#38910: Pathophysiology: The Hepatobiliary System

Each liver lobule is composed of plate like "spokes" of hepatic cells that radiate from a "hub" or central vein that passes through the connective tissue between lobules. The central veins are branches of the portal vein that, together with the portal artery, furnish the blood supply of the liver. Bile is manufactured in the hepatic plates, each of which is generally two cells thick. Tiny bile canaliculi, or bile channels, lying between the hepatic plates carry the bile to bile ducts. Like tributaries forming ever larger streams, the bile ducts merge to form larger ducts. Eventually, they form two hepatic ducts, one from the right lobe and one from the left. These in turn join to form a single hepatic duct that merges with the cystic duct to form the common bile duct. Bile manufactured by the liver, together with bile stored and later secreted by the gallbladder, leaves the hepatic-biliary system via the common bile duct [5].

The septa between lobules contain venules and arterioles, both of which drain into the hepatic sinusoids, where venous and arterial blood mingle. This mingling is related to the detoxifying and metabolic functions of the hepatic system. Plasma, including proteins, can diffuse out of the blood. For example, nutritive or toxic substances carried from the intestine in the blood diffuse through the epithelial lining of the sinusoids into the hepatic cells, where they are metabolized, stored, or altered. The sinusoids are also lined by Kupffer cells, phagocytic cells that remove bacteria and other foreign substances from blood that passes through the liver [5].

The liver is richly supplied with both arterial and venous blood. Each minute, approximately 1,100 mL arrives from the hepatic portal vein and 400 mL from the hepatic artery to mix in the sinusoids before returning to the heart via the inferior vena cava. Portal venous blood coming from the intestines has a low concentration of oxygen but a high concentration of substances absorbed by the intestine during digestion. Blood coming from the hepatic artery is high in oxygen but low in nutrients. The pressure of blood in the portal and haptic veins is low, allowing easy diffusion of nutrients and other substances along the concentration gradients. Oxygen-rich blood from the hepatic artery maintains the integrity of the liver; if perfusion is absent or diminished, necrosis of hepatic cells will occur [5].

Arterial and venous vessels, bile ducts, and lymphatic vessels travel together through the liver in so-called portal tracts. The direction of flow is from the portal tracts through the sinusoids and into the central veins of the liver lobules. Thus, oxygen and nutrient supply is richest in the hepatic cells nearest the portal tracts and poorest near the central veins. The cells adjacent to the central veins, due to their relatively poor nutritional state, are more susceptible to damage from circulatory disturbances (e.g., shock, heart failure) and more vulnerable to toxins than the outermost cells [5].

The liver is capable of storing a considerable quantity of blood, the amount depending on the pressure relationships in the arteries and veins. If pressure in the hepatic veins increases by a few millimeters of mercury (e.g., in the presence of congestive heart failure, cirrhosis, or hepatic congestion), as much as 300–400 mL of blood may be stored. If hemorrhage occurs anywhere in the body, the liver releases this stored blood into the circulatory system to maintain circulatory volume [6].

The phagocytic Kupffer cells lining the sinusoids normally remove 99% to 100% of bacteria from blood entering the liver. Kupffer cells multiply in response to increased levels of foreign particles in the blood. Because blood entering the liver through the portal vein contains intestinal bacteria, the Kupffer cells play an important role in the body's defense against infection. Any condition that damages these cells or inhibits their replication increases the body's susceptibility to infection [6].

The hepatic cells of each liver lobule continually secrete small amounts of bile, a thick, greenish-yellow, slightly alkaline fluid. When first secreted from the liver through the canaliculi, bile is composed of water, bile salts, bilirubin, cholesterol, fatty acids, and lecithin as well as sodium, potassium, calcium, chloride, and bicarbonate ions [5,6].

Bile is concentrated in the gallbladder, which contracts during digestion to send it into the duodenum, where it functions as kind of "biological detergent" to emulsify fat particles. The bile salts decrease the surface tension of fat particles so the agitation of the intestinal tract can break them into small globules easily acted upon by digestive enzymes. Lecithin acts similarly. Fat is digested much more slowly if bile is not present [5,6].

Bile salts also improve absorption of lipids. The salts combine with fatty acids and monoglycerides to form small complexes called micelles. The ion charges provided by the bile salts enhance diffusion of the micelles across the intestinal mucosa into the bloodstream [5,6].

If absorption of fats is diminished because of absence of bile, vitamins A, D, E, and K, which are fat-soluble, cannot be absorbed. Bile salts are "recycled" from 15 to 20 times in a process known as enterohepatic circulation. An estimated 90% to 95% of bile salts secreted are reabsorbed in the distal ileum and carried in the portal vein back to the hepatic cells, which reabsorb and then resecrete them [5,6].

Bilirubin (bile pigment), a major waste product of hemoglobin metabolism, is excreted by the liver. Normally, erythrocytes have a lifespan of about 120 days. They are then broken down by the reticuloendothelial cells, and the iron (heme) from the worn-out red cells is conserved for reuse in the synthesis of fresh hemoglobin. The remaining iron-free pigment is free (unconjugated) bilirubin, which is continually present in the bloodstream in small quantities. As blood passes through the liver, unconjugated bilirubin is removed. It is then combined (conjugated) with other substances and excreted via the bile ducts; a small amount of conjugated bilirubin returns to the blood [1,7].

Conjugated bilirubin is more soluble and less toxic than unconjugated bilirubin. In the intestines, conjugated bilirubin is converted into a highly soluble substance called urobilinogen, which is excreted primarily in the feces in an oxidized form known as stercobilin. About 5% of urobilinogen is absorbed into the bloodstream and excreted via the kidneys in an oxidized form called urobilin. Because stercobilin gives feces their brownish color, clay-colored stools are a classic sign of biliary tract abnormalities [1,7].

Carbohydrate Metabolism

The liver plays a major role in carbohydrate metabolism. One aspect of this role is a glucose buffer function that contributes to the maintenance of normal blood sugar levels. The liver can remove excess glucose from the blood, store it as glycogen, and reconvert and release it as glucose in response to hypoglycemia. If blood glucose concentrations fall and glycogen is not available, the liver can convert proteins or amino acids to glucose, a process known as gluconeogenesis. The liver is also capable of converting galactose to glucose [1,2].

Fat (Lipid) Metabolism

Synthesis of fat from carbohydrates and proteins occurs primarily in the liver. The lipoprotein produced in this process is transported in the bloodstream to the body's adipose tissue or storage. The liver is also capable of rapid metabolism of ingested fat in response to energy requirements. The liver can also synthesize lipoproteins, cholesterol, and other phospholipids [1,2].

Protein Metabolism

Before amino acids can be converted into carbohydrates or fat or used to supply caloric needs, a process known as deamination (liberation of ammonia) must occur. The liver is the principal site of deamination and the only site where ammonia is detoxified by conversion into urea. In addition, nearly all the plasma proteins are synthesized in the liver, as are several nonessential amino acids. Serum protein determination measures the liver's ability to maintain a normal level of serum albumin [1,2].

Vitamin Storage

The liver is capable of storing up to a four-month supply of vitamins B12and D and up to a 10-year supply of vitamin A for release as needed. Because of this storage capacity, excessive ingestion of vitamin A can have toxic effects on liver function [3,4].

Iron Storage

Except for the iron stored in hemoglobin, most of the body's iron is stored in the liver as ferritin. Stored iron is released when blood levels of iron fall, a process known as iron buffering [3,4].

Synthesis of Coagulation Factors

Prothrombin and factors VIII, IX, and X, necessary for effective blood coagulation, are synthesized in the liver. Vitamin K is necessary to promote synthesis for these clotting factors, but if bile secretion is inadequate, absorption of this fat-soluble vitamin cannot occur. The liver also synthesizes fibrinogen, another clotting factor [3,4].

Detoxification

Many chemicals are detoxified in the liver, including such medications as barbiturates, antidiuretic hormone (ADH), amphetamines, aldosterone, and estrogen. If these substances were not detoxified, they could be fatally toxic to body tissues or organs, or could have other adverse effects (e.g., feminization of men or masculinization of women) [4,5].

The hepatic cells can produce from 600–1,000 mL of bile in 24 hours, more than 10 times the 50–75 mL storage capacity of the gallbladder. The mucosa of the gallbladder concentrates bile by absorbing water and electrolytes. This leaves a solution of bile salts, cholesterol, lecithin, and bilirubin that is 5 to 10 times as concentrated as bile secreted by the liver [4,5].

When ingested fat enters the small intestine, a hormone called cholecystokinin is released from the intestinal mucosa. Cholecystokinin travels to the gallbladder via the bloodstream, initiating contraction of the smooth muscle in the wall of the gallbladder and relaxation of the sphincter of Oddi. Vagal stimulation also contributes to contraction of the gallbladder. While hormone secretin, produced by the jejuna and duodenal mucosa, weakly stimulates bile secretion by the liver, peristalsis stimulated by food further relaxes the sphincter of Oddi. These factors combine to produce the sending of bile into the duodenum with each gallbladder contraction and peristaltic wave. The gallbladder empties poorly in the absence of ingested fat but empties completely within an hour if fat is present. Approximately 94% of the bile salts released into the duodenum are reabsorbed and returned to the liver via the bloodstream [5,6].

Physical assessment of the patient with hepatobiliary dysfunction involves careful inspection of the skin, nails, and hair. Physical findings that suggest cirrhosis include:

If the patient is in a late stage of liver dysfunction, asterixis related to ammonia toxicity and impending coma will be observed; in these patients, the hands rapidly clench and unclench. Inflating a blood pressure cuff on the arm will worsen the tremor. Asterixis may also be seen in patients with cancer of the liver. In patients with hepatitis, however, only ecchymosis and jaundice will be apparent, unless the condition is long standing. Bruising and jaundice may sometimes accompany hepatic abscess; however, diminished appetite is often the only sign of this disorder. As mentioned previously, jaundice may also be secondary to an obstructive condition or an abnormality affecting bilirubin conjugation [20].

The abdomen should be auscultated before it is palpated. Diminished bowel sounds are common in patients with ascites. At the same time, auscultation of the lungs may elicit evidence of rales or rhonchi related to pulmonary edema. Listen for hepatic bruits, which may be heard with hepatic carcinoma [20].

Hepatomegaly and splenomegaly can be present in patients with hepatitis, cholecystitis, hepatic abscess, mononucleosis, cirrhosis, or liver cancer. Because of the danger of damaging or rupturing these organs, the one should generally avoid palpating the liver or spleen unless they are experienced in this type of examination. If enlargement is severe, these organs may be felt by very light palpation of the abdomen. Swollen lymph nodes may be palpable in the neck or in the groin with an infectious disorder such as mononucleosis [20].

If possible, percussion for measurement of liver size and the usual area of splenic dullness helps determine whether either organ is enlarged. The normal liver span at the midclavicular line (MCL) is 6–12 cm. When percussing liver size, begin low in the abdomen, below the umbilicus, and percuss up the right MCL. The percussion note heard initially is tympany, reflecting air in the bowel. The lower border of the liver is identified when the percussion note changes to dullness. To identify the upper liver border, begin above the nipple, percussing downward along the right MCL. When the percussion note changes from resonance to dullness, the upper liver border has been located. Measure the distance between these two points to determine liver size. Abnormal findings include feeling the liver more than 1 cm below the costal margin [20].

The normal adult spleen lies behind the ninth and eleventh ribs, at or slightly posterior to the left midaxillary line (MAL). The spleen can be located by percussing downward in the intercostal space (ICS) at the left MAL, beginning in the eighth left ICS. The percussion note should change from resonance to splenic dullness at about the tenth left ICS. A large area of dullness may indicate feces in the splenic flexure of the colon, a full stomach, or splenomegaly. Note that patients who have had organ transplants may have undergone splenectomy [20].

Three assessment techniques can be used to determine whether fluid is present in the abdomen:

Abdominal girth should be measured daily. Measurements taken at the same location (at the level of the umbilicus) assist in evaluating progression and/or treatment of ascites [20].

Blood samples for determination of white blood cell count (WBC), prothrombin time (PT), hemoglobin level (Hb), and hematocrit (Hct) may be drawn at any time. Hemoglobin and hematocrit values are unaffected by early stages of hepatic disease but may drop if there is hemorrhage from esophageal varices and in response to malnourishment. Prothrombin time will increase with vitamin K deficiency, as may occur with cirrhosis, hepatitis, cholecystitis, cholelithiasis, mononucleosis, or liver cancer. Leukocyte levels increase in patients with mononucleosis, hepatitis, and abscesses [23,24,25].

Elevated serum enzyme levels occur when hepatic cells are damaged and enzymes are released into the blood. Specific values that are likely to be elevated with liver or gallbladder disease include:

LDH, AST, and ALT values are significantly increased in obstructive jaundice and mononucleosis; they are also markedly elevated in acute and toxic hepatitis, cirrhosis, and hepatic neoplasia. Alkaline phosphatase levels, important in measuring biliary obstruction, are extremely elevated in obstructive jaundice, significantly elevated in liver cancer and mononucleosis, and slightly elevated in hepatitis (viral or toxic) and cirrhosis. Elevation of GGT is the most accurate enzymatic indicator of hepatic disease. Enzyme levels will rise as the disease progresses, peaking at the time of maximum cell death, and then begin to fall [23,24].

Changes in serum lipid values are related to the type of disorder. Serum lipids are elevated in obstructive disorders of the biliary system, such as cholelithiasis or neoplasia. They are decreased in disorders causing the destruction of hepatic cells (e.g., cirrhosis, hepatitis) [23,24].

Studies of bilirubin values are important in determining the cause of jaundice and hyperbilirubinemia. Direct or conjugated bilirubin levels will be elevated if biliary ducts are obstructed and conjugated bilirubin cannot be excreted. Indirect or unconjugated bilirubin levels will be high if parenchymal (liver lobule) cells have been damaged [23,24].

Elevated levels of urobilinogen in the urine indicate parenchymal liver disease, such as cirrhosis, toxic or infectious hepatitis, or infectious mononucleosis, or they may indicate cholelithiasis. By impairing the excretion of bilirubin in the stool, these conditions lead to increased excretion by the kidneys. Urine that contains bilirubin develops a yellow foam when shaken. Fecal levels of urobilinogen are decreased if the bile ducts are obstructed, but this test is rarely performed because of the difficulty in obtaining accurate values. A 24-hour urine collection would be done to determine the presence and level of urobilinogen [23,24].

Blood ammonia values rise when cirrhosis is present, because the disease impairs the conversion of ammonia to urea for renal excretion. Bleeding esophageal varices exacerbate ammonia toxicity, because the ammonia produced by the action of intestinal bacteria on the protein in blood adds rapidly to already elevated serum ammonia levels. Hepatic coma can result [23,24].

Changes in serum protein levels are common in hepatic and biliary disorders. Serum albumin levels drop (hypoalbuminemia) and gamma globulin levels rise when parenchymal cell damage occurs. Serum antigen-antibody levels help identify and type hepatitis. For example, hepatitis B surface antigen (HBsAg) is present in the blood of persons who have hepatitis B and also in those who are carriers of the disease. Patients with hepatitis B surface antibodies (anti-HBs) in their blood have immunity to hepatitis B [23,24].

For some patients, especially those for whom oral cholecystography or cholangiography are contraindicated, ultrasound offers a noninvasive alternative. This technique is being used with increasing frequency to investigate ambiguous findings obtained by other techniques. It is useful in differentiating benign cysts and tumors from malignancies. Liver abscesses and dilation of intrahepatic ducts can be identified by ultrasound, as can gallstones, biliary tumors, and tumors of the extrahepatic ducts. In a patient with jaundice, dilation of the extrahepatic ducts suggests extrahepatic obstruction. If the ducts appear normal, jaundice is likely to be related to extrahepatic or prehepatic conditions. Hepatic icterus is related to abnormalities of bilirubin conjugation or excretion. Extrahepatic icterus is related to obstruction of the hepatic, common, or cystic bile ducts. Prehepatic icterus is associated with an abnormality that takes effect before circulating bilirubin reaches the liver (e.g., hemolysis of neonatal icterus) [23].

Nursing Implications

To ensure that the gallbladder is a maximum size for the test, the patient must be kept NPO after midnight on the day of testing. Were the patient to eat, contraction and emptying of the gallbladder would reduce its size, making it more difficult to visualize. NPO orders are not necessary for visualization of the liver. If barium contrast studies have been performed prior to the ultrasonography, a laxative will be ordered to cleanse the bowel of residual contrast medium [23].

In explaining the procedure to the patient, the nurse can offer reassurance that the study is not painful. The patient should be prepared for the copious amount of lubricant that will be applied to the skin to enhance the transmission of the sound waves. The rationale for any NPO order should be explained. The procedure will take about 20 minutes [26,27].

For the liver scan, a radionuclide is administered intravenously. Thirty minutes later, a detecting device is passed over the patient's abdomen to record the distribution of radioactive particles in the liver. Although this technique exposes the patient to far less radiation than x-rays, it can only demonstrate filling defects greater than 2 cm in diameter. It is contraindicated for pregnant patients and those who might have difficulty lying still during the scan, which takes about one hour [23,28,29].

No special preparation is required for this study. The procedure should be fully explained to the patient, including that small amounts of radioactive substances are used. Some patients may be apprehensive about the amount of time required for the scan, and it is helpful to explain that the scanning device does not emit radiation but rather records radiation emanating from the injected radioisotope. Pregnant healthcare providers should not be assigned to the patient for at least 24 hours after the radionuclide injection [26,27,28].

For dye clearance studies, the patient fasts for 12 hours prior to the test. Dye is injected intravenously (about 5 mg/kg of body weight). Blood is drawn 45 minutes after the injection and inspected for the presence of dye. Normally, less than 5% of the dye will be found in the serum; the presence of a greater proportion of the dye indicates liver cell damage, as the impaired cells cannot absorb the dye from the blood. If hepatic damage is known to exist, lower dosages of dye are administered. The indocyanine green (ICG) clearance test is the most widely used quantitative liver function test [23,28,30].

An oral cholecystography, or gallbladder series, provides visualization of the gallbladder following oral ingestion of a radiopaque iodinated dye. In the first test of the series, gallstones (when present) may be visualized as dark shadows in a dye-filled gallbladder. Satisfactory visualization of the gallbladder can be obtained only if the gallbladder has concentrated the dye. Adequate concentrating depends on correct dosage of the dye, adequate absorption of the dye from the gastrointestinal tract (no nausea or vomiting), and absence of food in the digestive tract (NPO after midnight). If nonvisualization occurs, the test is repeated the next day with a doubled dosage of dye. Hepatocellular dysfunction, cystic duct obstruction, or inflammation of the biliary mucosa will prevent visualization. The patient's allergy history should be determined prior to testing [23,28].

In the second phase of the series, the patient is given a fatty meal immediately following the first phase, and x-rays are taken to determine how well the gallbladder empties. The x-rays are repeated every 30 minutes until the dye is gone and the gallbladder can no longer be visualized. This may take one to five hours, but usually takes no more than three [23].

This is an older study that is rarely used today, as ultrasound or computed tomography (CT) are more accurate, faster techniques for identifying gallstones without exposure to iodine. Ultrasonography is typically the preferred modality, because it is less invasive, more accurate cholelithiasis, and can be safely used with most patients. In general, use of oral cholecystography is limited to cases in which gallstones are strongly suspected but ultrasonography does not show them. If it is indicated, oral cholecystography is contraindicated for pregnant women, patients too ill to swallow the tablets or to eat a meal, and persons allergic to iodine [23].

Patients undergoing oral cholecystography are required to swallow seven or eight tablets of absorbable iodine dye the evening prior to the test. After the tablets are swallowed, only water may be given until midnight; after midnight, patients are kept NPO. Nursing implications include [26,27]:

Oral and intravenous cholangiography allowed for visualization of the hepatic and common bile ducts in addition to the gallbladder and cystic duct. It was historically used for patients with acute inflammatory disorders, those with proven gallstones, and those who are NPO or unable to tolerate the orally ingested dye used in cholecystography [23,26,27,28]. However, these studies have become obsolete, having been replaced by more advanced technologies, such as the endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTHC) and magnetic resonance cholangiopancreatography (MRCP) [31].

Cholangiography may be performed during a surgical procedure to ascertain that all calculi have been removed from the common bile duct, reducing the probability of complications or follow-up surgery. Dye is injected to enhance visualization [23,28].

A T-Tube cholangiography may be taken 7 to 10 days following a cholangiography. The T-tube is placed during surgery. Later, dye is injected via the T-tube so the common bile duct may be visualized and its patency ascertained [23,28]. As with other older modalities, this technique has been largely superseded by MRCP and ERCP.

As noted, ERCP, PTHC, and ultrasound have become the most valuable studies for assessment of the biliary tract [31]. ERCP studies allow visualization of the bile ducts as well as benign masses, cysts, and malignant neoplasms [23,32,33].

With ERCP, a type of fibrotic endoscope termed a duodenoscope is inserted into the duodenum via the esophagus. Intravenously administered secretin immobilizes the duodenum, facilitating visualization of the ampulla of Vater. Contrast material combined with a broad-spectrum antibiotic are administered through a small cannula inserted into the ampulla, and films are taken periodically for approximately an hour. The antibiotic is given to prevent gram-negative sepsis that may occur if bacteria are forced in the bloodstream by the pressure of the dye injections. Perforation of the esophagus, stomach, or duodenum is another possible complication of ERCP, so this technique is not used for combative patients [23,32,33].

A consent form is necessary for this procedure. On teaching the patient about the procedure, explain that an impulse to gag will be felt when the tube is passed. The patient is kept NPO after midnight. Meperidine and atropine are administered intramuscularly before the patient is taken to the radiology department. Emotional support should be given as needed. After the procedure, the patient's pulse, temperature, and blood pressure are monitored for signs of shock that may arise from perforation or hemorrhage and for signs of sepsis. Pancreatitis may occur in response to the pressure exertion on the pancreatic duct during the procedure; therefore, a serum amylase test should be performed on the day following an ERCP [26,27].

Like ERCP, PTHC is used for icteric patients with serum bilirubin levels greater than 3.5 mg/dL. During this procedure, a combination of contrast medium and antibiotic is injected into the intrahepatic bile duct to visualize the biliary system. The area below the right costal margin is locally anesthetized, and a spinal needle is inserted directly into the liver, guided by fluoroscopy. When bile appears through the needle, it is withdrawn by syringe. Radiopaque dye is then injected directly into the biliary tree. Fluoroscopy is used to determine filling of the biliary tract [23,28,34].

The patient is intravenously sedated during the procedure, which takes about one hour. If obstruction is found, a catheter may be left in place for drainage of bile. A PTHC is contraindicated for patients who have prolonged clotting times or iodine allergy, for patients who have had recent gastrointestinal contrast studies or are unlikely to tolerate surgery, and for combative patients. Bile peritonitis, hemorrhage, and sepsis are possible complications [23].

A consent form is required for this procedure, and coagulation studies as well as information regarding possible iodine allergy must be verified. The patient is kept NPO after midnight. A laxative may be prescribed if gastrointestinal studies using barium have been recently administered. An intravenous infusion is started for venous access, and the patient is premedicated with meperidine and atropine before leaving the unit. After the procedure, the patient is kept NPO. Vital signs should be monitored as for any postsurgical patient. A sterile closed system should be maintained if a catheter has been left in place [26,27].

The purpose of a liver biopsy is to obtain a sample of tissue for histologic examination. Prior to the procedure, ultrasound may be done to determine the precise location of the liver. A coagulation profile should be obtained so the risk of hemorrhage can be calculated. The patient's blood is typed and crossmatched in case a transfusion is needed. Biopsy is contraindicated if the platelet count is below 100,000/mcL [23,28,35].

For percutaneous liver biopsy, the patient is assisted into a supine or left lateral position. The skin is aseptically cleansed and anesthetized, and a small incision is made to allow insertion of a specialized needle into the liver. In the case of transjugular biopsy, the right jugular vein is punctured under ultrasound guidance, and a guide wire is passed through, followed by placement of a 9-French sheath. The wire is then negotiated through the heart at to the right hepatic vein. Placement is verified with hepatic venogram with contrast. A stiffening cannula is placed, then the biopsy needle is introduced. With both techniques, a small core of hepatic tissue is then withdrawn and sent for microscopic evaluation. Following the procedure, the patient should assume the right lateral position to keep pressure on the liver to prevent hemorrhage [23,28,35].

These procedures require a consent form. The patient is kept NPO after midnight. Nursing responsibilities include:

The patient should remain immobile on the right side on bedrest for 24 hours and be closely observed for signs of hemorrhage, extravasation of fluid from the biopsy site, peritonitis, and pain. Pain in the right upper quadrant and right shoulder area is common. The patient should be reassured about this while being encouraged to report any change in pain level. Analgesics, if given, must be non-hepatotoxic and must not affect clotting [26,27].

Mild or moderate pain may occur in relation to hepatomegaly or splenomegaly associated with hepatitis, hepatic abscess, or infectious mononucleosis. Moderate pain may accompany late cirrhosis and chronic hepatitis. With cancer of the liver, whether the liver is a primary or a metastatic site, pain becomes severe and intractable. Severe, colicky pain in the right upper quadrant is common with cholelithiasis or cholecystitis [36,37].

Regardless of whether icterus is prehepatic or hepatic, pruritus will be associated with the jaundice. The patient may scratch the skin until it bleeds. The condition may be intensified by damp clothing or bedding caused by perspiration or by poor ventilation [36,37].

If pruritus is severe and the patient scratches frequently, skin integrity may be broken. In cirrhosis and cancer of the liver, edema and negative nitrogen balance cause the skin to be susceptible to breakdown. If the patient is does not frequently move, pressure injuries can form within 12 to 24 hours [36,37]

Disturbance in self-concept may be related to body image alteration and role performance. Softening of the skin, loss of body hair, or gynecomastia may be related to impaired estrogen detoxification. In some, these feminizing changes disturb the patient's sense of masculinity. Ascites and icterus further affect self-image. Complications associated with severe disease such as cancer or cirrhosis (e.g., ascites, pleural effusion) may necessitate the patient changing occupation or retiring. Loss of occupational role can severely damage self-esteem.

Sexual dysfunction may also accompany impairment of estrogen detoxification. Loss of libido may occur in both sexes, and male patients may become impotent. The patient may be hesitant to discuss these matters with healthcare professionals [36,37].

Cirrhosis is often (but not invariably) part of a progressive disease that begins with fatty infiltration of the liver (steatosis) that progresses to fibrosis of the liver due to inflammation. If not adequately treated, cirrhosis can progress to hepatic failure. Cirrhosis may be related to nutritional disorders, biliary obstruction, hepatotoxicity, iron storage disorders, and alcohol ingestion. Histologic examination of the liver reveals fatty infiltration, cellular necrosis, and disruption of the lobes. Gross inspection reveals a "hobnail" appearance; the hepatic surface is often stippled and nodular [51].

Portal hypertension results in compensatory development of collateral blood vessels in the esophagus. These vessels, called esophageal varices, dilate as portal hypertension increases. Because such vessels are inadequate to accommodate the increased blood flow, hemorrhage may occur [51].

Patients with cirrhosis often have a characteristic appearance. Anorexia develops early in the course of the disease, resulting in significant weight loss. The skin is typically orange-yellow, the eyes are sunken, and the facial bones are prominent. The limbs are emaciated, but the abdomen is enlarged due to peripheral edema or ascites. Other symptoms include spider angiomas, palmar erythema, and changes in mental status [51].

Hemorrhage of esophageal varices may be controlled temporarily by administering infusions of vasopressin, somatostatin, octreotide, or terlipressin to promote diffuse arterial vasoconstriction and to lower portal pressure by constricting the splanchnic arterial bed. The infusion may be given systemically or via the superior mesenteric artery and administered for five days, according to current guidelines [52]. This provides only temporary control and is associated with complications, including systemic arterial hypertension and coronary vasoconstriction, possibly leading to myocardial infarction. Whole blood should be available for immediate infusion [52,53,54]. If medication administration is unsuccessful, gastric lavage with ice-cold saline, use of the Minnesota tube or Sengstaken-Blakemore tube, or portal-systemic shunting may be implemented to control bleeding temporarily.

As noted, hepatic encephalopathy is a complication of advanced cirrhosis [52,54,55]. Lactulose and antibiotics may be used to manage these patients.

Injection sclerotherapy, an alternative long-term control measure, may be performed as a bedside procedure. The patient can be sedated using diazepam (Valium), meperidine hydrochloride (Demerol), propofol, fentanyl (Sublimaze), midazolam (Versed), or ketamine (Ketalar). The medications used are at the discretion of the anesthesia provider and surgeon based on the patient's medical history. It is important to be familiar with each, along with their respective reversal agents [57,58]. Sclerosing solutions are then injected directly into the bleeding varices by means of fiberoptics endoscopy. Potential complications include chest pain, transient fever, ulceration of the injection sites, and formation of strictures. Most are self-resolving; strictures may be treated by dilatation. Perforation, a major complication, is rare. If perforation does occur, it is treated by keeping the patient NPO, suctioning gastric contents, and administering antibiotic therapy; surgery is seldom required [52,55,56].

Prophylactic antibiotics are also administered to lower rates of infection, death, and early rebleeding. IV ceftriaxone has demonstrated the most positive results in randomized controlled trials [52].

It is important to emphasize that patients with cirrhosis must abstain from alcohol. Because cirrhosis is a chronic condition, most nursing interventions will be related to the patient's comfort. Teaching patients and the public about the effects of alcohol may have preventive benefits [59,60,61,62].

Nursing measures for patients with esophageal hemorrhage include explaining treatments to the patient and assessing frequently to determine whether hemorrhage has ceased. As with any hemorrhage, the nurse is responsible for monitoring blood replacement therapy and administering vitamin K, as ordered. Bleeding esophageal varices create a crisis for patient and family. Timely explanations of ongoing interventions and anticipated results will help the patient cope with panic and fear of death. Providing nursing care in a decisive, supportive manner helps the patient regain control and to participate in the therapy. To provide optimum crisis care, the nurse should assess the family support structure and provide information and support to significant others as well as the patient. Fluid restrictions are generally maintained at 1,000 mL per 24-hour period [59,60,61].

The metabolism of alcohol leads to chemical attack on certain membranes of the liver. But whether the damage is caused by acetaldehyde or other metabolites is unknown. Acetaldehyde is known to impede the mitochondrial electron transport system, which is responsible for oxidative metabolism and generation of ATP; as a result, the hydrogen ions that are generated in the mitochondria are shunted into lipid synthesis and cytogenesis. Abnormal accumulations of these substances are found in hepatocytes (fatty liver) and blood. Binding of acetaldehyde to other molecules impairs the detoxification of free radicals and synthesis of proteins. Acetaldehyde also promotes collagen synthesis and fibrogenesis. The lesions of hepatocellular injury tend to be most prevalent in the centrilobular area that surrounds the central vein, where the pathways for alcohol metabolism are concentrated. This is the part of the lobule that has the lowest oxygen tension; it is thought that the low oxygen concentration in this area of the liver may contribute to the damage [64,65].

The amount of alcohol required to produce chronic liver disease varies widely, depending on body size, age, sex, and ethnicity, but the high end of the range is about 80 g/day for 10 to 12 years. This amount of alcohol can be in the form of 8 ounces of 86 proof (41% alcohol) whiskey, two bottles of wine, or six 12-ounce bottles of beer. Even after alcohol intake has stopped and all alcohol has been metabolized, the processes that damage liver cells may continue for many weeks and months. Clinical and chemical effects often become worse before the disease resolves. The accumulation of fat usually disappears within a few weeks, and cholestasis and inflammation also subside with time. However, fibrosis and scaring remain. The liver lobules become distorted as new liver cells regenerate and form nodules [64,65].

Although the mechanism by which alcohol exerts its toxic effects on liver structure is somewhat uncertain, the changes that develop can be divided into three states: fatty changes, alcoholic hepatitis, and cirrhosis [65].

According to the American Association for the Study of Liver Diseases, because abstinence is the single most important factor in improving survival from alcohol-associated liver disease, multidisciplinary management with addiction specialists and referral to treatment for alcohol use disorder, particularly in patients with moderate to severe alcohol use disorder or clinically evident liver disease, is mandatory.

(https://journals.lww.com/hep/fulltext/2020/01000/diagnosis_and_treatment_of_alcohol_associated.25.aspx Last Accessed: August 12, 2024)

Level of Evidence: Expert Opinion/Consensus Statement

Fatty liver is characterized by the accumulation of fat in hepatocytes, a condition called steatosis. The liver becomes yellow and enlarges as a result of excessive fat accumulation. 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 the ingestion of alcohol usually do not produce symptoms and are reversible after the alcohol intake has been discontinued [65,68].

Alcoholic hepatitis is the intermediate state between fatty changes and cirrhosis. It often is seen after an abrupt increase in alcohol intake and is common in binge drinkers. 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 people may be asymptomatic. The condition is always serious and sometimes fatal, with an associated mortality rate of 34%. The immediate prognosis correlates with severity of liver cell injury. In those who continue to drink, the acute phase often is followed by persistent alcoholic hepatitis with progression to cirrhosis in a matter of one to two years [65,68].

Alcoholic cirrhosis and malnutrition is the end result of repeated bouts of drinking-related liver injury and designates the onset of end-stage alcoholic liver disease. The gross appearance of the early cirrhotic liver is one of fine, uniform nodules on its surface. The condition has traditionally been called monocular or Laënnec cirrhosis. With more advanced cirrhosis, regenerative processes cause the nodules to become larger and more irregular in size and shape. As this occurs, the nodules cause the liver to become relobulized through the formation of new portal tracts and venous outflow channels. The nodules may compress the hepatic veins, curtailing blood flow out of the liver and producing portal hypertension, extrahepatic portosystemic shunts, and cholestasis [64,65,69].

The pathogenesis of MASLD is thought to involve both lipid accumulations with hepatocytes and formation of free radicals, in a manner similar to that which occurs with alcohol metabolism. The primary metabolic abnormalities leading to lipid accumulation are poorly understood but are thought to include alteration in pathways for uptake, synthesis, degradation, or secretion of hepatic lipids and resulting from insulin resistance. Obesity increases the synthesis and reduces the oxidation of free fatty acids. Type 2 diabetes or insulin resistance also increases adipose tissue lipolysis and the subsequent production of free fatty acids. When the capacity of the liver to export triglyceride is exceeded, excess fatty acids contribute to the formation of fatty liver. Abnormal lipid peroxidation ensues, followed by direct hepatocyte injury, release of toxic byproducts, inflammation, and fibrosis [65,71].

MASLD is usually asymptomatic, although fatigue and discomfort in the right upper quadrant of the abdomen may be present. Mildly to moderately elevated serum levels of AST, ALT, or both are the most common and often the only abnormal laboratory findings. Other abnormalities, including hypoalbuminemia, a prolonged prothrombin time, and hyperbilirubinemia, may be present in persons with cirrhotic-stage liver disease. The diagnosis if MASLD requires the presence of >5% macrovesicular steatosis, inflammation, and liver cell ballooning, typically with a predominantly centrilobular distribution; this is usually demonstrated by imaging. Exclusion of alcohol as a cause of the disorder is also required [65,72].

In adults with MASLD, the European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) recommend dietary and behavioral therapy-induced weight loss to improve liver injury, as assessed histologically or noninvasively.

(https://www.journal-of-hepatology.eu/article/S0168-8278(24)00329-5/fulltext Last Accessed: August 12, 2024)

Level of Evidence/Strength of Recommendation: 1, Strong Recommendation, Strong Consensus

The aim of treatment is to slow progression of MASLD and to prevent liver-related illness. Weight loss and exercise improve insulin resistance and are recommended in conjunction with treatment of associated metabolic disturbances. Alcohol use should be avoided. Disease progression is slow and the magnitude of disease-related morbidity and mortality is uncertain. One study has shown the use of statins and antioxidants such as vitamins A and E have been effective in reducing the odds of hepatic steatosis in patients with MASLD. Liver transplantation is an alternative for some with end-stage liver disease, but MASLD may reoccur in up to 39% of people post-liver transplantation [65,72,73,74].

Primary biliary cholangitis (PBC), formerly primary biliary cirrhosis, is a chronic disease of the liver characterized by the autoimmune destruction of intrapolar bile ducts causing cholestasis. The disease is seen most commonly in women 40 to 60 years of age. Familial occurrences of the disease are found between parents and children and among siblings. With the possible exception of a reportedly higher risk of a polymorphism of the gene for the vitamin D receptor, there are no clear genetic influences for the disorder. As with other autoimmune disorders, possible environmental triggers include infections and chemical agents [63].

Clinical Manifestations

Primary biliary cholangitis is characterized by an insidious onset and progressive scarring and destruction of liver tissue. The liver becomes enlarged and takes on a green hue because of the accumulated bile. The earliest symptoms are unexplained pruritus, weight loss, and fatigue, followed by dark urine and pale stools. Osteoporosis occurs in 51% of women with the disorder. Jaundice is a late manifestation of the disorder, as are other signs of liver failure. Serum alkaline phosphatase levels are typically elevated [63].

Diagnosis and Treatment

Diagnosis of primary biliary cholangitis is made when two of the following signs and symptoms are present [63]:

Treatment is largely symptomatic. Ursodeoxycholic acid (ursodiol), the only drug approved for treating primary biliary cholangitis, increases bile flow, decreases the toxicity of bile contents, and has been shown to decrease the rate of clinical deterioration. Cholestyramine, a bile acid-binding drug, may prove beneficial for treatment of pruritus. Colchicine, which acts to prevent leukocyte migration and phagocytosis, and methotrexate, a drug with immunosuppressive properties, have also resulted in reported benefits in terms of symptom relief. Corticosteroids have been shown to improve liver histology and serum liver function tests, but are associated with serious long-term side effects. Liver transplantation remains the only effective treatment for advanced disease. Primary biliary cirrhosis does not recur after liver transplantation if appropriate immunosuppression is used [63].

Secondary biliary cholangitis results from prolonged obstruction of the extrabiliary tree. The most common cause is cholelithiasis. Other causes of secondary biliary cirrhosis are malignant neoplasms of the biliary tree or head of the pancreas and strictures of the common duct caused by previous surgical procedures. Extrahepatic biliary cholangitis may benefit from surgical procedures designed to relieve the obstruction. The presence of dark urine is a sign that indicates emergent medical attention is necessary [64,66,67].

Both drug-induced and toxic hepatitis are manifested by inflammation of hepatic cells, hyperplasia of Kupffer cells, and bile stasis; however, toxic hepatitis is also associated with acute cellular necrosis. The onset of both forms is similar to that of viral hepatitis from which they must be quickly distinguished if detoxification is to be initiated. Anorexia, jaundice, and hepatomegaly are common. In toxic hepatitis, the illness may progress rapidly, with rising fever, subdermal hemorrhage, and severe vomiting. Delirium, coma, and convulsions develop, and the patient dies within a few days. If the toxin is promptly identified and exposure is discontinued, however, the patient may recover quite rapidly. Cirrhosis sometimes develops after recovery [76,78].

Drug-induced hepatitis may develop after repeated exposures have sensitized the patient to a drug. For this reason, any medication that causes pruritus or other symptoms of sensitivity should be immediately withdrawn and the sensitivity noted on the patient's record. Chills, fever, rash, pruritus, arthralgia, and nausea are early signs of drug-induced hepatitis. Icterus, hepatomegaly, and hepatic tenderness follow. The urine is dark. Symptoms may subside once the drug is withdrawn, but drug-induced hepatitis may be fatal, and postnecrotic cirrhosis also may develop [78,79,80,81]. The anesthetic agent halothane has been linked to episodes of drug-induced hepatitis; therefore, anesthetics should be rotated for patients undergoing repeated surgical procedures [81].

Treatment is directed at the removal of the toxin or sensitizing agent, if known. Early diagnosis is important. The history can yield useful findings regarding exposure to toxins or medications. Attention should focus on occupational history, possible exposure to hepatotoxins during hobby activities (e.g., furniture finishing), and medication history, including over-the-counter medications and self-prescribed vitamin therapy. Once the disease has been diagnosed, nursing care focuses on comfort measures and the replacement of blood, fluids, and electrolytes [75,78].

Patients with hepatic abscess will have a high fever and a painfully enlarged liver, anemia, elevated WBC levels, and icterus. As the temperature rises, the patient has alternating episodes of chills and diaphoresis; toxic shock can occur within hours. If identified soon enough, the infective agent can be controlled with antimicrobial therapy. Sometimes, septicemia cannot be reversed, and the patient dies [76].

Non-aspirin analgesics, intravenous fluid therapy, and parenteral antimicrobial agents may be prescribed. Occasionally, surgical intervention may be indicated to drain large abscessed areas or to resect an abscessed portion of the liver. This is done rarely, however, because coagulation abnormalities associated with liver dysfunction increase the risk of severe hemorrhage. The most common surgical intervention is percutaneous drainage. This may be done intermittently, or continuous catheter drainage may be employed [76].

Continual assessment is a crucial part of nursing care. A patient history should include inquiry regarding recent (within past six months) infection and presence of diabetes or insulin resistance [20].

Hourly monitoring of temperature and vital signs may be required to estimate whether the patient is becoming septic or whether antimicrobial therapy is taking effect. Hepatic abscess is accompanied by pain and fever, so supportive care with comfort measures is necessary. If surgical intervention is indicated or drainage initiated, the nurse will teach the patient about the procedure, provide reassurance, and assess for hemorrhage [20].

The World Health Organization (WHO) estimates the annual worldwide incidence of hepatitis A to be 1.5 million per year [86]. Within the United States, diagnosed cases of hepatitis A virus must be reported to the local health authorities, who in turn report the incidence to the Centers for Disease Control and Prevention (CDC). Many persons who contract hepatitis A virus, however, do not have clinical symptoms. Therefore, the CDC must estimate the actual incidence of hepatitis A virus infection based upon CDC reports and projections. For the 10-year period 1999 to 2009, the CDC estimates that 749,000 cases occurred within the United States [87].

Since the introduction of hepatitis A vaccine in 1995, the incidence of hepatitis A in the United States has declined by 95% [87]. However, after falling to a low of 1,239 cases reported in 2014, a series of outbreaks from 2013 to 2023 resulted in a dramatic increase in cases, reaching 12,474 reported cases in 2018 and 18,846 in 2019 [88]. According to the CDC, the increase in incidence was primarily the result of contaminated organic fruit, including strawberries, pomegranate seeds, blackberries, and a mixed antioxidant blend [88].

Hepatitis A is transmitted via the fecal-oral route, most commonly from contaminated water or food. After the virus is ingested, it is transported from the intestines to the liver, where it invades the hepatocytes. The virus uses the hepatocytes for viral replication and is then released into the bloodstream and excreted in the stool. HAV that is acquired percutaneously travels directly from the bloodstream to the liver to invade the hepatocytes; viral replication and excretion follow the same pattern as in fecal-oral transmission.

Clinical Manifestations

Signs and symptoms of hepatitis A infection can vary from subclinical disease to fulminant (sudden and intense) illness. In symptomatic patients, the incubation period (i.e., time from exposure to onset of illness) is in the range of 15 to 50 days (average: 28 days). Clinical symptoms and signs include nausea, vomiting, headache, fever, chills, abdominal discomfort, hepatomegaly, and right upper quadrant tenderness. For most patients, symptoms are mild and subside in three to seven days. Others will have more significant disease and will progress to an icteric phase (jaundice). For these patients, recovery typically occurs after about three weeks.

Fulminant infection occurs in less than 1% of the cases. Some of these patients may have such severe damage that they require a liver transplant. Fatalities from hepatitis A are extremely rare. There is no known chronic carrier state.

Laboratory studies reflect leukopenia, atypical lymphocytes, and elevated ALT and AST levels. As discussed, anti-HAV IgM can be detected early in the disease, usually appearing in detectable levels 2 to 3 weeks after exposure, then declining to undetectable levels in 12 to 24 weeks. IgG levels begin to rise three to four weeks after exposure and remain elevated throughout life.

Therapeutic Measures and Prevention

Treatment of HAV is supportive and directed at maintaining adequate nutrition and controlling symptoms. Ingestion of alcohol and/or hepatotoxic medications is avoided. For patients with fulminant hepatic failure resulting from HAV, corticosteroids may be used. However, clinical research has not demonstrated improved outcomes in patients receiving corticosteroids when compared with those who did not receive steroid treatment [89].

As with any other disease, prevention is the most effective strategy. Hepatitis A vaccine is licensed in the United States for use in individuals 1 year of age and older. Immunoglobulin (Ig) can provide short-term protection, both pre- and post-exposure (administered within two weeks after exposure for maximum protection).

The U.S. Food and Drug Administration (FDA) has approved two single-antigen HAV vaccines and one combination vaccine for use in the United States, all of which are inactivated vaccines. The single-antigen vaccines are Havrix and VAQTA. Both are administered to adults in a dose of 1 mL intramuscularly. The dose for children is 0.5 mL [90]. Single-antigen vaccines are considered interchangeable. A second dose of either vaccine can be administered, regardless of which vaccine was administered as the first dose.

An alternative to single-antigen HAV vaccines is Twinrix, which contains inactivated HAV and HBV recombinant vaccines. It is immunogenic against HAV and HBV but requires three injections of 1 mL intramuscularly. The suggested schedule is an initial injection followed by boosters at one and six months. This vaccine is not approved for use in children. Immunity is expected to persist for at least 20 years (and possibly longer) in those who receive all three doses [90,91].

Passive immunization with human Ig, preferably administered within two weeks of known or anticipated exposure, provides short-term protection against HAV infection for persons who have not been vaccinated. The single human Ig product licensed for hepatitis A prophylaxis in the United States is GamaSTAN S/D.

Sanitation strategies are also important in controlling HAV. If in water, the virus is inactivated by boiling the water for five minutes. Hand hygiene using alcohol-based hand sanitizers containing 60% to 95% ethanol are ineffective against HAV, even when in contact with the virus for a full two minutes [92,93]. Therefore, handwashing with soap and water for at least 20 seconds is recommended rather than hygiene using hand sanitizers. If handwashing with soap and water is not an option, cleansing the hands with povidone-iodine for at least 30 seconds may be considered.

Specific Nursing Measures

Persons with hepatitis A may often be cared for at home. Hospitalized patients will require enteric isolation and interventions for alternation in comfort (pruritus and pain), nutritional intake, and fluid volume; impairment of skin integrity and O₂/CO₂ exchange; and disturbances in self-concept. Persons giving care in the home should wear gloves if contact with feces is possible. Gowns should be worn in any situation in which gross soiling occurs. Careful attention to handwashing is essential for patients and for those giving care [95].

Discharge planning for hospitalized patients includes encouraging the patient to get ample rest, ingest a well-balanced diet, and avoid alcohol and over-the-counter medications for at least six months. There is no chronic carrier state with hepatitis A. The patient will not progress to chronic hepatitis or cirrhosis [95].

The hepatitis B virus is one of the smallest viruses known to cause disease in animals. Ten HBV genotypes, labeled A through J, and 30 subtypes have been identified [96]. The genotype of the virus influences the likelihood of developing cirrhosis and the response of the virus to therapy with interferon.

HBV consists of a core and an envelope. The envelope contains HBsAg proteins, glycoprotein, and lipids. The core of HBV includes viral DNA, enzymes necessary for replication, and antigenic protein particles distinctly different from those found in the envelope. The viral DNA is circular and predominantly double stranded, but with a single-stranded arc. The core antigen is termed HBcAg.

The U.S. Preventive Services Task Force recommends screening for hepatitis B virus infection in adolescents and adults at increased risk for infection.

(https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/hepatitis-b-virus-infection-screening Last Accessed: August 12, 2024)

Strength of Recommendation: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

HBV is a bloodborne pathogen that is typically acquired parenterally, perinatally, or through sexual interaction. As with HIV infection, sexual contact and use of contaminated needles for drug injection are the primary risk factors for HBV [97]. However, HBV is considered 50 to 100 times more infectious than HIV, requiring a much smaller inoculum for transmission. Thus, a needlestick injury from a source patient who is coinfected with both HBV and HIV is more likely to transmit HBV, even when the needle is solid (e.g., a suture needle) and even when blood is not visible. Because HBV does not transfer across the placenta, perinatal transmission occurs when an infant is exposed to the blood of an infected mother at the time of delivery. Parenteral exposures include occupational exposure of healthcare workers (1%), use of injected drugs (15%), tattoos, ear and body piercing, acupuncture, and blood transfusions received prior to 1980. Rare cases of transfusion-associated HBV continue to occur, indicating that the virus was present in the blood but with antigen levels below the level of laboratory detection [98].

Clinical Manifestations

The incubation period for HBV can be as little as 45 days or as long as 180 days, but most commonly is 60 to 90 days. The severity of primary HBV infection varies from subclinical to fulminant illness. The age of the patient, the integrity of the immune system, and the infecting dose of the virus influence the severity of acute disease. Persons younger than 5 years of age exhibit mild symptoms or no symptoms, while 70% of infected adults exhibit significant clinical symptoms [99].

Signs and symptoms associated with acute HBV infection are similar to those of other acute viral hepatitis syndromes and include malaise, nausea, abdominal discomfort, icterus, and dark urine. Physical examination of the patient typically reveals an enlarged, tender liver and a yellowish hue to the skin. The spleen is palpable in some patients. In patients with fulminant hepatitis, progressive signs of hepatic encephalopathy (e.g., somnolence, confusion, stupor, coma) are common.

Therapeutic Measures

The American Association for the Study of Liver Diseases (AASLD) recommends antiviral therapy for adults with immune-active chronic hepatitis B infection (hepatitis Be antigen negative or positive) to decrease the risk of liver-related complications.

(https://journals.lww.com/hep/pages/articleviewer.aspx?year=2018&issue=04000&article=00034&type=Fulltext Last Accessed: August 12, 2024)

Level of Evidence/Strength of Recommendation: Moderate/Strong

There is no specific treatment for acute HBV infection; management is primarily supportive. Control of nausea and vomiting, maintenance of fluid and electrolyte balance, avoidance of potentially hepatotoxic drugs and alcohol, and extended periods of rest are the typical therapies.

In less than 1% of cases, fulminant acute liver failure develops. Treatment for fulminant hepatic failure includes compensating for coagulation defects, correcting acid-base as well as fluid and electrolyte disturbances, prevention of hypoglycemia, administering prophylactic antibiotics, and therapies to reduce ammonia levels and combat cerebral edema. With aggressive therapy, improved intensive care and the use of orthotopic liver transplantation, the mortality rate for fulminant acute hepatic failure has gone down to 40% [100].

Preventive Measures

As with hepatitis A, prevention is the best method for dealing with hepatitis B. Hepatitis B vaccine has been available since the 1980s and has been recommended as a routine childhood immunization since the early 1990s. Hepatits B vaccine is available in the United States in seven different formulations. Of those seven formulations, only Engerix-B and Recombivax-HB are approved for neonates and in pregnancy. Other HBV vaccines include Heplisav-B and PreHevbrio. Combination vaccines that include HBV vaccine in the formulation include Twinrix (providing immunization against HAV and HBV), Pediarix (containing diphtheria toxoid, tetanus toxoid, acellular pertussis antigens, recombinant HBsAg, and inactivated poliovirus) and Vaxelis (containing diphtheria toxoid, tetanus toxoid, acellular pertussis antigens, inactivated poliovirus, recombinant HBsAg, and Haemophilus influenzae type b) [99].

Hepatitis B vaccine is typically administered as a series of three intramuscular injections, the second and third doses given at one month and six months, respectively, after the first dose [99]. In 2017, a two-dose series hepatitis B vaccine for unvaccinated or incompletely vaccinated individuals 18 years of age and older was approved by the FDA [101,102]. In addition, evidence has indicated that two injections may be sufficient to achieve protection if administered in adolescence [99]. The ACIP recommends all adults 19 to 59 years of age and adults 60 years of age and older with risk factors for hepatitis B infection should receive hepatitis B vaccination [103]. Hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) should be administered to infants weighing at least 2,000 grams born to persons with hepatitis B infection within 12 hours of birth, followed by completion of the vaccine series and postvaccination serologic testing. These neonates should receive hepatitis B vaccination within 24 hours of birth, followed by completion of the vaccine series. If the HBsAg-exposed neonate weighs less than 2,000 grams, the first dose of vaccine should not be counted as part of the three-dose series. Instead, the series is administered when the infant attains a weight of 2,000 grams or 1 month of age, whichever comes first, and at 2 and 7 months of age. All unvaccinated children and adolescents younger than 19 years of age also should receive the vaccine [94].

Persons who have not been immunized (or did not respond to the vaccine) and are exposed to hepatitis B virus may achieve passive protection from infection by receiving HBIG within seven days of exposure. The usual dose of HBIG is 0.06 mL/kg. For persons who have not been immunized, an accelerated schedule of immunizations is recommended following the dose of HBIG. For documented nonresponders, a second dose of HBIG is appropriate.

Strict adherence to Standard Precautions is recommended in order to prevent exposure to hepatitis B virus or other bloodborne pathogens. Careful handling of needles is also imperative. Because of the hardiness of HBV even in adverse conditions, caution should be used when cleansing objects contaminated with blood or body secretions, regardless of whether or not the body fluids have dried.

Hepatitis B can be inactivated on surfaces with the use of 1:10 bleach solution or hospital-grade disinfectant. Unlike hepatitis A virus, alcohol-based hand sanitizers, used for 30 seconds, are effective against HBV [92].

HCV is a single-stranded RNA virus, with properties similar to those of the flaviviruses, a genus of the family of Flaviviridae that includes yellow fever and St. Louis encephalitis viruses. The genome contains a single open reading frame that encodes a polyprotein of about 3,000 amino acids. The transcript is cleaved into single proteins, including three structural proteins (one core and two envelope proteins) and four nonstructural proteins. The virus is genetically unstable, which leads to multiple genotypes and subtypes.

HCV is considered a bloodborne pathogen. The most common source of infection is percutaneous or parenteral exposure through transfusion, use of injectable drugs, and occupational injury of healthcare providers with a contaminated sharp object. The blood supply in the United States has been tested for hepatitis C since the early 1990s. Now that more advanced screening tests for HCV are used in blood banks, the risk is considered to be less than 1 chance per 2 million units transfused [104]. Therefore, the annual incidence rate of HCV transmission from transfusion therapy since 1994 is less than one case per 100,000 population. In 2016, the CDC issued a health advisory due to an increasing number of acute HCV infections among persons undergoing hemodialysis [105].

Hepatitis C virus is the leading cause of end-stage liver disease and the leading reason for liver transplantation in the United States [104,106]. Chronic HCV infection has also been associated with membranoproliferative glomerulonephritis, cryoglobulinemia, and B-cell lymphoma [104]. Coinfection of HCV with HIV occurs in 50% to 90% of persons who acquired HIV through injection drug use [107].

The U.S. Preventive Services Task Force recommends screening for hepatitis C virus 5nfection in adults 18 to 79 years of age.

(https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/hepatitis-c-screening Last Accessed: August 12, 2024)

Strength of Recommendation: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

HCV occurs throughout the world, with endemic rates varying widely. The WHO estimates that 10% of the population of the Middle East, Africa, and Eastern Europe are infected with HCV. In the United States, an estimated 1.8% of the population (approximately 4 million people) is infected with HCV, and only about half of those infected are aware that they are. Rates of HCV in the United States have increased dramatically since 2010. This has been primarily attributed to the nation's opioid crisis and increased infection among injecting drug users. In 2021, 5,023 new cases of acute HCV were reported, an increase of 492% since 2010 and 129% since 2014 [108]. After adjusting for under-ascertainment and under-reporting, an estimated 69,800 acute hepatitis C cases occurred in 2021 [108]. In addition, 107,540 cases of newly identified chronic hepatitis C were reported in 2021 [108].

Clinical Manifestations

The incubation period for HCV varies widely, from a mean of 7 to 10 weeks and a range of 2 to 20 weeks. HCV antibody is detectable in 80% of cases 15 weeks after exposure and in 97% of cases by 6 months after exposure. People with recently acquired acute infection typically have detectable HCV RNA levels as early as one to two weeks after exposure to the virus [104]. During the acute phase of the infection, 60% to 70% of HCV positive persons will be asymptomatic; approximately 20% of patients will develop mild jaundice, and the remaining persons will have generalized nonspecific symptoms, such as anorexia, nausea, fatigue, malaise, and abdominal pain. During this phase, serum ALT and AST levels are elevated then return to normal range. Fulminant acute hepatitis associated with HCV is rare [100,109].

After the acute infection, 15% to 25% of patients will demonstrate an absence of HCV RNA in the serum and normalization of liver enzymes, within six months indicating resolution of the infection and clearance of the virus from the body. The presence of detectable HCV RNA in persons who test positive for HCV antibody is 74% in the general population. However, the rate of progression to chronic infection is higher in some subpopulations. In particular, the progression rate is more than 90% in African American individuals and as high as 98% in African American men. In those persons in whom HCV RNA remains detectable, indicating continued presence of the virus, 30% to 40% will maintain normal ALT levels and will show no evidence of chronic liver disease. The remaining 60% to 70% of chronically infected patients will have fluctuating ALT levels indicative of chronic liver disease and risk of subsequent progression to cirrhosis. On rare occasions, a patient will demonstrate positive HCV RNA without the presence of HCV antibody. Therefore, in a patient who exhibits chronic hepatitis without apparent cause, assessment of HCV RNA may be indicated [104,110].

Chronic hepatitis from HCV infection usually progresses slowly, with cirrhosis developing in 20% to 25% of patients over a period of 20 to 30 years. However, persons with HCV infection whose daily ethanol consumption exceeds 50 g (about 3.5 standard drinks) per day are twice as likely as nondrinkers to develop cirrhosis and progress to cirrhosis more quickly (in as little as 10 years) [111]. Of those with cirrhosis, 25% eventually develop hepatocellular carcinoma. Persons who ingest alcohol or who were older than 40 years of age at the onset of infection have a more rapid progression of cirrhosis. Men have a higher incidence of cirrhosis than women. Persons with MASLD and those receiving immunosuppressive therapy are also more likely to progress to cirrhosis [112].

Because acute HCV infection can be asymptomatic, the first indication of the presence of chronic HCV infection may be elevated liver enzymes on laboratory testing obtained in connection with another clinical condition or routine health examination. In evaluating the cause of liver enzyme elevation, a hepatitis panel is typically ordered. Testing for the presence of HCV RNA has become the accepted method of confirming current HCV infection (acute or chronic) [104]. Qualitative HCV RNA testing determines whether or not hepatitis C viral particles are present in the blood and can therefore differentiate between resolved and continued infection. Quantitative HCV RNA testing evaluates the amount of hepatitis C virus in the blood and can be used to guide therapy [104,113]. In most commercial laboratories, a positive HCV antibody test triggers a reflex test for quantitative HCV RNA; qualitative HCV RNA is rarely performed.

Therapeutic Measures

Based upon genetic characteristics, eight genotypes and more than 90 different subtypes of HCV virus have been identified. Because the genotypes respond differently to therapy, genotypic testing should be performed for persons with chronic progressive HCV infection who are considering antiviral therapy [104]. In the United States, genotype 1 accounts for 60% to 75% of HCV infections and genotypes 2 and 3 account for about 25% [114].

The treatment of HCV infection has advanced rapidly following the introduction of anti-HCV protease inhibitors in 2011. These newer, direct-acting antiviral drug combinations are highly effective and relatively free of side effects; thus, therapy is now considered for virtually all patients diagnosed with HCV infection [115]. In order to provide healthcare professionals with timely guidance, the IDSA and the AASLD have developed evidence-based recommendations for the diagnosis and management of hepatitis C infection, last updated in 2023. However, due to the rapidly evolving nature of new therapies and other developments, the ISDA and the AASLD recommend reviewing current recommendations online, available at https://www.hcvguidelines.org [115].

The ISDA/AASLD 2023 guidelines emphasize that treatment is recommended for all patients with chronic HCV infection, except those with a short life expectancy that cannot be remediated by HCV therapy, liver transplantation, or another directed therapy [115]. Prior to treatment, patients should be educated regarding proper administration of medications, adherence, and prevention of reinfection. Pretreatment assessment to facilitate decision making regarding the treatment strategy and to determine the need for initiating additional measures for the management of cirrhosis (e.g., hepatocellular carcinoma screening) is recommended in all patients.

During treatment, routine laboratory monitoring of hepatic function or inflammation is not indicated in persons without advanced liver disease. Because of drug-drug interactions between warfarin and direct-acting antiviral therapy, periodic INR should be assessed for patients on warfarin in order to evaluate for subtherapeutic anticoagulation. Drug-drug interactions of direct-acting antiviral therapy and medications used to treat type 2 diabetes can lead to hypoglycemia. Thus, persons on oral diabetes medications should be counseled about the potential for this interaction. No other laboratory studies are required for monitoring.

HCV quantitative RNA should be assessed 12 to 24 weeks after the conclusion of the recommended course of therapy. Persons with sustained virological response at 12 weeks or greater have less than 1% chance of re-emergence of the original infection. They can, however, become re-infected if high-risk practices are continued or re-initiated.

Achieving and maintaining SVR has positive effects on both hepatic and extrahepatic manifestations of HCV infection. These improvements include fibrosis regression, reduction in portal hypertension, reduction in the incidence of hepatocellular carcinoma, reduced incidence of myocardial infarction, reduced incidence of stroke, lower rate of insulin resistance and type 2 diabetes, improved quality of life, and lower all-cause mortality rate [116].

Even in compliant patients, treatment failures can occur. Factors that correlate with treatment failure include degree of fibrosis; the presence of advanced fibrosis in genotype 3 is particularly prone to treatment failure. Other factors that can affect treatment success include age older than 55 years, male sex, and Hispanic or Black ethnicity/race. Fortunately, prior treatment with interferon-based regimens does not usually prevent achieving SVR with direct-acting antiviral therapy. However, prior incomplete or inconsistent treatment with direct-acting antiviral therapy can lead to medication-resistant infection and treatment failure [117]. Patients who experience treatment failure should be referred to a specialist for re-treatment. Monitoring of liver function should be continued by the specialist or primary care provider at least every six months until retreatment is initiated [115].

As noted, infants who are noted perinatally exposed to HCV should have HCV RNA testing at 2 to 6 months of age. Repeat HCV RNA testing, with genotype determination, should be performed when the child is 3 years of age. If viremia remains and genotype 1, 4, 5, or 6 is identified, a weight-based course of ledipasvir-sofosbuvir can be initiated, with an expected SVR in 98% of children. For children with genotype 1-6 and no evidence of fibrosis level 3 or 4, treatment with a weight-based dose of either sofosbuvir-velpatasvir or glecaprevir-pibrentasvir can be accomplished. After successful treatment with any of these three regimens, liver damage caused by HCV usually resolves and these children show no evidence or residual effects [115,118].

For patients with cirrhosis secondary to chronic HCV or HBV infection that has gone untreated or failed therapy, liver transplantation may be indicated. Replacing the liver, however, does not cure the infection. The transplanted liver will also become infected, and immunosuppressive agents facilitate the progression of this infection. At present, chronic viral hepatitis is the most common diagnosis of persons receiving liver transplants in the United States [104].

Preventive Measures

There is no vaccine to prevent hepatitis C. The best way to prevent hepatitis C is by avoiding behaviors that can spread the disease, especially injecting drugs with non-sterile injection equipment. Hepatitis C can spread when a person comes into contact with blood from an infected person. Injecting drugs is the most common way HCV is transmitted in the United States. For people who inject drugs, community-based prevention programs, such as medication-assisted treatment and syringe services programs, can reduce the transmission of HCV.

Although the risk of sexual transmission of HCV is considered to be low, avoiding unprotected sexual exposure by using condoms has been shown to reduce the chance of sexually transmitted infections.

HDV is an RNA virus, the core of which is distinctively different from other viruses. However, due to a defect in replication, HDV is unable to synthesize a viral coat. It must borrow a coat from HBV in order to complete the replication process. Therefore, HDV cannot cause infection independently but instead must exist as a coinfection (acquired at the same time as HBV) or a superinfection (HDV acquired in a patient who is chronically infected with HBV). In the United States, the infection primarily occurs as a coinfection among intravenous drug users. In some areas of the world in which chronic HBV infection is endemic (including the Amazon Basin of South America, China, and Southeast Asia), HDV is more commonly a superinfection [119,120].

Patients coinfected with HBV and HDV tend to have a more severe case of acute hepatitis. The mortality rate in coinfection has been reported to be as high as 20%. Superinfection with HDV results in rapid progression of cirrhosis, with 70% to 80% of coinfected individuals showing signs of liver failure, compared to 15% to 30% of patients with chronic HBV and no cirrhosis [121]. Prevention of HDV is accomplished through the same means as prevention of hepatitis B. A 12-month course of peginterferon alfa-2a is the recommended treatment for patients with elevated HDV-RNA levels and ALT elevation [96]. Nearly 25% of patients involved in an efficacy study of peginterferon alfa-2a treatment showed sustained clearance of HDV RNA over 48 weeks [122]. Given the limited efficacy of current therapies, it is reasonable to refer patients to specialized centers that offer access to experimental therapies for HDV [96]. Immunization against hepatitis B is effective prevention of HDV also because if the individual is immune to HBV, he/she cannot become infected with HDV. Avoidance of bloodborne pathogen exposure through observance of Standard Precautions is a primary mechanism of prevention for persons already chronically infected with HBV.

Like hepatitis A, hepatitis E virus is spread through the fecal-oral route, and like HAV, HEV was also first identified via electron microscope examination of stools of infected patients. HEV has been associated with outbreaks in India, Burma, Pakistan, Russia, China, northern and central Africa, Peru, and Mexico. Outbreaks are usually associated with a contaminated water supply. No outbreaks have occurred in the United States or Western Europe, though individual cases have been identified in persons who have recently traveled to areas in which the virus is endemic [119,123].

HEV most often affects young adults. The incubation period is two to nine weeks, with an average of six weeks. Signs and symptoms are similar to HAV, but with a higher incidence of jaundice, which can be prolonged. The disease is self-limited in the majority of patients. The fatality rate in acute HEV is between 1% and 2%, except in pregnant women. In pregnant women with HEV infection, mortality can reach as high as 30% [123]. No cases of chronic liver disease associated with HEV have been reported.

The treatment of HEV is nonspecific and is directed toward supportive care. Because the incidence of HEV is low and most cases resolve without negative sequelae, the development of a vaccine against HEV has not been a priority for pharmaceutical companies or national and international health agencies. Primary preventive strategies, therefore, concentrate on improved sanitation [123,124].

Clinical manifestations of the disorder covers a spectrum that extends from no apparent symptoms to signs of inflammatory liver disease or cirrhosis. Physical examination may reveal no abnormalities but may also reveal hepatomegaly, splenomegaly, jaundice, and signs and symptoms of chronic liver disease. In asymptomatic cases, the disorder may be discovered when abdominal serum enzyme levels are identified during performance of routine screening tests [126,127].

The American Association for the Study of Liver Diseases recommends that all patients with autoimmune hepatitis should be screened for celiac and thyroid diseases at diagnosis. Further, these patients should be assessed for rheumatoid arthritis, inflammatory bowel disease, autoimmune hemolytic anemia, diabetes, and other extrahepatic autoimmune diseases based on symptomatology and medical provider concern.

(https://journals.lww.com/hep/fulltext/2020/08000/diagnosis_and_management_of_autoimmune_hepatitis.24.aspx Last Accessed: August 12, 2024)

Level of Evidence: Expert Opinion/Consensus Statement

The differential diagnosis of autoimmune hepatitis includes measures to exclude other causes of liver disease, including hepatitis B and C. A characteristic laboratory finding is that of a marked elevation in serum gamma globulins [126,127].

Corticosteroid and immunosuppressants drugs are the treatments of choice for this type of hepatitis. Although some people remain in remission after drug treatment is withdrawn, most require long-term maintenance therapy. Liver transplantation may be required for those who are refractory to or intolerant of immunosuppressive therapy and in whom end-stage liver disease develops. All hepatotoxic medications should be avoided, even analgesics such as acetaminophen [125,126,127].

Major symptoms of cholecystitis are intense pain, tenderness, and rigidity in the right upper quadrant of the abdomen associated with nausea, vomiting, and the usual signs of inflammation. Jaundice and icteric color of the sclera may be present if there is an obstruction. If the gallbladder is filled with frankly purulent matter, the condition is called empyema of the gallbladder. Although chronic cholecystitis may be related to an acute attack, it is almost always associated with cholestasis. Stools may be clay colored due to a stone obstructing flow of bile [128,129].

Laparoscopic cholecystectomy may be indicated after acute inflammation has been relieved by medical intervention. The condition typically resolves following treatment of cholelithiasis [128,129].

Hepatocellular cancer (HCC) accounted for 41,210 new cases liver cancer in the United States in 2023, making it the most common form of liver cancer. Globally, HCC was identified as the cause for nearly 906,000 new liver cancer cases and 830,000 deaths in 2020 [130]. In recent decades, there has been increased incidence in developed countries as a consequence of chronic HCV infection, and the incidence in the United States has more than tripled since 1980. Although primary tumors of the liver are relatively rare in developed countries of the world, the liver shares with the lung the distinction of being the most common site of metastatic tumor [125].

The American Association for the Study of Liver Diseases recommends that patients at high risk of developing hepatocellular carcinoma be entered into surveillance programs, provided they would be candidates for hepatocellular carcinoma treatment.

(https://journals.lww.com/hep/fulltext/2023/12000/aasld_practice_guidance_on_prevention,_diagnosis,.27.aspx Last Accessed: August 12, 2024)

Level of Evidence/Strength of Recommendation: Level 2/Strong

Among the factors identified as etiologic agents in liver cancer are chronic viral hepatitis (HBV, HCV, HDV), cirrhosis, smoking, heavy alcohol consumption, obesity, and long-term exposure to environmental agents (e.g., aflatoxin). The exact pathogenesis is unclear. With HBV and HCV, both of which become integrated into the host DNA, repeated cycles of cell death and regeneration afford the potential for development of cancer-producing mutations. Aflatoxin, produced by food spoilage molds (e.g., Aspergillus flavus and Aspergillus parasiticus), is a known human carcinogen and is endemic in certain areas. A particularly susceptible site for aflatoxin mutation is the TP53 tumor suppressor gene [125].

Clinical Manifestations and Diagnosis

The manifestations of HCC often are insidious in onset and masked by those related to cirrhosis or chronic hepatitis. The initial signs and symptoms include weakness, anorexia, weight loss, fatigue abdominal swelling, a sensation of abdominal fullness, and a dull, aching abdominal pain. Ascites, which can obscure weight loss, is common. Jaundice, if present, usually is mild. There may be a rapid increase in liver size and worsening of ascites in people with pre-existing cirrhosis. Usually, the liver is enlarged when these symptoms appear. Various paraneoplastic syndromes (disturbances due to ectopic hormone or growth factor productions by the tumor) have been associated with hepatocellular cancer, including erythrocytosis, hypoglycemia, and hypercalcemia. Serum α-fetoprotein is present during fetal life but barely detectable in the serum after 2 years of age. When high levels of α-fetoprotein are found in adults, it is usually indicative of hepatocellular carcinoma, although not all primary liver cancers produce α-fetoprotein.

Additional imaging, such as ultrasonography, computed tomography (CT) scan, and magnetic resonance imaging (MRI), are recommended for diagnosis. Liver biopsy may be used to confirm the diagnosis [131,132,133,134]. Genetic testing can reveal susceptibility

Treatment

There is no agreement on a single treatment strategy for patients with HCC. Selection of treatment is complex due to several factors, including [135]:

Several treatments for HCC are associated with long-term survival, including surgical resection, liver transplant, and ablation. There are no large, robust, randomized studies that compare treatments considered effective for early-stage disease, nor are there studies comparing these treatments with best supportive care. Often, patients with HCC are evaluated by a multidisciplinary team that includes hepatologists, radiologists, interventional radiologists, radiation oncologists, transplant surgeons, surgical oncologists, pathologists, and medical oncologists.

Best survival rates are achieved when the HCC can be removed either by surgical resection or liver transplant. Surgical resection is usually performed in patients with localized HCC and enough functional hepatic reserve. For patients with decompensated cirrhosis and a solitary lesion (<5 cm) or early multifocal disease (up to three lesions, ≤3 cm in diameter), the best option is liver transplant, but the limited availability of liver donors restricts the use of this approach.

Transarterial chemoembolization, multikinase inhibitors, and immunotherapy are noncurative treatments for HCC that improve survival. For patients with recurrent disease with metasteses and/or vascular involvement, palliative therapy is the most appropriate approach [135].

Cholangiocarcinoma, with an incidence of 1.6 per 100,000 in North America, occurs much less frequently than hepatocellular carcinoma [136]. The etiology, clinical features, and prognosis vary considerably with the part of the biliary tree that is the site of origin. Distal and perihilar bile duct cancers frequently cause biliary tract obstruction, leading to the following symptoms [137]:

Intrahepatic bile duct cancer may be relatively indolent and difficult to differentiate clinically from metastatic adenocarcinoma deposits in the liver.

Cholangiocarcinoma is not associated with the same risk factors as hepatocellular carcinoma. Instead, most of the risk factors revolve around long-standing inflammation and injury of the bile duct epithelium. Bile duct cancer may occur more frequently in patients with a history of primary sclerosing cholangitis, chronic ulcerative colitis, choledochal cysts, or infections with the liver fluke Clonorchis sinensis [137].

Treatment

The treatment of bile duct cancer depends primarily on whether the cancer can be completely removed by surgery. Localized intrahepatic and extrahepatic bile duct cancer may be completely resected. However, these tumors represent a very small number of cases that are usually in the distal common bile duct. Among patients treated with surgical resection, long-term prognosis varies depending on primary tumor extent, margin status, lymph node involvement, and additional pathological features [137].

Extended resections of hepatic duct bifurcation tumors (also known as Klatskin or hilar tumors) to include adjacent liver, either by lobectomy or removal of portions of segments 4 and 5 of the liver, may be performed. If major hepatic resection is necessary to achieve a complete resection, postoperative hepatic reserve should be evaluated [137].

Unfortunately, most cases of intrahepatic, distal, and perihilar bile duct cancer are unresectable and cannot be completely removed. Often, the cancer invades directly into the portal vein, the adjacent liver, along the common bile duct, and to adjacent lymph nodes. Portal hypertension may result from invasion of the portal vein. Spread to distant parts of the body is uncommon, but intra-abdominal metastases, particularly peritoneal metastases, do occur. Transperitoneal and hematogenous hepatic metastases also occur with bile duct cancer of all sites. Moreover, most patients who undergo resection will develop recurrent disease within the hepatobiliary system or, less frequently, at distant sites.

In locally advanced disease, trials have evaluated chemoradiotherapy with the goal of improved local control and potential downstaging for surgical resection [137]. These approaches have not been compared with standard therapy, and the curative potential is unknown. For patients with unresectable bile duct cancer, management is directed at palliation.

Metastatic tumors of the liver are much more common than primary tumors. Common sources include colorectal cancer and those spread from breast, colon, lung, or urogenital cancer. In addition, tumors of neuroendocrine origin can spread to the liver. It often is difficult to distinguish primary from metastatic tumors with the use of CT scans, MRI, or ultrasonography. The diagnosis may be confirmed by biopsy [132,133].

Patients with stage I disease have cancer confined to the gallbladder wall that can be completely resected. Patients with stage I tumors that are discovered incidentally and resected during routine cholecystectomy have five-year survival rates of nearly 100% [138]. Previously unsuspected gallbladder cancer that is incidentally discovered in the mucosa of the gallbladder during pathological examination is curable in more than 80% of patients. However, symptomatic gallbladder cancer that is suspected prior to surgery often penetrates the muscularis and serosa. This type of gallbladder cancer is curable in less than 5% of patients [138].

Treatment options for localized and locally advanced gallbladder cancer include [138]:

During laparoscopic removal of an unsuspected cancer, implantation of carcinoma at all port sites (including the camera site) is possible. All port sites are typically excised completely, even for stage I cancers.

Patients with T2 (tumor invades the perimuscular connective tissue on the peritoneal or hepatic side) or T3 (tumor perforates the serosa and/or directly invades the liver and/or one other adjacent organ or structure) disease have higher rates of unsuspected invasive disease at the time of diagnosis [138]. Eligible patients may undergo re-exploration to resect liver tissue near the gallbladder bed, portal lymph nodes, and lymphatic tissue in the hepatoduodenal ligament. Retrospective analyses suggest that extended re-resection can delay recurrences and potentially improve survival [138].

For patients with locoregional lymph node involvement (at the cystic duct, common bile duct, hepatic artery, and portal vein), long-term disease-free survival can occasionally be achieved with radical resection. In patients with jaundice, preoperative percutaneous transhepatic biliary drainage for relief of biliary obstruction should be considered [138].

Surgery with curative intent is not considered possible in patients with metastatic spread beyond the locoregional lymph nodes or to distant organs [138].

The use of EBRT with or without chemotherapy as a primary treatment has been reported to produce short-term disease control in small groups of patients. Similar benefits have been reported for radiation therapy, with or without chemotherapy, administered after resection [138]. However, there is limited evidence supporting the use of adjuvant radiation therapy, even for patients with high-risk localized disease [138].

Calculi formed in the gallbladder may move into the cystic duct, the common bile duct, or even into the liver via the hepatic ducts. Calculus obstruction of the pancreatic duct may cause pancreatitis [141,143].

The most common symptom of cholelithiasis is colicky pain believed to be related to spasms of the sphincter of Oddi. Pain may also be related to obstruction and distention of a bile duct. Usually, the pain is felt in the epigastrium or the right upper quadrants of the abdomen, but it may radiate up the back between the scapulae to the right shoulder or around the abdomen to the back, making it difficult for the patient to assume a comfortable position. Some patients will report laying in the supine position often worsens the discomfort. Biliary colic may occur at varying intervals following meals or may wake the patient from sleep. Usually, symptoms occur at progressively shorter intervals after ingestion of almost any food. Occasionally, however, a single pain episode will never be repeated [129,139,140,141].

In addition to the characteristic pain, nausea and vomiting are common, as is elevated temperature. Distention of the bile ducts stimulates the vomiting center. If the common bile duct is obstructed by a calculus, greenish-yellow jaundice develops. Pruritus often develops before the jaundice is visible in the sclera. Icterus is accompanied by pale stools and dark, frothy urine. Ecchymoses may be evident [139,140,141].

Laboratory and diagnostic studies assist in confirming the diagnosis. White blood cell levels, direct bilirubin levels, prothrombin time, alkaline phosphatase, and serum lipid levels will be elevated. Urine urobilinogen levels will decrease, but bilirubin will be found in the urine. Abdominal ultrasound and increased alkaline phosphatase (ALP) levels can help establish a diagnosis of cholelithiasis. Cholecystography, cholangiography, or endoscopic retrograde cholangiopancreatography (ERCP) may be required [139,140,141].

If symptoms are mild, a low-fat diet may be sufficient to control them. The diet would be high in proteins and carbohydrates [144]. Depending on the patient's nutritional status, intravenous glucose and protein supplementation may be indicated. A nutritious diet promotes healing and helps prevent hepatic damage. Vitamin K may be required if coagulation abnormalities are demonstrated [145].

For acute attacks, treatment often includes medications such as butylscopolamine, flopropione, and nonsteroidal anti-inflammatory drugs (NSAIDs). For patients at risk for the development or exacerbation of cholelithiasis, oral ursodeoxycholic acid (UDCA) is recommended for prophylaxis [146].

There are a variety of options for minimally invasive management. Extracorporeal shock wave lithotripsy (ESWL) and oral chemical dissolution therapy were previously used, but both have largely been replaced in recent years. . Both techniques are rarely used in clinical practice in recent years.

Today, many patients with recurrent and/or severe disease undergo ERCP with or without stent placement. If surgical Management is indicated, the preferred approach is laparoscopic cholecystectomy [146].

In addition to comfort measures and administering analgesics and other prescribed medications, nurses can consult with the dietitian and the patient to work out a palatable low-fat diet. The patient may find a list of preferred, appropriate foods useful [59].

Patient A is a man, 60 years of age, who is admitted to the hospital for treatment of acute gastrointestinal bleeding. The patient had a similar episode five weeks ago. An upper endoscopic exam at that time revealed a bleeding esophageal varix for which he received band ligation therapy. He is well-known to the medical community for chronic alcohol use. He has lost several jobs for drinking in the workplace or showing up for work drunk. He has lost his driver's license for drunk driving, and his drinking has placed a significant strain on his marriage. He and his wife are currently separated. He has tried several self-help programs to stop drinking as well as Alcoholics Anonymous, all with little success.

Patient A has been hospitalized five times during the previous 30 months. Most recently, he was discharged five weeks ago following treatment for bleeding esophageal varices. He has a 44-year history of cigarette smoking (one pack per day), was diagnosed five years ago with alcoholic cirrhosis, and currently drinks an unknown amount to liquor daily. He previously reported drinking 6 to 12 beers per day for many years.

On previous admissions, Patient A has been treated for acute pancreatitis twice, alcohol withdrawal seizures, delirium tremens, ascites, coagulopathy, esophageal varices, peptic ulcer disease, anemia, and gastritis, all of which were determined to be related to his alcohol use. Medications at last discharge included:

Patient A was found unconscious and face down in a pool of bright red, bloody vomitus by his neighbor. He is resuscitated and taken to the hospital by ambulance and is admitted to the intensive care unit (ICU). Upon admittance to the ICU, a full physical exam is conducted (Table 1) and laboratory blood testing is ordered (Table 2). Intravenous infusion with a solution of D5W and colloid is started through a central line. Oxygen is started at 3 L/min. Octreotide is administered to help stop the bleeding. An echocardiogram is conducted.

Based on the results of the assessment, Patient A is diagnosed with acute alcohol-related pancreatitis.

Patient B is a woman, 48 years of age, who presents to the emergency department complaining of a four-week history of progressive abdominal swelling and discomfort. She has no other gastrointestinal symptoms and has a normal appetite and normal bowel habits. Her past medical history is significant only for three pregnancies, one of which was complicated by hemorrhage, requiring a blood transfusion. She has been married for 20 years, exercises, does not smoke, and drinks only occasionally. On pointed questioning, she admits that she was "wild' in her youth and did use cocaine once or twice at parties many years ago. She does not currently use illicit drugs. She tested HIV-negative at the time of the birth of her last child.

On examination, her temperature is 100.3 degrees F, her heart rate is 88 bpm, and her blood pressure is 94/60 mm Hg. She is thin, her complexion is sallow, her sclerae are icteric, her chest is clear, and her heart if regular with no murmur. Her abdomen is distended and with mild diffuse tenderness, hypoactive bowel sounds, shifting dullness to percussion, and a fluid wave. She has no peripheral edema. Laboratory studies are normal except for the following:

Patient B is diagnosed with ascites caused by portal hypertension as a complication of hepatic cirrhosis. Paracentesis is performed to evaluate the ascitic fluid to try to determine its likely etiology, as well as evaluate for the complication of spontaneous bacterial peritonitis.

Patient C is a Black man, 33 years of age, who presents to the office for an acute visit with nausea and diarrhea that he has had for the past week. Along with these symptoms, he has had a low-grade fever, some right upper quadrant abdominal pain, and has noticed that his eyes seem yellow.

Patient C has no significant medical history and takes no medications regularly. He denies alcohol, tobacco, or IV drug use. He works as a pastor in a local church that went on a mission to build a medical clinic in a rural area of Central America about five weeks ago. While there, he had a mild case of diarrhea, but otherwise has felt well.

On examination, Patient C is a well-developed man who appears to be moderately ill. His temperature is 99.8°F, his blood pressure is 110/80 mm Hg, his pulse is 90 beats/minute, and his respiratory rate is 14 breaths/minute. He has a prominent yellow color to his eyes and under his tongue. His mucous membranes are moist. Lung and cardiac examinations are normal. His abdomen has normal bowel sounds and tenderness in the right upper quadrant. His liver edge is palpable just below the costal margin. There are no other masses felt, no rebound, and no guarding. On rectal examination, he has clay-colored soft stool that is hemoccult negative.

Based on the examination and history, Patient C is diagnosed with jaundice, likely related to acute hepatitis A infection. Antihepatitis A IgM testing confirms infection. The most probable source of infection is ingestion of contaminated food or water while on his mission.

For this patient, treatment focuses on supportive care and palliation of symptoms. The infection is also reported to the local health department. Close household or sexual contacts are provided with hepatitis A prophylaxis.

Patient E is a Hispanic woman, 42 years of age, who presents to the emergency department complaining of 24 hours of severe, steady epigastric abdominal pain, radiating to her back, with several episodes of nausea and vomiting;. She has had similar painful episodes in the past, usually in the evening following heavy meals, but they always resolved spontaneously within an hour or two. This time, the pain has not improved, so she is seeking medical attention.

Patient E has no prior medical history and takes no medications. She is married, has three children, and does not drink alcohol or smoke cigarettes.

On examination, Patient E is afebrile. She is experiencing tachycardia, with a heart rate of 104 beats per minute. Her blood pressure is 115/17 mm Hg, and she has shallow respirations of 22 breaths per minute. She is moving uncomfortably on the stretcher, her skin is warm and diaphoretic, and she has scleral icterus. Her abdomen is soft and mildly distended, with marked right upper quadrant and epigastric tenderness to palpation, hypoactive bowel sounds, and no masses or organomegaly appreciated. Her stool is negative for occult blood. Laboratory studies are significant for:

Right upper quadrant abdominal ultrasonography shows a distended gallbladder, with several stones.

Based on the assessment, Patient E is diagnosed with acute pancreatitis resulting from choledocolithiasis. The patient is started on systemic antibiotics and prepared for removal of the stones.