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

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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

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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

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