Acute hepatitis is an inflammatory process causing liver cell death
either by necrosis or by triggering apoptosis (programmed cell death).
A wide range of clinical entities can cause global hepatocyte injury
of sudden onset. Worldwide, acute hepatitis is most commonly caused
by infection with one of several types of viruses. Although these
viral agents can be distinguished by serologic laboratory tests
based on their antigenic properties, all produce clinically similar
illnesses. Other less common infectious agents can result in liver
injury (Table 14–1). Acute hepatitis
is also sometimes caused by exposure to drugs (eg, isoniazid) or
poisons (eg, ethanol).
The severity of illness in acute hepatitis ranges from asymptomatic
and clinically inapparent to fulminant and fatal. The presentation
of acute hepatitis can be quite variable. Some patients are relatively
asymptomatic, with abnormalities noted only by laboratory studies.
Others may have a range of symptoms and signs, including anorexia,
fatigue, weight loss, nausea, vomiting, right upper quadrant abdominal
pain, jaundice, fever, splenomegaly, and ascites. The extent of
hepatic dysfunction can also vary tremendously, correlating roughly
with the severity of liver injury. The relative extent of cholestasis versus
hepatocyte necrosis is also highly variable. The potential interrelationship
of acute hepatitis, chronic hepatitis, and cirrhosis is illustrated
in Figure 14–8.
Clinical syndromes associated with hepatitis: acute hepatitis
(1), which is sometimes associated with intrahepatic cholestasis
(2). Fulminant hepatitis (3) is associated with massive necrosis
and has a high mortality rate. Chronic viral hepatitis may lead
to a carrier state without (4) or with (5) continuing hepatocyte
necrosis. Chronic hepatitis associated with continuing necrosis
often progresses to cirrhosis, whereas that associated simply with
a carrier state does not.
(Redrawn, with permission, from Chandrasoma P,
Taylor CE. Concise Pathology, 3rd ed. Originally
published by Appleton & Lange. Copyright © 1998 by
the McGraw-Hill Companies, Inc.)
Acute hepatitis is commonly caused by one of five major viruses
(Table 14–9): hepatitis A virus
(HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis
D virus (HDV), and hepatitis E virus (HEV).
Table 14–9 Characteristics of Various Types of Viral Hepatitis. |Favorite Table|Download (.pdf)
Table 14–9 Characteristics of Various Types of Viral Hepatitis.
|Hepatitis A||Hepatitis B||Hepatitis C||Hepatitis D||Hepatitis E|
|Jaundice||Uncommon in children||More common in hepatitis A||Uncommon||Common||Common|
|Duration of enzyme elevation||Short||Prolonged||Like hepatitis B||Like hepatitis B|
|Location of virus|
|Severity of acute disease||Mild||Moderate||Mild||Moderate to severe||Severe|
|Mortality rate||Low (< 0.1%)||Low (< 0.5%)||None (in acute disease)||High (5%)||Moderate (+ 3%)|
|Associated with malignancy||No||Yes||Yes||Yes||No|
|Vaccine||Yes||Yes||No||No (vaccinate against HBV)||No|
Table 14–9 summarizes important
characteristics of these viral agents. Other viral agents that can
cause acute hepatitis, though less commonly, include the Epstein-Barr
virus (cause of infectious mononucleosis), cytomegalovirus, varicella virus,
measles virus, herpes simplex virus, rubella virus, and yellow fever
virus. A newly discovered DNA virus, SEN virus, may be associated
with transfusion-associated acute hepatitis not attributable to
HAV, a small RNA virus, causes liver disease both by direct killing
of hepatocytes and by the host’s immune response to infected
hepatocytes. It is spread by the fecal-oral route from infected
individuals. Although most cases are mild, hepatitis A occasionally
causes fulminant liver failure and massive hepatocellular necrosis,
resulting in death. Regardless of the severity, patients who recover
do so completely, show no evidence of residual liver disease, and
have antibodies that protect them from reinfection.
HBV is a DNA virus that is transmitted by sexual contact or by
contact with infected blood or other bodily fluids. This virus does
not kill the cells it infects. Rather, the infected hepatocytes die
almost exclusively as a consequence of attack by the immune system
after recognition of viral antigens on the hepatocyte surface. Although
most cases of hepatitis B infection are asymptomatic or produce
only mild disease before clearance of the virus, an excessive immune
response may produce fulminant hepatic failure. In even fewer patients—typically
those with mild acute disease—the immune response is inadequate
to clear the virus completely, and chronic hepatitis develops. It
is estimated that approximately 1.25 million Americans are infected
with HBV, and an estimated 70,000 new infections occur each year. Additionally,
complications of HBV-induced liver disease results in up to 5000
deaths each year in the United States.
HCV is a RNA virus, also transmitted by blood and body fluids,
causes a form of hepatitis similar to HBV infection but with a far
greater proportion of cases (60–85%) progressing
to chronic hepatitis. Approximately 4 million Americans are infected
with HCV, and about 30,000 new infections occur each year. End-stage
liver disease from HCV accounts for 8000–10,000 deaths
each year. End-stage liver disease due to HCV is the most common
indication for liver transplantation in the United States.
HDV, also known as delta agent, is a defective RNA virus that
requires helper functions of HBV to cause infection. Thus, individuals
who are chronically infected with HBV are at high risk for HDV infection,
whereas those who have been vaccinated against HBV are at no risk.
HDV infection occurs either as coinfection with HBV or superinfection
in the setting of chronic HBV. HDV infection causes a much more severe form of hepatitis
both in terms of the proportion of fulminant cases and in the percentage
of cases that progress to chronic hepatitis. In North America, HDV
coinfection primarily occurs in high-risk groups such as injection
drug users and hemophiliacs, and in up to 9% of those high-risk
patients who are HBV-coinfected individuals. In the United States,
the prevalence of HDV coinfection in the general HBV-infected population
is not well known.
HEV is an unclassified RNA virus, and like HAV, it is spread
via the fecal-oral route. The clinical disease resembles hepatitis
A, but HEV infection may result in fulminant hepatitis in pregnant
Most cases of drug-induced liver disease present as acute hepatitis,
although some present as cholestasis or other patterns (Table 14–7). The incidence of drug-induced
hepatitis has been rising; acetaminophen is now the most common
cause of fulminant hepatitis in the United States and the United
Kingdom. Hepatic toxins can be further subdivided into those for which
hepatic toxicity is predictable and dose dependent for most individuals
(eg, acetaminophen) and those that cause unpredictable (idiosyncratic)
reactions without relationship to dose. Tables 14–10 and 14–11 summarize
speculations on the mechanisms of idiosyncratic and dose-related
drug-induced hepatic disease. Idiosyncratic reactions to drugs may
be due to genetic predisposition in susceptible individuals to certain
pathways of drug metabolism that generate toxic intermediates. Prominent
examples of drugs causing acute liver failure that have been withdrawn
from the U.S. market include bromfenac, a nonsteroidal anti-inflammatory drug (NSAID), and
troglitazone sulfate, a thiazolidinedione used as an insulin-sensitizing
agent in diabetes mellitus. Other thiazolidinediones such as rosiglitazone
and pioglitazone do not seem to have the same complication, although
routine testing of transaminases has been recommended for those
taking the drugs. HMG-CoA reductase inhibitors such as atorvastatin, lovastatin,
and others are associated with elevated levels of transaminases
in less than 3% of patients and with few cases of acute
Table 14–10 Idiosyncratic Drug Reactions and the Cells that Are Affected. |Favorite Table|Download (.pdf)
Table 14–10 Idiosyncratic Drug Reactions and the Cells that Are Affected.
|Type of Reaction||Effect on Cells||Examples of Drugs|
|Hepatocellular||Direct effect or production by enzyme-drug adduct leads to
cell dysfunction, membrane dysfunction, cytotoxic T-cell response||Isoniazid, trazodone, diclofenac, nefazodone, venlafaxine,
|Cholestasis||Injury to canalicular membrane and transporters||Chlorpromazine, estrogen, erythromycin and its derivatives|
|Immunoallergic||Enzyme-drug adducts on cell surface induce IgE response||Halothane, phenytoin, sulfamethoxazole|
|Granulomatous||Macrophages, lymphocytes infiltrate hepatic lobule||Diltiazem, sulfa drugs, quinidine|
|Microvesicular fat||Altered mitochondrial respiration, oxidation leads to lactic
acidosis and triglyceride accumulation||Didanosine, tetracycline, acetylsalicylic acid, valproic
|Autoimmune||Cytotoxic lymphocyte response directed at hepatocyte membrane
components||Nitrofurantoin, methyldopa, lovastatin, minocycline|
|Fibrosis||Activation of stellate cells||Methotrexate, excess vitamin A|
|Vascular collapse||Causes ischemic or hypoxic injury||Nicotinic acid, cocaine, methylene-dioxymethamphetamine|
|Oncogenesis||Encourages tumor formation||Oral contraceptives, androgens|
|Mixed||Cytoplasmic and canalicular injury, direct damage to bile
ducts||Amoxicillin-clavulanate, carbamazepine, herbs, cyclosporine,
Table 14–11 Postulated Mechanisms of Drug-Induced Liver Disease. |Favorite Table|Download (.pdf)
Table 14–11 Postulated Mechanisms of Drug-Induced Liver Disease.
|Alteration of the physical properties of membranes||Estrogens|
|Inhibition of membrane enzymes (eg, Na+-K+ ATPase)||Chlorpromazine metabolites|
|Interference with hepatic uptake processes||Rifampin|
|Impairment of cytoskeletal function||Chlorpromazine metabolites|
|Formation of insoluble complexes in bile||Chlorpromazine|
|Conversion to reactive intermediates||Acetaminophen|
|Electrophils producing covalent modifications of tissue macromolecules|
|Free radicals producing lipid peroxidation||Carbon tetrachloride|
|Redox cycling with production of oxygen radicals||Nitrofurantoin|
The time course of acute hepatitis is highly variable. In hepatitis
A jaundice is typically seen 4–8 weeks after exposure, whereas
in hepatitis B jaundice occurs usually from 8–20 weeks
after exposure (Figure 14–9). Drug-
and toxin-induced hepatitis typically occurs at any time during
or shortly after exposure and resolves with discontinuance of the
offending agent. This is usually the case for both idiosyncratic
and dose-dependent reactions.
(A) Serum antibody and antigen levels in hepatitis
A and hepatitis B. (AST, aspartate amino-transferase, a marker for
hepatocellular injury and necrosis; IgM anti-HAV, early antibody
response to hepatitis A infection; IgG anti-HAV, late antibody response
to hepatitis A infection; HBsAg, hepatitis B surface antigen, a
marker of active viral gene expression; HBeAg, hepatitis B early
antigen, a marker of infectivity.) Antibodies to the surface or
early antigens (anti-HBs or anti-HBe) indicate immunity.
(Redrawn, with permission, from Chandrasoma P,
Taylor CE. Concise Pathology, 3rd ed. Originally
published by Appleton & Lange. Copyright © 1998 by
the McGraw-Hill Companies, Inc.)
(B) Course of acute, resolving HCV infection. ALT,
Alanine aminotransferase, HCV RNA, hepatitis C viral load, anti-HCV,
(Redrawn, with permission, from Hoofnagle JH.
Course and outcome of hepatitis C. Hepatology. 2002 Nov;36(5 Suppl 1):S21–9.)
Acute hepatitis typically resolves in 3–6 months. Hepatic injury
continuing for more than 6 months is arbitrarily defined as chronic
hepatitis and suggests, in the absence of continued exposure to
a noxious agent, that immune or other mechanisms are at work.
The viral agents responsible for acute hepatitis first infect
the hepatocyte. During the incubation period, intense viral replication
in the liver cell leads to the appearance of viral components (first
antigens, later antibodies) in urine, stool, and body fluids. Liver
cell death and an associated inflammatory response then ensue, followed
by changes in laboratory tests of liver function and the appearance
of various symptoms and signs of liver disease.
Liver damage—The host’s
immunologic response plays an important though incompletely understood
role in the pathogenesis of liver damage. In hepatitis B, for example, the
virus is probably not directly cytopathic. Indeed, there are asymptomatic
HBV carriers who have normal liver function and histologic features.
Instead, the host’s cellular immune response has an important
role in causing liver cell injury. Patients with defects in cell-mediated immunity
are more likely to remain chronically infected with HBV than to
clear the infection. Histologic specimens from patients with HBV-related
liver injury demonstrate lymphocytes next to necrotic liver cells.
It is thought that cytolytic T lymphocytes become sensitized to
recognize hepatitis B viral antigens (eg, small quantities of hepatitis
B surface antigen [HBsAg]) and host antigens on
the surfaces of HBV-infected liver cells.
Extrahepatic manifestations—Immune factors
may also be important in the pathogenesis of the extrahepatic manifestations
of acute viral hepatitis. For example, in hepatitis B, a serum sickness-like
prodrome characterized by fever, urticarial rash and angioedema,
and arthralgias and arthritis appears to be related to immune complex–mediated
tissue damage. During the early prodrome, circulating immune complexes
are composed of HBsAg in high titer in association with small quantities of
anti-HBs. These circulating immune complexes are deposited in blood
vessel walls, leading to activation of the complement cascade. In
patients with arthritis, serum complement levels are depressed,
and complement can be detected in circulating immune complexes containing HBsAg,
anti-HBs, immunoglobulin (Ig) G, IgM, IgA, and fibrin. Cryoglobulinemia
is a common finding in chronic hepatitis C infection.
Immune factors are thought to be important in the pathogenesis
of some clinical manifestations in patients who become chronic HBsAg
carriers after acute hepatitis. For example, in patients developing
glomerulonephritis with nephrotic syndrome, histopathologic investigation
demonstrates deposition of HBsAg, immunoglobulin, and complement
in the glomerular basement membrane. In patients developing polyarteritis
nodosa, similar deposits have been demonstrated in affected small
and medium-sized arteries.
Other, more rare, extrahepatic manifestations include papular
acrodermatitis, and Guillain-Barré syndrome for HBV, and
idiopathic thrombocytopenic purpura, lichen planus, Sjögren’s
syndrome, and porphyria cutanea tarda for HCV.
Ethanol has both direct and indirect toxic effects on the liver as
well as effects on many other organ systems of the body. Its direct
effects may result from increasing the fluidity of biologic membranes
and thereby disrupting cellular functions. Its indirect effects
on the liver are in part a consequence of its metabolism. Ethanol
is sequentially oxidized to acetaldehyde and then to acetate, with
the generation of NADH and adenosine triphosphate (ATP). As a result
of the high ratio of reduced to oxidized NAD that is generated,
the pathways of fatty acid oxidation and gluconeogenesis are inhibited,
whereas fatty acid synthesis is promoted. Ethanol can also quantitatively
and qualitatively alter the pattern of gene expression in various
tissues but especially in the liver, resulting in impaired homeostasis
and greater sensitivity to other toxins. These and other biochemical
mechanisms may contribute to the common observation of fat accumulation
in the liver of alcoholics and the tendency of hypoglycemia to develop
in alcoholics whose liver glycogen has been depleted by fasting.
Ethanol metabolism also affects the liver by generating acetaldehyde,
which reacts with primary amino groups to inactivate enzymes, resulting
in direct toxicity to the hepatocyte in which it is generated. Furthermore,
proteins so modified may activate the immune system against antigens
that were previously tolerated as “self.”
There is considerable variation among individuals in the amount
of ethanol required to cause acute liver injury. Whether nutritional,
genetic, or other factors are responsible for these differences
has not been determined. The mechanisms thought to be responsible
for ethanol-induced liver injury are listed in Table
Table 14–12 Mechanisms of Hepatocyte Injury by Ethanol. |Favorite Table|Download (.pdf)
Table 14–12 Mechanisms of Hepatocyte Injury by Ethanol.
|Disorganizes the lipid portion of cell membranes, leading
to adaptive changes in their composition|
|Increased fluidity and permeability of membranes|
|Impaired assembly of glycoproteins into membranes|
|Impaired secretion of glycoproteins|
|Impaired binding and internalization of large ligands|
|Formation of abnormal mitochondria|
|Impairment of transport of small ligands|
|Impairment of membrane-bound enzymes|
|Adaptive changes in lipid composition, leading to increased
|Abnormal display of antigens on the plasma membrane|
|Alters the capacity of liver cells to cope with environmental
|Induces xenobiotic metabolizing enzymes|
|Directly inhibits xenobiotic metabolizing enzymes|
|Induces deficiency in mechanisms protecting against injury
due to reactive metabolites|
|Enhances the toxicity of O2|
|Oxidation of ethanol produces acetaldehyde, a toxic
and reactive intermediate|
|Inhibits export of proteins from the liver|
|Modifies hepatic protein synthesis in fasted animals|
|Alters the metabolism of cofactors essential for enzymatic
activity—pyridoxine, folate, choline, zinc, vitamin E|
|Alters the oxidation-reduction potential of the liver cell|
In uncomplicated acute hepatitis, the typical histologic findings
consist of (1) focal liver cell degeneration and necrosis, with
cell dropout, ballooning, and acidophilic degeneration (shrunken
cells with eosinophilic cytoplasm and pyknotic nuclei); (2) inflammation
of portal areas, with infiltration by mononuclear cells (small lymphocytes,
plasma cells, eosinophils); (3) prominence of Kupffer cells and
bile ducts; and (4) cholestasis (arrested bile flow) with bile plugs.
Characteristically, although the regular pattern of the cords of
hepatocytes is disrupted, the reticulin framework is preserved.
This reticular framework provides scaffolding for liver cells when they
Recovery from acute hepatitis from any cause is characterized
histologically by regeneration of hepatocytes, with numerous mitotic
figures and multinucleated cells, and by a largely complete restoration
of normal lobular architecture.
Less commonly in acute hepatitis (1–5% of patients),
there will be a more severe histologic lesion called bridging
hepatic necrosis (also called subacute, submassive, or confluent
necrosis). Bridging is said to occur between lobules because necrosis involves
contiguous groups of hepatocytes, resulting in large areas of hepatic
cell loss and collapse of the reticulin framework. Necrotic zones
(“bridges”) consisting of condensed reticulin,
inflammatory debris, and degenerating liver cells link adjacent
portal or central areas or may involve entire lobules.
Rarely, in massive hepatic necrosis or fulminant hepatitis (<
1% of patients), the liver becomes small, shrunken, and soft
(acute yellow atrophy). Histologic examination reveals massive hepatocyte
necrosis in most of the lobules, leading to extensive collapse and
condensation of the reticulin framework and portal structures (bile
ducts and vessels).
The pathology of alcoholic hepatitis is different from that of viral
hepatitis in some ways. The specific pathologic features of alcoholic
hepatitis include accumulation of Mallory’s hyalin and
infiltration of polymorphonuclear leukocytes.
Acute viral hepatitis usually is manifested in three phases:
the prodrome, the icteric phase, and the convalescent phase.
Prodrome—The prodrome, typically
lasting 3 or 4 days, is characterized by three sets of symptoms
and signs: (1) nonspecific constitutional symptoms and signs: malaise,
fatigue, and mild fever; (2) GI symptoms and signs: anorexia, nausea,
vomiting, altered senses of olfaction and taste (loss of taste for
coffee or cigarettes), and right upper quadrant abdominal discomfort
(reflecting the enlarged liver); and (3) extrahepatic symptoms and
signs: headache, photophobia, cough, coryza, myalgias, urticarial
skin rash, arthralgias or arthritis (10–15% of
patients with HBV), and, rarely, hematuria and proteinuria.
Icteric phase—The icteric phase typically
lasts for 1–4 weeks. The constitutional symptoms
usually improve, although mild weight loss may occur. Pruritus occurs
if cholestasis is severe. Right upper quadrant abdominal pain as
a result of the enlarged and tender liver, which was present in
the prodromal phase, continues. Splenomegaly is noted in 10–20% of
Jaundice may be observed as a yellowing of the scleras, skin, or
mucous membranes. Jaundice is generally not appreciated on physical
examination before the serum bilirubin rises above 2.5 mg/dL
(41.75 μmol/L). Direct hyperbilirubinemia is
elevation of the level of conjugated bilirubin in the bloodstream. Its
occurrence indicates unimpaired ability of hepatocytes to conjugate
bilirubin but a defect in the excretion of bilirubin into the bile
as a result of intrahepatic cholestasis or posthepatic obstructive
biliary tract disease, with overflow of conjugated bilirubin out
of hepatocytes and into the bloodstream.
Changes in stool color (lightening) and urine color (darkening)
often precede clinically evident jaundice. This reflects loss of
bilirubin metabolites from the stool as a consequence of disrupted
bile flow. Water-soluble (conjugated) bilirubin metabolites are
excreted in the urine, whereas water-insoluble metabolites accumulate
in tissues, giving rise to jaundice. Note that in most cases of
acute viral hepatitis the degree of liver impairment is sufficiently
mild that jaundice does not develop.
Ecchymoses suggest coagulopathy, which may be due to loss of
vitamin K absorptive capacity from the intestine (caused by cholestasis)
or decreased coagulation factor synthesis. Rarely, loss of clearance
of activated clotting factors triggers disseminated intravascular
coagulation. Coagulopathy in which the prothrombin time can be corrected
by vitamin K injections but not by oral vitamin K suggests cholestatic
disease, because vitamin K uptake from the gut is dependent on bile
flow. If the prothrombin time cannot be corrected with either oral
or parenteral vitamin K, inability to synthesize clotting factor polypeptides
(eg, as a result of massive hepatocellular dysfunction) should be
suspected. Correction of prothrombin time with oral vitamin K alone
suggests a nutritional deficiency rather than liver disease as the
basis for the coagulopathy.
Tests for serum levels of various enzymes normally localized
primarily within hepatocytes provide an indication of the extent
of liver cell necrosis. For unclear reasons, perhaps related to
liver cell polarity, certain forms of liver disease typically result
in disproportionate elevations in some parameters. Thus, in alcoholic
hepatitis but not in viral hepatitis, AST is often disproportionately
elevated relative to ALT (AST:ALT ratio > 2.0). One hypothesis is
that this is due to pyridoxine deficiency in alcoholics. Likewise,
in cholestasis, alkaline phosphatase is commonly disproportionately
elevated relative to AST or ALT.
Measurement of antigen and antibody titers is a convenient way
to assess whether an episode of acute hepatitis is due to viral
infection. Moreover, because IgM antibodies are produced early after
exposure to antigens (ie, soon after onset of illness), the presence
of IgM antibodies to either HAV or to core antigen of HBV (HBcAg)
is strong evidence that an episode of acute hepatitis is due to
the corresponding viral infection. Several months after onset of
illness, IgM antibody titers wane and are replaced by antibodies
of the IgG class, indicating immunity to recurrence of infection
by the same virus. Presence of hepatitis B “e” antigen
(HBeAg) correlates well with a high degree of infectivity (Table 14–13). However, more sensitive
DNA tests have shown low levels of viral DNA in the blood of many
who are HBeAg negative and who are thus still infectious. Subtle
or profound mental status changes are seen in fulminant hepatic
necrosis. Encephalopathy is believed to be related in part to failure
of detoxification of ammonia, which normally occurs through the
urea cycle. Other products such as γ-aminobutyric
acid (GABA) may not be metabolized. Although ammonia is a neurotoxin,
it remains unclear whether it is the major agent of CNS dysfunction
or whether elevated blood levels of GABA (or other compounds) may
act synergistically to alter mental status because of its role as
a major inhibitory neurotransmitter.
Table 14–13 Commonly Encountered Serologic Patterns in Hepatitis B Infection. |Favorite Table|Download (.pdf)
Table 14–13 Commonly Encountered Serologic Patterns in Hepatitis B Infection.
|+||–||IgM||+||–||Acute HBV infection, high infectivity|
|+||–||IgG||+||–||Chronic HBV infection, high infectivity|
|+||–||IgG||–||+||Late acute or chronic HBV infection, low infectivity|
1. HBsAg of one subtype and heterotypic anti-HBs (common)
Process of seroconversion from HBsAg to anti-HBs (rare)
1. Acute HBV infection
2. Anti-HBc window
1. Low-level HBsAg carrier
2. Remote past infection
|–||+||IgG||–||+/–||Recovery from HBV infection|
1. Immunization with HBsAg (after vaccination)
2. Remote past
In addition to encephalopathic changes caused by accumulation
of toxins, acute hepatic failure is associated with encephalopathy
from cerebral edema caused by increased intracranial pressure, perhaps
related to alterations in the blood-brain barrier.
Renal dysfunction may complicate fulminant hepatic failure. Affected
patients may develop prerenal azotemia when the glomerular filtration
rate falls secondary to intravascular volume depletion. A state
of intravascular volume depletion can be induced by the combination
of decreased oral intake, vomiting, and formation of ascites. If
uncorrected, this process can lead to acute tubular necrosis and
acute renal failure. Other causes of renal dysfunction in fulminant
hepatic failure include toxins (eg, acetaminophen or Amanita poisoning)
or hepatorenal syndrome. Serum creatinine is a more accurate measure
than blood urea nitrogen of renal impairment in fulminant hepatic
failure resulting from decreased hepatic urea production. Other
complications of fulminant hepatic failure include cardiovascular
dysfunction as a result of systemic vasodilation and hypotension,
pulmonary edema, coagulopathy, sepsis, and hypoglycemia.
Convalescent phase—The convalescent
phase is characterized by complete disappearance of constitutional
symptoms but persistent abnormalities in liver function tests. Symptoms
and signs gradually improve.
- 22. Describe the range of clinical
presentations of acute hepatitis.
- 23. Which viruses can cause hepatitis?
- 24. What are some extrahepatic manifestations
of viral hepatitis?
- 25. What is the basis for the extrahepatic
manifestations of viral hepatitis?
Chronic hepatitis is a category of disorders characterized by the
combination of liver cell necrosis and inflammation of varying severity
persisting for more than 6 months. It may be due to viral infection;
drugs and toxins; genetic, metabolic, or autoimmune factors; or
unknown causes. The severity ranges from an asymptomatic stable
illness characterized only by laboratory test abnormalities to a
severe, gradually progressive illness culminating in cirrhosis,
liver failure, and death. Based on clinical, laboratory, and biopsy
findings, chronic hepatitis is best assessed with regard to (1)
distribution and severity of inflammation, (2) degree of fibrosis,
and (3) etiology, which has important prognostic implications. A
simplified scoring system for assessment of liver biopsies for chronic
hepatitis is presented in Table 14–14.
Table 14–14 Simplified Scoring System for Chronic Hepatitis. |Favorite Table|Download (.pdf)
Table 14–14 Simplified Scoring System for Chronic Hepatitis.
|A. Portal inflammation and interface hepatitis|
|0 Absent or minimal|
|1 Portal inflammation only|
|2 Mild or localized interface hepatitis|
|3 Moderate or more extensive interface hepatitis|
|4 Severe and widespread interface hepatitis|
|B. Lobular activity|
|1 Inflammatory cells but no hepatocellular damage|
|2 Focal necrosis or apoptosis|
|3 Severe hepatocellular damage|
|4 Damage includes bridging confluent necrosis|
|0 No fibrosis|
|1 Fibrosis confined to portal tracts|
|2 Periportal or portal–portal septa
but intact vascular relationships|
|3 Fibrosis with distorted structure but no obvious
|4 Probable or definite cirrhosis|
Patients may present with fatigue, malaise, low-grade fever, anorexia,
weight loss, mild intermittent jaundice, and mild hepatosplenomegaly.
Others are initially asymptomatic and present late in the course
of the disease with complications of cirrhosis, including variceal
bleeding, coagulopathy, encephalopathy, jaundice, and ascites. In
contrast to chronic persistent hepatitis, some patients with chronic
active hepatitis, particularly those without serologic evidence
of antecedent HBV infection, present with extrahepatic symptoms
such as skin rash, diarrhea, arthritis, and various autoimmune disorders
Table 14–15 Autoimmune Disorders and Extrahepatic Manifestations Associated with Chronic Active Hepatitis. |Favorite Table|Download (.pdf)
Table 14–15 Autoimmune Disorders and Extrahepatic Manifestations Associated with Chronic Active Hepatitis.
|Autoimmune hemolytic anemia|
|Primary pulmonary hypertension|
|Amenorrhea and other menstrual abnormalities|
Either type of chronic hepatitis can be caused by infection with several
hepatitis viruses (eg, hepatitis B with or without hepatitis D superinfection
and hepatitis C); a variety of drugs and poisons (eg, ethanol, isoniazid,
acetaminophen), often in amounts insufficient to cause symptomatic
acute hepatitis; genetic and metabolic disorders (eg, α1-antiprotease [α1-antitrypsin] deficiency,
Wilson’s disease); or immune-mediated injury of unknown
origin. Table 14–1 summarizes known causes
of chronic hepatitis. Less than 5% of otherwise healthy adults
with acute hepatitis B remain chronically infected with HBV; the
risk is higher in those who are immunocompromised or of young age (eg,
chronic infection develops in approximately 90% of neonates).
Among those chronically infected, about two-thirds develop mild
chronic hepatitis and one-third develop severe chronic hepatitis
(see later discussion). Superinfection with HDV of a patient with
chronic HBV infection is associated with a much higher rate of chronic
hepatitis than is seen with isolated hepatitis B infection. Hepatitis
D superinfection of patients with hepatitis B is also associated
with a high incidence of fulminant hepatic failure. Finally, 60–85% of individuals
with acute post-transfusional or community-acquired hepatitis C
develop chronic hepatitis.
Many cases of chronic hepatitis are thought to represent an immune-mediated
attack on the liver occurring as a result of persistence of certain
hepatitis viruses or after prolonged exposure to certain drugs or
noxious substances (Table 14–16).
In some, no mechanism has been recognized. Evidence that the disorder is
immune mediated is that liver biopsies reveal inflammation (infiltration
of lymphocytes) in characteristic regions of the liver architecture
(eg, portal versus lobular). Furthermore, a variety of autoimmune
disorders occur with high frequency in patients with chronic hepatitis
Table 14–16 Drugs Implicated in the Etiology of Chronic Hepatitis. |Favorite Table|Download (.pdf)
Viral hepatitis is the most common cause of chronic liver disease
in the United States. In approximately 5% of cases of HBV infection
and 60–85% of hepatitis C infections, the immune response
is inadequate to clear the liver of virus, resulting in persistent
infection. The individual becomes a chronic carrier, intermittently
producing the virus and hence remaining infectious to others. Biochemically,
these patients are often found to have viral
DNA integrated into their genomes in a manner that results in abnormal
expression of certain viral proteins with or without production
of intact virus. Viral antigens expressed on the hepatocyte cell
surface are associated with class I HLA determinants, thus eliciting
lymphocyte cytotoxicity and resulting in hepatitis. The severity
of chronic hepatitis is largely dependent on the activity of viral
replication and the response by the host’s immune system.
Chronic hepatitis B infection predisposes the patient to the development
of hepatocellular carcinoma even in the absence of cirrhosis. It
remains unclear whether hepatitis B infection is the initiator or
simply a promoter in the process of tumorigenesis. In hepatitis
C infection, hepatocellular carcinoma develops only in the setting
Chronic liver disease in response to some poisons or toxins may
represent triggering of an underlying genetic predisposition to
immune attack on the liver. In alcoholic hepatitis, however, repeated
episodes of acute injury ultimately cause necrosis, fibrosis, and
regeneration, leading eventually to cirrhosis (Figure
14–10). As in other forms of liver disease, there is
considerable variation in the extent of symptoms before development
Changes in the hepatic subendothelial space during fibrosing
liver injury. Cellular and matrix alterations in the space of Disse
are critical events in the pathogenesis of hepatic fibrosis. The
activation of lipocytes, characterized by proliferation and increased
fibrogenesis, is associated with the replacement of the normal low-density
matrix with a high-density matrix. These alterations are likely
to underlie, at least in part, the loss of both endothelial fenestrations
(pores) and hepatocytic microvilli typical of chronic liver injury.
(Redrawn, with permission, from Bissell DM. The
cellular basis of hepatic fibrosis. N Engl J Med. 1993;328:1828.)
Fatty Liver Disease
In light of increasing obesity in the United States, there has been
a significant increase in the prevalence of nonalcoholic fatty liver
disease (NAFLD), a form of chronic liver disease that is associated
with the metabolic syndrome. NAFLD occurs in disorders that cause
predominantly macrovesicular fat accumulation in the liver. Conditions
such as obesity, diabetes mellitus, hypertriglyceridemia, and insulin
resistance are considered risk factors for development of NAFLD.
An estimated 3–6% of the U.S. population with
an aggressive form of NAFLD known as nonalcoholic steatohepatitis
are, in particular, at higher risk of progressive liver disease,
cirrhosis, and hepatocellular carcinoma.
Some patients develop chronic hepatitis in the absence of evidence
of preceding viral hepatitis or exposure to noxious agents (Figure 14–11). These patients typically
have serologic evidence of disordered immunoregulation, manifested
as hyperglobulinemia and circulating autoantibodies. Nearly 75% of
these patients are women, and many have other autoimmune disorders.
A genetic predisposition is strongly suggested. Most patients with
autoimmune hepatitis show histologic improvement in liver biopsies
after treatment with systemic corticosteroids. The clinical response,
however, can be variable. Primary biliary cirrhosis and autoimmune
cholangitis represent cholestatic forms of an autoimmune-mediated
Chronic hepatitis, showing marked lymphocytic infiltration
and fibrosis of the portal areas. The lymphocytes extend into the
peripheral part of the lobule through the limiting plate. There
is ongoing necrosis of hepatocytes in the peripheral part of the
lobule (piecemeal necrosis).
(Reproduced, with permission, from Chandrasoma
P, Taylor CE. Concise Pathology, 3rd ed. Originally
published by Appleton & Lange. Copyright © 1998 by
the McGraw-Hill Companies, Inc.)
All forms of chronic hepatitis share the common histopathologic
features of (1) inflammatory infiltration of hepatic portal areas
with mononuclear cells, especially lymphocytes and plasma cells,
and (2) necrosis of hepatocytes within the parenchyma or immediately
adjacent to portal areas (periportal hepatitis, or “piecemeal
In mild chronic hepatitis, the overall architecture of the liver
is preserved. Histologically, the liver reveals a characteristic
lymphocyte and plasma cell infiltrate confined to the portal triad
without disruption of the limiting plate and no evidence of active
hepatocyte necrosis. There is little or no fibrosis, and what there
is generally is restricted to the portal area; there is no sign
of cirrhosis. A “cobblestone” appearance of liver
cells is seen, indicating regeneration of hepatocytes.
In more severe cases of chronic hepatitis, the portal areas are
expanded and densely infiltrated by lymphocytes, histiocytes, and
plasma cells. There is necrosis of hepatocytes at the periphery
of the lobule, with erosion of the limiting plate surrounding the
portal triads (piecemeal necrosis; Figure 14–11). More
severe cases also show evidence of necrosis and fibrosis between
portal triads. There is disruption of normal liver architecture
by bands of scar tissue and inflammatory cells that link portal
areas to one another and to central areas (bridging necrosis). These
connective tissue bridges are evidence of remodeling of hepatic
architecture, a crucial step in the development of cirrhosis. Fibrosis
may extend from the portal areas into the lobules, isolating hepatocytes
into clusters and enveloping bile ducts. Regeneration of hepatocytes
is seen with mitotic figures, multinucleated cells, rosette formation,
and regenerative pseudolobules. Progression to cirrhosis is signaled
by extensive fibrosis, loss of zonal architecture, and regenerating
Some patients with mild chronic hepatitis are entirely asymptomatic
and identified only in the course of routine blood testing; others
have an insidious onset of nonspecific symptoms such as anorexia,
malaise, and fatigue or hepatic symptoms such as right upper quadrant
abdominal discomfort or pain. Fatigue in chronic hepatitis may be
related to a change in the hypothalamic-adrenal neuroendocrine axis
brought about by altered endogenous opioidergic neurotransmission.
Jaundice, if present, is usually mild. There may be mild tender hepatomegaly
and occasional splenomegaly. Palmar erythema and spider telangiectases
are seen in severe cases. Other extrahepatic manifestations are
unusual. By definition, signs of cirrhosis and portal hypertension
(eg, ascites, collateral circulation, and encephalopathy) are absent.
Laboratory studies show mild to moderate increases in serum aminotransferase,
bilirubin, and globulin levels. Serum albumin and the prothrombin
time are normal until late in the progression of liver disease.
The clinical manifestations of chronic hepatitis probably reflect
the role of a systemic genetically controlled immune disorder in
the pathogenesis of severe disease. Acne, hirsutism, and amenorrhea
may occur as a reflection of the hormonal effects of chronic liver
disease. Laboratory studies in patients with severe chronic hepatitis
are invariably abnormal to various degrees. However, these abnormalities
do not correlate with clinical severity. Thus, the serum bilirubin,
alkaline phosphatase, and globulin levels may be normal and aminotransferase
levels only mildly elevated at the same time that a liver biopsy
reveals severe chronic hepatitis. However, an elevated prothrombin
time usually reflects severe disease.
The natural history and treatment of chronic hepatitis varies
depending on its cause. The complications of severe chronic hepatitis
are those of progression to cirrhosis: variceal bleeding, encephalopathy,
coagulopathy, hypersplenism, and ascites. These are largely due
to portosystemic shunting rather than diminished hepatocyte reserve
(see later discussion).
- 26. What are the categories of chronic
hepatitis based on histologic findings on liver biopsy?
- 27. What are the causes of chronic hepatitis?
- 28. What are the consequences of chronic
Cirrhosis is an irreversible distortion of normal liver architecture
characterized by hepatic injury, fibrosis, and nodular regeneration.
The clinical presentations of cirrhosis are a consequence of both
progressive hepatocellular dysfunction and portal hypertension (Figure 14–12). As with other presentations
of liver disease, not all patients with cirrhosis develop life-threatening
complications. Indeed, in nearly 40% of cases of cirrhosis,
it is diagnosed at autopsy in patients who did not manifest obvious
signs of end-stage liver disease.
Clinical effects of cirrhosis of the liver.
(Redrawn, with permission, from Chandrasoma P,
Taylor CE. Concise Pathology, 3rd ed. Originally
published by Appleton & Lange. Copyright © 1998 by
the McGraw-Hill Companies, Inc.)
The causes of cirrhosis are listed in Table
14–1. The initial injury can be due to a wide range
of processes. A crucial feature is that the liver injury is not
acute and self-limited but rather chronic and progressive. In the
United States, alcohol abuse is the most common cause of cirrhosis.
In other countries, infectious agents (particularly HBV and HCV)
are the most common causes. Other causes include chronic biliary
obstruction, drugs, metabolic disorders, chronic congestive heart
failure, and primary (autoimmune) biliary cirrhosis.
Increased or altered synthesis of collagen and other connective tissue
or basement membrane components of the extracellular matrix is implicated
in the development of hepatic fibrosis and thus in the pathogenesis
of cirrhosis. The role of the extracellular matrix in cellular function
is an important area of research, and studies suggest that it is
involved in modulating the activities of the cells with which it
is in contact. Thus, fibrosis may affect not only the physics of
blood flow through the liver but also the functions of the cells
Hepatic fibrosis appears to occur in three situations: (1) as an
immune response, (2) as part of the process of wound healing, and
(3) in response to agents that induce primary fibrogenesis. HBV
and Schistosoma species are good examples of agents
producing fibrosis on an immunologic basis. Agents such as carbon
tetrachloride that attack and kill hepatocytes directly can produce
fibrosis as part of wound healing. In both immune responses and
wound healing, the fibrosis is triggered indirectly by the effects
of cytokines released from invading inflammatory cells. Finally,
certain agents such as ethanol and iron may cause primary fibrogenesis
by directly increasing collagen gene transcription and thus increasing also
the amount of connective tissue secreted by cells.
The actual culprit in all of these mechanisms
of increased fibrogenesis may be the fat-storing cells (stellate
cells) of the hepatic reticuloendothelial system. In response to
cytokines, they differentiate from quiescent stellate cells in which
vitamin A is stored into myofibroblasts, which lose their vitamin A
storage capacity and become actively engaged in extracellular matrix
production. In addition to the stellate cells, fibrogenic cells
are also derived from portal fibroblasts, circulating fibrocytes, bone
marrow, and epithelial-mesenchymal cell transition. It appears that
hepatic fibrosis occurs in two stages (Figure
14–13). The first stage is characterized by a change
in extracellular matrix composition from non-cross-linked, non-fibril-forming
collagen to collagen that is more dense and subject to cross-link
formation. At this stage, liver injury is still reversible. The
second stage involves formation of subendothelial collagen cross-links,
proliferation of myoepithelial cells, and distortion of hepatic
architecture with the appearance of regenerating nodules. Cirrhosis
remains a dynamic state in which certain interventions, even at
these advanced stages, may yield benefits such as regression of
scar tissue and improvements in clinical outcomes.
Pathways of hepatic stellate cell activation. Features
of stellate cell activation can be distinguished between those that
stimulate initiation and those that contribute to perpetuation.
Initiation is provoked by soluble stimuli that include oxidant stress
signals (reactive oxygen intermediates), apoptotic bodies, lipopolysaccharide
(LPS), and paracrine stimuli from neighboring cell types including
hepatic macrophages (Kupffer cells), sinusoidal endothelium, and hepatocytes.
Perpetuation follows, characterized by a number of specific phenotypic
changes including proliferation, contractility, fibrogenesis, altered
matrix degradation, chemotaxis, and inflammatory signaling. FGF,
fibroblast growth factor; ET-1, endothelin-1; NK, natural killer;
NO, nitric oxide; MT, membrane type.
(Redrawn from Friedman SL. Mechanisms of hepatic
fibrogenesis. Gastroenterology. 2008 May;134(6):1655-69.)
Regardless of the possible effects on hepatocyte function, the increased
fibrosis markedly alters the nature of blood flow in the liver,
resulting in important complications discussed later.
The manner in which alcohol causes chronic liver disease and cirrhosis
is not well understood. However, chronic alcohol abuse is associated
with impaired protein synthesis and secretion, mitochondrial injury,
lipid peroxidation, formation of acetaldehyde and its interaction
with cellular proteins and membrane lipids, cellular hypoxia, and
both cell-mediated and antibody-mediated cytotoxicity. The relative
importance of each of these factors in producing cell injury is
unknown. Genetic, nutritional, and environmental factors (including
simultaneous exposure to other hepatotoxins) also influence the
development of liver disease in chronic alcoholics. Finally, acute
liver injury (eg, from exposure to alcohol or other toxins) from
which a person with a normal liver would fully recover may be sufficient
to produce irreversible decompensation (eg, hepatorenal syndrome)
in a patient with underlying hepatic cirrhosis.
Grossly, the liver may be large or small, but it always has a
firm consistency. Liver biopsy is the only method of definitively
Histologically, all forms of cirrhosis are characterized by three
findings: (1) marked distortion of hepatic architecture, (2) scarring
as a result of increased deposition of fibrous tissue and collagen,
and (3) regenerative nodules surrounded by scar tissue. When the
nodules are small (< 3 mm) and uniform in size, the process is
termed micronodular cirrhosis. In macronodular
cirrhosis, the nodules are > 3 mm and variable in size. Cirrhosis
from alcohol abuse is usually micronodular but can be macronodular
or both micronodular and macronodular. Scarring may be most severe
in central regions, or dense bands of connective tissue may join
portal and central areas.
More specific histopathologic findings may help to establish
the cause of cirrhosis. For example, invasion and destruction of
bile ducts by granulomas suggests primary (autoimmune) biliary cirrhosis;
extensive iron deposition in hepatocytes and bile ducts suggests
hemochromatosis; and alcoholic hyalin and infiltration with polymorphonuclear cells
suggest alcoholic cirrhosis.
The clinical manifestations of progressive hepatocellular dysfunction
in cirrhosis are similar to those of acute or chronic hepatitis
and include constitutional symptoms and signs: fatigue, loss of
vigor, and weight loss; GI symptoms and signs: nausea, vomiting,
jaundice, and tender hepatomegaly; and extrahepatic symptoms and
signs: palmar erythema, spider angiomas, muscle wasting, parotid
and lacrimal gland enlargement, gynecomastia and testicular atrophy
in men, menstrual irregularities in women, and coagulopathy.
Clinical manifestations of portal hypertension include ascites,
portosystemic shunting, encephalopathy, splenomegaly, and esophageal
and gastric varices with intermittent hemorrhage (Table
Table 14–17 Manifestations of Cirrhosis. |Favorite Table|Download (.pdf)
Table 14–17 Manifestations of Cirrhosis.
|Due to portal hypertension with portal-to-systemic
|Ascites and increased risk of spontaneous bacterial peritonitis|
|Increased risk of sepsis|
|Increased risk of disseminated intravascular coagulation|
|Splenomegaly with thrombocytopenia|
|Bile acid deficiency with malabsorption of fat and fat-soluble
|Due to loss of hepatocytes|
|Coagulopathy due to deficient clotting factor synthesis|
|Peripheral edema due to hypoalbuminemia|
Portal hypertension is defined by a portal venous pressure gradient
greater than 5 mm Hg. Portal hypertension is due to a rise in intrahepatic
vascular resistance. The cirrhotic liver loses the physiologic characteristic
of a low-pressure circuit for blood flow seen in the normal liver.
The increased blood pressure within the sinusoids is transmitted
back to the portal vein. Because the portal vein lacks valves, this
elevated pressure is transmitted back to other vascular beds, resulting
in splenomegaly, portal-to-systemic shunting, and many of the complications
of cirrhosis discussed later.
Ascites is the presence of excess fluid in the peritoneal cavity. Patients
with ascites develop physical examination findings of increasing
abdominal girth, a fluid wave, a ballotable liver, and shifting
dullness. Ascites can develop in patients with conditions other
than liver disease, including protein-calorie malnutrition (from
hypoalbuminemia) and cancer (from lymphatic obstruction). In patients
with liver disease, ascites is due to portal hypertension.
It is useful to recognize that liver disease with ascites formation
occurs in a wide clinical spectrum. At one end is fully compensated
portal hypertension with no ascites present because the volume of
ascites generated is less than the approximately 800–1200
mL/d capacity of the peritoneal lymphatic drainage. At
the other extreme is the typically fatal hepatorenal syndrome, in
which patients with liver disease, usually with massive ascites,
succumb to rapidly progressing acute renal failure. The hepatorenal
syndrome seems to be precipitated by intense and inappropriate renal
vasoconstriction and is characterized by extreme sodium retention
typical of prerenal azotemia but in the absence of true volume depletion
(see Chapter 16). Nonetheless, the presence
of clinically apparent ascites in a patient with liver disease is
associated with poor long-term survival.
Over the years, various mechanisms have been proposed to explain
ascites formation. No single hypothesis of pathogenesis easily explains
all findings at all points in time during the natural history of
portal hypertension. Portal hypertension and inappropriate renal
retention of sodium are important elements of all theories. The
end result of ascites occurs when excess peritoneal fluid exceeds
the capacity of lymphatic drainage, leading to increased hydrostatic
pressure. The fluid can then be seen to visibly weep from the lymphatics
and pool in the abdominal cavity as ascites.
The underfill/vasodilatation hypothesis proposes that
the primary event in ascites formation is vascular, with reduced effective
circulating volume leading to the activation of the renin-angiotensin
system and subsequent renal sodium retention. The classic underfill
hypothesis postulates that elevated hepatic sinusoidal pressure
leads to sequestration of blood in the splanchnic venous bed. This
results in underfilling of the central vein with diversion of intravascular
volume to the hepatic lymphatics, which, like the central vein,
drain the space of Disse. The peripheral arterial vasodilatation
or splanchnic vasodilatation hypothesis adds the idea that, with portal-to-systemic
shunting, vasodilatory products (eg, nitric oxide) that are normally
cleared by the liver are instead delivered to the systemic circulation,
where they cause peripheral arteriolar vasodilation, particularly
in the splanchnic arterial bed. The resultant reduced arterial vascular
resistance (Figure 14–14) is associated
with decreased central filling pressures, decreased renal arterial
perfusion, reflex renal arterial vasoconstriction, and increased
renal tubular sodium resorption. Retention of sodium expands the
intravascular volume, which exacerbates portal venous hypertension.
The imbalance between hydrostatic versus oncotic pressure in the
portal vein results in ascites formation. Although the splanchnic vasodilatation
hypothesis accounts for many of the findings in ascites formation,
the use of transhepatic intrajugular portal-to-systemic shunting
(TIPS) as a means of decompressing the portal vein in patients with
ascites provides a counterargument. As a result of the procedure,
peripheral arteriolar vasodilation appears to increase (perhaps
as a result of shunting of vasodilators such as nitric oxide that
are normally cleared by the liver), yet ascites is generally dramatically improved.
Proposed mechanism for ascites formation in cirrhosis
through the splanchnic vasodilation hypothesis. This hypothesis
incorporates elements of the underfill and vasodilation theories.
(Redrawn, with permission, from Gines P et al.
Management of cirrhosis and ascites. N Engl J Med. 2004;350:1646.)
Those who support the overflow hypothesis have proposed that
the primary event in the development of ascites is inappropriate
renal sodium retention. In this view, ascites is the consequence
of overflow of fluid from the intravascular volume-expanded portal
system into the peritoneal cavity. But what triggers the inappropriate
renal sodium retention? One possibility is that there may exist
a hepatorenal reflex by which elevated sinusoidal pressure triggers
increased sympathetic tone or endothelin-1 secretion. Either of
these pathways could cause an inappropriate degree of renal vasoconstriction, a
decrease in glomerular filtration rate, and, by tubuloglomerular
feedback (see Chapter 16), sodium retention.
Note that endothelin-1 is both a renal vasoconstrictor and a stimulant of
epinephrine secretion, which in turn stimulates more endothelin-1
secretion. Alternatively, it is possible that an as yet unidentified
product from the diseased liver interferes with atrial natriuretic
peptide (ANP) action at the kidney or is in some other way responsible
for an inappropriate increase in renal sodium retention. Supporters
of the overflow hypothesis point to the fact that many cirrhotic
patients have sodium handling defects in the absence of ascites
and do not have a measurable increase in renin-angiotensin activity.
However, studies have shown that the renal sodium retention in these patients
can be reversed by the use of an angiotensin II receptor antagonist.
Most likely, multiple mechanisms contribute to the development
of ascites and to its perpetuation, worsening, or improvement in
diverse clinical situations. Regardless of the initial events, once
fully established, many if not all of the mechanisms described in Figure 14–14 are likely to contribute
to ascites formation.
Up to 10% of patients with liver disease can develop
a poorly understood form of renal disease, called hepatorenal syndrome,
which has a dismal prognosis. This disorder is distinct from both
prerenal azotemia and acute tubular necrosis. It is characterized
by a progressively rising serum creatinine that shows a lack of
improvement after 48 hours of diuretic withdrawal and volume expansion
with intravenous albumin, and diminished urine volume in the absence
of shock, parenchymal renal disease, and use of nephrotoxic agents.
Type 1 hepatorenal syndrome is rapidly progressive, with a doubling
of the serum creatinine concentration to a level greater than 2.5
mg/dL in less than 2 weeks, whereas type 2 is slowly progressive. Hepatorenal
syndrome typically occurs in patients with massive tense ascites
and is often precipitated by overly aggressive attempts at diuresis
in the hospital or an episode of spontaneous bacterial peritonitis.
Hepatorenal syndrome is characterized by severe vasoconstriction
of the renal circulation. The urine produced is notable for an extremely
low sodium content (< 10 mmol/L) and an absence of casts,
resembling the findings in prerenal azotemia. Yet when central venous
pressures are measured, the patient does not show intravascular volume
depletion and the disorder does not respond to hydration with normal
saline. The renal abnormalities of the hepatorenal syndrome appear
to be functional because no pathologic changes are identifiable
in the kidney. In addition, when a kidney is transplanted from a
patient dying of hepatorenal syndrome, it functions well in a recipient
without liver disease. It remains to be determined whether this
form of renal failure represents loss of an as yet unrecognized
hormone produced by the liver that affects the kidneys or is the
consequence of some combination of local hemodynamic effects resulting
in diminished renal perfusion. Small nonrandomized studies showing
some efficacy of vasoconstrictor drugs (vasopressin analogues or α-adrenergic
agents) combined with albumin in treating hepatorenal syndrome suggest
that hemodynamic changes may be the major cause.
The role of nitric oxide as an intracellular second messenger
with vasodilatory effects on vascular beds and the role of endothelins,
peptides synthesized by vascular endothelium that have vasoconstrictive
properties, have been identified. A speculated role for nitric oxide–mediated
peripheral arterial vasodilation combined with sympathetic nervous
system and endothelin-mediated renal vasoconstriction has been proposed
to explain the salt and water retention of cirrhosis. Those same
mechanisms, in the extreme case, may give rise to the hepatorenal
and Peripheral Edema
Progressive worsening of hepatocellular function in cirrhosis can
result in a fall in the concentration of albumin and other serum
proteins synthesized by the liver. As the concentration of these
plasma proteins decreases, the plasma oncotic pressure is lowered,
thereby tilting the balance of hemodynamic forces toward the development
of both peripheral edema and ascites.
These hemodynamic changes further contribute to an avid sodium-retaining
state despite total body water and sodium overload seen by urinalysis
in the cirrhotic patient. Serum sodium may be low as a result of
superimposed water retention caused by antidiuretic hormone release
triggered by volume stimuli. A low serum potassium and metabolic
alkalosis may be observed as a consequence of elevated aldosterone levels
responding to renin release (and angiotensin II release) by the
kidneys, which sense afferent intravascular depletion.
Spontaneous bacterial peritonitis is the development of infected
ascites in the absence of a clear event (such as bowel perforation)
that would account for the entry of pathogenic organisms into the
peritoneal space. Symptoms and signs include fever, hypotension,
abdominal pain or tenderness, decreased or absent bowel sounds,
and abrupt onset of hepatic encephalopathy in a patient with ascites.
Patients with large-volume ascites or very low ascitic fluid protein
levels are at increased risk for this complication. Ascitic fluid
is an excellent culture medium for a variety of pathogens, including
Enterobacteriaceae (chiefly Escherichia coli),
group D streptococci (enterococci), Streptococcus pneumoniae, and
viridans streptococci. The greater risk in patients with low ascitic
fluid protein levels may be due to a low level of opsonic activity
in the fluid.
The exact pathogenesis of spontaneous bacterial peritonitis is
unknown. Peritonitis may occur because of bacterial seeding of the
ascitic fluid via the blood or lymph or by bacteria traversing the
gut wall. Enteric organisms may enter the portal venous blood via
the portosystemic collaterals, bypassing the reticuloendothelial
system of the liver.
Varices and Bleeding
As blood flow through the liver is progressively impeded, hepatic
portal venous pressure rises. In response to the elevated portal
venous pressure, there is a decrease in blood vessel wall thickness
and enlargement of blood vessels that anastomose with the portal
vein, such as those on the surface of the bowel and lower esophagus.
These enlarged vessels are termed varices. Gastroesophageal
varices occur in approximately 50% of patients with cirrhosis.
Physical examination may reveal enlargement of hemorrhoidal and
periumbilical vessels. Gastroesophageal varices are of more significance
clinically, however, because of their tendency to rupture. The resulting massive
bleeding is often life threatening because varices in these sites
are not easy to tamponade. GI bleeding from varices and other sources
(eg, duodenal ulcer, gastritis) in patients with cirrhosis is often
exacerbated by concomitant coagulopathy (see later discussion).
Hepatic encephalopathy is manifested by waxing and waning alterations
in mental status that occur as a consequence of advanced decompensated
liver disease or portal-to-systemic shunting (see Table
14–18 for a list of common precipitants). Abnormalities
range from subtle alterations in mental status to profound obtundation.
Changes in the sleep pattern starting with hypersomnia and progressing
to reversal of the sleep-wake cycle are often an early sign. Cognitive
changes include a full spectrum of mental abnormalities, ranging
from mild confusion, apathy, agitation, euphoria, and restlessness,
to marked confusion and even coma. Motor changes range from fine
tremor, slowed coordination, and asterixis to decerebrate posturing
and flaccidity. Asterixis is a phenomenon of intermittent
myoelectrical silence manifested by many muscle groups and enhanced
by fatigue. It is best demonstrated by asking the patient to flex
the wrists with fingers extended (“stop traffic”)
and then observing a flapping motion of the fingers. It is thought
to be due to decreased sensory input to the brainstem
reticular formation, leading to transient lapses in posture. Cerebral
edema, which is an important accompanying feature in patients with
encephalopathy in acute liver disease, is not seen in cirrhotic
patients with encephalopathy.
Table 14–18 Common Precipitants of Hepatic Encephalopathy. |Favorite Table|Download (.pdf)
Table 14–18 Common Precipitants of Hepatic Encephalopathy.
|Increased nitrogen load|
|Excess dietary protein|
|Opioids, tranquilizers, sedatives|
|Superimposed acute liver disease|
|Progressive liver disease|
Common precipitants of encephalopathy are onset of GI bleeding,
increased dietary protein intake, and an increased catabolic rate
resulting from infection (including spontaneous bacterial peritonitis).
Similarly, because of compromised first-pass clearance of ingested
drugs, affected patients are exquisitely sensitive to sedatives
and other drugs normally metabolized in the liver. Other causes
include electrolyte imbalance as a result of diuretics, vomiting,
alcohol ingestion or withdrawal, or procedures such as TIPS.
The pathogenesis of hepatic encephalopathy is poorly understood.
One proposed mechanism postulates that the encephalopathy is caused
by toxins in the gut such as ammonia, derived from metabolic degradation
of urea or protein; glutamine, derived from degradation of ammonia;
or mercaptans, derived from degradation of sulfur-containing compounds.
Because of anatomic or functional portal-systemic shunts, these
toxins bypass the liver’s detoxification processes and
produce alterations in mental status. Increased levels of ammonia,
glutamine, and mercaptans can be found in the blood and cerebrospinal
fluid. However, blood ammonia and spinal fluid glutamine levels
correlate poorly with the presence and severity of encephalopathy.
Alternatively, there may be impairment of the normal blood-brain
barrier, rendering the CNS susceptible to various noxious agents.
Increased levels of other substances, including metabolic products
such as short-chain fatty acids and endogenous benzodiazepine-like
metabolites, have also been found in the blood. Importantly, some
patients show improvement in encephalopathy when treated with flumazenil,
a benzodiazepine receptor antagonist.
A third proposed mechanism postulates a role for GABA, the principal
inhibitory neurotransmitter of the brain. GABA is produced in the
gut, and increased levels are found in the blood of patients with
A fourth proposal postulates that there is an increased entry of
aromatic amino acids into the CNS, resulting in increased synthesis
of “false” neurotransmitters such as octopamine and
decreased synthesis of normal neurotransmitters such as norepinephrine.
Factors contributing to coagulopathy in cirrhosis include loss of
hepatic synthesis of clotting factors, some of which have a half-life
of just a few hours. Under these circumstances, a minor or self-limited
source of bleeding can become massive.
Hepatocytes are also functionally involved in the maintenance
of a normal coagulation cascade through the absorption of vitamin
K (a fat-soluble vitamin whose absorption is dependent on bile flow),
which is necessary for the activation of some clotting factors (II,
VII, IX, X). An ominous sign of the severity of liver disease is
the development of a coagulopathy that does not respond to parenteral
vitamin K, suggesting deficient clotting factor synthesis rather
than impaired absorption of vitamin K because of fat malabsorption.
Finally, loss of the liver’s capacity to remove activated
clotting factors and fibrin degradation products may play a role
in the increased susceptibility to disseminated intravascular
coagulation, a syndrome of coagulation factor consumption
that results in uncontrolled simultaneous clotting and bleeding.
Enlargement of the spleen is a consequence of elevated portal venous
pressure and consequent engorgement of the organ. Thrombocytopenia
and hemolytic anemia occur because of sequestering of formed elements
of the blood in the spleen, from which they are normally cleared
as they age and are damaged.
Hepatocellular carcinoma (HCC) occurs in up to 5% of
cirrhotic patients per year. There has been a rise in the incidence of
HCC in the United States over the past few decades, which is likely
secondary to an increased prevalence of NAFLD, HCV infections, and
chronic hepatitis B infections due to immigration from countries
with a high prevalence of HBV. Several etiologic factors have been
identified in the development of this tumor.
Malignant transformation is heightened in any form
of chronic liver disease, particularly cirrhosis.
The risk of developing HCC is increased 100-fold in chronic HBV
carriers, even in the absence of cirrhosis. In the setting of chronic
HBV infection, 30–50% of cases of HCC occur in
the absence of cirrhosis.
The risk of developing HCC in the setting of HCV cirrhosis is
approximately 1–4% per year.
Mycotoxins—metabolites of saprophytic fungi—are known
hepatic carcinogens and have been proposed to act synergistically
with cirrhosis and HBV infection in increasing the risk of liver
Hormonal factors have been implicated by experimental studies.
The tumor is known to have a male predominance.
Up to one-third of patients with decompensated cirrhosis have
problems associated with oxygenation. The hepatopulmonary syndrome
is associated with advanced liver failure, hypoxemia, and intrapulmonary
shunting as a result of vasodilatation. The cause of the vasodilatation
is unknown, but substances such as nitric oxide, endothelin, and
arachidonic acid are thought to be involved. As a result of ventilation-perfusion
mismatch, patients often present with platypnea, dyspnea that worsens
in the upright position. Liver transplantation leads to resolution
of the hepatopulmonary syndrome. However, pulmonary hypertension
affects some patients with advanced liver failure and is a contraindication
to liver transplantation. Additionally, patients with cirrhosis
may present with hepatic hydrothorax. Hepatic hydrothorax is defined
as the presence of a pleural effusion due to small defects in the
diaphragm of patients with cirrhosis without evidence of underlying
Other findings on physical examination of patients with cirrhosis
include spider angiomas (prominent blood vessels with
a central arteriole and small vessels radiating from it seen in
the skin, particularly on the face and upper trunk), Dupuytren’s
contractures (fibrosis of the palmar fascia), testicular
atrophy, gynecomastia(enlargement of breast tissue
in men), palmar erythema, lacrimal and parotid gland enlargement,
and diminished axillary and pubic hair (Figure
14–12). These findings are largely a consequence of
estrogen excess resulting from decreased clearance of endogenous
estrogens by the diseased liver combined with decreased hepatic
synthesis of steroid hormone-binding globulin. Both of these mechanisms
result in tissues receiving higher than normal concentrations of
estrogens. In addition, a longer half-life of androgens may allow
a greater degree of peripheral aromatization (conversion to estrogens
by, eg, adipose tissue, hair follicles), further increasing estrogen-like
effects in patients with cirrhosis. Xanthomas of the eyelids and
extensor surfaces of tendons of the wrists and ankles can occur
with chronic cholestasis such as occurs in primary biliary cirrhosis.
Finally, profound muscle wasting and cachexia in cirrhosis probably reflect
diminution of the liver’s synthesis of carbohydrate, lipid,
and amino acids.
- 29. What are the defining features
- 30. What are the three categories of
hepatic fibrosis? Name one agent causing each.
- 31. What are the two postulated stages
in the development of cirrhosis?
- 32. What are some ways alcohol may injure
- 33. What are the major clinical manifestations
- 34. For each major clinical manifestation
of cirrhosis, suggest a reasonable hypothesis to account for its