Hepatocirrhosis (cirrhosis) is the irreversible end result of the fibrous scarring and hepatocellualr regeneration that consti-tute the major responses of the liver to a variety of longstand-ing inflammatory, toxic, metabolic, and congestive insults. In cirrhosis, the normal hepatic lobular architecture is replaced by interconnecting bands of fibrous tissue surrounding nodules de. rived from loci of regenerating hepatocytes.

Regenerative nodules may be small (£¼3 ram, micronodu-lar cirrhosis), a typical feature of alcoholic cirrhosis, or large (£¾3 ram, macronodular cirrhosis). The latter, also termed postnecrotic cirrhosis, is more commonly seen as a sequel to chronic active hepatitis. The pathologic features of cirrhosis determine its natural history and clinical manifestations. Thus, fibrous scarring and disruption of the hepatic architec-ture distort the vascular bed and lead to portal hypertension and intrahepatic shunting. Normal hepatocyte function is dis-turbed by the resulting inadequacy of blood flow and ongoing direct toxic, inflammatory, and/or metabolic damage to hepa-tocytes.

Clinical and Laboratory Features

Clinical features of cirrhosis (often called "stigmata of chronic liver disease") are attributable to hepatocellular dys-function and portal hypertension (Table 26). Hepatocellular dysfunction leads to impaired protein synthesis (hypoalbumine-mia and prolongation of prothrombin time), hyperbiliru-binemia, which may result in jaundice, low blood urea nitro-gen levels, and elevated ammonia levels. Hypersplenism, re-suiting from splenomegaly, results in thrombocytopenia and leukopenia, but it is usually of little clinical significance and does not warrant splenectomy.

Specific Causes

Most of the conditions that may lead to cirrhosis (Table43-2) are rarely encountered. Alcohol consumption and hepatitis C virus infection are by far the most common causes of cirrhosis in the Western world, whereas hepatitis B is a ma-jor cause in developing countries. Cryptogenic cirrhosis re-mains a diagnosis of exclusion.

Alcohol

Alcoholic cirrhosis may coexist with alcoholic hepatitis, Features of hepatocellular dysfunction are thus often marked and may improve with abstinence. Micronodular cirrhosis is the rule but is not specific for alcoholic cirrhosis. Data suggest that hepatitis C virus infection in patients with alcoholism may cause a more severe and rapidly progressive liver disease. Evi-dence of malnutrition and vitamin deficiency is frequently found, particularly in patients with severe alcoholism. Anemia of mixed origin is common, often with macrocytic indices.

Primary Biliary Cirrhosis

Primary biliary cirrhosis is seen more commonly in wom-en, with a male-to-female ratio of 1 : 9. It typically presents in patients between the ages of 30 and 65 years and results from progressive, immune-mediated destruction of the interlobular bile ducts. Cholestatic features predominate, with high serum levels of alkaline phosphatase and y-glutamyltransferase. Fa-tigue and pruritus are major early symptoms, followed later in the course of the disease by xanthomas, hyperpigmentation, steatorrhea, and bone pain resulting from osteoporosis or os-teomalacia. Commonly associated conditions include Sj6gren's syndrome, scleroderma, and the CREST syndrome (calci-nosis, Raynaud's syndrome, esophageal dysfunction, sclero-dactyly, telangiectasia). Antimitochondrial antibodies are pre-sent in high titer, and serum IgM levels are elevated. Serum cholesterol levels are elevated in > 50% of patients with pre-mary biliary cirrhosis, mainly because of elevations of high-density lipoproteins. Liver biopsy may show characteristic de-structive lesions of the bile ducts and is of value in confirming the diagnosis. Jaundice is a prominent feature late in the course of the disease. Treatment with ursodeoxycholic acid (replaces endogenous toxic bile acids) improves pruritus, slows the pro-gression of disease, and thus delays the need for liver trans-plantation and prolongs life.

Major Complications

The major sequelae of cirrhosis are as follows:

1. Portal hypertension and hepatocellular dysfunction, which may result in:

a. Variceal hemorrhage

b. Ascites, which can be further complicated by sponta-neous bacterial peritonitis

c. Hepatic encephalopathy

d. Hepatorenal syndrome

e. Hepatopulmonary syndrome

2. Hepatocellular carcinoma :

The pathophysiologic interrelationships among the com-plications of hepatocirrhosis.

Portal Hypertension

The distortion of hepatic architecture in cirrhosis leads to a marked increase in resistance to portal venous flow which, in turn, leads to an increase in portal venous pressure. In alcoholic liv-er disease, increased resistance to sinusoidal blood flow may also re-sult from hepatocyte swelling (hydropic degeneration)(Figure 4).

Although cirrhosis is the most important cause of portal hypertension, any process leading to increased resistance to portal blood flow into (presinusoidal) or through the liver (sinusodial) or to hepatic venous outflow from the liver (postsinusoidal) results in portal hypertension. Hydrostatic pressure within any vascular system is proportional to both re-sistance and blood flow. In cirrhosis, increases in splanchnic blood flow may also result from increased cardiac output, which further aggravates portal hypertension.

Portal hypertension leads to the formation of venous col-lateral vessels between the portal and systemic circulations. Collateral vessels may form at several sites, the most important clinically being those connecting the portal vein to the azygos vein that form dilated, tortuous veins (varices) in the submu-cosa of the gastric fundus and esophagus. The normal portal pressure gradient (hepatic vein-portal vein) is 0.5 to 0.8 kPa (4 to 6 mm Hg). When the gradient is more than 1.6 kPa (12 mm Hg), esophageal varices may rupture(Table 27).

Variceal Hemorrhage

Hemorrhage occurs most frequently from varices in the esophagus and is a common and serious complication of portal hypertension that has a mortality rate of 30% to 60 %. Large varices bleed most commonly, and bleeding occurs when high tension in the walls of these vessels leads to rupture. Bleeding may present as hematemesis, hematochezia, melena, or any combination of these entities. Bleeding may lead to shock, it may stop spontaneously, or it may recur. Impaired hepatic synthesis of coagulation factors (hepatocellular dysfunction) and thrombocytopenia (hypersplenism) may further complicate the management of variceal bleeding. The management of esophageal varices includes early medical intervention to pre-vent bleeding as well as the treatment of acute variceal hemor-rhage. Nonselective 1; blockers (propranolol and nadolol) and mononitrates (isosorbide mononitrate) are effective in prevent-ing variceal hemorrhage by reducing portal blood flow and pressure. Screening for varices is appropriate in patients with cirrhosis who have clinical features of portal hypertension, par-ticularly those patients who have telangiectasias on physical ex-amination and thrombocytopenia. Somatostatin (or its syn-thetic analogue, octreotide) and vasopressin are given intra-venously to reduce splanchnic blood flow and are used in the a-cute setting of esophageal hemorrhage until endoscopic or sur-gical therapy is performed. Intravenous nitroglycerin should be given with vasopressin to minimize systemic vasoconstricitive toxicity. Endoscopic therapy includes injection with sclerosing solutions and/or band ligation. A metaanalysis has shown that band ligation may be more effective to prevent recurrent bleed-ing, and it is accociated with fewer adverse effects. Repeated courses can lead to variceal obliteration. Balloon tamponade (Sengstaken-Blakemore tube, Linton tube, or Minnesota tube) is an effective temporary measure for patients in whom endoscopic therapy has failed. These patients may need to un-dergo portal decompression either by a variely of surgical pro-cedures or by transjugular intrahepatic portosystemic shunt placement. The patients' candidacy for liver transplantation affects the surgeon's choice of portal decompressive procedure.

Hepatic Dysfunction

Cirrhosis results in impaired synthesis of proteins by hepa-tocytes and leads to hypoalbuminemia and deficient production of coagulation factors and diminished capacity for hepatic detoxification.

Ascites

Ascites is the accumulation of excess fluid in the peri-toneal cavity. Although cirrhosis is the most common cause of ascites, this condition may have numerous other causes (Table 28). The serumascites albumin gradient has replaced the ex-udative-transudative classification of ascites. A high serum-as-cites albumin gradient (¡Ý11 g/L) signifies portal hyperten-sion but does not determine its cause. Ascites becomes clinical-ly detectable when accumulations reach > 500 ml. Shifting dullness to percussion is the most sensitive clinical sign of as-cites, but ultrasonography more readily detects small fluid vol-umes.

Several theories explain the formation of ascites in cirrho-sis. Initially, systemic arterial vasodilatation (peripheral arte-rial vasodilation theory) results in excess renal reabsorpation of sodium and water and leads to hypervolemia and overflow of fluid into the peritoneum (overflow theory), thus causing as-cites. Ascites causes an "ineffective" intravascular volume (un-derflow theory) that results in enhanced production of renin, aldosterone, and antidiuretic hormone and thereby further in-creases sodium and water retention and perpetuates ascites for-mation.

Treatment of ascites consists initially of sodium restric-tion, preferably less than 2 g/day. Restricted fluid intake may be necessary if hyponatremia (< 120 mmol/L) is present. The administration of spironolactone, an aldosterone antagonist, supplemented with a loop diuretic (e. g. , furosemide) is often effective. Diuresis should be monitored closely, because ag-gressive diuretic therapy may result in hypokalemia and a de-pleted plasma volume, leading to hepatic encephalopathy and impaired renal function. Refractory ascites occurs in about 10% of patients with cirrhosis and is defined as persistent tense ascites despite maximal diuretic therapy (spironolactone, 400 mg/day, and furosemide, 160 mg/day) or if azoternia de-velops (creatinine > 176.8 umol/L) while the patient is re-ceiving submaximal doses. Treatment in these patients in-cludes repeated large-volume paracentesis (many physicians si-multaneously give intravenous albumin, at 6 to 8 g/L of ascitic fluid removed, but whether this is of any benefit is unclear and may not be necessary if¡Ü5 g/L is removed), surgically im-planted peritoneovenous shunts (LeVeen or Denver), tran-sjugular intrahepatic portosystemic shunt, portacaval anasto-moses, or liver transplantation.

Two important complications occur in patients with cir-rhotic ascites: spontaneous bacterial peritonitis and the hepa-torenal syndrome. These complications are discussed in the next two sections.

Spontaneous Bacterial Peritionitis

Infection of ascitic fluid, usually with Enterobacteriaceae or Pneumococcus, may occur in patients with cirrhosis. Fever, abdominal pain, and tenderness may be present, or the infec-tion may be clinically silent. Hepatic encephalopathy may be precipitated. The diagnosis is strongly suspected if the ascetic fluid polymorphonuclear leukocyte count is more than 250/uL, and the diagnosis may be confirmed by culture. Treatment with a third-generation cephalosporin for 5 to 7 days is usual. Prophylactic therapy is indicated in patients with a prior episode of spontaneous bacterial peritonitis, in patients with cirrhosis and ascites who are hospitalized with upper gastroin-testinal bleeding, and in other selected patients (i. e. , patients with an ascitic fluid total protein concentration < 10 g/L and candidates for liver transplantation). Prophylaxis with nor-floxacin (400 mg/day), ciprofloxacin (750 mg once weekly), or trimethoprim-sulfamethoxazole (160 mg/800 mg. Monday through Friday) has been shown to be effective.

Hepatorenal Syndrome

Serious liver disease from any cause may be complicated by a form of functional renal failure termed the hepatorenal syndrome. It almost invariably occurs in the presence of signif-icant hepatic synthetic dysfunction and severe ascites. This syndrome occurs in approximately 4 % of patients with decom-pensated cirrhosis, and some prospective series have deter-mined that the probability of developing it in patients admitted to the hospital for the treatment of ascites may be as high as 32% at 2 years. Typically, the kidneys are histologically nor-mal, with the capacity of regaining normal function in the event of recovery of liver function. Severe cortical vasocon-striction has been demonstrated angiographically, and it re-verses when these kidneys have been transplanted in patients who do not have cirrhosis. The renal dysfunction is character-ized by a declining glomerular filtration rate, oliguria, low urine sodium (< 10 mmol/L), normal urinary sediment, and azotemia, often with a disproportionately high ratio of blood urea nitrogen to creatinine. The decline in renal function often follows one of three events in a patient with cirrhosis and as-cites: sepsis, a vigorous attempt to reduce ascites with diuret-ics, or large-volume paracentesis.

The hepatorenal syndrome is usually progressive and fa-tal, with a mortality of 95 %. It should be diagnosed only after plasma volume depletion (a common cause of reversible, prere-nal azotemia in patients with cirrhosis, particularly with di-uretic use) and other forms of acute renal injury have been ex-cluded.

Patients should be given volume expanders to treat possi-ble prerenal azotemia. Successful reversal of hepatorenal syn-drome has been documents using low-dose vasopressin, oc-treotide, or norepinephrine, which raise systemic vascular re-sistance and thereby increase renal blood flow. Liver trans-plantation has become an accepted treatment for the hepatore-nal syndrome.