CIRRHOSIS
Cirrhosis is a pathologically defined entity that
is associated with a spectrum of characteristic clinical manifestations. The
cardinal pathologic features reflect irreversible chronic injury of the hepatic
parenchyma and include extensive fibrosis in association with the formation of
regenerative nodules.
These
features result from hepatocyte necrosis, collapse of the supporting reticulin
network with subsequent connective tissue deposition, distortion of the vascular
bed, and nodular regeneration of remaining liver parenchyma.
Classification of the various types of cirrhosis
based on either etiology or
morphology alone is unsatisfactory. A single pathologic pattern may result from
a variety of insults, while the same insult may produce several morphologic
patterns. Nevertheless, most types of cirrhosis may be usefully classified by a
mixture of etiologically and morphologically defined entities as follows:
Etiology
1) alcoholic;
2) cryptogenic
3) posthepatitic;
4) biliary (primary biliary cirrhosis
and secondary biliary cirrhosis);
5) cardiac;
6) metabolic,
7) inherited, and drug-related.
On the clinical findings:
Stages: initial,
manifesting, terminal
Activity: Active C,
non-active C.
Степень печеночно-клеточной
функциональной недостаточности:
- легкая (компенсированная),
- средней тяжести
(субкомпенсированая),
- тяжелая (декомпенсированая).
Форма портальной гипертензии:
скрытая, умеренная, развернутая (внутрипеченочная, подпеченочная,
надпеченочная и смешанная).
Развитие сочетанных клинических
синдромов:
- гепато-лиенальный (splenomegaly, hypersplenism),
- hepatopancreatic syndrome,
- hepatorenal syndrome.
COMPLICATIONS OF CIRRHOSIS
These include:
- portal
hypertension and its consequences (e.g., gastroesophageal varices and
splenomegaly),
- ascites,
- hepatic
encephalopathy,
- spontaneous
bacterial peritonitis,
- and
hepatocellular carcinoma.
Тhe most common histologic classification divides cirrhosis into micronodular,
macronodular, and mixed forms.
- In micronodular cirrhosis, the regenerating
nodules are no larger than the original lobules, i.e. approximately 1 mm in
diameter or less.
- Macronodular cirrhosis is
characterized by larger nodules, which
measure several centimeters in diameter and may contain central veins.
This form corresponds
more or less to postnecrotic (posthepatic) cirrhosis but does not necessarily
follow episodes of massive necrosis and stromal collapse.
- Mixed macro- and micronodular cirrosis
signifies that the features of cirrhosis are variable.
There is a
limited interrelationship among the histologic form of cirrhosis, the etiology,
and the prognosis.
Child’s
criteria for hepatic functional reserve
|
|
A minimal
|
B moderate
|
C advanced
|
|
Serum bilirubin
|
< 20
|
20-30
|
> 30
|
|
Serum albumin g|L
|
< 35
|
30-35
|
< 30
|
|
Ascites
|
None
|
Easily controlled
|
Poorly controlled
|
|
Neurologic disorder
|
None
|
Minimal
|
Advance “coma”
|
|
Nutrition
|
Excellent
|
Good
|
Poor, “wasting”
|
A – 1
unit, B – 2 units, C – 3 units
5-7
units - initial stage
8-10 - manifest stage
11 and
> - final stage.
alcoholic cirrhosis
is usually a
progressive disease, appropriate therapy and strict avoidance of alcohol may
arrest the disease at most stages and permit functional improvement. In
addition, there is strong evidence that concomitant chronic hepatitis C virus
(HCV) infection significantly accelerates development of alcoholic cirrhosis.
Clinical Features
SIGNS AND SYMPTOMS
Alcoholic
cirrhosis may be clinically silent, and many cases (10 to 40%) are discovered
incidentally at laparotomy or autopsy. In many cases symptoms are insidious in
onset, occurring usually after ≥10 years of excessive alcohol use and
progressing slowly over subsequent weeks and months. Anorexia and malnutrition lead to weight loss and a reduction in
skeletal muscle mass. The patient may
experience easy bruising, increasing weakness, and fatigue. Eventually the
clinical manifestations of hepatocellular dysfunction and portal hypertension
ensue, including progressive jaundice, bleeding from gastroesophageal varices,
ascites, and encephalopathy. The abrupt onset of one of these complications may
be the first event prompting the patient to seek medical attention. In other
cases, cirrhosis first becomes evident when the patient requires treatment of
symptoms related to alcoholic hepatitis.
A firm,
nodular liver may be an early sign of disease; the liver may be either
enlarged, normal, or decreased in size. Other frequent findings include jaundice,
palmar erythema, spider angiomas, parotid and lacrimal gland enlargement, clubbing
of fingers, splenomegaly, muscle wasting, and ascites with or without peripheral
edema. Men may have decreased body hair and/or gynecomastia and
testicular atrophy, which, like the cutaneous findings, result from
disturbances in hormonal metabolism, including increased peripheral formation
of estrogen due to diminished hepatic clearance of the precursor
androstenedione. Testicular atrophy may reflect hormonal abnormalities or
the toxic effect of alcohol on the testes. In women, signs of virilization or
menstrual irregularities may occasionally be encountered. Dupuytren's
contractures resulting from fibrosis of the palmar fascia with resulting
flexion contracture of the digits are associated with alcoholism but are not
specifically related to cirrhosis.
Although the cirrhotic patient may
stabilize if drinking is discontinued, over a period of years, the patient may
become emaciated, weak, and chronically jaundiced. Ascites and other signs of
portal hypertension may become increasingly prominent. Ultimately, most patients
with advanced cirrhosis die in hepatic coma, commonly precipitated by
hemorrhage from esophageal varices or intercurrent infection. Progressive renal
dysfunction often complicates the terminal phase of the illness.
BILIARY CIRRHOSIS
Biliary cirrhosis results from injury
to or prolonged obstruction of either the intrahepatic or extrahepatic biliary
system. It is associated with impaired biliary excretion, destruction of
hepatic parenchyma, and progressive fibrosis. Primary biliary cirrhosis (PBC)
is characterized by chronic inflammation and fibrous obliteration of
intrahepatic bile ductules. Secondary biliary cirrhosis (SBC) is the result of
long-standing obstruction of the larger extrahepatic ducts. Although primary
and secondary biliary cirrhosis are separate pathophysiologic entities with
respect to the initial insult, many clinical features are similar.
PRIMARY BILIARY CIRRHOSIS
Etiology and
Pathogenesis
The cause of
PBC remains unknown. Several observations suggest that a disordered immune
response may be involved. PBC is frequently associated with a variety of
disorders presumed to be autoimmune in nature, such as the syndrome of calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly,
telangiectasia (CREST); the sicca syndrome (dry eyes
and dry mouth); autoimmune thyroiditis; type 1 diabetes mellitus; and IgA
deficiency.
Most
important, a circulating IgG antimitochondrial antibody (AMA) is detected in
>90% of patients with PBC and only rarely in other forms of liver disease.
Clinical Features
SIGNS AND
SYMPTOMS
Among
patients with symptomatic disease, 90% are women age 35 to 60. Often the
earliest symptom is pruritus, which may be either generalized or limited
initially to the palms and soles. In addition, fatigue is commonly a
prominent early symptom. After several months or years, jaundice and gradual
darkening of the exposed areas of the skin (melanosis) may ensue. Other early
clinical manifestations of PBC reflect impaired bile excretion. These include steatorrhea
and the malabsorption of lipid-soluble vitamins. Protracted elevation of
serum lipids, especially cholesterol, leads to subcutaneous lipid deposition
around the eyes (xanthelasmas) and over joints and tendons (xanthomas).
Over a period of months to years, the itching, jaundice, and hyperpigmentation
slowly worsen.
LABORATORY
FINDINGS
PBC is
increasingly diagnosed at a presymptomatic stage, prompted by the finding of a
twofold or greater elevation of the serum alkaline phosphatase during routine
screening. Serum 5′-nucleotidase activity and γ-glutamyl transpeptidase levels are
also elevated. In this setting, serum bilirubin is usually normal and aminotransferase
levels minimally increased. The diagnosis is supported by a positive AMA test
(titer > 1:40).
TREATMENT
While there is
no specific therapy for PBC, ursodiol has been shown to improve biochemical and
histologic features and might improve survival, particularly liver
transplantation–free survival (although this remains unproven). Ursodiol should
be given in doses of 13 to 15 mg/kg per day, but lower doses are sometimes just
as effective in reducing serum alkaline phosphatase and aminotransferase levels.
Ursodiol should be given with food and can be taken in a single dose daily.
Side effects are rare: gastrointestinal intolerance (diarrhea) and skin rashes
occur but are uncommon. Isolated instances of severe exacerbation of pruritus
have been reported in patients with advanced disease. Ursodiol probably works
by replacing the endogenously produced hydrophobic bile acids with urosdeoxycholate,
a hydrophilic and relatively nontoxic bile acid.
SECONDARY
BILIARY CIRRHOSIS
Etiology
SBC results from prolonged partial or total
obstruction of the common bile duct or its major branches. In adults,
obstruction is most frequently caused by postoperative strictures or gallstones,
usually with superimposed infectious cholangitis. Chronic pancreatitis may lead
to biliary stricture and secondary cirrhosis.
Pathology and
Pathogenesis
Unrelieved
obstruction of the extrahepatic bile ducts leads to (1) bile stasis and focal
areas of centrilobular necrosis followed by periportal necrosis, (2) proliferation
and dilatation of the portal bile ducts and ductules, (3) sterile or infected
cholangitis with accumulation of polymorphonuclear infiltrates around bile
ducts, and (4) progressive expansion of portal tracts by edema and fibrosis.
Clinical
Features
The symptoms, signs, and biochemical
findings of SBC are similar to those of PBC. Jaundice and pruritus are usually
the most prominent features. In addition, fever and/or right upper quadrant
pain, reflecting bouts of cholangitis or biliary colic, are typical.
TREATMENT
Relief of obstruction to bile flow,
by either endoscopic or surgical means, is the most important step in the
prevention and therapy of SBC.
POSTHEPATITIC AND CRYPTOGENIC
CIRRHOSIS
Posthepatitic
or postnecrotic cirrhosis represents the final common pathway of many types of
chronic liver disease. Coarsely nodular cirrhosis and multilobular cirrhosis are terms synonymous with
posthepatitic cirrhosis. The term cryptogenic cirrhosis
has been used interchangeably with posthepatitic cirrhosis, but this designation
should be reserved for those cases in which the etiology of cirrhosis is unknown
(approximately 10% of all patients with cirrhosis).
Posthepatitic
cirrhosis is characterized morphologically by irregular nodules
of regenerating hepatocytes, varying in size from microscopic to several centimeters
in diameter.
Clinical
Features
In patients
with cirrhosis of known etiology in whom there is progression to a posthepatitic
stage, the clinical manifestations are an extension of those resulting from the
initial disease process. Usually clinical symptoms are related to portal hypertension
and its sequelae, such as ascites, splenomegaly, hypersplenism, encephalopathy,
and bleeding gastroesophageal varices. The hematologic and liver function
abnormalities resemble those seen with other types of cirrhosis. In a few patients
with posthepatitic cirrhosis, the diagnosis may be made incidentally at operation,
at postmortem, or by a needle biopsy of the liver performed to investigate abnormal
liver function tests or hepatomegaly.
CARDIAC CIRRHOSIS
Prolonged,
severe right-sided congestive heart failure may lead to chronic liver injury
and cardiac cirrhosis. The characteristic pathologic features of fibrosis and
regenerative nodules distinguish cardiac cirrhosis from both reversible passive
congestion of the liver due to acute heart failure and acute hepatocellular
necrosis (“ischemic hepatitis” or “shock liver”) resulting from systemic
hypotension and hypoperfusion of the liver.
The
signs and symptoms of heart failure usually overshadow the liver disease. With
prolonged right-sided heart failure the liver becomes enlarged, firm, and usually
nontender.
TREATMENT
Prevention or
treatment of cardiac cirrhosis depends on the diagnosis and therapy of the
underlying cardiovascular disorder. Improvement in cardiac function frequently
results in improvement of liver function and stabilization of the liver
disease.
MAJOR COMPLICATIONS OF CIRRHOSIS
PORTAL HYPERTENSION
Clinical Features
The major clinical manifestations of
portal hypertension include hemorrhage from gastroesophageal varices,
splenomegaly with hypersplenism, ascites, and acute and chronic hepatic
encephalopathy. These are related, at least in part, to the development of
portal-systemic collateral channels. The absence of valves in the portal venous
system facilitates retrograde (hepatofugal) blood flow from the high-pressure
portal venous system to the lower-pressure systemic venous circulation. Major
sites of collateral flow involve the veins around the cardioesophageal junction
(esophagogastric varices), the rectum (hemorrhoids), retroperitoneal space, and
the falciform ligament of the liver (periumbilical or abdominal wall
collaterals). Abdominal wall collaterals appear as tortuous epigastric vessels
that radiate from the umbilicus toward the xiphoid and rib margins (caput
medusae).
A frequent marker of the presence of
cirrhosis in a patient being followed for chronic liver disease is a
progressive decrease in platelet count. A low-normal platelet count can be the
first clue to progression to cirrhosis. Ultimately, a marked decrease in
platelets (to 30,000 to 60,000/µL) and white blood cells can occur.
VARICEAL BLEEDING
Pathogenesis
While vigorous hemorrhage may arise
from any portal-systemic venous collaterals, bleeding is most common from
varices in the region of the gastroesophageal junction. The factors
contributing to bleeding from gastroesophageal varices are not entirely
understood but include the degree of portal hypertension (>12 mmHg) and the
size of the varices.
Clinical
Features and Diagnosis
Variceal bleeding often occurs
without obvious precipitating factors and usually presents with painless but
massive hematemesis with or without melena. Associated signs range from mild
postural tachycardia to profound shock, depending on the extent of blood loss
and degree of hypovolemia. Endoscopy is the best approach to evaluate upper
gastrointestinal hemorrhage in patients with known or suspected portal
hypertension
The medical
management of acute variceal hemorrhage includes the use of vasoconstrictors
(somatostatin/octreotide or vasopressin), balloon tamponade, and endoscopic
variceal ligation (EVL) or sclerosis of varices (sclerotherapy). Intravenous
infusion of vasopressin at a rate of 0.1 to 0.4 U/min
results in generalized vasoconstriction leading to diminished blood flow in the
portal venous system. Intravenous infusion of vasopressin is as effective as
selective intraarterial administration. Control of bleeding can be achieved in
up to 80% of cases, but bleeding recurs in more than half after the vasopressin
is tapered and discontinued. Furthermore, a number of serious side effects, including cardiac and gastrointestinal tract
ischemia, acute renal failure, and hyponatremia, may be associated with vasopressin
therapy. Concurrent use of venodilators such as nitroglycerin as an intravenous
infusion or isosorbide dinitrate sublingually may enhance the effectiveness of
vasopressin and reduce complications. Somatostatin and its
analogue, octreotide, are direct splanchnic
vasoconstrictors. In some studies somatostatin, given as an initial 250-µg
bolus followed by constant infusion (250 µg/h), has been found to be as effective
as vasopressin. Octreotide at doses of 50 to 100 µg/h is also effective. These
agents are preferable to vasopressin, offering equivalent efficacy with fewer
complications. If bleeding is too vigorous or endoscopy is not available, balloon tamponade of the bleeding varices may be
accomplished with a triple-lumen (Sengstaken-Blakemore) or four-lumen (Minnesota
Portal Hypertensive Gastropathy
Although variceal hemorrhage is the
most commonly encountered bleeding complication of portal hypertension, many
patients will develop a congestive gastropathy due to the venous hypertension.
In this condition, identified by endoscopic examination, the mucosa appears
engorged and friable. Indolent mucosal bleeding occurs rather than the brisk
hemorrhage typical of a variceal source. β-Adrenergic blockade with propranolol (reducing
splanchnic arterial pressure as well as portal pressure) is sometimes effective
in ameliorating this condition. Proton pump inhibitors or other agents useful
in the treatment of peptic disease are usually not helpful.
SPLENOMEGALY
Congestive splenomegaly is common in
patients with severe portal hypertension.
Clinical Features
Although usually asymptomatic,
splenomegaly may be massive and contribute to the thrombocytopenia or
pancytopenia of cirrhosis. In the absence of cirrhosis, splenomegaly in
association with variceal hemorrhage should suggest the possibility of splenic
vein thrombosis.
ASCITES
Definition
Ascites is the accumulation of excess
fluid within the peritoneal cavity.
ASCITES
Ascites is the accumulation of excess
fluid within the peritoneal cavity.
Regardless of the initiating event, a
number of factors contribute to accumulation of fluid in the abdominal cavity
(Fig. 282-2). Elevated levels of serum epinephrine and norepinephrine have been
well documented. Increased central sympathetic outflow
is found in patients with cirrhosis and ascites but not in those with cirrhosis
alone. Increased sympathetic output results in diminished natriuresis by
activation of the renin-angiotensin system and diminished
sensitivity to atrial natriuretic peptide. Portal
hypertension plays an important role in the formation of ascites by raising
hydrostatic pressure within the splanchnic capillary bed. Hypoalbuminemia
and reduced plasma oncotic pressure also favor the extravasation
of fluid from plasma to the peritoneal cavity, and thus ascites is infrequent
in patients with cirrhosis unless both portal hypertension and hypoalbuminemia
are present. Hepatic lymph may weep freely from the surface of the cirrhotic
liver due to distortion and obstruction of hepatic sinusoids and lymphatics and
contributes to ascites formation.
Renal factors also play an
important role in perpetuating ascites. Patients with ascites have increased
renal sodium reabsorption by both proximal and distal tubules, the latter due
largely to increased plasma renin activity and secondary hyperaldosteronism.
Treatment
Salt restriction is the cornerstone
of therapy. A diet containing 800 mg sodium (2 g NaCl) is often adequate to
induce a negative sodium balance and permit diuresis. Response to salt restriction
alone is more likely to occur if the ascites is of recent onset, the underlying
liver disease is reversible, a precipitating factor can be corrected, or the
patient has a high urinary sodium excretion (>25 mmol/d) and normal renal
function. Fluid restriction of approximately 1000 mL/d does little to enhance
diuresis but may be necessary to correct hyponatremia. If sodium restriction
alone fails to result in diuresis and weight loss, diuretics should be
prescribed. Because of the role of hyperaldosteronism in sustaining salt
retention, spironolactone or other distal tubule–acting diuretics (triamterene,
amiloride) are the drugs of choice. More potent, proximally acting diuretics
(furosemide, bumetanide, torasemide) may be added to the regimen. Thus,
spironolactone is initially given at a dose of 100 mg/d with or without
furosemide, 40 mg/d, and both agents may be increased by 100- and 40-mg
increments respectively: total dose should not exceed 400 mg/d and 160 mg/d,
respectively. An indication of the minimum effective dose of spironolactone may
be obtained by monitoring urinary electrolyte concentrations for a rise in sodium
and fall in potassium concentrations, reflecting effective competitive
inhibition of aldosterone. Great caution should be exercised to avoid plasma
volume depletion, azotemia, and hypokalemia, which may lead to encephalopathy.
In patients
with massive ascites, ascites refractory to diuretics, or intolerable diuretic
side-effects, large-volume (4-6 L) paracentesis is effective. When this is
done, it is safest to give intravenous albumin concomitantly at a dosage of 10
g|L of ascites fluid removed to protect the intravascular volume. Large volume paracentesis
can be repeated daily until ascites is largely resolved. If possible, diuretics
should be continued in the hope of preventing recurrent ascites.
HEPATIC ENCEPHALOPATHY
Hepatic (portal-systemic)
encephalopathy is a complex neuropsychiatric syndrome characterized by
disturbances in consciousness and behavior, personality changes, fluctuating
neurologic signs, asterixis or “flapping tremor,” and distinctive electroencephalographic
changes.
Pathogenesis
Perhaps the
most common predisposing factor is gastrointestinal
bleeding, which leads to an increase in the production of ammonia
and other nitrogenous substances, which are then absorbed. Similarly, increased dietary protein may precipitate
encephalopathy as a result of increased production of nitrogenous substances by
colonic bacteria. Electrolyte disturbances,
particularly hypokalemic alkalosis secondary to overzealous use of diuretics,
vigorous paracentesis, or vomiting, may precipitate hepatic encephalopathy.
Clinical Features
Disturbances
of sleep with reversal of sleep/wake cycles are among the earliest signs
of encephalopathy. Alterations in personality, mood disturbances, confusion,
deterioration in self-care and handwriting, and daytime somnolence are additional
clinical features of encephalopathy. Fetor hepaticus,
a unique musty odor of the breath and urine believed to be due to mercaptans,
may be noted in patients with varying stages of hepatic encephalopathy.
TREATMENT.
Early
recognition and prompt treatment of hepatic encephalopathy are essential.
Patients with acute, severe hepatic encephalopathy (stage IV) require the usual
supportive measures for the comatose patient. Specific treatment of hepatic encephalopathy
is aimed at (1) elimination or treatment of precipitating factors and (2)
lowering of blood ammonia (and other toxin) levels by decreasing the absorption
of protein and nitrogenous products from the intestine.
-In the
setting of acute gastrointestinal bleeding, blood in the bowel should be
promptly evacuated with laxatives (and enemas if necessary) in order to
reduce the nitrogen load.
-Protein
should be excluded from the diet, and constipation should be avoided. Protein
is restricted to 60-80 g|d, and vegetable protein is better tolerated than meat
protein.
-Acutely, lactulose
syrup can be administered in a dose of 30 to 60 mL every hour until
diarrhea occurs; thereafter the dose is adjusted (usually 15 to 30 mL three
times daily) so that the patient has two to four soft stools daily. When rectal
use is indicated, because of the patient’s inability to take medicines orally,
the dose is 300 mL of lactulose in 700 mL of saline or sorbitol as a retention
enema for 30-60 minutes; it may be repeated every 4-6 hours.
-Intestinal
ammonia production by bacteria can also be decreased by oral administration
of a “nonabsorbable” antibiotic such as neomycin (0.5 to 1.0 g every 6 h) for
5-7 days. However, despite poor absorption, neomycin may reach sufficient
concentrations in the bloodstream to cause renal toxicity. Equal benefits may
be achieved with broad-spectrum antibiotics such as metronidazole. Flumazenil,
a short-acting benzodiazepine antagonist, may have a role in management of
hepatic encephalopathy precipitated by use of benzodiazepines, if there is a
need for urgent therapy. Hemoperfusion to remove toxic substances and therapy
directed primarily toward coincident cerebral edema in acute encephalopathy are
also of unproven value. The efficacy of extracorporeal liver assist devices
employing hepatocytes of porcine or human origin to bridge patients to recovery
or transplantation is as yet unproven but is currently being studied.
Liver
Transplantation
Liver
Transplantation is indicated in selected cases of irreversible, progressive
chronic liver diseases, fulminant hepatic failure, and certain metabolic diseases
in which the metabolic defect is in the liver.
Absolute
contraindications include:
-
sepsis
-
malignancy
-
advanced cardiopulmonary disease
-
HIV infection
-
Lack of patient’s understanding.
Relative
contraindications:
-
portal and mesenteric vein thrombosis,
-
chronic hepatitis B with viral replication,
-
active alcohol or drug abuse. Alcoholics should be
abstinent for 6 months.
Immunosurrression
is achieved with cyclosporine,
corticosteroids and azathioprine and may be complicated by infections, renal
failure, and neurologic disorders as well as graft rejection, vascular
occlusion, or bile leaks.
Prognosis
The prognosis
in advanced cirrhosis has shown little change over the years.
