The Hepatobiliary System

Chapter 13 The Hepatobiliary System



Ivan Damjanov, MD, PhD




1 What are the main diseases of the liver and the biliary system?



image Disorders of bilirubin metabolism and excretion resulting in jaundice

image Acute and chronic hepatitis caused by viruses, bacteria, and other pathogens

image Diseases caused by drugs, toxins, and alcohol

image Metabolic and genetic diseases

image Autoimmune diseases

image Cholelithiasis

image Tumors


2 What are the most common morphologic signs of liver injury?


Hepatocytes are the main target of liver injury. Morphologically, liver injury can manifest in several forms:


image Vacuolar change: Affected hepatocytes are enlarged and have a swollen, clear cytoplasm. This hydropic swelling of hepatocytes is a common response to injury. It is reversible, but if intensified or prolonged, it may lead to liver cell necrosis.

image Apoptosis: The hepatocytes undergoing apoptosis appear rounded and detach from the other liver cells. They have a pyknotic nucleus, which ultimately disappears, leaving the remaining cytoplasm as a “round red body,” also known as acidophilic body. Apoptosis of single hepatocytes is a typical feature of viral hepatitis, but it may be induced by other liver diseases as well.

image Necrosis: Irreversible injury of hepatocytes induced by ischemia, toxins, and viruses typically involves portions of the liver acinus. It is customary to describe necrosis as either focal (random) or zonal, if limited to one of the three zones of the liver acinus. Zone 3 necrosis (also known as centrolobular necrosis) is the most common form of necrosis and is found in ischemic liver injury (e.g., in hypotensive shock) but also in many forms of toxic liver injury.


Key Points: The Hepatobiliary System



1. The liver is a central metabolic organ involved in all metabolic pathways; thus it is affected by most systemic diseases and is a common site of adverse drug reactions.

2. The liver is the source of bile and thus a cause of biliary diseases and jaundice.

3. End-stage liver disease, called cirrhosis, is a fatal disease that can be treated only by liver transplantation.


3 How does the liver respond to injury?



image Inflammation: Injured liver cells must be removed. To this end, the body sends in inflammatory cells that react with injured hepatocytes. For example, hepatocytes infected with hepatitis virus elicit a T-cell response. These lymphocytes enter the liver and kill the infected hepatocytes, which are thereafter removed by macrophages.

image Regeneration: Liver cells are stable facultative mitotic cells that can enter into the mitotic cycle on demand and by dividing replace the damaged cells. Regeneration of the liver is a major response of the liver to injury. In experimental animals, it has been shown that the liver can regenerate even after two thirds of it has been removed. Massive necrosis induced by toxins and viruses typically elicits a major regeneration wave, but in many instances, this is not sufficient to save the patient’s life. However, focal necrosis and apoptosis are easily repaired.

image Fibrosis: Extensive necrosis, especially if accompanied by persistent inflammation or toxic influences, cannot be repaired by regeneration. Portions of the liver are replaced by connective tissue scars. Fibrosis associated with nodular regeneration of the remaining hepatocytes is typical of end-stage liver disease, known as cirrhosis.


4 How is liver function evaluated clinically?


Liver function is evaluated with laboratory tests colloquially known as liver function tests (LFTs). These tests were designed to monitor the following:


image Liver cell integrity (known as necroinflammatory indices)

image Hepatic secretory function

image Biliary excretory function

image Hepatic catabolic function


5 Discuss the necroinflammatory indices, that is, the laboratory tests used to monitor the integrity of liver cells


The most widely used tests are those measuring the blood concentration of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In massive liver necrosis (e.g., after acetaminophen intoxication), blood levels of AST and ALT increase 50 times over the normal values. In viral hepatitis, levels of AST and ALT are 4 to 6 times above the normal values.



6 Which tests are used to measure hepatic secretory function?



image Albumin: Normally, the blood contains 3.5 to 5.0 g/dL (35–50 g/L) albumin, the most copious plasma protein. Chronic liver injury will reduce blood concentration of albumin to less than 3 g/dL.

image Coagulation proteins: The easiest way to estimate the concentration of the coagulation factors is by measuring the prothrombin time (PT), which is normally 10 to 13 seconds. Prolonged PT is a sensitive index of liver function loss.


7 Discuss the tests used to measure biliary excretion



image Bilirubin: Bilirubin that has been conjugated in the liver to be excreted into the intestine may accumulate in the blood of patients who have bile duct obstruction.

image Alkaline phosphatase: This enzyme is found along the liver cell membrane lining the intercellular canaliculi. Obstructive jaundice interferes with the normal biliary elimination of this enzyme, which then appears in the blood. Elevated levels of alkaline phosphatase in blood are typical of obstructive jaundice.

image Gamma-glutamyltransferase (GGT): In contrast to alkaline phosphatase, which is found in many other organs, GGT is primarily a hepatic enzyme. Elevation of GGT is a reliable sign of biliary obstruction. However, GGT is also induced in liver cells by alcohol or phenobarbital and some other drugs that stimulate the P450 system. GGT is thus a marker of liver cell injury (especially alcohol-induced injury).


8 Which tests are used for estimating liver catabolic functions?


Catabolic functions of the liver include the detoxification of many metabolites. However, it is impractical to measure these functions and, in practice, the only function that is monitored is the capacity of the liver to remove ammonia. Elevation of blood ammonia is a good marker of severe liver injury.



JAUNDICE



9 Define jaundice


Jaundice, or icterus, is a yellow discoloration of the skin, sclerae, and mucous membranes due to increased levels of bilirubin in circulation. Normally, blood contains 0.5 to 1.2 mg/dL of bilirubin. Jaundice becomes apparent when the blood levels of bilirubin reach the concentration of 2.5 to 3.0 mg/dL.



10 Describe how bilirubin is formed


Bilirubin is produced at a constant rate of approximately 4 mg/kg body weight per day. Accordingly, 200 to 300 mg of bilirubin is produced daily in the body. Bilirubin stems from the following:


image Normal hemolysis of senescent red blood cells (85%)

image Inefficient hematopoiesis (i.e., heme not utilized for the synthesis of hemoglobin in nascent red blood cells in the bone marrow; 10%)

image Release of hemoproteins (e.g., cytochrome P450) from senescent hepatocytes and other somatic cells (5%)


11 How is bilirubin processed?


The major steps in the processing and excretion of bilirubin derived from senescent red blood cells are as follows:


image Release of heme, a tetrapyrrole component of hemoglobin

image Transformation of heme into biliverdin in the fixed macrophages of the spleen and the liver

image Reduction of biliverdin to bilirubin, which is released into the circulation

image Binding of bilirubin to albumin (Bilirubin bound to albumin is not water soluble and does not appear in urine. In clinical laboratories, it is measured as indirect bilirubin.)

image Transport of albumin-bound bilirubin to the liver (It is worth remembering that this bilirubin is called unconjugated or indirect bilirubin.)

image Uptake of bilirubin by hepatocytes

image Conjugation of bilirubin to glucuronic acid (This is accomplished by a microsomal hepatic enzyme, bilirubin–uridine diphosphate–glucuronyltransferase [UGT]. The bilirubin glucuronidating isoform of this enzyme is called UGT1A1.)

image Excretion of water-soluble bilirubin glucuronides in bile (This bilirubin is called conjugated or direct bilirubin.)

image Deconjugation of some bilirubin glucuronides by bacteria in the intestine (This process leads to the formation of colorless urobilinogen, 80% of which is excreted in feces together with the remaining conjugated bilirubin.)

image Recirculation of urobilinogen in an enterohepatic cycle (Approximately 20% of urobilinogen is recirculated and returned to the liver. A small amount of urobilinogen is excreted in urine.)


12 Why is it important to fractionate bilirubin in the serum?


Fractionation of bilirubin is used for elucidating the causes and pathogenesis of jaundice. Pathologists can fractionate total serum bilirubin and determine the ratio of unconjugated bilirubin, also known as indirect bilirubin, to conjugated bilirubin (CB), also known as direct bilirubin. Normally, blood contains less than 1.2 mg/dL (20 μmol/L) of bilirubin, most of it in an unconjugated form (95%).


According to laboratory analysis, hyperbilirubinemia can be classified as follows:


image Predominantly unconjugated (CB < 20%)

image Mixed (CB 20%–50%)

image Predominantly conjugated (CB > 50%)


Key Points: Jaundice



1. There are three forms of jaundice: hemolytic, hepatic, and obstructive jaundice.

2. Jaundice can be caused by inborn errors of metabolism.

3. Hepatic jaundice, characterized by elevation of conjugated and unconjugated bilirubin, is most often caused by viral or drug-induced hepatitis.

4. Obstructive jaundice can be caused by hepatic and extrahepatic lesions, primarily those affecting the common bile duct.


13 Describe the main forms of jaundice


Three pathogenetic forms of jaundice are recognized clinically (Fig. 13-1):


image Prehepatic hemolytic jaundice: Bilirubin is predominantly in an unconjugated form.

image Hepatic jaundice: Bilirubin is partially in a conjugated and partially in an unconjugated form.

image Posthepatic obstructive jaundice: Bilirubin is mostly in a conjugated form.

image

Figure 13-1 Jaundice. Three pathogenetic forms of jaundice are recognized: prehepatic jaundice resulting from hemolysis, hepatic jaundice resulting from liver cell injury, and posthepatic jaundice resulting from the obstruction of major extrahepatic biliary ducts.


(Modified from James EC, Corry RJ, Perry JF, Jr: Principles of Basic Surgical Practice. Philadelphia, Hanley & Belfus, 1987, p. 271.)



14 Is bilirubin present in urine in all forms of jaundice?


Unconjugated bilirubin, typically found in hemolytic jaundice, circulates bound to albumin. This bilirubin–albumin complex does not pass into the urine. On the other hand, conjugated bilirubin typically found in the blood of patients suffering from hepatocellular or obstructive jaundice is water soluble and will readily pass into urine.



15 What are the main causes of predominantly unconjugated hyperbilirubinemia?


Unconjugated bilirubinemia is most often caused by hemolysis. The most important clinical conditions in this category are as follows:


image Autoimmune hemolytic anemia

image Transfusion reaction due to the hemolysis of donor red blood cells (RBCs) by recipient’s natural anti-AB antibodies

image Malaria (infestation of RBCs with parasites, leading to hemolysis)

image Erythroblastosis fetalis (transplacental immunization of the mother to fetal RBC antigens, reacting with RBCs of the second baby and causing severe hemolysis in the fetus or neonate. This results in kernicterus, i.e., deposition of bilirubin in basal ganglia of the baby’s brain.)

image Resorption of bilirubin from internal hemorrhages (e.g., massive hematoma and intestinal hemorrhage)

image Inefficient hematopoiesis in the bone marrow (e.g., pernicious anemia and thalassemia)


16 Can unconjugated hyperbilirubinemia be caused by liver disease?


Yes. This typically occurs because of impaired uptake of bilirubin or impaired conjugation of bilirubin taken up by the liver cells.


Impaired uptake by damaged hepatocytes is seen in viral hepatitis or drug-induced liver injury (e.g., probenecid-related jaundice).


Defect of conjugation of bilirubin is the cause of unconjugated hyperbilirubinemia in some genetic disorders, such as Crigler–Najjar syndrome or Gilbert syndrome.



17 What is the cause of jaundice in genetic diseases characterized by unconjugated hyperbilirubinemia?


Crigler–Najjar syndrome, which occurs in two forms (severe, fatal Type I and a milder Type II), and Gilbert syndrome are caused by defective function of UGT and present with unconjugated hyperbilirubinemia.



18 Name the most common genetic form of jaundice


Gilbert’s syndrome is the most common form of hereditary jaundice, affecting approximately 5% of the population at large. This autosomal dominant disorder has been linked to a mutation of the gene encoding UGT1A1. This mutation is associated with reduced enzymatic activity of UGT1A1, resulting in fluctuating hyperbilirubinemia.



19 How does Gilbert syndrome present clinically?


Gilbert syndrome presents as mild jaundice unrelated to any other symptoms. It is typically diagnosed during the investigation of jaundice that has appeared in the course of some common disease (e.g., flu) that usually does not affect the liver. Jaundice may also be precipitated by minor stress (e.g., medical school examinations), exercise, or fasting. Jaundice is not accompanied by any other symptoms and subsides on its own. Patients should be assured that the disease is not progressive and that no treatment is required.



20 Could genetic diseases present as benign isolated conjugated hyperbilirubinemia?


Rare genetic disease related to abnormal processing and biliary excretion of bilirubin from liver cells may cause conjugated hyperbilirubinemia. The most important diseases in this category are Dubin–Johnson syndrome, a jaundice caused by the mutation of the multidrug resistance protein 2 (MRP2) and Rotor syndrome, a disease of unknown genetics.



21 List common causes of mixed hyperbilirubinemia


Mixed hyperbilirubinemia is a sign of “hepatic jaundice” and it is typically seen in:


image Viral hepatitis

image Alcoholic hepatitis

image Drug-induced hepatitis

image Cirrhosis (usually mild)


22 What is the difference between intrahepatic and extrahepatic biliary obstruction?


Intrahepatic and extrahepatic biliary obstruction cause elevation of conjugated bilirubin. In both conditions, hyperbilirubinemia is associated with an elevation of alkaline phosphatase in blood. However, because the intrahepatic cholestasis may cause or even result from liver cell or bile ductular injury, it is usually accompanied by additional laboratory abnormalities (e.g., elevation of LFTs), immunologic abnormalities (such as antimitochondrial antibodies in primary biliary cirrhosis), or virologic data (e.g., hepatitis B virus antibodies). Extrahepatic biliary obstruction often presents with progressively worsening jaundice and pale (“acholic”) stools and few other symptoms. Prolonged jaundice of any type is associated with itching.



23 What are the most important causes of intrahepatic cholestasis?



image Viral hepatitis

image Drug-induced hepatitis

image Sepsis

image Postsurgical jaundice

image Benign cholestasis of pregnancy

image Primary biliary cirrhosis

image Autoimmune hepatitis

image Primary sclerosing cholangitis


24 List the most important causes of extrahepatic biliary obstruction in adults



image Stones in the common bile duct

image Carcinoma of the pancreas

image Carcinoma of the common bile duct and ampulla of Vater

image Postsurgical stenosis of bile ducts


25 What are the most common causes of biliary obstruction in infants and children?



image Congenital atresia of bile ducts, which is usually idiopathic

image Cystic fibrosis

A mnemonic for remembering the causes of obstructive jaundice is gallstone:


Gallstones

Adenocarcinoma (of pancreas or common bile duct)

Liver diseases (primary biliary cirrhosis and primary sclerosing cholangitis)

Lymph node enlargement in the hilus

Surgery (postsurgical scarring)

Treatment related (drugs and cholangiography)

Outside invasion (e.g., ascaris and other worms)

Neonatal atresia of bile ducts

Extraneous compression (e.g., cysts and adhesions)


HEPATIC FAILURE



26 Compare acute and chronic liver failure


Acute liver failure is a disease of sudden onset that may cause death in a few days or weeks. Typically, it is associated with massive hepatic necrosis following viral infection, adverse drug reaction, or ingestion of toxins. Chronic liver failure develops over a period of years and is typically associated with cirrhosis. Cirrhosis is used as a synonym for end-stage chronic liver disease and, as such, it may be caused by a number of preexisting diseases.



27 What are the features of acute liver failure?



image Jaundice of sudden onset

image Shrinkage of the liver best seen on ultrasound examination

image Massive elevation of AST, ALT, and lactate dehydrogenase

image Hypoglycemia

image Bleeding tendency with prolongation of PT

image Hepatic encephalopathy and hyperammonemia

image Electrolyte disturbances, water retention, and renal failure


28 What are the clinical features of chronic liver failure?



image Cirrhosis with changes in the shape and size of the liver best visible by computed axial tomography (CAT) scan

image Portal hypertension

image Splenomegaly

image Hypoalbuminemia

image Ascites

image Bleeding tendency and prolonged PT, low plasma fibrinogen

image Hepatorenal syndrome resulting in water and sodium retention

image Hepatopulmonary syndrome resulting in dyspnea

image Endocrine changes associated with gynecomastia, palmar erythema, and spider nevi

image Hepatic encephalopathy with fetor hepaticus and asterixis

image Increased incidence of infections (e.g., peritonitis due to infection of ascites)

A mnemonic for the consequences of liver failure is jaundice:


Jaundice

Ascites

Urinary failure (i.e., hepatorenal syndrome)

Neurologic (i.e., hepatic encephalopathy)

Dyspnea (i.e., hepatopulmonary syndrome)

Infections (increased incidence)

Coagulopathy (prolonged PT and bleeding esophageal varices)

Endocrine (gynecomastia, spider angiomas, and testicular atrophy)


Key Points: Hepatic Failure



1. Hepatic failure may develop suddenly or slowly over a period of time.

2. The main signs and symptoms of liver failure are consequences of metabolic disturbances and portal hypertension.


29 Define portal hypertension


The portal system drains the venous blood from the gastrointestinal system into the liver. It comprises the portal vein and its tributaries—the splenic vein, the mesenteric veins, and the gastric veins. In normal circumstances, the blood flows through the portal system under low pressure (7 mmHg). Portal hypertension is elevation of the portal venous blood pressure over the normal value of 12 mmHg.



30 What are the main forms of portal hypertension?


Three forms of portal hypertension are recognized depending on the site of obstruction:


image Presinusoidal: This is due to obstruction of the portal vein or its major intrahepatic branches. Typically, this occurs in portal vein thrombosis or fibrosis of bile ducts (e.g., schistosomiasis) that affects the adjacent blood vessels in the liver.

image Sinusoidal: This is due to intrahepatic obstruction of blood flow through the sinusoids. It accounts for 90% of all cases of portal hypertension and is typically a feature of cirrhosis.

image Postsinusoidal: This is due to obstruction of the hepatic vein and its tributaries by thrombi (e.g., Budd–Chiari syndrome) or tumors.


31 What are the consequences of portal hypertension?



image Ascites

image Splenomegaly

image Anastomoses between the portal and systemic veins


32 Where do portal–systemic anastomoses develop in portal hypertension?


Shunting of portal venous blood into the systemic circulation occurs at three anatomic sites:


image Esophageal and gastric veins: Esophageal varices are the most common site of massive bleeding in patients with chronic liver disease. Exsanguination from ruptured esophageal varices is a major cause of death in cirrhosis.

image Hemorrhoidal venous plexus: Hemorrhoids are a common cause of hematochezia.

image Periumbilical veins: Varices develop rarely in this location but can be seen on physical examination as whorls of dilatated veins (caput medusae).


33 Discuss the pathogenesis of ascites in cirrhosis


The pathogenesis of ascites is not fully understood, but it appears to be a consequence of several disturbances found in patients with cirrhosis (Fig. 13-2):


image Portal hypertension: Increased hydrostatic pressure leads to transudation of fluid into the abdominal cavity.

image Hypoalbuminemia: Cirrhotic livers cannot produce albumin in adequate amounts, and hypoalbuminemia is a common finding in these patients. Hypoalbuminemia is associated with reduced oncotic pressure of the plasma and reduced reentry of fluid into the blood vessels at the venular side of the microcirculation.

image Lymphatic overflow: The lymph flow through the thoracic duct in patients with cirrhosis exceeds the capacity of this duct to drain the lymph from the portal area, and it “overflows” into the abdominal cavity.

image Hyperaldosteronism: The escape of fluids from blood vessels into the abdominal cavity is recognized by the volume regulatory sensors as “depletions” of circulating fluid mass, which triggers a release of aldosterone. Aldosterone acts at the level of renal tubules, conserving sodium and water, which then flows over into the abdominal cavity, further contributing to the formation of ascites.

image

Figure 13-2 Pathogenesis of ascites.



34 What is the pathogenesis of hepatorenal syndrome?


Hepatorenal syndrome is defined as sudden functional renal failure (i.e., without an underlying kidney disease) in a patient with end-stage liver failure. The exact pathogenesis of this complication of cirrhosis is not known, but all data indicate that the renal failure is caused by hypoperfusion of kidneys. It presents with oliguria and retention of water and sodium. If the patient dies, his or her kidneys can be transplanted into another person and will function normally.



35 Explain the pathogenesis of palmar erythema, gynecomastia, and spider angiomas in patients with cirrhosis


These signs of end-stage liver disease are related to hyperestrinism. Hyperestrinism results from decreased degradation of steroid hormones in the diseased liver. Weak estrogens normally produced in all men are then converted in peripheral fat tissues into more potent estrogens, which in turn act on the breast to produce gynecomastia or on the blood vessels of the skin to induce palmar erythema and spider angiomas.



36 Explain the bleeding tendency commonly found in patients with cirrhosis



image Reduced concentration of coagulation factors in blood: One should remember that most of the plasma coagulation factors are produced in the liver. Loss of synthetic activity of hepatocytes results in hypofibrinogenemia and reduced levels of all other coagulation proteins. Typically PT and activated partial thromboplastin time are prolonged.

image Thrombocytopenia: The low platelet count is caused by splenomegaly, which leads to a sequestration of platelets and their destruction in the spleen.

image Disseminated intravascular coagulation (DIC): Irregular blood flow through the liver makes the hepatocytes prone to ischemia and necrosis. Necrosis, typically precipitated by sudden onset of hepatic hypoperfusion (e.g., after massive bleeding from the esophageal varices), will result in a release of thromboplastin and activation of the coagulation cascade. Patients with cirrhosis are also prone to infections, which may potentiate DIC.

Massive uncontrollable bleeding is a major cause of death in patients with cirrhosis.



INFECTIOUS DISEASES



37 Discuss the most important infectious diseases affecting the liver



image Viral diseases: These diseases are most often caused by hepatotropic viruses (e.g., hepatitis virus A, B, and C) but also may occur in the course of other viral infections (e.g., herpes simplex and cytomegalovirus [CMV]).

image Bacterial diseases: These diseases are caused by ascending infection from the intestine or by hematogenous dissemination of bacteria from other organs.

image Parasitic diseases: These diseases occur most often in the tropics and include a variety of intestinal infestations (e.g., amebiasis and schistosomiasis).


38 What is viral hepatitis?


Although hepatitis may be caused by many viruses, the term viral hepatitis is reserved in clinical practice for infections caused by the hepatotropic viruses. Only six viruses have been definitively identified (A–E and G). One of these is a DNA virus (hepatitis B virus [HBV]), one is an incomplete RNA virus (hepatitis virus type D [HDV]), and the remaining four are RNA viruses.



39 Do all hepatitis viruses belong to the same group, and do they share the same structural properties?


Hepatitis viruses do not belong to the same group: Hepatitis A virus (HAV) is a picornavirus, HBV is a hepadna virus, hepatitis C virus (HCV) is a flavivirus, and hepatitis E virus (HEV) is a calicivirus. Accordingly, immunity against one virus will not protect against other viruses.



Key Points: Infectious Diseases



1. Infection by hepatotropic viruses is the most important form of infectious hepatitis.

2. Viral hepatitis can occur in an acute and chronic form, and in some instances it can progress to cirrhosis or even predispose to liver cancer.


40 Is liver biopsy useful for diagnosing acute viral hepatitis?


Liver biopsy is rarely used in the diagnostic workup of a patient suspected of having acute viral hepatitis. The main reasons for the uncommon use of liver biopsy for diagnosing acute viral hepatitis are as follows:


image The changes caused by various hepatotropic viruses are nonspecific. Microscopically, acute HAV cannot be distinguished from HBV or other hepatitides of this type.

image Serologic tests for hepatitis viruses, which are much more specific and less expensive, are the diagnostic method of choice for diagnosing viral hepatitides.

image Liver biopsy is an invasive procedure. It is used only after all other approaches have found negative results. It is performed by highly trained specialists and requires hospitalization of the patient. It carries a small risk for potentially serious complications (e.g., bleeding).


41 Which viral diseases are best diagnosed by liver biopsy?


When a patient develops acute viral hepatitis, serologic tests will usually identify the causative pathogen. However, if the serologic tests for viral hepatitides are negative, liver biopsy may provide insight into the clinical problem. For example, if the disease is caused by herpes virus or CMV, the liver biopsy may disclose intranuclear viral particles. However, because many drugs may produce “virus hepatitis-like changes,” even this approach will not yield absolutely diagnostic results. Accordingly, liver biopsy is used in clinical practice as the last resort for evaluating acute liver diseases. It is useful for estimating the extent of liver injury and is widely used for estimating the extent and degree of chronic hepatitis and for documenting cirrhosis. Liver biopsy is also used for evaluating liver transplant rejection.

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Jul 23, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on The Hepatobiliary System

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