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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

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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

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