Cirrhosis and Its Complications: Introduction

Cirrhosis is a condition that is defined histopathologically and has a variety of clinical manifestations and complications, some of which can be life-threatening. In the past, it has been thought that cirrhosis was never reversible; however, it has become apparent that when the underlying insult that has caused the cirrhosis has been removed, there can be reversal of fibrosis. This is most apparent with the successful treatment of chronic hepatitis C; however, reversal of fibrosis is also seen in patients with hemochromatosis who have been successfully treated and in patients with alcoholic liver disease who have discontinued alcohol use.

Regardless of the cause of cirrhosis, the pathologic features consist of the development of fibrosis to the point that there is architectural distortion with the formation of regenerative nodules. This results in a decrease in hepatocellular mass, and thus function, and an alteration of blood flow. The induction of fibrosis occurs with activation of hepatic stellate cells, resulting in the formation of increased amounts of collagen and other components of the extracellular matrix.

Clinical features of cirrhosis are the result of pathologic changes and mirror the severity of the liver disease. Most hepatic pathologists provide an assessment of grading and staging when evaluating liver biopsy samples. These grading and staging schemes vary between disease states and have been developed for most conditions, including chronic viral hepatitis, nonalcoholic fatty liver disease, and primary biliary cirrhosis. Advanced fibrosis usually includes bridging fibrosis with nodularity designated as stage 3 and cirrhosis designated as stage 4. Patients who have cirrhosis have varying degrees of compensated liver function, and clinicians need to differentiate between those who have stable, compensated cirrhosis and those who have decompensated cirrhosis. Patients who have developed complications of their liver disease and have become decompensated should be considered for liver transplantation. Many of the complications of cirrhosis will require specific therapy. Portal hypertension is a significant complicating feature of decompensated cirrhosis and is responsible for the development of ascites and bleeding from esophagogastric varices, two complications that signify decompensated cirrhosis. Loss of hepatocellular function results in jaundice, coagulation disorders, and hypoalbuminemia and contributes to the causes of portosystemic encephalopathy. The complications of cirrhosis are basically the same regardless of the etiology. Nonetheless, it is useful to classify patients by the cause of their liver disease (Table 302-1); patients can be divided into broad groups with alcoholic cirrhosis, cirrhosis due to chronic viral hepatitis, biliary cirrhosis, and other less-common causes such as cardiac cirrhosis, cryptogenic cirrhosis, and other miscellaneous causes.

Table 302-1 Causes of Cirrhosis

Alcoholism Cardiac cirrhosis

Chronic viral hepatitis Inherited metabolic liver disease

Hepatitis B Hemochromatosis

Hepatitis C Wilson's disease

Autoimmune hepatitis 1 Antitrypsin deficiency

Nonalcoholic steatohepatitis Cystic fibrosis

Biliary cirrhosis Cryptogenic cirrhosis

Primary biliary cirrhosis

Primary sclerosing cholangitis

Autoimmune cholangiopathy

Alcoholic Cirrhosis

Excessive chronic alcohol use can cause several different types of chronic liver disease, including alcoholic fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Furthermore, use of excessive alcohol can contribute to liver damage in patients with other liver diseases, such as hepatitis C, hemochromatosis, and those patients who have fatty liver disease related to obesity. Chronic alcohol use can produce fibrosis in the absence of accompanying inflammation and/or necrosis. Fibrosis can be centrilobular, pericellular, or periportal. When fibrosis reaches a certain degree, there is disruption of the normal liver architecture and replacement of liver cells by regenerative nodules. In alcoholic cirrhosis, the nodules are usually

Pathogenesis

Alcohol is the most commonly used drug in the United States, and more than two-thirds of adults drink alcohol each year. Thirty percent have had a binge within the past month, and over 7% of adults regularly consume more than two drinks per day. Unfortunately, more than 14 million adults in the United States meet the diagnostic criteria for alcohol abuse or dependence. In the United States, chronic liver disease is the 10th most common cause of death in adults, and alcoholic cirrhosis accounts for approximately 40% of deaths due to cirrhosis.

Ethanol is mainly absorbed by the small intestine and, to a lesser degree, through the stomach. Gastric alcohol dehydrogenase (ADH) initiates alcohol metabolism. Three enzyme systems account for metabolism of alcohol in the liver. These include cytosolic ADH, the microsomal-oxidizing system (MEOS), and peroxisomal catalase. The majority of ethanol oxidation occurs via ADH to form acetaldehyde, which is a highly reactive molecule that may have multiple effects. Ultimately, acetaldehyde is metabolized to acetate by aldehyde dehydrogenase (ALDH). Intake of ethanol increases intracellular accumulation of triglycerides by increasing fatty acid uptake and by reducing fatty acid oxidation and lipoprotein secretion. Protein synthesis, glycosylation, and secretion are impaired. Oxidative damage to hepatocyte membranes occurs due to the formation of reactive oxygen species; acetaldehyde is a highly reactive molecule that combines with proteins to form protein-acetaldehyde adducts. These adducts may interfere with specific enzyme activities, including microtubular formation and hepatic protein trafficking. With acetaldehyde-mediated hepatocyte damage, certain reactive oxygen species can result in Kupffer cell activation. As a result, profibrogenic cytokines are produced that initiate and perpetuate stellate cell activation, with the resultant production of excess collagen and extracellular matrix. Connective tissue appears in both periportal and pericentral zones and eventually connects portal triads with central veins forming regenerative nodules. Hepatocyte loss occurs, and with increased collagen production and deposition, together with continuing hepatocyte destruction, the liver contracts and shrinks in size. This process generally takes from years to decades to occur and requires repeated insults.

Clinical Features

The diagnosis of alcoholic liver disease requires an accurate history regarding both amount and duration of alcohol consumption. Patients with alcoholic liver disease can present with nonspecific symptoms such as vague right upper quadrant pain, fever, nausea and vomiting, diarrhea, anorexia, and malaise. Alternatively, they may present with more specific complications of chronic liver disease, including ascites, edema, or upper gastrointestinal (GI) hemorrhage. Many cases present incidentally at the time of autopsy or elective surgery. Other clinical manifestations include the development of jaundice or encephalopathy. The abrupt onset of any of these complications may be the first event prompting the patient to seek medical attention. Other patients may be identified in the course of an evaluation of routine laboratory studies that are found to be abnormal. On physical examination, the liver and spleen may be enlarged, with the liver edge being firm and nodular. Other frequent findings include scleral icterus, palmar erythema, spider angiomas, parotid gland enlargement, digital clubbing, muscle wasting, or the development of edema and ascites. Men may have decreased body hair and gynecomastia as well as testicular atrophy, which may be a consequence of hormonal abnormalities or a direct toxic effect of alcohol on the testes. In women with advanced alcoholic cirrhosis, menstrual irregularities usually occur, and some women may be amenorrheic. These changes are often reversible following cessation of alcohol.

Laboratory tests may be completely normal in patients with early compensated alcoholic cirrhosis. Alternatively, in advanced liver disease, many abnormalities usually are present. Patients may be anemic either from chronic GI blood loss, nutritional deficiencies, or hypersplenism related to portal hypertension, or as a direct suppressive effect of alcohol on the bone marrow. A unique form of hemolytic anemia (with spur cells and acanthocytes) called Zieve's syndrome can occur in patients with severe alcoholic hepatitis. Platelet counts are often reduced early in the disease, reflective of portal hypertension with hypersplenism. Serum total bilirubin can be normal or elevated with advanced disease. Direct bilirubin is frequently mildly elevated in patients with a normal total bilirubin, but the abnormality typically progresses as the disease worsens. Prothrombin times are often prolonged and usually do not respond to administration of parenteral vitamin K. Serum sodium levels are usually normal unless patients have ascites and then can be depressed, largely due to ingestion of excess free water. Serum aminotransferases (ALT, AST) are typically elevated, particularly in patients who continue to drink, with AST levels being higher than ALT levels, usually by a 2:1 ratio.

Diagnosis

Patients who have any of the above-mentioned clinical features, physical examination findings, or laboratory studies should be considered to have alcoholic liver disease. The diagnosis, however, requires accurate knowledge that the patient is continuing to use and abuse alcohol. Furthermore, other forms of chronic liver disease (e.g., chronic viral hepatitis, metabolic or autoimmune liver diseases) must be considered or ruled out or, if present, an estimate of relative causality along with the alcohol use should be determined. Liver biopsy can be helpful to confirm a diagnosis, but generally when patients present with alcoholic hepatitis and are still drinking, liver biopsy is withheld until abstinence has been maintained for at least 6 months in order to determine residual, nonreversible disease.

In patients who have had complications of cirrhosis and who continue to drink, there is a

Alcoholic Cirrhosis: Treatment

Abstinence is the cornerstone of therapy for patients with alcoholic liver disease. In addition, patients require good nutrition and long-term medical supervision in order to manage underlying complications that may develop. Complications such as the development of ascites and edema, variceal hemorrhage, or portosystemic encephalopathy all require specific management and treatment. Glucocorticoids are occasionally used in patients with severe alcoholic hepatitis in the absence of infection. Survival has been shown to improve in certain studies. Treatment is restricted to patients with a discriminant function (DF) value of >32. The DF is calculated as the serum total bilirubin plus the difference in the patient's prothrombin time compared to control (in seconds) multiplied by 4.6. In patients for whom this value is >32, there is improved survival at 28 days with the use of glucocorticoids.

Other therapies that have been used include oral pentoxifylline, which decreases the production of tumor necrosis factor (TNF-) and other proinflammatory cytokines. In contrast to glucocorticoids, with which complications can occur, pentoxifylline is relatively easy to administer and has few if any side effects. A variety of nutritional therapies have been tried with either parenteral or enteral feedings; however, it is unclear whether any of these modalities have significantly improved survival.

Recent studies have used parenterally administered inhibitors of TNF- such as infliximab or etanercept. Early results have shown no adverse events; however, there was no clear-cut improvement in survival. Anabolic steroids, propylthiouracil, antioxidants, colchicine, and penicillamine have all been used but do not show clear-cut benefit and are not recommended.

As mentioned above, the cornerstone to treatment is cessation of alcohol use. Recent experience with medications that reduce craving for alcohol such as acamprosate calcium has been favorable. Patients may take other necessary medications even in the presence of cirrhosis. Acetaminophen use is often discouraged in patients with liver disease; however, if no more than 2 g of acetaminophen per day are consumed, there generally are no problems.

Cirrhosis Due to Chronic Viral Hepatitis B or C

Of patients exposed to the hepatitis C virus (HCV), approximately 80% develop chronic hepatitis C, and of those, about 20-30% will develop cirrhosis over 20-30 years. Many of these patients have had concomitant alcohol use, and the true incidence of cirrhosis due to hepatitis C alone is unknown. Nonetheless, this represents a significant number of patients. It is expected that an even higher percentage will go on to develop cirrhosis over longer periods of time. In the United States, approximately 5 million people have been exposed to the hepatitis C virus, with about 3½-4 million who are chronically viremic. Worldwide, about 170 million individuals have hepatitis C, with some areas of the world (e.g., Egypt) having up to 15% of the population infected. HCV is a noncytopathic virus, and liver damage is probably immune-mediated. Progression of liver disease due to chronic hepatitis C is characterized by portal-based fibrosis with bridging fibrosis and nodularity developing, ultimately culminating in the development of cirrhosis. In cirrhosis due to chronic hepatitis C, the liver is small and shrunken with characteristic features of a mixed micro- and macronodular cirrhosis seen on liver biopsy. In addition to the increased fibrosis that is seen in cirrhosis due to hepatitis C, an inflammatory infiltrate is found in portal areas with interface hepatitis and occasionally some lobular hepatocellular injury and inflammation. In patients with HCV genotype 3, steatosis is often present.

Similar findings are seen in patients with cirrhosis due to chronic hepatitis B. Of patients exposed to hepatitis B, about 5% develop chronic hepatitis B, and about 20% of those patients will go on to develop cirrhosis. Special stains for HBc (hepatitis B core) and HBs (hepatitis B surface) antigen will be positive, and ground glass hepatocytes signifying HBsAg (hepatitis B surface antigen) may be present. In the United States, there are about 1.25 million carriers of hepatitis B, whereas in other parts of the world where hepatitis B virus (HBV) is endemic (i.e., Southeast Asia, sub-Saharan Africa), up to 15% of the population may be infected having acquired the infection vertically at the time of birth. Thus, over 300-400 million individuals are thought to have hepatitis B worldwide. Approximately 25% of these individuals may ultimately develop cirrhosis.

Clinical Features and Diagnosis

Patients with cirrhosis due to either chronic hepatitis C or B can present with the usual symptoms and signs of chronic liver disease. Fatigue, malaise, vague right upper quadrant pain, and laboratory abnormalities are frequent presenting features. Diagnosis requires a thorough laboratory evaluation, including quantitative HCV RNA testing and analysis for HCV genotype, or hepatitis B serologies to include HBsAg, anti-HBs, HBeAg (hepatitis B e antigen), anti-HBe, and quantitative HBV DNA levels.

Cirrhosis Due to Chronic Viral Hepatitis B or C: Treatment

Management of complications of cirrhosis revolves around specific therapy for treatment of whatever complications occur, whether they be esophageal variceal hemorrhage, development of ascites and edema, or encephalopathy. In patients with chronic hepatitis B, numerous studies have shown beneficial effects of antiviral therapy, which is effective at viral suppression, as evidenced by reducing aminotransferase levels and HBV DNA levels, and improving histology by reducing inflammation and fibrosis. Several clinical trials and case series have demonstrated that patients with decompensated liver disease can become compensated with the use of antiviral therapy directed against hepatitis B. Currently available therapy includes lamivudine, adefovir, entecavir, and tenofovir. Interferon can also be used for treating hepatitis B, but it should not be used in cirrhotics.

Treatment of patients with cirrhosis due to hepatitis C is a little more difficult because the side effects of pegylated interferon and ribavirin therapy are oftentimes difficult to manage in patients with cirrhosis. Dose-limiting cytopenias (platelets, white blood cells, red blood cells) or severe side effects can result in discontinuation of treatment. Nonetheless, if patients can tolerate treatment, and if it is successful, the benefit is great and disease progression is reduced.

Cirrhosis from Autoimmune Hepatitis and Nonalcoholic Fatty Liver Disease

Other causes of posthepatitic cirrhosis include autoimmune hepatitis and cirrhosis due to nonalcoholic steatohepatitis. Many patients with autoimmune hepatitis (AIH) present with cirrhosis that is already established. Typically, these patients will not benefit from immunosuppressive therapy with glucocorticoids or azathioprine since the AIH is "burned out." In this situation, liver biopsy does not show a significant inflammatory infiltrate. Diagnosis in this setting requires positive autoimmune markers such as antinuclear antibody (ANA) or anti-smooth-muscle antibody (ASMA). When patients with AIH present with cirrhosis and active inflammation accompanied by elevated liver enzymes, there can be considerable benefit from the use of immunosuppressive therapy.

Patients with nonalcoholic steatohepatitis are increasingly being found to have progressed to cirrhosis. With the epidemic of obesity that continues in Western countries, more and more patients are identified with nonalcoholic fatty liver disease. Of these, a significant subset have nonalcoholic steatohepatitis and can progress to increased fibrosis and cirrhosis. Over the past several years, it has been increasingly recognized that many patients who were thought to have cryptogenic cirrhosis in fact have nonalcoholic steatohepatitis. As their cirrhosis progresses, they become catabolic and then lose the telltale signs of steatosis seen on biopsy. Management of complications of cirrhosis due to either AIH or nonalcoholic steatohepatitis is similar to that for other forms of cirrhosis.

Biliary Cirrhosis

Biliary cirrhosis has pathologic features that are different from either alcoholic cirrhosis or posthepatitic cirrhosis, yet the manifestations of end-stage liver disease are the same. Cholestatic liver disease may result from necroinflammatory lesions, congenital or metabolic processes, or external bile duct compression. Thus, two broad categories reflect the anatomic sites of abnormal bile retention: intrahepatic and extrahepatic. The distinction is important for obvious therapeutic reasons. Extrahepatic obstruction may benefit from surgical or endoscopic biliary tract decompression, whereas intrahepatic cholestatic processes will not improve with such interventions and require a different approach.

The major causes of chronic cholestatic syndromes are primary biliary cirrhosis (PBC), autoimmune cholangitis, primary sclerosing cholangitis (PSC), and idiopathic adulthood ductopenia. These syndromes are usually clinically distinguished from each other by antibody testing, cholangiographic findings, and clinical presentation. However, they all share the histopathologic features of chronic cholestasis, such as cholate stasis, copper deposition, xanthomatous transformation of hepatocytes, and irregular so-called biliary fibrosis. In addition, there may be chronic portal inflammation, interface activity, and chronic lobular inflammation. Ductopenia is a result of this progressive disease as patients develop cirrhosis.

Primary Biliary Cirrhosis

PBC is seen in about 100-200 individuals per million, with a strong female preponderance and a median age of around 50 years at the time of diagnosis. The cause of PBC is unknown; it is characterized by portal inflammation and necrosis of cholangiocytes in small and medium-sized bile ducts. Cholestatic features prevail, and biliary cirrhosis is characterized by an elevated bilirubin level and progressive liver failure. Liver transplantation is the treatment of choice for patients with decompensated cirrhosis due to PBC. A variety of therapies have been proposed, but ursodeoxycholic acid (UDCA) is the only approved treatment that has some degree of efficacy by slowing the rate of progression of the disease.

Antimitochondrial antibodies (AMA) are present in about 90% of patients with PBC. These autoantibodies recognize intermitochondrial membrane proteins that are enzymes of the pyruvate dehydrogenase complex (PDC), the branched chain-2-oxoacid dehydrogenase complex, and the 2-oxogluterate dehydrogenase complex. Most relate to pyruvate dehydrogenase. These autoantibodies are not pathogenic but rather are useful markers for making a diagnosis of PBC.

Pathology

Histopathologic analyses of liver biopsies of patients with PBC have resulted in identifying four distinct stages of the disease as it progresses. The earliest lesion is termed chronic nonsuppurative destructive cholangitis and is a necrotizing inflammatory process of the portal tracts. Medium and small bile ducts are infiltrated with lymphocytes and undergo duct destruction. Mild fibrosis and sometimes bile stasis can occur. With progression, the inflammatory infiltrate becomes less prominent, but the number of bile ducts is reduced and there is proliferation of smaller bile ductules. Increased fibrosis ensues with the expansion of periportal fibrosis to bridging fibrosis. Finally, cirrhosis, which may be micronodular or macronodular, develops.

Clinical Features

Currently most patients with PBC are diagnosed well before the end-stage manifestations of the disease are present, and, as such, most patients are actually asymptomatic. When symptoms are present, they most prominently include a significant degree of fatigue out of proportion to what would be expected for either the severity of the liver disease or the age of the patient. Pruritus is seen in approximately 50% of patients at the time of diagnosis and can be debilitating. It may be intermittent and usually is most bothersome in the evening. In some patients, pruritus can develop toward the end of pregnancy, and there are examples of patients having been diagnosed with cholestasis of pregnancy rather than PBC. Pruritus that presents prior to the development of jaundice indicates severe disease and a poor prognosis.

Physical examination can show jaundice and other complications of chronic liver disease including hepatomegaly, splenomegaly, ascites, and edema. Other features that are unique to PBC include hyperpigmentation, xanthelasma, and xanthomata, which are related to the altered cholesterol metabolism seen in this disease. Hyperpigmentation is evident on the trunk and the arms and is seen in areas of exfoliation and lichenification associated with progressive scratching related to the pruritus. Bone pain resulting from osteopenia or osteoporosis is occasionally seen at the time of diagnosis.

Laboratory Findings

Laboratory findings in PBC show cholestatic liver enzyme abnormalities with an elevation in -glutamyl transpeptidase and alkaline phosphatase (ALP) along with mild elevations in aminotransferases (ALT and AST). Immunoglobulins, particularly IgM, are typically increased. Hyperbilirubinemia usually is seen once cirrhosis has developed. Thrombocytopenia, leukopenia, and anemia may be seen in patients with portal hypertension and hypersplenism. Liver biopsy shows characteristic features as described above and should be evident to any experienced hepatopathologist. Up to 10% of patients with characteristic PBC will have features of AIH as well and are defined as having "overlap" syndrome. These patients are treated as PBC patients and may progress to cirrhosis with the same frequency as typical PBC patients.

Diagnosis

PBC should be considered in patients with chronic cholestatic liver enzyme abnormalities. It is most often seen in middle-aged women. AMA testing may be negative, and it should be remembered that as many as 10% of patients with PBC may be AMA-negative. Liver biopsy is most important in this setting of AMA-negative PBC. In patients who are AMA-negative with cholestatic liver enzymes, PSC should be ruled out by way of cholangiography.

Primary Biliary Cirrhosis: Treatment

Treatment of the typical manifestations of cirrhosis are no different for PBC than for other forms of cirrhosis. UDCA has been shown to improve both biochemical and histologic features of the disease. Improvement is greatest when therapy is initiated early; the likelihood of significant improvement with UDCA is low in patients with PBC who present with manifestations of cirrhosis. UDCA is given in doses of 13-15 mg/kg per day; the medication is usually well-tolerated, although some patients have worsening pruritus with initiation of therapy. A small proportion of patients may have diarrhea or headache as a side effect of the drug. UDCA has been shown to slow the rate of progression of PBC, but it does not reverse or cure the disease. Patients with PBC require long-term follow-up by a physician experienced with the disease. Certain patients may need to be considered for liver transplantation should their liver disease decompensate.

The main symptoms of PBC are fatigue and pruritus, and symptom management is important. Several therapies have been tried for treatment of fatigue, but none of them have been successful; frequent naps should be encouraged. Pruritus is treated with antihistamines, narcotic receptor antagonists (naltrexone), and rifampin. Cholestyramine, a bile salt sequestering agent, has been helpful in some patients but is somewhat tedious and difficult to take. Plasmapheresis has been utilized rarely in patients with severe intractable pruritus. There is an increased incidence of osteopenia and osteoporosis in patients with cholestatic liver disease, and bone density testing should be performed. Treatment with a bisphosphonate should be instituted when bone disease is identified.

Primary Sclerosing Cholangitis

As in PBC, the cause of PSC remains unknown. PSC is a chronic cholestatic syndrome that is characterized by diffuse inflammation and fibrosis involving the entire biliary tree, resulting in chronic cholestasis. This pathologic process ultimately results in obliteration of both the intra- and extrahepatic biliary tree, leading to biliary cirrhosis, portal hypertension, and liver failure. The cause of PSC remains unknown despite extensive investigation into various mechanisms related to bacterial and viral infections, toxins, genetic predisposition, and immunologic mechanisms, all of which have been postulated to contribute to the pathogenesis and progression of this syndrome.

Pathologic changes that can occur in PSC show bile duct proliferation as well as ductopenia and fibrous cholangitis (pericholangitis). Oftentimes, liver biopsy changes in PSC are not pathognomonic, and establishing the diagnosis of PSC must involve imaging of the biliary tree. Periductal fibrosis is occasionally seen on biopsy specimens and can be quite helpful in making the diagnosis. As the disease progresses, biliary cirrhosis is the final end-stage manifestation of PSC.

Clinical Features

The usual clinical features of PSC are those found in cholestatic liver disease, with fatigue, pruritus, steatorrhea, deficiencies of fat-soluble vitamins, and the associated consequences. As in PBC, the fatigue is profound and nonspecific. Pruritus can oftentimes be debilitating and is related to the cholestasis. The severity of pruritus does not correlate with the severity of the disease. Metabolic bone disease, as seen in PBC, can occur with PSC and should be treated (see above).

Laboratory Findings

Patients with PSC typically are identified in the course of an evaluation of abnormal liver enzymes. Most patients have at least a twofold increase in ALP and may have elevated aminotransferases as well. Albumin levels may be decreased, and prothrombin times are prolonged in a substantial proportion of patients at the time of diagnosis. Some degree of correction of a prolonged prothrombin time may occur with parenteral vitamin K. A small subset of patients have aminotransferase elevations greater than five times the upper limit of normal and may have features of AIH on biopsy. These individuals are thought to have an overlap syndrome between PSC and AIH. Autoantibodies are frequently positive in patients with the overlap syndrome but are typically negative in patients who only have PSC. One autoantibody, the perinuclear antineutrophil cytoplasmic antibody (P-ANCA) is positive in about 65% of patients with PSC. Over 50% of patients with PSC also have ulcerative colitis (UC); accordingly, once a diagnosis of PSC is established, colonoscopy should be performed looking for evidence of UC.

Diagnosis

The definitive diagnosis of PSC requires cholangiographic imaging. Over the last several years, MRI with magnetic resonance cholangiopancreatography (MRCP) has been utilized as the imaging technique of choice for initial evaluation. Once patients are screened in this manner, some investigators feel that endoscopic retrograde cholangiopancreatography (ERCP) should also be performed to be certain whether or not a dominant stricture is present. Typical cholangiographic findings in PSC are multifocal stricturing and beading involving both the intrahepatic and extrahepatic biliary tree. However, though involvement may be of the intrahepatic bile ducts alone or of the extrahepatic bile ducts alone, more commonly both are involved. These strictures are typically short and with intervening segments of normal or slightly dilated bile ducts that are distributed diffusely, producing the classic beaded appearance. The gallbladder and cystic duct can be involved in up to 15% of cases. Patients with high-grade, diffuse stricturing of the intrahepatic bile ducts have an overall poor prognosis. Gradually, biliary cirrhosis develops, and patients will progress to decompensated liver disease with all the manifestations of ascites, esophageal variceal hemorrhage, and encephalopathy.

Primary Sclerosing Cholangitis: Treatment

There is no specific proven treatment for PSC, although studies are currently ongoing using high-dose (20 mg/kg per day) UDCA to determine its benefit. Endoscopic dilatation of dominant strictures can be helpful, but the ultimate treatment is liver transplantation. A dreaded complication of PSC is the development of cholangiocarcinoma, which is a relative contraindication to liver transplantation. Symptoms of pruritus are common, and the approach is as mentioned previously for this problem in patients with PBC (see above).

Cardiac Cirrhosis

Definition

Patients with long-standing right-sided congestive heart failure may develop chronic liver injury and cardiac cirrhosis. This is an increasingly uncommon, if not rare, cause of chronic liver disease given the advances made in the care of patients with heart failure.

Etiology and Pathology

In the case of long-term right-sided heart failure, there is an elevated venous pressure transmitted via the inferior vena cava and hepatic veins to the sinusoids of the liver, which become dilated and engorged with blood. The liver becomes enlarged and swollen, and with long-term passive congestion and relative ischemia due to poor circulation, centrilobular hepatocytes can become necrotic, leading to pericentral fibrosis. This fibrotic pattern can extend to the periphery of the lobule outward until a unique pattern of fibrosis causing cirrhosis can occur.

Clinical Features

Patients typically have signs of congestive heart failure and will manifest an enlarged firm liver on physical examination. ALP levels are characteristically elevated, and aminotransferases may be normal or slightly increased with AST usually higher than ALT. It is unlikely that patients will develop variceal hemorrhage or encephalopathy.

Diagnosis

The diagnosis is usually made in someone with clear-cut cardiac disease who has an elevated ALP and an enlarged liver. Liver biopsy shows a pattern of fibrosis that can be recognized by an experience hepatopathologist. Differentiation from Budd-Chiari syndrome (BCS) can be made by seeing extravasation of red blood cells in BCS, but not in cardiac hepatopathy. Venoocclusive disease can also affect hepatic outflow and has characteristic features on liver biopsy. Venoocclusive disease can be seen under the circumstances of conditioning for bone marrow transplant with radiation and chemotherapy; it can also be seen with the ingestion of certain herbal teas as well as pyrrolizidine alkaloids. This is typically seen in Caribbean countries and rarely in the United States. Treatment is based on management of the underlying cardiac disease.

Other Types of Cirrhosis

There are several other less common causes of chronic liver disease that can progress to cirrhosis. These include inherited metabolic liver diseases such as hemochromatosis, Wilson's disease, 1 antitrypsin (1 AT) deficiency, and cystic fibrosis. For all of these disorders, the manifestations of cirrhosis are similar, with some minor variations, to those seen in other patients with other causes of cirrhosis.

Hemochromatosis is an inherited disorder of iron metabolism that results in a progressive increase in hepatic iron deposition which, over time, can lead to a portal-based fibrosis progressing to cirrhosis, liver failure, and hepatocellular cancer. While the frequency of hemochromatosis is relatively common, with genetic susceptibility occurring in 1 in 250 individuals, the frequency of end-stage manifestations due to the disease is relatively low, and fewer than 5% of those patients who are genotypically susceptible will go on to develop severe liver disease from hemochromatosis. Diagnosis is made with serum iron studies showing an elevated transferrin saturation and an elevated ferritin level, along with abnormalities identified by HFE mutation analysis. Treatment is straightforward, with regular therapeutic phlebotomy.

Wilson's disease is an inherited disorder of copper homeostasis with failure to excrete excess amounts of copper, leading to an accumulation in the liver. This disorder is relatively uncommon, affecting 1 in 30,000 individuals. Wilson's disease typically affects adolescents and young adults. Prompt diagnosis before end-stage manifestations become irreversible can lead to significant clinical improvement. Diagnosis requires determination of ceruloplasmin levels, which are low; 24-hour urine copper levels, which are elevated; typical physical examination findings, including Kayser-Fleischer corneal rings, and characteristic liver biopsy findings. Treatment consists of copper chelating medications.

1AT deficiency results from an inherited disorder that causes abnormal folding of the 1AT protein, resulting in failure of secretion of that protein from the liver. It is unknown how the retained protein leads to liver disease. Patients with 1AT deficiency at greatest risk for developing chronic liver disease have the ZZ genotype, but only about 10-20% of such individuals will develop chronic liver disease. Diagnosis is made by determining 1AT levels and genotype. Characteristic PAS-positive, diastase-resistant globules are seen on liver biopsy. The only effective treatment is liver transplantation, which is curative.

Cystic fibrosis is an uncommon inherited disorder affecting Caucasians of Northern European descent. A biliary-type cirrhosis can occur, and some patients derive benefit from the chronic use of UDCA.

Major Complications of Cirrhosis

The clinical course of patients with advanced cirrhosis is often complicated by a number of important sequelae that can occur regardless of the underlying cause of the liver disease. These include portal hypertension and its consequences of gastroesophageal variceal hemorrhage, splenomegaly, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, and hepatocellular carcinoma (Table 302-2).

Table 302-2 Complications of Cirrhosis

Portal hypertension Coagulopathy

Gastroesophageal varices Factor deficiency

Portal hypertensive gastropathy Fibrinolysis

Splenomegaly, hypersplenism Thrombocytopenia

Ascites Bone disease

Spontaneous bacterial peritonitis Osteopenia

Hepatorenal syndrome Osteoporosis

Type 1 Osteomalacia

Type 2 Hematologic abnormalities

Hepatic encephalopathy Anemia

Hepatopulmonary syndrome Hemolysis

Portopulmonary hypertension Thrombocytopenia

Malnutrition Neutropenia

Portal Hypertension

Portal hypertension is defined as the elevation of the hepatic venous pressure gradient (HVPG) to >5 mmHg. Portal hypertension is caused by a combination of two simultaneously occurring hemodynamic processes: (1) increased intrahepatic resistance to the passage of blood flow through the liver due to cirrhosis and regenerative nodules, and (2) increased splanchnic blood flow secondary to vasodilatation within the splanchnic vascular bed. Portal hypertension is directly responsible for the two major complications of cirrhosis, variceal hemorrhage and ascites. Variceal hemorrhage is an immediate life-threatening problem with a 20-30% mortality associated with each episode of bleeding. The portal venous system normally drains blood from the stomach, intestines, spleen, pancreas, and gallbladder, and the portal vein is formed by the confluence of the superior mesenteric and splenic veins. Deoxygenated blood from the small bowel drains into the superior mesenteric vein along with blood from the head of the pancreas, the ascending colon, and part of the transverse colon. Conversely, the splenic vein drains the spleen and the pancreas and is joined by the inferior mesenteric vein, which brings blood from the transverse and descending colon as well as from the superior two-thirds of the rectum. Thus, the portal vein normally receives blood from almost the entire GI tract.

The causes of portal hypertension are usually subcategorized as prehepatic, intrahepatic, and posthepatic (Table 302-3). Prehepatic causes of portal hypertension are those affecting the portal venous system before it enters the liver; they include portal vein thrombosis and splenic vein thrombosis. Posthepatic causes encompass those affecting the hepatic veins and venous drainage to the heart; they include BCS, venoocclusive disease, and chronic right-sided cardiac congestion. Intrahepatic causes account for over 95% of cases of portal hypertension and are represented by the major forms of cirrhosis. Intrahepatic causes of portal hypertension can be further subdivided into presinusoidal, sinusoidal, and postsinusoidal causes. Postsinusoidal causes include venoocclusive disease, while presinusoidal causes include congenital hepatic fibrosis and schistosomiasis. Sinusoidal causes are related to cirrhosis from various causes.

Table 302-3 Classification of Portal Hypertension

Prehepatic

Portal vein thrombosis

Splenic vein thrombosis

Massive splenomegaly (Banti's syndrome)

Hepatic

Presinusoidal

Schistosomiasis

Congenital hepatic fibrosis

Sinusoidal

Cirrhosis-many causes

Alcoholic hepatitis

Postsinusoidal

Hepatic sinusoidal obstruction (venoocclusive syndrome)

Posthepatic

Budd-Chiari syndrome

Inferior vena caval webs

Cardiac causes

Restrictive cardiomyopathy

Constrictive pericarditis

Severe congestive heart failure

Cirrhosis is the most common cause of portal hypertension in the United States, and clinically significant portal hypertension is present in >60% of patients with cirrhosis. Portal vein obstruction may be idiopathic or can occur in association with cirrhosis or with infection, pancreatitis, or abdominal trauma.

Coagulation disorders that can lead to the development of portal vein thrombosis include polycythemia vera; essential thrombocytosis; deficiencies in protein C, protein S, antithrombin 3, and factor V Leiden; and abnormalities in the gene regulating prothrombin production. Some patients may have a subclinical myeloproliferative disorder.

Clinical Features

The three primary complications of portal hypertension are gastroesophageal varices with hemorrhage, ascites, and hypersplenism. Thus, patients may present with upper GI bleeding, which on endoscopy is found to be due to esophageal or gastric varices, with the development of ascites along with peripheral edema, or with an enlarged spleen with associated reduction in platelets and white blood cells on routine laboratory testing.

Esophageal Varices

Over the last decade, it has become common practice to screen known cirrhotics with endoscopy to look for esophageal varices. Such screening studies have shown that approximately one-third of patients with histologically confirmed cirrhosis have varices. Approximately 5-15% of cirrhotics per year develop varices, and it is estimated that the majority of patients with cirrhosis will develop varices over their lifetime. Furthermore, it is anticipated that roughly one-third of patients with varices will develop bleeding. Several factors predict the risk of bleeding, including the severity of cirrhosis (Child's class); the height of wedged-hepatic vein pressure; the size of the varix; the location of the varix; and certain endoscopic stigmata, including red wale signs, hematocystic spots, diffuse erythema, bluish color, cherry-red spots, or white-nipple spots. Patients with tense ascites are also at increased risk for bleeding from varices.

Diagnosis

In patients with cirrhosis who are being followed chronically, the development of portal hypertension is usually revealed by the presence of thrombocytopenia; the appearance of an enlarged spleen; or the development of ascites, encephalopathy and/or esophageal varices with or without bleeding. In previously undiagnosed patients, any of these features should prompt further evaluation to determine the presence of portal hypertension and liver disease. Varices should be identified by endoscopy. Abdominal imaging, either by CT or MRI, can be helpful in demonstrating a nodular liver and in finding changes of portal hypertension with intraabdominal collateral circulation. If necessary, interventional radiologic procedures can be performed to determine wedged and free hepatic vein pressures that will allow for the calculation of a wedged-to-free gradient, which is equivalent to the portal pressure. The average normal wedged-to-free gradient is 5 mmHg, and patients with a gradient >12 mmHg are at risk for variceal hemorrhage.

Variceal Hemorrhage: Treatment

Treatment for variceal hemorrhage as a complication of portal hypertension is divided into two main categories: (1) primary prophylaxis and (2) prevention of re-bleeding once there has been an initial variceal hemorrhage. Primary prophylaxis requires routine screening by endoscopy of all patients with cirrhosis. Once varices that are at increased risk for bleeding are identified, then primary prophylaxis can be achieved either through nonselective beta blockade or by variceal band ligation. Numerous placebo-controlled clinical trials of either propranolol or nadolol have been reported in the literature. The most rigorous studies were those that only included patients with significantly enlarged varices or with hepatic vein pressure gradients >12 mmHg. Patients treated with beta blockers have a lower risk of variceal hemorrhage than those treated with placebo over 1 and 2 years of follow-up. There is also a decrease in mortality related to variceal hemorrhage. Unfortunately, overall survival was improved in only one study. Further studies have demonstrated that the degree of reduction of portal pressure is a significant feature to determine success of therapy. Therefore, it is has been suggested that repeat measurements of hepatic vein pressure gradients may be used to guide pharmacologic therapy; however, this may be cost prohibitive. Several studies have evaluated variceal band ligation and variceal sclerotherapy as methods for providing primary prophylaxis.

Endoscopic variceal ligation (EVL) has achieved a level of success and comfort with most gastroenterologists who see patients with these complications of portal hypertension. Thus, in patients with cirrhosis who are screened for portal hypertension and are found to have large varices, it is recommended that they receive either beta blockade or primary prophylaxis with EVL.

The approach to patients once they have had a variceal bleed is first to treat the acute bleed, which can be life-threatening, and then to prevent further bleeding. Prevention of further bleeding is usually accomplished with repeated variceal band ligation until varices are obliterated. Treatment of acute bleeding requires both fluid and blood product replacement as well as prevention of subsequent bleeding with EVL.

The medical management of acute variceal hemorrhage includes the use of vasoconstricting agents, usually somatostatin or Octreotide. Vasopressin was used in the past but is no longer commonly used. Balloon tamponade (Sengstaken-Blakemore tube or Minnesota tube) can be used in patients who cannot get endoscopic therapy immediately or who need stabilization prior to endoscopic therapy. Control of bleeding can be achieved in the vast majority of cases; however, bleeding recurs in the majority of patients if definitive endoscopic therapy has not been instituted. Octreotide, a direct splanchnic vasoconstrictor, is given at dosages of 50-100 g/h by continuous infusion. Endoscopic intervention is employed as first-line treatment to control bleeding acutely. Some endoscopists will use variceal injection therapy (sclerotherapy) as initial therapy, particularly when bleeding is vigorous. Variceal band ligation is used to control acute bleeding in over 90% of cases and should be repeated until obliteration of all varices is accomplished. When esophageal varices extend into the proximal stomach, band ligation is less successful. In these situations, when bleeding continues from gastric varices, consideration for transjugular intrahepatic portosystemic shunt (TIPS) should be made. This technique creates a portosystemic shunt by a percutaneous approach using an expandable metal stent, which is advanced under angiographic guidance to the hepatic veins and then through the substance of the liver to create a direct portocaval shunt. This offers an alternative to surgery for acute decompression of portal hypertension. Encephalopathy can occur in as many as 20% of patients after TIPS and is particularly problematic in elderly patients and in those patients with preexisting encephalopathy. TIPS should be reserved for those individuals who fail endoscopic or medical management or who are poor surgical risks. TIPS can sometimes be used as a bridge to transplantation. Surgical esophageal transsection is a procedure that is rarely used and generally is associated with a poor outcome.

Prevention of Recurrent Bleeding

(Fig. 302-1) Once patients have had an acute bleed and have been managed successfully, attention should be paid to preventing recurrent bleeding. This usually requires repeated variceal band ligation until varices are obliterated. Beta blockade may be of adjunctive benefit in patients who are having recurrent variceal band ligation; however, once varices have been obliterated, the need for beta blockade is lessened. Despite successful variceal obliteration, many patients will still have portal hypertensive gastropathy from which bleeding can occur. Nonselective beta blockade may be helpful to prevent further bleeding from portal hypertensive gastropathy once varices have been obliterated.

Figure 302-1

Management of recurrent variceal hemorrhage. This algorithm describes an approach to management of patients who have recurrent bleeding from esophageal varices. Initial therapy is generally with endoscopic therapy often supplemented by pharmacologic therapy. With control of bleeding, a decision needs to be made as to whether patients should go on to a surgical shunt or TIPS (if they are Child's class A) and be considered for transplant, or if they should have TIPS and be considered for transplant (if they are Child's class B or C). TIPS, transjugular intrahepatic portosystemic shunt.

Portosystemic shunt surgery is less commonly performed with the advent of TIPS; nonetheless, this procedure should be considered for patients with good hepatic synthetic function who could benefit by having portal decompressive surgery.

Splenomegaly and Hypersplenism

Congestive splenomegaly is common in patients with portal hypertension. Clinical features include the presence of an enlarged spleen on physical examination and the development of thrombocytopenia and leukopenia in patients who have cirrhosis. Some patients will have fairly significant left-sided and left upper quadrant abdominal pain related to an enlarged and engorged spleen. Splenomegaly itself usually requires no specific treatment, although splenectomy can be successfully performed under very special circumstances.

Hypersplenism with the development of thrombocytopenia is a common feature of patients with cirrhosis and is usually the first indication of portal hypertension.

Ascites

Definition

Ascites is the accumulation of fluid within the peritoneal cavity. Overwhelmingly, the most common cause of ascites is portal hypertension related to cirrhosis; however, clinicians should remember that malignant or infectious causes of ascites can be present as well, and careful differentiation of these other causes are obviously important for patient care.

Pathogenesis

The presence of portal hypertension contributes to the development of ascites in patients who have cirrhosis (Fig. 302-2). There is an increase in intrahepatic resistance, causing increased portal pressure, but there is also vasodilatation of the splanchnic arterial system, which in turn results in an increase in portal venous inflow. Both of these abnormalities result in increased production of splanchnic lymph. Vasodilating factors such as nitric oxide are responsible for the vasodilatory effect. These hemodynamic changes result in sodium retention by causing activation of the renin-angiotensin-aldosterone system with the development of hyperaldosteronism. The renal effects of increased aldosterone leading to sodium retention also contribute to the development of ascites. Sodium retention causes fluid accumulation and expansion of the extracellular fluid volume, which results in the formation of peripheral edema and ascites. Sodium retention is the consequence of a homeostatic response caused by underfilling of the arterial circulation secondary to arterial vasodilatation in the splanchnic vascular bed. Because the retained fluid is constantly leaking out of the intravascular compartment into the peritoneal cavity, the sensation of vascular filling is not achieved, and the process continues. Hypoalbuminemia and reduced plasma oncotic pressure also contribute to the loss of fluid from the vascular compartment into the peritoneal cavity. Hypoalbuminemia is due to decreased synthetic function in a cirrhotic liver.

Figure 302-2

Development of ascites in cirrhosis. This flow diagram illustrates the importance of portal hypertension with splanchnic vasodilatation in the development of ascites. *Antinatriuretic factors include the renin-angiotensin-aldosterone system and the sympathetic nervous system.

Clinical Features

Patients typically note an increase in abdominal girth that is often accompanied by the development of peripheral edema. The development of ascites is often insidious, and it is surprising that some patients wait so long and become so distended before seeking medical attention. Patients usually have at least 1-2 L of fluid in the abdomen before they are aware that there is an increase. If ascitic fluid is massive, respiratory function can be compromised, and patients will complain of shortness of breath. Hepatic hydrothorax may also occur in this setting, contributing to respiratory symptoms. Patients with massive ascites are often malnourished and have muscle wasting and excessive fatigue and weakness.

Diagnosis

Diagnosis of ascites is by physical examination and is often aided by abdominal imaging. Patients will have bulging flanks, may have a fluid wave, or may have the presence of shifting dullness. This is determined by taking patients from a supine position to lying on either their left or right side and noting the movement of the dullness to percussion. Subtle amounts of ascites can be detected by ultrasound or CT scanning. Hepatic hydrothorax is more common on the right side and implicates a rent in the diaphragm with free flow of ascitic fluid into the thoracic cavity.

When patients present with ascites for the first time, it is recommended that a diagnostic paracentesis be performed to characterize the fluid. This should include the determination of total protein and albumin content, blood cell counts with differential, and cultures. In the appropriate setting, amylase may be measured and cytology performed. In patients with cirrhosis, the protein concentration of the ascitic fluid is quite low, with the majority of patients having an ascitic fluid protein concentration 1.1 g/dL, then the cause of the ascites is most likely due to portal hypertension; this is most often in the setting of cirrhosis. When the gradient is 250 mm3, then the question of ascitic fluid infection should be strongly considered. Ascitic fluid cultures should be obtained using bedside inoculation of culture media.

Ascites: Treatment

Patients with small amounts of ascites can usually be managed with dietary sodium restriction alone. Most average diets in the United States contain 6 to 8 g of sodium per day and if patients eat at restaurants or fast food outlets, the amount of sodium in their diet can exceed this amount. Thus, it is often extremely difficult to get patients to change their dietary habits to ingest

Figure 302-3

Treatment of refractory ascites. In patients who develop azotemia in the course of receiving diuretics in the management of their ascites, some will require repeated large-volume paracentesis (LVP), some may be considered for transjugular intrahepatic portosystemic shunt (TIPS), and some would be good candidates for liver transplantation. These decisions are all individualized.

Spontaneous Bacterial Peritonitis

SBP is a common and severe complication of ascites characterized by spontaneous infection of the ascitic fluid without an intraabdominal source. In patients with cirrhosis and ascites severe enough for hospitalization, SBP can occur in up to 30% of individuals and can have a 25% in-hospital mortality rate. Bacterial translocation is the presumed mechanism for development of SBP, with gut flora traversing the intestine into mesenteric lymph nodes, leading to bacteremia and seeding of the ascitic fluid. The most common organisms are Escherichia coli and other gut bacteria; however, gram-positive bacteria, including Streptococcus viridans, Staphococcus aureus, and Enterococcus sp., can also be found. If more than two organisms are identified, secondary bacterial peritonitis due to a perforated viscus should be considered. The diagnosis of SBP is made when the fluid sample has an absolute neutrophil count >250/mm3. Bedside cultures should be obtained when ascitic fluid is tapped. Patients with ascites may present with fever, altered mental status, elevated white blood cell count, and abdominal pain or discomfort, or they may present without any of these features. Therefore, it is necessary to have a high degree of clinical suspicion, and peritoneal taps are important for making the diagnosis. Treatment is with a second-generation cephalosporin, with cefotaxime being the most commonly used antibiotic. In patients with variceal hemorrhage, the frequency of SBP is significantly increased, and prophylaxis against SBP is recommended when a patient presents with upper GI bleeding. Furthermore, in patients who have had an episode(s) of SBP and recovered, once-weekly administration of antibiotics is used as prophylaxis for recurrent SBP.

Hepatorenal Syndrome

The hepatorenal syndrome (HRS) is a form of functional renal failure without renal pathology that occurs in about 10% of patients with advanced cirrhosis or acute liver failure. There are marked disturbances in the arterial renal circulation in patients with HRS; these include an increase in vascular resistance accompanied by a reduction in systemic vascular resistance. The reason for renal vasoconstriction is most likely multifactorial and is poorly understood. The diagnosis is made usually in the presence of a large amount of ascites in patients who have a step-wise progressive increase in creatinine. Type 1 HRS is characterized by a progressive impairment in renal function and a significant reduction in creatinine clearance within 1-2 weeks of presentation. Type 2 HRS is characterized by a reduction in glomerular filtration rate with an elevation of serum creatinine level, but it is fairly stable and is associated with a better outcome than that of Type 1 HRS.

HRS is often seen in patients with refractory ascites and requires exclusion of other causes of acute renal failure. Treatment has unfortunately been difficult, and in the past, dopamine or prostaglandin analogs were used as renal vasodilating medications. Carefully performed studies have failed to show clear-cut benefit from these therapeutic approaches. Currently, patients are treated with midodrine, an -agonist, along with octreotide and intravenous albumin. The best therapy for HRS is liver transplantation; recovery of renal function is typical in this setting. In patients with either type 1 or type 2 HRS, the prognosis is poor unless transplant can be achieved within a short period of time.

Hepatic Encephalopathy

Portosystemic encephalopathy is a serious complication of chronic liver disease and is broadly defined as an alteration in mental status and cognitive function occurring in the presence of liver failure. In acute liver injury with fulminant hepatic failure, the development of encephalopathy is a requirement for a diagnosis of fulminant failure. Encephalopathy is much more commonly seen in patients with chronic liver disease. Gut-derived neurotoxins that are not removed by the liver because of vascular shunting and decreased hepatic mass get to the brain and cause the symptoms that we know of as hepatic encephalopathy. Ammonia levels are typically elevated in patients with hepatic encephalopathy, but the correlation between severity of liver disease and height of ammonia levels is often poor, and most hepatologists do not rely on ammonia levels to make a diagnosis. Other compounds and metabolites that may contribute to the development of encephalopathy include certain false neurotransmitters and mercaptans.

Clinical Features

In acute liver failure, changes in mental status can occur within weeks to months. Brain edema can be seen in these patients, with severe encephalopathy associated with swelling of the gray matter. Cerebral herniation is a feared complication of brain edema in acute liver failure, and treatment is meant to decrease edema with mannitol and judicious use of intravenous fluids.

In patients with cirrhosis, encephalopathy is often found as a result of certain precipitating events such as hypokalemia, infection, an increased dietary protein load, or electrolyte disturbances. Patients may be confused or exhibit a change in personality. They may actually be quite violent and difficult to manage; alternatively, patients may be very sleepy and difficult to arouse. Because precipitating events are so commonly found, they should be sought carefully. If patients have ascites, this should be tapped to rule out infection. Evidence of GI bleeding should be sought, and patients should be appropriately hydrated. Electrolytes should be measured and abnormalities corrected. In patients presenting with encephalopathy, asterixis is often present. Asterixis can be elicited by having patients extend their arms and bend their wrists back. In this maneuver, patients who are encephalopathic have a "liver flap"-i.e., a sudden forward movement of the wrist. This requires patients to be able to cooperate with the examiner and obviously cannot be elicited in patients who are severely encephalopathic or in hepatic coma.

The diagnosis of hepatic encephalopathy is clinical and requires an experienced clinician to recognize and put together all of the various features. Often when patients have encephalopathy for the first time, they are unaware of what is transpiring, but once they have been through the experience for the first time, they can identify when this is developing in subsequent situations and can often self-medicate to impair the development or worsening of encephalopathy.

Hepatic Encephalopathy: Treatment

Treatment is multifactorial and includes management of the above-mentioned precipitating factors. Sometimes hydration and correction of electrolyte imbalance is all that is necessary. In the past, restriction of dietary protein was considered for patients with encephalopathy; however, the negative impact of that maneuver on overall nutrition is thought to outweigh the benefit when treating encephalopathy, and it is thus discouraged. There may be some benefit to replacing animal-based protein with vegetable-based protein in some patients with encephalopathy that is difficult to manage. The mainstay of treatment for encephalopathy, in addition to correcting precipitating factors, is to use lactulose, a nonabsorbable disaccharide, which results in colonic acidification. Catharsis ensues, contributing to the elimination of nitrogenous products in the gut that are responsible for the development of encephalopathy. The goal of lactulose therapy is to promote 2-3 soft stools per day. Patients are asked to titrate their amount of ingested lactulose to achieve the desired effect. Poorly absorbed antibiotics are often used as adjunctive therapies for patients who have had a difficult time with lactulose. The alternating administration of neomycin and metronidazole has commonly been employed to reduce the individual side effects of each: neomycin for renal insufficiency and ototoxicity and metronidazole for peripheral neuropathy. More recently, rifaximin has been very effective in treating encephalopathy without the known side effects of neomycin or metronidazole. Zinc supplementation is sometimes helpful in patients with encephalopathy and is relatively harmless. The development of encephalopathy in patients with chronic liver disease is a poor prognostic sign, but this complication can be managed in the vast majority of patients.

Malnutrition in Cirrhosis

Because the liver is principally involved in the regulation of protein and energy metabolism in the body, it is not surprising that patients with advanced liver disease are commonly malnourished. Once patients become cirrhotic, they are more catabolic, and muscle protein is metabolized. There are multiple factors that contribute to the malnutrition of cirrhosis, including poor dietary intake, alterations in gut nutrient absorption, and alterations in protein metabolism. Dietary supplementation for patients with cirrhosis is helpful in preventing patients from becoming catabolic.

Abnormalities in Coagulation

Coagulopathy is almost universal in patients with cirrhosis. There is decreased synthesis of clotting factors and impaired clearance of anticoagulants. In addition, patients may have thrombocytopenia from hypersplenism due to portal hypertension. Vitamin K-dependent clotting factors are Factors II, VII, IX, and X. Vitamin K requires biliary excretion for its subsequent absorption; thus, in patients with chronic cholestatic syndromes, vitamin K absorption is frequently diminished. Intravenous or intramuscular vitamin K can quickly correct this abnormality. More commonly, the synthesis of vitamin K-dependent clotting factors is diminished because of a decrease in hepatic mass, and under these circumstances administration of parenteral vitamin K does not improve the clotting factors or the prothrombin time. Platelet function is often abnormal in patients with chronic liver disease, in addition to decreases in platelet levels due to hypersplenism.

Bone Disease in Cirrhosis

Osteoporosis is common in patients with chronic cholestatic liver disease because of malabsorption of vitamin D and decreased calcium ingestion. The rate of bone resorption exceeds that of new bone formation in patients with cirrhosis resulting in bone loss. Dual x-ray absorptiometry (DEXA) is a useful method for determining osteoporosis or osteopenia in patients with chronic liver disease. When a DEXA scan shows decreased bone mass, treatment should be administered with bisphosphonates that are effective at inhibiting resorption of bone and efficacious in the treatment of osteoporosis.

Hematologic Abnormalities in Cirrhosis

Numerous hematologic manifestations of cirrhosis are present, including anemia from a variety of causes including hypersplenism, hemolysis, iron deficiency, and perhaps folate deficiency from malnutrition. Macrocytosis is a common abnormality in red blood cell morphology seen in patients with chronic liver disease, and neutropenia may be seen as a result of hypersplenism.