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:
4) biliary (primary biliary cirrhosis and secondary biliary cirrhosis);
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
- portal hypertension and its consequences (e.g., gastroesophageal varices and splenomegaly),
- 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
Serum albumin g|L
A – 1 unit, B – 2 units, C – 3 units
5-7 units - initial stage
8-10 - manifest stage
11 and > - final stage.
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.
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 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.
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.
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).
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
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.
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.
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.
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.
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.
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
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.
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 (
) tube with
esophageal and gastric balloons. 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.
Congestive splenomegaly is common in patients with severe portal hypertension.
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 is the accumulation of excess fluid within the peritoneal cavity.
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.
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 (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.
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.
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.
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 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:
- advanced cardiopulmonary disease
- HIV infection
- Lack of patient’s understanding.
- 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.
The prognosis in advanced cirrhosis has shown little change over the years.