uric acid is filtered at the glomeruli, reabsorbed in the proximal convoluted tubule, followed by secretion in the lower portion of the proximal tubule, and further reabsorption in the distal tubule