Pre-Clinical Sciences II - Gastrointestinal System - Liver Disorders - PDF

Department of Pathophysiology Pre-Clinical Sciences II Gastrointestinal System Disorders of Liver-1 Dr. Smriti Agnihotri MBBS, MD Professor and Co-chair E-Mail: [email protected] Office: GB27 phone: (268) 484-8900, ext. 1078 Office hours- by appointment Goals and learning objectives GI2.28: A...

Department of Pathophysiology Pre-Clinical Sciences II Gastrointestinal System Disorders of Liver-1 Dr. Smriti Agnihotri MBBS, MD Professor and Co-chair E-Mail: [email protected] Office: GB27 phone: (268) 484-8900, ext. 1078 Office hours- by appointment Goals and learning objectives GI2.28: Apply knowledge of the structure and functions of the liver to intrepret liver function tests and understand their significance for making clinical diagnoses Given a clinical scenario or image, the student should be able to: GI1.20.7. Describe the microscopic structure and organization of the liver (classical hepatic lobule, portal lobule, and hepatic acinus) and their functional correlates. (Year-1 Histology) GI1.20.9. Describe the boundaries, contents, and clinical importance of space of Disse. (Year-1 Histology) GI2.28.1. Analyze liver function tests and their clinical correlation. GI2.29: Apply knowledge of gross anatomy, histology, cell biology, and pathophysiology of the liver to understand the patterns and types of liver injury and their complications, and the role of pharmacotherapy in their management Given a clinical scenario or image, the student should be able to: GI2.29.1. Recognize the major morphologic patterns seen in response to liver injury and repair– steatosis, cholestasis, Mallory hyaline, ballooning, Councilman bodies, acidophilic apoptotic bodies, bridging necrosis, ductular reactions. GI1.20.7. Describe the microscopic structure and organization of the liver (classical hepatic lobule, portal lobule, and hepatic acinus) and their functional correlates. (Year-1 Histology) • The normal adult liver weighs: 1400-1600gm • It has dual blood supply • The portal vein supplies 60 to 70 % of blood flow to liver. • The hepatic artery : 30 to 40 % Two concepts: The hepatic lobule the hepatic acinus Lobular model : hexagonal • The terminal hepatic vein (CV) is at the center of a lobule and the portal tracts with portal triad ( portal vein, hepatic artery and bile ductules) are at the periphery. • Regions : "periportal and centrilobular." Acinar model : here, three zones are defined, on the basis of blood flow • 6/lobule, triangular • Apex - Central Vein • Base - Periphery • Zone 1: closest to the blood supply • Zone 3: the farthest Integration with anatomy: Liver is resistant to infarction as it has a dual blood supply. Review Zone 1 is first and zone 3 is last to receive O2. Zone II is affected in yellow fever. Histology of Liver Hepatic parenchyma : • Cribriform, anastomosing sheets or "plates" of hepatocytes • Between abutting hepatocytes are bile canaliculi → which empty into the terminal bile ducts within the portal tracts. Vascular sinusoids (blue arrow) : These are lined by: • Fenestrated and discontinuous endothelial cells • Scattered Kupffer cells(Macrophages) of the mo nonuclear phagocyte system Perisinusoidal space (space of Disse ): Deep to the endothelial cells and contains stellate cells (Ito cells) which serve following functions: • Store vitamin A and secrete extracellular matrix components. • In pathologic conditions----make excess collagen , leading to hepatic fibrosis and eventually cirrhosis. Histology of the liver Liver Function Tests Functions of the Liver: 1. Metabolic………………glucose metabolism, lipid metabolism 2. Synthetic………………. albumin, coagulation proteins I, II, V, VII-XIII, specific binding proteins 3. Storage………………...glycogen, triglycerides, iron, copper, lipid and soluble vitamins 4. Catabolic……………...ammonia->urea, contain hormones + proteins, detoxification of many foreign compounds, drugs and chemicals. 5. Excretory………………bile excretion Liver Function Tests Tests to evaluate Liver Function: 1. Biochemical tests 2. Radiologic tests 3. Pathologic tests Serum Biochemical Tests- “Liver Function Tests”: 1. Detect the presence of liver disease 2. Distinguish among different types of liver disorders •acute hepatocellular damage •obstruction to the biliary tract •chronic liver disease 3. Gauge the extent of known liver damage 4. Follow the response to treatment • Lack sensitivity and specificity • Best to use them as a battery Basic Test parameters in LFT:​​ Total Bilirubin​​ 0.1-1.0 mg/dL Conjugated Bilirubin​​ 0.0-0.3 mg/dL AST/SGOT​​ 8-20 U/L ALT/SGPT​​ 8-20 U/L ALP​​ 20-70 U/L​​ GGT​​ Total Albumin​​ 3.5-5.5 g/dL Glucose​​ Fasting: 70-110 mg/dL PT​​ 11-15 Seconds​​ Serum Ammonia​​ Tests of hepatocyte integrity or injury Aminotransferases (ALT and AST) • • Serum aspartate aminotransferase (AST) : synonymous with SGOT : 8 -20 U/L (NBME) Serum alanine aminotransferase (ALT) :synonymous with SGPT : 8-20 U/L (NBME) Enzyme AST ALT Location Primarily a mitochondrial enzyme, Found in Liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas and erythrocytes. Primarily a cytosolic enzyme Found primarily in in liver. More specific indicator of liver injury. Significance: Striking elevations of aminotransferase > 1000 U/L occur most exclusively in disorders with extensive hepatocellular injury like: o Viral hepatitis o Ischemic liver injury o Toxin or drug mediated liver injury Pattern of aminotransferase elevation can be helpful diagnostically: • In most acute hepatocellular disorders, the ALT is higher than or equal to the AST. • the AST:ALT ratio is typically <1 in patients with chronic viral hepatitis and non-alcoholic fatty liver disease, a number of groups have noted that as cirrhosis develops, this ratio rises to >1. • An AST:ALT ratio >2:1 is suggestive, whereas a ratio >3:1 is highly suggestive, of alcoholic liver disease. A low level of ALT in the serum is due to an alcoholinduced deficiency of pyridoxal phosphate Bilirubin metabolism Biliary excretory function: Substances normally secreted in bile Bilirubin • A breakdown product of heme • Useful in detecting and following liver disease and hemolytic disorders Types: • Conjugated/Direct fraction - water-soluble, can therefore be excreted by the kidney • Unconjugated /Indirect fraction - insoluble in water, bound to albumin in the blood so not excreted by the kidney Normal values: • Total serum bilirubin = 0.2 and 0.9 mg/dL. • If the direct-acting fraction is <15% of the total, the bilirubin can be considered to all be indirect. • Upper limit of normal for Conjugated bilirubin is 0.3 mg/dL. ↑Unconjugated fraction of bilirubin: is rarely due to liver disease. • Hemolytic disorders • Crigler-Najjar • Gilbert’s syndromes ↑Conjugated fraction of bilirubin: • Liver or biliary tract disease Isolated unconjugated hyperbilirubinemia (bilirubin elevated but <15% direct) workup for hemolysis Gilbert Syndrome Urine dipstick test To see bilirubin and urobilinogen Enzymes that reflect cholestasis 1. Serum alkaline phosphatase (ALP) : 20-70 U/L • The level of serum alkaline phosphatase elevation is not helpful in distinguishing between intrahepatic and extrahepatic cholestasis. • In the absence of jaundice or elevated aminotransferases, an elevated alkaline phosp hatase of liver origin often, but not always, suggests early cholestasis. Enzyme Location in the organs ALP Liver, bone and placenta GGT Primarily in Liver 2. Serum γ-glutamyl transpeptidase (GGT ): • GGT is a microsomal enzyme • Runs parallel to ALP Because ALP can be derived from other body tissue (e.g., bone, intestine, placenta), a concurrent elevation of GGT (an enzyme of intrahepatic biliary canaliculi) or 5′-nucleotidase helps to support a cholestatic mechanism. Enzyme Location in the liver ALP In or near the bile canalicular membrane of hepatocytes GGT In the endoplasmic reticulum and in bile duct epithelial cells Hepatocyte synthetic function 1. Proteins secreted into the blood : Serum albumin: • Synthesized exclusively by hepatocytes. • Hypoalbuminemia is more common in chronic liver disorders such as cirrhosis and usually reflects severe liver damage 2. Coagulation factors : Prothrombin time: • The prothrombin time may be elevated in hepatitis and cirrhosis as well as in disorders that lead to vitamin K deficiency such as obstructive jaundice or fat malabsorption of any kind. Hepatocyte metabolic function • Serum ammonia: Ammonia is produced in the body during normal protein metabolism and by intestinal bacteria • The liver detoxifies ammonia by converting it to urea, which is excreted by the kidneys. Liver Function Tests-Summary Hepatocyte integrity Biliary excretory function Bile canalicular damage 1. Cytosolic hepatocellular enzymes ↑ • Serum aspartate aminotransferase (AST) • Serum alanine aminotransferase (ALT) • Serum lactate dehydrogenase (LDH) 2. Substances normally secreted in bile ↑ • Serum bilirubin • Total: unconjugated plus conjugated • Direct: conjugated only • Urine bilirubin • Serum bile acids 3. Plasma membrane enzymes (from damage to bile canaliculus) ↑ • Serum alkaline phosphatase • Serum γ-glutamyl transpeptidase (GGT) Hepatocyte synthetic function 4. Proteins secreted into the blood • Serum albumin↓ • Coagulation factors ↓ • Prothrombin time (PT) and partial thromboplastin time (PTT): fibrinogen, prothrombin, factors V, VII, IX, and X Hepatocyte metabolic function 5. Hepatocyte metabolism • Serum ammonia ↑ • Aminopyrine breath test (hepatic demethylation) ↓ in alkaline phosphatase t 66T serumbilirubinA holestats Directfraction S indirect Q. How to differentiate between hepatocellular pattern of liver injury from cholestatic pattern? É A serum aminotransferase t GOT É serum bilirubin maybe 9 indirectfraction A It Direct compared w alkaline phosphatase Type of Disorder Bilirubin Aminotransferases Alkaline Phosphatase Albumin Prothrombin Time Hemolysis/Gilbert’s syndrome Normal to 86 μmol/L (5 mg/dL) 85% due to indirect fractions No bilirubinuria Normal Normal Normal Acute hepatocellular necrosis (viral and drug hepatitis, hepatotoxins, acute heart failure) Both fractions may be elevated Peak usually follows aminotransferases Bilirubinuria Elevated, often >500 IU, ALT > AST Normal to <3× normal elevation Normal Usually normal. If >5× above control and not corrected by parenteral vitamin K, suggests poor prognosis Chronic hepatocellular disorders Both fractions may be elevated Bilirubinuria Elevated, but usually <300 IU Normal to <3× normal elevation Often decreased Often prolonged Fails to correct with parenteral vitamin K Alcoholic hepatitis, cirrhosis Both fractions may be elevated Bilirubinuria AST:ALT >2 suggests alcoholic hepatitis or cirrhosis Normal to <3× normal elevation Often decreased Often prolonged Fails to correct with parenteral vitamin K Intra- and extrahepatic cholestasis Both fractions may be elevated Normal to moderate elevation Elevated, often >4× normal elevation Normal, unless chronic Normal If prolonged, will correct with parenteral vitamin K Normal Normal (Obstructive jaundice) Infiltrative diseases (tumor, granulomata); partial bile duct obstruction conjugated Bilirubinuria Usually normal Elevated, often >4× toelevation normal Rarely >500 I Fractionate, or confirm Normal to slight elevation liver origin with 5′nucleotidase or γ glutamyl transpeptidase Normal auld Evaluation of Liver Function -Harrison's Principles of Internal Medicine, 20e. Chapter 330. TABLE 330-1 Liver Function Tests: O 2. A 20-year-old medical student present to his primary care provider for a routine checkup as one of his friends died in the playground while playing football. Physical examination is unremarkable except icterus. Lab values are shown in the image. Which of the following function of the liver is abnormal in this patient? FASTIAT A. B. C. D. E. Parameter Result Total Bilirubin 4.7 0.1-1.0 mg/dL Conj. Bilirubin 0.4 0.0-0.3 mg/dL AST/SGOT 17 8-20 U/L 22 8-20 U/L 45 20-70 U/L 34 10-46 U/L 5.3 3.5-5.5 g/dL 86 70-110 mg/dL 12 11-15 Seconds 20 <50mg/dl ALT/SGPT ALP I GGT Biliary excretory function S. Albumin Bile canalicular integrity PALP AGOT Glucose PT Hepatocyte integrity Hepatocyte metabolic function A SAmmonia S. Ammonia Hepatocyte synthetic function Albumin A PT IS Normal Goals and learning objectives GGI2.29: Apply knowledge of gross anatomy, histology, cell biology, and pathophysiology of the liver to understand the patterns and types of liver injury and their complications, and the role of pharmacotherapy in their management Given a clinical scenario or image, the student should be able to: GI2.29.1. Recognize the major morphologic patterns seen in response to liver injury and repair– steatosis, cholestasis, Mallory hyaline, ballooning, Councilman bodies, acidophilic apoptotic bodies, bridging necrosis, ductular reactions. Patterns of Liver Injury F Injured or dysfunctional may demonstrate several potentially reversible or irreversible morphologic changes Reversible: • Fatty Change (steatosis) • Bilirubin (cholestasis) • Ballooning swellingof hepatocyte Irreversible: • Necrosis • Apoptosis Repair: • Regeneration and Ductular reaction • Fibrosis or Scar formation • Regression Microvescicular steatosis Patterns of Liver Injury - Fatty Change (steatosis) Definition : triglyceride accumulation in the hepatocyte E • Represent reversible cell injury. ped ul 1. Macrovesicular steatosis: seen in Obesity or Diabetes 2. Microvesicular steatosis : Seen in Reye syndrome, Acute fatty liver of pregnancy • Both microvesicular and macrovesicular steatosis : seen in Alcoholic fatty liver, affecting virtually every hepatocyte. • Pathologic steatosis :>5% of hepatocytes involved microvascular Macrovescicular steatosis glylogent Hyo gives clear appearance speyesynd macrovascularesignetringappeance O O O Hepatocyte Patterns of Liver Injury - Bilirubin accumulation (cholestasis) Slowing of bite flow feathery degeneration o • The hallmark of cholestasis is accumulation of green-brown plugs of bile pigment in hepatocytes and dilated canaliculi • Rupture of canaliculi can lead to extravasation of bile, which is phagocytosed by Kupffer cells. • Accumulation of bile salts in hepatocytes - swollen, foamy appearance of the cytoplasm (“feathery degeneration”). (1) Hepatocytes are enlarged (2) dilated canalicular spaces (3) Apoptotic cells (4) Kupffer cells, frequently contain regurgitated bile pigments hepatic Extrahepatic 7 CannomaBile plug head pancreas I Patterns of Liver Injury Ballooning Po g ups Ballooned hepatocyte. • • • Cell swelling, cytoplasmic clearing, and clumping of intermediate filaments Mallory hyaline – prominent clumping of intermediate filaments Alcohol-induced or nonalcoholic steatohepatitis, ischemic, toxic injury or with cholestasis Mallory hyaline Patterns of Liver Injury - Necrosis • Two types of hepatocyte injury in irreversible cell injury: hepatocyte necrosis and apoptosis Hepatocyte Necrosis : • Defective plasma membrane transporter function and mitochondrial dysfunction- cell death • Necrotic cells are phagocytosed by macrophages, which cluster and mark sites of hepatocyte necrosis • seen in ischemic/hypoxic injury Morphological types of necrosis: Confluent necrosis: • A zonal loss of contiguous hepatocytes which begin in zone 3 near the central vein • The resulting space is filled by cellular debris, macrophages, and remnants of the reticulin meshwork Bridging necrosis: • Central veins → portal tracts • Portal tracts → portal tracts Pan-acinar necrosis: • Entire lobule is obliterated Confluent necrosis is seen in the perivenular region (zone 3) O Patterns of Liver Injury - Apoptosis Apoptosis - “programmed” cell death • Hepatocyte shrinkage • Nuclear chromatin condensation (pyknosis) Acidophilic apoptotic bodies: • Councilman bodies: in yellow fever by William Thomas Councilman • Acidophil bodies: Acute and Chronic hepatitis cuspateactivation mechanism do Acidophilic apoptotic body Pattern of liver injury: Repair/Regeneration Patterns of Liver Injury – Scar formation 1. Stellate cell activation: wasoretasffay • Inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), produced by Kupffer cells, macrophages, and other cell types • Altered interactions with extracellular matrix (ECM) • Toxins and reactive oxygen species (ROS) 2.Conversion of stellate cells into myofibroblasts: • ads are Inbetweeners Kupffer cells or recruited macrophages, lymphocytes and activated stellate cells secrete: • Platelet-derived growth factor receptor β Myohbroblast • Transforming growth factor β (TGF-β) c 3. Persistent injury or inflammation: • Extracellular matrix deposition and scarring, in the space of Disse leads to the loss of sinusoidal endothelial cell fenestration (Sinusoidal capillarization) 4. Cirrhosis: end point where fibrous septa encircle regenerative hepatocytes and give rise to diffuse scarring (cirrhosis) • Cell involved in laying down of collagen in the liver? Steller cells Ito all • Enzymes reflecting bile duct injury? Alkaline phosphatase 66T 5 nucelotidase AIT t AST S ALP T bilirubin I CB UCB • Parameters for hepatocellular pattern of injury ? • Parameters for cholestatic pattern of injury? ALPS ASTAALT TUCB 966T • What is the AST: ALT ratio in alcoholic liver disease? Ast ALT Thank you