LIVER AND LIVER FUNCTION TEST

Ma. Dara Mae M. Velasco

GROSS ANATOMY
liver is a large and complex organ weighing approximately 1.21.5 kg in the healthy adult. It is located beneath and is attached to the diaphragm It is divided unequally into two lobes by the falciform ligament, with the right lobe being approximately six times larger than the left lobe.

GROSS ANATOMY
- blood supply from two sources: a. the hepatic artery - 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. b. the portal vein - portal vein supplies nutrient-rich blood from the digestive tract, and it is responsible for providing approximately 75% of the total blood supply to the liver. - Approximately 1,500 mL of blood passes through the liver per minute. - The liver is drained by a collecting system of veins that empties into the hepatic veins and ultimately into the inferior vena cava

MICROSCOPIC ANATOMY
Two major cell types: A. hepatocytes making up approximately 80% of the volume of the organ, are large cells that radiate outward from the central vein in plates to the periphery of the lobule.These cells perform the major functions associated with the liver and are responsible for the regenerative properties of the liver B. kupffer cells macrophages that line the sinusoids of the liver and act as active phagocytes capable of engulfing bacteria, debris, toxins, and other substances flowing through the sinusoids

Excretory and Secretory

One of the most important functions of the liver substances into the bile or urine such as the major heme waste product, bilirubin. Bile is made up of bile acids or salts, bile pigments, cholesterol, and other substances extracted from the blood body produces approximately 3 L of bile per day and excretes 1 L of what is produced

Formation of bile
1. 2. 3. 4. 5. 6. 7. 8. RBCs are phagocytized in the spleen. Hemoglobin is catabolized into globin, iron and heme. Heme ring is broken open and converted to unconjugated ( indirect ) bilirubin. RE cells in the spleen secrete unconjugated bilirubin into the plasma, where bilirubin is bound by albumin. Albumin bilirubin complex travels to the liver. Hepatocytes conjugates bilirubin with gluconic acid and UDPGT enzyme. Conjugated bilirubin secreted into the bile ducts ( GI tract ) GI bacterial normal flora convert conjugated bilirubin into urobilinogen. Urobilinogen may be excreted into the stool, reabsorbed into the plasma and excreted in the urine

Synthetic
The liver has extensive synthetic capacity carbohydrates, lipids, and proteins

Synthetic
metabolism of carbohydrates is one of the most important functions of the liver. (1) use the glucose for its own cellular energy requirements, (2) circulate the glucose for use at the peripheral tissues, (3) store glucose as glycogen (principal storage form of glucose) within the liver itself or within other tissues.

Synthetic
Lipids are synthesized in the liver under normal circumstances The liver gathers free fatty acids from the diet, and those produced by the liver itself, and breaking them down to produce acetyl-CoA. Acetyl-CoA can then enter several pathways to form triglycerides, phospholipids, or cholesterol. The liver is also involved in the metabolism of lipids and their removal from the body through the use of lipoproteins and apoproteins

Synthetic
Almost all proteins are synthesized by the liver except for the immunoglobulins and adult hemoglobin positive and negative acute-phase reactants and coagulation proteins also serves to store a pool of amino acids through protein degradation

Detoxification and Drug Metabolism

gatekeeper between substances absorbed by the gastrointestinal tract and those released into systemic circulation Every substance that is absorbed in the gastrointestinal tract must first pass through the liver; this is referred to as first pass It may either bind the material reversibly so as to inactivate the compound, or it may chemically modify the compound so it can be excreted most important mechanism is the drugmetabolizing system of the liver (cytochrome P450 isoenzymes)

LIVER FUNCTION ALTERATIONS DURING DISEASE

Jaundice (icterus) French word jaune, which means yellow, Jaundice, or is used to describe the yellow discoloration of the skin, eyes, and mucous membranes most often resulting from the retention of bilirubin; however, it may also occur due to the retention of other substances jaundice is usually not noticeable to the naked eye until bilirubin levels reach 3.0 mg/dL icterus is most commonly used in the clinical laboratory to refer to a serum or plasma sample with a yellow discoloration due to an elevated bilirubin level

LIVER FUNCTION ALTERATIONS DURING DISEASE

Reference ranges
Total Bilirubin ( conjugated + unconjugated ) 0.2 - 1.0 mg / dl Conjugated bilirubin 0.0 - 0.2 mg / dl Fullterm newborns 2.0 6.0 mg / dl

Jaundice is evident at 3.0 mg / dl

General classifications of jaundice

Prehepatic Hepatic Posthepatic

Prehepatic
Before it reaches the liver metabolism
Excess RBC destruction ( Not impaired liver function ) Increased unconjugated bilirubin

Hepatic

intrinsic liver defect or disease can be due to disorders of bilirubin metabolism and transport defects, due to diseases resulting in hepatocellular injury or destruction Gilbert disease, Crigler-Najjar syndrome, and physiologic jaundice of the newborn are hepatic causes of jaundice that result in elevations in unconjugated bilirubin Dubin-Johnson and Rotor syndrome are hepatic causes of jaundice that result in elevations in conjugated bilirubin.

 Gilberts Syndrome

Defective bilirubin transport into hepatocyte Most common cause of jaundice Relatively benign intermittent unconjugated hyperbilirubinemia in the absence of hemolysis and underlying liver disease UGT (uridine diphosphoglucose glucuronyltransferase) superfamily

Crigler Najjar Syndrome chronic nonhemolytic unconjugated hyperbilirubinemia Rare and more serious disorder of bilirubin metabolism resulting from a molecular defect within the gene involved with bilirubin conjugation UDPG deficiency Hepatocytes lack UDPG enzyme cannot conjugate bilirubin

type 1 - complete absence of enzymatic bilirubin conjugation type II mutation causing a severe deficiency of the enzyme responsible for bilirubin conjugation

Dubin Johnson
rare inherited disorder caused by a deficiency of the canalicular multidrug resistance/ multispecific organic anionic transporter protein Defective excretion of conjugated bilirubin leading to hyperbilirubinemia and bilirubinuria Dubin-Johnson is a condition that is obstructive in nature, so much of the conjugated bilirubin circulates bound to albumin

distinguishing feature is the appearance of dark-stained granules on a liver biopsy sample.

Rotors Syndrome

Defective secretion of conjugated bilirubin clinically similar to Dubin-Johnson syndrome but the defect causing Rotor syndrome is not known due to a reduction in the concentration or activity of intracellular binding proteins such as ligandin. liver biopsy does not show dark pigmented granules

Physiological Jaundice of the newborn

Immature liver at birth Temporary deficiency of UDPG Small / moderate elevated unconjugated bilirubin lasting a few days

Posthepatic

Impaired ability of liver to excrete bile into the GI tract ( gallstones, tumors )

prevent the flow of conjugated bilirubin into the bile canaliculi stool loses its source of normal pigmentation and becomes clay-colored.

Cirrhosis
scar tissue replaces normal, healthy liver tissue blocking the flow of blood through the organ and prevents the liver from functioning properly signs and symptoms appear, including fatigue, nausea, unintended weight loss, jaundice, bleeding from the gastrointestinal tract, intense itching, and swelling in the legs and abdomen cause of cirrhosis is chronic alcoholism and chronic hepatitis C virus infection. Chronic hepatitis B and D virus infection, autoimmune hepatitis, inherited disorders (e.g., 1-antitrypsin deficiency, Wilson disease, hemachromatosis, and galactosemia), nonalcoholic steatohepatitis, blocked bile ducts, drugs, toxins, and infections Liver damage from cirrhosis cannot easily be reversed, but treatment can stop or delay further progression of the disorder

Tumors
May also be classified as : a. Benign - include hepatocellular adenoma (rare condition occurring almost exclusively in females of child-bearing age) and hemangiomas (masses of atypical blood vessels usually mesenchymal in origin with no known etiology b. Malignant - Malignant tumors of the liver include hepatocellular carcinoma (HCC), hepatocarcinoma, and hepatoma

Tumors
Classified as 1. Primary begins in the liver cells 2. Metastatic -occurs when tumors from other parts of the body spread (metastasize) to the liver. This type is more common. Cancers that commonly spread to the liver include colon, lung, and breast cancer May also be classified as : a. Benign b. Malignant

Reye Syndrome
group of disorders caused by infectious, metabolic, toxic, or drug induced disease found almost exclusively in children often preceded by a viral syndrome such as varicella, gastroenteritis, or an upper respiratory tract infection such as influenza Ingestion of aspirin the course of the viral infection acute illness characterized by noninflammatory encephalopathy and fatty degeneration of the liver with a clinical presentation of profuse vomiting accompanied with varying degrees of neurologic impairment such as fluctuating personality changes and deterioration in consciousness

Drug- and Alcohol-Related Disorders

Acute liver failure liver is a primary target organ for adverse drug reactions because it plays a central role in drug metabolism Toxicity via immune-mediated injury to the hepatocytes most important is ethanol ethanol causes very mild, transient, and unnoticed injury to the liver; however, with heavier and prolonged consumption, it can lead to alcoholic cirrhosis

Drug- and Alcohol-Related Disorders

The elimination of alcohol requires the enzymes alcohol dehydrogenase and acetaldehyde dehydrogenase to convert alcohol to acetaldehyde and subsequently to acetate. The acetate can then be oxidized to water and carbon dioxide, or it may enter the citric acid cycle. liver abnormalities that may range from alcoholic fatty liver with inflammation (steatohepatitis) to scar tissue formation, as in hepatic fibrosis, to the destruction of normal liver structure seen in hepatic cirrhosis.

Drug- and Alcohol-Related Disorders

This type of liver injury may be categorized into three stages: a. alcoholic fatty liver - represents the mildest category characterized by slight elevations in AST, ALT, and GGT, and on biopsy, fatty infiltrates are noted in the vacuoles of the liver. tends to affect young to middle-aged people with a history of moderate alcohol consumption. A complete recovery within 1 month is seen when the drug is removed.

Drug- and Alcohol-Related Disorders

This type of liver injury may be categorized into three stages: a. alcoholic hepatitis moderately elevated AST, ALT, GGT, and ALP and elevations in total bilirubin up to 30 mg/dL. Serum proteins, especially albumin, are decreased and the prothrombin time is prolonged. Prognosis is dependent on the type and severity of damage to the liver alcoholic cirrhosis

Drug- and Alcohol-Related Disorders

This type of liver injury may be categorized into three stages: c. alcoholic cirrhosis Prognosis associated with alcoholic cirrhosis is dependent on the nature and severity of associated conditions such as a gastrointestinal bleeding or ascitis the 5-year survival rate is 60% in those who abstain from alcohol and 30% in those who continue to drink. This condition appears to be more common in males than in female Laboratory abnormalities include increased liver function tests (AST, ALT, GGT, ALP, total bilirubin), decreased albumin, and a prolonged prothrombin time. A liver biopsy if the only method by which a definitive diagnosis may be made

 LECTURE 2