The document discusses various laboratory tests used to evaluate liver function and disease. It describes tests for hepatocellular damage like ALT and AST, tests for cholestasis like alkaline phosphatase, and tests for liver synthetic function like albumin. Common causes of abnormal liver enzymes are also summarized, along with risk factors for liver disease.

5. Hepatic excretion Total serum bilirubin, urine bilirubin Cholestasis tests Serum alkaline phosphatase Hepatic enzymes ALT, AST

6. Serum proteins PT, PTT, serum albumin Markers of specific liver diseases Serum ferritin, ceruloplasmin Specific tests for viral hepatitis IgM anti-HAV, anti-HBS, HCV-RNA

7. High risk behaviour: IV drug use Multiple sexual partners High risk sexual activity Tattoos Nonsterile body piercing Alcohol abuse Systemic illness Diabetis mellitus Obesity Hyperlipidemia Hemochromatosis Autoimmune disease Possible metastatic cancer Chronic inflammatory bowel disease

8. Medications Acetaminophen Herbal medications HMG-COA reductase inhibitors (statins) Anticonvulsants drugs Isotretinoin Antibiotics Antituberculosis drugs Others Travel to or residence in less developed regions or countries Exposure to blood or needle stick injuries Receipt of blood products Hemodialysis Ingesting of contaminated foods

9. INTIAL INVESTIGATIONS Initial evaluation of laboratory tests must involve patient’s symptoms: Risk factors for liver disease, Concomitant conditions Medications or drug use, history and physical examination findings, Potentially be a laboratory error. Marked abnormalities of liver chemistry tests + Signs and symptoms of chronic liver disease or hepatic decompensation

10. Test for hepatocellular damage AST ALT Test for cholestasis Alkaline Phosphatase Test for Biliary Excretion Total Bilirubin, Direct Bilirubin Test for liver synthetic function Albumin Protime

11. ENZYME ELEVATIONS IN LIVER DISEASE Hepatocellular injury (hepatitis in all types) Cholestasis (Biliary obstruction, hepatic infiltration)

12. TRANSMINASE Catalyze the transfer of amino groups to form the hepatic metabolites pyruvate and oxaloacetate Released from damaged hepatocyte into the blood after hepatocellular injury or death ALT found in the cytosol of the liver Found in low concentration in tissues other than in the liver Specific to hepatocellular injury Maybe elevated in non hepatic conditions such as myopathic disorders Diurnal variation and affected by exercise

13. ALAT (Alanine-Amino-Transferase ) Damage to 1 gm is sufficient to produce measurable rises in serum enzyme levels Search enzyme Mainly located in the periportal hepatocyte (zone 1) and mean half life of 48 hours (+/- 10 h) Highly concentrated in the liver parenchyma Increase in activity sign for hepatocellular damages (inflammation) Tracing enzyme for liver diseases

14. AST Found in the cytosol and mitochondria of the liver Abundantly expressed in several non-hepatic tissues including heart, skeletal muschle and blood

15. ASAT (Aspartate-Amino-Transferase) Mitochondrial enzymes (GOT, GLDH) are released for cell necrosis accompanied by destruction of mitochondria SGOT > SGPT Necrosis type (SGPT>SGOT Inflammation Type) SGOT: SGPT DeRitis Quotient: more severe Prognosis all the more serious the more the activity of SGOT exceeds SGPT Mean half life SGOT is 17+/- 5 hours High activity in hepatocytes, myocardium, and in the skeletal muscles Increase in activity sign for liver disorders, heart attacks and damages in skeletal muscles

16. Additional test to identify the cause of elevated aminotransferase in asymptomatic patient

17. Bilirubin Normal heme degradation product that is excreted from the body predominately via secretion into bile. Insoluble in water and requires conjugation (glucuronidation) into the water-soluble bilirubin mono- and di-glucuronide forms before biliary secretion Bilirubin-UGT, the enzyme that conjugates bilirubin, is expressed shortly after birth.

18. JAUNDICE Most visible manifestation of liver and biliary tract Condition characterized by yellowish discoloration of skin,sclerae as a result of elevated bilirubin concentration

19. Hemoglobin (1-2 X 10 8 eryhtrocytes /hr) globin heme Iron of heme is degraded in the reticuloendothelial cells of the liver, bone marrow and spleen amino acids ( reutilized or catabolized )

20. Heme O2 NADPH + H+ NADP+ Fe3+ CO Biliverdin NADPH + H+ NADP Biliverdin reductase Bilirubin Macrophage Bilirubin -Albumin complex Blood Heme oxygenase NADPH + H+ NADP Biliverdin reductase Bilirubin Bilirubin diglucoronide BILE

21. Causes of an Isolated Unconjugated Hyperbilirubinemia Gilbert’s syndrome Neonatal jaundice Hemolysis Blood transfusion (hemolysis) Resorption of a large hematoma Shunt hyperbilirubinemia Crigler-Najjar syndrome Ineffective erythropoiesis

22. Causes of Conjugated Hyperbilirubinemia Bile duct obstruction Hepatitis Cirrhosis Medications/toxins Primary biliary cirrhosis Primary sclerosing cholangitis Sepsis Total parenteral nutrition Intrahepatic cholestasis of pregnancy Benign recurrent cholestasis Vanishing bile duct syndromes Dubin-Johnson syndrome Rotor syndrome

23. Medications That Can Cause Elevations of the Serum Bilirubin or Alkaline Phosphatase Anabolic steroids Gold salts Allopurinol Imipramine Amoxicillin-clavulanic acid Indinivir Captopril Iprindole Carbamazepine Nevirapine Chlorpropamide Methyltestosterone Cyproheptadine. Methylenedioxymethamphetamine Diltiazem Oxaprozin Erythromycin Pizotyline Estrogens Quinidine Floxuridine Tolbutamide Flucloxacillin Total parenteral hyperalimentation Fluphenazine Trimethoprim-sulfamethoxazole

24. CHOLESTASIS Syndrome due to the impairment of the formation of bile secondary to drugs, infectious autoimmune, metabolic or genetic disorder Secretion of bile depends on: Function of a number of membrane transport systems in hepatocytes and bile duct epithelial cells (Cholangiocytes) Structural function integrity of bile-secretory apparatus

25. Bile plugs

26. ALKALINE PHOSPHATASE Family of enzymes are zinc metalloenzymes In the liver, the enzyme has been immuno-localized to the microvilli of the bile canaliculus. Under normal conditions, it is predominantly is caused by liver and bone isoenzymes, (intestinal enzymes about 20% of total activity) Dependent on a host of factors including the method of determination, patient age and gender, and the postprandial state. Elevated by cholestatic or infiltrative diseases of the liver and by diseases causing obstruction to the biliary system, bone diseases, medications, and tumors of hepatic and non-hepatic origin. Important clinical issue is the determination of whether the alkaline phosphatase abnormality is of hepatobiliary or non-hepatic origin.

27. ALKALINE PHOSPHATASE Formed in the osteoblasts, small intestine, liver, bile duct system, duodenum kidneys, prostate, placenta Half live 3-7 days Physiologic increase occurs at growing age

28. Sources of elevated alkaline phosphatase: liver and bone Women in the third trimester of pregnancy In persons with blood type O or B, serum alkaline phosphatase levels may increase after the ingestion of a fatty meal Vary with age. Rapidly growing adolescents can have serum alkaline phosphatase levels that are twice those of healthy adults (bone ) Normally increase between the ages of 40 and 65 years, particularly in women.

29. Causes of Elevated Serum Alkaline Phosphatase Hepatobiliary Bile duct obstruction Primary biliary cirrhosis Primary sclerosing cholangitis Medications Infiltrating diseases of the liver Hepatic metastasis Hepatitis Cirrhosis Vanishing bile duct syndromes Benign recurrent cholestasis Nonhepatic Bone disease Pregnancy Chronic renal failure Lymphoma and other malignancies Congestive heart failure Childhood growth Infection/inflammation

30. ALK + AMA is positive: primary biliary cirrhosis. If: the AMA (-) ultrasonography (-), alkaline phosphatase level remains >50% :liver biopsy ERCP, MRCP. If the increase in the alkaline phosphatase level is <50%: observation

31. Infiltrating Diseases of the Liver That Can Cause Elevations of the Serum Alkaline Phosphatase Sarcoidosis Tuberculosis Fungal infection Other granulomatous diseases Amyloidosis Lymphoma Metastatic malignancy Hepatocellular carcinoma

32.  ‑ GT activity Does not correlate with the results for GPT and GOT Rise in  ‑GT is found in biliary tract diseases, liver-cell membrane damage and liver-cell regeneration, but also as a result of the induction of microsomal enzyme systems by drugs. Not liver-cell specific Not cholestasis-specific (about 3% non-response). Not proof of liver-cell damage Not proof of alcohol abuse. It is instead: Initially only a sign of increased activity of the detoxification function induced by alcohol, chemicals, medications or toxins, or evidence of cholestasis or liver-cell regeneration. Clinical experience shows that an increase in  ‑GT activity is found, for example, in some intrahepatic and extrahepatic diseases

33. Graduated chemical laboratory program for the diagnosis or differential diagnosis of hepatobiliary diseases Minimum Necessary Maximum 1.Enzymatic activity: GPT,  -GT  GOT, GLDH  LDH 2.Synthesis output ChE, Quick value  Albumins  Ammonia, galactose 3.Excretory output: AP, bile pigments in urine  Bilirubin, LAP  Bile acids, iron, copper, cholesterol, indocyanine green, LP-X  Enzyme tracing grid Enzyme quotients  4.Mesenchymal activity:  -Globulins  Immunoglobulins,  A, G, M Copper, procollagen III peptide 5.Immunological activity: HBs-Ag, HBc-Ab, AMA,  HA-Ab HBs-Ab, ANA  HBe-Ag, Hbe-Ab, HBV-DNA, HDV, HCV-Ab, SMA, LMA,  1 -fetoprotein

34. TESTS WHEN IS IT LIKELY ABNORMAL SPECIFICITY FOR LIVER DISEASE OTHERS Hepatitis (viral, autoimmune, drug induced, NAFLD, iron overload) Hepatitis (particularly alcoholic), hepatitic fibrosis, cirrhosis Sensitive and specific Less sensitive And specific than ALT Acute obstructive jaundice (within first 24 hours) Cardiac or skeletal muscle injury ALT AST Enzyme elevations in liver disease Hepatocellular injury

35. TESTS WHEN IS IT LIKELY ABNORMAL SPECIFICITY FOR LIVER DISEASE OTHERS More specific than GGT More sensitive than ALP May not indicate significant liver disease Bone disease, pregnancy Medications, hepatic congestion ( CHF ) ALK GGT Enzyme elevations in Liver Disease Cholestasis Cholestasis Cholestasis, Alcohol

36. USG CT scan MRI Sensitivity ++ ++ +++ Specificity + +++ ++++ Cost + +++ ++++

37. Screening of High-risk Populations Tumor markers *Alpha-fetoprotein (AFP) Ultrasonography (US) *Easy *Simple *Low stress

38. Screening and Early Diagnosis of Primary Liver Cancer Yang B et al. National Medical Journal of China (Zhonghua Yi Xue Za Zhi) 1999 AFP US AFP w/ or w/o US SENSITIVITY 69% 84% 92% SPECIFICITY 95% 97.1% 92.5% PPV 3.3% 6.6% 3.0% NPV 99.9% 99.9% 100%