Metabolic and Genetic Disorders. Some of these diseases are listed in Table 59-1. A description of all

the metabolic disorders causing liver disease is beyond the scope of this chapter.

In hemochromatosis of the liver, an inborn error of metabolism causes an increased absorption of iron

from the gastrointestinal tract. The pathophysiology of iron-induced hepatotoxicity is related to lipid

peroxidation induced by iron in periportal regions of the liver. Activation of stellate cells by cytokines

released from Kupffer cells that have phagocytosed necrotic hepatocytes injured by iron toxicity is also

contributory.93 Over time, the reaction progresses to bridging fibrosis and eventually to a mixed

micronodular–macronodular cirrhosis. Treatment includes reduction of iron intake, repeated

phlebotomy, and orthotopic liver transplantation.94

Wilson disease is an autosomal, recessively inherited disease caused by a deficiency in hepatocyte

transport of copper into the bile. The disease is characterized biochemically by low serum ceruloplasmin

levels and clinically by corneal pigmentation (Kayser–Fleischer rings), neuropsychiatric disease, and

hepatic cirrhosis.95 As copper accumulates in the liver, periportal inflammation develops that leads to

piecemeal and lobular necroses, bridging fibrosis, and a mixed micronodular–macronodular cirrhosis.

Treatment options include chelating agents, such as penicillamine, trientine, zinc salts, and orthotopic

liver transplantation.

Venous Outflow Obstruction. Cirrhosis may also result from obstruction of the hepatic veins. Causes

include chronic right-sided heart failure as a result of severe tricuspid regurgitation, constrictive

pericarditis, and the Budd–Chiari syndrome (BCS).

Hepatic dysfunction secondary to passive vascular congestion in the setting of right-sided heart failure

and increased right-sided heart pressures is caused by the transmission of increased pressure to the

hepatic venous system. This increased pressure leads to sinusoidal congestion, perivenular atrophy,

hemorrhagic necrosis, and distortion and enlargement of sinusoidal fenestrations.96 Increased pressure

also causes perisinusoidal edema that eventually exceeds the clearance capabilities of hepatic

lymphatics, so that ascites develops.97 Grossly, the liver is described as having a “nutmeg” appearance

in which areas of hemorrhage are interspersed with relatively normal yellowish parenchyma.97

Histologically, perivenular fibrosis progresses to bridging fibrosis that spares the portal regions. Portal

sparing is characteristic of “cardiac cirrhosis.” In addition to causing ascites, chronic vascular congestion

can lead to fibrosis in the space of Disse, which compromises nutrient delivery and contributes to portal

hypertension and zone 3 hepatocellular injury.98

5 BCS is a rare disease caused by mechanical obstruction of the hepatic veins (Table 59-3).

Obstruction may occur at the level of the terminal hepatic veins, the major hepatic veins, or the vena

cava and may be caused by obstructing webs or membranes (most commonly in Africa and Asia) or

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

The range of presentations is wide; some patients are completely asymptomatic, whereas acute

hepatic failure or cirrhosis develops in others.99 These variations in symptoms are related to the degree

and rate of progression of hepatic outflow obstruction. Patients classically present with abdominal pain,

hepatomegaly, and ascites. The diagnosis can be made by duplex Doppler ultrasonography, which has a

sensitivity of 85% to 95%.100 Identification of collateral vessels to subscapular or intercostal vessels on

ultrasonography on ultrasound is a highly sensitive and specific finding.101 Computed tomography (CT)

and magnetic resonance imaging (MRI) offer optimal characterization of intrahepatic vascular anatomy

and are currently used for the planning of complex interventions.102 Medical management consists of

anticoagulation and symptomatic management. Interventional radiologic procedures have now taken

the forefront in management of BCS, in which accessible strictures may be treated with angioplasty or

stenting. For patients unsuitable for reestablishment of hepatic venous outflow through the above

means, transjugular intrahepatic portosystemic shunting (TIPS) is able to decompress both the inferior

vena cava and the portal system.101 In patients with fulminant BCS or in those who develop chronic

decompensated cirrhosis, liver transplantation becomes an option.

ETIOLOGY

Table 59-3 Etiology

1502

Diagnosis

Although cirrhosis can be asymptomatic for decades, significant information can be obtained by

performing a thorough history and physical examination. A history of alcohol abuse, hepatitis, toxin or

drug exposure, upper gastrointestinal bleeding, enlarging hemorrhoids, infections, and alteration in

mental status suggests the possibility of liver disease. Physical findings associated with cirrhosis are

listed in Table 59-4. In addition to these findings, fetor hepaticus, purpura and bruising, decreased body

hair, and white nails are common.

Laboratory tests of liver function are indicated if liver disease is suggested by the history and physical

examination. Although levels of bilirubin, aspartate aminotransferase, alanine aminotransferase, and

alkaline phosphatase are elevated in hepatic disease, the increases are not specific for liver pathology,

and levels may be normal even in the setting of significant disease. A very common finding in patients

with cirrhosis is thrombocytopenia, caused by hypersplenism and portal hypertension. The platelet

growth factor thrombopoietin, which is produced by the liver, has been shown to be decreased in

patients with cirrhosis, and this deficit may contribute to the thrombocytopenia associated with hepatic

disease.103

The definitive diagnosis of cirrhosis usually requires biopsy, either percutaneous or operative, or

gross inspection during laparoscopy or laparotomy. Regardless of the method selected, it is crucial to

obtain a large enough specimen to make the diagnosis. Current recommendations suggest that at least

11 portal tracts need to be assessed.104 Several staging systems exist for the grading of fibrosis and

cirrhosis, including the International Association for Study of the Liver (IASL), Batts–Ludwig, and

Metavir systems. The AASLD recommends the Batts–Ludwig system as it gives a verbal diagnosis rather

than numeric categories, and thus may be easier to interpret.104

DIAGNOSIS

Table 59-4 Physical Findings in Cirrhosis

1503

Noninvasive methods to diagnose cirrhosis include ultrasonography, CT, and MRI, which generally

reveal an atrophic, nodular liver and an enlarged spleen. More recent work suggests that subtle changes

in the hepatic veins may be early markers of cirrhosis.102 Ultrasonographic criteria for cirrhosis include

the demonstration of multiple nodular irregularities on the ventral liver surface that are clearly separate

from the anterior abdominal wall. Parenchymal texture is altered in the setting of fibrosis, though this

feature can be subtle. When these criteria are used, ultrasonography has been shown to have a

sensitivity, specificity, and accuracy of approximately 90% in the diagnosis of cirrhosis.105 Ultrasoundbased transient elastography, a measure of liver stiffness, is playing an increasingly large role in the

noninvasive assessment of fibrosis, with some studies demonstrating a 95% area under the receiver

operating characteristic curve (AUROC) for diagnosing grade IV fibrosis (cirrhosis).106

More recently, several laboratory indexes have been found to correlate well with histologic grade of

cirrhosis.106,107 The NAFLD fibrosis score, for example, consists of age, BMI, diabetes, platelet count,

albumin level, and AST/ALT ratio.108 The AUROC of this scoring system in diagnosing stage 3 or greater

fibrosis was 85% in a recent meta-analysis.109 The Fibrotest (LabCorp) is a patented panel of biomarkers

consisting of GGT, haptoglobin, bilirubin, apolipoprotein A1, and alpha-2-macroglobulin. The AUROC of

Fibrotest for fibrosis greater than or equal to stage 2 has been shown to be up to 87%.110 Indirect

evidence of cirrhosis includes endoscopically discovered varices of the esophagus, and the presence of

splenomegaly detected by CT or MRI.

Complications

Renal

Renal complications in cirrhosis are intrinsic to functional dysregulation of vascular tone throughout the

body.111 Several elements come into play and renal dysfunction is characterized by avid sodium

retention despite normovolemia or hypervolemia, dilutional hyponatremia secondary to free water

overload, ascites, and ultimately renal failure and the hepatorenal syndrome (HRS). The paradoxical

arterial vasoconstriction of the renal arterial bed in the face of global fluid overload is critical to the

pathophysiology of HRS.112 Among the complications of cirrhosis, HRS confers the highest risk of

mortality.113 Although HRS is the most dramatic renal complication of liver failure, renal dysfunction in

patients with advanced liver disease is generally multifactorial.112 Renal insufficiency may develop in a

patient with cirrhosis as a direct consequence of the underlying condition (i.e., PBC, amyloidosis), as a

consequence of excessive diuretic use in the treatment of ascites and fluid overload, or as a secondary

reaction to the release of cytokines or hormones by the liver that alter renal function.

DIAGNOSIS

Table 59-5 Differential Diagnosis of Acute Azotemia in Patients with Liver Disease

Much progress has been made in the understanding of the pathophysiology of HRS focusing on the

dysregulation of arterial tone in the end stages of liver disease. Empiric observations that support a

functional or “secondary effect” theory include the lack of anatomic renal abnormalities in patients with

cirrhosis-related renal dysfunction, the normal function of previously dysfunctional kidneys transplanted

into otherwise healthy recipients, and resolution of renal abnormalities after successful hepatic

transplantation. Recent clinical studies have defined the critical role of optimizing colloid balance in the

patient with cirrhosis

114 and the exploration of regulators of renal blood flow such as terlipressin in

counteracting the deranged vascular tone.115

Sodium Retention. Patients with cirrhosis who do not have ascites have relatively normal sodiumhandling capabilities. Patients in whom ascites develops have a marked inability to excrete sodium.

Because of this deficit, sodium intake in excess of renal excretion contributes to fluid overload. Three

1504