Hepatobiliary Disorders
INTRODUCTION
The liver is the largest internal organ in the body, weighing slightly more than 3 lb (1,200 to 1,600 g) in the average adult. It’s also one of the busiest, performing well over 100 separate functions. The most important of these are the formation and secretion of bile; detoxification of harmful substances; storage of vitamins; metabolism of carbohydrates, fats, and proteins; and production of plasma proteins. This remarkably resilient organ serves as the body’s warehouse and is essential to life.
Lobular structure
Located above the right kidney, stomach, pancreas, and intestines and immediately below the diaphragm, the liver divides into a left and a right lobe separated by the falciform ligament. The right lobe is six times larger than the left. Glisson’s capsule, a network of connective tissue, covers the entire organ and extends into the parenchyma along blood vessels and bile ducts. Within the parenchyma, cylindrical lobules comprise the basic functional units of the liver, consisting of cellular plates that radiate from a central vein, somewhat like spokes in a wheel. Small bile canaliculi fit between the cells in the plates and empty into terminal bile ducts, which join two larger ones that merge into a single hepatic duct upon leaving the liver. The hepatic duct then joins the cystic duct to form the common bile duct.
The liver receives blood from two major sources: the hepatic artery and the portal vein. The two vessels carry approximately 1,500 ml of blood to the liver per minute, nearly 75% of which is supplied by the portal vein. Sinusoids—offshoots of the hepatic artery and portal vein—run between each row of hepatic cells. Phagocytic Kupffer’s cells, part of the reticuloendothelial system, line the sinusoids, destroying old or defective red blood cells and detoxifying harmful substances. The liver has a large lymphatic supply; consequently, cancer frequently metastasizes there.
Liver function
One of the liver’s most important functions is the conversion of bilirubin, a breakdown product of hemoglobin, into bile. Liberated by the spleen into plasma and bound loosely to albumin, bilirubin reaches the liver in an unconjugated (water-insoluble) state. The liver then conjugates or dissociates it, converting it to a water-soluble derivative before excreting it as bile. All hepatic cells continually form bile.
The liver also detoxifies many substances through inactivation or through conjugation. Inactivation involves reduction, oxidation, and hydroxylation. An important liver function is the inactivation of many drugs that are metabolized primarily in the liver. Such drugs must be used with caution in hepatic disease because their effects may be markedly prolonged.
ELDER TIPIn elderly people, the blood supply to the liver decreases, and certain liver enzymes become less active. As a result, the liver loses some of its ability to metabolize drugs, and higher levels of drugs remain in the circulation, causing more intense drug effects. This increases the risk of drug toxicity.
As still another example of its amazing versatility, the liver forms vitamin A from certain vegetables and stores vitamins K, D, and B12. It also stores iron in the form of ferritin.
Metabolic functions
The liver figures indispensably in the metabolism of the three major food groups: carbohydrates, fats, and proteins. In carbohydrate metabolism, the liver plays one of its most vital roles by extracting excess glucose from the blood and reserving it for times when blood glucose levels fall below normal, when it releases glucose into the circulation, and then replenishes the supply by a process called glyconeogenesis. To prevent dangerously low blood glucose levels, the liver can also convert galactose or amino acids into glucose (gluconeogenesis). The liver also forms many critical chemical compounds from the intermediate products of carbohydrate metabolism.
The liver performs more than half the body’s preliminary breakdown of fats because liver cells metabolize fats more quickly and efficiently than do other body cells. Liver cells break fats down into glycerol and fatty acids and convert the fatty acids into small molecules that can be oxidized. The liver also produces substantial quantities of cholesterol and phospholipids, manufactures lipoproteins, and synthesizes fat from carbohydrates and proteins to be transported in lipoproteins for eventual storage in adipose tissue.
Like so many of its functions, the liver’s role in protein metabolism is essential to life. The liver deaminates amino acids so they can be used for energy or converted into fats or carbohydrates. It forms urea to remove ammonia from body fluids and forms all plasma proteins (as much as 50 to 100 g/day) except gamma globulin. The liver is such an effective synthesizer
of protein that it can replenish as much as half its plasma proteins in 4 to 7 days. The liver also synthesizes nonessential amino acids and forms other important chemical compounds from amino acids.
of protein that it can replenish as much as half its plasma proteins in 4 to 7 days. The liver also synthesizes nonessential amino acids and forms other important chemical compounds from amino acids.
Production of plasma proteins
The liver synthesizes most of the body’s large molecules of plasma proteins, including all of the albumin, which binds many substances in plasma and maintains colloid osmotic pressure.
Normally, plasma proteins and amino acid levels maintain equilibrium in the blood. When amino acid levels decrease, the plasma proteins split into amino acids to restore this equilibrium. Reacting to decreased levels of amino acids, the liver steps up production of the plasma proteins. The liver may synthesize approximately 400 g of protein daily; for this reason, significant liver damage leads to hyperproteinemia, which in turn disrupts the colloid osmotic pressure and amino acid levels.
The liver also produces most of the plasma proteins necessary for blood coagulation, including prothrombin and fibrinogen, which are the most abundant. The liver forms prothrombin in a process dependent on vitamin K and the production of bile. Fibrinogen, a large-molecule protein formed entirely by the liver, is an essential factor in the coagulation cascade.
Together, the plasma proteins maintain colloid osmotic pressure throughout the capillaries. Because the plasma protein molecules are too large to cross the capillary membrane, they concentrate at the capillary line and produce an osmotic pressure of pull. This constant colloid osmotic pressure at the arteriolar and venular sections of the capillary provides the major osmotic force regulating the return of fluid to the intravascular compartment.
Because of their large molecular size, the plasma proteins don’t easily cross into the interstitial spaces. Their only route for return to the bloodstream is through lymphatic drainage. The lymphatic vessels drain into the lymphatic and thoracic ducts, which drain directly into the superior vena cava.
Assessing for liver disease
In many cases, a careful physical examination and patient history can detect hepatic disease. Watch especially for its cardinal signs: jaundice (a result of increased serum bilirubin levels), ascites (commonly with hemoconcentration, edema, and oliguria), and hepatomegaly. Other signs and symptoms may include right upper quadrant abdominal pain, lassitude, anorexia, nausea, and vomiting. The presence of a palpable left lobe is always pathologic and usually suggestive of chronic liver disease. Another primary sign is portal hypertension (portal vein pressure greater than 6 cm H2O) revealed by the presence of caput medusae (dilated veins seen on the abdomen). Surgical insertion of a catheter into the portal vein allows measurement of portal vein pressure.
ALERTCarefully assess the patient’s neurologic status because neurologic symptoms, such as those associated with hepatic encephalopathy (confusion, muscle tremors, and asterixis), may signal the onset of life-threatening hepatic failure.
Other common signs of hepatic disease include pallor (commonly linked to cirrhosis or carcinoma), parotid gland enlargement (in alcohol-induced liver damage), Dupuytren’s contracture, gynecomastia, testicular atrophy, decreased axillary or pubic hair, bleeding disorders (ecchymosis and purpura), spider angiomas, and palmar erythema.
Careful abdominal palpation and auscultation can also detect hepatocellular carcinoma or metastasis, which turns the liver rock-hard and causes abdominal bruits. In hepatitis, the liver is usually enlarged; palpation may elicit tenderness at the liver’s edge. In cirrhosis, the atrophic liver is difficult to palpate. In neoplastic disease or hepatic abscess, auscultation may detect a pleural friction rub.
Comprehensive history essential
Ask if the patient has ever had jaundice, anemia, or a splenectomy. Ask about occupational or other exposure to toxins (carbon tetrachloride, beryllium, or vinyl chloride), which may predispose him to hepatic disease. Consider recent travel or contact with persons who have traveled to areas where hepatic disease is endemic.
Make sure to ask about alcohol consumption, a significant factor in suspected hepatic disease. Remember, an alcoholic may deliberately underestimate his alcohol intake, so interview the patient’s family as well. Ask about recent contact with a jaundiced person and about any recent blood or plasma transfusions, blood tests, body piercings, tattoos, or dental work. Find out if the patient takes any drugs that may cause liver damage, such as sedatives, tranquilizers, analgesics, and diuretics that cause potassium loss. Ask if the onset of symptoms
was abrupt or insidious or if it followed abdominal injury that could have damaged the liver. Ask if the patient bruises or bleeds easily. Check for light or clay-colored stools and dark urine, and ask about any change in bowel habits. Also ask if the patient’s weight has fluctuated recently.
was abrupt or insidious or if it followed abdominal injury that could have damaged the liver. Ask if the patient bruises or bleeds easily. Check for light or clay-colored stools and dark urine, and ask about any change in bowel habits. Also ask if the patient’s weight has fluctuated recently.
Liver function studies
Numerous tests are available to detect hepatic disease. Perhaps the most useful tests are liver function studies, which measure serum enzymes and other substances. Typical findings in hepatic disease include:
increased bilirubin levels
increased alkaline phosphatase and 5′-nucleotidase levels
elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT): possible hepatocellular damage, viral hepatitis, or acute hepatic necrosis
elevated gamma-glutamyltransferase levels: sensitive for alcoholic liver disease
hypoalbuminemia: subacute or massive hepatic necrosis or cirrhosis
hyperglobulinemia: chronic inflammatory disorders
prolonged prothrombin time or partial thromboplastin time: hepatitis or cirrhosis
elevated serum ammonia levels: hepatic encephalopathy
decreased serum total cholesterol levels: liver disease
positive antinuclear antibodies (ANA) test (in chronic active hepatitis and the presence of hepatitis B antigen)
Liver function studies are less reliable after liver trauma. For instance, tests done long after the injury might miss an initial rise in serum AST and ALT levels. Several less specific blood tests for detecting hepatic disease are urine urobilinogen, lactate dehydrogenase, and ornithine carbamoyl transferase.
Other useful diagnostic tests include the following:
Plain abdominal X-rays may indicate gross hepatomegaly and hepatic masses by elevation or distortion of the diaphragm and may show calcification in the gallbladder, biliary tree, pancreas, and liver.
Abdominal ultrasounds show fatty infiltration, hepatomegaly, gallbladder inflammation or obstruction, ascites, and cirrhosis. Doppler ultrasound demonstrates blood flow.
Magnetic resonance imaging shows masses, fatty infiltration, and cirrhosis and its complications.
Percutaneous transhepatic cholangiography distinguishes mechanical biliary obstruction from intrahepatic cholestasis.
Angiography demonstrates hepatic arterial circulation (altered in cirrhosis) and helps diagnose primary or secondary hepatic tumor masses.
Radioisotope liver scans (scintiscans) may show an area of decreased uptake (a “hole”) using a colloidal or bengal scan or an area of increased uptake (a “hot spot”) using a gallium scan in hepatoma or hepatic abscess.
Computed tomography (CT) scan produces in-depth, three-dimensional images of the biliary tract (the liver as well as the pancreas) that help distinguish between obstructive and nonobstructive jaundice and also helps identify space-occupying hepatic lesions.
Portal and hepatic vein manometry localizes obstructions in the extrahepatic portion of the portal vein and portal inflow system or increased pressure in the presinusoidal vessels.
Percutaneous or transvenous liver biopsy can determine the cause of unexplained hepatomegaly, hepatosplenomegaly, cholestasis, or persistently abnormal liver function tests; it’s also useful when systemic infiltrative disease (such as sarcoidosis) or primary or metastatic hepatic tumors are suspected.
Laparoscopy visualizes the serosal lining, liver, gallbladder, spleen, and other organs and is useful in unexplained hepatomegaly, ascites, or an abdominal mass.
Gallbladder anatomy
The gallbladder is a pear-shaped organ that lies in the fossa on the underside of the liver and is capable of holding 50 ml of bile. Attached to the large organ above by connective tissue, the peritoneum, and blood vessels, the gallbladder is divided into four parts: the fundus, or broad inferior end; the body, which is funnel-shaped and bound to the duodenum; the neck, which empties into the cystic duct; and the infundibulum, which lies between the body and the neck and sags to form Hartmann’s pouch. The hepatic artery supplies the cystic and hepatic ducts with blood, which drains out of the gallbladder through the cystic vein. Rich lymph vessels in the submucosal layer also drain the gallbladder as well as the head of the pancreas.
The biliary duct system provides a passage for bile from the liver to the intestine and regulates bile flow. The gallbladder itself collects, concentrates, and stores bile. The
normally functioning gallbladder also removes water and electrolytes from hepatic bile, increases the concentration of the larger solutes, and reduces its pH to less than 7. In gallbladder disease, bile becomes more alkaline, altering bile salts and cholesterol and predisposing the organ to stone formation.
normally functioning gallbladder also removes water and electrolytes from hepatic bile, increases the concentration of the larger solutes, and reduces its pH to less than 7. In gallbladder disease, bile becomes more alkaline, altering bile salts and cholesterol and predisposing the organ to stone formation.
Mechanisms of contraction
The gallbladder responds to sympathetic and parasympathetic innervation. Sympathetic stimulation inhibits muscle contraction, mild vagal stimulation causes the gallbladder to contract and the sphincter of Oddi to relax, and stronger stimulation causes the sphincter to contract. The gallbladder also responds to substances released by the intestine. For instance, after chyme (semiliquid, partially digested food) enters the duodenum from the stomach, the duodenum releases cholecystokinin (CCK) and pancreozymin (PCZ) into the bloodstream and stimulates the gallbladder to contract. The gallbladder also produces secretin, which stimulates the liver to secrete bile and CCK-PCZ. The gallbladder may also respond to some type of hormonal control, a theory based in part on the fact that the gallbladder empties more slowly during pregnancy.
Assessing for gallbladder disease
During your physical examination of a patient with suspected gallbladder disease, look for its telltale signs and symptoms: pain, jaundice (a result of blockage of the common bile duct), fever, chills, indigestion, nausea, and intolerance of fatty foods. Pain may range from vague discomfort (as when pressure within the common bile duct gradually increases) to deep visceral pain (as when the gallbladder suddenly distends). Abrupt onset of pain with epigastric distress indicates gallbladder inflammation or obstruction of bile outflow by a stone or spasm.
The onset of jaundice also varies. If the gallbladder is healthy, jaundice may be delayed several days after bile duct blockage; if the gallbladder is absent or diseased, jaundice may appear within 24 hours after the blockage. Other effects of obstruction—pruritus, steatorrhea, and bleeding tendencies—may accompany jaundice. Gallbladder disorders rarely cause internal bleeding, but when they do—as in cholecystitis or obstructive clots in the biliary tree from GI bleeding—they can be fatal.
Diagnostic tests
After taking a thorough patient history and carefully assessing the clinical features, the next step in accurate diagnosis of gallbladder disease is to perform diagnostic testing.
Diagnostic tests for gallbladder disease include the following:
Magnetic resonance cholangiopancreatography (MRCP), CT, or ultrasound are used to diagnose gallbladder disease. An MRCP uses magnetic resonance imaging that creates images of the bile and pancreatic ducts. The CT identifies gallstones and pancreatic cancer and is the preferred method for assessing pancreatitis. The ultrasound visualizes the bile ducts, liver, and pancreas. It is less effective in obese patients.
Percutaneous transhepatic cholangiography differentiates extrahepatic from intrahepatic obstructive jaundice and helps detect biliary masses and calculi. Needle insertion in a bile duct permits withdrawal of bile and injection of dye. Fluoroscopic tests evaluate the filling of the hepatic and biliary trees. The test also permits palliative internal or external placement of biliary catheters for free flow
of bile.
Endoscopic ultrasound is used to diagnose and stage gallbladder cancer. An endoscope with an ultrasound transducer on the end is passed down into the intestines, where it can visualize the bile ducts, gallbladder, and pancreatic ducts.
In endoscopic retrograde cholangiopancreatography, duodenal endoscopy with dye injection and fluoroscopy are used to cannulate and visualize bile ducts and pancreatic ducts. This test is useful in locating obstruction, calculi, carcinoma, or stricture and for obtaining bile or pancreatic juice for analysis. Internal stents can be inserted to allow free flow of bile or pancreatic juice.
A hepatobiliary iminodiacetic acid scan (HIDA) creates pictures of liver, gallbladder, bile duct, and small intestine. It is a nuclear scan, which requires that the patient take nothing by mouth after midnight, the night before the test. A radioactive tracer is administered intravenously and then filmed by the HIDA camera. The test takes approximately 2 hours.
In gallbladder ultrasound, sound waves are used to visualize the gallbladder and locate obstruction, stones, and tumors. This test is 95% accurate in detecting stones.
Other appropriate tests for biliary disease are the same as those for hepatic disease.
LIVER DISORDERS
Viral hepatitis
Viral hepatitis is a fairly common systemic disease, marked by hepatic cell destruction, necrosis, and autolysis, leading to anorexia, jaundice, and hepatomegaly. In most patients, hepatic cells eventually regenerate with little or no residual damage. However, old age and serious underlying disorders make complications more likely. The prognosis is poor if edema and hepatic encephalopathy develop.
Hepatitis occurs in these forms:
Type A (infectious or short-incubation hepatitis) is an acute-onset infection and most often affects children and young adults.
Type B (serum or long-incubation hepatitis) is an insidious-onset infection and affects all agegroups. Routine screening of donor blood for the hepatitis B surface antigen (HBsAg) has decreased the incidence of posttransfusion cases, but transmission by needles shared by drug abusers and sexual transmission remain major problems.
Type C accounts for about 20% of all viral hepatitis cases. Most cases are related to injectable drug use.
Type D (delta hepatitis) is responsible for about 50% of all cases of fulminant hepatitis, which has a high mortality. Developing in 1% of patients, fulminant hepatitis causes unremitting liver failure with encephalopathy. It progresses to coma and commonly leads to death within 2 weeks. Type D is uncommon in the United States.
Type E (formerly grouped with type C under the name non-A, non-B hepatitis) occurs primarily among patients who have recently returned from an endemic area (such as India, Africa, Asia, or Central America); it’s more common in young adults and more severe in pregnant women.
Causes and incidence
The major forms of viral hepatitis result from infection with the causative viruses: A, B, C, D, or E. (See Viral hepatitis from A to E, page 278.)
Type A hepatitis is highly contagious and is usually transmitted by the fecaloral route. However, it may also be transmitted parenterally, sexually (especially with oral or anal contact), and perinatally. Hepatitis A usually results from ingestion of contaminated food, milk, or water. Many outbreaks of this type are traced to ingestion of seafood from polluted water. In 2008, there were more than 25,000 acute cases of hepatitis A infection reported in the United States.
Type B hepatitis, once thought to be transmitted only by the direct exchange of contaminated blood, is now known to be transmitted also by contact with bodily fluids. As a result, nurses, physicians, laboratory technicians, and dentists are frequently exposed to type B hepatitis, in many cases as a result of wearing defective gloves. Transmission also occurs during intimate sexual contact as well as through perinatal transmission. Hepatitis B may also be transmitted by the parenteral route through equipment that has been contaminated. An estimated 38,000 new cases of hepatitis B virus (HBV) and 3,000 deaths from HBV occurred in the United States in 2008.
Historically, hepatitis C is transmitted through transfused blood from asymptomatic donors. Hepatitis C may be transmitted parenterally through the use of contaminated equipment. Hepatitis C accounted for 18,000 new infections and 12,000 deaths in the United States in 2008. Most exposures (60%) occur through the use of illicit I.V. drugs. However, sexual transmission is responsible for a small number of cases. Approximately, 3.2 million people in the United States have chronic hepatitis C infection.
Type D hepatitis is found only in patients with an acute or chronic episode of hepatitis B and requires the presence of HBsAg. The type D virus depends on the double-shelled type B virus to replicate. For this reason, type D infection can’t outlast a type B infection. About 15 million people are infected with hepatitis D worldwide. It’s more common in adults than in children. People with a history of illicit I.V. drug use and people who live in the Mediterranean basin have a higher incidence.
Type E hepatitis is transmitted enterically, much like type A. Because this virus is inconsistently shed in feces, detection is difficult. In the United States, the prevalence of hepatitis E is less than 2%. It’s typically found in developing countries that lie near the Equator. Incidence is highest among people ages 15 to 40.
Other proposed causative factors, such as non-ABCDE viral hepatitis and type F, are under investigation.
Viral hepatitis from A to E
The following chart compares the features of each type of viral hepatitis.
Feature | Hepatitis A | Hepatitis B | Hepatitis C | Hepatitis D | Hepatitis E |
Incubation | 15 to 45 days | 30 to 180 days | 15 to 160 days | 14 to 64 days | 14 to 60 days |
Onset | Acute | Insidious | Insidious | Acute | Acute |
Age-group most affected | Children, young adults | Any age | More common in adults | Any age | Ages 20 to 40 |
Transmission | Fecaloral, sexual (especially oralanal contact), nonpercutaneous (sexual), maternalneonatal), percutaneous (rare) | Blood-borne; parenteral route, sexual, maternal-neonatal; virus is shed in all body fluids | Blood-borne; parenteral route | Parenteral route; most people infected with hepatitis D are also infected with hepatitis B | Primarily fecaloral |
Severity | Mild | Usually severe | Moderate | Can be severe and lead to fulminant hepatitis | Highly virulent with common progression to fulminant hepatitis and hepatic failure, especially in pregnant patients |
Prognosis | Generally good | Worsens with age and debility | Moderate | Fair; worsens in chronic cases; can lead to chronic hepatitis D and chronic liver disease | Good unless pregnant |
Progression to chronicity | None | Occasional | 10% to 50% of cases | Occasional | None |
Signs and symptoms
Assessment findings are similar for the different types of hepatitis. Typically, signs and symptoms progress in several stages.
In the prodromal (preicteric) stage, the patient typically complains of easy fatigue and anorexia (possibly with mild weight loss), generalized malaise, depression, headache, weakness, arthralgia, myalgia, photophobia, and nausea with vomiting. He also may describe changes in his senses of taste and smell.
Assessment of the patient’s vital signs may reveal a fever of 100° to 102° F (37.8° to 38.9° C). As the prodromal stage ends, usually 1 to 5 days before the onset of the clinical jaundice stage, inspection of urine and stool specimens may reveal dark-colored urine and clay-colored stools.
If the patient has progressed to the clinical jaundice stage, he may report pruritus, abdominal pain or tenderness, and indigestion. Early in this stage, he may complain of anorexia; later, his appetite may return. Inspection of the sclerae, mucous membranes, and skin may reveal jaundice, which can last for 1 to 2 weeks. Jaundice indicates that the damaged liver is unable to remove bilirubin from the blood; however, its presence doesn’t indicate the severity of the disease. Occasionally, hepatitis occurs without jaundice (anicteric hepatitis).
During the clinical jaundice stage, inspection of the skin may detect rashes, erythematous patches, or urticaria, especially if the patient has hepatitis B or C. Palpation may disclose abdominal tenderness in the right upper quadrant, an enlarged and tender liver and, in some cases, splenomegaly and cervical adenopathy.
During the recovery (posticteric) stage, most of the patient’s symptoms decrease or subside. On palpation, a decrease in liver enlargement may be noted. The recovery phase commonly lasts from 2 to 12 weeks, although sometimes this phase lasts longer in the patient with hepatitis B, C, or E.
Diagnosis
A hepatitis profile, which identifies antibodies specific to the causative virus and establishes the type of hepatitis, is routine in suspected viral hepatitis.
Type A: Detection of an antibody to hepatitis A confirms the diagnosis.
Type B: The presence of HBsAg or hepatitis B IgM antibodies confirms the diagnosis.
Type C: Hepatitis C antibody positively confirms exposure (usually 4 to 10 weeks after exposure). Hepatitis C serum RNA is detectable 2 to 3 weeks after exposure.
Type D: Detection of intrahepatic delta antigens or immunoglobulin antidelta antigens in acute disease (or IgM and IgG in chronic disease) establishes the diagnosis.
Type E: Detection of hepatitis E antigens confirms the diagnosis.
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