Liver injury leading to cirrhosis impairs hepatic function. Steatosis from ethanol is
characterized by lipid deposition in the hepatocytes, which is followed by liver
inflammation (steatohepatitis), hepatocyte death, and collagen deposition leading to
5 Oxidative stress appears to play a role in ethanol-induced liver injury. It is
important to note that not all heavy drinkers experience liver cirrhosis.
as sex, genetic predisposition, and chronic viral infection also play a role in the
development and progression of ethanol-induced liver disease.
Hepatitis C virus (HCV) affects millions of people worldwide. Approximately a
third of those chronically infected are predicted to progress to cirrhosis or
8 The progression of liver disease in patients with HCV is
dependent on both patient and viral factors. Multiple mechanisms are proposed to
play a role in liver injury associated with HCV infection, such as diminished immune
clearance of HCV, oxidative stress, hepatic steatosis, increased iron stores, and
increased rate of hepatocyte apoptosis.
9 Because not all patients infected with HCV
experience cirrhosis, factors other than viral clearance, such as individual immune
response, age, sex, hepatic iron content, and HCV genotype, are all implicated as
cofactors in the development of cirrhosis.
Among other causes, autoimmune hepatitis, primary biliary cirrhosis, primary
sclerosing cholangitis, biliary atresia, metabolic disorders (e.g., Wilson disease and
hemochromatosis), chronic inflammatory conditions (e.g., sarcoidosis), and vascular
derangements can lead to hepatic fibrosis and cirrhosis.
Americans have nonalcoholic fatty liver disease (NAFLD), which in most cases have
no symptoms. Risk factors commonly associated with the development of NAFLD
include obesity, hyperlipidemia, and diabetes. Although corticosteroids can cause
fatty liver, NAFLD diagnosis excludes corticosteroids and other causes of fatty
liver. Nonalcoholic steatohepatitis (NASH) is a more serious form of NAFLD,
which can lead to cirrhosis. Evidence suggests that insulin resistance and lipid
peroxidation play a role in the pathogenesis of this condition.
cause of end-stage liver disease, the most frequent complications of portal
hypertension are esophageal or gastric varices, ascites, hepatic encephalopathy, and
The portal vein begins as a confluence of the splenic, superior mesenteric, inferior
mesenteric, and gastric veins and ends in the sinusoids of the liver (Fig. 25-1). Blood
in the portal vein contains substances absorbed from the intestine and delivers these
substances to the liver to be metabolized before entering the systemic circulation.
Once the portal blood reaches the liver, it crosses through a high-resistance capillary
system within the hepatic sinusoids.
In cirrhosis, increased intrahepatic resistance results from intrahepatic
vasoconstriction that is hypothesized to be caused by a deficiency in intrahepatic
Increased intrahepatic resistance also results from an enhanced
activity of vasoconstrictors and structural changes from liver regeneration, sinusoidal
Portal hypertension results from both an increase in resistance to portal flow and
an increase in portal venous inflow because of splanchnic vasodilatation from
increased NO production in the extrahepatic circulation.
Figure 25-1 Schematic diagram of the portal venous system.
Direct portal pressure measurement is invasive and not routinely performed. The
hepatic venous pressure gradient (HVPG), which reflects the gradient between the
portal vein and vena cava pressure, is another accurate, safe, and less-invasive
procedure, widely accepted as the portal venous pressure gradient.
portal pressure is generally below 6 mm Hg, and in cirrhotic patients, it may increase
to 7 to 9 mm Hg. Clinically significant portal hypertension develops when portal
pressure exceeds 10 to 12 mm Hg, resulting in complications such as esophageal
17,19 Portal hypertension can be further classified as prehepatic
(e.g., splenic, portal vein thrombosis), intrahepatic (e.g., hepatic cirrhosis and
fibrosis), or posthepatic portal hypertension (e.g., inferior vena cava obstruction,
20–22 Persistent portal hypertension may (a) change both
blood flow and the lymphatic circulation and lead to ascites formation; (b) increase
pressure in the vessels that branch off the portal vein, such as the coronary veins,
leading to the formation of esophageal varices; and (c) lead to the development of
increased abdominal collateral circulation. Hepatic encephalopathy and hepatorenal
syndrome are other complications associated with advanced cirrhosis and portal
20–22 The American Association for the Study of Liver Diseases and
European Association for the Study of the Liver Single-Topic Conference classified
cirrhosis into two main categories, compensated and decompensated. Patients can be
cirrhotic with a portal pressure less than 10 mm Hg and an absence of the
complications of cirrhosis (e.g., ascites, variceal hemorrhage, or encephalopathy)
and thus would be considered to be compensated. This is in contrast to a patient
presenting with ascites, esophageal hemorrhage, hepatic encephalopathy, and/or
hepatorenal syndrome, which are present in decompensated cirrhosis.
compensated cirrhosis are managed by treatment of the underlying cause as well as
prevention (primary prophylaxis) and early diagnosis of the complications. For
patients with decompensated cirrhosis, the aim is to treat the complications and
prevent sequela (secondary prevention).
Laboratory evaluations in cirrhosis may not reflect the extent of the parenchymal
necrosis, regeneration, and fibrotic nodular scarring. Conventional liver “function”
tests, such as the serum aminotransferases (aspartate aminotransferase [AST,
formerly known as SGOT], alanine aminotransferase [ALT, formerly known as
SGPT]), and alkaline phosphatase, are actually better characterized as liver “injury”
tests and are modestly helpful to the clinician screening for hepatobiliary disease and
monitoring injury progression. These tests, however, do not quantitatively measure
the functional capacity of the liver. The aminotransferases are released during the
normal turnover of liver cells (see Chapter 2, Interpretation of Clinical Laboratory
Tests). High serum concentrations of aminotransferases suggest enzyme release from
injured hepatocytes. Serum concentrations of AST and ALT may initially rise very
high with acute liver injury and then fall when the etiology is removed or necrosis is
so severe that few hepatocytes remain.
Because alkaline phosphatase is present in high concentrations in biliary canaliculi
(as well as bone, intestines, kidneys, placenta, and white blood cells [WBCs]), its
concentration increases more with biliary than hepatocellular injury. High serum
concentrations of gamma glutamyl transpeptidase and bilirubin are also suggestive of
biliary injury. Elevated serum concentrations of alkaline phosphatase, AST, and/or
ALT may suggest hepatic injury, but because they are also found in other tissues, their
elevation is not diagnostic for liver disease.
Serum concentrations of proteins (e.g., albumin), clotting factors, prothrombin time
(PT), and international normalized ratio (INR) provide insight into liver function.
Albumin is synthesized entirely by the liver; therefore, concentrations reflect
hepatocellular function to some degree. However, changes in albumin concentration
are nonspecific, because they are influenced by other factors, including poor
nutrition, renal wasting (proteinuria), and gastrointestinal (GI) losses. Prothrombin
time is also nonspecific, since it is prolonged in vitamin K deficiency from poor
nutrition or fat malabsorption as well as biliary obstruction (cholestasis).
Child-Turcotte-Pugh Classification of Severity of Liver Disease
Albumin (g/dL) >3.5 2.8–3.5 <2.8
Ascites None Mild to moderate Severe
Encephalopathy (grade) None Mild to moderate (1 and 2) Severe (3 and 4)
Sources: Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage
in cirrhosis [published correction appears in N Engl J Med. 2011;364:490]. N Engl J
Med. 2010;362:823; Gitto S et al. Allocation priority in non-urgent liver
transplantation: an overview of proposed scoring systems. Dig Liver Dis.
A number of the factors described above are included in the Child–Turcotte–Pugh
classification of liver disease severity (Table 25-1).
28,29 This scoring system helps
clinicians grade disease severity, and predicts the long-term risk of mortality and
quality of life. A person with Child–Turcotte–Pugh class A cirrhosis may survive 15
to 20 years, whereas those with class C may survive only 1 to 3 years.
limitation of the Child–Turcotte–Pugh classification is the subjective nature of some
factors, such as ascites and hepatic encephalopathy, which are subject to clinical
interpretation and may be altered by therapy.
31,32 As a general guide, and not a rule,
class A patients are considered to be compensated, and classes B and C
An alternate method for assessing survival in patients with liver disease is the
Model for End-Stage Liver Disease (MELD) score, which is calculated by the
Because of the good correlation between the MELD score and short-term (3-
month) mortality as well as the objective nature of the system, it replaced the Child–
Turcotte–Pugh score in the United Network for Organ Sharing (UNOS) prioritization
of organ allocation of cadaveric livers for transplantation.
from 6 (less ill) to 40 (gravely ill) with highest scores given priority for organ
allocation with the exception of Status 1A adult patients (acute and severe onset of
liver failure, who have a life expectancy of hours to a few days without liver
transplantation) who are given highest priority.
QUESTION 1: R.W. is a 54-year-old man with a 2-week history of nausea, vomiting, and lower abdominal
any medications and has no known drug allergies.
Physical examination reveals an afebrile, jaundiced, and cachectic male in moderate distress. Spider
angiomas were found on his face and upper chest. In addition, palmar erythema was noted.
laboratory data are as follows:
Blood urea nitrogen (BUN), 15 mg/dL
Serum creatinine (SCr), 1.4 mg/dL
Total/direct bilirubin, 18.8/10.7 mg/dL
What subjective and objective evidence are compatible with alcoholic cirrhosis in R.W.?
R.W.’s liver function tests (elevated ALT, AST, alkaline phosphatase, and
bilirubin) and physical findings (enlarged, palpable liver edge; jaundice; spider
angiomas; palmar erythema; and cachexia) are consistent with advanced alcoholic
cirrhosis in a patient with a history of chronic alcohol abuse. The prolonged PT and
hypoalbuminemia suggest impaired hepatic synthesis of both albumin and vitamin K–
dependent clotting factors. The low albumin contributes to both ascites and edema.
The bilirubin of 18.8 mg/dL suggests that vitamin K absorption may be a factor in the
prolonged PT. The presence of ascites (an enlarged fluid-filled
abdomen) and prominent abdominal veins are suggestive of portal hypertension. A
biopsy of the liver may establish the presence and severity of cirrhosis. R.W.’s
prolonged PT, however, will increase the risk of bleeding from a liver biopsy. His
positive guaiac finding could be indicative of bleeding esophageal varices or from
another GI source. This needs to be confirmed by endoscopy. He is oriented to
person, place, and time, but full hepatic encephalopathy evaluation is needed. R.W.’s
calculated MELD score is 22, which predicts a 90-day mortality of approximately
33 A patient’s MELD score may increase or decrease for a period of time
depending on the patient’s clinical status and treatment. A number of MELD scores
will be calculated if R.W. is listed as a transplantation candidate to determine his
36 Muscle wasting and poor nutrition are the most common
causes of weight loss in patients with alcoholic cirrhosis (see Chapter 90, Substance
CASE 25-1, QUESTION 2: What physiologic mechanism predisposes R.W. to fluid accumulation in the
Ascites, or accumulation of fluid in the peritoneal cavity, is the most commonly
encountered clinical symptom of cirrhosis.
24,37 This complication can be detected
during physical examination when more than 3 L of fluid have accumulated. In
addition to an obviously enlarged abdomen, R.W. was found to have a positive fluid
wave and shifting dullness, indicating that the abdominal enlargement is not simply
obesity. If the diagnosis is in doubt, which sometimes occurs in obese patients,
ascites can be confirmed with ultrasound. Generally speaking, in obesity the
abdomen enlarges over time (months to years), in contrast to ascites where
abdominal enlargement can occur over a few weeks.
38 Once ascites develops, the 1-
year patient survival rate falls to ~50%.
In cirrhosis, high hepatic venous pressure leads to high intrasinusoidal pressure
and development of ascites across the hepatic capsule.
to the generalized vasodilation in cirrhosis is increased cardiac output as well as
sodium and water retention through activation of the renin–angiotensin–aldosterone
40 R.W.’s hypoalbuminemia (2.3 g/dL), RAAS activation, exudation
of fluid from the splanchnic capillary bed and the liver surface when the drainage
capacity of the lymphatic system is exceeded, and decreased ability of fluid to be
contained within the vascular space owing to impaired hepatic albumin synthesis
contributes to the development of ascites.
CASE 25-1, QUESTION 3: What are the therapeutic goals in the treatment of R.W.’s ascites?
The goals of treatment for R.W.’s ascites are to treat the cause of cirrhosis by
ceasing alcohol consumption; mobilize ascitic fluid; diminish abdominal discomfort,
back pain, and difficulty in ambulation; as well as to prevent complications (e.g.,
bacterial peritonitis, hernias, pleural effusions, hepatorenal syndrome, and
38 After the initial resolution of significant edema, the goal is a
weight loss of 0.5 kg/day, which corresponds to a net fluid volume loss of about 0.5
L/day. Treatment of ascites in R.W. should be undertaken cautiously and gradually
because acid–base imbalances, hypokalemia, or intravascular volume depletion
caused by overly aggressive therapy can lead to compromised renal function, hepatic
41,42 The initial medical management of ascites involves
restriction of sodium intake and the use of diuretics to promote salt and water
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