Liver Disease

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Contents 1 Liver Disease 1.1 GENERAL DIAGNOSIS 1.1.1 Unconjugated Hyperbilirubinemias 1.1.2 Cholestatic Syndromes 1.2 ACUTE HEPATITIS 1.2.1 Etiology and Epidemiology 1.2.2 Hepatitis A Virus. 1.2.3 Hepatitis E Virus. 1.2.4 Hepatitis B Virus. 1.2.5 Hepatitis D Virus. 1.2.6 Hepatitis C Virus. 1.2.7 Clinical Presentation and Natural History 1.2.8 Laboratory Studies 1.2.9 Clinical Variants 1.2.10 Acute Liver Failure. 1.2.11 Cholestatic Hepatitis. 1.2.12 Relapsing Hepatitis. 1.2.13 Consultation and Hospitalization 1.2.14 Management 1.2.15 Typical Viral Hepatitis. 1.2.16 Clinical Variants 1.2.17 Acute Liver Failure. 1.2.18 Cholestatic Hepatitis. 1.2.19 Prevention 1.2.20 HAV Infection. 1.2.21 HEV Infection. 1.2.22 HBV Infection. 1.2.23 HDV Infection. 1.2.24 HCV Infection. 1.2.25 Drug-induced Hepatitis 1.2.26 Alcoholic Hepatitis 1.2.27 Epidemiology and Pathophysiology. 1.2.28 Clinical Presentation and Natural History. 1.2.29 Complications and Clinical Variants. 1.2.30 Laboratory Studies. 1.2.31 Consultation and Hospitalization. 1.2.32 Management. 1.3 CHRONIC LIVER DISEASE 1.3.1 Chronic Viral Hepatitis 1.3.2 Epidemiology and Etiology. 1.3.3 Clinical Presentation and Natural History. 1.3.4 Laboratory Studies. 1.3.5 Diagnosis. 1.3.6 Management. 1.3.7 HBV Infection. 1.3.8 HBsAg Carriers. 1.3.9 HCV Infection. 1.3.10 Liver Transplantation. 1.3.11 Autoimmune Hepatitis 1.3.12 Etiology and Classification. 1.3.13 Clinical Presentation and Natural History. 1.3.14 Laboratory Studies and Diagnosis. 1.3.15 Differential Diagnosis. 1.3.16 Management. 1.3.17 Cirrhosis 1.3.18 Alcoholic Cirrhosis. 1.3.19 Clinical Presentation and Natural History. 1.3.20 Laboratory Studies and Diagnosis. 1.3.21 Complications, Consultation, and Hospitalization. 1.3.22 Management. 1.3.23 Primary Biliary Cirrhosis. 1.3.24 Etiology and Epidemiology. 1.3.25 Clinical Presentation and Natural History. 1.3.26 Laboratory Studies and Diagnosis. 1.3.27 Consultation and Hospitalization. 1.3.28 Management. 1.3.29 Wilson's Disease. 1.3.30 Management. 1.3.31 Iron Overload Disease. 1.3.32 Management. 1.4 COMPLICATIONS OF CIRRHOSIS 1.4.1 Esophagogastric Varices 1.4.2 Management. 1.4.3 Hepatic Encephalopathy 1.4.4 Management. 1.4.5 Ascites 1.4.6 Management. 1.5 REFERENCES

[edit] Liver Disease

Raymond S. Koff

[edit] GENERAL DIAGNOSIS

Accurate diagnosis and optimal management of patients with liver disease are common concerns of primary care physicians. Since liver diseases are prevalent and screening tests for liver disease are widely available, both symptomatic and asymptomatic patients often seek assistance. Effective approaches are essential to avoid diagnostic or management errors. Clinical assessment has been enhanced by the development of serologic tests for viral hepatitis, noninvasive hepatobiliary imaging, and increased sophistication in the use of invasive procedures.

[edit] Unconjugated Hyperbilirubinemias

Hyperbilirubinemias result from overproduction of bilirubin, impaired hepatic uptake, and impaired conjugation of bilirubin in the absence of intrinsic liver disease. They are suspected in the jaundiced patient whose urine is normal in color and lacking in detectable bilirubin. Causes of bilirubin overproduction include hemolysis, ineffective erythropoiesis, and breakdown of large hematomas. When evidence of these is absent and the patient seems generally healthy, impaired bilirubin uptake and conjugation resulting from Gilbert syndrome are suspected. In Gilbert syndrome, other liver tests are usually normal, a family history of unconjugated hyperbilirubinemia may be present, and fasting for 2 or more days may raise the serum bilirubin to levels that trigger recognition of jaundice. Patients should be reassured that they do not have a serious disorder. Affected patients should carry identification indicating that they have Gilbert syndrome.

[edit] Cholestatic Syndromes

Decreased flow of hepatic bile is known as cholestasis (Box 104-1). The associated pruritus, presumably related to serum retention and sequestration in the skin of poorly defined pruritogenic bile salts, may be extremely distressing. Intrahepatic cholestasis results from parenchymal liver disease or disorders affecting the small intrahepatic bile ducts. Extrahepatic biliary obstruction leading to cholestasis may result from stones, strictures, or cancer in larger bile ducts. Cholestasis is accompanied by elevation of serum bilirubin, bile acids, cholesterol, and alkaline phosphatase. Serum aminotransferase levels are usually only slightly elevated, and serum albumin is at near-normal levels. Malabsorption of fat-soluble vitamins may result from inadequate bile salt micelle formation, leading to hypoprothrombinemia that is responsive to parenteral administration of vitamin K. If cholestasis is prolonged, vitamin D deficiency may result in osteomalacia.

Box 104-1 - Clinical and Laboratory Features of Cholestasis

Clinical Features Jaundice Dark urine Light-colored stools Pruritus Laboratory Features Increased serum bilirubin Increased serum bile acids Increased serum cholesterol Increased serum alkaline phosphatase Slight increase in serum alanine (ALT) and aspartate (AST) transaminases Prolonged prothrombin time (PT) Normal serum albumin

Drug-induced liver injury, alcoholic hepatitis, and acute viral hepatitis top the list of likely causes of intrahepatic cholestasis. Primary biliary cirrhosis, postoperative intrahepatic cholestasis, and gram-negative or gram-positive septicemia should also be considered. It is critical to distinguish patients with intrahepatic cholestasis from those with extrahepatic bile duct obstruction, who may require surgery. In addition to the clinical and laboratory manifestations of cholestasis, patients with extrahepatic cholestasis are at risk for ascending cholangitis, with fever, chills, and right upper quadrant pain. After many months or years of unrelieved extrahepatic obstruction, secondary biliary cirrhosis may develop.

In all patients with jaundice, ultrasonographic examination of the biliary tree to detect dilation of ducts, presence of gallstones, and level of anatomic obstruction is the first step. Ductal dilation may be found in as many as 90% of patients with extrahepatic obstruction of 2 or more weeks' duration. In patients with obstruction of shorter duration, dilation of the ducts may not be detected. If evidence of obstruction is present on ultrasonography or if obstruction is still suspected despite absence of ductal dilation, endoscopic retrograde cannulation of the common bile duct and pancreatic ducts is undertaken for diagnosis and possible endoscopic intervention (i.e., removal of impacted stones). If ultrasonography and cholangiographic techniques indicate the absence of extrahepatic cholestasis, needle biopsy of the liver may provide a specific diagnosis of intrinsic liver disease.

[edit] ACUTE HEPATITIS

Viral hepatitis is encountered often in the office and clinic; more than 250,000 new infections occur annually in the United States. The major objectives of management are supportive care of the symptomatic patient and interruption of hepatitis transmission by patient education and, where available, by immunoprophylaxis.

[edit] Etiology and Epidemiology

Most cases of acute viral hepatitis seen in clinical practice in the United States result from hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV) (Fig. 104-1). A very small proportion of reported HBV infections actually may be coinfections with the hepatitis D virus (HDV), a defective virus requiring the simultaneous presence of HBV for its expression. Although rare in the United States,infections resulting from hepatitis E virus (HEV) are common in developing nations.

In addition to acute infection, HBV, HDV, and HCV may result in persistent infection associated with chronic hepatitis, cirrhosis, and an increased risk of hepatocellular carcinoma, one of the most prevalent nondermatologic malignancies in the world. In contrast, HAV and HEV infections do not lead to persistent infection.

[edit] Hepatitis A Virus.

Infection by HAV, a 27-nm picornavirus containing ribonucleic acid (RNA), leads to the formation of a specific antibody: anti-HAV. In acute-phase sera, anti-HAV belongs to the immunoglobulin M (IgM) class, whereas in convalescent sera, immunoglobulin G (IgG) anti-HAV predominates. Anti-HAV confers prolonged, probably lifelong immunity to reinfection. The incubation period of HAV infection is about 30 days; viremia is short-lived and occurs during the late incubation period and early acute phase. Fecal shedding of HAV is more prolonged, beginning during the second half of the incubation period and persisting for several days and rarely for weeks after the onset of symptoms or jaundice. Peak fecal HAV shedding and maximal communicability occur at the onset of illness in most patients. Fecal-oral spread is the predominant mode of HAV transmission and is responsible for community-wide outbreaks^[1] (Table 104-1). HAV outbreaks have occurred in day-care centers, neonatal intensive care units, and institutions, as well as among injection drug users (IDUs), homosexual and bisexual men, and recipients of certain clotting factor concentrates. Contaminated water and foods, such as raw or inadequately cooked clams, oysters, and mussels, have been implicated in common-source epidemics. Parenteral transmission of HAV appears to be rare because of the brief period of viremia, although outbreaks among IDUs are well known. Maternal-neonatal HAV transmission is not an established epidemiologic entity.

Table 104-1 Routes of Hepatitis Virus Transmission

Mode of spread	HAV	HEV	HBV	HDV	HCV
Percutaneous
Inoculation	Injection drug users	No	Yes	Yes	Yes
Transfusion	Very rare	No	Uncommon		Rare since 1992
Permucosal
Fecal-oral	Community-wide outbreaks	Waterborne outbreaks	No	No	No
Sexual	Homosexual and bisexual men	No	Yes	Yes	Low frequency
Maternal-neonatal	No	Rare	Yes	Yes	Low frequency

[edit] Hepatitis E Virus.

HEV, a 32-nm agent believed to belong to the alpha-like supergroup of RNA viruses, is responsible for large waterborne outbreaks of hepatitis in developing nations; it is the most common cause of sporadic hepatitis in young adults in the third world. Pregnant women who acquire HEV infection appear to be at very high risk for acute liver failure. Cases in the United States are seen in travelers or visitors from endemic regions. The incubation period is about 6 weeks, with a range of 2 to 9 weeks. Assays for serologic identification of anti-HEV are available.

[edit] Hepatitis B Virus.

Although this 42-nm virus has not been efficiently propagated in cell culture, cloning of HBV deoxyribonucleic acid (DNA) in bacteria and yeast has permitted expression of HBV antigens. The surface of HBV contains a specific antigenic material, the hepatitis B surface antigen (HBsAg), which is also found in excess of the intact virus in the form of smaller 22-nm spheres and tubular particles in the circulation of HBV-infected patients (Fig. 104-2). HBV DNA and the hepatitis B core antigen (HBcAg) have been identified in the core of the virus. The HBeAg, derived from HBcAg, is found in the serum of most individuals with active HBV replication. HBsAg is the first serologic marker of HBV to appear and precedes elevation of the serum alanine aminotransferase (ALT). HBeAg appears a few days to a week or so later but disappears well before HBsAg (Fig. 104-3). HBeAg is detected only in HBsAg-positive sera and is a marker of infectivity. In one HBV variant, however, HBeAg is not expressed but viral replication still occurs. Antibody to HBeAg (anti-HBe) becomes detectable as HBeAg declines in titer.

IgM antibody to HBcAg (IgM anti-HBc) appears in sera after HBsAg and HBeAg become detectable and persists for several months. It is replaced by an IgG anti-HBc, which persists for decades. In some patients, HBsAg may no longer be detectable during the acute phase of infection. In this circumstance, IgM anti-HBc is invariably present. Antibody to HBsAg (anti-HBs) is the last serologic marker of HBV to appear, usually in the late convalescent phase. This antibody is neutralizing, persists for decades, and is highly correlated with immunity to reinfection. HBV infection is self-limited in 95% to 98% of adults, and persistent infection occurs more often in neonates, infants, and young children.^[2] Persistent infection is characterized by the prolonged presence of HBsAg and anti-HBc with little or no detectable anti-HBs. Some carriers are asymptomatic; others have chronic hepatitis. The prevalence of the carrier state varies widely, but 0.2% to 0.5% of the U.S. population are HBsAg positive. Among Asian-Americans, Pacific islanders, Native Alaskans, IDUs, homosexual men, and immunosuppressed populations, the carrier rate may exceed 5%.

The long incubation period of HBV infection, averaging from 60 to 90 days, is responsible for the efficiency of blood-borne spread. Viremia begins late in the incubation and persists for several weeks to months or, in the case of individuals destined to become carriers, years. Although screening of blood donors for HBsAg has dramatically reduced the frequency of transfusion-associated HBV infection, transfusion of blood products that cannot be sterilized, injection drug use, and accidental needle sticks or splashing accidents in unvaccinated health care workers remain sources of HBV transmission. Permucosal transfer of HBV plays an even more important role. HBV has been identified in semen, menstrual blood, and saliva, and transmission from acutely infected patients and HBsAg carriers has been established by follow-up study of their sexual contacts. Permucosal transfer during parturition is responsible for maternal-neonatal spread. Women who are HBsAg carriers, particularly those who are HBeAg positive, and women with acute disease in the third trimester may infect their infants. Since infection early in life often results in persistent infection, maternal-neonatal spread serves to perpetuate HBV infection in successive generations. Neither food nor water has been implicated in the spread of HBV.

[edit] Hepatitis D Virus.

Individuals with acute or persistent HBV infection appear to be at risk of coinfection or superinfection with HDV, a 36-nm defective agent. This HBsAg-enveloped RNA virus requires the helper functions of HBV for its expression, and during the course of HDV infection, HBV replication is temporarily suppressed. The incubation period of HDV infection is 3 to 7 weeks. Acute HDV infection can be recognized by the appearance of IgM anti-HDV, HDV antigen, and HDV RNA in serum. HDV is believed to be spread percutaneously, in a manner similar to HBV, and in the United States, IDUs appear to be at highest risk. HDV coinfection with HBV leads to either a self-limited hepatitis or acute liver failure. HDV superinfection of HBsAg carriers may lead to acute self-limited hepatitis, acute liver failure, or rapidly progressive chronic hepatitis.

[edit] Hepatitis C Virus.

This lipid-enveloped 55-nm RNA virus demonstrates considerable genomic heterogeneity. Six genotypes and multiple subtypes have been identified. Current assays for antibodies to HCV have 95% sensitivity and specificity but do not distinguish between active and resolved infections. Polymerase chain reaction (PCR) amplification to detect HCV RNA in serum permits the identification of viremia. Viremic patients may be acutely infected or may have chronic infection. Although HCV usually has an incubation period of about 7 to 10 weeks, the range is extremely wide. HCV has been identified in serum during the late incubation period, the acute phase of illness, and for prolonged periods after convalescence in those with persistent infection. HCV RNA has been identified in hepatocytes and lymphocytes; HCV may be present in low concentrations in some body fluids.

HCV is a blood-borne pathogen spread predominantly by percutaneous transmission. Injection drug use, cocaine snorting, maintenance hemodialysis, and transfusion before 1992 are known risk factors. However, the introduction of anti-HCV screening of blood donors has dramatically reduced the frequency of transfusion-associated HCV infection. Sexual transmission occurs but is less common than with HBV. Maternal-neonatal spread occurs infrequently unless the mother is also HIV positive or has high titers of HCV RNA. Tattooing and body piercing may also be risk factors.

[edit] Clinical Presentation and Natural History

The spectrum of illness in acute viral hepatitis is broad. Many patients have no recognized clinical illness and do not seek care. In others the presence of viral hepatitis may be signaled by recognition of biochemical abnormalities or serologic markers of recent infection. Patients with anicteric illness may have transient gastrointestinal (GI) or upper respiratory symptoms suggestive of a nonspecific viral infection, short-lived anorexia and fatigue, and a day or two of fever. The decision to seek medical aid is often delayed and then canceled as the illness wanes. In contrast, viral hepatitis with jaundice has a longer, more striking clinical presentation, although it is usually self-limited as well. The illness may begin with a prodrome of malaise, anorexia, nausea and vomiting, fatigue, influenza-like symptoms, diarrhea, arthralgias, right upper quadrant abdominal discomfort, low-grade fever, and distaste for or actual aversion to cigarettes and their smoke. This may last a few days to a few weeks. A transient syndrome resembling serum sickness with polyarthritis, urticaria or maculopapular rashes, angioneurotic edema, and hematuria may be the earliest manifestation of hepatitis B but is unusual in the other infections. Deposition of immune complexes in the joints, skin, small blood vessels, and kidneys appears to be responsible.

Prodromal symptoms resolve with the development of jaundice, which is usually preceded by the appearance of dark-brown urine. Mild hepatic enlargement with mild tenderness is typical, and the spleen is enlarged in about 20%. Jaundice typically is maximal during the second week after onset and then disappears during the next 2 to 8 weeks, marking clinical recovery in most patients. Symptomatic improvement occurs concomitantly with the resolution of the biochemical abnormalities.

The natural history of acute viral hepatitis remains incompletely defined (Table 104-2). HAV infection, whether silent or symptomatic with or without jaundice, is rarely fatal (fatalities from acute liver failure are seen in about 2% of patients over 40 years old). In symptomatic HBV infection with jaundice the case fatality rate approaches 1% and is adversely influenced by increasing age, debility, the coexistence of malignancy, and coinfection or superinfection with HDV. HCV is rarely associated with acute liver failure. Persistent infection, chronic hepatitis, cirrhosis, and hepatocellular carcinoma are sequelae of HBV, HDV, and HCV infections.

Table 104-2 Natural History of Viral Hepatitis

Outcome or sequela	Estimated frequency (%)
		HAV	HEV	HBV	HDV	HCV
Complete recovery	>99	>90-99✢	95-97	95	15
Acute liver failure	<0.1-2	<1-10	1	1-2	<0.1
Persistent viremia	0	0	2-5†	1-5	85
Chronic hepatitis	0	0	1-3	1-5	75
Progression to cirrhosis	0	0	33	33-50	2-20
Progression from cirrhosis to hepatocellular carcinoma	0	0	5-40	5-40‡	15-40

✢Among pregnant women, case fatality rates may exceed 10% in acute HEV infection.

†Carrier rates of 50%-80% may follow HBV infection in neonates and infants.

‡HDV infection may promote the development of hepatocellular carcinoma in HBV-infected chronic hepatitis/cirrhosis patients.

[edit] Laboratory Studies

During the prodrome and early acute phase of the illness, leukocyte counts may be normal or low normal. Atypical lymphocytes may be seen. Serum aminotransferase elevations are detected during the prodrome and rise progressively. ALT levels are usually higher than those of aspartate aminotransferase (AST). In icteric patients, serum bilirubin levels usually peak in the second week of the acute illness and vary between 5 and 20 mg/dl. Serum alkaline phosphatase levels are either normal or mildly increased. Serum albumin is usually normal or slightly decreased, whereas serum globulins may be mildly elevated. The prothrombin time (PT) is normal or minimally prolonged, usually to within a few seconds over the control values. Serologic studies defining the responsible virus are undertaken during the acute phase of illness and, if necessary, during convalescence (Table 104-3).

Table 104-3 Serologic Diagnosis of Viral Hepatitis

Agent	Acute phase	Convalescence
HAV	Presence of IgM anti-HAV	Development of IgG anti-HAV
HEV	Presence of IgM anti-HEV and/or HEV RNA	Loss of HEV RNA; development of IgG anti-HEV
HBV	Presence of HBsAg and/or IgM anti-HBc	Loss of HBsAg: development of anti-HBs and IgG anti-HBc
HDV	Presence of HDV RNA or HDV antigen or IgM anti-HDV in HBsAg-positive patient	Loss of HDV RNA or antigen; development of IgG anti-HDV or loss of anti-HDV
HCV	Presence or development of anti-HCV, presence of HCV RNA	Loss of HCV RNA

The presence of anti-HAV of the IgM class in acute-phase sera is diagnostic for acute HAV infection. Anti-HAV of the IgG class is a marker of prior HAV infection. The presence of HBsAg or, if HBsAg is absent, IgM anti-HBc in acute-phase sera is indicative of HBV infection. The development of anti-HBs in late convalescent-phase sera is also indicative of HBV infection or immunization to HBsAg (see Prevention). The diagnosis of HDV infection is only considered in HBsAg-positive individuals. Diagnosis of acute HCV infection requires detection of anti-HCV or HCV RNA.

[edit] Clinical Variants

[edit] Acute Liver Failure.

The most dreaded variant of viral hepatitis, acute liver failure, is seen almost exclusively in patients with symptomatic hepatitis with jaundice and is characterized histopathologically by massive hepatic necrosis. Acute liver failure is manifested by signs of hepatic encephalopathy accompanied by profound PT prolongation. Decreased liver size is a characteristic feature, and GI bleeding and ascites are common complications. The course in 65% to 95% of patients is rapidly downhill, with death occurring in 1 to 4 weeks of onset. Early referral for liver transplant is mandatory. Sepsis, cerebral edema, respiratory and renal failure, and refractory hypotension punctuate the course and contribute to the mortality. Hypoglycemia is observed in about 5% of patients. Survivors have no evidence of chronic liver disease.

[edit] Cholestatic Hepatitis.

This uncommon variant is usually caused by HAV infection. Serum bilirubin levels as high as 30 mg/dl and severe pruritus may persist for many weeks, although other symptoms of hepatitis are less prominent. Serum ALT levels are elevated early in the course but may decline with time, whereas serum alkaline phosphatase levels may remain elevated by twofold to sixfold. Although the course is prolonged, the prognosis is excellent, with full recovery anticipated. If the diagnosis of viral hepatitis cannot be confirmed by serologic studies, further studies are necessary to exclude other causes of cholestasis.

[edit] Relapsing Hepatitis.

Several weeks to a few months after clinical recovery from acute hepatitis, recurrent symptoms and liver test abnormalities may be detected. HAV appears to be the most common virus associated with relapsing disease. During the relapse, IgM anti-HAV remains positive, and fecal shedding of HAV may recur. Despite the prolonged course and multiple relapses in some patients, full recovery is invariable, and chronic hepatitis is not seen. Cutaneous vasculitis and arthralgias may occur in some patients.

[edit] Consultation and Hospitalization

Most patients with uncomplicated viral hepatitis are managed at home. Consultation with a specialist is necessary for patients with severe clinical variants (e.g., acute liver failure) for whom a gastroenterologist-hepatologist may expedite management. Referral is also reasonable when the diagnosis remains uncertain after initial evaluation and observation. Hospitalization is restricted to those few patients with dehydration as a result of persistent vomiting in whom parenteral fluids are given until adequate oral intake can be resumed. Hospitalization is also indicated for patients with acute liver failure.

[edit] Management

[edit] Typical Viral Hepatitis.

Treatment is largely supportive. The goals are to provide adequate nutrition, reduce discomfort and distressing symptoms, avoid exposure to known or suspected hepatotoxic drugs, and interrupt transmission of infection when possible (see Prevention). Limited experience with HCV suggests that treatment with α-interferon during the acute phase may reduce the risk of chronic infection. Interferon treatment of other forms of acute viral hepatitis is not recommended. Monitoring is necessary to identify clinical variants and to intervene as needed. A clear discussion of the illness, its typical course, and reassurance about the generally self-limited nature of the disorder may reduce anxiety and prevent psychogenic disability.

Adequate caloric intake of a balanced diet may require multiple small meals. Because anorexia and nausea usually worsen during the day, breakfasts are often best tolerated, and the bulk of calories may be consumed in the morning. Self-selection of foods is usually highly satisfactory, and no foods need to be restricted on medical grounds. High-protein diets have no important influence on recovery rates. Enforced bed rest has no value, but if fatigue is extreme, bed rest for a few days may be beneficial. Mild physical exercise is generally well tolerated. Restrictions in physical activity are progressively lifted as symptoms diminish, the sense of well-being returns, and biochemical studies reflect waning of the hepatitis. Complete resumption of normal activities should not be hampered by the persistence of minor ALT or AST elevations during convalescence.

All nonessential medications are discontinued. Oral contraceptives may be continued during the illness, however, and do not adversely influence the course. Alcohol ingestion is prohibited until the convalescent phase, when social use may be resumed without harm. Corticosteroid therapy has no benefit. Drug treatment of severe nausea and vomiting remains unsatisfactory. For patients who cannot retain oral fluids or food, home health care or brief hospitalization is required. Intravenous glucose with supplemental potassium, sodium, thiamine, and vitamin B complex is used to restore body water, provide calories, and maintain electrolyte balance.

Monitoring the course of hepatitis requires semiweekly or weekly visits to the physician's office or clinic, supplemented by telephone contact. At each visit, symptoms and physical findings are reviewed and serum bilirubin, ALT, and PT measured. Progressive PT prolongation necessitates further evaluation for severe disease. When the clinical illness is over, further monitoring is done at 3 months to determine, in the case of HBV, that HBsAg has cleared and ALT levels are once again normal. Persistent abnormalities after HBV or HCV infection may be rechecked at 6 months and, if present, require further evaluation for chronic hepatitis.

[edit] Clinical Variants

[edit] Acute Liver Failure.

Patients with liver failure should be hospitalized in centers with liver transplantation programs as soon as their illness is identified. Previous survival rates of 10% to 35% are now 65% to 70% if liver transplantation is promptly performed before the development of irreversible brain injury.

[edit] Cholestatic Hepatitis.

No specific therapy is available. Pruritus may respond to oral administration of the anion-exchange resin cholestyramine or to treatment with ursodeoxycholic acid. A brief course of corticosteroids may accelerate recovery.

[edit] Prevention

[edit] HAV Infection.

Immunoglobulin may be given as postexposure immunoprophylaxis (0.02 ml/kg) to household and intimate contacts of an index case within 2 weeks of exposure. Protective efficacy approaches 90%, and the duration of protection is about 2 to 3 months. Casual contact is not an indication for prophylaxis. Preexposure immunoprophylaxis with inactivated HAV vaccine is recommended for high-risk populations (Box 104-2). Protective efficacy for HAV vaccines in the preexposure setting should approach 100%, and protection may last 10 to 20 or more years. HAV vaccines may also be effective in the control of community-wide, common-source, and institutional outbreaks. Transient pain at the injection site is the major adverse effect of HAV vaccine.

Box 104-2 - High-risk Groups Recommended for Hepatitis A Immunoprophylaxis

Travelers to endemic regions Military and peace-keeping personnel Sewage and waste water plant workers Caregivers of children Injection drug users Men who have sex with men Food handlers in endemic areas Patients with chronic liver diseases Patients with clotting disorders

[edit] HEV Infection.

Passive immunoprophylaxis is not available. A recombinant vaccine is under study.

[edit] HBV Infection.

Universal preexposure immunization with recombinant HBV vaccine (HBsAg subunit vaccine) of neonates, infants, children, and adolescents through 18 years of age may eventually result in HBV eradication in the United States.^[2][3] Until that time, postexposure prevention will continue to require use of hepatitis B immunoglobulin (HBIG), containing large amounts of anti-HBs, together with HBV vaccine. This is indicated in three major settings: (1) after accidental inoculation, ingestion, or splashing of HBV-positive blood or secretions onto mucous membranes or conjunctivae in nonvaccinated individuals; (2) for the susceptible sexual contacts of the acutely infected patient; and (3) for the neonate of HBsAg-positive mothers. In the first two settings, intramuscular HBIG (0.04 to 0.07 ml/kg) is given as early as possible and may be repeated 1 month later. For the neonate at risk, HBIG (0.5 ml) is given shortly after birth (within hours) and HBV vaccine administered in a three-or four-dose schedule beginning early within the first week of life. Combined immunization can prevent 95% of neonatal infections.

Preexposure immunoprophylaxis with HBV vaccine is recommended for certain patient groups and high-risk populations (Box 104-3). Preexposure HBV vaccine protective efficacy rates are about 90% to 95%. They are administered intramuscularly, into the deltoid or, in infants, the anterolateral thigh muscle. In the three-dose schedule, after the initial injection a second injection is given at 1 month and a third 6 to 12 months after the first. In the four-dose schedule the third dose is given 2 months after the first, and the fourth is given 12 months after the first. The recombinant vaccines induce seroprotective levels of anti-HBs in more than 95% of recipients. Booster doses are recommended only in immunosuppressed patients whose antibody levels fall below the seroprotective threshold. Except for transient soreness at the injection site in 10% to 15% and fever of less than 24-hours' duration in fewer than 3%, no important adverse reactions have been attributed to the vaccine.

Box 104-3 - Patient and High-risk Groups Recommended For Preexposure Hepatitis B Immunoprophylaxis

Patient Groups Neonates/infants of HBsAg-negative women Catch-Up Vaccination of Adolescents (Through 18 Years of Age) High-risk Populations Family/household contacts of HBsAg carriers Health care workers Homosexual and bisexual men Individuals with multiple sexual partners or sexually transmitted diseases Injection drug users Patients with non-HBV chronic liver disease Patients with hemophilia or thalassemia Hemodialysis patients Prisoners Pacific islanders and Native Alaskans

[edit] HDV Infection.

Active immunization against HBV is the only current method of preventing HDV infection.

[edit] HCV Infection.

Conventional immunoglobulin preparations are ineffective. A hyperimmune globulin and a prototype recombinant vaccine are currently in early trials.

[edit] Drug-induced Hepatitis

Drug-associated liver disease may simulate acute viral hepatitis and its variants or extrahepatic bile duct obstruction. It may also induce chronic liver disease, including chronic hepatitis, cirrhosis, granulomatous disease, and even malignant disorders of the liver.

Because drug hepatotoxicity is often severe and rarely anticipated, the physician should document all drug exposures in any patient with abnormal liver tests or jaundice. All prescribed and over-the-counter medications, including herbal remedies, vitamins, and food supplements, regardless of where purchased, are enumerated. Consumption of medications prescribed for other household members should be questioned. Although most drug-induced hepatotoxicity occurs within the first few months after the drug is taken, hepatic injury may not become manifest until after several months of drug use. Rarely, drug-induced injury is seen after a year or more of drug use.

Liver disease induced by drugs is occasionally accompanied by extrahepatic clinical manifestations that can cause confusion with other forms of liver disease. For example, the presence of rash, arthralgias, and fever may be seen in liver injury resulting from sensitizing drugs as well as in viral hepatitis. The absence of extrahepatic features, however, does not exclude drug-induced hepatotoxicity. Similarly, although the presence of eosinophilia suggests drug sensitivity, it is not an invariable finding.

Practitioners must become familiar with the hepatotoxicity of commonly prescribed drugs and maintain a high index of suspicion when dealing with less well-known and newer agents. If liver injury is recognized, all nonessential drugs are discontinued. Although consistent with drug-induced disease, improvement is not necessarily diagnostic, and further evaluation for other causes of liver disease is necessary. Drug rechallenge is potentially dangerous, requires informed consent, and should not be undertaken unless the drug is essential and cannot be substituted. Drug rechallenge is rarely required for the patient's care. Suspected drug-induced liver injury should be reported to the pharmaceutical manufacturer and to the Food and Drug Administration (FDA) on their adverse-reaction forms.

After discontinuation of the suspected drug, liver tests should be sequentially measured to ascertain that improvement in laboratory studies occurs concomitantly with clinical improvement. Many patients show clinical and biochemical improvement within a few days of drug discontinuation. For some drugs, however, liver injury progresses and peaks at variable times thereafter; acute liver failure occasionally ensues. Progression of disease for more than a few days after drug discontinuation requires reassessment to ensure that other hepatic disorders have not been missed. Referral to a gastroenterologist-hepatologist is appropriate.

Clinically important drug-induced liver disease should be distinguished from transient minor aminotransferase elevations in the asymptomatic patient. A number of drugs, in many different therapeutic classes, may produce minor increases in serum enzyme levels in as many as 15% of patients during the first several weeks of treatment. This adaptive phenomenon, in which enzyme levels may be as high as two or three times the upper limits of normal, is not a precursor of symptomatic drug hepatotoxicity. If the patient is asymptomatic when the abnormality is found, the drug may be continued if (1) it is still needed, (2) enzyme levels are sequentially measured and do not exceed three times the upper limit of normal, and (3) the patient fails to develop symptoms suggestive of hepatotoxicity. The drug must be immediately discontinued if these conditions cannot be met.

[edit] Alcoholic Hepatitis

Although a form of drug-induced liver disease, the contribution of alcoholic hepatitis to the development, morbidity, and mortality of cirrhosis mandate that it receive special attention. Management of the patient with alcoholic hepatitis presents issues that are distinctly different from those concerned with viral or drug-induced hepatitis.

[edit] Epidemiology and Pathophysiology.

Alcoholic liver disease is one of the most common causes of liver disease in the United States, and alcoholic hepatitis, both as a precursor and a part of alcoholic cirrhosis, is responsible for a large proportion of hospital admissions for alcohol-related liver disease, including many of those directly related to cirrhosis and its complications. In contrast to alcoholic fatty liver, which is a universal feature of excessive alcohol consumption, alcoholic hepatitis is seen in only about 10% to 20% of heavy imbibers. The bulk of men with recognized alcoholic hepatitis have consumed more than 70 gm of alcohol daily for more than 10 years.^[4] In women the threshold appears to be as low as 20 to 40 gm for the same period. The role of malnutrition or nutrient deficiency in the pathophysiology remains to be established. Direct ethanol toxicity, mediated by acetaldehyde and acetaldehyde adducts, may play a role in the initiation of liver injury, but perpetuation of injury may be linked to cell-mediated immune mechanisms.

[edit] Clinical Presentation and Natural History.

Early in alcoholic hepatitis, most patients are asymptomatic. Denial of excessive alcohol ingestion is common, and family members may be unaware of the patient's alcohol abuse. Minor abnormalities of liver chemistries (e.g., AST elevations with normal ALT levels) may provide the sole clue to the presence of liver disease. In some patients a workup for pancreatitis or erosive gastritis may reveal incidental evidence of alcoholic hepatitis. In other patients the diagnosis of alcoholic liver disease is preceded by hepatitis-like complaints, such as anorexia, nausea, vomiting, abdominal pain, malaise, fever, and weight loss. Jaundice may be striking, particularly in patients who have had repeated bouts of alcoholic hepatitis superimposed on alcoholic cirrhosis. The clinical picture occasionally resembles that of extrahepatic bile duct obstruction. There is a broad spectrum of severity, and case fatality rates of 2% to 10% are reported. Hepatomegaly with or without mild tenderness is a characteristic feature of alcoholic hepatitis. Spider angiomas are common, and ascites may be present in as many as 25% of patients without cirrhosis. When cirrhosis is present, the frequency of ascites in alcoholic hepatitis may exceed 80%.

With discontinuation of alcohol, most patients recover over weeks to months. If cirrhosis is absent and abstinence is maintained, the lesion is reversible. In some patients, particularly those with underlying alcoholic cirrhosis, the disease is rapidly progressive over weeks and ultimately leads to death from hepatic failure despite alcohol withdrawal. In as many as one quarter to one third of patients with alcoholic hepatitis, markers of active HCV infection may be present. The degree to which chronic HCV infection contributes to the morbidity and mortality of alcoholic liver disease remains to be determined.

[edit] Complications and Clinical Variants.

The major complication of alcoholic hepatitis is the development of alcoholic cirrhosis. Even in the absence of cirrhosis, evidence of portal hypertension may be recognized. Ascites, splenomegaly, and esophagogastric varices may reflect elevation of portal venous pressure because of the combined effects of perivenular fibrosis, venoocclusive disease, hepatic inflammation, hepatic triglyceride accumulation, and increased hepatocyte water content. The management of portal hypertension and its manifestations in alcoholic hepatitis is identical to that for portal hypertension in the cirrhotic patient. However, to the extent that the underlying lesions of alcoholic hepatitis are reversible with abstinence, portal pressure falls and clinical manifestations of portal hypertension abate.

Alcoholic hepatitis may simulate extrahepatic biliary tract obstruction. The presence of jaundice, fever, leukocytosis, and liver tests compatible with cholestasis suggests ascending cholangitis. Painless, unrecognized pancreatitis leading to compression of the common bile duct may be responsible for a few such cases. In a smaller number of patients, choledocholithiasis resulting from gallstones may be responsible. In most patients with alcoholic hepatitis, evaluation with ultrasonography fails to disclose bile duct dilation, and cholangiography confirms the absence of an obstructing anatomic lesion. Evidence of cholestasis subsides with resolution of alcoholic hepatitis. The precise mechanism responsible for cholestasis in these patients remains to be established.

[edit] Laboratory Studies.

Anemia is present in about two thirds of patients and reflects folate deficiency, alcohol-induced marrow depression, iron deficiency secondary to GI bleeding as a result of alcoholic gastritis, or hemolysis. Even without folate deficiency or reticulocytosis the mean corpuscular volume of the red cell may be strikingly increased. Leukopenia may occur (10% to 20%), and leukocytosis is seen in about 40% of patients. A leukemoid reaction is seen in fewer than 5%. Thrombocytopenia may be present in about 10% to 15%. Serum bilirubin is elevated, but the range of values may be extreme, and levels exceeding 30 mg/dl are found in about 10% of patients. In about 80% to 90% the serum AST level is at least twice as high as the ALT, which is often normal or only slightly elevated. Peak levels of AST exceed 300 IU in fewer than 10% of patients. The serum alkaline phosphatase is usually elevated, often to levels two or three times the upper limit of normal. Serum albumin levels may be depressed, and globulins are elevated because of increases in IgG and IgA levels. PT is prolonged in severe disease.

[edit] Consultation and Hospitalization.

Liver biopsy is useful in confirming the diagnosis and in determining the reversibility of the liver lesion. Consultation is also necessary when the clinical picture suggests extrahepatic bile duct obstruction. Hospitalization is necessary for symptomatic patients who have fever, persistent vomiting, or signs of hepatic failure (e.g., hepatic encephalopathy). Home management is particularly difficult because cessation of alcohol ingestion can rarely be ensured, and failure to improve may indicate continuing alcohol consumption. Consultation with an alcoholism treatment program may be initiated during hospitalization or on an ambulatory basis.

[edit] Management.

Specific drug therapy is not available. Mortality of severe alcoholic hepatitis is manifested by spontaneous hepatic encephalopathy and a calculated discriminant function greater than 32 based on the serum bilirubin and prothrombin time (PT), as follows:

Discriminant function = 4.6×(Patient's PT in seconds − Control PT in seconds) + Serum bilirubin (mg/dl)

Discriminant function of 32 or greater is associated with a 50% case fatality rate in alcoholic hepatitis. This value can be reduced with corticosteroids. The efficacy of corticosteroid treatment is reduced in patients with acute GI bleeding. The major objectives of management are to ensure alcohol withdrawal, provide supportive care during the symptomatic illness, and offer extended counseling and intensive medical supervision supporting continued abstinence.

[edit] CHRONIC LIVER DISEASE

[edit] Chronic Viral Hepatitis

Chronic viral hepatitis refers to a virus-induced necroinflammatory disorder persisting for more than 6 months. It is characterized histopathologically by the presence of hepatocyte necrosis, a dense mononuclear and plasma cell infiltration of the portal triads variably spilling into the adjacent parenchyma, with or without fibrosis. Progression of fibrosis, with distortion of the normal hepatic architecture and development of cirrhosis, is seen in some patients. Patients with chronic viral hepatitis, particularly those with cirrhosis, also are at risk for the development of hepatocellular carcinoma.

[edit] Epidemiology and Etiology.

Chronic viral hepatitis attributed to persistent HBV, HBV/HDV, and HCV infections is the major cause of nonalcoholic chronic hepatitis in the United States. No more than 5% of adult patients with acute HBV infection will develop chronic hepatitis B. As many as 85% of patients with HCV infection, however, develop chronic hepatitis C. Approximately 40% of the chronic viral hepatitis cases in the United States are attributable to HCV infection, about 25% to HBV infection, and about 5% to HBV and HDV infection. The remainder are attributed to currently unknown agents.

[edit] Clinical Presentation and Natural History.

Many patients with chronic viral hepatitis are asymptomatic or have nonspecific symptoms such as fatigue. In a small percentage, end-stage liver disease, with the complications of cirrhosis, may be the earliest clinical manifestation of the disease. Some patients may be identified on follow-up after acute viral hepatitis, and their serum ALT levels remain elevated or fluctuate in and out of the normal range for prolonged periods. Multiphasic health screening tests demonstrating elevation of serum ALT or positive tests for HBsAg or anti-HCV may be the sole abnormalities pointing to the presence of chronic viral hepatitis. Other patients are identified through blood donor screening programs. Recently, public education programs designed to identify and test individuals with a history of risk factors for the acquisition of HCV or HBV have been endorsed by government agencies.

Although chronic viral hepatitis can remain clinically and biochemically unchanged over many years, the disease may progress silently to cirrhosis after decades. In a very small proportion of patients the disease is rapidly progressive, and evidence of hepatic failure or cirrhosis manifests within 5 years. As many as 50% of patients with chronic hepatitis B may develop cirrhosis; 10% to 20% of those with chronic hepatitis C develop cirrhosis. A large number of HBV-infected individuals with detectable HBsAg have repeatedly normal biochemical tests and little evidence of disease on liver biopsy. These “healthy” HBsAg carriers represent the largest reservoir of HBV-infected and infectious individuals. Although patients are at risk for important sequelae, the natural history of the HBsAg carrier state remains incompletely defined.

[edit] Laboratory Studies.

Serum aminotransferase levels are variably elevated and occasionally may be normal, even on sequential studies. Peak serum ALT levels are usually increased less than tenfold. Serum AST levels are equal to or lower than the ALT levels. Hyperbilirubinemia is variable, and many patients have normal levels. If present, increases in serum alkaline phosphatase levels are usually mild. Hypoalbuminemia and PT prolongation are found in severe disease.

[edit] Diagnosis.

Criteria for the diagnosis of chronic viral hepatitis include laboratory documentation of liver disease for 6 or more months. Persistently elevated or fluctuating serum ALT levels may be sufficient to raise suspicion of chronic viral hepatitis. In patients with chronic hepatitis B, tests for HBsAg are positive, and in those with biochemically active disease, HBeAg and HBV DNA are usually detected. In a small proportion of patients with HBsAg-positive chronic hepatitis, positive tests for HDV infection indicate superinfection by this agent. HBsAg-positive, HBV DNA– positive, chronic hepatitis B patients without HBeAg are infected by a HBV variant (the precore mutation). Positive tests for anti-HCV and the presence of HCV RNA are characteristically found in chronic hepatitis C. Liver biopsy may be undertaken to confirm the diagnosis and to assess the severity of the lesion but is not a requirement for the initiation of therapy.

[edit] Management.

Consultation is necessary for liver biopsy, for patients with clinical or biochemical evidence of incipient hepatic failure, and for initiation of antiviral therapy.

[edit] HBV Infection.

Treatment with injections of 5 million units (daily) or 10 million units (three times weekly) of interferon alfa-2b for 4 to 6 months is indicated for patients with compensated chronic hepatitis B, who have HBeAg and HBV DNA and elevated serum aminotransferase levels.^[5] Treatment has resulted in HBV clearance, biochemical resolution, and histologic improvement in 30% to 40% of patients. These responses are maintained for at least a decade and probably longer. During treatment, adverse reactions are common and include a flulike syndrome, bone marrow suppression, and depression. Patients must be monitored frequently, and dose reductions may be necessary in as many as 25% of treated patients. Unfortunately, interferon treatment of patients with HBV and HDV chronic hepatitis has produced few sustained responses. Patients with decompensated disease, signs of liver failure, GI bleeding, ascites, or encephalopathy should not be treated except by experienced investigators following a defined protocol.

Treatment with other antiviral drugs (e.g., lamivudine) is well tolerated and apparently as effective as interferon-α in chronic hepatitis B. Long-term maintenance therapy may be required and drug resistance frequently develops.

[edit] HBsAg Carriers.

Counseling of the carrier and the family is necessary to avoid maladaptive anxiety reactions, depression, and the social isolation responses associated with stigmatization of the carrier as someone with inordinately high personal health risks and high risks of infectivity. The HBsAg carrier state is not invariably lifelong, however, and HBsAg may be cleared with time. Effective antiviral or immunologic measures to accelerate clearance of HBV in carriers without active liver disease are not yet available. Susceptible household and family members living with carriers and neonates of carrier women should receive the HBV vaccine.

[edit] HCV Infection.

Treatment of patients with compensated chronic hepatitis C with interferon-α, 3 million units or 9 μg per injection (depending on the preparation) three times weekly for 12 months, produces a sustained biochemical and virologic response in about 10% to 20% 6 months after treatment. Higher doses, daily therapy, pegylated interferons (interferon attached to polyethylene glycol [PEG] for slow, sustained release), and combination therapy with the guanosine analog ribavirin may increase the sustained response rate to 40% or even higher in some patient groups. Retreatment of relapsed patients may result in a sustained response in about 50%. In contrast, retreatment of nonresponders to an initial course of interferon has been disappointing.

[edit] Liver Transplantation.

In patients with lifethreatening, end-stage chronic hepatitis B in whom HBV replication is active, liver transplantation is not curative, and the newly grafted liver is likely to be infected. An accelerated course of HBV infection may lead to liver failure and the need for recurrent transplantation. Immunotherapy with hepatitis B immune globulin and antiviral treatment with interferon or lamivudine may reduce or postpone the risk of graft infection. In contrast, although HCV infection may recur when transplantation is undertaken in the patient with end-stage chronic hepatitis C, clinically important injury of the graft is uncommon. Treatment to reduce the risk of posttransplant chronic hepatitis C in the new liver is under study.

[edit] Autoimmune Hepatitis

Autoimmune hepatitis is a chronic, progressive, inflammatory disease of the liver of unknown etiology, predominantly affecting young women and frequently associated with hypergammaglobulinemia.^[6] Several markers of autoimmunity and extrahepatic autoimmune manifestations may be present, suggesting an immunologically mediated disorder; a response to immunosuppressive therapy also is characteristic.

[edit] Etiology and Classification.

Autoimmune hepatitis may take a variety of serologic forms, based on the presence of different autoantibodies. The best known is classic autoimmune hepatitis, also known as type I autoimmune hepatitis, a disease found predominantly in women and associated with antinuclear and anti–smooth muscle (antiactin) antibodies. Evidence of genetic susceptibility and an association with HLA-A1-B8-DR3 haplotypes has been found.

[edit] Clinical Presentation and Natural History.

Jaundice and fatigue accompanied by extrahepatic manifestations of systemic disease may be presenting features. Abdominal pain, severe acne, arthralgias or polyarthritis, amenorrhea, pleuritic pain, diarrhea, and fever may be prominent. In the absence of jaundice these features may fail to raise the suspicion of underlying liver disease unless hepatomegaly or splenomegaly is detected. In the fully expressed disorder, jaundice is present in as many as 80% of patients, hepatomegaly is found in a similar percentage, and the spleen is enlarged in about 50%. Spider angiomas may be present, and signs of portal hypertension (e.g., ascites) may develop. Complications of cirrhosis may be presenting features or sequelae.

The course of the disease is variable. Inactive phases may occur in as many as 20% of untreated patients, and the lesion may resolve before the development of cirrhosis. However, severe disease, if untreated, is associated with high morbidity and mortality, particularly within the first few years after diagnosis. Approximately one third of patients succumb to hepatic failure within 5 years, and about three-fourths have died at the end of 10 years, if untreated.

[edit] Laboratory Studies and Diagnosis.

Anemia, leukopenia, and thrombocytopenia may be present and may reflect hypersplenism. Elevations of gamma globulin and IgG levels are typically found. High titers of antinuclear and anti– smooth muscle antibodies are typical. Liver biopsy reveals the lesions of chronic hepatitis with or without cirrhosis.

[edit] Differential Diagnosis.

Drug-induced chronic hepatitis may closely simulate autoimmune hepatitis. In general, implicated drugs cause an acute hepatitis–like illness; women are at highest risk, and regression usually occurs after cessation of the offending drug. Drugs associated with chronic hepatitis include isoniazid, nitrofurantoin, and phenytoin. Chronic viral hepatitis must be considered, as well as other disorders that may masquerade as autoimmune hepatitis, such as Wilson's disease and α₁-antitrypsin deficiency. Iron overload may be considered, although the serum aminotransferase levels tend to be lower than in autoimmune hepatitis.

[edit] Management.

Corticosteroids with or without azathioprine are the mainstays of treatment. In severe disease, corticosteroid treatment prolongs life but may not reduce the risk of progression to cirrhosis. Side effects temper enthusiasm for corticosteroid therapy, and prednisone-azathioprine regimens require frequent white cell and platelet counts to monitor for azathioprine toxicity.

Therapy may be initiated with high-dose prednisone (60 mg) daily, moderate-dose prednisone (30 mg), or even a maintenance dose of 10 to 20 mg. Azathioprine may be added from the beginning or shortly thereafter. The high-dose and moderate-dose prednisone regimens are tapered to maintenance levels (10 to 20 mg) over 4 to 8 weeks. Symptomatic improvement on these regimens is expected within 3 months and biochemical remission within 6 months. Histologic remission may be delayed for 1 to 2 years. Treatment should be continued for 1 to 2 years before an attempt is made to discontinue therapy. Relapse is common, and repeated courses or maintenance regimens may be needed. After induction of remission with prednisone and azathioprine, prednisone may be discontinued, and azathioprine alone may maintain remission in some patients. Liver transplantation has been successful for patients with end-stage liver disease. Recurrence is uncommon.

[edit] Cirrhosis

Cirrhosis is one of the 10 leading causes of death for both sexes in the United States. Cirrhosis implies irreversible hepatic injury in which diffuse disorganization of the lobular architecture results from the combined effects of connective tissue proliferation and nodular regeneration of surviving hepatocytes. Hepatic necrosis and inflammation appear to be responsible for collapse and collagenization (fibrosis) of the reticulin framework of hepatocyte cords. Total liver cell mass is reduced. Distortion of the microcirculation of the liver and collagen deposition lead to impaired sinusoidal transport and reduced extraction of protein-bound substrates, as well as increased resistance to blood flow. Portal venous hypertension, intrahepatic anastomotic channels between inflow and outflow veins, and extrahepatic collaterals between the portal and systemic veins are sequelae.

[edit] Alcoholic Cirrhosis.

After chronic HCV infection, alcoholic cirrhosis is the second major cause of cirrhosis and end-stage liver disease in the United States.

[edit] Clinical Presentation and Natural History.

Alcoholic cirrhosis may be clinically latent and discovered incidentally, during evaluation of unrelated illness, or as a consequence of complications, such as portal hypertension. Cirrhosis may be detected during the workup of impotence, infertility, hepatosplenomegaly, or minimal abnormalities of liver biochemical tests. Evaluation of alcoholic hepatitis may lead to identification of underlying cirrhosis. Since alcoholic cirrhosis is usually not detected until after 10 or more years of excessive alcohol ingestion, children and adolescents are unaffected. The incidence of the disease peaks in midlife, and affected men exceed affected women by about 2:1. Presenting features may include jaundice, particularly in patients with alcoholic hepatitis or those with far-advanced disease. Associated complaints include nausea, vomiting, anorexia, fatigue, weight loss, low-grade fever, and decreased libido. Evidence of portal hypertension, hepatic encephalopathy, or abnormalities of hemostasis may be presenting features.

The liver may be enlarged, with a rounded edge and a firm consistency. In advanced disease, however, the liver may be smaller than normal, and the liver edge may be grossly irregular because of macroscopic nodular regeneration. Splenomegaly is common, and venous collaterals in the abdominal walls may be striking. Spider angiomas, palmar erythema, evidence of muscle wasting, and an emaciated appearance accompanied by parotid gland enlargement are typically found. Gynecomastia and testicular atrophy are frequent findings.

The course of alcoholic cirrhosis depends on the stage and activity of the disease at diagnosis, subsequent alcohol consumption, and the occurrence of complications, which in themselves are life-threatening. Variceal bleeding because of portal hypertension, progressive hepatic encephalopathy, intercurrent bacterial infections, and hepatocellular carcinoma are the major causes of death. Life expectancy is reduced in alcoholic cirrhotic patients. Five-year survival rates vary between 25% and 60%.

[edit] Laboratory Studies and Diagnosis.

Hematologic abnormalities are similar to those found in alcoholic hepatitis, and liver chemistries may reflect the presence of alcoholic hepatitis superimposed on alcoholic cirrhosis. Patients without evidence of acute alcoholic hepatitis have a wide spectrum of biochemical abnormalities. In patients who have abstained for prolonged periods, results of liver tests may be completely normal despite established cirrhosis. In most patients, particularly those who continue to imbibe, mild elevations of serum bilirubin, serum AST, and serum alkaline phosphatase are found. Patients with progressive disease may have PT prolongation resulting from reduced synthesis of prothrombin precursor proteins, impaired conversion of the inactive protein to the active molecule, and consumption coagulopathy. Hypoalbuminemia is common in severe cases and malnourished patients. Serum globulins and the gamma globulin fraction may be mildly to moderately elevated. Hyponatremia, hypokalemia, and low blood urea nitrogen levels are characteristic. However, cirrhosis may be complicated by the development of progressive azotemia, the hepatorenal syndrome (see Ascites).

The clinical diagnosis of alcoholic cirrhosis is based on recognition of the characteristic clinical features, physical findings, and laboratory studies in the alcoholic patient. Since alcoholic hepatitis, a reversible disorder, may simulate alcoholic cirrhosis, an irreversible one, and because both may be present, liver biopsy is a useful confirmatory procedure. Histologic examination helps define the stage of the disease and exclude other disorders that may affect the alcoholic patient (e.g., iron overload disease).

[edit] Complications, Consultation, and Hospitalization.

Complications of alcoholic cirrhosis, such as variceal bleeding, infection, nonresponsive ascites, and progressive hepatic failure, are indications for consultation and should prompt hospitalization. Surgery in a patient with alcoholic cirrhosis often is associated with excessive operative morbidity-mortality and should be avoided or delayed unless failure to intervene is life-threatening.

[edit] Management.

No specific therapy is known to reverse cirrhosis or to halt disease progression in the patient who continues to consume alcohol. Complete abstinence is the major goal of management, since compliance with such a regimen may lead to clinical and biochemical improvement and slow the rate of loss of hepatic mass. Although a balanced and nutritious diet containing more than 2000 kcal and 1 gm of protein per kilogram of body weight is prescribed, except for patients with hepatic encephalopathy, dietary treatment has limited value in the patient who continues to drink. Thiamine and multivitamins may be given, as well as supplemental folic acid, magnesium, and pyridoxine or pyridoxal phosphate.

Because occult sepsis is common, careful evaluation for bacterial infection is warranted even in the absence of high fever or shaking chills. Patients with cirrhosis, including those with nonalcoholic disease, should be cautioned about the high risk of Vibrio septicemia resulting from ingestion of raw or undercooked mollusks. The primary care physician should seek evidence of encephalopathy, fluid retention, and GI bleeding at each visit. Successful long-term management requires that the physician be sympathetic and supportive but also firm in stressing a program of abstinence. Referral to a formal alcohol withdrawal program may be useful. Counseling of the patient's family and employer may facilitate adherence to such a program. Psychotropic drugs (e.g., hypnotics, sedatives, tranquilizers) are best avoided, since their administration is potentially hazardous in this setting. Disulfiram has induced acute liver failure in a number of patients and should not be used.

[edit] Primary Biliary Cirrhosis.

This chronic, progressive inflammatory disease of the liver is characterized by destruction of the intrahepatic bile ducts and eventual development of cirrhosis. In contrast to secondary biliary cirrhosis, a complication of prolonged anatomic obstruction of the extrahepatic biliary tree, the extrahepatic biliary tree is normal in patients with primary biliary cirrhosis.

[edit] Etiology and Epidemiology.

Although the cause is unknown, an autoimmune mechanism may be involved; cytotoxic T lymphocytes infiltrate and attack the bile duct epithelium, granulomas surround injured bile ducts, circulating antibodies against mitochondria are present in nearly all patients, immune complexes may be found in the circulation, and other autoimmune disorders are seen in 10% to 15% of patients. A disorder resembling primary biliary cirrhosis has been described in a few patients after exposure to chlorpromazine, tolbutamide, methyltestosterone, and oral contraceptives.

The disease primarily affects women between ages 35 and 65; the range is wide, however, and onset in the third and eighth decades of life has been described. Fewer than 15% of patients are men. Familial cases of primary biliary cirrhosis are documented, and some family members may have the antimitochondrial antibody characteristic of the disease, but no association with HLA types has been recognized.

[edit] Clinical Presentation and Natural History.

As many as 50% of affected patients are asymptomatic at diagnosis. These patients are usually identified through evaluation of unexplained hepatomegaly or by elevated serum alkaline phosphatase or, more rarely, serum aminotransferase levels during routine evaluation. Many patients remain asymptomatic for decades, although the liver lesion may progress silently. Pruritus with or without fatigue is usually the earliest symptom, followed months to years later by jaundice, xanthomas, and the clinical picture of prolonged and slowly progressive intrahepatic cholestasis. Weight loss, right upper quadrant abdominal pain, anorexia, nausea and vomiting, and increased skin pigmentation are described in 5% to 15% of patients. The CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactyly, telangiectasia), Sjögren's syndrome, or renal tubular acidosis may be present. Although variceal bleeding, ascites, and hepatic failure are terminal features of disease progression, these are presenting features in a few patients. Bone thinning secondary to osteomalacia and osteoporosis may lead to vertebral collapse.

Hepatomegaly is present in 50% to 75% of patients at diagnosis and splenomegaly in 10% to 50%. Hyperpigmentation and xanthomas are present in 10% to 30% at diagnosis, but the frequency of physical abnormalities increases with time. The rate of progression of the disease is highly variable. In asymptomatic patients, life expectancy may be minimally reduced. In symptomatic cases, average survival appears to vary between 6 and 12 years, but the range is wide. Jaundice, weight loss, ascites, bridging fibrosis, and cirrhosis on presentation are correlated with a poor prognosis.

[edit] Laboratory Studies and Diagnosis.

Isolated elevation of serum alkaline phosphatase of liver origin, exceeding twice the upper limits of normal with or without mild increases in serum aminotransferase levels, is an early feature. Mild elevations of serum bilirubin and hypercholesterolemia are present in about half of asymptomatic patients and may become more prominent with time. Elevated serum IgM levels may be found in about 50% of patients. In patients with cholestasis, malabsorption of vitamin K, secondary to impaired bile salt excretion, leads to PT prolongation. Antimitochondrial antibodies are found in 95% of patients, and the titer exceeds 1:500 in about half. Antimitochrondrial antibodies also are found in some patients with autoimmune chronic hepatitis, but low titers are characteristic.

The diagnosis can be confirmed by liver biopsy, which demonstrates destruction of portal triad bile ducts; these ducts are surrounded by mononuclear and plasma cells resembling lymphoid follicles, with or without granulomas and piecemeal necrosis. Portal fibrosis, bridging fibrosis, and cirrhosis may be present. Cholestasis is prominent in most specimens and may be accompanied by increased hepatic copper concentrations. Patients with a suggestive liver biopsy but absent anti–mitochondrial antibodies may require endoscopic retrograde cholangiography to exclude secondary biliary cirrhosis.

[edit] Consultation and Hospitalization.

Consultation is necessary for liver biopsy and for patients with progressive disease manifested by hepatic failure or complications of cirrhosis. In the latter circumstances, referral to a liver transplantation center is appropriate.

[edit] Management.

Ursodeoxycholic acid (UDCA), in a dosage of 13 to 15 mg/kg, has improved biochemical tests and pruritus and is generally well tolerated. UDCA has not had a major effect on the histologic lesion but appears to delay the development of hepatic failure and improve survival.^[7] UDCA is the current treatment of choice. Corticosteroids, azathioprine, andd-penicillamine have been studied but cannot be recommended. Colchicine has been used, but evidence of efficacy is minimal. Methotrexate also has been used, but efficacy is uncertain and pulmonary fibrosis may complicate treatment. The efficacy and safety of the combination of UDCA plus methotrexate is under study.

Supportive, symptomatic therapy includes oral administration of vitamins D, A, and K and oral vitamin E and calcium supplements. Pruritus nonresponsive to UDCA may be controlled by administration of cholestyramine with each meal. Rifampin, naltrexone, plasmapheresis, or ultraviolet light may lessen pruritus for those who cannot obtain relief with UDCA or cholestyramine.

Liver transplantation should be considered for patients with intractable pruritus, bilirubin levels of 10 mg/dl or greater, or evidence of hepatic failure. Posttransplantation recurrence of disease has been reported but is rare.

[edit] Wilson's Disease.

This rare, autosomal recessive disorder of copper metabolism affects children and young adults and leads to chronic hepatitis and cirrhosis. If untreated, Wilson's disease inevitably leads to progressive and fatal liver and central nervous system (CNS) damage.

The gene for Wilson's disease has been localized to the long arm of chromosome 13 at the ATP7B site. More than 40 mutations have been identified in this gene, which controls the expression of a liver-specific copper transporter protein. About 1 in 30,000 individuals are homozygous for two copies of the abnormal gene. Production of the defective protein results in impaired biliary excretion of copper from the hepatocyte and the accumulation of toxic amounts of copper in the liver and subsequently in the brain, cornea, lens, and kidney.

Liver involvement, resembling acute viral hepatitis or acute liver failure often complicated by hemolytic anemia and chronic hepatitis with or without cirrhosis (or cryptogenic cirrhosis), is the usual presenting manifestation of affected children and young adolescents. In adults, neurologic or psychiatric features may be more prominent, and liver disease may be inapparent, although it is invariably present. Parkinson-like tremors, dysphagia, dysarthria, and dystonia are typically seen. Emotional lability, adolescent adjustment problems, depression, and psychosis are well-known findings. Golden-brown Kayser-Fleischer rings, a result of the deposition of copper in Descemet's membrane of the cornea, are usually demonstrable by slit-lamp examination in patients with CNS involvement.

Liver chemistries are usually abnormal but nonspecific, reflecting variable degrees of hepatocyte necrosis, fatty infiltration, and inflammation. Reduced serum levels of ceruloplasmin, the copper-binding serum glycoprotein, are found in 95% of patients, but only 85% of children with symptomatic liver disease have low levels. Hypouricemia, hypophosphatemia, uricosuria, aminoaciduria, and phosphaturia may be present. Diagnosis requires a high index of suspicion as well as documentation of low serum ceruloplasmin levels, increased urine copper, and increased hepatic copper concentrations in specimens obtained by biopsy.^[8]

[edit] Management.

Testing for mutations in the Wilson's disease gene is not yet practical. If Wilson's disease is suspected, the patient should be referred to a specialist familiar with the disease. Screening of family members may permit detection of asymptomatic Wilson's disease. Both the propositus and identified asymptomatic individuals require lifelong treatment with the copper-chelating agentsd-penicillamine or triethylene tetramine to reduce copper stores. Oral zinc salts and avoidance of high-copper foods may be useful adjunctive maneuvers. Successful decoppering prevents disease when begun early, improves liver and neurologic symptoms, and prolongs survival. Liver transplantation is indicated for those with acute liver failure and patients with decompensated cirrhosis who are unresponsive to decoppering.

[edit] Iron Overload Disease.

The accumulation of excessive amounts of iron in the liver and extrahepatic tissues may result from a genetic disorder or a complication of chronic hemolysis, transfusion therapy, porphyria cutanea tarda, alcoholic cirrhosis, portacaval anastomosis, or dietary iron overload. Hepatic fibrosis, cirrhosis, complications of portal hypertension, and an increased risk of hepatocellular carcinoma are sequelae of the progressive liver disease in untreated patients and may be accompanied by diabetes, dilated cardiomyopathy, hypogonadism, hyperpigmentation, and arthropathy. This section discusses the genetic disorder.

Genetic iron overload, the most common inherited liver disease, is transmitted as an autosomal recessive disease. The responsible gene, the HFE gene, has been localized to the short arm of chromosome 6. The most common mutation of this gene, the C282Y mutation, is found in both copies of the gene in homozygous patients and in one copy among heterozygotes. Other mutations also have been reported, but their role is less clear. Precisely how the C282Y mutation in the HFE gene results in enhanced intestinal iron absorption and altered iron metabolism is unknown.

Although iron accumulation begins early in life, clinical manifestations may not be seen until the fifth decade or later. Iron overload is about 10 times more common in men than women and usually begins earlier. Most patients identified by laboratory studies are asymptomatic. Those with early symptoms most frequently have weakness, lethargy, arthralgias, loss of libido, and weight loss. Hepatomegaly, splenomegaly, and signs of cirrhosis and portal hypertension may be found. The development of hepatocellular carcinoma is the most devastating complication of liver involvement. Diabetes is present in a minority of patients at diagnosis but diabetic retinopathy, renal involvement, and neuropathy may complicate the course. Impotence and testicular atrophy in men and secondary amenorrhea and early menopause in women may be seen. Patients with iron overload disease appear to be at increased risk of Listeria, Yersinia, and pathogenic Vibrio infections.

Serum aminotransferase levels may be slightly elevated but usually do not exceed three times the upper limits of normal. Diagnosis requires demonstration of increased serum iron levels and decreased transferrin levels, yielding atransferrin saturation usually in excess of 60%, elevated serum ferritin levels (often above 1000 ng/ml), and quantitative evidence of increased hepatic iron concentration, permitting estimation of the hepatic iron index. The latter is defined as the hepatic iron concentration (in micromoles of iron per gram dry liver) divided by the age of the patient (in years). A hepatic iron index greater than 1.9 is generally considered diagnostic, but exceptions exist.^[9]

[edit] Management.

Patients with suspected iron overload disease should be referred to a specialist for definitive diagnosis (liver biopsy with quantitative hepatic iron determinations) and initiation of iron depletion by phlebotomy. Subsequent management can be undertaken by the primary care physician. Phlebotomies are undertaken weekly or biweekly and continued at that rate until the hemoglobin falls because of mild iron deficiency anemia. Transferrin saturation may decline precipitously just before the decrease in hemoglobin levels. Maintenance of iron balance thereafter may require occasional phlebotomy. Siblings and other first-degree relatives of the propositus may be tested for HFE mutations and iron parameters. If they are homozygous for the C282Y mutation or have evidence of iron overload, phlebotomy therapy must be initiated, since effective iron depletion prevents all clinical manifestations and results in normal life expectancy. Treatment of patients with clinical complications of iron overload disease may reverse some but not all manifestations (Table 104-4).

Table 104-4 Results of Effective Iron Depletion in Patients with Hemochromatosis

Complication	Expected result of treatment
None present	Normal life expectancy
Hyperpigmentation	Usually resolves
Hepatomegaly	Often improves
Cardiac dysfunction	Improvement may occur
Glucose intolerance	May improve but rarely disappears
Arthropathy	Minimal improvement
Cirrhosis	No change
Progression of cirrhosis to hepatocellular carcinoma	No change
Hypogonadism	No change

[edit] COMPLICATIONS OF CIRRHOSIS

Regardless of the etiology of cirrhosis, the complications are often life-threatening in themselves and may contribute to reduced life expectancy. The primary care physician must be familiar with these complications, recognize them early, and plan a course of appropriate management. Early consultation with an experienced gastroenterologist-hepatologist may be helpful, since management of the major complications of cirrhosis is difficult and the efficacy and safety of many therapeutic measures remain controversial. Furthermore, early referral for consideration for hepatic transplantation is recommended for most patients with cirrhosis, except those with alcoholic cirrhosis who have continued to drink.

[edit] Esophagogastric Varices

Portal hypertension secondary to cirrhosis leads to the development of extensive collateral channels between the left gastric and azygos veins in 30% to 75% of patients. These esophagogastric varices are most prominent in the lower third of the esophagus and fundus of the stomach. They may be asymptomatic for prolonged periods, but when varices are large and associated with marked elevations of portal pressure, the risk of hemorrhage is 25% to 35%. No specific precipitants of bleeding from esophagogastric varices are recognized. Impaired hemostasis may contribute to the initiation or perpetuation of variceal bleeding in some patients. Thrombocytopenia in cirrhosis may reflect hypersplenism secondary to congestive splenomegaly resulting from portal hypertension, disseminated intravascular consumptive coagulation, or alcohol-induced bone marrow depression. Prolongation of the PT in cirrhosis may be multifactorial (see Alcoholic Cirrhosis) and may also contribute to bleeding.

Hematemesis and melena are the cardinal manifestations of bleeding esophagogastric varices. Because patients with cirrhosis may bleed from other lesions, such as erosive gastritis, peptic ulcer disease, and Mallory-Weiss tears, endoscopic visualization of the bleeding site is essential as soon as hemodynamic stabilization is achieved after emergency hospital admission. Hemorrhage from esophagogastric varices is associated with reduced survival (Table 104-5).

Table 104-5 Risks and Survival with Bleeding Esophagogastric Varices

Risk/survival	Mortality (%)
Development of varices	25-35
Mortality for hemorrhage	30-50
Recurrent hemorrhage in survivors	30-70
5-year survival after hemorrhage	5-20

[edit] Management.

Consultation with a gastroenterologist is appropriate for patients with cirrhosis. In those with large varices, treatment with nonselective β-adrenergic blockers reduces the risk of the first variceal bleed by about 40%. In patients without contraindications to β-blockers and who can tolerate therapy, it should be continued indefinitely. For the patient with acute variceal hemorrhage, resuscitation in the intensive care unit is essential to establish airway protection and hemodynamic stability. Transfusion of whole blood and, if necessary, fresh-frozen plasma and platelet concentrates may improve circulating blood volume and improve clotting. Endoscopy is mandatory for both diagnosis and endoscopic treatment (injection of varices by sclerotherapy or variceal ligation by banding). Pharmacologic therapy with vasopressin and nitroglycerin or octreotide through a peripheral vein may provide temporary control of hemorrhage. The combination of endoscopic and pharmacologic therapy may be superior to either alone, but improved survival rates have yet to be shown. Prevention of recurrent bleeding may be achieved by endoscopic variceal ligation, which appears superior to sclerotherapy, or by use of nonselective β-blockers.

For patients with variceal bleeding that fails to respond to conventional treatment, the construction of a transjugular intrahepatic portal-systemic shunt (TIPS) by an interventional radiologist or a surgically constructed distal splenorenal shunt may be effective. This approach may be most appropriate for the liver transplantation candidate in whom bleeding cannot be controlled by other techniques and immediate transplantation is not possible.

[edit] Hepatic Encephalopathy

This neuropsychiatric syndrome is a complication of cirrhosis, portal-systemic shunting, or acute liver failure. Hepatic encephalopathy may develop insidiously or abruptly and may be transient, recurrent, or chronic. The pathogenesis remains uncertain; both hepatic detoxification of intestine-derived neuroactive compounds and hepatic production of substances essential for normal CNS function may be impaired. Elevated CNS and peripheral blood levels of ammonia, methanethiol, false neurotransmitter amines, aromatic amino acids, short-chain fatty acids, γ-aminobutyric acid, and benzodiazepine ligands have been reported. With the exception of the encephalopathy seen in acute liver failure, which is often associated with cerebral edema and responds poorly to treatment, most episodes of hepatic encephalopathy are precipitated by exogenous factors (Table 104-6). Correction of these factors leads to reversal of the encephalopathy.

Table 104-6 Precipitants of Hepatic Encephalopathy in Cirrhosis

Precipitating factor	Examples
Drug administration	Antianxiety agents (particularly benzodiazepines), sedative-hypnotics, analgesics
Electrolyte and acid-base abnormalities	Hypokalemia, metabolic alkalosis, severe hyponatremia, azotemia
Hypovolemia	Overzealous diuresis, dehydration
Increased gastrointestinal intraluminal nitrogenous materials	Gastrointestinal bleeding, excessive dietary protein, azotemia, constipation
Miscellaneous catabolic states	Infection; surgical anesthesia; portacaval, splenorenal, or other portal-systemic shunting; superimposed acute hepatic injury; hypoxemia

The earliest phases of hepatic encephalopathy may be subclinical or subtle and difficult to recognize unless formal neuropsychologic (trail-making) testing is undertaken. Electroencephalography and study of sensory-evoked potentials have been used to assess subclinical encephalopathy but have little value in diagnosis of the overt syndrome. Episodic slowing of speech and alertness and reversal of sleep patterns may be followed by confusion, slurred speech, and movement disturbances. Asterixis, the flapping tremor, is usually present, as is constructional apraxia. Muscle rigidity, pyramidal tract signs, and seizures are prominent features in some patients. Those with longstanding hepatic encephalopathy may have psychosis, choreoathetosis, dementia, or myelopathy. The diagnosis of hepatic encephalopathy is clinical based on the characteristic clinical picture in advanced liver disease. An elevated arterial ammonia level may be found but is not diagnostic; normal levels do not exclude hepatic encephalopathy. Because other disorders may resemble hepatic encephalopathy, further evaluation may be necessary (Box 104-4). The clinical importance of abnormalities on cerebral imaging in hepatic encephalopathy remains uncertain.

Box 104-4 - Disorders Simulating Hepatic Encephalopathy

Subdural hematoma, brain tumor, brain abscess Meningitis Sepsis Alcohol intoxication or withdrawal Drug overdose Uremia Respiratory failure Hyperosmolar states Hypoglycemia

In its early phases and in acute episodes with an identifiable precipitant, the syndrome is completely reversible and the brain histologically normal. In some forms of chronic hepatic encephalopathy and myelopathy, however, reversibility is less likely, and structural changes may be found.

[edit] Management.

Hospitalization is usually required if encephalopathy is more than mild. In addition to initiating supportive therapy to maintain vital functions, identification of other causes of encephalopathy and possible precipitating factors and their elimination or correction are the first steps of treatment. Concurrently, encephalopathy is controlled by intestine-cleansing enemas, restriction of dietary protein to near-zero levels, and oral or nasogastric tube administration of lactulose, a synthetic nonabsorbable disaccharide that acts as a cathartic, lowers the pH in the lumen of the colon, traps ammonia as ammonium ions, favors the bacterial assimilation of ammonia, and reduces the concentration of short-chain fatty acids in the colon. Overdoses of lactulose may induce severe diarrhea with crampy abdominal distress, bloating, and electrolyte disturbances. If lactulose fails, neomycin may be used (0.5 gm every 6 hours) with or without continued lactulose. Metronidazole and vancomycin may be effective, but experience with these agents is limited. For patients with intractable or recurrent encephalopathy or those only responsive to low protein intake, liver transplantation should be considered.

[edit] Ascites

The accumulation of fluid in the peritoneal cavity is a cardinal feature of advanced liver disease (cirrhosis and alcoholic hepatitis are the major causes) but may also be seen in peritoneal tuberculosis, nephrotic syndrome, congestive heart failure, and neoplastic diseases. In patients with advanced liver disease, retention of sodium and water leading to ascites formation is caused by the combined effects of portal hypertension, increased hepatic lymph production, hypoalbuminemia, splanchnic venous pooling, and peripheral arterial vasodilation resulting from release of vasodilator factors and arteriovenous shunting (Box 104-5). The precise mechanisms and the sequence in which they occur remain controversial. Systemic vasodilation with arterial underfilling, enhanced sympathetic efferent discharge, release of arginine vasopressin through nonosmotic baroreceptor mechanisms, and activation of the renin-angiotensin-aldosterone system may result in decreased renal perfusion pressure and increased proximal sodium and water reabsorption. Distal renal tubular sodium reabsorption is also increased, and free water clearance is impaired.

Box 104-5 - Mechanisms of Ascites Formation

Initiating Factors Portal hypertension and splanchnic venous pooling Increased hepatic lymph flow with accumulation in peritoneal space Hypoalbuminemia and decreased colloid osmotic pressure Peripheral arteriolar dilation resulting from vasodilator factors and arteriovenous shunting Secondary Factors Enhanced sympathetic efferent discharge Nonosmotic release of arginine vasopressin Activation of renin-angiotensin-aldosterone system Resistance to atrial natriuretic factor Impaired escape from aldosterone-induced sodium retention Consequences Avid distal renal tubular sodium reabsorption Increased proximal renal sodium reabsorption Impaired free water clearance

Although ascites may be insidious and unrecognized by the patient, its development portends premature death (Fig. 104-4). When extensive, ascites may lead to abdominal discomfort, respiratory compromise, umbilical hernia, impaired sense of well-being, and early satiety. Spontaneous bacterial peritonitis is rarely seen in the cirrhotic patient without ascites; it should be considered in every cirrhotic patient with ascites. When clinical examination at the bedside is equivocal, abdominal ultrasonography may confirm the presence of fluid. Diagnostic paracentesis with removal of 50 to 100 ml of fluid is necessary in all patients with new-onset ascites and in those with longstanding ascites in whom fever, abdominal pain, leukocytosis, azotemia, or hepatic encephalopathy may indicate a complicating disorder. In uncomplicated ascites secondary to cirrhosis, the serum-ascitic albumin gradient is typically 1.1 gm/dl or more. The ascitic fluid total protein is usually less than 2.5 gm/dl in the ascites of cirrhosis but may exceed this level in cardiac ascites. Cell counts in uncomplicated ascites are usually less than 400 leukocytes/mm³, with fewer than 25% polymorphonuclear neutrophils (PMNs). The presence of more than 250 PMNs strongly suggests bacterial infection. In spontaneous bacterial peritonitis the serum-ascitic albumin gradient is unchanged, the cell count is elevated, PMNs predominate, and lactic acid dehydrogenase of ascitic fluid may be increased. Bacterial culture of the fluid is mandatory.