Biochemical Assessment of Liver Disorders - PHM143H1 PDF

Biochemical Assessment of Liver Disorders PHM143H1 – Pathobiology and Pathology 01.29.2024 Felix Leung, PhD, FCACB Division Head of Clinical Biochemistry, Sinai Health System Assistant Professor, University of Toronto f...

Biochemical Assessment of Liver Disorders PHM143H1 – Pathobiology and Pathology 01.29.2024 Felix Leung, PhD, FCACB Division Head of Clinical Biochemistry, Sinai Health System Assistant Professor, University of Toronto [email protected] Objectives To present the clinical significance of routinely available blood and urine laboratory tests and test profiles in relation to liver disorders To explain how selected pathological processes alter the biochemical profile To review a spectrum of liver disorders emphasizing the derangements in the biochemistry test profile PHM1431H1 Syllabus: Describe the normal function of the liver. Summarize the purpose and types of liver function tests. Compare and contrast various mechanisms of damage, which lead to cirrhosis or portal hypertension. Outcomes By the end of this lecture, you should be able to: 1. Describe basic anatomy and metabolic functions of the liver, especially as it pertains to clinical biochemistry tests. 2. Describe a biochemical test profile given a liver disorder. 3. Describe the likely liver disorder given a biochemical test profile. Liver Anatomy Liver is the largest internal organ in the human body Approximately 900-1900 g in males and 600-1800 g in females Anatomically divided into four lobes: Right Left Caudate Quadrate Critical role in wide range of physiological processes Metabolism and detoxification Macromolecule synthesis Endocrine and exocrine functions Liver Anatomy *Four lobes are only visible via posterior view Liver Anatomy Liver is perfused via two main vessels in the right lobe Hepatic artery from the aorta (accounts for about 25% of cardiac output) Portal vein from the digestive system (nutrient-rich blood) Liver exerts digestive (exocrine) functions via the common bile duct Bile secreted through hepatic ducts and stored in gallbladder Liver Anatomy The liver can be “divided” into hepatic lobules Hexagonal functional units consisting of portal triads, hepatocytes and sinusoids centered around a central vein Portal triad found at each corner of lobule Portal arteriole Portal venule Bile duct(s) Lymphatics Nerves ‘Triad’ is a misnomer! Liver Anatomy Liver Anatomy The acinus is the functional unit of the liver Centered around connection between two portal triads and extends towards two central veins Divided into 3 zones in order of proximity to portal triad Zone 1: first hepatocytes to receive incoming blood Zone 3: last hepatocytes to receive incoming blood Zone 2: intermediate range Liver Basics: Anatomy Susceptibility Metabolic Zone Functions c Potential Bile Hypoxia Toxins stasis Gluconeogenesis Zone 1 Beta oxidation High Low High High 1 Urea cycle Glycolysis Zone 3 Lipogenesis Low High Low Low 3 CYP450 metabolism metabolism *Note that zone comparisons are relative to each other (ex. enough hypoxia can cause death of Zone 1 hepatocytes) Liver Anatomy Liver Anatomy ‘Classic’ lobule describes flow of perfused blood from portal triad towards central vein Sinusoidal capillary system allows for maximal exposure of blood to hepatocytes Hepatocytes concurrently excrete bile into the bile canaliculi to be excreted via bile ducts Acini “organizes” liver into functional units that consider the sinusoidal and biliary systems Hepatocytes of Zones 1, 2 and 3 have varying functions and susceptibilities related to their location within an acinus Liver Function Most sources estimate the number of functions the liver serves to be around 500 Biosynthesis Storage Endocrine Cholesterol Glucose IGF-1 Lipoproteins Vitamins (A, D, E, K, B12) Thrombopoeitin Glucose Trace elements (Fe, Cu, Zn) Angiotensinogen Protein Synthesis Detoxification Exocrine Albumin Drugs (Phase I/II conjugation) Bile salts Clotting Factors Nitrogenous waste (urea) Globulins Bilirubin (bile) Plus many, many, many more…. Liver Function Liver “function” usually encompasses intrahepatic (within the liver) and extrahepatic (after the liver) processes Intrahepatic includes synthetic, metabolic and detoxification functions Extrahepatic includes secretion of bilirubin and bile salts Laboratory tests can assess intrahepatic processes via function and integrity tests Function tests are indicative of capacity of hepatocytes to carry out biological functions Integrity tests are indicative of intactness of hepatocyte Tests for extrahepatic processes assess patency of biliary system (cholestasis) Function does not equal integrity! Liver Function: Bilirubin Linear Catabolic product of heme Yellow pigment (jaundice) Bilirubin is mainly metabolized in the liver and excreted via bile Increasing levels may indicate failing liver Folded High bilirubin levels can also be a result of inborn errors of metabolism Toxic to neonates i.e. kernicterus Liver Function: Bilirubin Majority of bilirubin (85%) derived from haemoglobin Remainder from other heme proteins Bilirubin is highly insoluble on its own Travels to the liver bound to albumin Requires glucuronidation to be excretable Majority is di-glucuronide (90%) Liver Function: Bilirubin Homeostatic conditions maintain low plasma concentrations of bilirubin via bile excretion Liver Biochemistry Hepatocyte cBil uBil Conjugation GGT Albumin Bile Canaliculi Sinusoid ALP GGT ALT Clotting Factors AST Liver Biochemistry Alanine aminotransferase (ALT) Hepatocyte integrity; more specific for hepatocyte injury Aspartate aminotransferase (AST) Hepatocyte integrity; less specific for hepatocyte injury Alkaline phosphatase (ALP) Biliary tract patency Gamma-glutamyltransferase (GGT) Hepatocyte integrity and biliary tract patency Bilirubin Hepatocyte function and biliary tract patency Albumin Hepatocyte function (protein synthesis) Prothrombin time Hepatocyte function (protein synthesis) Liver Biochemistry Liver Integrity Tests Biliary Tract Patency ALT Tests AST ALP GGT GGT Direct Bil (conjugated) Liver Function Tests Total Bil* Remember: Function does not Direct Bil* (conjugated) equal to integrity. Often, Indirect Bil* (unconjugated) institutions will have a “liver Albumin function” panel that includes both Prothrombin Time function and integrity tests. This *TBil = DBil + IBil; usually total and is therefore a misnomer! direct are measured and indirect is calculated Liver Biochemistry Specialized Tests Ammonia metabolic insufficiency ɑ-fetoprotein hepatoma 5’-nucleotidase cholestasis Lactate dehydrogenase metastases, congestion ɑ1-antitrypsin cirrhosis etiology Caeruloplasmin cirrhosis etiology Iron, Ferritin, TIBC cirrhosis etiology Viral antigens & antibodies hepatitis Immunoglobulins chronic disease Autoantibodies chronic disease Acetaminophen overdose Liver Biochemistry Many “liver” tests are routinely offered in any core laboratory ALT, AST, ALP, bilirubin (total and direct), albumin, PT/INR Inexpensive tests and relatively non-invasive Tests can help identify if liver disease is present Hepatocellular injury/leak, biliary tract obstruction, liver insufficiency Tests may have other uses as well in addition to diagnosis of liver disease Monitoring disease activity/response to treatment Provide prognostic information Liver Disease: Cholestasis Cholestasis refers to inability of bile to flow from liver to duodenum Most often of an obstructive (extrahepatic) etiology Gallstones Tumours (cholangiocarcinoma, pancreatic carcinoma) Primary sclerosing cholangitis Other causes include infections, autoimmune disease, genetic disorders and drug/toxin-induced Liver Disease: Cholestasis Bilirubin and urobilinogen in the urine Liver Disease: Cholestasis In a patient with diffuse biliary tract obstruction (primary biliary cirrhosis): ALP Very high; 10-20x upper limit of normal (ULN) TBil High; parallel fold increase as ALP DBil High; should account for most of TBil AST/ALT Normal or slightly elevated Albumin Normal Relative sparing of hepatocytes and preservation of liver function Liver Disease: Cholestasis In a patient with focal biliary tract obstruction (gallstone): ALP Very high GGT Very high DBil High; not as high as ALP increase AST/ALT Normal or slightly elevated Albumin Normal Relative sparing of hepatocytes, liver function and bile duct patency Liver Disease: Cholestasis How do you explain the lab profile of the following primary sclerosing cholangitis patient: ALP Low; below lower limit of normal (LLN) TBil Very high DBil Low AST/ALT Low Liver Disease: Hepatitis Hepatitis is the inflammation of liver tissue Can be classified according to duration: acute, fulminant, chronic Can be classified according to cause: infectious (viral), alcoholic, toxic, autoimmune, ischemic, inherited, NAFLD (change this acronym) Any chronic insult to the liver can leads to cirrhosis (extensive liver fibrosis + additional correlates) Cirrhosis associated with multiple morbidities such as ascites, portal hypertension, hepatorenal syndrome and hepatocellular carcinoma Laboratory tests may give an indication of degree of damage and/or chronicity Liver Disease: Hepatitis In a patient with alcoholic hepatitis: AST/ALT High; 10x ULN ALT Very high; >10x ULN DBil Very high IBil Very high Acute toxic insult results in massive necrosis and indiscriminate hepatocellular damage; release of cellular contents into circulation Liver Disease: Hepatitis Viral hepatitis is most common form of infectious hepatitis Mostly due to hepatotropic viruses (Hep A, B, C, D, E) Other viruses can also cause hepatitis too (EBV, CMV, HSV) Acute hepatitis Chronic Hepatitis Transmission Incubation Progression hepatitis hepatitis Self-resolving or A Oral 15-50 days Yes No or fulminant (rare) Self-resolving or Blood B 1-6 months 50-70% 5% or chronic Mucosal disease Cirrhosis and C Blood 1-6 months Rare 70-80% liver cancer Liver Disease: Hepatitis In a patient with acute viral hepatitis (Hepatitis A): AST Very high; >10x ULN ALT Very high; >10x ULN TBil Normal or slightly elevated Albumin Normal Acute viral hepatitis causes release of enyzmes mostly due to immune response against virus; otherwise liver function is preserved unless progresses to fulminant hepatitis Liver Disease: Hepatitis In a patient with chronic viral hepatitis (Hepatitis C): AST High; waxing and waning ALT High; waxing and waning TBil Elevated Albumin Decreased Chronic viral hepatitis will often be asymptomatic while viral infection smoulders over time; eventually damage will surpass regenerative capacity of liver and complications ensue Liver Disease: Hepatitis How do you explain the lab profile of the following acute hepatitis patient: ALT 1040 U/L (Normal