THE LIVER AND HEPATOBILIARY SYSTEM

THE LIVER AND HEPATOBILIARY SYSTEM Anca Bacârea, Alexandru Schiopu

The liver and biliary system

Metabolic functions of the liver • It produces bile; • It metabolizes hormones and drugs; • In its capacity for metabolizing drugs and hormones, the liver serves as an excretory organ. In this respect, the bile, which carries the end-products of substances metabolized by the liver, is much like the urine, which carries the body wastes filtered by the kidneys. • It synthesizes proteins, glucose, and clotting factors; • It stores vitamins and minerals; • It changes ammonia produced by deamination of amino acids to urea; • It converts fatty acids to ketones

Carbohydrate metabolism • The liver is especially important in maintaining glucose homeostasis. • It stores excess glucose as glycogen and releases it into the circulation when blood glucose levels fall. • The liver converts galactose and fructose to glucose and it synthesizes glucose from amino acids, glycerol, and lactic acid as a means of maintaining blood glucose during periods of fasting or increased need. • The liver also converts excess carbohydrates to triglycerides for storage in adipose tissue.

Lipid metabolism • Certain aspects of lipid metabolism occur mainly in the liver. These include: • The oxidation of fatty acids to supply energy for other body functions; • To derive energy from neutral fats (triglycerides), the fat must first be split into glycerol and fatty acids, and then the fatty acids split into acetyl-coenzyme A (acetyl-CoA). Acetyl-CoA can be used by the liver to produce adenosine triphosphate (ATP) or it can be converted to acetoacetic acid and released into the bloodstream and transported to other tissues, where it is used for energy. • The acetyl-CoA units from fat metabolism also are used to synthesize cholesterol and bile acids. • The synthesis of large quantities of cholesterol, phospholipids, and most lipoproteins; • Cholesterol can be esterified and stored, it can be exported bound to lipoproteins or it can be converted to bile acids. • The formation of triglycerides from carbohydrates and proteins.

Protein metabolism • The liver has the greatest rate of protein synthesis per gram of tissue. • It produces the proteins for its own cellular needs and secretory proteins that are released into the circulation. The most important of these secretory proteins is albumin. • Albumin contributes significantly to the plasma colloidal osmotic pressure and to the binding and transport of numerous substances, including some hormones, fatty acids, bilirubin, and other anions. • The liver also produces other important proteins, such as fibrinogen and the blood clotting factors.

Bile production and cholestasis • The secretion of bile, approximately 600 to 1200 mL daily, is one of the many functions of the liver. • Bile functions in the digestion and absorption of fats and fat-soluble vitamins from the intestine, and it serves as a vehicle for excretion of bilirubin, excess cholesterol, and metabolic end-products that cannot be eliminated in the urine. • Bile contains water, electrolytes, bile salts, bilirubin, cholesterol, and certain products of organic metabolism. • Approximately 94% of bile salts that enter the intestine are reabsorbed into the portal circulation by an active transport process that takes place in the distal ileum. From the portal circulation, the bile salts pass into the liver, where they are recycled. Normally, bile salts travel this entire circuit approximately 18 times before being expelled in the feces. • This system for recirculation of bile is called the enterohepatic circulation.

Bilirubin elimination • Bilirubin is formed during the breakdown of senescent red blood cells. • In the process of degradation, the heme portion of the hemoglobin molecule is oxidized to form biliverdin, which is then converted to free bilirubin. • Free bilirubin, which is insoluble in plasma, is transported in the blood attached to plasma albumin. Even when it is bound to albumin, this bilirubin is still called free bilirubin. • As it passes through the liver, free bilirubin is released from the albumin carrier molecule and moved into the hepatocytes. Inside the hepatocytes, free bilirubin is converted to conjugated bilirubin, making it soluble in bile. • Conjugated bilirubin is secreted as a constituent of bile, and in this form it passes through the bile ducts into the small intestine.

Bilirubin elimination • In the intestine, approximately one half of the bilirubin is converted into a highly soluble substance called urobilinogen by the intestinal flora. • Urobilinogen is either absorbed into the portal circulation or excreted in the feces. • Most of the urobilinogen that is absorbed is returned to the liver to be re-excreted into the bile. • A small amount of urobilinogen, approximately 5%, is absorbed into the general circulation and then excreted by the kidneys. • Usually, only a small amount of bilirubin (0.1 to 1.2 mg/dL) is found in the blood. Laboratory measurements of bilirubin usually measure the free and the conjugated bilirubin as well as the total bilirubin. These are reported as the direct (conjugated) bilirubin and the indirect (unconjugated or free) bilirubin.

Bilirubin elimination

Jaundice (icterus) • Jaundice (i.e., icterus), which results from an abnormally high accumulation of bilirubin in the blood, is a yellowish discoloration to the skin and deep tissues. • Jaundice becomes evident when the serum bilirubin levels rise above 2.0 to 2.5 mg/dL. • Bilirubin has a special affinity for elastic tissue. The sclera of the eye, which contains considerable elastic fibers, usually is one of the first structures in which jaundice can be detected.

Causes • The four major causes of jaundice are: • Excessive destruction of red blood cells • Impaired uptake of bilirubin by the liver cells • Decreased conjugation of bilirubin • Obstruction of bile flow in the canaliculi of the hepatic lobules or in the intrahepatic or extrahepatic bile ducts. • From an anatomic standpoint, jaundice can be categorized as: • Prehepatic • Intrahepatic • Posthepatic

Prehepatic (Excessive Red Blood Cell Destruction) Hemolytic blood transfusion reaction Hereditary disorders of the red blood cell Sickle cell anemia Thalassemia Spherocytosis Acquired hemolytic disorders Hemolytic disease of the newborn Autoimmune hemolytic anemias Intrahepatic Decreased bilirubin uptake by the liver Decreased conjugation of bilirubin Hepatocellular liver damage Hepatitis Cirrhosis Cancer of the liver Drug-induced cholestasis Posthepatic (Obstruction of Bile Flow) Structural disorders of the bile duct Cholelithiasis Congenital atresia of the extrahepatic bile ducts Bile duct obstruction caused by tumors Causes

Manifestations • In prehepatic jaundice there is: • Mild jaundice • The unconjugated bilirubin is elevated • The stools are of normal color • There is no bilirubin in the urine • Intrahepatic jaundice usually interferes with all phases of bilirubin metabolism—uptake, conjugation, and excretion: • Both conjugated and unconjugated bilirubin are elevated • The urine often is dark because of the presence of bilirubin • Posthepatic or obstructive jaundice, also called cholestatic jaundice, occurs when bile flow is obstructed between the liver and the intestine: • Conjugated bilirubin levels usually are elevated • The stools are clay colored because of the lack of bilirubin in the bile • The urine is dark • The levels of serum alkaline phosphatase are markedly elevated • The aminotransferase levels are slightly increased • Blood levels of bile acids often are elevated in obstructive jaundice. As the bile acids accumulate in the blood, pruritus develops.

Tests of hepatobiliary function • The history and physical examination; • Elevated serum enzyme tests usually indicate liver injury earlier than do other indicators of liver function. • The key enzymes are alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which are present in liver cells. • In most cases of liver damage, there are parallel increases in ALT and AST. The most dramatic rise is seen in cases of acute hepatocellular injury, such as occurs with viral hepatitis, hypoxic or ischemic injury, and acute toxic injury. • The liver’s synthetic capacity is reflected in measures of serum protein levels and prothrombin time (i.e., synthesis of coagulation factors). Hypoalbuminemia caused by depressed synthesis may complicate severe liver disease. • Serum bilirubin, γ-glutamyltransferase (GGT), and alkaline phosphatase measure hepatic excretory function. • Ultrasonography and computed tomography (CT) scanning; • Selective angiography; • Liver biopsy.

Hepatitis • Hepatitis refers to inflammation of the liver. • It can be caused by: • Hepatotropic viruses that primarily affect liver cells or hepatocytes; • Reactions to chemical agents, drugs, and toxins; • Autoimmune diseases; • Infectious mononucleosis that cause secondary hepatitis.

Acute viral hepatitis • The known hepatotropic viruses include hepatitis A virus (HAV), hepatitis B virus (HBV), the hepatitis B-associated delta virus (HDV), hepatitis C virus (HCV), and hepatitis E virus (HEV). • Although all of these viruses cause acute hepatitis, they differ in the mode of transmission and incubation period, mechanism, degree, and chronicity of liver damage, and ability to evolve to a carrier state. • There are two mechanisms of liver injury in viral hepatitis: • Direct cellular injury; • Immune responses against viral antigens in infected hepatocytes; • It is thought that the extent of inflammation and necrosis depends on the person’s immune response.

Acute viral hepatitis • A prompt immune response during the acute phase of the infection would be expected to cause cell injury but at the same time eliminate the virus. • People who respond with fewer symptoms and a marginal immune response are less likely to eliminate the virus, and hepatocytes expressing the viral antigens persist, leading to the chronic or carrier state. • Fulminant hepatitis would be explained in terms of an accelerated immune response with severe liver necrosis.

Manifestations • The manifestations of acute hepatitis can be divided into three phases: • 1. Theprodromal period - preicterus phase • Is marked by nonspecific symptoms, which vary from abrupt to insidious. There are usually complaints of malaise, easy fatigability, nausea, and loss of appetite. Weight loss, low-grade fever, headaches, muscle aches and pains, vomiting, and diarrhea are less constant symptoms. In some persons, the nonspecific symptoms are more severe sometimes accompanied by right upper quadrant abdominal pain and liver enlargement and tenderness. • Serum levels of AST and ALT show variable increases and precede a rise in serum bilirubin that accompanies the onset of the icterus or jaundice phase of infection. • 2. Theicterus or jaundice phase • If it occurs, usually follows the prodromal phase by 5 to 10 days. Jaundice is less likely to occur with HCV infection. • The symptoms may become worse with the onset of jaundice, followed by progressive clinical improvement. • Severe pruritus and liver tenderness are common duringthe icterus period.

Manifestations • The manifestations of acute hepatitis can be divided into three phases: • 3. Theconvalescent phase • It is characterized by an increased sense of well-being, return of appetite, and disappearance of jaundice. • The acute illness usually subsides gradually during a 2- to 3-week period, with complete clinical recovery by approximately 9 weeks in hepatitis A and 16 weeks in uncomplicated hepatitis B. • Infection with HBV and HCV can produce a carrier state, in which the person does not have symptoms but harbors the virus and can transmit the disease. Evidence also indicates a carrier state for HDV infection.

Carrier state • There are two types of carriers: • Healthy carriers who have few or no ill effects • Those with chronic disease who may or may not have symptoms • Factors that increase the risk of becoming a carrier are age at time of infection and immune status. • Persons at high risk for becoming carriers are: • Infants of HBV-infected mothers • Persons with impaired immunity • Those who have received multiple transfusions or blood products • Those who are on hemodialysis • Drug addicts

Chronic viral hepatitis • Chronic viral hepatitis is the principal cause of chronic liver disease, cirrhosis, and hepatocellular cancer in the world and now ranks as the chief reason for liver transplantation in adults. • Chronic hepatitis B accounts for 5% to 10% of chronic liver disease and cirrhosis in the United States. Hepatitis B is less likely than hepatitis C to progress to chronic infection. • Chronic hepatitis C accounts for most cases of chronic viral hepatitis. HCV infection becomes chronic in 75% to 80% of cases. • Chronic HCV infection often smolders during a period of years, silently destroying liver cells. Most persons with chronic hepatitis C are asymptomatic. Because the course of acute hepatitis C often is mild, many persons do not recall the events of the acute infection.

Autoimmune hepatitis • Chronic autoimmune hepatitis is a chronic inflammatory liver disease of unknown origin, but it is associated with circulating autoantibodies and high serum gamma globulin levels. • Autoimmune hepatitis accounts for only approximately 10% of chronic hepatitis cases in the United States. • The pathogenesis of the disorder is one of a genetically predisposed person exposed to an environmental agent that triggers an autoimmune response directed at liver cell antigens. • The factors surrounding the genetic predisposition and the triggering events that lead to the autoimmune response are unclear. • The resulting immune response produces a necrotizing inflammatory response that eventually leads to destruction of liver cells and development of cirrhosis. • Autoimmune hepatitis is mainly a disease of young women, although it can occur at any age and in men or women.

Alcohol-induced liver disease • The spectrum of alcoholic liver disease includes fatty liver disease, alcoholic hepatitis, and cirrhosis. • Because only approximately 10% to 15% of alcoholics have cirrhosis, it was suggested that other conditions such as genetic and environmental factors contribute to its occurrence. • Fatty liver • It is characterized by the accumulation of fat in hepatocytes, a condition called steatosis. • The pathogenesis of fatty liver is not completely understood and can depend on the amount of alcohol consumed, dietary fat content, body stores of fat, hormonal status, and other factors. • There is evidence that ingestion of large amounts of alcohol can cause fatty liver changes even with an adequate diet. • The fatty changes that occur with ingestion of alcohol usually do not produce symptoms and are reversible after the alcohol intake has been discontinued.

Alcohol-induced liver disease • Alcoholic hepatitis is the intermediate stage between fatty changes and cirrhosis. • It often is seen after an abrupt increase in alcohol intake. • Alcoholic hepatitis is characterized by inflammation and necrosis of liver cells. • This stage usually is characterized by hepatic tenderness, pain, anorexia, nausea, fever, jaundice, ascites, and liver failure, but some individuals may be asymptomatic. • The condition is always serious and sometimes fatal. • In persons who survive and continue to drink, the acute phase often is followed by persistent alcoholic hepatitis, with progression to cirrhosis in a matter of 1 to 2 years.

Cirrhosis • Cirrhosis represents the end stage of chronic liver disease in which the normal architecture of the liver is replaced by fibrous septa that encompass regenerative nodules of hepatic tissue. • Although cirrhosis usually is associated with: • Alcoholism • Viral hepatitis • Toxic reactions to drugs and chemicals • Biliary obstruction • Metabolic disorders that cause the deposition of minerals in the liver: • Hemochromatosis (i.e., iron deposition) • Wilson’s disease (i.e., copper deposition)

Cirrhosis • The manifestations of cirrhosis are variable, ranging from asymptomatic hepatomegaly to hepatic failure. Often there are no symptoms until the disease is far advanced. • The most common signs and symptoms of cirrhosis are: • Weight loss (sometimes masked by ascites) • Weakness • Anorexia • Diarrhea frequently is present, although some persons may report constipation • Hepatomegaly • Splenomegaly and thrombocytopenia • Bleeding caused by decreased clotting factors; Jaundice • Abdominal pain because of liver enlargement or stretching of Glisson’s capsule • The late manifestations of cirrhosis are related to portal hypertension and liver failure

Portal hypertension • Portal hypertension is characterized by increased resistance to flow in the portal venous system and sustained portal vein pressure above 12 mm Hg (normal, 5–10 mm Hg). • Venous blood returning to the heart from the abdominal organs collects in the portal vein and travels through the liver before entering the vena cava. • Portal hypertension can be caused by a variety of conditions that increase resistance to hepatic blood flow, including prehepatic, posthepatic, and intrahepatic obstructions. • Complications of portal hypertension arise from the increased pressure and dilatation of the venous channels behind the obstruction. • Collateral channels open that connect the portal circulation with the systemic circulation. • The major complications of the increased portal vein pressure and the opening of collateral channels are: • Ascites • Splenomegaly • Formation of portosystemic shunts (i.e., esophageal varices, anorectal varices, and caput medusae).

Pathogenesis • Prehepatic obstruction • Portal vein thrombosis and external compression caused by cancer or enlarged lymph nodes that produce obstruction of the portal vein before it enters the liver. • Posthepatic • Any obstruction to blood flow through the hepatic veins beyond the liver lobules, either within or distal to the liver. • It is caused by conditions such as: • Thrombosis of the hepatic veins • Venoocclusive disease • Severe right-sided heart failure that impede the outflow of venous blood from the liver • Intrahepatic obstructions (with hepatic referring to the liver lobules, rather than the entire liver) • Conditions that cause obstruction of blood flow within the liver • Alcoholic cirrhosis is the major cause of portal hypertension

Complications of portal hypertension

THE LIVER AND HEPATOBILIARY SYSTEM