17 Liver Diseases - Bài viết - Bệnh Học
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17 Liver Diseases

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Liver Diseases

Shelby Sullivan

Mauricio Lisker-Melman

Evaluation of Liver Function

General Principles

Classification

Liver disease is classified according to the duration of abnormalities as either acute (<6 months) or chronic (>6 months).

Diagnosis

Laboratory Studies

Serum enzymes. Hepatic disorders associated predominantly with elevation in aminotransferases are referred to as hepatocellular; hepatic disorders with predominant elevation in alkaline phosphatase (AP) are referred to as cholestatic.

Elevation of serum aspartate and alanine aminotransferases (AST and ALT, respectively) indicates hepatocellular injury and necrosis. Markedly elevated levels (>1,000 U/L) typically occur with acute hepatocellular injury (e.g., viral, drug induced, or ischemic), whereas mild to moderate elevations may be seen in a variety of conditions (e.g., acute or chronic hepatocellular injury, infiltrative diseases, biliary obstruction). The ratio of serum AST to ALT is typically >2 in alcoholic liver disease. In viral hepatitis, this ratio is characteristically <1.

AP is an enzyme that is present in a variety of tissues (bone, intestine, kidney, leukocytes, liver, and placenta). The concomitant elevation of other hepatic enzymes (e.g., γ-glutamyl transpeptidase (GGT) or 5′-nucleotidase) assists in establishing the hepatic origin of AP. Serum AP level is often elevated in biliary obstruction, space-occupying lesions or infiltrative disorders of the liver, and conditions that cause intrahepatic cholestasis (primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced cholestasis). The degree of elevation of AP does not differentiate the site or cause of cholestasis.

GGT is an enzyme that is present in a variety of tissues. Increases in GGT and AP tend to occur in similar hepatic diseases. GGT may be elevated in individuals who ingest barbiturates, phenytoin, or alcohol even when other liver enzyme and bilirubin levels are normal.

5′-nucleotidase is comparable to AP in sensitivity in detecting biliary obstruction, cholestasis, and infiltrative hepatobiliary diseases.

Synthetic products

Serum albumin concentration is frequently decreased in chronic liver disease. However, chronic inflammation, expanded plasma volume, and gastrointestinal or renal losses may also lead to hypoalbuminemia. Because the half-life of albumin is relatively long (20 days), serum levels may be normal in acute liver disease.

Several important proteins involved in hemostasis and fibrinolysis (coagulation factors [except factor VIII, which is produced by the liver and endothelium] α2-antiplasmin, antithrombin, heparin cofactor II, high molecular weight kininogen, prekallikrein, protein C, and protein S) are synthesized by the liver. The synthesis of factors II, VII, IX, and X and proteins C and S depends on the presence of vitamin K. The adequacy of hepatic synthetic function can be estimated by the prothrombin time (PT) and the international normalized ratio (INR) (see Chapter 18, Disorders of Hemostasis). PT/INR prolongation may result from impaired coagulation factor synthesis or vitamin K deficiency. Normalization of PT/INR after administration of vitamin K indicates vitamin K deficiency.

Cholesterol is synthesized in the liver. Patients with advanced liver disease may have very low cholesterol levels. However, in primary biliary cirrhosis, levels of serum cholesterol may be markedly elevated.

Other synthetic products whose levels can be measured in specific liver diseases are α1-antitrypsin and ceruloplasmin.

Excretory products

Bilirubin is a degradation product of hemoglobin and nonerythroid hemoproteins (e.g., cytochrome, catalase). Total serum bilirubin is composed of conjugated (direct) and unconjugated (indirect) fractions. Unconjugated hyperbilirubinemia occurs as a result of excessive bilirubin production (neonatal or physiologic jaundice, hemolysis and hemolytic anemias, ineffective erythropoiesis, and resorption of hematomas), reduced hepatic bilirubin uptake (Gilbert's syndrome and drugs such as rifampin and probenecid), or impaired bilirubin conjugation (Gilbert's or Crigler-Najjar's syndrome). Elevation of conjugated and unconjugated fractions occurs in Dubin-Johnson's and Rotor's syndromes and in conditions associated with intrahepatic (from hepatocellular, canalicular, or ductular damage) and extrahepatic (from mechanical obstruction) cholestasis.

Bile acids are produced in the liver and are secreted into the intestine, where they are required for lipid digestion and absorption. Elevated levels of serum bile acids are specific but not sensitive markers of hepatobiliary disease. Levels of individual bile acids are not useful in the differential diagnosis of liver disorders.

α-Fetoprotein is normally produced by fetal liver cells. Its production falls to normal adult levels of <10 ng/mL within 1 year of life. An α-fetoprotein level of >400 ng/mL or a rapid doubling time is very suggestive of hepatocellular carcinoma (HCC); however, mild to moderate elevations can also be seen in states of acute and chronic liver inflammation.

Imaging

Ultrasonography is used to screen for dilation of the biliary tree and to detect gallstones and cholecystitis in patients with right-sided abdominal pain associated with abnormal liver blood tests. It can reveal and characterize liver masses, abscesses, and cysts. Color-flow doppler ultrasonography can assess patency and direction of blood flow in the portal and hepatic veins. Ultrasonography is a frequently used modality for screening of hepatocellular carcinoma.

Helical computed tomography (CT) scan with IV contrast is useful in the evaluation of parenchymal liver disease. It has the added feature of contrast enhancement to define space-occupying lesions (e.g., abscess and tumor) and allows calculation of liver volume. Triple-phase CT (noncontrast, arterial phase, and venous phase) is indicated for liver mass evaluation. A delayed phase is useful when cholangiocarcinoma is suspected.

Magnetic resonance imaging (MRI) offers information similar to that provided by CT scan and the additional advantage of better characterization of liver lesions, fatty infiltration, and iron deposition. It is the modality of choice in patients with an allergy to iodinated contrast and renal failure.

Magnetic resonance cholangiopancreatography (MRCP) is a specialized version of MRI that provides an alternative noninvasive diagnostic modality for visualizing the intra- and extrahepatic bile ducts.

Percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP) involve the instillation of contrast into the biliary tree. They are most useful after the preliminary determination of biliary tree abnormalities detected by ultrasonography, CT, or MRI/MRCP.

Technetium-99m red blood cell (RBC) scan is helpful in confirming the diagnosis of hepatic hemangioma. Other imaging techniques have diminished its usefulness.

Positron emission tomography (PET) is an emerging modality that uses differences in metabolism among normal, inflammatory, and malignant tissues. PET scans are helpful in assessing the presence of hepatic metastasis in colorectal cancer. PET scans may also be helpful in diagnosing cholangiocarcinoma.

Liver Biopsy

Percutaneous liver biopsy can be performed with or without radiographic (ultrasound or CT) guidance. In the presence of coagulopathy, thrombocytopenia, and/or ascites, a biopsy can be obtained by the transjugular route. Suspicious liver lesions are usually biopsied with ultrasonographic or CT guidance. Laparoscopy is an alternative method for obtaining liver tissue. Percutaneous liver biopsy is generally safe and usually is performed as an outpatient procedure. Bleeding, pain, infection, injury to neighboring organs, and (rarely) death are potential complications.

Viral Hepatitis

General Principles

The hepatotropic viruses include hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), and hepatitis E (HEV) (Tables 17-1 and 17-2). Nonhepatotropic viruses (viruses that indirectly affect the liver) include Epstein-Barr virus, cytomegalovirus, herpes virus, measles, Ebola, and others.

Definitions

Acute viral hepatitis is defined by the sudden onset of significant aminotransferase elevation as a consequence of diffuse necroinflammatory liver injury. Symptoms may be variable. This condition may resolve or progress to fulminant failure or chronic hepatitis.

Chronic viral hepatitis is defined as the presence of persistent (at least 6 months) necroinflammatory injury that can lead to cirrhosis. Histopathologic classification of chronic viral hepatitis is based on etiology, grade, and stage. Grading and staging are measures of the severity of the necroinflammatory process and fibrosis, respectively.

Hepatits A Virus

General Principles

Epidemiology

HAV is the most common cause of viral hepatitis worldwide.

Approximately 30% of acute viral hepatitis in the United States is caused by HAV.

High-risk groups include people living in or traveling to underdeveloped countries, men having sex with men, and staff and attendees at daycare centers.

HAV is an RNA virus that belongs to the picornavirus family.

Mode of Transmission

HAV infection is usually transmitted via the fecal÷oral route.

Large-scale outbreaks due to contamination of food and drinking water can occur.

The period of greatest infectivity is 2 weeks before the onset of clinical illness; fecal shedding continues for 2÷3 weeks after the onset of symptoms.
TABLE 17-1 Clinical and Epidemiologic Features of Hepatotropic Viruses
Organism
Hepatitis A
Hepatitis B
Hepatitis C
Hepatitis D
Hepatitis E
Incubation
15÷45 d
30÷180 d
15÷150 d
30÷150 d
30÷60 d
Transmission
Fecal÷oral
Blood
Sexual
Perinatal
Blood
Sexual (rare)
Perinatal (rare)
Blood
Sexual (rare)
Fecal÷oral
Risk groups
Residents of and travelers to endemic regions
Children and caregivers in daycare centers
Injection drug users
Multiple sexual partners
Men having sex with men
Infants born to infected mothers
Health care workers
Transfusion recipients
Injection drug users
Transfusion recipients
Any person with hepatitis B virus
Injection drug users
Residents of and travelers to endemic regions
Fatality rate
1.0%
1.0%
<0.1%
2%÷10%
1%
Carrier state
No
Yes
Yes
Yes
No
Chronic hepatitis
None
2%÷10% in adults; 90% in children <5 yr
70%÷85%
Variable
None
Cirrhosis
No
Yes
Yes
Yes
No

TABLE 17-2 Viral Hepatitis Serologies
Hepatitis Acute Chronic Recovered/latent Vaccinated
HAV IgM anti-HAV+ NA IgG anti-HAV+ IgG anti-HAV+
HBV IgM anti-HBc+ IgG anti-HBc+ IgG anti-HBc+ Anti-HBs+ only
HBeAg+ HBeAg± HBeAg-
HBsAg+ Anti-HBea Anti-HBe±a
HBV DNA+ HBsAg+ HBsAg-
HBV DNAa Anti-HBs Ab+
HBV DNA-
All tests possibly negative
Anti-HCV Ab+ in 8÷10 wk
Anti-HCV Ab+
HCV RNA+
HCV RNA+
Anti-HCV Ab+
HCV RNA-b
HDV IgM anti-HDV+c
HDV Ag+c
IgG anti-HDV+c IgG anti-HDV+c NA+d
HEV Available from CDC and research specialty laboratories NA Available from CDC and research specialty laboratories NA
Ab, antibody; CDC, Centers for Disease Control and Prevention; HAV, hepatitis A virus; HBc, hepatitis B core antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; NA, not applicable.
aHBeAg is present during periods of high replication along with HBV DNA. Anti-HBe is present during periods of low replication when HBeAg and HBV DNA may be undetectable.
bNegative HCV RNA results should be interpreted with caution. Differences are found in thresholds for detection among assays and among laboratories.
cMarkers of HBV infection are also present, because HDV cannot replicate in the absence of HBV.
dAlthough no vaccine is available for HDV, immunity to HBV protects against HDV infection.



Although the period of viremia is brief, sexual transmission and parenteral transmission may occur.

Clinical Features

HAV can be silent (subclinical), especially in children and young adults. Symptoms vary from mild illness to fulminant hepatic failure (FHF). Malaise, fatigue, pruritus, headache, abdominal pain, myalgias, arthralgias, nausea, vomiting, anorexia, and fever are common but nonspecific symptoms.

Physical examination may reveal jaundice, hepatomegaly, and in rare cases lymphadenopathy, splenomegaly, or a vascular rash.

Diagnosis

The diagnosis of acute HAV is made by the detection of IgM anti-HAV antibody.

The recovery phase and immunity phase are characterized by IgG anti-HAV antibody.

Liver biopsy is rarely needed.

Clinical Course

Almost all cases of acute HAV hepatitis will resolve in 4÷6 weeks.

Prolonged cholestatic disease, characterized by persistent jaundice, is more frequently seen in adults.

Acute liver failure is relatively rare, but risk increases with age: 0.1% in patients younger than 15 years old to >1% in patients older than 40 years old.

HAV does not induce chronic hepatitis or cirrhosis.

Treatment

No specific treatment is available.

Supportive treatment is recommended.

Liver transplantation may be an option for FHF.

Prophylaxis

Preexposure prophylaxis (Appendix C, Immunizations and Postexposure Therapies)

HAV vaccine should be given to travelers to endemic areas, men who have sex with men, illegal drug users, persons with high occupational risk for infection (research personnel working with HAV or HAV-infected primates), persons who have clotting factor disorders, and persons with chronic liver disease. In the United States, children residing in areas where the incidence of hepatitis A is twice the national average and people living in communities with local outbreaks of HAV should be vaccinated. Vaccinations should be administered at 0 and 6 months.

Vaccination should be initiated at least 4 weeks before travel to an endemic area. For individuals who require immediate protection, the first dose of HAV vaccine can be administered concomitantly with immunoglobulin (Ig) 0.02 mL/kg IM injection, at different anatomic injection sites.

Travelers who are allergic to a vaccine component or who elect not to undergo vaccination should receive a single dose of Ig (0.02 mL/kg IM if the desired duration of protection is up to 3 months or 0.06 mL/kg if the desired duration is 2÷5 months). The dose should be repeated if the travel period exceeds 5 months.

Postexposure prophylaxis. (Appendix C, Immunizations and Postexposure Therapies.)

Ig (0.02 mL/kg IM) should be given within 2 weeks of the last exposure to unvaccinated individuals.

Household and sexual contacts and persons who have shared illegal drugs with a person who has serologically confirmed acute HAV should receive Ig and the first dose of vaccine at different anatomic sites.

Ig should be administered to all previously unvaccinated staff and attendees of daycare centers if one or more cases of HAV are recognized in children or employees or if cases are recognized in two or more households of center attendees. HAV vaccine can be administered at the same time as Ig at different anatomic sites.

If a food handler is diagnosed with HAV, Ig should be administered to other food handlers at the same establishment and to patrons who can be identified and treated within 2 weeks of exposure.

Hepatitis B Virus

General Principles

Epidemiology

Two billion people worldwide have been infected and more than 350 million people are chronic carriers.

In endemic areas such as Asia and sub-Saharan Africa, infection is usually acquired in childhood, while in Western countries where HBV is relatively rare, the infection is acquired in adulthood.

HBV causes 60%÷80% of hepatocellular carcinoma worldwide.

High-risk groups include individuals with a history of multiple blood transfusions, patients on hemodialysis, health care workers, injection drug users, household and heterosexual contacts of hepatitis B carriers, men having sex with men, residents and employees of residential care facilities, travelers (>6 months) to hyperendemic regions, and natives of Alaska, Asia, and the Pacific Islands.

Mode of Transmission

Parenteral routes (e.g., needlestick injury, injection drug use, and transfusion)

Sexual contact

Vertical or perinatal transmission (from mother to infant)

Clinical Features

Acute hepatitis B can be silent (subclinical), especially in children and young adults. Symptoms vary from mild illness to FHF. Malaise, fatigue, pruritus, headache, abdominal pain, myalgias, arthralgias, nausea, vomiting, anorexia, and fever are common but nonspecific symptoms.

Chronic hepatitis B runs an indolent course, sometimes for decades. Fatigue is a common symptom. The disease may only become clinically apparent late in the natural course, when symptoms typically seen in end-stage liver disease (ESLD) appear.

Extrahepatic manifestations include polyarteritis nodosa, glomerulonephritis, cryoglobulinemia, serum sickness÷like illness, papular acrodermatitis (predominantly in children), and aplastic anemia.

Diagnosis

HBV is a DNA virus that belongs to the hepadnavirus family. It contains a number of antigens that elicit a corresponding antibody response.

Hepatitis B surface antigen (HBsAg) is detectable in serum in acute and chronic HBV infection and disappears after clearance of the virus.

Hepatitis B core antigen (HBcAg) is not found in serum but can be detected within liver cells by immunoperoxidase staining during active viral replication.

Hepatitis B e antigen (HBeAg) appears shortly after HBsAg in the serum and its persistence is indicative of active viral replication and a high degree of infectivity.

Antibody against HBsAg (anti-HBs) appears after the disappearance of HBsAg and after vaccination. Anti-HBs confers immunity (except in rare cases of chronic HBV infection with very low titers of heterotypic anti-HBs).

IgM antibody against HBcAg (IgM anti-HBc) usually is present in acute infection and occasionally can be detected during periods of high viral replication in chronic disease.

IgG anti-HBc is detectable in chronic infection and, in association with anti-HBs, after recovery. Rarely, patients with isolated IgG anti-HBc can reactivate HBV in the setting of immunosuppression (e.g., transplantation).

Antibody against HBeAg (anti-HBe) usually indicates low-level replication and a lower degree of infectivity. Some patients harbor HBV mutants (e.g., precore, core promoter), in which case the conventional serologic markers may vary.

HBV viral DNA (HBV DNA) is the most accurate marker of viral replication. It is detected by polymerase chain reaction (PCR) and reported as copies per milliliter or International Units per milliliter.

For use of HBV markers in clinical practice, see Table 17-3.

Genotype determination is not part of the daily practice of most clinicians; however, their clinical significance is growing.

Liver biopsy is useful to score the degree of inflammation (grade) and fibrosis (stage) in patients with chronic hepatitis. Special staining techniques are helpful to identify HBsAg and HBcAg.

Clinical Course

Incubation period after HBV infection ranges from 30÷160 days.

Depending on the age of the person at infection, people may have spontaneous resolution or progression to chronicity.

Children younger than 5 years old: 90% will develop chronic HBV infection.

Adults: 5%÷10% will develop chronic HBV.

Chronic hepatitis B

Spontaneous clearance of HBsAg occurs in 1% of patients annually.

Thirty percent progress to cirrhosis.

Five to ten percent progress to HCC with or without preceding cirrhosis. The risk of HCC is dependant on the degree of viral replication.

Treatment

Goals of treatment

Clearance of HBV DNA

HBeAg and HBsAg seroconversion (i.e., antigen disappearance and appearance of antibodies)

Normalization of liver enzymes

Normalization of histology

Current treatment options

The interferons (IFN) are glycoproteins with antiviral, immunomodulatory, and antiproliferative actions. The addition of polyethylene glycol (PEG) to the standard IFN (α2a and 2b) molecules (pegylation) results in prolonged half-life with improved bioavailability. IFN-α2a and 2b is administered subcutaneously thrice weekly for 4÷6 months, or peginterferon alfa for 48 weeks. HBeAg seroconversion is achieved in 30% of treated patients, and HBsAg seroconversion in 5%÷10%. They do not induce resistant mutations. Their use is contraindicated in patients with decompensated liver disease. Common adverse events from IFN therapy include flu-like syndrome (headache, fatigue, myalgias, arthralgias, fever, and chills), neuropsychiatric disorders (depression, irritability, and concentration impairment), reversible bone marrow suppression (neutropenia, thrombocytopenia, and anemia), and other effects (alopecia, thyroiditis, injection site reactions).

Lamivudine is a nucleoside analog with antiviral activity. It is administered orally at 100 mg daily. Treatment success is proportional to treatment duration. Its use has been diminished by a high rate of induction of resistant mutants (15%÷20% per year of treatment).

Adefovir is a nucleotide analog with antiviral activity. It is administered orally at 10 mg daily. Treatment success is proportional to treatment duration. Adefovir can be used as a treatment option for patients with lamivudine resistance. It is safely used in patients with advanced or decompensated liver disease. In patients with renal impairment, dose adjustment is needed. Fifteen to twenty-nine percent of nucleotide naïve patients will develop resistance to adefovir after 4÷5 years of treatment.

Entecavir is a nucleoside analog with antiviral activity. It is admistered orally at 0.5 mg daily in naïve nucleoside patients and 1 mg daily in patients with known lamivudine resistance mutations. In patients with renal impairment, dosage adjustment is needed. Resistant mutants are very rare in nucleoside-naïve treated patients after 3 years of therapy. In lamivudine resistant patients, resistance mutations to entecavir are more frequent (15% after 3 years of treatment).

Telbivudine is a nucleoside analog. It was recently approved for treatment of HBV in the United States. Preliminary reports show robust antiviral activity with a mild to moderate rate of induction of resistant mutants at 2 years of therapy.

New agents, regimens, and combination therapies are currently under investigation.

Liver transplantation is indicated for patients with advanced liver disease due to infection with HBV. Immunoprophylaxis with hepatitis B immunoglobulin (HBIg) combined with a nucleoside or nucleotide analog is obligatory to diminish hepatitis B recurrence.

Prophylaxis

Preexposure prophylaxis (See Appendix C, Immunizations and Postexposure Therapies)

HBV vaccine should be considered for everyone, particularly in individuals with a history of multiple blood transfusions, patients on hemodialysis, health care workers, injection drug users, household and heterosexual contacts of hepatitis B carriers, men having sex with men, residents and employees of residential care facilities, travelers (>6 months) to hyperendemic regions, and natives of Alaska, Asia, and the Pacific Islands.

Many countries have included HBV vaccination (0, 1, and 6 months) in their infant or adult immunization programs. The Centers for Disease Control and Prevention has recommended a universal vaccination program for infants and sexually active adolescents in the United States.

Prevaccination screening for previous exposure or infection is recommended in high-risk groups to avoid vaccinating recovered individuals or those with chronic infection.

For patients who require rapid immunity, the dosage schedule can be escalated to 0, 1, and 2 months, but a follow-up booster at 6 months is required for long-lasting immunity.

Additional doses, higher doses, or revaccination can be considered in nonresponders and hyporesponders (anti-HBs <10 International Units/mL) to elicit protective levels of immunity. Booster doses may be needed in immunosuppressed individuals in whom anti-HBs levels fall below 10 International Units/mL on annual testing.

Postexposure prophylaxis (see Appendix C)

Infants born to HBsAg-positive mothers should receive HBV vaccine and HBIg, 0.5 mL, within 12 hours of birth. Immunized infants should be tested at approximately 12 months of age for HBsAg, anti-HBs, and anti-HBc. The presence of HBsAg indicates that the infant is actively infected. The presence of both anti-HBs and anti-HBc suggests that infection occurred but was probably modified by immunoprophylaxis and that immunity is likely to be prolonged. The presence of anti-HBs alone is indicative of vaccine-induced immunity.

Susceptible sexual partners of individuals with HBV and victims of needlestick injury (with HBV contamination) should receive HBIg (0.04÷0.07 mL/kg) and the first dose of HBV vaccine at different sites on the body as soon as possible (preferably within 48 hours but no more than 7 days after exposure). A second dose of HBIg can be administered 30 days after exposure, and the vaccination schedule should be completed.

Postexposure prophylaxis with HBIg and lamivudine or adefovir should be used after liver transplantation for ESLD that results from HBV (see Chapter 15, Solid Organ Transplant Medicine).

Hepatitis C Virus

General Principles

Epidemiology

HCV is a global health problem with approximately 200 million carriers worldwide.

HCV is an RNA virus that belongs to the Flaviviridae family.

The incidence of HCV in the U.S. has decreased from 240,000 cases per year in 1985 to 18,000 cases in 2003.

In the United States, 4 million people have been infected with this virus, and 8,000÷10,000 people die of HCV-related chronic liver disease per year.

HCV is a frequent cause of HCC.

Risk factors for HCV infection include a history of multiple blood transfusions, hemodialysis, injection drug use, multiple sexual partners, and occupational exposure with blood and blood-derived products. Other risk factors may include tattooing, body piercing, sharing “straws” for intranasal cocaine use, sharing razors, and history of military service.

Modes of Transmission

Parenterally (e.g., transfusion, injection drug use, needlestick injury)

Sexually and from mother to offspring, although at a much lower frequency than HBV

Clinical Features

Acute hepatitis can be silent (subclinical), especially in children and young adults. Symptoms vary from mild illness to FHF. Malaise, fatigue, pruritus, headache, abdominal pain, myalgias, arthralgias, nausea, vomiting, anorexia, and fever are common but nonspecific symptoms.

Chronic hepatitis runs an indolent course, sometimes for decades. Fatigue is a common symptom. The disease may only become clinically apparent late in the natural course, when symptoms typically seen in ESLD appear.

Extrahepatic manifestations include mixed cryoglobulinemia (10%÷25% of patients with HCV), glomerulonephritis, porphyria cutanea tarda, cutaneous necrotizing vasculitis, lichen planus, lymphoma, and other autoimmune disorders.

Diagnosis

Antibodies against HCV (anti-HCV) may be undetectable for the first 8 weeks after infection. Positive tests are usually diagnostic in patients with elevated liver enzymes and with risk factors for the infection. The antibody does not confer immunity. The test has a sensitivity of 95%÷99% and a lower specificity. A false-positive test in the setting of autoimmune hepatitis or hypergammaglobulinemia may be detected. A false-negative test may be seen in immunosuppressed individuals and in patients on hemodialysis.

HCV RNA can be detected by PCR in serum as early as 1÷2 weeks after infection. It determines the presence of actual virus and ongoing infection. Different HCV RNA tests are available and vary in detection sensitivity. Viral concentrations are expressed in international units per milliliter (International Units/mL). This test is useful both for diagnosis and treatment follow-up/response.

Tests to detect HCV genotypes, subtypes, or serotypes are commercially available. HCV genotype influences the duration, dosage, and response to treatment. Genotype 1 accounts for 75% and genotypes 2 and 3 account for 20% of HCV infection in the United States.

The recombinant immunoblot assay (RIBA) is a supplementary test that has been replaced by PCR.

Liver biopsy is useful to score the degree of inflammation (grade) and fibrosis (stage) in the liver of chronically infected patients.

Clinical Course

The incubation period is 15÷150 days.

Acute hepatitis is frequently clinically silent.

Fifteen percent of people infected with HCV will have spontaneous resolution.

Chronic HCV will occur in 85% of infected people.

Progression to cirrhosis is slow (two to three decades) and is seen in a quarter of patients with chronic HCV.

HCC develops in approximately 1%÷2% of patients per year, and rarely occurs in the absence of cirrhosis.

Treatment

Acute infection

IFN-α (standard or pegylated) for 6 months has been associated with a high rate of sustained HCV RNA clearance.

The role of ribavirin in addition is under investigation.

Chronic infection

A combination of SC pegylated-interferon (PEG-IFN) and oral ribavirin 400÷600 mg twice daily is administered for 6÷12 months. Peginterferon alfa-2a 180 mcg/wk and peginterferon alfa-2b 1.5 mcg/kg/wk are both efficacious. Sustained virologic response (SVR), defined as clearance of HCV RNA from serum 6 months after completion of treatment, occurs in approximately 55% of all patients. HCV genotype, viral load, and fibrosis score determination are important in patient management. Genotype 1 HCV infection is less susceptible to treatment and requires 12 months of therapy with a 35%÷45% SVR. Genotypes 2 and 3 are more susceptible to treatment and require 6 months of therapy with an 80%÷85% SVR. Side effects of ribavirin include teratogenicity, hemolytic anemia, and pulmonary symptoms (dyspnea, cough, and pneumonitis). Contraindications to treatment with ribavirin include pregnancy

or unwillingness to practice birth control, chronic renal insufficiency, and the inability to tolerate anemia (15%÷30%).

Liver transplantation may be indicated in advanced viral disease, but disease recurrence is frequent (see Chapter 15, Solid Organ Transplant).

Prophylaxis

No preexposure prophylaxis or vaccine exists.

Hepatitis D Virus

HDV is a small RNA virus with an envelope consisting of HBsAg.

It is found throughout the world, and is endemic to the Mediterranean basin, the Middle East, and portions of South America. Outside these areas, infections occur primarily in individuals who have received transfusions or in injection drug users. HDV requires the presence of HBV for infection and replication.

High-risk groups are similar to HBV (see HBV Epidemiology).

HDV infection clinically presents as a coinfection (acute hepatitis B and D), as a superinfection (chronic hepatitis B with acute hepatitis D), or as a latent infection (e.g., in the liver transplant setting).

Diagnosis is made by finding HDV RNA or HDV antigen in serum or liver and by detecting antibody to the HDV antigen.

In patients with coinfection, the course is transient and self-limited. The rate of progression to chronicity is similar to the one reported for acute HBV. In superinfection, the HBV carriers may present with a severe acute hepatitis exacerbation with frequent progression to chronic HDV infection.

IFN-α is the treatment of choice for chronic hepatitis D.

Although there is no vaccine to prevent HDV in carriers of HBV, both infections can be prevented by timely administration of the HBV vaccine.

Hepatitis E Virus

HEV is an RNA virus that belongs to the Caliciviridae family.

It has been implicated in epidemics in India, Southeast Asia, Africa, and Mexico. Reported cases in the United States have been in travelers to endemic areas.

Transmission closely resembles that of HAV (i.e., fecal÷oral route).

Acute hepatitis E is clinically indistinguishable from other acute viral hepatitis. HEV infection is associated with a high fatality rate in pregnant women in the second and third trimesters.

There is no chronic infection associated with HEV.

Treatment is supportive.

There is not pre- or postexposure prophylaxis.

Drug-Induced Liver Toxicity

General Principles

Drug-induced liver toxicity (DILT) is the most common circumstance for a drug to be removed from the market.

DILT causes approximately 50% of the cases of acute liver failure in the United States, with acetaminophen being the most common causative agent.

Less commonly DILT can cause chronic liver disease, cirrhosis, and hepatocellular carcinoma.

Pathophysiology

Intrinsic hepatotoxicity results from the direct hepatotoxic effects of the drug or its metabolite. This mechanism is predictable and dose dependent. Examples include carbon tetrachloride, elemental phosphorus, and acetaminophen in supratherapeutic doses.

Idiosyncratic hepatotoxicity can be divided into hypersensitivity (allergic) responses and metabolic hepatotoxicity mechanisms (nonallergic). These reactions depend on multiple variables and are not predictable.

Hypersensitivity responses occur as a result of stimulation of the immune system by a metabolite of a drug alone or after haptenization (covalently binding) to a liver protein. (e.g., allopurinol, diclofenac). The latency of the reaction is variable. Repeated challenge with the same agent leads to prompt recurrence of the reaction.

Metabolic hepatotoxicity occurs in susceptible patients as a result of altered drug clearance or accelerated production of hepatotoxic metabolites (e.g., isoniazid, ketoconazole). The latency of the reaction is variable.

Mechanisms of Injury

There are three major classifications of DILT that occur as a result of both intrinsic and idiosyncratic hepatotoxicity:

Hepatocellular injury refers to injury to the liver cell.

Cholestatic injury refers to injury to the biliary system.

Mixed hepatocellular and cholestatic refers to injury to both the liver cell and the biliary system.

Other less common types of DILT include formation of chronic hepatitis, chronic cholestasis, granulomatous formation, fibrosis or cirrhosis, and carcinogenesis.

Clinical Presentation

The acute presentation can be clinically silent. When symptoms are present they are nonspecific and include nausea/vomiting, general malaise, fatigue, and abdominal pain.

In the acute setting, the majority of patients will recover after cessation of the offending drug.

Fever and rash may also be seen in association with hypersensitivity reactions.

Diagnosis

Clinical suspicion

Temporal relation of the injury to drug initiation

Biochemical abnormalities

Hepatocellular injury: AST and ALT elevation more than two times the upper limit of normal

Cholestatic injury: alkaline phosphatase and conjugated bilirubin elevation more than two times the upper limit of normal

Mixed injury includes increases in all of the above biochemical abnormalities to more than two times the upper limit of normal.

Resolution of injury after the offending drug has been stopped

Liver biopsy is sometimes needed

Treatment

Treatment includes cessation of exposure to the offending drug and institution of supportive measures.

An attempt to remove the agent from the gastrointestinal (GI) tract should be made in most cases of acute toxic ingestion using lavage or cathartics (see Chapter 25, Medical Emergencies, Overdoses).

Liver transplantation may be an option for patients with FHF.

Management of acetaminophen overdose is a medical emergency (see Chapter 25, Medical Emergencies, Overdoses).

Alcoholic Liver Disease

General Principles

Alcohol is a toxic substance to the liver.

The spectrum of alcoholic liver disease is broad, and a single patient may be affected by more than one of the following conditions: fatty liver, alcoholic hepatitis, or alcoholic cirrhosis.

Epidemiology

A significant medical and socioeconomic problem. Although ethyl alcohol exerts a direct toxic effect on the liver, significant liver damage develops in only 10%÷20% of chronic alcoholics. Average alcohol consumption can be measured by units per week. One unit is equal to 7 g of alcohol, one glass of wine, or one 240-mL can of 3.5%÷4% beer. Approximately 30÷40 units of alcohol per week can induce cirrhosis in 3%÷8% of individuals over 12 years.

Fatty liver is the most commonly observed abnormality, and occurs in up to 90% of alcoholics.

Alcoholic cirrhosis is a common cause of ESLD, cirrhosis, and hepatocellular carcinoma.

Additional factors (e.g., genetic, nutritional, environmental) may be important in the pathogenesis of alcoholic liver disease.

Diagnosis

Clinical Presentation

Fatty liver

Patients are usually asymptomatic.

Clinical findings include hepatomegaly and mild liver enzyme abnormalities.

Fatty liver may be reversible with abstinence.

Alcoholic hepatitis

Alcoholic hepatitis may be clinically silent or severe enough to lead to rapid development of hepatic failure and death.

Clinical features include fever, upper abdominal pain, anorexia, nausea, vomiting, weight loss, and jaundice.

In severe cases, patients may have hepatic encephalopathy, ascites, and gastrointestinal bleeding.

Patients frequently give a history of drinking up until the onset of symptoms.

Prognosis depends on the severity of presentation and alcohol abstinence. The in-hospital mortality for severe cases is up to 50%.

Alcoholic cirrhosis

The presentation is variable, from clinically silent disease to decompensated cirrhosis with complications of portal hypertension (see Portal Hypertension).

Patients have a history of current or past long-term alcohol use.

Prognosis is variable and depends on the degree of decompensation and alcohol abstinence.

Laboratory Studies

In alcoholic fatty liver laboratory tests may be normal or may demonstrate mild elevation in serum aminotransferases (AST higher than ALT) and AP.

In alcoholic hepatitis, liver laboratory test typically demonstrates elevation in serum aminotransferases (AST higher than ALT) and AP. Hyperbilirubinemia and prolongation of PT may also be seen.

Laboratory abnormalities associated with a poor prognosis include renal failure, leukocytosis, a markedly elevated total bilirubin, and prolongation of the PT that does not normalize with vitamin K.

A discriminant function (DF) = 4.6 × (PTpatient ÷ PTcontrol) + serum bilirubin, can be determined to assess in-hospital mortality.

In alcoholic cirrhosis, liver abnormalities may vary depending on disease severity.

Liver Biopsy

The typical histopathologic findings in alcoholic liver disease include Mallory hyaline bodies, neutrophilic infiltrate, necrosis of hepatocytes, collagen deposition, and fatty change.

The indication of liver biopsy depends on the clinical assessment of the patient. It may be helpful for differential diagnosis.

Treatment

Behavioral

Abstinence from alcohol

Rehabilitation (i.e., Alcoholics Anonymous, private counseling, etc.)

Medications

Treatment of acute alcoholic hepatitis with corticosteroids is controversial. However, there is evidence that patients with a DF >32 and hepatic encephalopathy may benefit from steroid therapy.

Oral prednisone can be started at 40÷60 mg/d and subsequently tapered as clinically indicated.

Pentoxifylline (400 mg PO tid) is a nonselective phosphodiesterase inhibitor with anti-inflammatory properties and an excellent safety profile that has shown improved survival in severe (DF >32) alcoholic hepatitis.

S-Adenosylmethionine, antioxidants, tumor necrosis factor inhibitors, and glutathione prodrugs are under investigation in alcoholic liver disease.

Surgical

Patients with cirrhosis and ESLD may be evaluated for liver transplant, but are required to abstain from alcohol for 6 months.

Complications

Potentially dangerous interactions may occur between alcohol and a variety of medications, including sedative-hypnotics, anticoagulants, and acetaminophen, even in the absence of alcoholic liver disease, because of shared metabolic pathways.

Immune-Mediated Liver Disease

Autoimmune Hepatitis

General Principles

Definition

Autoimmune hepatitis (AIH) is a chronic inflammation of the liver of unknown cause, associated with circulating auto-antibodies and hypergammaglobulinemia.

Epidemiology

AIH occurs worldwide.

It occurs most often in women (10÷30 years and late middle age).

In North America, cirrhosis is present at initial presentation more often in black patients than in Caucasian patients.

Diagnosis

Clinical Presentation

In approximately 30% of cases, the presentation is acute and similar to viral hepatitis. Patients may present in FHF or with asymptomatic elevation of serum ALT. It presents with cirrhosis in at least 25% of patients.

The most common symptoms at presentation include fatigue, jaundice, myalgias, anorexia, diarrhea, acne, and right upper quadrant abdominal discomfort.

Extrahepatic manifestations may be found in 30%÷50% and include celiac sprue, Coombs' positive hemolytic anemia, autoimmune thyroiditis, Graves' disease, rheumatoid arthritis, ulcerative colitis, and other less common presentations.

Autoimmune hepatitis is not associated with any specific physical examination findings.

Patients with AIH may overlap with findings consistent with other liver diseases (e.g., primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune cholangitis).

Laboratory Studies

Elevated levels of serum aminotransferases, circulating autoantibodies (antinuclear antibody, smooth muscle antibody, and liver÷kidney microsomal antibody), and hypergammaglobulinemia.

Liver Biopsy

Liver biopsy is essential for the diagnosis.

“Piecemeal necrosis” or interface hepatitis with lobular or panacinar inflammation (lymphocytic and plasmacytic infiltration) are the histologic hallmarks of the disease.

Treatment

Medications

Therapy is initiated with either prednisone alone (40÷60 mg/d) or a combination of prednisone (40÷60 mg/d) and azathioprine (1÷2 mg/kg/d).

Prednisone is tapered with biochemical and clinical improvement to an eventual discontinuation of treatment. Some patients require lifelong low-dose therapy.

Remission (normalization of serum bilirubin, immunoglobulin levels, AST, ALT; disappearance of symptoms; resolution of histologic changes) is achieved in 65% and 80% of patients within 1.5 and 3 years, of treatment, respectively.

Relapses occur in at least 20%÷50% of patients after cessation of therapy. Relapses require retreatment.

Refractory disease (i.e., remission not achieved with standard-dose prednisone or azathioprine) may require “salvage” therapy with cyclosporine, tacrolimus, or mycophenolate mofetil.

Surgery

Liver transplantation should be considered in patients with ESLD.

After transplantation, recurrent AIH is seen in 17% of patients. De novo AIH, defined as AIH in patients transplanted for nonautoimmune diseases has been described in 3%÷5% of transplant recipients.

Primary Biliary Cirrhosis

General Principles

Definition

Primary biliary cirrhosis (PBC) is a cholestatic hepatic disorder of unknown etiology with autoimmune features.

Epidemiology

It most often affects middle-aged women (90%÷95%).

Although PBC is seen worldwide, it is more commonly described in North America and Northern Europe.

Diagnosis

Clinical Presentation

The course is highly variable.

Fatigue, jaundice, and pruritus are often the most troublesome symptoms.

Extrahepatic manifestations include keratoconjunctivitis sicca, renal tubular acidosis, gallstones, thyroid disease, scleroderma, Raynaud's phenomenon, CREST syndrome.

PBC progresses along a path of increasingly severe histologic damage (florid bile duct lesion, ductular proliferation, fibrosis, and cirrhosis). Ultimately, patients progress to cirrhosis with liver failure in 10÷15 years from diagnosis.

Laboratory Studies

Antimitochondrial antibodies are present in >90% of patients.

Typical features include elevated levels of AP, hyperbilirubinemia, cholesterol, IgM, and bile acids.

Liver Biopsy

Liver biopsy may be helpful for both diagnosis and staging.

Treatment

Medications

Ursodeoxycholic acid (13÷15 mg/kg/d PO) improves liver function test abnormalities and appears to delay progression of disease when given long term (>4 years).

Symptom-specific therapy for pruritus, steatorrhea, and malabsorption are outlined below.

No curative therapy is available.

Surgery

Liver transplantation may be necessary in advanced disease.

Recurrent PBC after transplantation has been documented.

Primary Sclerosing Cholangitis

General Principles

Definition

Primary sclerosing cholangitis (PSC) is a cholestatic liver disorder characterized by inflammation, fibrosis, and eventual obliteration of the extrahepatic and intrahepatic bile ducts.

Epidemiology

Most patients are middle-aged men.

PSC is frequently associated with inflammatory bowel disease (70% with ulcerative colitis).

Diagnosis

Clinical Presentation

Clinical manifestations include intermittent episodes of jaundice, hepatomegaly, pruritus, weight loss, and fatigue.

Cholangitis is a frequent complication in patients with severe strictures of the biliary ducts.

Patients may progress to cirrhosis and ESLD.

Cholangiocarcinoma is the most frequent neoplasm associated with PSC and occurs in 6%÷20% of patients.

Laboratory Studies

PSC should be considered in individuals with inflammatory bowel disease who have increased levels of AP even in the absence of symptoms of hepatobiliary disease.

Imaging

PSC is confirmed by demonstration of strictures or irregularities of the intrahepatic and extrahepatic bile ducts by ERCP or MRCP.

Liver Biopsy

Liver biopsy is helpful in the diagnosis of small-duct PSC, in the exclusion of other diseases, and in staging.

Treatment

Medical

High-dose ursodeoxycholic acid (20 mg/kg) may be beneficial in improving ductal damage and liver fibrosis.

Episodes of cholangitis should be managed with IV antibiotics and endoscopic therapy as outlined below.

Endoscopic Therapy

ERCP can be performed to dilate and stent dominant strictures.

Surgery

Colectomy for ulcerative colitis does not affect the course of PSC.

Patients with advanced disease or recurrent cholangitis should be referred for liver transplantation.

Cholangiocarcinoma is in general a contraindication to liver transplantation.

Recurrent PSC after liver transplantation has been documented.

Complications of Cholestasis

General Principles

Any condition that blocks bile excretion (in the liver cells or biliary ducts) is defined as cholestasis. Laboratory manifestations of cholestasis include elevated levels of AP and bilirubin.

Cholestasis can lead to nutritional deficiencies, osteoporosis, and pruritus.

Nutritional Deficiencies

Etiology

Nutritional deficiencies result from fat malabsorption (see Chapter 2, Nutritional Support).

Fat-soluble vitamin deficiency (vitamins A, D, E, K) is often present in advanced disease and is particularly common in patients with steatorrhea.

Diagnosis

Patients may give a history of oily or foul-smelling diarrhea.

Stool can be tested for fecal fat. Both spot tests and 24-hour collections can be done.

25-hydroxy vitamin D serum concentrations reflect the total body stores of vitamin D. Vitamin D deficiency in the setting of malabsorption and steatorrhea is a good clinical marker for total body concentrations of other fat-soluble vitamins.

Treatment

In patients with steatorrhea, a low-fat diet (40÷60 g/d) helps to decrease symptoms but may compromise total energy intake.

Fat-soluble vitamin replacement can be accomplished by water-soluble preparations of vitamin A, 10,000÷50,000 International units PO daily; vitamin K, 5÷10 mg PO daily; and vitamin E, 30÷100 International Units PO daily.

Vitamin D deficiency can be corrected by 25-hydroxyvitamin D3 (25-cholecalciferol), 50,000 Units PO 3× weekly.

Serum levels of 25-hydroxy vitamin D should be monitored to assess the adequacy of replacement therapy and avoid toxicity.

Zinc deficiency may occur in some patients and is corrected with zinc sulfate, 220 mg PO daily (50 mg elemental zinc) for 4 weeks.

Osteoporosis

Definition

Osteoporosis is defined as a decrease in the amount of bone (mainly trabecular bone), leading to a decrease in the integrity of the bone and an increase in the risk of fractures.

Etiology

Osteoporosis is more commonly seen in clinical cholestasis due to PBC.

It may result from increased bone resorption, decreased bone formation, or both.

Diagnosis

Bone mineral density through dual energy x-ray absorptiometry (DEXA) should be measured in all patients at the time of diagnosis and during follow-up.

Treatment

Treatment of bone disease includes exercise, oral calcium supplementation (1.0÷1.5 g/d), bisphosphonate therapy, and vitamin D supplementation.

Pruritus

Pathophysiology

The pathophysiology is debated and may be due to the accumulation of bile acid compounds or endogenous opioid agonists.

Diagnosis

Patients with cholestasis may present with itching in the setting of a normal or elevated bilirubin level.

Treatment

Medications

Pruritus is best treated with cholestyramine, a basic anion exchange resin. It binds bile acids and other anionic compounds in the intestine and inhibits their absorption. The dose is 4 g mixed with water before and after the morning meal, with additional doses before lunch and dinner to control symptoms. The maximum recommended dose is 16 g/d.

Cholestyramine should not be given concurrently with vitamins or other medications, as it may impair absorption.

Colestipol, another similar resin, is also available.

Antihistamines (diphenhydramine or doxepin, 25 mg PO at bedtime) and petrolatum may provide symptomatic relief.

Rifampin (300÷600 mg/d) and naltrexone (25÷50 mg/d) are reserved for intractable pruritus.

Other

Plasmapheresis, charcoal hemoperfusion, and partial external biliary diversion are invasive therapeutic procedures that can also be administered when medical therapy has failed.

Liver transplantation is a last resort option for intractable pruritus

Metabolic Liver Disease

General Principles

A number of treatable metabolic disorders present with hepatocellular dysfunction, including Wilson's disease and hereditary hemochromatosis.

Other infrequent disorders include glycogen storage disease, phospholipidosis, and α1-antitrypsin deficiency.

Wilson's Disease

General Principles

Wilson's disease (WD) is an autonomic-recessive disorder (ATP7B gene on chromosome 13) that results in progressive copper overload in the liver, brain, kidney, and cornea.

Incidence is 1 in 30,000.

WD is a rare cause of FHF, chronic hepatitis, and cirrhosis in the United States.

Diagnosis

Clinical Presentation

The diagnosis of WD should be considered in patients with unexplained liver disease with or without neuropsychiatric symptoms, first-degree relatives with WD, or individuals with FHF (with or without hemolysis).

The average age at presentation of liver dysfunction is 6÷20 years, but it can manifest later in life.

Neuropsychiatric disorders usually occur later, most of the time in association with cirrhosis. The manifestations include asymmetric tremor, dysarthria, ataxia, and psychiatric features.

Other extrahepatic manifestations include Kayser-Fleischer rings on slit-lamp examination (gold to brown rings due to copper deposition in the Descemet membrane in the periphery of the cornea), hemolytic anemia, renal tubular acidosis, arthritis, and osteopenia.

Laboratory Data

Data include low serum ceruloplasmin level (<20 mg/dL), elevated serum free copper level (>25 mcg/dL), and elevated 24-hour urinary copper level (>100 mg).

Radiology Studies

Brain imaging (basal ganglia changes) findings are nonspecific.

Liver Biopsy

The liver histology (massive necrosis, steatosis, glycogenated nuclei, chronic hepatitis, fibrosis, cirrhosis) findings are nonspecific and depend on the presentation and stage of the disease.

Elevated hepatic copper levels of >250 mcg/g dry weight (normal <40 mcg/g) on biopsy are highly suggestive of WD.

Treatment

Medical

Treatment is with copper-chelating agents.

Zinc salts 50 mg tid are indicated in patients with chronic hepatitis and cirrhosis in the absence of hepatic failure. Zinc may be associated with the use of penicillamine and trientine. Other than gastric irritation, zinc has an excellent safety profile.

Penicillamine 1÷2 g/d (in divided doses bid or qid) plus pyridoxine 25 mg/d to avoid its deficiency during treatment. It is indicated in patients with hepatic failure. Use may be limited by side effects (hypersensitivity, bone marrow suppression, proteinuria, systemic lupus erythematosus, Goodpasture syndrome). Penicillamine should never be given as initial treatment to patients with neurologic symptoms.

Trientine 1÷2 g/d (in divided doses bid or qid). This has similar side effects as penicillamine, but at a lower frequency. The risk of neurologic worsening with trientine is less than with penicillamine.

Tetrathiomolybdate (TM) 120 mg/d (20 mg tid with meals and 60 mg at bedtime away from food) with zinc therapy. This is the treatment of choice for patients presenting with neurologic symptoms. TM has a good safety profile. Anemia, leukopenia, and mild elevations of aminotransferases may be seen during treatment.

Liver Transplantation

Liver transplantation is the only therapeutic option in FHF or in progressive dysfunction despite chelation therapy.

In the absence of neurologic symptoms, liver transplantation has a good prognosis and requires no further medical treatment.

Hereditary Hemochromatosis

General Prinicples

Hereditary hemochromatosis (HH) is an autosomal-recessive disorder of iron overload. The gene responsible (HFE gene) is on chromosome 6. This systemic disorder is related to abnormal iron absorption in the duodenum that leads to excessive and damaging iron deposition in the liver, heart, pancreas, skin, and endocrine system.

This is the most common inherited form of iron overload affecting Caucasian populations.

One in 200÷400 Caucasian individuals are homozygous for the HFE gene mutations.

It is usually not diagnosed until middle age (40÷60 years).

Diagnosis

Clinical Presentation

Presentation varies from asymptomatic disease to cirrhosis.

Associated findings include slate-colored skin, diabetes, cardiomyopathy, arthritis, hypogonadism, or hepatic dysfunction.

Patients with cirrhosis are at increased risk for the development of hepatocellular carcinoma despite therapy.

Laboratory Data

The diagnosis is suggested by high fasting transferrin saturation (>45%).

The diagnosis is subsequently confirmed by the presence of specific mutations in the HFE. The most common mutation associated with HH is C282Y. Less frequent mutations include the H63D and S65C and the compound heterozygous C282Y/H63D.

Iron overload in the presence of genotypes not associated with HH requires further assessment with ancillary tests.

Imaging

MRI is the modality of choice for noninvasive quantification of iron storage in the liver. It allows for repeated measures and minimizes sampling error.

Liver Biopsy

Biochemical tests, HFE genotype determination, and imaging have replaced the role of liver biopsy in establishing the diagnosis.

Liver biopsy is most helpful in staging the disease, especially in individuals who are at increased risk of having advanced fibrosis or cirrhosis.

In patients with iron overload without typical HFE gene mutations, liver biopsy is still a valuable diagnostic tool.

Treatment

Therapy consists of phlebotomy (500 mL blood/wk) until iron depletion is confirmed by a ferritin level <50 ng/mL and a transferring saturation of <40%. Thereafter, maintenance phlebotomy of 1÷2 units of blood three to four times a year is continued for life.

Deferoxamine is an iron-chelating agent used in the setting of HH if the patient's hemodynamics cannot tolerate phlebotomy. It binds free iron and facilitates urinary excretion.

Liver Transplantation

Liver transplantation may be considered in cases of HH with cirrhosis.

Screening

Once a diagnosis has been made, the patient's family members should undergo screening for HH by measuring fasting transferrin saturation and ferritin levels.

Genetic testing may also be performed.

Prognosis

The survival rate in appropriately treated noncirrhotic patients is identical to that of the general population.

Patients who undergo liver transplantation for hemochromatosis tend to have poorer 1- and 5-year survival rates when compared to other liver transplant recipients.

α1-Antitrypsin deficiency

General Principles

α1-Antitrypsin deficiency (α1AT) is an autosomal-recessive disease associated with accumulation of misfolded α1-antitrypsin in the endoplasmic reticulum of hepatocytes. The gene associated with the disease is located on chromosome 14. α1AT can also be associated with emphysema in early adulthood, as well as other extrahepatic manifestations including panniculitis, pancreatic fibrosis, and membranoproliferative glomerulonephritis.

Incidence is 1 in 1,600.

The most common allele is protease inhibitor M (PiM—normal variant), followed by PiS and PiZ (deficient variants). Blacks have lower frequency of these alleles.

The disease may present as neonatal cholestasis or later in life as chronic hepatitis, cirrhosis, or hepatocellular carcinoma.

Diagnosis

Clinical Presentation

Patients may present with cholestasis, mild abnormalities in aminotransferases, and cirrhosis.

The presence of significant pulmonary and hepatic disease in the same patient is very rare (1%÷2%).

Chronic hepatitis, cirrhosis, or hepatocellular carcinoma may develop in 10%÷15% of patients with the PiZZ phenotype during the first 20 years of life. Controversy exists as to whether liver disease develops in heterozygotes (PiMZ, PiSZ, PiFZ, etc.).

Laboratory Data

Low serum α1-antitrypsin level (10%÷15% of normal)

Decreased α-1 globulin level on serum electrophoresis

The patient should also be tested for α1AT phenotype.

Liver Biopsy

The liver biopsy is essential for the diagnosis and shows characteristic periodic acid-Schiff÷positive, diastase-resistant globules in the periportal hepatocytes.

Treatment

Currently, there is no specific medical treatment.

Gene therapy for α1AT deficiency is a potential future alternative.

Transplantation is curative, with survival rates of 90% at 1 year and 80% at 5 years.

Miscellaneous Disorders

Ischemic Hepatitis

General Principles

Ischemic hepatitis results from liver hypoperfusion. Synonyms include shock liver and hypoxic hepatitis.

Clinical circumstances include severe blood loss, severe burns, cardiac failure, heat stroke, sepsis, and sickle cell crisis.

Diagnosis

Clinical Presentation

Ischemic hepatitis presents as acute and transient rise of liver enzymes in the thousands during or following a hypotensive episode.

Laboratory Studies

Laboratory studies show a rapid rise and fall in levels of serum AST, ALT (>1,000 mg/dL), and lactic dehydrogenase within 1÷3 days of the insult with subsequent slow decline in aminotransferases if the underlying cause is corrected.

Total bilirubin, alkaline phosphatase, and INR may initially be normal but subsequently rise as a result of reperfusion injury.

Liver Biopsy

Liver biopsy is not usually needed for diagnosis.

Centrilobular necrosis and sinusoidal distortion with inflammatory infiltrates in zone 3 (central areas) are the classic histologic features.

Treatment

Correct the underlying condition that caused the circulatory collapse.

Prognosis

Prognosis is determined by the rapid and effective treatment of the underlying cause.

Vascular Diseases

General Principles

Vascular diseases of the liver can be due to impaired arterial or venous blood flow. The portal vein and the hepatic artery provide two-thirds and one-third of hepatic blood flow, respectively.

Hepatic Vein Thrombosis

Definition

Hepatic vein thrombosis (HVT; previously known as Budd-Chiari's syndrome) causes a hepatic venous outflow obstruction with multiple etiologies and a variety of clinical consequences.

Etiology

Thrombosis is the main factor leading to obstruction of the hepatic venous system, frequently in association with myeloproliferative disorders, antiphospholipid antibody syndrome, paroxysmal nocturnal hemoglobinuria, factor V Leiden, protein C and S deficiency, and contraceptive use.

Another cause is membranous obstruction of the inferior vena cava (IVC).

HVT can occur during pregnancy and in the postpartum period.

Less than 20% of cases are idiopathic.

Diagnosis

Clinical Presentation

Patients may present with an acute, subacute, or chronic illness characterized by ascites, hepatomegaly, and right upper quadrant abdominal pain.

Other symptoms may include jaundice, encephalopathy, gastrointestinal bleeding, and lower extremity edema.

Laboratory Studies

Serum-to-ascites albumin gradient is >1.1 g/dL. Serum albumin, bilirubin, AST, ALT, and PT are mildly abnormal.

Laboratory evaluation of prothrombotic conditions should be performed (see Chapter 18, Disorders of Hemostasis).

Imaging

Doppler ultrasound can be used as a screening test.

Definitive diagnosis is made with magnetic resonance venography or hepatic venography.

Treatment

Nonsurgical

Nonsurgical treatment includes anticoagulants, thrombolytics, diuretics, angioplasty, stents, and transjugular intrahepatic portosystemic shunt (TIPS).

Surgical

Decompression procedures and liver transplantation are therapeutic options.

Sinusoidal Obstruction Syndrome

Definition

Sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease) refers to alterations in the liver microcirculation that may occur in the absence of vascular occlusion.

Etiology

It is seen in bone marrow transplant recipients after conditioning therapy with total body irradiation and high-dose cytoreductive chemotherapy, in renal transplant recipients who are immunosuppressed with azathioprine, and in association with ingestion of pyrrolizidine alkaloids (Jamaican bush teas).

Diagnosis

Clinical Presentation

Diagnosis is based on the triad of hepatomegaly, weight gain (2%÷5% of baseline body weight), and hyperbilirubinemia (>2 mg/dL), generally occurring within 3 weeks after bone marrow transplantation.

The severity of SOS varies from mild to moderate to severe disease.

The clinical presentation depends on the severity of the disease.

Laboratory Studies

The laboratory findings correlate with the clinical disease, from mild to significant elevations in aminotransferases and bilirubin.

Procedures

A useful approach to the diagnosis is the transjugular measurement of the hepatic venous pressure. A concomitant liver biopsy can be performed during the same procedure.

The typical histology shows centrilobular congestion with hepatocellular necrosis and accumulation of hemosiderin-laden macrophages. The terminal hepatic venules exhibit minimal edema without obvious fibrin deposition or thrombosis.

Treatment

Treatment is largely supportive.

Defibrotide, a single-stranded polydeoxyribonucleotide drug, has shown promise in uncontrolled clinical trials.

Prophylaxis

Altering the myeloablative therapy and reducing the dose of radiation may decrease the incidence of SOS.

Other preventative measures like anticoagulation, pretreatment with ursodeoxycholic acid, pentoxifylline, and prostaglandin E have not been proven to be consistently effective.

Prognosis

Prognosis depends on the severity of disease.

Portal Vein Thrombosis

Etiology

Portal vein thrombosis (PVT) is a disease of both children and adults. In adults it is seen in a variety of clinical settings, including abdominal trauma, cirrhosis, malignancy, hypercoagulable states, and intra-abdominal infections, pancreatitis, and after portocaval shunt surgery or splenectomy.

Diagnosis

Clinical Presentation

PVT can present as an acute or a chronic condition.

The acute phase may go unrecognized. Symptoms include abdominal pain/distension, nausea, anorexia, weight loss, diarrhea, or features of the underlying disorder.

Chronic PVT may present with variceal hemorrhage or other manifestations of portal hypertension.

Imaging

Ultrasonographic Doppler examination is sensitive and specific for establishing the diagnosis.

Angiography, CT, or magnetic resonance angiography can also be used.

Laboratory Data

In patients with no obvious etiology, a prothrombotic workup should be performed.

Treatment

Medical

Anticoagulation should be considered in the setting of acute PVT.

Other

In the chronic setting treatment should focus on the complications of portal hypertension including nonselective beta-blockers, endoscopic banding for varices, and diuretics for ascites.

Transjugular intrahepatic portosystemic shunt (TIPS) should be considered in selected cases.

Portosystemic surgery carries a high morbidity and mortality, especially in patients with PVT in association with cirrhosis.

Hepatic Abscess

Hepatic abscess may be classified as either pyogenic or amebic.

Pyogenic Abscess

Etiology

Pyogenic abscess can result from hematogenous infection, spread from intra-abdominal infection, or ascending infection from the biliary tract.

Approximately 20% of cases are cryptogenic in origin.

Diagnosis

Clinical Presentation

Clinical features include fever, chills, weight loss, jaundice, and abdominal pain from tender hepatomegaly.

Laboratory Studies

Laboratory studies may demonstrate leukocytosis and elevated AP.

More than half the patients have positive blood cultures at the time of presentation.

Imaging

Diagnosis is confirmed by CT, MRI, or ultrasonography.

Treatment

Medications

Treatment includes a prolonged course of antibiotic therapy.

Drainage

In select cases, treatment is by imaging-guided percutaneous or surgical drainage.

Follow-Up

Repeated imaging is recommended to document resolution.

Amebic Abscess

Amebic abscess should be considered in patients from endemic areas.

Diagnosis

Clinical Presentation

Diagnosis requires a high index of clinical suspicion.

Clinical features include fever, chills, and tender hepatomegaly.

Laboratory Studies

Specific serologic tests for Entamoeba histolytica such as the indirect hemagglutination determination are helpful in establishing the diagnosis in low-prevalence areas.

Treatment

Medication

Amebic abscesses are treated with metronidazole.

Drainage

Imaging-guided drainage is reserved for amebic abscesses at risk for rupture or when pyogenic coinfection is suspected.

Granulomatous Hepatitis

Definition

Granulomatous hepatitis is the consequence of a nonspecific reaction to a wide spectrum of diverse etiologic stimuli.

Etiology

Etiologies include infections (e.g., brucellosis, syphilis, mycobacterial, fungal, and rickettsial diseases), sarcoidosis, drug-induced injury, lymphoma, and idiopathic causes.

Diagnosis

Clinical Presentation

Patients may present with fever, hepatosplenomegaly, and signs of portal hypertension on physical examination.

Laboratory Studies

Laboratory studies show elevated liver enzyme levels (particularly AP).

Liver Biopsy

Liver biopsy is the most accurate and specific way to diagnose granulomatous hepatitis.

Treatment

Medical

Specific therapy is directed at the underlying cause.

If the clinical suspicion for tuberculosis is high, an empiric trial of antituberculous therapy may be warranted despite negative mycobacterial cultures.

Nonalcoholic Fatty Liver Disease

General Principles

Nonalcoholic fatty liver disease (NALFD) is a clinicopathologic syndrome that encompasses several clinical entities that range from simple steatosis to steatohepatitis, fibrosis, and end-stage liver disease in the absence of significant alcohol consumption.

Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD and is defined as steatosis with hepatocellular ballooning plus lobular inflammation. Pathologic findings in NASH also include pericellular or perisinusoidal fibrosis.

The exact mechanisms leading to excess hepatic fat and hepatic cellular damage are incompletely understood.

Epidemiology

NAFLD is a worldwide phenomenon.

It is the most common liver disease in the United States, affecting 20%÷35% of the adult population.

NAFLD is associated with an increasing prevalence of type II diabetes, metabolic syndrome, and obesity in the U.S. population.

It affects both children and adults, and the incidence increases with age.

Approximately 25% of patients with NASH progress to cirrhosis over a 10- to 15-year period.

Up to 70% of cases of cryptogenic cirrhosis have NASH as the underlying etiology.

Cirrhosis due to NALFD may also by complicated by HCC (13% of all cases of HCC).

Etiology

It is usually associated with insulin resistance to glucose metabolism and features of the metabolic syndrome (see Chapter 21, Diabetes Mellitus and Related Disorders).

Secondary causes include hepatotoxic drugs (amiodarone, nifedipine, estrogens), surgical procedures (jejunoileal bypass, extensive small-bowel resection, biliary and pancreatic diversions), and miscellaneous conditions (total parenteral nutrition, hypobetalipoproteinemia, environmental toxins).

Diagnosis

Clinical Presentation

The disease may vary from asymptomatic to advanced ESLD and HCC.

Laboratory Data

Liver enzyme elevations are mild. Up to 80% of patients will have normal liver enzymes.

Biochemical abnormalities may reflect the stage of the disease (e.g., cholestasis, hypoalbuminemia, increased INR).

Imaging

Imaging studies such as ultrasonography, CT scan, and MRI may detect moderate to severe steatosis.

Magnetic resonance spectroscopy offers a quantitative measurement of liver fat content, but is not commonly available.

Liver Biopsy

Liver biopsy remains the gold standard by which the diagnosis is made. However, the decision to perform a liver biopsy should take into account the specific clinical questions that are relevant to each case.

Treatment

Medical

No established specific treatment is available for NAFLD.

Therapies to correct or control associated conditions are warranted (weight loss through diet and exercise, tight control of diabetes and insulin resistance, appropriate treatment of hyperlipidemia, and discontinuation of possible offending agents).

Liver Transplantation

Liver transplantation should be considered in patients with ESLD, although recurrence can develop.

Acute and Chronic Complications of Hepatic Insufficiency

Acute Hepatic Insufficiency

Fulminant Hepatic Failure

General Principles

FHF is defined as the acute onset of altered mental status and coagulopathy within 8÷24 weeks of initial symptoms of liver disease in an otherwise healthy individual.

Epidemiology

Acetaminophen hepatotoxicity and viral hepatitis are the most common causes of FHF.

Other causes include AIH, drug and toxin exposure, ischemia, acute fatty liver of pregnancy, WD, and Reye's syndrome.

In 20% of cases, no clear cause is identified.

Diagnosis

Clinical Presentation

Patients may present with mild to severe mental status changes in the setting of moderate to severe acute hepatitis and coagulopathy.

Jaundice may or may not be initially present.

A history of acetaminophen overdose, toxin ingestion, or risk factors for viral hepatitis may be obtained.

Patients can develop cardiovascular collapse, acute renal failure, cerebral edema, and sepsis.

Laboratory Data

Aminotransferases are typically elevated, and in many cases are >1,000 International Units/L.

INR is ≥1.5.

Initial workup to determine the etiology of FHF should include:

Acute viral hepatitis panel

Serum drug screen, which includes acetaminophen

Ceruloplasmin

AIH serologies

Pregnancy test

Treatment

Supportive therapy in the intensive care unit (ICU) setting of a tertiary center with liver transplant capabilities is essential.

Precipitating factors should be identified and treated if possible.

Blood glucose, electrolytes, acid-base, coagulation parameters, and fluid status should be monitored serially.

Vitamin K, fresh frozen plasma, and the use of recombinant activated factor VIIa should be considered in the setting of active bleeding or when invasive procedures are required.

Cerebral edema and intracranial hypertension are related to severity of encephalopathy. In patients that reach grade III or IV encephalopathy, intracranial pressure monitoring should be considered (intracranial pressure should be maintained below 20÷25 mm Hg, cerebral perfusion pressure should be maintained above 50 mm Hg). Therapies to decrease cerebral edema include mannitol (0.5÷1 g/kg IV), hyperventilation (reduce PaCO2 to 25÷30 mm Hg), hypothermia (32÷34°C), and barbiturates.

Transplantation should be urgently considered in cases of FHF.

Prognosis

Prior to transplantation survival was <15%; in the posttransplant era survival is >65%.

Death often results from progressive liver failure, GI bleeding, cerebral edema, sepsis, or arrhythmia.

Poor prognostic indicators in acetaminophen-induced FHF include arterial pH <7.3, INR >6.5, creatinine >2.3 mg/dL, and encephalopathy grade III÷IV.

Chronic Hepatic Insufficiency

Cirrhosis is a chronic diffuse condition characterized by replacement of liver cells by fibrotic tissue, which creates a nodular-appearing distortion of the normal liver architecture. This fibrosis represents the end result of a variety of etiologies of liver injury.

Hepatic Encephalopathy

Hepatic encephalopathy is the syndrome of disordered consciousness and altered neuromuscular activity that is seen in patients with acute or chronic hepatocellular failure or portosystemic shunting.

Mechanisms of Injury

The pathogenesis of hepatic encephalopathy is controversial, and numerous mediators have been implicated.

Precipitating factors include azotemia; acute liver failure; use of a tranquilizer, opioid, or sedative-hypnotic medication; GI hemorrhage; hypokalemia and alkalosis (diuretics and diarrhea); constipation; infection; high-protein diet; progressive hepatocellular dysfunction; and portosystemic shunts (surgical or TIPS).

Diagnosis

Presentation varies from subtle mental status changes to coma.

Asterixis (flapping tremor) is present in stages I÷II of encephalopathy. This motor disturbance is not specific to hepatic encephalopathy.

The electroencephalogram shows slow, high-amplitude, and triphasic waves.

Determination of blood ammonia level is not a sensitive or specific test for hepatic encephalopathy.

Treatment

Diet

The rationale and benefit of dietary protein restriction is controversial. Once the patient is able to eat, a diet containing 30÷40 g of protein per day is initiated. Special diets (vegetable protein or branched-chain amino acid enriched) may be beneficial in patients with encephalopathy that is refractory to the usual measures.

Medications

Medications include nonabsorbable disaccharides (lactulose, lactitol, and lactose in lactase-deficient patients) and antibiotics (neomycin, metronidazole, and rifaximin).

The initial dose of lactulose is 15÷45 mL PO bid÷qid. Maintenance dose should be adjusted to produce three to five soft stools per day. Oral lactulose should not be given to patients with an ileus or possible bowel obstruction.

Lactulose enemas (prepared by the addition of 300 mL lactulose to 700 mL distilled water) can also be administered.

Neomycin can be given by mouth (500÷1,000 mg q6h) or as a retention enema (1% solution in 100÷200 mL isotonic saline). Approximately 1%÷3% of the administered dose of neomycin is absorbed, with the attendant risk of ototoxicity and nephrotoxicity. The risk of toxicity is increased in patients with renal insufficiency. Because lactulose is as effective as neomycin, it is preferred for initial and maintenance therapy.

Metronidazole (250 mg PO q8h) is useful for short-term therapy when neomycin is unavailable or poorly tolerated. Long-term metronidazole is not recommended due to its associated toxicities.

Rifaximin 400 mg PO tid is a new antibiotic with a very good safety profile that is used as an alternative to neomycin and metronidazole.

Combination therapy with lactulose and any of the antibiotics mentioned above should be considered in cases that are refractory to either agent alone.

Portal Hypertension

Portal hypertension is the main complication of cirrhosis, and is characterized by increased resistance to portal flow and increased portal venous inflow. Portal hypertension is established by determining the pressure difference between the hepatic vein and the portal vein (pressure gradient >10 mm Hg).

Direct and indirect clinical consequences of portal hypertension include esophageal and gastric varices, portal hypertensive gastropathy, ascites, hepatorenal syndrome, and spontaneous bacterial peritonitis.

Etiology

Causes of portal hypertension in patients without cirrhosis include idiopathic portal hypertension, schistosomiasis, congenital hepatic fibrosis, sarcoidosis, cystic fibrosis, arteriovenous fistulas, splenic and portal vein thrombosis, myeloproliferative diseases, nodular regenerative hyperplasia, and focal nodular hyperplasia.

Diagnosis

Clinical Presentation

Portal hypertension frequently complicates cirrhosis and presents with ascites, GI bleeding from esophageal or gastric varices or portal hypertensive gastropathy, and splenomegaly.

Imaging

Ultrasonography, CT, and MRI showing cirrhosis, splenomegaly, collateral venous circulation, and ascites are suggestive of portal hypertension.

Diagnostic Procedures

Upper endoscopy showing varices (esophageal or gastric) or portal hypertensive gastropathy

Transjugular portal pressure measurements

Treatment

Treatment of gastrointestinal bleeding due to portal hypertension is covered in Chapter 16, Gastrointestinal Diseases.

Ascites

Ascites is the abnormal (>25 mL) accumulation of fluid within the peritoneal cavity. Causes of ascites besides cirrhosis include cancer (peritoneal carcinomatosis), heart failure, tuberculosis, pancreatic disease, nephrotic syndrome, surgery or trauma to the lymphatic system or ureters, and serositis.

Diagnosis

Clinical Presentation

Presentation ranges from ascites detected only by imaging methods to a distended, bulging abdomen on physical examination. Percussion of the abdomen reveals shifting dullness.

Imaging

Ultrasonography, CT, and MRI are sensitive methods to detect ascites.

Laboratory Studies

A serum to ascites albumin gradient (SAAG) that is >1.1 g/dL indicates portal hypertension÷related ascites (97% specificity).

An SAAG of <1.1 g/dL is found in nephrotic syndrome, peritoneal carcinomatosis, serositis, tuberculosis, and biliary or pancreatic ascites.

Diagnostic Procedures

Paracentesis should be performed for diagnosis (e.g., new-onset ascites, suspicion of malignant ascites, or spontaneous bacterial peritonitis [SBP]) or as a therapeutic maneuver when tense ascites causes significant discomfort or respiratory compromise.

Routine diagnostic testing should include fluid cell and differential counts, albumin, total protein, and culture.

Amylase and triglyceride measurement, cytology, and mycobacterial smear/culture can be performed to confirm specific diagnoses.

Bleeding and intestinal perforation are possible complications.

Rapid large-volume paracentesis (>5 L) may lead to circulatory collapse, encephalopathy, and renal failure. Concomitant administration of IV albumin (5÷8 g/L ascites removed) can be used to minimize these complications, especially in the setting of renal insufficiency or the absence of peripheral edema.

Treatment

Dietary

Dietary salt restriction (2 g salt or 88 mmol Na+/d) should be initiated and continued thereafter unless the renal ability to excrete sodium spontaneously improves.

In selected cases, it may be necessary to restrict sodium intake further.

The use of potassium-containing salt substitutes can lead to serious hyperkalemia.

Routine water restriction is not necessary. If dilutional hyponatremia (serum Na+ <120 mmol/L) occurs, fluid restriction to 1,000÷1,500 mL/d usually suffices.

Medications

Diuretic therapy can be initiated along with salt restriction. The goal of diuretic therapy should be a daily weight loss of no more than 1.0 kg in patients with edema and approximately 0.5 kg in those without edema until ascites is adequately controlled. Diuretics should not be administered to individuals with an increasing serum creatinine level.

Spironolactone (100 mg PO in a single daily dose with food) is the diuretic of choice. The daily dose can be increased by 50÷100 mg every 7÷10 days until satisfactory weight loss, a maximum dose of 400 mg, or side effects occur. Hyperkalemia and gynecomastia are common side effects. Amiloride or triamterene (potassium-sparing diuretics) are substitutes that can be used in patients in whom painful gynecomastia develops.

Loop diuretics, such as furosemide (20÷40 mg, increasing to a maximum dose of 160 mg PO daily) or bumetanide (0.5÷2.0 mg PO daily), can be added to spironolactone.

Patients should be observed closely for signs of dehydration, electrolyte disturbances, encephalopathy, muscle cramps, and renal insufficiency. Nonsteroidal anti-inflammatory agents may blunt the effect of diuretics and increase the risk of renal dysfunction.

Nonoperative

TIPS has been proven effective in the management of refractory ascites (fluid overload that is nonresponsive to a sodium-restricted diet and high-dose diuretic therapy).

Complications include shunt occlusion, bleeding, infection, cardiopulmonary compromise, and hepatic encephalopathy.

Spontaneous Bacterial Peritonitis

SBP is an infectious complication of portal hypertension÷related ascites. Risk factors for SBP include ascitic fluid protein concentration <1 mg/dL, variceal hemorrhage, and a prior episode of SBP.

Diagnosis

Clinical Manifestations

Clinical manifestations include abdominal pain and distention, fever, decreased bowel sounds, and worsening of hepatic encephalopathy. However, the disease may be present in the absence of specific clinical signs. Cirrhotic patients with ascites and evidence of any clinical deterioration should undergo diagnostic paracentesis to exclude SBP.

Laboratory

The diagnosis is likely when the ascitic fluid contains >250 neutrophils/microliter Gram stain reveals the organism in only 10%÷20% of samples. A positive culture confirms the diagnosis.

Cultures are more likely to be positive when 10 mL ascitic fluid is inoculated into two blood culture bottles at the bedside.

The most common organisms are Escherichia coli, Klebsiella, and Streptococcus pneumoniae. Blood cultures are positive in approximately one-half of cases with SBP. Polymicrobial infection is uncommon and should lead to the suspicion of secondary bacterial peritonitis.

Treatment

In suspected cases (fever, abdominal pain, or tenderness) without more than 250 neutrophils/microliter, empiric antibiotic therapy with a third-generation cephalosporin (e.g., ceftriaxone, 1 g IV daily, or cefotaxime, 1÷2 g IV q6÷8h, depending on renal function; see Appendix E) or a quinolone (ciprofloxacin, 400 mg IV q12h) is appropriate for 5 days. Paracentesis should be repeated if no clinical improvement occurs in 48÷72 hours, especially if the initial ascitic fluid culture was negative.

Concomitant use of albumin 1.5 g/kg body weight at diagnosis and 1 g/kg body weight on day 3 improves survival and prevents renal failure in SBP.

Norfloxacin (400 mg PO daily) can be used as secondary prophylaxis by reducing the frequency of recurrent episodes of SBP. However, the use of antibiotic prophylaxis has not been clearly shown to improve survival and does select resistant gut flora.

Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a unique form of functional renal impairment in the setting of acute or, more commonly, chronic liver disease. Common precipitating factors include systemic bacterial infections, SBP, and large-volume paracentesis without volume expansion.

Diagnosis

Major and minor diagnostic criteria are summarized in Table 17-4.

Type I HRS is characterized by the acute onset of rapidly progressive (<2 weeks), oliguric renal failure unresponsive to volume expansion. There is a doubling of the initial serum creatinine to a level >2.5 mg/dL or a 50% reduction in the creatinine clearance to a level <20 mL/min.

Type II HRS progresses more slowly but relentlessly and often clinically manifests as diuretic-resistant ascites.

TABLE 17-4 Diagnostic Criteria of Hepatorenal Syndrome
Major criteria
Low glomerular filtration rate, as indicated by serum creatinine >1.5 mg/dL or 24-hr creatinine clearance <40 mL/min
Absence of shock, ongoing bacterial infection, fluid losses, and current treatment with nephrotoxic drugs
No sustained improvement in renal function (decrease in serum creatinine to 1.5 mg/dL or increase in creatinine clearance to 40 mL/min) after diuretic withdrawal and expansion of plasma volume with 1.5 L of a plasma expander
Proteinuria <500 mg/dL and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease
Additional criteria
Urine volume <500 mL/d
Urine sodium <10 mEq/L
Urine osmolality greater than plasma osmolality
Urine red blood cells <50/high-power field
Serum sodium concentration <130 mEq/L
Note: All major criteria must be present for the diagnosis of hepatorenal syndrome. Additional criteria are not necessary for the diagnosis but provide supportive evidence.
Adapted from Arroyo V, Gines P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996;23:164.

Treatment

Medical

No clear or established treatments are available for HRS. Systemic vasoconstrictors including vasopressin analogs (terlipressin), somatostatin analogs (octreotide), and α-adrenergic agonists (midodrine and norepinephrine) with plasma expansion have shown a beneficial role in uncontrolled studies.

Nonmedical

TIPS is a potential treatment alternative; however, data are limited.

Hemodialysis may be indicated in patients listed for liver transplantations.

Liver Transplantation

In suitable candidates, liver transplantation may be curative.

Prognosis

Without treatment, patients with type I HRS have a short-term fatal prognosis, with death occurring within 2÷3 months of onset. Patients with type II HRS have a median survival of approximately 6 months.

Hepatocellular Carcinoma (HCC)

Epidemiology

HCC frequently occurs in patients with cirrhosis, especially when associated with viral hepatitis (HBV or HCV), alcoholic cirrhosis, α1AT deficiency, and hemochromatosis.

HCC is the fifth most common cancer in men and the ninth most common cancer in women worldwide.

It constitutes 84% of primary liver cancer in the United States (mean age at diagnosis is 65).

TABLE 17-5 Child-Turcotte-Pugh Scoring System to Assess Severity of Liver Disease
Clinical and biochemical measurements Points scored for increasing abnormality
1 2 3
>3.5 2.8÷3.5 <2.8
Bilirubin (mg/dL) <2 2÷3 >3
For cholestatic diseases: bilirubin (mg/dL) <4 4÷10 >10
PT (seconds prolonged)a or <4 4÷6 >6
INRa <1.7 1.7÷2.3 >2.3
Ascites Absent Mild Moderate
Encephalopathy (grade) 0 1 and 2 3 and 4
Class Total points
A 5÷6  
B 7÷9  
C 10÷15  
aEither the prothrombin time (PT) or international normalized ratio (INR) can be used for scoring.
         

Diagnosis

Clinical Presentation

Clinical presentation is directly proportional to the stage of disease. Early disease is asymptomatic, while patients with late-stage disease may present with right upper quadrant abdominal pain, weight loss, and hepatomegaly.

Suspect HCC in a well-controlled cirrhotic patient who develops manifestations of liver decompensation.

Laboratories

α-Fetoprotein is the most widely used screening test. The sensitivity and specificity of the test are dependant on the cutoff value. A cutoff of 400 ng/mL or a rapid doubling time (weeks to months) is highly specific.

Imaging

Liver ultrasound, triple-phase CT, and MRI are adequate and frequently used for detection of HCC.

Liver Biopsy

Liver biopsy should be considered for those cases where the combination of imaging and α-fetoprotein values are not diagnostic.

Treatment

Hepatic resection is the treatment of choice in noncirrhotic patients and may also be considered in well-compensated cirrhotic patients (Child-Pugh class A; see Table 17-5).

Liver transplantation is the treatment of choice for cirrhotic patients (single HCC <5 cm or up to three nodules <3 cm).

Alternative therapy for unresectable tumors includes percutaneous alcohol or acetic acid injection, arterial chemoembolization, microwave coagulation therapy, or radiofrequency ablation.

Prognosis

Early diagnosis is essential, as surgical resection and liver transplantation can improve long-term survival. However, survival remains very poor: 1-year and 3-year survival rates are 36% and 17%, respectively.

Liver Transplantation

General Principles

Liver transplantation is an effective therapeutic option for both irreversible acute and chronic liver diseases for which available therapies have failed.

Whole cadaveric livers and partial livers (split-liver, reduced-size, and living-related) are used in the United States as sources for liver transplantation.

Epidemiology

In the United States, over 17,000 patients are awaiting liver transplants, approximately 5,000 transplants are performed in the United States each year, and approximately 2,000 patients per year die while on the waiting list.

The disparity between supply and demand of suitable livers for transplantation continues to increase.

Indications

Patients that fulfill criteria for FHF are potential candidates for liver transplantation.

Patients with chronic liver disease should be considered for transplant evaluation when they have a decline in hepatic synthetic or excretory functions, ascites, hepatic encephalopathy, or complications such as HRS, hepatocellular carcinoma, recurrent SBP, or variceal bleeding.

The prioritization for liver transplantation in chronic liver disease is determined by the Model for End-Stage Liver Disease (MELD) score. The MELD score is determined by the use of an equation that takes into account serum bilirubin, serum creatinine, and INR.

Contraindications

Severe and uncontrolled extrahepatic infection

Advanced cardiac or pulmonary disease

Extrahepatic malignancy

Multiorgan failure

Unresolved psychosocial issues

Medical noncompliance issues

Ongoing substance abuse (e.g., alcohol and illegal drugs)

Protocol

Candidates for liver transplantation are evaluated by a multidisciplinary team that includes hepatologists, transplant surgeons, transplant nurse coordinators, social workers, psychologists, and financial coordinators.

Immunosuppressive, infectious, and long-term complications are discussed in Chapter 15, Solid Organ Transplant Medicine.

Suggested Readings

Adams LA, Angulo P. Recent concepts in non-alcoholic fatty liver disease. Diabet Med 2005;22:1129÷1133.

Brewer GJ, Askari FK. Wilson's disease: clinical management and therapy. J Hepatol 2005;42(Suppl):S13÷21.

Cardenas A. Hepatorenal syndrome: a dreaded complication of end-stage liver disease. Am J Gastroenterol 2005;100:460÷467.

Czaja AJ, Bianchi FB, Carpenter HA, et al. Treatment challenges and investigational opportunities in autoimmune hepatitis. Hepatology 2005;41:207÷215.

Garcia-Tsao G. Portal hypertension. Curr Opin Gastroenterol 2005;21:313÷322.

Harrison SA, Bacon BR. Relation of hemochromatosis with hepatocellular carcinoma: epidemiology, natural history, pathophysiology, screening, treatment, and prevention. Med Clin North Am 2005;89:391÷409.

Jalan R. Acute liver failure: current management and future prospects. J Hepatol 2005;42(Suppl):S115÷123.

Maddrey WC. Drug-induced hepatotoxicity: 2005. J Clin Gastroenterol 2005;39:S83÷89.

Marrero JA. Screening tests for hepatocellular carcinoma. Clin Liver Dis 2005;9:235÷251.

Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology 2005;41:1179÷1197.

Runyon BA. Management of adult patients with ascites due to cirrhosis. Hepatology 2004;39:841÷856.

Schilsky ML, Oikonomou I. Inherited metabolic liver disease. Curr Opin Gastroenterol 2005;21:275÷282.

Sobhonslidsuk A, Reddy KR. Portal vein thrombosis: a concise review. Am J Gastroenterol 2002;97:535÷541.

Willner IR, Reuben A. Alcohol and the liver. Curr Opin Gastroenterol 2005;21:323÷330.

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