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74
Overview of Cirrhosis
PATRICK S. KAMATH AND VIJAY H. SHAH
CHAPTER OUTLINE
Pathogenesis...........................................................................1254 Prognosis................................................................................1259
Diagnosis.................................................................................1254 Treatment................................................................................1259
Natural History.........................................................................1257 Reversal of Fibrosis................................................................. 1260
Cirrhosis, a final pathway for a wide variety of chronic liver fibrosis. Injury to epithelial cells, either through apoptosis,
diseases (Box 74-1), is a pathologic entity defined as diffuse inflammation, or sterile necrosis, culminates in the recruit-
hepatic fibrosis with the replacement of the normal liver archi- ment and activation of hepatic stellate cells.5 The macrophage
tecture by nodules. The rate of progression of chronic liver is also important in fibrosis owing to release of inflammatory
disease to cirrhosis may be quite variable, from weeks in cytokines, which in turn lead to transactivation of hepatic stel-
patients with complete biliary obstruction to decades in late cells into myofibroblasts. Studies have also indicated an
patients with chronic hepatitis C. Cirrhosis is 1 of the leading important role for the sinusoidal endothelial cell in fibrosis
causes of mortality in the United States and particularly afflicts development. Sinusoidal endothelial cells act through auto-
persons in the most productive years of their lives. The protean crine and paracrine signaling pathways to participate in
complications of cirrhosis (Box 74-2) are discussed in other angiogenesis. Angiogenesis may lead to fibrosis through para-
chapters. crine release of hepatic stellate cell activating molecules from
angiogenic sinusoidal endothelial cells. Therefore, multiple
cell types in the liver participate in fibrogenesis, although the
PATHOGENESIS hepatic stellate cell is most directly implicated in this process
because of its abundant capacity to produce matrix.
The liver cell type most implicated in the pathogenesis of
liver fibrosis is the hepatic stellate cell. In normal liver, the
hepatic stellate cell is viewed as a pericyte that lies albuminal DIAGNOSIS
to the sinusoidal endothelial cell in the space of Disse1 (see
Chapter 71). On activation, a hepatic stellate cell transforms Although cirrhosis is strictly speaking a histologic diagnosis
into a myofibroblast (Fig. 74-1).2 Activation is characterized (Fig. 74-2), a combination of clinical, laboratory, and imaging
by increases in the expression of smooth muscle actin, motility, features can help confirm a diagnosis of cirrhosis. Several
and contractility. Most importantly for the development of physical findings suggestive of cirrhosis result in part from
liver fibrosis, the stellate cell begins to generate various forms alterations in the metabolism of estrogen by the cirrhotic liver.
of matrix, which lead to liver fibrosis.2 Fibronectin is the An intense red coloration of the thenar and hypothenar emi-
earliest form of matrix produced by stellate cells, which ulti- nences suggests palmar erythema. Terrys nails are character-
mately produce other forms of matrix, including collagen 1.3 ized by proximal nail bed pallor, which can also involve the
Matrix deposition in turn leads to further hepatic stellate cell entire nail plate, with predominant involvement of the thumb
activation and changes in the hepatic angioarchitecture.3 The and index finger. Clubbing of the fingernails may result from
canonical pathways that are most implicated in activation of the presence of arteriovenous shunts in the lung as a result
the hepatic stellate cell include kinase activation pathways of portal hypertension. Gynecomastia is the enlargement of
mediated through platelet-derived growth factor (PDGF), the male breast with palpable tissue. Spider telangiectasias
transforming growth factor (TGF)-, and integrin signaling (or angiomata) are dilated arterioles characterized by a promi-
pathways. nent central arteriole with radiating vessels. Compression of
In addition to the hepatic stellate cell, other cells, including the central arteriole with a pinhead results in blanching fol-
the portal fibroblast,4 may ultimately culminate in the myofi- lowed by reformation of the spider after release of pressure
broblast phenotype that deposits collagen matrix. The portal on the arteriole. In general, more than 2 to 3 spider telangiec-
fibroblast resides closer than hepatic stellate cells to the portal tasias are considered abnormal. Dilated abdominal veins
tract and is implicated in the liver fibrosis that develops in (caput medusae) with flow away from the umbilicus, toward
response to portal-based, cholestatic injury, as in PBC and the inferior vena cava in the infraumbilical area and toward
PSC.4 It is hypothesized that epithelial cell injury in the peri- the superior vena cava in the supraumbilical area, suggest
portal region leads to transformation of portal fibroblasts into intrahepatic portal hypertension. On the other hand, dilata-
myofibroblasts. tion of veins in the flank with blood draining toward the
Cell types other than myofibroblasts are also important in superior vena cava suggests inferior vena caval obstruction.
the fibrosis process. For example, epithelial cell injury is the Parotid enlargement is also a feature of cirrhosis, especially
initiating step in most forms of liver injury that leads to alcoholic cirrhosis.
1254
Chapter 74 Overview of Cirrhosis 1255
Fibrogenesis Fibrosis
Resolution
Epithelial cell Proteases
Matrix
(hepatocyte, cholangiocyte)
on
ati
ctiv
Dea
Activation Apoptosis
Kupffer cell
Sen
esce
Hepatic stellate cell nce
or portal fibroblast
Myofibroblast
Endothelial cell
FIGURE 74-1. Schematic overview of the pathogenesis of fibrosis and reversal of fibrosis in cirrhosis. Epithelial cell injury in combination
with cytokine release by Kupffer cells and paracrine molecule release by sinusoidal endothelial cells leads to activation of hepatic
stellate cells (or portal fibroblasts) into myofibroblasts. Reversal of fibrosis results from myofibroblast deactivation, apoptosis, or
senescence. Matrix proteases can also achieve fibrosis resolution (see text for details).
A B
C D
FIGURE 74-2. Histologic stages of hepatic fibrosis. A, A normal portal tract containing a portal vein branch, hepatic artery branch, and
interlobular bile duct. The acinar parenchyma shows mild steatosis but no fibrosis. This is stage 0 fibrosis. (H&E.) B, A Massons tri-
chrome stain highlights in blue a normal (minimal) amount of collagen in a portal tract in stage 0. C, In stage 1 (of 4), there is a significant
increase in collagen (fibrosis) in the portal tract. (H&E.) D, The fibrosis in stage 1 is highlighted in blue by a Massons trichrome stain.
The fibrosis expands the portal tract but does not involve the surrounding periportal acinar parenchyma.
Chapter 74 Overview of Cirrhosis 1257
E F
FIGURE 74-2, contd E, Periportal fibrosis characterizes stage 2. Expansion of the portal tract by fibrosis in blue is seen. The collagen is
not confined to the portal tract but also extends to involve the surrounding periportal acinar parenchyma (arrows). (Massons trichrome
stain.) F, In stage 3, bridging fibrosis is seen. Multiple portal tracts demonstrate increased fibrosis in blue and connect with one another,
forming fibrous bridges (arrows). (Massons trichrome stain.) G, In cirrhosis (stage 4), the normal liver architecture is completely distorted
and replaced by regenerative nodules that are separated by fibrous septa in blue. (Massons trichrome stain.) (Images courtesy Taofic
Mounajjed, MD, Rochester, Minn.)
for a liver biopsy has been addressed in a systematic fashion.9 carcinoma characterizes decompensated cirrhosis. In compen-
The most commonly used scoring systems are outlined in sated cirrhosis, these complications are absent. Four clinical
Table 74-1. A serum AST/platelet ratio index (APRI) of greater stages of cirrhosis have been proposed, with stages 1 and 2
than 2 suggests cirrhosis, as does a Bonacini cirrhosis discrimi- representing compensated cirrhosis, and stages 3 and 4 repre-
nant score of 7 or greater. A Bonacini score of less than 3, or a senting decompensated cirrhosis. Stage 1 cirrhosis is charac-
Lok index of less than 0.2, argues against a diagnosis of cir- terized by absence of both ascites and varices; stage 2 cirrhosis
rhosis. Ascites and a platelet count of less than 160,000/mm3 is characterized by the presence of varices without bleeding
render the diagnosis of cirrhosis more likely, whereas the and the absence of ascites; stage 3 cirrhosis is characterized by
absence of hepatomegaly or a firm liver, or a platelet count of ascites with or without esophageal varices; and stage 4 cir-
160 103/mm3 or greater, makes cirrhosis unlikely. rhosis is characterized by variceal bleeding with or without
ascites. In the future, it is possible that staging of cirrhosis will
consider not only clinical and histologic parameters, but also
hemodynamic and biological data.10
NATURAL HISTORY Most deaths in patients with cirrhosis occur as a result of
hepatic decompensation; however, in the compensated stages,
Cirrhosis may be classified broadly as compensated or decom- the most common cause of death is cardiovascular disease,
pensated. The development of complications of variceal hemor- followed by stroke, malignancy, and renal disease.11 Complica-
rhage, ascites, encephalopathy, jaundice, or hepatocellular tions of portal hypertension, hepatocellular carcinoma (HCC),
1258 Section IX Liver
A B
C D
E F
FIGURE 74-3. Imaging in cirrhosis. A, A transverse US image of the right lobe of liver demonstrates the characteristic heterogeneous
liver parenchyma with surface nodularity (arrowheads). B, Axial contrast-enhanced CT image shows a nodular left lobe of the liver
(white arrow). Note the gastric and esophageal varices (black arrow) and splenomegaly (asterisk). C, T2-weighted and D, contrast-
enhanced T1-weighted MRIs show hypointense siderotic nodules (white arrows) and an enlarged left lobe and splenomegaly. E, A
contrast-enhanced MRI shows a heterogeneous liver with an enlarged left lobe. F, A stiffness map from magnetic resonance elastog-
raphy shows increased stiffness of the liver (dotted outline), with a mean stiffness value of 9.2 kilopascals. The normal liver stiffness
value is less than 2.93 kilopascals. (F, From Yin M, Talwalker JA, Glaser KJ, etal. Assessment of hepatic fibrosis with magnetic reso-
nance elastography. Clin Gastroenterol Hepatol 2007; 5:1207-13.e2. Other images courtesy Sudhakar Venkatesh, MD, Rochester, Minn.)
Chapter 74 Overview of Cirrhosis 1259
The modified Bonacini CDS has a range of possible values from 0 to 11; higher score and a decrease in the serum albumin level are also asso-
scores identify patients with a higher likelihood of cirrhosis, and lower scores ciated with decompensation.
identify patients with a lower likelihood of cirrhosis.
The Lok index is an odds ratio normalized to possible values between 0 and 1; a
higher fraction (i.e., probability) increases the likelihood of cirrhosis, whereas a
lower fraction reduces the likelihood of cirrhosis. (See also http://
www.haltctrial.org/cirrhosis.html.)
Adapted from Udell JA, Wang CS, Tinmouth J, etal. Does this patient with liver
TREATMENT
disease have cirrhosis? JAMA 2012; 307:832-42, with permission.
Management of compensated cirrhosis includes surveillance
for HCC with US of the liver every 6 months (see Chapter 96),
screening for esophageal varices by upper GI endoscopy (see
Chapters 20 and 92), cessation of alcohol use, weight loss, and
and sepsis12 are the usual causes of mortality in patients with other lifestyle changes, although the cost-effectiveness of
decompensated cirrhosis. screening for HCC has been questioned.19 Immunization
against HAV, HBV, pneumococcal pneumonia, and influenza
is recommended. Live-attenuated vaccines are not contraindi-
PROGNOSIS cated in patients with cirrhosis. Delaying the progression of
compensated cirrhosis to a decompensated state may be
Liver-related mortality is the eighth leading disease cause of achieved by treating the underlying cause of cirrhosis (e.g.,
death in the United States. Among persons 45 to 64 years of chronic hepatitis B and C),20 abstinence from alcohol, and
age, cirrhosis is the third leading cause of death. As compared weight loss. The use of low molecular weight heparin has been
with the general population, persons with compensated cir- reported to delay decompensation even in patients without
rhosis have a 5-fold increased risk of death, whereas patients portal vein thrombosis.21
with decompensated cirrhosis have a 10-fold increased risk. In general, acetaminophen may be used in persons with
The median survival in patients with compensated cirrhosis cirrhosis in doses of up to 2g daily (see Chapter 88). Aspirin
is 9 to 12 years, compared with 2 years in those with decom- and other NSAIDs should be avoided in patients with decom-
pensated cirrhosis. pensated cirrhosis, including those with ascites. Aminoglyco-
In a nationwide Danish population study, the overall sur- sides are contraindicated, but other antibiotics are acceptable,
vival probability in patients with cirrhosis was 66% at 1 year, as are statins for treatment of hyperlipidemia. In patients with
38% at 5 years, and 22% at 10 years.13 The majority of deaths diabetes mellitus, oral hypoglycemic agents may be used if the
were related to cirrhosis. Most deaths among patients with cirrhosis is compensated, but in patients with decompensated
compensated cirrhosis occurred as a result of transition to a cirrhosis, insulin is preferred. Patients with cirrhosis have
decompensated state. In the Danish study,13 the median sur- protein-calorie malnutrition, and frequent high-calorie small
vival in patients without complications was 48 months, with meals, as well as bedtime snacks, are recommended. Fat-
a 1-year survival rate of 83% in those with compensated cir- soluble vitamins and zinc levels require monitoring, with
rhosis, 80% in those with variceal bleeding, 71% in those with replacement if required.
ascites, 51% in those with ascites and variceal bleeding, and Problems that occur in patients with cirrhosis for which
36% in those with hepatic encephalopathy. there are no clear management solutions include fatigue,
Prognosis depends not only on the clinical stage of the muscle cramps, and sexual dysfunction. Fatigue is a major
disease but also on the presence of comorbidities. Generic factor in reducing a patients quality of life and may be a
scores to determine mortality risk include the Child-Turcotte- manifestation of covert encephalopathy. Fatigue is more
Pugh score (Child-Pugh class) and the MELD score and common in patients with obesity, depression, and sleep apnea.
its modifications (see Chapters 73 and 97), as well as von A search for reversible causes of fatigue, including anemia and
1260 Section IX Liver