considered, recent reports have identified obesity as a major risk factor for cancer deaths with a 4.5-fold

increase of the relative risk for liver cancer in obese subjects.64

The current understanding of NAFLD and progression to NASH and cirrhosis involves a two-hit model,

which is nicely explained in a review by Bohinc and Diehl.25 In this model, insulin resistance leads to

hepatic steatosis (the first hit), which sensitizes the hepatic parenchyma to environmental and

extracellular insults (the second hit) leading to inflammation, necrosis, and fibrosis.25 Dietary fructose

has been identified as an important culprit in the development of hepatic steatosis by decreasing

intracellular ATP and transforming to lipid in the absence of insulin.65 Ongoing hepatic insults lead to

activation of the inflammasome, a protein scaffold that results in the secretion of the inflammatory

cytokines IL-1β and IL-18, further amplifying hepatic inflammation and injury. Inflammasome

activation is increased by gut-derived bacterial endotoxin. This inflammation promotes increased Hh

signaling and stellate cell activation with resultant fibrosis.66

Therapy for NASH centers on lifestyle modification, with a modest weight loss of 5% to 10%

associated with significant histologic improvements in disease severity.61 Now that the role of gut

microflora is understood to play a major role in the pathogenesis of NASH and other liver diseases, the

use of probiotics, most commonly lactobacilli and bifidobacteria, is being explored in the treatment of

NASH. A recent meta-analysis of four randomized controlled trials demonstrated probiotics significantly

decreased transaminases, total cholesterol, TNF-α, and insulin resistance.67

4 Hepatitis. Viral hepatitis is the most common cause of cirrhosis worldwide, accounting for at least

50% of cases. Hepatitis A, B, C, D, and E have all been proved to cause acute hepatitis, characterized

histologically by lymphocytic parenchymal and portal inflammations, focal necrosis, ballooning

degeneration, cholestasis, Kupffer cell and macrophage hypertrophy and hyperplasia, and lobular

disarray. Only hepatitis B, C, and D have been shown to progress to chronic hepatitis, defined by

persistent liver cell necrosis and inflammation lasting longer than 6 months. Chronic infection with

hepatitis B virus (HBV) develops in fewer than 5% of patients who experience acute HBV infection. The

development of cirrhosis in approximately 10% to 20% of chronically infected persons produces an

overall rate of cirrhosis of approximately 1%. Hepatitis B remains a major public health problem in

Asian countries and Africa, with up to 10% of the population showing evidence of chronic infection. The

widespread use of antiviral medications effective against hepatitis B effectively suppresses viral

replication to undetectable levels in up to 90% of patients, and may reverse fibrosis and even cirrhosis.

Even with effective suppression of viral replication, however, HBV is not truly “cured” since the virus is

incorporated into the host genome. This has important consequences as HCC can still develop in the

noncirrhotic liver of HBV-infected patients.68 In addition, public health strategies with systematic

vaccination of newborns should substantially decrease the incidence of new infections.

In contrast, hepatitis C poses a much higher risk of chronic infection, and therapeutic strategies

eradicate viral replication in a minority of patients. Of patients with hepatitis C virus (HCV), 90%

become chronically infected, and chronic hepatitis develops in 60% of these patients. Among patients

with chronic hepatitis, 30% progress to cirrhosis,46 so that the incidence of cirrhosis in patients initially

infected with hepatitis C is approximately 10%. Standard treatment for HCV was previously based on

the combination of pegylated interferon and ribavirin, with sustained viral response (SVR) rates of up to

80% in patients with genotypes 2 and 3,69 but results for the more common genotype 1 were only 40%

to 50%, with the best reporting an SVR rate of 65%.70 Compounding the limited efficacy of interferonbased therapy is the high rate of adverse events that prevents many patients from completing therapy.

The recent release of a new wave of oral antiviral therapies, termed direct-acting antivirals (DAAs),

and allowing interferon-free regimens, however, has demonstrated more promising results (Table 59-2).

The fixed dose combination of 90-mg ledipasvir and 400-mg sofosbuvir is sold under the trade name

Harvoni (Gilead Sciences) and is recommended as first-line therapy by the American Society for the

Study of Liver Disease (AASLD) for the treatment of HCV genotypes 1a, 1b, and 4.71 Ledipasvir is an

inhibitor of the HCV protein NS5A, which limits viral replication. Sofosbuvir is a nucleotide inhibitor of

the NS5B polymerase that terminates viral replication. In the ION-1 trial that leads to approval of the

combination of these two agents for the treatment of HCV genotype 1, SVR rates of 97% to 99% were

demonstrated after 12 weeks of therapy. No patients who received the 12-week regimen had adverse

effects leading to early treatment discontinuation.72 For treatment of genotype 4, the SYNERGY trial

demonstrated an SVR rate of 95% by intention to treat analysis following 12 weeks of

ledipasvir/sofosbuvir therapy.71 Ledipasvir/sofosbuvir is also recommended as first-line therapy for

genotype 6. Sofosbuvir also has significant activity against genotypes 2 and 3 when combined with

ribavirin, and genotypes 5 and 6 when combined with ribavirin and pegylated interferon.71 Simeprevir

1499

is a novel NS3/4A protease inhibitor recommended as first-line therapy for HCV for genotypes 1a and

1b when used in combination with sofosbuvir. In the COSMOS trial, combination simeprevir/sofosbuvir

for genotype 1 HCV demonstrated 95% SVR after 12 weeks of therapy in noncirrhotics, and 100% SVR

after 24 weeks of therapy in cirrhotics.73

ETIOLOGY

Table 59-2 Causes of Cholestasis

Another novel all-oral HCV regimen is the combination of ombitasvir, paritaprevir, ritonavir, and

dasabuvir, marketed as the Viekira Pak (AbbVie). Ombitasvir inhibits NS5A, paritaprevir inhibits the

NS3/4A protease, ritonavir is a CYP3A4 inhibitor without any HCV activity used to increase sensitivity

to paritaprevir, and dasabuvir is a nonnucleotide NS5B polymerase inhibitor. The combination is

recommended as first-line therapy for genotype 1a when used with weight-based ribavirin, genotype 1b

(with ribavirin for cirrhotics), and genotype 4 (with ribavirin).71 Against HCV genotype 1, SVR rates of

95.3% to 97% have been demonstrated.74,75

These results represent a revolution in the therapy of HCV that makes cure of HCV a possibility. In

patients who respond to therapy, progression to cirrhosis is eliminated and it is generally thought that

HCC does not develop. In patients who do not respond to therapy, cirrhosis develops in approximately

40%, and HCC develops in 16% of these patients.73

Hepatitis D virus (HDV) is an RNA virus that requires the presence of HBV to be pathogenic.

Superinfection of HBV-positive patients with HDV leads to a more rapid clinical course, with

progression to cirrhosis in 70% to 80% of patients.74 Among patients with compensated cirrhosis of viral

origin, HCC developed in approximately 20% with HCV, 9% with HBV, and 41% with both HBV and

HCV.46 The progressive increase in hepatitis-infected individuals in the United States precedes an

epidemic in HCC, which has been well documented and is expected to peak over the coming decade.75

Cholestasis. Cholestasis, defined as a decrease or absence of bile flow into the duodenum, may be

caused by intrahepatic or extrahepatic biliary obstruction or defects in the ability of hepatocytes to

excrete bile. Causes of cholestasis are presented in Table 59-2. Prolonged biliary obstruction leads to

proliferation of bile ducts, formation of bile lakes caused by disruption of bile ducts, fibrosis, and

ultimately secondary biliary cirrhosis as a result of the direct toxic effects of bile salts on hepatobiliary

elements.

Immune or Inflammatory Cirrhosis. Although cholestasis is a generically toxic insult to the liver that

can cause cirrhosis, several diseases that are characterized by cholestasis seem to be caused by

underlying immune or inflammatory disorders affecting either small (primary biliary cirrhosis [PBC]) or

large (primary sclerosing cholangitis [PSC]) bile ducts. PBC is a chronic, slowly progressive disease that

1500

most commonly affects middle-aged women; it is characterized by portal inflammation, destruction of

intrahepatic bile ducts, and progression to cirrhosis. Approximately 95% of patients are women, and

95% of these women express antimitochondrial antibodies in serum.76 The autoimmune inflammatory

process damages both the bile ducts and, eventually, the hepatocytes as a result of leakage of bile acids

into surrounding parenchyma.77 Patients present with fatigue, jaundice, and pruritus, but as many as

60% of patients may be asymptomatic.78 PBC progresses in the majority of patients; median survival

times are approximately 10 to 15 years in asymptomatic patients and 7 years in symptomatic

patients.79,80 Poor prognostic factors include hyperbilirubinemia, advanced age, hepatosplenomegaly,

and symptomatic disease.

Medical management of PBC is with the exogenous bile acid ursodeoxycholic acid (13 to 15

mg/kg/d). Complete response, as evidenced by normalization of liver enzymes without histologic

progression, is seen in up to 30% of patients and can even lead to a normal life expectancy. Therapy for

nonresponders includes immunosuppression with methotrexate, colchicine, or steroids, although the

efficacy of these medications is in question.81 Liver transplantation is ultimately required as the

definitive treatment in most patients, and the parameters for liver transplantation and its timing are

relatively predictable and have been well studied.82

PSC is a chronic, progressive cholestatic liver disease of unknown cause characterized by diffuse

segmental intrahepatic or extrahepatic biliary ductular strictures with associated fibrosis and

inflammation. The disease has no cure and often leads to secondary biliary cirrhosis, portal

hypertension, hepatic failure, and cholangiocarcinoma if hepatic transplantation is not performed. PSC

is strongly associated with inflammatory bowel diseases, most commonly ulcerative colitis, and

probably shares an underlying disturbance related to disturbed mucosal immunity of the gastrointestinal

tract.83 Approximately 70% of patients with PSC also have ulcerative colitis.83 Conversely,

approximately 5% of patients with ulcerative colitis have PSC, though subtler forms of the disease may

be present but clinically asymptomatic. PSC is thought to be autoimmune in nature; elevated levels of

autoantibodies and an increased expression of human leukocyte antigen (HLA) class II molecules on

biliary epithelial cells have been observed.84,85 Approximately two-thirds of patients are male and

younger than 45 years of age at the time of diagnosis.86 Patients with PSC may be completely

asymptomatic (up to 44%) or have signs of advanced disease at the time of diagnosis.83 Commonly, the

diagnosis is made in symptomatic patients after endoscopic retrograde cholangiopancreatography

(ERCP) has been performed to evaluate elevated liver enzymes, including alkaline phosphatase and γglutamyltransferase. Symptomatic patients have a waxing and waning course and may present with

complaints of fatigue (75%), pruritus (25% to 70%), jaundice (30% to 69%), abdominal pain (16% to

37%), and weight loss (10% to 34%).83 Complications secondary to progression to cirrhosis are less

common and include ascites, variceal bleeding, and acute cholangitis.

The diagnosis of PSC is suggested by a history of inflammatory bowel disease in the setting of

elevated liver enzymes and is established by cholangiography. The disease process may range from a

single dominant stricture to, more commonly, diffuse multifocal sclerosis of the intrahepatic and

extrahepatic bile ducts. Pathologically, bile ductular proliferation, periductal fibrosis and inflammation,

ductopenia, and, less commonly, obliterative fibrous cholangitis may be present. PSC may be considered

a premalignant condition. Like ulcerative colitis, PSC confers a significant risk of malignant

transformation of the biliary mucosa, which is one of the considerations in considering patients for

transplantation.87 Cholangiocarcinoma develops in 1% to 2% of patients per year after the diagnosis of

PSC, with an overall risk of up to 10%.88 Screening for premalignant changes with ERCP and cytologic

examination and serum testing of CA19-9 have been helpful, though both have limited specificity and

sensitivity. Recently, it has been proposed that newer analysis methods of biliary material obtained at

screening ERCP, including fluorescence in situ hybridization (FISH), may be used for chromosomal

abnormalities associated with cancer with an increase in the sensitivity.89

There is no generally accepted medical therapy to treat PSC, so therapeutic efforts are directed

toward complications of the disease. The major complications include biliary obstruction, cirrhosis, and

cholangiocarcinoma. Dominant strictures, defined as stenosis less than 1.5 mm in the common bile duct

or less than 1 mm in the hepatic duct, are readily treated endoscopically by means of dilation and/or

stent placement.90,91 Transplantation should be performed before cancer develops and, generally, the

discovery of cancer has been considered an absolute contraindication to transplantation because of poor

outcomes. Highly selected patients with localized tumors may be transplanted with an acceptable

survival rate with intensive preoperative therapy including radiation and chemotherapy, as proposed by

Shaw and implemented on a larger scale by the Mayo group.92

1501

 

inexorable consequence of ongoing hepatic injury. HSCs are located in the perisinusoidal space of Disse

(Fig. 59-2).16 In the normal liver, these cells are quiescent and are primarily responsible for the storage

of vitamin A.17 Injured hepatocytes release soluble factors that activate HSCs to differentiate into

myofibroblastic HSCs, as evidenced by cellular enlargement and proliferation, an increase in rough

endoplasmic reticulum, loss of vitamin A droplets, expression of actin filaments, and increased

expression of “fibril-forming” collagen types I, III, and V.18 They also express components of the

extracellular matrix, including heparan sulfate, dermatan, chondroitin sulfate,19 laminin,20 and

fibronectin.21 Kupffer cells secrete TGF-β1, which appears to be critical for the activation of HSCs.5,22

Both TGF-β and PDGF have been shown to enhance proliferation and fibrogenesis in animal models,5,7,23

with TGF-β being the primary stimulator of collagen synthesis and fibrosis. Further evidence implicating

TGF-β in the production of hepatic fibrosis is the observation that levels of TGF-β are reduced by

therapy with interferon-α in patients who are positive for hepatitis C. This reduction has been

correlated with a regression of hepatic fibrosis.24

CLASSIFICATION

Table 59-1 Classification of Cirrhosis

In addition to the well-characterized effects of TGF-β1 and PDGF on activating HSCs, more recent

research has demonstrated the central role of Hedgehog (Hh) in activation of HSCs and promotion of

fibrosis.25 Hh is a molecule involved in signaling pathways that help determine cell fate during

embryogenesis. The Hh ligand binds to its cell surface receptor patched. Binding of Hh to patched

releases another effector, named smoothened, from a chronic state of inactivation. Activation of

smoothened leads to downstream activation of a number of proteins involved in nuclear transcription,

thereby leading to changes in cell fate and differentiation.25 In the liver, the two primary forms of Hh

are Sonic Hedgehog (SHh) and Indian Hedgehog (IHh), which are expressed by hepatocytes, bile duct

cells, and HSCs. In the healthy liver, quiescent HSCs and endothelial cells keep Hh inactive by

production of inhibitory proteins. When the liver is injured, however, numerous cell types including

hepatocytes, cholangiocytes, HSCs, progenitor cells, lymphocytes, duct cells, and endothelial cells

produce elevated levels of Hh under the influence of cytokines such as PDGF and TGF-β.25–30 Activation

of the Hh pathway tends to be self-sustaining and resistant to negative feedback as long as the injury

process continues.31 It is this surge in Hh levels within the local hepatic milieu that signals quiescent

HSCs to activate. The critical role of Hh signaling in HSC activation and fibrogenesis was recently

demonstrated by Michelotti et al.,32 who showed that deletion of the Hh intermediary smoothened was

sufficient to inhibit both HSC activation and fibrosis formation.

1495

Figure 59-2. Matrix and cellular alterations in hepatic fibrosis. A: In normal liver, a modest amount of low-density matrix is

present in the subendothelial space of Disse. B: In the fibrotic liver, the accumulation of fibril-forming matrix in this region leads

to “capillarization” of the sinusoid and functional changes in all neighboring cell types.

Another interesting concept that has been gaining increasing recognition is the role of the gut

microflora in the development of cirrhosis. Alcoholics, for example, are known to have a greater

susceptibility to small intestinal bacterial overgrowth along with alterations in their gut microflora. This

bacterial overgrowth and dysbiosis lead to increased levels of LPS, which reach the liver to stimulate

Kupffer cells to produce proinflammatory cytokines. The end result is the generation of mitochondrial

damage, reactive oxygen species, and ongoing hepatic inflammation.33–35 A similar role for alterations

in gut microflora has been demonstrated in nonalcoholic fatty liver disease (NAFLD).36,37

As a result of the activation of stellate cells and a subsequent enhancement in collagen and

extracellular matrix synthesis, the space of Disse becomes thickened, so that “capillarization” develops

and the normal fenestrated architecture of the sinusoidal endothelium is lost.38 Obliteration of

sinusoidal fenestrations may be the essential component of fibrosis-induced hepatocellular dysfunction

in cirrhosis, preventing the normal flow of nutrients to hepatocytes and increasing vascular resistance.39

In addition, production of endothelin-1, a potent vasoconstrictor, by endothelial or stellate cells can

cause contraction of the myofilaments within the stellate cell, influencing blood flow to injured areas

and contributing to portal hypertension.40 Initially, fibrosis may be reversible if the inciting agents are

removed. With sustained injury, the process of fibrosis becomes irreversible and leads to cirrhosis.

Growing attention has been given to approaches that might disconnect hepatic injury from the

inexorable path of fibrosis.41

Among the most promising agents currently receiving the greatest attention in the treatment of

fibrosis are the antioxidants.4 The combination of N-acetylcysteine and metformin taken for 12 months

has demonstrated reduction of fibrosis severity in patients with nonalcoholic steatohepatitis (NASH).42

The glutathione donor S-adenosylmethionine (SAMe) has demonstrated improved mortality in alcoholic

cirrhosis, and vitamin E has been shown to improve hepatic fibrosis in the setting of NAFLD.4 While the

results of studies utilizing these agents have had mixed results, ongoing investigations should establish

their role in the treatment of fibrosis. Other studies have focused on utilization of inducible pluripotent

stem cells and embryonic stem cells to replenish functional hepatocytes and restore liver function.

Mesenchymal stem cells have been studied for their ability to reduce the profibrotic and

proinflammatory milieus in the setting of hepatic damage. While these studies are in early stages, their

potential is exciting.43,44

Classification Systems

Morphology

In 1977, the World Health Organization divided cirrhosis into three categories based on the

morphologic characteristics of hepatic nodules (Fig. 59-3).45

1496

Micronodular Pattern. Nodules are almost always less than 3 mm in diameter, are relatively uniform

in size, are regularly distributed throughout the liver, and rarely contain portal tracts or efferent veins.

Micronodular livers are usually of normal size or are mildly enlarged, and the fibrous septa vary in

thickness. These changes reflect relatively early disease and are characteristic of a wide range of disease

processes, including alcoholism, biliary obstruction, venous outflow obstruction, hemochromatosis, and

Indian childhood cirrhosis.

Macronodular Pattern. In this category, nodules vary considerably in size and are larger than 3 mm in

diameter, with some nodules measuring several centimeters. Portal structures and efferent veins are

present but display architectural distortion. These livers are usually coarsely scarred with variably thick

and thin septa and may be either normal or reduced in size. Two separate subcategories are recognized

based on the nature of the fibrous septa. In the first category, characteristic of “posthepatitis” pathology

and found in Wilson disease, fine, sometimes incomplete septa link portal tracts; these are difficult to

see on gross inspection of the liver. The second is characteristic of “postnecrotic” disease, commonly

found in patients with viral hepatitis, and is characterized by coarse, thick septa that are readily

apparent on gross examination. Because of the relatively large size of the nodules relative to the size of

biopsy specimens, diagnosis by biopsy may be difficult in macronodular cirrhosis.

Figure 59-3. A: Small, shrunken liver and a fairly regular pattern of nodularity. This appearance is rather typical of end-stage

cirrhosis, regardless of the cause. B: Photomicrograph of cirrhotic liver tissue, showing irregular nodules of regenerating

hepatocytes surrounded by scar. Trichrome stain. (From Stal P, Broome U, Scheynius A, et al. Kupffer cell iron overload induces

intercellular adhesion molecule-1 expression on hepatocytes in genetic hemochromatosis. Hepatology 1995;21:1308–1316.)

Mixed Pattern. This description is applied to livers in which both micronodules and macronodules are

present in approximately equal proportions.

Etiology

Another commonly used method for classifying cirrhosis is by etiology. The causes of cirrhosis and the

morphologic and histologic characteristics of the liver, however, overlap significantly. Oxidative stress

leading to chronic injury and inflammation appears to be a common theme of these disorders, which

leads to both scar formation and an increased risk of liver cancer.

Alcohol. The relationship between alcohol and liver disease has been well established. In 1849,

Rokitansky, referring to the association of alcohol intake and liver disease, coined the term Laennec

cirrhosis.46 Consumption of at least 30 g of alcohol per day in women and 50 g of alcohol per day in men

over at least 5 years is considered to the minimum threshold alcohol intake for cirrhosis to develop.47

More than 50% of alcoholics with cirrhosis and two-thirds of patients with alcoholic hepatitis and

cirrhosis die within 4 years of diagnosis.48 Alcoholic cirrhosis is the second leading indication for liver

transplantation overall, accounting for 40% of liver transplants in Europe and 25% in the United

States.49–51 Cirrhosis, however, develops in only 10% to 30% of heavy drinkers.52 The reasons why

cirrhosis develops in some alcoholics but not in others are not clear and may depend on a variety of

factors, such as genetic predisposition, nutritional effects, concomitant drug use, and viral infection.

Alcoholic liver disease usually begins with a transition of normal architecture to fatty liver and

1497

alcoholic hepatitis, indicated histologically by the presence of megamitochondria, Mallory bodies

(eosinophilic accumulations of intermediate filaments with cytokeratin proteins), inflammation and

necrosis, and ultimately fibrosis (Fig. 59-4). Classically, the morphology of alcoholic cirrhosis is a

micronodular pattern.

2 Although alcohol may directly activate stellate cells to produce collagen independently of

inflammation and necrosis,53 the key mediator in alcohol-induced liver disease is acetaldehyde, the

product of alcohol metabolism by the enzyme alcohol dehydrogenase. Acetaldehyde (ADH) produces

numerous deleterious effects on the liver, including the following: direct activation of stellate cells

54;

inhibition of DNA repair55; depletion of glutathione, which impairs mitochondrial function and the

ability to handle free radical production; damage to microtubules, which causes protein and water

sequestration52; and formation of reduced nicotinamide adenine dinucleotide (NADH), which opposes

gluconeogenesis and inhibits fatty acid oxidation, so that steatosis and hyperlipidemia develop.52 ADH is

most active in the perivenular/centrilobular zone 3 of the hepatic lobule; as a result, relatively high

concentrations of acetaldehyde are found in this area of the liver. In addition, zone 3 is hypoxic because

of its distance from portal venous and hepatic arterial inflow. These two factors are presumably

responsible for the characteristic initial perivenular location of alcohol-induced liver disease.

Figure 59-4. Alcoholic hepatitis. Mallory bodies (arrows) are evident within the swollen, clear cytoplasm of several hepatocytes.

This hyaline material is chemotactic for leukocytes, many of which are seen within the field. Hematoxylin and eosin (H&E) stain

× 470.

Other effects of ADH include induction of lipid peroxidation with subsequent loss of integrity of cell

membranes, which causes the characteristic “ballooning degeneration” of alcohol-induced liver disease.

In addition to its direct hepatic effects, ADH is now known to play a major role in the derangement of

the gut–liver axis which plays a key role in alcohol-induced liver injury.56 In the “leaky gut hypothesis,”

ADH increases the permeability of the intestinal barrier,57 allowing bacterial endotoxin (LPS) access to

the liver via the portal circulation. Excess circulating endotoxin then activates Kupffer cells through

interaction with Toll-like Receptor 4 (TLR4) to set off the inflammatory cascade responsible for the

development of alcoholic liver disease.35 Necrosis and inflammation in the perivenular region activate

the stellate cells in the space of Disse, so that fibrosis develops. With continued ingestion of alcohol and

hepatic injury, expansion of the areas of fibrosis toward the periportal regions leads to bridging fibrosis

and ultimately cirrhosis.

3 Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis. As noted earlier, this entity has

become a major health problem in the United States and adds even further to the litany of health

consequences of obesity. NASH, as this disease was previously called, is only one stage in the NAFLD

process.58 NAFLD is now the most common cause of chronic liver disease in the United States, affecting

up to 30% to 46% of the population.59,60 NASH-related cirrhosis is expected to surpass viral hepatitis as

the leading indication for liver transplantation by 2025.25 It is characterized by infiltration of the liver

with fat, with or without inflammation (hepatitis), which shares pathologic features of alcohol-induced

liver injury but occurs in patients who do not abuse alcohol. NAFLD is associated with obesity,

hyperlipidemia, cardiovascular disease, and noninsulin-dependent diabetes, with 90% of NAFLD patients

having at least one of these risk factors and 30% having three or more.61 It now appears that most

patients traditionally diagnosed with cryptogenic cirrhosis have NAFLD.62 In addition to liver injury and

cirrhosis, NAFLD is a major risk factor for primary liver cancer HCC and, in addition to hepatitis virus

infection, accounts for the rapid rise in the incidence of HCC in Western countries.63 More broadly

1498

 

43. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the

United States, 1999 through 2002. Ann Intern Med 2006;144(10):705–714.

44. El-Serag HB, Hampel H, Yeh C, et al. Extrahepatic manifestations of hepatitis C among United

States male veterans. Hepatology 2002;36:1439–1445.

45. Bichko V, Netter HJ, Wu TT, et al. Pathogenesis associated with replication of hepatitis delta virus.

Infect Agents Dis 1994;3:94–97.

46. Le Gal F, Gault E, Ripault MP, et al. Eighth major clade for hepatitis delta virus. Emerg Infect Dis

2006;12:1447–1450.

47. Niro GA, Rosina F, Rizzetto M. Treatment of hepatitis D. J Viral Hepat 2005;12:2–9.

48. Kaymakoglu S, Karaca C, Demir K, et al. Alpha interferon and ribavirin combination therapy of

chronic hepatitis D. Antimicrob Agents Chemother 2005;49:1135–1138.

49. Lu L, Li C, Hagedorn CH. Phylogenetic analysis of global hepatitis E virus sequences: genetic

diversity, subtypes and zoonosis. Rev Med Virol 2006;16:5–36.

50. Centers for Disease Control (CDC). Enterically transmitted non-A, non-B hepatitis–East Africa.

MMWR Morb Mortal Wkly Rep 1987;36:241–244.

51. Khuroo MS, Teli MR, Skidmore S, et al. Incidence and severity of viral hepatitis in pregnancy. Am J

Med 1981;70:252–255.

52. Asher LV, Innis BL, Shrestha MP, et al. Virus-like particles in the liver of a patient with fulminant

hepatitis and antibody to hepatitis E virus. J Med Virol 1990;31:229–233.

53. Brochot E, Choukroun G, Duverlie G. Ribavirin for chronic hepatitis E virus infection. N Engl J Med

2014;370(25):2446–2447.

54. Yousfi MM, Douglas DD, Rakela J. Other hepatitis viruses. In: Zakim D, Boyer TD, eds. Hepatology.

A Textbook of Liver Disease. 4th ed. Philadelphia, PA: WB Saunders; 2003:1063–1072.

55. Schiff GM. Hepatitis caused by other viruses. In: Shiff ER, Sorrell MF, Maddrey WC, eds. Schiff’s

Diseases of the Liver. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:869–877.

56. Hewlett G, Hallenberger S, Rubsamen-Waigmann H. Antivirals against DNA viruses (hepatitis B and

the herpes viruses). Curr Opin Pharmacol 2004;4:453–464.

57. Hinedi TB, Koff RS. Cholestatic hepatitis induced by Epstein-Barr virus infection in an adult. Dig Dis

Sci 2003;48:539–541.

58. Feranchak AP, Tyson RW, Narkewicz MR, et al. Fulminant Epstein-Barr viral hepatitis: orthotopic

liver transplantation and review of the literature. Liver Transpl Surg 1998;4:469–476.

59. Hoofnagle JH, Carithers RL Jr, Shapiro C, et al. Fulminant hepatic failure: summary of a workshop.

Hepatology 1995;21:240–252.

60. Mas A, Rodes J. Fulminant hepatic failure. Lancet 1997;349:1081–1085.

61. Akdogan M, Camci C, Gurakar A, et al. The effect of total plasma exchange on fulminant hepatic

failure. J Clin Apheresis 2006;21:96–99.

62. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology

2005;41(5):1179–1197.

63. Ichai P, Samuel D. Etiology and prognosis of fulminant hepatitis in adults. Liver Transpl

2008;14:S67–S79.

64. Larson AM. Acute liver failure. Dis Mon 2008;54:458–485.

65. Sanyal AJ, Stravitz RT. Acute liver failure. In: Boyer TD, Wright TL, Manns MP, eds. Zakim and

Boyer’s Hepatology: A Textbook of Liver Disease. 5th ed. Philadelphia, PA: Saunders Elsevier;

2006:383–415.

66. Lee WM, Squires RH Jr, Nyberg SL, et al. Acute liver failure: summary of a workshop. Hepatology

2008;47:1401–1415.

67. Williams R, Wendon J. Indications for orthotopic liver transplantation in fulminant liver failure.

Hepatology 1994;20:S5–S10.

68. Schilsky ML, Tavill AS. Wilson disease. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff’s Diseases

of the Liver. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:1169–1186.

69. Kramer DJ, Canabal JM, Arasi LC. Application of intensive care medicine principles in the

management of the acute liver failure patient. Liver Transpl 2008;14:S85–S89.

70. Raschke RA, Curry S, Rempe S, et al. Results of a protocol for the management of patients with

1491

fulminant liver failure. Crit Care Med 2008; 36(8):2244–2213.

71. O’Grady JG. Postoperative issues and outcome for acute liver failure. Liver Transpl 2008;14:S97–

S101.

72. Heeman U, Treichel U, Loock J, et al. Stange albumin dialysis in cirrhosis with superimposed acute

liver injury. J Hepatology 2002;36(4 Pt 1):949–958.

73. Rifai K, Ernst T, Kretschmer U, et al. Prometheus (R)-a new extracorporeal system for the

treatment of liver failure. J Hepatol 2003;39(6):984–990.

74. Mindikoglu AL, Magder LS, Regev A. Outcome of liver transplantation for drug induced acute liver

failure in the United States: analysis of the United Network for Organ Sharing database. Liver

Transpl 2009;15(7):719–729.

1492

Chapter 59

Cirrhosis and Portal Hypertension

Michael R. Marvin, Robert M. Cannon, and Jean C. Emond

Key Points

1 Although the causes of cirrhosis and the morphologic and histologic changes seen in the liver overlap

significantly, oxidative stress leading to chronic injury and inflammation appears to be a common

theme.

2 The key mediator in alcohol-induced liver disease is acetaldehyde, which produces numerous

deleterious effects on the liver.

3 Nonalcoholic fatty liver disease or nonalcoholic steatohepatitis (NASH) is characterized by

infiltration of the liver with fat and is associated with obesity, hyperlipidemia, and noninsulindependent diabetes.

4 Viral hepatitis is the most common cause of cirrhosis worldwide, accounting for at least 50% of

cases.

5 Budd–Chiari syndrome is a rare disease caused by mechanical obstruction of the hepatic veins owing

to obstructing webs or membranes (most commonly in Asia and Africa) or thrombosis secondary to

hypercoagulable states and neoplasms (most commonly in the West).

6 Hepatorenal syndrome is a complication of cirrhosis, usually associated with ascites, characterized

by progressive renal failure in the absence of intrinsic renal disease.

7 Hepatic encephalopathy is a neuropsychiatric syndrome that occurs in the setting of hepatic disease

and is characterized by variable alterations in mental status ranging from deficits detectable only by

detailed psychometric tests to confusion, lethargy, and ultimately coma.

8 Portal hypertension is defined as a portal pressure above the normal range of 5 to 8 mm Hg and can

be secondary to cirrhosis (hepatic), portal vein thrombosis (presinusoidal), or hepatic venous

obstruction (postsinusoidal).

9 The Child–Turcotte–Pugh score is a scoring scale that incorporates clinical and laboratory data as a

mean to assess the functional status of the liver, estimate hepatic reserve, and predict morbidity and

mortality of liver disease. The model for end-stage liver disease (MELD) score is a highly reliable

prognostic marker for cirrhosis, is calculated from standard laboratory tests, and has replaced the

Child–Turcotte–Pugh score in liver transplant candidate stratification.

10 The use of the transjugular intrahepatic portosystemic shunt (TIPS) has become first-line therapy for

refractory or recurrent bleeding esophageal varices, with 6-month and 1-year patency rates and

prevention of rebleeding in 92% and 82% of patients, respectively.

11 Although the surgical interventions for treatment of bleeding varices are divided into three main

types – liver transplantation, shunt procedures, and devascularization procedures – the only

definitive procedure in patients with cirrhosis is orthotopic liver transplant.

12 Spontaneous bacterial peritonitis is a potentially lethal complication of unknown etiology associated

with portal hypertension with ascites that occurs in up to 10% of patients.

CIRRHOSIS

Background and Definition

Cirrhosis is the end result of multiple, varied, repeated, or chronic pathologic insults to the liver with

subsequent repair that cause a derangement in the hepatic architecture; the primary histologic features

are marked fibrosis, destruction of vascular and biliary elements, regeneration, and nodule formation

(Fig. 59-1). In addition to progressive decrease of hepatic function, portal hypertension is the most

prominent clinical manifestation associated with cirrhosis, but it is possible to have portal hypertension

1493

in the absence of cirrhosis. The continuum of cirrhosis to liver cancer and its devastating clinical

consequences requires us to consider hepatocellular carcinoma (HCC) as a central complication of

cirrhosis. Although the only definitive cure for cirrhosis remains liver transplantation, advances in the

medical management of both the inciting factors of cirrhosis as well as its complications have led to

remarkable improvements to both the quantity and quality of life in patients suffering from cirrhosis.

Pathophysiology

1 Cirrhosis is caused by a wide range of pathologic entities, including the viral hepatitides, alcohol,

metabolic disorders, drug toxicity, and biliary obstruction, among others (Table 59-1). Triggered by the

underlying cause, the liver is exposed to a broad range of pathologic injuries leading to hepatocyte

death and the gradual loss of architectural integrity made permanent by the development of fibrosis.

The capacity of the liver to regenerate is a distinct feature of the liver metaphorically represented in the

Promethean myth, and the liver is able to absorb injury without structural alteration. However, the

capacity of the liver to regenerate is finite, and understanding the deviation from successful

regeneration with restoration of hepatocyte mass and normal architecture to the path leading to

fibrogenesis and cirrhosis remains a central question in liver biology.1,2 Significant progress in our

understanding of the evolution of liver fibrosis, which ends with cirrhosis, has been gained in recent

years.

The pathway from the injuring agent to fibrosis is of growing interest, and the central role of

oxidative stress and chronic inflammation in many forms of liver injury has received growing attention.

Oxidative stress and chronic inflammation appear to be the final common pathway in the development

of cirrhosis. With ongoing inflammation, hepatocyte stress and death via apoptosis and necrosis lead to

activation of hepatic stellate cells (HSCs), which appear to be the key mediator in the development of

fibrosis.3 Apoptotic bodies in particular appear to play a major role in the activation of HSCs as well as

Kupffer cells, the resident macrophages of the liver.4 Activation of these cells in turn leads to

elaboration of proinflammatory and profibrogenic cytokines such as transforming growth factor beta 1

(TGF-β1) and platelet-derived growth factor (PDGF), creating a self-sustaining cycle.5–10

Figure 59-1. Evolution of cirrhosis. Fibrosis develops in nonregenerative necrotic areas, producing scars. The pattern of nodularity

and scars reflects the type of response to injury (e.g., uniform vs. nonuniform necrosis) and the extent of injury.

Alcoholic liver disease has long been known to be associated with consequences of oxidative stress in

the liver with failure of homeostatic mechanisms.11 Obesity and metabolic syndrome, a major health

problem in the United States, may produce hepatic injury and may potentiate the effects of viral

injury.12,13 In addition to direct oxidative stress, hepatocyte injury is mediated by a variety of

mechanisms including proinflammatory cytokines

1 and failure of reparative or modulatory pathways.14

The failure of protective or reparatory mechanisms is also widely studied.15 Over time, fibrosis is the

1494

 

chronic liver disease is present. Altered mental status accompanied by jaundice and elevated serum

transaminases and prothrombin time is the hallmark of presentation. Rapid loss of liver mass can lead to

multisystem organ failure and death.64 Encephalopathy may be accompanied by myopathy and

neuropathy, loss of vascular tone with hypotension, cardiac dysfunction, acute lung injury,

gastrointestinal bleeding, pancreatitis, acute renal failure, and/or disseminated intravascular

coagulopathy. Intracranial hypertension is recognized in 50% or greater of patients with stage IV coma.

Therefore, neurocritical care with ability to respond to hemodynamic fluctuations becomes an important

component of management. Other precepts are maintenance of normoxia, euglycemia, control of

seizure, therapeutic hypothermia, osmotic therapy, and judicious hyperventilation.69

Initial management includes identification and treatment of infection, titration of intravascular

volume expansion, and selection of fluids to minimize cerebral edema. Hypertonic saline may be

considered to maintain serum sodium in the mildly hypernatremic range. Norepinephrine is the

vasopressor of choice and early initiation of renal replacement therapy is important for tight control of

intravascular volume. Mild reduction in blood CO2

tension can also restore cerebral vasoreactivity and

autoregulation.69

Advanced cerebral edema is associated with hyperventilation, hypertension, papillary abnormalities,

decerebrate posturing, and ultimately uncal herniation and death. Arterial ammonia levels greater than

200 μg/dL may be correlated with herniation.64 Although powered controlled trials are still needed to

determine the role of intracranial pressure monitoring,70 management should aim to keep the cerebral

perfusion pressure (mean arterial pressure–intracranial pressure) over 50 mm Hg and the intracranial

pressure below 25 mm Hg. Sustained pressures greater than these values for longer than 2 hours usually

signifies irreversible brain damage.64 Mannitol intravenous bolus doses of 0.5 to 1 g/kg are effective in

decreasing cerebral edema by maintaining osmotic diuresis and can be repeated provided serum

osmolarity does not exceed 320 mOsm/L.62 Profound coagulopathy (INR >7) and/or planned invasive

procedures warrant correction of coagulopathy with fresh frozen plasma (FFP) in combination with

recombinant activate factor VII (rFVIIa).62

Liver Transplantation

Establishing the cause of ALF is an important determination of outcomes following liver transplantation,

with the best results achieved with Wilson disease and the worst seen with idiosyncratic drug reactions.

Overall survival rates following liver transplantation at 1 year are 20% below those seen for elective

transplants performed for chronic disease but are similar to those achieved in patients with chronic

disease who go to transplant from the ICU.71

5 Patients who are at high risk of progression to death should be identified and listed for

transplantation in a timely fashion. Likewise, it is also crucial to identify patients who have become too

sick to benefit from liver transplant. Relative contraindications to liver transplant include: sustained

cerebral hypoperfusion (CPP <40 mm Hg) for longer than 2 hours, high doses of vasopressor, acute

respiratory distress syndrome (ARDS) requiring high inspired FiO2 and elevated PEEP.69

Life Support Systems

Various biologic and charcoal-based sorbent systems have been tested to date with no demonstrable

clinical impact. Total plasma exchange has been studied retrospectively when used to stabilize patients

until a transplant can be obtained or self-regeneration occurs.63 Sorbent systems have shown transient

detoxification with no long-term benefits at the expense of worsening coagulopathy. Porcine cell-based

and hepatoblastoma-derived extracorporeal systems, the molecular adsorbents recirculating system

(MARS),72 and the Prometheus system73 are available only for clinical trials and their future in the

management of ALF remains uncertain.62

STAGING

Table 58-2 King’s College Criteria of Poor Prognostic Indicators

1488

Prognosis

Accurate prognosis in ALF is important to avoid unnecessary liver transplantation, and the traditionally

accepted King’s College Criteria are most commonly used for this purpose (Table 58-3). Of note is that

the Model for End-Stage Liver Disease (MELD) system cannot be applied in ALF.62

ALF due to acetaminophen overdose, hepatitis A, shock liver, or pregnancy-related disease show a

50% or more transplant-free survival, while most other etiologies show only a 25% transplant free

survival.62 Other proposed but not widely accepted poor prognostic criteria include alpha fetoprotein

levels, ratio of factor VIII and V levels, liver histology, and serum phosphate levels.

Recipients who underwent liver transplant for drug induced ALF in the United States from 1987 to

2006 were retrospectively studied and the most common drug groups were identified as acetaminophen,

antituberculosis medicines, antiepileptics, and other antibiotics. Patients aged 7 years or younger with

antiepileptic toxicity had the highest risk of death following liver transplantation compared to all other

groups. Mechanical ventilation and elevated serum creatinine were identified as other predictors of poor

survival after transplant.74

References

1. Kaplan GG, Gregson DB, Laupland KB. Population-based study of the epidemiology of and the risk

factors for pyogenic liver abscess. Clin Gastroenterol Hepatol 2004;2:1032–1038.

2. Webb TH, Lillemoe KD, Pitt HA. Liver abscess. Hosp Phys 1989;25:46–59.

3. Rahimian J, Wilson T, Oram V, et al. Pyogenic liver abscess: recent trends in etiology and

mortality. Clin Infect Dis 2004;39:1654–1659.

4. Hanbidge AE, Buckler PM, O’Malley ME, et al. From the RSNA refresher courses: imaging

evaluation for acute pain in the right upper quadrant. Radiographics 2004;24:1117–1135.

5. Zibari GB, Maguire S, Aultman DF, et al. Pyogenic liver abscess. Surg Infect (Larchmt) 2000;1:15–21.

6. Lipsett PA, Huang CJ, Lillemoe KD, et al. Fungal hepatic abscesses: characterization and

management. J Gastrointest Surg 1997;1:78–84.

7. Sharara AI, Rockey DC. Pyogenic liver abscess. Curr Treat Options Gastroenterol 2002;5:437–442.

8. Tan YM, Chung AY, Chow PK, et al. An appraisal of surgical and percutaneous drainage for

pyogenic liver abscesses larger than 5 cm. Ann Surg 2005;241:485–490.

9. Yang CC, Yen CH, Ho MW, et al. Comparison of pyogenic liver abscess caused by non-Klebsiella

pneumoniae and Klebsiella pneumoniae. J Microbiol Immunol Infect 2004;37:176–184.

10. Wells CD, Arguedas M. Amebic liver abscess. South Med J 2004;97:673–682.

11. Yang DM, Kim HN, Kang JH, et al. Complications of pyogenic hepatic abscess: computed

tomography and clinical features. J Comput Assist Tomogr 2004;28:311–317.

12. Mortele KJ, Segatto E, Ros PR. The infected liver: radiologic-pathologic correlation. Radiographics

2004;24:937–955.

13. Lucey MR. Hepatic infection and acute hepatic failure. In: Greenfield LJ, Mulholland ML, Oldham

KT, et al., eds. Surgery: Scientific Principles and Practice. 3rd ed. Philadelphia, PA: Lippincott

Williams & Wilkins; 2001;943–958.

14. Lodhi S, Sarwari AR, Muzammil M, et al. Features distinguishing amoebic from pyogenic liver

abscess: a review of 577 adult cases. Trop Med Int Health 2004;9:718–723.

15. Ahsan T, Jehangir MU, Mahmood T, et al. Amoebic versus pyogenic liver abscess. J Pak Med Assoc

2002;52:497–501.

16. Sayek I, Tirnaksiz MB, Dogan R. Cystic hydatid disease: current trends in diagnosis and

1489

management. Surg Today 2004;34:987–996.

17. DiazGranados CA, Duffus WA, Albrecht H. Parasitic diseases of the liver. In: Zakim D, Boyer TD,

eds. Hepatology. A Textbook of Liver Disease. 4th ed. Philadelphia, PA: WB Saunders; 2003:1073–

1107.

18. Dunn MA. Parasitic diseases. In: Shiff ER, Sorrell MF, Maddrey WC, eds. Schiff’s Diseases of the Liver.

8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:1533–1548.

19. Kjossev KT, Losanoff JE. Classification of hydatid liver cysts. J Gastroenterol Hepatol 2005;20:352–

359.

20. Bastid C, Ayela P, Sahel J. Percutaneous treatment of a complex hydatid cyst of the liver under

sonographic control. Report of the first case. Gastroenterol Clin Biol 2005;29:191–192.

21. Chautems R, Buhler LH, Gold B, et al. Surgical management and long-term outcome of complicated

liver hydatid cysts caused by Echinococcus granulosus. Surgery 2005;137:312–316.

22. Gollackner B, Längle F, Auer H, et al. Radical surgical therapy of abdominal cystic hydatid disease:

factors of recurrence. World J Surg 2000;24:717–721.

23. Smego RA Jr, Sebanego P. Treatment options for hepatic cystic echinococcosis. Int J Infect Dis

2005;9:69–76.

24. Godyn JJ, Siderits R, Hazra A. Schistosoma mansoni in colon and liver. Arch Pathol Lab Med

2005;129:544–545.

25. Qiu DC, Hubbard AE, Zhong B, et al. A matched, case-control study of the association between

Schistosoma japonicum and liver and colon cancers, in rural China. Ann Trop Med Parasitol

2005;99:47–52.

26. El-Zayadi AR. Curse of schistosomiasis on Egyptian liver. World J Gastroenterol 2004;10:1079–1081.

27. Feinstone SM, Kapikian AZ, Purceli RH. Hepatitis A: detection by immune electron microscopy of a

virus like antigen associated with acute illness. Science 1973;182:1026.

28. Lemon SM, Jansen RW, Brown EA. Genetic, antigenic and biological differences between strains of

hepatitis A virus. Vaccine 1992;10(suppl 1):S40–S44.

29. Wasley A, Samandari T, Bell BP. Incidence of hepatitis A in the United States in the era of

vaccination. JAMA 2005;294:194–201.

30. Wheeler C, Vogt TM, Armstrong GL, et al. An outbreak of hepatitis A associated with green onions.

N Engl J Med 2005;353:890–897.

31. Sanyal AJ, Stravitz RT. Acute liver failure. In: Zakim D, Boyer TD, eds. Hepatology. A Textbook of

Liver Disease. 4th ed. Philadelphia, PA: WB Saunders; 2003:445–496.

32. Gane E, Sallie R, Saleh M, et al. Clinical recurrence of hepatitis A following liver transplantation for

acute liver failure. J Med Virol 1995;45:35–39.

33. Craig AS, Schaffner W. Prevention of hepatitis A with the hepatitis A vaccine. N Engl J Med

2004;350:476–481.

34. Poland GA, Jacobson RM. Clinical practice: prevention of hepatitis B with the hepatitis B vaccine. N

Engl J Med 2004;351:2832–2838.

35. Ganem D, Prince AM. Hepatitis B virus infection–natural history and clinical consequences. N Engl J

Med 2004;350:1118–1129.

36. Wands JR. Prevention of hepatocellular carcinoma. N Engl J Med 2004;351:1567–1570.

37. Schiodt FV, Atillasoy E, Shakil AO, et al. Etiology and outcome for 295 patients with acute liver

failure in the United States. Liver Transpl Surg 1999;5:29–34.

38. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733–1745.

39. Liaw YF, Sung JJ, Chow WC, et al; Cirrhosis Asian Lamivudine Multicentre Study Group.

Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med

2004;351:1521–1531.

40. Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B.

N Engl J Med 2007;357:2576–2588.

41. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001;345(1):41–52.

42. Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States,

National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med 2014;160(5):293–

300.

1490

 

Figure 58-15. Clinical course of chronic hepatitis D infection.

HEPATITIS E VIRUS

Molecular Structure

Hepatitis E virus (HEV) is a nonenveloped single-stranded RNA virus. It is 30 nm in diameter and is

most similar to other viruses of the Caliciviridae family. There are three large open reading frames, the

first of which is 1,693 codons and codes for nonstructural proteins. The second is 660 codons and

encodes structural proteins. The third is smaller and of undetermined function. There are thought to be

four genotypes.49

Epidemiology/Risk Factors for Transmission

Hepatitis E is enterically transmitted and is epidemiologically similar to HAV. Infection has been

prominently observed in Asia, Africa, the Middle East, and Central America. In addition, vertical

transmission from mother to child has been documented and can be a source of perinatal morbidity and

mortality.

Clinical Features

HEV generally causes a self-limited acute infection, although chronic infection has been described in

organ transplant recipients. The incubation period usually lasts 3 to 8 weeks, and most individuals

recover without chronic findings after a transient cholestatic episode (Fig. 58-16). However, young

adults and women in late stages of pregnancy may develop fulminant cases of hepatitis E. Mortality

from HEV is 0.5% to 4% in the general population but up to 20% in pregnant women.50–52 Diagnosis is

aided by detection of serum or fecal genomes during the acute phase. In addition, one can demonstrate

anti-HEV IgM or IgG in follow-up.

Figure 58-16. Clinical course of chronic hepatitis E infection. (Reproduced with permission from Expert Reviews in Molecular

Medicine: (99)00129—5 h.htm; 6 December 1999.)

Treatment

Infection in most cases is self-limited; however, in immunosuppressed organ transplant patients HEV can

1484

cause persistent hepatitis and cirrhosis. There are no randomized controlled trials evaluating treatment

options, but there are observational studies that report benefit with ribavirin treatment in organ

transplant recipients.53

CYTOMEGALOVIRUS

Cytomegalovirus (CMV) is a member of the Beta-Herpesviridae family. It is usually associated with mild

hepatitis but may occasionally cause ALF. Transmission can be intrauterine, perinatal, or postnatal;

through intimate contact of infected fluids such as blood, saliva, or urine, or through transplanted

organs. Infection is lifelong due to the latency of the virus and can be detected in up to 70% of

individuals in US cities. Organ injury can occur as a result of primary infection or due to reactivation of

latent infection. In the neonatal period congenital infection can be severe and fatal. In

immunocompetent adults liver dysfunction tends to be found in association with CMV mononucleosis. In

immunosuppressed adults, infection leads to liver dysfunction with jaundice and at times liver failure.

Acalculous cholecystitis is another presentation.31,54,55 CMV antigenemia and PCR to detect CMV DNA

have made diagnosis rapid. Liver biopsy is important to establish the diagnosis of hepatitis. Pathologic

examination shows inflammation and injury ranging from fatty changes to necrosis to fibrosis. Giant

multinucleated cells and large nuclear inclusions can be encountered in hepatocytes and bile duct

epithelial cells.31,54,55

First-line treatment is with ganciclovir or valganciclovir. Second-line agents for cases of resistant

CMV include foscarnet, or cidofovir. Anti-CMV immune globulin can be used as an adjunct.56

EPSTEIN–BARR VIRUS

Epstein–Barr virus (EBV) is a DNA virus and member of the Herpesviridae family. Infection persists for

life due to latency of the virus and it is usually transmitted by close personal or intimate contact via oral

secretions. Some degree of liver involvement is encountered in almost all cases of primary EBV also

known as mononucleosis. It is usually mild without major clinical manifestations and resolves

spontaneously. The presence of jaundice may reflect either more severe hepatitis or an associated

hemolytic anemia. Occasional cases of ALF have been reported in both the immunocompetent and

immunocompromised population. Leukocytosis is usually present, with the presence of atypical

lymphocytes being a hallmark. Detection of heterophile antibodies, or the “monospot test” is highly

specific but somewhat insensitive with false-negative rates as high as 25% early in infection. If acute

EBV is suspected and heterophile antibodies are not detected EBV-specific antibody testing can be used

which are highly sensitive and specific. Treatment is supportive. Acyclovir has activity against EBV but

clinical trials have not shown a clear benefit to use of acyclovir. Liver transplant has been reported in

rare life-threatening situations.54,56–58

HERPES SIMPLEX VIRUS

The prevalence of antibodies to HSV-1 is around 75% in most populations and around 20% to HSV-2.

Fulminant hepatitis is a rare complication of HSV infection; those at risk include the neonates, the

immunocompromised, the malnourished, and the pregnant adults. Fulminant hepatitis is usually

associated with multiorgan failure and is associated with a high mortality rate. Clinical features include

high fever, anorexia with nausea, abdominal pain, leucopenia, and coagulopathy. Liver biopsy is

important in establishing the diagnosis. Microscopic examination shows diffuse eosinophilic intranuclear

inclusion bodies, multinucleated cells, widespread necrosis, and inflammation. Cowdry A-type

intranuclear inclusions are typical. Confirmation is by PCR. Approved antivirals include acyclovir,

famciclovir, and valacyclovir. Treatment with intravenous acyclovir should be initiated prior to

confirmation of etiology given that progression of disease is extremely rapid and lethal. Liver

transplantation can be considered even in cases of disseminated disease.54–56

VARICELLA ZOSTER VIRUS

Herpesvirus varicella (also called varicella zoster virus [VZV]) is usually associated with mild hepatitis

1485

but may occasionally cause ALF. Up to one-fourth of children with varicella (chickenpox) may exhibit

temporary mild biochemical liver abnormalities. Reye syndrome may be encountered during the

convalescence period especially in those who receive aspirin. In such cases mortality can be as high as

30%. Fulminant fatal hepatic failure is uncommon, but generally affects immunocompromised patients.

Confirmation of the diagnosis can be achieved by isolation of the virus from affected tissues. Varicella

zoster immune globin should be considered after exposure to the virus in immunocompromised or

pregnant patients who lack immunity to VZV. Current therapies for VZV infection in immunocompetent

and immunocompromised hosts include acyclovir, valacyclovir, and famciclovir. CDC guidelines should

be followed for infection control.31,54,56

ACUTE LIVER FAILURE

Definition

ALF is an uncommon but serious condition with approximately 2,000 cases per year in the United

States

59 and which carries a high mortality rate of 60% to 80%.60 It is characterized by rapid

deterioration of liver function as well as development of hepatic encephalopathy in an individual with

no previous liver disease. Currently, emergency liver transplantation is the only therapeutic option

available, and the King’s College Criteria are widely accepted as the standard of guidance. ALF is

responsible for about 5% of all liver related deaths and approximately 5% of all liver transplants are

performed for this indication.61

The most widely accepted definition includes an international normalized ratio (INR) greater than 1.5

and any degree of mental alteration (encephalopathy) in a patient without pre-existing liver disease and

with an illness of less than 26 weeks’ duration. Patients with Wilson disease, vertically acquired

hepatitis B, or autoimmune hepatitis can be considered to have ALF if the disease process has started

within 26 weeks.62 Although the literature suggests hyperacute (<7 days) and subacute (>21 days but

<26 weeks) forms, they do not have prognostic significance except in the case of hyperacute failure

due to acetaminophen toxicity which may carry a better prognosis.63

Diagnosis

A high index of suspicion is vital in early recognition of the disease process. Patients with evidence of

moderate to severe hepatitis and any degree of encephalopathy require hospitalization since the process

may proceed to death rapidly.64 Likewise early transfer to an intensive care unit (ICU) setting in a liver

transplant center is important (especially before the onset of grade III or IV encephalopathy) since

worsening encephalopathy can potentially hamper transportation efforts due to concerns over increased

intracranial pressure (ICP). Detailed history taking from accompanying persons including medications

and herbal supplements taken and recent social history is essential. Stigmata of chronic liver disease

should be assayed during the physical examination although jaundice may be a relatively late

manifestation of the disease process. The initial recommended laboratory testing is listed in Table 58-

2.64 Lastly, transjugular liver biopsy can be considered as part of the initial workup to rule out

neoplastic infiltration or HSV/herpes zoster virus (HZV) infection, although it is not always necessary,

beneficial, or safe in all cases.63

Table 58-2 Management in Acute Liver Failure: Initial Laboratory Evaluations

1486

Etiology

Etiology is important in ALF in that it may dictate administration of appropriate antidotes or to better

anticipate prognosis and the potential need for liver transplantation.65 Etiology seems to have

geographic variation. In the United States, the most common reported cause of ALF is acetaminophen

overdose (45% of cases), followed by unknown (15%), drug related (10%), hepatitis B virus (7%),

autoimmune hepatitis (5%), and Wilson disease (2%).66 In the United Kingdom, acetaminophen toxicity

is reported in over 60% of cases, whereas in France, frequency of reported etiologies is viral due to

hepatitis A and B (30%), acetaminophen (20%), other drug over dose (18%), and unknown (17%).63,67

Drug-induced Liver injury. Intrinsic hepatotoxins are usually dose dependent, while idiosyncratic

responses are dose independent. Acetaminophen toxicity is dose dependent with serious injury seen with

levels greater than 10 g/day but sometimes reported in cases with levels as low as 3 to 4 g/day range.

Glutathione becomes depleted with excess free NAPQI (a toxic byproduct of acetaminophen) reacting

with hepatocytes, causing liver injury.65 In the presence of poor nutritional state or alcoholism,

glutathione levels are chronically depleted further contributing to toxicity. Stevens–Johnson syndrome

caused by phenytoin, amoxicillin-clavulanate, carbamazepine, or halothane, is a form of hypersensitivity

idiosyncratic reaction, while isoniazid, valproate, and amiodarone mainly cause metabolic idiosyncratic

reactions.

Viral Hepatitis. In those with HAV, ALF occurs around 0.5% of the time; age over 40 and other preexisting liver disease represent increased risk. In those with HBV, ALF occurs in 1.5% of cases. ALF may

occur due to new infection or reactivation of a chronic carrier state. HDV coinfection and HEV should be

suspected in endemic areas. VZV, HSV, and CMV are other rare viral causes of ALF.65

Other. Acute Budd–Chiari syndrome, veno-occlusive disease, medications and herbs, and

malignancies involving the liver (i.e., lymphoma, angiosarcoma) are less common causes of ALF.64

Acute fatty liver of pregnancy (AFLP), and HELLP (Hemolysis, Elevated liver enzymes, Low platelets)

are important diagnoses to be considered among pregnant women presenting with manifestations of

ALF. AFLP occurs during the third trimester of pregnancy due to deficiencies in 3-hydroxyacyl-CoA

dehydrogenase in both the mother and fetus with rapid deposition of triglycerides and free fatty acids

into hepatocytes. HELLP also occurs in the third trimester or immediately postpartum. Autoimmune

hepatitis (AIH) can present acutely with absence of autoimmune markers, where the diagnosis is made

by exclusion and transjugular liver biopsy. In the fulminant form of Wilson disease, chelator treatment

is ineffective and diagnosis is usually based on familial history of liver disease in a young adult with

Coombs-negative hemolysis and low serum alkaline phosphatase or uric acid levels. Kayser–Fleischer

rings are present in 50% of patients.62 Diagnosis is usually confirmed by hepatic copper content greater

than 250 μg/g in patients homozygous for Wilson disease, and the rate of urinary excretion may exceed

100 μg/24 hours.68 Heat stroke, mushroom ingestion, EBV, and parvovirus B19 are rare causes of ALF.63

Clinical Features, Management, and Treatment

Acute liver injury in the absence of hepatic encephalopathy is a reversible entity unless an underlying

1487

 

Figure 58-9. Clinical course of acute hepatitis B infection.

In Western Europe and North America the prevalence of chronic infection is less than 1% but ranges

between 10% and 20% in endemic areas including southeast Asia, China, and sub-Saharan Africa. It is

estimated that there 1 million deaths each year as a result of cirrhosis and HCC associated with chronic

HBV worldwide.

Treatment

Primary prevention by means of vaccination constitutes the best treatment approach for HBV infection.

Individuals at high risk include health care workers, visitors to highly endemic areas, men who have sex

with men, sex workers, and intravenous drug users. The hepatitis B vaccine is given as a series of three

intramuscular doses and has almost 100% efficacy among immunocompetent persons. Hepatitis B

immune globulin has a reported efficacy of 90% in the prevention of newborn infections and

approximately 75% in cases of needle sticks or sexual infections in people exposed to the virus with no

prior immunity. It is administered as soon as possible after exposure together with the first dose of the

hepatitis B vaccine series.

Figure 58-10. Clinical course of chronic hepatitis B. A: A benign chronic carrier has continued production of hepatitis B surface

antigen but there is an absence of serum markers of viral replication. B: A pattern of continuing liver injury and serum markers of

active viral replication.

Therapy is usually directed at HBeAg-positive cases that have an increased risk of cirrhosis and HCC.

HBeAg-negative patients with high viral load may also benefit from treatment. Effectively controlled

infection is determined by loss of HBsAg and absent viremia by PCR on antiviral treatment. The

endpoint of treatment is loss of HBeAg and seroconversion to detectable HBeAb. In clinical trials about

half of patients achieved this endpoint after 5 years of treatment but many patients will require a longer

duration of therapy, in some cases, lifelong. Patients with chronic hepatitis B and cirrhosis or advanced

fibrosis showed a reduction in the risk of HCC after continuous treatment with lamivudine.35,39

Lamivudine is an orally effective antiviral agent that competitively inhibits the DNA polymerase. Its

administration is associated with a more rapid seroconversion to HBeAg-positive status, a more rapid

loss of HBeAg, improved aminotransferase levels, and a 3 to 4 log reduction in circulating levels of HBV

1480

DNA in the first 3 months of therapy. It is also associated with improved liver histologic findings in

cases of chronic hepatitis.

Agents available to treat hepatitis B include interferon (IFN), lamivudine, entecavir, adefovir,

telbivudine, and tenofovir. The most widely used, well-tolerated, and effective agents include the

nucleoside analogues lamivudine, entecavir, and tenofovir. Lamivudine is effective and low cost; its

major limitation is the development of drug resistance. Entecavir and tenofovir are active against

lamivudine-resistant variants and can be considered for first-line treatment in individuals if cost is not a

limiting factor. Both lamivudine and tenofovir are active against human immunodeficiency virus (HIV),

so these agents are preferred in individuals coinfected with HIV and HBV.

Liver transplantation is the treatment of choice in patients with hepatic failure. Recurrence of viral

infection in the allograft can be as high as 80% in HBeAg-positive cases where no postoperative

prophylaxis is administered. The combination of lamivudine and hepatitis B immune globulin

posttransplantation reduced the reinfection rate to less than 10% and increased the 5-year survival rate

to 80%.35 Other posttransplant pharmacologic regimens are currently being examined.40

HEPATITIS C VIRUS

Molecular Structure

Hepatitis C virus (HCV) is a lipid enveloped, 9.4-kb, single-stranded RNA virus of the family

Flaviviridae, genus Hepacivirus.41 Six genotypes have been identified, which differ from one another by

as much as 30% at the sequence level. Quasispecies within genotypes demonstrate further genetic

heterogeneity and reflect the high rate of mutation seen in viral replication. Over 70% of US cases are

due to genotype 1 virus.

Epidemiology/Risk Factors for Transmission

There are more than 185 million individuals infected with HCV worldwide, translating to a global

prevalence of 2.8%. In the United States, there are an estimated 3.6 million HCV-infected individuals,

approximately 1% of the population, but this is likely an underestimate as these estimates do not

include high-risk homeless or incarcerated populations.42,43

Figure 58-11. Clinical course in acute hepatitis C.

The most commonly identified risk factors are exposure to blood or blood products prior to 1992 and

intravenous drug use. Other risk factors include intranasal drug use due to mucosal exposure to blood

on drug paraphernalia, anal intercourse in men who have sex with men due to blood-mucosal exposure,

occupational exposure, hemodialysis, tattooing, and perinatal transmission. In the United States, more

than 80% of infections have been identified in adults born between 1945 and 1965.41 Due to this

observation, the CDC now recommends screening all individuals in this birth cohort irrespective of

reported risk factors.

Clinical Features

The usual incubation period of HCV is 5 to 10 weeks. Most acutely infected patients are asymptomatic

and therefore the infection goes unappreciated. Initial laboratory findings after infection include

elevated ALT levels (500 to 1,000 IU/mL) and high HCV RNA titers (Fig. 58-11). HCV clearance is

spontaneous in about 15% to 20% of individuals following primary infection. Hepatitis C infection by

1481

itself is almost never associated with ALF. Liver damage in the setting of chronic infection is due to host

immune response rather than viral hepatotoxicity. Ongoing chronic hepatic injury leads to progressive

fibrosis and cirrhosis which typically occurs over decades, in most cases undetected until the appearance

of overt liver failure (Fig. 58-12). The incidence of hepatic decompensation (variceal hemorrhage,

ascites, jaundice, encephalopathy) in the setting of cirrhosis is approximately 5% per year. Hepatitis C

cirrhosis is strongly associated with the development of HCC. Extrahepatic manifestations of hepatitis C

include membranoproliferative glomerulonephritis, cryoglobulinemia, diabetes, porphyria cutanea

tarda, lichen planus, vitiligo, and non-Hodgkin lymphoma.44

Figure 58-12. Clinical course in chronic hepatitis C.

The diagnosis of chronic hepatitis C is based on serologic demonstration of persistent HCV RNA and

HCV antibodies. HCV RNA can be detected weeks earlier than antibodies, which typically appear 2 to 8

weeks after the initial infection.

Treatment

With the recent advent of highly effective, well-tolerated antiviral therapy, all individuals who develop

hepatitis C should be offered treatment. The goal of treatment is a sustained virologic response or

absence of HCV RNA in serum 3 to 6 months after stopping treatment. Therefore, unlike HBV, therapy

in HCV is ideally curative.

In the past, the mainstay of therapy included IFN alpha combined with ribavirin (RBV) given for 48

weeks. This combination had poor tolerability and poor efficacy, with SVR rates for genotype 1

infections ranging from 35% to 45% depending on stage of disease and patient characteristics. In 2011,

the first directly acting antivirals (DAAs) designed to specifically inhibit HCV proteins became available.

Inhibitors of the HCV NS3A protease, boceprevir and telaprevir, were the first to be introduced but they

still had to be given in combination with IFN and RBV. These first PI-based regimens increased SVR

rates up to about 60% to 70%, but they compounded the toxicities of IFN and RBV, with high rates of

serious adverse events including death. In 2013, more effective antivirals were introduced which

allowed for IFN-free, ribavirin-free treatment regimens. With 12 to 24 weeks of treatment, DAA

combinations have SVR rates between 95% and 100% and very few side effects. New antivirals include

second-generation protease inhibitors nucleotide and nonnucleotide analog inhibitors of the HCV NS5B

polymerase and inhibitors of the HCV NS5A replication complex. Over the next several years, many

additional DAAs are expected to be approved. Determining the optimal combination for treatment will

depend on factors such as genotype, comorbidities, and drug-drug interactions.

4 Transplantation is the treatment of choice in cases of irreversible decompensated cirrhosis due to

HCV and in cases of HCC due to HCV. Thus, HCV has become the most common indication for liver

transplantation in the United States and many countries worldwide. In many cases, treatment cannot

completely reverse all hepatic damage from HCV and risk of HCC remains. Therefore, even if access to

HCV diagnosis and effective treatment is optimal, the need for liver transplantation due to HCV is

expected to continue for decades.

HEPATITIS D VIRUS

Molecular Structure

The hepatitis D virus (HDV), or delta agent, is an incomplete RNA virus that requires the presence of

1482

HBV for viral assembly and propagation. The only enzymatic activity of HDV is a ribozyme that cleaves

circular RNA and makes it linear. The HDV genome is a 1,680 nucleotide, single-stranded circular

RNA.45 Eight genotypes have been proposed.46 A single HDV antigen is encoded, it is a structural

component of the virion, and a lipoprotein envelope is provided by HBV.

Epidemiology/Risk Factors for Transmission

HDV is found in approximately 5% of HBV carriers. Due to its dependence on HBV, HDV always occurs

in association with HBV infection. Transmission is similar to that of HBV, via parenteral or sexual

exposure to blood or body fluids. HDV hepatitis occurs only in HBsAg- positive patients.

Figure 58-13. Synchronous infection with hepatitis B virus and hepatitis D virus.

Clinical Features

Acute infection is diagnosed by the presence of anti-HDV IgM. Anti-HBc IgM distinguishes coinfection

from superinfection (Figs. 58-13 and 58-14). The diagnosis in patients with chronic liver disease is made

by the presence of HBsAg and antibodies against HDV in the serum and confirmed by the presence of

HDV antigen in the liver or HDV RNA in the serum (Fig. 58-15). ALF is seen with both coinfection (HDV

and HBV simultaneously infects the host) and superinfection (HDV infects a host already infected with

HBV). Superinfection seems to be associated with a higher mortality rate. Chronic HDV and HBV

infection may coexist. Cirrhosis is observed in at least two-thirds of patients and occurs at a younger age

than in patients infected with HBV alone.47,48

Treatment

Treatment and prevention of HDV are associated with that of hepatitis B, with which it always coexists.

Vaccination for HBV is contributing to the decline in the incidence of HDV. Alpha IFN is the only

currently available treatment for chronic HDV.

Figure 58-14. Superinfection of chronic hepatitis B carrier with hepatitis D.

1483

 

1476

Figure 58-7. Hepatic schistosomiasis. A hepatic granuloma surrounds a degenerating egg of Schistosoma mansoni. (Reproduced with

permission from Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.)

Preferred treatment of schistosomiasis is praziquantel, with cure efficacy around 90%. Treated

patients should also undergo evaluation and management of any esophageal varices that may have

developed.17,18

VIRAL HEPATITIDES

3 Viral hepatitis represents an important cause of chronic liver disease, cirrhosis, and hepatocellular

cancer. Infection is pandemic in the United States and worldwide. Hepatitis C has become the most

common indication for liver transplant in the United States and its recurrence has been the most

common cause for graft loss after transplant. Liver transplant for hepatitis B has shown greatly

improved results in recent years due to improved antiviral treatment. Hepatitis C is now following the

same trajectory with the advent of effective antivirals.

The mechanism of liver injury is largely a host inflammatory response to virus. Table 58-1

summarizes current understanding of the characteristics of the five viruses most commonly associated

with clinical hepatitis, their modes of transmission, and the consequences of infection.

GB Virus, formerly known as hepatitis G virus (HGV) does not appear to be deleterious to the liver.

Other viral infections can produce acute hepatitis, particularly in immunocompromised hosts (e.g.,

Epstein–Barr virus, cytomegalovirus, herpes simplex virus, and varicella zoster virus). In some cases the

hepatitis caused by these viruses in association with systemic symptoms can be severe and liver

involvement may be the dominant manifestation of the patient’s illness.

HEPATITIS A VIRUS

Molecular Structure

Hepatitis A virus (HAV) was identified in 197327 and belongs to the Picornaviridae family, genus

Hepatovirus. Four distinct genotypes have been identified and all four genotypes belong to a single

serotype.28 HAV is a single-stranded RNA virus that is 27 nm in diameter and is nonenveloped. The viral

genome is 7,474 nucleotides in length and is divided into 5- and 3-in untranslated regions and a single

long open reading frame that encodes a 2,227 amino acid polypeptide. Upon processing this peptide

yields four structural and seven nonstructural proteins.

Epidemiology/Risk Factors for Transmission

Hepatitis A has been long known (epidemic jaundice, catarrhal jaundice, campaign jaundice) and

continues to occur worldwide. The incidence in the United States has declined with effective vaccination

but remains around 1.2 per 100,000.29

The major mode of transmission is fecal–oral and it is more common in lower socioeconomic areas

where sanitation is poor. Common risk factors in the United States are international travel, especially to

Mexico or Central/South America; household contact with an infected family member; homosexual

activity in men; ingestion of contaminated foods (shellfish, green onions, frozen strawberries) or

waterborne outbreaks; children in daycare centers; and injection drug use.30 Humans are the only host

for HAV and the liver is the only affected tissue.

1477

Clinical Features

Hepatitis A infection almost universally results in an acute, self-limited illness and can produce either

icteric or anicteric syndromes (Fig. 58-8). The incubation period is 28 days. The anicteric prodrome lasts

from 2 days to 3 weeks and typically consists of fatigue, malaise, nausea, vomiting, anorexia, fever, and

right upper quadrant pain. The diagnosis may be missed in cases without jaundice. In cases where

jaundice becomes manifest, it persists for 1 to 6 weeks. Transaminase levels are typically above 1,000

IU/mL, serum bilirubin above 10 mg/dL, and alkaline phosphatase values are elevated as well. Serum

IgM antibodies are detected in 95% of patients and are the gold standard of diagnosis. IgG antibodies

become elevated as jaundice subsides and may persist for years.

Table 58-1 Classification of Viral Hepatitis

HAV leads to fulminant liver failure in 0.01% to 0.35% of cases of acute HAV infection. This rare

event mostly occurs in patients with underlying liver disease, especially chronic hepatitis C infection

and less commonly hepatitis B infection or alcoholic liver disease. The risk of fulminant failure is also

higher in people over 40 years of age, intravenous drug abusers, men who have sex with men, and in

inhabitants of endemic areas.31

Figure 58-8. Clinical course of hepatitis A infection.

Treatment

Most patients with HAV infection recover with supportive care; approximately 20% require

hospitalization in large outbreaks. Infection control measures such as hand washing and isolation should

be a top priority to prevent spread of virus. Fecal shedding of virus occurs even prior to onset of

symptoms and jaundice. Spontaneous recovery and survival even in cases of acute liver failure (ALF)

may be as high as 50%. Liver transplantation is indicated in cases in which recovery seems unlikely.

Recurrence of HAV in the allograft may be encountered and administration of immunoglobulin may be

beneficial in such instances.31,32

1478

A formalin-inactivated HAV vaccine is safe and effective in almost all recipients after two doses.

Vaccination is recommended by the CDC for children 2 years of age or older in states or countries with

high rates of infection (20 or more cases per year per 100,000 population) as well as in individuals at

high risk such as persons infected with hepatitis B or C. Immune globulin administered within the first

14 days of exposure prevents disease in more than 85% of cases. Close contacts of patients with recent

onset of the illness, people exposed to contaminated foods, and selected travelers to endemic areas

benefit the most.33

HEPATITIS B VIRUS

Molecular Structure

Hepatitis B Virus (HBV) is a DNA virus that belongs to the hepadnavirus family. It is the smallest DNA

virus with the ability to infect humans. HBV virions are 40 to 42 nm in diameter, with a double shell

and an outer lipoprotein envelope. The viral nucleocapsid, or core, contains a 3.2-kb partially duplex

DNA and a polymerase. Replication resembles that of retroviruses, in which the viral DNA polymerase

acts as a reverse transcriptase. The HBV polymerase lacks proofreading activity. This is associated with

an estimated 105 to 106 mutations per nucleotide per year and the resultant development of mutant

forms of the virus.34–36

Epidemiology/Risk Factors for Transmission

It is estimated that over 350 million people worldwide are infected by HBV. In the developing world,

perinatal infection is the most common mode of transmission. In the United States, transmission is

primarily sexual as the virus is present in semen and vaginal fluids in addition to blood. Infection from

intravenous drug use and occupational infections due to percutaneous exposure also occur. There are no

known animal reservoirs or evidence that insects are involved in transmission of HBV. The hepatitis B

virus replicates mainly in hepatocytes but is not itself cytotoxic. Liver injury is due to the resultant host

immune response.

Clinical Features

The incubation period for HBV is 8 weeks. The presence of serum hepatitis B surface antigen (HBsAg)

may precede jaundice. Acute infection is associated with detectable serum HBV DNA, hepatitis B early

antigen (HBeAg), and IgM to hepatitis B core. HBeAg is a useful marker of viral replication except in

patients with mutant viruses where it may be undetectable despite active replication (Fig. 58-9). In such

cases detection of HBV DNA is diagnostic. Serum anti-HBc IgM becomes detectable with the onset of

jaundice. In most patients, when HBV does not develop into chronic hepatitis, anti-HBc IgM becomes

undetectable after 6 months. On occasion, however, it may persist for years after the acute infection or

may recur as an amnestic phenomenon in reactivating chronic hepatitis B, thus limiting its usefulness as

a marker of acute HBV infection.

Although HBV accounts for 40% of ALF in developing countries, it is estimated that the incidence in

the United States is about 10%. Hepatitis B becomes fulminant in about 1% of acute infections. Women,

elderly individuals, and those who sustain superinfection with another virus (such as HCV) seem to be

at greater risk. Furthermore, the risk of ALF seems to be proportional to antibody titers of HBcAg and

HBsAg. Some cases of ALF may be due to reactivation of HBV in patients with chronic infection. In cases

of reactivation, reappearance of HBc IgM antibodies aids in the diagnosis. Spontaneous survival after

HBV ALF is in the 25% range.37,38

Most patients with acute HBV infection in the Western world recover completely. Approximately 25%

of these patients will develop jaundice but do not become HBV carriers. They will usually retain HBcAb

and HBsAb markers with no detectable HBsAg or HBV DNA. Approximately 10% of Western adults with

HBV infection do progress to become chronic carriers, as determined by the presence of HBsAg in serum

for more than 6 months (Fig. 58-10). Most HBV carriers have a benign state with HBV DNA integrating

into their native genome. The remainder of HBV carriers develop ongoing liver injury and usually have

detectable HBeAg or HBV DNA and have free episomal HBV sequences in addition to the ones integrated

into their native genomes.

1479

 

antibiotics are crucial, without which mortality rates are high. Other contributors to poor outcome

include: multiple abscesses, non-Klebs pathogens, mixed bacterial and fungal abscesses, presence of

respiratory symptoms, presence of malignancy, and large size (>5 cm).8,9

AMEBIC LIVER ABSCESS

Amebic liver abscesses are caused by Entamoeba histolytica, a protozoan. Systemic infection, or

amebiasis, is most commonly asymptomatic, clinical manifestations include amebic dysentery and

extraintestinal manifestations. Amebic liver abscess is the most common extraintestinal manifestation

and is due to ascending portal infection. Amebiasis is most prevalent in tropical and subtropical regions

with poor sanitation, as fecal–oral transmission is the most common route of infection. It is estimated

that 40 to 50 million are infected each year worldwide, and in the United States the highest rates are

seen in immigrants from endemic areas. Again, most infections are asymptomatic, but amebic

dysentery, and pulmonary, cardiac, and brain involvement can occur, along with hepatic abscess.

Hepatic abscess occurs in only around 5% of cases of amebiasis. Men are affected 10 times more

commonly than women, peak incidence is in the third, fourth, or fifth decade of life, and corticosteroid

usage is a risk factor.2,10 Ingested cysts pass through the stomach and reach the intestine. There the cyst

wall is degraded and trophozoites are released. These infective particles multiply in the colonic lumen

and then may enter mesenteric veins and eventually the liver. Amebic trophozoites there cause

obstruction of venules, thrombosis and infarction of hepatic parenchyma, with resultant abscess

formation (Fig. 58-2).

Figure 58-1. Computed tomogram of a pyogenic hepatic abscess in a liver transplant recipient with occlusion of the hepatic artery.

Amebic liver abscesses range in size from several millimeters to massive (Fig. 58-3). Clinical

presentation is typically 8 to 20 weeks following return from endemic area and usually manifests as

right upper quadrant pain and fever. Cough, sweating, malaise, weight loss, and hiccough may be

present. Amebic abscesses are more common in the right lobe and tend to be singular. Lesions may

show an enhancing rim and when drained contained a dark, hemorrhagic, proteinaceous fluid often

referred to as “anchovy paste” (Fig. 58-4). Abscesses have been described in the past as acute or

chronic, and as benign or aggressive. Bacterial superinfection of amebic abscesses can occur and amebic

abscesses can rupture into surrounding tissues or spaces, most frequently into the chest.1,2,10–14 E.

histolytica is not found in stool specimens of infected patients but diagnostic antibodies are present in the

serum 7 to 10 days after the onset of symptoms in almost all patients.15 Chest x-ray is frequently

abnormal but CT scan is the diagnostic test of choice, often displaying the enhancing wall and a

surrounding edema. MRI will likewise be diagnostic.2,10,12

Treatment is based on amebicidal drugs to eliminate liver organisms and a luminal agent to eliminate

intraluminal cysts even if not seen in the stool given the low sensitivity of microscopy to identify

organisms. Preferred tissue agents include metronidazole 500 to 750 mg three times a day for 7 to 10

days. Tinidazole 2 g orally for 5 days is an alternative treatment that is better tolerated. To eradicate

intraluminal cysts, the following regimens can be used: paromomycin (25 to 30 mg/kg/day orally three

times a day for 7 days), diiodohydroxyquin (650 mg orally three times a day for 20 days), or diloxanide

1473

furoate (500 mg orally three times daily for 10 days for adults). Metronidazole treats both intestinal

and extraintestinal sites. Amebic abscesses can almost always be treated with medical therapy alone.

Percutaneous drainage is considered in cases with poor response, when superinfection is suspected, or if

there is risk of rupture. Open surgical drainage is almost never required and would be considered only

in severe complicated cases.2,10,13

Figure 58-2. Amebic abscess of the liver. A photomicrograph of the margin of an amebic abscess shows fibroblastic proliferation

surrounding the cavity and amebic trophozoites in the lumen. (Reproduced with permission from Rubin E, Farber JL. Pathology.

3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.)

Figure 58-3. Sonogram (A) and computed tomogram (B) in a patient with multiple amebic abscesses (arrows).

ECHINOCOCCUS (HYDATID DISEASE)

Echinococcal infection, also called hydatid disease, is a parasitic disease due to echinococcal tapeworms

including Echinococcus granulosus or E. multilocularis in humans. Echinococcus is endemic in the

Mediterranean or other parts of the world in sheep rearing economies but is uncommon in the United

States. The liver is most commonly affected by E. granulosus. Dogs are the definitive host and the life

cycle of the organism is such that when the canine host ingests infected viscera (from sheep or cattle)

scoleces released in the intestine develop into adult worms. Humans, an intermediate host, acquire

echinococcal eggs by ingestion of contaminated foods or with infected animals. The echinococcal egg is

digested in the duodenum and yields an embryo (oncospheres). Embryos invade the intestinal wall and

reach the liver via the portal circulation. Surviving embryos lodge in the hepatic capillaries and develop

into hydatid cysts. Though the liver is the most common location of hydatid cysts (50% to 75% of cases)

the lungs can also be affected (25% of cases). E. granulosus and E. vogeli cause liver cysts while E.

multilocularis is associated with alveolar disease.12,16,17,18

1474

Figure 58-4. Amebic abscesses of the liver. The cut surface of the liver shows multiple abscesses containing “anchovy paste”

material. (Reproduced with permission from Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams &

Wilkins; 1999.)

Liver involvement with echinococcal cyst can lead to venous obstruction, portal hypertension, sepsis,

and cholangitis. Hydatid cysts are fluid filled, round, and contain three layers of host tissue: an outer 2-

to 4-mm-thick fibrous pericyst composed of compressed and fibrotic liver tissue, a 2-mm-thick middle

anuclear hyaline layer or ectocyst, and an internal germinal layer or endocyst derived from the

parasites. As the cyst matures, invagination of the germinal layer leads to development of daughter

cysts in the periphery (Fig. 58-5). Calcifications are frequently observed radiographically in both viable

and nonviable cysts.12,17,18

Cysts may grow at an annual rate of around 1 to 3 cm/year. Enlarging cysts can cause symptoms of

abdominal pain, biliary obstruction, and jaundice, or less commonly portal hypertension. Masses may be

palpable clinically on examination. Involvement of the biliary tree is variable. Biliary findings result due

to communication between the pericyst and the bile ducts or due to rupture of the cyst into the biliary

tree. Fistulous communication between the cyst and the biliary tract may result in superinfection of the

cyst, cholangitis, and biliary obstruction. This bacterial contamination occurs in around 25% of cases.

Occasionally, cysts may rupture into the peritoneal cavity causing abdominal pain and anaphylaxis.

Multiple intra-abdominal cysts may develop due to intraperitoneal leakage. Hepatic hydatid cysts may

perforate the diaphragm and lead to empyema, biliary-bronchial fistula, or pericardial collection.19

Laboratory tests may be normal or reveal biliary obstruction, and eosinophilia is frequently present.

Serologic ELISA-based screening tests are associated with high false-positive and negative rates.

Confirmatory electrophoresis when available has a higher accuracy rate. Hydatid cysts have a

stereotypic appearance on radiographic studies. US imaging may show daughter cysts, a calcified rim,

and the so-called water lily sign of the curved bands of the delaminated endocyst. CT scan shows a

hypoattenuating lesion with daughter cysts (75%) and a calcified rim (50%). MRI often well displays

daughter cysts, pericyst, and the “hydatid sand” of free scoleces. ERCP may be helpful in cases

involving the biliary tree.12,16

Figure 58-5. A partly opened hepatic hydatid cyst. Brood capsule and daughter cysts are visible in the cavity. (Reproduced with

permission from Kean BH, Sun T, Ellsworth RM. Color Atlas/Text of Ophthalmic Parasitology. New York: Igaku-Shoin; 1991:188.)

2 Open surgical resection is the treatment of choice for symptomatic or complicated hydatid cysts

1475

(Fig. 58-6). Surgical extirpation aims to remove the cyst intact without spillage of cyst contents.

Alternatively, some have described aspiration of cyst contents prior to resection to minimize the result

of any cyst spillage. After aspiration injection with ethyl alcohol or 20% sterile saline is undertaken to

kill remaining scoleces. In cases where the aspirate is bilious and a communication with the biliary tree

is thus suspected the cyst should be resected without alcohol injection to prevent the occurrence of

sclerosing cholangitis. Laparoscopic resection and percutaneous aspiration techniques have been

reported, especially in conjunction with albendazole. Albendazole should be started 1 week prior to

surgery and generally continued for at least 4 weeks postoperatively. It is poorly absorbed and should

be given with a high-fat meal to increase bioavailability (15 mg/kg/day up to maximum of 400 mg

twice daily). Mebendazole may be used as an alternative therapy but is less well absorbed.

Postoperative morbidity and mortality are low following resection but not zero and recurrence after

surgery is reported from 2% to 25%, and is associated with residual cysts or intraoperative spillage of

cyst contents.16–23

Figure 58-6. The external surface of the liver of a patient with echinococcosis before operation. (Reproduced with permission from

Sun T. Parasitic Disorders: Pathology, Diagnosis, and Management. 2nd ed. Baltimore, MD: Lippincott Williams & Wilkins; 1999.)

SCHISTOSOMA

Schistosoma mansoni, S. japonicum, S. haematobium, and S. mekongi are species of trematode fluke that

infect humans in endemic areas or visitors to these sites. Liver disease is especially severe with S.

mansoni, S. japonicum, and S. mekongi. The life cycle of Schistosoma species alternates between sexual

reproduction in humans and asexual multiplication in water snails. Cercariae enter the human host by

penetrating the skin. An irritating maculopapular rash that lasts for several days is an early

manifestation of infection. Schistosomes live in the intestinal lumen and eggs reach the liver via the

portal circulation where they cause an inflammatory reaction.17,18,24

Infection in the liver is characterized by the presence of inflammatory granuloma surrounding

schistosomal eggs. Acute schistosomiasis is seen typically in nonimmune visitors to endemic areas and

presents as hepatomegaly and severe splenomegaly, often in children and adolescents. Severe cases with

high egg infestation can lead to widespread hepatic necrosis and death. In contrast, chronic

schistosomiasis is seen in young and middle-aged adults. It is usually asymptomatic until manifestations

of portal hypertension declare themselves, such as variceal hemorrhage. Patients will typically present

with hepatosplenomegaly, no ascites, and preserved synthetic function due to the presinusoidal nature

of the condition. Hepatocellular carcinoma (HCC), colon cancer, and follicular lymphoma of the spleen

have been reported in association with hepatic schistosomiasis.12,17,18,25,26

Diagnosis is typically made via the presence of schistosomal eggs in the stool (Kato–Katz smears),

epidemiologic data, and biochemical or serologic findings. Typical laboratory features include

eosinophilia and elevated alkaline phosphatase. Serum transaminases are typically normal. ELISA serum

antibody tests are highly sensitive. Biopsy will show prominent granuloma formation and severe portal

fibrosis (Fig. 58-7). Imaging studies are not typically useful in diagnosis of acute infection. In chronic

cases US may show portal vein wall thickening. Hypertrophy of the left lobe, splenomegaly, and

engorged venous collaterals may all be observed as well. CT may show fibrosis around portal vein

branches as well presenting as low attenuation rings through the liver parenchyma.